Pyrazolopyrimidines, compositions containing them, and uses thereof - Patent Application 20070122997

Abstract

The present invention relates to pyrazolopyrimidine compounds, pharmaceutical compositions containing same, and their use in the treatment or prevention of diseases and disorders associated with the cannabinoid CB1 receptor. For example, the pyrazolopyrimidine compounds, or tautomeric forms and / or salts thereof, are represented by formula I: [Formula 1] JPEG2025505553000119.jpg5157 (in the formula, R 1 ~R 4 is as defined herein.

Description

[Technical Field]

[0001] Related Applications This application claims priority under applicable law to U.S. Provisional Application No. 63 / 268,021, filed February 15, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] FIELD OF THE DISCLOSURE This disclosure relates generally to compounds, particularly pyrazolopyrimidine compounds, pharmaceutical compositions containing them, and their uses and methods of use in the treatment and prevention of diseases and disorders. [Background technology]

[0003] Activation of the cannabinoid CB1 receptor is generally known to increase appetite, increase lipid synthesis and storage, inhibit the action of insulin and leptin, and promote inflammation and fibrosis. Therefore, research has focused on developing CB1 receptor inhibitors for the potential treatment of obesity and its associated metabolic disorder, known as metabolic syndrome. Rimonabant was shown to be effective in treating metabolic syndrome, but was withdrawn from the market due to its neuropsychiatric (i.e., CNS-related) side effects. There remains a need for the development of alternative compounds that target the CB1 receptor for the treatment or prevention of disorders associated therewith. Summary of the Invention

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

[0005] Example 1. Compound of Formula I:

[0006] [ka] (In the formula, R 1 and R 2 each independently represents an optionally substituted C- 10 Aryl and optionally substituted C5- 10 heteroaryl; R 3 optionally substituted C1- 12 Alkyl, optionally substituted C1- 12 Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted C- 10 Aryl, and optionally substituted C5- 10 Heteroaryl, optionally substituted -X 1 -C3- 10 Cycloalkyl, optionally substituted -X 1 -C3- 10 Heterocycloalkyl, optionally substituted -X 1 -C6- 10 aryl, and optionally substituted -X 1 -C5- 10 heteroaryl; R 4 optionally substituted NH2, C1- 12 Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted -X 2 -C3- 10 Cycloalkyl, and optionally substituted -X 2 -C3- 10 heterocycloalkyl; X 1 However, O and NR 5 Selected from R 5 is H or optionally substituted C alkyl; X 2However, O and NR 6 Selected from R 6 is H or optionally substituted C alkyl; or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof. Example 2.R 4 is NH2. Example 3.R 4 optionally substituted C1- 12 Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted -X 2 -C3- 10 Cycloalkyl, and optionally substituted -X 2 -C3- 10 The compound of embodiment 1, wherein the compound is selected from heterocycloalkyl. Example 4.R 4 optionally substituted C1- 12 Compounds according to embodiment 3, which are alkoxy, preferably optionally substituted C1-6 alkoxy, more preferably optionally substituted C1-4 alkoxy. Example 5.R 4 optionally substituted C1- 12 Alkylamino or C1- 12 The compound of embodiment 3, which is dialkylamino, preferably optionally substituted C1-6 alkylamino or C1-6 dialkylamino, more preferably optionally substituted C1-4 alkylamino or C1-4 dialkylamino. Example 6. The alkyl or alkoxy is OH, CO2H, CO2NH2, CO2NHC 1-6 Alkyl, CON(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 1-6The compound of embodiment 4 or 5, which is substituted with at least one group selected from alkyl, preferably OH. Example 7.R 4 optionally substituted C3- 10 Cycloalkyl or optionally substituted C3- 10 The compound of embodiment 3, which is heterocycloalkyl, preferably optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl, more preferably optionally substituted C4-5 cycloalkyl or optionally substituted C4-5 heterocycloalkyl. Example 8. The compound of embodiment 7, wherein the heterocycloalkyl is linked to the pyrazolopyrimidine core via a nitrogen atom from the heterocycloalkyl. Example 9. The compound of embodiment 7 or 8, wherein the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups. Example 10.R 4 optionally replaced by -X 2 -C3- 10 cycloalkyl or optionally substituted -X 2 -C3- 10 Heterocycloalkyl, preferably optionally substituted -X 2 -C3-6 cycloalkyl or optionally substituted -X 2 -C3-6 heterocycloalkyl, more preferably optionally substituted -X 2 -C4-5 cycloalkyl or optionally substituted -X 2 -C4-5 heterocycloalkyl. Example 11.X 2 But NR 6 and preferably R 6 The compound of any one of embodiments 3-10, wherein is H or C1-3 alkyl, preferably methyl. Example 12. The cycloalkyl or heterocycloalkyl is OH, CO2H, CO2NH2, CO2NHC, each of which is optionally substituted.1-6 Alkyl, CON(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, which is optionally substituted with at least one group selected from cycloalkyl or heterocycloalkyl, C 1-6 Linked via alkyl, preferably OH, or C 1-6 Alkyl or C 1-3 The compound of any one of embodiments 7-11, wherein OH is linked via alkyl. Example 13.R 3 optionally replaced by C 1-6 alkyl group, optionally substituted C alkoxy, or optionally substituted C 1-6 Alkylamino or diC 1-6 The compound of any one of embodiments 1-12, which is alkylamino. Example 14.R 3 optionally substituted C aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl, or C 4-7 Heterocycloalkyl group or X on the pyrazolopyrimidine core 1 C6 aryl linked via 5-6 Heteroaryl, C 4-7 Cycloalkyl, or C 4-7 The compound of any one of embodiments 1-12, which is heterocycloalkyl. Example 15. The aryl group has the following formula:

[0007] [ka] (In the formula, R 7 may independently in each occurrence be a halogen, OH, OR 9 , CN, NO2, C(O)R 9 , C(O)N(R 8 )2, C(R10 )=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 but independently in each occurrence, 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, C 4-10 forming a heterocycloalkyl group, R 9 but independently in each occurrence, 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 but independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C6 aryl, and C 5-6 heteroaryl; c is 0, 1, 2, 3, 4, or 5; The compound of embodiment 14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted. Example 16.R 7 CN, optionally substituted C 1-6 Alkyl groups (e.g., CH3, CF3, etc.), and OR 9 Selected from R 9 optionally replaced by C 1-6 The compound of embodiment 15, wherein the group is an alkyl group. Example 17. The aryl or heteroaryl group has the following formula:

[0008] [ka] (In the formula, X 3 , X 4 , X 5 , X 6 , and X 7 are each independently N and CR 11 Selected from X 3 , X 4 , X 5 , X 6 , and X 7 At most three of the are N or two adjacent X 3 , X 4 , X 5 , X 6 , and X 7 one of which is absent and the other is O, S, or NR 10 and R 8 , R 9 , and R 10 is as defined in embodiment 15; R 11may independently in each occurrence be 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); The compound of embodiment 14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted. Example 18.X 3 , X 4 , X 5 , X 6 , and X 7 Preferably, one of X 4 and X 6 and n is 0 or 1. The compound of embodiment 17, wherein one of Example 19.X 4 is N and X 3 , X 6 , and X 7 and each is CH. Example 20.X 5 But, CR 11 and R11 CN, optionally substituted C 1-6 Alkyl groups (e.g., CH3, CF3, etc.), and OR 9 Selected from R 9 optionally replaced by C 1-6 The compound of any one of embodiments 17-19, which is an alkyl group. Example 21. The cycloalkyl or heterocycloalkyl group has the following formula:

[0009] [ka] (In the formula, X 8 But N and CR 11 is selected from X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 are each independently O, NR 12 , SO2, and C(R 13 )2 and X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 At most two of are or contain O, N, or S, and / or X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 up to three of are absent, 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 which together form a bridge via one to three additional bridging atoms, e.g., carbon atoms; R 8 , R 9, and R 10 is as defined in embodiment 15, and R 11 is as defined in embodiment 17; R 12 independently in each occurrence 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, selected from R 13 may independently in each occurrence be 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 4-10heterocycloalkyl, or two R 13 together with their neighboring atoms, C 4-10 Cycloalkyl or C 4-10 forming a heterocycloalkyl group, The compound of embodiment 14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted. Example 22.X 8 is N. Example 23.X 11 But NR 12 23. The compound of embodiment 21 or 22, wherein Example 24.X 11 But C(R 13 23. The compound of embodiment 21 or 22, wherein R is 1 or 2; Example 25. At least one R 13 independently in each occurrence, 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 The compound of any one of embodiments 21-24, wherein the alkyl is selected from: Example 26.X 12 The compound of any one of embodiments 21-25, wherein: Example 27.X 9 and X 14 The compound of any one of embodiments 21-26, wherein: Example 28.X 1 The compound of any one of embodiments 1-27, wherein: Example 29.X 1 But there is NR 5 and preferably R 5 The compound of any one of embodiments 1-27, wherein is H. Example 30.R 2The compound of any one of embodiments 1-29, wherein is optionally substituted C6 aryl or optionally substituted C5-6 heteroaryl. Example 31.R 2 But the following formula:

[0010] [ka] (In the formula, X 15 , X 16 , X 17 , X 18 , and X 19 are each independently N and CR 11 Selected from X 15 , X 16 , X 17 , X 18 , and X 19 At most three of the 15 , X 16 , X 17 , X 18 , and X 19 one of which is absent and the other is O, S, or NR 10 and R 10 is as defined in embodiment 15, and R 11 is as defined in embodiment 17), The compound of embodiment 30, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted. Example 32.X 15 , X 16 , X 17 , X 18 , and X 19 However, each 11 32. The compound of embodiment 31, wherein: Example 33.X 15 But, CR 11 and R 11 However, halogens and OR 9 33. The compound of embodiment 31 or 32, selected from: Example 34.X 16 , X 17 , X 18 , and X 19 However, each 11 and R 11 The compound of any one of embodiments 31-33, wherein is hydrogen. Example 35.R 2 The compound of embodiment 33 or 34, wherein is a 2-methoxyphenyl or 2-chlorophenyl group. Example 36.X 15 , X 16 , X 17 , X 18 , and X 19 The compound of embodiment 31, wherein one of Example 37.X 16 is N or CH. Example 38.X 17 But, CR 11 and R 11 is cyano, halogen, alkyl halide, or OR 9 , preferably cyano. Example 39.R 2 is a 4-cyanophenyl or 6-cyano-3-pyridyl group. Example 40.R 1 The compound of any one of embodiments 1-39, wherein is an optionally substituted C6 aryl. Example 41.R 1 is a 4-chlorophenyl group. Example 42. The compound of embodiment 1, wherein the compound is selected from compounds 1-78 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Example 43. The compound of embodiment 42, wherein the compound is selected from compounds 1-77 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Example 44. The compound of embodiment 42, wherein the compound is compound 78, or a pharmaceutically acceptable salt thereof. Example 45. The compound of 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. Example 46. The compound of 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, or an isomer or tautomer thereof, as defined herein, or a pharmaceutically acceptable salt thereof. Example 47. The compound of 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. Example 48. The compound of 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), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, as defined herein. Example 49. A pharmaceutical composition comprising a compound as defined in any one of embodiments 1 to 48, together with a pharmaceutically acceptable carrier, diluent, or excipient. Example 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 an appetite-related disorder or one of its complications, a glucose regulation-related disorder or one of its complications, a fibrosis-related disorder or one of its complications, a metabolism-related disorder or one of its complications, a skin and hair growth and healing-related disorder, a gastrointestinal tract-related disorder, an obesity-related disorder or one of its complications, or a combination thereof. Example 51. The use of embodiment 50, wherein one of said appetite-related disorders or complications thereof is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome. Example 52. The use according to embodiment 50, wherein one of the disorders or complications associated with glucose regulation is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (through beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy. Example 53. The use of embodiment 50, wherein one of the fibrosis-related disorders 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 fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease. Example 54. The use according to embodiment 50, wherein one of said metabolic-related disorders or complications thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.). Example 55. The use of embodiment 50, wherein one of said obesity-related disorders or complications thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder. Example 56. The use according to embodiment 50, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma. Example 57. The use according to embodiment 50, wherein said gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease. Example 58. A method for the treatment of a disorder selected from appetite-related disorders or complications thereof, glucose regulation-related disorders or complications thereof, fibrosis-related disorders or complications thereof, metabolism-related disorders or complications thereof, skin and hair growth and healing-related disorders, gastrointestinal tract-related disorders, obesity-related disorders or complications thereof, or combinations thereof, comprising administering to a subject in need thereof a compound as defined in any one of embodiments 1 to 48 or a pharmaceutical composition as defined in embodiment 49. Example 59. The method of embodiment 58, wherein said appetite-related disorder or complication thereof is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome. Example 60. The method of embodiment 58, wherein said glucose regulation-related disorder or complication thereof is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (through beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy. Example 61. The method of embodiment 58, wherein said fibrosis-related disorder or complication thereof is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease. Example 62. The method of embodiment 58, wherein said metabolic-related disorder or complication thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.). Example 63. The method of embodiment 58, wherein said obesity-related disorder or complication thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder. Example 64. The method of embodiment 58, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma. Example 65. The method of embodiment 58, wherein said gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0011] Further objects and features of the present compounds, compositions, methods and uses will become more apparent upon reading the following non-limiting description of exemplary embodiments and examples section, which should not be construed as limiting the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] All technical terms and expressions used herein have the same definition as that generally understood by those skilled in the art to which this technology pertains.However, the definitions of some terms and expressions used are provided below.If the definitions of terms in the publications, patents and patent applications incorporated herein by reference are contrary to the definitions set forth herein, the definitions in this specification shall prevail.The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subject matter disclosed.

[0013] The chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a drawn carbon atom, appears to have incomplete valences, it is assumed that the valences are satisfied by one or more hydrogen atoms, although not necessarily explicitly drawn. The hydrogen atoms should be assumed to be part of the compound.

[0014] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing a "compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense, including "and / or," unless the context clearly dictates otherwise. Furthermore, when the terms "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0015] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within one or more standard deviations, according to practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within 10-fold, preferably within 5-fold, and more preferably within 2-fold of a value. When a particular value is described in this application and claims, unless otherwise specified, the term "about" should be assumed to mean within an acceptable error range for the particular value.

[0016] As used herein, the terms "compound," "compounds described herein," "compounds of the present application," "pyrazolopyrimidine," "pyrazolopyrimidine compound," and equivalent expressions refer to compounds described in the present application, e.g., those encompassed by structural formula I, optionally with reference to any of the applicable embodiments, and also include exemplary compounds, e.g., compounds 1-78, their pharmaceutically acceptable salts, their tautomeric forms and isomers, and, where applicable, their solvates, esters, and prodrugs. Where a zwitterionic form is possible, the compound may be depicted as its neutral form for practical purposes, but it is understood that the compound also includes its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified by either their chemical structure or their chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure shall prevail.

[0017] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, tautomers, and geometric (or conformational)) forms of the structure, where applicable, e.g., R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, tautomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of this specification. The present compounds also encompass all possible tautomers of the depicted compounds, if present, unless otherwise specified. This term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to, 2 H(D), 3 H(T), 11 C. 13 C. 14 C. 15 N, 18 O. 17The compounds may also exist in solvated forms, including unsolvated forms as well as hydrated forms. The compounds may also exist in multiple crystalline forms or in amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0018] When a particular enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer or may be enantiomerically enriched. "Enantiomerically enriched" means that the compound is composed of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) on chiral supports, or by the formation and crystallization of chiral salts, or may be prepared by asymmetric synthesis.

[0019] The expression "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like, within the scope of sound medical judgment, and is compatible with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S.M. Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compound of the present invention, or can be prepared separately by reacting the free base function of the compound with a suitable organic or inorganic acid (acid addition salt), or by reacting the acidic function of the compound with a suitable organic or inorganic base (base addition salt).

[0020] The term "solvate" refers to a physical association of one of the present compounds with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may involve hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" encompasses both solution-phase solvates and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and solvates of other physiologically acceptable solvents, such as Class 3 solvents listed in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Thus, the compounds described herein also include each of their solvates and mixtures thereof.

[0021] As used herein, the expression "pharmaceutically acceptable ester" refers to an ester of a compound formed by the process herein, including those that readily decompose in vivo in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, where each alkyl or alkenyl moiety advantageously has six or fewer carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates of hydroxyl groups, and alkyl esters of acidic groups. Other ester groups include sulfonates or sulfates.

[0022] As used herein, the expression "pharmaceutically acceptable salt" refers to prodrugs of compounds formed by the processes herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to yield any compound depicted by the formulas of the present description.

[0023] Unless otherwise specified, abbreviations may be used throughout this application and are intended to have the meanings commonly understood by the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Suc (succinimide).

[0024] The number of carbon atoms in a hydrocarbon substituent is indicated by the prefix "C x -C y " or "C x - y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. However, the prefix "C x -C y " or "C x - y " is associated with a group that by definition incorporates one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), x and y define the minimum and maximum number of atoms in the period, respectively, including carbon atoms and heteroatoms.

[0025] The term "heteroatom" includes atoms other than carbon and hydrogen, such as, but not limited to, nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, substituted forms of nitrogen, and any quaternized form of a basic nitrogen.

[0026] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing 1 to 20 carbon atoms. For example, a "C alkyl" contains 1 to 8 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals, and the like.

[0027] As used herein, the term "alkenyl" refers to a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically 2 to 20 carbon atoms. For example, a "C2-8 alkenyl" contains 2 to 8 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.

[0028] As used herein, the term "alkynyl" refers to a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically 2 to 20 carbon atoms. For example, a "C2-8 alkynyl" contains 2 to 8 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0029] The terms "cycloalkyl," "alicyclic," "carbocyclic," and equivalent expressions refer to groups containing saturated or partially unsaturated (non-aromatic) carbocyclic rings in monocyclic or polycyclic ring systems, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbocyclic ring systems, having 3 to 15 ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups. The term "C3- n "Cycloalkyl" refers to cycloalkyl groups having from 3 to the indicated "n" number of carbon atoms in their ring structure. Unless the carbon number is otherwise specified, "lower cycloalkyl" groups as used herein have at least 3 and no more than 8 carbon atoms in their ring structure.

[0030] As used herein, the terms "heterocycloalkyl," "heterocyclyl," and the like are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocycloalkyl moiety, as defined above, that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms. As an example, in a saturated or partially unsaturated ring having one to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocycloalkyl can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure, and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, and the like. Examples of aryl include aryl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolidinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like.Heterocycloalkyl groups also include groups in which the heterocycloalkyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthrizinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, when the radical or point of attachment is on the heterocycloalkyl ring. Heterocycloalkyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocycloalkyl, where the alkyl and heterocyclyl portions are independently optionally substituted. For example, the term "C3- n "Heterocycloalkyl" refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0031] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0032] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," "aryloxy," or "aryloxyalkyl," refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of 6 to 15 ring members, at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the expression "aryl ring." In certain embodiments herein, "aryl" refers to an aromatic ring or ring system, including, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl, and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyls include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthymidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. n "Aryl" refers to an aryl group having 6 to the indicated "n" number of atoms in the ring structure.

