Purine compound, composition containing purine compound and application of purine compound

Abstract

This document relates to purine compounds, pharmaceutical compositions comprising the purine compounds 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 have the formula (I): wherein R1 to R4 are as defined herein. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 381,036, filed Oct. 26, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes. TECHNICAL FIELD

[0003] The present disclosure generally relates to compounds, particularly purine compounds, pharmaceutical compositions containing them, and their use and methods of use in the treatment and prevention of diseases and disorders. BACKGROUND ART

[0004] It is well known that activation of the cannabinoid CB 1 receptor increases appetite, increases lipid biosynthesis and storage, inhibits the action of insulin and leptin, and promotes inflammation and fibrosis. Accordingly, research has focused on developing CB 1 receptor inhibitors for the potential treatment of obesity and related metabolic disorders (termed metabolic syndrome). Rimonabant was shown to be effective in treating metabolic syndrome but caused neuropsychiatric (i.e., CNS-related) side effects, which led to its withdrawal from the market.

[0005] There remains a need to develop alternative compounds targeting the CB 1 receptor to treat or prevent related disorders. SUMMARY OF THE INVENTION

[0006] According to one aspect, the present technology relates to compounds and their pharmaceutically acceptable salts, their pharmaceutical compositions, their uses, and methods of treatment including their administration. More specifically, the following embodiments are provided:

[0007] Embodiment 1. A compound of formula I:

[0008]

[0009] Wherein,

[0010] R 1 is optionally substituted C 6 aryl;

[0011] R 2 is optionally substituted C 6 aryl or C 5 -C 6 heteroaryl;

[0012] R 3 is optionally substituted and selected from R 7 O-, N(R 8 ) 2-, C 4-10 heterocycloalkyl and C 5-6 heteroaryl groups;

[0013] R 4 is an optionally substituted group selected from R 5 O- and N(R 6 ) 2 - groups;

[0014] R 5 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups;

[0015] R 6 is H or selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups, where at least one R 6 is not H, or two R 6 groups together with the nitrogen atom to which they are attached form a C 4 -C 10 heterocycloalkyl or C 5 -C6 Heteroaryl;

[0016] wherein R 5 or R 6 at least one of said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is substituted by at least one hydroxy group or C 1 -C 4 alkyl substituted and optionally further substituted by other substituents;

[0017] R 7 is optionally substituted C 1 -C 6 alkyl; and

[0018] R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 10 heterocycloalkyl;

[0019] wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted;

[0020] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment 2. The compound of Embodiment 1, wherein the compound is a compound of Formula II:

[0022]

[0023] wherein,

[0024] R 4 is as defined in Embodiment 1;

[0025] X 1 is C and X 2 to X 6 are each independently selected from N and CR 21 and n is 1, wherein at most three of X 2 to X 6 are N; or

[0026] X 1 is C or N and X 2 to X 5 are each independently selected from CR 21 、O、S、N or NR 11 , n is 0 i.e. X 6 is absent and is replaced by a bond between X 1 and X 5 wherein X1 Up to X 5 At most three of which are not C or CR 21 ;

[0027] X 7 and X 8 Each independently selected from O, S, SO 2 , NR 36 or C(R 35 ) 2 , where when X 7 and X 8 One of them is O, S or NR 36 then the other is C(R 35 ) 2 ;

[0028] R 9 Each occurrence is independently selected from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl and C 5 -C 6 heteroarylC 1 -C 3 alkyl;

[0029] R 10 Each occurrence is independently selected from H or from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl and C 5 -C 6Heteroaryl C 1 -C 3 group of an alkyl, or two R 10 groups together with the nitrogen atom to which they are attached form an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0030] R 11 is independently selected from H or from an 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 group of an alkyl;

[0031] R 12 is independently selected from 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, and p is 0, 1, 2 or 3, preferably 0 or 1;

[0032] R 21 is independently selected from hydrogen, halogen, OH, OR 9 , CN, NO 2 , C(O)R 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 2 N(R 10 ) 2 , N(R11 )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, 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;

[0033] R 31 to R 35 are each independently selected from hydrogen, halogen, OH, OR 9 、CN, NO 2 、C(O)OH, C(O)OR 9 、C(O)R 9 、C(O)N(R 10 ) 2 、C(R 11 )=NR 11 、SO 2 R 9 、SO 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, 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;

[0034] R 36 is selected from hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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;

[0035] or two of R 31 to R 36 together with the atoms to which they are adjacent form a ring, preferably a bridged heterocycle or a spiro heterocycle; and

[0036] m is 0, 1, 2 or 3;

[0037] wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted;

[0038] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0039] Embodiment 3. The compound of Embodiment 2, wherein m is 0 and X 7 and X 8 are each independently C(R 35 )2 , preferably X 7 is CH 2 .

[0040] Embodiment 4. The compound of Embodiment 3, wherein X 8 is C(R 35 ) 2 , wherein one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl.

[0041] Embodiment 5. The compound of Embodiment 3, wherein X 8 is C(R 35 ) 2 and the two Rs 35 together with the adjacent carbon atom form a spiro C 4-5 heterocycle.

[0042] Embodiment 6. The compound of Embodiment 2, wherein m is 1 and X 7 and X 8 are each independently C(R 35 ) 2 , preferably X 7 is CH 2 .

[0043] Embodiment 7. The compound of Embodiment 6, wherein X 8 is C(R 35 ) 2 , wherein one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10) 2 or optionally substituted C 1-6 alkyl.

[0044] Embodiment 8. The compound of Embodiment 6, wherein X 8 is C(R 35 ) 2 and the two R 35 together with the adjacent carbon atom form a spiro C 4-5 heterocycle.

[0045] Embodiment 9. The compound of Embodiment 2, wherein m is 2 and X 7 and X 8 are each independently C(R 35 ) 2 .

[0046] Embodiment 10. The compound of Embodiment 9, wherein X 8 is CH 2 and X 7 is C(R 35 ) 2 , wherein one of the two R 35 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 other of the two R 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl.

[0047] Embodiment 11. The compound of Embodiment 10, wherein one of the two R 35 is C(O)N(R 10 ) 2 or N(R 11 )C(O)R 9 , and the other of the two R 35 is OR 9 or optionally substituted C 1-4 alkyl.

[0048] Embodiment 12. The compound of Embodiment 11, wherein the other of the two R 35 is OR 9 and R 9 is C 1-6 alkyl, preferably C2-4 Alkyl

[0049] Embodiment 13. The compound of Embodiment 11, wherein the two R 35 Another one of which is OR 9 And R 9 Is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl and sec-butyl, preferably ethyl or isopropyl, and most preferably isopropyl

[0050] Embodiment 14. The compound of Embodiment 9, wherein X 8 Is CH 2 And X 7 Is C(R 35 ) 2 And the two R 35 Together with the adjacent carbon atom form a spiro C 4-5 Heterocycle

[0051] Embodiment 15. The compound of Embodiment 9, wherein X 7 Is CH 2 And X 8 Is C(R 35 ) 2 , wherein one of the two R 35 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 other of the two R 35 Is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 Or optionally substituted C 1-6 Alkyl

[0052] Embodiment 16. The compound of Embodiment 15, wherein one of the two R 35 Is C(O)N(R 10 ) 2 Or N(R 11 )C(O)R 9 , and the other of the two R 35 Is OR 9 Or optionally substituted C 1-4 Alkyl

[0053] Embodiment 17. The compound of Embodiment 16, wherein the other of the two R 35 Is OR 9 And R9 is C 1-6 alkyl, preferably C 2-4 alkyl.

[0054] Embodiment 18. The compound of Embodiment 16, wherein the other of the two R 35 is OR 9 and R 9 is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl and sec-butyl, preferably ethyl or isopropyl, and most preferably isopropyl.

[0055] Embodiment 19. The compound of Embodiment 9, wherein X 7 is CH 2 and X 8 is C(R 35 ) 2 and the two R 35 together with the adjacent carbon atoms form a spiro C 4-5 heterocycle.

[0056] Embodiment 20. The compound of Embodiment 2, wherein m is 2 or 3, X 7 is O, S, SO 2 or NR 36 , and X 8 is C(R 35 ) 2 .

[0057] Embodiment 21. The compound of Embodiment 20, wherein m is 2.

[0058] Embodiment 22. The compound of Embodiment 20, wherein m is 3.

[0059] Embodiment 23. The compound of any one of Embodiments 20 to 22, wherein X 7 is O, SO 2 or NR 36 .

[0060] Embodiment 24. The compound of Embodiment 23, wherein X 7 is NR 36 and R 36 is selected from hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 ) 2 and optionally substituted C 1-6 alkyl.

[0061] Embodiment 25. The compound of any one of Embodiments 20 to 24, wherein one of the two R 35 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 substituted C 1-6 alkyl, and the other of said two R 35 is hydrogen, fluorine, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl, or one of said R 35 forms a bridged ring together with R 33 and the atoms adjacent to them.

[0062] Embodiment 26. The compound of Embodiment 25, wherein both R 35 are hydrogen.

[0063] Embodiment 27. The compound of Embodiment 25, wherein one of said two R 35 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 other of said two R 35 is hydrogen.

[0064] Embodiment 28. The compound of Embodiment 25, wherein one of said R 35 forms C 33 alkylene together with R 1-3 .

[0065] Embodiment 29. The compound of any one of Embodiments 2 to 27, wherein R 33 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears.

[0066] Embodiment 30. The compound of any one of Embodiments 2 to 29, wherein R 34 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears.

[0067] Embodiment 31. The compound of any one of Embodiments 2 to 30, wherein R 31 and R 32 are each a hydrogen atom.

[0068] Embodiment 32. The compound of Embodiment 1 or 2, wherein R 3 is selected from the groups C1-C7, C10, C15, C16, C18-C22, C24-C28, C32-C40 and C47-C69, preferably C1, C16 or C18, more preferably C18.

[0069] Embodiment 33. The compound of Embodiment 1, wherein the compound is a compound of Formula III:

[0070]

[0071] wherein,

[0072] R 13 is an optionally substituted group selected from R 7 O-, N(R 8 ) 2 - and C 5-6 heteroaryl;

[0073] R 4 , R 7 and R 8 are as defined in Embodiment 1; and

[0074] R 12 , X 1 to X 6 , n and p are as defined in Embodiment 2;

[0075] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 34. The compound of Embodiment 33, wherein R 13 is R 7 O-.

[0077] Embodiment 35. The compound of Embodiment 34, wherein R 7 is an optionally substituted C 1 -C 4 alkyl.

[0078] Embodiment 36. The compound of Embodiment 33, wherein R 13 is N(R 8 ) 2 -.

[0079] Embodiment 37. The compound of Embodiment 36, wherein one R 8 is an optionally substituted C 4 -C 10 heterocycloalkyl and the other R 8 is hydrogen or an optionally substituted C 1 -C 6 alkyl.

[0080] Embodiment 38. The compound of Embodiment 36, wherein 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 alkyl.

[0081] Embodiment 39. The compound of Embodiment 36, wherein 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 alkyl.

[0082] Embodiment 40. The compound of Embodiment 33, wherein R 13 is selected from C8, C9, C11-C14, C17, C23, C29-C31 and C41-C46.

[0083] Embodiment 41. The compound of any one of Embodiments 2 to 40, wherein R 12 is Cl and p is 1, preferably forming 4-chlorophenyl.

[0084] Embodiment 42. The compound of any one of Embodiments 2 to 40, wherein p is 0, i.e., R 12 is absent, thereby forming an unsubstituted phenyl.

[0085] Embodiment 43. The compound of any one of Embodiments 2 to 42, wherein n is 1, X 1 is C, and X 2 to X 6 are each independently CR 21 .

[0086] Embodiment 44. The compound of any one of Embodiments 2 to 42, wherein n is 1, X 1 is C, one of X 2 to X 6 is N and the others are CR 21 .

[0087] Embodiment 45. The compound of any one of Embodiments 2 to 42, wherein n is 0, X 6 is absent, and X 1 is C.

[0088] Embodiment 46. The compound of Embodiment 45, wherein X 2 to X5 One or both of which are N or NR 11 And the others are CR 21 , preferably R 11 Is C 1 -C 6 Alkyl.

[0089] Embodiment 47. The compound of Embodiment 45, wherein X 2 To X 5 One of which is S and the others are CR 21 .

[0090] Embodiment 48. The compound of any one of Embodiments 43 to 47, wherein all CR 21 Are CH.

[0091] Embodiment 49. The compound of Embodiment 43, wherein one CR 21 Is not CH, preferably R 21 Is selected from halogen, CN, N(C 1-6 Alkyl) 2 And C 1-6 Alkyl, more preferably halogen or CN, most preferably halogen (such as Cl).

[0092] Embodiment 50. The compound of Embodiment 44, wherein one CR 21 Is not CH, preferably R 21 Is selected from halogen, CN, N(C 1-6 Alkyl) 2 And C 1-6 Alkyl, more preferably halogen, CN and C 1-6 Alkyl, most preferably CN.

[0093] Embodiment 51. The compound of any one of Embodiments 45 to 47, wherein one CR 21 Is not CH, preferably R 21 Is selected from halogen, 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.

[0094] Embodiment 52. The compound of any one of Embodiments 1 to 51, wherein R 2 Is selected from groups B1 to B23 as defined herein.

[0095] Embodiment 53. The compound of Embodiment 52, wherein R 2 Is selected from groups B1 to B4, for example R 2 Is B1.

[0096] Embodiment 54. The compound of Embodiment 52, wherein R 2 is selected from groups B5 to B8, B12 to B19, and B21 to B23, for example R 2 is B14.

[0097] Embodiment 55. The compound of Embodiment 52, wherein R 2 is selected from groups B9 to B11 and B20.

[0098] Embodiment 56. The compound of any one of Embodiments 1 to 55, wherein R 4 is an R 5 O-group, wherein R 5 is as defined in Embodiment 1 and is a C 1 -C 4 alkyl substituted by at least one hydroxyl group or hydroxyl group.

[0099] Embodiment 57. The compound of Embodiment 56, wherein R 5 is a C 2 -C 6 alkyl, C 4 -C 10 heteroalkyl, or C 4 -C 10 heteroalkyl C 1 -C 3 alkyl substituted by a hydroxyl group and optionally substituted by other substituents.

[0100] Embodiment 58. The compound of Embodiment 57, wherein 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.

[0101] Embodiment 59. The compound of Embodiment 57, wherein R 5 is a C 4 -C 6 heteroalkyl or C 4 -C 6 heteroalkyl C 1 -C 3 alkyl substituted by a hydroxyl group and optionally substituted by other substituents, preferably the C 4 -C 6 heteroalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl.

[0102] Embodiment 60. A compound according to any one of Embodiments 1 to 55, wherein R 4 is an N(R 6 ) 2 -group, wherein R 6 is as defined in Embodiment 1 and at least one R 6 is substituted by at least one hydroxyl group or a C 1 -C 4 alkyl substituted by a hydroxyl group and is optionally substituted by one or more other substituents.

[0103] Embodiment 61. A compound according to Embodiment 60, wherein one R 6 is a C 1 -C 4 alkyl substituted by at least one hydroxyl group or a C 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 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl and is optionally substituted by one or more other substituents.

[0104] Embodiment 62. A compound according to Embodiment 61, wherein one R 6 is a C 1 -C 4 alkyl substituted by a hydroxyl group or a C 2 -C 6 alkyl or C 3 -C 7 cycloalkyl C 1 -C 3 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl.

[0105] Embodiment 63. A compound according to Embodiment 60, wherein the two R 6 groups together with the nitrogen atom to which they are attached form a C 1 -C 4C substituted by an alkyl group and optionally substituted by one or more other substituents 4 -C 10 heterocycloalkyl or C 5 heteroaryl.

[0106] Embodiment 64. The compound of Embodiment 63, wherein the two R 6 groups together with the nitrogen atom to which they are adjacent form a C substituted by at least one hydroxyl group or hydroxyl group and optionally substituted by one or more other substituents 1 -C 4 alkyl substituted and optionally substituted by one or more other substituents 4 -C 7 heterocycloalkyl.

[0107] Embodiment 65. The compound of Embodiment 64, wherein the C 4 -C 7 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl substituted by at least one hydroxyl group or hydroxyl group and optionally substituted by one or more other substituents 1 -C 4 alkyl substituted and optionally substituted by one or more other substituents.

[0108] Embodiment 66. The compound of Embodiment 63, wherein the two R 6 groups together with the nitrogen atom to which they are adjacent form a C substituted by at least one hydroxyl group or hydroxyl group and optionally substituted by one or more other substituents 1 -C 4 alkyl substituted and optionally substituted by one or more other substituents 5 heteroaryl.

[0109] Embodiment 67. The compound of Embodiment 66, wherein the C 5 heteroaryl is selected from imidazole and pyrrole groups substituted by at least one hydroxyl group or hydroxyl group and optionally substituted by one or more other substituents 1 -C 4 alkyl substituted and optionally substituted by one or more other substituents.

[0110] Embodiment 68. The compound of any one of Embodiments 1 to 55, wherein R 4 is selected from groups D5-D9, D12, D13, D19-D21, D23, D25, D27, D28, D30-D32, D36, D37, D43-D49, D52, D53, D67, D71, D75, D76 and D78-D81.

[0111] Embodiment 69. The compound of Embodiment 68, wherein R 4 is selected from groups D6-D9, D43-D47, D75 and D76.

[0112] Embodiment 70. The compound of Embodiment 69, wherein R 4 is selected from the groups D6 - D9 and D43 - D47, preferably D9.

[0113] Embodiment 71. The compound of Embodiment 68, wherein R 4 is selected from the groups D12, D19, D21, D23, D30 - D32, D36, D37, D48, D49 and D78 - D81, preferably D19 or D21.

[0114] Embodiment 72. The compound of Embodiment 68, wherein R 4 is selected from the groups D5, D13, D20, D52, D53, D67 and D71, preferably D20.

[0115] Embodiment 73. Compound of formula IV:

[0116]

[0117] wherein X 1 to X 8 , R 12 , R 31 to R 34 are defined as in any one of the above embodiments; and

[0118] R 14 is N(R 16 ) 2 - or optionally substituted C 5 -C 6 heteroaryl; and

[0119] R 16 is selected from H or from the groups of 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl, or two R 16The group, together with its adjacent nitrogen atom, forms an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0120] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0121] Embodiment 74. The compound of Embodiment 73, wherein R 14 is N(R 16 ) 2 -.

[0122] Embodiment 75. The compound of Embodiment 74, wherein 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 cycloalkylC 1 -C 3 alkyl or C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, and the other R 16 is hydrogen or C 1 -C 6 alkyl.

[0123] Embodiment 76. The compound of Embodiment 75, wherein one R 16 is C 2 -C 6 alkyl substituted with one or more substituents, and the other R 16 is hydrogen or C 1 -C 6 alkyl.

[0124] Embodiment 77. The compound of Embodiment 76, wherein the substituents are selected from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0125] Embodiment 78. The compound of Embodiment 74, wherein the two R 16 groups, together with their adjacent nitrogen atom, form an optionally substituted C 4 -C 10 heterocycloalkyl or C5 Heteroaryl

[0126] Embodiment 79. The compound of Embodiment 78, wherein the two R 16 groups together with the nitrogen atom to which they are adjacent form an optionally substituted C 4 -C 7 heterocycloalkyl group linked through said nitrogen atom.

[0127] Embodiment 80. The compound of Embodiment 79, wherein the C 4 -C 7 heterocycloalkyl group is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

[0128] Embodiment 81. The compound of Embodiment 78, wherein the two R 16 groups together with the nitrogen atom to which they are adjacent form an optionally substituted heteroaryl group linked through said nitrogen atom. 5 Heteroaryl

[0129] Embodiment 82. The compound of Embodiment 81, wherein the heteroaryl group is selected from optionally substituted imidazole and pyrrole groups. 5

[0130] Embodiment 83. The compound of Embodiment 73, wherein R 14 is an optionally substituted C 5 -C 6 heteroaryl group.

[0131] Embodiment 84. The compound of Embodiment 73, wherein R 14 is selected from D3-D5, D11-D16, D19-D28, D30-D32, D36, D37, D39-D41, D48-D54, D56, D57, D63-D67, D71 and D78-D81.

[0132] Embodiment 85. A compound of formula V:

[0133]

[0134] wherein X 1 to X 6 , R 12 , R 13 , R 14 , n and p are as defined in any one of the above embodiments;

[0135] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 86. A compound of formula VI:

[0137] ​

[0138] wherein X 1 to X 8 , R 12 , R 31 to R 34 , m, n and p are as defined in any one of the above embodiments; and

[0139] R 15 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups;

[0140] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0141] Embodiment 87. The compound of Embodiment 86, wherein R 15 is optionally substituted C 1 -C 6 alkyl, C 4 -C 10 heterocycloalkyl or C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl.

[0142] Embodiment 88. The compound of Embodiment 87, wherein R 15 is C 1 -C 6 alkyl substituted with one or more substituents selected, for example, from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0143] Embodiment 89. The compound of Embodiment 87, wherein R 15is an optionally substituted C 4 -C 6 heterocycloalkyl or C 4 -C 6 heterocycloalkyl C 1 -C 3 alkyl, preferably the C 4 -C 6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl and piperazinyl.

[0144] Embodiment 90. The compound of Embodiment 86, wherein the OR 15 group is selected from D6-D10, D17, D29, D33-D35, D43-D47, D55, D68-D70 and D72-D77.

[0145] Embodiment 91. Compound of Formula VII:

[0146]

[0147] wherein X 1 to X 6 , R 12 , R 13 , R 15 , n and p are defined as in any one of the above embodiments;

[0148] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0149] Embodiment 92. Compound of Formula VIII:

[0150]

[0151] wherein X 1 to X 8 , R 12 , R 31 to R 34 , m, n and p are defined as in any one of the above embodiments; and

[0152] R 24 is selected from 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, wherein R 9 to R 11As defined previously;

[0153] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0154] Embodiment 93. A compound of Formula IX:

[0155]

[0156] wherein X 1 to X 6 , R 12 , R 13 , R 24 , n and p are as defined in any one of the above embodiments;

[0157] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0158] Embodiment 94. A compound according to Embodiment 92 or 93, wherein R 24 is selected from the groups D1, D2, D18, D38, D42 and D58 - D62.

[0159] 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.

[0160] Embodiment 96. A compound according to Embodiment 95, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0161] Embodiment 97. A compound according to Embodiment 95, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 98. The compound of Embodiment 95, wherein the compound is selected from 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.

[0163] Embodiment 99. The compound of Embodiment 1, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 100. The compound of Embodiment 99, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 101. The compound of Embodiment 99, wherein the compound is selected from 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, 135-137, 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.

[0166] Embodiment 102. The compound of Embodiment 99, wherein the compound is selected from 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, 165-167, 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.

[0167] Embodiment 103. A pharmaceutical composition comprising the compound as defined in any one of Embodiments 1 to 102, and a pharmaceutically acceptable carrier, diluent or excipient.

[0168] Embodiment 104. Use of the compound as defined in any one of Embodiments 1 to 102 or the pharmaceutical composition as defined in Embodiment 103 for the treatment of the following conditions: one of the conditions related to appetite or its complications, one of the conditions related to glucose regulation or its complications, one of the fibrosis-related conditions or its complications, one of the metabolism-related conditions or its complications, a condition related to skin and hair growth and healing, a condition related to the gastrointestinal tract, a condition related to obesity or its complications, or a combination thereof.

[0169] Embodiment 105. The use according to Embodiment 104, wherein one of the appetite-related disorders or its complications is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome and syndrome.

[0170] Embodiment 106. The use according to Embodiment 104, wherein one of the glucose regulation-related disorders or its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic diseases (due to β-cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

[0171] Embodiment 107. The use according to Embodiment 104, wherein one of the fibrosis-related disorders or 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 fibrosis disorders (such as scleroderma), fibrotic nephropathy and chronic kidney disease.

[0172] Embodiment 108. The use according to Embodiment 104, wherein one of the metabolism-related disorders or its complications is selected from metabolic syndrome and hyperlipidemia (such as hypertriglyceridemia, hypertriglyceridemia in the case of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0173] Embodiment 109. The use according to Embodiment 104, wherein one of the obesity-related disorders or its complications is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcers, coronary artery disease, atherosclerotic diseases, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies in the liver, ovary, cervix, uterus, breast, prostate or gallbladder.

[0174] Embodiment 110. The use according to Embodiment 104, wherein the disorders of the skin and hair are selected from hair loss (male pattern hair loss and hair loss associated with metabolic syndrome), excessive scar formation (scars and keloids) and scleroderma.

[0175] Use of Embodiment 111. The use of Embodiment 104, wherein the gastrointestinal-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0176] Embodiment 112. A method for treating a disorder selected from an appetite-related disorder or its complication, a glucose regulation-related disorder or its complication, a fibrosis-related disorder or its complication, a metabolism-related disorder or its complication, a disorder related to skin and hair growth and healing, a gastrointestinal-related disorder, an obesity-related disorder or its complication, or a combination thereof, comprising administering to a subject in need a compound as defined in any one of Embodiments 1 to 102 or a pharmaceutical composition as defined in Embodiment 103.

