Substituted pyrazolopyrimidines and their uses

Abstract

The present disclosure provides compounds that are PIKfyve kinase inhibitors and can be used to treat neurological diseases treatable by inhibiting PIKfyve. Pharmaceutical compositions containing such compounds and methods of treatment using such compounds are also provided.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 960,412, filed on January 13, 2020, and U.S. Provisional Application No. 63 / 074,388, filed on September 3, 2020, the disclosures of each of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure provides compounds that are phosphoinositide kinase inhibitors, particularly FYVE - containing finger phosphoinositide kinases (“PIKfyve”) inhibitors, and can thus be used to treat central nervous system diseases. Also provided are pharmaceutical compositions containing such compounds and methods for preparing such compounds. Background Art

[0004] Phosphoinositide kinases (PIKs) catalyze the phosphorylation of phosphatidylinositol, a component of eukaryotic cell membranes, and related phospholipids called phosphoinositides. Phosphoinositides are involved in the regulation of a variety of cellular processes, including cell proliferation, survival, cytoskeletal organization, vesicle trafficking, glucose transport, and platelet function. Fruman et al., “Phosphoinositide Kinases,” Ann. Review. Biochem. 1998, 67, 481 - 507. Phosphorylated derivatives of phosphatidylinositol regulate cytoskeletal function, membrane trafficking, and receptor signaling by recruiting protein complexes to the cell and endosomal membranes.

[0005] The FYVE-containing phosphatidylinositol kinase (PIKfyve; also known as type III phosphatidylinositol-3-phosphate 5-kinase or PIPKIII) is a ubiquitously expressed PIK with both lipid kinase activity and protein kinase activity. In its capacity as a lipid kinase, the enzyme phosphorylates the D-5 position in endosomal phosphatidylinositol and phosphatidylinositol-3-phosphate (PI3P) to generate the corresponding 5-phosphorylated phospholipid analogs. Shisheva et al., Cell Biol. Int. 2008, 32(6), 591. PI3P is found in cell membranes and plays a role in protein trafficking, protein degradation, and autophagy. Nascimbeni et al., FEBS J. 2017, 284, 1267-1278. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosomal carrier vesicles from early endosomes. Enlarged endosome / lysosome structures are observed in cells expressing the dominant negative form of PIKfyve or siRNA. Ikonomov et al., J. Biol. Chem. 2001, 276(28), 26141-26147; Rutherford et al., J. Cell Sci. 2006, 119, 3944-3957. Inhibition of PIKfyve activity increases PI3P levels, thereby stimulating autophagy and improving motor neuron health. The phosphorylated inositols generated by PIKfyve localize to various cell membranes and organelles, which is consistent with the various functions of PIKfyve in endolysosomal trafficking, endomembrane homeostasis, and the biogenesis of endosomal carrier vesicles (ECVs) / multivesicular bodies (MVBs) from early endosomes. In addition, PIKfyve is required for the endocytic vacuole pathway and nuclear migration. Thus, PIKfyve contributes to maintaining the proper morphology of endosomes and lysosomes.

[0006] In mammalian cells, PI3P levels are regulated by the interaction of PIKfyve and the phosphoinositide 5-phosphatase FIG4. Zolov et al., “In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P,” Proc. Natl. Acad. Sci. USA 2012, 109(43), 17472-17477. Typically, FIG4 is located on the cytoplasmic surface of endolysosomal vesicles in a complex. Inhibition of PIKfyve will mimic overexpression of FIG4, thereby increasing PI3P levels, stimulating autophagy, and improving motor neuron health. Many diseases are associated with FIG4 deficiency, such as deleterious FIG4 mutations or reduced FIG4 function, and are therefore suitable as target diseases for treatment with PIKfyve inhibitors, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (including type 4J (CMT4J)), and Yunis-Varon syndrome.

[0007] Exemplary diseases associated with FIG4 deficiency are amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (including type 4J (CMT4J)), Yunis-Varon syndrome, polymicrogyria (including polymicrogyria with seizures), occipitotemporal polymicrogyria, Pick’s disease, Parkinson’s disease, Parkinson’s disease with Lewy bodies, Lewy body dementia, Lewy body disease, frontotemporal dementia, neuronal intranuclear inclusions and intranuclear inclusion diseases of polyglutamine, Marinesco-Sjögren syndrome, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, autophagy, peripheral neuropathy, leukodystrophy, motor neuropathy, sensory neuropathy. Bharadwaj et al., Hum. Mol. Genet. 2016, 25(4), 682-692.

[0008] PIKfyve inhibitors can be used for a range of neurological disorders such as tauopathies (including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and chronic traumatic encephalopathy), traumatic brain injury (TBI), cerebral ischemia, ALS, frontotemporal dementia (FTD), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, CMT, lysosomal storage diseases (including but not limited to Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV), and several types of neuropathy. Other therapeutic targets for intervention with PIKfyve inhibitors include Huntington's disease and mental disorders (such as ADHD, schizophrenia, mood disorders (including but not limited to major depressive disorder, bipolar disorder type I, and bipolar disorder type II)). Gardiner et al., “Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts,” JAMA Neurol. 2019, 76(6), 650-656; PCT Publication No. WO2016 / 210372; US Publication No. US2018 / 0161335. Summary of the Invention

[0009] Embodiment 1. A compound of formula (I):

[0010]

[0011] Wherein:

[0012] When X is N, then Y is CR a , and when Y is N, then X is CH;

[0013] R a and R 1 One of them is H, and the other is phenyl or heteroaryl, each optionally substituted by one, two or three R d substituents;

[0014] Wherein each R d substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -O-C 1-4 alkyl, halo, cyano, nitro, azido, halo-C 1-4 alkyl, -O-C 1-4 -haloalkyl, -NR g Rh 、 -NR g C(=O)R h 、 -NR g C(=O)NR g R h 、 -NR g C(=O)OR h 、 =NOR g 、 -NR g S(=O) 1-2 R h 、 -NR g S(=O) 1-2 NR g R h 、 =NSO 2 R g 、 -C(=O)R g 、 -C(=O)OR g 、 -OC(=O)OR g 、 -OC(=O)R g 、 -C(=O)NR g R h 、 -OC(=O)NR g R h 、 -OR g 、 -SR g 、 -S(=O)R g 、 -S(=O) 2 R g 、 -OS(=O) 1-2 R g 、 -S(=O) 1-2 OR g 、 -S(=O) 1-2 NR g R h 、 phenyl, -C 1-4 alkyl - phenyl, monocyclic cycloalkyl, -C 1-4 alkyl - cycloalkyl, monocyclic heteroalkyl, or monocyclic heteroaryl;

[0015] wherein each phenyl, monocyclic cycloalkyl, monocyclic heteroalkyl, or monocyclic heteroaryl of R d is optionally substituted by one, two, or three substituents R e ;

[0016] wherein each R e substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, halo, cyano, nitro, azido, -OH, halo - C 1-4 alkyl, -O - C 1-4 alkyl, or -O - C1-4 - haloalkyl;

[0017] R g and R h are each independently H or C 1-4 alkyl;

[0018] or R g and R h together with the atom to which they are attached form a monocyclic cycloalkyl or heterocycloalkyl, optionally substituted by C 1-4 alkyl;

[0019] wherein each of R 2 and R 3 is H or C 1-4 alkyl, cycloalkyl, C 1-4 alkylcycloalkyl, heterocyclic group, heterocycloalkyl, or R 2 and R 3 together with the nitrogen to which they are attached form a heterocyclic group, optionally substituted by one, two or three R j substituents;

[0020] wherein each R j substituent is independently C 1-4 alkyl, oxo group, -OH, -NR k R l 、halogen, halo-C 1-4 alkyl, -O-C 1-4 alkyl, or -O-C 1-4 - haloalkyl;

[0021] wherein each of R k and R l are each independently H or C 1-4 alkyl;

[0022] R 4 is -C(O)NR x R y , or phenyl or heteroaryl, each optionally substituted by one, two or three R z substituents;

[0023] wherein R x is H or C 1-4 alkyl and R y is H, C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -R r 、monocyclic cycloalkyl, -C 1-4alkyl(monocyclic cycloalkyl), monocyclic heterocyclic group, -O-monocyclic heterocyclic group, or monocyclic heterocycloalkyl, each optionally substituted by one, two or three R o substituents;

[0024] or R x and R y together with the nitrogen to which they are attached form a heterocyclic group or monocyclic heterocycloalkyl, optionally substituted by C 1-4 alkyl;

[0025] wherein each R r is C 1-4 alkyl or -NR p R q ; and

[0026] each R z substituent is independently C 1-4 alkyl, halo, -OH, or -OC 1-4 alkyl, C 1-4 alkylNR m R n 、C(O)NHC 1-4 alkyl-NR m R n 、or -NR m R n ;

[0027] wherein R m and R n are each independently H, C 1-4 alkyl, or C 1-4 alkylNR p R q ; or R m and R n together with the nitrogen to which they are attached form a heterocyclic group or monocyclic heterocycloalkyl, optionally substituted by one or two R o substituents;

[0028] wherein each R o substituent is independently C 1-4 alkyl, -OH, -OC 1-4 alkyl, halo, cyano, or -NR p R q ;

[0029] wherein R p and R q are each independently H or C 1-4 alkyl, or R p and R q together with the nitrogen to which they are attached form a heterocyclic group; and

[0030] R 5is H, C 1-4 alkyl, halo, -OH, or -OC 1-4 alkyl;

[0031] or a pharmaceutically acceptable salt thereof.

[0032] Embodiment 2. The compound according to Embodiment 1, wherein X is CH and Y is N.

[0033] Embodiment 3. The compound according to Embodiment 1, wherein X is N and Y is CR a .

[0034] Embodiment 4. The compound according to Embodiment 1, wherein R a is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0035] Embodiment 5. The compound according to Embodiment 1, wherein R a is H or methyl.

[0036] Embodiment 6. The compound according to Embodiment 1, wherein R a is H.

[0037] Embodiment 7. The compound according to Embodiment 1, wherein R a or R 1 is an optionally substituted phenyl.

[0038] Embodiment 8. The compound according to Embodiment 1, wherein R a or R 1 is an optionally substituted monocyclic heteroaryl.

[0039] Embodiment 9. The compound according to Embodiment 1, wherein R a or R 1 is an optionally substituted pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, or pyridazine.

[0040] Embodiment 10. The compound according to Embodiment 1, wherein R a or R 1 is an optionally substituted pyridine or pyrimidine.

[0041] Embodiment 11. The compound according to Embodiment 1, wherein R a or R 1 is an optionally substituted pyridine.

[0042] Embodiment 12. The compound according to Embodiment 1, wherein R a or R 1is replaced by an R d and said R d is C 1-4 alkyl or a halogen group.

[0043] Embodiment 13. The compound according to Embodiment 1, wherein R a or R 1 is replaced by an R d and said R d is methyl, NH 2 , fluorine, chlorine, or bromine.

[0044] Embodiment 14. The compound according to Embodiment 1, wherein R a or R 1 is phenyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, bromine, -OCH 3 and -OCF 3 .

[0045] Embodiment 15. The compound according to Embodiment 1, wherein R a or R 1 is unsubstituted phenyl or tolyl.

[0046] Embodiment 16. The compound according to Embodiment 1, wherein R a or R 1 is unsubstituted phenyl or m-tolyl.

[0047] Embodiment 17. The compound according to Embodiment 1, wherein R a or R 1 is unsubstituted pyridyl.

[0048] Embodiment 18. The compound according to Embodiment 1, wherein R a or R 1 is 4-pyridyl.

[0049] Embodiment 19. The compound according to Embodiment 1, wherein R 2 and R 3 together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or -2-oxa-6-azaspiro[3.3]heptane, each optionally substituted by one, two or three R j substituents.

[0050] Embodiment 20. The compound according to Embodiment 1, wherein R 2 and R 3Form morpholine together with the nitrogen to which they are attached, optionally substituted by one or two R j substituents.

[0051] Embodiment 21. The compound according to Embodiment 1, wherein each R j substituent is independently methyl, hydroxy, -OCH 3 , oxo, halo, -CF 3 , or -OCF 3 .

[0052] Embodiment 22. The compound according to Embodiment 1, wherein R k and R l are each independently H or methyl.

[0053] Embodiment 23. The compound according to Embodiment 1, wherein R 4 is an optionally substituted phenyl.

[0054] Embodiment 24. The compound according to Embodiment 1, wherein R 4 is an optionally substituted heteroaryl.

[0055] Embodiment 25. The compound according to Embodiment 1, wherein R 4 is an optionally substituted pyrazole, thiazole, oxazole, pyridine or pyrimidine.

[0056] Embodiment 26. The compound according to Embodiment 1, wherein R 4 is an optionally substituted pyridine.

[0057] Embodiment 27. The compound according to Embodiment 1, wherein R 4 is pyridine.

[0058] Embodiment 28. The compound according to Embodiment 1, wherein R 4 is 4-pyridyl.

[0059] Embodiment 29. The compound according to Embodiment 1, wherein R 4 is optionally substituted by one or two R z substituents.

[0060] Embodiment 30. The compound according to Embodiment 1, wherein R 4 is phenyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 .

[0061] Embodiment 31. The compound according to Embodiment 1, wherein R 4 is -C(O)NR x R y .

[0062] Embodiment 32. The compound according to Embodiment 1, wherein R x is H.

[0063] Embodiment 33. The compound according to Embodiment 1, wherein R x is methyl or ethyl, optionally substituted by one, two or three R o substituents.

[0064] Embodiment 34. The compound according to Embodiment 1, wherein R x is methyl.

[0065] Embodiment 35. The compound according to Embodiment 1, wherein R y is H.

[0066] Embodiment 36. The compound according to Embodiment 1, wherein R y is C 1-4 alkyl, -C 1-4 alkyl(monocyclic cycloalkyl), monocyclic cycloalkyl, monocyclic heterocycloalkyl, monocyclic heterocyclic group, -O-monocyclic heterocyclic group, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, optionally substituted by one, two or three R o substituents.

[0067] Embodiment 37. The compound according to Embodiment 1, wherein R y is C 1-4 alkyl, optionally substituted by one, two or three R o substituents.

[0068] Embodiment 38. The compound according to Embodiment 1, wherein R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted by one, two or three R o substituents.

[0069] Embodiment 39. The compound according to Embodiment 1, wherein R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropyl, (dimethylamino)ethyl, or (dimethylamino)butyl.

[0070] Embodiment 40. The compound according to Embodiment 1, wherein R y is methoxy.

[0071] Embodiment 41. The compound according to Embodiment 1, wherein R y is -SO 2 -methyl.

[0072] Embodiment 42. The compound according to Embodiment 1, wherein R y is monocyclic cycloalkyl or -C 1-2 alkyl(monocyclic cycloalkyl), each optionally substituted by one, two or three R o substituents.

[0073] Embodiment 43. The compound according to Embodiment 1, wherein R y is monocyclic cycloalkyl, optionally substituted by one, two or three R o substituents.

[0074] Embodiment 44. The compound according to Embodiment 1, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted by one, two or three R o substituents.

[0075] Embodiment 45. The compound according to Embodiment 1, wherein R y is cyclopropyl.

[0076] Embodiment 46. The compound according to Embodiment 1, wherein R y is cyclopentyl.

[0077] Embodiment 47. The compound according to Embodiment 1, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.

[0078] Embodiment 48. The compound according to Embodiment 1, wherein R y is monocyclic heterocyclic group or -O-monocyclic heterocyclic group, optionally substituted by one, two or three R o substituents.

[0079] Embodiment 49. The compound according to Embodiment 1, wherein R y is optionally substituted tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy.

[0080] Embodiment 50. The compound according to Embodiment 1, wherein R y is oxetanyl, or oxetanyloxy.

[0081] Embodiment 51. The compound according to Embodiment 1, wherein R y is a monocyclic heterocycloalkyl, optionally substituted by one, two or three R o substituents.

[0082] Embodiment 52. The compound according to Embodiment 1, wherein R y is optionally substituted by one or two R o substituents, and R o is methyl.

[0083] Embodiment 53. The compound according to Embodiment 1, wherein R x is methyl and R y is methyl, ethyl, cyclopropyl, methoxy, or cyclopentyl.

[0084] Embodiment 54. The compound according to Embodiment 1, wherein R x and R y together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl, optionally substituted by C 1-4 alkyl.

[0085] Embodiment 55. The compound according to Embodiment 1, wherein R x and R y together with the nitrogen to which they are attached form a monocyclic heterocyclic group, optionally substituted by C 1-4 alkyl.

[0086] Embodiment 56. The compound according to Embodiment 1, wherein R x and R y together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptyl, or 2-oxa-6-azaspiro[3.3]heptyl, each optionally substituted by methyl.

[0087] Embodiment 57. The compound according to Embodiment 1, wherein each R z is independently C 1-4 alkyl, halo, -OH, -OC 1-4 alkyl, C 1-4 alkylNR m R n or -NR m R n .

[0088] Embodiment 58. The compound according to Embodiment 1, wherein each R z is independently methyl, -OH, halo, or -OCH 3 .

[0089] Embodiment 59. The compound according to Embodiment 1, wherein R z is C m alkyl substituted by -NR n R 2-3 .

[0090] Embodiment 60. The compound according to Embodiment 1, wherein R m and R n are each independently H or C 1-4 alkyl.

[0091] Embodiment 61. The compound according to Embodiment 1, wherein R m and R n are each methyl.

[0092] Embodiment 62. The compound according to Embodiment 1, wherein R m and R n together with the nitrogen to which they are attached form a monocyclic heterocyclic group, optionally substituted by one or two R o substituents.

[0093] Embodiment 63. The compound according to Embodiment 1, wherein R m and R n together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide, each optionally substituted by one or two R o substituents.

[0094] Embodiment 64. The compound according to Embodiment 1, wherein R m and R n together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, or morpholine, each optionally substituted by one or two R o substituents.

[0095] Embodiment 65. The compound according to Embodiment 1, wherein each R o substituent is C 1-4 alkyl.

[0096] Embodiment 66. The compound according to Embodiment 1, wherein each R o substituent is -OH.

[0097] Embodiment 67. The compound according to Embodiment 1, wherein each R o substituent is -NR p R q .

[0098] Embodiment 68. The compound according to Embodiment 1, wherein R p and R q are each independently H or methyl.

[0099] Embodiment 69. The compound according to Embodiment 1, wherein R p and R q together with the nitrogen to which they are attached form a heterocyclic group.

[0100] Embodiment 70. The compound according to Embodiment 1, wherein R p and R q together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-1-azaspiro[3.3]heptyl, or 2-oxa-6-azaspiro[3.3]heptyl.

[0101] Embodiment 71. The compound according to Embodiment 1, wherein R 5 is H, methyl, ethyl, chlorine, bromine, fluorine, -OH, or -OCH 3 .

[0102] Embodiment 72. The compound according to Embodiment 1, wherein R 5 is H.

[0103] Embodiment 73. A compound of formula (II):

[0104]

[0105] wherein

[0106] R 1a is phenyl or pyridinyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, CO 2 R p , -C(O)NR p R q , fluorine, chlorine, bromine, NH 2 and -OCH 3 ; and

[0107] R 4a is -C(O)NR x R y , or is phenyl or pyridinyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 ;

[0108] wherein Rx is H or C 1-4 is an alkyl group, and R y is H, C 1-4 is an alkyl group, -O-C 1-4 is an alkyl group, -SO 2 -C 1-4 is an alkyl group, C 1-4 is an alkyl group-SO 2 -R r is a monocyclic cycloalkyl group, -C 1-4 is an alkyl group (monocyclic cycloalkyl group), a monocyclic heterocyclic group, -O-monocyclic heterocyclic group, or a monocyclic heterocycloalkyl group, each optionally substituted by one or two substituents selected from the following: C 1-4 is an alkyl group, -OH, -OC 1-4 is an alkyl group, a halogen group, or a cyano group or -NR p R q ;

[0109] wherein each R r is C 1-4 is an alkyl group or -NR p R q ;

[0110] wherein R p and R q are each independently H or C 1-4 is an alkyl group;

[0111] Or R x and R y together with the nitrogen to which they are attached form a heterocyclic group, optionally substituted by C 1-4 is an alkyl group;

[0112] or a pharmaceutically acceptable salt thereof.

[0113] Embodiment 74. A compound selected from:

[0114] 7-Morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine;

[0115] 7-Morpholino-N-(5-phenyl-1H-pyrazol-3-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[0116] 7-Morpholino-N-[5-(o-tolyl)-1H-pyrazol-3-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[0117] 7-Morpholino-N-[3-(m-tolyl)-1H-pyrazol-5-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[0118] N-(5-Methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[0119] 7-Morpholino-2-(4-pyridinyl)-N-[5-(4-pyridinyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine;

[0120] 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine;

[0121] 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-(o-tolyl)-1H-pyrazol-5-amine;

[0122] 4-[5-(4-Phenylpyrazol-1-yl)-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0123] 4-[5-[4-(m-Tolyl)pyrazol-1-yl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0124] 4-[2-(4-Pyridinyl)-5-[4-(4-pyridinyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0125] 4-[5-(4-Methylpyrazol-1-yl)-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0126] 4-[5-(3-Phenylpyrazol-1-yl)-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0127] 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0128] 4-[2-(4-Pyridinyl)-5-[3-(4-pyridinyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0129] 4-[5-(3-Methylpyrazol-1-yl)-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0130] 4-(2-(Pyridin-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;

[0131] 4-(2-(Pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine;

[0132] N-Ethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0133] N-Cyclopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0134] (R)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0135] (S)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0136] N-(2-Methoxyethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0137] N,N-Dimethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0138] N-Ethyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0139] N-Cyclopropyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0140] N-(Cyclopropylmethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0141] Azetidin-1-yl(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone;

[0142] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(pyrrolidin-1-yl)methanone;

[0143] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone;

[0144] Morpholino(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone;

[0145] (4-Methylpiperazin-1-yl)(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone;

[0146] N-Methoxy-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0147] N-Methoxy-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0148] N-(Methylsulfonyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0149] N-Cyclopentyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0150] N-Cyclopentyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0151] N-Isopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0152] N-(1,3-Dimethoxypropan-2-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0153] N-(2-(Dimethylamino)ethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0154] N-(4-(Dimethylamino)butyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0155] 7-Morpholino-N-(oxetan-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0156] 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0157] N-(((3-(Hydroxymethyl)oxetan-3-yl)methyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0158] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;

[0159] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone;

[0160] 7-Morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0161] N-[(3S)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0162] N-[(3R)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0163] 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0164] 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3R)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0165] N-[(3S)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0166] N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0167] N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0168] 7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]-N-tetrahydropyran-4-yl-pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0169] 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0170] 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0171] 3-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine;

[0172] 5-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine;

[0173] 4-[2-(1-Methylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0174] 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0175] 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0176] 4-[5-(3-Phenylpyrazol-1-yl)-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0177] 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0178] 4-[2-(1-Methylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0179] 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0180] 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0181] 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0182] 3-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine;

[0183] 5-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine;

[0184] 4-[5-(3-Phenylpyrazol-1-yl)-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0185] N-Isopropyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0186] N-[(1R)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0187] N-[(1S)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0188] 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0189] N-Cyclopentyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0190] 4-[5-(4-Phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0191] 4-[5-(4-Phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0192] N-Isopropyl-7-morpholino-5-(4-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide;

[0193] 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0194] 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0195] N,N-Dimethyl-2-[3-methyl-5-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0196] 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0197] 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0198] 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0199] 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0200] 4-[5-(3-Phenylpyrazol-1-yl)-2-pyridazin-3-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0201] Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate;

[0202] N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]propanamide;

[0203] N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0204] N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(2-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0205] N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0206] N,N-Dimethyl-2-[5-methyl-3-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0207] N,N-Dimethyl-2-[5-methyl-3-[5-[3-(4-methyl-2-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0208] N,N-Dimethyl-2-[5-methyl-3-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine;

[0209] 2-[3-[5-[3-(3-chlorophenyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]-5-methyl-pyrazol-1-yl]-N,N-dimethyl-ethylamine;

[0210] 5-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine;

[0211] N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethanamine;

[0212] 2-[3-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]-5-methyl-pyrazol-1-yl]-N,N-dimethyl-ethanamine;

[0213] 4-[5-[3-(3-chlorophenyl)pyrazol-1-yl]-2-(1-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0214] 4-[5-[3-(5-methyl-3-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0215] 4-[5-[3-(2-methyl-4-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0216] 4-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine;

[0217] 4-[5-[3-(3-chlorophenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0218] 4-[5-[3-(3-bromophenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0219] 4-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0220] 4-[5-[3-(6-methyl-2-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0221] 6-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine;

[0222] 4-[2-(3-methylisoxazol-5-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0223] 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0224] 4-[2-(1-Methylpyrazol-4-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0225] 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0226] 4-[5-(3-Phenylpyrazol-1-yl)-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0227] 4-[2-(1-Methylpyrazol-4-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0228] 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0229] Methyl 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate;

[0230] 3-[1-[7-Morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide;

[0231] 3-[1-[7-Morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzonitrile;

[0232] 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0233] 4-[2-(3-Methylisoxazol-5-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0234] 3-[1-[7-Morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoic acid; and

[0235] 4-[2-(1-Methylpyrazol-3-yl)-5-[3-[3-(trideuteriomethyl)phenyl]pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine;

[0236] and its pharmaceutically acceptable salts.

