Pyrazolopyrimidine compound, composition containing pyrazolopyrimidine compound and application of pyrazolopyrimidine compound

Abstract

This document relates to pyrazolopyrimidine compounds, pharmaceutical compositions comprising the compounds and their use in the treatment or prevention of diseases and disorders associated with the cannabinoid CB1 receptor. For example, the pyrazolopyrimidine compound, or tautomeric forms and / or salts thereof, has Formula I: Formula I wherein R1 to R4 are as defined herein. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority under applicable law to U.S. Provisional Application No. 63 / 268,021, filed on February 15, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure relates generally to compounds, particularly pyrazolopyrimidine compounds, pharmaceutical compositions containing them, and their uses and methods of use in treating and preventing diseases and disorders. Background Art

[0004] It is well known that activation of the cannabinoid CB1 receptor increases appetite, increases lipid biosynthesis and storage, inhibits the effects of insulin and leptin, and promotes inflammation and fibrosis. Therefore, research has focused on developing CB1 receptor inhibitors for potential treatment of obesity and its associated metabolic disorders (called metabolic syndrome). Rimonabant has been shown to be effective in treating metabolic syndrome, but causes 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 CB1 receptor to treat or prevent conditions associated therewith. Summary of the invention

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

[0007] Embodiment 1. Compound of formula I:

[0008]

[0009] in,

[0010] R 1 and R 2 are each independently selected from optionally substituted C 6-10 Aryl and optionally substituted C 5-10 heteroaryl;

[0011] R 3 Selected from optionally substituted C 1-12 Alkyl, optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted C 6-10 Aryl and optionally substituted C5-10 Heteroaryl, optionally substituted -X 1 -C 3-10 Cycloalkyl, optionally substituted -X 1 -C 3-10 Heterocycloalkyl, optional

[0012] Replaced by -X 1 -C 6-10 Aryl and optionally substituted -X 1 -C 5-10 heteroaryl;

[0013] R 4 is selected from optionally substituted NH2, C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl;

[0014] X 1 Selected from O and NR 5 , where R 5 is H or optionally substituted C 1-6 Alkyl; and

[0015] X 2 Selected from O and NR 6 , where R 6 is H or optionally substituted C 1-6 alkyl;

[0016] or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 2. The compound according to embodiment 1, wherein R 4 is NH2.

[0018] Embodiment 3. The compound according to embodiment 1, wherein R 4 Selected from optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl.

[0019] Embodiment 4. The compound according to embodiment 3, wherein R 4 is an optionally substituted C 1-12 Alkoxy, preferably optionally substituted C 1-6 Alkoxy, more preferably optionally substituted C 1-4 Alkoxy.

[0020] Embodiment 5. The compound according to embodiment 3, wherein R 4 is an optionally substituted C 1-12 Alkylamino or C 1-12 dialkylamino, preferably optionally substituted C 1-6 Alkylamino or C 1-6 dialkylamino, more preferably optionally substituted C 1-4 Alkylamino or C 1-4 Dialkylamino.

[0021] Embodiment 6. A compound according to Embodiment 4 or 5, wherein the alkyl or alkoxy group is replaced by at least one selected from OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 The alkyl group is preferably substituted with OH.

[0022] Embodiment 7. The compound according to Embodiment 3, wherein R 4 is an optionally substituted C 3-10 Cycloalkyl or optionally substituted C 3-10 Heterocycloalkyl, preferably optionally substituted C 3-6 Cycloalkyl or optionally substituted C 3-6 Heterocycloalkyl, more preferably optionally substituted C 4-5 Cycloalkyl or optionally substituted C 4-5 Heterocycloalkyl.

[0023] Embodiment 8. A compound according to Embodiment 7, wherein the heterocycloalkyl group is linked to the pyrazolopyrimidine core via a nitrogen atom from the heterocycloalkyl group.

[0024] Embodiment 9. The compound of Embodiment 7 or 8, wherein the heterocycloalkyl group is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

[0025] Embodiment 10. The compound according to embodiment 3, wherein R 4 is an optionally substituted -X 2 -C 3-10Cycloalkyl or optionally substituted -X 2 -C 3-10 Heterocycloalkyl, preferably optionally substituted -X 2 -C 3-6 Cycloalkyl or optionally substituted -X 2 -C 3-6 Heterocycloalkyl, more preferably optionally substituted -X 2 -C 4-5 Cycloalkyl or optionally substituted -X 2 -C 4-5 Heterocycloalkyl.

[0026] Embodiment 11. A compound according to any one of Embodiments 3 to 10, wherein X 2 NR 6 , preferably wherein R 6 H or C 1-3 Alkyl group, preferably methyl group.

[0027] Embodiment 12. A compound according to any one of Embodiments 7 to 11, wherein the cycloalkyl or heterocycloalkyl is substituted by at least one selected from OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 alkyl, each of which is optionally substituted, and wherein the groups are optionally substituted by C 1-6 The alkyl group is connected to the cycloalkyl or heterocycloalkyl group, preferably OH or via C 1-6 Alkyl or C 1-3 Alkyl-linked OH.

[0028] Embodiment 13. A compound according to any one of Embodiments 1 to 12, wherein R 3 is an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 1-6 Alkylamino or di-C 1-6 Alkylamino.

[0029] Embodiment 14. A compound according to any one of Embodiments 1 to 12, wherein R 3 is an optionally substituted C6 aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl or C 4-7 Heterocycloalkyl, or through X 1 C6 aryl, C5-6 Heteroaryl, C 4-7 Cycloalkyl or C 4-7 Heterocycloalkyl.

[0030] Embodiment 15. The compound of Embodiment 14, wherein the aryl group has the formula:

[0031]

[0032] in,

[0033] R 7 is independently selected at each occurrence from halogen, OH, OR 9 、CN、NO2、C(O)R 9 ,

[0034] C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0035] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2.

[0036] P(O)(OR 8 )2、B(OR 8 2. 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;

[0037] R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Heterocycloalkyl, C6 aryl and C 5-10 heteroaryl, or two R 8Together with their neighboring atoms, they form C 4-10 Heterocycloalkyl;

[0038] R 9 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl;

[0039] R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl; and

[0040] c is 0, 1, 2, 3, 4 or 5;

[0041] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0042] Embodiment 16. The compound according to embodiment 15, wherein R 7 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

[0043] Embodiment 17. The compound of Embodiment 14, wherein the aryl or heteroaryl group has the formula:

[0044]

[0045] in,

[0046] X 3 , X 4 , X 5 , X 6 and X 7 Each independently selected from N and CR 11 , where X 3 , X 4 , X 5 , X 6 and X 7 At most three of them are N, or two of them are adjacent X 3 , X 4, X 5 , X 6 and X 7 One of the is absent and the other is O, S, or NR 10 ;

[0047] R 8 , R 9 and R 10 As defined in embodiment 15; and

[0048] R 11 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、

[0049] C(O)R 9 、C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0050] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2.

[0051] P(O)(OR 8 )2、B(OR 8 2. 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;

[0052] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0053] Embodiment 18. The compound according to embodiment 17, wherein X 3 , X 4 , X 5 , X 6 and X 7 One of them is N, preferably X 4and X 6 one.

[0054] Embodiment 19. The compound according to embodiment 18, wherein X 4 N and X 3 , X 6 and X 7 Each is CH.

[0055] Embodiment 20. A compound according to any one of Embodiments 17 to 19, wherein X 5 CR 11 , and R 11 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

[0056] Embodiment 21. A compound according to Embodiment 14, wherein the cycloalkyl or heterocycloalkyl has the formula:

[0057]

[0058] in,

[0059] X 8 Selected from N and CR 11 ;

[0060] X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Each independently selected from O, NR 12 , SO2 and C(R 13 )2, where X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 At most two of them are or contain O, N or S, and / or where X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Up to 3 of X are absent to form a 4-, 5- or 6-membered ring, and / or X 8 , X 9 , X 10 , X 11 , X12 , X 13 and X 14 Two or three of them are bridged together by one to three additional bridging atoms, such as carbon atoms;

[0061] R 8 , R 9 and R 10 As defined in embodiment 15, and R 11 As defined in embodiment 17;

[0062] R 12 is independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)N(R 8 2. SO2R 9 SO2N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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; and

[0063] R 13 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、

[0064] C(O)R 9 、C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0065] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2.

[0066] P(O)(OR 8 )2、B(OR8 2. 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 two R 13 Together with their neighboring atoms, they form C 4-10 Cycloalkyl or C 4-10 Heterocycloalkyl;

[0067] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0068] Embodiment 22. The compound according to embodiment 21, wherein X 8 is N.

[0069] Embodiment 23. The compound according to Embodiment 21 or 22, wherein X 11 NR 12 .

[0070] Embodiment 24. The compound according to Embodiment 21 or 22, wherein X 11 C(R 13 )2.

[0071] Embodiment 25. A compound according to any one of Embodiments 21 to 24, wherein at least one R 13 independently selected at each occurrence from OH, OR 9 、C(O)N(R 8 )2、N(R 10 )C(O)R 9 、N(R 8 )2 and optionally substituted C 1-6 alkyl.

[0072] Embodiment 26. A compound according to any one of Embodiments 21 to 25, wherein X 12 Does not exist.

[0073] Embodiment 27. A compound according to any one of Embodiments 21 to 26, wherein X 9 and X 14 Does not exist.

[0074] Embodiment 28. A compound according to any one of Embodiments 1 to 27, wherein X 1 Does not exist.

[0075] Embodiment 29. A compound according to any one of Embodiments 1 to 27, wherein X 1 Exists and is NR 5 , preferably wherein R 5 For H.

[0076] Embodiment 30. A compound according to any one of Embodiments 1 to 29, wherein R 2 is an optionally substituted C6 aryl group or an optionally substituted C 5-6 Heteroaryl.

[0077] Embodiment 31. The compound according to embodiment 30, wherein R 2 Has the following formula:

[0078]

[0079] in,

[0080] X 15 , X 16 , X 17 , X 18 and X 19 Each independently selected from N and CR 11 , where X 15 , X 16 , X 17 , X 18 and X 19 At most three of them are N, or two of them are adjacent X 15 ,

[0081] X 16 , X 17 , X 18 and X 19 One of the is absent and the other is O, S, or NR 10 ;

[0082] Where R 10 As defined in embodiment 15, and R 11 As defined in embodiment 17; and

[0083] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0084] Embodiment 32. The compound according to embodiment 31, wherein X 15 , X 16 , X 17 , X 18 and X 19 Each is CR 11 .

[0085] Embodiment 33. The compound according to Embodiment 31 or 32, wherein X 15 CR 11 , where R 11 Selected from halogen and OR 9 .

[0086] Embodiment 34. A compound according to any one of Embodiments 31 to 33, wherein X 16 , X 17 , X 18 and X 19 Each is CR 11 , where R 11 For hydrogen.

[0087] Embodiment 35. The compound according to embodiment 33 or 34, wherein R 2 It is 2-methoxyphenyl or 2-chlorophenyl.

[0088] Embodiment 36. The compound according to embodiment 31, wherein X 15 , X 16 , X 17 , X 18 and X 19 One of them is N.

[0089] Embodiment 37. The compound according to embodiment 31, wherein X 16 is N or CH.

[0090] Embodiment 38. A compound according to any one of Embodiments 31 to 33 and 37, wherein X 17 CR 11 , and where R 11 is cyano, halogen, haloalkyl or OR 9 , preferably cyano.

[0091] Embodiment 39. The compound according to embodiment 38, wherein R 2 It is 4-cyanophenyl or 6-cyano-3-pyridyl.

[0092] Embodiment 40. A compound according to any one of Embodiments 1 to 39, wherein R 1 is an optionally substituted C6 aryl group.

[0093] Embodiment 41. A compound according to embodiment 40, wherein R 1 It is 4-chlorophenyl.

[0094] Embodiment 42. A compound according to Embodiment 1, wherein the compound is selected from Compounds 1 to 78 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 43. A compound according to Embodiment 42, wherein the compound is selected from Compounds 1 to 77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 44. The compound of Embodiment 42, wherein the compound is Compound 78, or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 45. A compound according to Embodiment 43, wherein the compound is selected from compounds 1-18, 20-31, 33-61, 63-68 and 70-77 or compounds 1-18, 20-29, 31, 36-61, 63-68 and 70-77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 46. A compound according to Embodiment 43, wherein the compound is selected from compounds 1-17, 20-22, 25-27, 37, 38, 42-46, 48-61, 63-68, 70-77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0099] Embodiment 47. A compound according to Embodiment 43, wherein the compound is selected from compounds 1-5, 7-11, 13-15, 21, 22, 27, 42, 43, 45, 50-58, 60, 61, 63, 64, 70(R), 70(S), 71(S), 72(R), 72(S) as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 48. A compound according to Embodiment 43, wherein the compound is selected from compounds 1, 2, 4, 7-9, 11, 13, 15, 21, 27, 43, 45, 50-53, 56-58, 60, 61, 63, 64, 70(R), 71(S), 72(R), 72(S) as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 49. A pharmaceutical composition comprising a compound as defined in any one of Embodiments 1 to 48, and a pharmaceutically acceptable carrier, diluent or excipient.

[0102] Embodiment 50. Use of a compound as defined in any one of Embodiments 1 to 48 or a pharmaceutical composition as defined in Embodiment 49 for the treatment of a disorder related to appetite or one of its complications, a disorder related to glucose regulation or one of its complications, a disorder related to fibrosis or one of its complications, a disorder related to metabolism or one of its complications, a disorder related to skin and hair growth and healing, a disorder related to the gastrointestinal tract, a disorder related to obesity or one of its complications, or a combination thereof.

[0103] Embodiment 51. The use according to embodiment 50, wherein the appetite-related disorder or one of its complications is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome and syndrome.

[0104] Embodiment 52. The use according to embodiment 50, wherein the disorder related to glucose regulation or one of its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

[0105] Embodiment 53. The use according to embodiment 50, wherein the fibrosis-related disorder or one of its complications is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrosis disorders (such as scleroderma), fibrosing kidney disease and chronic kidney disease.

[0106] Embodiment 54. The use according to embodiment 50, wherein the metabolism-related disorder or one of its complications is selected from metabolic syndrome and hyperlipidemia (e.g. hypertriglyceridemia, hypertriglyceridemia in the presence of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0107] Embodiment 55. The use according to embodiment 50, wherein the obesity-related disorder or one of its complications is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual disorders, degenerative arthritis, venous stasis ulcers, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate or gallbladder.

[0108] Embodiment 56. The use according to embodiment 50, wherein the disorder of the skin and hair is selected from the group consisting of alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids) and scleroderma.

[0109] Embodiment 57. The use according to embodiment 50, wherein the disorder related to the gastrointestinal tract is selected from constipation, irritable bowel syndrome and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0110] Embodiment 58. A method of treating a disorder selected from appetite-related disorders or complications thereof, glucose regulation-related disorders or complications thereof, fibrosis-related disorders or complications thereof, metabolism-related disorders or complications thereof, skin and hair growth and healing-related disorders, gastrointestinal-related disorders, obesity-related disorders or complications thereof, or a combination thereof, comprising administering to a subject in need thereof a compound as defined in any one of Embodiments 1 to 48 or a pharmaceutical composition as defined in Embodiment 49.

[0111] Embodiment 59. The method of embodiment 58, wherein the appetite-related disorder or complications thereof 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.

[0112] Embodiment 60. A method according to embodiment 58, wherein the condition related to glucose regulation or its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

[0113] Embodiment 61. The method of embodiment 58, wherein the fibrosis-related disorder or its complications are 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), fibrosing kidney disease and chronic kidney disease.

[0114] Embodiment 62. A method according to embodiment 58, wherein the metabolism-related disorder or its complications are selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the presence of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0115] Embodiment 63. The method of embodiment 58, 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 disorders, degenerative arthritis, venous stasis ulcers, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of liver, ovarian, cervical, uterine, breast, prostate or gallbladder malignancies.

[0116] Embodiment 64. The method of embodiment 58, wherein the disorder of the skin and hair is selected from the group consisting of alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

[0117] Embodiment 65. The method of embodiment 58, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0118] Other objects and features of the compounds, compositions, methods and uses of the present invention will become more apparent upon reading the non-limiting description of the following illustrative embodiments and examples, which should not be construed as limiting the scope of the present invention. DETAILED DESCRIPTION

[0119] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by those skilled in the art. However, the definitions of some of the terms and expressions used are provided below. If the definition of a term in a publication, patent, or 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 only used for the purpose of organization and should not be construed as limiting the disclosed subject matter.

[0120] The chemical structures described herein are drawn according to conventional standards. In addition, when a drawn 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 as part of the compound.

[0121] The terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting. It should be noted that, unless otherwise clearly specified in the content, the singular forms "a", "an" and "the" also include plural forms. Thus, for example, a composition containing "a compound" is also covered by a mixture of two or more compounds. It should also be noted that, unless otherwise clearly specified in the context, the term "or" is generally used in a sense including "and / or". In addition, with respect to the terms "including", "comprising", "having" 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 "comprising".

[0122] The term "about" or "approximately" means within an acceptable error range for a particular value determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" may mean within 1 or more than 1 standard deviation. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude of a value, preferably within 5 times, more preferably within 2 times. Where specific values ​​are described in the present application and claims, unless otherwise stated, the term "about" shall be presumed to mean within an acceptable error range for that specific value.

[0123] As used herein, the terms "compound", "compound described herein", "compound of the present application", "pyrazolopyrimidines", "pyrazolopyrimidine compounds" and equivalent expressions refer to the compounds described in the present application, for example, compounds covered by Structural Formula I, optionally with reference to any applicable embodiment, and also include exemplary compounds, such as compounds 1 to 78, their pharmaceutically acceptable salts, their tautomeric forms and isomers, and their solvates, esters and prodrugs (if applicable). When a zwitterionic form may exist, for practical purposes, the compound may be drawn as its neutral form, but it should be understood that the compound also includes its zwitterionic form. The embodiments herein may also exclude one or more of these compounds. The compound may be identified by its chemical structure or its chemical name. When the chemical structure conflicts with the chemical name, the chemical structure shall prevail.

[0124] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, tautomeric, and geometric (or conformational)) forms of the structure, as applicable; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers 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 stated, the compounds of the invention also include all possible tautomeric forms of the compounds shown, if any. The term also includes isotopically labeled compounds in which the atomic mass of one or more atoms is different from the most abundant atomic mass found in nature. Examples of isotopes that may 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 may also exist in unsolvated forms as well as solvated forms, including hydrated forms. The compounds may exist in a variety of 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 present invention.

[0125] When a particular enantiomer is preferred, in some embodiments, it can be provided in a form that is substantially free of the corresponding enantiomer, or it 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 the 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 a chiral salt, or prepared by asymmetric synthesis.

[0126] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of this specification, which are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc. within the scope of reasonable medical judgment, and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). These salts can be prepared in situ during the final separation and purification process of the compounds of this specification, or can be prepared separately by reacting the free base functional group of the compound with a suitable organic acid or inorganic acid (acid addition salt) or by reacting the acidic functional group of the compound with a suitable organic base or inorganic base (base addition salt).

[0127] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (including water and non-aqueous solvent molecules). The physical association may include hydrogen bonding. In some cases, the solvate will be able to separate, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates and other physiologically acceptable solvents, such as the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997)) 3 types of solvents described. Therefore, the compounds described herein also include each of their solvates and mixtures thereof.

[0128] As used herein, the expression "pharmaceutically acceptable ester" refers to an ester of a compound formed by the method of this specification sheet, which can be hydrolyzed in vivo, and includes those esters that are easily decomposed 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 (particularly alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, wherein 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 ethylsuccinates of hydroxy groups, and alkyl esters of acid groups. Other ester groups include sulfonates or sulfates.

[0129] The expression "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs of compounds formed by the methods of the present specification, which are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use. The term "prodrug" as used herein refers to such a compound, which can be converted in vivo by metabolic means (e.g., by hydrolysis) to obtain any compound depicted by the general formula of the present specification.

[0130] Abbreviations may also be used throughout the application, and unless otherwise indicated, such abbreviations are intended to have the meanings generally 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-butyloxycarbonyl) and Su or Suc (succinimide).

[0131] The number of carbon atoms in a hydrocarbon substituent can 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 When relating to a group that by definition contains one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), x and y define the minimum and maximum number of atoms, respectively, in the ring, including carbon atoms as well as heteroatoms.

[0132] 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, substituted forms of nitrogen, and any quaternized form of a basic nitrogen.

[0133] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group, which generally contains 1 to 20 carbon atoms. 1-8 The "alkyl" group 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 and the like.

[0134] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically containing 2 to 20 carbon atoms. 2-8 "Alkenyl" contains two to eight carbon atoms. Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0135] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically containing 2 to 20 carbon atoms. 2-8 "Alkynyl" contains two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0136] The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalent expressions refer to a group containing a saturated or partially unsaturated (non-aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including a spirocyclic (sharing one atom), a fused ring (sharing at least one bond) or a bridged ring (sharing two or more bonds) carbocyclic ring system, having three to fifteen ring members. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, and the like. The term "cycloalkyl" includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C 3-n "Cycloalkyl" refers to cycloalkyl groups having from 3 to the indicated "n" number of carbon atoms in the ring structure. Unless the number of carbon atoms is otherwise specified, "lower cycloalkyl" as used herein has at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0137] As used herein, the terms "heterocycloalkyl", "heterocyclyl" and the like are used interchangeably and refer to a chemically stable 3 to 7-membered monocyclic or 7-10-membered bicyclic heterocycloalkyl moiety that 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 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl). Heterocycloalkyl may be attached to its side group at any heteroatom or carbon atom to produce a chemically stable structure, and any ring atom may be optionally substituted. Examples of heterocycloalkyl include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithiophenyl, tetrahydrothiophenyl, thiomorpholinyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Thiazepine 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolizinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, etc. Heterocycloalkyl also includes groups in which the heterocycloalkyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolyl, 3H-indolyl, chromanyl, benzopyranyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl, wherein the attachment group or point of attachment is located on the heterocycloalkyl ring. The heterocycloalkyl may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclylalkyl group, wherein the alkyl and heterocyclyl portions are independently optionally substituted. 3-n "Heterocycloalkyl" refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms (including carbon atoms and heteroatoms) in the ring structure.

[0138] 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 encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0139] 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 6 to 15 ring members in total, wherein n is an integer from 1 to 3, wherein at least one ring in the system is aromatic, and wherein 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, azulenyl, anthracenyl, etc., which may carry 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 term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimide, naphthimide, fluorenyl, phenanthridinyl or tetrahydronaphthyl. 6-n "Aryl" refers to aromatic groups having from 6 to the indicated "n" number of atoms in the ring structure.

[0140] The term "heteroaryl", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refers to an aromatic group having 4n+2 conjugated π (pi) electrons, wherein n is an integer from 1 to 3 (e.g., having 5 to 18 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in the cyclic array); and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" is as defined above. A heteroaryl group can be a single ring, 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 groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2

[0013] The term "heteroaryl" refers to an alkyl radical substituted with a heteroaryl radical, wherein the alkyl radical and the heteroaryl radical are independently optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term "C 5-n "Heteroaryl" refers to heteroaryl groups having from 5 to the indicated "n" number of atoms (including carbon atoms and heteroatoms) in the ring structure.

[0141] The term "halogen" or "halo" denotes a halogen atom, ie a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0142] As described herein, the compounds of this specification may contain "optionally substituted" parts. In general, the term "substituted" refers to that one or more hydrogens of a specified part are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent 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 a specified group, the substituent may be the same or different at each position. The combination of substituents envisioned in this specification is preferably a combination that results in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to that when subjected to conditions that allow it to be produced, detected, and in certain embodiments, to be recovered, purified, and used for one or more purposes disclosed herein, the compound does not change substantially.

[0143] Examples of substituents include, but are not limited to, halogen (F, Cl, Br, I), OH, CO2H, alkoxy, oxo, thio, NO2, CN, CF3, CHF2, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocycloalkyl, dialkylamino, diarylamino, diheteroarylamino, dicycloalkylamino, diheterocycloalkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-cycloalkylamino, N-alkyl-N-heterocycloalkylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocycloalkyl, C(O)alkyl, C(O)alkenyl, C C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OC O2 aryl, OCO2 heteroaryl, OCO2 heterocycloalkyl, OC(O)NH2, OC(O)NH alkyl, OC(O)NH alkenyl, OC(O)NH alkynyl, OC(O)NH cycloalkyl, OC(O)NH aryl, OC(O)NH heteroaryl, OC(O)NH heterocycloalkyl, OP(O)(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, NHC(O) alkyl, NHC(O) alkenyl, NHC(O) alkynyl, NHC(O) cycloalkyl, NHC(O) aryl, NHC(O) heteroaryl, NHC(O) heterocycloalkyl, NHCO2 alkyl, NHCO2 alkenyl, NHCO2 alkynyl, NHCO2 cycloalkyl, NHCO2 aryl, NHCO2 heteroaryl, NHCO2 heterocycloalkyl, NHC(O)NH2, NHC(O)NH alkyl, NHC(O)NH alkenyl, NHC(O)NH alkenyl, NHC(O)NH cycloalkyl, NHC(O)NH aryl, NHC(O)NH heteroaryl, NHC(O)NH heterocycloalkyl, NHC(S)NH2, NHC(S)NH alkyl, NHC(S)NH alkenyl, NHC(S)NH alkynyl, NHC(S)NH cycloalkyl, NHC(S)NH aryl, NHC(S)NH heteroaryl,NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NH alkyl, NHC(NH)NH alkenyl, NHC(NH)NH alkenyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl, NHC(NH) alkyl, NHC(NH) alkenyl, NHC(NH) alkenyl, NHC(NH) cycloalkyl, NHC(NH) aryl, NHC(NH) heteroaryl, NHC(NH) heterocycloalkyl, C(NH)NH alkyl, C(NH)NH alkenyl, C(NH)NH alkynyl, C(NH)NH cycloalkyl, C(NH)NH aryl, C(NH)NH heteroaryl, C(NH)NH heterocycloalkyl, S(O) alkyl, S(O) alkenyl, S(O) alkynyl, S(O) cycloalkyl, S(O) aryl, S(O)2 alkyl, S(O) 2 alkenyl, S(O)2 alkynyl, S(O)2 cycloalkyl, S(O)2 aryl, S(O) heteroaryl, S(O) heterocycloalkyl, SO2NH2, SO2NH alkyl, SO2NH alkenyl, SO2NH alkynyl, SO2NH cycloalkyl, SO2NH aryl, SO2NH heteroaryl, SO2NH heterocycloalkyl, NHSO2 alkyl, NHSO2 alkenyl, NHSO2 alkynyl, NHSO2 cycloalkyl, NHSO2 aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl or methylthiomethyl. Each of these substituents may be further substituted if possible.

[0144] Thus, this document relates to pyrazolopyrimidine 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 that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Thus, the following embodiments exist alone or in combination where applicable.

[0145] The compounds of the present invention have a pyrazolopyrimidine core structure to which are attached defined substituents. Exemplary compounds as defined herein are shown by general formula I:

[0146]

[0147] in,

[0148] R1 and R 2 are each independently selected from optionally substituted C 6-10 Aryl and optionally substituted C 5-10 miscellaneous

[0149] Aryl;

[0150] R 3 Selected from optionally substituted C 1-12 Alkyl, optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted C 6-10 Aryl and optionally substituted C 5-10 Heteroaryl, optionally substituted -X 1 -C 3-10 Cycloalkyl, optionally substituted -X 1 -C 3-10 Heterocycloalkyl, optional

[0151] Replaced by -X 1 -C 6-10 Aryl and optionally substituted -X 1 -C 5-10 heteroaryl;

[0152] R 4 is selected from NH2, optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl;

[0153] X 1 Selected from O and NR 5 , where R 5 is H or optionally substituted C 1-6 alkyl; and

[0154] X 2 Selected from O and NR 6 , where R 6 is H or optionally substituted C 1-6 alkyl;

[0155] or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0156] For example, R 1It may be an optionally substituted C6 aryl group, such as 4-chlorophenyl.

[0157] In some instances, R 4 is NH2. Alternatively, R 4 Selected from optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl.

[0158] In some instances, R 4 is an optionally substituted C 1-12 Alkoxy, preferably optionally substituted C 1-6 Alkoxy, more preferably optionally substituted C 1-4 In other examples, R 4 is an optionally substituted C 1-12 Alkylamino or C 1-12 dialkylamino, preferably optionally substituted C 1-6 Alkylamino or C 1-6 dialkylamino, more preferably optionally substituted C 1-4 Alkylamino or C 1-4 For example, the alkyl or alkoxy group is preferably replaced by one or more selected from OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 The alkyl group is preferably substituted with OH.

[0159] In yet other embodiments, R 4 is an optionally substituted C 3-10 Cycloalkyl or optionally substituted C 3-10 Heterocycloalkyl, preferably optionally substituted C 3-6 Cycloalkyl or optionally substituted C 3-6 Heterocycloalkyl, more preferably optionally substituted C 4-5 Cycloalkyl or optionally substituted C 4-5 Heterocycloalkyl. For example, the heterocycloalkyl is connected to the pyrazolopyrimidine core via a nitrogen atom from the heterocycloalkyl. In one embodiment, the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

[0160] In a further example, R 4 is an optionally substituted -X 2 -C 3-10 Cycloalkyl or optionally substituted -X 2 -C 3-10 Heterocycloalkyl, preferably optionally substituted -X 2 -C 3-6 Cycloalkyl or optionally substituted -X 2 -C 3-6 Heterocycloalkyl, more preferably optionally substituted -X 2 -C 4-5 Cycloalkyl or optionally substituted -X 2 -C 4-5 Heterocycloalkyl. 2 NR 6 When R 6 H or C 1-3 Alkyl group, preferably methyl group.

[0161] R 4 The cycloalkyl or heterocycloalkyl present in the 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 alkyl, each of which is optionally substituted, and wherein the groups are optionally substituted by C 1-6 The alkyl group is connected to the cycloalkyl or heterocycloalkyl group, preferably OH or via C 1-6 Alkyl or through C 1-4 Alkyl or C 1-3 Alkyl-linked OH.

[0162] In some instances, R 3 It may be an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 1-6 Alkylamino or di-C 1-6 Alkylamino.

[0163] In other instances, R 3 is an optionally substituted C6 aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl or C 4-7 Heterocycloalkyl, or through X 1 C6 aryl, C 5-6 Heteroaryl, C4-7 Cycloalkyl or C 4-7 Heterocycloalkyl.

[0164] In some instances, R 3 is or contains an aryl group of the formula:

[0165]

[0166] in,

[0167] R 7 is independently selected at each occurrence from halogen, OH, OR 9 、CN、NO2、C(O)R 9 ,

[0168] C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0169] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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;

[0170] R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Heterocycloalkyl, C6 aryl and C 5-10 heteroaryl, or two R 8 With it

[0171] Their neighboring atoms together form C 4-10Heterocycloalkyl;

[0172] R 9 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl; and

[0173] R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl; and

[0174] c is 0, 1, 2, 3, 4, or 5;

[0175] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0176] Preferably, R 7 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

[0177] Or, R 3 is or contains an aryl or heteroaryl group of the formula:

[0178]

[0179] in,

[0180] X 3 , X 4 , X 5 , X 6 and X 7 Each independently selected from N and CR 11 , where X 3 , X 4 , X 5 , X 6 and X 7 At most three of them are N, or two of them are adjacent X 3 , X 4 , X 5 , X 6 and X 7One of the is absent and the other is O, S, or NR 10 ;

[0181] R 8 , R 9 and R 10 as defined herein; and

[0182] R 11 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、C(O)R 9 ,

[0183] C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0184] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2.

[0185] P(O)(OR 8 )2、B(OR 8 2. 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;

[0186] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0187] In some instances, X 3 , X 4 , X 5 , X 6 and X 7 One is N, preferably X 4 and X 6 One, X 4 N and X 3 , X 6and X 7 Each is CH. In some embodiments, X 5 CR 11 , and R 11 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

[0188] On the other hand, when R 3 When it is or contains a cycloalkyl group or a heterocycloalkyl group, the cycloalkyl group or the heterocycloalkyl group may have the following formula:

[0189]

[0190] in,

[0191] X 8 Selected from N and CR 11 ;

[0192] X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Each independently selected from O, NR 12 , SO2 and C(R 13 )2, where X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 At most two of them are or contain O, N or S, and / or where X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Up to 3 of X are absent to form a 4-, 5- or 6-membered ring, and / or X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Two or three of them are bridged together by one to three additional bridging atoms, such as carbon atoms;

[0193] R 8 , R 9 , R 10 and R 11As defined herein;

[0194] R 12 is independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)N(R 8 2. SO2R 9 SO2N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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; and

[0195] R 13 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、C(O)R 9 ,

[0196] C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 ,

[0197] N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2.