[0033] The term "heteroaryl," e.g., "heteroaralkyl" or "heteroaralkoxy," used alone or as part of a larger moiety, refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 (e.g., having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array), and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" is as defined above. A heteroaryl can be a single ring or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocycloalkyl rings. Non-limiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl). ]pyridinyl), pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, as well as pteridinylcarbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl groups include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term "C5- n "Heteroaryl" refers to a heteroaryl group having from 5 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0034] The terms "halogen" or "halo" refer to a halogen atom, ie, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0035] As described herein, the compounds herein may contain "optionally substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at any or each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. The combinations of substituents envisioned herein preferably result in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0036] Examples of substituents include, but are not limited to, halogen (F, CI, Br, I), OH, COH, alkoxy, oxo, thioxo, NO, CN, CF, CHF, NH, NH alkyl, NH alkenyl, NH alkynyl, NH cycloalkyl, NH aryl, NH heteroaryl, NH heterocycloalkyl, dialkylamino, diarylamino, diheteroarylamino, dicycloalkylamino, diheterocycloalkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N -Cycloalkylamino, N-alkyl-N-heterocycloalkylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocycloalkyl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocyclo alkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl OCO2 heterocycloalkyl, OC(O)NH2, OC(O)NH alkyl, OC(O)NH alkenyl, OC(O)NH alkynyl, OC(O)NH cycloalkyl, OC(O)NH aryl, OC(O)NH heteroaryl, OC(O)NH heterocycloalkyl, OP(O)(Oalkyl)2, OP(O)(OH)2, OP(O)(Oalkenyl)2, OP(O)(Oalkynyl)2, OP(O)(Ocycloalkyl)2, OP(O)(Oaryl)2, OP(O)(Oheteroaryl)2, OP(O)(Oheterocycloalkyl)2,NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O) NHaryl, NHC(O)NHheteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NHaryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(N H)NHheteroaryl, NHC(NH)NHheterocycloalkyl, NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S (O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocycloalkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl,Examples of the substituents include NHSOaryl, NHSOheteroaryl, NHSOheterocycloalkyl, CHNH, CHSOCH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, and methylthiomethyl. Each of these substituents may also be further substituted, if possible.

[0037] Thus, this document relates to pyrazolopyrimidine compounds as defined herein and in the following paragraphs. When referring to a chemical moiety, the recitation of a list of chemical groups in any definition of a variable includes a definition of that variable as any single group or combination of the listed groups. Similarly, the recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Thus, the following embodiments exist alone or, where applicable, in combination:

[0038] The compounds exhibit a pyrazolopyrimidine core structure attached to the defined substituents. Exemplary compounds defined herein have the general formula I:

[0039] [ka] (In the formula, R 1 and R 2 each independently represents an optionally substituted C- 10 Aryl and optionally substituted C5- 10 heteroaryl; R 3 optionally substituted C1- 12 Alkyl, optionally substituted C1- 12Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted C- 10 Aryl, and optionally substituted C5- 10 Heteroaryl, optionally substituted -X 1 -C3- 10 Cycloalkyl, optionally substituted -X 1 -C3- 10 Heterocycloalkyl, optionally substituted -X 1 -C6- 10 aryl, and optionally substituted -X 1 -C5- 10 heteroaryl; R 4 is NH2, optionally substituted C1- 12 Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted -X 2 -C3- 10 Cycloalkyl, and optionally substituted -X 2 -C3- 10 heterocycloalkyl; X 1 However, O and NR 5 Selected from R 5 is H or optionally substituted C alkyl; X 2 However, O and NR 6 Selected from R 6 is H or optionally substituted C alkyl; or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0040] For example, R 1may be an optionally substituted C6 aryl, such as a 4-chlorophenyl group.

[0041] In some instances, R 4 is NH2. Alternatively, R 4 is an optionally substituted C1- 12 Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C3- 10 Cycloalkyl, optionally substituted C3- 10 Heterocycloalkyl, optionally substituted -X 2 -C3- 10 Cycloalkyl, and optionally substituted -X 2 -C3- 10 heterocycloalkyl.

[0042] In some instances, R 4 is an optionally substituted C1- 12 Alkoxy, preferably optionally substituted C1-6 alkoxy, more preferably optionally substituted C1-4 alkoxy. 4 is an optionally substituted C1- 12 Alkylamino or C1- 12 Dialkylamino, preferably optionally substituted C alkylamino or C dialkylamino, more preferably optionally substituted C alkylamino or C dialkylamino. For example, alkyl or alkoxy is preferably OH, COH, CONH, CONHC. 1-6 Alkyl, CON(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 It is substituted with one or more groups selected from alkyl, preferably OH.

[0043] In yet another example, R 4 is an optionally substituted C3-10 Cycloalkyl or optionally substituted C3- 10 The heterocycloalkyl is preferably an optionally substituted C3-6 cycloalkyl or an optionally substituted C3-6 heterocycloalkyl, more preferably an optionally substituted C4-5 cycloalkyl or an optionally substituted C4-5 heterocycloalkyl. For example, the heterocycloalkyl is linked to the pyrazolopyrimidine core via a nitrogen atom from the heterocycloalkyl. In one embodiment, the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

[0044] For further examples, R 4 is optionally replaced by -X 2 -C3- 10 cycloalkyl or optionally substituted -X 2 -C3- 10 Heterocycloalkyl, preferably optionally substituted -X 2 -C3-6 cycloalkyl or optionally substituted -X 2 -C3-6 heterocycloalkyl, more preferably optionally substituted -X 2 -C4-5 cycloalkyl or optionally substituted -X 2 -C4-5 heterocycloalkyl. X 2 NR 6 Preferably, R 6 is H or C1-3 alkyl, preferably methyl.

[0045] R 4 Each of the cycloalkyl or heterocycloalkyl groups present in 1-6 Alkyl, CON(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 1-6alkyl, which may optionally be substituted with one or more groups selected from cycloalkyl or heterocycloalkyl, 1-6 Linked via alkyl, preferably OH, or C 1-6 via alkyl or C 1-4 Alkyl or C 1-3 It is OH linked via an alkyl.

[0046] In some instances, R 3 is an optionally substituted C 1-6 alkyl group, optionally substituted C alkoxy, or optionally substituted C 1-6 Alkylamino or diC 1-6 It may also be alkylamino.

[0047] In other examples, R 3 is an optionally substituted C6 aryl, C 5-6 Heteroaryl, C 4-7 Cycloalkyl, or C 4-7 Heterocycloalkyl group or X on the pyrazolopyrimidine core 1 C6 aryl linked via 5-6 Heteroaryl, C 4-7 Cycloalkyl, or C 4-7 It is heterocycloalkyl.

[0048] In some instances, R 3 is an aryl group of the formula:

[0049] [ka] (In the formula, R 7 may independently in each occurrence be a 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(R10 )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 but independently in each occurrence, 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, C 4-10 forming a heterocycloalkyl group, R 9 but independently in each occurrence, 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 but independently in each occurrence, 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 5-6heteroaryl; c is 0, 1, 2, 3, 4, or 5; The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted.

[0050] Preferably, R 7 is CN, optionally substituted C 1-6 Alkyl groups (e.g., CH3, CF3, etc.), and OR 9 Selected from R 9 optionally replaced by C 1-6 It is an alkyl group.

[0051] Alternatively, R 3 is an aryl or heteroaryl group of the formula:

[0052] [ka] (In the formula, X 3 , X 4 , X 5 , X 6 , and X 7 are each independently N and CR 11 Selected from X 3 , X 4 , X 5 , X 6 , and X 7 At most three of the are N or two adjacent X 3 , X 4 , X 5 , X 6 , and X 7 one of which is absent and the other is O, S, or NR 10 and R 8 , R 9 , and R 10 is as defined herein; R 11 may independently in each occurrence be hydrogen, halogen, OH, OR9 , 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), The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted.

[0053] In some instances, X 3 , X 4 , X 5 , X 6 , and X 7 Preferably, one of X 4 and X 6 One of the is N and X 4 is N and X 3 , X 6 , and X 7 are each CH. In one embodiment, X 5 is CR 11 and R 11 is CN, optionally substituted C 1-6 Alkyl groups (e.g., CH3, CF3, etc.), and OR9 Selected from R 9 is an optionally substituted C 1-6 It is an alkyl group.

[0054] On the other hand, R 3 When is or contains a cycloalkyl or heterocycloalkyl group, the cycloalkyl or heterocycloalkyl group has the formula:

[0055] [ka] (In the formula, X 8 But N and CR 11 is selected from X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 are each independently O, NR 12 , SO2, and C(R 13 )2 and X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 At most two of are or contain O, N, or S, and / or X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 up to three of are absent, 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 which together form a bridge via one to three additional bridging atoms, e.g., carbon atoms; R 8 , R 9 , R10 , and R 11 is as defined herein; R 12 independently in each occurrence 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, selected from R 13 may independently in each occurrence be 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 R13 together with their neighboring atoms, C 4-10 Cycloalkyl or C 4-10 forming a heterocycloalkyl group, The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted.

[0056] In some preferred examples, X 8 is N. In some preferred embodiments, X 11 is NR 12 or X 11 is C(R 13 )2. In another example, X 12 does not exist and / or X 9 and X 14 does not exist.

[0057] In some examples of the compounds, at least one R 13 independently in each occurrence: 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.

[0058] Basic R 3 is X 1 A linker may be included, for example, X 1 is O as defined above, but NR 5 Preferably, X 1 is NR 5 and R 5 is H. In another example, X 1 does not exist.

[0059] Some of the compounds of formula I include R 2 A group, optionally substituted C aryl or optionally substituted C heteroaryl, for example, R2 is a functional group of the formula:

[0060] [ka] (In the formula, X 15 , X 16 , X 17 , X 18 , and X 19 are each independently N and CR 11 Selected from X 15 , X 16 , X 17 , X 18 , and X 19 At most three of the 15 , X 16 , X 17 , X 18 , and X 19 one of which is absent and the other is O, S, or NR 10 and R 10 and R 11 is as defined herein), The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted.

[0061] In some instances, X 15 , X 16 , X 17 , X 18 , and X 19 are respectively CR 11 For example, X 15 is CR 11 and R 11 is halogen and OR 9 and / or X 16 , X 17 , X 18 , and X 19 are respectively CR 11 and R 11 is hydrogen. In one embodiment, R 2is a 2-methoxyphenyl or 2-chlorophenyl group; or X 15 , X 16 , X 17 , X 18 , and X 19 At least one of X is N. In some compounds, X 16 may be N or CH. In the same or other compounds, X 17 is CR 11 R may be 11 is cyano, halogen, alkyl halide, or OR 9 , preferably cyano. For example, R 2 may be a 4-cyanophenyl group or a 6-cyano-3-pyridyl group.

[0062] Non-limiting examples of compounds of formula I are:

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

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

[0076] For example, the compound may be Compound 78, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Alternatively, the compound may be selected from Compounds 1-77, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, as defined herein. For example, preferred examples may be selected from Compounds 1-18, 20-31, 33-61, 63-68, and 70-77, or preferably from Compounds 1-18, 20-29, 31, 36-61, 63-68, and 70-77, or more preferably 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), or 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, as defined herein.

[0077] These compounds can be prepared by conventional chemical synthesis, such as those described in the Examples section below. As one skilled in the art will appreciate, additional methods of synthesizing compounds of the formulae herein will be apparent to those skilled in the art. In addition, the various synthetic steps may be performed in an alternative sequence or order to obtain the desired compounds.

[0078] The compounds defined herein can be formulated in pharmaceutical compositions for administration to a subject, where the compounds are typically mixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0079] The phrase "pharmaceutically acceptable carrier, diluent, or excipient" and equivalent phrases refers to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated.

[0080] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, and intralesional injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0081] For example, solid dosage forms for oral administration include capsules, tablets, pills and granules.In a preferred alternative, the composition is a solid dosage form comprising the compound as described herein and at least one binder as defined in the preceding paragraph, and the binder preferably comprises microcrystalline cellulose.

[0082] Pharmaceutically acceptable carriers, diluents, or excipients that can be used in the oral compositions of the present disclosure include, but are not limited to, binders, sweeteners, disintegrants, diluents, flavorings, coating agents, preservatives, lubricants, and / or polymers. Examples of binders include cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, as well as other binders such as acacia gum, gelatin, corn starch, tragacanth gum, sodium alginate, or polyethylene glycol (PEG). Examples of sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Examples of diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate, or dicalcium phosphate. Flavoring agents include peppermint oil, oil of wintergreen, cherry, orange, or raspberry flavoring. Coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac, or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Examples of excipients may further include a polymer selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC), hypromellose-acetate-succinate (HPMCAS), and mixtures thereof.

[0083] The present composition can also be used as a filler in soft and hard-filled capsules.The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology.They can optionally contain emulsifying agents, and can optionally be of a composition that releases active ingredient only or preferentially in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.The composition can also be in microencapsulated form with one or more of the above-mentioned excipients.

[0084] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and their mixtures.In addition to inert diluents, these oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, surfactants, sweeteners, flavorings and fragrances.

[0085] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution.In addition, sterile fixed oils are conventionally used as solvents or suspending media.For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides.In addition, fatty acids such as oleic acid can be used to prepare injectables.

[0086] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0087] In order to prolong the effect of a compound provided, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the compound then depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oil vehicle.Injectable depot forms can be made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of compound to polymer and the properties of the specific polymer used, the compound release rate can be controlled.

[0088] 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.

[0089] The dosage forms for topical or transdermal administration of the compounds herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any necessary preservatives or buffers, if necessary.Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this specification.In addition, this specification contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body.Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0090] The pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation art and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0091] The amount of compound that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated and the particular mode of administration.

[0092] As used herein, the term "effective amount" refers to an amount of a compound that elicits the biological or medical response of a tissue, system, animal, or human that is desired, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or its symptoms, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. This term also includes amounts within that range that are effective to enhance normal physiological function.

[0093] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have disappeared, e.g., to prevent or delay their recurrence.

[0094] As used herein, the term "patient" or "subject" refers to an animal, such as a mammal. Thus, a subject may refer to, for example, a mouse, rat, dog, cat, horse, cow, pig, guinea pig, primate, including humans and the like, etc. Preferably, the subject is a human.

[0095] The present compound is useful for treating diseases and disorders that show the inhibition of cannabinoid receptor CB1.Therefore, the present invention contemplates the use of the present compound for treating the diseases or disorders defined herein, the use of the present compound in the manufacture of medicines for treating the diseases or disorders defined herein, the compounds defined herein for use in treating the diseases or disorders, and the method for treating the diseases or disorders defined herein, comprising administering one of the present compounds to a subject in need thereof.Such diseases and disorders may generally be related to diabetes and metabolic disorders (such as metabolic syndrome).Preferably, the compound does not interact or does not primarily interact with CB1 receptor in brain tissue, while selectively targeting CB1 receptor in peripheral tissue (such as adipose tissue, liver, muscle, lung, kidney, macrophage, splenic beta cell, and gastrointestinal tract), thereby avoiding or reducing CNS-related side effects.

[0096] The effects of the compounds may include reduced food intake, reduced body weight, reversal of insulin and leptin resistance, reversal of hepatic steatosis (fatty liver), and improvement of dyslipidemia. Examples of diseases and disorders to be treated include obesity, diabetes mellitus (type I or type II), non-alcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), pro-opiomelanocortin (POMC) deficiency obesity, leptin receptor (LepR) deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl (BB) syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases of the skin, liver, lung, or kidney such as idiopathic pulmonary fibrosis (IPF), progressive fibrotic interstitial lung disease, Hermansky-Pudl syndrome pulmonary fibrosis (HPS-PF), liver cirrhosis, renal fibrosis, scleroderma, and gout. In addition, skin disorders include reducing scar formation (scar, keloid) and alopecia, especially male pattern baldness and those related to metabolic syndrome.For example, obesity comorbidities are selected from metabolic syndrome, dementia, heart disease, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorder, menstrual irregularities, osteoarthritis, venous stasis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, asthma, obesity asthma, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and the increased incidence of liver, ovary, cervix, uterus, breast, prostate or gallbladder malignant tumor.In a preferred example, disease or disorder includes diabetes (type I or type II), obesity, and non-alcoholic fatty liver disease (for example, non-alcoholic fatty liver disease).Examples of diabetes (for example, type I) comorbidities include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0097] The diseases, disorders and conditions to be treated, including those mentioned above, can be divided into various categories, and some conditions may coexist in a given subject.Examples of categories include appetite-related disorders and their complications, glucose regulation-related disorders and their complications, fibrosis-related disorders and their complications, metabolism-related disorders and their complications, skin and hair growth and healing-related disorders, gastrointestinal tract-related disorders, and obesity-related disorders and their complications.

[0098] Examples of appetite-related disorders and their complications include, but are not limited to, Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

[0099] Examples of disorders related to glucose regulation and their complications include, but are not limited to, type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

[0100] Examples of fibrosis-related disorders or their complications include, but are not limited to, progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrotic kidney disease, skin fibrosis disorders (such as scleroderma), and chronic kidney disease.

[0101] Examples of metabolic disorders or their complications include, but are not limited to, metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0102] Examples of obesity-related disorders or their complications include, but are not limited to, sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0103] Examples of skin and hair disorders include alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma, among others.

[0104] Examples of disorders related to the gastrointestinal tract include constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0105] Other disorders may also benefit from the compounds, including muscle wasting disorders including muscular dystrophies (such as Duchenne muscular dystrophy (DMD)), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy, and others.

[0106] The solid compounds and compositions may also be used in methods for preventing or reversing the deposition of adipose tissue in a subject, which is expected to contribute to a reduction in the incidence or severity of obesity, which in turn will reduce the incidence or severity of associated comorbidities.

[0107] The present disclosure provides a method for treating a disorder (described herein) in a subject, the method comprising administering a compound or composition of the present disclosure to a subject identified as needing the treatment. Identifying patients who need treatment for the above-mentioned disorders is well within the ability and knowledge of those skilled in the art. Certain methods for identifying patients at risk of developing the above-mentioned disorders that can be treated by the subject method are understood in the medical arts, such as family history and the presence of risk factors associated with the development of the disease state in the subject patient. A clinician skilled in the art can easily identify such candidate patients, for example, by using clinical tests, physical examinations, medical / family history, and genetic testing.

[0108] A method for evaluating the effectiveness of treatment in a subject includes determining the pre-treatment symptoms of the disorder by methods known in the art, and then administering a therapeutically effective amount of a compound of the present invention to the subject. After an appropriate period (e.g., 1 week, 2 weeks, 1 month, 6 months) after administration of the compound, the symptoms of the disorder are reassessed. Modulation (e.g., reduction) of the symptoms and / or biomarkers of the disorder indicates the effectiveness of the treatment. The symptoms and / or biomarkers of the disorder may be determined periodically throughout the treatment. For example, the symptoms and / or biomarkers of the disorder may be checked every few days, weeks, or months to further evaluate the effectiveness of the treatment. A reduction in the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0109] The pharmaceutical compositions provided herein are preferably adapted for oral administration.These formulations can be administered with or without food.The compositions are formulated in unit dosage form for ease of administration and uniformity of dosage.As used herein, the expression "unit dosage form" refers to a physically separate pharmaceutical unit suitable for the patient to be treated.However, it will be understood that the total daily dosage of the solid dispersion and composition of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.