[0177] Embodiment 113. The method of Embodiment 112, wherein the appetite-related disorder or its complication is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorder), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and syndrome.

[0178] Embodiment 114. The method of Embodiment 112, wherein the glucose regulation-related disorder or its complication is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic diseases (due to β-cell protection and / or increased insulin production), and related nephropathy, neuropathy, and retinopathy.

[0179] Embodiment 115. The method of Embodiment 112, wherein the fibrosis-related disorder or its complication is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), liver cirrhosis, and other liver fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrosis disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease.

[0180] Embodiment 116. The method of Embodiment 112, wherein the metabolism-related disorder or its complication is selected from metabolic syndrome and hyperlipidemia (such as hypertriglyceridemia, hypertriglyceridemia with low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0181] Embodiment 117. The method of Embodiment 112, wherein the obesity-related disorder or its complication is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcer, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of liver, ovarian, cervical, uterine, breast, prostate or gallbladder malignancies.

[0182] Embodiment 118. The method of Embodiment 112, wherein the disorder of the skin and hair is selected from hair loss (male pattern hair loss and hair loss associated with metabolic syndrome), excessive scar formation (scars and keloids), and scleroderma.

[0183] Embodiment 119. The method of Embodiment 112, wherein the gastrointestinal-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0184] After reading the following non-limiting description of the exemplary embodiments and examples section, other objects and features of the compounds, compositions, methods, and uses of the present invention will become more apparent, which should not be construed as limiting the scope of the present invention. Detailed Description

[0185] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by those skilled in the art to which this technology belongs. However, definitions of some terms and expressions used are provided below. If the definition of a term in a publication, patent, and patent application incorporated herein by reference is contrary to the definition set forth in this specification, the definition in this specification shall prevail. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter disclosed.

[0186] The chemical structures described herein are drawn according to conventional standards. Additionally, when an atom such as a carbon atom appears to contain an incomplete valence, it is assumed that the valence will be satisfied by one or more hydrogen atoms, even if these hydrogen atoms are not necessarily explicitly drawn. Hydrogen atoms should be considered part of the compound.

[0187] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. It should be noted that unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" also include the plural forms. Thus, for example, reference to a composition containing "a compound" also encompasses mixtures of two or more compounds. It should also be noted that unless the context clearly dictates otherwise, the term "or" is generally used in its inclusive sense of "and / or". In addition, with respect to the terms "comprise", "comprising", "include", "including", "have" or variations thereof used in the specific embodiments and / or claims, these terms are intended to be inclusive in a manner similar to the term "include".

[0188] The term "about" or "approximately" means within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which acceptable error range will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, in accordance with the practice in the art, "about" can mean within one or more standard deviations. 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. Or, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a particular value, preferably within 5-fold, more preferably within 2-fold. Where a particular value is described in the present application and claims, unless otherwise stated, it should be assumed that the term "about" means within the acceptable error range of that particular value.

[0189] As used herein, the terms "compound", "compounds described herein", "compounds of the present application", "purines", "purine compounds" and equivalent expressions refer to the compounds described in the present application, for example, the compounds covered by Structural Formulas I to IX, optionally with reference to any applicable embodiments, and also include exemplary compounds such as Compounds 1 to 240, their pharmaceutically acceptable salts and tautomeric forms, as well as their solvates, esters and prodrugs (if applicable). When zwitterionic forms are possible, for practical purposes, the compound may be depicted in its neutral form, but it should be understood that the compound also includes its zwitterionic forms. Embodiments herein may also exclude one or more of these compounds. Compounds may be identified by their chemical structure or their chemical name. When there is a conflict between the chemical structure and the chemical name, the chemical structure shall prevail.

[0190] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, tautomeric, and geometric (or conformational)) forms of the structure, if applicable; for example, the R and S configurations for each asymmetric center, unless otherwise indicated. Thus, single stereoisomers as well as enantiomeric, diastereomeric, tautomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of this specification. Unless otherwise indicated, the compounds of the invention also include all possible tautomeric forms (if any) of the compounds shown. The term also includes isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass of the most abundant atom found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include, but are not limited to 2 H(D), 3 H(T), 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, any isotope of sulfur, etc. The compounds can also exist in unsolvated forms as well as solvated forms including hydrated forms. The compounds can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to fall within the scope of the invention.

[0191] When a particular enantiomer is preferred, in some embodiments, it can be provided in a form substantially free of the corresponding enantiomer or can be enantiomerically enriched. "Enantiomerically enriched" means that the compound consists of a significantly higher proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% (by weight) of the preferred enantiomer. In other embodiments, the compound consists of at least about 95%, 98%, or 99% (by weight) of the preferred enantiomer. The preferred enantiomer can be separated from a racemic mixture by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) on a chiral support, or by the formation and crystallization of chiral salts, or by asymmetric synthesis.

[0192] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present specification which are suitable, within the scope of reasonable medical judgment, for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and having a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). These salts can be prepared in situ during the final isolation and purification of the compounds of the present specification, or can be prepared separately by reacting the free base functional group of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting the acidic functional group of the compound with a suitable organic or inorganic base (base addition salts).

[0193] The term "solvate" refers to the physical association of a compound of the present invention with one or more solvent molecules (including water and non-aqueous solvent molecules). This physical association may include hydrogen bonding. In some cases, the solvate will be capable of separation, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" encompasses both the solution phase and separable 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 those solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compounds described herein also include each of their solvates and mixtures thereof.

[0194] As used herein, the expression "pharmaceutically acceptable ester" refers to an ester of a compound formed by the methods of the present specification which is capable of being hydrolyzed in vivo and includes those esters which are readily decomposable in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, ester groups derived from pharmaceutically acceptable aliphatic carboxylic acids (especially alkanoic acids, alkenoic acids, cycloalkanoic acids, and alkanedioic acids, where each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms). Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates of hydroxyl groups, and alkyl esters of acid groups. Other ester groups include sulfonates or sulfates.

[0195] As used herein, the expression "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds formed by the methods of this specification which are suitable, within the scope of reasonable medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., have a reasonable benefit / risk ratio, and are effective for their intended uses. As used herein, the term "prodrug" refers to a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to any compound depicted by the general formulae of this specification.

[0196] Abbreviations may also be used throughout the application and, unless otherwise indicated, such abbreviations are intended to have the meanings commonly understood in the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (isobutyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (benzyloxycarbonyl), Boc or BOC (tert-butoxycarbonyl), and Su or Suc (succinimide).

[0197] The number of carbon atoms in a hydrocarbon substituent may be 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. However, when the prefix "C x -C y " or "C x-y " is associated with a group which by definition contains one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), x and y respectively define the minimum and maximum number of atoms in the group (e.g., the one or more rings), including carbon atoms as well as heteroatoms.

[0198] The term "heteroatom" includes atoms other than carbon and hydrogen, such as but not limited to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, any substituted form of nitrogen, and any quaternized form of basic nitrogen.

[0199] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon group which typically contains from 1 to 20 carbon atoms. For example, "C 1-8 alkyl" contains from one to eight carbon atoms. Examples of alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl groups, etc.

[0200] As used herein, the term "alkenyl" denotes a straight-chain or branched-chain hydrocarbon group containing one or more double bonds and typically containing from 2 to 20 carbon atoms. For example, "C 2-8"Alkenyl" contains two to eight carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0201] As used herein, the term "alkynyl" denotes a straight-chain or branched-chain hydrocarbon group containing one or more triple bonds and generally containing 2 to 20 carbon atoms. For example, "C 2-8 alkynyl" contains two to eight carbon atoms. Representative alkynyls include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

[0202] The terms "cycloalkyl", "alicyclic", "carbocyclic" and equivalent expressions refer to groups containing saturated or partially unsaturated (non-aromatic) carbocyclic rings in a monocyclic or polycyclic ring system, which ring system includes spiro rings (sharing one atom), fused rings (sharing at least one bond) or bridged rings (sharing two or more bonds) carbocyclic ring systems, having three to fifteen ring members. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, bicyclo[4.3.0]nonyl, norbornyl, etc. The term "cycloalkyl" includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C 3-n cycloalkyl" refers to a cycloalkyl having 3 to the indicated "n" carbon atoms in the ring structure. Unless the number of carbon atoms is otherwise specified, as used herein, "lower cycloalkyl" has at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0203] As used herein, the terms "heterocycloalkyl", "heterocyclic group", etc. are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocycloalkyl moiety, which is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. For example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl). The heterocycloalkyl can be attached to its side group at any heteroatom or carbon atom, thus producing a chemically stable structure, and any ring atom can be optionally substituted. Examples of heterocycloalkyl include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidoneyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholinyl, thioxazolidinyl, azetidinyl, oxetidinyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl group, diaza group, thiaza group, 1,2,3,6 - tetrahydropyridyl, 2 - pyrrolinyl, 3 - pyrrolinyl, 2H - pyranyl, 4H - pyranyl, dioxolanyl, dithiolanyl, dithiacyclopentanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, 3 - azabicyclo[3.1.0]hexanyl, 3 - azabicyclo[4.1.0]heptanyl, quinuclidinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, etc. Heterocycloalkyl also includes groups in which the heterocycloalkyl ring is fused with one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H - indolyl, chromanyl, benzopyranyl, phenanthridinyl, 2 - azabicyclo[2.2.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl, where the linking group or point of attachment is on the heterocycloalkyl ring. Heterocycloalkyl can be monocyclic or bicyclic. The term "heterocycloalkylalkyl" refers to an alkyl group substituted by a heterocycloalkyl group, where the alkyl and heterocycloalkyl moieties are independently and optionally substituted. The term "C 3-n heterocycloalkyl" refers to a heterocycloalkyl having 3 to the indicated "n" atoms (including carbon atoms and heteroatoms) in the ring structure.

[0204] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to cover rings having one or more sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0205] The term "aryl", used alone or as part of a larger moiety, such as in "aralkyl", "aralkyloxy", "aryloxy" or "aryloxyalkyl", refers to an aromatic group having 4n + 2 conjugated π (pi) electrons in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of 6 to 15 ring members, where n is an integer from 1 to 3, where at least one ring in the system is aromatic, and where each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the expression "aryl ring". In certain embodiments of the present specification, "aryl" refers to an aromatic ring or ring system, including but not limited to phenyl, biphenyl, naphthyl, azulyl, anthracenyl, etc., which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include but are not limited to benzyl, phenethyl, etc. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused with one or more non - aromatic rings, such as indanyl, indenyl, phthalimido, naphthalimido, fluorenyl, phenanthridinyl or tetrahydronaphthyl, etc. The term "C 6-n aryl" refers to an aryl having 6 to the indicated "n" atoms in the ring structure.

[0206] The term "heteroaryl", used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroaryloxy", 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 a cyclic array); and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" is as defined above. A heteroaryl can be monocyclic, or two or more fused rings. The term "heteroaryl" as used herein also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocycloalkyl rings. Non-limiting examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indazolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridyl (e.g., pyrrolo[3,2-b]pyridyl or pyrrolo[3,2-c]pyridyl), pyrazolopyridyl (e.g., pyrazolo[1,5-a]pyridyl), furanopyridyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl can be monocyclic or bicyclic. A heteroaryl includes a ring optionally substituted. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl, where the alkyl and heteroaryl moieties are independently optionally substituted. Examples include, but are not limited to, pyridylmethyl, pyrimidinylethyl, etc. For example, the term "C 5-n heteroaryl" refers to a heteroaryl having 5 to the indicated "n" atoms (including carbon atoms and heteroatoms) in the ring structure.

[0207] The term "halogen" or "halo" means a halogen atom, i.e., a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0208] As described herein, the compounds of the present specification may contain "optionally substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the designated moiety are replaced by suitable substituents. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at any or each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the designated group, the substituents may be the same or different at each position. Combinations of substituents contemplated in the present specification are preferably combinations that result in the formation of chemically stable or chemically viable compounds. As used herein, the term "chemically stable" means that a compound does not substantially change when subjected to conditions that permit its generation, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0209] Examples of substituents include, but are not limited to, halogen (F, Cl, Br, I), OH, CO 2 H, alkoxy, oxo, thio, NO 2 、CN, CF 3 、CHF 2 、NH 2 、NH alkyl, NH alkenyl, NH alkynyl, NH cycloalkyl, NH aryl, NH heteroaryl, NH heterocycloalkyl, dialkylamino, diarylamino, diheteroarylamino, dicycloalkylamino, diheterocycloalkylamino, N-alkyl-N-aryl amino, N-alkyl-N-heteroaryl amino, N-alkyl-N-cycloalkyl amino, N-alkyl-N-heterocycloalkyl amino, 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, CO 2 alkyl, CO 2 alkenyl, CO 2 alkynyl, CO 2 cycloalkyl, CO 2 aryl, CO 2 heteroaryl, CO 2 heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH 2 、C(O)NH alkyl, C(O)NH alkenyl, C(O)NH alkynyl, C(O)NH cycloalkyl, C(O)NH aryl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, OCO 2 alkyl, OCO 2 alkenyl, OCO 2 alkynyl, OCO 2Cycloalkyl, OCO 2 Aryl, OCO 2 Heteroaryl, OCO 2 Heterocycloalkyl, OC(O)NH 2 , 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)(O alkyl) 2 , OP(O)(OH) 2 , OP(O)(O alkenyl) 2 , OP(O)(O alkynyl) 2 , OP(O)(O cycloalkyl) 2 , OP(O)(O aryl) 2 , OP(O)(O heteroaryl) 2 , OP(O)(O heterocycloalkyl) 2 , P(O)(O alkyl) 2 , P(O)(OH) 2 , P(O)(O alkenyl) 2 , P(O)(O alkynyl) 2 , P(O)(O cycloalkyl) 2 , P(O)(O aryl) 2 , P(O)(O heteroaryl) 2 , P(O)(O heterocycloalkyl) 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, NHC(O) cycloalkyl, NHC(O) aryl, NHC(O) heteroaryl, NHC(O) heterocycloalkyl, NHCO 2 alkyl, NHCO 2 alkenyl, NHCO 2 alkynyl, NHCO 2 cycloalkyl, NHCO 2 aryl, NHCO 2 heteroaryl, NHCO 2 heterocycloalkyl, NHC(O)NH 2, NHC(O)NH alkyl, NHC(O)NH alkenyl, NHC(O)NH alkynyl, NHC(O)NH cycloalkyl, NHC(O)NH aryl, NHC(O)NH heteroaryl, NHC(O)NH heterocycloalkyl, NHC(S)NH 2 , 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)NH 2 , NHC(NH)NH alkyl, NHC(NH)NH alkenyl, NHC(NH)NH alkynyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl, NHC(NH) alkyl, NHC(NH) alkenyl, NHC(NH) alkynyl, 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) 2 alkyl, S(O) 2 alkenyl, S(O) 2 alkynyl, S(O) 2 cycloalkyl, S(O) 2 aryl, S(O) heteroaryl, S(O) heterocycloalkyl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH alkenyl, SO 2 NH alkynyl, SO 2 NH cycloalkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO 2 NH heterocycloalkyl, NHSO 2 alkyl, NHSO 2 alkenyl, NHSO 2 alkynyl, NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NHSO 2 heterocycloalkyl, CH 2 NH 2 , CH 2 SO 2 CH 3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocycle, heterocycloalkyl, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl or methylthiomethyl. Each of these substituents may also be further substituted, if possible.

[0210] Accordingly, this document relates to purine compounds as 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 defining the variable as any single group or combination of the listed groups. Similarly, the recitation of an embodiment of a variable herein includes the embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Accordingly, the following embodiments exist alone or in combination as applicable.

[0211] The compounds of the invention have a purine core structure to which the defined substituents are attached. Exemplary compounds as defined herein are represented by the following general formula:

[0212]

[0213] Wherein,

[0214] R 1 and R 2 are each independently selected from optionally substituted C 6-10 aryl and optionally substituted C 5-10 heteroaryl;

[0215] R 3 is selected from optionally substituted R 7 O-, N(R 8 ) 2 -, or C 5-6 heteroaryl;

[0216] R 4 is selected from Cl, CN, C(O)OH and optionally substituted from 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)-, R 5 O-, N(R 6 ) 2 -, C 1 -C 6 alkyl, C 5 -C 6Group of heteroaryl;

[0217] R 5 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl group;

[0218] R 6 is H or selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl group, where at least one R 6 is not H, or two R 6 groups together with the nitrogen atom to which they are attached form a C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0219] R 7 is optionally substituted C 1 -C 6 alkyl; and

[0220] R 8Independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 10 heterocycloalkyl;

[0221] R 9 Independently selected from 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;

[0222] R 10 Independently selected from H or from 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 groups, or two R 10 groups together with the nitrogen atom to which they are attached form an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0223] R 11 independently selected from H or an optionally substituted C at each occurrence 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups;

[0224] wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted;

[0225] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0226] R 1 Non-limiting examples of include groups A1 and A2:

[0227]

[0228] R 2 Non-limiting examples of include groups B1 to B23:

[0229]

[0230]

[0231] R 3 Non-limiting examples of include groups C1 to C69:

[0232]

[0233]

[0234]

[0235]

[0236] R 4 Non-limiting examples of include groups D1 to D81:

[0237]

[0238]

[0239]

[0240] Exemplary compounds as defined herein are further represented by Compounds 1 to 240 as defined in Table 1 below, or their isomers or tautomers, or their pharmaceutically acceptable salts.

[0241] Table 1. Exemplary Compounds and Group Definitions

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] In a preferred embodiment, the group R 4 comprises a hydroxyl-substituted functional group, and the technology of the present invention relates to compounds of Formula I:

[0250]

[0251] wherein,

[0252] R 1 is an optionally substituted C 6 aryl;

[0253] R 2 is an optionally substituted C 6 aryl or C 5 -C 6 heteroaryl;

[0254] R 3 is an optionally substituted group selected from R 7 O-, N(R 8 ) 2 -, C 4-10 heterocycloalkyl and C 5-6 heteroaryl;

[0255] R 4 is an optionally substituted group selected from R5 O- and N(R 6 ) 2 - groups;

[0256] R 5 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups;

[0257] R 6 is H or is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 5 -C 6 heteroaryl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl groups, where at least one R 6 is not H, or two R 6 groups together with the nitrogen atom to which they are attached form a C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0258] wherein R 5 or R 6at least one of the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is substituted by at least one hydroxyl group or a C substituted by a hydroxyl group 1 -C 4 alkyl and is optionally further substituted by other substituents;

[0259] R 7 is optionally substituted C 1 -C 6 alkyl; and

[0260] R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 10 heterocycloalkyl;

[0261] wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted;

[0262] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0263] In another embodiment, the compound is a compound of formula II:

[0264]

[0265] wherein,

[0266] R 4 is as defined for formula I;

[0267] X 1 is C and X 2 to X 6 are each independently selected from N and CR 21 and n is 1, wherein at most three of X 2 to X 6 are N; or

[0268] X 1 is C or N and X 2 to X 5 are each independently selected from CR 21 、O、S、N or NR 11 ,n is 0, that is, X 6 does not exist but forms a bond between X 1 and X 5 ,wherein at most three of X 1 to X 5 are not C or CR 21 ;

[0269] X7 and X 8 are each independently selected from O, S, SO 2 , NR 36 or C(R 35 ) 2 , provided that when one of X 7 and X 8 is O, S or NR 36 , the other is C(R 35 ) 2 ;

[0270] R 9 is independently selected, each time it appears, from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl and C 5 -C 6 heteroarylC 1 -C 3 alkyl;

[0271] R 10 is independently selected, each time it appears, from H or from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl and C 5 -C 6 heteroarylC 1 -C 3 alkyl, or two R 10 groups together with the nitrogen atom to which they are attached form an optionally substituted C4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0272] R 11 independently selected from H or from 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 groups;

[0273] R 12 independently selected from 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, and p is 0, 1, 2 or 3, preferably 0 or 1;

[0274] R 21 independently selected from hydrogen, halogen, OH, OR 9 , CN, NO 2 , C(O)R 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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, 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;

[0275] R 31 to R 35 are each independently selected from hydrogen, halogen, OH, OR 9 , CN, NO 2 , C(O)OH, C(O)OR 9 , C(O)R 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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, 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;

[0276] R 36 is selected from hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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;

[0277] or two of R 31 to R 36 together with the atoms to which they are adjacent form a ring, preferably a bridged heterocycle or a spiro heterocycle; and

[0278] m is 0, 1, 2 or 3;

[0279] wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted;

[0280] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0281] According to some examples, m is 0 and X 7 and X 8 are each independently C(R 35 ) 2 , preferably X 7 is CH 2 . For example, X 8 is C(R 35 )2 , wherein the two Rs 35 one of which 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ), 2 or optionally substituted C 1-6 alkyl. Alternatively, X 8 is C(R 35 ), 2 and the two Rs 35 together with the carbon atom adjacent to them form a spiro C 4-5 heterocycle.

[0282] In other instances, m is 1 and X 7 and X 8 are each independently C(R 35 ), 2 , preferably X 7 is CH 2 . For example, X 8 is C(R 35 ), 2 wherein one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ), 2 or optionally substituted C 1-6 alkyl. Alternatively, X 8 is C(R 35 ), 2 and the two Rs 35 together with the carbon atom adjacent to them form a spiro C 4-5 heterocycle.

[0283] According to a further instance, m is 2 and X 7 and X 8 are each independently C(R35 ) 2 For example, X 8 is CH 2 and X 7 is C(R 35 ) 2 , where one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl. In some preferred examples, R 35 is C(O)N(R 10 ) 2 or N(R 11 )C(O)R 9 , and the other of the two Rs 35 is OR 9 or optionally substituted C 1-4 alkyl. For example, R 35 is OR 9 and R 9 is C 1-6 alkyl, preferably C 2-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, isobutyl or sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0284] In other examples, m is 2 and X 7 and X 8 are each independently C(R 35 ) 2 , for example, X 8 is CH 2 and X 7 is C(R 35 ) 2 and the two Rs 35 together with the carbon atom adjacent to them form a spiro C 4-5 heterocycle. Alternatively, X 7 is CH 2 and X 8 is C(R 35 ) 2 , where one of the two Rs 35 is fluorine, C(O)R9 , 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 other of said two R 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl. For example, one of said two R 35 is C(O)N(R 10 ) 2 or N(R 11 )C(O)R 9 , and the other of said two R 35 is OR 9 or optionally substituted 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, isobutyl or sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0285] In other instances, m is 2 and X 7 and X 8 are each independently C(R 35 ) 2 , for example, X 7 is CH 2 and X 8 is C(R 35 ) 2 and the two R 35 together with the carbon atoms adjacent to them form a spiro C 4-5 heterocycle.

[0286] In still other instances of the compounds of formula II, m is 2 or 3, X 7 is O, S, SO 2 or NR 36 , preferably O, SO 2 or NR 36 , and X 8 is C(R 35 ) 2 . For example, X 7 is NR 36 and R 36 is selected from hydrogen, C(O)R 9, C(O)OR 9 , C(O)N(R 10 ) 2 and optionally substituted C 1-6 alkyl. In other embodiments, one of the two R 8 in X 35 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 substituted C 1-6 alkyl, and the other of the two R 35 is hydrogen, fluorine, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl, or one of the R 35 forms a bridged ring together with R 33 and the atoms adjacent to them. For example, both R 8 in X 35 are hydrogen. Or, one of the two R 35 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 other of the two R 35 is hydrogen. In another alternative, R 35 forms C 33 alkylene together with R 1-3 .

[0287] In some instances of the compound of formula II, R 33 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears, and / or R 34 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears, and / or R 31 and R 32 are each a hydrogen atom.

[0288] In the context of formula II, R 3Examples of the group include C1-C7, C10, C15, C16, C18-C22, C24-C28, C32-C40 and C47-C69 groups as defined above, preferably C1, C16 or C18, more preferably C18.

[0289] In a further embodiment, the compound is a compound of formula III:

[0290]

[0291] Wherein,

[0292] R 13 is an optionally substituted group selected from R 7 O-, N(R 8 ) 2 - and C 5-6 heteroaryl group;

[0293] R 4 , R 7 and R 8 are as defined for formula I; and

[0294] R 12 , X 1 to X 6 , n and p are as defined for formula II;

[0295] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0296] According to some examples, R 13 is R 7 O-. For example, R 7 can be an optionally substituted C 1 -C 4 alkyl.

[0297] In other examples, R 13 is N(R 8 ) 2 -, preferably one of the R 8 is an optionally substituted C 4 -C 10 heterocycloalkyl and the other R 8 is hydrogen or an optionally substituted C 1 -C 6 alkyl, or one of the R 8 is an optionally substituted C 4 -C 7 heterocycloalkyl and the other R 8 is hydrogen or an optionally substituted C 1 -C 4 alkyl, or R 8 is an optionally substituted C1 -C 6 alkyl, and the other R 8 is hydrogen or optionally substituted C 1 -C 6 alkyl.