[0237] Embodiment 75. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt according to any one of Embodiments 1 to 74 or 87, and a pharmaceutically acceptable excipient.

[0238] Embodiment 76. A method of inhibiting PIKfyve kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 74 or 87 or a pharmaceutical composition according to Embodiment 75.

[0239] Embodiment 77. A method of treating a neurological disorder associated with PIKfyve activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 74 or 87 or a pharmaceutical composition according to Embodiment 75.

[0240] Embodiment 78. The method according to Embodiment 77, wherein the neurological disorder is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (CMT; including type 4J (CMT4J)) and Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Lewy body Parkinson's disease, Lewy body dementia, Lewy body disease, frontotemporal dementia, polyglutamine neuronal nuclear inclusions and intranuclear inclusion body disease, Marinesco-Sjögren syndrome, tauopathy, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (TBI), cerebral ischemia, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, lysosomal storage disease, Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV, neuropathy, Huntington's disease, mental disorder, ADHD, schizophrenia, mood disorder, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0241] Embodiment 79. The method according to Embodiment 78, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT.

[0242] Embodiment 80. The method according to Embodiment 79, wherein the disease is ALS.

[0243] Embodiment 81. The method according to embodiment 78, wherein the disease is a tauopathy, such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.

[0244] Embodiment 82. The method according to embodiment 78, wherein the disease is a lysosomal storage disease, such as Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, or mucolipidosis type IV.

[0245] Embodiment 83. The method according to embodiment 78, wherein the disease is a mental disorder, such as ADHD, schizophrenia; or a mood disorder, such as major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0246] Embodiment 84. The compound according to any one of embodiments 1 to 74 or 87, which is used as a medicament.

[0247] Embodiment 85. The method according to embodiment 84, wherein the compound is used for treating a neurological disease treatable by inhibiting the PIKfyve kinase.

[0248] Embodiment 86. Use of the compound according to any one of embodiments 1 to 74 or 87 in the manufacture of a medicament for treating a neurological disease in a subject, in which PIKfyve contributes to the pathology and / or symptoms of the disease in the subject.

[0249] Embodiment 87. The compound and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 74, wherein one or more hydrogen atoms attached to the carbon atoms of the compound are replaced by deuterium atoms. Detailed Description

[0250] Unless otherwise specified, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0251] "Alkyl" means a straight-chain saturated monovalent hydrocarbon group of one to six carbon atoms or a branched-chain saturated monovalent hydrocarbon group of three to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), etc.

[0252] Unless otherwise specified, "alkylene" means a straight-chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched-chain saturated divalent hydrocarbon group of three to six carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0253] "Alkylsulfonyl" means -SO 2An R group, where R is an alkyl group as defined above, such as methylsulfonyl, ethylsulfonyl, etc.

[0254] "Amino" means -NH 2 .

[0255] "Alkoxy" means an -OR group, where R is an alkyl group as defined above, such as methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, etc.

[0256] "Alkoxyalkyl" means a straight-chain monovalent hydrocarbon group of one to six carbon atoms or a branched-chain monovalent hydrocarbon group of three to six carbon atoms substituted by an alkoxy group as defined above (in one embodiment, one or two alkoxy groups), such as 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl or 3-methoxypropyl, 2-ethoxyethyl, etc.

[0257] "Alkoxycarbonyl" means a -C(O)OR group, where R is an alkyl group as defined above, such as methoxycarbonyl, ethoxycarbonyl, etc.

[0258] "Acyl" means a -COR group, where R is an alkyl group, a haloalkyl group or a cycloalkyl group, such as acetyl, propionyl, cyclopropylcarbonyl, etc. When R is an alkyl group, the group is also referred to as alkylcarbonyl herein.

[0259] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon group having three to ten carbon atoms (where one or two carbon atoms may be replaced by an oxo group), such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

[0260] "Carboxyl" means -COOH.

[0261] "Halo" means fluorine, chlorine, bromine or iodine; in one embodiment, it means fluorine or chlorine.

[0262] "Haloalkyl" means an alkyl group as defined above, said alkyl group being substituted by one or one to five halogen atoms (in one embodiment, fluorine or chlorine), including those substituted by different halogens, such as -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , etc. When the alkyl group is substituted only by fluorine, it may be referred to as fluoroalkyl in the present disclosure.

[0263] "Haloalkoxy" means an -OR group, where R is a haloalkyl group as defined above, such as -OCF3 , -OCHF 2 etc. When R is a haloalkyl in which the alkyl group is substituted only by fluorine, it may be referred to as a fluoroalkoxy group in the present disclosure text.

[0264] "Hydroxyalkyl" means a straight-chain or branched-chain monovalent hydrocarbon group of one to six carbon atoms or a monovalent hydrocarbon group of three to six carbon atoms substituted by one or two hydroxy groups, provided that if there are two hydroxy groups, they are not on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl. Additional examples include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0265] "Heterocyclic group" means a saturated or unsaturated monovalent monocyclic or bicyclic group (fused bicyclic or bridged bicyclic or spiro compound) of 4 to 10 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O, and S(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are C. Additionally, one or two ring carbon atoms in the heterocyclic group ring may optionally be replaced by a -CO- group. More specifically, the term heterocyclic group includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-yl, 3-oxa-8-azabicyclo[3.2.1]octan-yl, 6-oxa-1-azaspiro[3.3]heptan-yl, 2-oxa-6-azaspiro[3.3]heptan-yl, etc. When the heterocyclic group ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic.

[0266] "Heterocyclic alkyl" or "heteroalkyl" means a -(alkylene)-R group, where R is a heterocyclic group ring as defined above, such as tetrahydrofuranylmethyl, piperazinylmethyl, morpholinoethyl, etc.

[0267] "Heterocyclic amino" means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein one or two ring atoms are selected from N, O, or S(O) na heteroatom of formula [[ID=]], where n is an integer from 0 to 2, the remaining ring atoms being C, provided that at least one of said ring atoms is N. Additionally, one or two ring carbon atoms in the heterocyclic amino ring may optionally be replaced by a -CO- group. When the heterocyclic amino ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic.

[0268] "Heterocyclic aminoalkyl" means a -(alkylene)-R group, where R is a heterocyclic amino as described above.

[0269] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms, where one or more (in one embodiment, one, two or three) ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.

[0270] As used herein, "mammal" means domesticated animals (such as dogs, cats and horses) and humans. In one embodiment, the mammal is a human.

[0271] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0272] "Oxo" means =(O) group, and "carbonyl" means >C(O) group.

[0273] "Optional" or "optionally" means that the subsequent described event or circumstance may occur but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "heterocyclic group optionally substituted by alkyl" means that the alkyl may be present but is not required to be present, and the description includes both the case where the heterocyclic group is substituted by alkyl and the case where the heterocyclic group is not substituted by alkyl.

[0274] As used herein, the phrases "parenteral administration" ("parenteral administration" and "administered parenterally") mean a mode of administration other than enteral and topical administration, usually by injection, and include but are not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0275] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without producing excessive toxicity, irritation, allergic reaction, or other problems or complications, while having a reasonable benefit / risk ratio that is commensurate.

[0276] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0277] "Treating" or "treatment" of a disease includes:

[0278] (1) Preventing the disease, e.g., causing a clinical symptom of the disease not to occur in a mammal that may have been exposed to or is predisposed to the disease but has not yet experienced or exhibited symptoms of the disease;

[0279] (2) Inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or

[0280] (3) Relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0281] "Therapeutically effective amount" means an amount of a compound of formula (I) (or any embodiment thereof described herein) that is sufficient to treat a disease when administered to a mammal for treating the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0282] The compounds described herein may, in some cases, exist as diastereoisomers, enantiomers or other stereoisomeric forms. All chiral, diastereoisomeric, racemic forms (in their individual forms and mixtures thereof) are within the scope of the present disclosure, unless a specific stereochemistry or isomeric form is specifically indicated. Compounds of the present disclosure containing asymmetrically substituted atoms may be isolated in optically active, optically enriched, optically pure or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be effected by chromatography or by formation of diastereoisomers and separation by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, the disclosure of which is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0283] Certain compounds of formula (I) (or any embodiment thereof described herein) and / or their pharmaceutically acceptable salts may exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as their individual forms and mixtures, are within the scope of the present disclosure. For example, the pyrazole tautomers shown below are equivalent structures. The depiction of one such structure is intended to encompass both structures.

[0284]

[0285] In addition, as used herein, the term alkyl includes all possible isomeric forms of said alkyl, although only a few examples are listed. In addition, when cyclic groups such as heteroaryl, heterocyclic group, etc. are substituted, they include all positional isomers.

[0286] Pharmaceutically acceptable salts of the compounds of formula (I) (or any embodiment thereof described herein) are within the scope of the present disclosure. In addition, the compounds described herein include hydrates and solvates of the compounds or their pharmaceutically acceptable salts.

[0287] The present disclosure also includes prodrugs of the compounds of formula (I) (or any embodiment thereof described herein) and / or their pharmaceutically acceptable salts. The term prodrug is intended to represent a covalently attached carrier that, when administered to a mammalian subject, is capable of releasing the active ingredient of formula (I) (or any embodiment thereof described herein). Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques generally modify appropriate functional groups in a given compound. However, these modified functional groups are regenerated in vivo or by conventional manipulation to the original functional groups. Prodrugs of the compounds of formula (I) (or any embodiment thereof described herein) include compounds in which a hydroxyl group, an amino group, a carboxyl group, or a similar group is modified. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl), amides (e.g., trifluoroacetamido, acetamido, etc.) of the hydroxyl or amino functional groups in the compounds of formula (I). Prodrugs of the compounds of formula (I) (or any embodiment thereof described herein) and / or their pharmaceutically acceptable salts are also within the scope of the present disclosure.

[0288] The present disclosure also includes polymorphic forms (amorphous as well as crystalline) and deuterated forms of the compounds of formula (I) (or any embodiment thereof described herein) and / or their pharmaceutically acceptable salts.

[0289] In some embodiments, the compounds disclosed herein are used in different enriched isotope forms, e.g., enriched in 2 H, 3 H, 11 C, 13 C and / or 14 C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0290] Unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention except for the replacement of hydrogen with deuterium or tritium or the replacement of carbon with 13 C or 14 C-enriched carbon are within the scope of the present disclosure.

[0291] The compounds of the present disclosure optionally contain non-natural proportions of atomic isotopes at one or more atoms that make up such compounds. For example, the compounds can be labeled with isotopes (e.g., like deuterium (2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C)). Labeled with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 isotope substitutions of I are all considered. All isotope variants of the compounds of the present invention, whether radioactive or not, are covered within the scope of the present invention.

[0292] In certain embodiments, the compounds disclosed herein have some or all of the 2 H atoms replaced by 1 H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0293] Deuterium-substituted compounds are synthesized using various methods described in the following references: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, page 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0294] Deuterated starting materials are readily available and subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0295] In one aspect is a compound of formula (I):

[0296]

[0297] Wherein:

[0298] X is N or CH, Y is N or CR a , provided that when X is N, then Y is CR a , when Y is N, then X is CH;

[0299] R a and R 1 One of is H, and the other is phenyl or heteroaryl, each optionally substituted by one, two or three R d substituents;

[0300] Wherein each R d substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -O-C 1-4 alkyl, halo, cyano, nitro, azido, halo-C 1-4 alkyl, -O-C1-4 -haloalkyl, -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、=NOR g 、-NR g S(=O) 1-2 R h 、-NR g S(=O) 1-2 NR g R h 、=NSO 2 R g 、-C(=O)R g 、-C(=O)OR g 、-OC(=O)OR g 、-OC(=O)R g 、-C(=O)NR g R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-S(=O)R g 、-S(=O) 2 R g 、-OS(=O) 1-2 R g 、-S(=O) 1-2 OR g 、-S(=O) 1-2 NR g R h 、phenyl, -C 1-4 alkyl-phenyl, monocyclic cycloalkyl, -C 1-4 alkyl-cycloalkyl, monocyclic heteroalkyl, or monocyclic heteroaryl;

[0301] wherein each phenyl, monocyclic cycloalkyl, monocyclic heteroalkyl, or monocyclic heteroaryl of R d is optionally substituted by one, two or three substituents R e ;

[0302] wherein each R e substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, halo, cyano, nitro, azido, -OH, halo-C1-4 alkyl, -O-C 1-4 alkyl, or -O-C 1-4 -haloalkyl;

[0303] R g and R h are each independently H or C 1-4 alkyl;

[0304] or R g and R h together with the atom to which they are attached form a monocyclic cycloalkyl or heterocycloalkyl, optionally substituted by C 1-4 alkyl;

[0305] wherein each of R 2 and R 3 is H or C 1-4 alkyl, cycloalkyl, C 1-4 alkylcycloalkyl, heterocyclic group, heterocycloalkyl, or R 2 and R 3 together with the nitrogen to which they are attached form a monocyclic heterocyclic group, optionally substituted by one, two or three R j substituents;

[0306] wherein each R j substituent is independently C 1-4 alkyl, oxo group, -OH, -NR k R l 、halo group, halo-C 1-4 alkyl, -O-C 1-4 alkyl, or -O-C 1-4 -haloalkyl;

[0307] wherein each of R k and R l are each independently H or C 1-4 alkyl;

[0308] R 4 is -C(O)NR x R y ,or is phenyl or heteroaryl, each optionally substituted by one, two or three R z substituents;

[0309] wherein R x is H or C 1-4 alkyl and R y is H, C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -Rr , a monocyclic cycloalkyl group, -C 1-4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclic group, -O-monocyclic heterocyclic group, or monocyclic heteroalkyl group, each optionally substituted by one, two or three R o substituents;

[0310] Or R x and R y together with the nitrogen to which they are attached form a heterocyclic group or monocyclic heteroalkyl group, optionally substituted by C 1-4 alkyl;

[0311] wherein each R r is C 1-4 alkyl or -NR p R q ; and

[0312] each R z substituent is independently C 1-4 alkyl, halogen, -OH, or -OC 1-4 alkyl, C 1-4 alkylNR m R n , C(O)NHC 1-4 alkyl-NR m R n , or -NR m R n ;

[0313] wherein R m and R n are each independently H, C 1-4 alkyl, or C 1-4 alkylNR p R q , or R m and R n together with the nitrogen to which they are attached form a heterocyclic group or monocyclic heteroalkyl group, optionally substituted by one or two R o substituents;

[0314] wherein each R o substituent is independently C 1-4 alkyl, -OH, -OC 1-4 alkyl, halogen, cyano, or -NR p R q ;

[0315] wherein R p and R q are each independently H or C 1-4 alkyl, or R p and R q together with the nitrogen to which they are attached form a heterocyclic group; and

[0316] R 5 is H, C 1-4 alkyl, halo, -OH, or -OC 1-4 alkyl;

[0317] or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, X is CH and Y is N. In some embodiments, X is N and Y is CR a . In some embodiments, R a is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R a is H or methyl. In some embodiments, R a is H.

[0319] In some embodiments, R a or R 1 is an optionally substituted phenyl. In some embodiments, R a or R 1 is tolyl. In some embodiments, R a or R 1 is m-tolyl. In some embodiments, R a or R 1 is an optionally substituted monocyclic heteroaryl. In some embodiments, R a or R 1 is an optionally substituted pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, or pyridazine. In some embodiments, R a or R 1 is an optionally substituted pyridine or pyrimidine. In some embodiments, R a or R 1 is an optionally substituted pyridine. In some embodiments, R a or R 1 is methylpyridine. In some embodiments, R a or R 1 is optionally substituted with one or two R d substituents.

[0320] In some embodiments, each R d substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -O-C 1-4 alkyl, halo, cyano, nitro, azido, halo-C 1-4 alkyl, -O-C 1-4-haloalkyl, -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、=NOR g 、-NR g S(=O) 1-2 R h 、-NR g S(=O) 1-2 NR g R h 、=NSO 2 R g 、-C(=O)R g 、-C(=O)OR g 、-OC(=O)OR g 、-OC(=O)R g 、-C(=O)NR g R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-S(=O)R g 、-S(=O) 2 R g 、-OS(=O) 1-2 R g 、-S(=O) 1-2 OR g 、-S(=O) 1-2 NR g R h 、phenyl, -C 1-4 alkyl-phenyl, monocyclic cycloalkyl, -C 1-4 alkyl-cycloalkyl, monocyclic heteroalkyl, or monocyclic heteroaryl, wherein R d of phenyl, monocyclic cycloalkyl, monocyclic heteroalkyl and monocyclic heteroaryl are each optionally substituted by one or two substituents R e In some embodiments, each R d substituent is independently C 1-4 alkyl, halo-C 1-4 alkyl, phenyl, -C 1-4 alkyl-phenyl, pyridyl, phenylthio, cycloalkyl, or -C 1-4 alkyl-cycloalkyl, wherein phenyl, pyridyl and phenylthio are each optionally substituted by one or two substituents R eSubstituted. In some embodiments, each R d substituent is independently methyl, ethyl, isopropyl, -CF 3 , -OCH 3 , -OCF 3 , phenyl, pyridyl, phenylthio, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, wherein the phenyl, cycloalkyl, and heteroaryl of R d are each optionally substituted with one or two substituents R e . In some embodiments, each R d is independently selected from C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 . In some embodiments, R a or R 1 is substituted with one R d and R d is C 1-4 alkyl. In some embodiments, R a or R 1 is substituted with one R d , and R d is methyl. In some embodiments, R a or R 1 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 . In some embodiments, R a or R 1 is unsubstituted phenyl or tolyl. In some embodiments, R a or R 1 is unsubstituted phenyl or m-tolyl. In some embodiments, R a or R 1 is unsubstituted pyridyl. In some embodiments, R a or R 1 is 4-pyridyl.

[0321] In some embodiments, each R e substituent is independently C 1-4 alkyl, halo, halo-C 1-4 alkyl, -O-C 1-4 alkyl, or -O-C 1-4 -haloalkyl. In some embodiments, each R e substituent is independently methyl, -CF3 , fluorine, chlorine, -OCH 3 , or -OCF 3 . In some embodiments, each R d substituent is independently methyl, ethyl, isopropyl, -CF 3 , phenyl, pyridyl, phenylthio, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, wherein each R e is independently methyl, -CF 3 , fluorine, chlorine, -OCH 3 or -OCF 3 .

[0322] In some embodiments, R g and R h are each independently H or methyl.

[0323] In some embodiments, R 2 and R 3 together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide, each optionally substituted with one, two, or three R j substituents. In some embodiments, R 2 and R 3 together with the nitrogen to which they are attached form morpholine, optionally substituted with one or two R j substituents.

[0324] In some embodiments, each R j substituent is independently methyl, hydroxy, -OCH 3 , halo, -CF 3 , or -OCF 3 .

[0325] In some embodiments, R k and R l are each independently H or methyl.

[0326] In some embodiments, R 4 is an optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted heteroaryl. In some embodiments, R 4 is an optionally substituted monocyclic heteroaryl. In some embodiments, R 4 is an optionally substituted pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, or pyridazine. In some embodiments, R 4 is an optionally substituted pyrazole, pyridine, or pyrimidine. In some embodiments, R 4is an optionally substituted pyridine. In some embodiments, R 4 is pyridine. In some embodiments, R 4 is 4-pyridyl. In some embodiments, R 4 is optionally substituted with one or two R z substituents. In some embodiments, R 4 is phenyl or pyridyl, each optionally substituted with one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 .

[0327] In some embodiments, R 4 is -C(O)NR x R y . In some embodiments, R x is H. In some embodiments, R x is methyl or ethyl, optionally substituted with one, two or three R o substituents. In some embodiments, R x is methyl. In some embodiments, R y is H. In some embodiments, R y is C 1-4 alkyl, -C 1-4 alkyl (monocyclic cycloalkyl), monocyclic cycloalkyl, monocyclic heterocycloalkyl, monocyclic heterocyclic group, -O-monocyclic heterocyclic group, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, optionally substituted with one, two or three R o substituents. In some embodiments, R y is C 1-4 alkyl, optionally substituted with one, two or three R o substituents. In some embodiments, R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two or three R o substituents. In some embodiments, R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropyl, (dimethylamino)ethyl, or (dimethylamino)butyl. In some embodiments, R y is methoxy. In some embodiments, R y is -SO 2 -methyl.

[0328] In some embodiments, R y is monocyclic cycloalkyl or -C1-2 Alkyl(monocyclic cycloalkyl), each optionally substituted by one, two or three R o substituents. In some embodiments, R y is monocyclic cycloalkyl, optionally substituted by one, two or three R o substituents. In some embodiments, R y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted by one, two or three R o substituents. In some embodiments, R y is cyclopropyl. In some embodiments, R y is cyclopentyl. In some embodiments, R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl. In some embodiments, R y is monocyclic heterocyclic group or -O-monocyclic heterocyclic group, optionally substituted by one, two or three R o substituents. In some embodiments, R y is optionally substituted tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy.

[0329] In some embodiments, R y is oxetanyl, or oxetanyloxy. In some embodiments, R y is monocyclic heterocycloalkyl, optionally substituted by one, two or three R o substituents. In some embodiments, wherein R y is optionally substituted oxetanylmethyl, or (3-(hydroxymethyl)oxetan-3-yl)methyl. In some embodiments, R x is methyl, and R y is methyl, ethyl, cyclopropyl, methoxy, or cyclopentyl.

[0330] In some embodiments, R x and R y together with the nitrogen to which they are attached form monocyclic heterocycloalkyl, optionally substituted by C 1-4 alkyl. In some embodiments, R x and R y together with the nitrogen to which they are attached form monocyclic heterocyclic group, optionally substituted by C 1-4 alkyl. In some embodiments, R x and R yTogether with the nitrogen to which they are attached, form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.

[0331] In some embodiments, each R z is independently C 1-4 alkyl, halo, -OH, -OC 1-4 alkyl, C 1-4 alkylNR m R n 或 -NR m R n , where each alkyl is optionally substituted with -NR m R n In some embodiments, each R z is independently methyl, -OH, halo, or -OCH 3 . In some embodiments, R z is C m alkyl substituted with -NR n R 2-3 .

[0332] In some embodiments, R m and R n are each independently H or C 1-4 alkyl. In some embodiments, R m and R n are each methyl. In some embodiments, R m and R n , together with the nitrogen to which they are attached, form a monocyclic heteroalkyl, optionally substituted with one or two R o substituents. In some embodiments, R m and R n , together with the nitrogen to which they are attached, form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide, each optionally substituted with one or two R o substituents. In some embodiments, R m and R n , together with the nitrogen to which they are attached, form pyrrolidine, piperidine, piperazine, or morpholine, each optionally substituted with one or two R o substituents.

[0333] In some embodiments, each R o substituent is C 1-4 alkyl. In some embodiments, each R o substituent is methyl. In some embodiments, each Ro The substituent is -OH. In some embodiments, each R o The substituent is -NR p R q . In some embodiments, R p and R q are each independently H or methyl.

[0334] In some embodiments, R p and R q together with the nitrogen to which they are attached form a heterocyclic group. In some embodiments, R p and R q together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0335] In some embodiments, R 5 is H, methyl, ethyl, chlorine, bromine, fluorine, -OH, or -OCH 3 . In some embodiments, R 5 is H.

[0336] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

[0337]

[0338] wherein

[0339] R 1a is phenyl or pyridinyl, each optionally substituted with one or two substituents selected from: C 1-4 alkyl, CO 2 R p , -C(O)NR p R q , fluorine, chlorine, bromine, NH 2 and -OCH 3 ; and

[0340] R 4a is -C(O)NR x R y , or is phenyl or pyridinyl, each optionally substituted with one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 ;

[0341] wherein R x is H or C1-4 alkyl, and R y is H, C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -R r , monocyclic cycloalkyl, -C 1-4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclic group, -O-monocyclic heterocyclic group, or monocyclic heterocycloalkyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -OH, -OC 1-4 alkyl, halo, or cyano or -NR p R q ;

[0342] wherein each R r is C 1-4 alkyl or -NR p R q ;

[0343] wherein R p and R q are each independently H or C 1-4 alkyl

[0344] or R x and R y together with the nitrogen to which they are attached form a monocyclic heterocyclic group, optionally substituted by C 1-4 alkyl;

[0345] or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, R 1a is phenyl or pyridyl, each optionally substituted by methyl or -CF 3 . In some embodiments, R 1a is phenyl or m-tolyl. In some embodiments, R 1a is pyridyl. In some embodiments, R 1a is 4-pyridyl. In some embodiments, R 4a is phenyl or pyridyl, each optionally substituted by methyl or -CF 3 . In some embodiments, R 4a is phenyl or m-tolyl. In some embodiments, R 4a is pyridyl. In some embodiments, R 4a is 4-pyridyl.

[0347] In some embodiments, in the compounds of formula (I):

[0348]

[0349] wherein R 1 、R 2 、R 3 、R 4 、R 5 、X and Y are as defined herein, or

[0350] in the compound of formula (II):

[0351]

[0352] wherein R 1a and R 4a are as defined herein; and

[0353] one or more hydrogen atoms attached to the carbon atoms of the said compound are replaced by deuterium atoms.