[0110] The amount of composition that can be included in a single dosage form varies depending on the patient being treated (e.g., child vs. adult) and the particular compound included in the composition. Provided compositions can be formulated so that a total daily dose of, for example, 0.01 to 100 mg / kg body weight / day or 0.01 to 20 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions. A single-dose composition may contain such amounts, or the total daily dose may be divided into multiple dosage forms to be taken, for example, once, twice, or three times daily. For example, a single dose may contain 5 to 500 mg of active ingredient, or 20 to 200 mg. A treatment regimen may involve administering to a patient a total amount of about 10 mg to about 1000 mg of the compound herein per day, either in a single dose or divided into multiple doses.

[0111] It will be understood that the total daily dose of compound will be determined by the attending physician within the scope of sound medical judgment.For example, the specific dose or treatment regimen for any specific patient will depend on various factors, including age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, the judgment of treating physician and the severity of the symptoms associated with disease or disorder.

[0112] Depending on the disease or disorder to be treated, additional therapeutic agents may also be present in the composition of the present disclosure or may be separately co-administered.Non-limiting examples of additional therapeutic agents that can be used in combination with the present solid dispersions and formulations include antidiabetic drugs, cholesterol-lowering drugs, anti-inflammatory agents, antibacterial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer drugs, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compounds.Treatment can also be supplemented with other treatments or interventions, such as surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes), biological response modifiers (e.g., interferon, interleukin, tumor necrosis factor (TNF)), and drugs used to attenuate the adverse effects of the present compound or co-administered components.

[0113] The recitation of an embodiment for a variable herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. [Example]

[0114] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the invention. These examples are better understood with reference to the accompanying drawings.

[0115] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stability, and the like used in the specification and claims should be understood to be modified in all instances by the term "about." At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors resulting from variations in experiments, testing measurements, statistical analyses and the like.

[0116] Example 1 - Preparation of Starting Materials (i) Preparation of 1-(trifluoromethylsulfonyl)piperazine A solution of tert-butyl 4-(trifluoromethylsulfonyl)piperazine-1-carboxylate (200 mg, 628.3 μmol, 1 equiv) in hydrochloric acid / dioxane (4 M, 6.0 mL, 38.2 equiv) was stirred for 1 hour at 25° C. The mixture was concentrated to give 1-(trifluoromethylsulfonyl)piperazine (130 mg, as the HCl salt) as a white solid.

[0117] (ii) Preparation of 4-methylpiperidine-4-carboxamide A solution of tert-butyl 4-methyl-4-carboxamidopiperidine-1-carboxylate (200 mg, 628.3 μmol, 1 equiv) in hydrochloric acid / dioxane (4 M, 6.0 mL, 38.2 equiv) was stirred for 1 hour at 25° C. The mixture was concentrated to give the product 4-methylpiperidine-4-carboxamide (130 mg, as the HCl salt) as a white solid.

[0118] (iii) Preparation of 1-methylsulfonylpiperazine Step 1: To a solution of tert-butyl piperazine-1-carboxylate hydrochloride (1 g, 4.49 mmol, 1 equiv.) in dichloromethane (10 mL) was added methylsulfonyl methanesulfonate (1.56 g, 8.98 mmol, 2 equiv.) and triethylamine (681 mg, 6.74 mmol, 0.94 mL, 1.5 equiv.) 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 90 mL of dichloromethane (30 mL×3). The combined organic layers were washed with 60 mL of brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-methylsulfonylpiperazine-1-carboxylate (1 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=3.48-3.33(m,4H), 3.14-3.00(m,4H), 2.87(s,3H), 1.41(s,9H).

[0119] Step 2: To a solution of tert-butyl 4-methylsulfonylpiperazine-1-carboxylate from Step 1 (800 mg, 3.03 mmol, 1 equiv) in dioxane (2 mL) was added hydrochloric acid / dioxane (4 M, 4 mL, 5.3 equiv). 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).

[0120] (iv) Preparation of 2-(azetidin-3-yl)acetamide Step 1: To a solution of 2-(1-tert-butoxycarbonylazetidin-3-yl) acetonitrile (1 g, 4.65 mmol, 1 equiv.) in N,N-dimethylformamide (10 mL) in acetic acid (1 g, 4.65 mmol, 1 equiv.), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 2.65 g, 6.97 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (2.10 g, 16.26 mmol, 2.83 mL, 3.5 equiv.) were added. The mixture was stirred at 25° C. for 0.5 hours. Ammonium chloride (547 mg, 10.22 mmol, 2.2 equiv.) was added to the mixture, and the mixture was stirred at 25° C. for 15 hours. The reaction mixture was washed with water (50 mL) and extracted with 150 mL of ethyl acetate (50 mL × 3). The combined organic layers were washed with 100 mL (50 mL × 2) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the cleavage 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).

[0121] Step 2: A solution of tert-butyl 3-(2-amino-2-oxo-ethyl)azetidine-1-carboxylate (550 mg, 2.57 mmol, 1 equiv) from Step 1 in hydrochloric acid / dioxane (4 M, 5 mL, 7.79 equiv) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 2-(azetidin-3-yl)acetamide (400 mg) as a yellow oil.

[0122] (v) Preparation of N-(4-methyl-4-piperidyl)acetamide Step 1: To a solution of tert-butyl 4-amino-4-methyl-piperidine-1-carboxylate (1 g, 4.67 mmol, 1 equiv.) and triethylamine (708 mg, 7.00 mmol, 0.97 mL, 1.5 equiv.) in dichloromethane (10 mL), acetyl chloride (439.55 mg, 5.60 mmol, 399.59 μL, 1.2 equiv.) was added dropwise at 0 °C. After the addition, the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluting with 0–10% methanol / dichloromethane at 30 mL / min). The cleaved fraction was concentrated under reduced pressure to give tert-butyl 4-acetamido-4-methyl-piperidine-1-carboxylate (1.13 g) as a pale yellow oil.

[0123] Step 2: A solution of tert-butyl 4-acetamido-4-methyl-piperidine-1-carboxylate (0.37 g, 1.44 mmol, 1 equiv) from Step 1 in HCl / dioxane (4 M, 4 mL, 11.08 equiv) was stirred for 1 h at 25° C. The reaction mixture was concentrated under reduced pressure to give N-(4-methyl-4-piperidyl)acetamide (270 mg, as the HCl salt) as a white solid, which was used directly in the next step without further purification.

[0124] (vi) Preparation of 2-[(3R)-pyrrolidin-3-yl]acetamide Step 1: To a solution of 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid (1 g, 4.36 mmol, 1 equiv.) in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 2.49 g, 6.54 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (1.97 g, 15.27 mmol, 2.66 mL, 3.5 equiv.) were added. The mixture was stirred at 25°C for 0.5 hours. Then, ammonium chloride (513 mg, 9.60 mmol, 2.2 equiv.) was added to the mixture, and the mixture was stirred at 25°C for 15 hours. The reaction mixture was washed with water (50 mL) and extracted with 150 mL of ethyl acetate (50 mL x 3). The combined organic layers were washed with 100 mL (50 mL × 2) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient at 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).

[0125] Step 2: A solution of tert-butyl (3R)-3-(2-amino-2-oxo-ethyl)pyrrolidine-1-carboxylate (800 mg, 3.50 mmol, 1 equiv) from Step 1 in hydrogen chloride / dioxane (4 M, 8 mL, 9.13 equiv) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 2-[(3R)-pyrrolidin-3-yl]acetamide (500 mg, as the HCl salt) as a yellow oil.

[0126] (vii) Preparation of 2-[(2R)-azetidin-2-yl]acetic acid To a solution of 2-[(2R)-1-tert-butoxycarbonylazetidin-2-yl]acetic acid (50 mg, 0.23 mmol, 1 equiv) in dichloromethane (1.5 mL) was added trifluoroacetic acid (6.8 mmol, 0.5 mL, 29.07 equiv), and the mixture was stirred for 1 hour at 25° C. The mixture was concentrated under reduced pressure to give the product 2-[(2R)-azetidin-2-yl]acetic acid (53 mg, as the 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).

[0127] (viii) Preparation of N-ethyl-2-(methylamino)acetamide Step 1: A mixture of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (3 g, 15.86 mmol, 1 equiv.), N,N-diisopropylethylamine (6.15 g, 47.57 mmol, 8.29 mL, 3 equiv.), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 7.23 g, 19.03 mmol, 1.2 equiv.) in N,N-dimethylformamide (15 mL) was stirred at 25° C. for 30 minutes. Then, ethylamine hydrochloride (2.59 g, 31.71 mmol, 2 equiv.) 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 200 mL of ethyl acetate (100 mL × 2). The combined organic layers were washed with 200 mL (100 mL × 2) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent: 0-65% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fractions were concentrated under reduced pressure to give tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]-N-methyl-carbamate (0.6 g) as a pale yellow solid.

[0128] Step 2: A mixture of tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]-N-methyl-carbamate (0.58 g, 2.68 mmol, 1 equiv) from Step 1 in hydrogen chloride / dioxane (5 mL) was stirred for 2 hours at 25° C. The reaction mixture was concentrated under reduced pressure to give N-ethyl-2-(methylamino)acetamide (409 mg, crude, HCl salt) as a white solid.

[0129] (ix) Preparation of (3S)-piperidine-3-carboxamide A mixture of tert-butyl (3S)-3-carbamoylpiperidine-1-carboxylate (1 g, 4.38 mmol, 1 equivalent) and trifluoroacetic acid (4.62 g, 40.52 mmol, 3 mL, 9.25 equivalents) in dichloromethane (9 mL) was stirred for 2 hours at 25° C. The reaction mixture was concentrated under reduced pressure to give the 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.

[0130] (x) Preparation of 4-ethoxypiperidine-4-carboxamide Step 1: 1-tert-Butoxycarbonyl-4-hydroxy-piperidine-4-carboxylic acid (1 g, 4.1 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (1.7 g, 12.2 mmol, 3 equiv.) and benzyl bromide (32.6 mmol, 3.9 mL, 8 equiv.) 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 afford 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).

[0131] Step 2: To a solution of O-4-benzyl O-1-tert-butyl 4-hydroxypiperidine-1,4-dicarboxylate from Step 1 (1.2 g, 3.6 mmol, 1 equiv.) in tetrahydrofuran (15 mL), sodium hydride (286 mg, 7.2 mmol, 60% purity, 2 equiv.) was added, and the mixture was stirred at 25° C. for 0.5 h. Iodoethane (1.7 g, 10.7 mmol, 0.86 mL, 3 equiv.) was then added dropwise, and the resulting mixture was stirred at 60° C. for 15 h. The mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was then washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide 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).

[0132] Step 3: A mixture of O-4-benzyl O-1-tert-butyl 4-ethoxypiperidine-1,4-dicarboxylate (700 mg, 1.9 mmol, 1 equiv.) from Step 2 and 10% palladium on carbon (100 mg) in ethanol (10 mL) was degassed and purged with hydrogen three times, after which the mixture was stirred under a hydrogen atmosphere at 25° C. for 15 hours. 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 afford 1-tert-butoxycarbonyl-4-ethoxy-piperidine-4-carboxylic acid (420 mg) as a white solid. 1H 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).

[0133] Step 4: 1-tert-Butoxycarbonyl-4-ethoxy-piperidine-4-carboxylic acid (420 mg, 1.5 mmol, 1 equiv.) from Step 3, ammonium chloride (181 mg, 3.4 mmol, 2.2 equiv.), and 1-hydroxybenzotriazole (311 mg, 2.3 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 (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (442 mg, 2.3 mmol, 1.5 equiv.) was added. N,N-diisopropylethylamine (437 mg, 3.4 mmol, 0.59 mL, 2.2 equiv.) was added dropwise. The resulting solution was stirred at 25 °C for 3 h. 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, and 15 mL of brine, and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give tert-butyl 4-carbamoyl-4-ethoxy-piperidine-1-carboxylate (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).

[0134] Step 5: To a solution of tert-butyl 4-carbamoyl-4-ethoxy-piperidine-1-carboxylate (380 mg, 1.40 mmol, 1 equiv) in dichloromethane (4 mL), trifluoroacetic acid (27.0 mmol, 2 mL, 19.3 equiv) was added 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.

[0135] (xi) Preparation of 2-amino-N-ethyl-acetamide Step 1: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (4 g, 22.83 mmol, 1 equiv.), ethanamine (4.10 g, 50.23 mmol, 5.94 mL, 2.2 equiv., HCl salt), and 1-hydroxybenzotriazole (3.70 g, 27.40 mmol, 1.2 equiv.) in dichloromethane (40 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.25 g, 27.40 mmol, 1.2 equiv.) was added, and N,N-diisopropylethylamine (7.08 g, 54.79 mmol, 9.55 mL, 2.4 equiv.) was added 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 subsequently washed with 100 mL each of saturated aqueous sodium bicarbonate 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.

[0136] Step 2: A mixture of tert-butyl N-[2-(ethylamino)-2-oxo-ethyl]carbamate (2.4 g, 11.87 mmol, 1 equiv) from Step 1 in hydrochloric acid / dioxane (6 mL) was stirred for 2 hours at 25° C. 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. 1H 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).

[0137] (xii) Preparation of 1-amino-3-[(4-methoxyphenyl)methyl]thiourea To a solution of 1-(isothiocyanatomethyl)-4-methoxy-benzene (6.5 g, 36.3 mmol, 1.0 equiv) in ethanol (65 mL) was added hydrazine hydrate (2.7 g, 54.4 mmol, 2.6 mL, 1.5 equiv) 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.

[0138] (xiii) Preparation of 4-isopropoxypiperidine-4-carboxamide Step 1: Sodium hydride (3.01 g, 75.3 mmol, 60% purity, 3.0 equiv.) was added in portions over 20 minutes at 25° C. to a flask containing isopropanol (1.96 mol, 150 mL, 78.1 equiv.). The resulting mixture was stirred at 25° C. for 0.5 hours and then slowly transferred to a 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.) at 0° C., 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 (2×100 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent gradient of 0% to approximately 50% ethyl acetate / petroleum ether at 50 mL / min) to afford 1-(tert-butyl)4-isopropyl 4-isopropoxypiperidine-1,4-dicarboxylate (620 mg, 1.88 mmol) as a colorless oil. 1H 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).

[0139] Step 2: To a solution of 11-(tert-butyl)4-isopropyl 4-isopropoxypiperidine-1,4-dicarboxylate (600 mg, 1.82 mmol, 1 equiv.) from Step 1 in ethyl alcohol (10 mL) and water (1 mL), lithium hydroxide (218 mg, 9.11 mmol, 5 equiv.) was added, 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×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×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-tert-butoxycarbonyl-4-isopropoxy-piperidine-4-carboxylic acid (480 mg, 1.67 mmol) as a colorless oil. 1 H 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).

[0140] Step 3: A mixture of 1-tert-butoxycarbonyl-4-isopropoxy-piperidine-4-carboxylic acid (440 mg, 1.53 mmol, 1 equiv) from Step 2, saturated ammonium chloride solution (180 mg, 3.37 mmol, 2.2 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (440 mg, 2.30 mmol, 1.5 equiv), 1-hydroxybenzotriazole (310 mg, 2.30 mmol, 1.5 equiv), and N,N-diisopropylethylamine (435 mg, 3.37 mmol, 0.59 mL, 2.2 equiv) 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 tert-butyl 4-carbamoyl-4-isopropoxy-piperidine-1-carboxylate (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).

[0141] Step 4: To a solution of tert-butyl 4-carbamoyl-4-isopropoxy-piperidine-1-carboxylate from Step 3 (410 mg, 1.43 mmol, 1 equiv) in dioxane (2 mL) was added dioxane hydrochloride solution (4 M, 2 mL, 5.59 equiv) and the mixture was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 4-isopropoxypiperidine-4-carboxamide (400 mg, crude, hydrochloride salt) 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).

[0142] (xiv) Preparation of azetidine-3-carboxamide Step 1: 1-tert-Butoxycarbonylazetidine-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), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.43 g, 17.9 mmol, 1.2 equiv.) was added. 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 h. 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).

[0143] Step 2: To a solution of tert-butyl 3-carbamoylazetidine-1-carboxylate from Step 1 (500 mg, 2.50 mmol, 1.0 equiv) in dichloroethane (9 mL) was added trifluoroacetic acid (40.52 mmol, 3 mL, 16.2 equiv) 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(brs,1H), 7.23(brs,1H), 4.14-3.88(m,5H), 3.71-3.39(m,1H).

[0144] (xv) Preparation of 3-methylazetidine-3-carboxamide 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.). Di-tert-butyl dicarbonate (3.29 g, 15.08 mmol, 3.47 mL, 2.0 equiv.) was then added dropwise to the mixture, which was stirred at 25 °C for 3 h. 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 (ISCO®, 20 g SepaFlash® silica flash column, eluent gradient of 0% to approximately 50% ethyl acetate / petroleum ether at 40 mL / min). The collected 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).

[0145] Step 2: Dissolve tert-butyl 3-cyano-3-methyl-azetidine-1-carboxylate (200 mg, 1.02 mmol, 1.0 equiv) from Step 1 and dimethylphosphinite platinum dimethylphosphinate ( 2+A mixture of 3-carbamoyl-3-methyl-azetidine-1-carboxylate (435 mg, 1.02 mmol, 1.0 equiv.) 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 that was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent gradient of approximately 50% to approximately 100% ethyl acetate / petroleum ether at 40 mL / min). The collected 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).

[0146] Step 3: A mixture of tert-butyl 3-carbamoyl-3-methyl-azetidine-1-carboxylate (200 mg, 0.93 mmol, 1.0 equiv) from Step 2 and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 14.5 equiv) in dichloromethane (3 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to provide 3-methylazetidine-3-carboxamide (210 mg, 0.92 mmol, trifluoroacetate salt) as a pale yellow oil, which was used directly in the next step without further purification.

[0147] (xvi) Preparation of (2R)-N-methylazetidine-2-carboxamide Step 1: (2R)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (2.0 g, 9.94 mmol, 1.0 equiv.), ethanamine 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), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.86 g, 14.9 mmol, 1.5 equiv.) was added. 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 h. 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 (ISCO®, 25 g SepaFlash® silica flash column, eluent gradient of about 0% to about 20% ethyl acetate / petroleum ether at 30 mL / min) to give 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).

[0148] Step 2: In a round-bottom flask, tert-butyl (2R)-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 hours. The reaction mixture was concentrated under reduced pressure to afford (2R)-N-methylazetidine-2-carboxamide (850 mg, 3.73 mmol, trifluoroacetate salt) as a colorless oil. 1 H NMR(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).

[0149] (xvii) Preparation of (2S)-3-(methylamino)propane-1,2-diol Step 1: A solution of [(2R)-oxiran-2-yl]methanol (3.67 g, 49.5 mmol, 3.27 mL, 1.2 equiv) and N-methyl-1-phenyl-methanamine (5.0 g, 41.3 mmol, 5.32 mL, 1.0 equiv) in methanol (100 mL) was stirred at 70° C. for 15 h. 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).

[0150] 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 palladium (10%) on carbon (100 mg, 5.12 mmol), and the mixture was degassed and purged with hydrogen three times before stirring under a hydrogen atmosphere at 25° C. 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 H NMR(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).