[0298] In formula I or III, R 3 or R 13 group examples include C8, C9, C11-C14, C17, C23, C29-C31 and C41-C46 groups as defined above.

[0299] In some compounds of formula II and formula III, R 12 is Cl and p is 1, preferably forming 4-chlorophenyl. In other compounds, p is 0, i.e., R 12 is absent, thus forming an unsubstituted phenyl.

[0300] In some examples of compounds of formula II and formula III, n is 1, X 1 is C and X 2 to X 6 are each independently CR 21 , or n is 1, X 1 is C, one of X 2 to X 6 is N and the others are CR 21 . Or, n is 0, X 6 is absent, and X 1 is C, preferably one or two of X 2 to X 5 are N or NR 11 and the others are CR 21 , preferably R 11 is C 1 -C 6 alkyl, or one of X 2 to X 5 is S and the others are CR 21 . In these examples, all CR 21 groups can be CH. Or, one CR 21 is not CH, preferably R 21 is selected from halogen, CN, N(C 1-6 alkyl) 2 and C 1-6 alkyl, more preferably halogen or CN, most preferably halogen (such as Cl), or one CR 21 is not CH, preferably R 21 is selected from halogen, CN, N(C 1-6 alkyl) 2 and C 1-6alkyl, more preferably halogen, CN and C 1-6 alkyl, most preferably CN, or a CR 21 not CH, preferably R 21 selected from halogen, 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.

[0301] R in formula I, II or III 2 Examples include groups B1 to B23 as defined herein. For example, R 2 can be selected from groups B1 to B4, for example R 2 is B1. Alternatively, R 2 is selected from groups B5 to B8, B12 to B19 and B21 to B23, for example R 2 is B14. In still other instances, R 2 can be selected from groups B9 to B11 and B20.

[0302] In some instances, the compound is a compound of formula I, II or III, wherein R 4 is R 5 O-group, wherein R 5 is as defined above and is C 1 -C 4 alkyl substituted by at least one hydroxyl or hydroxyl group 5 can be C 2 -C 6 alkyl, C 4 -C 10 heteroalkyl or C 4 -C 10 heteroalkyl C 1 -C 3 alkyl. In some instances, 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. In other instances, R 5 is C 4 -C 6 heteroalkyl or C 4 -C 6 heteroalkyl C 1 -C 3Alkyl, preferably said C 4 -C 6 Heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

[0303] In other instances, the compound is a compound of formula I, II or III, and R 4 is an N(R 6 ) 2 -group, wherein R 6 is as defined herein and at least one R 6 is substituted by at least one hydroxyl group or a C 1 -C 4 alkyl substituted by hydroxyl groups and optionally substituted by one or more other substituents. In one embodiment of these instances, one R 6 is a C 1 -C 4 alkyl substituted by at least one hydroxyl group or a C 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 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl and optionally substituted by one or more other substituents, preferably R 6 is a C 1 -C 4 alkyl substituted by hydroxyl groups or a C 2 -C 6 alkyl or C 3 -C 7 cycloalkyl C 1 -C 3 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl. In another embodiment of these instances, the two R 6 groups together with the nitrogen atom to which they are attached form a C 1 -C 4 alkyl substituted by at least one hydroxyl group or a C 4 -C10 Heterocycloalkyl or C 5 For example, the two R 6 The groups together with their adjacent nitrogen atoms form a C 1 -C 4 alkyl and optionally substituted with one or more other substituents. 4 -C 7 Heterocycloalkyl, preferably wherein the C 4 -C 7 Heterocycloalkyl is selected from C 1 -C 4 alkyl and optionally substituted with one or more other substituents; or the two R 6 The groups together with their adjacent nitrogen atoms form a C 1 -C 4 alkyl and optionally substituted with one or more other substituents. 5 Heteroaryl, preferably the C 5 Heteroaryl is selected from C 1 -C 4 Imidazole and pyrrole groups substituted with alkyl and optionally substituted with one or more other substituents.

[0304] R in Formula I, II or III 4 Examples of include groups D5-D9, D12, D13, D19-D21, D23, D25, D27, D28, D30-D32, D36, D37, D43-D49, D52, D53, D67, D71, D75, D76, and D78-D81 as defined herein. For example, R 4 It can be selected from the groups D6-D9, D43-D47, D75 and D76, preferably D6-D9 and D43-D47, preferably D9, or from the groups D12, D19, D21, D23, D30-D32, D36, D37, D48, D49 and D78-D81, preferably D19 or D21, preferably D5, D13, D20, D52, D53, D67 and D71, preferably D20.

[0305] 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 isomers or tautomers thereof, or pharmaceutically acceptable salts 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 isomers or tautomers thereof, or pharmaceutically acceptable salts thereof. More preferably, the compound is selected from 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, 135-137, 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 isomers or tautomers thereof, or pharmaceutically acceptable salts thereof.Most preferably, the compound is selected from 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, 165-167, 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.

[0306] In yet another embodiment, the compound is a compound of formula IV:

[0307]

[0308] wherein X 1 to X 8 , R 12 , R 31 to R 34 , m, n and p are as defined herein; and

[0309] R 14 is N(R 16 ) 2 - or an optionally substituted C 5 -C 6 heteroaryl; and

[0310] R 16 is selected from H or a group selected from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, C 5 -C 6 heteroarylC 1 -C 3 alkyl, or two R 16The group, together with its adjacent nitrogen atom, forms an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 -C 6 heteroaryl;

[0311] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0312] In some instances, R 14 is N(R 16 ) 2 -. In other embodiments, one R 16 is an optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 10 heterocycloalkyl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl or C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, and the other R 16 is hydrogen or C 1 -C 6 alkyl. For example, one R 16 is a C 2 -C 6 alkyl substituted with one or more substituents, and the other R 16 is hydrogen or C 1 -C 6 alkyl, and the substituents are preferably selected from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In another embodiment, the two R 16 groups, together with their adjacent nitrogen atom, form an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 heteroaryl connected through said nitrogen. For example, the two R 16 groups, together with their adjacent nitrogen atom, form an optionally substituted C 4 -C 7 heterocycloalkyl connected through said nitrogen, preferably the C 4 -C 7 heterocycloalkyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl. Alternatively, the two R 16The group, together with its adjacent nitrogen atom, forms an optionally substituted C 5 heteroaryl, preferably the C 5 heteroaryl is selected from optionally substituted imidazole and pyrrole groups.

[0313] In other instances, R 14 is an optionally substituted C 5 -C 6 heteroaryl.

[0314] Examples of the R 14 group include D3-D5, D11-D16, D19-D28, D30-D32, D36, D37, D39-D41, D48-D54, D56, D57, D63-D67, D71, and D78-D81 as defined herein.

[0315] In yet another embodiment, the compound of the invention is a compound of formula V:

[0316]

[0317] wherein X 1 to X 6 , R 12 , R 13 , R 14 , n, and p are as previously defined;

[0318] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0319] In a further embodiment, the compound of the invention is a compound of formula VI:

[0320]

[0321] wherein X 1 to X 8 , R 12 , R 31 to R 34 , m, n, and p are as previously defined; and

[0322] R 15 is selected from 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 3Alkyl, C 4 -C 10 Heterocycloalkyl C 1 -C 3 Alkyl, C 5 -C 6 Heteroaryl C 1 -C 3 groups of alkyl;

[0323] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0324] According to some examples, 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 alkyl. For example, R 15 is C 1 -C 6 alkyl substituted with one or more substituents selected, for example, from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or R 15 is optionally substituted C 4 -C 6 heterocycloalkyl or C 4 -C 6 heterocycloalkyl C 1 -C 3 alkyl, preferably the C 4 -C 6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl, and piperazinyl.

[0325] Examples of the OR 15 group include D6-D10, D17, D29, D33-D35, D43-D47, D55, D68-D70, and D72-D77.

[0326] In a further embodiment, the compound of the present invention is a compound of formula VII:

[0327]

[0328] wherein X 1 to X 6 , R 12 , R 13 , R 15 , n, and p are as previously defined;

[0329] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0330] In another embodiment, the compound is a compound of formula VIII:

[0331]

[0332] wherein X 1 to X 8 , R 12 , R 31 to R 34 are as previously defined; and

[0333] R 24 is selected from 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, wherein R 9 to R 11 are as previously defined;

[0334] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0335] In a further embodiment, the compound is a compound of formula IX:

[0336]

[0337] wherein X 1 to X 6 , R 12 , R 13 , R 24 , n and p are as previously defined;

[0338] or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0339] In some instances of the compounds of formula VIII and formula IX, R 24 is selected from the groups D1, D2, D18, D38, D42 and D58 - D62.

[0340] In other embodiments, the compounds of the present invention are selected from Compounds 1 to 240 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0341] 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.

[0342] In a further embodiment, 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.

[0343] In yet another embodiment, the compound is selected from 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.

[0344] The compounds of the present invention can be prepared by conventional chemical synthesis, for example, by the chemical synthesis described in the following Examples section. Those skilled in the art will understand that other methods for synthesizing the compounds of the general formula of the present invention will be apparent to those of ordinary skill in the art. Additionally, the individual synthesis steps can be carried out in an alternating sequence or order to obtain the desired compound.

[0345] The compounds defined herein can be formulated into pharmaceutical compositions for administration to a subject, and the compound is generally admixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0346] The term "pharmaceutically acceptable carrier, diluent, or excipient" and equivalent terms mean a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound formulated therewith.

[0347] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, and intralesional injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0348] 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 that comprises a compound as described herein and at least one binder as defined in the preceding paragraph, which preferably comprises microcrystalline cellulose.

[0349] 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, flavoring agents, coating agents, preservatives, lubricants, and / or polymers. Examples of binders include cellulose-based substances such as microcrystalline cellulose and carboxymethyl cellulose, and other binders such as gum arabic, gelatin, corn starch, tragacanth, sodium alginate, or polyethylene glycol (PEG). Examples of sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Disintegrants include corn starch, methyl cellulose, 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, wintergreen oil, cherry, orange, or raspberry flavorings. 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, α-tocopherol, ascorbic acid, methyl paraben, propyl paraben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Examples of excipients may also include polymers selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), and mixtures thereof.

[0350] The compositions of the present invention can also be used as fillers in soft and hard filled capsules. Solid dosage forms such as tablets, lozenges, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well-known in the art of pharmaceutical formulation. They optionally may contain opacifying agents and may also be compositions that release the active ingredient only in or preferentially in a certain part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The compositions can also be in microencapsulated form containing one or more of the excipients as described above.

[0351] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, these oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, surfactants, sweetening agents, flavoring agents, and fragrances.

[0352] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution U.S.P., and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono - or di - glycerides of fatty acids. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0353] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0354] To prolong the action of the compounds provided, it is generally desirable to slow the absorption of the compound following subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-co-glycolide. The rate of release of the compound can be controlled according to the compound-to-polymer ratio and the nature of the particular polymer used.

[0355] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0356] Dosage forms for topical or transdermal administration of the compounds of this specification include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if required, under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this specification. Additionally, the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body, is also contemplated in this specification. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0357] The pharmaceutically acceptable compositions provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0358] The amount of the compound that can be combined with the carrier materials to produce a single dosage form composition will vary depending on the patient to be treated and the particular mode of administration.

[0359] As used herein, the term "effective amount" refers to the amount of a compound that will elicit a biological or medical response of a tissue, system, animal, or human that is sought by, for example, a researcher or clinician. In addition, the term "therapeutically effective amount" refers to any amount that causes a disease, disorder, or symptom thereof to be treated, cured, prevented, or improved, or causes a decrease in the rate of progression of a disease or disorder, compared to a corresponding subject who has not received that amount. The term also includes within its scope amounts that effectively enhance normal physiological functions.

[0360] As used herein, the terms "treat" and "treatment" refer to reversing, alleviating a disease or disorder or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., based on a symptom history and / or based on genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

[0361] The term "patient" or "subject" as used herein refers to an animal, such as a mammal. Thus, a subject can refer to, for example, a mouse, a rat, a dog, a cat, a horse, a cow, a pig, a guinea pig, a primate including a human, and the like. Preferably, the subject is a human.

[0362] The compounds of the present invention can be used to treat diseases and disorders that require inhibition of the cannabinoid receptor CB 1 Thereby, the present invention relates to the use of the compounds of the present invention for treating the diseases or disorders defined herein, the use of the compounds of the present invention in the preparation of a medicament for treating the diseases or disorders defined herein, the compounds defined herein for treating the said diseases or disorders, and a method for treating the diseases or disorders defined herein, including administering one of the compounds of the present invention to a subject in need thereof. Such diseases and disorders may generally be associated with diabetes and metabolic disorders (such as metabolic syndrome). Preferably, the compound selectively targets the CB 1 receptor in peripheral tissues (such as adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic β-cells, and gastrointestinal tract), and does not interact with or mainly does not interact with the CB 1 receptor in the brain tissue, thereby avoiding or reducing CNS-related side effects.

[0363] The effects of the compounds of the present invention may include reducing food intake, reducing body weight, reversing insulin and leptin resistance, reversing hepatic steatosis (fatty liver), and improving dyslipidemia. Examples of diseases and disorders to be treated include obesity, diabetes (type I or type II), non-alcoholic and alcoholic fatty liver diseases (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC)-deficient obesity, leptin receptor (LepR)-deficient obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl (BB) syndrome, syndrome, dyslipidemia prone 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-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis, renal fibrosis, scleroderma and gout. In addition, skin disorders include reduced scar formation (scars, keloids) and hair loss, especially hair loss associated with male pattern hair loss and metabolic syndrome. For example, comorbidities of obesity are selected from metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcers, hypoventilation syndrome, sleep apnea, snoring, asthma, obesity-related asthma, coronary artery disease, atherosclerotic diseases, pseudotumor cerebri, osteoarthritis, hypercholesterolemia, and increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate or gallbladder. In a preferred example, the disease or disorder includes diabetes (type I or type II), obesity and non-alcoholic fatty liver disease (such as non-alcoholic steatohepatitis). Examples of comorbidities of diabetes (such as type I) include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0364] The diseases, disorders and conditions to be treated, including those described above, can be classified into various categories, and certain conditions can also coexist in the same 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-related disorders, and obesity-related disorders and their complications.

[0365] Examples of disorders related to appetite 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, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and syndrome.

[0366] 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 diseases (due to β-cell protection and / or increased insulin production), and related nephropathy, neuropathy, and retinopathy.

[0367] Examples of fibrosis-related disorders and 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 non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrotic nephropathy, skin fibrosis disorders (such as scleroderma), and chronic kidney disease.

[0368] Examples of disorders related to metabolism and their complications include, but are not limited to, metabolic syndrome and hyperlipidemia (such as hypertriglyceridemia, hypertriglyceridemia in the context of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0369] Examples of disorders related to obesity and their complications include, but are not limited to, sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcers, coronary artery disease, atherosclerotic diseases, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0370] Examples of disorders of the skin and hair include hair loss (male pattern hair loss and hair loss associated with metabolic syndrome), excessive scar formation (scars and keloids), scleroderma, etc.

[0371] Examples of disorders related to the gastrointestinal tract include constipation, irritable bowel syndrome, inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease, etc.

[0372] Other disorders may also benefit from the compounds of the present invention, including muscular atrophy disorders, including muscular dystrophy (such as Duchenne muscular dystrophy (DMD)), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy, and the like.

[0373] The solid compounds and compositions of the present invention can also be used in methods for preventing or reversing adipose tissue deposition in a subject, which is expected to contribute to reducing the incidence or severity of obesity, and thus reducing the incidence or severity of related comorbidities.

[0374] This specification provides methods for treating disorders in a subject (such as those described herein), which include administering a compound or composition of this specification to a subject determined to be in need thereof. The determination of patients in need of treatment for the above disorders is entirely within the capabilities and knowledge of those skilled in the art. The medical field knows certain methods for determining patients at risk of developing the above disorders treatable by the methods of the present invention, such as family history, and the presence of risk factors in the subject patient related to the development of the disease state. Clinicians in the art can easily identify such candidate patients by utilizing, for example, clinical trials, physical examinations, medical history / family history, and genetic testing.

[0375] Methods for evaluating the efficacy of a treatment in a subject include determining the pre-treatment symptoms of the disorder by methods well known in the art, and then administering a therapeutically effective amount of a compound of this specification to the subject. After an appropriate period of time (e.g., 1 week, 2 weeks, 1 month, 6 months) after administering the compound, the symptoms of the disorder are re-evaluated. Modulation (e.g., reduction) of the symptoms and / or biomarkers of the disorder indicates the efficacy of the treatment. The symptoms and / or biomarkers of the disorder can be determined periodically throughout the course of the treatment. For example, the symptoms and / or biomarkers of the disorder can be checked every few days, weeks, or months to evaluate the further efficacy of the treatment. Reduction of the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0376] The pharmaceutical compositions provided herein are preferably suitable for oral administration. Such formulations can be administered with or without food. The compositions are formulated into unit dosage forms to facilitate administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete dosage units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the solid dispersions and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment.

[0377] The amount of the composition that can be included in a single dosage form will vary depending on the patient to be treated (e.g., children and adults, etc.) and the specific compound included in the composition. The provided compositions can be formulated such 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 can contain such an amount, or the total daily dose can be divided and administered in multiple dosage forms, for example, once, twice, or three times a day. For example, a single dose can contain 5 to 500 mg or 20 to 200 mg of the active ingredient. The treatment regimen can include administering a total amount of from about 10 mg to about 1000 mg of the compounds of the present specification to the patient in a single dose or divided into multiple doses per day.

[0378] It should be understood that the total daily dose of the compound will be determined by the attending physician within the scope of reasonable medical judgment. For example, the specific dose or treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, gender, diet, time of administration, rate of excretion, drug combination, judgment of the treating physician, and the severity of the symptoms associated with the disease or disorder.

[0379] Depending on the disease or disorder to be treated, additional therapeutic agents can also be present in the compositions of the present disclosure or administered jointly separately. Non-limiting examples of additional therapeutic agents that can be used in combination with the solid dispersions and formulations of the present invention include anti-diabetic agents, cholesterol-lowering agents, anti-inflammatory agents, anti-microbial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, anti-cancer agents, anti-viral agents, cytokines, growth factors, immunomodulators, prostaglandins, or anti-angiogenic compounds. Other treatments or interventions can also be added to this treatment, such as surgery, radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF)), and agents for alleviating the adverse reactions of the compounds of the present invention or co-administered components.

[0380] The recitation of embodiments of variables herein includes the embodiment as any single embodiment or in combination with any other embodiment or part thereof. The recitation of embodiments herein includes the embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0381] Examples

[0382] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.

[0383] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stability, etc. used in this specification and the claims are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should be construed in accordance with the number of significant figures reported and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the property sought to be obtained. While the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors resulting from variations in experimental, testing measurements, statistical analysis, etc.

[0384] Abbreviations:

[0385] -DIPEA: N,N-Diisopropylethylamine

[0386] -DMSO: Dimethyl sulfoxide

[0387] -NMP: N-Methyl-2-pyrrolidone

[0388] -DCM: Dichloromethane

[0389] Example 1 - Preparation of Starting Materials

[0390] (i) Preparation of 6-Chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (B-2)

[0391] 4-Chloroaniline (5.6 g, 44.2 mmol, 1.06 eq) was added to a solution of 4,6-dichloro-2-methylthio-5-nitro-pyrimidine (10 g, 41.7 mmol, 1 eq) and potassium carbonate (17.2 g, 125 mmol, 3 eq) in N,N-dimethylformamide (50 mL) at 0 °C with stirring. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was added to water (200 mL) with stirring to obtain a yellow solid. The residue was purified by silica flash column chromatography ( 120 g Silica Flash Column, eluent with a 0 - 50% ethyl acetate / petroleum ether gradient, 100 mL / min) to give 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine as a yellow solid (intermediate B-2, 10 g, 30.2 mmol, 72.4% yield). 1 H NMR (400 MHz, CDCl 3-d) δ = 9.66 (br s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.42 - 7.35 (m, 2H), 2.49 (s, 3H).

[0392] (ii) Preparation of 1-hydroxy-N-methyl-cyclopropanecarboxamide

[0393] 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) were added triethylamine (15.6 g, 154 mmol, 3.5 equiv), methylamine 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), and the resulting mixture was stirred at 25 °C for 15 h. 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 chromatography ( 25 g Silica Flash Column, eluent with a 0 - 20% dichloromethane / methanol gradient, 20 mL / min) to give 1-hydroxy-N-methyl-cyclopropanecarboxamide as a white solid (2.4 g, 20.8 mmol, 47.2% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.84 (br s, 1H), 6.14 (s, 1H), 2.63 (d, J = 4.8 Hz, 3H), 1.05 - 0.92 (m, 2H), 0.85 - 0.61 (m, 2H).

[0394] (iii) Preparation of 1-(methylaminomethyl)cyclopropanol

[0395] To a solution of 1-hydroxy-N-methyl-cyclopropanecarboxamide (500 mg, 4.34 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) at 0 °C was added lithium aluminum hydride (494 mg, 13.0 mmol, 3 equiv), and then the mixture was stirred at 60 °C for 1 h. Sodium sulfate decahydrate was added to the reaction mixture until no more bubbles evolved, and the mixture was filtered and concentrated under reduced pressure to give the crude product. Compound 1-(methylaminomethyl)cyclopropanol was obtained as a yellow oil (400 mg, 3.95 mmol, 91.0% yield).

[0396] (iv) Preparation of 2-[(5-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane

[0397] 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). 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, and then the mixture was stirred at 25 °C for 1 h. The mixture was diluted with (200 mL) and extracted with ethyl acetate (100 mL * 3), washed with brine (200 mL), dried over anhydrous sodium carbonate, filtered and concentrated to give a residue. The residue was purified by flash silica chromatography ( 50 g Silica Flash Column, eluent: 0 - 60% ethyl acetate / petroleum ether gradient, 50 mL / min) to obtain 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 H NMR (400 MHz, DMSO-d 6 ) δ = 7.77 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 5.30 (s, 2H), 3.50 - 3.43 (m, 2H), 0.87 - 0.81 (m, 2H), 0.03 (s, 9H). P2: 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.01 (d, J = 0.8 Hz, 1H), 7.05 (d, J = 0.8 Hz, 1H), 5.28 (s, 2H), 3.50 - 3.46 (m, 2H), 0.86 - 0.82 (m, 2H), 0.03 (s, 9H).

[0398] (v) Preparation of trimethyl-[2-[(5-tributylstannylimidazol-1-yl)methoxy]ethyl]silane

[0399] To a solution of 2-[(5-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (2.90 g, 8.94 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -10 °C was added chloro(isopropyl)magnesium (2.0 M, 6.70 mL, 1.5 eq), and the mixture was stirred at -10 °C for 1 hour. Then, tributyl(chloro)stannane (3.49 g, 10.7 mmol, 1.2 eq) was added dropwise at -10 °C, and the resulting mixture was stirred at 25 °C for 15 hours. The mixture was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (100 mL), washed with water (50 mL), washed with brine (50 mL), filtered and concentrated in vacuo. The brown oil was purified by flash silica chromatography ( 25 g Silica Flash Column, eluent: 0 - 80% ethyl acetate / petroleum ether gradient, 30 mL / min) to give trimethyl-[2-[(5-tributylstannylimidazol-1-yl)methoxy]ethyl]silane as a yellow solid (2.1 g, 4.31 mmol, 48.1% yield). 1 H NMR (400 MHz, CDCl 3 -d) δ = 7.74 (s, 1H), 7.09 (d, J = 0.6 Hz, 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 = 7.3 Hz, 11H), -0.01 (s, 9H).

[0400] (vi) Preparation of 2-(1H-imidazol-4-yl)ethyl acetate

[0401] To a solution of 2-(1H-imidazol-4-yl)ethanol (1.2 g, 10.70 mmol, 1 eq) and triethylamine (3.25 g, 32.11 mmol, 4.47 mL, 3 eq) in dichloromethane (15 mL) at 0 °C was added acetyl chloride (1.26 g, 16.0 mmol, 1.15 mL, 1.5 eq) dropwise, and the resulting mixture was stirred at 25 °C for 15 hours. 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 carbonate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography ( 20 g Purified by silica flash column (eluent: 0 - 10% methanol / dichloromethane, 20 mL / min). The fraction was concentrated under reduced pressure to obtain compound 2-(1H-imidazol-4-yl)ethyl acetate as a pale yellow oil (0.36 g, 2.34 mmol, 21.8% yield).

[0402] (vii) Preparation of 4-methylpiperidine-4-carboxamide

[0403] To a solution of tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (5 g, 20.63 mmol, 1 equiv.) in dichloromethane (25 mL) was added hydrochloride / dioxane (4 M, 25 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum to obtain 4-methylpiperidine-4-carboxamide as a white solid (3.6 g, 20.2 mmol, 97.6% yield, hydrochloride).