[0354] In some embodiments, one or more hydrogen atoms attached to the carbon atoms of R 1 、R 2 、R 3 、R 4 、R 5 、R 1a or R 4a are replaced by deuterium atoms.

[0355] In some embodiments, one or more hydrogen atoms attached to the carbon atoms of R d 、R e R g 、R h 、R j 、R k 、R l 、R m 、R n 、R o 、R p 、R q 、R r 、R x 、R y 、or R z are replaced by deuterium atoms. In some embodiments, one or more R d 、R e R g 、R h 、R j 、R k 、R l 、R m 、R n 、R o 、R p 、R q 、Rr , R x , R y , or R z The group is a C 1-4 alkyl group in which one or more hydrogen atoms attached to a carbon atom are replaced by deuterium atoms. In some embodiments, one or more R d , R e R g , R h , R j , R k , R l , R m , R n , R o , R p , R q , R r , R x , R y , or R z The group is a methyl group in which one or more hydrogen atoms attached to a carbon atom are replaced by deuterium atoms. In some embodiments, one or more R d , R e R g , R h , R j , R k , R l , R m , R n , R o , R p , R q , R r , R x , R y , or R z The group is -CD 3 .

[0356] In some embodiments, the compound of formula (I) or formula (II) contains -D replacing at least one -H, or -D 3 substituting at least one CH 3 substituent.

[0357] For example, in 4-[2-(1-methylpyrazol-3-yl)-5-[3-[3-(trideuteriomethyl)phenyl]pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine (Compound 123), the methyl group on the benzene ring of the "(m-tolyl)pyrazol-1-yl" group in 4-[2-(1-methylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine (Compound 61) is replaced by a -CD 3 group.

[0358] is a compound selected from the following in some embodiments:

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376] and its pharmaceutically acceptable salts.

[0377] Treatment methods, administrations and pharmaceutical compositions

[0378] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount by any accepted mode of administration for agents having similar utilities. The therapeutically effective amount of the compounds of formula (I) can range from about 0.01 to about 500 mg / kg of patient body weight per day, and said therapeutically effective amount can be administered as a single dose or multiple doses. In one embodiment, the dose level will be about 0.1 to about 250 mg / kg per day. In another embodiment, the dose level will be about 0.5 to about 100 mg / kg per day. Suitable dose levels can be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range, the dose can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the composition can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient (specifically about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient). The actual amount of the compound of the present disclosure (i.e., the active ingredient) will depend on various factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being used, the route and form of administration, and other factors.

[0379] Generally, the compounds of the present disclosure are administered as a pharmaceutical composition by any of the following routes: oral administration, systemic (e.g., transdermal, intranasal, or by suppository) administration, or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred mode of administration is oral using a convenient daily dosage regimen (which can be adjusted according to the degree of affliction). The composition can take the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0380] The pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers (including excipients and adjuvants). The formulation can be modified according to the chosen route of administration. The pharmaceutical composition can also include the compounds described herein in free base form or in pharmaceutically acceptable salt form.

[0381] Methods for formulating pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid or liquid compositions. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain non-toxic auxiliary substances such as wetting agents or emulsifying agents, pH buffering agents and other pharmaceutically acceptable additives. Alternatively, the compositions described herein can be lyophilized or in powder form for reconstitution prior to use with a suitable vehicle (e.g., sterile pyrogen-free water). The active ingredient can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in coarse emulsions.

[0382] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0383] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of injectable formulations can include sterile suspensions, solutions or emulsions in an oily or aqueous vehicle. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. The injection can be formulated for bolus injection or continuous infusion.

[0384] For parenteral administration, the compound can be formulated with a pharmaceutically acceptable parenteral vehicle into a unit dose injectable form (e.g., solution, suspension, emulsion). Such vehicles can be inherently non-toxic and non-therapeutic. The vehicle can be water, saline, Ringer's solution, dextrose solution and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffering agents and preservatives).

[0385] Sustained release formulations can also be prepared. Examples of sustained release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), poly(lactide), copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPO TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)) and poly-D-(-)-3-hydroxybutyric acid.

[0386] The pharmaceutical formulation of the compositions described herein can be prepared for storage by mixing the compound with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The formulation can be a lyophilized formulation or an aqueous solution. The acceptable carrier, excipient, and / or stabilizer can be non-toxic to the recipient at the dosages and concentrations employed. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; polypeptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycols.

[0387] The compounds of the present disclosure can be used in a method of treatment in combination with one or more other combination agents (e.g., one, two, or three other drugs) for preventing, treating, controlling, ameliorating a disease or disorder for which the compounds of the present disclosure are useful or reducing the risk of said disease or disorder. In some embodiments, combining the drugs together is safer or more effective than either drug alone. In some embodiments, the compounds disclosed herein and one or more combination agents have complementary activities that do not adversely affect one another. Such molecules can be present in combination in amounts effective for the intended purpose. Accordingly, one or more such other drugs can be administered concomitantly or sequentially with the compounds of the present disclosure by the routes and in the amounts commonly used. When the compounds of the present disclosure are used in combination with one or more other drugs, in some embodiments, the agents are administered together in a single pharmaceutical composition in unit dosage form. Accordingly, the pharmaceutical compositions of the present disclosure also include those pharmaceutical compositions that contain one or more other active ingredients in addition to the compounds of the present disclosure. The weight ratio of the compounds of the present disclosure to the second active agent can vary and will depend on the effective doses of each ingredient. Generally, the effective doses of each will be used. In some embodiments, the combination therapy includes therapies in which the compounds of the present disclosure and one or more other drugs are administered separately, and in some cases, two or more agents are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients can be used at lower doses than when used alone. In some embodiments, the combination agent is a drug for alleviating the symptoms of ALS. In some embodiments, the combination agent is selected from NAD supplements (such as nicotinamide riboside, sold under the trade name or Tru offer), vitamin B 12(Oral or injection), glycopyrrolate, atropine, scopolamine, baclofen, tizanidine, mexiletine, SSRI, benzodiazepine, Neudexta, riluzole, and edaravone, and combinations thereof.

[0388] The compounds, pharmaceutical compositions, and methods of the present disclosure can be used to treat subjects such as, but not limited to, mammals, humans, non-human mammals, domesticated animals (e.g., laboratory animals, household pets, or livestock), non-domesticated animals (e.g., wild animals), dogs, cats, rodents, mice, hamsters, cows, birds, chickens, fish, pigs, horses, goats, sheep, or rabbits. In a preferred embodiment, the compounds, pharmaceutical compositions, and methods of the present disclosure are used to treat humans.

[0389] The compounds, pharmaceutical compositions, and methods described herein can be used as therapeutic agents, e.g., for the treatment of a subject in need thereof. A therapeutic effect can be obtained in a subject by alleviating, suppressing, mitigating, or eradicating a disease state, including but not limited to its symptoms. A therapeutic effect in a subject suffering from a disease or disorder or pre-disposed to suffer from or in the process of developing the disease or disorder can be obtained by alleviating, suppressing, preventing, mitigating, or eradicating the disorder or disease, or pre-disorder or pre-disease state.

[0390] In practicing the methods described herein, a therapeutically effective amount of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, typically for the treatment and / or prevention of a disorder or its progression. The pharmaceutical composition can affect the physiological functions of the subject, such as the immune system, inflammatory response, or other physiological actions. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.

[0391] Treatment (treat and / or treating) can refer to any indication of successful treatment or improvement of a disease or disorder. Treatment can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or disorder, or it can include reducing the frequency of symptoms of a disease, defect, disorder, or adverse condition, etc., experienced by a patient. Treatment can be used herein to refer to a method that results in a certain level of treatment or improvement of a disease or disorder, and a range of outcomes for that purpose can be considered, including but not limited to complete prevention of the disorder.

[0392] Prevention (prevent, preventing, etc.) can refer to preventing a disease or disorder in a patient. For example, if an individual at risk of developing a disease is treated with the methods of the present disclosure and does not develop the disease thereafter, the individual has at least for a period of time prevented the disease.

[0393] A therapeutically effective amount can be an amount of a compound or pharmaceutical composition or an active component thereof that is sufficient to provide a beneficial effect or otherwise reduce a non-beneficial event that is harmful to an individual to whom the composition is administered. A therapeutically effective dose can be a dose that results in one or more desired or wanted (e.g., beneficial) effects due to the administration of that dose, such administration occurring one or more times within a given time period. The exact dose can depend on the therapeutic purpose and can be determined by those skilled in the art using known techniques.

[0394] Taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administration, and other factors known to the practitioner, the compounds or pharmaceutical compositions described herein that are useful in therapy can be formulated and the dosage established in a manner consistent with good medical practice. The compounds or pharmaceutical compositions can be prepared according to the preparation descriptions set forth herein.

[0395] Those of ordinary skill in the art will understand that the amount, duration, and frequency of administration of the pharmaceutical compositions or compounds described herein to a subject in need thereof depend on several factors, including, for example, but not limited to, the health status of the subject, the specific disease or disorder of the patient, the grade or level of the patient's specific disease or disorder, additional therapeutic agents that the subject is receiving or has received, and the like.

[0396] The methods, compounds, and pharmaceutical compositions described herein can be used for administration to a subject in need thereof. Generally, administration of the compound or pharmaceutical composition can include an administration route, non-limiting examples of which include intravenous, intra-arterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneal. Additionally, the pharmaceutical composition or compound can be administered to the subject by an alternative administration route, such as by inhalation, oral, dermal, intranasal, or intrathecal administration.

[0397] The pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration and one or more additional administrations. One or more additional administrations can be given to a subject in need thereof minutes, hours, days, weeks, or months after the first administration. Any one of the additional administrations can be given to a subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days, or less than 1 day after the first administration. One or more administrations can occur more than once / day, more than once / week, or more than once / month. The compound or pharmaceutical composition can be administered daily to a subject in need thereof in a cycle of 21 days, 14 days, 10 days, 7 days, 4 days, or over a time period of one to seven days.

[0398] The compounds, pharmaceutical compositions, and methods provided herein can be used to treat a variety of diseases or disorders or to prevent diseases or disorders in a subject, or for other therapeutic applications in a subject in need thereof. In one aspect, the present disclosure relates to a method for treating a neurological disease mediated by PIKfyve activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, the disease is associated with FIG4 deficiency.

[0399] In some embodiments, the neurological disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (CMT; including type 4J (CMT4J)) and Eunice Kennedy Shriver-NCL, autophagy, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, Lewy body dementia, Lewy body disease, frontotemporal dementia, neuronal intranuclear inclusions and intranuclear inclusion diseases of polyglutamine, Marinesco-Sjögren syndrome, tauopathies, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, motor neuropathy, sensory neuropathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (TBI), cerebral ischemia, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, lysosomal storage diseases, Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV, neuropathy, Huntington's disease, mental disorders, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0400] In some embodiments, the neurological disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT. In some embodiments, the neurological disease is ALS.

[0401] In some embodiments, the neurological disease is a tauopathy, such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.

[0402] In some embodiments, the neurological disease is a lysosomal storage disease, such as Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, or mucolipidosis type IV.

[0403] In some embodiments, the neurological disease is a mental disorder, such as ADHD, schizophrenia; or a mood disorder, such as major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0404] The present disclosure further provides any compound disclosed herein for use in a method of treating a human or animal body by therapy. The therapy can be effected by any mechanism disclosed herein (such as inhibiting a disease disclosed herein, reducing said disease or reducing the progression of said disease). The present disclosure further provides any compound disclosed herein for preventing or treating any disorder disclosed herein. The present disclosure also provides any compound or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any disorder disclosed herein. The present disclosure also provides the use of any compound disclosed herein in the manufacture of a medicament for preventing or treating any disease or disorder disclosed herein.

[0405] Examples

[0406] The preparation of the compounds and intermediates of formula (I) is given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be regarded as limiting the scope of the present disclosure, but merely illustrative and representative.

[0407] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or can be prepared by methods known to those skilled in the art according to procedures shown in the literature such as: Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes illustrate only some of the ways in which the compounds of the present disclosure can be synthesized, and various modifications can be made to these schemes and will be suggested to those skilled in the art referring to the present disclosure. If desired, conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, etc. can be used to separate and purify the starting materials and intermediates of the reaction and the final products. Such materials can be characterized using conventional means (including physical constants and spectral data).

[0408] Unless otherwise specified, the reactions described herein occur at atmospheric pressure at a temperature in the range from about -78 °C to about 150 °C, or from about 0 °C to about 125 °C, or at about room (or ambient) temperature (e.g., about 20 °C).

[0409] The compounds and species of formula (I) and sub-formulas described herein, including those in which the substituents are as defined herein, can be prepared as shown and described below.

[0410] Unless otherwise specified, all reagents are used without further purification. 1H NMR spectra are obtained on a Bruker 300 MHz instrument at room temperature in CDCl 3 3, DMSO-d 6 6, or CD 3 3OD. When more than one conformational isomer is detected, the chemical shifts of the most abundant conformational isomer are reported. 1 ​1 The chemical shifts in the \(^1H\) NMR spectra were recorded in parts per million (ppm) on the \(\delta\) scale relative to an internal standard from the residual solvent. The splitting patterns were designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. The LC-MS conditions are described as follows:

[0411] LCMS column: Agilent Zorbax XDB C18 4.6×50 mm, 3.5 μm

[0412] a. Mobile phase, solvent A: water (containing 0.1% formic acid); solvent B: MeOH

[0413] b. Flow rate: 1.0 mL / minute

[0414] c. Run time: 2-minute gradient (20% - 90% B), then 3 minutes at 90% B,

[0415] d. Temperature: 30 °C

[0416] HPLC column: Agilent SB-C18 4.6×150 mm, 3.5 μm

[0417] a. Mobile phase, solvent A: water (containing 0.02% TFA); solvent B: MeOH

[0418] b. Flow rate: 1.0 mL / minute

[0419] c. Run time: 0.5 minute at 10% B, 9.5-minute gradient (10% - 90% B), then 10 minutes at 90% B,

[0420] d. Temperature: 30 °C

[0421] Preparative LC column: Phenomenex Luna 5u 100A, 21.2×250 mm, 5 μm

[0422] a. Mobile phase, solvent A: water; solvent B: MeOH

[0423] b. Flow rate: 10 mL / minute

[0424] c. Run time: 1 minute at 20% B, 30-minute gradient (20% - 80% B), then 10 minutes at 90% B

[0425] d. Temperature: ambient temperature

[0426] The following abbreviations were used in the text: PE = petroleum ether, EA or EtOAc = ethyl acetate, DMSO = dimethyl sulfoxide, DMF = N,N-dimethylacetamide, MeOH = methanol, EtOH = ethanol, Et2 O = diethyl ether, EDCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, MTBE = methyl tert-butyl ether, DCM = dichloromethane, TEA = triethylamine, DIPEA = diisopropylethylamine, TFA = trifluoroacetic acid, TLC = thin layer chromatography, (BPin)2 = bis(pinacolato)diboron, HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol, DIBAL-H = diisobutylaluminum hydride, MeI = methyl iodide, hex = hexane, n-Hex = n-hexane, DCE = 1,2-dichloroethane, TBSCl = tert-butyldimethylsilyl chloride, Tf 2 O = trifluoromethanesulfonic anhydride, n-BuLi = n-butyllithium, DMAP = 4-dimethylaminopyridine, KOAc = potassium acetate, NaOAc = sodium acetate, TFAA = trifluoroacetic anhydride, m-CPBA = meta-chloroperoxybenzoic acid, DME = 1,2-dimethoxyethane, PS-TPP = polymer-supported triphenylphosphine, MSA = methanesulfonic acid, SEMCl = 2-(trimethylsilyl)ethoxymethyl chloride, dba = dibenzylideneacetone, dppf = 1,1'-bis(diphenylphosphino)ferrocene, Pd / C = palladium on carbon, rt = room temperature, h = hour, hrs = hours.

[0427] Intermediate A: 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0428]

[0429] Preparation of A.2: To a solution of A.1 (200.0 g, 1.46 mol, 172.4 mL, 1.0 equivalent) in toluene (1800 mL) at 25 °C was added NaH (116.6 g, 2.92 mol, 60% purity, 2.0 equivalents). The mixture was heated to 90 °C, and then MeCN (280.1 g, 6.83 mol, 359.2 mL, 4.68 equivalents) was added dropwise. This mixture was stirred at 90 °C for 8 h, and then TLC (petroleum ether / ethyl acetate = 5 / 1) indicated that most of the starting material had been consumed. The reaction mixture was filtered to obtain a yellow solid, and then the yellow solid cake was partitioned between water (1000 mL) and DCM (800 mL). The pH of the mixture was adjusted to pH = 5 - 6 with 1 M HCl solution, and then the organic layer was separated and the aqueous phase was extracted with DCM (3 x 600 mL). The combined organic layers were concentrated to give A.2 (160.0 g, crude) as a yellow solid.

[0430] Preparation of A.3: To a solution of A.2 (150.0 g, 1.03 mol, 1.0 equivalent) in EtOH (800 mL) was added NH2 NH 2 -H 2 O (78.6 g, 1.54 mol, 76.3 mL, 98% purity, 1.5 eq). The mixture was stirred at 90 °C. After 2 h, TLC (dichloromethane / methanol = 10 / 1, R f = 0.3) showed that most of the starting material had been consumed. The reaction mixture was concentrated to give a crude product, and this product was then crystallized from ethanol (200 mL) to give a yellow solid. After isolating the yellow solid, it was maintained under reduced pressure to remove the last traces of solvent. Purified A.3 was obtained as a yellow solid (85.0 g, 530.6 mmol, 51.7% yield).

[0431] Preparation of A.4: At 25 °C, sodium ethoxide (84.9 g, 1.25 mol, 2.5 eq) was added to a solution of A.3 (80.0 g, 499.4 mmol, 1.0 eq) and diethyl malonate (80.0 g, 499.4 mmol, 75.4 mL, 1.0 eq) in EtOH (480 mL). The mixture was stirred at 90 °C for 8 h, and then TLC (dichloromethane / methanol = 10 / 1, R f = 0.3) determination showed that the starting material had been consumed. This mixture was filtered to give A.4 as a yellow solid (80.0 g, crude); LC-MS (ESI+): m / z 229 (MH + +).

[0432] Preparation of A.5: At 25 °C, N,N-dimethylaniline (13.8 g, 113.9 mmol, 14.4 mL, 1.3 eq) was added to a solution of A.4 (20.0 g, 87.6 mmol, 1.0 eq) in POCl 3 (322.5 g, 2.10 mol, 195.4 mL, 24.0 eq). This mixture was heated at 110 °C with stirring. TLC (dichloromethane / methanol = 10 / 1, R f = 0.8) showed that the starting material had been consumed after 12 h. The mixture was concentrated in vacuo to give a yellow solid. This solid was poured into ice water (200 mL) and filtered to give A.5 as a yellow solid (14.0 g); LC-MS (ESI+): m / z 265 / 267 (MH + +). 1 1H NMR (300 MHz, DMSO-d 6 ) δ: 8.74 (d, J = 5.4 Hz, 2H), 8.03 (d, J = 5.7 Hz, 2H), 7.77 (s, 1H) and 7.62 (s, 1H) ppm.

[0433] Intermediate A: At 25 °C, morpholine (1.31 g, 15.0 mmol, 1.33 mL, 2.0 equiv) was added to a solution of A.5 (2.0 g, 7.54 mmol, 1.0 equiv) in Et 3 N (1.53 g, 15.0 mmol, 2.10 mL, 2.0 equiv) and 1,4-dioxane (12 mL). The mixture was stirred at 25 °C; after 3 h, TLC (petroleum ether / ethyl acetate = 1 / 1, R f = 0.5) showed consumption of the starting material. The reaction mixture was filtered to isolate the solid product, which was then purified by recrystallization from MeOH (30 mL) to give Intermediate A, 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (1.80 g, 5.70 mmol, 75.5% yield) as a yellow solid; LC-MS (ESI+): m / z 316 / 318 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ: 8.70 (d, J = 3.9 Hz, 2H), 7.99 (d, J = 4.8 Hz, 2H), 7.25 (s, 1H), 6.53 (s, 1H) and 3.92 - 3.85 (m, 8H) ppm.

[0434] Intermediate B: 5-Amino-N,N-dimethyl-3-(4-methylphenyl)-1H-pyrazole-1-sulfonamide

[0435]

[0436] At 0 °C, NaH (94 mg, 2.35 mmol) was added to a solution of 3-(4-methylphenyl)-1H-pyrazol-5-amine (250 mg, 1.57 mmol) in THF (5 mL). After stirring at 0 °C for 1 h, dimethylamine sulfonyl chloride (270 mg, 1.88 mmol) was added to the solution. The reaction was monitored by TLC. When complete, the reaction mixture was quenched with saturated NH 4 Cl solution. The aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 20% EtOAc / PE to 33% EtOAc / PE to afford 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (Intermediate B, 212 mg, 0.79 mmol); LC-MS: m / z 281 (MH + ). 1HNMR(300MHz, DMSO-d 6 ) δ: 7.67 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 5.7 (s, 1H), 4.82 (s, 2H), 3.02 (s, 6H) and 2.37 (s, 3H) ppm.

[0437] Example 1: 7-Morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine hydrochloride

[0438] Step 1: Preparation of 3-(4-Fluorophenyl)-N,N-dimethyl-5-((7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazole-1-sulfonamide

[0439]

[0440] A solution of 4-(5-Chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Intermediate A, 60 mg, 0.19 mmol), 5-Amino-3-(4-fluorophenyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide (Intermediate B, 76 mg, 0.28 mmol), Cs 2 CO 3 (142 mg, 0.44 mmol), Pd(OAc) 2 (4.2 mg, 0.019 mmol) and Xantphos (10.2 mg, 0.019 mmol) in DMF / 1,4-dioxane (7:1, 5 mL) was heated to 90 °C for 30 min under microwave conditions. The reaction mixture was concentrated directly, and the resulting residue was purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford (50 mg, 0.09 mmol) of impure 3-(4-Fluorophenyl)-N,N-dimethyl-5-((7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1H-pyrazole-1-sulfonamide as a yellow solid; LC-MS (ESI + ): m / z 560 (MH + ).

[0441] Step 2: Preparation of 7-Morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine hydrochloride

[0442]

[0443] To a solution of N,N-dimethyl-5-((7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-3-phenyl-1H-pyrazole-1-sulfonamide (50 mg, 0.09 mmol) in DCM was added HCl / Et 2 O (1 mL). The reaction was stirred at ambient temperature for 2 h. A large amount of solid precipitated. After concentration, the residue was triturated in MeOH / Et 2 O (1 / 20, 2 mL); 7-morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine hydrochloride (Example 1, 18.6 mg, 0.04 mmol) was obtained as a white solid; LC-MS (ESI+): m / z 453 (MH+). 1 HNMR (300 MHz, DMSO-d 6 ) δ: 10.06 (s, 1H), 8.95 (d, J = 6.6 Hz, 2H), 8.50 (d, J = 6.3 Hz, 2H), 7.66 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.16 (s, 1H), 6.97 (s, 1H), 6.32 (s, 1H), 3.94 - 3.86 (m, 4H), 3.69 - 3.63 (m, 4H) and 2.39 (s, 3H) ppm.

[0444] Example 2: 7-Morpholino-N-(5-phenyl-1H-pyrazol-3-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine

[0445]

[0446] Compound 2 was prepared from intermediate A and the protected pyrazole according to the same two-step procedure used for Example 1. The protected pyrazole was prepared from 3-phenyl-1H-pyrazol-5-amine according to the procedure for preparing intermediate B. Compound 2, 7-morpholino-N-(5-phenyl-1H-pyrazol-3-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine gave the following data: LC-MS (ESI + ): m / z 439 (MH + ). 1 HNMR (300 MHz, DMSO-d 6) δ: 12.84 (s, 1H), 9.89 (s, 1H), 8.70 (d, J = 5.7 Hz, 2H), 7.99 (d, J = 5.7 Hz, 2H), 7.77 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.27 (s, 1H), 3.89 - 3.78 (m, 4H) and 3.63 - 3.57 (m, 4H) ppm.

[0447] Example 3: 7 - Morpholino - N - [5 - (o - tolyl) - 1H - pyrazol - 3 - yl] - 2 - (4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 5 - amine

[0448]

[0449] According to the same two - step procedure used in Example 1, compound 3 was prepared from intermediate A and the protected pyrazole. The protected pyrazole was prepared from 3 - (2 - methylphenyl) - 1H - pyrazol - 5 - amine according to the procedure for preparing intermediate B. Compound 3, 7 - morpholino - N - [5 - (o - tolyl) - 1H - pyrazol - 3 - yl] - 2 - (4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 5 - amine was obtained; LC - MS (ESI+): m / z 453 (MH + ). 1H NMR (300 MHz, CD 3 OD) δ: 8.62 (d, J = 6.3 Hz, 2H), 8.03 (d, J = 6.3 Hz, 2H), 7.46 (d, J = 6.6 Hz, 1H), 7.32 - 7.24 (m, 3H), 6.81 (s, 1H), 6.54 (s, 1H), 6.06 (s, 1H), 4.04 - 3.97 (m, 4H), 3.75 - 3.65 (m, 4H) and 2.45 (s, 3H) ppm.