[0151] (xviii) Preparation of (2S)-2-(methylamino)propanamide Step 1: (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic 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 the dropwise addition of N,N-diisopropylethylamine (2.80 g, 21.6 mmol, 2.2 equiv.). The resulting solution was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, dissolved in dichloromethane (100 mL), 10% citric acid (100 mL) was added, and 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 tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (1.54 g, 7.61 mmol) as a yellow solid. 1H 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).

[0152] Step 2: In a round-bottom flask, tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (500 mg, 2.47 mmol, 1.0 equiv) from Step 1 and hydrochloride salt were added in dioxane (4 M, 10 mL, 16.2 equiv), and the resulting mixture was stirred for 0.5 h at 25° C. 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).

[0153] (xix) Preparation of 2-(azetidin-3-yloxy)acetamide Step 1: To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.77 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added sodium hydride (231 mg, 5.77 mmol, 60% purity, 1.0 equiv), and the resulting mixture was stirred at 25° C. for 0.5 h. Then, 2-bromoacetamide (876 mg, 6.35 mmol, 1.1 equiv) was added, and the resulting mixture was stirred at 25° C. for 2.5 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were 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 (ISCO®, 40 g SepaFlash® silica flash column, eluent gradient of approximately 80% to approximately 100% ethyl acetate / petroleum ether at 40 mL / min). The collected fractions were concentrated under reduced pressure to give the compound tert-butyl 3-(2-amino-2-oxo-ethoxy)azetidine-1-carboxylate (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).

[0154] Step 2: A mixture of tert-butyl 3-(2-amino-2-oxo-ethoxy)azetidine-1-carboxylate (0.5 g, 2.17 mmol, 1.0 equiv) from Step 1 in hydrochloride / dioxane (4 M, 8 mL, 14.7 equiv) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give the 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.

[0155] (xx) [(2S)-pyrrolidin-2-yl]methanol- 15 Preparation of N-d7 Step 1: Proline- 15N-d7 (250 mg, 2.03 mmol) was dissolved in methanol and chlorotrimethylsilane was added. The reaction was stirred at room temperature overnight and evaporated to give solid proline- 15 N-d7 methyl ester (hydrochloride) was obtained.

[0156] Step 2: Proline from Step 1 15 N-d7 methyl ester (hydrochloride), di-tert-butyl decarbonate (552 mg, 2.53 mmol), and potassium carbonate (1.4 g, 10 mmol) were suspended in acetonitrile and stirred overnight at room temperature. 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 obtained and used directly in the next step.

[0157] Step 3: Lithium aluminum hydride (386 mg, 10.15 mmol) was suspended in dry tetrahydrofuran and the solution was cooled to 0° C. in an ice bath. N-tert-butyloxycarbonylproline- from Step 2 in tetrahydrofuran 15 A solution of N-d7 methyl ester was added dropwise. The progress of the reaction was monitored by thin layer chromatography. Upon completion, the reaction was quenched at 0°C by adding 0.7 mL of water, 1.4 mL of 4N aqueous sodium hydroxide, ether, and another 1.4 mL of water. The solid was filtered through Celite™ and washed three times with ethyl acetate. The solvent was evaporated to produce an oily N-tert-butyloxy[(2S)-pyrrolidin-2-yl]methanol.

[0158] Step 4: N-tert-butyloxy[(2S)-pyrrolidin-2-yl]methanol from step 3 was dissolved in 1,4-dioxane and 12 M hydrogen chloride in 1,4-dioxane was added to reach a final concentration of 4 M hydrogen chloride. The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the product was co-evaporated three times with acetonitrile to give [(2S)-pyrrolidin-2-yl]methanol-15 N-d7 (hydrochloride salt) was obtained.

[0159] (xxi) Preparation of 1,1-(d6) dimethyl-1,2-dihydroxyethane Step 1: At 0°C, to a solution of ethyl 2-(benzyloxy)acetate (1000 mg, 5.15 mmol) in tetrahydrofuran was added methyl-d3-magnesium iodide (15.45 mL, 15.45 mmol) as a 1 M solution in tetrahydrofuran. The reaction was allowed to reach room temperature and stirred for 3 hours. At 0°C, ammonium chloride was added, 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 hexanes. The solvent was evaporated to give 1,1-(d6)dimethyl-2-benzyloxy-1-ethanol.

[0160] 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. The reaction was filtered through Celite™ and the filtrate was evaporated to give an oil which was co-evaporated twice with dry tetrahydrofuran to give 1,1-(d6)dimethyl-1,2-dihydroxyethane.

[0161] Example 2 - Preparation of Intermediates I-1(a) to I-1(d)

[0162] [ka] (i) Intermediate I-1(a)(R 2 :2-Cl-phenyl):

[0163] [ka]

[0164] Step 1: To a solution of 3-(2-chlorophenyl)-3-oxo-propanenitrile (30 g, 167 mmol, 1 equiv.) in ethanol (300 mL), hydrazine hydrate (16.7 g, 334 mmol, 16 mL, 2 equiv.) was added, and the mixture was stirred at 90° C. for 16 hours. The mixture was concentrated under reduced pressure to remove ethanol. Then, 200 mL of water was added, and the mixture was extracted with 600 mL of ethyl acetate (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-pyrazol-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).

[0165] Step 2: A mixture of 3-(2-chlorophenyl)-1H-pyrazol-5-amine (32 g, 165.3 mmol, 1 equiv.) from Step 1, iodine (46.1 g, 181.8 mmol, 1.1 equiv.), and potassium carbonate (25.1 g, 181.8 mmol, 1.1 equiv.) in acetonitrile (240 mL) and water (60 mL) was stirred at 25° C. for 16 hours. The mixture was poured into water (500 mL) and extracted with 600 mL of ethyl acetate (3×200 mL). The organic phase was then washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica column (petroleum ether:ethyl acetate=1:1) to give 3-(2-chlorophenyl)-4-iodo-1H-pyrazol-5-amine (40 g) as a dark brown oil. 1 H NMR (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).

[0166] Step 3: A mixture of 3-(2-chlorophenyl)-4-iodo-1H-pyrazol-5-amine (40 g, 125.2 mmol, 1 equiv.) from Step 2, di-tert-butyl dicarbonate (82 g, 375.6 mmol, 86.3 mL, 3 equiv.), triethylamine (400.6 mmol, 55.8 mL, 3.2 equiv.), and 4-dimethylaminopyridine (3.1 g, 25 mmol, 0.2 equiv.) in dichloromethane (400 mL) was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica column (petroleum ether:ethyl acetate=5:1) to give tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-iodo-pyrazole-1-carboxylate (45 g) as a yellow solid.

[0167] Step 4: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)-4-iodo-pyrazole-1-carboxylate from Step 3 (24 g, 38.7 mmol, 1 equiv), (4-chlorophenyl)boronic acid (18.2 g, 116.2 mmol, 3 equiv), potassium carbonate (10.7 g, 77.4 mmol, 2 equiv), and Pd(dppf)Cl (1.42 g, 1.94 mmol, 0.05 equiv) in dioxane (240 mL) and water (48 mL) was stirred at 80° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica 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.

[0168] 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 equiv.) from Step 4 in hydrogen chloride in methanol (4 M, 410 mL, 24 equiv.) was stirred for 1 hour at 25° C. The mixture was then concentrated under reduced pressure to provide 3-(2-chlorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-5-amine (39 g, as the HCl salt) as a yellow solid.

[0169] Step 6: To a solution of sodium ethoxide (39 g, 572.5 mmol, 5 equiv.) in ethanol (390 mL), 3-(2-chlorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-5-amine (39 g, 114.5 mmol, 1 equiv., as the HCl salt) from Step 5 and dimethyl malonate (343.5 mmol, 39.5 mL, 3 equiv.) were added, and the mixture was then stirred at 80° C. for 2 hours. The ethanol was removed, and the pH was adjusted to 5 with 1 M hydrochloric acid (200 mL). The mixture was then extracted with 600 mL of ethyl acetate (3×200 mL). The organic phase was then washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide 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).

[0170] 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 equiv.) from Step 6 in phosphorus oxychloride (303.9 mmol, 28.2 mL, 13 equiv.) was added N,N-dimethylaniline (35.1 mmol, 4.4 mL, 1.5 equiv.) at 0° C., and the mixture was then stirred at 100° C. for 2 hours. After cooling, the mixture was poured into water (200 mL). The mixture was then extracted with 300 mL of ethyl acetate (3×100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was purified by silica 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).

[0171] (ii) Intermediate I-1(b)(R 2 :2-MeO-phenyl):

[0172] [ka]

[0173] Step 1: To a solution of lithium diisopropylamide (2 M, 15.8 mL, 1.05 equiv.) in tetrahydrofuran (100 mL), acetonitrile (32.5 mmol, 1.7 mL, 1.08 equiv.) was added, and the mixture was stirred at −78° C. for 1 h. Then, a solution of methyl 2-methoxybenzoate (5 g, 30.1 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at −78° C. for 1 h. The mixture was warmed to 25° C. and stirred at 25° C. for 2 h. The mixture was quenched by adding water (50 mL). The aqueous layer was acidified to pH=3 with 1 M hydrochloric acid and extracted with 150 mL of ethyl acetate (3×50 mL). The combined organic phase was then washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica column (petroleum ether: ethyl acetate = 3:1) to give 3-(2-methoxyphenyl)-3-oxo-propanenitrile (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).

[0174] Step 2: To a solution of 3-(2-methoxyphenyl)-3-oxo-propanenitrile (2.1 g, 11.99 mmol, 1 equiv.) from Step 1 in ethanol (21 mL), hydrazine hydrate (1.17 mL, 24.0 mmol, 2 equiv.) was added, and the mixture was stirred at 90° C. for 16 hours. The mixture was concentrated to remove ethanol, and 20 mL of water was added to the mixture. The mixture was then extracted with 60 mL of ethyl acetate (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 column (ethyl acetate:methanol=10:1) to give 3-(2-methoxyphenyl)-1H-pyrazol-5-amine (1.4 g) as a yellow solid. 1H NMR (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).

[0175] Step 3: To a solution of 3-(2-methoxyphenyl)-1H-pyrazol-5-amine (1.4 g, 7.4 mmol, 1 equiv.) from Step 2 and iodine (2.1 g, 8.1 mmol, 1.1 equiv.) in acetonitrile (14 mL) and water (3.5 mL), potassium carbonate (1.1 g, 8.1 mmol, 1.1 equiv.) was added, and the mixture was stirred at 25° C. for 3 hours. The mixture was poured into water (50 mL). The mixture was then extracted with 90 mL of ethyl acetate (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 silica column (petroleum ether:ethyl acetate=1:1) to give 4-iodo-3-(2-methoxyphenyl)-1H-pyrazol-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).

[0176] Step 4: A solution of 4-iodo-3-(2-methoxyphenyl)-1H-pyrazol-5-amine (1.9 g, 6.03 mmol, 1 equiv.) from Step 3, di-tert-butyl dicarbonate (4.0 g, 18.1 mmol, 4.2 mL, 3 equiv.), triethylamine (19.3 mmol, 2.7 mL, 3.2 equiv.), and 4-dimethylaminopyridine (147 mg, 1.2 mmol, 0.2 equiv.) in dichloromethane (20 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica 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 H NMR (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).

[0177] Step 5: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-iodo-3-(2-methoxyphenyl)pyrazole-1-carboxylate from Step 4 (1.9 g, 3.1 mmol, 1 equiv), (4-chlorophenyl)boronic acid (1.5 g, 9.3 mmol, 3 equiv), potassium carbonate (853 mg, 6.2 mmol, 2 equiv), and XPhos Pd G3 (130 mg, 154.4 μmol, 0.05 equiv) in dioxane (19 mL) and water (3.8 mL) was stirred at 80° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica 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. 1H 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).

[0178] 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 equiv) from Step 5 in hydrochloric acid / ethyl acetate (4 M, 13.00 mL, 24.00 equiv) was stirred for 1 hour at 25° C. The mixture was concentrated under reduced pressure to give crude 4-(4-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-5-amine (800 mg, as the HCl salt) as a yellow solid.

[0179] Step 7: To a solution of 4-(4-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-5-amine (800 mg, 2.4 mmol, 1 equiv., as the HCl salt) from Step 6 and sodium ethoxide (809 mg, 11.9 mmol, 5 equiv.) in ethanol (8 mL), dimethyl propanedioate (943 mg, 7.14 mmol, 0.82 mL, 3 equiv.) was added, and the mixture was stirred at 80° C. for 2 hours. The ethanol was removed, and the pH was adjusted to 3 with 1 M hydrochloric acid (10 mL). The mixture was then extracted with 15 mL of ethyl acetate (3×5 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide 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).

[0180] 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 equiv.) from Step 7 in phosphorus oxychloride (6.2 mmol, 0.57 mL, 13 equiv.), N,N-dimethylaniline (713.7 μmol, 0.09 mL, 1.5 equiv.) was added at 0° C., and the mixture was then stirred at 100° C. for 1 hour. The mixture was poured into water (20 mL). The mixture was then extracted with 30 mL of ethyl acetate (3×10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was purified by silica 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) as a yellow oil. 1 H 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).

[0181] (iii) Intermediate I-1(c)(R 2 :4-CN-phenyl):

[0182] [ka] Step 1: To a solution of lithium diisopropylamide (2 M, 32.6 mL, 1.05 equiv) in tetrahydrofuran (200 mL) was added acetonitrile (67.0 mmol, 3.53 mL, 1.08 equiv) and the mixture was stirred at −78° C. for 2 hours under nitrogen. A solution of methyl 4-cyanobenzoate (10 g, 62.0 mmol, 1.0 equiv) in tetrahydrofuran (30 mL) was then 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 the addition of water (150 mL). The aqueous layer was acidified to pH 3 with 1 M aqueous hydrochloric acid and extracted with 450 mL of ethyl acetate (3×150 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluting with a 0% to 100% ethyl acetate / petroleum ether gradient at 50 mL / min). 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).

[0183] 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 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluting with 0% to approximately 10% methanol / ethyl acetate at 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. 1H NMR (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).

[0184] Step 3: To a solution of 4-(5-amino-1H-pyrazol-3-yl)benzonitrile (3.7 g, 20.09 mmol, 1.0 equiv) from Step 2 and iodine (3.80 g, 14.98 mmol, 3.02 mL, 1.2 equiv) in acetonitrile (20 mL) and water (5 mL), potassium carbonate (3.33 g, 24.1 mmol, 1.2 equiv) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were 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 (ISCO®, 80 g SepaFlash® silica flash column, eluting with a 0% to approximately 85% ethyl acetate / petroleum ether gradient at 40 mL / min). The obtained fraction was concentrated under reduced pressure to obtain 4-(5-amino-4-iodo-1H-pyrazol-3-yl)benzonitrile (5.6 g, 18.1 mmol) as a dark brown solid.

[0185] 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) from Step 3, 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), di-tert-butyl dicarbonate (11.82 g, 54.18 mmol, 12.45 mL, 3.0 equiv) was added dropwise 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 × 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 (ISCO®, 80 g SepaFlash® silica flash column, eluting with a 0% to approximately 80% ethyl acetate / petroleum ether gradient at 50 mL / min). The cleavage 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.

[0186] 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]phosphane 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 resulting 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 layers were concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluting with a 0% to approximately 100% ethyl acetate / petroleum ether gradient at 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.

[0187] Step 6: A mixture of tert-butyl 5-[bis(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-3-(4-cyanophenyl)pyrazole-1-carboxylate (7 g, 11.8 mmol, 1.0 equiv.) from Step 5 in hydrochloride / dioxane (50 mL, 4 M) was stirred at 25° C. for 6 hours. The reaction mixture was added dropwise to a saturated solution of sodium bicarbonate (200 mL), and the resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ammonia monohydrate conditions). Fractions were 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 (2.2 g, 7.46 mmol) as a gray solid. 1 H 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).

[0188] Step 7: A mixture of 4-[5-amino-4-(4-chlorophenyl)-1H-pyrazol-3-yl]benzonitrile (500 mg, 1.70 mmol, 1 equiv.) and diethyl propanedioate (5.30 g, 33.1 mmol, 5 mL, 19.5 equiv.) was stirred at 120° C. for 2 hours to form ethyl 3-[[4-(4-chlorophenyl)-3-(4-cyanophenyl)-1H-pyrazol-5-yl]amino]-3-oxo-propanoate (approximately 693 mg). After cooling to room temperature, the reaction mixture was directly diluted with methanol (3 mL), THF (3 mL), and water (3 mL), and 4-dimethylaminopyridine (1.04 g, 8.48 mmol, 5.0 equiv.) 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 the mixture was filtered to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, eluting with a 0% to approximately 30% methanol / dichloroethane gradient at 30 mL / min) to give 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).

[0189] 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 phosphoryl chloride (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 then stirred at 100° C. for 2 hours. The mixture was added to water (10 mL), extracted with ethyl acetate (2×30 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 (ISCO®, 25 g SepaFlash® silica flash column, eluting with a 0% to approximately 50% ethyl acetate / petroleum ether gradient at 50 mL / min) to give 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=8.3Hz,2H), 7.83(s,1H), 7.74(d,J=8.1Hz,2H), 7.54(d,J=8.4Hz,2H), 7.42(d,J=8.4Hz,2H).

[0190] (iv) Intermediate I-1(d)(R 2 :6-CN-pyridin-3-yl):

[0191] [ka]

[0192] Step 1: A mixture of 5-formylpyridine-2-carbonitrile (10 g, 75.7 mmol, 1.0 equiv.) and aniline (21.2 g, 227 mmol, 20.7 mL, 3.0 equiv.) was stirred at 25° C. for 1 hour. Isopropanol (80 mL) was added to the mixture, which was then filtered. The filter cake was dried to obtain the product, 5-[(E)-phenyliminomethyl]pyridine-2-carbonitrile (13.6 g), as a yellow solid. The product was dissolved in ethanol (136 mL), and a solution of phenoxyphosphonoyloxybenzene (41.0 g, 131.3 mmol, 33.6 mL, 75% purity, 2.0 equiv.) in ethanol (20 mL) was added thereto, and the reaction mixture was stirred at 25° C. for 2 hours. The resulting 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 pale yellow solid.

[0193] Step 2: A mixture of 5-[anilino(diphenoxyphosphoryl)methyl]pyridine-2-carbonitrile (21.3 g, 48.3 mmol, 1.0 equiv.) from Step 1, 4-chlorobenzaldehyde (7.5 g, 53.1 mmol, 1.1 equiv.), and cesium carbonate (20.4 g, 62.7 mmol, 1.3 equiv.) 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 equiv.) 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 600 mL of ethyl acetate (3×200 mL). The organic phase was then washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting 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 pale yellow solid. 1H 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).

[0194] Step 3: To a solution of 5-[2-(4-chlorophenyl)acetyl]pyridine-2-carbonitrile (8.6 g, 33.4 mmol, 1.0 equiv.) from Step 2 in tetrahydrofuran (170 mL) was added phenyltrimethylammonium tribromide (13.8 g, 36.8 mmol, 1.1 equiv.), and the mixture was stirred at 25° C. for 16 hours. The mixture was poured into water (300 mL) and extracted with 450 mL of ethyl acetate (3×150 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).