[0404] (viii) Preparation of (2R)-1-(methylamino)propan-2-ol

[0405] To a solution of tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (5 g, 28.53 mmol, 1 equiv.) in tetrahydrofuran (50 mL) at 0 °C was added lithium aluminum hydride (3.25 g, 85.60 mmol, 3 equiv.), and then 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 obtain (2R)-1-(methylamino)propan-2-ol as a colorless oil (2 g, crude).

[0406] (ix) Preparation of (2S)-1-(methylamino)propan-2-ol

[0407] To a solution of tert-butyl N-[(2S)-2-hydroxypropyl]carbamate (3 g, 17.1 mmol, 1 equiv.) in tetrahydrofuran (50 mL) at 0 °C was added lithium aluminum hydride (1.95 g, 51.36 mmol, 3 equiv.), and then 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 obtain (2S)-1-(methylamino)propan-2-ol as a colorless oil (1 g, crude).

[0408] (x) Preparation of 1,4-dimethylimidazole-2-carbaldehyde and 1,5-dimethyl-1H-imidazole-2-carbaldehyde

[0409] 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) as a yellow oil and 1,5-dimethyl-1H-imidazole-2-carbaldehyde. 1 H NMR(400MHz,CDCl 3 -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).

[0410] (xi) Preparation of (2S)-2-(methylamino)propan-1-ol

[0411] To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methylethyl]carbamate (5 g, 28.5 mmol, 1 equiv) in tetrahydrofuran (50 mL) at 0 °C was added lithium aluminum hydride (3.25 g, 85.6 mmol, 3 equiv), and then 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 (2S)-2-(methylamino)propan-1-ol (2 g, 22.4 mmol, 78.6% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d 6 )δ=3.25-3.20(m,2H),2.48-2.40(m,1H),2.25(s,3H),0.87(d,J=6.4Hz,3H).

[0412] (xii) Preparation of (2R)-2-(methylamino)propan-1-ol

[0413] To a solution of tert-butyl N-[(1R)-2-hydroxy-1-methylethyl]carbamate (5 g, 28.5 mmol, 1 equiv) in tetrahydrofuran (50 mL) at 0 °C was added lithium aluminum hydride (3.25 g, 85.6 mmol, 3 equiv), and then 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. 11H NMR (400 MHz, DMSO-d 6 ) δ = 3.23 - 3.20 (m, 2H), 2.48 - 2.40 (m, 1H), 2.25 (s, 3H), 0.87 (d, J = 6.4 Hz, 3H).

[0414] (xiii) Preparation of dimethyl((methylamino)methyl)phosphine oxide

[0415] To a solution of 1,3,5-trimethyl-1,3,5-triazane (5 g, 38.7 mmol, 5.44 mL, 1 equiv) in toluene (50 mL) was added methylphosphonylmethane (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 chromatography ( 120 g Silica Flash Column, eluent 0 - 20% methanol / dichloromethane, 100 mL / min) to give dimethyl((methylamino)methyl)phosphine oxide as a colorless oil (2.5 g, 20.6 mmol, 53.3% yield). 1 1H NMR (400 MHz, CDCl 3 3-d) δ = 2.86 - 2.59 (m, 2H), 2.51 - 2.22 (m, 3H), 1.55 - 1.24 (m, 6H)

[0416] (xiv) Preparation of 5-formyl-6-methyl-pyridine-2-carbonitrile

[0417] 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), triphenylphosphine palladium (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 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and 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 chromatography ( 40 g Purify by silica flash column with an eluent of 0 - 50% ethyl acetate / petroleum ether gradient at 40 mL / min. Concentrate the fractions under reduced pressure to obtain compound 6-methyl-5-vinyl-pyridine-2-carbonitrile as a white solid (460 mg, 3.19 mmol, 25.87% yield).

[0418] Step 2: Stir a mixture of 6-methyl-5-vinyl-pyridine-2-carbonitrile (360 mg, 2.50 mmol, 1.0 equiv), dipotassium; dioxo(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) at 25 °C for 2 h. Filter the reaction mixture and wash the cake with acetone (3 mL × 3). Dilute the filtrate with water (50 mL) and extract with ethyl acetate (20 mL × 3). Wash the combined organic layers with brine (50 mL), dry over anhydrous sodium carbonate, filter, and concentrate under reduced pressure to obtain a residue. Purify the residue by flash silica chromatography ( 20 g Purify by silica flash column with an eluent of 0 - 50% ethyl acetate / petroleum ether gradient at 30 mL / min. Concentrate the fractions under reduced pressure to obtain compound 5-formyl-6-methyl-pyridine-2-carbonitrile as a light yellow solid (142 mg, 0.97 mmol, 38.9% yield). 1 H NMR (400 MHz, CDCl 3 ) δ = 10.40 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 2.96 (s, 3H).

[0419] (xv) Preparation of 5-formyl-4-methyl-pyridine-2-carbonitrile

[0420] Step 1: Suspend 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), triphenylphosphine palladium (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) in N 2Stir at 90 °C for 1 hour under an atmosphere. Cool the reaction mixture to room temperature and filter. Wash the obtained filter cake with ethanol (5 mL * 3). Concentrate the filtrate under reduced pressure to obtain a residue. The residue is purified by flash silica chromatography ( 40 g Silica Flash Column, eluent with a 0 - 10% ethyl acetate / petroleum ether gradient, 40 mL / min). Concentrate the fractions under reduced pressure to obtain 4-methyl-5-vinyl-pyridine-2-carbonitrile as a white solid (0.55 g, 3.74 mmol, 36.9% yield).

[0421] Step 2: Stir a mixture of 4-methyl-5-vinyl-pyridine-2-carbonitrile (550 mg, 3.81 mmol, 1 equivalent), potassium osmate(VI) dihydrate (1.04 g, 2.82 mmol, 0.74 equivalent), and sodium periodate (2.45 g, 11.44 mmol, 3.0 equivalents) in acetone (6 mL) and water (1 mL) at 25 °C for 3 hours. Filter the reaction mixture and wash the filter cake with acetone (3 mL * 3). Dilute the obtained filtrate with water (100 mL) and extract with ethyl acetate (50 mL * 2). Wash the combined organic layers with brine (100 mL), dry over anhydrous sodium carbonate, filter, and concentrate under reduced pressure. The obtained residue is purified by flash silica chromatography ( 20 g Silica Flash Column, eluent with a 0 - 50% ethyl acetate / petroleum ether gradient, 40 mL / min). Concentrate the fractions under reduced pressure to obtain 5-formyl-4-methyl-pyridine-2-carbonitrile as a pale yellow solid (140 mg, 0.96 mmol, 25.1% yield). 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 10.34 (s, 1H), 9.03 (s, 1H), 8.12 (s, 1H), 2.69 (s, 3H).

[0422] (xvi) Preparation of 4-ethoxypiperidine-4-carboxamide

[0423] Stir a mixture of tert-butyl 4-carbamoyl-4-ethoxypiperidine-1-carboxylate (650 mg, 2.39 mmol, 1.0 equivalent) and hydrochloric acid / dioxane (4 M, 6 mL, 10.1 equivalents) in dioxane (2 mL) at 25 °C for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain 4-ethoxypiperidine-4-carboxamide as a white solid (600 mg, crude). 1 1H NMR (400 MHz, MeOD-d 4) 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 = 7.2 Hz, 3H).

[0424] (xvii) Preparation of 3 - methylazetidin - 3 - ol

[0425] A solution of tert - butyl 3 - hydroxy - 3 - methyl - azetidine - 1 - carboxylate (2 g, 10.68 mmol, 1 equiv) in hydrochloric acid / dioxane (4 M, 20 mL) was stirred at 25 °C for 1 h. 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) as a white solid. 1 H NMR (400 MHz, CDCl 3 -d) δ = 5.06 (br s, 2H), 3.71 (s, 2H).

[0426] (xviii) Preparation of tert - butyl 3 - methoxy - 3 - methyl - azetidine - 1 - carboxylate

[0427] Step 1: Under stirring, sodium hydride (1 g, 32.05 mmol, 60% purity, 3 equiv) was added to a solution of tert - butyl 3 - hydroxy - 3 - methyl - azetidine - 1 - carboxylate (2 g, 10.68 mmol, 1 equiv) in tetrahydrofuran (20 mL), and then methyl iodide (9 g, 64.09 mmol, 4 mL, 6 equiv) was added. The mixture was stirred at 25 °C for 1 h. 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 chromatography ( 40 g Silica Flash Column, eluent: 0 - 30% ethyl acetate / petroleum ether gradient, 100 mL / min) to give a spot (Rf = 0.6) of tert - butyl 3 - methoxy - 3 - methyl - azetidine - 1 - carboxylate (1.9 g, 9.44 mmol, 88.3% yield) as a white oil. 1 H NMR (400 MHz, CDCl3 - d) δ = 3.89 (d, J = 8.9 Hz, 2H), 3.65 (d, J = 9.0 Hz, 2H), 3.22 (s, 3H), 1.44 (br s, 3H), 1.43 (s, 9H).

[0428] Step 2:A solution of tert-butyl 3-methoxy-3-methylazetidine-1-carboxylate (300 mg, 1.49 mmol, 1 equiv) in HCl / dioxane (4 M, 3 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford the crude product 3-methoxy-3-methylazetidine (195 mg, crude, hydrochloride) as a white solid, which was used in the next step without further purification.

[0429] (xix) Preparation of 4-carbamoyl-4-isopropoxypiperidin-1-ium trifluoroacetate

[0430] Sodium hydride 60% dispersed in mineral oil (3.9 mg, 98 mmol) was added portionwise over 20 min to a flask containing 2-propanol (150 mL) at room temperature. The heterogeneous solution was stirred at this temperature for 20 min 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 NH 4 Cl (10 mL) was added and the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 2x NH 4 Cl. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated. The material obtained was purified by normal phase flash chromatography (loading DCM, 25 g) using 0 - 30% EtOAc in hexanes to afford the desired intermediate ester compound (1.53 g, 19%).

[0431] 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 stirred vigorously at 80 °C and complete conversion was observed by LCMS over the weekend. The reaction mixture was concentrated under reduced pressure and acidified to pH = 1 with 3N HCl. The aqueous solution was extracted with EtOAc, the organic layers were combined, dried over anhydrous Na 2 SO 4It was dried and concentrated to obtain the carboxylic acid as a clear oil (1.40 g, 80%), which was used as such 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 minutes. Then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. EtOAc (100 mL) was added and the solution was washed 5 times with saturated NH 4 Cl and dried over anhydrous Na 2 SO 4 It was dried and concentrated. The residue was purified by normal-phase flash chromatography (loading DCM, 50 g) using 0 - 100% ACN in DCM to give the desired intermediate amide compound (350 mg, 25%).

[0432] 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, at which point 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.

[0433] (xx) Preparation of ethyl 4-ethoxypiperidine-4-carboxylate

[0434] A solution of 1-boc-4-piperidone (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 anhydrous ethanol (25 mL) and added dropwise to the solution over 20 minutes. Then the mixture was stirred at room temperature for 19 h and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL x 2) and water (60 mL). The organic layer was dried over MgSO 4It was dried and concentrated in vacuo 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 as an oil (2.41 g, 99%). Trifluoroacetic acid (2.2 mL, 28.4 mmol) was added to tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (351 mg, 1.16 mmol) in DCM (8.5 mL). The solution was stirred at room temperature for 1.5 h and analyzed. The reaction mixture was evaporated and co-evaporated with diethyl ether and lyophilized to give a yellow oil containing ethyl 4-ethoxypiperidine-4-carboxylate (148 mg, 40% yield), which was used without further purification and analysis.

[0435] Preparation of Intermediate of Example 2-A-2

[0436]

[0437] Preparation of Intermediate A-2:

[0438] Method A: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthiopurine (Intermediate A-1) (1 equiv) and the nucleophile NHRaRb (1.5 equiv) in N,N-dimethylformamide (5 mL) was added a base (3 equiv). The mixture was stirred at 60 °C for 12 h. The reaction mixture was added to water (50 mL) with stirring. The mixture was filtered to give a yellow solid residue. The residue was purified by flash silica chromatography ( 20 g Silica Flash Column, eluent with a 0 - 45% ethyl acetate / petroleum ether gradient, 100 mL / min) to give Intermediate A-2 as an off-white solid (70 - 89% yield).

[0439] Reaction Scale: 500 mg of Intermediate A-1.

[0440] Method B: A mixture of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthiopurine (Intermediate A-1) (1 equiv), the nucleophile NHRaRb (5 equiv) and a base (2 equiv) in N,N-dimethylformamide (8 mL) was stirred at 60 °C for 1 - 2 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL), then extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium carbonate, 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.

[0441] Reaction Scale:500 mg of Intermediate A-1.

[0442] Method C: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-purine (Intermediate A-1) (1.0 equivalent) in N,N-dimethylformamide (3 mL) was added a base (2.0 equivalents) and a nucleophile NHRaRb (5.0 equivalents). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL × 3). The combined organic layers were washed with brine 20 mL (10 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 20 g Silica FlashColumn, eluent with a 0–100% ethyl acetate / petroleum ether gradient, 30 mL / min) and the organic phase was concentrated under reduced pressure to give Intermediate A-2 as a yellow solid (93-xx% yield).

[0443] Reaction Scale: 300 mg of Intermediate A-1.

[0444] Method D: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-purine (Intermediate A-1) (1.0 equivalent) in N,N-dimethylformamide (2 mL) was added a base (3.0 equivalents) and a nucleophile NHRaRb (1.2 equivalents). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL × 3). The combined organic layers were washed with brine 20 mL (10 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 20 g Silica FlashColumn, eluent with a 0–100% ethyl acetate / petroleum ether gradient, 30 mL / min) and the organic phase was concentrated under reduced pressure to give Intermediate A-2 as a yellow solid (xx-87% yield).

[0445] Reaction Scale: 200 mg of Intermediate A-1.

[0446] Method E: To a vial containing a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equiv) and nucleophile NHRaRb (1 equiv) in NMP (2.4 mL) was added base (2 equiv). 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 recovered by filtration through a Buchner funnel and washed with cold water to give crude Intermediate A-2 (94% yield).

[0447] Reaction Scale: 400 mg of Intermediate A-1.

[0448] Method F: 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) was added nucleophile NHRaRb (1.7 equiv). 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 for the next step.

[0449] Reaction Scale: 100 mg of Intermediate A-1.

[0450] Table 2. Reaction conditions and data for Intermediate A-2

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457] Preparation of Example 3-A-3 Intermediate

[0458]

[0459] Preparation of Intermediate A-3:

[0460] Method A: Water (0.3 mL) was added to a solution of intermediate A-2 (1 equivalent) and potassium peroxymonosulfate (10 equivalents) in N-methylpyrrolidone (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 obtain intermediate A-3 as a yellow or brown solid (90 - 93% yield).

[0461] Reaction Scale: 200 mg of intermediate A-2.

[0462] Method B: Aqueous solution of potassium peroxymonosulfate (6 equivalents) in water (1 mL) was added to a solution of intermediate A-2 (1 equivalent) in N-methyl-2-pyrrolidone (10 mL). The resulting mixture was stirred at 60 °C for 27 hours. The reaction mixture was added to water (100 mL) and filtered. The obtained filter cake was purified by flash silica chromatography ( 20 g SilicaFlash Column, eluent with 0 - 80% ethyl acetate / petroleum ether gradient, 40 mL / min). The fractions were concentrated under reduced pressure to obtain intermediate A-3 as a white solid (46% yield).

[0463] Reaction Scale: 500 mg of intermediate A-2.

[0464] Method C: Potassium peroxymonosulfate (1.17 g, 6.95 mmol, 10 equivalents) was added to a solution of intermediate A-2 (1.0 equivalent) in N-methyl-2-pyrrolidone (5 mL) and water (0.5 mL). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was added dropwise to water (40 mL), filtered, and the filter residue was concentrated under reduced pressure to obtain intermediate A-3 as a light yellow solid (73 - 94% yield).

[0465] Reaction Scale: 300 mg of intermediate A-2.

[0466] Method D: Aqueous solution of potassium peroxymonosulfate (8.0 equivalents) in water (2 mL) was added to a solution of intermediate A-2 (1.0 equivalent) in N-methyl-2-pyrrolidone (10 mL). 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 carbonate, filtered, and concentrated under reduced pressure to obtain intermediate A-3 as a yellow solid (crude).

[0467] Reaction Scale: 500 mg of intermediate A-2.

[0468] 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 layers were washed with brine (100 mL), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give intermediate A-3 as a yellow solid (crude), which was used directly in the next step without further purification.

[0469] Reaction Scale: 500 mg of intermediate A-2.

[0470] Method F: The crude intermediate A-2 (1 equivalent) was dissolved in NMP (5.5 mL), and then water (0.55 mL) was added dropwise to ensure that the solution remained clear. Then potassium peroxymonosulfate (3 equivalents) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added slowly, and the precipitate was recovered by filtration through a Buchner funnel. The solid was washed with water and then lyophilized to give intermediate A-3 (90% yield).

[0471] Method G: Potassium peroxymonosulfate (3.5 equivalents), NMP (1.6 mL) and water (160 μL) were added to an 8 mL vial containing the crude intermediate A-2 at 60 °C overnight. Water was added, and the obtained precipitate was filtered on a Buchner funnel to give intermediate A-3 (97% yield), which was used in the next step without purification.

[0472] Reaction Scale: 100 mg of intermediate A-2.

[0473] Table 3. Reaction conditions and data for intermediate A-3

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480] Preparation of Example 4-B-3 Intermediate

[0481]

[0482] (i) Preparation of intermediate B-3 (36) (NRaRb: 4-methyl-piperidine-4-carboxamide):

[0483] To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-2, Example 2i) (1 g, 3.02 mmol, 1 equiv) and 4-methylpiperidine-4-carboxamide (539 mg, 3.02 mmol, 1 equiv, hydrochloride) in N,N-dimethylformamide (5 mL) was added potassium carbonate (417.32 mg, 3.02 mmol, 1 equiv). The mixture was stirred at 25 °C for 12 h. Then the reaction mixture was poured into water (100 mL) with stirring. The mixture was filtered to give a yellow solid residue. The yellow solid was purified by silica flash chromatography ( 40 g Silica Flash Column, eluent 0 - 30% ethyl acetate / petroleum ether gradient, 100 mL / min) to give 1-[6-(4-chloroanilino)-2-methylthio-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 1H NMR (400 MHz, DMSO-d 6 ) δ = 10.28 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 7.29 (s, 1H), 7.04 - 6.96 (m, 1H), 3.62 (br d, J = 13.6 Hz, 2H), 3.28 - 3.14 (m, 2H), 2.40 (s, 3H), 2.09 (br d, J = 14.2 Hz, 2H), 1.61 - 1.29 (m, 2H).

[0484] (ii) Preparation of Intermediate B-3(112) (NRaRb: 3-methyl-azetidin-3-ol):

[0485] To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylthio-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) 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 h. The reaction mixture was added to water (20 mL) and the mixture was filtered to give a yellow solid. The residue was purified by silica flash chromatography ( 20 g Purified by silica flash column with an eluent of 0 - 40% ethyl acetate / petroleum ether gradient at 80 mL / min to obtain a yellow solid spot of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (Intermediate B-3(112), 170 mg, 0.44 mmol, 58% yield, 98.6% purity) (Rf = 0.4). 1 H NMR(400MHz,DMSO-d 6 )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).

[0486] (iii) Preparation of Intermediate B-3(c) (NRaRb: 3-methyl-azetidine-3-carbonitrile):

[0487] To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-2, Example 2i) (1 g, 3.02 mmol, 1.0 equivalent) and 3-methyl-3-azetidinecarbonitrile hydrochloride (480 mg, 3.62 mmol, 1.2 equivalents) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.95 g, 9.06 mmol, 3.0 equivalents). 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 cake was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-methylthio-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-d 6 )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).

[0488] (iv) Preparation of Intermediate B-3(114) (NRaRb: 3-methoxy-3-methyl-azetidin-1-yl):

[0489] A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-2, 600 mg, 1.81 mmol, 1.0 eq), 3-methoxy-3-methyl-azetidine (274 mg, 1.99 mmol, 1.1 eq) and potassium carbonate (751 mg, 5.44 mmol, 3 eq) in N,N-dimethylformamide (6 mL) was stirred at 25 °C for 1 h. The reaction mixture was washed with water (20 mL) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine 40 mL (20 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 40 g Silica Flash Column, eluent with 0 - 100% ethyl acetate / petroleum ether gradient, 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-methylthio-5-nitro-pyrimidin-4-amine as a yellow solid (Intermediate B-3(114), 250 mg, 625 μmol, 34.5% yield).

[0490] (v) Preparation of Intermediate B-3(118) (NRaRb: 4-methyl-piperidine-4-carboxylate):

[0491] Cesium carbonate (1.48 g, 4.53 mmol, 3.0 eq) was added to a solution of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-2, 500 mg, 1.51 mmol, 1.0 eq) and ethyl 4-methylpiperidine-4-carboxylate (345 mg, 1.66 mmol, 1.1 eq) in N,N-dimethylformamide (5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was added to water (50 mL) with stirring, the mixture was filtered, the residue was washed with ethanol (20 mL) and concentrated under reduced pressure to give ethyl 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate as a yellow solid (Intermediate B-3(118), 600 mg, 1.20 mmol, 79.3% yield). 1 H NMR (400 MHz, DMSO-d 6)δ = 10.28 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 4.21 - 4.07 (m, 2H), 3.67 (d, J = 14.0 Hz, 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).

[0492] (vi) Preparation of Intermediate B-3(120) (NRaRb: 4-ethoxypiperidine-4-carboxamide):

[0493] A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitropyrimidin-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 at 25 °C for 1 h. The reaction mixture was washed with water (20 mL) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine 40 mL (20 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylthio-5-nitropyrimidin-4-yl]-4-ethoxypiperidine-4-carboxamide (Intermediate B-3(120), 590 mg, 1.12 mmol, 67.6% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ = 10.29 (s, 1H), 7.68 - 7.58 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.35 - 7.19 (m, 2H), 3.77 - 3.62 (m, 2H), 3.45 - 3.41 (m, 2H), 3.35 (d, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.98 - 1.90 (m, 2H), 1.19 (s, 2H), 1.05 (t, J = 7.2 Hz, 3H).

[0494] (vii) Preparation of Intermediate B-3(135) (NRaRb: 4-isopropoxypiperidine-4-carboxamide):

[0495] A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylthio-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) and cesium carbonate (2.95 g, 9.06 mmol, 3.0 equiv) in N,N-dimethylformamide (12 mL) was stirred at 25 °C for 4 h. 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 carbonate, filtered and concentrated under reduced pressure, and purified by flash silica gel chromatography ( 40 g Silica Flash Column, eluent was 0 - 50% ethyl acetate / petroleum ether gradient, 50 mL / min) to give 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (Intermediate B-3(135), 1.08 g, 2.20 mmol, 73% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 6.0 Hz, 6H).

[0496] Preparation of Intermediate for Example 5 - B - 5

[0497]

[0498] (i) Preparation of Intermediate B - 5(36) (NRaRb: 4-methylpiperidine-4-carboxamide / Nu: (2S)-2-(hydroxymethyl)pyrrolidin-1-yl):

[0499] 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) was added potassium oxone (3.66 g, 21.74 mmol, 10 equiv) and water (1 mL). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added to water (100 mL) with stirring. The mixture was filtered to give the residue as a yellow solid, 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). 1 H NMR (400 MHz, DMSO-d6) δ = 10.36 (s, 1H), 7.66 - 7.56 (m, 2H), 7.45 (d, J = 8.9 Hz, 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, 13.7 Hz, 2H), 1.20 - 1.10 (m, 3H).

[0500] 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 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (basic conditions) to give the compound 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide as a yellow solid (Intermediate B-5(36), 500 mg, 1.02 mmol, 70.3% yield). 1 H NMR (400 MHz, CDCl 3-d) δ = 10.92 - 10.56 (m, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.47 (br d, J = 8.8 Hz, 1H), 7.39 - 7.29 (m, 2H), 5.68 (br d, J = 5.1 Hz, 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).

[0501] (ii) Preparation of Intermediate B-5(48) (NRaRb: 4-Methyl-piperidine-4-carboxamide / Nu: 2-Hydroxyethyl(methyl)amino):

[0502] Step 1: Synthesize 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3(36), Example 3i) as described in Step 1 of Example 4i.

[0503] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (1 g, 2.13 mmol, 1 equivalent) in 2-(methylamino)ethanol (2 g, 32.0 mmol, 2.57 mL, 15 equivalents) was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1 / 0 to 0 / 1) and concentrated in vacuo to give 1-[6-(4-chloroanilino)-2-[2-hydroxyethyl(methyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide as a yellow solid (580 mg, 1.25 mmol, 58.6% yield). The yellow solid was dissolved to purity with methanol (1 mL) and dimethyl sulfoxide (2 mL). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 28% - 58%, 9 min) to give 1-[6-(4-chloroanilino)-2-[2-hydroxyethyl(methyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide as a yellow solid (Intermediate B-5(48), 105 mg, 182.07 μmol, 28.1% yield). 1 H NMR(400MHz,CDCl 3-d) δ = 11.00 - 10.52 (m, 1H), 7.61 (br d, J = 8.6 Hz, 1H), 7.49 (br d, J = 8.3 Hz, 1H), 7.33 (br d, J = 8.6 Hz, 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).