[0198] P(O)(OR 8 )2、B(OR 8 2. 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 two R 13 Together with their neighboring atoms, they form C4-10 Cycloalkyl or C 4-10 Heterocycloalkyl;

[0199] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0200] In some preferred embodiments, X 8 is N. In some preferred embodiments, X 11 NR 12 or X 11 C(R 13 ) 2. In other examples, X 12 does not exist, and / or X 9 and X 14 Does not exist.

[0201] In some examples of the compounds, at least one R 13 independently selected at each occurrence from OH, OR 9 、C(O)N(R 8 )2、N(R 10 )C(O)R 9 、N(R 8 )2 and optionally substituted C 1-6 alkyl.

[0202] The presence of group R 3 Can include X 1 Connector, such as X 1 Can be O or NR as defined above 5 , preferably X 1 NR 5 And R 5 is H. In other examples, X 1 Does not exist.

[0203] Some compounds of formula I, R 2 The group is an optionally substituted C6 aryl group or an optionally substituted C 5-6 Heteroaryl. For example, R 2 It may be a functional group of the formula:

[0204]

[0205] in,

[0206] X 15 , X 16 , X 17 , X 18 and X 19 Each independently selected from N and CR 11 , where X 15 , X 16 , X17 , X 18 and X 19 At most three of them are N, or two of them are adjacent X 15 ,

[0207] X 16 , X 17 , X 18 and X 19 One of the is absent and the other is O, S, or NR 10 ;

[0208] Where R 10 and R 11 as defined herein; and

[0209] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

[0210] In some instances, X 15 , X 16 , X 17 , X 18 and X 19 Each is CR 11 For example, X 15 CR 11 , where R 11 Selected from halogen and OR 9 , and / or X 16 , X 17 , X 18 and X 19 Each is CR 11 , where R 11 In one embodiment, R 2 is 2-methoxyphenyl or 2-chlorophenyl. 15 , X 16 , X 17 , X 18 and X 19 At least one of is N. In some compounds, X 16 It can be N or CH. In the same or other compounds, X 17 Can be CR 11 , where R 11 is cyano, halogen, haloalkyl or OR 9 , preferably cyano. For example, R 2 It may be 4-cyanophenyl or 6-cyano-3-pyridyl.

[0211] Non-limiting examples of compounds of Formula I include:

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

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

[0226] For example, the compound can be compound 78, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Alternatively, the compound can be selected from compounds 1 to 77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. For example, preferred examples can be selected from compounds 1-18, 20-31, 33-61, 63-68, and 70-77, or preferably selected from compounds 1-18, 20-29, 31, 36-61, 63-68, and 70-77, or more preferably selected from compounds 1-17, 20-22, 25-27, 37, 38, 42-46, 48-61, 63-68, 70-77, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Alternatively, the compound is selected from compounds 1-5, 7-11, 13-15, 21, 22, 27, 42, 43, 45, 50-58, 60, 61, 63, 64, 70(R), 70(S), 71(S), 72(R), 72(S) as defined herein, or selected from compounds 1, 2, 4, 7-9, 11, 13, 15, 21, 27, 43, 45, 50-53, 56-58, 60, 61, 63, 64, 70(R), 71(S), 72(R), 72(S), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0227] These compounds can be prepared by conventional chemical synthesis, for example, by the chemical synthesis described in the Examples section below. It will be appreciated by the skilled artisan that other methods for synthesizing compounds of the general formula herein are obvious to one of ordinary skill in the art. In addition, the various synthetic steps can be performed in an alternating sequence or order to obtain the desired compound.

[0228] The compounds defined herein may be formulated into pharmaceutical compositions for administration to a subject, typically in admixture with at least one pharmaceutically acceptable carrier, diluent or excipient.

[0229] The expression "pharmaceutically acceptable carrier, diluent or excipient" and equivalent expressions refer to a non-toxic carrier, diluent or excipient that does not destroy the pharmacological activity of the compound formulated therewith.

[0230] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic and intralesional injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0231] For example, solid dosage forms for oral administration include capsules, tablets, pills and granules.In a preferred alternative, the composition is a solid dosage form comprising a compound as described herein and at least one binder as defined in the preceding paragraph, the binder preferably comprising microcrystalline cellulose.

[0232] Pharmaceutically acceptable carriers, diluents or adjuvants that can be used in the oral compositions of the present disclosure include, but are not limited to, adhesives, sweeteners, disintegrants, diluents, flavoring agents, coating agents, preservatives, lubricants and / or polymers. Examples of adhesives include cellulose-based materials, such as microcrystalline cellulose and carboxymethyl cellulose, and other adhesives, 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, methylcellulose, polyvinyl pyrrolidone, 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 flavoring. Coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. The example of adjuvant may also include polymers selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate-succinate (HPMCAS) and mixtures thereof.

[0233] The compositions of the present invention can also be used as fillers in soft-filled and hard-filled capsules. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the field of pharmaceutical formulation. They can optionally contain sunscreens and can also belong to compositions that release the active ingredient only in or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The composition can also be in a microencapsulated form containing one or more excipients as described above.

[0234] 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 form may also contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, these oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, surfactants, sweeteners, flavoring agents, and aromatics.

[0235] Injectable products, such as sterile injectable aqueous or oily suspensions, can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable products can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution USP and isotonic sodium chloride solution. In addition, routine use of sterile fixed oils as solvents or suspension media. For this reason, any soft fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0236] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0237] In order to prolong the effect of the compound provided, it is generally desired to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which may depend on crystal size and crystalline form. Alternatively, the delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. The injectable depot form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of compound release can be controlled according to the ratio of the compound to the polymer and the properties of the specific polymer used.

[0238] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0239] The dosage form of the compound for topical or transdermal administration of this specification includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any required preservative or buffer that may be needed. Ophthalmic preparations, ear drops and eye drops are also considered within the scope of this specification. In addition, this specification also contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or being dispersed in the appropriate medium. Absorption enhancers can also be used to increase the flux of compounds through the skin. Rate control can be provided by providing a rate control membrane or by dispersing the compound in a polymer matrix or a gel to control the rate.

[0240] 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 art of pharmaceutical formulation and can be prepared as solutions in saline with the use of benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0241] The amount of compound that may be combined with the carrier materials to produce a single dosage composition will vary depending upon the patient being treated and the particular mode of administration.

[0242] 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 being that is being sought, for example, by a researcher or clinician. In addition, the term "therapeutically effective amount" refers to any amount that results in treatment, cure, prevention or amelioration of a disease, condition or its symptoms, or a decrease in the rate of progression of a disease or condition, as compared to a corresponding subject not receiving that amount. The term also includes within its scope amounts that are effective to enhance normal physiological function.

[0243] As used herein, the terms "treat" and "treat" refer to reversing, alleviating a disease or condition as described herein or one or more symptoms thereof, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0244] As used herein, the term "patient" or "subject" refers to an animal, such as a mammal. Thus, a subject may refer to, for example, a mouse, rat, dog, cat, horse, cow, pig, guinea pig, primates including humans, etc. Preferably, the subject is a human.

[0245] The compounds of the present invention can be used to treat diseases and conditions that require inhibition of cannabinoid receptor CB1. Therefore, this article relates to the use of the compounds of the present invention for treating diseases or conditions defined herein, the use of the compounds of the present invention in the preparation of drugs for treating diseases or conditions defined herein, compounds defined herein for treating the diseases or conditions, and methods for treating diseases or conditions defined herein, including administering one of the compounds of the present invention to a subject in need. Such diseases and conditions may generally be associated with diabetes and metabolic disorders (e.g., metabolic syndrome). Preferably, the compound selectively targets CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophage, pancreatic beta cell, and gastrointestinal tract), without or primarily interacting with CB1 receptors in brain tissue, thereby avoiding or reducing side effects associated with CNS.

[0246] The effects of the compounds of the invention may include reduced food intake, reduced body weight, reversal of insulin and leptin resistance, reversal of hepatic steatosis (fatty liver), and improvement of dyslipidemia. Examples of diseases and conditions to be treated include obesity, diabetes (type I or II), nonalcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LepR) deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl (BB) syndrome, Syndrome, dyslipidemia that is prone to develop into arteriosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases of the skin, liver, lung or kidney, such as idiopathic pulmonary fibrosis (IPF), progressive fibrosing interstitial lung disease, Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis, renal fibrosis, scleroderma and gout. In addition, the disease of skin includes reducing scarring (scars, keloids) and alopecia, particularly the alopecia associated with male pattern baldness and metabolic syndrome. For example, the comorbidity of obesity is selected from metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual disorders, degenerative arthritis, venous stasis ulcers, hypoventilation syndrome, sleep apnea, snoring, asthma, obese asthma, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and the incidence of liver, ovarian, cervical, uterine, breast, prostate or gallbladder malignancies increases. In preferred examples, the disease or disorder includes diabetes (type I or II), obesity and non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis). Examples of comorbidities of diabetes (e.g., type I) include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0247] Diseases, disorders and conditions to be treated, including those described above, can be classified into various categories, and certain conditions can also be present simultaneously in the same given subject. Examples of categories include disorders related to appetite and their complications, disorders related to glucose regulation and their complications, disorders related to fibrosis and their complications, disorders related to metabolism and their complications, disorders related to skin and hair growth and healing, disorders related to the gastrointestinal tract, and disorders related to obesity and their complications.

[0248] Examples of appetite-related disorders and their complications include, but are not limited to, Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and syndrome.

[0249] Examples of disorders related to glucose regulation and their complications include, but are not limited to, type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and related nephropathy, neuropathy, and retinopathy.

[0250] 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 fibrotic disorders (e.g., nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrosing kidney disease, skin fibrotic disorders (e.g., scleroderma), and chronic kidney disease.

[0251] Examples of metabolic-related disorders and their complications include, but are not limited to, metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0252] Examples of obesity-related disorders and their complications include, but are not limited to, sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual disorders, degenerative arthritis, venous stasis ulcers, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breast, prostate, or gallbladder.

[0253] Examples of disorders of the skin and hair include hair loss (male pattern baldness and hair loss associated with metabolic syndrome), excessive scarring (scars and keloids), scleroderma, and the like.

[0254] Examples of gastrointestinal tract-related disorders include constipation, irritable bowel syndrome, inflammatory bowel syndrome including ulcerative colitis and Crohn's disease, among others.

[0255] Other disorders may also benefit from the compounds of the invention, including muscle wasting disorders, including muscular dystrophies (such as Duchenne muscular dystrophy (DMD)), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy, and the like.

[0256] The solid compounds and compositions of the present invention may also be used in methods of preventing or reversing adipose tissue deposition in a subject, which is expected to help reduce the incidence or severity of obesity and, in turn, the incidence or severity of related comorbidities.

[0257] This specification provides a method for treating a disease (as described herein) of a subject, comprising administering a compound or composition of this specification to a subject determined to be in need. The determination of patients who need to treat the above-mentioned disease is completely within the capabilities and knowledge of those skilled in the art. The medical field knows certain methods for determining patients with a risk of the above-mentioned disease that can be treated by the method of the present invention, such as family history, and the presence of risk factors associated with the occurrence of the disease state in the patient being tested. Clinicians in the art can easily determine such candidate patients by utilizing, for example, clinical trials, physical examinations, medical history / family history, and genetic testing.

[0258] The method for evaluating the efficacy of treatment in a subject includes determining the pre-treatment symptoms of the disease by methods known in the art, and then administering a therapeutically effective amount of the compound of the present specification to the subject. After a suitable period of time (e.g., 1 week, 2 weeks, 1 month, 6 months) after the compound is administered, the symptoms of the disease are reassessed. The adjustment (e.g., reduction) of the symptoms of the disease and / or biomarkers indicates the efficacy of the treatment. The symptoms and / or biomarkers of the disease can be regularly determined throughout the treatment process. For example, the symptoms and / or biomarkers of the disease can be checked every few days, weeks, or months to assess the further efficacy of the treatment. The reduction of the symptoms and / or biomarkers of the disease indicates that the treatment is effective.

[0259] The pharmaceutical compositions provided herein are preferably suitable for oral administration. Such preparations can be administered with or without food. The compositions are formulated into unit dosage forms for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to physically discrete dosage units suitable for patients to be treated. However, it should be understood that the total daily dosage of the solid dispersions and compositions disclosed herein will be determined by the attending physician within the scope of reasonable medical judgment.

[0260] The amount of the composition that can be included in a single dosage form will vary according to the patient to be treated (e.g., children and adults, etc.) and the specific compound included in the composition. The provided composition can be formulated so that a total daily dose of, for example, 0.01 to 100 mg / kg body weight / day or 0.01 to 20 mg / kg body weight / day can be administered to patients receiving these compositions. A single-dose composition may contain such an amount, or the total daily dose may be divided into multiple dosage forms for administration, for example, once, twice, or three times a day. For example, a single dose may contain 5 to 500 mg or 20 to 200 mg of active ingredient. The treatment regimen may include administering a total amount of about 10 mg to about 1000 mg of the present specification to a patient in a single dose or divided into multiple doses every day.

[0261] It should be understood that the total daily dose of the compound will be determined by the attending physician within the scope of sound medical judgment. For example, the specific dose or treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the disease or disorder.

[0262] According to the disease to be treated or illness, additional therapeutic agents can also be present in the compositions of the present disclosure or be co-administered individually. The non-limiting examples of additional therapeutic agents that can be used in combination with the solid dispersion of the present invention and the preparation include antidiabetic agents, cholesterol-lowering agents, anti-inflammatory agents, antimicrobial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins or anti-angiogenic hyperplasia compounds. Other treatments or interventions can also be supplemented for the treatment, such as surgery, radiotherapy (for example, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes), biological response modifiers (for example, interferon, interleukin, tumor necrosis factor (TNF)) and agents for alleviating the adverse reactions of the compounds of the present invention or co-administered components.

[0263] The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0264] Example

[0265] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.These examples will be better understood with reference to the accompanying drawings.

[0266] Unless otherwise stated, all numerals used in this specification and claims to represent the amount of ingredients, reaction conditions, concentrations, properties, stability, etc. should be understood to be modified by the term 'about' in all cases. At least, each numerical parameter should be interpreted at least according to the number of reported significant figures and applying common rounding techniques. Therefore, unless otherwise indicated, the numerical parameters mentioned in this specification and the attached claims are approximate values, which can vary according to the properties attempted to be obtained. Although the numerical ranges and parameters of the wide range of embodiments are approximate values, the numerical values ​​listed in the specific examples are reported as accurately as possible. However, any numerical value essentially contains certain errors caused by differences in experiments, test measurements, statistical analysis, etc.

[0267] Example 1 - Preparation of starting materials

[0268] (i) Preparation of 1-(trifluoromethylsulfonyl)piperazine

[0269] A solution of tert-butyl 4-(trifluoromethylsulfonyl)piperazine-1-carboxylate (200 mg, 628.3 μmol, 1 eq) in hydrochloric acid / dioxane (4 M, 6.0 mL, 38.2 eq) was stirred for 1 h at 25° C. The mixture was concentrated to give 1-(trifluoromethylsulfonyl)piperazine (130 mg as HCl salt) as a white solid.

[0270] (ii) Preparation of 4-methylpiperidine-4-carboxamide

[0271] A solution of tert-butyl 4-methyl-4-carboxamidepiperidine-1-carboxylate (200 mg, 628.3 μmol, 1 eq) in hydrochloric acid / dioxane (4 M, 6.0 mL, 38.2 eq) was stirred for 1 h at 25° C. The mixture was concentrated to give the product 4-methylpiperidine-4-carboxamide (130 mg as HCl salt) as a white solid.

[0272] (iii) Preparation of 1-methylsulfonylpiperazine

[0273] Step 1: To a solution of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (1 g, 4.49 mmol, 1 eq.) in dichloromethane (10 mL) was added methylsulfonyl methanesulfonate (1.56 g, 8.98 mmol, 2 eq.) and triethylamine (681 mg, 6.74 mmol, 0.94 mL, 1.5 eq.) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was washed with water (30 mL) and extracted with dichloromethane 90 mL (30 mL×3). The combined organic layer was washed with brine 60 mL (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-methylsulfonylpiperazine-1-carboxylate (1 g) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ = 3.48-3.33 (m, 4H), 3.14-3.00 (m, 4H), 2.87 (s, 3H), 1.41 (s, 9H).

[0274] Step 2: To a solution of tert-butyl 4-methylsulfonylpiperazine-1-carboxylate (800 mg, 3.03 mmol, 1 eq) from step 1 in dioxane (2 mL) was added hydrochloric acid / dioxane (4 M, 4 mL, 5.3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1-methylsulfonylpiperazine (530 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.28 (s, 2H), 3.40-3.32 (m, 4H), 3.18 (s, 4H), 2.98 (s, 3H).

[0275] (iv) Preparation of 2-(azetidin-3-yl)acetamide

[0276] Step 1: To a solution of 2-(1-tert-butyloxycarbonylazetidin-3-yl)acetic acid (1 g, 4.65 mmol, 1 eq.) in N,N-dimethylformamide (10 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 2.65 g, 6.97 mmol, 1.5 eq.) and N,N-diisopropylethylamine (2.10 g, 16.26 mmol, 2.83 mL, 3.5 eq.). The mixture was stirred at 25° C. for 0.5 h. Ammonium chloride (547 mg, 10.22 mmol, 2.2 eq.) was added to the mixture, and the mixture was stirred at 25° C. for 15 h. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate 150 mL (50 mL×3). The combined organic layer was washed with 100 mL of brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 40g The resulting mixture was purified by silica gel flash column (gradient of 0 to 100% ethyl acetate in petroleum ether at a flow rate of 30 mL / min) and fractions were concentrated under reduced pressure to give tert-butyl 3-(2-amino-2-oxo-ethyl)azetidine-1-carboxylate (580 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.48-6.69 (m, 2H), 3.90 (s, 2H), 3.49 (s, 2H), 2.77-2.67 (m, 1H), 2.34 (d, J = 8.0Hz, 2H), 1.36 (s, 9H).

[0277] Step 2: A solution of tert-butyl 3-(2-amino-2-oxo-ethyl)azetidine-1-carboxylate (550 mg, 2.57 mmol, 1 eq) from step 1 in hydrochloric acid / dioxane (4 M, 5 mL, 7.79 eq) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2-(azetidin-3-yl)acetamide (400 mg) as a yellow oil.

[0278] (v) Preparation of N-(4-methyl-4-piperidinyl)acetamide

[0279] Step 1: Acetyl chloride (439.55 mg, 5.60 mmol, 399.59 μL, 1.2 equiv) was added dropwise to a solution of 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1 g, 4.67 mmol, 1 equiv) and triethylamine (708 mg, 7.00 mmol, 0.97 mL, 1.5 equiv) in dichloromethane (10 mL) at 0 ° C. After addition, the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mLx2). The combined organic layer was washed with a saturated solution of sodium bicarbonate (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 20g Purification was performed on a silica gel flash column with 0 to 10% methanol in dichloromethane at a flow rate of 30 mL / min. Fractions were concentrated under reduced pressure to give 4-acetamido-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.13 g) as a light yellow oil.

[0280] Step 2: A solution of 4-acetamido-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.37 g, 1.44 mmol, 1 eq) from step 1 in HCl / dioxane (4 M, 4 mL, 11.08 eq) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give N-(4-methyl-4-piperidinyl)acetamide (270 mg as HCl salt) as a white solid, which was used directly in the next step without further purification.

[0281] (vi) Preparation of 2-[(3R)-pyrrolidin-3-yl]acetamide

[0282] Step 1: To a solution of 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid (1 g, 4.36 mmol, 1 eq.) in N,N-dimethylformamide (10 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 2.49 g, 6.54 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.97 g, 15.27 mmol, 2.66 mL, 3.5 eq.). The mixture was stirred at 25° C. for 0.5 h. To the mixture was then added ammonium chloride (513 mg, 9.60 mmol, 2.2 eq.), and the mixture was stirred at 25° C. for 15 h. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate 150 mL (50 mL×3). The combined organic layer was washed with 100 mL of brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 40g The resulting product was purified by silica gel flash column (gradient with 0 to 100% ethyl acetate in petroleum ether at a flow rate of 30 mL / min) and the solution was concentrated under reduced pressure to give tert-butyl (3R)-3-(2-amino-2-oxo-ethyl)pyrrolidine-1-carboxylate (800 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.52-6.60 (m, 2H), 3.45-3.36 (m, 1H), 3.23-3.09 (m, 1H), 2.82 (t, J = 9.2Hz, 1H), 2 .45-2.30(m,1H),2.19-2.06(m,2H),1.97-1.82(m,1H),1.55-1.45(m,1H),1.39(s,9H),1.31-1.21(m,2H).

[0283] Step 2: A solution of (3R)-tert-butyl 3-(2-amino-2-oxo-ethyl)pyrrolidine-1-carboxylate (800 mg, 3.50 mmol, 1 eq) from step 1 in hydrogen chloride / dioxane (4 M, 8 mL, 9.13 eq) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2-[(3R)-pyrrolidin-3-yl]acetamide (500 mg as HCl salt) as a yellow oil.

[0284] (vii) Preparation of 2-[(2R)-azetidin-2-yl]acetic acid

[0285] To a solution of 2-[(2R)-1-tert-butoxycarbonylazetidin-2-yl]acetic acid (50 mg, 0.23 mmol, 1 eq) in dichloromethane (1.5 mL) was added trifluoroacetic acid (6.8 mmol, 0.5 mL, 29.07 eq), and the mixture was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give the product 2-[(2R)-azetidin-2-yl]acetic acid (53 mg as TFA salt) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 13.07-12.75 (m, 1H), 4.50 (m, 1H), 3.88-3.76 (m, 1H), 3.74-3. 64(m,1H),2.95-2.82(m,1H),2.78-2.69(m,1H),2.40-2.31(m,1H),2.22-2.09(m,1H).

[0286] (viii) Preparation of N-ethyl-2-(methylamino)acetamide

[0287] Step 1: A mixture of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (3 g, 15.86 mmol, 1 eq.), N,N-diisopropylethylamine (6.15 g, 47.57 mmol, 8.29 mL, 3 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 7.23 g, 19.03 mmol, 1.2 eq.) in N,N-dimethylformamide (15 mL) was stirred at 25° for 30 min, and then ethylamine hydrochloride (2.59 g, 31.71 mmol, 2 eq.) was added to the mixture, and the mixture was stirred at 25° C. for 3.5 hours. The reaction mixture was washed with water (200 mL) and extracted with ethyl acetate 200 mL (100 mL×2). The combined organic layer was washed with 200 mL of brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 40g The reaction mixture was purified by silica gel flash column with a gradient of 0 to 65% ethyl acetate in petroleum ether at a flow rate of 40 mL / min. Fractions were concentrated under reduced pressure to give tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]-N-methyl-carbamate (0.6 g) as a light yellow solid.

[0288] Step 2: A mixture of N-[2-(ethylamino)-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (0.58 g, 2.68 mmol, 1 eq.) from step 1 in hydrogen chloride / dioxane (5 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give N-ethyl-2-(methylamino)acetamide (409 mg, crude, HCl salt) as a white solid.

[0289] (ix) Preparation of (3S)-piperidine-3-carboxamide

[0290] A mixture of (3S)-tert-butyl 3-carbamoylpiperidine-1-carboxylate (1 g, 4.38 mmol, 1 eq) and trifluoroacetic acid (4.62 g, 40.52 mmol, 3 mL, 9.25 eq) in dichloromethane (9 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound (3S)-piperidine-3-carboxamide (1 g, 4.13 mmol, TFA salt) as a white solid, which was used directly in the next step without further purification.

[0291] (x) Preparation of 4-ethoxypiperidine-4-carboxamide

[0292] Step 1: 1-tert-Butyloxycarbonyl-4-hydroxy-piperidine-4-carboxylic acid (1 g, 4.1 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL), then potassium carbonate (1.7 g, 12.2 mmol, 3 eq) and benzyl bromide (32.6 mmol, 3.9 mL, 8 eq) were added and the resulting mixture was stirred at 25 °C for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate 1: 1) to give O-4-benzyl O-1-tert-butyl 4-hydroxypiperidine-1,4-dicarboxylate (1.2 g, 3.6 mmol) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ=7.50-7.29(m,5H),5.21(s,2H),4.05-3.85(m,2H),3.24-3.05(m,2H),2.02-1.92(m,2H),1.59(br d,J=12.1Hz,2H),1.45(s,9H).

[0293] Step 2: Sodium hydride (286 mg, 7.2 mmol, 60% purity, 2 equivalents) was added to a solution of O-4-benzyl O-1-tert-butyl 4-hydroxypiperidine-1,4-dicarboxylate (1.2 g, 3.6 mmol, 1 equivalent) in tetrahydrofuran (15 mL) from step 1, and the mixture was stirred at 25 ° C for 0.5 hours. Then, iodoethane (1.7 g, 10.7 mmol, 0.86 mL, 3 equivalents) was added dropwise, and the resulting mixture was stirred at 60 ° C for 15 hours. The mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (2x50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate 1:1) to give O-4-benzyl O1-tert-butyl 4-ethoxypiperidine-1,4-dicarboxylate (700 mg) as a colorless oil. 1 H NMR(400MHz, CDCl3)δ=7.44-7.27(m,5H),5.17(s,2H),3.87-3.62(m,2H),3.38-3.3 2(m,2H),3.25-3.09(m,2H),1.91-1.86(m,4H),1.43(s,9H),1.16(t,J=7.0Hz,3H).

[0294] Step 3: A mixture of O-4-benzyl O-1-tert-butyl 4-ethoxypiperidine-1,4-dicarboxylate (700 mg, 1.9 mmol, 1 equivalent) and 10% palladium on carbon (100 mg) in ethanol (10 mL) was degassed and purged with hydrogen three times, and then the mixture was stirred at 25 ° C for 15 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (dichloromethane: methanol 3: 1) to give 1-tert-butoxycarbonyl-4-ethoxy-piperidine-4-carboxylic acid (420 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 3.79-3.51 (m, 2H), 3.40-3.36 (m, 2H), 3.04 (br d, J = 2.2Hz, 2H), 1.85-1.59 (m, 4H), 1.39 (s, 9H), 1.22-0.98 (m, 3H).

[0295] Step 4: 1-tert-Butyloxycarbonyl-4-ethoxy-piperidine-4-carboxylic acid (420 mg, 1.5 mmol, 1 eq.) from step 3, ammonium chloride (181 mg, 3.4 mmol, 2.2 eq.) and 1-hydroxybenzotriazole (311 mg, 2.3 mmol, 1.5 eq.) were added to a round bottom flask equipped with a magnetic stir bar. The solid mixture was dissolved in N,N-dimethylformamide (5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (442 mg, 2.3 mmol, 1.5 eq.) was added, and N,N-diisopropylethylamine (437 mg, 3.4 mmol, 0.59 mL, 2.2 eq.) was added dropwise. The resulting solution was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, then dissolved in 30 mL of dichloromethane, washed with 30 mL of 10% citric acid, 15 mL of saturated sodium bicarbonate, 15 mL of brine, and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give 4-carbamoyl-4-ethoxy-piperidine-1-carboxylic acid tert-butyl ester (396 mg, 1.5 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.95 (s, 1H), 7.37-6.98 (m, 2H), 3.76-3.61 (m, 2H), 3.30- 3.26(m,2H),3.13-2.93(m,2H),1.74-1.62(m,4H),1.39(s,9H),1.19-1.12(m,3H).

[0296] Step 5: To a solution of 4-carbamoyl-4-ethoxy-piperidine-1-carboxylic acid tert-butyl ester (380 mg, 1.40 mmol, 1 eq.) in dichloromethane (4 mL) was added trifluoroacetic acid (27.0 mmol, 2 mL, 19.3 eq.) and the mixture was stirred for 1 hour at 25° C. The mixture was concentrated to give the product 4-ethoxypiperidine-4-carboxamide (399 mg, crude, TFA salt) as a yellow oil.

[0297] (xi) Preparation of 2-amino-N-ethyl-acetamide

[0298] Step 1: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (4 g, 22.83 mmol, 1 eq.), ethylamine (4.10 g, 50.23 mmol, 5.94 mL, 2.2 eq., HCl salt) and 1-hydroxybenzotriazole (3.70 g, 27.40 mmol, 1.2 eq.) in dichloromethane (40 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.25 g, 27.40 mmol, 1.2 eq.) and N,N-diisopropylethylamine (7.08 g, 54.79 mmol, 9.55 mL, 2.4 eq.) dropwise. The mixture was stirred at 25 °C for 2 hours. The mixture was then diluted with additional dichloromethane (200 mL) and washed with 100 mL of 10% (w / v) aqueous citric acid. The organic layer was separated and then washed with 100 mL each of saturated aqueous sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]carbamate (2.5 g) as a colorless oil, which was used directly in the next step without further purification.

[0299] Step 2: A mixture of tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]carbamate (2.4 g, 11.87 mmol, 1 eq.) from step 1 in hydrochloric acid / dioxane (6 mL) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give 2-amino-N-ethyl-acetamide (1.6 g, HCl salt) as a white solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ = 8.59 (s, 1H), 8.25 (s, 2H), 3.52-3.45 (m, 2H), 3.20-3.06 (m, 2H), 1.04 (t, J = 7.2Hz, 3H).

[0300] (xii) Preparation of 1-amino-3-[(4-methoxyphenyl)methyl]thiourea

[0301] To a solution of 1-(isothiocyanatomethyl)-4-methoxy-benzene (6.5 g, 36.3 mmol, 1.0 eq) in ethanol (65 mL) was added hydrazine hydrate (2.7 g, 54.4 mmol, 2.6 mL, 1.5 eq) and the mixture was stirred for 2 hours at 25° C. The mixture was filtered and the filter cake was dried to give 1-amino-3-[(4-methoxyphenyl)methyl]thiourea (6.4 g) as a white solid.

[0302] (xiii) Preparation of 4-isopropoxypiperidine-4-carboxamide

[0303] Step 1: Sodium hydride (3.01 g, 75.3 mmol, 60% purity, 3.0 equiv) was added in portions to a flask containing isopropanol (1.96 mol, 150 mL, 78.1 equiv) at 25 °C over 20 minutes. The resulting mixture was stirred at 25 °C for 0.5 hours and then slowly transferred to a 0 °C solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol, 1.0 equiv) in bromoform (100 mmol, 8.78 mL, 4.0 equiv) and the mixture was stirred at the same temperature for 10 minutes. Saturated ammonium chloride (10 mL) was added and the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with water (2x100 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 40g Purification by silica gel flash column, eluent gradient from 0% to about 50% ethyl acetate in petroleum ether, flow rate 50 mL / min) gave 1-(tert-butyl) 4-isopropyl 4-isopropoxypiperidine-1,4-dicarboxylate (620 mg, 1.88 mmol) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ = 5.04-4.95 (m, 1H), 3.76-3.62 (m, 1H), 3.60-3.44 (m, 2H), 3.34-3. 07(m,2H),1.93-1.64(m,4H),1.38(s,9H),1.20(d,J=6.3Hz,6H),1.09(d,J=6.0Hz,6H).

[0304] Step 2: Lithium hydroxide (218 mg, 9.11 mmol, 5 equivalents) was added to a solution of 1-(tert-butyl) 4-isopropyl 4-isopropoxypiperidine-1,4-dicarboxylate (600 mg, 1.82 mmol, 1 equivalent) in ethanol (10 mL) and water (1 mL) from step 1, and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate (30 mL x 2). Citric acid was added to the aqueous phase to adjust the pH to 3, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-tert-butyloxycarbonyl-4-isopropoxy-piperidine-4-carboxylic acid (480 mg, 1.67 mmol) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ = 3.79-3.65 (m, 1H), 3.56-3.43 (m, 2H), 3.24-3.06 (m, 2H), 1.76 (s, 4H), 1.39 (s, 9H), 1.09 (d, J = 6.0Hz, 6H).