[0450] Example 4: 7 - Morpholino - N - [3 - (m - tolyl) - 1H - pyrazol - 5 - yl] - 2 - (4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 5 - amine hydrochloride

[0451]

[0452] Compound 4 was prepared from intermediate A and the protected pyrazole according to the same two-step procedure used for Example 1. The protected pyrazole was prepared from 3-(3-methylphenyl)-1H-pyrazol-5-amine according to the procedure for preparing intermediate B. Compound 4, 7-morpholino-N-[3-(m-tolyl)-1H-pyrazol-5-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine hydrochloride; LC-MS (ESI+): m / z 453 (MH + ) 1 HNMR (300 MHz, DMSO-d 6 ) δ: 10.03 (s, 1H), 8.94 (d, J = 6.0 Hz, 2H), 8.47 (d, J = 5.1 Hz, 2H), 7.59 - 7.54 (m, 2H), 7.47 - 7.32 (m, 1H), 7.19 - 7.15 (m, 2H), 6.98 (s, 1H), 6.30 (s, 1H), 3.95 - 3.86 (m, 4H), 3.71 - 3.63 (m, 4H) and 2.38 (s, 3H) ppm

[0453] Example 5: N-(5-Methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine

[0454]

[0455] Compound 5 was prepared from intermediate A and the protected pyrazole according to the same two-step procedure used for Example 1. The protected pyrazole was prepared from 3-(3-methyl)-1H-pyrazol-5-amine according to the procedure for preparing intermediate B. Compound 5, N-(5-methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; LC-MS (ESI+): m / z 377 (MH + ) 1 HNMR (300 MHz, CD 3 OD) δ: 8.60 (dd, J = 3.6, 1.2 Hz, 2H), 7.99 (dd, J = 3.6, 1.2 Hz, 2H), 6.69 (s, 1H), 6.21 (s, 1H), 6.02 (s, 1H), 3.97 - 3.95 (m, 4H), 3.49 - 3.47 (m, 4H) and 2.29 (s, 3H) ppm

[0456] Example 6: 7-Morpholino-2-(4-pyridyl)-N-[5-(4-pyridyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine

[0457]

[0458] Compound 6 was prepared from intermediate A and the protected pyrazole according to the same two-step procedure used for Example 1. The protected pyrazole was prepared from 3-(pyridin-4-yl)-1H-pyrazol-5-amine according to the procedure for preparing intermediate B. Compound 6, 7-morpholino-2-(4-pyridinyl)-N-[5-(4-pyridinyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine, was obtained: LC-MS (ESI+): m / z 440 (MH + ) 1 HNMR (300 MHz, CD 3 OD) δ: 8.89 (d, J = 5.1 Hz, 2H), 8.34 (d, J = 5.4 Hz, 2H), 8.63 (d, J = 5.1 Hz, 2H), 8.48 (d, J = 5.1 Hz, 2H), 7.22 (s, 1H), 6.91 (s, 1H), 6.02 (s, 1H), 4.05 - 3.95 (m, 4H) and 3.82 - 3.80 (m, 4H) ppm

[0459] Example 7: 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine

[0460]

[0461] A solution of 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (intermediate A, 30 mg, 0.095 mmol), 3-phenyl-1H-pyrazol-5-amine (22.5 mg, 0.143 mmol), sodium tert-butoxide (18.3 mg, 0.191 mmol), Pd 2 (dba) 3 (4.2 mg, 0.005 mmol) and Xantphos (2.1 mg, 0.005 mmol) in DMF (3 mL) was heated to 110 °C for 30 minutes under microwave conditions. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 1-(7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine as a white solid (compound 7, 14.2 mg, 0.03 mmol); LC-MS (ESI+): m / z 439 (MH + ) 1 HNMR (300 MHz, DMSO-d 6) δ: 8.72 (d, J = 5.7 Hz, 2H), 7.98 (d, J = 5.7 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H), 7.45 - 7.40 (m, 3H), 7.19 (s, 1H), 7.12 (s, 2H), 7.03 (s, 1H), 5.92 (s, 1H) and 3.94 - 3.83 (m, 8H) ppm.

[0462] Example 8: 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-(o-tolyl)-1H-pyrazol-5-amine

[0463]

[0464] According to the procedure for Example 7, compound 8 was prepared from intermediate A and 3-(2-methylphenyl)-1H-pyrazol-5-amine; LC-MS (ESI+): m / z 453 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ: 8.73 (d, J = 3.9 Hz, 2H), 7.85 (d, J = 4.8 Hz, 2H), 7.60 (d, J = 4.5 Hz, 1H), 7.31 - 7.26 (m, 3H), 7.09 (s, 1H), 6.82 (s, 1H), 6.08 (s, 2H), 5.74 (s, 1H), 4.03 - 3.98 (m, 4H), 3.87 - 3.82 (m, 4H) and 2.56 (s, 3H) ppm.

[0465] Example 9: 4-[5-(4-Phenylpyrazol-1-yl)-2-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0466]

[0467] To a solution of 4-phenyl-1H-pyrazole (29.4 mg, 0.20 mmol) in DMF (5 mL) at 0 °C was added NaH (14 mg, 0.34 mmol). The mixture was stirred for 30 minutes. Then 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (intermediate A, 62 mg, 0.19 mmol) was added to the mixture. The reaction mixture was heated to 80 °C and stirred overnight. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 4-[5-(4-phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine as an off-white solid (Compound 9, 17.5 mg, 0.04 mmol); LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.73 (d, J = 6.0 Hz, 2H), 8.05 (s, 1H), 7.85 (d, J = 5.4 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.33 - 7.28 (m, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4.06 - 4.03 (m, 4H) and 3.95 - 3.92 (m, 4H) ppm.

[0468] Intermediate C

[0469] Step 1: Synthesis of tert-butyl 4-(3-methylphenyl)-1H-pyrazole-1-carboxylate

[0470]

[0471] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1 g, 3.4 mmol), 1-bromo-3-methylbenzene (581 mg, 3.4 mmol), CsF (775 mg, 5.1 mmol), Pd 2 (PPh 3 ) 2 Cl 2 (392 mg, 0.34 mmol) in 1,4-dioxane / H 2 O (30 mL, 2 / 1) was heated at 80 °C overnight. The reaction was confirmed complete by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 15% EtOAc / PE to 33% EtOAc / PE. tert-Butyl 4-(3-methylphenyl)-1H-pyrazole-1-carboxylate (117 mg, 0.45 mmol) was obtained; LC-MS (ESI+): m / z 259 (MH + ).1 HNMR (300 MHz, CDCl 3 ) δ: 8.29 (s, 1H), 7.99 (s, 1H), 7.34 - 7.28 (m, 3H), 7.13 - 7.10 (m, 1H), 2.39 (s, 3H) and 1.68 (s, 9H) ppm.

[0472] Step 2: Synthesis of 4-(3-methylphenyl)-1H-pyrazole hydrochloride, Intermediate C

[0473]

[0474] To a solution of tert-butyl 4-(3-methylphenyl)-1H-pyrazole-1-carboxylate (117 mg, 0.45 mmol) in DCM was added HCl / Et 2 O (1 mL). The reaction was stirred overnight at ambient temperature. A large amount of solid precipitated. After concentration, the residue was triturated in MeOH / Et 2 O (1 / 20, 2 mL); 4-(3-methylphenyl)-1H-pyrazole hydrochloride (Intermediate C, 90 mg, 0.46 mmol) was obtained as a white solid; LC-MS (ESI+): m / z 159 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ: 8.13 (s, 2H), 7.38 - 7.20 (m, 4H) and 2.42 (s, 3H) ppm.

[0475] Example 10: 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0476]

[0477] To a solution of 4-(3-methylphenyl)-1H-pyrazole hydrochloride (Intermediate C, 40 mg, 0.21 mmol) in DMF (5 mL) at 0 °C was added NaH (16.8 mg, 0.42 mmol). The mixture was stirred for 30 min. To this mixture was added 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Intermediate A, 65 mg, 0.20 mmol). The resulting reaction mixture was heated to 80 °C overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (10 mL) and the aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 30% EtOAc / PE to EtOAc to afford 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine as an off-white solid (Compound 10, 15.5 mg, 0.035 mmol); LC-MS (ESI+): m / z 438 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ: 8.86 (s, 1H), 8.72 (d, J = 6.0 Hz, 2H), 8.04 (s, 1H), 7.85 (d, J = 6.0 Hz, 2H), 7.44 - 7.41 (m, 2H), 7.35 - 7.32 (m, 1H), 7.15 - 7.09 (m, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 4.06 - 4.03 (m, 4H), 3.95 - 3.92 (m, 4H) and 2.42 (s, 3H) ppm.

[0478] Example 11: 4-[2-(4-Pyridyl)-5-[4-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0479]

[0480] Compound 11 was prepared by the reaction of Intermediate A with 4-(4-pyridyl)-1H-pyrazole according to the conditions used for Example 9 and Example 10. Compound 11, 4-[2-(4-pyridyl)-5-[4-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine, was obtained; LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ: 9.01 (s, 1H), 8.73 (d, J = 6.0 Hz, 2H), 8.64 (d, J = 6.0 Hz, 2H), 8.11 (s, 1H), 7.85 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 6.0 Hz, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 4.06 - 4.03 (m, 4H) and 3.98 - 3.96 (m, 4H) ppm.

[0481] Example 12: 4-[5-(4-Methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0482]

[0483] According to the conditions for Example 9 and Example 10, Compound 12 was prepared by the reaction of Intermediate A with 4-methylpyrazole. Compound 12, 4-[5-(4-methylpyrazol-1-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine, was obtained; LC-MS (ESI+): m / z 362 (MH + ). 1 HNMR (300 MHz, DMSO-d 6 ) δ: 8.70 (d, J = 5.7 Hz, 2H), 8.45 (s, 1H), 7.98 (d, J = 6.0 Hz, 2H), 7.72 (s, 1H), 7.17 (s, 1H), 6.91 (s, 1H), 3.89 (s, 8H), and 2.13 (s, 3H) ppm.

[0484] Example 13: 4-[5-(3-Phenylpyrazol-1-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0485]

[0486] To a solution of 3-phenylpyrazole (29.4 mg, 0.20 mmol) in DMF (5 mL) at 0 °C was added NaH (14 mg, 0.34 mmol). The mixture was stirred for 30 minutes. 4-(5-Chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Intermediate A, 62 mg, 0.19 mmol) was added to the mixture. The reaction mixture was heated to 80 °C and stirred overnight. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography by gradient elution with 2% MeOH / DCM to 3% MeOH / DCM to give 4-[5-(3-phenylpyrazol-1-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine (Compound 13, 17.5 mg, 0.04 mmol) as an off-white solid; LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl 3) δ: 8.72 (d, J = 6.0 Hz, 2H), 8.65 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 4.8, 1.5 Hz, 2H), 7.50 - 7.39 (m, 3H), 7.12 (s, 1H), 6.87 - 6.84 (m, 2H), 4.08 - 4.05 (m, 4H), and 3.96 - 3.93 (m, 4H) ppm.

[0487] Example 14: 4-[5-[3-(m - Tolyl)pyrazol - 1 - yl]-2-(4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine 4-[5-[3-(3 - Methylphenyl)pyrazol - 1 - yl]-2-(4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0488]

[0489] According to the conditions used in Example 13, compound 14 was prepared by the reaction of intermediate A with 3-(3 - methylphenyl)pyrazole. Compound 14, 4-[5-[3-(m - Tolyl)pyrazol - 1 - yl]-2-(4 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine, was obtained; LC - MS (ESI+): m / z 438 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ: 8.72 (d, J = 6.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 5.7 Hz, 2H), 7.77 - 7.71 (m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.12 (s, 1H), 6.86 - 6.83 (m, 2H), 4.08 - 4.05 (m, 4H), 3.96 - 3.93 (m, 4H), and 2.45 (s, 3H) ppm.

[0490] Example 15: 4-[2-(4 - Pyridyl)-5-[3-(4 - pyridyl)pyrazol - 1 - yl]pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0491]

[0492] According to the conditions used in Example 13, compound 15 was prepared by the reaction of intermediate A with 3-(4 - pyridyl)pyrazole. Compound 15, 4-[2-(4 - pyridyl)-5-[3-(4 - pyridyl)pyrazol - 1 - yl]pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine, was obtained; LC - MS (ESI+): m / z 425 (MH+ )。 1 HNMR (300 MHz, CDCl 3 ) δ: 8.74 - 8.70 (m, 5H), 7.86 - 7.81 (m, 4H), 7.09 (s, 1H), 6.93 - 6.89 (m, 2H), 4.09 - 4.06 (m, 4H) and 3.98 - 3.96 (m, 4H) ppm。

[0493] Example 16: 4-[5-(3-Methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0494]

[0495] According to the conditions used in Example 13, Compound 16 was prepared by the reaction of Intermediate A with 3-(4-pyridyl)pyrazole. Compound 16, 4-[5-(3-Methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine, was obtained; LC-MS (ESI+): m / z 362 (MH + )。 1 HNMR (300 MHz, CDCl 3 ) δ: 8.70 (dd, J = 4.5, 1.5 Hz, 2H), 8.49 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 4.5, 1.5 Hz, 2H), 6.97 (s, 1H), 6.83 (s, 1H), 6.31 (d, J = 2.7 Hz, 1H), 4.05 - 4.02 (m, 4H), 3.92 - 3.89 (m, 4H) and 2.39 (s, 3H) ppm。

[0496] Intermediate D: 4-(5-Chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0497]

[0498] D.2: Synthesis of 3-(Pyridin-2-yl)-1H-pyrazol-5-amine

[0499]

[0500] To a solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (2.5 g, 17.1 mmol) in EtOH (75 mL) was added NH 2 NH 2 .H 2O(1.71 g, 34.2 mmol). The reaction mixture was heated to reflux overnight. After completion of the reaction as indicated by TLC analysis, the reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 3% MeOH / DCM to afford 3-(pyridin-2-yl)-1H-pyrazol-5-amine as a brown solid (1.34 g, 8.37 mmol). LC-MS (ESI+): m / z 161 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ: 8.58 (d, J = 4.2 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.24 - 7.20 (m, 1H), 6.09 (s, 1H).

[0501] D.3: 2-(Pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

[0502]

[0503] Small pieces of sodium (580 mg, 25.2 mmol) were carefully added to a solution of anhydrous EtOH (10 mL) at ambient temperature. After all of the sodium had dissolved, the solution was concentrated to afford fresh NaOEt as a white solid. The freshly prepared NaOEt was added to a mixture of diethyl malonate (40 mL) and 3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.34 g, 8.37 mmol). The mixture was heated to 110 °C and stirred at this temperature overnight. After the reaction mixture was cooled to ambient temperature, a large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to afford crude 2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione as a yellow solid (3.89 g, 17.1 mg). The crude product was used directly in the next step without further purification. LC-MS (ESI+): 229 (MH + ).

[0504] D.4: Synthesis of 5,7-dichloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

[0505]

[0506] A solution of the crude 2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (3.89 g, 17.1 mmol) in phenylphosphonic dichloride (20 mL) was heated to 110 °C overnight. The reaction mixture was treated with saturated NaHCO 3The solution was quenched and made basic to pH 8. The aqueous solution was extracted with DCM / MeOH (15:1, 6 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 265 / 267 (MH + ).

[0507] Intermediate D: Synthesis of 4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0508]

[0509] To a solution of crude 5,7-dichloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine (0.78 g, 2.83 mmol) in 1,4-dioxane (50 mL) was added morpholine (0.49 g, 5.65 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a yellow solid (400 mg, 1.27 mmol). LC-MS (ESI+): m / z 316 / 318 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.71 (d, J = 4.5 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.33 - 7.26 (m, 1H), 7.17 (s, 1H), 6.12 (s, 1H), 4.03 - 3.99 (m, 4H), 3.88 - 3.85 (m, 4H).

[0510] Intermediate E: 4-(5-chloro-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0511]

[0512] Intermediate E was prepared by the same method used for the preparation of Intermediate D, except that the starting material used in the first step was 3-oxo-3-(pyridin-3-yl)propanenitrile instead of 3-oxo-3-(pyridin-2-yl)propanenitrile.

[0513] Example 17: 4-(2-(Pyridin-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine.

[0514]

[0515] Compound 17 was prepared by the reaction of intermediate E with 3-(m-tolyl)-1H-pyrazole according to the conditions for Example 18. LC-MS (ESI + ): m / z 438 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.65 (d, J = 2.7 Hz, 2H), 8.24 (d, J = 8.1 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.43 - 7.33 (m, 2H), 7.26 - 7.20 (m, 1H), 7.10 (s, 1H), 6.84 - 6.82 (m, 2H), 4.06 - 4.04 (m, 4H), 3.96 - 3.94 (m, 4H), 2.45 (s, 3H).

[0516] Example 18: 4-(2-(Pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine.

[0517]

[0518] A suspension of 4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (intermediate D, 150 mg, 0.48 mmol), 3-(m-tolyl)-1H-pyrazole (82.7 mg, 0.52 mmol), Cs2CO3 (312 mg, 0.96 mmol) and CuI (18 mg, 0.014 mmol) in DMF (10 mL) was heated at 120 °C overnight. After completion of the reaction as indicated by TLC analysis, the reaction mixture was quenched with water (20 mL) and extracted with DCM / MeOH (15:1, 3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 5% MeOH / DCM to afford 4-(2-(pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a white solid (Compound 18, 40.6 mg, 0.093 mmol). LC-MS (ESI+): m / z 438 (MH + ).1 HNMR (300 MHz, CDCl 3 ) δ 8.72 (d, J = 4.8 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.38 - 7.26 (m, 2H), 7.22 - 7.20 (m, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.07 - 4.06 (m, 4H), 3.96 - 3.94 (m, 4H), 2.45 (s, 3H).

[0519] Intermediate F: 7 - morpholino - 5 - (3 - (m - tolyl)-1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxylic acid

[0520]

[0521] F.2: Ethyl 5,7 - dioxo - 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate

[0522]

[0523] Small pieces of sodium (890 mg, 38.7 mmol) were carefully added to a solution of anhydrous EtOH (10 mL) at ambient temperature. After all the sodium had dissolved, the solution was concentrated to afford fresh NaOEt as a white solid. The freshly prepared NaOEt was added to a mixture of diethyl malonate (40 mL) and ethyl 5 - amino - 1H - pyrazole - 3 - carboxylate (2 g, 12.9 mmol). The mixture was heated to 120 °C and stirred at this temperature overnight. After the reaction mixture was cooled to room temperature, a large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to afford ethyl 5,7 - dioxo - 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate (5.92 g, 26.5 mmol) as a yellow solid. The crude product was used directly in the next step without further purification. LC - MS (ESI+): m / z 224 (MH + ).

[0524] Synthesis of ethyl 5,7 - dichloropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate

[0525]

[0526] A solution of ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate (5.92 g, 26.5 mmol) in phenylphosphonic dichloride (15 mL) was heated at 120 °C overnight. The reaction mixture was quenched with saturated NaHCO 3 solution until it was basic (pH 8). The aqueous solution was extracted with DCM / MeOH (15:1, 6 x 40 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 260 / 262 (MH+).

[0527] F.4) Synthesis of ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate

[0528]

[0529] Morpholine (3.2 g, 37.3 mmol) was added to a solution of crude ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (4.83 g, 18.6 mmol) in 1,4-dioxane (60 mL). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate (3.3 g, 10.6 mmol) as a yellow solid. LC-MS (ESI+): m / z 311 / 313 (MH+). 1 HNMR (300 MHz, CDCl 3 ) δ 6.98 (s, 1H), 6.18 (s, 1H), 4.49 - 4.41 (m, 2H), 3.98 - 3.96 (m, 4H), 3.92 - 3.82 (m, 4H), 1.33 (t, J = 8.4 Hz, 3H).

[0530] F.5: Ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

[0531]

[0532] Ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate (3.2 g, 10.6 mmol), 3-(m-tolyl)-1H-pyrazole (2.0 g, 12.8 mmol), Cs 2 CO 3(6.9 g, 21.3 mmol) and CuI (400 mg, 2.1 mmol) in a suspension in DMF (120 mL) were heated to 110 °C overnight. After completion of the reaction as indicated by TLC analysis, the reaction mixture was quenched with water (20 mL) and extracted with DCM / MeOH (15:1, 3 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 5% MeOH / DCM to afford ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (3.8 g, 8.8 mmol) as a white solid. LC-MS (ESI+): m / z 433 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.38 - 7.33 (m, 1H), 7.22 - 7.20 (m, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.50 - 4.43 (m, 2H), 4.03 - 4.01 (m, 4H), 3.93 - 3.91 (m, 4H), 2.45 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H).

[0533] Intermediate F: 7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0534]

[0535] To a solution of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (3.8 g, 8.8 mmol) in THF (160 mL) was added 2N aqueous NaOH solution (30 mL). The reaction was heated to 40 °C for 3 h. After completion of the reaction as indicated by TLC analysis, 1M aqueous HCl was added to the reaction mixture until pH 4. The resulting solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to afford ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate F, 3.5 g, 8.7 mmol) as a white solid. LC-MS (ESI+): m / z 405 (MH + ). 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 3.89 (s, 8H), 2.40 (s, 3H).

[0536] Example 19: N-Ethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0537]

[0538] A solution of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate F, 100 mg, 0.25 mmol), ethylamine hydrochloride (22.3 mg, 0.27 mmol), EDCl (118.8 mg, 0.62 mmol) and DMAP (76 mg, 0.62 mmol) in DCM was stirred overnight at ambient temperature. After completion of the reaction as indicated by TLC analysis, the reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford ethyl N-ethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound 19, 58 mg, 0.13 mmol) as a yellow solid. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.64(d, J = 2.7 Hz, 1H), 7.75 - 7.71(m, 2H), 7.35(t, J = 7.5 Hz, 1H), 7.22 - 7.20(m, 1H), 7.18(s, 1H), 7.02(s, 1H), 6.94 - 6.83(m, 1H), 6.82(d, J = 2.7 Hz, 1H), 4.05 - 4.02(m, 4H), 3.92 - 3.83(m, 4H), 3.60 - 3.49(m, 2H), 2.45(s, 3H), 1.29(t, J = 7.2 Hz, 3H).

[0539] Example 20: N-Cyclopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0540]

[0541] According to the method used in Example 19, compound 20 was prepared from intermediate F and aminocyclopropane. LC-MS (ESI+): m / z 444 (MH + ). 1 HNMR (300 MHz, CDCl 3 )δ8.64(d, J = 2.4 Hz, 1H), 7.75 - 7.71(m, 2H), 7.35(t, J = 7.5 Hz, 1H), 7.22 - 7.20(m, 1H), 7.18(s, 1H), 7.02(s, 2H), 6.83(d, J = 2.7 Hz, 1H), 4.03 - 4.01(m, 4H), 3.84 - 3.82(m, 4H), 2.94 - 2.90(m, 1H), 2.45(s, 3H), 0.94 - 0.88(m, 2H), 0.72 - 0.69(m, 2H).

[0542] Example 21: (R)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0543]

[0544] According to the procedure used in Example 19, compound 21 was prepared from intermediate F and (R)-1-cyclopropylethylamine. LC-MS (ESI+): m / z 472 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.64 (d, J = 2.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.05 - 4.03 (m, 4H), 3.87 - 3.85 (m, 4H), 3.65 - 3.63 (m, 1H), 2.45 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H), 0.98 - 0.96 (m, 1H), 0.59 - 0.49 (m, 3H), 0.49 - 0.46 (m, 1H).

[0545] Example 22: (S)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0546]

[0547] According to the procedure for Example 19, compound 22 was prepared from intermediate F and (S)-1-cyclopropylethylamine. LC-MS (ESI+): m / z 472 (MH + ). 1 HNMR (300 MHz, CDCl 3 )δ8.64 (d, J = 2.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.05 - 4.03 (m, 4H), 3.87 - 3.85 (m, 4H), 3.65 - 3.63 (m, 1H), 2.45 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H), 0.98 - 0.96 (m, 1H), 0.59 - 0.49 (m, 3H), 0.49 - 0.46 (m, 1H).

[0548] Example 23: N-(2-Methoxyethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0549]

[0550] According to the procedure for Example 19, compound 23 was prepared from intermediate F and 3-(methoxy)ethylamine. LC-MS (ESI+): m / z 462 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 HZ, 2H), 7.22 - 7.20 (m, 1H), 7.17 (s, 1H), 7.01 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.05 - 4.02 (m, 4H), 3.87 - 3.84 (m, 4H), 3.72 - 3.67 (m, 2H), 3.62 - 3.58 (m, 2H), 3.42 (s, 3H), 2.45 (s, 3H).

[0551] Example 24: N,N-Dimethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0552]

[0553] According to the procedure for Example 19, compound 24 was prepared from intermediate F and dimethylamine. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 HZ, 1H), 7.22 - 7.20 (m, 1H), 7.11 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.77 (s, 1H), 4.00 - 3.98 (m, 4H), 3.89 - 3.88 (m, 4H), 3.31 (s, 3H), 3.18 (s, 3H), 2.45 (s, 3H).