[0504] (iii) Preparation of Intermediate B-5(103) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy):

[0505] Step 1: Synthesize 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3(36), Example 3i) as described in Step 1 of Example 4i.

[0506] Step 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 stirred at 25 °C under nitrogen for 10 minutes. Then 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (300 mg, 640 μmol, 1.0 equiv) was added to the mixture. The mixture was stirred at 25 °C under nitrogen 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 the residue as a yellow solid, 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).

[0507] (iv) Preparation of Intermediate B-5(110) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)-methyl-amino):

[0508] Step 1:Synthesize 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3(36), Example 3i) as described in Step 1 of Example 4i.

[0509] Step 2: To 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). The mixture was stirred at 120 °C for 1 h. Methanol (1 mL) was added to the reaction mixture to purity. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 44%-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 HNMR(400MHz,DMSO-d 6 )δ = 7.77(d, J = 8.8 Hz, 1H), 7.66(d, J = 8.8 Hz, 1H), 7.40(t, J = 8.8 Hz, 2H), 7.26(d, J = 2.0 Hz, 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).

[0510] (v) Preparation of Intermediate B-5(111) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)amino):

[0511] Step 1:Synthesize 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3(36), Example 3i) as described in Step 1 of Example 4i.

[0512] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Compound 1, 400 mg, 0.85 mmol, 1.0 equivalent) and 1-amino-2-methyl-propan-2-ol (Compound 2, 2.28 g, 25.6 mmol, 30 equivalents) was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature and 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 carbonate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography ( 20 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 20 mL / min). The fractions were concentrated under reduced pressure to give the compound 1-[6-(4-chloroanilino)-2-[(2-hydroxy-2-methyl-propyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide as a yellow solid (Intermediate B-5(111), 230 mg, 0.48 mmol, 56.4% yield).

[0513] (vi) Preparation of Intermediate B-5(112) (NRaRb: 3-methyl-azetidin-3-ol / Nu: 2-hydroxy-2-methyl-propoxy):

[0514] Step 1: To a solution of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (Intermediate B-3(112), Example 3ii) (170 mg, 0.45 mmol, 1.0 equivalent) in N-methylpyrrolidone (5 mL) and water (0.5 mL) was added potassium hydrogensulfate oxone (749 mg, 4.45 mmol, 10 equivalents). The mixture was stirred at 60 °C for 12 h. 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 as a yellow solid (150 mg, 344.41 μmol, 77.3% yield, 95.0% purity).1 1H NMR (400 MHz, DMSO-d 6 ) 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 (brs, 2H), 3.20 (s, 3H), 1.40 (s, 3H).

[0515] Step 2: Sodium hydride (39 mg, 0.97 mmol, 60% purity, 4.0 equiv) was added to a solution of 2-methylpropane-1,2-diol (109 mg, 1.21 mmol, 5 equiv) in tetrahydrofuran (3 mL). The mixture was stirred at 25 °C for 10 min. 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 min. 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 prep-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 μm; mobile phase: [water (formic acid)-ACN]; B%: 36% - 66%, 10 min) to give the compound 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol as a yellow solid (Intermediate B-5(112), 100 mg, 0.23 mmol, 96.8% yield). 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 10.41 (s, 1H), 7.72 - 7.59 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 5.74 (s, 1H), 4.64 (s, 1H), 3.99 (s, 4H), 1.38 (s, 3H), 1.13 (s, 6H).

[0516] (vii) Preparation of Intermediate B-5(113) (NRaRb: 3-methyl-azetidine-3-carbonitrile / Nu: 2-hydroxy-2-methyl-propoxy):

[0517] Step 1:To a solution of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (Intermediate B-3(113), Example 3iii) (1.1 g, 2.81 mmol, 1.0 equiv) in N-methyl-2-pyrrolidone (20 mL) and water (2 mL) was added potassium peroxymonosulfate (4.73 g, 28.14 mmol, 10 equiv). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to 80 mL of water, filtered, and the filter cake was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile as a yellow solid (1.1 g, 2.45 mmol, 87.0% yield). 1 H NMR(400MHz,DMSO-d 6 )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).

[0518] Step 2: To 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 h. The reaction mixture was washed with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate 90 mL (30 mL×3). The combined organic layers were washed with brine 60 mL (30 mL×2), dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 40g Silica FlashColumn, eluent was 0-100% ethyl acetate / petroleum ether gradient to 0-100% methanol / ethyl acetate, 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 as a yellow solid (Intermediate B-5(113), 230 mg, 0.50 mmol, 21% yield).

[0519] (viii) Preparation of Intermediate B-5(114) (NRaRb: 3-methoxy-3-methyl-azetidin-1-yl / Nu: 2-methyl-2-propanol):

[0520] Step 1: To a solution of N-(4-chlorophenyl)-6-(3-methoxy-3-methyl-azetidin-1-yl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-3(114), Example 3iv) (230 mg, 0.58 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (3 mL) and water (0.3 mL) was added potassium peroxymonosulfate (977 mg, 5.81 mmol, 10 eq). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to 20 mL of water, filtered, and the filter cake 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 as a white solid (210 mg, 0.49 mmol, 84.4% yield).

[0521] Step 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 eq) in N-methyl-2-pyrrolidone (3 mL) was added 2-methylpropane-1,2-diol (211 mg, 2.34 mmol, 5.0 eq) and potassium tert-butoxide (157 mg, 1.40 mmol, 3.0 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was washed with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL, 10 mL×3). The combined organic layers were washed with brine (20 mL, 10 mL×2), dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 12 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 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-2-propanol (Intermediate B-5(113), 50 mg, 0.11 mmol, 24.0% yield) as a yellow solid.

[0522] (ix) Preparation of Intermediate B-5(118) (NRaRb: 4-methyl-piperidine-4-carboxylic acid / Nu: 2-hydroxy-2-methyl-propoxy):

[0523] Step 1: To a solution of ethyl 1-[6-(4-chloroanilino)-2-methylthio-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) was added potassium peroxymonosulfate (2.17 g, 12.88 mmol, 10 equiv). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to 50 mL of water, filtered, and the filter cake was concentrated under reduced pressure to give ethyl 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate as a yellow solid (590 mg, 1.14 mmol, 88.2% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.37 (s, 1H), 7.64 - 7.58 (m, 2H), 7.45 (d, J = 8.8 Hz, 2H), 4.26 - 4.07 (m, 2H), 3.71 (d, J = 14.0 Hz, 2H), 3.30 (d, J = 2.8 Hz, 2H), 3.22 (s, 3H), 2.10 (d, J = 14.0 Hz, 2H), 1.64 - 1.53 (m, 2H), 1.25 - 1.19 (m, 6H).

[0524] Step 2: To 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) was added 2-methylpropane-1,2-diol (443 mg, 4.92 mmol, 5 equiv) and potassium tert-butoxide (331 mg, 2.95 mmol, 3.0 equiv). The mixture was stirred at 80 °C for 1 h. The reaction mixture was added to an aqueous citric acid solution (20 mL) (pH = 3) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine 20 mL (10 mL × 2), dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20 g Purified by a SilicaFlash Column with an eluent of 0 - 100% petroleum ether gradient / ethyl acetate at 30 mL / min. The organic phase was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylic acid as a yellow solid (Intermediate B-5(118), 191 mg, 0.40 mmol, 40.4% yield). 1 H NMR(400MHz,DMSO-d 6 )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).

[0525] (x) Preparation of Intermediate B-5(120) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy):

[0526] Step 1: To a solution of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3(120), Example 3vi) (590 mg, 1.26 mmol, 1.0 equivalent) in N-methyl-2-pyrrolidone (6 mL) and water (0.6 mL) was added potassium peroxymonosulfate (2.12 g, 12.64 mmol, 10 equivalents). 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 cake was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide as a light yellow solid (300 mg, 0.52 mmol, 40.9% yield). 1 H NMR(400MHz,DMSO-d 6 )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).

[0527] Step 2: To 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 eq) in N-methyl-2-pyrrolidone (5 mL) was added 2-methylpropane-1,2-diol (226 mg, 2.51 mmol, 5 eq) and potassium tert-butoxide (169 mg, 1.50 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was washed with water (20 mL) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine 60 mL (30 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 20 g Silica Flash Column, eluent 0 - 100% ethyl acetate / methanol, 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.

[0528] (xi) Preparation of Intermediate B-5(131) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (3R)-3-hydroxypyrrolidin-1-yl):

[0529] Step 1: 1-[6-(4-Chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3(36), Example 3i) was synthesized as described in Step 1 of Example 4i from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide.

[0530] 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 eq) and (3R)-pyrrolidin-3-ol (1.05 g, 12.05 mmol, 1 mL, 5.7 eq) was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified with triturated methanol (8 mL) at 25 °C. Then the filter cake was collected and concentrated under reduced pressure to give the 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 (400 MHz, DMSO-d 6 ) δ = 10.63 (d, J = 5.6 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.41 (d, J = 8.9 Hz, 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).

[0531] (xii) Preparation of Intermediate B-5(132) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)amino):

[0532] Step 1: 1-[6-(4-Chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide was synthesized from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3(120), Example 3vi) as described in Step 1 of Example 4x.

[0533] 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 eq) in 1-amino-2-methyl-propan-2-ol (322 mg, 3.61 mmol, 10 eq) was stirred at 120 °C for 1 h. Water (5 mL) was added to the reaction mixture, and the mixture was filtered. The filter residue was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 12g Purified by silica flash column (eluent: 0 - 100% dichloromethane / methanol, 20 mL / min), and the organic phase was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-[(2-hydroxy-2-methyl-propyl)amino]-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide as a yellow solid (Intermediate B-5(132), 110 mg, 0.21 mmol, 58.7% yield).

[0534] (xiii) Preparation of Intermediate B-5(133) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: (2S)-2-(hydroxymethyl)pyrrolidin-1-yl):

[0535] Step 1: Synthesize 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3(120)) as described in Step 1 of Example 4x.

[0536] 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 equivalent) in [(2S)-pyrrolidin-2-yl]methanol (365 mg, 3.61 mmol, 0.35 mL, 10 equivalents) was stirred at 120 °C for 1 hour. The residue was purified by flash silica chromatography ( 12g Silica Flash Column, eluent: 0 - 100% dichloromethane / methanol, 20 mL / min), and the organic phase was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide as a yellow solid (Intermediate B-5(133), 180 mg, 0.34 mmol, 94.5% yield).

[0537] (xiv) Preparation of Intermediate B-5(135) (NRaRb: 4-isopropoxy-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy):

[0538] Step 1:A mixture of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (Intermediate B-3(135)) (1.00 g, 2.08 mmol, 1 eq.) and potassium oxomonopersulfate (3.50 g, 20.79 mmol, 10 eq.) in N-methylpyrrolidone (16 mL) and water (4 mL) was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 40 g Silica Flash Column, eluent: 50 - 100% ethyl acetate / petroleum ether gradient, 40 mL / min). The fractions were concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide as a yellow solid (700 mg, 1.36 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.38 (s, 1H), 7.66 - 7.59 (m, 2H), 7.49 - 7.42 (m, 2H), 7.39 - 7.24 (m, 2H), 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).

[0539] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (350 mg, 0.69 mmol, 1.0 eq.) and a nucleophile (10.3 mmol, 1 mL, 15.1 eq.) was heated at 120 °C for 1 h. The mixture was triturated with ethyl acetate (10 mL), filtered to give Intermediate B-5(135) as a yellow solid (200 mg, 374.5 μmol, 55% yield). 1 H NMR (400 MHz, DMSO-d 6) 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 = 6.0 Hz, 6H).

[0540] (xv) Preparation of Intermediate B-5(136) (NRaRb: 4-Isopropoxypiperidine-4-carboxamide / Nu: (2S)-2-(Hydroxymethyl)pyrrolidin-1-yl):

[0541] Step 1: Synthesize 1-[6-(4-Chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (Intermediate B-3(135)) as described in Step 1 of Example 4xiv.

[0542] Step 2: A mixture of 1-[6-(4-Chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (350 mg, 0.68 mmol, 1 equivalent) and [(2S)-Pyrrolidin-2-yl]methanol (10.3 mmol, 1 mL, 15 equivalents) was heated at 120 °C for 1 hour. The mixture was triturated with ethyl acetate (10 mL), filtered, and 1-[6-(4-Chloroanilino)-2-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-isopropoxypiperidine-4-carboxamide (Intermediate B-5(136), 200 mg, 0.37 mmol, 54.8% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 6.0 Hz, 6H).

[0543] Example 6 - Preparation of Intermediate by General Synthesis Procedure C

[0544]

[0545] (i) Preparation of Intermediate C-1:

[0546] To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-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). 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-methylthio-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Intermediate C-1, 850 mg, 1.61 mmol, 79.7% yield) as an off-white solid.

[0547] (ii) Preparation of Intermediate C-2:

[0548] See Example 9, synthesis of Compound 68.

[0549] (iii) Preparation of Intermediate C-8:

[0550] 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 chromatography ( 25 Silica Flash Column, eluent with 10 - 100% ethyl acetate / petroleum ether gradient, 50 mL / min) to give 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. 11H NMR (400 MHz, 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).

[0551] Step 2: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2,4-dimethoxyphenyl)methylamino]purin-6-yl]-4-methylpiperidine-4-carboxamide (290 mg, 448.52 μmol, 1 equiv) in trifluoroacetic acid (3 mL, 90 equiv) was stirred at 65 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by silica flash column chromatography ( 25 g Silica Flash Column, eluting with a 0 - 50% MeOH / DCM gradient at 30 mL / min) to afford 1-[2-amino-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methylpiperidine-4-carboxamide (Intermediate C-8) as a yellow solid (180 mg, 362.62 μmol, 80.8% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.63 (d, J = 7.1 Hz, 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).

[0552] Example 7 - Preparation of Intermediate by General Synthetic Procedure D

[0553]

[0554] (i) Preparation of Intermediate D-1:

[0555] To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-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) was added 4-(trifluoromethyl)piperidine (436 mg, 2.85 mmol, 1.2 equiv), and the resulting mixture was stirred at 60 °C for 15 h. 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-methylthio-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-1, 1.20 g, 2.23 mmol, 93.9% yield) as a red solid. 1 H NMR(400MHz,DMSO-d 6 )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).

[0556] (ii) Preparation of Intermediate D-2:

[0557] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-1) (1.15 g, 2.14 mmol, 1.0 equiv) in N-methylpyrrolidone (15 mL) was added an aqueous solution (1.5 mL) of potassium hydrogensulfate oxone (1.08 g, 6.42 mmol, 3.0 equiv), and the mixture was stirred at 25 °C for 15 h. 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-piperidinyl]purine (Intermediate D-2, 1.10 g, 1.98 mmol, 92.7% yield) as a red solid. 1 H NMR(400MHz,DMSO-d 6 )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).

[0558] (iii) Preparation of Intermediate D-3:

[0559] Preparation from D-2:

[0560] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-2) (400 mg, 0.72 mmol, 1.0 equiv) in N-methylpyrrolidone (3.5 mL) and water (0.35 mL) was added oxone (potassium peroxymonosulfate) (121 mg, 0.72 mmol, 1.0 equiv), and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was added to water (15 mL), and the solid was filtered. The solid was triturated with ethanol (15 mL) and filtered to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine as an off-white solid (Intermediate D-3, 300 mg, 0.53 mmol, 72.9% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ=7.74 (br d, J=7.0 Hz, 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=11.4 Hz, 2H), 1.67 - 1.45 (m, 2H).

[0561] Example 8 - Preparation of Other Intermediates

[0562] (i) Preparation of Intermediate J:

[0563]

[0564] Preparation of Intermediate J-1:

[0565] 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 min, then 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-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 h. The reaction mixture was added to water (60 mL) and filtered; 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.

[0566] Method B: A mixture of ethanol (109.24 mg, 2.37 mmol, 2.0 eq) and sodium hydride (142.27 mg, 3.56 mmol, 60% purity, 3 eq) in N,N-dimethylformamide (8 mL) was stirred at 25 °C for 30 minutes. Then, 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-purine (Intermediate A-1) (500 mg, 1.19 mmol, 1.0 eq) 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 carbonate, 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.

[0567] Table 4. Reaction Conditions and Data for Intermediate J-1

[0568]

[0569]

[0570] Preparation of Intermediate J-2:

[0571] Method A: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-isopropoxy-2-methylthio-purine (Intermediate J-1(86)) (0.8 g, 1.80 mmol, 1 eq) in N-methyl-2-pyrrolidone (12 mL) was added a solution of potassium hydrogensulfate oxone (2.82 g, 16.7 mmol, 9.3 eq) in water (3 mL). The resulting mixture was stirred at 60 °C for 40 hours. The reaction mixture was added to water (120 mL) and filtered. The obtained filter cake was purified by flash silica chromatography ( 40 g Silica Flash Column, eluent: 0 - 80% ethyl acetate / petroleum ether gradient, 50 mL / min). The 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.

[0572] Method B: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-ethoxy-2-methylthio-purine (0.59 g, 1.37 mmol, 1.0 equiv) in N-methyl-2-pyrrolidone (10 mL) was added an aqueous solution (2 mL) of potassium hydrogensulfate oxalate (1.84 g, 10.94 mmol, 8.0 equiv). The resulting mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with water (20 mL) and filtered; the obtained filter cake was purified by trituration with acetonitrile (2 mL) at 25 °C to give Intermediate J-2(99) (378.5 mg, crude) as an off-white solid.

[0573] Table 5. Reaction Conditions and Data for Intermediate J-2

[0574]

[0575] (ii) Preparation of Intermediate L-1:

[0576] To a solution of 4,6-dichloro-2-methylthio-5-nitro-pyrimidine (Intermediate B-1) (5 g, 20.8 mmol, 1 equiv) in N,N-dimethylformamide (20 mL) at 0 °C 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), and the mixture was stirred at 0 °C for 1 h. Then the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate (300 mL, 100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 80 g Silica Flash Column, eluent with a 0 - 100% ethyl acetate / petroleum ether gradient, 60 mL / min) and the organic phase was concentrated under reduced pressure to give 6-chloro-2-methylthio-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 HNMR(400 MHz, DMSO-d 6 ) δ = 7.52 (d, J = 7.6 Hz, 2H), 7.47 - 7.30 (m, 3H), 7.25 - 7.19 (m, 1H), 2.40 (s, 3H).

[0577] (iii) Preparation of Intermediates K-2 and K-3:

[0578] Preparation of Intermediate K-2

[0579] At 0 °C, potassium carbonate (9.97 g, 72.11 mmol, 3.0 eq) and 4-chloroaniline (3.07 g, 24.04 mmol, 1.0 eq) were added to a solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Intermediate K-1) (5 g, 24.04 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL). The mixture was stirred at 0 °C for 1 hour. Then the mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was added dropwise to 150 mL of water, filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The residue was added to 50 mL of ethanol, filtered, and the filter cake 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 obtain 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 (400 MHz, DMSO-d 6 ) δ=10.00 (s, 1H), 7.63 - 7.55 (m, 2H), 7.47 - 7.40 (m, 2H), 2.46 - 2.38 (m, 3H).

[0580] Preparation of Intermediates K-3(127) and K-3(134)

[0581] K-3(127): N,N-Diisopropylethylamine (259 mg, 2.01 mmol, 0.35 mL, 3 eq) and 4-methylpiperidine-4-carboxamide (143 mg, 0.80 mmol, 1.2 eq) were added 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 eq) in N,N-dimethylformamide (2 mL). 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 cake was concentrated under reduced pressure to obtain 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 light yellow solid. 1 H NMR (400 MHz, DMSO-d 6)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 = 14.0 Hz, 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).

[0582] 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 h. The reaction mixture was added dropwise to 20 mL of water, filtered, and the filter cake 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 (400 MHz, DMSO-d 6 )δ = 10.12 (s, 1H), 7.74 - 7.66 (m, 2H), 7.44 - 7.37 (m, 2H), 7.30 (s, 1H), 7.24 (s, 1H), 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).

[0583] Example 9 - Preparation of Compounds 1 to 240

[0584] (i) General Synthesis Method A:

[0585]

[0586] Preparation of Compound A-4:

[0587] Method A: The crude Intermediate A-3 was dissolved in the nucleophile Nu-H (1 mL) and the reaction mixture was stirred at 100 °C overnight. Ethyl acetate (15 mL) was added and the solution was washed 5 times with saturated NH 4 Cl and dried over anhydrous Na 2 SO 4Dry and concentrate. The crude residue was purified on a Buchi semi-prep (C18 column) using 20 - 60% ACN in AmF (with DMSO injection). The fractions were lyophilized to give Compound A-4 (57% yield).

[0588] Reaction Scale: 50 mg of Intermediate A-3

[0589] Method B: 60% Sodium hydride dispersed in mineral oil (2 eq) was added to a vial containing ethylene glycol (600 μL) in NMP (200 μL). The solution was stirred at 40 °C for 10 minutes, then a solution of Intermediate A-3 (1 eq) in NMP (200 μL) was added in one portion. The reaction mixture was stirred at 80 °C overnight, at which point complete conversion was observed by LCMS. One drop of water was added and the reaction mixture was purified on a Buchi semi-prep (C18 column) using 20 - 60% ACN in AmF (direct injection of the reaction mixture). The desired fraction was the lyophilized Compound A-4 as an off-white powder (57% yield).

[0590] Reaction Scale: 40 mg of Intermediate A-3

[0591] Method C: Potassium carbonate (2 eq), nucleophile Nu-H (11 eq) and DMF (1.2 mL) were added to Intermediate A-3 in an 8 mL vial and the mixture was stirred at 110 °C for 19 h. The reaction mixture was purified by reverse phase flash chromatography using 10% - 100% MeCN in 10 mM AmF (product eluted at 72% MeCN) to give Compound A-4 (73% yield).

[0592] Reaction Scale: 120 mg of Intermediate A-3

[0593] Method D: A solution of Intermediate A-3 (74) (1 eq) in nucleophile (Nu-H) (15 eq) was stirred at 140 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3 - 100 C18 Ultra 150*50mm*3μm; mobile phase: [water (formic acid)-ACN]) to give Compound A-4 as a white solid.

[0594] Reaction Scale: 100 mg of Intermediate A-3

[0595] 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 prep-HPLC (column: C18 150*25 mm*10 μm; mobile phase: [water - ACN]), the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give compound A-4 as a white solid.

[0596] Reaction Scale: 120 mg of intermediate A-3

[0597] Table 6. Reaction conditions and data for compound A-4

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611] (iv) General synthetic method B:

[0612]

[0613] The preparation of Compound B can be seen in the following detailed protocol.

[0614] (v) General synthetic method C:

[0615]

[0616] The preparation of Compound C can be seen in the following detailed protocol.

[0617] (vi) General synthesis method D:

[0618]

[0619] The preparation of Compound D can be seen in the following detailed protocol.

[0620] (vii) General synthesis method E:

[0621]

[0622] Preparation of Compound E-3:

[0623] Method for compound 144: Step 1, heat a suspension of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-1H-purine-2,6(3H,9H)-dione (400 mg, 1.07 mmol) in phosphoryl chloride (4.4 mL, 47 mmol) to 100 °C. Stir the solution at this temperature for 1 week. After 1 week, 20% of the SM still remained, but the reaction stopped there. Concentrate the reaction mixture under reduced pressure, dissolve the residue in DCM, and then transfer it to a separatory funnel containing saturated NaHCO 3 and neutralize the solution. Dry it with anhydrous Na 2 SO 4 and then concentrate. Purify the residue by normal-phase flash chromatography (loading DCM, 25 g) using 50 - 100% DCM in hexane to obtain 2,6-dichloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (220 mg, 50%).

[0624] Step 2. Add N,N - diisopropylethylamine (188 μL, 1.07 mmol) 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). Stir the reaction mixture at room temperature until complete conversion is observed by LCMS (3 h). Slowly add water (15 mL) to the reaction mixture and filter off the suspension through a Buchner funnel. Purify 15 mg of the crude product on a semi - prep system (injecting the reaction mixture) using a 40 - 70% ACN gradient in 10 mM AmB (pH 4), and obtain 1-(2 - chloro - 8-(2 - chlorophenyl)-9-(4 - chlorophenyl)-9H - purin - 6 - yl)-4-(ethylamino)piperidine - 4 - carboxamide (Compound 144, 10.5 mg) after lyophilizing the pure fractions. 1 H NMR(400MHz,DMSO - d 6 )δ7.70(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).

[0625] (viii) General synthetic method F:

[0626]

[0627] Preparation of Compound F:

[0628] 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 h. 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.

