Substituted pyrazolo-pyrimidines and uses thereof

Abstract

The present disclosure provides compounds that are inhibitors of PIKfyve kinase, useful for treating neurological diseases treatable by inhibition of PIKfyve. Pharmaceutical compositions containing such compounds and methods of treatment using such compounds are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 960,412, filed January 13, 2020, and U.S. Provisional Patent Application No. 63 / 074,388, filed September 3, 2020, the entire disclosures of each of which are incorporated herein by reference.

[0002] The present disclosure provides compounds that are phosphoinositide kinase inhibitors, particularly FYVE-type finger-containing phosphoinositide kinase ("PIKfyve") inhibitors, and thus are useful in treating central nervous system disorders. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided. [Background technology]

[0003] Phosphoinositide kinases (PIKs) catalyze the phosphorylation of phosphatidylinositol, a component of eukaryotic cell membranes, and related phospholipids called phosphoinositides. Phosphoinositides are involved in regulating diverse 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 cellular and endosomal membranes.

[0004] FYVE-type finger-containing phosphoinositide kinase (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) is a ubiquitously expressed PIK with both lipid and protein kinase activities. As a lipid kinase, this enzyme phosphorylates the D-5 position of endosomal phosphatidylinositol and phosphatidylinositol-3-phosphate (PI3P) to generate the corresponding 5-phosphate phospholipid analogs. Shisheva et al., Cell Biol. Int. 2008, 32(6), 591. PI3P plays a role in protein transport, protein degradation, and autophagy and is found in the plasma membrane. 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 were observed in cells expressing PIKfyve dominant-negative 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, stimulates autophagy, and improves motor neuron health. The phosphorylated inositides generated by PIKfyve are localized to various plasma membranes and organelles, consistent with the diverse functions of PIKfyve, including intralysosomal trafficking, endomembrane homeostasis, and biogenesis of endosomal carrier vesicles (ECVs) / multivesicular bodies (MVBs) from early endosomes. Furthermore, PIKfyve is required for the endocytic-vacuolar pathway and nuclear transport. Thus, PIKfyve helps maintain the proper morphology of endosomes and lysosomes.

[0005] In mammalian cells, PI3P levels are regulated by the reciprocal activity of PIKfyve and the phosphatase FIG4 phosphoinositide 5-phosphate (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. Normally, FIG4 is localized on the cytoplasmic surface of intralysosomal vesicles in a complex. Inhibition of PIKfyve mimics overexpression of FIG4, thereby increasing PI3P levels, stimulating autophagy, and improving motor neuron health. Numerous diseases, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (including CMT4J), and Yunis-Varon syndrome, are correlated with FIG4 defects, such as deleterious FIG4 mutations or reduced FIG4 function, and are therefore suitable targets for treatment with PIKfyve inhibitors.

[0006] Exemplary diseases associated with FIG4 deficiency include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (including CMT4J), Yunis-Varon syndrome, polymicrogyria (including polymicrogyria with epileptic seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, neuronal and intranuclear polyglutamine inclusion disease, Marinesco and Hirano body disease, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, autophagy, peripheral neuropathy, leukoencephalopathy, motor neuropathy, and sensory neuropathy. (Bharadwaj et al., Hum. Mol. Genet. 2016, 25(4), 682-692)

[0007] PIKfyve inhibitors are useful 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 disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV), and several other neurological disorders. Other therapeutic targets for intervention with PIKfyve inhibitors include Huntington's disease and psychiatric disorders (such as ADHD, schizophrenia, and 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; WO 2016 / 210372; U.S. Patent Application Publication No. 2018 / 0161335. Summary of the Invention

[0008] Embodiment 1. A compound of formula (I):