[0195] 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 afford 5-[4-(4-chlorophenyl)-5-[(4-methoxyphenyl)methylamino]-1H-pyrazol-3-yl]pyridine-2-carbonitrile (4 g, 9.62 mmol) as a yellow gum.

[0196] 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 resulting residue. The mixture was extracted with 300 mL (3×100 mL) of ethyl acetate, 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.

[0197] 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 equiv) from Step 5 and diethyl propanedioate (48.8 g, 304 mmol, 46.0 mL, 19.6 equiv) was stirred at 120° C. for 2 hours. Then, 4-dimethylaminopyridine (9.4 g, 76.9 mmol, 5.0 equiv), 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. 1 H NMR (400MHz, DMSO-d6) δ=8.72(d,J=1.6Hz,1H), 8.01-7.88(m,2H), 7.39(d,J=8.4Hz,2H), 7.24(d,J=8.4Hz,2H), 4.30(s,1H).

[0198] 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 equiv.) from Step 6 and phosphorus oxychloride (60.0 mmol, 5.6 mL, 13 equiv.), N,N-dimethylaniline (6.9 mmol, 0.88 mL, 1.5 equiv.) was added, and the mixture was stirred at 100° C. for 1 hour. The mixture was poured into water (100 mL) and extracted with 150 mL of ethyl acetate (3×50 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 column (petroleum ether: ethyl acetate = 2:1) to give the product 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.

[0199] Example 3 - Preparation of Intermediates I-2(a) to I-2(y)

[0200] [ka] (i) Intermediate I-2(a)(R 2 :2-Cl-phenyl;R 3 :4-(ethylamino)-4-carboxamido-piperidin-1-yl): To a solution of intermediate I-1(a) from Example 2(i) (60 mg, 146.7 μmol, 1 equiv.) in acetone (1 mL) was added triethylamine (161.3 μmol, 0.022 mL, 1.1 equiv.), followed by a solution of 4-(ethylamino)piperidine-4-carboxamide (25.1 mg, 146.7 μmol, 1 equiv.) in water (0.2 mL), and the mixture was stirred at 25° C. for 2 hours. Then, 0.8 mL of water was 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 pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.62-7.46(m,4H), 7.42-7.30(m,5H), 7.07(br s,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).

[0201] (ii) Intermediate I-2(b)(R 2 :2-Cl-phenyl;R 3 :4-(trifluoromethylsulfonyl)piperazin-1-yl): To a solution of intermediate I-1(a) from Example 2(i) (50 mg, 122.2 μmol, 1 equiv.) and 1-(trifluoromethylsulfonyl)piperazine from Example 1(i) (31.1 mg, 122.2 μmol, 1 equiv., HCl salt) in acetone (1 mL), water (0.2 mL), triethylamine (366.7 μmol, 0.05 mL, 3 equiv.) was added and the mixture was stirred at 25° C. for 1 hour. Then, 4 mL of water was added to the mixture, and the mixture was extracted with 9 mL of ethyl acetate (3×3 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to provide a residue. The residue was purified by silica 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).

[0202] (iii) Intermediate I-2(c)(R 2 :2-Cl-phenyl R 3 :4-methyl-4-carboxamido-piperidin-1-yl): To a solution of intermediate I-1(a) from Example 2(i) (100 mg, 244.44 μmol, 1 equiv.) and 4-methylpiperidine-4-carboxamide from Example 1(ii) (43 mg, 244.4 μmol, 1 equiv., HCl salt) in acetone (2 mL), water (0.4 mL), triethylamine (733.3 μmol, 0.1 mL, 3 equiv.) was added and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to give a residue which was purified by silica 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.

[0203] (iv) Intermediate I-2(d)(R 2 :2-Cl-phenyl;R 3 :1,1-dioxothiane-4-amino): To a solution of intermediate I-1(a) from Example 2(i) (50 mg, 122.2 μmol, 1 equiv.) and 1,1-dioxothian-4-amine (22.7 mg, 122.2 μmol, 1 equiv., HCl salt) in acetone (1 mL), water (0.2 mL), and tetrahydrofuran (0.5 mL), triethylamine (366.7 μmol, 0.05 mL, 3 equiv.) was added and the mixture was stirred at 40° C. for 16 hours. Water (4 mL) was added to the mixture, and the mixture was extracted with 9 mL of ethyl acetate (3×3 mL). The combined organic phase was then washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to provide a residue. The residue was purified by silica 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).

[0204] (v) Intermediate I-2(e)(R 2 :2-Cl-phenyl;R 3 :isopropoxy): To a solution of intermediate I-1(a) (29 mg, 488.9 μmol, 0.04 mL, 1 equiv.) from Example 2(i) in tetrahydrofuran (4 mL) was added potassium t-butoxide (66 mg, 586.7 μmol, 1.2 equiv.), followed by 5,7-dichloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine (200 mg, 488.9 μmol, 1 equiv.), and the mixture was stirred at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica 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 pale 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).

[0205] (vi) Intermediate I-2(f)(R 2 :2-Cl-phenyl;R 3 :4-hydroxy-4-methyl-piperidin-1-yl): To a solution of intermediate I-1(a) from Example 2(i) (200 mg, 488.88 μmol, 1 equiv.) and 4-methylpiperidin-4-ol (56 mg, 488.88 μmol, 1 equiv.) in acetone (1 mL) and water (0.2 mL) was added triethylamine (148 mg, 1.47 mmol, 0.2 mL, 3 equiv.). 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×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column and eluent of 0-55% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 1-[5-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidin-4-ol (Intermediate I-2(f), 210 mg) as a yellow solid. 1 H 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).

[0206] (vii) Intermediate I-2(g)(R 2 :2-Cl-phenyl;R 3 :4-(methylsulfonyl)piperazin-1-yl): A mixture of intermediate I-1(a) from Example 2(i) (60 mg, 146.66 μmol, 1 equiv.), 1-methylsulfonylpiperazine from Example 1(iii) (59 mg, 293.33 μmol, 2 equiv.), and triethylamine (74 mg, 733.32 μmol, 0.10 mL, 5 equiv.) in acetone (1.2 mL) and water (0.24 mL) was stirred for 1 hour at 25° C. The reaction mixture was washed with water (20 mL) and extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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.

[0207] (viii) Intermediate I-2(h)(R 2 :2-Cl-phenyl;R 3 (3R)-carboxamido-piperidin-1-yl): A mixture of intermediate I-1(a) from Example 2(i) (100 mg, 244.44 μmol, 1 equiv.), (3R)-piperidine-3-carboxamide (31 mg, 244.44 μmol, 1 equiv.), and triethylamine (74 mg, 733.32 μmol, 0.10 mL, 3 equiv.) in acetone (2 mL) and water (0.4 mL) was stirred for 1 hour at 25° C. 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 × 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 pale yellow solid, which was used directly in the next step without further purification.

[0208] (ix) Intermediate I-2(i)(R 2 :2-Cl-phenyl;R 3 2-(azetidin-3-yl)acetamide): To a solution of intermediate I-1(a) from Example 2(i) (400 mg, 977.77 μmol, 1 equiv.) in acetone (4 mL) and water (0.8 mL) was added triethylamine (495 mg, 4.89 mmol, 0.68 mL, 5 equiv.) and 2-(azetidin-3-yl)acetamide from Example 1(iv) (294.52 mg, 1.96 mmol, 2 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was then filtered and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluting with 0–100% 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).

[0209] (x) Intermediate I-2(j)(R 2 :2-Cl-phenyl;R 3 :4-Methyl-4-piperidylacetamide): To a solution of intermediate I-1(a) (50 mg, 122.2 μmol, 1 equiv.) from Example 2(i) in a mixed solvent of acetone (1 mL) and water (0.2 mL), N-(4-methyl-4-piperidyl)acetamide (24 mg, 122.22 μmol, 1 equiv., HCl salt) from Example 1(v) and triethylamine (37 mg, 366.7 μmol, 0.05 mL, 3 equiv.) were added, and the reaction mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). 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 (ISCO®, 12 g SepaFlash® silica flash column, eluting with a 50-100% ethyl acetate / petroleum ether gradient at 30 mL / min). The cleaved fraction was 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-piperidyl]acetamide (Intermediate I-2(j), 40 mg) as a pale yellow solid.

[0210] (xi) Intermediate I-2(k)(R 2 :2-Cl-phenyl;R 3 (3R)-3-(aminocarboxymethyl)pyrrolidin-1-yl): To a solution of intermediate I-1(a) (100 mg, 244.44 μmol, 1 equiv.) from Example 2(i) in acetone (2 mL) and water (0.4 mL) was added triethylamine (124 mg, 1.22 mmol, 0.17 mL, 5 equiv.) and 2-[(3R)-pyrrolidin-3-yl]acetamide (80 mg, 488.88 μmol, 2 equiv., 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 60 mL of ethyl acetate (30 mL×2). The combined organic layers were washed with 40 mL of brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna® C18, 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], B%: 57% to 87%, 10 min) 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).

[0211] (xii) Intermediate I-2(l)(R 2 :2-Cl-phenyl;R 3 (3S)-carboxamido-piperidin-1-yl): A mixture of intermediate I-1(a) (500 mg, 1.22 mmol, 1 equiv.) from Example 2(i), (3S)-piperidine-3-carboxamide (355.21 mg, 1.47 mmol, 1.2 equiv., TFA salt) from Example 1(ix), and triethylamine (371.03 mg, 3.67 mmol, 510.35 μL, 3 equiv.) 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 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluting with a 50–100% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleaved fraction was concentrated under reduced pressure to obtain the 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 pale yellow solid.

[0212] (xiii) Intermediate I-2(m)(R 2 :2-Cl-phenyl;R 3 :4-carboxamido-4-ethoxypiperidin-1-yl): A mixture of intermediate I-1(a) from Example 2(i) (500 mg, 1.2 mmol, 1 equiv.), triethylamine (3.7 mmol, 0.51 mL, 3 equiv.), and 4-ethoxypiperidine-4-carboxamide from Example 1(x) (349 mg, 1.22 mmol, 1 equiv., TFA) 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 give 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 pale 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).

[0213] (xiv) Intermediate I-2(n)(R 2 :2-Cl-phenyl;R 3 :6-(trifluoromethyl)-3-pyridyl): To a mixture of intermediate I-3(a) from Example 4(i) (70 mg, 0.166 mmol, 1 equiv.), [6-(trifluoromethyl)-3-pyridyl]boronic acid (64 mg, 0.332 mmol, 2 equiv.), and cuprous 2-hydroxy-3-methyl-benzoate (107 mg, 0.499 mmol, 3 equiv.) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (10 mg, 8.32 μmol, 0.05 equiv.) and the mixture was stirred at 60° C. for 2 hours. The mixture was then filtered and concentrated under reduced pressure to provide 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-pyridyl]pyrazolo[1,5-a]pyrimidine (Intermediate I-2(n), 100 mg, crude) as a yellow solid.

[0214] (xv) Intermediate I-2(o)(R 2 :2-Cl-phenyl;R 3 :4-(trifluoromethyl)-1-piperidyl): To a solution of intermediate I-1(a) (60 mg, 0.15 mmol, 1.0 equiv.) from Example 2(i) in acetone (1 mL) was added triethylamine (0.02 mL, 0.16 mmol, 1.1 equiv.) and a solution of 4-(trifluoromethyl)piperidine (22 mg, 0.15 mmol, 1.0 equiv.) in water (0.2 mL), 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-piperidyl]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).

[0215] (xvi) Intermediate I-2(p)(R 2 :6-CN-pyridin-3-yl;R 3 :3-cyano-3-methyl-azetidin-1-yl): 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 for 1 hour at 25° C. The reaction mixture was diluted with water (5 mL), filtered, and the resulting filter cake was dried under reduced pressure to provide 5-[5-chloro-3-(4-chlorophenyl)-7-(3-cyano-3-methyl-azetidin-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. 1H NMR(400MHz,DMSO-d6)δ=8.91(dd,J=0.8,1.9Hz,1H), 8.13(dd,J=1.3,5.9Hz,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).

[0216] (xvii) Intermediate I-2(q)(R 2 :6-CN-pyridin-3-yl;R 3 :3-Methoxy-3-methyl-azetidin-1-yl): A mixture of intermediate I-1(d) from Example 2(iv) (60 mg, 0.15 mmol, 1.0 equiv.), 3-methoxy-3-methylazetidine hydrochloride (23 mg, 0.16 mmol, 1.1 equiv.), and triethylamine (45 mg, 0.45 mmol, 0.06 mL, 3.0 equiv.) 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 provide 5-[5-chloro-3-(4-chlorophenyl)-7-(3-methoxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carbonitrile (intermediate I-2(q), 55 mg, 0.12 mmol) as a yellow solid, which was used directly 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).

[0217] (xviii) Intermediate I-2(r)(R 2 :6-CN-pyridin-3-yl;R 3 :4-(trifluoromethylsulfonyl)piperazin-1-yl): 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, and the mixture was filtered, and the filter cake was dried to provide 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 pale 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).

[0218] (xix) Intermediate I-2(s)(R 2 :6-CN-pyridin-3-yl;R 3 :4-methyl-4-carboxamido-piperidin-1-yl): To a mixture of intermediate I-1(d) (100 mg, 0.25 mmol, 1.0 equiv.) from Example 2(iv) and 4-methylpiperidine-4-carboxamide (45 mg, 249.6 μmol, 1.0 equiv., hydrochloride salt) from Example 1(ii) in acetone (2 mL) and water (0.4 mL), triethylamine (748.8 μmol, 0.1 mL, 3.0 equiv.) 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 pale yellow solid. 1H 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).

[0219] (xx) Intermediate I-2(t)(R 2 :6-CN-pyridin-3-yl;R 3 :4-carboxamido-4-ethoxypiperidin-1-yl): To a solution of intermediate I-1(d) from Example 2(iv) (80 mg, 0.20 mmol, 1.0 equiv) in acetone (2 mL) and water (0.4 mL) were added trimethylamine (0.60 mmol, 0.08 mL, 3.0 equiv) and 4-ethoxypiperidine-4-carboxamide (44 mg, 0.21 mmol, 1.05 equiv, hydrochloride salt) prepared in Example 1(x), and the mixture was stirred for 2 hours at 25° C. The mixture was then added to water (10 mL) and filtered to give 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)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,1) H), 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).

[0220] (xxi) Intermediate I-2(u)(R 2 :2-Cl-phenyl;R 3:4-carboxamido-4-isopropoxypiperidin-1-yl): A mixture of intermediate I-1(a) (600 mg, 1.47 mmol, 1 equiv.) from Example 2(i), 4-isopropoxypiperidine-4-carboxamide (392 mg, 1.76 mmol, 1.2 equiv.) from Example 1(xiii), and triethylamine (742 mg, 7.33 mmol, 1.02 mL, 5 equiv.) 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 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent gradient of 0% to approximately 100% ethyl acetate / petroleum ether at 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 H NMR(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=12.4H) z,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).

[0221] (xxii) Intermediate I-2(v)(R 2 :6-CN-pyridin-3-yl;R 3 :3-carbamoylazetidin-1-yl): A mixture of intermediate I-1(d) from Example 2(iv) (110 mg, 0.27 mmol, 1.0 equiv.), azetidine-3-carboxamide from Example 1(xiv) (64 mg, 0.30 mmol, 1.1 equiv., trifluoroacetate salt), and triethylamine (83 mg, 0.82 mmol, 0.12 mL, 3.0 equiv.) in acetone (1 mL) and water (0.2 mL) was stirred for 1 hour at 25° C. The reaction mixture was diluted with water (5 mL), filtered, and the resulting filter cake was dried under reduced pressure to provide the compound 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)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).

[0222] (xxiii) Intermediate I-2(w)(R 2 :6-CN-pyridin-3-yl;R 3 :3-carbamoyl-3-methylazetidin-1-yl): A mixture of intermediate I-1(d) from Example 2(iv) (70 mg, 0.17 mmol, 1.0 equiv.), 3-methylazetidine-3-carboxamide from Example 1(xv) (44 mg, 0.19 mmol, 1.1 equiv., trifluoroacetate salt), and triethylamine (53 mg, 0.52 mmol, 0.07 mL, 3.0 equiv.) in acetone (1 mL) and water (0.2 mL) was stirred for 3 hours at 25° C. 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 pale yellow solid, which was used directly 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).

[0223] (xxiv) Intermediate I-2(x)(R 2 :2-Cl-phenyl;R 3 :3-(2-amino-2-oxo-ethoxy)azetidin-1-yl): 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 salt) 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 mL × 3). 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 (ISCO®, 20 g SepaFlash® silica flash column, eluent gradient of 30% to approximately 100% ethyl acetate / petroleum ether at 30 mL / min). The collected 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 pale yellow solid.

[0224] (xxv) Intermediate I-2(y)(R 2 :6-CN-pyridin-3-yl;R 3 :4-carbamoyl-4-isopropoxypiperidin-1-yl): To a solution of intermediate I-1(d) from Example 2(iv) (100 mg, 0.25 mmol, 1.0 equiv) in acetone (2 mL) and water (0.4 mL) were added trimethylamine (0.75 mmol, 0.10 mL, 3.0 equiv) and 4-isopropoxypiperidine-4-carboxamide (56 mg, 0.25 mmol, 1.0 equiv, hydrochloride salt), and the mixture was stirred for 2 hours at 25° C. The mixture was added to water (10 mL) and filtered to provide 1-[5-chloro-3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-4-isopropoxy-piperidine-4-carboxamide (130 mg, 0.24 mmol) as a yellow solid. 1H 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).

[0225] Example 4 - Preparation of Intermediates I-3(a) to I-3(d)

[0226] [ka] (i) Intermediate I-3(a)(R 2 :2-Cl-phenyl): To a solution of intermediate I-1(a) (2 g, 4.9 mmol, 1 equiv.) from Example 2(i) in tetrahydrofuran (20 mL) was added sodium thiomethoxide (411 mg, 5.9 mmol, 1.2 equiv.), and the mixture was stirred at 25° C. for 2 hours. The mixture was poured into water (50 mL). The mixture was then extracted with 45 mL of ethyl acetate (3×15 mL). The organic phase was then washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica 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), 1.8 g) as a yellow solid.

[0227] (ii) Intermediate I-3(b)(R 2 :2-MeO-phenyl): To a solution of intermediate I-1(b) (140 mg, 345.96 μmol, 1 equiv.) from Example 2(ii) in tetrahydrofuran (2 mL) was added sodium thiomethoxide (22 mg, 311.4 μmol, 0.9 equiv.), and the mixture was stirred at 0° C. for 3 hours. The mixture was poured into water (10 mL). The mixture was then extracted with 15 mL of ethyl acetate (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was then purified by silica 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.

[0228] (iii) Intermediate I-3(c)(R 2 :4-CN-phenyl): To a solution of intermediate I-1(c) from Example 2(iii) (276 mg, 69 mmol, 1.0 equiv.) in tetrahydrofuran (3 mL), sodium thiomethoxide (58 mg, 0.83 mmol, 1.2 equiv.) was added, 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 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluting with a 0% to approximately 100% ethyl acetate / petroleum ether gradient at 40 mL / min). The fractions were concentrated in vacuo 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.