[0629] Method B: A vial was charged with lithium hydroxide (0.4 mg, 18 μmol). Water (250 μL) was added, then hydrogen peroxide (2.5 μL, 23.9 μmol) (30 w% aqueous solution) was added in one portion. Then 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 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 5 times with saturated NH 4 Cl and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by reverse phase flash chromatography (loading DMSO, C18 12 g) using 10 - 60% ACN in 10 mM AmF (pH 4), and after lyophilization afforded 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).

[0630] Method C: To a solution of sodium hydroxide (178 mg, 4.44 mmol, 5.0 equiv) in water (3 mL) and ethanol (3 mL) was added 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), and the mixture was stirred at 60 °C for 3 h. The mixture was diluted with water (10 mL), washed with ethyl acetate (2×10 mL), acidified to pH = 3 with hydrochloric acid (1 N) in the aqueous phase, 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 prep-HPLC (column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min) to give the crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 10 min) to give Intermediate F-3, 6-(4-carbamoyl-4-methyl-1-piperidinyl)-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.

[0631] Method D: To a solution of 6-(4-carbamoyl-4-methyl-1-piperidinyl)-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) was added 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). The mixture was stirred at 25 °C for 0.5 h. Then dimethylamine 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 prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 40%-70%, 8 min) and prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 40%-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-piperidinyl)-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.

[0632] Table 7. Reaction conditions and data for Compounds F-1 to F-4

[0633]

[0634] (ix) General synthetic method G:

[0635]

[0636] Preparation of Compound G-4:

[0637] Method: Step 1, Intermediate G-1 (515 μmol) was dissolved in NMP (3.1 mL), and then water (300 μL) was added dropwise to ensure that the solution remained clear. Then Oxone (950 mg, 1.55 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Water (30 mL) was added slowly, and the precipitate was recovered by filtration through a Buchner funnel. The solid was washed with water and then lyophilized to give Intermediate G-2 (92% yield).

[0638] Step 2. Cesium carbonate (494 μmol) was added to a solution of intermediate G-2 (165 μmol) in a nucleophile (6.6 mmol). The solution was heated to 100 °C overnight. LCMS showed that the major product was the desired product. EtOAc (15 mL) was added, and the solution was washed 5 times with saturated NH 4 Cl and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by reverse-phase flash chromatography (loading DMSO, C18 12 g) using 10 - 60% ACN in 10 mM AmF (pH 4). The fractions were concentrated in vacuo. The residue was dissolved in DCM, dried over anhydrous Na 2 SO 4 filtered, and concentrated to give intermediate G-3 (78% yield).

[0639] Step 3. Triethylamine (361 μmol) was added to a solution of intermediate G-3 (120 μmol) and phenyl carbamate (181 μmol) in DCM (1.2 mL) at room temperature. Complete conversion was observed by LCMS after 90 minutes. The reaction mixture was concentrated to dryness, and the residue was purified by reverse-phase flash chromatography (loading DMSO, C18 12 g) using 10 - 70% ACN in 10 mM AmF (pH 4), and lyophilized to give compound G-4 (11% yield).

[0640] Reaction Scale: 265 mg of intermediate G-1.

[0641] Table 8. Reaction conditions and data for compound G-4

[0642]

[0643] (x) General synthetic method H:

[0644]

[0645] Preparation of Compound H-2:

[0646] Method A: Step 1, Add dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (0.2 eq) to a mixture of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 eq), 2-(trifluoromethyl)pyridine-5-boronic acid (1.6 eq), and sodium carbonate (4 eq) in dioxane (10 mL) and water (1.6 mL). Stir the reaction mixture at 70 °C for 4 hours. Filter the reaction mixture through Celite (rinsed with EtOAc and a trace amount of MeCN). Partially concentrate the filtrate in vacuo, then dilute with water (15 mL) and extract with ethyl acetate (70 mL x 2). Dry the organic phase over magnesium sulfate and evaporate to give crude 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (Intermediate H-1, quantitative conversion).

[0647] Step 2, Dissolve the crude Intermediate H-1 (1 eq) in NMP (8 mL), then add water (600 μL) dropwise to ensure the solution remains clear. Then add Oxone (3 eq) in one portion and stir the reaction mixture at room temperature for 16 hours, and LCMS shows low conversion. Add more oxone (3 eq), and continue the reaction for 24 hours, for a total of 40 hours. After completion of the reaction, add water (50 mL), and extract the mixture with DCM (80 mL x 2), dry over MgSO 4 and concentrate. Add water (600 μL) and oxone (3.2 eq) to the residue (NMP solution), and heat the reaction at 60 °C for 20 hours. Add water (50 mL), and extract the mixture with DCM (90 mL x 2), dry over MgSO 4 and evaporate to a yellow oil. Add water (6 mL) to the oil (no precipitate). Then add MeCN (3 mL), and lyophilize the resulting mixture, then perform flash chromatography using 0% to 40% ethyl acetate in hexanes to give Intermediate 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylsulfonyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (81% yield).

[0648] Step 3, A solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylsulfonyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (1 equivalent) in a nucleophile Nu-H (30 equivalents) was stirred at 100 °C for 21 h. The compound was precipitated by standing at room temperature. The compound was injected onto a C-18 column for purification using DMF, trace water and trace MeCN. Purification was carried out using 15% to 80% MeCN in AmF buffer, and the product was impure. All fractions containing the product were evaporated to give a yellow solid. The solid was taken up in MeCN (3 mL) and water (15 mL), then filtered, rinsed with water, and dried to give Compound H-2.

[0649] Reaction Scale: 200 mg of Intermediate A-1

[0650] Method B: Step 1, To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthiopurine (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 equivalent). The mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate 150 mL (50 mL × 3). The combined organic layers were washed with brine 200 mL (100 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure. The resulting residue was stirred with ethanol (100 mL), filtered, and the filter cake was concentrated under reduced pressure to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-6-[6-(trifluoromethyl)-3-pyridyl]purine as a white solid (87.1% yield). 1 HNMR(400MHz,CDCl 3 )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).

[0651] Step 2, To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-6-[6-(trifluoromethyl)-3-pyridyl]purine (Intermediate H-1) (1 equiv) in NMP (10 mL) and water (1 mL) was added potassium oxone (3.16 g, 18.78 mmol, 10 equiv). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to 50 mL of water, filtered, and the filter cake was concentrated under reduced pressure to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine as a pale yellow solid (crude), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ = 10.26 (d, J = 1.6 Hz, 1H), 9.43 (dd, J = 1.7, 8.3 Hz, 1H), 7.91 (d, J = 8.3 Hz, 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).

[0652] Step 3, A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (1 equiv), nucleophile Nu-H (5 equiv) and potassium carbonate (2 equiv) in N,N-dimethylformamide (1 mL) was stirred at 100 °C for 2 h. 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*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 63% - 93%, 8 min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Compound H-2 as a white solid.

[0653] Reaction Scale: 1 g of Intermediate A-1

[0654] Method C: Steps 1 and 2 can be implemented 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 a nucleophile Nu-H (30 equivalents) is stirred at 120 °C for 2 hours. The reaction mixture is cooled to room temperature and purified by reverse-phase HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-ACN]; B%: 67%-97%, 10 minutes). The fractions are concentrated under reduced pressure to remove acetonitrile. The residue is lyophilized to obtain Compound H-2 as a yellow solid.

[0655] Reaction Scale: 70 mg of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine

[0656] Preparation of Compound H-4:

[0657] Method D: In Step 1, sodium hydride 60% dispersed in mineral oil (1.5 equivalents) is added in one portion to a solution of Intermediate H-3 (1 equivalent) in NMP (1.6 mL) at room temperature. The reaction mixture is stirred for 5 minutes, and then methyl iodide (2 equivalents) is added. Complete conversion is observed by LCMS after 5 minutes. The reaction mixture is transferred to a separatory funnel containing saturated NH 4 Cl. The aqueous solution is extracted with EtOAc, the organic layers are combined, dried over anhydrous Na 2 SO 4 and concentrated to obtain the crude intermediate (quantitative conversion).

[0658] In Step 2, the solid is dissolved in NMP (3.0 mL). Water (300 μL) is added, and then oxone (3 equivalents) is added. The reaction mixture is stirred at room temperature for 2 hours. Then water (35 mL) is added, and the precipitate is recovered by Buchner funnel.

[0659] In Step 3, the resulting sulfone is a solid, which is dissolved in 2-(methylamino)ethanol (Nu-H) (25 equivalents) and heated at 100 °C overnight. The reaction mixture is injected into a reverse-phase column (C18 12 g) and purified using 40-70% ACN in 10 mM AmF (pH 4) to obtain Compound H-4 (33% yield).

[0660] Reaction Scale: 150 mg of Intermediate H-3

[0661] Preparation of Compound H-5:

[0662] Method E: To a solution of intermediate A-2 (1 equivalent) in tetrahydrofuran (6 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2 equivalents), tris(dibenzylideneacetone)dipalladium(0) (0.1 equivalent), and cuprous 2-hydroxy-3-methylbenzoate (3 equivalents). The mixture was stirred at 60 °C for 12 h. 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 (silica) and concentrated in vacuo. The residue was purified by Pre-HPLC (column: C18; mobile phase: [water (formic acid)-ACN]) and dried by lyophilization. Then the crude compound was purified by normal-phase HPLC (column: Welch Ultimate XB-CN 250×50×10 μm; mobile phase: [hexane-ethanol (0.1% ammonium hydroxide)]) and concentrated in vacuo to give compound H-5 as an off-white solid.

[0663] Reaction Scale: 300 mg of intermediate A-2

[0664] Method F: Step 1, To a solution of intermediate A-2 (1.0 equivalent) in tetrahydrofuran (5 mL) was added trimethyl-[2-[(5-tributylstannyl-1H-imidazol-1-yl)methoxy]ethyl]silane (2 equivalents), palladium(II) tris(triphenylphosphine) (0.1 equivalent), and cuprous 2-hydroxy-3-methylbenzoate (3.0 equivalents). 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 prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min) to give the intermediate as a yellow oil (100 mg, 0.15 μmol, 15.5% yield).

[0665] 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) was added trifluoroacetic acid (2 mL), and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo, then tetrahydrofuran (10 mL) was added and sodium hydroxide (30 mg) was added. The resulting mixture was stirred at 80 °C for 1 h, then concentrated in vacuo, and the residue was triturated with N,N-dimethylformamide (5 mL), filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]; B%: 16%-46%, 10 min) to give Compound H-5 as an off-white solid.

[0666] Reaction Scale: 500 mg of Intermediate A-2

[0667] Table 9. Reaction conditions and data for Compounds H-2, H-4 and H-5

[0668]

[0669]

[0670] (xi) General synthetic method I:

[0671]

[0672] Preparation of Compound I-2:

[0673] Method A: Step 1, an amine derivative (1.2 equiv) was added to a vial containing a solution of Intermediate A-1 (1 equiv) and N,N-diisopropylethylamine (2.2 equiv) in NMP (4.0 mL). The reaction mixture was stirred at room temperature until complete conversion was observed by LCMS overnight. Water (50 mL) was slowly added to the reaction mixture, and the precipitate was recovered by filtration through a Buchner funnel. The solid was washed with water and dried in vacuo. The crude intermediate material was obtained as a solid (89% yield) and was used in the next reaction without any purification.

[0674] The solid was dissolved in DCM (10.0 mL) and acetone (1 mL), and tetrabutylammonium bromide (0.05 equiv) was added, then an aqueous solution (5.0 mL) of oxone (2.6 mmol) was added. The biphasic solution was stirred vigorously at 40 °C overnight, and 70% conversion to the desired sulfone was observed by LCMS. DCM was added, and the organic solution was washed 3 times with brine, then with anhydrous Na 2 SO 4Dry and concentrate under reduced pressure to obtain the crude intermediate (59% yield).

[0675] The crude intermediate was then dissolved in the nucleophile (Nu-H) (2.6 eq) and NMP (200 μL). The reaction mixture remained turbid after heating at 100 °C but became clearer as the product formed. Complete conversion was observed by LCMS overnight. EtOAc (30 mL) was added, and the solution was washed 5 times with saturated NH 4 Cl and dried over anhydrous Na 2 SO 4 Concentrate. 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).

[0676] Step 2, Trifluoroacetic acid (14 eq) was added to a solution of Intermediate I-1 (1 eq) in DCM (700 μL) at room temperature. The solution was stirred for 1 h and complete conversion was observed by LCMS. The reaction mixture was concentrated to dryness, diluted in DCM and washed 3 times with saturated NaHCO 3 The organic layer was dried over anhydrous Na 2 SO 4 filtered and concentrated under reduced pressure to give crude Compound I-2 (quantitative conversion).

[0677] Reaction Scale: 1 g of Intermediate A-1

[0678] Preparation of Compound I-3:

[0679] Method B: Sodium triacetoxyborohydride (3 eq) was added portionwise to a solution of Intermediate I-2 (1 eq) and formaldehyde (5 eq) (37% aqueous solution) 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 NaHCO 3 (3x) and 1 M NaOH (2x). The residue obtained after concentration was purified by reverse-phase flash chromatography (loaded with DMSO, C18 12 g, 4 CV) using 10 - 100% ACN in 10 mM AmF (pH 4) to give the solid Compound I-3 (58% yield).

[0680] Reaction Scale: 125 mg of Intermediate I-2

[0681] Table 10. Reaction conditions and data for Compounds I-2, I-3 and I-5

[0682]

[0683]

[0684] (xii) General synthetic method J:

[0685]

[0686] Preparation of Compound J-3:

[0687] 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 h. 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.

[0688] Reaction Scale: 80 mg of intermediate J-2

[0689] 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 h. The reaction mixture was cooled to room temperature and filtered to obtain a filtrate. The filtrate was purified by prep-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% ammonium hydroxide in methanol]) to obtain compound J-3 as a white solid.

[0690] Reaction Scale: 300 mg of intermediate J-2

[0691] Method C: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-ethoxy-2-methylsulfonyl-purine (1 eq), nucleophile (Nu-H) (5 eq), and potassium carbonate (2 eq) in N,N-dimethylformamide (1.5 mL) was stirred at 100 °C for 6 h. 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*50mm*3μm; mobile phase: [water (formic acid)-ACN]; B%: 45%-75%, 7 min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Compound J-3 as a white solid.

[0692] Reaction Scale: 120 mg of Intermediate J-2

[0693] Method D: Intermediate J-2 (1 eq) 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 5 times with saturated NH 4 Cl, dried over anhydrous Na 2 SO 4 and concentrated. The crude residue was purified by Buchi semi-prep (C18 column) using 20-60% ACN in AmF (with DMSO injection). The fractions were lyophilized to give Compound J-3.

[0694] Reaction Scale: 50 mg of Intermediate J-2

[0695] Method E: To Intermediate J-2 (1 eq) in an 8 mL vial was added potassium carbonate (2.2 eq), nucleophile (Nu-H) (11 eq), 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%-100% MeCN in 10 mM AmF (product eluted at 72% MeCN) to give Compound J-3.

[0696] Reaction Scale: 120 mg of Intermediate J-2

[0697] Table 11. Reaction Conditions and Data for Compound J-3

[0698]

[0699]

[0700] (xiii) General Synthetic Method K:

[0701]

[0702] Preparation of Compound K-4:

[0703] To a mixture of intermediate K-3 (1 equiv) and aldehyde derivative (5 equiv) in ethanol (2.5 mL) was added iron (10 equiv) and acetic acid (1 mL), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]; B%: 40%-70%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give compound K-4 as a yellow solid.

[0704] Reaction Scale: 220 mg of intermediate K-3.

[0705] Table 12. Reaction conditions and data for compound K-4

[0706]

[0707]

[0708] (xiv) General synthetic method L:

[0709]

[0710] Preparation of Compound L-5:

[0711] For the method of compound 95: Step 1, to a solution of 6-chloro-2-methylthio-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 cake was washed with 50 mL of (petroleum ether:ethyl acetate = 10:1), and concentrated under reduced pressure to give 1-(6-anilino-2-methylthio-5-nitro-pyrimidin-4-yl)-4-methyl-piperidine-4-carboxamide (intermediate L-2, 600 mg, 1.49 mmol) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)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),7.01(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).

[0712] Step 2. To a solution of 1-(6-anilino-2-methylthio-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 h. The reaction mixture was washed with water (30 mL) and extracted with ethyl acetate 90 mL (30 mL × 3). The combined organic layers were washed with brine 100 mL (50 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica flash column chromatography ( 40 g Silica Flash Column, eluent with a gradient of 0 - 100% ethyl acetate / petroleum ether, 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,CDCl 3 -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).

[0713] Step 3, Sodium hydride (105 mg, 2.62 mmol, 60% purity, 3.0 equiv) was added to a mixture of 2-methylpropane-1,2-diol (236 mg, 2.62 mmol, 3 equiv) in tetrahydrofuran (5 mL), and the mixture was 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 the mixture was stirred at 25 °C for 50 minutes. The reaction mixture was added dropwise to water (20 mL) and extracted with ethyl acetate 30 mL (10 mL × 3). The combined organic layers were washed with brine 20 mL (10 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica chromatography ( 20 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 30 mL / min), and the organic phase was concentrated under reduced pressure to obtain the crude product. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-ACN]; B%: 32% - 62%, 10 minutes), and the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was freeze-dried to obtain 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 (400 MHz, CDCl 3 -d) δ = 10.48 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.24 - 7.19 (m, 1H), 5.73 - 5.28 (m, 2H), 4.17 (s, 2H), 3.69 (d, J = 13.2 Hz, 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).

[0714] 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 eq) and 2-chlorobenzaldehyde (253 mg, 1.80 mmol, 0.20 mL, 10 eq) in ethanol (1 mL) was added iron (101 mg, 1.80 mmol, 10 eq) and acetic acid (0.4 mL), and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL×3). The combined organic layers were washed with brine 20 mL (10 mL×2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 39%-69%, 8 min), and the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give a crude product. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]; B%: 45%-65%, 10 min), and 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 (400 MHz, 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, 1H), 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 = 10.0 Hz, 2H), 1.16 (s, 3H), 1.14 (s, 6H). LCMS: (ES+) m / z = 535.4 (M + H).

[0715] (xv) General synthetic method M:

[0716]

[0717] Preparation of Compound M-2:

[0718] Method A: Step 1, Add 4-methyl-piperidine-4-carboxamide (1.7 equivalents) 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 equivalent) and N,N-diisopropylethylamine (7 equivalents) in NMP (1.1 mL). Stir the reaction mixture at room temperature for 2.5 hours. Add water, and filter the formed precipitate through a Buchner funnel. The aqueous filtrate is also extracted with DCM, and the DCM extract is evaporated and combined with the filtered material to obtain a crude intermediate, which is used for the next step.

[0719] Step 2, Add oxone (3.5 equivalents), NMP (1.6 mL), and water (160 μL) to the 8 mL vial containing the crude intermediate at 60 °C overnight. Add water and filter the obtained precipitate on a Buchner funnel to obtain the intermediate (97% yield), which is used for the next step without purification.

[0720] Step 3, Add potassium carbonate (2 equivalents), 1-Boc-2-pyrrolidinemethanol derivative (11 equivalents), and DMF (1.2 mL) to the intermediate in an 8 mL vial, and stir the mixture at 110 °C for 19 hours. Purify the reaction mixture by reverse-phase flash chromatography using 10% - 100% MeCN in 10 mM AmF (the product elutes at 72% MeCN) to obtain Intermediate M-1 (73% yield).

[0721] Reaction Scale: 100 mg of Intermediate A-1.

[0722] Method B: Step 1, Add DCM (1.1 mL) and trifluoroacetic acid (360 μL) to Intermediate M-1 (1 equivalent). First, stir the solution at room temperature for 1 hour. Then add additional trifluoroacetic acid (800 μL) and continue the reaction for 2.5 hours. Quench the mixture with saturated NaHCO 3 (20 mL) and extract with DCM (2x). Dry the organic layer (MgSO 4 ) and evaporate in vacuo to obtain the intermediate deprotected pyrrolidine (quantitative yield).

[0723] Step 2, Stir a solution of the intermediate deprotected pyrrolidine (1 equivalent) and formaldehyde (6 equivalents) (37% aqueous solution) in MeOH (3.7 mL) and AcOH (739 μL) at room temperature for 3 minutes, then cool on ice. Add sodium triacetoxyborohydride (3 equivalents) in portions, and stir the mixture at room temperature for 30 minutes. Quench the reaction mixture with saturated NaHCO 3(25 mL) was diluted 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 the white emulsion tended to settle at the bottom. The combined DCM layers were dried over MgSO 4 and evaporated in vacuo. The residue was then purified on a 12 g C-18 column using 0%-80% MeCN in 10 mM aqueous ammonium formate (the product eluted at 32% MeCN) to give compound M-2 (47% yield).

[0724] Reaction Scale: 100 mg of intermediate M-1

[0725] Table 13. Reaction conditions and data for compound M-2

[0726]

[0727] (xvi) General synthetic method N:

[0728]

[0729] Preparation of Compound N-4:

[0730] Method A: Step 1, to a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-purine (intermediate A-1) (1 equiv) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3 equiv) and the secondary amine derivative (1.2 equiv). The mixture was stirred at 60 °C for 16 h. The reaction mixture was washed with water (20 mL) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine 40 mL (20 mL × 2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 20 g SilicaFlash Column, eluent with a 0-100% ethyl acetate / petroleum ether gradient, 30 mL / min) and the organic phase was concentrated under reduced pressure to give intermediate N-1 as a pale yellow solid (92% yield).

[0731] Step 2, to a mixture of intermediate N-1 (1 equiv) in N-methyl-2-pyrrolidone (5 mL) and water (0.5 mL) was added potassium peroxymonosulfate (10 equiv). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to water 40 mL, filtered, and the filter cake was concentrated under reduced pressure to give intermediate N-2 as a yellow solid (crude).

[0732] 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 h. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate (30 mL, 10 mL × 3). The combined organic layers were washed with brine (20 mL, 10 mL × 2), dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 40 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 60 mL / min) and the organic phase was concentrated under reduced pressure to give intermediate N-3 as a white solid (92% yield).

[0733] Step 4: To a mixture of intermediate N-3 (1 equivalent) in ethanol (1 mL) and water (0.1 mL) was added hydrogen(dimethylphosphonato-κP)[hydrobis(dimethylphosphonato-κP)]platinum(II) (1 equivalent). The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium hydroxide or ammonium bicarbonate)-ACN]) to give compound N-4 as a white solid.

[0734] Reaction Scale: 500 mg of intermediate A-1

[0735] Method B: Step 1: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylthio-purine (intermediate A-1) (1.0 equivalent) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.0 equivalents) and secondary amine derivative (1.2 equivalents). The mixture was stirred at 60 °C for 2 h. The reaction mixture was added dropwise to water (30 mL), filtered, and the filter cake was concentrated under reduced pressure to give intermediate N-1 as a light yellow solid (94% yield).

[0736] 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 h. The reaction mixture was added dropwise to water (40 mL), filtered, and the filter cake was concentrated under reduced pressure to give intermediate N-2 as a yellow solid (crude).

[0737] Step 3. A solution of intermediate N-2 (1.0 eq) in nucleophile (Nu-H) (10 eq) was stirred at 140 °C for 12 h. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-ACN]; B%: 60%-90%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give intermediate N-3 as a white solid (54% yield).

[0738] Step 4. To a solution of intermediate N-3 (1.0 eq) in ethanol (1 mL) and water (0.1 mL) was added hydrogen(bis(dimethylphosphito-kp))platinum(II) (1.0 eq). The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-ACN]; B%: 39%-69%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give compound N-4 as a white solid.

[0739] Reaction Scale: 500 mg of intermediate A-1

[0740] Table 14. Reaction conditions and data of compound N-4

[0741]

[0742] (xvii) General synthesis method O:

[0743]

[0744] Preparation of Compound O-5:

[0745] Method A: Step 1, add N,N-diisopropylethylamine (1.17 g, 9.06 mmol, 1.58 mL, 3 equivalents) and azetidine-3-carbonitrile hydrochloride (430 mg, 3.62 mmol, 1.2 equivalents) to a solution of 6-chloro-N-(4-chlorophenyl)-2-methylthio-5-nitro-pyrimidin-4-amine (Intermediate B-2) (1 g, 3.02 mmol, 1 equivalent) in N,N-dimethylformamide (10 mL). Stir the mixture at 60 °C for 1 hour. Dropwise add the reaction mixture to 50 mL of water, filter, and concentrate the filtrate under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-1, crude product) as a light yellow solid. 1 H NMR(400MHz,DMSO-d 6 )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).

[0746] Step 2, add potassium peroxymonosulfate (5.36 g, 31.85 mmol, 10 equivalents) to a solution of 1-[6-(4-chloroanilino)-2-methylthio-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). Stir the mixture at 60 °C for 1 hour. Dropwise add the reaction mixture to 50 mL of water, filter, and concentrate the filtrate under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-2, 74% yield) as a light yellow solid. 1 HNMR(400MHz,DMSO-d 6 )δ=10.43(s,1H),7.62-7.56(m,2H),7.48-7.43(m,2H),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).