[0009] [ka] (In the formula, If X is N, then Y is CR a and when Y is N, X is CH; R a and R 1 one of which is H and the other is optionally one, two or three R d phenyl or heteroaryl substituted with a substituent; Each R dThe substituents are independently: C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, -OC 1~4 Alkyl, halo, cyano, nitro, azido, halo-C 1~4 Alkyl, -OC 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 , =NSO2R 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)2R 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 heterocycloalkyl, or monocyclic heteroaryl; R dEach phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl optionally contains one, two, or three substituents R e is replaced by; Each R e The substituents are independently: C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, halo, cyano, nitro, azido, -OH, halo-C 1~4 Alkyl, -OC 1~4 Alkyl, or -OC 1~4 -haloalkyl; R g and R h are each independently H or C 1~4 is alkyl; or R g and R h together with the atoms to which they are attached, and sometimes C 1~4 forming a monocyclic cycloalkyl or heterocycloalkyl substituted with alkyl; R 2 and R 3 Each of is H, or C 1~4 Alkyl, cycloalkyl, C 1~4 alkylcycloalkyl, heterocyclyl, heterocycloalkyl, or R 2 and R 3 together with the nitrogen to which they are attached, optionally one, two or three R j forming a heterocyclyl substituted with a substituent; Each R j The substituents are independently: C 1~4 Alkyl, oxo, -OH, -NR k R l , Halo, Halo-C 1~4 Alkyl, -OC 1~4 Alkyl, or -OC 1~4 -haloalkyl; R k and R l are each independently H or C 1~4 is alkyl; R 4is -C(O)NR x R y or optionally one, two or three R z phenyl or heteroaryl substituted with a substituent; R x is H or C 1~4 alkyl, and R y is H, and optionally one, two or three R o C substituted with a substituent 1~4 Alkyl, -OC 1~4 Alkyl, -SO2-C 1~4 Alkyl, C 1~4 Alkyl-SO2-R r , monocyclic cycloalkyl, -C 1~4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, -O-monocyclic heterocyclyl, or monocyclic heterocycloalkyl; or R x and R y together with the nitrogen to which they are attached, and sometimes C 1~4 forming an alkyl-substituted heterocyclyl or monocyclic heterocycloalkyl; Each R r is C 1~4 Alkyl or -NR p R q and; Each R z The substituents are independently: C 1~4 Alkyl, halo, -OH, or -OC 1~4 Alkyl, C 1~4 Alkyl NR m R n , C(O)NHC 1~4 Alkyl-NR m R n , or -NR m R n and; R m and R n are independently H, C 1~4 Alkyl or C 1~4 Alkyl NR p R q or R m and Rn together with the nitrogen to which they are attached, optionally one or two R o forming a substituted heterocyclyl or monocyclic heterocycloalkyl; Each R o The substituents are independently: C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, halo, cyano, or -NR p R q and; 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 heterocyclyl; R 5 is H, C 1~4 Alkyl, halo, -OH, or -OC 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0010] Embodiment 2. The compound of embodiment 1, wherein X is CH and Y is N.

[0011] Embodiment 3. X is N and Y is CR a 2. The compound of embodiment 1, wherein

[0012] Embodiment 4.R a The compound of embodiment 1, wherein is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0013] Embodiment 5.R a is H or methyl.

[0014] Embodiment 6.R a is H.

[0015] Embodiment 7.R a or R1 is optionally substituted phenyl.

[0016] Embodiment 8.R a or R 1 is an optionally substituted monocyclic heteroaryl.

[0017] Embodiment 9.R a or R 1 is an optionally substituted pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, or pyridazine.

[0018] Embodiment 10.R a or R 1 is an optionally substituted pyridine or pyrimidine.

[0019] Embodiment 11.R a or R 1 is an optionally substituted pyridine.

[0020] Embodiment 12.R a or R 1 is one R d is substituted with R d C 1~4 The compound of embodiment 1, wherein the aryl is alkyl or halo.

[0021] Embodiment 13.R a or R 1 is one R d is substituted with R d The compound of embodiment 1, wherein is methyl, NH2, fluoro, chloro, or bromo.

[0022] Embodiment 14.R a or R 1 However, depending on the case, C 1~4The compound of embodiment 1, which is phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF3, fluoro, chloro, bromo, -OCH3, and -OCF3.

[0023] Embodiment 15.R a or R 1 is unsubstituted phenyl or tolyl.

[0024] Embodiment 16.R a or R 1 is unsubstituted phenyl or m-tolyl.

[0025] Embodiment 17.R a or R 1 The compound of embodiment 1, wherein is unsubstituted pyridyl.

[0026] Embodiment 18.R a or R 1 is 4-pyridyl.

[0027] Embodiment 19.R 2 and R 3 together with the nitrogen to which they are attached, may each optionally contain one, two or three R j The compound of embodiment 1, which forms a substituted pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, or 2-oxa-6-azaspiro[3.3]heptane.

[0028] Embodiment 20.R 2 and R 3 together with the nitrogen to which they are attached, may optionally be one or two R j The compound of embodiment 1, which forms a substituted morpholine.

[0029] Embodiment 21. Each R jThe compound of embodiment 1, wherein the substituents are independently methyl, hydroxy, -OCH3, oxo, halo, -CF3, or -OCF3.

[0030] Embodiment 22.R k and R l is independently H or methyl.

[0031] Embodiment 23.R 4 is optionally substituted phenyl.

[0032] Embodiment 24.R 4 is an optionally substituted heteroaryl.

[0033] Embodiment 25.R 4 The compound of embodiment 1, wherein is an optionally substituted pyrazole, thiazole, oxazole, pyridine, or pyrimidine.