[0229] (iv) Intermediate I-3(d)(R 2 :6-CN-pyridin-3-yl): To a solution of intermediate I-1(d) from Example 2(iv) (300 mg, 0.75 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was added sodium thiomethoxide (63 mg, 0.90 mmol, 1.2 equiv), 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 (3×0 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).

[0230] Example 5 - Preparation of Intermediates I-4(a) to I-4(d)

[0231] [ka] (i) Intermediate I-4(a)(R 2 :4-Cl-phenyl;R 4 :(2S)-2-(hydroxymethyl)pyrrolidin-1-yl)): To a solution of intermediate I-3(a) from Example 4(i) (170 mg, 404.1 μmol, 1 equiv.) and [(2S)-pyrrolidin-2-yl]methanol (123 mg, 1.21 mmol, 0.12 mL, 3 equiv.) in acetonitrile (4 mL), N,N-diisopropylethylamine (3.6 mmol, 0.62 mL, 8.8 equiv.) was added, and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated to give a residue. The residue was purified by silica 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).

[0232] (ii) Intermediate I-4(b)(R 2 :4MeO-phenyl;R 4 :(2S)-2-(hydroxymethyl)pyrrolidin-1-yl)): To a solution of intermediate I-3(b) from Example 4(ii) (80 mg, 192.2 μmol, 1 equiv.) and [(2S)-pyrrolidin-2-yl]methanol (58 mg, 576.5 μmol, 3 equiv.) in acetonitrile (1 mL), N,N-diisopropylethylamine (0.29 mL, 1.7 mmol, 8.8 equiv.) was added, 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 then purified by silica 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 pale 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).

[0233] (iii) Intermediate I-4(c)(R 2 :4-CN-phenyl;R 4 :(2S)-2-(hydroxymethyl)pyrrolidin-1-yl)): A mixture of intermediate I-3(c) from Example 4(iii) (210 mg, 0.51 mmol, 1.0 equiv), [(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 the 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 pale 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).

[0234] (iv) Intermediate I-4(d)(R 2 :6-CN-pyridin-3-yl;R 4 :N-(2-hydroxy-2-methyl-propyl)-methylamino): To a solution of intermediate I-3(d) from Example 4(iv) (70 mg, 0.17 mmol, 1.0 equiv), 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 to 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).

[0235] Example 6 - Preparation of Compounds 1-78 (i) Compound 1:

[0236] [ka] To a solution of intermediate I-2(a) from Example 3(i) (40 mg, 73.6 μmol, 1 equiv.) and [(2S)-pyrrolidin-2-yl]methanol (22.3 mg, 220.6 μmol, 0.021 mL, 3 equiv.) in acetonitrile (1 mL), N,N-diisopropylethylamine (647.2 μmol, 0.11 mL, 8.8 equiv.) was added and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated to provide a residue. The residue was purified twice by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 55% to 85%, 10 min) 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, purity 98.9%) as an off-white solid. 1 H NMR (400MHz, methanol-d4) δ=7.54-7.36(m,6H), 7.17(d,J=7.2Hz,2H), 5.76(d,J=4.4Hz,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=6.8Hz,3H). LCMS:(ES + ) m / z = 608.2 (M+H) + .

[0237] (ii) Compound 2:

[0238] [ka] To a solution of intermediate I-2(o) (50 mg, 95.1 μmol, 1.0 equiv.) from Example 3(xv) and [(2S)-pyrrolidin-2-yl]methanol (29 mg, 0.29 mmol, 3.0 equiv.) in acetonitrile (1 mL), N,N-diisopropylethylamine (0.84 mmol, 0.15 mL, 8.8 equiv.) was added, 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™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 70% to 100%, 8 min). The fractions were then concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[4-(trifluoromethyl)-1-piperidyl]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) ,3H), 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).

[0239] (iii) Compound 3:

[0240] [ka] To a mixture of intermediate I-4(b) from Example 5(ii) (36 mg, 74.8 μmol, 1 equivalent), (3-cyanophenyl)boronic acid (22 mg, 149.7 μmol, 2 equivalents), and copper(I) 3-methylsalicylate (48 mg, 224.5 μmol, 3 equivalents) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (9 mg, 7.5 μmol, 0.1 equivalent). The mixture was then stirred at 60° C. for 3 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex® Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 64% to 94%, 10 min) and preparative HPLC (column: Phenomenex® Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 69% to 89%, 10 min) 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, purity 100%) 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).

[0241] (iv) Compound 4:

[0242] [ka] To a mixture of intermediate I-4(a) from Example 5(i) (50 mg, 103 μmol, 1 equiv.), [4-(trifluoromethyl)phenyl]boronic acid (39 mg, 206.0 μmol, 2 equiv.), and copper(I) 3-methylsalicylate (66 mg, 309.0 μmol, 3 equiv.) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (12 mg, 10.3 μmol, 0.1 equiv.) and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to provide a residue. The residue was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 70% to 100%, 10 min), 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, purity 100%) 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).

[0243] (v) Compound 5:

[0244] [ka] To a mixture of intermediate I-4(a) from Example 5(i) (50 mg, 103 μmol, 1 equiv.), (4-methoxyphenyl)boronic acid (31 mg, 206.0 μmol, 2 equiv.), and copper(I) 3-methylsalicylate (66 mg, 309.0 μmol, 3 equiv.) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (12 mg, 10.3 μmol, 0.1 equiv.) and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to provide a residue. The residue was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 68%-98%, 10 min), 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, purity 100%) 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).

[0245] (vi) Compound 6:

[0246] [ka] To a mixture of intermediate I-4(b) from Example 3(ii) (36 mg, 74.8 μmol, 1 equiv.), [4-(trifluoromethyl)phenyl]boronic acid (28 mg, 149.7 μmol, 2 equiv.), and copper(I) 3-methylsalicylate (48 mg, 224.5 μmol, 3 equiv.) in tetrahydrofuran (1 mL) was added tetrakis(triphenylphosphine)palladium (9 mg, 7.5 μmol, 0.1 equiv.) and the mixture was stirred at 60° C. for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 70% to 100%, 10 min) 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, purity 98%) as a yellow solid. 1 H 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).

[0247] (vii) Compound 7:

[0248] [ka] To a solution of intermediate I-2(b) from Example 3(ii) (45 mg, 76.2 μmol, 1 equiv) and [(2S)-pyrrolidin-2-yl]methanol (23 mg, 228.5 μmol, 0.02 mL, 3 equiv) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.12 mL, 670.2 μmol, 8.8 equiv) and the mixture was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 67%-97%, 10 min), 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, 24.76 mg, 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).

[0249] (viii) Compound 8:

[0250] [ka] A mixture of intermediate I-4(a) from Example 5(i) (1.35 g, 2.8 mmol, 1 equiv.), [6-(trifluoromethyl)-3-pyridyl]boronic acid (1.1 g, 5.6 mmol, 2 equiv.), copper(I) 3-methylsalicylate (1.8 g, 8.3 mmol, 3 equiv.), and tetrakis(triphenylphosphine)palladium (321 mg, 278 μmol, 0.1 equiv.) in tetrahydrofuran (13.5 mL) was stirred at 60° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was triturated with ethyl acetate (30 mL), filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC, and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[6-(trifluoromethyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (compound 8, 747 mg, purity 98.8%) 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).

[0251] (ix) Compound 9:

[0252] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (55 mg, 106.8 μmol, 1 equiv) and [(2S)-pyrrolidin-2-yl]methanol (32 mg, 320.5 μmol, 0.03 mL, 3 equiv) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.16 mL, 940.1 μmol, 8.8 equiv) and the mixture was then stirred at 80° C. for 16 hours. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 51%-81%, 8 min), 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, purity 99.2%) 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), 3.7 2-3.63(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).

[0253] (x) Compound 10:

[0254] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (55 mg, 106.8 μmol, 1 equiv) and 2-(methylamino)ethanol (24 mg, 320.5 μmol, 0.03 mL, 3 equiv) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (0.16 mL, 940.1 μmol, 8.8 equiv) and the mixture was stirred at 80° C. for 16 hours. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 47%-77%, 9 min), 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, purity 100%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.54-7.39(m,6H), 7.17(d,J=8.8Hz,2H), 5.86(s,1H), 3.94-3.8 3(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).

[0255] (xi) Compound 11:

[0256] [ka] To a solution of intermediate I-2(d) from Example 3(iv) (30 mg, 57.5 μmol, 1 equiv) and [(2S)-pyrrolidin-2-yl]methanol (17 mg, 172.5 μmol, 0.02 mL, 3 equiv) in acetonitrile (1 mL) was added N,N-diisopropylethylamine (505.9 μmol, 0.09 mL, 8.8 equiv) and the mixture was stirred at 80° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 54%-84%, 10 min), and then the fractions were concentrated to remove acetonitrile and lyophilized to give [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[(1,1-dioxothian-4-yl)amino]pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-2-yl]methanol (compound 11, 19.01 mg, purity 98.2%) 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 ,1H), 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).

[0257] (xii) Compound 12:

[0258] [ka] To a solution of intermediate I-2(e) from Example 3(v) (80 mg, 185 μmol, 1 equiv) and 2-(methylamino)ethanol (42 mg, 554.6 μmol, 0.05 mL, 3 equiv) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (1.6 mmol, 0.28 mL, 8.8 equiv) and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated to provide a residue. The residue was purified twice by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], first purification with B%: 55% to 85%, 8 min, second purification with B%: 67% to 97%, 10 min), and 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, purity 98.7%) 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).

[0259] (xiii) Compound 13:

[0260] [ka] A mixture of intermediate I-2(c) from Example 3(iii) (70 mg, 136 μmol, 1 equiv.), 2-methylpropane-1,2-diol (61 mg, 679.83 μmol, 5 equiv.), and potassium 2-methylpropane-2-oleate (46 mg, 407.90 μmol, 3 equiv.) 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™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 56% to 86%, 10 min). The cleaved fraction was 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, purity 100%) 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).

[0261] (xiv) Compound 14:

[0262] [ka] To a solution of intermediate I-2(f) from Example 3(vi) (80 mg, 164 μmol, 1 equiv.) and 2-methylpropane-1,2-diol (44 mg, 492.00 μmol, 3 equiv.) in THF (1 mL) was added potassium tert-butoxide (55 mg, 492.00 μmol, 3 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was diluted with ethyl acetate (10 mL×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™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 66% to 86%, 10 min) to give 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. 1 H NMR(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).

[0263] (xv) Compound 15:

[0264] [ka] To a solution of 2-methylpropane-1,2-diol (37 mg, 406.21 μmol, 3 equiv.) in THF (2 mL) was added sodium hydride (16 mg, 406.21 μmol, 60% purity, 3 equiv.), and the solution was stirred at 25° C. for 0.5 h. Intermediate I-2(b) (80 mg, 135.4 μmol, 1 equiv.) from Example 3(ii) was added to the mixture, which was stirred at 25° C. for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 65% to 95%, 10 min) 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, 52.8 mg) 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).

[0265] (xvi) Compound 16:

[0266] [ka] To a solution of 2-methylpropane-1,2-diol (30 mg, 335 μmol, 3 equiv.) in THF (2 mL) was added sodium hydride (14 mg, 335 μmol, 60% purity, 3 equiv.), and the solution was stirred at 25° C. for 0.5 h. Intermediate I-2(g) (60 mg, 112 μmol, 1 equiv.) from Example 3(vii) was added to the mixture, which was stirred at 25° C. for 2 h. The reaction mixture was washed with water (10 mL) and extracted with 20 mL of ethyl acetate (10 mL×2). The combined organic layers were washed with 20 mL of brine (10 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 56% to 86%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile, and then lyophilized to obtain a white solid, 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, purity 100%). 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).

[0267] (xvii) Compound 17(S):

[0268] [ka] 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 h under a N atmosphere, after which 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 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL×3). 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 reverse-phase HPLC (column: Waters™ Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 54% to 84%, 8 min). The cleaved 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, purity 100%) 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).

[0269] (xviii) Compound 17(R):

[0270] [ka] A mixture of intermediate I-2(h) from Example 3(viii) (130 mg, 259.6 μmol, 1 equiv), 2-methylpropane-1,2-diol (117 mg, 1.30 mmol, 5 equiv), and potassium 2-methylpropane-2-oleate (87 mg, 778.74 μmol, 3 equiv) in N,N-dimethylformamide (1 mL) was stirred at 80° C. for 2 hours. The reaction mixture was diluted with N,N-dimethylformamide (2 mL) and purified by reverse-phase HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 52%-82%, 10 min) 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, purity 100%) 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).

[0271] (xix) Compound 18:

[0272] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (80 mg, 155 μmol, 1 equiv.) and (2S)-pyrrolidine-2-carboxylic acid (54 mg, 466.2 μmol, 3 equiv.) in acetonitrile (2 mL), N,N-diisopropylethylamine (1.4 mmol, 0.24 mL, 8.8 equiv.) was added and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 26% to 56%, 8 min) and preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 48% to 78%, 10 min) to give (2S)-1-[7-(4-carbamoyl-4-methyl-1-piperidyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-2-carboxylic acid (compound 18, 13.69 mg, purity 100%) as an off-white solid. 1 H 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=3.6,8.0Hz,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%.

[0273] (xx) Compound 19:

[0274] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (50 mg, 97 μmol, 1 equivalent) and 2-[(2R)-azetidin-2-yl]acetic acid from Example 1(vii) (44 mg, 194.2 μmol, 2 equivalents, TFA salt) in tetrahydrofuran (2.5 mL) was added potassium t-butoxide (54 mg, 485.6 μmol, 5 equivalents) and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium hydroxide v / v)-acetonitrile], B%: 12% to 42%, 9 min) to give 2-[(2R)-1-[7-(4-carbamoyl-4-methyl-1-piperidyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidin-2-yl]acetic acid (compound 19, 14.72 mg, purity 100%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.53-7.41(m,6H), 7.16(d,J=8.8Hz,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).

[0275] (xxi) Compound 20:

[0276] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (50 mg, 97 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 854.65 μmol, 0.15 mL, 8.8 equiv.) and 2-methyl-1-(methylamino)propan-2-ol (50 mg, 485.60 μmol, 0.04 mL, 5 equiv.). The mixture was stirred at 120° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 56%-86%, 8 min). The cleaved fraction was 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, purity 100%) 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).

[0277] (xxii) Compound 21:

[0278] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (50 mg, 97 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 854.65 μmol, 0.15 mL, 8.8 equiv.) and (3R)-pyrrolidin-3-ol (42 mg, 485.59 μmol, 0.04 mL, 5 equiv.). The mixture was stirred at 120° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 57% to 77%, 10 min). The cleaved fraction was 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, purity 100%) 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).

[0279] (xxiii) Compound 22:

[0280] [ka] A mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 155 μmol, 1 equiv.), 3-(methylamino)propanamide (48 mg, 466.17 μmol, 3 equiv.), and N,N-diisopropylethylamine (176.73 mg, 1.37 mmol, 0.24 mL, 8.8 equiv.) 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™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (NH4HCO3)-ACN], B%: 45%-75%, 10 min). The cleaved fraction was concentrated under reduced pressure to give 1-[5-[(3-amino-3-oxopropyl)-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).

[0281] (xxiv) Compound 23:

[0282] [ka] A mixture of intermediate I-2(h) (100 mg, 200 μmol, 1 equiv.) from Example 3(viii), 3-(methylamino)propanamide (61.18 mg, 599.03 μmol, 3 equiv.), and N,N-diisopropylethylamine (227.10 mg, 1.76 mmol, 0.3 mL, 8.8 equiv.) 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™ Xbridge 150 × 25 mm × 5 μm, Mobile phase: [water (NH4HCO3)-ACN], B%: 42% to 72%, 10 min). The cleaved fraction was 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). (xxv) Compound 24:

[0283] [ka]

[0284] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 903.90 μmol, 0.16 mL, 8.8 equiv.) and 3-(methylamino)propanamide (52 mg, 513.58 μmol, 5 equiv.). The mixture was stirred at 140° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 33% to 63%, 2 min). The cleaved fraction was 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, purity 98.4%) 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).

[0285] (xxvi) Compound 25:

[0286] [ka] To a solution of intermediate I-2(c) (50 mg, 97 μmol, 1 equiv.) 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 equiv.) and N,N-dimethyl-2-(methylamino)acetamide (34 mg, 291.36 μmol, 3 equiv.). 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™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (ammonium bicarbonate)-ACN], B%: 50% to 80%, 8 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile and then lyophilized to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 49% to 79%, 10 min). The cleaved fraction was 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, purity 100%) 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).

[0287] (xxvii) Compound 26:

[0288] [ka] To a solution of N-ethyl-2-(methylamino)acetamide (44 mg, 291 μmol, 5 equivalents) 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 equivalents) and intermediate I-2(c) (30 mg, 58 μmol, 1 equivalent) 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 provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 51% to 81%, 2 min). The cleaved fraction was 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, purity 100%) 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).

[0289] (xxviii) Compound 27:

[0290] [ka] A mixture of intermediate I-2(j) from Example 3(x) (40 mg, 76 μmol, 1 equiv.), 3-(methylamino)propanamide (23 mg, 226.90 μmol, 3 equiv.), and N,N-diisopropylethylamine (86 mg, 665.58 μmol, 0.12 mL, 8.8 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (2 mL). The mixture was purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 51%-81%, 10 min). The resulting liquid was concentrated under reduced pressure to remove acetonitrile and lyophilized to give 3-[[7-(4-acetamido-4-methyl-1-piperidyl)-2-(2-chlorophenyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-methyl-amino]propanamide (Compound 27, 19.88 mg, purity 100%) as a white solid. 1 H 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).

[0291] (xxix) Compound 28:

[0292] [ka] To a solution of intermediate I-2(k) from Example 3(xi) (40 mg, 80 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (91 mg, 702.87 μmol, 0.12 mL, 8.8 equiv.) and 3-(methylamino)propanamide (41 mg, 399.35 μmol, 5 equiv.). The mixture was stirred at 140° C. for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 34% to 64%, 2 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give a white solid, 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, purity 100%). 1 H 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).

[0293] (xxx) Compound 29:

[0294] [ka] A mixture of intermediate I-2(h) (80 mg, 160 μmol, 1 equiv.) from Example 3(viii), N,N-dimethyl-2-(methylamino)acetamide (56 mg, 479.23 μmol, 3 equiv.), and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 0.25 mL, 8.8 equiv.) 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). The resulting mixture was purified by reverse-phase HPLC (Waters™ Xbridge 150 × 25 mm, 5 μm column, mobile phase: [water (NH4HCO3)-ACN], B%: 48%–78%, 10 min). The cleaved fraction was 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. 1 H 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).

[0295] (xxxi) Compound 30:

[0296] [ka] To a solution of intermediate I-2(k) from Example 3(xi) (40 mg, 80 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (91 mg, 702.87 μmol, 0.12 mL, 8.8 equiv.) and 1-dimethylphosphoryl-N-methyl-methanamine (48 mg, 399.36 μmol, 5 equiv.). The mixture was stirred at 140° C. for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 46% to 76%, 10 min). The cleaved fraction was 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, purity 100%) as a white solid. 1 H 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).