[0554] Example 25: N-Ethyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0555]

[0556] According to the procedure for Example 37, compound 25 was prepared by N-methylation of compound 19. LC-MS (ESI+): m / z 446 (MH + ). 1HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 HZ, 1H), 7.22 - 7.20 (m, 1H), 7.11 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.78 (s, 1H), 4.02 - 3.98 (m, 4H), 3.92 - 3.88 (m, 4H), 3.69 - 3.64 (m, 2H), 3.28 (s, 1H), 3.14 (s, 2H), 2.45 (s, 3H), 1.32 - 1.28 (m, 3H).

[0557] Example 26: N - Cyclopropyl - N - methyl - 7 - morpholino - 5 - (3 - (m - tolyl)-1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0558]

[0559] According to the method used in Example 19, compound 26 was prepared from intermediate F and N - methyl(cyclopropyl)amine. LC - MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 HZ, 1H), 7.21 (d, J = 7.2 HZ, 1H), 7.10 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.74 (s, 1H), 3.99 - 3.98 (m, 4H), 3.89 - 3.88 (m, 4H), 3.17 (s, 3H), 3.03 - 2.96 (m, 1H), 2.45 (s, 3H), 0.88 - 0.82 (m, 1H), 0.80 - 0.59 (m, 3H).

[0560] Example 27: N - (Cyclopropylmethyl)-7 - morpholino - 5 - (3 - (m - tolyl)-1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0561]

[0562] According to the coupling procedure used in Example 19, compound 27 was prepared by the reaction of intermediate F with N - (cyclopropylmethyl)amine. LC - MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.64(d,J=2.7Hz,1H),7.76-7.71(m,2H),7.36(t,J=7.5HZ,1H),7.22-7.20(m,1H),7.18(s,1H),7.08-7.06(m,1H),7.02(s,1H),6.83(d,J=2.7Hz,1H),4.05-4.03(m,4H),3.88-3.85(m,4H),3.37(t,J=6.6HZ,1H),2.45(s,3H),1.11-1.09(m,1H),0.59-0.57(m,2H),0.33-0.31(m,2H).

[0563] Example 28: Azetidin-1-yl(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone

[0564]

[0565] According to the procedure for Example 19, compound 28 was prepared from azetidine and intermediate F. LC-MS(ESI+): m / z 444(MH + ). 1 HNMR(300MHz,CDCl 3 )δ8.64(d,J=2.7Hz,1H),7.83-7.66(m,2H),7.35(t,J=7.5HZ,1H),7.22-7.20(m,1H),7.13(s,1H),6.98(s,1H),6.82(d,J=2.4Hz,1H),4.65(t,J=7.5HZ,2H),4.28(t,J=7.5HZ,1H),4.01-3.98(m,4H),3.88-3.85(m,4H),2.45-2.37(m,5H).

[0566] Example 29: (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(pyrrolidin-1-yl)methanone

[0567]

[0568] Compound 29 was prepared by the same procedure as for Example 19 through the reaction of intermediate F with pyrrolidine. LC-MS(ESI+): m / z 458(MH + ). 1 HNMR(300MHz,CDCl 3)δ8.64(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.35(t, J = 7.5HZ, 1H), 7.22 - 7.20(m, 1H), 7.12(s, 1H), 6.94(s, 1H), 6.82(d, J = 2.4Hz, 1H), 4.00 - 3.88(m, 10H), 3.76 - 3.71(m, 2H), 2.45(s, 3H), 1.98 - 1.94(m, 4H).

[0569] Example 30: (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone

[0570]

[0571] Compound 30 was prepared by the reaction of intermediate F with piperidine through the same procedure as in Example 19. LC-MS(ESI+): m / z 472(MH + ). 1 HNMR(300MHz, CDCl 3 )δ8.63(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.35(t, J = 7.5HZ, 1H), 7.21(t, J = 7.5HZ, 1H), 7.10(s, 1H), 6.82(d, J = 2.4Hz, 1H), 6.71(s, 1H), 4.00 - 3.98(m, 4H), 3.90 - 3.88(m, 4H), 3.80 - 3.76(m, 4H), 2.45(s, 3H), 1.80 - 1.60(m, 6H).

[0572] Example 31: Morpholino(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone

[0573]

[0574] Compound 31 was prepared by the reaction of intermediate F with morpholine through the same procedure as in Example 19. LC-MS(ESI+): m / z 474(MH + ). 1 HNMR(300MHz, CDCl 3)δ8.63(d,J = 2.4Hz,1H),7.76 - 7.71(m,2H),7.36(t,J = 7.5HZ,1H),7.23 - 7.20(m,1H),7.13(s,1H),6.83(d,J = 2.4Hz,1H),6.77(s,1H),4.00 - 3.97(m,6H),3.90 - 3.86(m,8H),3.80 - 3.76(m,2H),2.45(s,3H).

[0575] Example 32: (4 - Methylpiperazin - 1 - yl)(7 - morpholino - 5-(3-(m - tolyl)-1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidin - 2 - yl)methanone

[0576]

[0577] Compound 32 was prepared by the reaction of intermediate F with N - (methyl)piperidine through the same procedure as for Example 19. LC - MS(ESI+): m / z 487(MH + ). 1 HNMR(300MHz,CDCl 3 )δ8.63(d,J = 2.7Hz,1H),7.76 - 7.71(m,2H),7.35(t,J = 7.5HZ,1H),7.21(t,J = 7.5HZ,1H),7.11(s,1H),6.83(d,J = 2.4Hz,1H),6.75(s,1H),3.99 - 3.96(m,4H),3.92 - 3.87(m,8H),2.60 - 2.54(m,2H),2.50 - 2.45(m,5H),2.35(s,3H).

[0578] Example 33: N - Methoxy - N - methyl - 7 - morpholino - 5-(3-(m - tolyl)-1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0579]

[0580] Compound 33 was prepared by the reaction of intermediate F with N - methoxy - N - methylamine through the same procedure as for Example 19. LC - MS(ESI+): m / z 448(MH + ). 1 HNMR(300MHz,CDCl 3)δ8.63(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.36(t, J = 7.5HZ, 1H), 7.21(t, J = 7.2HZ, 1H), 7.14(s, 1H), 6.92(s, 1H), 6.82(d, J = 2.7Hz, 1H), 4.13 - 4.11(m, 4H), 4.00 - 3.99(m, 4H), 3.82(s, 3H), 3.48(s, 3H), 2.45(s, 3H).

[0581] Example 34: N-Methoxy-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0582]

[0583] Compound 34 was prepared by the reaction of intermediate F with N-methoxyamine by the same procedure as for Example 19. LC-MS(ESI+): m / z 434(MH + ). 1 HNMR(300MHz, CDCl 3 )δ9.39(s, 1H), 8.64(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.36(t, J = 7.5HZ, 1H), 7.23 - 7.19(m, 2H), 7.04(s, 1H), 6.83(d, J = 2.4Hz, 1H), 4.05 - 4.02(m, 4H), 3.96(s, 3H), 3.84 - 3.83(m, 4H), 2.45(s, 3H).

[0584] Example 35: N-(Methylsulfonyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0585]

[0586] Compound 35 was prepared by the reaction of intermediate F with methylsulfonamide by the same procedure as for Example 19. LC-MS(ESI+): m / z 482(MH + ). 1 HNMR(300MHz, CDCl 3)δ 9.09 (s, 1H), 8.62 (d, J = 2.7 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.36 (t, J = 7.5 HZ, 1H), 7.25 - 7.21 (m, 2H), 7.09 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.05 - 4.02 (m, 4H), 3.83 - 3.82 (m, 4H), 3.47 (s, 3H), 2.45 (s, 3H).

[0587] Example 36: N-Cyclopentyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0588]

[0589] Compound 36 was prepared by the reaction of intermediate F with cyclopentylamine by the same procedure as in Example 19. LC-MS (ESI+): m / z 472 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 4.45 - 4.43 (m, 1H), 4.03 - 4.02 (m, 4H), 3.85 - 3.84 (m, 4H), 2.45 (s, 3H), 2.14 - 2.09 (m, 2H), 1.76 - 1.71 (m, 4H), 1.60 - 1.56 (m, 2H).

[0590] Example 37: N-Cyclopentyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0591]

[0592] At 0 °C, NaH (10 mg, 0.24 mmol) was added to a solution of N-cyclopentyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound 36, 55 mg, 0.11 mmol) in DMF (5 mL). After stirring at this temperature for 0.5 h, methyl iodide (25 mg, 0.17 mmol) was added to the above solution. After the reaction was indicated to be complete by TLC analysis, the reaction mixture was quenched with water (20 mL) and extracted with DCM / MeOH (15:1, 3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 5% MeOH / DCM to afford N-cyclopentyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound 37, 30 mg, 0.062 mmol) as a white solid. LC-MS (ESI+): m / z 486 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.10 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.71 (s, 1H), 4.76 - 7.71 (m, 1H), 4.03 - 4.02 (m, 4H), 3.89 - 3.87 (m, 4H), 3.11 (s, 1H), 3.03 (s, 2H), 2.45 (s, 3H), 2.02 - 1.52 (m, 8H).

[0593] Example 38: N-Isopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0594]

[0595] Compound 38 was prepared by the reaction of Intermediate F with isopropylamine by the same procedure as for Example 19. LC-MS (ESI+): m / z 446 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.64(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.35(t, J = 7.5Hz, 1H), 7.22 - 7.20(m, 1H), 7.17(s, 1H), 7.01(s, 1H), 6.83(d, J = 2.7Hz, 1H), 6.75(d, J = 8.1Hz, 1H), 4.36 - 4.27(m, 1H), 4.04 - 4.03(m, 4H), 3.86 - 3.84(m, 4H), 2.45(s, 3H), 1.31(d, J = 6.6Hz, 6H).

[0596] Example 39: N-(1,3-Dimethoxypropan-2-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0597]

[0598] Compound 39 was prepared by the reaction of intermediate F with N-(1,3-dimethoxypropan-2-yl)amine by the same procedure as for Example 19. LC-MS(ESI+): m / z 506(MH + ). 1 1H NMR(300MHz, CDCl 3 )δ8.64(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.44(d, J = 8.4Hz, 1H), 7.35(t, J = 7.5Hz, 1H), 7.22 - 7.20(m, 1H), 7.17(s, 1H), 7.00(s, 1H), 6.83(d, J = 2.4Hz, 1H), 4.42 - 4.40(m, 1H), 4.04 - 4.02(m, 4H), 3.87 - 3.85(m, 4H), 3.69 - 3.64(m, 2H), 3.57 - 3.52(m, 2H), 3.43(s, 6H), 2.45(s, 3H).

[0599] Example 40: N-(2-(Dimethylamino)ethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0600]

[0601] Compound 40 was prepared by the reaction of intermediate F with N-(2-(dimethylamino)ethyl)amine by the same procedure as for Example 19. LC-MS(ESI+): m / z 475(MH + ). 1HNMR (300 MHz, CD 3 OD) δ 8.66 (d, J = 2.7 Hz, 1H), 7.79 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.23 - 7.20 (m, 2H), 6.97 (d, J = 2.7 Hz, 1H), 6.92 (s, 1H), 3.98 - 3.95 (m, 8H), 3.83 - 3.79 (m, 2H), 3.37 - 3.35 (m, 2H), 2.95 (s, 6H), 2.43 (s, 3H).

[0602] Example 41: N-(4-(Dimethylamino)butyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0603]

[0604] Compound 41 was prepared by the reaction of intermediate F with N-(4-(dimethylamino)butyl)amine by the same procedure as for Example 19. LC-MS (ESI+): m / z 503 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.41 - 7.33 (m, 2H), 7.22 - 7.20 (m, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.05 - 4.03 (m, 4H), 3.88 - 3.86 (m, 4H), 3.58 - 3.52 (m, 2H), 2.82 - 2.80 (m, 2H), 2.60 (s, 6H), 2.43 (s, 3H), 1.81 - 1.79 (m, 4H).

[0605] Example 42: 7-Morpholino-N-(oxetan-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0606]

[0607] Compound 42 was prepared by the reaction of intermediate F with N-(oxetan-3-yl)amine by the same procedure as for Example 19. LC-MS (ESI+): m / z 460 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.63(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.42 - 7.33(m, 2H), 7.22 - 7.20(m, 2H), 7.01(s, 1H), 6.83(d, J = 2.4Hz, 1H), 5.36 - 5.26(m, 1H), 5.06(t, J = 7.2Hz, 2H), 4.68(t, J = 6.6Hz, 2H), 4.07 - 4.04(m, 4H), 3.86 - 3.85(m, 4H), 2.45(s, 3H).

[0608] Example 43: 7 - Morpholino - N - (oxetan - 3 - ylmethyl) - 5 - (3 - (m - tolyl) - 1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0609]

[0610] Compound 43 was prepared by the reaction of intermediate F with N - (oxetan - 3 - ylmethyl)amine by the same procedure as for Example 19. LC - MS(ESI+): m / z 474(MH + ). 1 HNMR(300MHz, CDCl 3 )δ8.64(d, J = 2.7Hz, 1H), 7.76 - 7.71(m, 2H), 7.35(t, J = 7.5Hz, 1H), 7.22 - 7.20(m, 3H), 7.01(s, 1H), 6.83(d, J = 2.4Hz, 1H), 4.87(t, J = 7.5Hz, 2H), 4.52(t, J = 6.0Hz, 2H), 4.03 - 4.01(m, 4H), 3.85 - 3.78(m, 6H), 3.40 - 3.30(m, 1H), 2.45(s, 3H).

[0611] Example 44: N - ((3 - (Hydroxymethyl)oxetan - 3 - yl)methyl) - 7 - morpholino - 5 - (3 - (m - tolyl) - 1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0612]

[0613] Compound 44 was prepared by the reaction of intermediate F with N - ((3 - (hydroxymethyl)oxetan - 3 - yl)methyl)amine by the same procedure as for Example 19. LC - MS(ESI+): m / z 504(MH + ). 1 HNMR(300MHz, DMSO - d 6)δ8.73(d,J=2.7Hz,1H),8.67-8.64(m,1H),7.83-7.80(m,2H),7.38(t,J=7.5Hz,1H),7.23(d,J=7.8Hz,1H),7.15(d,J=2.7Hz,1H),7.08(s,1H),6.84(s,1H),5.12(t,J=7.8HZ,1H),4.42(d,J=5.7Hz,2H),4.30(d,J=6.0Hz,2H),3.89(s,8H),3.68(d,J=5.1Hz,2H),3.60(d,J=5.4Hz,2H),2.40(s,3H).

[0614] Example 45: (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone

[0615]

[0616] Compound 45 was prepared by the reaction of intermediate F with 2-oxa-6-azaspiro[3.3]heptane by the same procedure as for Example 19. LC-MS(ESI+):m / z 486(MH + ). 1 HNMR(300MHz,CDCl 3 )δ8.64(d,J=2.7Hz,1H),7.76-7.71(m,2H),7.35(t,J=7.5Hz,1H),7.22-7.20(m,1H),7.15(s,1H),6.97(s,1H),6.83(d,J=2.4Hz,1H),4.91-4.83(m,4H),4.78(s,2H),4.39(s,2H),4.04-4.02(m,4H),3.88-3.87(m,4H),2.45(s,3H).

[0617] Example 46: (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone

[0618]

[0619] Compound 46 was prepared by the reaction of intermediate F with 6-oxa-1-azaspiro[3.3]heptane by the same procedure as for Example 19. LC-MS(ESI+):m / z 486(MH + ).1 HNMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.15 (s, 1H), 7.02 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 5.69 (d, J = 6.6 Hz, 2H), 4.69 (d, J = 6.6 Hz, 2H), 4.50 (t, J = 7.5 Hz, 2H), 3.99 - 3.97 (m, 4H), 3.88 - 3.84 (m, 4H), 2.69 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H).

[0620] Example 47: 7 - Morpholino - N - (oxetan - 3 - yloxy) - 5 - (3 - (m - tolyl) - 1H - pyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0621]

[0622] Synthesis of 2 - (oxetan - 3 - yloxy)isoindoline - 1,3 - dione

[0623]

[0624] To a solution of 2 - hydroxyisoindoline - 1,3 - dione (4.84 g, 27 mmol) in THF (120 mL) at 0 °C was added PPh 3 (8.5 g, 32.4 mmol), DEAD (6.56 g, 32.4 mmol) and oxetan - 3 - ol (2 g, 29.7 mmol). The reaction was heated to 30 °C overnight. After completion of the reaction as indicated by TLC analysis, the reaction mixture was quenched with aqueous NH 4 Cl and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 25% EtOAc / PE to 33% EtOAc / PE to afford impure 2 - (oxetan - 3 - yloxy)isoindoline - 1,3 - dione (2.3 g, 10.5 mmol) as a white solid. The purity was about 10%. LC - MS (ESI+): m / z 220 (MH + ).

[0625] Synthesis of O - (oxetan - 3 - yl)hydroxylamine

[0626]

[0627] To a solution of impure 2-(oxetan-3-yloxy)isoindoline-1,3-dione (1 g, 0.5 mmol) in MeOH (75 mL) was added NH 2 NH 2 .H 2 O (229 mg, 4.58 mmol). The reaction mixture was heated to 65 °C and stirred at this temperature for 1.5 h. The reaction mixture was concentrated directly. To the residue was added EtOAc (10 mL) and a large amount of solid precipitated. After filtration, the filtrate was concentrated to afford crude O-(oxetan-3-yl)hydroxylamine (400 mg, 4.49 mmol). The crude product was used directly in the next step without further purification.

[0628] Synthesis of 7-morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0629]

[0630] A solution of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (100 mg, 0.25 mmol), crude O-(oxetan-3-yl)hydroxylamine (400 mg, 4.49 mmol), EDCl (154 mg, 0.80 mmol) and DMAP (98 mg, 0.80 mmol) in DCM was stirred overnight at room temperature. After completion of the reaction as indicated by TLC analysis, the reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 7-morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound 47, 19 mg, 0.04 mmol). LC-MS (ESI+): m / z 476 (MH + ). 1 HNMR (300 MHz, DMSO-d 6)δ 12.08 (s, 1H), 8.72 (d, J = 2.7 Hz, 1H), 7.82 - 7.80 (m, 2H), 7.38 (t, J = 6.9 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 5.11 - 5.08 (m, 1H), 4.78 - 4.74 (m, 2H), 4.69 - 4.65 (m, 2H), 3.89 (s, 8H), 2.40 (s, 3H).

[0631] General Program 1

[0632] Compound 48: N - [(3S) - 1 - methylpyrrolidin - 3 - yl] - 7 - morpholino - 5 - [3 - (m - tolyl)pyrazol - 1 - yl]pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0633]

[0634] Synthesis of ethyl 5,7 - dioxo - 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate

[0635]

[0636] Small pieces of sodium (890 mg, 38.7 mmol) were carefully added to a solution of anhydrous EtOH (10 mL) at room temperature. After all the sodium had dissolved, the solution was concentrated to afford fresh NaOEt as a white solid. The freshly prepared NaOEt was added to a mixture of diethyl malonate (40 mL) and ethyl 5 - amino - 1H - pyrazole - 3 - carboxylate (2 g, 12.9 mmol). The mixture was heated to 120 °C and stirred overnight at this temperature. After the reaction mixture was cooled to room temperature, a large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to afford ethyl 5,7 - dioxo - 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate (5.92 g, 26.5 mmol) as a yellow solid. The crude product was used directly in the next step without further purification. LC - MS (ESI+): m / z 224 (MH + ).

[0637] Synthesis of ethyl 5,7 - dichloropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate

[0638]

[0639] A solution of ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate (5.92 g, 26.5 mmol) in phenylphosphonic dichloride (15 mL) was heated to 120 °C overnight. The reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 6 x 40 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 260 / 262 (MH + ).

[0640] Synthesis of ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate

[0641]

[0642] Morpholine (3.2 g, 37.3 mmol) was added to a solution of crude ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (4.83 g, 18.6 mmol) in 1,4-dioxane (60 mL). The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate (3.3 g, 10.6 mmol) as a yellow solid. LC-MS (ESI+): m / z 311 / 313 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 6.98 (s, 1H), 6.18 (s, 1H), 4.49 - 4.41 (m, 2H), 3.98 - 3.96 (m, 4H), 3.92 - 3.82 (m, 4H), 1.33 (t, J = 8.4 Hz, 3H).

[0643] Synthesis of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

[0644]

[0645] Ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate (3.2 g, 10.6 mmol), 3-(m-tolyl)-1H-pyrazole (2.0 g, 12.8 mmol), Cs 2 CO3 (6.9 g, 21.3 mmol) and CuI (400 mg, 2.1 mmol) in a suspension in DMF (120 mL) were heated to 110 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with DCM / MeOH (15:1, 3 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 5% MeOH / DCM to afford ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (3.8 g, 8.8 mmol) as a white solid. LC-MS (ESI+): m / z 433 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.38 - 7.33 (m, 1H), 7.22 - 7.20 (m, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.50 - 4.43 (m, 2H), 4.03 - 4.01 (m, 4H), 3.93 - 3.91 (m, 4H), 2.45 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H).

[0646] Synthesis of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0647]

[0648] To a solution of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (3.8 g, 8.8 mmol) in THF (160 mL) was added 2 M aqueous NaOH solution (30 mL). The reaction was heated to 40 and maintained for 3 h. The completion of the reaction was monitored by TLC. 1 M aqueous HCl solution was added to the reaction mixture until pH = 4. The resulting solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to afford 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid as a white solid (3.5 g, 8.7 mmol). LC-MS (ESI+): m / z 405 (MH + ). 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 3.89 (s, 8H), 2.40 (s, 3H).

[0649] Synthesis of (S)-N-(1-methylpyrrolidin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0650]

[0651] A solution of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (60 mg, 0.15 mmol), (S)-1-methylpyrrolidin-3-amine (16 mg, 0.16 mmol), EDCl (70.8 mg, 0.37 mmol) and DMAP (46 mg, 0.37 mmol) in DCM was stirred overnight at room temperature. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 3% MeOH / DCM to afford (S)-N-(1-methylpyrrolidin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide as a white solid (Compound 48 32 mg, 0.07 mmol). LC-MS (ESI+): m / z 487 (MH + ). 1 HNMR (300 MHz, DMSO-d 6)δ 8.72 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 7.5 Hz, 1H), 7.82 - 7.79 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.13 (J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.85 (s, 1H), 4.50 - 4.40 (m, 1H), 3.90 (s, 8H), 2.82 - 2.72 (m, 2H), 2.50 - 2.45 (m, 1H), 2.40 (s, 3H), 2.31 (s, 3H), 2.27 - 2.19 (m, 1H), 1.87 - 1.82 (m, 2H).

[0652] General Program 2

[0653] Compound 91: N,N - dimethyl - 2 - [5 - methyl - 3 - [7 - morpholino - 5 - [3 - (m - tolyl)pyrazol - 1 - yl]pyrazolo[1,5 - a]pyrimidin - 2 - yl]pyrazol - 1 - yl]ethylamine

[0654]

[0655] Synthesis of 2 - bromopyrazolo[1,5 - a]pyrimidine - 5,7(4H,6H) - dione

[0656]

[0657] To a solution of diethyl malonate (50 mL) and 3 - bromo - 1H - pyrazol - 5 - amine (5 g, 30.86 mmol) was added NaOEt (20% in anhydrous EtOH, 26 g). The mixture was heated to 120 °C to remove EtOH through a Dean - Stark separator. Then the reaction mixture was stirred at this temperature overnight. After the reaction mixture was cooled to room temperature, a large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to give crude 2 - bromopyrazolo[1,5 - a]pyrimidine - 5,7(4H,6H) - dione as a yellow solid (13.5 g, 59.2 mmol). The crude product was used directly in the next step without further purification. LC - MS (ESI+): m / z 230 / 232 (MH + ).

[0658] Synthesis of 2 - bromo - 5,7 - dichloropyrazolo[1,5 - a]pyrimidine

[0659]

[0660] A solution of crude 2-bromopyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (13.8 g, 56.7 mmol) in phenylphosphonic dichloride (100 mL) was heated to 120 °C overnight. In an ice bath, the reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 6 x 40 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (10 g, 37.8 mmol). The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 266 / 268 (MH + ).

[0661] Synthesis of 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0662]

[0663] Morpholine (6.58 g, 75.6 mmol) was added to a solution of crude 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (10 g, 37.8 mmol) in 1,4-dioxane (120 mL). The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a yellow solid (8.6 g, 27.2 mmol). LC-MS (ESI+): m / z 317 / 319 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 6.52 (s, 1H), 6.08 (s, 1H), 3.98 - 3.93 (m, 4H), 3.82 - 3.76 (m, 4H).

[0664] Synthesis of 4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0665]

[0666] To a solution of phenylmethanol (1.71 g, 15.8 mmol) in DMF (60 mL) was added NaH (1.27 g, 31.6 mmol). The mixture was stirred at 0 °C for 30 min. To the reaction was added a solution of 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine (5 g, 15.8 mmol) in DMF (20 mL). The reaction mixture was stirred at 0 °C for 2 h. The completion of the reaction was monitored by TLC. Water (200 mL) was added to the above solution and a large amount of solid precipitated. After filtration, the cake was washed twice with ether to afford 4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)morpholine (7.5 g, 19.3 mmol) as a white solid. LC-MS (ESI+): m / z 389 / 391 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 7.61 - 7.32 (m, 5H), 6.34 (s, 1H), 5.66 (s, 1H), 5.34 (s, 2H), 3.98 - 3.92 (m, 4H), 3.66 - 3.59 (m, 4H).