[0034] Embodiment 26.R 4 is an optionally substituted pyridine.

[0035] Embodiment 27.R 4 is pyridine.

[0036] Embodiment 28.R 4 is 4-pyridyl.

[0037] Embodiment 29.R 4 Sometimes one or two R z The compound of embodiment 1, wherein the compound is substituted with a substituent.

[0038] Embodiment 30.R 4 However, depending on the case, C 1~4The compound of embodiment 1, which is phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3.

[0039] Embodiment 31.R 4 -C(O)NR x R y 2. The compound of embodiment 1, wherein

[0040] Embodiment 32.R x is H.

[0041] Embodiment 33.R x But sometimes one, two or three R o The compound of embodiment 1, wherein the substituent is methyl or ethyl.

[0042] Embodiment 34.R x is methyl.

[0043] Embodiment 35.R y is H.

[0044] Embodiment 36.R y But sometimes one, two or three R o C substituted with a substituent 1~4 Alkyl, -C 1~4 Alkyl (monocyclic cycloalkyl), monocyclic cycloalkyl, monocyclic heterocycloalkyl, monocyclic heterocyclyl, -O-monocyclic heterocyclyl, -OC 1~4 Alkyl, -SO2-C 1~4 The compound of embodiment 1, wherein the aryl group is alkyl.

[0045] Embodiment 37.R y But sometimes one, two or three R o C substituted with a substituent 1~4 The compound of embodiment 1, wherein the aryl group is alkyl.

[0046] Embodiment 38.R y However, depending on the case, one, two or three R o The compound of embodiment 1, wherein the compound is methyl, ethyl, propyl, or isopropyl substituted with a substituent.

[0047] Embodiment 39.R y The compound of embodiment 1, wherein is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.

[0048] Embodiment 40.R y The compound of embodiment 1, wherein is methoxy.

[0049] Embodiment 41.R y is -SO2-methyl.

[0050] Embodiment 42.R y However, depending on the case, one, two or three R o Substituted monocyclic cycloalkyl or -C 1~2 The compound of embodiment 1, wherein the alkyl(monocyclic cycloalkyl).

[0051] Embodiment 43.R y But sometimes one, two or three R o The compound of embodiment 1, which is a monocyclic cycloalkyl substituted with a substituent.

[0052] Embodiment 44.R y However, depending on the case, one, two or three R o The compound of embodiment 1, which is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with a substituent.

[0053] Embodiment 45.R y is cyclopropyl.

[0054] Embodiment 46.Ry is cyclopentyl.

[0055] Embodiment 47.R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.

[0056] Embodiment 48.R y But sometimes one, two or three R o The compound of embodiment 1, which is a substituted monocyclic heterocyclyl or -O-monocyclic heterocyclyl.

[0057] Embodiment 49.R y is optionally substituted tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy.

[0058] Embodiment 50.R y is oxetanyl, or oxetanyloxy.

[0059] Embodiment 51.R y But sometimes one, two or three R o The compound of embodiment 1, which is a monocyclic heterocycloalkyl substituted with a substituent.

[0060] Embodiment 52.R y Sometimes one or two R o is substituted with a substituent, R o is methyl.

[0061] Embodiment 53.R x is methyl and R y is methyl, ethyl, cyclopropyl, methoxy, or cyclopentyl.

[0062] Embodiment 54.R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 The compound of embodiment 1, which forms a monocyclic heterocycloalkyl substituted with alkyl.

[0063] Embodiment 55.R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 The compound of embodiment 1, which forms a monocyclic heterocyclyl substituted with alkyl.

[0064] Embodiment 56.R x and R y are taken together with the nitrogen to which they are attached to 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.

[0065] Embodiment 57. Each R z independently, C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, C 1~4 Alkyl NR m R n or -NR m R n 2. The compound of embodiment 1, wherein

[0066] Embodiment 58. Each R z is independently methyl, —OH, halo, or —OCH 3 .

[0067] Embodiment 59.R z Ga-NR m R n C replaced with 2~3 The compound of embodiment 1, wherein the aryl group is alkyl.

[0068] Embodiment 60.R m and R n are each independently H or C 1~4 The compound of embodiment 1, wherein the aryl group is alkyl.

[0069] Embodiment 61.R m and R n and R are each methyl.

[0070] Embodiment 62.R m and R n together with the nitrogen to which they are attached, may optionally be one or two R o The compound of embodiment 1, wherein the compound forms a monocyclic heterocyclyl substituted with a substituent.

[0071] Embodiment 63.R m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o The compound of embodiment 1, which forms a substituted pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide.

[0072] Embodiment 64.R m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o The compound of embodiment 1, which forms a substituted pyrrolidine, piperidine, piperazine, or morpholine.