[0297] (xxxii) Compound 31:

[0298] [ka] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 equiv.) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 equiv.) and N-ethyl-2-(methylamino)acetamide from Example 1(viii) (47 mg, 0.3 mmol, 3 equiv.). The mixture was stirred at 80° C. for 48 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 53% to 73%, 10 min). The cleaved fraction was 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, purity 100%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.52-7.29(m,6H), 7.17-7.07(m,2H), 5.25(s,1H), 4.58(t,J=8.4Hz,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=7.6Hz,2H), 1.05(t,J=7.2Hz,3H). LCMS:(ES + ) m / z = 566.2 (M+H).

[0299] (xxxiii) Compound 32:

[0300] [ka] To a solution of intermediate I-2(i) (40 mg, 82 μmol, 1 equiv.) from Example 3(ix) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (93 mg, 0.72 mmol, 0.13 mL, 8.8 equiv.) and N,N-dimethyl-2-(methylamino)acetamide (29 mg, 0.25 mmol, 3 equiv.). The mixture was stirred at 80° C. for 16 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™ Luna C18 150×25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 51%-81%, 10 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile and then lyophilized to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 43% to 73%, 10 min), and the cleaved fraction was concentrated under reduced pressure to remove acetonitrile and then lyophilized to obtain a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], B%: 40% to 70%, 8 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile, followed by lyophilization 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, purity 98.3%) 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).

[0301] (xxxiv) Compound 33:

[0302] [ka] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 equiv) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 equiv) and 1-dimethylphosphoryl-N-methyl-methanamine (62 mg, 0.5 mmol, 5 equiv). The mixture was stirred at 140° C. for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 48% to 78%, 10 min). The cleaved fraction was 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, purity 98.9%) as an off-white solid. 1 H 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).

[0303] (xxxv) Compound 34:

[0304] [ka] A mixture of intermediate I-2(h) (80 mg, 160 μmol, 1 equiv.) from Example 3(viii), 1-dimethylphosphoryl-N-methyl-methanamine (58 mg, 0.48 mmol, 3 equiv.), and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 0.24 mL, 8.8 equiv.) 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). The resulting mixture was purified by reverse-phase HPLC (Column: Waters™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (NH4HCO3)-ACN], B%: 37% to 67%, 10 min). The cleaved fraction was 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. 1 H 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).

[0305] (xxxvi) Compound 35:

[0306] [ka] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 equiv.) and (2S)-pyrrolidine-2-carboxamide hydrochloride (77 mg, 0.5 mmol, 5 equiv.). The mixture was stirred at 140° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 41% to 71%, 2 min). The cleaved fraction was 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, purity 100%) as an off-white solid. 1 H 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).

[0307] (xxxvii) Compound 36:

[0308] [ka] To a solution of intermediate I-2(k) from Example 3(xi) (50 mg, 100 μmol, 1 equiv.) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (113 mg, 0.88 mmol, 0.15 mL, 8.8 equiv.) and N-ethyl-2-(methylamino)acetamide from Example 1(viii) (46 mg, 0.3 mmol, 3 equiv., as the HCl salt). The mixture was stirred at 80° C. for 48 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 55% to 75%, 10 min). The cleaved fraction was 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, purity 100%) as a white solid. 1 H 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).

[0309] (xxxviii) Compound 37:

[0310] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (40 mg, 77.7 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (88 mg, 0.68 mmol, 0.12 mL, 8.8 equiv.) and (2S)-pyrrolidine-2-carboxamide hydrochloride (58 mg, 0.39 mmol, 5 equiv.). The mixture was stirred at 140° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 54% to 74%, 2 min). The cleaved fraction was 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, purity 100%) as an off-white solid. 1 H 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).

[0311] (xxxix) Compound 38:

[0312] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (50 mg, 97 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (110 mg, 0.85 mmol, 0.15 mL, 8.8 equiv.) and N-methyl-3-(methylamino)propanamide (75 mg, 0.48 mmol, 5 equiv.). The mixture was stirred at 140° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 51% to 81%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give 1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-5-[methyl-[3-(methylamino)-3-oxopropyl]amino]pyrazolo[1,5-a]pyrimidin-7-yl]-4-methyl-piperidine-4-carboxamide (compound 38, 23.24 mg, purity 100%) as an off-white solid. 1 H 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).

[0313] (xl) Compound 39:

[0314] [ka] To a solution of intermediate I-2(i) from Example 3(ix) (50 mg, 103 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (117 mg, 0.9 mmol, 0.16 mL, 8.8 equiv.) and N-methyl-3-(methylamino)propanamide (78 mg, 0.51 mmol, 5 equiv.). The mixture was stirred at 120° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 36% to 66%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile, and then lyophilized to give an off-white solid, 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-propanamide (compound 39, 19.80 mg, purity 100%). 1 H 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).

[0315] (xli) Compound 40:

[0316] [ka] To a solution of intermediate I-2(c) from Example 3(iii) (30 mg, 58.2 μmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was added N,N-diisopropylethylamine (66 mg, 0.51 mmol, 0.09 mL, 8.8 equiv.) and 1-dimethylphosphoryl-N-methyl-methanamine (35 mg, 0.29 mmol, 5 equiv.). The mixture was stirred at 140° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 55% to 75%, 2 min). The cleaved fraction was 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, purity 100%) as an off-white solid. 1 H 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).

[0317] (xlii) Compound 41:

[0318] [ka] A mixture of intermediate I-2(h) from Example 3(viii) (140 mg, 0.28 mmol, 1 equiv.), N-methyl-3-(methylamino)propanamide (107 mg, 0.7 mmol, 2.5 equiv., HCl salt), and N,N-diisopropylethylamine (318 mg, 2.46 mmol, 0.43 mL, 8.8 equiv.) 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™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (ammonium bicarbonate)-ACN], B%: 47%-77%, 8 min). The cleaved fraction was 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. 1 H 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).

[0319] (xliiii) Compound 42:

[0320] [ka] To a solution of 2-methylpropane-1,2-diol (49 mg, 0.55 mmol, 3 equiv.) in N,N-dimethylformamide (1 mL) was added sodium hydride (22 mg, 0.55 mmol, 60% purity, 3 equiv.), and the mixture was stirred at 25° C. for 0.5 h. Intermediate I-2(m) from Example 3(xiii) (100 mg, 0.183 mmol, 1 equiv.) was then added, and the mixture was stirred at 25° C. for 1.5 h. The mixture was poured into ammonium chloride (10 mL) and extracted with 15 mL of ethyl acetate (3×5 mL). The organic phase was then washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex™ Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile], B%: 62% to 92%, 10 min) 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, 32.75 mg, purity 100%) as an off-white solid. 1 H 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).

[0321] (xliv) Compound 43:

[0322] [ka] To a solution of intermediate I-2(m) from Example 3(xiii) (120 mg, 0.22 mmol, 1 equiv) and 2-(methylamino)ethanol (21 mg, 0.27 mmol, 3 equiv) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (0.81 mmol, 0.14 mL, 8.8 equiv) and the mixture was stirred at 100° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 54%-84%, 8 min) 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, purity 100%) 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).

[0323] (xlv) Compound 44:

[0324] [ka] To a solution of intermediate I-2(m) from Example 3(xiii) (100 mg, 0.183 mmol, 1 equiv) and 2-methyl-1-(methylamino)propan-2-ol (57 mg, 0.55 mmol, 3 equiv) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (1.6 mmol, 0.28 mL, 8.8 equiv) and the mixture was stirred at 100° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 56%-86%, 8 min) 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, 47.65 mg, purity 100%) 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).

[0325] (xlvi) Compound 45:

[0326] [ka] 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. under a nitrogen atmosphere for 0.5 h. Then, intermediate I-2(n) (60 mg, 0.115 mmol, 1 equiv.) from Example 3(xiv) in tetrahydrofuran (0.5 mL) was added to the mixture. The mixture was stirred at 60° C. under a nitrogen atmosphere for 1 h. The reaction mixture was washed with aqueous ammonium chloride solution (10 mL) and extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with 40 mL of brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (Phenomenex™ Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (FA)-ACN], B%: 62% to 92%, 10 min). 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% pure) 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).

[0327] (xlvii) Compound 46:

[0328] [ka] A mixture of intermediate I-2(c) (35 mg, 67.98 μmol, 1 equiv.) from Example 3(iii), N-ethyl-2-(methylamino)acetamide (31.13 mg, 203.94 μmol, 3 equiv., HCl), and N,N-diisopropylethylamine (77.32 mg, 0.598 mmol, 104.20 μL, 8.8 equiv.) 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 diluted with N-methyl-2-pyrrolidone (1 mL). The resulting mixture was purified by reverse-phase HPLC (Phenomenex™ Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (FA)-ACN], B%: 46%–76%, 10 min). The cleaved 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).

[0329] (xlviii) Compound 47:

[0330] [ka] A mixture of intermediate I-2(c) (35 mg, 67.98 μmol, 1 equiv.) from Example 3(iii), 2-amino-N-ethyl-acetamide (28.27 mg, 204 μmol, 3 equiv., HCl salt) from Example 1(xi), and N,N-diisopropylethylamine (77.32 mg, 598 μmol, 104.2 μL, 8.8 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase HPLC (Phenomenex™ Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (FA)-ACN], B%: 46% to 76%, 10 min). The cleaved 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).

[0331] (xlix) Compound 48:

[0332] [ka] A mixture of intermediate I-2(m) (50 mg, 91.8 μmol, 1 equiv.) from Example 3(xiii), N-ethyl-2-(methylamino)acetamide (42.02 mg, 0.275 mmol, 3 equiv., HCl), and N,N-diisopropylethylamine (104.37 mg, 0.808 mmol, 141 μL, 8.8 equiv.) 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 (Phenomenex™ Luna C18 150 × 25 mm, 10 μm column, mobile phase: [water (FA)-ACN], B%: 49%–79%, 10 min). The cleaved 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).

[0333] (l) Compound 49:

[0334] [ka] A mixture of intermediate I-2(c) (50 mg, 97.1 μmol, 1.0 equiv.) from Example 3(iii), 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™ Luna C18 150 × 25 mm, 10 μm, mobile phase: [water (FA)-ACN], B%: 45% to 75%, 10 min). The resulting liquid was concentrated under reduced pressure to remove acetonitrile and lyophilized to give 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, 24.16 mg) 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).

[0335] (li) Compound 50:

[0336] [ka] To a solution of intermediate I-4(c) from Example 5(iii) (115 mg, 0.24 mmol, 1.0 equiv.), (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), palladium triphenylphosphine (28 mg, 24.2 μmol, 0.1 equiv.) was added, and the resulting mixture was stirred at 60 °C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 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 give 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. 1 H 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).

[0337] (lii) Compound 51:

[0338] [ka] 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 h. Intermediate I-2(p) (60 mg, 0.13 mmol, 1.0 equiv.) from Example 3(xvi) was then added to the mixture, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was then diluted with water (5 mL), 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 (ISCO®, 12 g SepaFlash® silica flash column, eluting with a gradient of approximately 20% to approximately 80% ethyl acetate / petroleum ether at 30 mL / min). The collected fractions were concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase HPLC (Phenomenex™ Luna C18 column, 150 × 25 mm, 10 μm column, mobile phase: [water (formic acid)-acetonitrile]; B%: 53% to 83%, 10 min). The fractions were 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. 1 H 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).

[0339] (liiii) Compound 52:

[0340] [ka] 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. Intermediate I-2(q) (55 mg, 0.12 mmol, 1.0 equiv.) from Example 3(xvii) was then added to the mixture, which was stirred at 25°C for 2 h. The reaction mixture was diluted with water (5 mL), 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™ Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 61%-91%, 10 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile and then lyophilized to give 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).

[0341] (liv) Compound 53:

[0342] [ka] 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. Intermediate I-2(r) from Example 3(xviii) (115 mg, 0.20 mmol, 1.0 equiv.) was then added, and the mixture was stirred at 25° C. for 1.5 h. The mixture was poured into ammonium chloride (10 mL) and extracted with 15 mL of ethyl acetate (3×5 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™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 60% to 90%, 8 min) to give 5-[3-(4-chlorophenyl)-5-(2-hydroxy-2-methyl-propoxy)-7-[4-(trifluoromethylsulfonyl)piperazin-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).

[0343] (lv) Compound 54:

[0344] [ka] 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 h. Intermediate I-2(s) from Example 3(xix) (110 mg, 0.22 mmol, 1.0 equiv) was then added and the mixture was stirred at 25° C. for 1.5 h. The mixture was poured into ammonium chloride (10 mL) and the mixture was extracted with 15 mL of ethyl acetate (3×5 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 44% to 74%, 8 min) to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)-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).

[0345] (lvi) Compound 55:

[0346] [ka] 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. Intermediate I-2(t) from Example 3(xx) (100 mg, 0.17 mmol, 1.0 equiv) was then 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™ Luna C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 56%-86%, 10 min) to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)-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).

[0347] (lvii) Compound 56:

[0348] [ka] 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.), copper(I) 3-methylsalicylate (66 mg, 309 μmol, 3.0 equiv.), and 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™ Xbridge 150 x 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 58%-88%, 8 min), preparative HPLC (column: Phenomenex™ Luna C18, 150 x 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 52%-82%, 10 min), silica column chromatography (petroleum ether: ethyl acetate), and preparative HPLC (column: Phenomenex™ Luna Purification by C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 53%-83%, 10 min) gave [(2S)-1-[2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(6-methyl-3-pyridyl)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).

[0349] (lviii) Compound 57:

[0350] [ka] 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. Intermediate I-2(u) (140 mg, 0.25 mmol, 1.0 equiv) from Example 3(xxi) was then added to the mixture, which was stirred at 25° C. for an additional 50 minutes. The reaction mixture was added to saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (2 mL) and purified by preparative HPLC (Phenomenex™ Luna C18 column, 150 × 25 mm, 10 μm column, mobile phase: [water (formic acid)-acetonitrile], B%: 62% to 92%, 10 min). The desired fraction was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give 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).

[0351] (lix) Compound 58:

[0352] [ka] To a solution of intermediate I-2(u) from Example 3(xxi) (250 mg, 0.45 mmol, 1.0 equiv) in N-methyl-2-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 resulting residue was dissolved in N,N-dimethylformamide (2 mL) and purified by preparative HPLC (Column: Waters™ Xbridge 150 x 25 mm, 5 μm, Mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 58%-88%, 8 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give 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).

[0353] (lx) Compound 59:

[0354] [ka] 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 h. Intermediate I-2(v) (60 mg, 0.13 mmol, 1.0 equiv.) from Example 3(xxii) was then added to the mixture, and the mixture was stirred at 25° C. for 1 h. 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 resulting residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluting with a gradient of approximately 50% to approximately 100% ethyl acetate / petroleum ether at 30 mL / min) and reverse-phase HPLC (Phenomenex™ Luna C18 column, 150 × 25 mm, 10 μm column, mobile phase: [water (formic acid)-acetonitrile], B%: 39% to 69%, 10 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile, and the remaining solution was lyophilized to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)-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).

[0355] (lxi) Compound 60:

[0356] [ka] 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 h. Intermediate I-2(w) from Example 3(xxiii) (80 mg, 0.17 mmol, 1.0 equiv) was then added to the mixture, which was then stirred at 25° C. for 1 h. 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 give a residue that was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent gradient of approximately 50% to approximately 100% ethyl acetate / petroleum ether at 30 mL / min) and reverse-phase HPLC (column: Phenomenex™ Luna C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 48% to 78%, 10 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile. The aqueous mixture was lyophilized to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)-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 H NMR (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).

[0357] (lxii) Compound 61:

[0358] [ka] A mixture of intermediate I-2(v) from Example 3(xxii) (60 mg, 0.13 mmol, 1.0 equiv), [(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 provide a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent gradient of approximately 50% to approximately 100% ethyl acetate / petroleum ether at 30 mL / min) and reverse-phase HPLC (Phenomenex™ Luna C18 column, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 23% to 53%, 10 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to give 1-[3-(4-chlorophenyl)-2-(6-cyano-3-pyridyl)-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 H NMR(400MHz,DMSO-d6)δ=8.87-8.85(m,1H), 8.12-8.05(m,2H), 7.55(s,1 H), 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).

[0359] (lxiii) Compound 62:

[0360] [ka] A mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 0.16 mmol, 1.0 equiv.), 1-(2,2-dimethyl-1,3-dioxan-5-yl)-N-methyl-methanamine (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×3). 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 (ISCO®, 20 g SepaFlash® silica flash column, eluent gradient of approximately 50% to approximately 100% ethyl acetate / petroleum ether at 30 mL / min). The cleavage fraction was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [gradient of acetonitrile in aqueous ammonium hydroxide], 9 min). The collected 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-dioxan-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. 1H 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).

[0361] (lxiv) Compound 63:

[0362] [ka] 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. Intermediate I-2(y) (130 mg, 0.24 mmol, 1.0 equiv) was then 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™ Luna C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 56%-86%, 10 min) to give 1-[9-(4-chlorophenyl)-8-(6-cyano-3-pyridyl)-2-(2-hydroxy-2-methyl-propoxy)purin-6-yl]-4-isopropoxy-piperidine-4-carboxamide (compound 63, 13.37 mg, 21.5 μmol) as a yellow solid. 1H 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).

[0363] (lxv) Compound 64:

[0364] [ka] 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.), and copper(I) 3-methylsalicylate (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 provide a residue. The residue was purified by preparative HPLC (column: Phenomenex™ Luna C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 54% to 84%, 10 min) and preparative HPLC (column: Waters™ Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 51% to 81%, 8 min) to give 5-[3-(4-chlorophenyl)-5-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-7-[6-(trifluoromethyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxamide (compound 64, 17.51 ​​mg, 27.97 μmol) as a yellow solid. 1H 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).

[0365] (lxvi) Compound 65:

[0366] [ka] To a mixture of intermediate I-2(c) from Example 3(iii) (80 mg, 0.16 mmol, 1.0 equiv.) and (2R)-N-methylazetidine-2-carboxamide from Example 1(xvi) (106 mg, 0.47 mmol, 3.0 equiv., trifluoroacetate salt) in tetrahydrofuran (2 mL) was added potassium t-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 (ISCO®, 12 g SepaFlash® silica flash column, eluent gradient of about 0% to about 50% ethyl acetate / petroleum ether at 30 mL / min) and preparative HPLC (column: Phenomenex™ Luna C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 47% to 77%, 10 min) 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, 15.83 μmol) as an off-white solid. 1H 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).

[0367] (lxvii) Compound 66:

[0368] [ka] 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 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase HPLC (Column: Waters™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 51%-81%, 8 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to give 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. 1H NMR(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).

[0369] (lxviii) Compound 67:

[0370] [ka] 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 hours. The mixture was purified by preparative HPLC (column: Phenomenex™ Synergi C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 48% to 78%, 7 min) 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. 1H 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).

[0371] (lxix) Compound 68:

[0372] [ka] 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)propanamide (129 mg, 0.93 mmol, 6.0 equiv., hydrochloride salt) from Example 1(xviii), and the resulting mixture was stirred at 140°C for 20 h. The mixture was poured into water (10 mL) and filtered. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent gradient of approximately 0% to approximately 50% ethyl acetate / petroleum ether at 20 mL / min), preparative HPLC (column: Phenomenex™ Luna Purification by C18, 150 × 25 mm, 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 47%-77%, 10 min) and preparative thin-layer chromatography (dichloromethane:methanol = 10:1) gave 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. 1H 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).