[0667] Synthesis of tert-butyl 3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazole-1-carboxylate

[0668]

[0669] A suspension of 4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)morpholine (7.5 g, 19.3 mmol), (1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)boronic acid (4.78 g, 21.2 mmol), Pd(PPh) 2 Cl 2 (1.35 g, 1.92 mmol) and CsF (8.77 g, 57.7 mmol) in 1,4-dioxane / H 2 O (330 mL, 10:1) was heated to 95 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 25% EtOAc / Hex to 33% EtOAc / Hex to afford tert-butyl 3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazole-1-carboxylate (4.2 g, 8.57 mmol) as a pale yellow oil. LC-MS (ESI+): m / z 491 (MH + ). 1HNMR (300 MHz, CDCl 3 ) δ 7.48 - 7.42 (m, 2H), 7.39 - 7.32 (m, 3H), 6.50 (s, 1H), 6.44 (s, 1H), 5.70 (s, 1H), 5.42 (s, 2H), 3.94 - 3.88 (m, 4H), 3.68 - 3.63 (m, 4H), 2.36 (s, 3H), 1.49 (s, 9H).

[0670] Synthesis of 4-(5-(Benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0671]

[0672] To a solution of tert-butyl 3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazole-1-carboxylate (4.2 g, 8.57 mmol) in DCM (40 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. A large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to afford crude 4-(5-(benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a white solid (4.5 g, 11.5 mmol). The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 391 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 7.48 - 7.42 (m, 2H), 7.39 - 7.32 (m, 3H), 6.58 (s, 1H), 6.51 (s, 1H), 5.70 (s, 1H), 5.42 (s, 2H), 3.98 - 3.92 (m, 4H), 3.68 - 3.61 (m, 4H), 2.38 (s, 3H).

[0673] Synthesis of 2-(3-(5-(Benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine and 2-(5-(5-(Benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine

[0674]

[0675] To a solution of crude 4-(5-(benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (4.5 g, 11.5 mmol) in DMF was added Cs 2 CO 3 (11.28 g, 34.62 mmol) and 2-chloro-N,N-dimethylethylamine hydrochloride (2 g, 13.85 mmol). The mixture was stirred at 80 °C overnight. TLC showed two new spots. LC-MS showed the desired product. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 70 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 5% MeOH / DCM to 10% MeOH / DCM to afford 2-(5-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (upper spot, 2.1 g, 4.5 mmol) and 2-(3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (lower spot, 0.6 g, 1.3 mmol) as white solids.

[0676] 2-(5-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (upper spot). LC-MS (ESI+): m / z 462 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 7.48 - 7.42 (m, 2H), 7.39 - 7.32 (m, 3H), 6.48 (s, 1H), 6.38 (s, 1H), 5.70 (s, 1H), 5.42 (s, 2H), 4.66 (t, J = 7.5 Hz, 2H), 3.98 - 3.92 (m, 4H), 3.70 - 3.64 (m, 4H), 2.76 (t, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 6H). 2-(3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (lower spot). LC-MS (ESI+): m / z 462 (MH + ). 1 HNMR (300 MHz, CDCl3 ) δ 7.48 - 7.42 (m, 2H), 7.39 - 7.32 (m, 3H), 6.64 (s, 1H), 6.50 (s, 1H), 5.65 (s, 1H), 5.42 (s, 2H), 4.33 (t, J = 6.9 Hz, 2H), 3.98 - 3.93 (m, 4H), 3.68 - 3.63 (m, 4H), 3.08 (t, J = 6.9 Hz, 2H), 2.46 (s, 6H), 2.36 (s, 3H).

[0677] Synthesis of 2-(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-5-ol

[0678]

[0679] At room temperature under a H 2 balloon, Pd / C was added to a solution of 2-(3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (0.6 g, 1.3 mmol) in MeOH and maintained for 4 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was directly concentrated to afford crude 2-(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-5-ol (0.4 g, 1.01 mmol) as a white solid. LC-MS (ESI+): m / z 372 (H + ).

[0680] Synthesis of 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine

[0681]

[0682] A solution of 2-(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-5-ol (0.4 g, 1.01 mmol) in phenylphosphonic dichloride (15 mL) was heated to 110 °C for 4 h. The reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 2 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. Purify the crude product by preparative TLC to afford 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (250 mg, 0.64 mmol) as a white solid. LC-MS (ESI+): m / z 390 / 392 (MH + ).

[0683] Synthesis of N,N-dimethyl-2-(5-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazol-1-yl)ethylamine

[0684]

[0685] A suspension of 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (39 mg, 0.10 mmol), 4-(m-tolyl)-1H-pyrazole (17 mg, 0.11 mmol), Cs 2 CO 3 (65 mg, 0.20 mmol) and Cu 2 O (2.8 mg, 0.02 mmol) in DMF (5 mL) was heated at 110 °C overnight. Monitor the completion of the reaction by TLC. Concentrate the reaction mixture directly and purify by silica gel column chromatography eluting with a gradient of 5% MeOH / DCM to 10% MeOH / DCM to afford N,N-dimethyl-2-(5-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazol-1-yl)ethylamine (Compound 91 9 mg, 0.018 mmol) as a white solid. LC-MS (ESI+): m / z 512 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.4 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.81 - 6.75 (m, 2H), 6.53 (s, 1H), 4.35 - 4.25 (m, 2H), 4.10 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 3.00 - 2.85 (m, 2H), 2.45 (s, 3H), 2.39 (s, 9H).

[0686] General Program 3

[0687] Compound 97: 2-[3-[5-[3-(3-chlorophenyl)-1H-pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]-5-methyl-1H-pyrazol-1-yl]-N,N-dimethylethanamine

[0688]

[0689] Synthesis of 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0690]

[0691] A suspension of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 1.18 mmol), 1-chloro-3-iodobenzene (280 mg, 1.18 mmol), CsF (488 mg, 3.21 mmol), and Pd(dppf)Cl 2 (225 mg, 0.30 mmol) in 1,4-dioxane / H 2 O (44 mL, 10:1) was heated to 60 °C overnight. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 10% EtOAc / Hex to 20% EtOAc / Hex to afford impure 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (377 mg, 1.44 mmol) as a yellow oil. LC-MS (ESI+): m / z 263 / 265 (MH + ).

[0692] Synthesis of 3-(3-chlorophenyl)-1H-pyrazole

[0693]

[0694] TFA (3 mL) was added to a solution of impure 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (377 mg, 1.44 mmol) in DCM. The reaction was stirred at room temperature for 2 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 179 / 181 (MH + ).

[0695] Synthesis of 2-(3-(5-(3-(3-chlorophenyl)-1H-pyrazol-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine

[0696]

[0697] A suspension of 3-(3-chlorophenyl)-1H-pyrazole (22 mg, 0.12 mmol), 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (40 mg, 0.10 mmol), Cs 2 CO 3 (68 mg, 0.20 mmol) and Cu 2 O (3 mg, 0.02 mmol) in DMF (10 mL) was heated at 110 °C overnight. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 2-(3-(5-(3-(3-chlorophenyl)-1H-pyrazol-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethylamine (Compound 97 15.2 mg, 0.03 mmol) as a white solid. LC-MS (ESI+): m / z 532 / 534 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.67 (d, J = 2.7 Hz, 1H), 7.96 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.46 - 7.33 (m, 2H), 7.00 (s, 1H), 6.81 - 6.78 (m, 2H), 6.53 (s, 1H), 4.26 - 4.22 (m, 2H), 4.06 - 4.00 (m, 4H), 3.95 - 3.89 (m, 4H), 2.84 - 2.80 (m, 2H), 2.38 (s, 3H), 2.33 (s, 6H).

[0698] General Program 4

[0699] Compound 96: N,N-dimethyl-2-[5-methyl-3-[5-[3-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl]-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl]-1H-pyrazol-1-yl]ethanamine

[0700]

[0701] Synthesis of (E)-3-(dimethylamino)-1-(2-methylpyridin-4-yl)prop-2-en-1-one

[0702]

[0703] A solution of 1-(2-methylpyridin-4-yl)ethanone (100 mg, 0.75 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine was heated to reflux for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford (E)-3-(dimethylamino)-1-(2-methylpyridin-4-yl)prop-2-en-1-one (135 mg, 0.71 mmol) as a yellow oil. LC-MS (ESI+): m / z 191 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.68 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 12.3 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J = 5.1 Hz, 1H), 5.63 (d, J = 12.3 Hz, 1H), 3.18 (s, 3H), 2.96 (s, 3H), 2.41 (s, 3H).

[0704] Synthesis of 2-methyl-4-(1H-pyrazol-3-yl)pyridine

[0705]

[0706] Hydrazine (0.3 mL) was added to a solution of (E)-3-(dimethylamino)-1-(2-methylpyridin-4-yl)prop-2-en-1-one (135 mg, 0.71 mmol) in ethanol (2 mL). The reaction mixture was heated to 60 °C for 30 min. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 2 4Dry, filter and concentrate under reduced pressure to afford 2-methyl-4-(1H-pyrazol-3-yl)pyridine as a yellow solid (109 mg, 0.68 mmol). LC-MS (ESI+): m / z 160 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.53 (d, J = 3.9 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.51 - 7.49 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 2.64 (s, 3H).

[0707] Synthesis of N,N-dimethyl-2-(5-methyl-3-(5-(3-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanamine

[0708]

[0709] A suspension of 2-methyl-4-(1H-pyrazol-3-yl)pyridine (20 mg, 0.12 mmol), 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (40 mg, 0.10 mmol), Cs 2 2CO 3 (68 mg, 0.20 mmol) and Cu 2 O (2 mg, 0.01 mmol) in DMF (4 mL) was heated at 110 °C overnight. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford N,N-dimethyl-2-(5-methyl-3-(5-(3-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanamine as a white solid (Compound 96 15.6 mg, 0.03 mmol). LC-MS (ESI+): m / z 513 (MH + ). 1 1H NMR (300 MHz, CDCl 3)δ8.70(d,J=2.7Hz,1H),8.57(d,J=5.4Hz,1H),7.68(s,1H),7.62-7.60(m,1H),7.00(s,1H),6.87(d,J=2.7Hz,1H),6.82(s,1H),6.53(s,1H),4.27-4.22(m,2H),4.05-4.00(m,4H),3.95-3.91(m,4H),2.85-2.81(m,2H),2.65(s,3H),2.38(s,3H),2.34(s,6H).

[0710] General Program 5

[0711] Compound 84: 4-[2-(2,5-dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine and

[0712] Compound 87: 4-[2-(1,5-dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0713]

[0714] Synthesis of 4-(2-bromo-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0715]

[0716] A suspension of 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine (5 g, 15.8 mmol), 3-phenyl-1H-pyrazole (2.75 g, 17.4 mmol), Cs 2 CO 3 (10.3 g, 31.6 mmol) and Cu 2 O (453 mg, 3.2 mmol) in DMF (80 mL) was heated at 110 °C overnight. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 20% EtOAc / HeX to 33% EtOAc / HeX to afford 4-(2-bromo-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (5.0 g, 11.4 mmol) as a yellow solid. LC-MS (ESI+): m / z 439 / 441 (MH + ). 1 HNMR(300MHz,CDCl3 )δ 8.59 (d, J = 2.7 Hz, 1H), 7.80 - 7.62 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.19 - 7.10 (m, 1H), 6.91 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.48 (s, 1H), 4.05 - 3.95 (m, 4H), 3.85 - 3.80 (m, 4H), 2.44 (s, 3H).

[0717] Synthesis of tert-butyl 5-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazole-1-carboxylate

[0718]

[0719] A suspension of 4-(2-bromo-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (200 mg, 0.46 mmol), (1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-5-yl)boronic acid (114 mg, 0.50 mmol), CsF (208 mg, 1.37 mmol) and Pd(dppf)Cl 2 (32 mg, 0.05 mmol) in 1,4-dioxane / H 2 O (22 mL, 10:1) was heated to 100 °C and maintained for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography eluting with a gradient of 20% EtOAc / Hex to 33% EtOAc / Hex to afford tert-butyl 5-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-1H-pyrazole-1-carboxylate (220 mg, 0.41 mmol) as a colorless oil. LC-MS (ESI+): m / z 541 (MH + ).

[0720] Synthesis of 4-(2-(5-methyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0721]

[0722] To a solution of 4-(2-(5-methyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (220 mg, 0.41 mmol) in DCM (5 mL) was added HCl / Et2 O solution (2 mL). The reaction completion was monitored by TLC. The reaction mixture was quenched with saturated NaHCO 3 solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 2 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to afford 4-(2-(5-methyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a pale yellow solid (138 mg, 0.31 mmol). LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.38 - 7.32 (m, 2H), 7.22 - 7.15 (m, 1H), 7.06 (s, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6.73 (s, 1H), 6.56 (brs, 1H), 4.05 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 2.45 (s, 3H), 2.40 (s, 3H).

[0723] Synthesis of 4-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine and 4-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0724]

[0725] To a suspension of 4-(2-(5-methyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (100 mg, 0.23 mmol) and Cs 2 CO 3 (222 mg, 0.68 mmol) in DMF (5 mL) was added CH 3 I (48 mg, 0.34 mmol) at room temperature. The reaction completion was monitored by TLC. The reaction was quenched with water (50 ml) and the solution was extracted with DCM (3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography eluting with a gradient of 5% MeOH / DCM to 8% MeOH / DCM to afford 4-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Compound 87, lower spot, 21 mg, 0.046 mmol) and 4-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Compound 84, upper spot, 42 mg, 0.092 mmol).

[0726] 4-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Compound 87, lower spot). LC-MS (ESI+): m / z 455 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 8.67 (d, J = 2.7 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.05 (s, 1H), 6.83 - 6.82 (m, 2H), 6.56 (s, 1H), 4.07 - 4.02 (m, 4H), 3.95 - 3.90 (m, 4H), 3.89 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H).

[0727] 4-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Compound 84, upper spot). LC-MS (ESI+): m / z 455 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 8.60 (d, J = 2.7 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.04 (s, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 4.17 (s, 3H), 4.02 - 3.90 (m, 4H), 3.88 - 3.85 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H).

[0728] General Program 6

[0729] Compound 57: 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0730]

[0731] Synthesis of 4-(2-bromo-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0732]

[0733] A suspension of 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine (3 g, 9.45 mmol), 4-(m-tolyl)-1H-pyrazole (1.5 g, 9.45 mmol), Cs 2 CO 3 (6.16 g, 18.9 mmol) and Cu 2 O (135 mg, 0.945 mmol) in DMF (150 mL) was heated at 110 °C overnight. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to afford 4-(2-bromo-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (4.5 g, 10.27 mmol) as a pale yellow solid. LC-MS (ESI+): m / z 439 / 441 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.81 (s, 1H), 8.02 (s, 1H), 7.47 - 7.33 (m, 2H), 7.30 - 7.26 (m, 1H), 7.13 - 7.11 (m, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 3.98 - 3.92 (m, 4H), 3.85 - 3.78 (m, 4H), 2.41 (s, 3H).

[0734] Synthesis of 4-(2-(pyrimidin-4-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0735]

[0736] In N 2Under the following conditions, 4-(2-bromo-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (100 mg, 0.23 mmol), 4-(tributylstannyl)pyrimidine (168 mg, 0.45 mmol), CuI (13 mg, 0.068 mmol) and Pd(PPh) 2 Cl 2 The suspension in DMF (3 mL) was heated to 100 °C and maintained for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution of 2% MeOH / DCM to 3% MeOH / DCM to afford 4-(2-(pyrimidin-4-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Compound 57, 24 mg, 0.055 mmol) as a pale yellow solid. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 9.33 (s, 1H), 8.89 (s, 1H), 8.86 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.53 - 7.42 (m, 2H), 7.34 - 7.29 (m, 2H), 7.14 - 7.12 (m, 1H), 7.06 (s, 1H), 4.10 - 4.00 (m, 4H), 3.92 - 3.81 (m, 4H), 2.42 (s, 3H).

[0737] General Program 7

[0738] Compound 58: 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0739]

[0740] Synthesis of 4-(2-(pyrimidin-5-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0741]

[0742] 4-(2-Bromo-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (100 mg, 0.23 mmol), pyrimidin-5-ylboronic acid (34 mg, 0.28 mmol), CsF (52 mg, 0.34 mmol) and Pd(dppf)Cl2 (16 mg, 0.023 mmol) in 1,4-dioxane / H 2 O (7.5 mL, 2:1) was heated at 80 °C overnight. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 1% MeOH / DCM to 2% MeOH / DCM to afford 4-(2-(pyrimidin-5-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine as a yellow solid (Compound 58, 21 mg, 0.048 mmol). LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 9.38 - 9.25 (m, 2H), 8.85 (s, 1H), 8.04 (s, 1H), 7.55 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.13 (d, J = 6.9 Hz, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 4.10 - 4.00 (m, 4H), 3.95 - 3.86 (m, 4H), 2.42 (s, 3H).

[0743] General Program 8

[0744] Compound 89: Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate

[0745]

[0746] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0747]

[0748] To a solution of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (370 mg, 0.94 mmol) in DCM (50 mL) was added methyl chloroformate (107 mg, 1.12 mmol). The mixture was stirred at room temperature for 10 min and then ammonium hydroxide (143 mg, 1.44 mmol) was added to the mixture. The reaction completion was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 10% MeOH / DCM to afford 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (326 mg, 0.84 mmol) as a white solid. LC-MS (ESI+): m / z 390 (MH + ). 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.73 (d, J = 2.7 Hz, 1H), 8.10 - 8.00 (m, 3H), 7.63 (s, 1H), 7.53 - 7.30 (m, 3H), 7.16 (d, J = 2.7 Hz, 1H), 7.04 (s, 1H), 6.83 (s, 1H), 3.95 - 3.85 (m, 8H).

[0749] Synthesis of (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanamine

[0750]

[0751] To a solution of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (200 mg, 0.26 mmol) in THF (50 mL) was added borane-tetrahydrofuran complex (2 mL, 1.02 mmol). The mixture was stirred at 60 °C overnight. The reaction completion was monitored by TLC. The reaction mixture was quenched with 1 M aqueous HCl and then the pH was adjusted to 8 using NaHCO 3 solution. The aqueous solution was extracted with DCM / MeOH (10:1, 3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 5% MeOH / DCM to afford (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanamine (110 mg, 0.29 mmol) as a white solid. LC-MS (ESI+): m / z 376 (MH + ).

[0752] Synthesis of ((7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methyl)carbamate

[0753]

[0754] To a solution of (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanamine (55 mg, 0.013 mmol) in DCM (50 mL) was added methyl chloroformate (13.8 mg, 0.016 mmol). The mixture was stirred at room temperature for 10 min and then Et 3 N (22 mg, 0.026 mmol) was added to the mixture. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 10% MeOH / DCM to afford ((7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methyl)carbamate (Compound 89, 16 mg, 0.037 mmol) as a white solid. LC-MS (ESI+): m / z 434 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.49 - 7.36 (m, 3H), 7.05 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 5.24 (brs, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.13 - 4.02 (m, 4H), 3.86 - 3.80 (m, 4H), 3.74 (s, 3H).

[0755] Example 48: N-[(3S)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0756]

[0757] Compound 48 was prepared by General Procedure 1. LC-MS (ESI+): m / z 487 (MH + +). 1 1H NMR (300 MHz, DMSO-d 6 6) δ 8.72 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 7.5 Hz, 1H), 7.82 - 7.79 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.13 (J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.85 (s, 1H), 4.50 - 4.40 (m, 1H), 3.90 (s, 8H), 2.82 - 2.72 (m, 2H), 2.50 - 2.45 (m, 1H), 2.40 (s, 3H), 2.31 (s, 3H), 2.27 - 2.19 (m, 1H), 1.87 - 1.82 (m, 2H).

[0758] Example 49: N-[(3R)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0759]

[0760] Compound 49 was prepared by General Procedure 1. LC-MS (ESI+): m / z 487 (MH + +). 1 1H NMR (300 MHz, DMSO-d 6 6) δ 8.72 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.85 (s, 1H), 4.46 - 4.42 (m, 1H), 3.90 (s, 8H), 2.83 - 2.73 (m, 2H), 2.69 - 2.63 (m, 1H), 2.50 (s, 3H), 2.40 (s, 3H), 2.28 - 2.23 (m, 1H), 1.98 - 1.85 (m, 2H).

[0761] Example 50: 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0762]

[0763] Compound 50 was prepared by General Procedure 1. LC-MS (ESI+): m / z 474 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.72 (d, J = 2.4 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.07 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.07 - 3.94 (m, 6H), 3.90 - 3.78 (m, 6H), 2.45 (s, 3H), 2.41 - 2.39 (m, 1H), 1.98 - 1.85 (m, 1H).

[0764] Example 51: 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0765]

[0766] Compound 51 was prepared by General Procedure 1. LC-MS (ESI+): m / z 474 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.4 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 - 7.18 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H), 7.00 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.04 - 3.94 (m, 6H), 3.90 - 3.78 (m, 6H), 2.45 (s, 3H), 2.41 - 2.34 (m, 1H), 1.98 - 1.85 (m, 1H).

[0767] Example 52: N-[(3R)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0768]

[0769] Compound 52 was prepared by General Procedure 1. LC-MS (ESI+): m / z 501 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.82 - 7.79 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 2.7 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 4.02 - 3.95 (m, 1H), 3.90 (s, 8H), 2.70 - 2.61 (m, 1H), 2.50 - 2.40 (m, 4H), 2.21 (s, 3H), 2.11 - 2.07 (m, 2H), 1.80 - 1.60 (m, 2H), 1.58 - 1.40 (m, 2H).

[0770] Example 53: N-[(3S)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0771]

[0772] Compound 53 was prepared by General Procedure 1. LC-MS (ESI+): m / z 501 (MH + ) 1 1H NMR (300 MHz, DMSO-d 6 ) δ 8.72 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 4.09 - 3.99 (m, 1H), 3.90 (s, 8H), 2.70 - 2.61 (m, 1H), 2.50 - 2.40 (m, 4H), 2.21 (s, 3H), 2.11 - 2.07 (m, 2H), 1.80 - 1.60 (m, 2H), 1.58 - 1.40 (m, 2H).

[0773] Example 54: N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0774]

[0775] Compound 54 was prepared by General Procedure 1. LC-MS (ESI+): m / z 501 (MH + ). 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.16 - 8.06 (m, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 3.90 - 3.80 (m, 9H), 2.95 - 2.86 (m, 2H), 2.40 (s, 3H), 2.32 - 2.21 (m, 5H), 1.91 - 1.73 (m, 4H).

[0776] Example 55: N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0777]

[0778] Compound 55 was prepared by General Procedure 1. LC-MS (ESI+): m / z 501 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.06 (s, 1H), 7.49 - 7.43 (m, 2H), 7.33 - 7.28 (m, 1H), 7.16 - 7.12 (m, 2H), 6.99 - 6.94 (m, 2H), 4.32 - 4.21 (m, 1H), 4.10 - 4.05 (m, 4H), 3.86 - 3.79 (m, 4H), 3.65 - 3.60 (m, 2H), 2.98 - 2.90 (m, 2H), 2.85 (s, 3H), 2.55 - 2.47 (m, 2H), 2.43 (s, 3H), 2.30 - 2.25 (m, 2H).

[0779] Example 56: 7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]-N-tetrahydropyran-4-yl-pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0780]

[0781] Compound 56 was prepared by General Procedure 1. LC-MS (ESI+): m / z 488 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ 8.86 (s, 1H), 8.04 (s, 1H), 7.44 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 7.14 - 7.09 (m, 2H), 7.03 (s, 1H), 6.86 - 6.83 (m, 1H), 4.30 - 4.21 (m, 1H), 4.10 - 4.00 (m, 6H), 3.85 - 3.75 (m, 4H), 3.61 - 3.54 (m, 2H), 2.41 (s, 3H), 2.08 - 2.03 (m, 2H), 1.71 - 1.58 (m, 2H).

[0782] Example 57: 4 - [5 - [4 - (m - Tolyl)pyrazol - 1 - yl] - 2 - pyrimidin - 4 - yl - pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0783]

[0784] Compound 57 was prepared by General Procedures 2 and 6. LC - MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ 9.33 (s, 1H), 8.89 (s, 1H), 8.86 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.53 - 7.42 (m, 2H), 7.34 - 7.29 (m, 2H), 7.14 - 7.12 (m, 1H), 7.06 (s, 1H), 4.10 - 4.00 (m, 4H), 3.92 - 3.81 (m, 4H), 2.42 (s, 3H).