[0747] 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 a nucleophile (Nu-H) (5 equivalents) was stirred at 140 °C for 1 h. * , ** The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography and the organic phase was concentrated under reduced pressure to give Intermediate O-3 as a yellow solid (59% yield).

[0748] Reaction Scale: 400 mg of Intermediate O-2

[0749] * For Compound 137: 80 °C, 1 h, in NMP (4 mL) containing tBuOK (3 equivalents). Extracted with EtOAc.

[0750] ** For Compound 140: 60 °C, 1 h.

[0751] Step 4: To a solution of Intermediate O-3 (1 equivalent) in ethanol (2.5 mL) and water (0.25 mL) was added hydrogen(bis(dimethylphosphito-kp))platinum(II) (1 equivalent). The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 12 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 20 mL / min) and the organic phase was concentrated under reduced pressure to give Intermediate O-4 as a yellow solid (86% yield).

[0752] Reaction Scale: 250 mg of Intermediate O-3

[0753] Step 5: To a mixture of Intermediate O-4 (1 equivalent) and an aldehyde derivative (5 equivalents) in ethanol (1.5 mL) was added iron (10 equivalents) and acetic acid (0.6 mL), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]), the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give Compound O-5 as a yellow solid.

[0754] Reaction Scale: 170 mg of Intermediate O-4

[0755] Method B: Step 1, A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylthio-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 at 25 °C for 2 hours. The reaction mixture was added dropwise to 200 mL of water, filtered, and the filter cake was concentrated under reduced pressure to obtain Intermediate O-1 (crude) as a yellow solid, which was used directly in the next step without further purification.

[0756] Reaction Scale: 2.3 g of Intermediate B-2

[0757] Step 2, A mixture of Intermediate O-1 (1 equivalent) and potassium hydrogensulfate oxalate (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, and the filter cake was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography ( 80 g Silica Flash Column, eluent with a gradient of 30 - 80% ethyl acetate / petroleum ether, 50 mL / min). The fractions were concentrated under reduced pressure to obtain Intermediate O-2 (crude) as a yellow solid.

[0758] Reaction Scale: 2.6 g of Intermediate O-1

[0759] Step 3, Sodium hydride (60% purity, 5.0 equivalents) was added to a solution of the nucleophile (Nu-H) (5 equivalents) in tetrahydrofuran (5 mL), and the resulting mixture was stirred at 25 °C for 0.5 hour. Then Intermediate O-2 (1 equivalent) was added to the mixture and the mixture was stirred at 25 °C for 1.5 hours. 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 carbonate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography ( 20 g Silica Flash Column, eluent with a gradient of 0 - 50% ethyl acetate / petroleum ether, 30 mL / min). The fractions were concentrated under reduced pressure to obtain Intermediate O-3 (89% yield) as a yellow solid.

[0760] Reaction Scale: 0.5 g of Intermediate O-2

[0761] Step 4: A mixture of intermediate O-3 (1 equivalent) and hydrogen(dimethylphosphonato-κP)[hydrobis(dimethylphosphinato-κP)]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 and filtered; the resulting filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica flash chromatography ( 20 g Silica Flash Column, eluent: 50 - 100% ethyl acetate / petroleum ether gradient, 40 mL / min). The fractions were concentrated under reduced pressure to give intermediate O-4 as a yellow solid (70% yield).

[0762] Reaction Scale: 300 mg of intermediate O-3

[0763] 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 h. 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 silica flash chromatography ( 20 g SilicaFlash Column, eluent: 50 - 100% ethyl acetate / petroleum ether gradient, 35 mL / min). The fractions were 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 fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give compound O-5 as a yellow solid.

[0764] Reaction Scale: 200 mg of intermediate O-4

[0765] Preparation of Compound O-8:

[0766] Method C: Step 1: A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylthio-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 equivalents) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 1 h. The reaction mixture was added dropwise to 80 mL of 1 N hydrochloric acid (pH = 3), filtered, and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by silica flash chromatography ( 20 g Purified by silica flash column with an eluent of 0 - 100% ethyl acetate / petroleum ether gradient at 30 mL / min, and the organic phase was concentrated under reduced pressure to obtain 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxylic acid as a yellow solid (1 g, 2.27 mmol, 82.5% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.39 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.67 - 4.25 (m, 2H), 4.18 (d, J = 10.8 Hz, 2H), 3.51 (q, J = 6.8 Hz, 2H), 2.39 (s, 3H), 1.19 - 1.13 (m, 3H).

[0767] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylthio-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 h. The mixture was concentrated under vacuum 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 under vacuum to obtain 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide as a yellow solid (390 mg, 0.89 mmol, 97.7% yield). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 6.8 Hz, 3H).

[0768] Step 3. To a solution of 1-[6-(4-chloroanilino)-2-methylthio-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (390 mg, 0.89 mmol, 1 eq.) in N-methyl-2-pyrrolidone (4 mL) and water (0.4 mL) was added potassium peroxymonosulfate (1.49 g, 8.89 mmol, 10 eq.). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to 100 mL of water, filtered, and the filter cake 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 as a yellow solid (380 mg, 0.81 mmol, 90.8% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ=10.43 (s, 1H), 7.59 (d, J=8.8 Hz, 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=6.8 Hz, 3H). LCMS: (ES + ) m / z=471.2 (M+H).

[0769] 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 eq.) in N-methyl-2-pyrrolidone (3 mL) was added potassium tert-butoxide (229 mg, 2.04 mmol, 3.0 eq.) and 2-methylpropane-1,2-diol (306 mg, 3.40 mmol, 5.0 eq.). The mixture was stirred at 80 °C for 1 h. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL×3). The combined organic layers were washed with brine 20 mL (10 mL×2), dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 20 g Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 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 as a yellow solid (200 mg, 0.37 mmol, 54% yield).

[0770] 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 ethanol (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 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in N,N-dimethylformamide (2 mL) and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; 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 give 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.

[0771] Table 15. Reaction conditions and data for O-5 and O-8 compounds

[0772]

[0773]

[0774] (xviii) General synthetic method P:

[0775]

[0776] Preparation of Compounds P-3 and P-5:

[0777] Method A (for P-3 compounds): Step 1, to the secondary amine derivative (3 equiv) was added 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equiv) and N,N-diisopropylethylamine (30 equiv). Then NMP (2.5 mL) was added, and the reaction mixture was stirred at room temperature overnight. After adding water, a precipitate and an emulsion were formed, which were filtered. The filtrate was extracted with ethyl acetate. The filtered precipitate was dissolved in the ethyl acetate extract, which was combined, dried over magnesium sulfate, and evaporated to form Intermediate P-1 as an oil (quantitative conversion). The residue was used in the next step without any purification.

[0778] Step 2, 4M sodium hydroxide (27 equivalents) was added to intermediate P-1 (1 equivalent) in THF (2.2 mL). 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 6M HCl. The formed precipitate was filtered on a Buchner funnel to obtain the crude intermediate carboxylic acid, which could be used without further purification.

[0779] A mixture of the intermediate carboxylic acid (1 equivalent), HATU (2.2 equivalents), and N,N-diisopropylethylamine (12 equivalents) in EtOAc (5.5 mL) was stirred at room temperature for 15 minutes, after which 0.5M ammonia in dioxane (2 equivalents) 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 x 2). The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give intermediate P-2 as a viscous oil (quantitative conversion), which could be used without further drying and purification.

[0780] Step 3, Intermediate P-2 (1 equivalent) was dissolved in NMP (3.5 mL), and then water (300 μL) was added dropwise to ensure that the solution remained clear. Then Oxone (3.2 equivalents) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Cold water was added and the obtained precipitate was filtered on a Buchner funnel. The filtered solid was purified on a C-18 column (loaded with a minimum of DMF and water) using 20% to 100% acetonitrile in aqueous AmF solution (the product eluted at 53% acetonitrile) to give the crude sulfone intermediate (43% yield).

[0781] A solution of the sulfone intermediate (1 equivalent) in the nucleophile (Nu-H) (100 equivalents) was stirred at 100 °C overnight. After the solution was cooled, it was directly injected into a C-18 column and purified using 3% to 100% acetonitrile in 10 mM ammonium formate aqueous solution as the eluent (the product eluted at 90% acetonitrile) to give compound P-3 (27% yield).

[0782] Reaction Scale: 185 mg of intermediate A-1

[0783] Method B (for compound P-5): 4M sodium hydroxide (70 equivalents) was added to a solution of intermediate P-4 (1 equivalent) in THF (1.56 mL). The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated in vacuo, acidified with a minimum amount of aqueous HCl, and lyophilized. The product was purified on a 12-g C-18 column using 15% to 100% MeCN in aqueous AmF buffer, and compound P-5 was obtained after lyophilization (73% yield).

[0784] Reaction Scale: 140 mg of Intermediate P-4

[0785] Table 16. Reaction Conditions and Data for Compounds P-3 and P-5

[0786]

[0787]

[0788] (xix) General Synthetic Method Q:

[0789]

[0790] Preparation of Compound Q-3:

[0791] Method for Compound 239: Step 1, at room temperature, to a solution of Intermediate Q-1 (44.0 mg, 79.2 μmol) in DCM (792 μL) was added dibenzyl N,N-diisopropylphosphoramidite technical grade, 90% (84.1 μL, 238 μmol), followed by addition of a solution of tetrazole (880 μL, 396 μmol) (0.45 M, in MeCN). The reaction mixture was stirred at this temperature for 5 minutes.

[0792] 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, 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.

[0793] 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 (loading DMSO, C18 12 g) using 10 - 60% ACN in 10 mM 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). 11H NMR (400 MHz, 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 (brm, 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) + .

[0794] (xx) Compound 1:

[0795] Dimethyl phosphite; dimethyl phosphite platinum (17 mg, 40.1 mol, 1.0 eq) was added to a solution of N-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-(4-cyano-4-methyl-1-piperidinyl)purin-2-yl]-2-methyl-propionamide (Compound 89) (22 mg, 40.1 μmol, 1.0 eq) in ethanol (0.9 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 15 h. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 42% - 72%, 7 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methylpropionylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 1, 16.84 mg, 11.5 μmol, 28.6% yield) as an off-white solid. 1 1H NMR (400 MHz, MeOD-d 4 ) δ = 7.60 (br d, J = 7.6 Hz, 1H), 7.53 - 7.19 (m, 7H), 4.84 - 4.61 (m, 2H), 4.09 - 3.59 (m, 2H), 3.01 - 2.80 (m, 1H), 2.32 - 2.11 (m, 2H), 1.75 - 1.47 (m, 2H), 1.28 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H). LCMS: (ES + ) m / z = 566.3 (M + H).

[0796] (xxi) Compound 3:

[0797] Sodium hydride (5 mg, 107 μmol, 60% purity, 1.2 equiv) was added to a solution of 4-methyl-1H-pyrazole (37 mg, 447 μmol, 5 equiv) in N,N-dimethylformamide (0.5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 0.5 h. 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 equiv) was added to the mixture, and the resulting mixture was stirred at 25 °C for 2 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 53%-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 (400 MHz, DMSO-d 6 ) 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 = 14.0 Hz, 2H), 2.08 (s, 3H), 1.50 - 1.45 (m, 2H), 1.18 (s, 3H). LCMS: (ES + ) m / z = 561.1 (M + H).

[0798] (xxii) Compound 4:

[0799] At 0 °C, sodium hydride (9 mg, 214 μmol, 60% purity, 1.2 equiv) was added to a solution of 3-methyl-1H-pyrazole (73 mg, 894 μmol, 5 equiv) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at 25 °C for 0.5 h. 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 equiv) was added to the mixture, and the resulting mixture was stirred at 25 °C for 2 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 53%-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-d 6 )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).

[0800] (xxiii) Compound 5:

[0801] 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) was added (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (193 mg, 0.89 mmol, 10 equiv), and the mixture was stirred under microwave at 200 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 40%-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 HNMR(400MHz,DMSO-d 6 )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).

[0802] (xxiv) Compound 6:

[0803] 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) was added potassium carbonate (40 mg, 286 μmol, 2 equiv), 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 (2 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 42%-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 (400 MHz, MeOD-d 4 ) 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 = 14.2 Hz, 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).

[0804] (xxv) Compound 7:

[0805] 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) was added potassium carbonate (74 mg, 536 μmol, 2 equiv), and the resulting mixture was stirred at 100 °C for 1 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 43% - 73%, 10 min) and dried by lyophilization to give a mixture (120 mg).

[0806] 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% - 35%, 5 min) to give two peaks.

[0807] One peak was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (NH 4 HCO 3 )-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. 1 H NMR (400 MHz, MeOD-d 4 ) 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 = 14.0 Hz, 2H), 1.66 - 1.51 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H), 1.28 (s, 3H). LCMS: (ES + ) m / z = 555.3 (M + H).

[0808] (xxvi) Compound 8:

[0809] Another peak was purified by Pre-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 43%-73%, 10 min) according to the procedure of Compound 7, and dried by lyophilization to obtain 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxypropoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide as a white solid (Compound, 93.20 mg, 167.79 μmol, 77.6% yield). 1 H NMR(400MHz,MeOD-d 4 )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).

[0810] (xxvii) Compound 9:

[0811] 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) was added potassium carbonate (40 mg, 0.29 mmol, 2.0 equiv), 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 (2 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 47%-77%, 10 min), then lyophilized to obtain the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxy-2-methyl-propoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide as a white solid (Compound 9, 37.57 mg, 65.09 μmol, 45.5% yield). 1 H NMR(400MHz,MeOD-d 4) 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 = 14.4 Hz, 2H), 1.70 - 1.52 (m, 2H), 1.32 - 1.26 (m, 9H). LCMS: (ES + ) m / z = 569.2 (M + H).

[0812] (xxviii) Compound 10:

[0813] 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) was added potassium carbonate (40 mg, 286 μmol, 2 equiv), 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 (2 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (NH 4 HCO 3 )-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 (400 MHz, MeOD-d 4 ) 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).

[0814] (xxix) Compound 11:

[0815] 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-methylsulfonylethylamine (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, and the resulting filtrate was purified by reverse phase HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]; B%: 36%-66%, 10 min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methylsulfonylethylamino)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,CDCl 3 -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).

[0816] (xxx) Compound 12:

[0817] 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20g Purify by silica flash column with an eluent of 0 - 100% ethyl acetate / petroleum ether gradient at 20 mL / min, and concentrate the organic phase under reduced pressure to obtain 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxyethylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (300 mg) as a yellow solid.

[0818] 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), benzyl bromide (63 mg, 0.37 mmol, 2 equiv), and potassium carbonate (51 mg, 0.37 mmol, 2 equiv) in acetonitrile (1 mL) was stirred at 80 °C for 16 h. Filter the reaction mixture and concentrate it under reduced pressure to obtain a residue. Dissolve the residue in acetonitrile (2 mL) and purify it by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 61% - 81%, 8 min) and prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 53% - 83%, 10 min) to obtain 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 (400 MHz, MeOD-d 4 ) 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 = 10.0 Hz, 2H), 1.24 (s, 3H). LCMS: (ES + ) m / z = 630.2 (M+H).

[0819] (xxxi) Compound 13:

[0820] 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) and [(2R)-pyrrolidin-2-yl]methanol (181 mg, 1.79 mmol, 0.17 mL, 10 equiv) was stirred at 140 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 53%-83%, 10 min) to afford 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-d 4 )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),3.89 - 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).

[0821] (xxxii) Compound 14:

[0822] 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 equiv), 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole; hydrochloride (66 mg, 447 μmol, 5 equiv) and potassium carbonate (99 mg, 715 μmol, 8 equiv) in N-methylpyrrolidone (0.5 mL) was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with N-methylpyrrolidone (1 mL). The resulting mixture was filtered to give a filtrate. The filtrate was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 66%-96%, 9 min). The fractions were 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,CDCl 3 -d) δ = 7.51 (d, J = 6.8 Hz, 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), 3.89 - 3.72 (m, 2H), 3.36 (d, J = 10.0 Hz, 2H), 2.78 - 2.68 (m, 2H), 2.20 - 2.10 (m, 2H), 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).

[0823] (xxxiii) Compound 15:

[0824] 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 68%-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-d 4 )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,4H),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).

[0825] (xxxiv) Compound 16:

[0826] 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 eq) and thiomorpholine (569 mg, 5.52 mmol, 0.5 mL, 10 eq) were added to N-methylpyrrolidone (3 mL) in a microwave tube. The sealed tube was heated at 160 °C under microwave for 1 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 60%-90%, 8 min) and concentrated in vacuo to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-thiomorpholinyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (100 mg, 172 μmol, 31.1% yield) as a yellow solid.

[0827] Step 2: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-thiomorpholinyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (90 mg, 154 μmol, 1 eq) in N-methylpyrrolidone (1 mL) was added potassium hydrogensulfate oxone (156 mg, 926.97 μmol, 6 eq) and water (0.2 mL). The mixture was stirred at 60 °C for 12 h. The yellow solid was purified by prep-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 48%-78%, 8 min) to give the 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. 1 H NMR (400 MHz, CDCl 3 -d) δ = 7.49 (d, J = 6.8 Hz, 1H), 7.40 - 7.28 (m, 5H), 7.14 (d, J = 8.6 Hz, 2H), 5.81 - 5.12 (m, 2H), 4.86 - 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).

[0828] (xxxv) Compound 17:

[0829] 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) was added potassium carbonate (40 mg, 286 μmol, 2 equiv), 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 (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 53%-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. 1 H NMR (400 MHz, MeOD-d 4 ) 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, 1H), 3.71 - 3.69 (m, 1H), 3.66 - 3.56 (m, 2H), 2.20 (d, J = 14.4 Hz, 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).

[0830] (xxxvi) Compound 18:

[0831] 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-formamidineacetamide (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 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-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-acetylformamidine)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-d 4 )δ=7.64-7.57(m,1H),7.49-7.40(m,5H),7.33-7.26(m,2H),4.81-4.78(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).

[0832] (xxxvii) Compound 19:

[0833] 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), 2-(methylamino)ethanol (935 mg, 12.45 mmol, 1 mL, 54 equiv) was stirred at 100 °C for 18 h. 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 (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 46%-76%, 8 min). The fractions were concentrated in vacuo 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-d 6 )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.

[0834] (xxxviii) Compound 20:

[0835] 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 equiv) and [(2S)-pyrrolidin-2-yl]methanol (186 mg, 1.84 mmol, 0.18 mL, 10 equiv) was stirred at 140 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 52%-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-d 4 )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).

[0836] (xxxix) Compound 21:

[0837] At 0 °C, sodium hydride (8 mg, 210 μmol, 60% purity, 1.2 equiv) was added to a solution of 4-methyl-1H-pyrazole (72 mg, 877 μmol, 5 equiv) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at 25 °C for 0.5 h. Then 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-3) (0.1 g, 175 μmol, 1 equiv) was added to the mixture. The resulting mixture was stirred at 25 °C for 2 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 70%-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-piperidinyl]purine (Compound 21, 78.63 mg, 137 μmol, 78.3% yield) as an off-white solid. 1 H NMR(400MHz,CDCl 3 -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,CDCl 3 -d)δ=-73.85(s,1F)。LCMS:(ES + )m / z=572.2(M+H)。

[0838] (xl) Compound 22:

[0839] To a solution of 3-methyl-1H-pyrazole (72 mg, 876.56 μmol, 5 eq) in N,N-dimethylformamide (1 mL) at 0 °C was added sodium hydride (8 mg, 210.37 μmol, 60% purity, 1.2 eq). The resulting mixture was stirred at 25 °C for 0.5 h. Then 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-3) (0.1 g, 175 μmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 25 °C for 2 h. 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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 67%-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-piperidinyl]purine (Compound 22, 23.98 mg, 41.89 μmol, 23.9% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d 6 )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=2.8Hz,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-d 6 )δ=-72.46(s,1F). LCMS:(ES + )m / z=572.1(M+H).

[0840] (xli) Compound 23:

[0841] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-3) (100 mg, 0.18 mmol, 1 equiv) and propane-1,3-diol (68 mg, 0.90 mmol, 5 equiv) in N,N-dimethylformamide (1 mL) was added potassium carbonate (50 mg, 0.36 mmol, 2 equiv), 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 Pre-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 Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 54%-84%, 9 min) and dried by lyophilization to give 3-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]oxypropan-1-ol (Compound 23, 57.46 mg, 101.45 μmol, 56.2% yield) as a white solid. 1 H NMR (400 MHz, MeOH-d 4 ) δ = 7.59 (d, J = 7.6 Hz, 1H), 7.46 - 7.36 (m, 5H), 7.27 (d, J = 8.8 Hz, 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 (377 MHz, MeOH-d 4 ) δ = -75.50 (s, 1F). LCMS: (ES + ) m / z = 566.2 (M + H).

[0842] (xlii) Compound 24:

[0843] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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) was added potassium carbonate (73 mg, 526 μmol, 2 equiv), 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 (2 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 66%-96%, 9 min) and dried by lyophilization to give a mixture (60 mg). The mixture was separated by chiral SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 μm); mobile phase: [0.1% ammonium hydroxide in ethanol]; B%: 30%-30%, 3.4 min) to give two peaks.

[0844] One peak was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 62%-92%, 10 min) and dried by lyophilization to give 2-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]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 (400 MHz, MeOD-d 4 ) 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 = 11.2 Hz, 2H), 1.71 - 1.55 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H). 19 F NMR (376 MHz, MeOD-d 4 ) δ = -75.51 (br s, 1F). LCMS: (ES + ) m / z = 566.3 (M + H).

[0845] (xliii) Compound 25:

[0846] Another peak was purified again by Pre-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 62%-92%, 10 min) according to the procedure of Compound 24 and dried by lyophilization to obtain 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]oxypropan-2-ol (Compound 25, 28.11 mg, 49.6 μmol, 46.8% yield) as a white solid. 1 H NMR (400 MHz, MeOD-d 4 ) 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 = 6.4 Hz, 3H). 19 F NMR (377 MHz, MeOD-d 4 ) δ = -75.51 (s, 1F). LCMS: (ES + ) m / z = 566.2 (M+H).

[0847] (xliv) Compound 26:

[0848] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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) was added potassium carbonate (48 mg, 351 μmol, 2 equiv), 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 (2 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 62%-92%, 9 min) and dried by lyophilization to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]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-d 4 )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,1H),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-d 4 )δ = -110.05(br s,1F). LCMS:(ES + )m / z = 573.2(M + H).

[0849] (xlv) Compound 27:

[0850] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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) was added sodium hydride (4 mg, 0.10 mmol, 60% purity, 1.2 equiv), 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).

[0851] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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) was added potassium carbonate (10 mg, 0.07 mmol, 2.0 equiv), 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).

[0852] To a solution of potassium tert-butoxide (8 mg, 0.07 mmol, 2.0 equiv) in tetrahydrofuran (0.5 mL) at 0 °C 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-piperidinyl]purine (20 mg, 0.04 mmol, 1.0 equiv), 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).

[0853] The three batches were combined and purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 67%-97%, 10 min) and dried by lyophilization to give the product 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methoxyethoxy)-6-[4-(trifluoromethyl)-1-piperidinyl]purine as an off-white solid (Compound 27, 56.92 mg, 99.57 μmol, 63.1% yield, 99.0% purity). 11H NMR (400 MHz, MeOD-d 4 ) δ = 7.59 (d, J = 7.6 Hz, 1H), 7.50 - 7.34 (m, 5H), 7.27 (d, J = 8.8 Hz, 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 = 13.2 Hz, 2H), 1.70 - 1.57 (m, 2H). 19 19F NMR (376 MHz, MeOD-d 4 ) δ = 75.514 (m, 1F). LCMS: (ES + ) m / z = 566.1 (M+H).

[0854] (xlvi) Compound 28:

[0855] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-3) (0.2 g, 0.35 μmol, 1 equiv), 2-methylsulfonylethylamine (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% - 87%, 10 min). The fractions were 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-piperidinyl]purine-2-amine (Compound 28, 13.62 mg, 22.2 μmol, 6.3% yield) as a white solid. 1 1H NMR (400 MHz, CDCl 3-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 - 3.85 (m, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 12.8 Hz, 2H), 2.88 (s, 3H), 2.43 - 2.38 (m, 1H), 2.03 (d, J = 12.8 Hz, 2H), 1.76 - 1.69 (m, 2H). LCMS: (ES+) m / z = 613.0 (M + H).

[0856] (xlvii) Compound 29:

[0857] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-3) (50 mg, 87.7 μmol, 1 equiv) and [(2R)-pyrrolidin-2-yl]methanol (89 mg, 0.88 mmol, 0.09 mL, 10 equiv) was stirred at 140 °C for 5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 80% - 100%, 10 min) to afford [(2R)-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]pyrrolidin-2-yl]methanol (Compound 29, 29.97 mg, 50.7 μmol, 57.8% yield) as a white solid. 1 H NMR (400 MHz, MeOD-d 4 ) δ = 7.61 - 7.55 (m, 1H), 7.50 - 7.32 (m, 5H), 7.29 - 7.21 (m, 2H), 5.52 (d, J = 12.8 Hz, 2H), 4.14 (s, 1H), 3.77 - 3.49 (m, 4H), 3.08 (t, J = 12.8 Hz, 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).