[0305] Step 3: A mixture of 1-tert-butoxycarbonyl-4-isopropoxy-piperidine-4-carboxylic acid (440 mg, 1.53 mmol, 1 eq.) from step 2, saturated ammonium chloride solution (180 mg, 3.37 mmol, 2.2 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (440 mg, 2.30 mmol, 1.5 eq.), 1-hydroxybenzotriazole (310 mg, 2.30 mmol, 1.5 eq.) and N,N-diisopropylethylamine (435 mg, 3.37 mmol, 0.59 mL, 2.2 eq.) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, then dissolved in 150 mL of dichloromethane, washed with 150 mL of 10% citric acid, 80 mL of saturated sodium bicarbonate solution and brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-carbamoyl-4-isopropoxy-piperidine-1-carboxylic acid tert-butyl ester (410 mg, 1.43 mmol) as a yellow oil. 1 H NMR (400MHz, DMSO-d6)δ=7.32-7.07(m,2H),3.67(s,1H),3.60-3.48(m,2H),3.2 4-3.05(m,2H),1.69(t,J=5.2Hz,4H),1.43-1.34(m,9H),1.10(d,J=6.0Hz,6H).

[0306] Step 4: To a solution of tert-butyl 4-carbamoyl-4-isopropoxy-piperidine-1-carboxylate (410 mg, 1.43 mmol, 1 eq.) from step 3 in dioxane (2 mL) was added dioxane hydrochloride solution (4 M, 2 mL, 5.59 eq.) and the mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure to give 4-isopropoxypiperidine-4-carboxamide (400 mg, crude, hydrochloride) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 3.85-3.76 (m, 1H), 3.31 (s, 4H), 2.18-2.07 (m, 4H), 1.22 (d, J = 6.0 Hz, 6H)

[0307] (xiv) Preparation of azetidine-3-carboxamide

[0308] Step 1: 1-tert-Butyloxycarbonylazetidine-3-carboxylic acid (3.00 g, 14.9 mmol, 1.0 equiv), ammonium chloride (1.75 g, 32.80 mmol, 2.2 equiv) and 1-hydroxybenzotriazole (2.42 g, 17.9 mmol, 1.2 equiv) were added to a round-bottom flask equipped with a magnetic stir bar. The solid mixture was dissolved in N,N-dimethylformamide (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.43 g, 17.9 mmol, 1.2 equiv) was added, and N,N-diisopropylethylamine (32.8 mmol, 5.71 mL, 2.2 equiv) was added dropwise. The resulting solution was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, then dissolved in dichloromethane (100 mL), washed with 10% citric acid (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 3-carbamoylazetidine-1-carboxylate (1.2 g, 5.99 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.57-7.24 (m, 1H), 7.14-6.82 (m, 1H), 4.08-3.60 (m, 4H), 3.25-3.16 (m, 1H), 1.38 (s, 9H).

[0309] Step 2: To a solution of tert-butyl 3-carbamoylazetidine-1-carboxylate (500 mg, 2.50 mmol, 1.0 eq) from step 1 in dichloroethane (9 mL) was added trifluoroacetic acid (40.52 mmol, 3 mL, 16.2 eq) and the mixture was stirred for 0.5 h at 25° C. The mixture was concentrated in vacuo to give azetidine-3-carboxamide (530 mg, 2.47 mmol, TFA salt) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 8.92-8.43 (m, 2H), 7.55 (br s, 1H), 7.23 (br s, 1H), 4.14-3.88 (m, 5H), 3.71-3.39 (m, 1H).

[0310] (xv) Preparation of 3-methylazetidine-3-carboxamide

[0311] Step 1: To a solution of 3-methylazetidine-3-carbonitrile hydrochloride (1.00 g, 7.54 mmol, 1.0 equiv) in dichloromethane (8 mL) was added triethylamine (2.29 g, 22.6 mmol, 3.15 mL, 3.0 equiv) and 4-dimethylaminopyridine (19 mg, 0.15 mmol, 0.02 equiv). Then, di-tert-butyl dicarbonate (3.29 g, 15.08 mmol, 3.47 mL, 2.0 equiv) was added dropwise to the mixture, which was stirred at 25 ° C for 3 hours. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure to give a white solid. The solid was purified by flash silica gel chromatography ( 20g The purified product was purified by silica gel flash column with a gradient of 0% to about 50% ethyl acetate / petroleum ether at a flow rate of 40 mL / min. The recovered fractions were concentrated under reduced pressure to give tert-butyl 3-cyano-3-methyl-azetidine-1-carboxylate (1.47 g, 7.49 mmol) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 4.29 (d, J = 8.6Hz, 2H), 3.81 (d, J = 8.7Hz, 2H), 1.67 (s, 3H), 1.45 (s, 9H).

[0312] Step 2: 3-cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.02 mmol, 1.0 equiv.) from step 1 and dimethylphosphite platinum dimethylphosphite ( 2+ A mixture of ) (435 mg, 1.02 mmol, 1.0 equiv) in ethanol (2 mL) and water (0.2 mL) was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography ( 20g The reaction mixture was purified by flash column with a gradient of about 50% to about 100% ethyl acetate / petroleum ether at a flow rate of 40 mL / min. The recovered fractions were concentrated under reduced pressure to give tert-butyl 3-carbamoyl-3-methyl-azetidine-1-carboxylate (0.20 g, 0.93 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.40-7.01 (m, 2H), 4.06-3.93 (m, 2H), 3.50 (d, J = 8.2Hz, 2H), 1.42 (s, 3H), 1.37 (s, 9H).

[0313] Step 3: A mixture of tert-butyl 3-carbamoyl-3-methyl-azetidine-1-carboxylate (200 mg, 0.93 mmol, 1.0 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 14.5 eq) from step 2 in dichloromethane (3 mL) was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-methylazetidine-3-carboxamide (210 mg, 0.92 mmol, trifluoroacetate) as a light yellow oil, which was used directly in the next step without further purification.

[0314] (xvi) Preparation of (2R)-N-methylazetidine-2-carboxamide

[0315] Step 1: (2R)-1-tert-Butyloxycarbonylazetidine-2-carboxylic acid (2.0 g, 9.94 mmol, 1.0 equiv), ethylamine hydrochloride (1.48 g, 21.87 mmol, 2.2 equiv) and 1-hydroxybenzotriazole (2.01 g, 14.91 mmol, 1.5 equiv) were added to a round-bottom flask equipped with a magnetic stir bar. The solid mixture was dissolved in N,N-dimethylformamide (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.86 g, 14.9 mmol, 1.5 equiv) was added, and N,N-diisopropylethylamine (2.83 g, 21.9 mmol, 2.2 equiv) was added dropwise. The resulting solution was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, then dissolved in dichloromethane (150 mL), washed with 10% citric acid (150 mL), saturated sodium bicarbonate (80 mL) and brine (80 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 1.8 g (8.40 mmol) of a yellow solid. A 900 mg portion of the yellow solid was purified by flash silica gel chromatography ( 25g Purification by silica gel flash column, eluent gradient from about 0% to about 20% ethyl acetate in petroleum ether, flow rate of 30 mL / min) gave tert-butyl (2R)-2-(methylcarbamoyl)azetidine-1-carboxylate (800 mg, 3.73 mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.89(br s,1H),4.45-4.32(m,1H),3.89-3.64(m,2H),2.62(d,J=4.8Hz,3H),2.43-2.18(m,1H),2.09-1.84(m,1H),1.35(br s,9H).

[0316] Step 2: In a round-bottom flask, (2R)-tert-butyl 2-(methylcarbamoyl)azetidine-1-carboxylate (800 mg, 3.73 mmol, 1.0 equiv) from step 1 was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL, 7.2 equiv) was added. The resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give (2R)-N-methylazetidine-2-carboxamide (850 mg, 3.73 mmol, trifluoroacetate) as a colorless oil. 1 HNMR (400MHz, DMSO-d6) δ=9.25(br s,1H),8.78(br s,1H),8.38(br d,J=2.5Hz,1H),4.87(br s,1H),3.96(br d,J=7.1Hz,1H),3.75(br s, 1H), 2.68 (d, J = 4.5Hz, 3H), 2.63-2.52 (m, 1H), 2.46-2.23 (m, 1H).

[0317] (xvii) Preparation of (2S)-3-(methylamino)propane-1,2-diol

[0318] Step 1: A solution of [(2R)-oxiran-2-yl]methanol (3.67 g, 49.5 mmol, 3.27 mL, 1.2 eq) and N-methyl-1-phenyl-methylamine (5.0 g, 41.3 mmol, 5.32 mL, 1.0 eq) in methanol (100 mL) was stirred at 70° C. for 15 hours. The mixture was concentrated in vacuo and purified by reverse phase HPLC to give (2S)-3-[benzyl(methyl)amino]propane-1,2-diol (3.1 g, 15.9 mmol) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ=7.43-7.16(m,5H),4.73-4.21(m,2H),3.72-3.61(m,1H),3.49(d,J=12.3Hz,2H),3.37(br d,J=4.9Hz,1H),3.31(br d,J=5.9Hz,1H),2.41(d,J=5.6Hz,1H),2.32(br d,J=6.6Hz,1H),2.13(s,3H).

[0319] Step 2: To a solution of (2S)-3-[benzyl(methyl)amino]propane-1,2-diol (1 g, 5.12 mmol, 1.0 equiv) from step 1 in methanol (20 mL) was added 10% palladium on carbon (100 mg, 5.12 mmol). The mixture was degassed and purged with hydrogen three times, then stirred at 25 °C under a hydrogen atmosphere for 15 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give (2S)-3-(methylamino)propane-1,2-diol (400 mg, 3.80 mmol) as a colorless oil. 1 HNMR (400MHz, DMSO-d6) δ = 4.62 (d, J = 4.8Hz, 1H), 4.51-4.41 (m, 1H), 3.61-3.51 (m, 1H), 3.34 (d, J = 4.8Hz, 1H), 3.30 (d, J = 2.0Hz, 2H), 3.24 (s, 3H), 3.22-3.18 (m, 1H).

[0320] (xviii) Preparation of (2S)-2-(methylamino)propionamide

[0321] Step 1: (2S)-2-[tert-Butyloxycarbonyl(methyl)amino]propionic acid (2.00 g, 9.84 mmol, 1.0 equiv), ammonium chloride (1.16 g, 21.6 mmol, 2.2 equiv) and 1-hydroxybenzotriazole (1.99 g, 14.8 mmol, 1.5 equiv) were added to a round-bottom flask equipped with a magnetic stir bar and dissolved in N,N-dimethylformamide (10 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.83 g, 14.8 mmol, 1.5 equiv) was added to the mixture, followed by N,N-diisopropylethylamine (2.80 g, 21.6 mmol, 2.2 equiv) dropwise. The resulting solution was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, dissolved in dichloromethane (100 mL), and 10% citric acid (100 mL) was added. The organic layer was washed with saturated sodium bicarbonate (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (1.54 g, 7.61 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.20 (br s, 1H), 6.96 (br s, 1H), 4.71-4.10 (m, 1H), 2.73 (s, 3H), 1.39 (s, 9H), 1.22 (d, J = 6.4Hz, 3H).

[0322] Step 2: In a round-bottom flask, N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (500 mg, 2.47 mmol, 1.0 eq.) and the hydrochloride salt in dioxane (4M, 10 mL, 16.2 eq.) were added and the resulting mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)propanamide (450 mg, hydrochloride salt) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=9.37(br s,1H),8.83(br s,1H),8.03(br s,1H),7.59(br s,1H),3.77-3.67(m,1H),2.48-2.44(m,3H),1.39(d,J=7.2Hz,3H).

[0323] (xix) Preparation of 2-(azetidin-3-yloxy)acetamide

[0324] Step 1: Sodium hydride (231 mg, 5.77 mmol, 60% purity, 1.0 eq.) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.77 mmol, 1.0 eq.) in N,N-dimethylformamide (10 mL), and the resulting mixture was stirred at 25 ° C for 0.5 hours. Then, 2-bromoacetamide (876 mg, 6.35 mmol, 1.1 eq.) was added, and the resulting mixture was stirred at 25 ° C for 2.5 hours. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 40g The reaction mixture was purified by flash column with a gradient of about 80% to about 100% ethyl acetate / petroleum ether at a flow rate of 40 mL / min. The recovered fractions were concentrated under reduced pressure to give compound 3-(2-amino-2-oxo-ethoxy)azetidine-1-carboxylic acid tert-butyl ester (0.6 g, 2.61 mmol) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 6.66-5.65 (m, 2H), 4.36-4.28 (m, 1H), 4.17-4.09 (m, 2H), 3.95-3.84 (m, 4H), 1.46 (s, 9H).

[0325] Step 2: A mixture of tert-butyl 3-(2-amino-2-oxo-ethoxy)azetidine-1-carboxylate (0.5 g, 2.17 mmol, 1.0 eq.) from step 1 in hydrochloride / dioxane (4 M, 8 mL, 14.7 eq.) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 2-(azetidin-3-yloxy)acetamide (0.36 g, 2.16 mmol, hydrochloride) as a white solid, which was used directly in the next step without further purification.

[0326] (xx)[(2S)-Pyrrolidin-2-yl]methanol- 15 Preparation of N-d7

[0327] Step 1: Add proline- 15 N-d7 (250 mg, 2.03 mmol) was dissolved in methanol and trimethylsilyl chloride was added. The reaction was stirred at room temperature overnight and evaporated to give proline- 15 N-d7 methyl ester (hydrochloride).

[0328] Step 2: Add the proline from step 1 to 15 N-d7 methyl ester (hydrochloride), di-tert-butyl dicarbonate (552 mg, 2.53 mmol) and potassium carbonate (1.4 g, 10 mmol) were suspended in acetonitrile and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the mixture was extracted five times with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-tert-butyloxycarbonylproline- 15 The N-d7 methyl ester was used as such in the next step.

[0329] Step 3: Lithium aluminum hydride (386 mg, 10.15 mmol) was suspended in anhydrous tetrahydrofuran and the solution was cooled to 0°C in an ice bath. N-tert-butyloxycarbonylproline- 15 Solution of N-d7 methyl ester in tetrahydrofuran. The progress of the reaction was monitored by thin layer chromatography. Upon completion, the reaction was terminated at 0°C by adding 0.7 mL of water, 1.4 mL of 4N aqueous sodium hydroxide solution, ether and another 1.4 mL of water. The solid was washed with Celite TM Filtered and washed three times with ethyl acetate.Evaporation of the solvent gave N-tert-butyloxy[(2S)-pyrrolidin-2-yl]methanol as an oil.

[0330] Step 4: Dissolve N-tert-butyloxy[(2S)-pyrrolidin-2-yl]methanol from step 3 in 1,4-dioxane and add 12M hydrogen chloride in 1,4-dioxane to a final concentration of 4M hydrogen chloride. Stir the reaction at room temperature for 2 hours. Remove the solvent under reduced pressure and co-evaporate the product with acetonitrile three times to give [(2S)-pyrrolidin-2-yl]methanol- 15 N-d7 (hydrochloride salt).

[0331] (xxi) Preparation of 1,1-(D6)dimethyl-1,2-dihydroxyethane

[0332] Step 1: To a solution of ethyl 2-(benzyloxy)acetate (1000 mg, 5.15 mmol) in tetrahydrofuran was added a 1 M solution of methyl-d3-magnesium iodide (15.45 mL, 15.45 mmol) in tetrahydrofuran at 0°C, the reaction was allowed to reach room temperature and stirred for 3 hours. Ammonium chloride was added at 0°C, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient of 10% to 30% ethyl acetate in hexane. The solvent was evaporated to give 1,1-(d6)dimethyl-2-benzyloxy-1-ethanol.

[0333] Step 2: 1,1-(d6)dimethyl-2-benzyloxy-1-ethanol from Step 1 was dissolved in tetrahydrofuran and hydrogenated (balloon) over 10% palladium on carbon for 2 hours overnight. TM Filter and evaporate the filtrate to an oil which is co-evaporated twice with anhydrous tetrahydrofuran to give 1,1-(d6)dimethyl-1,2-dihydroxyethane.

[0334] Example 2 - Preparation of Intermediates I-1(a) to I-1(d)

[0335]

[0336] (i) Intermediate I-1(a)(R 2 : 2-Cl-phenyl):

[0337]

[0338] Step 1: To a solution of 3-(2-chlorophenyl)-3-oxo-propionitrile (30 g, 167 mmol, 1 equivalent) in ethanol (300 mL) was added hydrazine hydrate (16.7 g, 334 mmol, 16 mL, 2 equivalents), and the mixture was stirred at 90 ° C for 16 h. The mixture was concentrated under reduced pressure to remove ethanol. 200 mL of water was then added, and the mixture was extracted with ethyl acetate 600 mL (3×200 mL). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-(2-chlorophenyl)-1H-pyrazole-5-amine (32 g) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 11.79 (br s, 1H), 7.74-7.65 (m, 1H), 7.54-7.41 (m, 1H), 7.40-7.26 (m, 2H), 5.87 (br s, 1H), 5.15-4.55 (m, 2H).

[0339] Step 2: A mixture of 3-(2-chlorophenyl)-1H-pyrazole-5-amine (32g, 165.3mmol, 1 equivalent), iodine (46.1g, 181.8mmol, 1.1 equivalent) and potassium carbonate (25.1g, 181.8mmol, 1.1 equivalent) from step 1 in acetonitrile (240mL) and water (60mL) was stirred at 25 ° C for 16h. The mixture was poured into water (500mL) and extracted with ethyl acetate 600mL (3×200mL). The organic phase was then washed with brine (500mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 1: 1) to give 3-(2-chlorophenyl)-4-iodo-1H-pyrazole-5-amine (40g) as a dark brown oil. 1 HNMR (400MHz, DMSO-d6) δ = 7.56 (dd, J = 1.2, 7.6Hz, 1H), 7.49-7.39 (m, 2H), 7.38-7.34 (m, 1H).

[0340] Step 3: A mixture of 3-(2-chlorophenyl)-4-iodo-1H-pyrazole-5-amine (40g, 125.2mmol, 1 equivalent), di-tert-butyl dicarbonate (82g, 375.6mmol, 86.3mL, 3 equivalents), triethylamine (400.6mmol, 55.8mL, 3.2 equivalents) and 4-dimethylaminopyridine (3.1g, 25mmol, 0.2 equivalents) in dichloromethane (400mL) from step 2 was stirred at 25 ° C for 3h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-iodo-pyrazole-1-carboxylic acid tert-butyl ester (45g) as a yellow solid.

[0341] Step 4: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-iodo-pyrazole-1-carboxylate (24 g, 38.7 mmol, 1 eq.) from step 3, (4-chlorophenyl)boronic acid (18.2 g, 116.2 mmol, 3 eq.), potassium carbonate (10.7 g, 77.4 mmol, 2 eq.) and Pd(dppf)Cl2 (1.42 g, 1.94 mmol, 0.05 eq.) in dioxane (240 mL) and water (48 mL) was stirred at 80° C. for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1) to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-(4-chlorophenyl)pyrazole-1-carboxylate (24 g) as a yellow oil.

[0342] Step 5: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-(4-chlorophenyl)pyrazole-1-carboxylate (41 g, 67.8 mmol, 1 eq) from step 4 in hydrogen chloride in methanol (4M, 410 mL, 24 eq) was stirred at 25 °C for 1 h. The mixture was then concentrated under reduced pressure to give 3-(2-chlorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-5-amine (39 g as HCl salt) as a yellow solid.

[0343] Step 6: To a solution of sodium ethoxide (39 g, 572.5 mmol, 5 eq.) in ethanol (390 mL) was added 3-(2-chlorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-5-amine (39 g, 114.5 mmol, 1 eq. as HCl salt) from step 5 and dimethyl malonate (343.5 mmol, 39.5 mL, 3 eq.), and the mixture was stirred at 80° C. for 2 h. The ethanol was removed and the pH was adjusted to 5 with 1 M hydrochloric acid (200 mL). The mixture was then extracted with ethyl acetate 600 mL (3×200 mL). The organic phase was then washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (200 mL) to give 2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-5,7-diol (8.7 g) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=12.47-12.08(m,1H),11.73-11.31(m,1H),7.52-7.38(m,4H),7.34(d,J=8.4Hz,2H),7.11(d,J=5.6Hz,2H),5.07(br s,1H).

[0344] Step 7: To a solution of 2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-5,7-diol (8.7 g, 23.4 mmol, 1 eq.) from step 6 in phosphorus oxychloride (303.9 mmol, 28.2 mL, 13 eq.) was added N,N-dimethylaniline (35.1 mmol, 4.4 mL, 1.5 eq.) at 0°C, and the mixture was stirred at 100°C for 2 h. After cooling, the mixture was poured into water (200 mL). The mixture was then extracted with ethyl acetate 300 mL (3×100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:1) to give 5,7-dichloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine (Intermediate I-1(a), 7.5 g) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ=7.43 (dd, J=1.5, 7.1Hz, 1H), 7.40-7.36 (m, 1H), 7.36-7.27 (m, 4H), 7.19 (d, J=8.4Hz, 2H), 6.99 (s, 1H).

[0345] (ii) Intermediate I-1(b)(R 2 : 2-MeO-phenyl):

[0346]

[0347] Step 1: To a solution of lithium diisopropylamide (2M, 15.8mL, 1.05 eq.) in tetrahydrofuran (100mL) was added acetonitrile (32.5mmol, 1.7mL, 1.08 eq.), and the mixture was stirred at -78°C for 1h. Then a solution of methyl 2-methoxybenzoate (5g, 30.1mmol, 1 eq.) in tetrahydrofuran (10mL) was added, and the mixture was stirred at -78°C for 1h. The mixture was warmed to 25°C and stirred at 25°C for 2h. The mixture was quenched by adding water (50mL). The aqueous layer was acidified to pH=3 with 1M hydrochloric acid and extracted with ethyl acetate 150mL (3×50mL). The combined organic phases were then washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1) to give 3-(2-methoxyphenyl)-3-oxo-propionitrile (2.1 g) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 7.87 (dd, J = 1.6, 7.6Hz, 1H), 7.62-7.53 (m, 1H), 7.11-6.99 (m, 2H), 4.09 (s, 2H), 3.98 (s, 3H).

[0348] Step 2: To a solution of 3-(2-methoxyphenyl)-3-oxo-propionitrile (2.1 g, 11.99 mmol, 1 equivalent) from step 1 in ethanol (21 mL) was added hydrazine hydrate (1.17 mL, 24.0 mmol, 2 equivalents), and the mixture was stirred at 90 ° C for 16 h. The mixture was concentrated to remove ethanol, and 20 mL of water was added to the mixture. The mixture was then extracted with ethyl acetate 60 mL (3×20 mL). The organic phase was then washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (ethyl acetate: methanol = 10: 1) to give 3-(2-methoxyphenyl)-1H-pyrazole-5-amine (1.4 g) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ = 7.53 (dd, J = 1.6, 7.6Hz, 1H), 7.30-7.17 (m, 1H), 7.03-6.86 (m, 2H), 5.96 (s, 1H), 3.92 (s, 3H).

[0349] Step 3: To a solution of 3-(2-methoxyphenyl)-1H-pyrazole-5-amine (1.4 g, 7.4 mmol, 1 equivalent) and iodine (2.1 g, 8.1 mmol, 1.1 equivalent) from step 2 in acetonitrile (14 mL) and water (3.5 mL), potassium carbonate (1.1 g, 8.1 mmol, 1.1 equivalent) was added, and the mixture was stirred at 25 ° C for 3 h. The mixture was poured into water (50 mL). The mixture was then extracted with ethyl acetate 90 mL (3×30 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by a silica gel column (petroleum ether: ethyl acetate = 1: 1) to give 4-iodo-3-(2-methoxyphenyl)-1H-pyrazole-5-amine (1.9 g, 6.03 mmol) as a dark brown oil. 1 H NMR (400MHz, CDCl3) δ=7.87 (dd, J=1.6, 7.6Hz, 1H), 7.43-7.35 (m, 1H), 7.07 (t, J=7.6Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 3.85 (s, 3H).

[0350] Step 4: A solution of 4-iodo-3-(2-methoxyphenyl)-1H-pyrazole-5-amine (1.9 g, 6.03 mmol, 1 equivalent), di-tert-butyl dicarbonate (4.0 g, 18.1 mmol, 4.2 mL, 3 equivalents), triethylamine (19.3 mmol, 2.7 mL, 3.2 equivalents) and 4-dimethylaminopyridine (147 mg, 1.2 mmol, 0.2 equivalents) in dichloromethane (20 mL) was stirred at 25 ° C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 5: 1) to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-iodo-3-(2-methoxyphenyl)pyrazole-1-carboxylate (2.4 g, 3.90 mmol) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ = 7.25-7.18 (m, 2H), 6.90-6.80 (m, 1H), 6.75 (d, J = 8.4Hz, 1H), 3.57 (s, 3H), 1.42 (s, 9H), 1.24 (s, 18H).

[0351] Step 5: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-iodo-3-(2-methoxyphenyl)pyrazole-1-carboxylate (1.9 g, 3.1 mmol, 1 eq) from step 4, (4-chlorophenyl)boronic acid (1.5 g, 9.3 mmol, 3 eq), potassium carbonate (853 mg, 6.2 mmol, 2 eq) and XPhos Pd G3 (130 mg, 154.4 μmol, 0.05 eq) in dioxane (19 mL) and water (3.8 mL) was stirred at 80° C. for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1) to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-3-(2-methoxyphenyl)pyrazole-1-carboxylate (1.3 g) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 7.57 (m, 1H), 7.37-7.32 (m, 1H), 7.22 (d, J = 8.8Hz, 2H), 7. 04-6.99(m,3H),6.75(d,J=8.0Hz,1H),3.30(s,3H),1.63(s,9H),1.37(s,18H).

[0352] Step 6: A solution of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-3-(2-methoxyphenyl)pyrazole-1-carboxylate (1.3 g, 2.17 mmol, 1 eq) from step 5 in hydrochloric acid / ethyl acetate (4 M, 13.00 mL, 24.00 eq) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give crude 4-(4-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-5-amine (800 mg as HCl salt) as a yellow solid.

[0353] Step 7: To a solution of 4-(4-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-5-amine (800 mg, 2.4 mmol, 1 eq. as HCl salt) and sodium ethoxide (809 mg, 11.9 mmol, 5 eq.) from step 6 in ethanol (8 mL) was added dimethyl malonate (943 mg, 7.14 mmol, 0.82 mL, 3 eq.), and the mixture was stirred at 80° C. for 2 h. The ethanol was removed and the pH was adjusted to 3 with 1 M hydrochloric acid (10 mL). The mixture was then extracted with ethyl acetate 15 mL (3×5 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (10 mL) to give 3-(4-chlorophenyl)-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5,7-diol (225 mg) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.29-11.95 (m, 1H), 11.37 (br s,1H),7.37-7.28(m,4H),7.11(d,J=7.6Hz,1H),7.06-7.00(m,2H),6.96(d,J=8.4Hz,1H),5.03(br s,1H),3.31(br s,3H).

[0354] Step 8: To a solution of 3-(4-chlorophenyl)-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5,7-diol (175 mg, 475.82 μmol, 1 eq.) from step 7 in phosphorus oxychloride (6.2 mmol, 0.57 mL, 13 eq.) was added N,N-dimethylaniline (713.7 μmol, 0.09 mL, 1.5 eq.) at 0°C, and the mixture was stirred at 100°C for 1 h. The mixture was poured into water (20 mL). The mixture was then extracted with ethyl acetate 30 mL (3×10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1) to give 5,7-dichloro-3-(4-chlorophenyl)-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (Intermediate I-1(b), 190 mg, crude product) as a yellow oil. 1H NMR (400MHz, CDCl3) δ = 7.56 (dd, J = 2.0, 7.2Hz, 1H), 7.46-7.37 (m, 3H), 7.30-7.29 (m, 1H) ,7.28-7.27(m,1H),7.13-7.06(m,1H),7.01(s,1H),6.90(d,J=8.4Hz,1H),3.40(s,3H).

[0355] (iii) Intermediate I-1(c)(R 2 : 4-CN-phenyl):

[0356]

[0357] Step 1: To a solution of lithium diisopropylamide (2M, 32.6mL, 1.05 equivalents) in tetrahydrofuran (200mL), acetonitrile (67.0mmol, 3.53mL, 1.08 equivalents) was added, and the mixture was stirred at -78°C for 2 hours under nitrogen. Then a solution of methyl 4-cyanobenzoate (10g, 62.0mmol, 1.0 equivalents) in tetrahydrofuran (30mL) was added, and the mixture was stirred at -78°C for 1 hour. The mixture was warmed to 25°C and stirred at 25°C for 2 hours. The mixture was then quenched by adding water (150mL). The aqueous layer was acidified to pH 3 with 1M aqueous hydrochloric acid solution and extracted with ethyl acetate 450mL (3x150mL). The combined organic phase was washed with brine (200mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography ( 120g The resulting fractions were concentrated under reduced pressure to give 4-(2-cyanoacetyl)benzonitrile (5.5 g, 32.3 mmol) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ = 8.06 (d, J = 8.3Hz, 2H), 7.87 (d, J = 8.3Hz, 2H), 4.15 (s, 2H).

[0358] Step 2: A mixture of 4-(2-cyanoacetyl)benzonitrile (5.3 g, 31.2 mmol, 1.0 equiv) from step 1 and hydrazine hydrate (3.12 g, 62.3 mmol, 3.03 mL, 2.0 equiv) in ethanol (50 mL) was stirred at 90° C. for 3 hours. The reaction mixture was cooled at room temperature and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography ( 80g Purification by silica gel flash column, eluting with 0% to about 10% methanol / ethyl acetate at a flow rate of 50 mL / min. Fractions were concentrated under reduced pressure to give 4-(5-amino-1H-pyrazol-3-yl)benzonitrile (4.8 g, 26.1 mmol) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ = 12.39-11.65 (m, 1H), 8.00-7.67 (m, 4H), 6.11-5.67 (m, 1H), 5.33-4.57 (m, 2H).

[0359] Step 3: To a solution of 4-(5-amino-1H-pyrazol-3-yl)benzonitrile (3.7 g, 20.09 mmol, 1.0 equiv) and iodine (3.80 g, 14.98 mmol, 3.02 mL, 1.2 equiv) in acetonitrile (20 mL) and water (5 mL) from step 2, potassium carbonate (3.33 g, 24.1 mmol, 1.2 equiv) was added, and the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 80g The fractions were concentrated under reduced pressure to give 4-(5-amino-4-iodo-1H-pyrazol-3-yl)benzonitrile (5.6 g, 18.1 mmol) as a dark brown solid.

[0360] Step 4: To a solution of 4-(5-amino-4-iodo-1H-pyrazol-3-yl)benzonitrile (5.6 g, 18.1 mmol, 1.0 equiv.), triethylamine (5.48 g, 54.2 mmol, 7.54 mL, 3.0 equiv.) and 4-dimethylaminopyridine (441 mg, 3.61 mmol, 0.2 equiv.) in dichloromethane (10 mL) was added dropwise di-tert-butyl dicarbonate (11.82 g, 54.18 mmol, 12.45 mL, 3.0 equiv.), and the mixture was stirred at 25 ° C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 80g The mixture was purified by silica gel flash column with a gradient of 0% to about 80% ethyl acetate / petroleum ether at a flow rate of 50 mL / min. The fractions were concentrated under reduced pressure to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(4-cyanophenyl)-4-iodo-pyrazole-1-carboxylate (7.1 g, 11.6 mmol) as a yellow solid.

[0361] Step 5: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(4-cyanophenyl)-4-iodo-pyrazole-1-carboxylate (7.00 g, 11.5 mmol, 1.0 equiv) from step 4, (4-chlorophenyl)boronic acid (5.38 g, 34.40 mmol, 3.0 equiv), dipotassium carbonate (3.17 g, 22.9 mmol, 2.0 equiv) and [2-(2-aminophenyl)phenyl]palladium(1+)dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine methanesulfonate (485 mg, 0.57 mmol, 0.05 equiv) in dioxane (50 mL) and water (10 mL) was stirred at 80° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (150 mL) and extracted with ethyl acetate (80 mL×3), and the combined organic layer was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 80g The mixture was purified by silica gel flash column with a gradient of 0% to about 100% ethyl acetate in petroleum ether at a flow rate of 50 mL / min. The fractions were concentrated under reduced pressure to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-3-(4-cyanophenyl)pyrazole-1-carboxylate (7.00 g) as a yellow solid.