[0785] Example 58: 4 - [5 - [4 - (m - Tolyl)pyrazol - 1 - yl] - 2 - pyrimidin - 5 - yl - pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0786]

[0787] Compound 58 was prepared by General Procedures 2 and 7. LC - MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl 3)δ 9.38 - 9.25 (m, 2H), 8.85 (s, 1H), 8.04 (s, 1H), 7.55 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.13 (d, J = 6.9 Hz, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 4.10 - 4.00 (m, 4H), 3.95 - 3.86 (m, 4H), 2.42 (s, 3H).

[0788] Example 59: 3-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0789]

[0790] Compound 59 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 453 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6 ) δ 9.09 (s, 1H), 8.40 (s, 1H), 8.16 (d, J = 6.3 Hz, 1H), 8.06 (d, J = 4.2 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.12 - 7.07 (m, 4H), 6.96 (s, 1H), 6.74 - 6.70 (m, 1H), 3.95 - 3.85 (m, 4H), 3.85 - 3.80 (m, 4H), 2.36 (s, 3H).

[0791] Example 60: 5-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine

[0792]

[0793] Compound 60 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 454 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.88 (s, 2H), 8.37 (s, 1H), 7.67 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.99 (s, 2H), 6.92 (d, J = 9.0 Hz, 2H), 3.89 (s, 8H), 2.36 (s, 3H).

[0794] Example 61: 4-[2-(1-Methylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0795]

[0796] Compound 61 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 441 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 8.66 (d, J = 2.7 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.42 (d, J = 2.1 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 - 7.15 (m, 1H), 7.05 (s, 1H), 6.83 - 6.81 (m, 2H), 6.76 (d, J = 2.1 Hz, 1H), 4.13 - 4.08 (m, 4H), 4.02 (s, 3H), 3.95 - 3.90 (m, 4H), 2.45 (s, 3H).

[0797] Example 62: 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0798]

[0799] Compound 62 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ) 1 HNMR (300 MHz, DMSO-d 6 +D 2 O) δ 8.71 (d, J = 2.4 Hz, 1H), 7.82 - 7.79 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.99 (s, 1H), 6.85 - 6.80 (m, 2H), 4.05 (s, 8H), 2.41 (s, 3H).

[0800] Example 63: 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0801]

[0802] Compound 63 was prepared by General Procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.90 (d, J = 4.8 Hz, 2H), 8.69 (d, J = 2.7 Hz 1H), 7.95 (d, J = 2.7 Hz, 2H), 7.50 - 7.31 (m, 5H), 7.15 (s, 1H), 6.85 (d, J = 2.7 Hz, 1H), 4.13 - 4.08 (m, 4H), 4.07 - 3.95 (m, 4H).

[0803] Example 64: 4-[5-(3-Phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0804]

[0805] Compound 64 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.65 (d, J = 2.7 Hz, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.50 - 7.30 (m, 4H), 7.11 (s, 1H), 6.85 (d, J = 2.7 Hz, 1H), 6.82 (s, 1H), 4.10 - 4.04 (m, 4H), 3.96 - 3.90 (m, 4H).

[0806] Example 65: 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0807]

[0808] Compound 65 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.63(d,J=2.7Hz,1H),7.76-7.61(m,2H),7.38-7.32(m,2H),7.22-7.15(m,1H),7.06(s,1H),6.81(d,J=2.7Hz,1H),6.73(s,1H),6.56(brs,1H),4.05-4.00(m,4H),3.95-3.85(m,4H),2.45(s,3H),2.40(s,3H).

[0809] Example 66: 4-[2-(1-Methylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0810]

[0811] Compound 66 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ8.66(d,J=2.7Hz,1H),7.94(d,J=6.9Hz,2H),7.48-7.32(m,4H),7.05(s,1H),6.82(s,2H),6.73(d,J=2.1Hz,1H),4.15-4.05(m,4H),4.02(s,3H),3.95-3.88(m,4H).

[0812] Example 67: 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0813]

[0814] Compound 67 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 413 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6 +D 2 6)δ8.73(d,J=2.7Hz,1H),8.02(d,J=7.2Hz,2H),7.78(d,J=2.1Hz,1H),7.53-7.40(m,3H),7.15(d,J=2.7Hz,1H),6.99(s,1H),6.80-6.78(m,2H),3.92(s,8H).

[0815] Example 68: 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0816]

[0817] Compound 68 was prepared by General Procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.90 (d, J = 2.7 Hz, 1H), 8.84 (d, J = 4.8 Hz 1H), 8.68 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.50 - 7.37 (m, 3H), 7.23 (s, 1H), 7.17 (s, 1H), 6.85 (d, J = 2.7 Hz, 1H), 4.13 - 4.06 (m, 4H), 3.95 - 3.90 (m, 4H).

[0818] Example 69: 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0819]

[0820] Compound 69 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 425 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 9.32 (s, 2H), 9.25 (s, 1H), 8.65 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 6.9 Hz, 2H), 7.63 - 7.37 (m, 3H), 7.17 (s, 1H), 6.86 - 6.85 (m, 2H), 4.06 - 4.01 (m, 4H), 3.95 - 3.90 (m, 4H).

[0821] Example 70: 3-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0822]

[0823] Compound 70 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 8.11 - 8.09 (m, 1H), 7.80 - 7.94 (m, 3H), 7.50 - 7.33 (m, 3H), 7.11 (s, 1H), 6.86 - 6.77 (m, 3H), 6.63 (s, 2H), 4.04 - 4.00 (m, 4H), 3.86 - 3.83 (m, 4H).

[0824] Example 71: 5 - [7 - Morpholino - 5 - (3 - phenylpyrazol - 1 - yl)pyrazolo[1,5 - a]pyrimidin - 2 - yl]pyrimidin - 2 - amine

[0825]

[0826] Compound 71 was prepared by General Procedures 2 and 7. LC - MS (ESI+): m / z 440 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.67 (s, 2H), 8.64 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.50 - 7.33 (m, 3H), 7.09 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 6.67 (s, 1H), 5.20 (s, 2H), 4.04 - 4.00 (m, 4H), 3.96 - 3.87 (m, 4H).

[0827] Example 72: 4 - [5 - (3 - phenylpyrazol - 1 - yl) - 2 - (2 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0828]

[0829] Compound 72 was prepared by General Procedures 2 and 6. LC - MS (ESI+): m / z 424 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.73 (d, J = 4.2 Hz, 1H), 8.69 (d, J = 2.7 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.84 - 7.80 (m, 1H), 7.49 - 7.30 (m, 4H), 7.16 (s, 1H), 7.11 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.11 - 4.03 (m, 4H), 3.96 - 3.87 (m, 4H).

[0830] Example 73: N-Isopropyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0831]

[0832] Compound 73 was prepared by General Procedure 1. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.18 (s, 1H), 7.01 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 6.77 - 6.74 (m, 1H), 4.36 - 4.27 (m, 1H), 4.09 - 4.00 (m, 4H), 3.90 - 3.80 (m, 4H), 1.31 (d, J = 6.6 Hz, 6H).

[0833] Example 74: N-[(1R)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0834]

[0835] Compound 74 was prepared by General Procedure 1. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.18 (s, 1H), 7.01 (s, 1H), 6.93 - 6.85 (m, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.09 - 4.00 (m, 4H), 3.90 - 3.80 (m, 4H), 3.71 - 3.60 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H), 1.00 - 0.90 (m, 1H), 0.57 - 0.40 (m, 3H), 0.34 - 0.31 (m, 1H).

[0836] Example 75: N-[(1S)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0837]

[0838] Compound 75 was prepared by General Procedure 1. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.18 (s, 1H), 7.01 (s, 1H), 6.93 - 6.85 (m, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.06 - 4.00 (m, 4H), 3.88 - 3.80 (m, 4H), 3.70 - 3.60 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H), 1.00 - 0.90 (m, 1H), 0.57 - 0.40 (m, 3H), 0.34 - 0.31 (m, 1H).

[0839] Example 76: 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0840]

[0841] Compound 76 was prepared by General Procedure 1. LC-MS (ESI+): m / z 460 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.25 - 7.15 (m, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.89 - 4.80 (m, 2H), 4.54 - 4.45 (m, 2H), 4.06 - 4.00 (m, 4H), 3.88 - 3.70 (m, 6H), 3.39 - 3.30 (m, 1H).

[0842] Example 77: N-Cyclopentyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0843]

[0844] Compound 77 was prepared by General Procedure 1. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl3 ) δ 8.65 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.18 (s, 1H), 7.01 (s, 1H), 6.91 - 6.88 (m, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.06 - 4.00 (m, 4H), 3.88 - 3.75 (m, 4H), 2.16 - 2.08 (m, 2H), 1.80 - 1.60 (m, 4H), 1.60 - 1.50 (m, 2H).

[0845] Example 78: 4-[5-(4-Phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0846]

[0847] Compound 78 was prepared by General Procedures 2 and 6. LC-MS (ESI+): m / z 424 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.73 (d, J = 3.6 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.33 - 7.20 (m, 2H), 7.16 (s, 1H), 7.01 (s, 1H), 4.11 - 4.03 (m, 4H), 3.96 - 3.88 (m, 4H).

[0848] Example 79: 4-[5-(4-Phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0849]

[0850] Compound 79 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 424 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6)δ 9.28 (d, J = 1.5 Hz, 1H), 9.12 (s, 1H), 8.68 - 8.60 (m, 1H), 8.43 - 8.41 (m, 2H), 7.83 (d, J = 7.5 Hz, 2H), 7.57 - 7.53 (m, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.32 - 7.29 (m, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 3.92 (s, 8H).

[0851] Example 80: N-Isopropyl-7-morpholino-5-(4-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0852]

[0853] Compound 80 was prepared by General Procedure 1. LC-MS (ESI+): m / z 432 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.04 (s, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.32 - 7.29 (m, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.76 - 6.70 (m, 1H), 4.39 - 4.27 (m, 1H), 4.08 - 4.00 (m, 4H), 3.85 - 3.80 (m, 4H), 1.31 (d, J = 6.6 Hz, 6H).

[0854] Example 81: 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0855]

[0856] Compound 81 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6 +D 2 6) δ 8.73 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.60 - 7.40 (m, 3H), 7.15 (d, J = 2.7 Hz, 1H), 6.98 (s, 1H), 6.74 (s, 1H), 6.54 (s, 1H), 3.91 (s, 8H), 2.39 (s, 3H).

[0857] Example 82: 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0858]

[0859] Compound 82 was prepared by General Procedures 2 and 6. LC-MS (ESI+): m / z 440 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 9.41 (s, 1H), 8.68 (d, J = 2.7 Hz, 2H), 8.58 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.50 - 7.33 (m, 4H), 7.15 (s, 2H), 6.85 (d, J = 2.7 Hz, 1H), 4.11 - 4.00 (m, 4H), 3.96 - 3.83 (m, 4H).

[0860] Example 83: N,N-Dimethyl-2-[3-methyl-5-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine

[0861]

[0862] Compound 83 was prepared by General Procedure 2. LC-MS (ESI+): m / z 512 (MH + ) 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.71 (d, J = 2.7 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.65 (s, 1H), 4.65 - 4.60 (m, 2H), 3.88 (s, 8H), 2.70 - 2.60 (m, 2H), 2.35 (s, 3H), 2.21 (s, 3H), 2.18 (s, 6H).

[0863] Example 84: 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0864]

[0865] Compound 84 was prepared by General Procedures 2 and 5. LC-MS (ESI+): m / z 455 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.60 (d, J = 2.7 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.04 (s, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 4.17 (s, 3H), 4.02 - 3.90 (m, 4H), 3.88 - 3.85 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H).

[0866] Example 85: 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0867]

[0868] Compound 85 was prepared by General Procedures 2 and 5. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.63 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.49 - 7.35 (m, 3H), 7.09 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 6.63 (s, 1H), 6.46 (s, 1H), 4.19 (s, 3H), 4.12 - 3.99 (m, 4H), 3.90 - 3.85 (m, 4H), 2.32 (s, 3H).

[0869] Example 86: 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0870]

[0871] Compound 86 was prepared by General Procedures 2 and 5. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl 3)δ8.63(d, J = 2.7Hz, 1H), 7.93(d, J = 7.2Hz, 2H), 7.49 - 7.35(m, 3H), 7.04(s, 1H), 6.79(d, J = 3.9Hz, 2H), 6.53(s, 1H), 4.12 - 3.99(m, 4H), 3.90 - 3.85(m, 4H), 3.78(s, 3H), 2.32(s, 3H).

[0872] Example 87: 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0873]

[0874] Compound 87 was prepared by General Procedures 2 and 5. LC-MS (ESI+): m / z 455 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ8.67(d, J = 2.7Hz, 1H), 7.79 - 7.73(m, 2H), 7.36(t, J = 7.8Hz, 1H), 7.22(d, J = 7.5Hz, 1H), 7.05(s, 1H), 6.83 - 6.82(m, 2H), 6.56(s, 1H), 4.07 - 4.02(m, 4H), 3.95 - 3.90(m, 4H), 3.89(s, 3H), 2.47(s, 3H), 2.36(s, 3H).

[0875] Example 88: 4-[5-(3-Phenylpyrazol-1-yl)-2-pyridazin-3-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0876]

[0877] Compound 88 was prepared by General Procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ9.21(d, J = 3.3Hz, 1H), 8.70(d, J = 2.7Hz, 1H), 8.30(d, J = 8.4Hz, 1H), 7.95(d, J = 8.4Hz, 2H), 7.61(t, J = 4.5Hz, 1H), 7.50 - 7.37(m, 4H), 7.15(s, 1H), 6.85(d, J = 2.7Hz, 1H), 4.11 - 4.02(m, 4H), 3.96 - 3.85(m, 4H).

[0878] Example 89: Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate

[0879]

[0880] Compound 89 was prepared by General Procedure 8. LC-MS (ESI+): m / z 434 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.49 - 7.36 (m, 3H), 7.05 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 5.24 (brs, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.13 - 4.02 (m, 4H), 3.86 - 3.80 (m, 4H), 3.74 (s, 3H).

[0881] Example 90: N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]acrylamide

[0882]

[0883] Compound 90 was prepared by General Procedure 8. LC-MS (ESI+): m / z 432 (MH + ) 1 HNMR (300 MHz, CDCl 3 ) δ 8.61 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.49 - 7.36 (m, 3H), 7.05 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.39 (s, 1H), 6.01 (brs, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.10 - 3.99 (m, 4H), 3.87 - 3.80 (m, 4H), 2.31 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0884] Example 91: N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine

[0885]

[0886] Compound 91 was prepared by General Procedure 2. LC-MS (ESI+): m / z 512 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.65 (d, J = 2.4 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.81 - 6.75 (m, 2H), 6.53 (s, 1H), 4.35 - 4.25 (m, 2H), 4.10 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 3.00 - 2.85 (m, 2H), 2.45 (s, 3H), 2.39 (s, 9H).

[0887] Example 92: N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(2-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethanamine

[0888]

[0889] Compound 92 was prepared by General Procedure 2. LC-MS (ESI+): m / z 499 (MH + ). 1 HNMR (300 MHz, CDCl 3 ) δ 8.71 - 8.68 (m, 2H), 8.13 (d, J = 8.1 Hz, 1H), 7.82 - 7.79 (m, 1H), 7.30 - 7.27 (m, 1H), 7.14 (d, J = 2.7 Hz, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.53 (s, 1H), 4.35 - 4.20 (m, 2H), 4.10 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 2.92 - 2.80 (m, 2H), 2.39 (s, 3H), 2.36 (s, 6H).

[0890] Example 93: N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethanamine

[0891]

[0892] Compound 93 was prepared by General Procedure 2. LC-MS (ESI+): m / z 499 (MH + ).1 HNMR(300MHz,CDCl 3 ) δ 8.72 - 8.69 (m, 3H), 7.81 (d, J = 6.0Hz, 2H), 7.00 (s, 1H), 6.90 (d, J = 6.6Hz, 1H), 6.82 (s, 1H), 6.53 (s, 1H), 4.30 - 4.20 (m, 2H), 4.10 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 2.91 - 2.80 (m, 2H), 2.38 (s, 3H), 2.35 (s, 6H).

[0893] Example 94: N,N - dimethyl - 2 - [5 - methyl - 3 - [5 - [3 - (6 - methyl - 2 - pyridyl)pyrazol - 1 - yl] - 7 - morpholino - pyrazolo[1,5 - a]pyrimidin - 2 - yl]pyrazol - 1 - yl]ethylamine

[0894]

[0895] Compound 94 was prepared by General Procedure 2. LC - MS(ESI+): m / z 513 (MH + ). 1 HNMR(300MHz,CDCl 3 ) δ 8.69 (s, 1H), 7.99 (d, J = 7.2Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.20 - 7.10 (m, 2H), 7.05 (s, 1H), 6.80 (s, 1H), 6.53 (s, 1H), 4.40 - 4.20 (m, 2H), 4.10 - 4.00 (m, 4H), 3.95 - 3.85 (m, 4H), 3.07 - 2.89 (m, 2H), 2.58 (s, 3H), 2.40 (s, 9H).

[0896] Example 95: N,N - dimethyl - 2 - [5 - methyl - 3 - [5 - [3 - (4 - methyl - 2 - pyridyl)pyrazol - 1 - yl] - 7 - morpholino - pyrazolo[1,5 - a]pyrimidin - 2 - yl]pyrazol - 1 - yl]ethylamine

[0897]

[0898] Compound 95 was prepared by General Procedures 2 and 4. LC - MS(ESI+): m / z 513 (MH + ). 1 HNMR(300MHz,CDCl 3)δ8.69(d, J = 2.7 Hz, 1H), 8.54(d, J = 5.1 Hz, 1H), 7.95(s, 1H), 7.14 - 7.10(m, 2H), 7.04(s, 1H), 6.81(s, 1H), 6.46(s, 1H), 4.35 - 4.20(m, 2H), 4.10 - 4.00(m, 4H), 3.95 - 3.85(m, 4H), 3.01 - 2.85(m, 2H), 2.46(s, 3H), 2.40(s, 9H).

[0899] Example 96: N,N - dimethyl - 2 - [5 - methyl - 3 - [5 - [3 - (2 - methyl - 4 - pyridyl)pyrazol - 1 - yl] - 7 - morpholino - pyrazolo[1,5 - a]pyrimidin - 2 - yl]pyrazol - 1 - yl]ethylamine

[0900]

[0901] Compound 96 was prepared by General Procedures 2 and 4. LC - MS(ESI+): m / z 513(MH + ). 1 1H NMR(300 MHz, CDCl 3 )δ8.70(d, J = 2.7 Hz, 1H), 8.57(d, J = 5.4 Hz, 1H), 7.68(s, 1H), 7.62 - 7.60(m, 1H), 7.00(s, 1H), 6.87(d, J = 2.7 Hz, 1H), 6.82(s, 1H), 6.53(s, 1H), 4.27 - 4.22(m, 2H), 4.05 - 4.00(m, 4H), 3.95 - 3.91(m, 4H), 2.85 - 2.81(m, 2H), 2.65(s, 3H), 2.38(s, 3H), 2.34(s, 6H).

[0902] Example 97: 2 - [3 - [5 - [3 - (3 - chlorophenyl)pyrazol - 1 - yl] - 7 - morpholino - pyrazolo[1,5 - a]pyrimidin - 2 - yl] - 5 - methyl - pyrazol - 1 - yl] - N,N - dimethyl - ethylamine

[0903]

[0904] Compound 97 was prepared by General Procedures 2 and 3. LC - MS(ESI+): m / z 532 / 534(MH + ). 1 1H NMR(300 MHz, CDCl 3)δ 8.67 (d, J = 2.7 Hz, 1H), 7.96 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.46 - 7.33 (m, 2H), 7.00 (s, 1H), 6.81 - 6.78 (m, 2H), 6.53 (s, 1H), 4.26 - 4.22 (m, 2H), 4.06 - 4.00 (m, 4H), 3.95 - 3.89 (m, 4H), 2.84 - 2.80 (m, 2H), 2.38 (s, 3H), 2.33 (s, 6H).

[0905] Example 98: 5-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0906]

[0907] Compound 98 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 432 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 8.64 (d, J = 2.7 Hz, 2H), 8.05 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.49 - 7.36 (m, 3H), 7.05 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.67 (s, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.96 (brs, 2H), 4.10 - 4.01 (m, 4H), 3.90 - 3.80 (m, 4H).

[0908] Example 99: N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine

[0909]

[0910] Compound 99 was prepared by General Procedure 2. LC-MS (ESI+): m / z 498 (MH + ). 1 1H NMR (300 MHz, CDCl 3)δ8.66(d, J = 2.7Hz, 1H), 7.94(d, J = 6.9Hz, 2H), 7.49 - 7.38(m, 3H), 7.04(s, 1H), 6.81(d, J = 2.7Hz, 1H), 6.80(s, 1H), 6.53(s, 1H), 4.30 - 4.25(m, 2H), 4.04 - 4.00(m, 4H), 3.95 - 3.90(m, 4H), 2.92 - 2.80(m, 2H), 2.38(s, 3H), 2.35(s, 6H).

[0911] Example 100: 2 - [3 - [5 - [3 - (3 - methoxyphenyl)pyrazol - 1 - yl] - 7 - morpholino - pyrazolo[1,5 - a]pyrimidin - 2 - yl] - 5 - methyl - pyrazol - 1 - yl] - N,N - dimethyl - ethylamine

[0912]

[0913] Compound 100 was prepared by General Procedure 2. LC - MS(ESI+): m / z 528(MH + ) 1 HNMR(300MHz, CDCl 3 )δ8.65(d, J = 2.7Hz, 1H), 7.61 - 7.52(m, 2H), 7.37(t, J = 8.1Hz, 1H), 7.02(s, 1H), 6.95 - 6.90(m, 1H), 6.81 - 6.78(m, 2H), 6.53(s, 1H), 4.28 - 4.23(m, 2H), 4.04 - 4.00(m, 4H), 3.95 - 3.85(m, 7H), 2.90 - 2.82(m, 2H), 2.38(s, 3H), 2.35(s, 6H).

[0914] Example 101: 4 - [5 - [3 - (3 - chlorophenyl)pyrazol - 1 - yl] - 2 - (1 - methylpyrazol - 3 - yl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0915]

[0916] Compound 101 was prepared by General Procedures 2 and 3. LC - MS(ESI+): m / z 461 / 463(MH + ) 1 HNMR(300MHz, CDCl 3)δ 8.67 (d, J = 2.7 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.47 - 7.33 (m, 3H), 7.02 (s, 1H), 6.84 - 6.77 (m, 3H), 4.10 - 4.00 (m, 7H), 3.95 - 3.91 (m, 4H).

[0917] Example 102: 4 - [5 - [3 - (5 - methyl - 3 - pyridyl)pyrazol - 1 - yl] - 2 - (3 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0918]

[0919] Compound 102 was prepared by General Procedure 2. LC - MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ 9.23 (s, 1H), 8.98 (s, 1H), 8.69 (d, J = 2.7 Hz, 1H), 8.66 - 8.64 (m, 1H), 8.46 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 7.50 - 7.40 (m, 1H), 7.07 (s, 1H), 6.87 (d, J = 2.7 Hz, 1H), 6.84 (s, 1H), 4.13 - 4.03 (m, 4H), 3.98 - 3.91 (m, 4H), 2.46 (s, 3H).

[0920] Example 103: 4 - [5 - [3 - (2 - methyl - 4 - pyridyl)pyrazol - 1 - yl] - 2 - (3 - pyridyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl]morpholine

[0921]

[0922] Compound 103 was prepared by General Procedures 2 and 4. LC - MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl 3)δ9.23(s,1H),8.98(s,1H),8.72(d,J=2.7Hz,1H),8.66-8.64(m,1H),8.25(d,J=7.8Hz,1H),7.75-7.71(m,2H),7.43-7.26(m,1H),7.07(s,1H),6.92-6.87(m,1H),6.84(s,1H),4.10-4.03(m,4H),3.98-3.93(m,4H),2.72(s,3H).

[0923] Example 104: 4-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine

[0924]

[0925] Compound 104 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 440 (MH + ). 1 1H NMR (300 MHz, CDCl 3 )δ8.67(d,J=2.7Hz,1H),8.40(d,J=5.4Hz,1H),7.95(d,J=6.9Hz,2H),7.49-7.36(m,4H),7.14(s,1H),7.11(s,1H),6.84(d,J=2.7Hz,1H),5.32(brs,2H),4.10-4.01(m,4H),3.95-3.85(m,4H).

[0926] Example 105: 4-[5-[3-(3-Chlorophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0927]

[0928] Compound 105 was prepared by General Procedures 2 and 3. LC-MS (ESI+): m / z 458 / 460 (MH + ). 1 1H NMR (300 MHz, DMSO-d 6)δ 9.23 (s, 1H), 8.76 (d, J = 2.7 Hz, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.57 - 7.40 (m, 3H), 7.26 - 7.25 (m, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 3.98 - 3.87 (m, 8H).

[0929] Example 106: 4-[5-[3-(3-Bromophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0930]

[0931] Compound 106 was prepared by General Procedures 2 and 7. LC-MS (ESI+): m / z 502 / 504 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.67 - 8.65 (m, 2H), 8.27 (d, J = 7.8 Hz, 1H), 8.13 (t, J = 1.5 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.08 (s, 1H), 6.83 (s, 1H), 6.82 (d, J = 6.6 Hz, 1H), 4.08 - 4.02 (m, 4H), 3.98 - 3.91 (m, 4H).