[0858] (xlviii) Compound 30:

[0859] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]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 chromatography ( 12 g Silica Flash Column, eluent was 0 - 50% ethyl acetate / petroleum ether gradient, 20 mL / min). The fractions were concentrated under reduced pressure and lyophilized to give the 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-piperidinyl]purine (Compound 30, 0.02 g, 32.59 μmol, 36.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.78 - 7.60 (m, 1H), 7.58 - 7.38 (m, 5H), 7.28 (d, J = 8.8 Hz, 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).

[0860] (xlix) Compound 31:

[0861] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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 h. 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 (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 80%-100%, 9 min). The fractions were 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-piperidinyl]purine (Compound 31, 20 mg, 34.9 μmol, 19.8% yield) as a white solid. 1 H NMR(400MHz,CDCl 3 -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), 1.58 - 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.

[0862] (l) Compound 32:

[0863] Step 1:8-(2-Chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-2) (300 mg, 541 μmol, 1 equiv) and thiomorpholine (558 mg, 5.41 mmol, 10 equiv) were added to N-methylpyrrolidone (3 mL) in a microwave tube. The sealed tube was heated at 160 °C under microwave for 1 h. 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 Pre-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 (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) and concentrated in vacuo to give the product 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]thiomorpholine as a white solid (60 mg, 101 μmol, 18.6% yield).

[0864] Step 2: To a solution of 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]thiomorpholine (50 mg, 84.2 μmol, 1 equiv) in N-methylpyrrolidone (0.5 mL) was added a solution of potassium hydrogensulfate oxone (85 mg, 505 μmol, 6 equiv) in water (0.1 mL). The mixture was stirred at 60 °C for 12 h. The residue was purified by Pre-HPLC (column: Phenomenex Synergi C18 150 * 25 mm * 10 μm; mobile phase: [water (formic acid)-ACN]; B%: 69%-99%, 10 min) and dried by lyophilization to give the product 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]-1,4-thiazinane 1,1-dioxide (Compound 32, 16.17 mg, 25.8 μmol, 30.6% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 -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, 2H), 4.30 (s, 4H), 3.13 - 2.93 (m, 6H), 2.52 - 2.29 (m, 1H), 2.02 (d, J = 11.6 Hz, 2H), 1.72 - 1.63 (m, 2H).19 FNMR(376MHz,CDCl 3 -d)δ=-73.89(s,1F)LCMS:(ES + )m / z=626.9(M+H)。

[0865] (li) Compound 33:

[0866] To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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) was added potassium carbonate (39 mg, 280 μmol, 2 equiv), 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 (2 mL * 3). The organic layer was dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by Pre-HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 70%-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-piperidinyl]purine (Compound 33, 50.81 mg, 85.8 μmol, 61.1% yield) as a white solid. 1 H NMR(400MHz,MeOD-d 4 )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-d 4 )δ=-75.51(s,1F)。LCMS:(ES + )m / z=592.2(M+H),Rt=1.160min.(Method 4)。

[0867] (lii) Compound 34:

[0868] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-2) (100 mg, 180 μmol, 1 equiv), N-formimidoylacetamide (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 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by prep-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-piperidinyl]purin-2-yl]formimidoyl]acetamide (Compound 34, 16.09 mg, 27.2 μmol, 15.0% yield) as an off-white solid. 1 H NMR (400 MHz, MeOD-d 4 ) δ = 7.67 - 7.60 (m, 1H), 7.53 - 7.41 (m, 5H), 7.37 - 7.29 (m, 2H), 5.03 - 4.92 (m, 2H), 3.28 - 3.04 (m, 2H), 2.78 - 2.54 (m, 1H), 2.18 (s, 3H), 2.08 (d, J = 11.6 Hz, 2H), 1.71 - 1.59 (m, 2H). LCMS: (ES + ) m / z = 591.3 (M+H).

[0869] (liii) Compound 35:

[0870] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidinyl]purine (Intermediate D-2) (200 mg, 361 μmol, 1 eq), [(2S)-pyrrolidin-2-yl]methanol (73 mg, 721 μmol, 0.07 mL, 2 eq) and potassium carbonate (150 mg, 1.08 mmol, 3 eq) in dimethyl sulfoxide (2 mL) was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 67%-97%, 9 min) to give [(2S)-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]purin-2-yl]pyrrolidin-2-yl]methanol (Compound 35, 6.44 mg, 10.9 μmol, 3.02% yield) as a white solid. 1 H NMR(400MHz,MeOD-d 4 )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),4.25 - 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).

[0871] (liv) Compound 36:

[0872] 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) was added iron (91 mg, 1.63 mmol, 10 equiv). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (formic acid)-ACN]; B%: 41%-71%, 7 min) to give a yellow solid. The yellow solid was then purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 51%-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 as a yellow solid (Compound 36, 10.04 mg, 17.3 μmol, 10.6% yield). 1 HNMR(400MHz,DMSO-d 6 )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).

[0873] (lv) Compound 37:

[0874] 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 residue was purified by flash silica chromatography ( X g Silica Flash Column, eluent 0 - 10% MeOH / DCM, 80 mL / min) to give a yellow solid (R f = 0.3). The white solid was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium hydroxide)-ACN]; B%: 50% - 80%, 8 min) to give a yellow solid. The yellow solid was then purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-ACN]; B%: 42% - 72%, 10 min) to give the compound 1-[9-(4-chlorophenyl)-8-(3-cyanophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]purin-6-yl]-4-methyl-piperidine-4-carboxamide as a yellow solid (Compound 37, 28.10 mg, 48.6 μmol, 29.7% yield). 1 H NMR (400 MHz, CDCl 3 -d) δ = 7.95 (s, 1H), 7.68 - 7.41 (m, 4H), 7.38 - 7.31 (m, 1H), 7.23 (d, J = 8.6 Hz, 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).

[0875] (lvi) Compound 38:

[0876] A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidinyl]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 h. The reaction mixture was diluted with 1 mL of N,N-dimethylformamide and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium hydroxide)-ACN]; B%: 66%-96%, 11 min) to give 1-[[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidinyl]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 (400 MHz, MeOD-d 4 ) δ = 7.60 - 7.57 (m, 1H), 7.51 - 7.31 (m, 5H), 7.25 (d, J = 8.8 Hz, 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 = 11.6 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.18 (s, 6H). LCMS: (ES + ) m / z = 593.2 (M+H).

[0877] (lvii) Compound 40:

[0878] 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 eq) and 2-methyl-1-(methylamino)propan-2-ol (184 mg, 1.79 mmol, 10 eq) was stirred at 140 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 55%-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 HNMR(400MHz,MeOD-d 4 )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).

[0879] (lviii) Compound 41:

[0880] 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 eq) and 1-(methylaminomethyl)cyclopropanol (181 mg, 1.79 mmol, 10 eq) in N-methylpyrrolidone (0.3 mL) was stirred at 140 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 25g SilicaFlash Column, eluent: 0 - 50% methanol / dichloroethane gradient, 30 mL / min) and prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 51% - 81%, 10 min) purification. 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(1-hydroxycyclopropyl)methyl-methyl-amino]purin-6-yl]-4-methyl-pipe...

Claims

1. A compound of formula I: Wherein, R 1 is an optionally substituted C 6 aryl; R 2 is an optionally substituted C 6 aryl or C 5 -C 6 heteroaryl; R 3 is an optionally substituted group selected from R 7 O-, N(R 8 ), 2 -, C 4-10 heterocycloalkyl, and C 5-6 heteroaryl groups; R 4 is an optionally substituted group selected from R 5 O- and N(R 6 ) 2 -; R 5 is selected from 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 groups; R 6 is H or is selected from C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 4 -C 10 -heteroalkyl, C 5 -C 6 -heteroaryl, C 3 -C 7 -cycloalkyl C 1 -C 3 -alkyl, C 4 -C 10 -heteroalkyl C 1 -C 3 -alkyl, C 5 -C 6 -heteroaryl C 1 -C 3 -alkyl groups, where at least one R 6 is not H, or two R 6 groups together with the nitrogen atom to which they are attached form a C 4 -C 10 -heteroalkyl or C 5 -C 6 -heteroaryl; wherein R 5 or R 6 at least one of the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl in 1 -C 4 is substituted by at least one hydroxy or hydroxy-substituted C-alkyl and optionally further substituted by other substituents; R 7 is an optionally substituted C 1 -C 6 alkyl; and R 8 independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 10 heterocycloalkyl each time it appears; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula II: Wherein, R 4 as defined in claim 1; X 1 is C and X 2 to X 6 are each independently selected from N and CR 21 and n is 1, wherein X 2 to X 6 at most three of which are N; or X 1 is C or N and X 2 to X 5 are each independently selected from CR 21 , O, S, N or NR 11 , where n is 0, i.e., X 6 does not exist and is replaced by a bond between X 1 and X 5 , where at most three of X 1 to X 5 are not C or CR 21 ; X 7 and X 8 each independently selected from O, S, SO 2 , NR 36 or C(R 35 ) 2 , provided that when one of X 7 and X 8 is O, S or NR 36 , the other is C(R 35 ) 2 ; R 9 independently selected from 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 cycloalkylC 1 -C 3 alkyl, C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl and C 5 -C 6 heteroarylC 1 -C 3 alkyl; R 10 independently selected from H or an optionally substituted C at each occurrence 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 4 -C 10 -heterocycloalkyl, C 5 -C 6 -heteroaryl, C 3 -C 7 -cycloalkylC 1 -C 3 -alkyl, C 4 -C 10 -heterocycloalkylC 1 -C 3 -alkyl and C 5 -C 6 -heteroarylC 1 -C 3 -alkyl groups, or two R 10 groups together with the nitrogen atom to which they are attached form an optionally substituted C 4 -C 10 -heterocycloalkyl or C 5 -C 6 -heteroaryl; R 11 independently selected from H or from optionally substituted C at each occurrence 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 group of alkyl; R 12 independently selected from 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, and p is 0, 1, 2 or 3, preferably 0 or 1; R 21 independently selected from hydrogen, halogen, OH, OR at each occurrence 9 , CN, NO 2 , C(O)R 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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, 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; R 31 to R 35 is independently selected from hydrogen, halogen, OH, OR 9 , CN, NO 2 , C(O)OH, C(O)OR 9 , C(O)R 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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, 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; R 36 selected from hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 ) 2 , C(R 11 )=NR 11 , SO 2 R 9 , SO 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; or R 31 to R 36 together with two adjacent atoms thereof form a ring, preferably a bridged heterocycle or a spiro heterocycle; and m is 0, 1, 2 or 3; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein m is 0 and X 7 and X 8 are each independently C(R 35 ) 2 , preferably X 7 is CH 2 .

4. The compound according to claim 3, wherein X 8 is C(R 35 ) 2 , where one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl.

5. The compound according to claim 3, wherein X 8 is C(R 35 ) 2 and the two Rs 35 together with the carbon atoms adjacent to them form a spiro C 4-5 heterocycle.

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

7. The compound according to claim 6, wherein X 8 is C(R 35 ) 2 , where one of the two Rs 35 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 other of the two Rs 35 is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl.

8. The compound according to claim 6, wherein X 8 is C(R 35 ) 2 and the two R 35 together with the carbon atoms adjacent to them form a spiro C 4-5 heterocycle.

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

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

11. The compound according to claim 10, wherein one of the two Rs 35 is C(O)N(R 10 ) 2 or N(R 11 )C(O)R 9 , and the other of the two Rs 35 is OR 9 or an optionally substituted C 1-4 alkyl group.

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

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

14. The compound according to claim 9, wherein X 8 is CH 2 and X 7 is C(R 35 ) 2 and the two R 35 together with the carbon atom adjacent to them form a spiro C 4-5 heterocycle.

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

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

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

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

19. The compound according to claim 9, wherein X 7 is CH 2 and X 8 is C(R 35 ) 2 and the two R 35 together with the carbon atom adjacent to them form a spiro C 4-5 heterocycle.

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

21. The compound according to claim 20, wherein m is 2.

22. The compound according to claim 20, wherein m is 3.

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

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

25. A compound according to any one of claims 20 to 24, wherein one of the two R 35 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 substituted C 1-6 alkyl, and the other of the two R 35 is hydrogen, fluorine, OH, OR 9 , N(R 10 ) 2 or optionally substituted C 1-6 alkyl, or one of the R 35 and R 33 together with the atoms adjacent to them form a bridged ring.

26. The compound according to claim 25, wherein the two Rs 35 are both hydrogen.

27. The compound according to claim 25, wherein one of the two Rs 35 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 other of the two Rs 35 is hydrogen.

28. The compound according to claim 25, wherein said R 35 one of which and R 33 together form C 1-3 alkylene.

29. The compound according to any one of claims 2 to 27, wherein R 33 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears.

30. A compound according to any one of claims 2 to 29, wherein R 34 is independently selected from hydrogen, fluorine and optionally substituted C 1-6 alkyl each time it appears.

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

32. The compound according to claim 1 or 2, wherein R 3 is selected from the groups C1-C7, C10, C15, C16, C18-C22, C24-C28, C32-C40 and C47-C69, preferably C1, C16 or C18, more preferably C18.

33. The compound according to claim 1, wherein the compound is a compound of formula III: Wherein, R 13 is an optionally substituted group selected from R 7 O-, N(R 8 ) 2 -, and C 5-6 heteroaryl group; R 4 , R 7 and R 8 As defined in claim 1; and R 12 、 X 1 to X 6 , n and p are as defined in claim 2; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 33, wherein R 13 is R 7 O-.

35. The compound according to claim 34, wherein R 7 is optionally substituted C 1 -C 4 alkyl.

36. The compound according to claim 33, wherein R 13 is N(R 8 ) 2 -.

37. The compound according to claim 36, wherein 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 alkyl.

38. The compound according to claim 36, wherein 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 alkyl.

39. The compound according to claim 36, wherein 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 alkyl.

40. The compound according to claim 33, wherein R 13 is selected from C8, C9, C11-C14, C17, C23, C29-C31 and C41-C46.

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

42. A compound according to any one of claims 2 to 40, wherein p is 0, i.e., R 12 is absent, thereby forming an unsubstituted phenyl group.

43. A compound according to any one of claims 2 to 42, wherein n is 1, X 1 is C, and X 2 to X 6 are each independently CR 21 .

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

45. A compound according to any one of claims 2 to 42, wherein n is 0, X 6 is absent, and X 1 is C.

46. The compound according to claim 45, wherein one or two of X 2 to X 5 are N or NR 11 and the others are CR 21 , preferably R 11 is C 1 -C 6 alkyl.

47. The compound according to claim 45, wherein one of X 2 to X 5 is S and the others are CR 21 .

48. A compound according to any one of claims 43 to 47, wherein all CR 21 are CH.

49. The compound according to claim 43, wherein one CR 21 is not CH, preferably R 21 is selected from halogen, CN, N(C 1-6 alkyl) 2 and C 1-6 alkyl, more preferably halogen or CN, most preferably halogen (e.g., Cl).

50. The compound according to claim 44, wherein one CR 21 is not CH, preferably R 21 is selected from halogen, CN, N(C 1-6 alkyl) 2 and C 1-6 alkyl, more preferably halogen, CN and C 1-6 alkyl, most preferably CN.

51. A compound according to any one of claims 45 to 47, wherein one CR 21 is not CH, preferably R 21 is selected from halogen, 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.

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

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

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

55. The compound according to claim 52, wherein R 2 is selected from groups B9 to B11 and B20.

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

57. The compound according to claim 56, wherein R 5 is a C 2 -C 6 alkyl group, a C 4 -C 10 heterocycloalkyl group or a C 4 -C 10 heterocycloalkyl C 1 -C 3 alkyl group, which is substituted by a hydroxyl group and optionally substituted by other substituents.

58. The compound according to claim 57, wherein 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. The compound according to claim 57, wherein R 5 is C substituted with a hydroxyl group and optionally substituted with other substituents 4 -C 6 heterocycloalkyl or C 4 -C 6 heterocycloalkyl C 1 -C 3 alkyl, preferably the C 4 -C 6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

60. A compound according to any one of claims 1 to 55, wherein R 4 is an N(R 6 ) 2 -group, wherein R 6 is as defined in claim 1 and at least one R 6 is substituted by at least one hydroxyl group or a C 1 -C 4 alkyl substituted by hydroxyl groups and is optionally substituted by one or more other substituents.

61. The compound according to claim 60, wherein one R 6 is C substituted by at least one hydroxyl group or hydroxyl-substituted C 1 -C 4 alkyl-substituted C 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 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl and is optionally substituted by one or more other substituents.

62. The compound according to claim 61, wherein one R 6 is C substituted by hydroxyl or hydroxyl-substituted C 1 -C 4 alkyl-substituted C 2 -C 6 alkyl or C 3 -C 7 cycloalkyl C 1 -C 3 alkyl, and the other R 6 is hydrogen or C 1 -C 6 alkyl.

63. The compound according to claim 60, wherein the two R 6 groups together with the nitrogen atom to which they are attached form a C 1 -C 4 -alkyl substituted by at least one hydroxyl or hydroxy group and optionally substituted by one or more other substituents and optionally substituted by a C 4 -C 10 heterocycloalkyl or C 5 heteroaryl.

64. The compound according to claim 63, wherein the two R 6 groups together with the nitrogen atom to which they are adjacent form a C 1 -C 4 -alkyl substituted by at least one hydroxyl group or hydroxyl group and optionally substituted by one or more other substituents, and is optionally a C 4 -C 7 heteroalkyl.

65. The compound according to claim 64, wherein said C 4 -C 7 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl which are substituted by at least one hydroxy or hydroxy-substituted C 1 -C 4 alkyl and optionally substituted by one or more other substituents.

66. The compound according to claim 63, wherein the two R 6 groups together with the nitrogen atom to which they are adjacent form a C 1 -C 4 alkyl-substituted and optionally substituted by one or more other substituents C 5 heteroaryl.

67. The compound according to claim 66, wherein said C 5 heteroaryl is selected from imidazole and pyrrole groups substituted by at least one hydroxyl group or C 1 -C 4 alkyl substituted and optionally substituted by one or more other substituents.

68. A compound according to any one of claims 1 to 55, wherein R 4 is selected from the groups D5 - D9, D12, D13, D19 - D21, D23, D25, D27, D28, D30 - D32, D36, D37, D43 - D49, D52, D53, D67, D71, D75, D76 and D78 - D81.

69. The compound according to claim 68, wherein R 4 is selected from the groups D6 - D9, D43 - D47, D75 and D76.

70. The compound according to claim 69, wherein R 4 is selected from the groups D6-D9 and D43-D47, preferably D9.

71. The compound according to claim 68, wherein R 4 is selected from the groups D12, D19, D21, D23, D30-D32, D36, D37, D48, D49 and D78-D81, preferably D19 or D21.

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

73. A compound of formula IV: wherein X 1 to X 8 , R 12 , R 31 to R 34 、m, n and p are defined as in any one of the preceding claims; and R 14 is N(R 16 ) 2 - or optionally substituted C 5 -C 6 heteroaryl; and R 16 selected from H or from 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 groups, or two R 16 groups together with the nitrogen atom to which they are attached form an optionally substituted C 4 -C 10 -heterocycloalkyl or C 5 -C 6 -heteroaryl; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

74. The compound according to claim 73, wherein R 14 is N(R 16 ) 2 -.

75. The compound according to claim 74, wherein 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 cycloalkylC 1 -C 3 alkyl or C 4 -C 10 heterocycloalkylC 1 -C 3 alkyl, and the other R 16 is hydrogen or C 1 -C 6 alkyl.

76. The compound according to claim 75, wherein one R 16 is C 2 -C 6 alkyl substituted by one or more substituents, and the other R 16 is hydrogen or C 1 -C 6 alkyl.

77. The compound according to claim 76, wherein the substituent is selected from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

78. The compound according to claim 74, wherein the two R 16 groups together with the nitrogen atom to which they are adjacent form an optionally substituted C 4 -C 10 heterocycloalkyl or C 5 heteroaryl, which is linked through said nitrogen atom.

79. The compound according to claim 78, wherein the two R 16 groups together with the nitrogen atom to which they are adjacent form an optionally substituted C 4 -C 7 heterocycloalkyl linked through said nitrogen.

80. The compound according to claim 79, wherein said C 4 -C 7 heterocycloalkyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

81. The compound according to claim 78, wherein the two R 16 groups together with the nitrogen atom to which they are adjacent form an optionally substituted C 5 heteroaryl group attached through said nitrogen atom.

82. The compound according to claim 81, wherein said C 5 heteroaryl is selected from optionally substituted imidazole and pyrrole groups.

83. The compound according to claim 73, wherein R 14 is an optionally substituted C 5 -C 6 heteroaryl.

84. The compound according to claim 73, wherein R 14 is selected from D3-D5, D11-D16, D19-D28, D30-D32, D36, D37, D39-D41, D48-D54, D56, D57, D63-D67, D71 and D78-D81.

85. A compound of formula V: wherein X 1 to X 6 , R 12 , R 13 , R 14 , n and p are defined as 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: wherein X 1 to X 8 , R 12 , R 31 to R 34 、m, n and p are defined as in any one of the preceding claims; and R 15 is selected from 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 groups; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

87. The compound according to claim 86, wherein 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 alkyl.

88. The compound according to claim 87, wherein R 15 is a C 1 -C 6 alkyl group substituted by one or more substituents, for example, the substituents are selected from F, OH, CN, alkoxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonic acid group, dialkylamino, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

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

90. The compound according to claim 86, wherein said OR 15 group is selected from D6 - D10, D17, D29, D33 - D35, D43 - D47, D55, D68 - D70 and D72 - D77.

91. A compound of formula VII: wherein X 1 to X 6 , R 12 , R 13 , R 15 , n and p are defined as 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: wherein X 1 to X 8 , R 12 , R 31 to R 34 , m, n and p are defined as in any one of the preceding claims; and R 24 Selected from 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, where R 9 to R 11 is as previously defined; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

93. A compound of formula IX: where X 1 to X 6 , R 12 , R 13 , R 24 , n and p are defined as in any one of the preceding claims; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

94. A compound according to claim 92 or 93, wherein R 24 is selected from the groups D1, D2, D18, D38, D42 and D58 - D62.

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

96. The compound according to claim 95, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

97. The compound according to claim 95, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

98. The compound according to claim 95, wherein the compound is selected from 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.

99. The compound according to claim 1, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

100. The compound according to claim 99, 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, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

101. The compound according to claim 99, wherein the compound is selected from 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 - 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 according to claim 99, wherein the compound is selected from 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 - 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 the compound as defined in any one of claims 1 to 102, and a pharmaceutically acceptable carrier, diluent or excipient.

104. Use of a compound as defined in any one of claims 1 to 102 or a pharmaceutical composition as defined in claim 103 for the treatment of the following conditions: one of the conditions related to appetite or its complications, one of the conditions related to glucose regulation or its complications, one of the fibrotic-related conditions or its complications, one of the conditions related to metabolism or its complications, conditions related to skin and hair growth and healing, conditions related to the gastrointestinal tract, one of the conditions related to obesity or its complications, or a combination thereof.

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

106. The use according to claim 104, wherein one of the conditions related to glucose regulation or its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic diseases (due to β-cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

107. The use according to claim 104, wherein one of the fibrotic-related conditions or 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 conditions (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrosis conditions (such as scleroderma), fibrotic nephropathy and chronic kidney disease.

108. The use according to claim 104, wherein one of the conditions related to metabolism or its complications is selected from metabolic syndrome and hyperlipidemia (such as hypertriglyceridemia, hypertriglyceridemia in the case of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

109. The use according to claim 104, wherein one of the conditions related to obesity or its complications is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal conditions, menstrual irregularities, degenerative arthritis, venous stasis ulcer, coronary artery disease, atherosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate or gallbladder.

110. The use according to claim 104, wherein the conditions of the skin and hair are selected from hair loss (male pattern hair loss and hair loss related to metabolic syndrome), excessive scar formation (scars and keloids), and scleroderma.

111. The use according to claim 104, wherein the conditions related to the gastrointestinal tract are selected from constipation, irritable bowel syndrome and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

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

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

114. The method according to claim 112, wherein the disorder related to glucose regulation or its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic diseases (due to β-cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

115. The method according to claim 112, wherein the fibrosis-related disorder or 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 fibrosis disorders (such as scleroderma), fibrotic nephropathy and chronic kidney disease.

116. The method according to claim 112, wherein the metabolism-related disorder or its complications is selected from metabolic syndrome and hyperlipidemia (such as hypertriglyceridemia, hypertriglyceridemia in the case of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

117. The method according to claim 112, wherein the obesity-related disorder or its complications is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcers, coronary artery disease, arteriosclerotic diseases, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate or gallbladder.

118. The method according to claim 112, wherein the disorders of the skin and hair are selected from hair loss (male pattern hair loss and hair loss associated with metabolic syndrome), excessive scar formation (scars and keloids), and scleroderma.

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

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