[0373] (lxx) Compound 69:

[0374] [ka] A mixture of intermediate I-2(x) (90 mg, 0.18 mmol, 1.0 equiv.) from Example 3(xxiv), N-ethyl-2-(methylamino)acetamide (82 mg, 0.54 mmol, 3.0 equiv., hydrochloride salt), 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 resulting filtrate was purified by reverse-phase HPLC (Column: Waters™ Xbridge 150 × 25 mm, 5 μm, Mobile phase: [water (ammonia hydroxide)-acetonitrile], B%: 40% to 70%, 9 min). The collected fractions were concentrated under reduced pressure to remove acetonitrile and lyophilized to give 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. 1H 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).

[0375] (lxxi) Compounds 70(R) and 71(R):

[0376] [ka] At room temperature, (R)-(-)-1,2-propanediol (152 mg, 146 μL, 2.00 mmol, 1.3 equiv.) and cesium carbonate (1.5 g, 4.62 mmol, 3.0 equiv.) were added to 4 mL of N,N-dimethylacetamide under nitrogen, and the mixture was stirred for 30 min. 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 to the reaction mixture, which was heated to 45-50 °C and stirred at this temperature for approximately 17 h under nitrogen. The reaction mixture was then cooled to 20-30 °C. Water (60 mL) was added, and the mixture was extracted with dichloromethane (80 mL × 3). The combined organic layers were washed with brine (32 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue (combined from two batches) was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The collected fractions were concentrated under reduced pressure and purified by chiral SFC separation (column: Daicel Chiralcel™ OD (250 mm × 30 mm, 10 μm), 40% methanol in supercritical CO2 as the mobile phase, flow rate 120 g / min, and cycle time 3.2 min) to give residue 1 (Rt: 3.81) and residue 2 (Rt: 5.31).

[0377] Water (40 mL) was added to each of the residues 1 and 2 from the SFC separation, and the mixtures were each stirred for 2 hours at 90° C. The mixtures were then cooled to 25° C., filtered, and the filter cakes were dried under reduced pressure to give the following: Compound 70(R) (359.95 mg, 641 μmol) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ 9.39(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. Compound 71(R) (191.13 mg, 339 μmol) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ 9.38(d,J=1.6Hz,1H), 8.81(dd,J=8.0,1.6Hz,1H), 8.17(d,J=8.4Hz,1H), 7.30-7.62(m,8H), 7.1 1(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 F NMR:(400MHz,DMSO-d6)δ -66.736.

[0378] (lxxii) Compounds 70(S) and 71(S):

[0379] [ka] 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 under nitrogen for approximately 12 hours. The reaction mixture was warmed to a maximum of 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. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The collected fractions were concentrated under reduced pressure, combined with a second batch of the same scale, and purified by chiral SFC separation as in Example 6 (lxxi) to give two residues.

[0380] Water (30 mL) was added to each of the two residues from the SFC separation, and the mixtures were each stirred for 2 hours at 85-90°C. The mixtures were then cooled to 20-30°C, filtered, and the filter cakes were dried under reduced pressure to give the following: Compound 70(S) (288.77 mg, 518 μmol) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ 9.40(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. Compound 71(S) (29.32 mg, 49.5 μmol) as a yellow solid. 1H NMR:(400MHz,DMSO-d6)δ 9.39(d,J=1.6Hz,1H), 8.81(dd,J=8.0,1.6Hz,1H), 8.17(d,J=8.0Hz,1H), 7.34-7.61(m,8H), 7.1 2(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 F NMR:(400MHz,DMSO-d6)δ -66.740.

[0381] (lxxiii) Compound 72(R):

[0382] [ka] Intermediate I-2(n) from Example 3(xiv) (765 mg, 1.47 mmol, 1.0 equiv.) was dissolved in N,N-dimethylacetamide (8.00 mL) at room temperature. (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 under nitrogen at 20-30°C for 1 hour. The reaction mixture was filtered under reduced pressure, and 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). The mixture was washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with isopropanol (5 mL) three times for 30 minutes each, and filtered each time. To the filter cake from the last filtration step, water (16 mL) was added, and the mixture was stirred under nitrogen at 85-90°C for 5 h. The suspension was then cooled to 20-30°C, filtered, and the filter cake was dried under vacuum to give compound 72(R) (545.2 mg, 915 μmol) as a yellow solid. 1H NMR:(400MHz,DMSO-d6)δ 9.39(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 F NMR:(400MHz,DMSO-d6)δ -66.680.

[0383] (lxxiv) Compound 72(S):

[0384] [ka] 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) at room temperature. (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 under nitrogen for 1 hour. 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 collected fractions were concentrated under vacuum. To the resulting residue, 5 mL of a hexane / methyl tert-butyl ether (10 / 1) mixture was added and stirred at 20-25 °C for 30 min. The mixture was filtered, and the filter cake was dried under vacuum. Water (40 mL) was added to the filter cake, and the mixture was stirred at 90 °C for 5 h. The suspension was then cooled to 25 °C and filtered. After adding water and / or acetonitrile in several cycles, heating at 90 °C, cooling, and filtering, the filter cake was dried under vacuum to give compound 72(S) (363.04 mg, 622 μmol) as a yellow solid. 1H NMR:(400MHz,DMSO-d6)δ 9.39(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.

[0385] (lxxv) Compounds 73 and 75:

[0386] [ka] N,N-Dimethylacetamide (5.00 mL) was charged to a flask at 25-35°C under nitrogen. 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 under nitrogen for 22 hours. Monitoring indicated an incomplete reaction. 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 collected eluate from the two fractions was adjusted to pH 7 with saturated aqueous sodium bicarbonate, 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 aqueous sodium bicarbonate (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then triturated 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 the following: Compound 73 (137 mg, 237 μmol) as a yellow solid (from a 500 mg batch).1 H NMR: (400MHz, DMSO-d6)δ 9.28(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. Compound 75 (75 mg, 131 μmol) (300 mg of のバッチから) was a yellow solid. 1 H NMR: (400MHz, DMSO-d6)δ 9.40(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), 4.37(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 F NMR: (400MHz, DMSO-d6)δ -66.728.

[0387] (1xxvi) Compound 74:

[0388]

change

[0389] (lxxvii) Compound 76:

[0390] [ka] [(2S)-pyrrolidin-2-yl]methanol- prepared in Example 1(xx) 15N-d7 (hydrochloride salt, 50 mg, 0.343 mmol) and intermediate I-2(n) from Example 3(xiv) (210 mg, 0.405 mmol) were dissolved in acetonitrile, and N,N-diisopropylethylamine (0.300 mL, 1.72 mmol) was added. The reaction was sealed and allowed to stand at 80°C overnight. Water was added to the mixture, which was then extracted five times with dichloromethane. The combined organic layers were 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 give compound 76 (118 mg) in good purity. 1 H NMR spectral analysis was consistent with that of compound 8, but the structure was further confirmed by the disappearance of signals for protons converted to deuterium atoms.

[0391] (lxxviii) Compound 77:

[0392] [ka] To a solution of 1,1-(d6)dimethyl-1,2-dihydroxyethane (100 mg, 1.04 mmol) prepared in Example 1(xxi) in tetrahydrofuran at room temperature was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M), and the reaction was stirred at room temperature for 30 minutes. Intermediate I-2(n) (260 mg, 0.5 mmol) from Example 3(xiv) was then added. The reaction was stirred at 75°C overnight. 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 (132 mg). 1 H NMR spectral analysis was consistent with that of compound 45, but the structure was further confirmed by the disappearance of signals for protons converted to deuterium atoms.

[0393] (lxxix) Compound 78:

[0394] [ka] 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. To the reaction mixture were added water (20 mL) and dichloroethane (30 mL). The organic phase was separated, washed with brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting 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 give the PMB-protected compound (500 mg, 805 μmol) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ 9.29(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.

[0395] 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, and 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 give 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 give a residue. The residue was combined with the product (46 mg) from a different batch, acetonitrile (5 mL) was added, and the mixture was stirred at 20-30 °C for 15 min. 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 h. The reaction mixture was cooled to 25 °C, filtered, and the filter cake was dried under reduced pressure to give compound 78 (58 mg, 112 μmol) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ 9.30(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 F NMR:(400MHz,DMSO-d6)δ -66.674.

[0396] Example 7 - Biological properties a) Assay Design Day 1: HEK293 cells were transfected in suspension using polyethyleneimine (PEI) transfection agent with the human CB1 or CB1b receptor and one of the following bioSensAll® assays: GAPL-Gi2, or the β-arrestin plasma membrane (PM) translocation biosensor (+GRK2). Immediately after transfection, cells were seeded directly into 96-well plates.

[0397] Day 4 (approximately 65 hours post-transfection): Cells were incubated with coelenterazine (luciferase substrate) and different test compounds before measuring the BRET signal.

[0398] b) Description of the BioSensAll® platform. In this project, we will use i) a Gα plasma membrane (GAPL) biosensor and ii) a β-arrestin plasma membrane translocation biosensor.

[0399] i) GAP1 sensors are used to monitor the activation of heterotrimeric G proteins at the plasma membrane upon 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 after receptor stimulation generally results in an increase in the BRET signal.

[0400] ii) Multimolecular β-arrestin membrane recruitment biosensors enable real-time spatiotemporal monitoring of β-arrestin 1 and β-arrestin 2 following GPCR activation. Specifically, these β-arrestin sensors were designed to detect protein recruitment to the plasma membrane (β-arrestin PM) by localization to a compartment that results in an increased BRET signal.

[0401] c) Cell culture conditions HEK293 cells were maintained in Dulbecco's modified Eagle's medium (DMEM) (Wisent; catalog no. 319-030-CL: without sodium pyruvate, with 4.5 g / L glucose, without L-glutamine) supplemented with 1% penicillin-streptomycin (Wisent; catalog no. 450-201-EL) and 2 or 10% fetal bovine serum (Wisent, catalog no. 090150).

[0402] d) Transfection and cell plating HEK293 cells were transfected with hCB1 or hCB1b and one of the bioSensAll® assays listed above. For each transfection condition: - the total amount of transfected DNA was kept constant at 1 μg per mL of cell culture transfected, and whenever necessary, salmon sperm DNA (Invitrogen, Cat. No. 15632011) was used as "carrier" DNA to supplement the plasmid DNA (i.e., biosensor and receptor); -PEI (polyethyleneimine 25 kDa linear, PolyScience, Cat. No. 23966) to DNA ratio (ug:ug) was fixed at 3:1.

[0403] Transfection was performed as follows: -DNA and PEI were first diluted separately in 150 mM NaCl, the volume of diluent in each tube corresponding to 5% of the cell culture volume to be transfected. Once the DNA and PEI were diluted, the PEI-containing solution was added to the DNA solution and the DNA / PEI mixture was immediately vortexed for 5 seconds. - The DNA / PEI mixture was incubated at room temperature for at least 20 minutes to allow the formation of DNA / PEI complexes. During the incubation, the HEK293 cells were detached, counted and resuspended in culture medium (composition specified above). At the end of the incubation period, the DNA / PEI mixture was added to the cells. The cells were finally dispersed in 96-well plates (White Opaque 96-well / microplates, Greiner, catalog number 655083 or CulturPlate-96, White Opaque 96-well microplates, PerkinElmer, catalog number 6005688) at a density of 30,000 cells per well.

[0404] e) BRET assay Approximately 48 hours after transfection: Using a -450-Select TS Biotek plate washer, the culture medium was aspirated and replaced with 100 μl per well of Hank's Balanced Salt Solution (HBSS) (Wisent, Cat. No. 319-067CL: no red phenol; with sodium bicarbonate, with calcium and magnesium, with HEPES). This process was repeated twice (i.e., two washes). After a wash step, increasing doses (12) of test compound (ranging from 0 to 600 nM) were injected into the wells using an HP D300 digital dispenser (Tecan). After 3 to 5 minutes, the EC75 of CP-55,940 (0.1 nM for the GAPL-Gi2 ​​assay and 100 nM for the β-arrestin PM translocation biosensor (+GRK2)) was added to columns 2 to 12 of each 96-well plate. Eight wells in column 1 of each plate were consistently reserved for controls (i.e., three untreated wells, two wells injected with the EC75 of CP-55,940, and three wells injected with the EC100 of CP-55,940). -The plates were then incubated overnight (16-18 hours) at 37 degrees Celsius and 5% CO2 in a humidified atmosphere. The next day, the BRET experiment was performed according to the following protocol: -10 μl of 20 μM e-Coelenterazine Prolume Purple (Methoxy e-CTZ) (Nanolight, Cat. No. 369) was added to each well to a final concentration of 2 μM. -Plates were incubated for 5 minutes at room temperature on an orbital shaker. -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 seconds.

[0405] f) calculation The BRET signal was determined by calculating the ratio of light emitted by the GFP acceptor (515 nm) to the light emitted by the luciferase donor (400 nm). All BRET ratios were normalized using the pre-established BRET values ​​for the positive and negative controls using the following formula: The normalized BRET ratio is referred to as universal BRET (uBRET). uBRET=((BRET ratio-A) / (BA))×10000 During the ceremony: A = BRET ratio obtained from negative control transfection B = BRET ratio obtained from positive control transfection

[0406] The resulting dose-response curves were fitted using a four-parameter logistic nonlinear regression model in GraphPad Prism 9.

[0407] The in vitro assay results of compounds 1 to 72 prepared in Example 6 are shown in Table 1.

[0408] [Table 1-1]

[0409] [Table 1-2]

[0410] Numerous modifications can be made to any of the above-described embodiments without departing from the scope of the present invention. The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir.

Claims

1. Compounds of Formula I: 【Chemical 1】 Formula I (In the formula, R １ is optionally substituted C ６ - １０ is aryl, R ２ is optionally substituted C ６ - １０ Aryl and optionally substituted C ５ - １０ heteroaryl; R ３ is optionally substituted C １ - ６ Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C ４ - ７ Cycloalkyl, optionally substituted C ４ - ７ Heterocycloalkyl, optionally substituted C ６ aryl, and optionally substituted C ５ - ６ Heteroaryl, optionally substituted -X １ -C ３ - １０ heterocycloalkyl; X １ But NR ５ and R ５ is H, R ４ But NH ２ , optionally substituted C １ - ６ Alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted C ３ - ６ heterocycloalkyl), or an enantiomer, diastereomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. R ４ is optionally substituted C ３ - ６ 2. The compound of claim 1, wherein the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

3. R ４ is optionally substituted C １ - ６ Alkoxy or optionally substituted C １ - ６ The compound of claim 1 which is alkylamino.

4. Said C １ - ６ Alkoxy or C １ - ６ Alkylamino is OH, CO ２ H, CO ２ NH ２ , CO ２ NHC １－６ Alkyl, CO ２ N (C １－６ alkyl) ２ , NHC(O)C １－６ Alkyl, N(C １－６ alkyl)C(O)C １－６ 4. The compound of claim 3, substituted with at least one group selected from alkyl.

5. R ３ is optionally substituted C １ - ６ Alkoxy, or optionally substituted C １－６ Alkylamino or diC １－６ The compound of claim 1 which is alkylamino.

6. R ３ is optionally substituted C ６ Aryl, C ５－６ Heteroaryl, C ４－７ Heterocycloalkyl groups or C linked to the pyrazolopyrimidine core via N ４－７ The compound of claim 1 which is a heterocycloalkyl.

7. R ３ is expressed by the following formula: 【Chemistry 2】 (In the formula, R ７ is independently in each occurrence a halogen, OH, OR ９ , CN, and optionally substituted C １－６ alkyl, R ９ independently in each occurrence, optionally substituted C １－６ alkyl, and c is 0, 1, or 2. The compound of claim 1.

8. R ３ is expressed by the following formula: 【Chemistry 3】 (In the formula, X ３ , X ４ , X ５ , X ６ , and X ７ each independently represents N and CR １１ is selected from X ３ , X ４ , X ５ , X ６ , and X ７ at most three of are N, R １１ is independently in each occurrence hydrogen, halogen, and C １－６ alkyl), The compound of claim 1.

9. R ３ is expressed by the following formula: 【Chemistry 4】 (In the formula, X ８ However, N and CR １１ is selected from X ９ , X １０ , X １１ , X １２ , X １３ , and X １４ are each independently NR １２ , S.O. ２ , and C(R １３ ) ２ is selected from X ８ , X ９ , X １０ , X １１ , X １２ , X １３ , and X １４ At most two of are N or S and / or X ９ , X １０ , X １１ , X １２ , X １３ , and X １４ are absent and form a 4-, 5-, or 6-membered ring; R １２ is hydrogen or SO ２ R ９ and R １３ is independently in each occurrence hydrogen, halogen, OH, OR ９ ,CN,C(O)N(R ８ ) ２ , S.O. ２ R ９ , N(R １０ ) C(O)R ９ , N(R ８ ) ２ , optionally halogenated C １－６ alkyl, R ８ is independently in each occurrence H or C １－６ alkyl, and R ９ But C １－６ Alkyl or halogenated C １－６ alkyl, and R １０ is H) The compound of claim 1.

10. X ３ , X ４ , X ５ , X ６ , and X ７ 9. The compound of claim 8, wherein one of: is N.

11. X ４ is N and X ３ , X ６ , and X ７ and each is CH.

12. X ５ But, CR １１ and R １１ is CN, optionally substituted C １－６ alkyl group, and OR ９ and R ９ is optionally substituted C １－６ The compound of claim 8 which is an alkyl group.

13. R ２ is expressed by the following formula: 【Chemistry 5】 (In the formula, X １５ , X １６ , X １７ , X １８ , and X １９ each independently represents N and CR １１ is selected from R １１ is independently in each occurrence hydrogen, halogen, OH, OR ９ , CN, and NO ２ is selected from R ９ But C １－６ Alkyl or halogenated C １－６ 2. The compound of claim 1, wherein:

14. X １５ , X １６ , X １７ , X １８ , and X １９ 14. The compound of claim 13, wherein one of is N.

15. X １５ But, CR １１ and R １１ is halogen and OR ９ and R ９ But C １－６ The compound of claim 13, wherein the compound is alkyl.

16. X １６ , X １７ , X １８ , and X １９ However, each １１ and R １１ The compound of claim 14 , wherein is hydrogen.

17. R ２ The compound of claim 1, wherein is a 2-methoxyphenyl or 2-chlorophenyl group.

18. R １ The compound according to claim 1, wherein is a 4-chlorophenyl group.

19. The compound is the following compound: 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 2. The compound of claim 1, selected from: or an enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

20. The compound is 【Chemistry 19】 2. The compound of claim 1, selected from: or an enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

21. The compound is 【Chemistry 20】 10. The compound of claim 1, which is: or an enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 together with a pharmaceutically acceptable carrier, diluent or excipient.

23. 23. The pharmaceutical composition of claim 22 for the treatment of an appetite-related disorder or one of its complications, a glucose regulation-related disorder or one of its complications, a fibrosis-related disorder or one of its complications, a metabolism-related disorder or one of its complications, a skin and hair growth and healing-related disorder, a gastrointestinal tract-related disorder, an obesity-related disorder or one of its complications, or a combination thereof.

24. 23. The pharmaceutical composition of claim 22, wherein the disorder is selected from type I diabetes, type II diabetes, obesity, and chronic kidney disease.

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