[0362] Step 6: A mixture of 5-[bis(tert-butyloxycarbonyl)amino]-4-(4-chlorophenyl)-3-(4-cyanophenyl)pyrazole-1-carboxylic acid tert-butyl ester (7g, 11.8mmol, 1.0 equivalent) from step 5 in hydrochloride / dioxane (50mL, 4M) was stirred at 25°C for 6 hours. The reaction mixture was added dropwise to a saturated solution of sodium bicarbonate (200mL), and the resulting mixture was extracted with ethyl acetate (100mLx3). The combined organic layer was washed with brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ammonia monohydrate condition). The fraction was concentrated under reduced pressure to remove acetonitrile, and the residue was lyophilized to give 4-[5-amino-4-(4-chlorophenyl)-1H-pyrazol-3-yl]benzonitrile (2.2g, 7.46mmol) as a gray solid. 1H NMR (400MHz, DMSO-d6) δ = 12.49-11.91 (m, 1H), 7.87-7.67 (m, 2H), 7.47 (d, J = 8.0Hz, 2H), 7.39 (d, J = 8.4Hz, 2H), 7.25-7.11 (m, 2H), 5.23-4.39 (m, 2H).

[0363] Step 7: A mixture of 4-[5-amino-4-(4-chlorophenyl)-1H-pyrazol-3-yl]benzonitrile (500 mg, 1.70 mmol, 1 eq.) and diethyl malonate (5.30 g, 33.1 mmol, 5 mL, 19.5 eq.) was stirred at 120°C for 2 hours to form 3-[[4-(4-chlorophenyl)-3-(4-cyanophenyl)-1H-pyrazol-5-yl]amino]-3-oxo-propionic acid ethyl ester (about 693 mg). After cooling to room temperature, the reaction mixture was directly diluted in methanol (3 mL), THF (3 mL) and water (3 mL), and 4-dimethylaminopyridine (1.04 g, 8.48 mmol, 5.0 eq.) was added. The resulting mixture was stirred at 80°C for 15 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and filtered to give a residue. The residue was purified by flash silica gel chromatography ( 25g Purification by silica gel flash column, eluting with a gradient of 0% to about 30% methanol in dichloroethane at a flow rate of 30 mL / min) gave 4-[3-(4-chlorophenyl)-5,7-dihydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (335 mg, 0.92 mmol) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ=12.42-12.05(m,1H),11.68-11.30(m,1H),7.82(d,J=8.0H z,2H),7.56(d,J=8.0Hz,2H),7.47(d,J=8.4Hz,2H),7.28(d,J=7.2Hz,2H),5.04(br s,1H).

[0364] Step 8: To a solution of 4-[3-(4-chlorophenyl)-5,7-dihydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (330 mg, 0.91 mmol, 1.0 equiv) from step 7 in phosphorus oxychloride (1.81 g, 11.8 mmol, 1.10 mL, 13 equiv) was added N,N-dimethylaniline (1.36 mmol, 0.17 mL, 1.5 equiv) at 0°C, and the mixture was stirred at 100°C for 2 hours. The mixture was added to water (10 mL), then extracted with ethyl acetate (2x30 mL), and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 25g The mixture was purified by silica gel flash column with a gradient of 0% to about 50% ethyl acetate in petroleum ether at a flow rate of 50 mL / min to afford 4-[5,7-dichloro-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate I-1(c), 295 mg, 0.74 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.94 (d, J = 8.3 Hz, 2H), 7.83 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H).

[0365] (iv) Intermediate I-1(d)(R 2 : 6-CN-pyridin-3-yl):

[0366]

[0367] Step 1: A mixture of 5-formylpyridine-2-carbonitrile (10 g, 75.7 mmol, 1.0 equivalent) and aniline (21.2 g, 227 mmol, 20.7 mL, 3.0 equivalent) was stirred at 25 ° C for 1 hour. Isopropanol (80 mL) was added to the mixture and then filtered. The filter cake was dried to give the product 5-[(E)-phenyliminomethyl]pyridine-2-carbonitrile (13.6 g) as a yellow solid. The product was dissolved in ethanol (136 mL), a solution of phenoxyphosphonooxybenzene (41.0 g, 131.3 mmol, 33.6 mL, 75% purity, 2.0 equivalent) in ethanol (20 mL) was added thereto, and the reaction mixture was stirred at 25 ° C for 2 hours. The obtained mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give 5-[anilino(diphenoxyphosphoryl)methyl]pyridine-2-carbonitrile (21.3 g) as a light yellow solid.

[0368] Step 2: A mixture of 5-[anilino(diphenoxyphosphoryl)methyl]pyridine-2-carbonitrile (21.3 g, 48.3 mmol, 1.0 eq.) from step 1, 4-chlorobenzaldehyde (7.5 g, 53.1 mmol, 1.1 eq.) and cesium carbonate (20.4 g, 62.7 mmol, 1.3 eq.) in tetrahydrofuran (213 mL) and isopropanol (53 mL) was stirred at 25° C. for 16 hours. Hydrochloric acid solution (3 M, 48.3 mL, 3.0 eq.) was then added and the mixture was stirred at 25° C. for 2 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate 600 mL (3×200 mL). The organic phase was then washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give 5-[2-(4-chlorophenyl)acetyl]pyridine-2-carbonitrile (8.6 g, 33.4 mmol) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (d, J = 1.6Hz, 1H), 8.59 (dd, J = 2.0, 8.0Hz, 1H), 8. 25(d,J=8.0Hz,1H),7.40(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),4.55(s,2H).

[0369] Step 3: To a solution of 5-[2-(4-chlorophenyl)acetyl]pyridine-2-carbonitrile (8.6 g, 33.4 mmol, 1.0 equivalent) from step 2 in tetrahydrofuran (170 mL), phenyltrimethylammonium tribromide (13.8 g, 36.8 mmol, 1.1 equivalent) was added, and the mixture was stirred at 25 ° C for 16 hours. The mixture was poured into water (300 mL) and extracted with ethyl acetate 450 mL (3x150 mL). The organic phase was then washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to give 5-[2-bromo-2-(4-chlorophenyl)acetyl]pyridine-2-carbonitrile (6.5 g, 19.4 mmol) as a pink solid. 1 H NMR (400MHz, DMSO-d6) δ=9.34 (d, J=2.0Hz, 1H), 8.64 (dd, J=2.0, 8.0Hz, 1H), 8.26 (d, J=8.0Hz, 1H), 7.61-7.57 (m, 2H), 7.52-7.47 (m, 2H), 7.20 (s, 1H).

[0370] Step 4: A mixture of 5-[2-bromo-2-(4-chlorophenyl)acetyl]pyridine-2-carbonitrile (3.8 g, 11.3 mmol, 1.0 equiv) from step 3, 1-amino-3-[(4-methoxyphenyl)methyl]thiourea (2.6 g, 12.5 mmol, 1.1 equiv) from Example 1(xii) and acetic acid (664.5 mmol, 38.0 mL, 58 equiv) in ethanol (38 mL) was stirred at 80° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give 5-[4-(4-chlorophenyl)-5-[(4-methoxyphenyl)methylamino]-1H-pyrazol-3-yl]pyridine-2-carbonitrile (4 g, 9.62 mmol) as a yellow gum.

[0371] Step 5: A mixture of 5-[4-(4-chlorophenyl)-5-[(4-methoxyphenyl)methylamino]-1H-pyrazol-3-yl]pyridine-2-carbonitrile (6.5 g, 15.6 mmol, 1.0 equiv) from step 4 and trifluoroacetic acid (1.8 mol, 130.0 mL, 112 equiv) was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure, and sodium carbonate (100 mL) was added to the obtained residue. The mixture was extracted with ethyl acetate 300 mL (3x100 mL), and the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-[5-amino-4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine-2-carbonitrile (4.6 g) as a yellow oil.

[0372] Step 6: A mixture of 5-[5-amino-4-(4-chlorophenyl)-1H-pyrazol-3-yl]pyridine-2-carbonitrile (4.6 g, 15.6 mmol, 1.0 eq.) from step 5 and diethyl malonate (48.8 g, 304 mmol, 46.0 mL, 19.6 eq.) was stirred at 120° C. for 2 hours. Then, 4-dimethylaminopyridine (9.4 g, 76.9 mmol, 5.0 eq.), tetrahydrofuran (63 mL), methanol (63 mL) and water (63 mL) were added to the mixture, which was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with ethanol (50 mL) and filtered. The filter cake was purified by silica gel chromatography (dichloromethane:methanol (3% ammonia monohydrate) = 10:1) to give 5-[3-(4-chlorophenyl)-5,7-dihydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (1.7 g, 4.6 mmol) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 8.72 (d, J = 1.6 Hz, 1H), 8.01-7.88 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.30 (s, 1H).

[0373] Step 7: To a mixture of 5-[3-(4-chlorophenyl)-5,7-dihydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (1.7 g, 4.6 mmol, 1.0 eq.) from step 6 and phosphorus oxychloride (60.0 mmol, 5.6 mL, 13 eq.) was added N,N-dimethylaniline (6.9 mmol, 0.88 mL, 1.5 eq.) and the mixture was stirred at 100°C for 1 hour. The mixture was poured into water (100 mL) and extracted with ethyl acetate 150 mL (3 x 50 mL). The organic phase was then washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate=2:1) ​​to give 5-[5,7-dichloro-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Intermediate I-1(d), 1.28 g, 3.2 mmol) as a yellow solid.

[0374] Example 3 - Preparation of Intermediates I-2(a) to I-2(y)

[0375]

[0376] (i) Intermediate I-2(a)(R 2 :2-Cl-phenyl; R 3 : 4-(ethylamino)-4-carboxamide-piperidin-1-yl):

[0377] To the solution of intermediate I-1 (a) (60 mg, 146.7 μmol, 1 equivalent) from Example 2 (i) in acetone (1 mL), triethylamine (161.3 μmol, 0.022 mL, 1.1 equivalent) was added, followed by addition of a solution of 4- (ethylamino) piperidine-4-carboxamide (25.1 mg, 146.7 μmol, 1 equivalent) in water (0.2 mL), and the mixture was stirred at 25 ° C for 2 hours. 0.8 mL of water was then added to the reaction mixture, and the mixture was filtered. The filter cake was dried to give 1- [5- chloro-2- (2- chlorophenyl) -3- (4- chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl] -4- (ethylamino) piperidine-4-carboxamide (intermediate I-2 (a), 40 mg) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 7.62-7.46 (m, 4H), 7.42-7.30 (m, 5H), 7.07 (brs, 1H), 6.59 (s, 1H), 4.13 (d, J = 12.4Hz, 2H), 3.75 (t, J=10.8Hz,2H),3.33-3.29(m,1H),2.41-2.32(m,2H),2.00(t,J=10.8Hz,2H),1.70(d,J=13.2Hz,2H),1.04(t,J=6.8Hz,3H).

[0378] (ii) Intermediate I-2(b)(R 2 :2-Cl-phenyl; R 3 : 4-(trifluoromethanesulfonyl)piperazin-1-yl):

[0379] To a solution of intermediate I-1(a) (50 mg, 122.2 μmol, 1 eq.) from Example 2(i) and 1-(trifluoromethylsulfonyl)piperazine (31.1 mg, 122.2 μmol, 1 eq., HCl salt) from Example 1(i) in acetone (1 mL), water (0.2 mL) was added triethylamine (366.7 μmol, 0.05 mL, 3 eq.) and the mixture was stirred at 25°C for 1 h. Then, 4 mL of water was added to the mixture and the mixture was extracted with ethyl acetate 9 mL (3×3 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column (ethyl acetate:methanol=10:1) to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethylsulfonyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine (Intermediate I-2(b), 45 mg) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ = 7.47-7.27 (m, 6H), 7.20-7.17 (m, 2H), 6.14 (s, 1H), 3.71 (br s, 8H).

[0380] (iii) Intermediate I-2(c)(R 2 :2-Cl-phenyl; R 3 : 4-toluene-4-carboxamide-piperidin-1-yl):

[0381] To a solution of intermediate I-1(a) (100 mg, 244.44 μmol, 1 eq.) from Example 2(i) and 4-methylpiperidine-4-carboxamide (43 mg, 244.4 μmol, 1 eq., HCl salt) from Example 1(ii) in acetone (2 mL), water (0.4 mL) was added triethylamine (733.3 μmol, 0.1 mL, 3 eq.) and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated to give a residue, which was purified by silica gel column (ethyl acetate:methanol=10:1) to give 1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Intermediate I-2(c), 110 mg) as a yellow oil.

[0382] (iv) Intermediate I-2(d)(R 2 :2-Cl-phenyl; R 3 :1,1-dioxothianiline-4-amino):

[0383] To a solution of intermediate I-1(a) (50 mg, 122.2 μmol, 1 eq.) from Example 2(i) and 1,1-dioxothiane-4-amine (22.7 mg, 122.2 μmol, 1 eq., HCl salt) in acetone (1 mL), water (0.2 mL) and tetrahydrofuran (0.5 mL) was added triethylamine (366.7 μmol, 0.05 mL, 3 eq.), and the mixture was stirred at 40° C. for 16 h. Water (4 mL) was added to the mixture, and the mixture was extracted with ethyl acetate 9 mL (3×3 mL). The combined organic phases were then washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column (ethyl acetate:methanol=10:1) to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-N-(1,1-dioxothian-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Intermediate I-2(d), 30 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.69 (d, J = 9.2Hz, 1H), 7.64-7.47 (m, 4H), 7.43-7.33 (m, 4H), 6.59 (s, 1H), 4. 21-4.09(m,1H),3.46-3.34(m,2H),3.16(d,J=12.4Hz,2H),2.40-2.26(m,2H),2.18(d,J=12.8Hz,2H).

[0384] (v) Intermediate I-2(e)(R 2 : 2-Cl-phenyl; R3: isopropoxy)

[0385] To a solution of intermediate I-1(a) (29 mg, 488.9 μmol, 0.04 mL, 1 eq.) from Example 2(i) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (66 mg, 586.7 μmol, 1.2 eq.), followed by 5,7-dichloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine (200 mg, 488.9 μmol, 1 eq.), and the mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 5: 1) to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-isopropoxy-pyrazolo[1,5-a]pyrimidine (intermediate I-2(e), 160 mg) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.61-7.54 (m, 3H), 7.51 (m, 1H), 7.38 (s, 4H), 7.01 (s, 1H), 5.47-5.15 (m, 1H), 1.48 (d, J = 6.0Hz, 6H).

[0386] (vi) Intermediate I-2(f)(R 2 :2-Cl-phenyl; R 3 : 4-hydroxy-4-methyl-piperidin-1-yl):

[0387] To a solution of intermediate I-1(a) (200 mg, 488.88 μmol, 1 eq.) and 4-methylpiperidin-4-ol (56 mg, 488.88 μmol, 1 eq.) from Example 2(i) in acetone (1 mL) and water (0.2 mL) was added triethylamine (148 mg, 1.47 mmol, 0.2 mL, 3 eq.). The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 12g The product was purified by silica gel flash column with a gradient of 0 to 55% ethyl acetate in petroleum ether as the eluent at a flow rate of 100 mL / min) to afford 1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidin-4-ol as a yellow solid (Intermediate I-2(f), 210 mg). 1H NMR (400MHz, DMSO-d6)δ=7.62-7.43(m,4H),7.41-7.26(m,4H),6.57(s,1H),4.27(br d,J=12.7Hz,2H),3.63-3.46(m,2H),1.75-1.54(m,4H),1.18(s,3H).

[0388] (vii) Intermediate I-2(g)(R 2 :2-Cl-phenyl; R 3 : 4-(methylsulfonyl)piperazin-1-yl):

[0389] A mixture of intermediate I-1(a) (60 mg, 146.66 μmol, 1 eq.) from Example 2(i), 1-methylsulfonylpiperazine (59 mg, 293.33 μmol, 2 eq.) from Example 1(iii) and triethylamine (74 mg, 733.32 μmol, 0.10 mL, 5 eq.) in acetone (1.2 mL) and water (0.24 mL) was stirred at 25° C. for 1 hour. The reaction mixture was washed with 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 x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine (Intermediate I-2(g), 60 mg) as a yellow solid.

[0390] (viii) Intermediate I-2(h)(R 2 :2-Cl-phenyl; R 3 : (3R)-formamide-piperidin-1-yl):

[0391] A mixture of intermediate I-1(a) from Example 2(i) (100 mg, 244.44 μmol, 1 eq), (3R)-piperidine-3-carboxamide (31 mg, 244.44 μmol, 1 eq) and triethylamine (74 mg, 733.32 μmol, 0.10 mL, 3 eq) in acetone (2 mL) and water (0.4 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Intermediate I-2(h), 130 mg) as a light yellow solid, which was used directly in the next step without further purification.

[0392] (ix) Intermediate I-2(i)(R 2 :2-Cl-phenyl; R 3 : 2-(azetidin-3-yl)acetamide):

[0393] To a solution of intermediate I-1(a) (400 mg, 977.77 μmol, 1 equivalent) from Example 2(i) in acetone (4 mL) and water (0.8 mL) was added triethylamine (495 mg, 4.89 mmol, 0.68 mL, 5 equivalents) and 2-(azetidine-3-yl)acetamide (294.52 mg, 1.96 mmol, 2 equivalents) from Example 1(iv). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20g The reaction mixture was purified by silica gel flash column, eluting with 0 to 100% dichloromethane / methanol at 30 mL / min, and the solution was concentrated under reduced pressure to give 2-[1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]azetidin-3-yl]acetamide (Intermediate I-2(i), 400 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.63-7.42 (m, 4H), 7.42-7.28 (m, 5H), 6.86 (s, 1H) ,6.01(s,1H),5.09-3.76(m,5H),3.17(d,J=5.2Hz,1H),3.09-2.96(m,1H).

[0394] (x) Intermediate I-2(j)(R 2 :2-Cl-phenyl; R 3 : 4-methyl-4-piperidinyl acetamide):

[0395] To a solution of intermediate I-1(a) (50 mg, 122.2 μmol, 1 eq.) from Example 2(i) in a mixed solvent of acetone (1 mL) and water (0.2 mL) was added N-(4-methyl-4-piperidinyl)acetamide (24 mg, 122.22 μmol, 1 eq., HCl salt) and triethylamine (37 mg, 366.7 μmol, 0.05 mL, 3 eq.) from Example 1(v), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mLx2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 12g The mixture was purified by flash column with silica gel, gradient of 50% to 100% ethyl acetate / petroleum ether as eluent, flow rate of 30 mL / min. The fractions were concentrated under reduced pressure to give N-[1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-4-piperidinyl]acetamide (Intermediate I-2(j), 40 mg) as a light yellow solid.

[0396] (xi) Intermediate I-2(k)(R 2 :2-Cl-phenyl; R 3 :(3R)-3-(aminocarboxymethyl)pyrrolidin-1-yl):

[0397] To a solution of intermediate I-1(a) (100 mg, 244.44 μmol, 1 eq.) from Example 2(i) in acetone (2 mL) and water (0.4 mL) were added triethylamine (124 mg, 1.22 mmol, 0.17 mL, 5 eq.) and 2-[(3R)-pyrrolidin-3-yl]acetamide (80 mg, 488.88 μmol, 2 eq., HCl salt) from Example 1(vi). The mixture was stirred at 25°C for 1 hour. The reaction mixture was washed with water (30 mL) and extracted with ethyl acetate 60 mL (30 mL×2). The combined organic layers were washed with brine 40 mL (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18, 150x25mmx10μm; mobile phase: [water (FA)-ACN]; B%: 57%-87%, 10min) to give 2-[(3R)-1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl]acetamide (Intermediate I-2(k), 100 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.61-7.43(m,4H),7.34(s,5H),6.83(s,1H),6.10(s,1H),4.53- 3.46(m,4H),2.63-2.57(m,1H),2.29-2.17(m,2H),2.15-2.03(m,1H),1.71-1.62(m,1H).

[0398] (xii) Intermediate I-2(l)(R 2 :2-Cl-phenyl; R 3 : (3S)-formamide-piperidin-1-yl):

[0399] A mixture of intermediate I-1(a) (500 mg, 1.22 mmol, 1 eq.) from Example 2(i), (3S)-piperidine-3-carboxamide (355.21 mg, 1.47 mmol, 1.2 eq., TFA salt) from Example 1(ix) and triethylamine (371.03 mg, 3.67 mmol, 510.35 μL, 3 eq.) in acetone (5 mL) and water (1 mL) was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20g The mixture was purified by flash column with silica gel, 50-100% ethyl acetate / petroleum ether gradient as eluent, flow rate 40 mL / min). The fractions were concentrated under reduced pressure to give compound (3S)-1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Intermediate I-2(l), 580 mg) as a light yellow solid.

[0400] (xiii) Intermediate I-2(m)(R 2 :2-Cl-phenyl; R 3 : 4-carboxamido-4-ethoxypiperidin-1-yl):

[0401] The intermediate I-1 (a) (500 mg, 1.2 mmol, 1 equivalent) from Example 2 (i), triethylamine (3.7 mmol, 0.51 mL, 3 equivalents), 4-ethoxypiperidine-4-carboxamide (349 mg, 1.22 mmol, 1 equivalent, TFA) from Example 1 (x) in water (1 mL) and acetone (5 mL) was stirred at 25 ° C for 2 hours. Then 4 mL of water was added to the mixture, and the mixture was filtered. The filter cake was dried to obtain the product 1- [5-chloro-2- (2-chlorophenyl) -3- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl] -4-ethoxy-piperidine-4-carboxamide (intermediate I-2 (m), 650 mg) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ=7.61-7.45(m,4H),7.39-7.31(m,5H),7.24(s,1H),6.62(s,1H),4.35(br d,J=12.4Hz,2H),3.47(br t,J=11.2Hz,2H),3.36(br d,J=7.2Hz,2H),2.07-1.98(m,2H),1.94-1.88(m,2H),1.20(t,J=7.2Hz,3H).

[0402] (xiv) Intermediate I-2(n)(R 2 :2-Cl-phenyl; R 3 : 6-(trifluoromethyl)-3-pyridyl):

[0403] To a mixture of intermediate I-3(a) from Example 4(i) (70 mg, 0.166 mmol, 1 eq), [6-(trifluoromethyl)-3-pyridyl]boronic acid (64 mg, 0.332 mmol, 2 eq), 2-hydroxy-3-methyl-benzoic acid cuprous (107 mg, 0.499 mmol, 3 eq) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (10 mg, 8.32 μmol, 0.05 eq), and the mixture was stirred at 60° C. for 2 hours. The mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate 3:1) to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[6-(trifluoromethyl)-3-pyridinyl]pyrazolo[1,5-a]pyrimidine (Intermediate I-2(n), 100 mg, crude) as a yellow solid.

[0404] (xv) Intermediate I-2(o)(R 2 :2-Cl-phenyl; R 3 : 4-(trifluoromethyl)-1-piperidinyl):

[0405] To the solution of intermediate I-1 (a) (60 mg, 0.15 mmol, 1.0 equiv) from Example 2 (i) in acetone (1 mL), triethylamine (0.02 mL, 0.16 mmol, 1.1 equiv) and 4- (trifluoromethyl) piperidine (22 mg, 0.15 mmol, 1.0 equiv) in water (0.2 mL) solution was added, and the mixture was stirred at 25 ° C for 2 hours. Water (0.8 mL) was added to the mixture, and the mixture was filtered. The filter cake was dried to give the product 5-chloro-2- (2-chlorophenyl) -3- (4-chlorophenyl) -7- [4- (trifluoromethyl) -1-piperidinyl] pyrazolo [1,5-a] pyrimidine (intermediate I-2 (o), 50 mg, crude) as a yellow solid.1 H NMR (400MHz, DMSO-d6) δ=7.63-7.47(m,4H),7.41-7.32(m,4H),6.66(s,1H),4.70(d,J=12 .4Hz,2H),3.21(t,J=12.0Hz,2H),2.82-2.70(m,1H),1.96(d,J=11.2Hz,2H),1.66(m,2H).

[0406] (xvi) Intermediate I-2(p)(R 2 :6-CN-pyridin-3-yl); R 3 : 3-cyano-3-methyl-azetidin-1-yl):

[0407] A mixture of intermediate I-1(d) from Example 2(iv) (50 mg, 0.12 mmol, 1.0 equiv), 3-methylazetidine-3-carbonitrile hydrochloride (18 mg, 0.14 mmol, 1.1 equiv) and triethylamine (38 mg, 0.37 mmol, 0.05 mL, 3.0 equiv) in acetone (1 mL) and water (0.2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with water (5 mL) and filtered, and the resulting filter cake was dried under reduced pressure to give 5-[5-chloro-3-(4-chlorophenyl)-7-(3-cyano-3-methyl-azetidine-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Intermediate I-2(p), 60 mg) as a yellow solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (dd, J = 0.8, 1.9 Hz, 1H), 8.13 ( dd, J = 1.3, 5.9 Hz, 2H), 7.52-7.48(m,2H),7.43-7.39(m,2H),6.20(s,1H),5.34-4.11(m,4H),1.73(s,3H).

[0408] (xvii) Intermediate I-2(q)(R 2 : 6-CN-pyridin-3-yl): R 3 : 3-methoxy-3-methyl-azetidin-1-yl):

[0409] The mixture of intermediate I-1 (d) (60 mg, 0.15 mmol, 1.0 equivalent) from Example 2 (iv), 3-methoxy-3-methylazetidine hydrochloride (23 mg, 0.16 mmol, 1.1 equivalent) and triethylamine (45 mg, 0.45 mmol, 0.06 mL, 3.0 equivalent) in acetone (1 mL) and water (0.2 mL) was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (5 mL) and filtered. The resulting filter cake was dried under reduced pressure to give 5- [5- chloro-3- (4- chlorophenyl) -7- (3- methoxy-3- methyl-azetidine -1- base) pyrazolo [1,5-a] pyrimidine -2- base] pyridine -2- carbonitrile (intermediate I-2 (q), 55 mg, 0.12 mmol) as a yellow solid, which was directly used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6)δ=8.91-8.88(m,1H),8.15-8.08(m,2H),7.52-7.47(m,2H) ),7.43-7.38(m,2H),6.09(s,1H),5.05-3.95(m,4H),3.26(s,3H),1.52(s,3H).

[0410] (xviii) Intermediate I-2(r)(R 2 :6-CN-pyridin-3-yl); R 3 : 4-(trifluoromethylsulfonyl)piperazin-1-yl):

[0411] To a mixture of intermediate I-1(d) (100 mg, 0.25 mmol, 1.0 equiv) from Example 2(iv) and 1-(trifluoromethylsulfonyl)piperazine (64 mg, 249.6 μmol, 1 equiv, hydrochloride salt) from Example 1(i) in acetone (2 mL) and water (0.4 mL) was added triethylamine (0.76 mg, 48.8 μmol, 0.1 mL, 3.0 equiv) and the mixture was stirred at 25° C. for 2 hours. Water (1.6 mL) was then added to the mixture, the mixture was filtered, and the filter cake was dried to give 5-[5-chloro-3-(4-chlorophenyl)-7-[4-(trifluoromethylsulfonyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Intermediate I-2(r), 115 mg) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.96 (d, J = 1.2Hz, 1H), 8.21-8.09 (m, 2H), 7.56-7. 50(m,2H),7.47-7.39(m,2H),6.76(s,1H),4.31-3.94(m,4H),3.75(m,4H).

[0412] (xix) Intermediate I-2(s)(R 2 :6-CN-pyridin-3-yl); R 3 : 4-methyl-4-formamide-piperidin-1-yl):

[0413] To the mixture of intermediate I-1 (d) (100 mg, 0.25 mmol, 1.0 equivalent) from Example 2 (iv) and 4-methylpiperidine-4-carboxamide (45 mg, 249.6 μmol, 1.0 equivalent, hydrochloride) from Example 1 (ii) in acetone (2 mL) and water (0.4 mL), triethylamine (748.8 μmol, 0.1 mL, 3.0 equivalent) was added, and the mixture was stirred at 25 ° C for 2 hours. Water (1.6 mL) was then added to the mixture, and the mixture was filtered. The filter cake was dried to give 1- [5- chloro-3- (4-chlorophenyl) -2- (6- cyano-3-pyridyl) pyrazolo [1,5-a] pyrimidin-7-yl] -4-methyl-piperidine-4-carboxamide (intermediate I-2 (s), 110 mg) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6)δ=8.90(s,1H),8.13(s,2H),7.53-7.49(m,2H),7.45-7.41(m,2H),7.32(s,1H),7.02(s,1H ), 6.61 (s, 1H), 4.29-4.18 (m, 2H), 3.53 (t, J = 10.4Hz, 2H), 2.19 (d, J = 14.0Hz, 2H), 1.64-1.51 (m, 2H), 1.20 (s, 3H).

[0414] (xx) Intermediate I-2(t)(R 2 :6-CN-pyridin-3-yl); R 3 : 4-carboxamido-4-ethoxypiperidin-1-yl):

[0415] To a solution of intermediate I-1(d) (80 mg, 0.20 mmol, 1.0 equiv) from Example 2(iv) in acetone (0.2 mL) and water (0.4 mL) were added triethylamine (0.60 mmol, 0.08 mL, 3.0 equiv) and 4-ethoxypiperidine-4-carboxamide (44 mg, 0.21 mmol, 1.05 equiv, hydrochloride) prepared as in Example 1(x), and the mixture was stirred at 25° C. for 2 hours. The mixture was then added to water (10 mL) and filtered to give 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate I-2(t), 102 mg, 0.19 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ=9.11-8.71(m,1H),8.26-8.05(m,2H),7.58-7.47(m,2H),7.46-7.39(m,2H),7.37 -7.31(m,1H),7.29-7.21(m,1H),6.68-6.62(m,1H),4.47-4.27(m,2H),3.63-3.45( m,2H),3.41-3.36(m,2H),2.13-2.02(m,2H),1.98-1.86(m,2H),1.19-1.14(m,3H).

[0416] (xxi) Intermediate I-2(u)(R 2 :2-Cl-phenyl; R 3 : 4-carboxamide-4-isopropoxypiperidin-1-yl):

[0417] A mixture of intermediate I-1(a) (600 mg, 1.47 mmol, 1 eq.) from Example 2(i), 4-isopropoxypiperidine-4-carboxamide (392 mg, 1.76 mmol, 1.2 eq.) from Example 1(xiii) and triethylamine (742 mg, 7.33 mmol, 1.02 mL, 5 eq.) in acetone (6 mL) and water (0.6 mL) was stirred at 25 ° C for 1 hour. The reaction mixture was washed with water (20 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography ( 20g The mixture was purified by flash column with silica gel, gradient of eluent from 0% to about 100% ethyl acetate / petroleum ether, flow rate of 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-isopropoxy-piperidine-4-carboxamide (Intermediate I-2(u), 623 mg, 1.08 mmol) as a white solid. 1 HNMR(400MHz, DMSO-d6)δ=7.60-7.45(m,4H),7.40-7.31(m,5H),7.24(s,1H),6.62(s,1H),4.21(d,J=12.4 Hz, 2H), 3.78-3.69 (m, 1H), 3.67-3.57 (m, 2H), 2.07-1.99 (m, 2H), 1.96-1.89 (m, 2H), 1.14 (d, J = 6.0Hz, 6H).

[0418] (xxii) Intermediate I-2(v)(R 2 :6-CN-pyridin-3-yl); R 3 : 3-carbamoylazetidin-1-yl):

[0419] A mixture of intermediate I-1(d) (110 mg, 0.27 mmol, 1.0 equiv) from Example 2(iv), azetidine-3-carboxamide (64 mg, 0.30 mmol, 1.1 equiv, trifluoroacetate) from Example 1(xiv) and triethylamine (83 mg, 0.82 mmol, 0.12 mL, 3.0 equiv) in acetone (1 mL) and water (0.2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with water (5 mL) and filtered, and the resulting filter cake was dried under reduced pressure to give compound 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]azetidine-3-carboxamide (intermediate I-2(v), 130 mg) as a yellow solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6)δ=8.90-8.87(m,1H),8.14-8.08(m,2H),7.62-7.57(m,1H),7.51-7.47(m ,2H),7.43-7.38(m,2H),7.20-7.15(m,1H),6.11(s,1H),4.87-4.35(m,2H),3.61-3.50(m,1H).