[0932] Example 107: 4-[5-[3-(3-Methoxyphenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0933]

[0934] Compound 107 was prepared by General Procedures 2 and 3. LC-MS (ESI+): m / z 454 (MH + ). 1 1H NMR (300 MHz, CDCl 3)δ 9.23 (s, 1H), 8.65 (d, J = 2.7 Hz, 2H), 8.26 (d, J = 7.8 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.46 - 7.36 (m, 2H), 7.10 (s, 1H), 6.96 - 6.91 (m, 1H), 6.84 - 6.80 (m, 2H), 4.10 - 4.03 (m, 4H), 3.98 - 3.90 (m, 4H), 3.89 (s, 3H).

[0935] Example 108: 4-[5-[3-(6-Methyl-2-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0936]

[0937] Compound 108 was prepared by General Procedure 2. LC-MS (ESI+): m / z 439 (MH + ). 1 1H NMR (300 MHz, CDCl 3 ) δ 9.25 (s, 1H), 8.71 - 8.62 (m, 2H), 8.26 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.17 - 7.13 (m, 3H), 6.83 (s, 1H), 4.10 - 4.03 (m, 4H), 3.98 - 3.90 (m, 4H), 2.66 (s, 3H).

[0938] Example 109: 6-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0939]

[0940] Compound 109 was prepared by the above method. LC-MS (ESI+): m / z 438 (MH + ).

[0941] Example 110: 4-[2-(3-Methylisoxazol-5-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0942]

[0943] Compound 110 was prepared by the above method. LC-MS (ESI+): m / z 441 (MH + ).

[0944] Example 111: 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0945]

[0946] Compound 111 was prepared by the above method. LC-MS (ESI+): m / z 443 (MH + )

[0947] Example 112: 4-[2-(1-methylpyrazol-4-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0948]

[0949] Compound 112 was prepared by the above method. LC-MS (ESI+): m / z 440 (MH + )

[0950] Example 113: 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0951]

[0952] Compound 113 was prepared by the above method. LC-MS (ESI+): m / z 426 (MH + )

[0953] Example 114: 4-[5-(3-phenylpyrazol-1-yl)-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0954]

[0955] Compound 114 was prepared by the above method. LC-MS (ESI+): m / z 429 (MH + )

[0956] Example 115: 4-[2-(1-methylpyrazol-4-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0957]

[0958] Compound 115 was prepared by the above method. LC-MS (ESI+): m / z 426 (MH +)。

[0959] Example 116: 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0960]

[0961] Compound 116 was prepared by the above method. LC-MS (ESI+): m / z 412 (MH + )。

[0962] Example 117: Methyl 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate

[0963]

[0964] Compound 117 was prepared by the above method. LC-MS (ESI+): m / z 481 (MH + )。

[0965] Example 118: 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide

[0966]

[0967] Compound 118 was prepared by the above method. LC-MS (ESI+): m / z 482 (MH + )。

[0968] Example 119: 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzonitrile

[0969]

[0970] Compound 119 was prepared by the above method. LC-MS (ESI+): m / z 448 (MH + )。

[0971] Example 120: 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0972]

[0973] Compound 120 was prepared by the above method. LC-MS (ESI+): m / z 427 (MH + )。

[0974] Example 121: 4-[2-(3-Methylisoxazol-5-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0975]

[0976] Compound 121 was prepared by the above method. LC-MS (ESI+): m / z 427 (MH + )

[0977] Example 122: 3-[1-[7-Morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoic acid

[0978]

[0979] Compound 122 was prepared by the above method. LC-MS (ESI+): m / z 467 (MH + )

[0980] Example 123: 4-[2-(1-Methylpyrazol-3-yl)-5-[3-[3-(trideuteriomethyl)phenyl]pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0981]

[0982] Compound 123 was prepared by the above method. LC-MS (ESI+): m / z 443

[0983] Biological Example 1: Inhibition of PIKfyve

[0984] Full-length human recombinant PIKFYVE (265 kDa), expressed as an N-terminal GST fusion protein in a baculovirus expression system, was obtained from Carna Biosciences (Kobe, Japan). The kinase substrate was prepared by mixing fluorescently labeled phosphatidylinositol 3-phosphate (PI3P) with phospho-L-serine (PS) at a ratio of 1:10 in 50 mM HEPES buffer pH 7.5 and sonicating

[0985] As follows, the kinase reaction was assembled in a 384-well plate (Greiner) with a total volume of 20 μL. The kinase protein was pre-diluted in a solution containing 25 mM HEPES (pH 7.5), 1 mM DTT, 2.5 mM MgCl 2 and 2.5 mM MnCl 2in assay buffer with 0.005% Triton X-100 and dispensed into 384-well plates (10 μL / well). Test compounds were serially pre-diluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). In all samples, the concentration of DMSO was balanced to 1%. All test compounds were tested at 12 concentrations. Apilimod was used as a reference compound and tested in the same manner in each assay plate. Control samples (0% inhibition, in the absence of inhibitor, only DMSO) and 100% inhibition (in the absence of enzyme) were assembled in quadruplicate and used to calculate the percent inhibition in the presence of the compound. The reaction was initiated by adding 10 μL of 2x PI3P / PS substrate supplemented with ATP. The final concentration of the enzyme was 2 nM, the final concentration of ATP was 10 mM, and the final concentration of the PI3P / PS substrate was 1 μM (PI3P). At room temperature, the kinase reaction was allowed to proceed for 3 h. After incubation, the reaction was quenched by adding 50 mL of stop buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100, 20 mM EDTA). The terminated plates were analyzed on a microfluidic electrophoresis instrument (Caliper 3000, Caliper Life Sciences / Perkin Elmer). Changes in the relative fluorescence intensities of the PI(3)P substrate and PI(3,5)P product peaks were measured. The activity in each test sample was determined as the ratio of product to sum (PSR): P / (S + P), where P is the peak height of the product and S is the peak height of the substrate. The percent inhibition (P inh ) was determined using the following equation:

[0986] P inh = (PSR 0％inh - PSR 化合物 ) / (PSR 0％inh - PSR 100％inh ) * 100

[0987] where PSR 化合物 is the product / sum ratio in the presence of the compound, PSR 0％inh is the product / sum ratio in the absence of the compound, and PSR 100％inh is the product / sum ratio in the absence of the enzyme. To determine the IC 50 (50% inhibition) of the test compounds, the %-inh data (P inh versus compound concentration) were fit using XLfit software (IDBS) with a four-parameter sigmoidal dose-response model.

[0988] The IC of certain compounds of the present disclosure is provided in Table 1 below 50 values.

[0989] Table 1.

[0990]

[0991] Biological Example 2: Cell Data

[0992] HEK / TDP Survival Assay: Immortalized human embryonic kidney 293T (HEK 293T) cells were transfected with a plasmid containing the TDP-43Q331K mutation, resulting in increased cell death biologically relevant to ALS patients. Cell death was measured as a decrease in the amount of ATP quantified by the luminescent Cell-Titer- (CTG) reagent (an indicator of metabolically active cells). The change in CTG of the compounds in this model was evaluated compared to the non-treated group. An increase in the signal indicates improved survival (rescue), and a decrease in the signal indicates decreased survival.

[0993] Cell rescue was measured in six replicates over 48 hours with eight different concentrations of the test compound in a 96-well format. The Promega Cell-Titer- luminescent cell viability assay was used to quantify ATP (an indicator of metabolically active cells) (see protocol: https: / / www.promega.com / - / media / files / resources / protocols / technical-manuals / 101 / celltiterglo-2-0-assay-protocol.pdf?la=en). The luminescent signal was detected using a PerkinElmer EnVision or Molecular Devices SpectraMax.

[0994] A three-step procedure was used to determine the effect of a given dose of the compound on cell viability. First, Hedge's g of the Cell Titer-Glo luminescence values was calculated using six untreated wells on each plate as controls. Second, since multiple experimental trials were performed on each compound dose pair, a meta-analysis was performed on these results to produce a single estimate of the effect size. Finally, the values for all compound dose pairs were corrected for multiple hypothesis testing using the empirical Bayes framework of Stephens, M. (False discovery rates: a new deal, Biostatistics, 18[2], 2017, 275-294) to produce confidence intervals for the measured effects and associated s values.

[0995] Briefly, this method calculates the local false flag rate for each experiment. Similar to Efron, B.'s local false discovery rate (Size, power and false discovery rates, Ann. Statist. 35[4], 2007, 1351 - 1377), this value measures the confidence in each effect flag (rather than the confidence that each effect is non - zero). The s - value reported in the previous figure is the expected error fraction when estimating the flags of all effects with a larger absolute local false flag rate, and its definition is similar to Storey, J.D.'s q - value (The positive false discovery rate: a Bayesian interpretation and the q - value, Ann. Statist. 31[6] 2003, 2013 - 2035).

[0996] Drugs that produce a labeled log s - value greater than 3 are considered hits. This threshold is determined by a separate calibration experiment, in which Cell Titer - is measured in a blank plate consisting of untreated cells to assess the noise inherent in the assay. The data are represented as the maximum rescue effect obtained from the dose - response curve.

[0997] iPSC MN survival assay: Fibroblasts from ALS patients with a known SOD1 A4V mutation were reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated into motor neurons. In culture, motor neurons derived from ALS patients showed increased mortality compared to motor neurons from healthy individuals under stress conditions (nutrient - depleted medium, Hank's buffered salt solution - HBSS). The SOD1 survival defect is associated with a subset of the ALS patient biology and can serve as a suitable cell - based model to measure compound - induced survival rescue.

[0998] Cell rescue was measured after six days for each compound at more than two different concentrations, with more than four replicates used in a 96 - well format to ensure a study power > 0.8. The cells were transduced with a GFP reporter gene and imaged daily to track survival. A broad - spectrum caspase inhibitor was used as a positive control.

[0999] Readout Based on Microscopic Images:Cells were transduced with a GFP reporter gene and imaged daily with blue laser to track viability. The imagers used included Biotek Cytation 5 and Thermo Fisher EVOS AutoFL 2. All images were processed uniformly consisting of rolling-cap background subtraction and contrast adjustment.

[1000] Cells were identified by their shape and each cell was tracked across the images and time points of each well. Survival was visually evaluated from the Kaplan-Meier curves. The survival of cells was modeled and tested using a mixed-effects Cox regression, where each well was modeled as a random effect and the group (control / treatment) was modeled as a fixed effect. The hazard ratio between treatment and control was estimated in the Cox regression, where a value of 1.0 indicates no change, a value > 1.0 indicates a decrease in survival rate in response to treatment, and a value < 1.0 indicates an increase in survival rate in response to treatment. Data are presented as the maximum reduction in hazard ratio scores measured at various concentrations.

[1001] Table 2

[1002]

[1003]

[1004] For purposes of clarity and understanding, the foregoing disclosure has been described in some detail by way of illustration and example. Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. Thus, the scope of the present disclosure should not be determined with reference to the above description, but rather should be determined with reference to the following appended claims and the full scope of equivalents of such claims.

Claims

1. A compound of formula (I): Wherein: X is N or CH, and Y is N or CR a , provided that when X is N, then Y is CR a , and when Y is N, then X is CH; R a and R 1 one of which is H, and the other is phenyl or pyridyl, each optionally substituted with one, two or three R d substituents; Each R d substituent is independently C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -O-C 1-4 alkyl, halo, cyano, nitro, halo-C 1-4 alkyl, -O-C 1-4 -haloalkyl, -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、=NOR g 、-NR g S(=O) 1-2 R h 、-NR g S(=O) 1-2 NR g R h 、=NSO 2 R g 、-C(=O)R g 、-C(=O)OR g 、-OC(=O)OR g 、-OC(=O)R g 、-C(=O)NR g R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-S(=O)R g 、-S(=O) 2 R g 、-OS(=O) 1-2 R g 、-S(=O) 1-2 OR g 、-S(=O) 1-2 NR g R h ; R g and R h each independently is H or C 1-4 alkyl; wherein R 2 and R 3 together with the nitrogen to which they are attached form a morpholinyl group, optionally substituted by one, two or three R j substituents; wherein R j is C 1-4 alkyl, oxo group, -OH, halogen group, halo-C 1-4 alkyl, -O-C 1-4 alkyl, or -O-C 1-4 -haloalkyl; R 4 is -C(O)NR x R y or is phenyl or a 5 - or 6 - membered heteroaryl, each optionally substituted by one or two R z substituents; wherein R x is H or C 1-4 alkyl and R y is H, C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -R r 、a 3- to 8-membered monocyclic cycloalkyl, -C 1-4 alkyl(3- to 8-membered monocyclic cycloalkyl), a 4- to 10-membered monocyclic heterocyclic group, -O-(4- to 10-membered monocyclic heterocyclic group), or a 4- to 10-membered monocyclic heterocyclic alkyl group, each optionally substituted by one, two or three R o substituents; or R x and R y together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic group, optionally substituted with C 1-4 alkyl; where each R r is C 1-4 alkyl or -NR p R q ; and Each R z substituent is independently C 1-4 alkyl, halo, -OH, or -OC 1-4 alkyl, C 1-4 alkylNR m R n , C(O)NHC 1-4 alkyl-NR m R n , or -NR m R n ; wherein R m and R n are each independently H, C 1-4 alkyl, or C 1-4 alkylNR p R q , or R m and R n together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic group, optionally substituted by one or two R o substituents; Each R o substituent is independently C 1-4 alkyl, -OH, -OC 1-4 alkyl, halogen, cyano, or -NR p R q ; wherein R p and R q are each independently H or C 1-4 alkyl, or R p and R q together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic group; and R 5 is H, C 1-4 alkyl, halogen, -OH, or -OC 1-4 alkyl; Or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CH and Y is N.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is N and Y is CR a .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a is H.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a or R 1 is phenyl, optionally substituted with one, two or three R d substituents.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a or R 1 is pyridyl, optionally substituted by one, two or three R d substituents.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a or R 1 is substituted by an R d and the R d is C 1-4 alkyl or halo group.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a or R 1 is substituted by an R d and the R d is methyl, NH 2 , fluorine, chlorine, or bromine.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a or R 1 is phenyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, bromine, -OCH 3 and -OCF 3 .

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a or R 1 is an unsubstituted phenyl or tolyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a or R 1 is unsubstituted phenyl or m-tolyl.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a or R 1 is an unsubstituted pyridyl group.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a or R 1 is 4-pyridyl.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R j is methyl, hydroxy, -OCH 3 , oxo, halo, -CF 3 , or -OCF 3 .

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, optionally substituted by one or two R z substituents.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazole, thiazole, oxazole, pyridine or pyrimidine, optionally substituted by one or two R z substituents.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazole, optionally substituted by one or two R z substituents.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is pyridine, optionally substituted by one or two R z substituents.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridine.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is 4-pyridyl.

21. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is phenyl or a 5- or 6-membered heteroaryl, optionally substituted by one or two R z substituents.

22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is phenyl, pyrazolyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 .

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(O)NR x R y .

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R x is H.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R x is methyl or ethyl, optionally substituted by one, two or three R o substituents.

26. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R x is methyl.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is H.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is C 1-4 alkyl, -C 1-4 alkyl(3- to 6-membered monocyclic cycloalkyl), 3- to 6-membered monocyclic cycloalkyl, 4- to 6-membered monocyclic heterocyclic alkyl, 4- to 6-membered monocyclic heterocycle, -O-(4- to 6-membered monocyclic heterocycle), -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, optionally substituted by one, two or three R o substituents.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is C o alkyl optionally substituted with one, two or three R 1-4 substituents.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted by one, two, or three R o substituents.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropyl, (dimethylamino)ethyl, or (dimethylamino)butyl.

32. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R y is a methoxy group.

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is -SO 2 -methyl.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is a 3- to 6-membered monocyclic cycloalkyl or -C 1-2 alkyl(3- to 6-membered monocyclic cycloalkyl), each optionally substituted by one, two or three R o substituents.

35. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is a 3- to 6-membered monocyclic cycloalkyl group, optionally substituted by one, two or three R o substituents.

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted by one, two, or three R o substituents.

37. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is cyclopropyl.

38. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is cyclopentyl.

39. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.

40. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is a 4- to 6-membered monocyclic heterocyclic group or -O-(4- to 6-membered monocyclic heterocyclic group), optionally substituted by one, two or three R o substituents.

41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy, optionally substituted with one, two, or three R o substituents.

42. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is oxetanyl or oxetanyloxy.

43. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R y is optionally substituted by one or two R o substituents, and R o is methyl.

44. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R x is methyl and R y is methyl, ethyl, cyclopropyl, methoxy, or cyclopentyl.

45. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R x and R y together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.

46. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R z is independently C 1-4 alkyl, halo, -OH, -OC 1-4 alkyl, C 1-4 alkylNR m R n or -NR m R n .

47. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R z is independently methyl, -OH, halogen, or -OCH 3 .

48. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R z is C m alkyl substituted by -NR n R 2-3 ​ 49. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R m and R n are each independently H or C 1-4 alkyl.

50. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R m and R n are each methyl.

51. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R m and R n together with the nitrogen to which they are attached form a 4- to 6-membered monocyclic heterocyclic group, optionally substituted with one or two R o substituents.

52. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R m and R n together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide, each optionally substituted by one or two R o substituents.

53. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R m and R n together with the nitrogen to which they are attached form pyrrolidine, piperidine, piperazine, or morpholine, each optionally substituted with one or two R o substituents.

54. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R o substituent is a C 1-4 alkyl group.

55. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R o substituent is -OH.

56. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R o substituent is -NR p R q .

57. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R p and R q are each independently H or methyl.

58. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R p and R q together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclic group.

59. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R p and R q together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptyl, or 2-oxa-6-azaspiro[3.3]heptyl.

60. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is H, methyl, ethyl, chlorine, bromine, fluorine, -OH, or -OCH 3 .

61. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 is H.

62. A compound of formula (II): Where R 1a is phenyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, CO 2 R p , -C(O)NR p R q , fluorine, chlorine, bromine, NH 2 and -OCH 3 ; and R 4a is -C(O)NR x R y or is phenyl, pyrazolyl or pyridyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -CF 3 , fluorine, chlorine, -OCH 3 and -OCF 3 ; wherein R x is H or C 1-4 alkyl, and R y is H, C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -R r 、a 3- to 6-membered monocyclic cycloalkyl, -C 1-4 alkyl(3- to 6-membered monocyclic cycloalkyl), a 4- to 6-membered monocyclic heterocyclic group, -O-(4- to 6-membered monocyclic heterocyclic group), or a 4- to 6-membered monocyclic heterocyclic group alkyl, each optionally substituted by one or two substituents selected from: C 1-4 alkyl, -OH, -OC 1-4 alkyl, halogen, or cyano or -NR p R q ; where each R r is C 1-4 alkyl or -NR p R q ; wherein R p and R q are each independently H or C 1-4 alkyl; or R x and R y together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic group, optionally substituted by C 1-4 alkyl; Or a pharmaceutically acceptable salt thereof.

63. A compound selected from: 7-Morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine; 7-Morpholino-N-(5-phenyl-1H-pyrazol-3-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; 7-Morpholino-N-[5-(o-tolyl)-1H-pyrazol-3-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; 7-Morpholino-N-[3-(m-tolyl)-1H-pyrazol-5-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-(5-Methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; 7-Morpholino-2-(4-pyridyl)-N-[5-(4-pyridyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine; 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine; 1-(7-Morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-(o-tolyl)-1H-pyrazol-5-amine; 4-[5-(4-Phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[4-(m-Tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(4-Pyridyl)-5-[4-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(4-Methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(4-Pyridyl)-5-[3-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-(2-(Pyridin-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(2-(Pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; N-Ethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Cyclopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; (R)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; (S)-N-(1-Cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(2-Methoxyethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N,N-Dimethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Ethyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Cyclopropyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(Cyclopropylmethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; Azetidin-1-yl(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone; (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(pyrrolidin-1-yl)methanone; (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone; Morpholino(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone; (4-Methylpiperazin-1-yl)(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone; N-Methoxy-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Methoxy-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(Methylsulfonyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Cyclopentyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Cyclopentyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Isopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1,3-Dimethoxypropan-2-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(2-(Dimethylamino)ethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(4-(Dimethylamino)butyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-N-(oxetan-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-((3-(Hydroxymethyl)oxetan-3-yl)methyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 7-Morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3S)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3R)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3R)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3S)-1-Methyl-3-piperidinyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-Methyl-4-piperidinyl)-7-morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]-N-tetrahydropyran-4-yl-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 3-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine; 5-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine; 4-[2-(1-Methylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(1-Methylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 3-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine; 5-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine; 4-[5-(3-Phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; N-Isopropyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(1R)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(1S)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-Cyclopentyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 4-[5-(4-Phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(4-Phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; N-Isopropyl-7-morpholino-5-(4-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 4-[2-(5-Methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; N,N-Dimethyl-2-[3-methyl-5-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(2,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(1,5-Dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-pyridazin-3-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate; N-[[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]propanamide; N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(2-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-[3-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; N,N-Dimethyl-2-[5-methyl-3-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; N,N-Dimethyl-2-[5-methyl-3-[5-[3-(4-methyl-2-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; N,N-Dimethyl-2-[5-methyl-3-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; 2-[3-[5-[3-(3-Chlorophenyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]-5-methyl-pyrazol-1-yl]-N,N-dimethyl-ethylamine; 5-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine; N,N-Dimethyl-2-[5-methyl-3-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrazol-1-yl]ethylamine; 2-[3-[5-[3-(3-Methoxyphenyl)pyrazol-1-yl]-7-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]-5-methyl-pyrazol-1-yl]-N,N-dimethyl-ethylamine; 4-[5-[3-(3-Chlorophenyl)pyrazol-1-yl]-2-(1-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(5-Methyl-3-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(2-Methyl-4-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine; 4-[5-[3-(3-Chlorophenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-Bromophenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-Methoxyphenyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(6-Methyl-2-pyridinyl)pyrazol-1-yl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 6-[7-Morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine; 4-[2-(3-Methylisoxazol-5-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(1-Methylpyrazol-4-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(1-Methylpyrazol-4-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-(3-Phenylpyrazol-1-yl)-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; Methyl 3-[1-[7-morpholino-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate; 3-[1-[7-Morpholino-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide; 3-[1-[7-Morpholino-2-(3-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzonitrile; 4-[5-[3-(m-Tolyl)pyrazol-1-yl]-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[2-(3-Methylisoxazol-5-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 3-[1-[7-Morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoic acid; and 4-[2-(1-Methylpyrazol-3-yl)-5-[3-[3-(trideuteriomethyl)phenyl]pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; and pharmaceutically acceptable salts thereof.

64. The compound and / or pharmaceutically acceptable salt according to claim 1, wherein one or more hydrogen atoms attached to the carbon atoms of the compound are replaced by deuterium atoms.

65. A pharmaceutical composition comprising the compound and / or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable excipient.

66. Use of the compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 65 in the manufacture of a medicament for inhibiting PIKfyve kinase in a subject in need thereof.

67. Use of the compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 65 in the manufacture of a medicament for treating a neurological disorder associated with PIKfyve activity in a subject in need thereof.

68. The use according to claim 67, wherein the neurological disorder is a tauopathy, lysosomal storage disease, mental disorder or mood disorder.

69. The use according to claim 67, wherein the neurological disorder is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (CMT); Charcot-Marie-Tooth disease type 4J (CMT4J) and Eunice-Varon syndrome, autophagy, polymicrogyria, Pick's disease, Parkinson's disease, Lewy body disease, frontotemporal dementia (FTD), neuronal intranuclear inclusions of polyglutamine and intranuclear inclusion disease, Marinesco-Sjögren syndrome and Hirano body disease, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (TBI), cerebral ischemia, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease, mucolipidosis type IV, neuropathy, Huntington's disease, ADHD, schizophrenia, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

70. The use according to claim 69, wherein the neurological disorder is polymicrogyria with seizures.

71. The use according to claim 69, wherein the neurological disorder is temporo-occipital polymicrogyria.

72. The use according to claim 69, wherein the neurological disease is Lewy body Parkinson's disease.

73. The use according to claim 69, wherein the neurological disease is Lewy body dementia.

74. The use according to claim 69, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease or CMT.

75. The use according to claim 74, wherein the disease is ALS.

76. The use according to claim 69, wherein the disease is Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia or chronic traumatic encephalopathy.

77. The use according to claim 69, wherein the disease is Fabry disorder, Gaucher disorder, Niemann-Pick disease type C, Tay-Sachs disease or mucolipidosis type IV.

78. The use according to claim 69, wherein the disease is ADHD, schizophrenia, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

79. The use of a compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a neurological disease in a subject, wherein PIKfyve contributes to the pathology and / or symptoms of the disease in the subject.

80. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is selected from 4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine and pharmaceutically acceptable salts thereof.

81. The compound according to claim 1, wherein the compound is 4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine.

82. The use according to any one of claims 66 to 79, wherein the compound or a pharmaceutically acceptable salt thereof is selected from 4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine and pharmaceutically acceptable salts thereof.

83. The use according to any one of claims 66 to 79, wherein the compound is 4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine.

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