[0420] (xxiii) Intermediate I-2(w)(R 2:6-CN-pyridin-3-yl); R 3 : 3-carbamoyl-3-methylazetidin-1-yl):

[0421] The mixture of intermediate I-1 (d) (70 mg, 0.17 mmol, 1.0 equivalent) from Example 2 (iv), 3-methylazetidine-3-carboxamide (44 mg, 0.19 mmol, 1.1 equivalent, trifluoroacetate) and triethylamine (53 mg, 0.52 mmol, 0.07 mL, 3.0 equivalent) in acetone (1 mL) and water (0.2 mL) was stirred at 25 ° C for 3 hours. The reaction mixture was diluted with water (5 mL) and filtered. The resulting filter cake was dried under reduced pressure to give 1- [5- chloro-3- (4- chlorophenyl) -2- (6- cyano -3- pyridyl) pyrazolo [1,5-a] pyrimidin-7-yl] -3- methyl-azetidine-3-carboxamide (intermediate I-2 (w), 80 mg, 0.17 mmol) as a light yellow solid, which was directly used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ=8.89(s,1H),8.11(d,J=1.1Hz,2H),7.56(br s,1H),7.49(br d,J=8.4Hz,2H),7.44-7.37(m,2H),7.20(br s,1H),6.09(s,1H),4.87-4.39(m,4H),1.57(s,3H).

[0422] (xxiv) Intermediate I-2(x)(R 2 :2-Cl-phenyl; R 3 : 3-(2-amino-2-oxo-ethoxy)azetidin-1-yl):

[0423] A mixture of intermediate I-1(a) (100 mg, 0.24 mmol, 1.0 equiv.) from Example 2(i), 2-(azetidin-3-yloxy)acetamide (49 mg, 0.29 mmol, 1.2 equiv., hydrochloride) from Example 1(xix) and triethylamine (0.73 mmol, 0.10 mL, 3.0 equiv.) in acetone (1 mL) and water (0.2 mL) was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 20g The obtained product was purified by flash column with a gradient of 30% to about 100% ethyl acetate / petroleum ether at a flow rate of 30 mL / min. The recovered fractions were concentrated under reduced pressure to give 2-[1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]azetidin-3-yl]oxyacetamide (Intermediate I-2(x), 100 mg, 0.20 mmol) as a light yellow solid.

[0424] (xxv) Intermediate I-2(y)(R 2 :6-CN-pyridin-3-yl); R 3 : 4-carbamoyl-4-isopropoxypiperidin-1-yl):

[0425] To a solution of intermediate I-1(d) (100 mg, 0.25 mmol, 1.0 eq) from Example 2(iv) in acetone (0.2 mL) and water (0.4 mL) were added triethylamine (0.75 mmol, 0.10 mL, 3.0 eq) and 4-isopropoxypiperidine-4-carboxamide (56 mg, 0.25 mmol, 1.0 eq, hydrochloride) and the mixture was stirred at 25° C. for 2 h. The mixture was added to water (10 mL) and filtered to give 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-isopropoxy-piperidine-4-carboxamide (130 mg, 0.24 mmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (d, J = 0.8Hz, 1H), 8.31-7.95 (m, 2H), 7.55-7.48 (m, 2H), 7.45-7.40 (m, 2H), 7.38 (s, 1H), 7.2 6(s,1H),6.65(s,1H),4.41-4.18(m,2H),3.84-3.72(m,1H),3.70-3.58(m,2H),2.09-1.92(m,4H),1.17(d,J=6.0Hz,6H).

[0426] Example 4 - Preparation of Intermediates I-3(a) to I-3(d)

[0427]

[0428] (i) Intermediate I-3(a)(R 2 : 2-Cl-phenyl):

[0429] To the solution of intermediate I-1(a) (2g, 4.9mmol, 1 equivalent) from Example 2(i) in tetrahydrofuran (20mL), sodium thiomethoxide (411mg, 5.9mmol, 1.2 equivalents) was added, and the mixture was stirred at 25°C for 2h. The mixture was poured into water (50mL). The mixture was then extracted with ethyl acetate 45mL (3×15mL). The organic phase was then washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 1: 1) to give 5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-methylsulfanyl-pyrazolo[1,5-a]pyrimidine (intermediate I-3(a), 1.8g) as a yellow solid.

[0430] (ii) Intermediate I-3(b)(R 2 : 2-MeO-phenyl):

[0431] To the solution of intermediate I-1(b) (140 mg, 345.96 μmol, 1 equivalent) from Example 2(ii) in tetrahydrofuran (2 mL), sodium thiomethoxide (22 mg, 311.4 μmol, 0.9 equivalent) was added, and the mixture was stirred at 0 ° C for 3 h. The mixture was poured into water (10 mL). The mixture was then extracted with ethyl acetate 15 mL (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 1: 1) to give 5-chloro-3-(4-chlorophenyl)-2-(2-methoxyphenyl)-7-methylsulfanyl-pyrazolo[1,5-a]pyrimidine (intermediate I-3(b), 80 mg) as a yellow oil.

[0432] (iii) Intermediate I-3(c)(R 2 : 4-CN-phenyl):

[0433] To a solution of intermediate I-1(c) (276 mg, 69 mmol, 1.0 equiv) from Example 2(iii) in tetrahydrofuran (3 mL) was added sodium thiomethoxide (58 mg, 0.83 mmol, 1.2 equiv), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (20 mLx3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 40g The mixture was purified by flash column with silica gel, gradient of 0% to about 100% ethyl acetate / petroleum ether as eluent, flow rate of 40 mL / min. The fractions were concentrated under reduced pressure to give 4-[5-chloro-3-(4-chlorophenyl)-7-methylsulfanyl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate I-3(c), 230 mg, 0.56 mmol) as a yellow solid.

[0434] (iv) Intermediate I-3(d)(R 2 : 6-CN-pyridin-3-yl):

[0435] To the solution of intermediate I-1 (d) (300 mg, 0.75 mmol, 1.0 equivalent) from Example 2 (iv) in tetrahydrofuran (3 mL), sodium thiomethoxide (63 mg, 0.90 mmol, 1.2 equivalent) was added, and the mixture was stirred at 25 ° C for 2 hours. The mixture was poured into water (50 mL). The resulting mixture was then extracted with ethyl acetate (3x0 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give 5- [5- chloro-3- (4- chlorophenyl) -7- methylsulfanyl -pyrazolo [1,5-a] pyrimidin-2-yl] pyridine -2-carbonitrile (intermediate I-3 (d), 300 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.86 (t, J = 1.6Hz, 1H), 8.14 (d, J = 1.6Hz, 2H), 7.55-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.23 (s, 1H), 2.80 (s, 3H).

[0436] Example 5 - Preparation of Intermediate I-4(a) Intermediate I-4(d)

[0437]

[0438] (i) Intermediate I-4(a)(R 2 :4-Cl-phenyl; R 4 : (2S)-2-(Hydroxymethyl)pyrrolidin-1-yl))

[0439] To the intermediate I-3 (a) (170 mg, 404.1 μmol, 1 equivalent) from Example 4 (i), [(2S)-pyrrolidin-2-yl] methanol (123 mg, 1.21 mmol, 0.12 mL, 3 equivalents) in acetonitrile (4 mL) solution, N, N-diisopropylethylamine (3.6 mmol, 0.62 mL, 8.8 equivalents) was added, and the mixture was stirred at 80 ° C for 16 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate 1: 1) to give [(2S) -1- [2- (2- chlorophenyl) -3- (4- chlorophenyl) -7- methylsulfanyl -pyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidin-2-yl] methanol (intermediate I-4 (a), 160 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.62-7.48 (m, 6H), 7.29 (d, J = 8.8Hz, 2H), 6.29 (br s,1H),5.06-4.68(m,1H),4.42-4.19(m,1H),3.77-3.65(m,2H),3.55(m,2H),2.69(s,3H),2.08(m,2H),1.98(m,2H).

[0440] (ii) Intermediate I-4(b)(R 2 :4MeO-phenyl; R 4 : (2S)-2-(Hydroxymethyl)pyrrolidin-1-yl))

[0441] To the intermediate I-3 (b) (80 mg, 192.2 μmol, 1 eq.) from Example 4 (ii), [(2S)-pyrrolidin-2-yl] methanol (58 mg, 576.5 μmol, 3 eq.) in acetonitrile (1 mL) was added N, N-diisopropylethylamine (0.29 mL, 1.7 mmol, 8.8 eq.), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate 1: 1) to give [(2S)-1-[3-(4-chlorophenyl)-2-(2-methoxyphenyl)-7-methylsulfanyl-pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (intermediate I-4 (b), 72 mg) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 7.53 (d, J = 8.8Hz, 2H), 7.51-7.43 (m, 1H), 7.35 (m, 1H), 7.27-7.19 (m, 2H), 7.12-7.01 (m, 2H), 6.21 (br s,1H),4.87(d,J=2.4Hz,1H),4.26(d,J=2.0Hz,1H),3.67(t,J=7.6Hz,2H),3 .58-3.48(m,2H),3.46(s,3H),2.65(s,3H),2.06(m,2H),1.99-1.91(m,2H).

[0442] (iii) Intermediate I-4(c)(R 2 :4-CN-phenyl; R 4 : (2S)-2-(Hydroxymethyl)pyrrolidin-1-yl))

[0443] A mixture of intermediate I-3 (c) (210 mg, 0.51 mmol, 1.0 equiv.) from Example 4 (iii), [(2S)-pyrrolidin-2-yl] methanol (155 mg, 1.53 mmol, 0.15 mL, 3.0 equiv.) and N,N-diisopropylethylamine (4.49 mmol, 0.78 mL, 8.8 equiv.) in acetonitrile (5 mL) was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The resulting filter cake was washed with acetonitrile (2 mL) to give compound 4- [3- (4-chlorophenyl) -5- [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -7- methylsulfanyl -pyrazolo [1,5-a] pyrimidin-2-yl] benzonitrile (intermediate I-4 (c), 175 mg, 0.36 mmol) as a light yellow solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4Hz, 2H), 7.48-7.42 (m, 2H), 7.41-7.34 (m, 2H), 6.40- 6.17(m,1H),5.00-4.71(m,1H),4.22(s,1H),3.69-3.57(m,2H),3.54-3.44(m,2H),2.67(s,3H),2.07-1.90(m,4H).

[0444] (iv) Intermediate I-4(d)(R 2 :6-CN-pyridin-3-yl); R 4 : N-(2-hydroxy-2-methyl-propyl)-methylamino):

[0445] To a solution of intermediate I-3(d) (70 mg, 0.17 mmol, 1.0 equiv) from Example 4(iv), 2-methyl-1-(methylamino)propan-2-ol (53 mg, 0.51 mmol, 3.0 equiv) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (88 mg, 0.68 mmol, 0.12 mL, 4.0 equiv), and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1-0:1) to give 5-[3-(4-chlorophenyl)-5-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-7-methylsulfanyl-pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Intermediate I-4(d), 60 mg, 125 μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.10 (d, J = 1.2Hz, 2H), 7.51-7.38 (m, 4H), 6. 70-6.31(m,1H),4.63(s,1H),3.65(s,2H),3.26(s,3H),2.70(s,3H),1.15(s,6H).

[0446] Example 6 - Preparation of Compounds 1 to 78

[0447] (i) Compound 1:

[0448]

[0449] To a solution of intermediate I-2(a) from Example 3(i) (40 mg, 73.6 μmol, 1 eq) and [(2S)-pyrrolidin-2-yl]methanol (22.3 mg, 220.6 μmol, 0.021 mL, 3 eq) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (647.2 μmol, 0.11 mL, 8.8 eq), and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 55%-85%, 10min) to give the product 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]-4-(ethylamino)piperidine-4-carboxamide (Compound 1, 17.21 mg, 98.9% purity) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.54-7.36 (m, 6H), 7.17 (d, J = 7.2 Hz, 2H), 5.76 (d, J = 4.4 Hz, 1H), 4.34 (br s, 1H), 3.84-3.52 (m, 8H), 2.60-2.49 (m, 2H), 2.33-1.81 (m, 8H), 1.14 (t, J = 6.8 Hz, 3H). LCMS: (ES + )m / z=608.2(M+H) + .

[0450] (ii) Compound 2:

[0451]

[0452] To a solution of intermediate I-2(o) from Example 3(xv) (50 mg, 95.1 μmol, 1.0 eq) and [(2S)-pyrrolidin-2-yl]methanol (29 mg, 0.29 mmol, 3.0 eq) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.84 mmol, 0.15 mL, 8.8 eq) and the mixture was stirred at 80 °C for 16 hours. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 70%-100%, 8min). The fractions were then concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethyl)-1-piperidinyl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 2, 32.07 mg) as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.55-7.38 (m, 6H), 7.18 (d, J = 8.8Hz, 2H), 5.78 (s, 1H), 4.37 (d, J = 12.0Hz, 3 H),3.94-3.48(m,4H),2.92(t,J=12.4Hz,2H),2.47(m,1H),2.16-1.98(m,6H),1.97-1.82(m,2H). LCMS: (ES + )m / z=590.3(M+H).

[0453] (iii) Compound 3:

[0454]

[0455] To a mixture of intermediate I-4(b) from Example 5(ii) (36 mg, 74.8 μmol, 1 eq), (3-cyanophenyl)boronic acid (22 mg, 149.7 μmol, 2 eq) and 3-methylsalicylate copper(I) (48 mg, 224.5 μmol, 3 eq) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (9 mg, 7.5 μmol, 0.1 eq). The mixture was then stirred at 60° C. for 3 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 64%-94%, 10min) and preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 69%-89%, 10min) to give 3-[3-(4-chlorophenyl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]benzonitrile (Compound 3, 9.82 mg, 100% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.41 (d, J = 7.6Hz, 1H), 8.05 (d, J = 7.6Hz, 1H), 7.83-7.74 (m, 1H), 7.54 (d ,J=8.4Hz,2H),7.44(t,J=7.6Hz,1H),7.36(d,J=7.2Hz,1H),7.27(d,J=8.4Hz,2H),7.11-7.00(m,2H),6.76(br s,1H),4.87(br s,1H),4.42-4.09(m,1H),3.76-3.52(m,4H),3.44(s,3H),2.12-1.94(m,4H). LCMS: (ES + )m / z=536.3(M+H).

[0456] (iv) Compound 4:

[0457]

[0458] To a mixture of intermediate I-4(a) from Example 5(i) (50 mg, 103 μmol, 1 eq), [4-(trifluoromethyl)phenyl]boronic acid (39 mg, 206.0 μmol, 2 eq) and 3-methylsalicylate copper(I) (66 mg, 309.0 μmol, 3 eq) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (12 mg, 10.3 μmol, 0.1 eq), and the mixture was stirred at 60° C. for 16 h. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 70%-100%, 10min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 4, 19.80 mg, 100% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(d, J = 8.4Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.58-7.39 (m, 6H), 7.34-7.25 ( m,2H),6.90-6.55(m,1H),5.05-4.74(m,1H),4.46-4.10(m,1H),3.75-3.55(m,4H),2.17-1.82(m,4H). LCMS: (ES + )m / z=583.2(M+H).

[0459] (v) Compound 5:

[0460]

[0461] To a mixture of intermediate I-4(a) from Example 5(i) (50 mg, 103 μmol, 1 eq), (4-methoxyphenyl)boronic acid (31 mg, 206.0 μmol, 2 eq) and 3-methylsalicylate copper(I) (66 mg, 309.0 μmol, 3 eq) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (12 mg, 10.3 μmol, 0.1 eq), and the mixture was stirred at 60° C. for 16 h. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 68%-98%, 10min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 5, 18.93 mg, 100% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.04 (d, J = 8.8Hz, 2H), 7.58-7.43 (m, 6H), 7.28 (d, J = 8.8Hz, 2H), 7.13 (d, J = 8.8Hz, 2H), 6.79-6 .52(m,1H),5.07-4.67(m,1H),4.46-4.12(m,1H),3.84(s,3H),3.77-3.64(m,2H),3.62-3.43(m,2H),2.20-1.95(m,4H). LCMS: (ES + )m / z=545.3(M+H).

[0462] (vi) Compound 6:

[0463]

[0464] To a mixture of intermediate I-4(b) from Example 3(ii) (36 mg, 74.8 μmol, 1 eq), [4-(trifluoromethyl)phenyl]boronic acid (28 mg, 149.7 μmol, 2 eq) and 3-methylsalicylate copper(I) (48 mg, 224.5 μmol, 3 eq) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (9 mg, 7.5 μmol, 0.1 eq), and the mixture was stirred at 60° C. for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 70%-100%, 10min) to give [(2S)-1-[3-(4-chlorophenyl)-2-(2-methoxyphenyl)-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 6, 12.13 mg, 98% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(d, J = 8.0Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.55 ( d,J=8.4Hz,2H),7.44(t,J=7.6Hz,1H),7.34(d,J=6.8Hz,1H),7.27(d,J=8.4H z,2H),7.10-6.99(m,2H),6.81-6.64(m,1H),5.13-4.76(m,1H),4.47-4.08( m,1H),3.79-3.66(m,2H),3.64-3.56(m,2H),3.43(s,3H),2.10-1.94(m,4H). LCMS: (ES + )m / z=579.3(M+H).

[0465] (vii) Compound 7:

[0466]

[0467] To a solution of intermediate I-2(b) from Example 3(ii) (45 mg, 76.2 μmol, 1 eq.) and [(2S)-pyrrolidin-2-yl]methanol (23 mg, 228.5 μmol, 0.02 mL, 3 eq.) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.12 mL, 670.2 μmol, 8.8 eq.), and the mixture was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 67%-97%, 10min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethylsulfonyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 7, 24.76mg, % purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.59-7.43 (m, 6H), 7.24 (d, J = 8.8Hz, 2H), 5.83 (br s,1H),5.04-4.80(m,1H),4.34-4.10(m,1H),3.81-3.60(m,12H),2.12-1.72(m,4H). LCMS: (ES + )m / z=655.2(M+H).

[0468] (viii) Compound 8:

[0469]

[0470] A mixture of intermediate I-4(a) (1.35 g, 2.8 mmol, 1 eq.) from Example 5(i), [6-(trifluoromethyl)-3-pyridyl]boronic acid (1.1 g, 5.6 mmol, 2 eq.), 3-methylsalicylate copper(I) (1.8 g, 8.3 mmol, 3 eq.) and tetrakis(triphenylphosphine)palladium (321 mg, 278 μmol, 0.1 eq.) in tetrahydrofuran (13.5 mL) was stirred at 60° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (30 mL) and filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC, and the fractions were then concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[6-(trifluoromethyl)-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 8, 747 mg, 98.8% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.90-8.69 (m, 1H), 8.16 (d, J = 8.4Hz, 1H), 7.58-7.49 (m, 5H), 7.48-7.43 (m, 1 H),7.30(d,J=8.4Hz,2H),7.05-6.79(m,1H),4.86(m,1H),4.52-4.12(m,1H),3.86-3.45(m,4H),2.21-1.86(m,4H). LCMS: (ES + )m / z=584.2(M+H).

[0471] (ix) Compound 9:

[0472]

[0473] To a solution of intermediate I-2(c) from Example 3(iii) (55 mg, 106.8 μmol, 1 eq) and [(2S)-pyrrolidin-2-yl]methanol (32 mg, 320.5 μmol, 0.03 mL, 3 eq) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.16 mL, 940.1 μmol, 8.8 eq), and the mixture was stirred at 80 °C for 16 h. The mixture was purified by preparative HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 51%-81%, 8min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give the product 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 9, 35.25 mg, 99.2% purity) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.54-7.38(m,6H),7.17(d,J=8.8Hz,2H),5.74(s,1H),4.33(s,1H),3.96-3.86(m,2H),3.80(m,1H),3.72- 3.63(m,2H),3.55(d,J=8.4Hz,1H),3.27(t,J=11.2Hz,2H),2.26(d,J=14.4Hz,2H),2.16-2.00(m,4H),1.78(m,2H),1.29(s,3H). LCMS: (ES + )m / z=579.3(M+H).

[0474] (x) Compound 10:

[0475]

[0476] To a solution of intermediate I-2(c) from Example 3(iii) (55 mg, 106.8 μmol, 1 eq) and 2-(methylamino)ethanol (24 mg, 320.5 μmol, 0.03 mL, 3 eq) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.16 mL, 940.1 μmol, 8.8 eq) and the mixture was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 47%-77%, 9min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give the product 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[2-hydroxyethyl(methyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 10, 27.62 mg, 100% purity) as a white solid. 1H NMR (400MHz, methanol-d4) δ = 7.54-7.39 (m, 6H), 7.17 (d, J = 8.8Hz, 2H), 5.86 (s, 1H), 3.94-3.83 ( m, 4H), 3.82-3.77 (m, 2H), 3.26 (s, 5H), 2.26 (d, J = 14.4Hz, 2H), 1.79 (m, 2H), 1.30 (s, 3H). LCMS: (ES + )m / z=553.3(M+H).

[0477] (xi) Compound 11:

[0478]

[0479] To a solution of intermediate I-2(d) from Example 3(iv) (30 mg, 57.5 μmol, 1 eq) and [(2S)-pyrrolidin-2-yl]methanol (17 mg, 172.5 μmol, 0.02 mL, 3 eq) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (505.9 μmol, 0.09 mL, 8.8 eq) and the mixture was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 54%-84%, 10min) was purified, and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[(1,1-dioxothianilan-4-yl)amino]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 11, 19.01 mg, 98.2% purity) as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.55-7.39 (m, 6H), 7.18 (d, J = 8.8Hz, 2H), 5.57 (s, 1H), 4.74-4.51 (m, 2H), 4.37 (d, J = 8.8Hz, 1H), 4.13-4.02 (m, 1 H),3.84-3.77(m,1H),3.69(m,2H),3.57(d,J=8.9Hz,1H),3.29-3.19(m,2H),2.55-2.43(m,2H),2.40-2.27(m,2H),2.18-2.02(m,4H). LCMS: (ES + )m / z=587.9(M+H).

[0480] (xii) Compound 12:

[0481]

[0482] To a solution of intermediate I-2(e) from Example 3(v) (80 mg, 185 μmol, 1 eq) and 2-(methylamino)ethanol (42 mg, 554.6 μmol, 0.05 mL, 3 eq) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (1.6 mmol, 0.28 mL, 8.8 eq) and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified twice by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; first purification using B%: 55%-85%, 8min; second purification using B%: 67%-97%, 10min), then the fractions were concentrated to remove acetonitrile and lyophilized to give 2-[[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-isopropoxy-pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]ethanol (Compound 12, 44.55 mg, 98.7% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.59-7.43 (m, 6H), 7.25 (d, J = 8.4Hz, 2H), 6.09 (s, 1H), 5.17 (m,1H),4.78(t,J=4.8Hz,1H),3.73-3.65(m,4H),3.22(s,3H),1.44(d,J=6.0Hz,6H). LCMS: (ES + )m / z=471.2(M+H).

[0483] (xiii) Compound 13:

[0484]

[0485] A mixture of intermediate I-2(c) from Example 3(iii) (70 mg, 136 μmol, 1 eq.), 2-methylpropane-1,2-diol (61 mg, 679.83 μmol, 5 eq.) and potassium 2-methylpropan-2-ol (46 mg, 407.90 μmol, 3 eq.) in N,N-dimethylformamide (0.5 mL) was stirred at 80° C. for 1 hour. The reaction mixture was diluted with N,N-dimethylformamide (1 mL) and purified by reverse phase HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -ACN]; B%: 56%-86%, 10min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 13, 42.58 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.61-7.44(m,4H),7.44-7.37(m,2H),7.36-7.30(m,2H),7.26(s,1H),6.96(s,1H),5.95(s,1H),4.68(s ,1H),4.14(s,2H),4.04-3.92(m,2H),3.36(s,1H),3.31(s,1H),2.18-2.08(m,2H),1.58-1.48(m,2H),1.22(s,6H),1.16(s,3H). LCMS: (ES+)m / z=570.1(M+H).

[0486] (xiv) Compound 14:

[0487]

[0488] To a solution of intermediate I-2(f) (80 mg, 164 μmol, 1 eq.) from Example 3(vi) and 2-methylpropane-1,2-diol (44 mg, 492.00 μmol, 3 eq.) in THF (1 mL) was added potassium tert-butoxide (55 mg, 492.00 μmol, 3 eq.). The mixture was stirred at 80 °C for 12 hours. The mixture was diluted with ethyl acetate (10 mL x 3), washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 66%-86%, 10min) to obtain 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidin-4-ol (Compound 14, 24.48 mg) as an off-white solid. 1HNMR(400MHz, DMSO-d6)δ=7.63-7.43(m,4H),7.43-7.37(m,2H),7.35-7.27(m,2H),5.95(s,1H),4.67(s,1H), 4.44(s,1H),4.14(s,2H),4.07-3.95(m,2H),3.50-3.37(m,2H),1.73-1.46(m,4H),1.22(s,6H),1.18(s,3H). LCMS: (ES + )m / z=541.4(M+H).

[0489] (xv) Compound 15:

[0490]

[0491] To a solution of 2-methylpropane-1,2-diol (37 mg, 406.21 μmol, 3 eq.) in THF (2 mL) was added sodium hydride (16 mg, 406.21 μmol, 60% purity, 3 eq.), and the solution was stirred at 25 ° C for 0.5 hours. Intermediate I-2 (b) (80 mg, 135.4 μmol, 1 eq.) from Example 3 (ii) was added to the mixture and stirred at 25 ° C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mLx3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 10min) to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethylsulfonyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-5-yl]oxy-2-methyl-propan-2-ol (Compound 15, 52.8mg) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 7.53-7.45 (m, 1H), 7.44-7.30 (m, 5H), 7.24 (d, J = 8.4Hz, 2H), 5.82 (s, 1H), 4.32 (s, 2H), 3.78 (br s, 8H), 1.36 (s, 6H). LCMS: (ES + )m / z=644.1(M+H).

[0492] (xvi) Compound 16:

[0493]

[0494] To a solution of 2-methylpropane-1,2-diol (30 mg, 335 μmol, 3 eq.) in THF (2 mL) was added sodium hydride (14 mg, 335 μmol, 60% purity, 3 eq.), and the solution was stirred at 25 ° C for 0.5 hours. Intermediate I-2 (g) (60 mg, 112 μmol, 1 eq.) from Example 3 (vii) was added to the mixture and stirred at 25 ° C for 2 hours. The reaction mixture was washed with water (10 mL) and extracted with ethyl acetate 20 mL (10 mL×2). The combined organic layer was washed with brine 20 mL (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 56%-86%, 10min), and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl]oxy-2-methyl-propan-2-ol (Compound 16, 22.21 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.60-7.44(m,4H),7.43-7.37(m,2H),7.36-7.29(m,2H),6.05(s ,1H),4.69(s,1H),4.15(s,2H),3.80(s,4H),3.32-3.29(m,4H),2.93(s,3H),1.23(s,6H). LCMS: (ES + )m / z=590.1(M+H).

[0495] (xvii) Compound 17(S):

[0496]

[0497] A mixture of 2-methylpropane-1,2-diol (199.75 mg, 2.22 mmol, 3 equiv) and LiHMDS (1 M, 2.22 mL, 3 equiv) in tetrahydrofuran (1 mL) was stirred at 80 ° C for 0.5 hours under N2 atmosphere, and then a solution of intermediate I-2 (l) (370 mg, 0.74 mmol, 1 equiv) from Example 3 (xii) in tetrahydrofuran (2 mL) was added to the mixture, and the mixture was stirred at 80 ° C for 5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (30 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mmx5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 54%-84%, 8min). The fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give (3S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 17(S), 78.68 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.59-7.45(m,5H),7.43-7.37(m,2H),7.37-7.29(m,2H),6.91(s,1H),5.99(s,1H),4.68( s,1H),4.27(t,J=14.8Hz,2H),4.15(s,2H),3.29-3.21(m,1H),3.09-2.99(m,1H),2.01-1.54(m,5H),1.23(s,6H). LCMS: (ES+)m / z=554.2(M+H).

[0498] (xviii) Compound 17(R):

[0499]

[0500] A mixture of intermediate I-2(h) from Example 3(viii) (130 mg, 259.6 μmol, 1 eq.), 2-methylpropane-1,2-diol (117 mg, 1.30 mmol, 5 eq.) and potassium 2-methylpropan-2-ol (87 mg, 778.74 μmol, 3 eq.) in N,N-dimethylformamide (1 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with N,N-dimethylformamide (2 mL) and purified by reverse phase HPLC (column: WatersTM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -ACN]; B%: 52%-82%, 10min) to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 17(R), 9.10 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.61-7.47(m,5H),7.47-7.30(m,4H),6.95-6.89(m,1H),6.00(s,1H),4.69(s,1H),4.34- 4.21(m,2H),4.15(s,2H),3.30-3.20(m,2H),3.11-2.98(m,1H),2.00-1.85(m,1H),1.81-1.57(m,3H),1.23(s,6H). LCMS: (ES+)m / z=554.2(M+H).

[0501] (xix) Compound 18:

[0502]

[0503] To a solution of intermediate I-2(c) from Example 3(iii) (80 mg, 155 μmol, 1 eq) and (2S)-pyrrolidine-2-carboxylic acid (54 mg, 466.2 μmol, 3 eq) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (1.4 mmol, 0.24 mL, 8.8 eq), and the mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 26%-56%, 8min) and preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 48%-78%, 10min) to give (2S)-1-[7-(4-carbamoyl-4-methyl-1-piperidinyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-2-carboxylic acid (Compound 18, 13.69 mg, 100% purity) as an off-white solid. 1H NMR (400MHz, methanol-d4) δ = 7.56-7.46 (m, 5H), 7.45-7.40 (m, 1H), 7.14 (d, J = 8.8Hz, 2H), 5.74 (br s,1H),4.68-4.59(m,1H),4.02-3.84(m,2H),3.80-3.59(m,2H),3.31-3.22(m,2H ), 2.41 (dt, J = 3.6, 8.0 Hz, 1H), 2.31-2.12 (m, 5H), 1.84-1.72 (m, 2H), 1.29 (s, 3H). LCMS: (ES + )m / z=593.3(M+H). SFC: ee value>99%.

[0504] (xx) Compound 19:

[0505]

[0506] To a solution of intermediate I-2(c) (50 mg, 97 μmol, 1 eq.) from Example 3(iii) and 2-[(2R)-azetidin-2-yl]acetic acid (44 mg, 194.2 μmol, 2 eq., TFA salt) from Example 1(vii) in tetrahydrofuran (2.5 mL) was added potassium tert-butoxide (54 mg, 485.6 μmol, 5 eq.), and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters TM Xbridge150x25mm, 5μm; mobile phase: [water (ammonium hydroxide v / v)-acetonitrile]; B%: 12%-42%, 9min) was purified to give 2-[(2R)-1-[7-(4-carbamoyl-4-methyl-1-piperidinyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidin-2-yl]acetic acid (Compound 19, 14.72 mg, 100% purity) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.53-7.41 (m, 6H), 7.16 (d, J = 8.8 Hz, 2H), 5.64 (s, 1H), 4.82-4.74 (m, 1H), 4.17-4.01 (m, 2H), 3.95-3.83 (m, 2H), 3.31-3.18 (m, 3H), 2.67 (m, 2H), 2.30-2.21 (m, 3H), 1.82-1.72 (m, 2H), 1.29 (s, 3H). LCMS: (ES + )m / z=593.3(M+H).

[0507] (xxi) Compound 20:

[0508]

[0509] To a solution of intermediate I-2(c) (50 mg, 97 μmol, 1 eq.) from Example 3(iii) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 854.65 μmol, 0.15 mL, 8.8 eq.) and 2-methyl-1-(methylamino)propan-2-ol (50 mg, 485.60 μmol, 0.04 mL, 5 eq.). The mixture was stirred at 120 °C for 2 hours. 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 preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 56%-86%, 8min) was purified, and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2-hydroxy-2-methyl-propyl)-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 20, 36.38 mg, 100% purity) as an off-white solid. 1 H NMR (400MHz, CDCl3) δ = 7.37-7.32 (m, 2H), 7.26-7.17 (m, 4H), 7.10 (d, J = 8.8Hz, 2H), 5.66 (d, J = 15.2Hz, 2H), 5.51 (s, 1H), 3.93-3. 80(m,2H),3.62(s,2H),3.30(t,J=10.0Hz,2H),3.12(s,3H),2.09(d,J=14.4Hz,2H),1.77-1.62(m,2H),1.20(s,3H),1.19(s,6H). LCMS: (ES + )m / z=581.2(M+H).

[0510] (xxii) Compound 21:

[0511]

[0512] To a solution of intermediate I-2(c) from Example 3(iii) (50 mg, 97 μmol, 1 eq.) in N-methyl-3-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 854.65 μmol, 0.15 mL, 8.8 eq.) and (3R)-pyrrolidin-3-ol (42 mg, 485.59 μmol, 0.04 mL, 5 eq.). The mixture was stirred at 120 °C for 2 hours. 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 preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 57%-77%, 10min), and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 21, 29.15 mg, 100% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.60-7.55(m,1H),7.54-7.43(m,5H),7.29-7.21(m,3 H),6.94(s,1H),5.65(s,1H),5.01(s,1H),4.41(s,1H),3.88(t,J=10.8Hz,2H) ,3.63-3.59(m,3H),3.55-3.41(m,1H),3.27-3.13(m,2H),2.13(d,J=14.0Hz,2 H), 2.07-1.99 (m, 1H), 1.97-1.87 (m, 1H), 1.53 (t, J = 10.8Hz, 2H), 1.15 (s, 3H). LCMS: (ES + )m / z=565.2(M+H).

[0513] (xxiii) Compound 22:

[0514]

[0515] A mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 155 μmol, 1 eq.), 3-(methylamino)propionamide (48 mg, 466.17 μmol, 3 eq.) and N,N-diisopropylethylamine (176.73 mg, 1.37 mmol, 0.24 mL, 8.8 eq.) in acetonitrile (1 mL) was stirred at 80° C. for 46 h. The reaction mixture was diluted with N,N-dimethylformamide (2 mL) and purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 10min). The fractions were concentrated under reduced pressure to give 1-[5-[(3-amino-3-oxo-propyl)-methyl-amino]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 22, 42.42 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.60-7.56(m,1H),7.55-7.44(m,5H),7.44-7.26(m,2H),7.25-7.20(m,2H),6.98-6.85(m,2H),5.84(s,1H),3.95-3 .85(m,2H),3.82(t,J=6.8Hz,2H),3.26-3.16(m,2H),3.14(s,3H),2.4 5(t,J=6.8Hz,2H),2.20-2.11(m,2H),1.59-1.49(m,2H),1.16(s,3H). LCMS: (ES+)m / z=580.2(M+H).

[0516] (xxiv) Compound 23:

[0517]

[0518] A mixture of intermediate I-2(h) (100 mg, 200 μmol, 1 eq.) from Example 3(viii), 3-(methylamino)propionamide (61.18 mg, 599.03 μmol, 3 eq.) and N,N-diisopropylethylamine (227.10 mg, 1.76 mmol, 0.3 mL, 8.8 eq.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100 °C for 20 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL). The resulting mixture was purified by reverse phase HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 10min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give (3R)-1-[5-[(3-amino-3-oxo-propyl)-methyl-amino]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 23, 47.44 mg, 100% purity) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 9.50 (s, 1H), 7.52-7.48 (m, 1H), 7.47-7.30 (m, 5H), 7.25-7.18 (m,2H),6.07(s,1H),5.75(s,1H),5.50(s,1H),5.27(s,1H),4.95(d,J=12.8Hz,1H),4 .09-3.92(m,2H),3.49-3.41(m,1H),3.24-3.14(m,4H),2.94-2.86(m,1H),2.67-2.6 4(m,2H),2.60-2.51(m,1H),1.89-1.79(m,2H),1.75-1.67(m,1H),1.09-1.00(m,1H). LCMS: (ES+)m / z=566.2(M+H).

[0519] (xxv) Compound 24:

[0520]

[0521] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 903.90 μmol, 0.16 mL, 8.8 eq.) and 3-(methylamino)propionamide (52 mg, 513.58 μmol, 5 eq.). The mixture was stirred at 140 °C for 2 hours. 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 preparative HPLC (column: Phenomenex TMLuna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 33%-63%, 2min), and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 3-[[7-[3-(2-amino-2-oxo-ethyl)azetidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]propanamide (Compound 24, 26.71 mg, 98.4% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.57-7.45 (m, 6H), 7.37 (d, J = 8.4Hz, 2H), 7.24-7.14 (m, 2H), 6.86 (d, J = 11.2Hz, 2H), 5.31-5.20 (m, 1H), 4.54-4.38(m,2H),4.04(s,2H),3.78(t,J=7.2Hz,2H),3.09(s,3H),3.03-2.92(m,1H),2.61-2.52(m,2H),2.43(t,J=6.8Hz,2H). LCMS: (ES + )m / z=552.2(M+H).

[0522] (xxvi) Compound 25:

[0523]

[0524] To a solution of intermediate I-2(c) (50 mg, 97 μmol, 1 eq.) from Example 3(iii) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 854.66 μmol, 0.15 mL, 8.8 eq.) and N,N-dimethyl-2-(methylamino)acetamide (34 mg, 291.36 μmol, 3 eq.). The mixture was stirred at 80 °C for 16 hours. 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 preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 50%-80%, 8min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to obtain a residue. The residue was dissolved in acetonitrile (2mL) and purified by preparative HPLC (column: Phenomenex TMLuna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 49%-79%, 10min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(dimethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 25, 17.26 mg, 100% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.58-7.46 (m, 4H), 7.38 (d, J = 8.4Hz, 2H), 7.27-7.20 (m, 3H), 6.98-6.90 (m, 1H), 5.84 (s, 1H), 4.48 (s ,2H),3.95-3.79(m,4H),3.17(s,3H),3.07(s,3H),2.86(s,3H),2.14(d,J=12.8Hz,2H),1.53(t,J=10.0Hz,2H),1.16(s,3H). LCMS: (ES + )m / z=594.4(M+H).

[0525] (xxvii) Compound 26:

[0526]

[0527] To a solution of N-ethyl-2-(methylamino)acetamide (44 mg, 291 μmol, 5 eq.) from Example 1(viii) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (66 mg, 513 μmol, 0.09 mL, 8.8 eq.) and intermediate I-2(c) (30 mg, 58 μmol, 1 eq.) from Example 3(iii), and the mixture was stirred at 140°C for 2 hours. 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 preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 51%-81%, 2min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 26, 34.10 mg, 100% purity) as a yellow solid.1 H NMR (400MHz, CDCl3) δ=7.48-7.45(m,2H),7.43-7.29(m,4H),7.23-7.17(m,2H),6.56(s,1H),5.70-5.32(m,3H),4.22(s,2H),4.08-3 .90(m,2H),3.42(t,J=9.6Hz,2H),3.28-3.17(m,5H),2.21(d,J=13.2Hz,2H),1.85-1.78(m,2H),1.33(s,3H),0.93(t,J=7.2Hz,3H). LCMS: (ES + )m / z=594.3(M+H).

[0528] (xxviii) Compound 27:

[0529]

[0530] A mixture of intermediate I-2(j) from Example 3(x) (40 mg, 76 μmol, 1 eq.), 3-(methylamino)propionamide (23 mg, 226.90 μmol, 3 eq.) and N,N-diisopropylethylamine (86 mg, 665.58 μmol, 0.12 mL, 8.8 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (2 mL). The mixture was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 51%-81%, 10min). The resulting liquid was concentrated under reduced pressure to remove acetonitrile and lyophilized to obtain 3-[[7-(4-acetamido-4-methyl-1-piperidinyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]propanamide (Compound 27, 19.88 mg, 100% purity) as a white solid. 1H NMR (400MHz, CDCl3) δ=7.50-7.42(m,4H),7.41-7.31(m,2H),7.21(d,J=8.4Hz,2H),6.42-6.29(m,1H),5.63(s,1H),5.25-5.14(m,2H),4.03-3.9 7(m,2H),3.97-3.89(m,2H),3.49-3.33(m,2H),3.18(s,3H),2.70-2.63 (m,2H),2.37-2.27(m,2H),2.01(s,3H),1.97-1.87(m,2H),1.50(s,3H). LCMS: (ES+)m / z=594.3(M+H).

[0531] (xxix) Compound 28:

[0532]

[0533] To a solution of intermediate I-2(k) from Example 3(xi) (40 mg, 80 μmol, 1 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (91 mg, 702.87 μmol, 0.12 mL, 8.8 eq.) and 3-(methylamino)propionamide (41 mg, 399.35 μmol, 5 eq.). The mixture was stirred at 140 °C for 6 hours. 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 preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 34%-64%, 2min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 3-[[7-[(3R)-3-(2-amino-2-oxo-ethyl)pyrrolidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]propanamide (Compound 28, 19.24 mg, 100% purity) as a white solid. 1H NMR (400MHz, CDCl3) δ = 7.48-7.39 (m, 4H), 7.39-7.28 (m, 2H), 7.18 (d, J = 8. 4Hz,2H),6.72(s,1H),5.65-5.29(m,2H),5.18(s,2H),4.13-4.01(m,2H),4 .01-3.86(m,3H),3.70-3.66(m,1H),3.11(s,3H),2.81-2.74(m,1H),2.63 (t,J=6.4Hz,2H),2.50-2.33(m,2H),2.32-2.20(m,1H),1.79-1.68(m,1H). LCMS: (ES + )m / z=566.2(M+H).

[0534] (xxx) Compound 29:

[0535]

[0536] A mixture of intermediate I-2(h) from Example 3(viii) (80 mg, 160 μmol, 1 eq.), N,N-dimethyl-2-(methylamino)acetamide (56 mg, 479.23 μmol, 3 eq.) and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 0.25 mL, 8.8 eq.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL), and the resulting mixture was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 48%-78%, 10min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give (3R)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(dimethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 29, 39.87 mg, 100% purity) as a yellow solid. 1H NMR (400MHz, CDCl3) δ = 9.61 (s, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.43-7.30 (m, 5H), 7.20-7.13 (m,2H),5.81(s,1H),5.47(s,1H),4.98(d,J=13.2Hz,1H),4.73(d,J=16.4Hz,1H),4.26( d,J=16.4Hz,1H),3.53-3.44(m,1H),3.30(s,3H),3.21-3.11(m,4H),3.04(s,3H),2.90- 2.83(m,1H),2.70-2.64(m,1H),2.62-2.53(m,1H),1.89-1.80(m,2H),1.75-1.63(m,1H). LCMS: (ES+)m / z=580.2(M+H).

[0537] (xxxi) Compound 30:

[0538]

[0539] To a solution of intermediate I-2(k) from Example 3(xi) (40 mg, 80 μmol, 1 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (91 mg, 702.87 μmol, 0.12 mL, 8.8 eq.) and 1-dimethylphosphoryl-N-methyl-methylamine (48 mg, 399.36 μmol, 5 eq.). The mixture was stirred at 140 °C for 6 hours. 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 preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 46%-76%, 10min), and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 2-[(3R)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[dimethylphosphorylmethyl(methyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl]acetamide (Compound 30, 22.02 mg, 100% purity) as a white solid. 1H NMR (400MHz, CDCl3) δ = 7.48-7.28 (m, 6H), 7.16 (d, J = 8.4Hz, 2H), 5.74-5.30 (m, 2H), 5.23 (s, 1H), 4.29-4.15 (m, 2H), 4.14-4.03 (m, 2H), 3.98-3. 87(m,1H),3.71-3.66(m,1H),3.30(s,3H),2.82-2.75(m,1H),2.51-2.3 4(m,2H),2.31-2.23(m,1H),1.80-1.74(m,1H),1.50(d,J=12.4Hz,6H). LCMS: (ES + )m / z=585.2(M+H).

[0540] (xxxii) Compound 31:

[0541]

[0542] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 eq.) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 eq.) and N-ethyl-2-(methylamino)acetamide (47 mg, 0.3 mmol, 3 eq.) from Example 1(viii). The mixture was stirred at 80 °C for 48 hours. 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 preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 53%-73%, 10min), and the fractions were concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 2-[1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]azetidin-3-yl]acetamide (Compound 31, 9.14 mg, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.52-7.29 (m, 6H), 7.17-7.07 (m, 2H), 5.25 (s, 1H), 4.58 (t, J = 8.4 Hz, 2H), 4.23 (s, 2H), 4.17-4.14 (m, 2H), 3.25-3.17 (m, 5H), 3.16-3.05 (m, 1H), 2.65 (d, J = 7.6 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H). LCMS: (ES + )m / z=566.2(M+H).

[0543] (xxxiii) Compound 32:

[0544]

[0545] To a solution of intermediate I-2(i) from Example 3(ix) (40 mg, 82 μmol, 1 eq.) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (93 mg, 0.72 mmol, 0.13 mL, 8.8 eq.) and N,N-dimethyl-2-(methylamino)acetamide (29 mg, 0.25 mmol, 3 eq.). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 51%-81%, 10min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to obtain a residue. The residue was dissolved in acetonitrile (2mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 10min) and the fraction was concentrated under reduced pressure to remove acetonitrile and then lyophilized to obtain a residue. The residue was dissolved in acetonitrile (2mL) and purified by preparative HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 40%-70%, 8min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 2-[1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(dimethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]azetidin-3-yl]acetamide (Compound 32, 5.25 mg, 98.3% purity) as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.49-7.33 (m, 6H), 7.11 (d, J = 8.8Hz, 2H), 5.25 (s, 1H), 4.57 (t, J = 8.4Hz, 2H), 4.50 ( s,2H),4.16-4.12(m,2H),3.20(s,3H),3.15(s,3H),3.13-3.05(m,1H),2.98(s,3H),2.65(d,J=7.6Hz,2H). LCMS: (ES + )m / z=566.2(M+H).

[0546] (xxxiv) Compound 33:

[0547]

[0548] To a solution of intermediate I-2(i) (50 mg, 103 μmol, 1 eq) from Example 3(ix) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 eq) and 1-dimethylphosphoryl-N-methyl-methylamine (62 mg, 0.5 mmol, 5 eq). The mixture was stirred at 140° C. for 6 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 48%-78%, 10 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 2-[1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[dimethylphosphorylmethyl(methyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]azetidin-3-yl]acetamide (Compound 33, 13.66 mg, 98.9% purity) as an off-white solid. 1H NMR (400MHz, CDCl3) δ=7.46-7.28(m,6H),7.15(d,J=8.8Hz,2H),5.55-5.25(m,2H),5.04(s,1H),4.66(t,J=8 .8Hz,2H),4.31-4.11(m,4H),3.28(s,3H),3.23-3.16(m,1H),2.67(d,J=7.6Hz,2H),1.50(d,J=12.4Hz,6H). LCMS: (ES + )m / z=571.2(M+H).

[0549] (xxxv) Compound 34:

[0550]

[0551] A mixture of intermediate I-2(h) from Example 3(viii) (80 mg, 160 μmol, 1 eq.), 1-dimethylphosphoryl-N-methyl-methylamine (58 mg, 0.48 mmol, 3 eq.) and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 0.24 mL, 8.8 eq.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 80° C. for 32 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL), and the resulting mixture was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 37%-67%, 10min). The fractions were concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give (3R)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[dimethylphosphorylmethyl(methyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 34, 33.92 mg, 100% purity) as a white solid. 1H NMR (400MHz, CDCl3) δ = 9.35 (s, 1H), 7.43-7.38 (m, 1H), 7.35-7.21 (m, 5H), 7.14-7.08 (m, 2H), 5.72 (s, 1H), 5.39 (s, 1H), 4.88 (br d,J=13.2Hz,1H),4.21-4.08(m,2H),3.42-3.34(m,1H),3.29(s,3H),3.21-3.10(m,1H),2.92-2.82(m ,1H),2.66-2.58(m,1H),2.53-2.42(m,1H),1.82-1.71(m,2H),1.68-1.59(m,1H),1.48-1.39(m,6H). LCMS: (ES+)m / z=585.2(M+H).

[0552] (xxxvi) Compound 35:

[0553]

[0554] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 eq) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 eq) and (2S)-pyrrolidine-2-carboxamide hydrochloride (77 mg, 0.5 mmol, 5 eq). The mixture was stirred at 140 °C for 2 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 41%-71%, 2 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give (2S)-1-[7-[3-(2-amino-2-oxo-ethyl)azetidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-2-carboxamide (Compound 35, 14.21 mg, 100% purity) as an off-white solid. 1H NMR(400MHz, CDCl3)δ=7.49-7.39(m,4H),7.39-7.28(m,2H),7.24-7.05(m ,3H),5.56-5.26(m,3H),4.91(s,1H),4.74(d,J=6.4Hz,1H),4.63(t,J=8.0 Hz,2H),4.25-4.10(m,2H),3.64(t,J=8.0Hz,1H),3.48-3.36(m,1H),3.24 -3.11(m,1H),2.65(d,J=7.6Hz,2H),2.51-2.41(m,1H),2.26-1.99(m,3H). LCMS: (ES + )m / z=564.3(M+H).

[0555] (xxxvii) Compound 36:

[0556]

[0557] To a solution of intermediate I-2(k) (50 mg, 100 μmol, 1 eq.) from Example 3(xi) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (113 mg, 0.88 mmol, 0.15 mL, 8.8 eq.) and N-ethyl-2-(methylamino)acetamide (46 mg, 0.3 mmol, 3 eq. as HCl salt) from Example 1(viii). The mixture was stirred at 80 °C for 48 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 55%-75%, 10min) and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 2-[(3R)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl]acetamide (Compound 36, 9.25 mg, 100% purity) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 7.94 (t, J = 5.2Hz, 1H), 7.59-7.41 (m, 6H), 7.35 (s, 1H), 7. 20(d,J=8.8Hz,2H),6.82(s,1H),5.34(s,1H),4.15(s,2H),4.04-3.89(m,2H),3.8 8-3.77(m,1H),3.52-3.42(m,1H),3.16(s,3H),3.13-3.05(m,2H),2.62-2.55(m,1 H),2.26-2.18(m,2H),2.13-2.02(m,1H),1.70-1.58(m,1H),1.00(t,J=7.2Hz,3H). LCMS: (ES + )m / z=580.2(M+H).

[0558] (xxxviii) Compound 37:

[0559]

[0560] To a solution of intermediate I-2(c) (40 mg, 77.7 μmol, 1 eq.) from Example 3(iii) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (88 mg, 0.68 mmol, 0.12 mL, 8.8 eq.) and (2S)-pyrrolidine-2-carboxamide hydrochloride (58 mg, 0.39 mmol, 5 eq.). The mixture was stirred at 140 °C for 2 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 54%-74%, 2 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[5-[(2S)-2-carbamoylpyrrolidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 37, 29.41 mg, 100% purity) as an off-white solid. 1H NMR (400MHz, CDCl3) δ = 7.49-7.40 (m, 4H), 7.39-7.29 (m, 2H), 7.22-7.14 (m, 2H), 6.95 (d, J = 1.6Hz, 1H), 5.70-5.32 (m, 4H), 4.74 (d, J = 4.0Hz, 1H), 4. 04-3.91(m,2H),3.70(t,J=7.6Hz,1H),3.55-3.45(m,1H),3.44-3.29(m,2 H),2.50-2.40(m,1H),2.29-2.04(m,5H),1.89-1.74(m,2H),1.32(s,3H). LCMS: (ES + )m / z=592.2(M+H).

[0561] (xxxix) Compound 38:

[0562]

[0563] To a solution of intermediate I-2(c) (50 mg, 97 μmol, 1 eq) from Example 3(iii) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 0.85 mmol, 0.15 mL, 8.8 eq) and N-methyl-3-(methylamino)propionamide (75 mg, 0.48 mmol, 5 eq). The mixture was stirred at 140 °C for 2 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 51%-81%, 10 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[methyl-[3-(methylamino)-3-oxo-propyl]amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 38, 23.24 mg, 100% purity) as an off-white solid. 1H NMR (400MHz, CDCl3) δ = 7.49-7.42 (m, 4H), 7.40-7.29 (m, 2H), 7.20 (d, J = 8.4 Hz,2H),6.67-6.41(m,1H),5.77-5.61(m,1H),5.58(s,1H),5.45-5.24(m,1 H),3.96(t,J=6.0Hz,4H),3.49-3.36(m,2H),3.13(s,3H),2.69-2.57(m,2H ), 2.52 (d, J = 4.4Hz, 3H), 2.26-2.16 (m, 2H), 1.85-1.79 (m, 2H), 1.33 (s, 3H). LCMS: (ES + )m / z=594.3(M+H).

[0564] (xl) Compound 39:

[0565]

[0566] To a solution of intermediate I-2(i) (50 mg, 103 μmol, 1 eq) from Example 3(ix) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 eq) and N-methyl-3-(methylamino)propionamide (78 mg, 0.51 mmol, 5 eq). The mixture was stirred at 120 °C for 2 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 36%-66%, 10 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 3-[[7-[3-(2-amino-2-oxo-ethyl)azetidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]-N-methyl-propionamide (Compound 39, 19.80 mg, 100% purity) as an off-white solid. 1H NMR(400MHz, CDCl3)δ=7.50-7.40(m,4H),7.39-7.29(m,2H),7.19-7.17(m ,2H),7.05-6.93(m,1H),5.54-5.24(m,2H),4.97(s,1H),4.65(t,J=8.4Hz ,2H),4.20-4.16(m,2H),3.95(t,J=6.4Hz,2H),3.26-3.13(m,1H),3.06(s ,3H),2.67(d,J=7.6Hz,2H),2.60(t,J=6.0Hz,2H),2.42(d,J=4.8Hz,3H). LCMS: (ES + )m / z=566.2(M+H).

[0567] (xli) Compound 40:

[0568]

[0569] To a solution of intermediate I-2(c) (30 mg, 58.2 μmol, 1 eq.) from Example 3(iii) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (66 mg, 0.51 mmol, 0.09 mL, 8.8 eq.) and 1-dimethylphosphoryl-N-methyl-methylamine (35 mg, 0.29 mmol, 5 eq.). The mixture was stirred at 140 °C for 2 hours. 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 preparative HPLC (column: Phenomenex Luna C18 150x25 mm, 10 μm; mobile phase: [water (FA)-ACN]; B%: 55%-75%, 2 min), and the fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[dimethylphosphorylmethyl(methyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 40, 22.88 mg, 100% purity) as an off-white solid. 1H NMR (400MHz, CDCl3) δ = 7.49-7.42 (m, 2H), 7.41-7.28 (m, 4H), 7.21-7.13 (m, 2H), 5.77-5.38 (m, 3H), 4.23 (d, J = 4.4Hz, 2H), 4.04 -3.91(m,2H),3.50-3.38(m,2H),3.33(s,3H),2.21(d,J=14.2Hz,2H),1.85-1.78(m,2H),1.50(d,J=12.8Hz,6H),1.33(s,3H). LCMS: (ES + )m / z=599.2(M+H).

[0570] (xlii) Compound 41:

[0571]

[0572] A mixture of intermediate I-2(h) from Example 3(viii) (140 mg, 0.28 mmol, 1 eq.), N-methyl-3-(methylamino)propionamide (107 mg, 0.7 mmol, 2.5 eq., HCl salt) and N,N-diisopropylethylamine (318 mg, 2.46 mmol, 0.43 mL, 8.8 eq.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100° C. for 28 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL), and the resulting mixture was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 47%-77%, 8min). The fractions were concentrated under reduced pressure to give (3R)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[methyl-[3-(methylamino)-3-oxo-propyl]amino]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide (Compound 41, 109.79 mg, 100% purity) as a white solid. 1H NMR (400MHz, CDCl3) δ = 9.49 (s, 1H), 7.52-7.31 (m, 6H), 7.22 (d, J = 8.8Hz, 2H), 6.24 (s, 1H),5.74(s,1H),5.48(s,1H),4.94(d,J=13.2Hz,1H),4.12-4.01(m,1H),3.95-3.85( m,1H),3.49-3.41(m,1H),3.26-3.20(m,1H),3.18(s,3H),2.96-2.87(m,1H),2.71-2. 66(m,1H),2.63-2.57(m,5H),2.57-2.51(m,1H),1.90-1.79(m,2H),1.76-1.67(m,1H). LCMS: (ES+)m / z=580.2(M+H).

[0573] (xliii) Compound 42:

[0574]

[0575] To a solution of 2-methylpropane-1,2-diol (49 mg, 0.55 mmol, 3 eq.) in N,N-dimethylformamide (1 mL) was added sodium hydride (22 mg, 0.55 mmol, 60% purity, 3 eq.), and the mixture was stirred at 25 ° C for 0.5 hours. Then, intermediate I-2 (m) (100 mg, 0.183 mmol, 1 eq.) from Example 3 (xiii) was added, and the mixture was stirred at 25 ° C for 1.5 hours. The mixture was poured into ammonium chloride (10 mL) and extracted with ethyl acetate 15 mL (3x5 mL). The organic phase was then washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mmx10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 62% -92%, 10min) to give 1- [2- (2-chlorophenyl) -3- (4-chlorophenyl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a] pyrimidin-7-yl] -4-ethoxy -piperidine-4-carboxamide (compound 42, 32.75mg, 100% purity) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ=7.59-7.45(m,4H),7.43-7.38(m,2H),7.36-7.29(m,3H),7.22(s,1H),6.01(s,1H),4 .68(s,1H),4.18-4.11(m,4H),3.35(d,J=6.8Hz,4H),2.06-1.96(m,2H),1.93-1.86(m,2H),1.23-1.17(m,9H). LCMS: (ES + )m / z=598.3(M+H).

[0576] (xliv) Compound 43:

[0577]

[0578] To a solution of intermediate I-2(m) from Example 3(xiii) (120 mg, 0.22 mmol, 1 eq) and 2-(methylamino)ethanol (21 mg, 0.27 mmol, 3 eq) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (0.81 mmol, 0.14 mL, 8.8 eq) and the mixture was stirred at 100° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters TM Xbridge 150x25mmx5μm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 54% -84%, 8min) to give 1- [2- (2-chlorophenyl) -3- (4-chlorophenyl) -5- [2-hydroxyethyl (methyl) amino] pyrazolo [1,5-a] pyrimidin-7-yl] -4-ethoxy -piperidine-4-carboxamide (compound 43, 42.13 mg, 100% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ=7.59-7.43(m,6H),7.31(s,1H),7.25(d,J=8.8Hz,3H),5.87(s,1H),4.89-4.63(m,1H),4.02(d,J=1 2.0Hz,2H),3.71-3.63(m,4H),3.36(s,2H),3.28-3.16(m,5H),2.09-1.96(m,2H),1.93-1.86(m,2H),1.19(t,J=6.8Hz,3H). LCMS: (ES + )m / z=583.3(M+H).

[0579] (xlv) Compound 44:

[0580]

[0581] To a solution of intermediate I-2(m) from Example 3(xiii) (100 mg, 0.183 mmol, 1 eq) and 2-methyl-1-(methylamino)propan-2-ol (57 mg, 0.55 mmol, 3 eq) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (1.6 mmol, 0.28 mL, 8.8 eq) and the mixture was stirred at 100° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters TM Xbridge 150x25mmx5μm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 56% -86%, 8min) to give 1- [2- (2-chlorophenyl) -3- (4-chlorophenyl) -5- [ (2-hydroxy-2-methyl-propyl) -methyl-amino] pyrazolo [1,5-a] pyrimidin-7-yl] -4-ethoxy -piperidine-4-carboxamide (compound 44, 47.65mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=7.58-7.45(m,6H),7.31(s,1H),7.25(d,J=8.4Hz,3H),5.93(s,1H),4.63(s,1H),4.02(d,J=10 .8Hz,2H),3.65(s,2H),3.40-3.31(m,5H),3.29-3.24(m,2H),2.06-1.97(m,2H),1.94-1.86(m,2H),1.22-1.14(m,9H). LCMS: (ES + )m / z=611.3(M+H).

[0582] (xlvi) Compound 45:

[0583]

[0584] To a solution of 2-methylpropane-1,2-diol (31 mg, 0.346 mmol, 3 equiv.) in tetrahydrofuran (0.5 mL) was added LiHMDS (1 M, 0.35 mL, 3 equiv.), and the mixture was stirred at 60 ° C for 0.5 hours under a nitrogen atmosphere. Intermediate I-2 (n) (60 mg, 0.115 mmol, 1 equiv.) from Example 3 (xiv) in tetrahydrofuran (0.5 mL) was then added to the mixture. The mixture was stirred at 60 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was washed with aqueous ammonium chloride (10 mL) and extracted with ethyl acetate 30 mL (10 mL×3). The combined organic layers were washed with brine 40 mL (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; B%: 62%-92%, 10min) was purified, and the organic phase was concentrated under reduced pressure to remove acetonitrile. The liquid was lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[6-(trifluoromethyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidin-5-yl]oxy-2-methyl-propan-2-ol (Compound 45, 51.40 mg, 100% purity) as a yellow solid. 1 H NMR (400MHz, MeOD-d4) δ = 9.38 (s, 1H), 8.83-8.74 (m, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.52-7.37(m,6H),7.26(d,J=8.6Hz,2H),6.97(s,1H),4.37(s,2H),1.37(s,6H). LCMS: (ES + )m / z=573.3(M+H).

[0585] (xlvii) Compound 46:

[0586]

[0587] A mixture of intermediate I-2(c) from Example 3(iii) (35 mg, 67.98 μmol, 1 eq.), N-ethyl-2-(methylamino)acetamide (31.13 mg, 203.94 μmol, 3 eq., HCl) and N,N-diisopropylethylamine (77.32 mg, 0.598 mmol, 104.20 μL, 8.8 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 120° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL), and the resulting mixture was purified by reverse phase HPLC (column: Phenomenex TM Luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; B%: 46%-76%, 10min). The fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 46, 25.85 mg, 97% purity) as an off-white solid. 1 H NMR (400MHz, CDCl3)δ=7.50-7.45(m,2H),7.44-7.31(m,4H),7.24-7.18(m,2H),6.63-6.53(m,1H),5.73-5.32(m,3H),4.24(s,2H),4.04- 3.95(m,2H),3.49-3.39(m,2H),3.25(s,3H),3.24-3.17(m,2H),2.27-2.17(m,2H),1.88-1.78(m,2H),1.34(s,3H),0.95(t,J=7.2Hz,3H). LCMS: (ES+)m / z=596.0(M+H).

[0588] (xlviii) Compound 47:

[0589]

[0590] A mixture of intermediate I-2(c) from Example 3(iii) (35 mg, 67.98 μmol, 1 eq.), 2-amino-N-ethyl-acetamide from Example 1(xi) (28.27 mg, 204 μmol, 3 eq., HCl salt) and N,N-diisopropylethylamine (77.32 mg, 598 μmol, 104.2 μL, 8.8 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 120° C. for 12 h. The reaction mixture was cooled to room temperature and purified by reverse phase HPLC (column: Phenomenex TM Luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; B%: 46%-76%, 10min). The fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 47, 15.93 mg, 97% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=8.05-7.96(m,1H),7.60-7.41(m,7H),7.32-7.19(m,3H),6.97(s,1H),5.85(s,1H),3.91(d,J= 5.6Hz,2H),3.85-3.75(m,2H),3.18-3.06(m,4H),2.17-2.08(m,2H),1.59-1.47(m,2H),1.15(s,3H),1.05-0.96(m,3H). LCMS: (ES+)m / z=580.2(M+H).

[0591] (xlix) Compound 48:

[0592]

[0593] A mixture of intermediate I-2(m) from Example 3(xiii) (50 mg, 91.8 μmol, 1 eq.), N-ethyl-2-(methylamino)acetamide (42.02 mg, 0.275 mmol, 3 eq., HCl) and N,N-diisopropylethylamine (104.37 mg, 0.808 mmol, 141 μL, 8.8 eq.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature and purified by reverse phase HPLC (column: Phenomenex TMLuna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 49%-79%, 10min). The fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[2-(ethylamino)-2-oxo-ethyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-ethoxy-piperidine-4-carboxamide (Compound 48, 25.40 mg, 99% purity) as an off-white solid. 1 H NMR(400MHz, CDCl3)δ=7.51-7.41(m,4H),7.40-7.31(m,2H),7.24-7.18(m,2H),6 .67-6.60(m,1H),6.38(d,J=3.6Hz,1H),5.60(s,1H),5.43(d,J=3.2Hz,1H),4.29- 4.20(m,4H),3.54-3.46(m,2H),3.46-3.37(m,2H),3.26(s,3H),3.25-3.18(m,2H ),2.40-2.30(m,2H),2.03-1.96(m,2H),1.30(t,J=6.8Hz,3H),0.97-0.91(m,3H). LCMS: (ES+)m / z=624.3(M+H).

[0594] (1) Compound 49:

[0595]

[0596] A mixture of intermediate I-2(c) from Example 3(iii) (50 mg, 97.1 μmol, 1.0 equiv), 1-amino-2-methyl-propan-2-ol (26 mg, 0.29 mmol, 3.0 equiv) and N,N-diisopropylethylamine (110 mg, 0.85 mmol, 8.8 equiv) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 120° C. for 15 hours. The reaction mixture was then cooled to room temperature and diluted with N-methyl-2-pyrrolidone (2 mL). The resulting mixture was purified by reverse phase HPLC (column: Phenomenex TMLuna C18 150x25mm, 10μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 10min). The resulting liquid was concentrated under reduced pressure to remove acetonitrile and lyophilized to obtain 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 49, 24.16mg) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.59-7.54(m,1H),7.53-7.41(m,5H),7.29-7.21(m,3H),7.17-7.06(m,1H),6.96(s,1H ),5.92(s,1H),4.61(s,1H),3.84-3.72(m,2H),3.37(d,J=6.0Hz,2H),3.19-3.08(m,2H),2.17-2.09(m,2H),1.59 -1.45(m,2H),1.18-1.12(m,9H). LCMS: (ES+)m / z=567.3(M+H).

[0597] (li) Compound 50:

[0598]

[0599] To a solution of intermediate I-4(c) (115 mg, 0.24 mmol, 1.0 equiv.) from Example 5(iii), (4-methoxyphenyl)boronic acid (73.42 mg, 483.20 μmol, 2.0 equiv.) and cuprous 2-hydroxy-3-methyl-benzoate (156 mg, 0.72 mmol, 3.0 equiv.) in tetrahydrofuran (2 mL) was added triphenylphosphine palladium (28 mg, 24.2 μmol, 0.1 equiv.), and the resulting mixture was stirred at 60 ° C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography ( 20g The product was purified by silica gel flash column with a gradient of 0 to 100% ethyl acetate in petroleum ether at a flow rate of 30 mL / min. The fractions were concentrated under reduced pressure and the resulting residue was further purified by trituration with methanol (2 mL) at 25 °C to afford 4-[3-(4-chlorophenyl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Compound 50, 79.10 mg, 147.57 μmol) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ=8.08(d,J=8.8Hz,2H),7.86(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),7.51-7.45(m,2H),7.42-7.36(m,2H),7.1 5(d,J=8.8Hz,2H),6.63(s,1H),4.99-4.66(m,1H),4.22(s,1H),3.87(s,3H),3.72-3.59(m,2H),3.58-3.44(m,2H),2.09-1.90(m,4H). LCMS: (ES+)m / z=536.3(M+H).

[0600] (lii) Compound 51:

[0601]

[0602] To a solution of 2-methylpropane-1,2-diol (35 mg, 0.39 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (16 mg, 0.39 mmol, 60% purity, 3.0 equiv) and the resulting mixture was stirred at 25 ° C for 0.5 hours. Then, intermediate I-2(p) (60 mg, 0.13 mmol, 1.0 equiv) from Example 3(xvi) was added to the mixture and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was then diluted with water (5 mL) and filtered, and the resulting filter cake was dried under reduced pressure to give a yellow solid. The solid was purified by flash silica gel chromatography ( 12g The recovered fractions were concentrated under reduced pressure and the resulting crude product was purified by reverse phase HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 53% -83%, 10 minutes) purification. The fraction was concentrated under reduced pressure to remove acetonitrile, and the residue was lyophilized to give 5- [3- (4-chlorophenyl) -7- (3-cyano-3-methyl-azetidin-1-yl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1, 5-a] pyrimidin-2-yl] pyridine-2-carbonitrile (Compound 51, 14.4 mg, 28.0 μmol) as a yellow solid. 1H NMR (400MHz, CDCl3) δ = 8.96-8.92 (m, 1H), 7.98-7.92 (m, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.38-7.31 (m, 4H), 5.3 2(s,1H),4.86(d,J=8.8Hz,2H),4.44(d,J=8.8Hz,2H),4.23(s,2H),2.57(s,1H),1.86(s,3H),1.31(s,6H). LCMS: (ES + )m / z=514.2(M+H).

[0603] (liii) Compound 52:

[0604]

[0605] To a solution of 2-methylpropane-1,2-diol (32 mg, 0.35 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (14 mg, 0.35 mmol, 60% purity, 3.0 equiv) and the resulting mixture was stirred at 25 °C for 0.5 h. To the mixture was added intermediate I-2(q) from Example 3(xvii) (55 mg, 0.12 mmol, 1.0 equiv) and stirred at 25 °C for 2 h. The reaction mixture was diluted with water (5 mL) and filtered, and the resulting filter cake was dried under reduced pressure to give a yellow solid. The solid was purified by reverse phase HPLC (column: Phenomenex TM Luna C18 150x25mmx10μm; mobile phase: [water (formic acid) -ACN]; B%: 61%-91%, 10 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to obtain 5-[3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)-7-(3-methoxy-3-methyl-azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Compound 52, 11.08 mg, 21.3 μmol) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ = 9.04-8.99 (m, 1H), 8.01-7.95 (m, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.41-7.34 (m, 4H), 5.30(s,1H),4.57-4.27(m,4H),4.25(s,2H),3.35(s,3H),3.00-2.53(m,1H),1.65(s,3H),1.32(s,6H). LCMS: (ES + )m / z=519.1(M+H).

[0606] (liv) Compound 53:

[0607]

[0608] To a solution of 2-methylpropane-1,2-diol (54 mg, 592.4 μmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (24 mg, 0.59 mmol, 60% purity, 3.0 equiv), and the mixture was stirred at 25 ° C for 0.5 h. Then, intermediate I-2 (r) (115 mg, 0.20 mmol, 1.0 equiv) from Example 3 (xviii) was added, and the mixture was stirred at 25 ° C for 1.5 hours. The mixture was poured into ammonium chloride (10 mL) and extracted with ethyl acetate 15 mL (3x5 mL). The organic phase was then washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%: 60%-90%, 8 minutes) to give 5-[3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)-7-[4-(trifluoromethylsulfonyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (Compound 53, 29.05 mg, 45.7 μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.93 (dd, J = 1.2, 1.6Hz, 1H), 8.12 (dd, J = 1.6, 2.8Hz, 2H), 7.51-7.42 (m, 4H), 6.12 (s, 1H), 4.68 (s, 1H), 4.09 (s, 2H), 3.90 (br s,4H),3.74(br s,4H),1.21(s,6H). LCMS: (ES + )m / z=636.2(M+H).

[0609] (lv) Compound 54:

[0610]

[0611] To a solution of 2-methylpropane-1,2-diol (59 mg, 651.7 μmol, 3.0 equiv.) in N,N-dimethylformamide (1 mL) was added sodium hydride (26 mg, 651.7 μmol, 60% purity, 3.0 equiv.), and the mixture was stirred at 25 ° C for 0.5 hours. Then, intermediate I-2 (s) (110 mg, 0.22 mmol, 1.0 equiv.) from Example 3 (xix) was added, and the mixture was stirred at 25 ° C for 1.5 hours. The mixture was poured into ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate 15 mL (3x5 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 44% -74%, 8 minutes) to give 1- [3- (4-chlorophenyl) -2- (6-cyano-3-pyridinyl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a] pyrimidin-7-yl] -4-methyl-piperidine-4-carboxamide (Compound 54, 24.70 mg, 44.1 μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (t, J = 1.6Hz, 1H), 8.11 (d, J = 1.6Hz, 2H), 7.53-7.40 (m, 4H), 7.29 (s, 1H), 6.98 (s, 1H), 5.97 (s, 1H) ,4.65(s,1H),4.07(s,2H),4.05-3.96(m,2H),3.43-3.35(m,2H),2.17(dd,J=2.0,12.8Hz,2H),1.63-1.53(m,2H),1.20(s,9H). LCMS: (ES + )m / z=560.3(M+H).

[0612] (lvi) Compound 55:

[0613]

[0614] To a solution of 2-methylpropane-1,2-diol (50 mg, 0.56 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (22.37 mg, 0.56 mmol, 60% purity, 3.0 equiv) and the mixture was stirred at 25°C for 0.5 h. Then, intermediate I-2(t) from Example 3(xx) (100 mg, 0.17 mmol, 1.0 equiv) was added and the resulting mixture was stirred at 25°C for 15 h. The mixture was added to aqueous ammonium chloride (1 mL), diluted with water (10 mL), and filtered to give a yellow solid which was purified by preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 56% -86%, 10 minutes) to give 1- [3- (4-chlorophenyl) -2- (6-cyano-3-pyridinyl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a] pyrimidin-7-yl] -4-ethoxy -piperidine-4-carboxamide (Compound 55, 41.78 mg, 70.8 μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.88-8.85 (m, 1H), 8.17-8.04 (m, 2H), 7.50-7.41 (m, 4H), 7.36-7.32 (m, 1H), 7.29-7.23 (m, 1H), 6.03 (s ,1H),4.66(s,1H),4.24-4.11(m,2H),4.07(s,2H),3.41-3.36(m,2H),2.10-2.00(m,2H),1.97-1.88(m,2H),1.23-1.13(m,9H). LCMS: (ES + )m / z=590.3(M+H).

[0615] (lvii) Compound 56:

[0616]

[0617] A mixture of intermediate I-4(a) from Example 5(i) (50 mg, 103 μmol, 1.0 equiv), (6-methyl-3-pyridyl)boronic acid (28 mg, 206 μmol, 2 equiv), 3-methylsalicylate copper(I) (66 mg, 309 μmol, 3.0 equiv), tetrakis(triphenylphosphine)palladium (6 mg, 5 μmol, 0.05 equiv) in tetrahydrofuran (1 mL) was stirred at 80° C. for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters TMXbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 58%-88%, 8 minutes), preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 52%-82%, 10 minutes), silica gel column chromatography (petroleum ether: ethyl acetate) and preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 53%-83%, 10 minutes) to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(6-methyl-3-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (Compound 56, 10.00 mg, 18.85 μmol) as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ = 8.95 (d, J = 1.6Hz, 1H), 8.34 (dd, J = 2.0, 8.0Hz, 1H), 7.37-7.20 (m, 7H), 7.18-7.14 (m, 2H), 6.27 (s, 1H), 4.45 (br s,1H),3.91-3.43(m,4H),2.58(s,3H),2.17-1.94(m,3H),1.84-1.77(m,1H),1.72-1.50(m,1H). LCMS: (ES + )m / z=530.3(M+H).

[0618] (lviii) Compound 57:

[0619]

[0620] To a solution of 2-methylpropane-1,2-diol (68 mg, 0.75 mmol, 3.0 equiv) in tetrahydrofuran (1.5 mL) was added sodium hydride (30 mg, 0.75 mmol, 60% purity, 3.0 equiv), and the mixture was stirred at 25 ° C for 10 minutes. Then, intermediate I-2 (u) (140 mg, 0.25 mmol, 1.0 equiv) from Example 3 (xxi) was added to the mixture, which was stirred for another 50 minutes at 25 ° C. The reaction mixture was added to a saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (2 mL) and purified by preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 62%-92%, 10 minutes) purification. The desired fraction was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to obtain 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-4-isopropoxy-piperidine-4-carboxamide (Compound 57, 58.79 mg, 0.09 mmol) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ=7.59-7.51(m,3H),7.51-7.44(m,1H),7.42-7.36(m,2H),7.35-7.29(m,3H),7.21(s,1H),6.00(s,1H),4.68(s ,1H),4.14(s,2H),4.05-3.95(m,2H),3.76-3.70(m,1H),3.46(t,J=10.0Hz,2H),2.04-1.86(m,4H),1.22(s,6H),1.13(d,J=6.0Hz,6H). LCMS: (ES + )m / z=612.1(M+H).

[0621] (lix) Compound 58:

[0622]

[0623] To a solution of intermediate I-2(u) (250 mg, 0.45 mmol, 1.0 equiv) from Example 3(xxi) in N-methyl-3-pyrrolidone (2.5 mL) was added [(2S)-pyrrolidin-2-yl]methanol (226 mg, 2.24 mmol, 0.22 mL, 5.0 equiv) and N,N-diisopropylethylamine (509 mg, 3.94 mmol, 0.69 mL, 8.8 equiv). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (2 mL) and purified by preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 58%-88%, 8 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to obtain 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]-4-isopropoxy-piperidine-4-carboxamide (Compound 58, 213 mg, 0.34 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.60-7.54 (m, 1H), 7.54-7.45 (m, 5H), 7.32 (s, 1H), 7.28-7.17 (m, 3H), 5.74 (s, 1H), 4.83 (d, J = 2.0Hz, 1H), 4. 20-4.19(m,1H),3.95-3.79(m,2H),3.77-3.71(m,1H),3.68-3.54(m,2H),3.48-3.35(m,4H),2.08-1.87(m,8H),1.13(d,J=6.0Hz,6H). LCMS: (ES + )m / z=623.1(M+H).

[0624] (1x) Compound 59:

[0625]

[0626] To a solution of 2-methylpropane-1,2-diol (35 mg, 0.39 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (16 mg, 0.39 mmol, 60% purity, 3.0 equiv), and the resulting mixture was stirred at 25 ° C for 0.5 hours. Then, intermediate I-2 (v) (60 mg, 0.13 mmol, 1.0 equiv) from Example 3 (xxii) was added to the mixture, and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution (5 mL), and the resulting mixture was filtered. The filter cake was dried under reduced pressure. The obtained residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, eluent is about 50% to about 100% ethyl acetate / petroleum ether gradient, flow rate is 30mL / min) and reverse phase HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 39% -69%, 10 minutes) purification. The recovered fraction was concentrated under reduced pressure to remove acetonitrile, and the remaining solution was lyophilized to obtain 1- [3- (4-chlorophenyl) -2- (6-cyano-3-pyridinyl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a] pyrimidin-7-yl] azetidine -3-carboxamide (Compound 59, 7.18 mg, 13.86 μmol) as a yellow solid. 1 H NMR(400MHz, CDCl3-d)δ=8.99-8.96(m,1H),7.95-7.91(m,1H),7.65-7.61(m,1H),7.38-7.31(m,4H),5.64-5 .48(m,2H),5.31(s,1H),4.77-4.61(m,4H),4.22(s,2H),3.63-3.51(m,1H),2.86-2.72(m,1H),1.30(s,6H). LCMS: (ES + )m / z=518.2(M+H).

[0627] (lxi) Compound 60:

[0628]

[0629] To a solution of 2-methylpropane-1,2-diol (45 mg, 0.50 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (20 mg, 0.50 mmol, 60% purity, 3.0 equiv), and the resulting mixture was stirred at 25 ° C for 0.5 hours. Then, intermediate I-2 (w) (80 mg, 0.17 mmol, 1.0 equiv) from Example 3 (xxiii) was added to the mixture, which was then stirred at 25 ° C for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution (5 mL), and the resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography ( 12g Silica gel flash column, eluent gradient from about 50% to about 100% ethyl acetate / petroleum ether, flow rate 30 mL / min) and reverse phase HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 48%-78%, 10 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile. The aqueous mixture was lyophilized to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridinyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-7-yl]-3-methyl-azetidine-3-carboxamide (Compound 60, 7.1 mg, 13.35 μmol) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ = 8.98 (d, J = 1.6Hz, 1H), 7.97-7.92 (m, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.38-7.31 (m, 4H), 5.74-5.41 (m,2H),5.31(s,1H),4.84-4.77(m,2H),4.33-4.25(m,2H),4.22(s,2H),2.93-2.61(m,1H),1.75(s,3H),1.30(s,6H). LCMS: (ES + )m / z=532.2(M+H).

[0630] (lxii) Compound 61:

[0631]

[0632] A mixture of intermediate I-3(v) (60 mg, 0.13 mmol, 1.0 equiv) from Example 3(xxii), [(2S)-pyrrolidin-2-yl]methanol (40 mg, 0.39 mmol, 0.04 mL, 3.0 equiv) and N,N-diisopropylethylamine (67 mg, 0.52 mmol, 0.09 mL, 4.0 equiv) in acetonitrile (1 mL) was stirred at 80 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (4 mL), and filtered. The filter cake was dried under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, eluent gradient from about 50% to about 100% ethyl acetate / petroleum ether, flow rate 30 mL / min) and reverse phase HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 23% -53%, 10 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to give 1- [3- (4-chlorophenyl) -2- (6-cyano-3-pyridinyl) -5- [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] pyrazolo [1, 5-a] pyrimidin-7-yl] azetidine-3-carboxamide (Compound 61, 11.23 mg, 21.2 μmol) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ = 8.87-8.85 (m, 1H), 8.12-8.05 (m, 2H), 7.55 (s, 1H),7.50-7.44(m,2H),7.41-7.35(m,2H),7.11(s,1H),5.22(s,1H),4.87 -4.78(m,1H),4.60-4.48(m,2H),4.47-4.35(m,2H),4.20-4.03(m,1H),3. 67-3.57(m,1H),3.57-3.46(m,2H),3.44-3.36(m,2H),2.02-1.88(m,4H). LCMS: (ES + )m / z=529.3(M+H).

[0633] (lxiii) Compound 62:

[0634]

[0635] A mixture of intermediate I-2(c) (80 mg, 0.16 mmol, 1.0 equiv.) from Example 3(iii), 1-(2,2-dimethyl-1,3-dioxane-5-yl)-N-methyl-methylamine (74 mg, 0.47 mmol, 3.0 equiv.) and N,N-diisopropylethylamine (177 mg, 1.37 mmol, 0.24 mL, 8.8 equiv.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 120 ° C for 5 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (10 mL x3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography ( 20g Silica gel flash column, eluent gradient from about 50% to about 100% ethyl acetate / petroleum ether, flow rate 30 mL / min) was purified. The fractions were concentrated under reduced pressure and the resulting crude product was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [gradient of acetonitrile in aqueous ammonium hydroxide solution]; 9 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[(2,2-dimethyl-1,3-dioxane-5-yl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 62, 32.72 mg, 51.3 μmol) as a white solid. 1 H NMR (400MHz, CDCl3)δ=7.53-7.45(m,4H),7.40-7.30(m,2H),7.21-7.15(m,2H),5.80(s,1H),5.71-5.28(m,2H),4.13-4.03(m,2H),3.99- 3.88(m,2H),3.82-3.68(m,4H),3.47-3.36(m,2H),3.22(s,3H),2.26-2.08(m,3H),1.88-1.76(m,2H),1.49(d,J=8.4Hz,6H),1.33(s,3H). LCMS: (ES+)m / z=637.2(M+H).

[0636] (lxiv) Compound 63:

[0637]

[0638] To a solution of 2-methylpropane-1,2-diol (63.8 mg, 0.71 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was added sodium hydride (28.3 mg, 0.71 nmol, 60% purity, 3.0 equiv), and the mixture was stirred at 25° C. for 0.5 h. Then, intermediate I-2(y) (130 mg, 0.24 mmol, 1.0 equiv) was added, and the resulting mixture was stirred at 25° C. for 15 h. The mixture was added to aqueous ammonium chloride (1 mL), then diluted with water (10 mL), and filtered to give a yellow solid, which was purified by preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 56% -86%, 10 minutes) to give 1- [9- (4-chlorophenyl) -8- (6-cyano-3-pyridinyl) -2- (2-hydroxy-2-methyl-propoxy) purin-6-yl] -4-isopropoxy -piperidine-4-carboxamide (compound 63, 13.37 mg, 21.5μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.22-8.00 (m, 2H), 7.53-7.42 (m, 4H), 7.36 (s, 1H), 7.24 (s, 1H), 6.03 (s, 1H), 4.66 (s,1H),4.22-3.97(m,4H),3.84-3.70(m,1H),3.55-3.44(m,2H),2.14-1.91(m,4H),1.20(s,6H),1.16(d,J=6.0Hz,6H). LCMS: (ES + )m / z=604.3(M+H).

[0639] (lxv) Compound 64:

[0640]

[0641] To a mixture of intermediate I-4(d) from Example 5(iv) (60 mg, 125 μmol, 1.0 equiv), [6-(trifluoromethyl)-3-pyridyl]boronic acid (48 mg, 250 μmol, 2.0 equiv), 3-methylsalicylate copper(I) (81 mg, 0.38 mmol, 3.0 equiv) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (7 mg, 6.3 μmol, 0.05 equiv) and the mixture was stirred at 60° C. for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex TMLuna C18 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 54%-84%, 10 minutes) and preparative HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 51%-81%, 10 minutes) to give 5-[3-(4-chlorophenyl)-5-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-7-[6-(trifluoromethyl)-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxamide (Compound 64, 17.51 ​​mg, 27.97 μmol) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.40 (br d, J = 1.6Hz, 1H), 8.83 (br d, J = 7.2Hz, 1H), 8.66 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.14 (br s,1H),8.11-8.05(m,2H),7.68(br s,1H),7.55-7.48(m,2H),7.46-7.40(m,2H),7.31-7.06(m,1H),4.62(s,1H),3.83-3.56(m,2H),3.30(s,3H),1.17(s,6H). LCMS: (ES + )m / z=596.2(M+H).

[0642] (lxvi) Compound 65:

[0643]

[0644] To a mixture of intermediate I-2(c) (80 mg, 0.16 mmol, 1.0 equiv) from Example 3(iii) and (2R)-N-methylazetidine-2-carboxamide (106 mg, 0.47 mmol, 3.0 equiv, trifluoroacetate) from Example 1(xvi) in tetrahydrofuran (2 mL) was added potassium tert-butoxide (131 mg, 1.17 mmol, 7.5 equiv) and the resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, eluent gradient from about 0% to about 50% ethyl acetate / petroleum ether, flow rate 30 mL / min) and preparative HPLC (column: Phenomenex TMLuna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 47% -77%, 10 minutes) to give 1- [2- (2-chlorophenyl) -3- (4-chlorophenyl) -5- [ (2R) -2- (methylcarbamoyl) azetidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl] -4-methyl-piperidine-4-carboxamide (Compound 65, 9.38 mg, 15.83μmol) as an off-white solid. 1 H NMR(400MHz, CDCl3)δ=8.32-8.17(m,1H),7.49-7.43(m,2H),7.41-7.30(m,4H), 7.24-7.16(m,2H),5.81-5.51(m,1H),5.41-5.32(m,1H),5.30(s,1H),4.92(t,J= 8.0Hz,1H),4.17-3.82(m,4H),3.55-3.32(m,2H),3.01-2.78(m,1H),2.69(d,J=4 .8Hz,3H),2.62-2.41(m,1H),2.26-2.10(m,2H),1.88-1.71(m,2H),1.33(s,3H). LCMS: (ES + )m / z=592.3(M+H).

[0645] (lxvii) Compound 66:

[0646]

[0647] A mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 0.16 mmol, 1.0 equiv), 2-[2-(methylamino)ethoxy]ethanol (56 mg, 0.47 mmol, 3.0 equiv) and N,N-diisopropylethylamine (177 mg, 1.37 mmol, 0.24 mL, 8.8 equiv) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 51%-81%, 8 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to obtain 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[2-(2-hydroxyethoxy)ethyl-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 66, 40.78 mg, 68.2 μmol) as a yellow solid. 1HNMR(400MHz, CDCl3)δ=7.54-7.43(m,4H),7.40-7.29(m,2H),7.22-7.14( m,2H),5.72-5.44(m,3H),3.98-3.89(m,2H),3.88-3.82(m,2H),3.81-3.77 (m,2H),3.76-3.70(m,2H),3.63-3.57(m,2H),3.41-3.31(m,2H),3.22(s, 3H),2.24-2.15(m,2H),2.15-2.10(m,1H),1.88-1.76(m,2H),1.32(s,3H). LCMS: (ES+)m / z=597.3(M+H).

[0648] (lxviii) Compound 67:

[0649]

[0650] To a mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 0.16 mmol, 1.0 equiv) and N,N-diisopropylethylamine (1.37 mmol, 0.24 mL, 8.8 equiv) in N-methylpyrrolidone (1 mL) was added (2S)-3-(methylamino)propane-1,2-diol (49 mg, 0.47 mmol, 3.0 equiv) and the resulting mixture was stirred at 120° C. for 15 h. The mixture was purified by preparative HPLC (column: Phenomenex TM Synergi C18, 150x25mm, 10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 48%-78%, 7 minutes) to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[[(2S)-2,3-dihydroxypropyl]-methyl-amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (Compound 67, 75.52 mg, 0.13 mmol) as a white solid. 1 H NMR(400MHz, CDCl3)δ=7.60-7.43(m,6H),7.29-7.16(m,3H),7.03-6.82(m,1H),5.91-5.72(m,1H),4.93-4.80(m,1H),4 .77-4.63(m,1H),3.97-3.71(m,4H),3.43-3.33(m,3H),3.20(s,5H),2.22-2.08(m,2H),1.66-1.40(m,2H),1.15(s,3H). LCMS: (ES +)m / z=592.3(M+H).

[0651] (lxix) Compound 68:

[0652]

[0653] To a mixture of intermediate I-2(c) (80 mg, 0.16 mmol, 1.0 equiv) from Example 3(iii) and N,N-diisopropylethylamine (177 mg, 1.37 mmol, 8.8 equiv) in N-methylpyrrolidone (1 mL) was added (2S)-2-(methylamino)propionamide (129 mg, 0.93 mmol, 6.0 equiv, hydrochloride) from Example 1(xviii) and the resulting mixture was stirred at 140°C for 20 hours. The mixture was poured into water (10 mL) and filtered. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, eluent gradient from about 0% to about 50% ethyl acetate / petroleum ether, flow rate 20 mL / min), preparative HPLC (column: Phenomenex TM Luna C18, 150x25mm, 10μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 47% -77%, 10 minutes) and preparative thin layer chromatography (dichloromethane: methanol = 10: 1) purification to give 1- [5- [ [(1S) -2-amino-1-methyl-2-oxo-ethyl] -methyl-amino] -2- (2-chlorophenyl) -3- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl] -4-methyl-piperidine-4-carboxamide (Compound 68, 14.32 mg, 23.4 μmol) as an off-white solid. 1 H NMR (400MHz, CDCl3)δ=7.48-7.42(m,2H),7.41-7.30(m,4H),7.22-7.17(m,2H),6.52(br s,1H),5.75-5.57(m,2H),5.56-5.47(m,1H),5.43-5.30(m,1H),5.22(br s,1H),4.17-3.74(m,2H),3.57-3.24(m,2H),3.03(s,3H),2.30-2.13(m,2H),1.98-1.72(m,2H),1.45(d,J=7.2Hz,3H),1.32(s,3H). LCMS: (ES + )m / z=580.3(M+H).

[0654] (1xx) Compound 69:

[0655]

[0656] A mixture of intermediate I-2(x) from Example 3(xxiv) (90 mg, 0.18 mmol, 1.0 equiv), N-ethyl-2-(methylamino)acetamide (82 mg, 0.54 mmol, 3.0 equiv, hydrochloride) and N,N-diisopropylethylamine (204 mg, 1.58 mmol, 0.27 mL, 8.8 equiv) in N-methyl-2-pyrrolidone (1 mL) was stirred at 120° C. for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by reverse phase HPLC (column: Waters TM Xbridge 150x25mm, 5μm; mobile phase: [water (ammonium hydroxide)-acetonitrile]; B%: 40%-70%, 9 minutes) purification. The recovered fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to obtain 2-[[7-[3-(2-amino-2-oxo-ethoxy)azetidin-1-yl]-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]-N-ethyl-acetamide (Compound 69, 22.79 mg, 39.13 μmol) as a white solid. 1 H NMR (400MHz, CDCl3) δ=7.47-7.32(m,6H),7.23-7.14(m,2H),6.72-6.34(m,2H),5.63-5.47(m,1H),5.03(s,1H),4.76 -4.64(m,2H),4.58-4.49(m,1H),4.42-4.32(m,2H),4.21(s,2H),3.98(s,2H),3.27-3.15(m,5H),0.98-0.88(m,3H). LCMS: (ES+)m / z=582.2(M+H).

[0657] (lxxi) Compounds 70(R) and 71(R):

[0658]

[0659] At room temperature, (R)-(-)-1,2-propylene glycol (152 mg, 146 μL, 2.00 mmol, 1.3 equivalents) and cesium carbonate (1.5 g, 4.62 mmol, 3.0 equivalents) were added to 4 mL of N, N-dimethylacetamide under nitrogen, and the mixture was stirred for 30 minutes. A solution of intermediate I-2 (n) (800 mg, 1.54 mmol, 1.0 equivalents) from Example 3 (xiv) in N, N-dimethylacetamide (4.00 mL) was added to the reaction mixture, which was heated to 45-50 ° C and stirred at this temperature under nitrogen for about 17 hours. The reaction mixture was then cooled to 20-30 ° C. Water (60 mL) was added, and the mixture was extracted with dichloromethane (80 mLx3). The combined organic layer was washed with brine (32 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue (combination of two batches) was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The recovered fractions were concentrated under reduced pressure and separated by chiral SFC (column: Daicel Chiralcel TM OD (250 mm x 30 mm, 10 μm), 40% methanol in supercritical CO2 as mobile phase, flow rate of 120 g / min and cycle time of 3.2 min) to obtain residue 1 (Rt: 3.81) and residue 2 (Rt: 5.31).

[0660] Water (40 mL) was added to the residues 1 and 2 obtained by SFC separation, and the mixtures were stirred at 90° C. for 2 hours. The mixtures were then cooled to 25° C., filtered, and the filter cakes were dried under reduced pressure to obtain:

[0661] Compound 70(R) (359.95 mg, 641 μmol) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6)δ9.39(s,1H),8.81(d,J=8.0Hz,1H),8.17(d,J=8.4Hz,1H),7.30-7.63(m,8H) ,7.17(s,1H),4.98(d,J=4.8Hz,1H),4.33(d,J=4.8Hz,2H),4.00-4.18(m,1H),1.21(d,J=6.4Hz,3H). 19 F NMR(400MHz,DMSO-d6)δ-66.736.

[0662] Compound 71(R) (191.13 mg, 339 μmol) as a yellow solid. 1H NMR: (400MHz, DMSO-d6) δ9.38(d,J=1.6Hz,1H),8.81(dd,J=8.0,1.6Hz,1H),8.17(d,J=8.4Hz,1H),7.30-7.6 2(m,8H),7.11(s,1H),5.27-5.44(m,1H),4.96(t,J=5.6Hz,1H),3.66(t,J=5.6Hz,2H),1.37(d,J=6.4Hz,3H). 19 FNMR: (400MHz, DMSO-d6)δ-66.736.

[0663] (lxxii) Compounds 70(S) and 71(S):

[0664]

[0665] At room temperature, (S)-(-)-1,2-propanediol (152 mg, 146 μL, 2.00 mmol, 1.3 equiv) was dissolved in 4 mL of N,N-dimethylacetamide under nitrogen, cesium carbonate (1.5 g, 4.62 mmol, 3.0 equiv) was added, and the mixture was stirred for 15 minutes. A solution of intermediate I-2 (n) (800 mg, 1.54 mmol, 1.0 equiv) from Example 3 (xiv) in N,N-dimethylacetamide (4.00 mL) was added dropwise to the reaction mixture, which was stirred at 20-30 ° C for about 12 hours under nitrogen. The reaction mixture was warmed to 45-50 ° C and stirred under nitrogen. The reaction mixture was then cooled to 20-30 ° C and filtered under reduced pressure. The filtrate was poured into water (100 mL), and the suspension was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate=10 / 1 to 1 / 1). The recovered fraction was concentrated under reduced pressure, merged with the second batch of the same scale, and purified by chiral SFC separation according to Example 6 (lxxi) to obtain two residues.

[0666] Water (30 mL) was added to the two residues obtained by SFC separation, and the mixtures were stirred at 85-90° C. for 2 hours. The mixtures were then cooled to 20-30° C., filtered, and the filter cakes were dried under reduced pressure to obtain:

[0667] Compound 70(S) (288.77 mg, 518 μmol) as a yellow solid. 1H NMR: (400MHz, DMSO-d6)δ9.40(s,1H),8.82(dd,J=8.0,1.6Hz,1H),8.18(d,J=8.0Hz,1H),7.35-7.61(m, 8H), 7.18 (s, 1H), 4.98 (d, J = 4.8Hz, 1H), 4.34 (d, J = 5.6Hz, 2H), 4.00-4.20 (m, 1H), 1.22 (d, J = 6.4Hz, 3H). 19 F NMR(400MHz,DMSO-d6)δ-66.736.

[0668] Compound 71(S) (29.32 mg, 49.5 μmol) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6)δ9.39(d,J=1.6Hz,1H),8.81(dd,J=8.0,1.6Hz,1H),8.17(d,J=8.0Hz,1H),7.34-7.6 1(m,8H),7.12(s,1H),5.32-5.44(m,1H),4.96(t,J=5.6Hz,1H),3.67(t,J=5.6Hz,2H),1.38(d,J=6.4Hz,3H). 19 FNMR: (400MHz, DMSO-d6)δ-66.740.

[0669] (lxxiii) Compound 72(R):

[0670]

[0671] At room temperature, intermediate I-2 (n) (765 mg, 1.47 mmol, 1.0 equiv) from Example 3 (xiv) was dissolved in N, N-dimethylacetamide (8.00 mL). (R) -3-Hydroxypyrrolidine (385 mg, 4.42 mmol, 367 μL, 3.00 equiv) and cesium carbonate (528 mg, 1.62 mmol, 1.10 equiv) were added, and the mixture was stirred at 20-30 ° C for 1 hour under nitrogen. The reaction mixture was filtered under reduced pressure, the filtrate was poured into water (150 mL), and the suspension was filtered under reduced pressure. The filter cake was dissolved in dichloromethane (25 mL), and the mixture was washed with water (50 mLx2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was ground with isopropanol (5 mL) three times for 30 minutes each time, and filtered each time. To the filter cake from the last filtration step was added water (16 mL), and the mixture was stirred under nitrogen at 85-90° C. for 5 hours. The suspension was then cooled to 20-30° C., filtered, and the filter cake was dried under reduced pressure to give Compound 72(R) (545.2 mg, 915 μmol) as a yellow solid. 1 HNMR: (400MHz, DMSO-d6)δ9.39(d,J=1.6Hz,1H),8.78(dd,J=8.4,2.0Hz,1H),8.16(d,J=8.4Hz,1H),7.42-7.60 (m,6H),7.27-7.36(m,2H),6.92(s,1H),5.00-5.24(m,1H),4.48(s,1H),3.49-3.83(m,4H),1.89-2.19(m,2H). 19 FNMR: (400MHz, DMSO-d6)δ-66.680.

[0672] (lxxiv) Compound 72(S):

[0673]

[0674] At room temperature, intermediate I-2(n) (600 mg, 1.15 mmol, 1.00 equiv) from Example 3(xiv) was dissolved in N,N-dimethylacetamide (6.00 mL). (S)-3-Hydroxypyrrolidine (302 mg, 3.47 mmol, 280 μL, 3.00 equiv) and cesium carbonate (414 mg, 1.27 mmol, 1.10 equiv) were added, and the mixture was stirred at 20-25 ° C for 1 hour under nitrogen. Water (90 mL) was added to the reaction mixture, which was stirred at room temperature for 20 minutes. The suspension was filtered and the filter cake was washed with water (20 mL). The filter cake was dissolved in dichloromethane (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1 / 1). The recovered fractions were concentrated in vacuo. 5mL hexane / methyl tert-butyl ether (10 / 1) mixture is added to the obtained residue, and stirred for 30 minutes at 20-25 ° C. The mixture is filtered, and the filter cake is dried under reduced pressure. Water (40mL) is added to the filter cake, and the mixture is stirred at 90 ° C for 5 hours. The suspension is then cooled to 25 ° C and filtered. After adding water and / or acetonitrile, 90 ° C heating, cooling and filtering for several cycles, the filter cake is dried under reduced pressure to obtain compound 72 (S) (363.04mg, 622 μmol) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δ9.39(d,J=1.6Hz,1H),8.78(dd,J=8.0,1.6Hz,1H),8.16(d,J=8.0Hz,1H),7 .24-7.62(m,8H),6.92(s,1H),5.00-5.24(m,1H),4.47(s,1H),3.45-3.88(m,4H),1.89-2.22(m,2H). 19 F NMR: (400MHz, DMSO-d6)δ-66.682.

[0675] (lxxv) Compounds 73 and 75:

[0676]

[0677] N, N-dimethylacetamide (5.00 mL) was charged into a flask under nitrogen and 25-35 ° C. The intermediate I-2 (n) (500 mg, 0.96 mmol, 1.00 equiv) from Example 3 (xiv) was added to the solvent, followed by (S)-(+)-2-amino-1-butanol (258 mg, 2.89 mmol, 275 μL, 3.01 equiv) and cesium carbonate (345 mg, 1.06 mmol, 1.10 equiv). The mixture was then stirred at 25-35 ° C for 22 hours under nitrogen. Monitoring showed that the reaction was incomplete. The reaction mixture was warmed to 50-60 ° C and stirred at this temperature for 8 hours under nitrogen. The reaction mixture was then cooled to 20-30 ° C and filtered under reduced pressure. The filtrate was purified and the two compounds were separated by reverse phase chromatography (0.1% TFA). The eluent of the two collected fractions was adjusted to pH=7 with saturated sodium bicarbonate aqueous solution, and the mixture was concentrated under reduced pressure to remove ACN. The aqueous phase was extracted with dichloromethane (25 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution (30 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then ground with ethanol (3 mL) at 20-30 ° C for 12 hours, or with ethanol / petroleum ether (1 / 50, 2 mL) at 20-30 ° C for 30 minutes. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain:

[0678] Compound 73 (137 mg, 237 μmol) (from 500 mg batch) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6)δ9.28(s,1H),8.68(d,J=8.0Hz,1H),8.15(d,J=8.4Hz,1H),7.67(d,J=7.6Hz,1H),7.40-7.59(m,6H),7.30(d,J=8.4Hz, 2H),6.71(s,1H),4.80(t,J=5.2Hz,1H),4.06(d,J=2.8Hz,1H),3.45-3. 68(m,2H),1.64-1.83(m,1H),1.51-1.66(m,1H),0.98(t,J=7.2Hz,3H). 19 F NMR: (400MHz, DMSO-d6)δ-66.667.

[0679] Compound 75 (75 mg, 131 μmol) (from 300 mg batch) as a yellow solid. 1H NMR: (400MHz, DMSO-d6)δ9.40(d,J=1.6Hz,1H),8.82(dd,J=1.6,8.4Hz,1H),8.18(d,J=8.4Hz,1H),7.34-7.61(m,8H),7.18(s,1H),4.3 7(dd,J=5.6,10.4Hz,1H),4.26(dd,J=6.4,10.4Hz,1H),2.97-3.09(m,1H),1.51-1.63(m,3H),1.28-1.43(m,1H),0.97(t,J=7.6Hz,3H). 19 FNMR: (400MHz, DMSO-d6)δ-66.728.

[0680] (1xxvi) Compound 74:

[0681]

[0682] N, N-dimethylacetamide (4.00 mL) was charged into a flask under nitrogen and 20-30° C. The intermediate I-2 (n) (400 mg, 769 μmol, 1.00 equivalent) from Example 3 (xiv) was added to the solvent, followed by 4-amino-1-butanol (206 mg, 2.31 mmol, 215 μL, 3.00 equivalent) and cesium carbonate (275 mg, 844 μmol, 1.10 equivalent), and the mixture was stirred at 20-30° C. for 4 hours under nitrogen. The reaction was then filtered under reduced pressure, and the filtrate was adjusted to pH=7 with trifluoroacetic acid. The filtrate was purified by reverse phase chromatography (0.1% TFA). The collected eluent was adjusted to pH=7 with saturated sodium bicarbonate aqueous solution, and the mixture was concentrated under reduced pressure to remove acetonitrile. The resulting suspension was extracted with dichloromethane (30 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with ethanol (3 mL) at 20-30 ° C for 1 hour. The suspension was filtered and the filter cake was dried under reduced pressure to give compound 74 (216 mg, 376 μmol, 99.6% purity) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6)δ9.35(s,1H),8.73(d,J=7.2Hz,1H),8.19(d,J=8.4Hz,1H),7.94(s,1H),7.46-7.64(m,6H ),7.28-7.42(m,2H),6.68(s,1H),4.53(t,J=5.2Hz,1H),3.44-3.59(m,4H),1.68-1.81(m,2H),1.55-1.67(m,2H).19 F NMR: (400MHz, DMSO-d6)δ-66.677.

[0683] (lxxvii) Compound 76:

[0684]

[0685] [(2S)-pyrrolidin-2-yl]methanol prepared in Example 1(xx) 15 N-d7 (hydrochloride, 50 mg, 0.343 mmol) and intermediate I-2 (n) (210 mg, 0.405 mmol) from Example 3 (xiv) were dissolved in acetonitrile, and N, N-diisopropylethylamine (0.300 mL, 1.72 mmol) was added. The reaction was sealed and placed at 80 ° C overnight. Water was added to the mixture, and then extracted with dichloromethane five times. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient of 10% to 40% ethyl acetate in 40% hexane / dichloromethane. The desired product was collected and concentrated under reduced pressure to obtain compound 76 (118 mg) with good purity. 1 H NMR spectroscopy analysis was consistent with compound 8, and the disappearance of the signal of the protons converted to deuterium atoms further confirmed the structure.

[0686] (lxxviii) Compound 77:

[0687]

[0688] At room temperature, 1,1-(d6) dimethyl-1,2-dihydroxyethane (100mg, 1.04mmol) prepared in Example 1 (xxi) was added to a solution of bis(trimethylsilyl)amide lithium (1.0M) in tetrahydrofuran, and the reaction was stirred at room temperature for 30 minutes. Intermediate I-2(n) (260mg, 0.5mmol) from Example 3(xiv) was then added. The reaction was stirred overnight at 75°C. Water was added to the reaction mixture, which was then extracted five times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography using a gradient of 10% to 30% ethyl acetate in 40% hexane / dichloromethane. The desired product was collected, concentrated under reduced pressure, and dried under high vacuum to give compound 77 (132mg). 1 H NMR spectroscopy analysis was consistent with compound 45, and the disappearance of the signal of the protons converted to deuterium atoms further confirmed the structure.

[0689] (lxxix) Compound 78:

[0690]

[0691] Step 1: To a solution of 4-methoxybenzylamine (158 mg, 1.15 mmol, 149 μL, 1.20 equiv) in N,N-dimethylacetamide (2.5 mL) was added cesium carbonate (626 mg, 1.92 mmol, 2.00 equiv) at 20-30°C, and the mixture was stirred under nitrogen at 20-30°C for 30 minutes. A solution of intermediate I-2(n) (500 mg, 958 μmol, 1.00 equiv) from Example 3(xiv) in N,N-dimethylacetamide (2.5 mL) was added dropwise to the mixture, which was then stirred under nitrogen for 4 hours. Water (20 mL) and dichloroethane (30 mL) were added to the reaction mixture. The organic phase was separated, washed with brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase chromatography (0.1% TFA). The eluent was adjusted to pH=8 with saturated sodium bicarbonate and concentrated under reduced pressure to remove acetonitrile. Dichloromethane (50 mL) was added to the mixture and extracted. The organic phase was separated, washed with brine (20 mL), and dried over Na2SO4. The filtrate was concentrated under reduced pressure to obtain the PMB-protected compound (500 mg, 805 μmol) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δ9.29(d,J=1.6Hz,1H),8.68(dd,J=8.0,1.6Hz,1H),8.39(t,J=5.2Hz,1H),8.14(d ,J=8.0Hz,1H),7.21-7.63(m,10H),6.96(d,J=8.8Hz,2H),6.69(s,1H),4.57(d,J=5.6Hz,2H),3.74(s,3H). 19 F NMR: (400MHz, DMSO-d6)δ-66.682.

[0692] Step 2: Trifluoroacetic acid (1.5 mL) and anisole (348 mg, 3.22 mmol, 349 μL, 4.00 equiv) were mixed in a flask. PMB protected compound (0.50 g, 805.87 μmol, 1.00 equiv) was added, the mixture was warmed to 50 ° C and stirred under nitrogen for 12 hours. The reaction mixture was cooled to 25 ° C, and saturated sodium bicarbonate (20 mL) and dichloromethane (30 mL) were added. The organic phase was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (0.1% TFA). The eluent was adjusted to pH = 8 with saturated sodium bicarbonate and concentrated under reduced pressure to remove acetonitrile. Dichloromethane (50 mL) was then added to the mixture. The organic phase was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was combined with the product (46 mg) from different batches, acetonitrile (5 mL) was added, and the mixture was stirred at 20-30 ° C for 15 minutes. The suspension was filtered, and the filter cake was washed with acetonitrile (3 mL). Deionized water (10 mL) was added to the filter cake, and stirred at 80 ° C for 3 hours. The reaction mixture was cooled to 25 ° C and filtered, and the filter cake was dried under reduced pressure to obtain compound 78 (58 mg, 112 μmol) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.69 (dd, J = 8.4, 1.6Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 7.17-7.59 (m, 10H), 6.62 (s, 1H). 19 FNMR: (400MHz, DMSO-d6)δ-66.674.

[0693] Example 7 - Biological Properties

[0694] a) Test equipment count

[0695] Day 1:

[0696] Using polyethyleneimine (PEI) transfection reagent, human CB1 or CB1b receptors and the following Assay One HEK293 cells were transfected in suspension with either GAPL-Gi2 ​​or β-arrestin membrane (PM) translocation biosensor (+GRK2). Immediately after transfection, cells were seeded directly into 96-well plates.

[0697] Day 4 (approximately 65 hours after transfection):

[0698] Before measuring the BRET signal, cells were incubated with coelenterazine (luciferase substrate) and different test compounds.

[0699] b) Description of the platform.

[0700] i) Gα plasma membrane (GAPL) biosensor and ii) β-arrestin membrane translocation biosensor were used in this project.

[0701] i) GAPL sensors are used to monitor the activation of heterotrimeric G proteins at the plasma membrane following receptor stimulation. Specifically, these multimolecular BRET sensors detect the plasma membrane recruitment of proteins that interact with active Gα subunits in a G protein family selective manner. G protein activation following receptor stimulation generally results in an increase in the BRET signal.

[0702] ii) Multimolecular β-arrestin membrane recruitment biosensors allow real-time spatiotemporal monitoring of β-arrestin1 and β-arrestin2 upon GPCR activation. Specifically, these β-arrestin sensors were designed to detect recruitment of the protein to the plasma membrane (β-arrestin PM), as well as localization to the compartment resulting in an increase in the BRET signal.

[0703] c) Cell culture strips Item

[0704] HEK293 cells were maintained in Dulbecco's modified Eagle's medium (DMEM) (Wisent; catalog number 319-030-CL: without sodium pyruvate, with 4.5 g / L glucose, and without L-glutamine) supplemented with 1% penicillin-streptomycin (Wisent; catalog number 450-201-EL) and 2% or 10% fetal bovine serum (Wisent, catalog number 090150).

[0705] d) Transfection and cell seeding

[0706] Use hCB1 or hCB1b and the above One assay was performed by co-transfecting HEK293 cells. For each transfection condition:

[0707] - The total amount of DNA transfected was kept constant at 1 μg per mL of cell culture to be transfected; when necessary, salmon sperm DNA (Invitrogen, catalog number 15632011) was used as "carrier" DNA to supplement the plasmid DNA (i.e. biosensor and receptor);

[0708] - The ratio of PEI (polyethyleneimine 25 kDa linear, PolyScience, catalog number 23966) to DNA (ug:ug) was fixed at 3:1.

[0709] Transfection was performed as follows:

[0710] - DNA and PEI are first diluted separately in 150 mM NaCl. The volume of the dilution in each tube corresponds to 5% of the culture volume of the cells to be transfected.

[0711] - Once the DNA and PEI are diluted, add the PEI-containing solution to the DNA solution and immediately vortex the DNA / PEI mixture for 5 seconds.

[0712] - Incubate the DNA / PEI mixture at room temperature for at least 20 minutes to allow the formation of DNA / PEI complexes.

[0713] - During the incubation period, HEK293 cells were detached, counted and resuspended in culture medium (composition specified above).

[0714] - At the end of the incubation period, the DNA / PEI mixture was added to the cells.

[0715] - The cells were finally plated at a density of 30,000 cells per well in 96-well plates (white opaque 96-well / microplates, Greiner, cat. no. 655083 or CulturPlate-96, white opaque 96-well microplates, PerkinElmer, cat. no. 6005688).

[0716] e) BRET assay

[0717] Approximately 48 hours after transfection:

[0718] - Using a 450-Select TS Biotek plate washer, aspirate the medium and replace with 100 μl Hank's Balanced Salt Solution Buffer (HBSS) (Wisent, catalog number 319-067CL: without phenol red; with sodium bicarbonate, calcium and magnesium, with HEPES) per well. This process is performed twice in total (ie, 2 washes).

[0719] -After the washing step, increasing doses (12) of the test compound (ranging from 0-600 nM) were injected into the wells using an HP D300 digital dispenser (Tecan). Three to five minutes later, CP-55,940 at an EC75 (0.1 nM for the GAPL-Gi2 ​​assay; 100 nM for the β-arrestin PM translocation biosensor (+GRK2)) was added to columns 2-12 of each 96-well plate. The 8 wells in column 1 on each plate were always reserved for controls (i.e., 3 untreated wells, 2 wells injected with an EC75 of CP-55,940, and 3 wells injected with an EC100 of CP-55,940).

[0720] - The plates were then incubated overnight (16-18 hours) at 37°C and 5% CO2 in a humidified atmosphere.

[0721] - The next day, perform the BRET experiment according to the following protocol:

[0722] - Add 10 μl of 20 μM e-Coelenterazine Prolume Purple (Methoxy e-CTZ) (Nanolight, Cat. No. 369) to each well for a final concentration of 2 μM.

[0723] - Incubate the plate at room temperature for 5 min on an orbital shaker.

[0724] - BRET readings were then collected on a Synergy NEO plate reader (BioTek Instruments, Inc., USA; filters: 400 nm / 70 nm, 515 nm / 20 nm) with an integration time of 0.4 sec.

[0725] f) Calculation

[0726] The BRET signal is determined by calculating the ratio of the light emitted by the GFP acceptor (515 nm) to the light emitted by the luciferase donor (400 nm). All BRET ratios are normalized using the following equation, with pre-set BRET values ​​for positive and negative controls. The normalized BRET ratio is called universal BRET (uBRET).

[0727] uBRET=((BRET ratio –A) / (BA))*10 000

[0728] in:

[0729] A = BRET ratio obtained from negative control transfection

[0730] B = BRET ratio obtained from transfection of positive control

[0731] The resulting dose-response curves were fit using a four-parameter logistic nonlinear regression model in GraphPad Prism 9.

[0732] Table 1 presents the in vitro assay results of compounds 1 to 72 prepared according to Example 6.

[0733] Table 1 - In vitro assay results

[0734]

[0735]

[0736]

[0737]

[0738] Numerous modifications may be made to any of the embodiments described above without departing from the scope of the present invention.Any reference, patent or scientific literature document mentioned in this document is incorporated herein by reference in its entirety for all purposes.

Claims

1. Compounds of formula I: in, R 1 and R 2 are each independently selected from optionally substituted C 6-10 Aryl and optionally substituted C 5-10 heteroaryl; R 3 Selected from optionally substituted C 1-12 Alkyl, optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted C 6-10 Aryl and optionally substituted C 5-10 Heteroaryl, optionally substituted -X 1 -C 3-10 Cycloalkyl, optionally substituted -X 1 -C 3-10 Heterocycloalkyl, optionally substituted -X 1 -C 6-10 Aryl and optionally substituted -X 1 -C 5-10 heteroaryl; R 4 is selected from NH2, optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl; X 1 Selected from O and NR 5 , where R 5 is H or optionally substituted C 1-6 alkyl; and X 2 Selected from O and NR 6 , where R 6 is H or optionally substituted C 1-6 alkyl; or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 4 is NH2.

3. The compound according to claim 1, wherein R 4 Selected from optionally substituted C 1-12 alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocycloalkyl, optionally substituted -X 2 -C 3-10 Cycloalkyl and optionally substituted -X 2 -C 3-10 Heterocycloalkyl.

4. The compound according to claim 3, wherein R 4 is an optionally substituted C 1-12 Alkoxy, preferably optionally substituted C 1-6 Alkoxy, more preferably optionally substituted C 1-4 Alkoxy.

5. The compound according to claim 3, wherein R 4 is an optionally substituted C 1-12 Alkylamino or C 1-12 dialkylamino, preferably optionally substituted C 1-6 Alkylamino or C 1-6 dialkylamino, more preferably optionally substituted C 1-4 Alkylamino or C 1-4 Dialkylamino.

6. The compound according to claim 4 or 5, wherein the alkyl or alkoxy group is replaced by at least one selected from OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 The alkyl group is preferably substituted with OH.

7. The compound according to claim 3, wherein R 4 is an optionally substituted C 3-10 Cycloalkyl or optionally substituted C 3-10 Heterocycloalkyl, preferably optionally substituted C 3-6 Cycloalkyl or optionally substituted C 3-6 Heterocycloalkyl, more preferably optionally substituted C 4-5 Cycloalkyl or optionally substituted C 4-5 Heterocycloalkyl.

8. The compound of claim 7, wherein the heterocycloalkyl group is linked to the pyrazolopyrimidine core via a nitrogen atom from the heterocycloalkyl group.

9. The compound according to claim 7 or 8, wherein the heterocycloalkyl group is selected from pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

10. The compound according to claim 3, wherein R 4 is an optionally substituted -X 2 -C 3-10 Cycloalkyl or optionally substituted -X 2 -C 3-10 Heterocycloalkyl, preferably optionally substituted -X 2 -C 3-6 Cycloalkyl or optionally substituted -X 2 -C 3-6 Heterocycloalkyl, more preferably optionally substituted -X 2 -C 4-5 Cycloalkyl or optionally substituted -X 2 -C 4-5 Heterocycloalkyl.

11. A compound according to any one of claims 3 to 10, wherein X 2 NR 6 , preferably wherein R 6 H or C 1-3 Alkyl group, preferably methyl group.

12. A compound according to any one of claims 7 to 11, wherein the cycloalkyl or heterocycloalkyl group is replaced by at least one selected from OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CO2N(C 1-6 Alkyl)2, P(O)(C 1-6 Alkyl)2, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 alkyl, each of which is optionally substituted, and wherein the groups are optionally substituted by C 1-6 The alkyl group is connected to the cycloalkyl or heterocycloalkyl group, preferably OH or via C 1-6 Alkyl or C 1-3 Alkyl-linked OH.

13. A compound according to any one of claims 1 to 12, wherein R 3 is an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 1-6 Alkylamino or di-C 1-6 Alkylamino.

14. A compound according to any one of claims 1 to 12, wherein R 3 is an optionally substituted C6 aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl or C 4-7 Heterocycloalkyl, or through X 1 C6 aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl or C 4-7 Heterocycloalkyl.

15. The compound of claim 14, wherein the aryl group has the formula: in, R 7 is independently selected at each occurrence from halogen, OH, OR 9 、CN、NO2、C(O)R 9 、C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 、N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Heterocycloalkyl, C6 aryl and C 5-10 heteroaryl, or two R 8 Together with their neighboring atoms, they form C 4-10 Heterocycloalkyl; R 9 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl; R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl and C 5-6 heteroaryl; and c is 0, 1, 2, 3, 4, or 5; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

16. The compound according to claim 15, wherein R 7 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

17. The compound of claim 14, wherein the aryl or heteroaryl group has the formula: in, X 3 , X 4 , X 5 , X 6 and X 7 Each independently selected from N and CR 11 , where X 3 , X 4 , X 5 , X 6 and X 7 At most three of them are N, or two of them are adjacent X 3 , X 4 , X 5 , X 6 and X 7 One of the is absent and the other is O, S, or NR 10 ; R 8 , R 9 and R 10 As defined in claim 15; and R 11 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、C(O)R 9 、C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 、N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

18. The compound according to claim 17, wherein X 3 , X 4 , X 5 , X 6 and X 7 One of them is N, preferably X 4 and X 6 one.

19. The compound according to claim 18, wherein X 4 N and X 3 , X 6 and X 7 Each is CH.

20. A compound according to any one of claims 17 to 19, wherein X 5 CR 11 , and R 11 is selected from CN, optionally substituted C 1-6 Alkyl (eg, CH3, CF3, etc.) and OR 9 , where R 9 is an optionally substituted C 1-6 alkyl.

21. The compound of claim 14, wherein the cycloalkyl or heterocycloalkyl group has the formula: in, X 8 Selected from N and CR 11 ; X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Each independently selected from O, NR 12 , SO2 and C(R 13 )2, where X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 At most two of them are or contain O, N or S, and / or where X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Up to 3 of X are absent to form a 4-, 5- or 6-membered ring, and / or X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 Two or three of them are bridged together by one to three additional bridging atoms, such as carbon atoms; R 8 , R 9 and R 10 As defined in claim 15, and R 11 As defined in claim 17; R 12 is independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)N(R 8 2. SO2R 9 SO2N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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; and R 13 is independently selected at each occurrence from hydrogen, halogen, OH, OR 9 、CN、NO2、C(O)R 9 、C(O)N(R 8 )2、C(R 10 )=NR 10 、SO2R 9 SO2N(R 8 )2、N(R 10 )C(O)R 9 、N(R 10 )SO2R 9 、N(R 10 )C(O)N(R 8 )2、N(R 10 )SO2N(R 8 )2、N(R 8 )2、P(O)(R 8 )2、P(O)(OR 8 )2、B(OR 8 2. 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 two R 13 Together with their neighboring atoms, they form C 4-10 Cycloalkyl or C 4-10 Heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

22. The compound according to claim 21, wherein X 8 is N.

23. The compound according to claim 21 or 22, wherein X 11 NR 12 .

24. The compound according to claim 21 or 22, wherein X 11 C(R 13 )2.

25. A compound according to any one of claims 21 to 24, wherein at least one R 13 independently selected at each occurrence from OH, OR 9 、C(O)N(R 8 )2、N(R 10 )C(O)R 9 、N(R 8 )2 and optionally substituted C 1-6 alkyl.

26. A compound according to any one of claims 21 to 25, wherein X 12 Does not exist.

27. A compound according to any one of claims 21 to 26, wherein X 9 and X 14 Does not exist.

28. A compound according to any one of claims 1 to 27, wherein X 1 Does not exist.

29. A compound according to any one of claims 1 to 27, wherein X 1 Exists and is NR 5 , preferably wherein R 5 For H.

30. A compound according to any one of claims 1 to 29, wherein R 2 is an optionally substituted C6 aryl group or an optionally substituted C 5-6 Heteroaryl.

31. The compound according to claim 30, wherein R 2 Has the following formula: in, X 15 , X 16 , X 17 , X 18 and X 19 Each independently selected from N and CR 11 , where X 15 , X 16 , X 17 , X 18 and X 19 At most three of them are N, or two of them are adjacent X 15 , X 16 , X 17 , X 18 and X 19 One of the is absent and the other is O, S, or NR 10 ; Where R 10 As defined in claim 15, and R 11 As defined in claim 17; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.

32. The compound according to claim 31, wherein X 15 , X 16 , X 17 , X 18 and X 19 Each is CR 11 .

33. The compound according to claim 31 or 32, wherein X 15 CR 11 , where R 11 Selected from halogen and OR 9 .

34. A compound according to any one of claims 31 to 33, wherein X 16 , X 17 , X 18 and X 19 Each is CR 11 , where R 11 For hydrogen.

35. The compound according to claim 33 or 34, wherein R 2 It is 2-methoxyphenyl or 2-chlorophenyl.

36. The compound according to claim 31, wherein X 15 , X 16 , X 17 , X 18 and X 19 One of them is N.

37. The compound according to claim 31, wherein X 16 It is N or CH.

38. A compound according to any one of claims 31 to 33 and 37, wherein X 17 CR 11 , and where R 11 is cyano, halogen, haloalkyl or OR 9 , preferably cyano.

39. The compound according to claim 38, wherein R 2 It is 4-cyanophenyl or 6-cyano-3-pyridyl.

40. A compound according to any one of claims 1 to 39, wherein R 1 is an optionally substituted C6 aryl group.

41. The compound according to claim 40, wherein R 1 It is 4-chlorophenyl.

42. The compound according to claim 1, wherein the compound is selected from compounds 1 to 78 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

43. The compound according to claim 42, wherein the compound is selected from compounds 1 to 77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

44. The compound of claim 42, wherein the compound is Compound 78, or a pharmaceutically acceptable salt thereof.

45. The compound of claim 43, wherein the compound is selected from compounds 1-18, 20-31, 33-61, 63-68 and 70-77 or compounds 1-18, 20-29, 31, 36-61, 63-68 and 70-77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

46. ​​The compound according to claim 43, wherein the compound is selected from compounds 1-17, 20-22, 25-27, 37, 38, 42-46, 48-61, 63-68, 70-77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

47. A compound according to claim 43, wherein the compound is selected from compounds 1-5, 7-11, 13-15, 21, 22, 27, 42, 43, 45, 50-58, 60, 61, 63, 64, 70(R), 70(S), 71(S), 72(R), 72(S) as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

48. The compound of claim 43, wherein the compound is selected from compounds 1, 2, 4, 7-9, 11, 13, 15, 21, 27, 43, 45, 50-53, 56-58, 60, 61, 63, 64, 70(R), 71(S), 72(R), 72(S) as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 48, and a pharmaceutically acceptable carrier, diluent or excipient.

50. Use of a compound as defined in any one of claims 1 to 48 or a pharmaceutical composition as defined in claim 49 for the treatment of a disorder related to appetite or one of its complications, a disorder related to glucose regulation or one of its complications, a disorder related to fibrosis or one of its complications, a disorder related to metabolism or one of its complications, a disorder related to skin and hair growth and healing, a disorder related to the gastrointestinal tract, a disorder related to obesity or one of its complications, or a combination thereof.

51. The use according to claim 50, wherein the appetite-related disorder or one of its complications is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome and syndrome.

52. The method of claim 50, wherein the disorder associated with glucose regulation or one of its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production) and associated nephropathy, neuropathy and retinopathy.

53. The use according to claim 50, wherein the fibrosis-related disorder or one of its complications is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrosis disorders (such as scleroderma), fibrosing nephropathy and chronic kidney disease.

54. purposes according to claim 50, wherein the disorder associated with metabolism or one of its complications is selected from metabolic syndrome and hyperlipidemia (e.g. hypertriglyceridemia, hypertriglyceridemia under low HDL-cholesterol conditions, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

55. The method of claim 50, wherein the obesity-related disorder or one of its complications is selected from sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual disorders, degenerative arthritis, venous stasis ulcers, coronary artery disease, arteriosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate or gallbladder.

56. Use according to claim 50, wherein the disorder of the skin and hair is selected from the group consisting of alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids) and scleroderma.

57. The use according to claim 50, wherein the gastrointestinal tract related disorder is selected from constipation, irritable bowel syndrome and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

58. A method of treating a condition selected from appetite-related conditions or complications thereof, glucose regulation-related conditions or complications thereof, fibrosis-related conditions or complications thereof, metabolism-related conditions or complications thereof, skin and hair growth and healing-related conditions, gastrointestinal-related conditions, obesity-related conditions or complications thereof, or a combination thereof, comprising administering to a subject in need thereof a compound as defined in any one of claims 1 to 48 or a pharmaceutical composition as defined in claim 49.

59. The method of claim 58, wherein the appetite-related disorder or complications thereof 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.

60. The method of claim 58, wherein the disorder associated with glucose regulation or a complication thereof is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production) and related nephropathy, neuropathy and retinopathy.

61. The method of claim 58, wherein the fibrosis-related disorder or complications thereof is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrotic disorders (e.g., non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (e.g., scleroderma), fibrotic kidney disease, and chronic kidney disease.

62. The method of claim 58, wherein the metabolism-related disorder or its complications are selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL-cholesterol, elevated LDL and / or total cholesterol and / or VLDL and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

63. The method of claim 58, wherein the obesity-related disorder or complications thereof is selected from the group consisting of sleep apnea, snoring, asthma, hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual disorders, degenerative arthritis, venous stasis ulcers, coronary artery disease, atherosclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignancies of the liver, ovaries, cervix, uterus, breast, prostate, or gallbladder.

64. The method of claim 58, wherein the disorder of the skin and hair is selected from the group consisting of alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

65. The method of claim 58, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

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