[0073] Embodiment 65. Each R o Substituent is C 1~4 The compound of embodiment 1, wherein the aryl group is alkyl.

[0074] Embodiment 66. Each R o The compound of embodiment 1, wherein the substituent is —OH.

[0075] Embodiment 67. Each R o The substituent is -NR p R q 2. The compound of embodiment 1, wherein

[0076] Embodiment 68.R p and R q is independently H or methyl.

[0077] Embodiment 69.R p and R q taken together with the nitrogen to which they are attached to form a heterocyclyl.

[0078] Embodiment 70.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.

[0079] Embodiment 71.R 5 The compound of embodiment 1, wherein is H, methyl, ethyl, chloro, bromo, fluoro, —OH, or —OCH 3 .

[0080] Embodiment 72.R 5 is H.

[0081] Embodiment 73. A compound of formula (II):

[0082] [ka] (In the formula, R 1a are C depending on the case 1~4 Alkyl, CO2R p , -C(O)NR p R qphenyl or pyridyl substituted with one or two substituents selected from fluoro, chloro, bromo, NH2, and —OCH3; R 4a is -C(O)NR x R y or C, respectively 1~4 phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; R x is H or C 1~4 alkyl, and R y is H, and in some cases C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, halo, or cyano or -NR p R q C substituted with one or two substituents selected from 1~4 Alkyl, -OC 1~4 Alkyl, -SO2-C 1~4 Alkyl, C 1~4 Alkyl-SO2-R r , monocyclic cycloalkyl, -C 1~4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, -O-monocyclic heterocyclyl, or monocyclic heterocycloalkyl; Each R r is C 1~4 Alkyl or -NR p R q and; R p and R q are each independently H or C 1~4 is alkyl, or R x and R y together with the nitrogen to which they are attached, and sometimes C 1~4 forming an alkyl-substituted heterocyclyl or a pharmaceutically acceptable salt thereof.

[0083] Embodiment 74. 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-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3S)-1-Methyl-3-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-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-pyridyl)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]ethanamine; 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]ethanamine; 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; 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; 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]ethanamine; 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]ethanamine; 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]ethanamine; 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-ethanamine; 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]ethanamine; 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; 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-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-bromophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate; 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide; 3-[1-[7-morpholino-2-(3-pyridyl)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.

[0084] 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.

[0085] Embodiment 76. A method for inhibiting PIKfyve kinase in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of embodiments 1 to 74 or 87, or a pharmaceutical composition described in embodiment 75.

[0086] Embodiment 77. A method of treating a neurological disease associated with PIKfyve activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of embodiments 1 to 74 or 87, or a pharmaceutical composition described in embodiment 75.

[0087] Embodiment 78. The neurological disease 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 epileptic seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, polyglutamine neuronal nuclear inclusions and intranuclear inclusion disease, Marinesco and Hirano body disease, tauopathy, Alzheimer's disease, 78. The method of embodiment 77, wherein the disorder is 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 disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV, a neuropathy, Huntington's disease, a psychiatric disorder, ADHD, schizophrenia, a mood disorder, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0088] Embodiment 79. The method of embodiment 78, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT.

[0089] Embodiment 80. The method of embodiment 79, wherein the disease is ALS.

[0090] Embodiment 81. The method of embodiment 78, wherein the disease is a tauopathy such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.

[0091] Embodiment 82. The method of embodiment 78, wherein the disease is a lysosomal storage disease such as Fabry disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, or mucolipidosis type IV.

[0092] Embodiment 83. The method of embodiment 78, wherein the disease is a psychiatric disorder such as ADHD, schizophrenia, or a mood disorder such as major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[0093] Embodiment 84. A compound according to any one of embodiments 1 to 74 or 87 for use as a medicament.

[0094] Embodiment 85 The compound of embodiment 84, which is for use in the treatment of a neurological disease treatable by inhibition of PIKfyve kinase.

[0095] Embodiment 86 Use of a compound of any one of embodiments 1 to 74 or 87 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 neurological disease.

[0096] Embodiment 87. A compound and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 74, wherein one or more hydrogen atoms bonded to a carbon atom of the compound are replaced by deuterium atoms. DETAILED DESCRIPTION OF THE INVENTION

[0097] Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this disclosure and have the following meanings:

[0098] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

[0099] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0100] "Alkylsulfonyl" means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0101] "Amino" means -NH2.

[0102] "Alkoxy" means an --OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0103] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with an alkoxy group (in one embodiment, one or two alkoxy groups), as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0104] "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0105] "Acyl" means a -COR group where R is alkyl, haloalkyl, or cycloalkyl, e.g., acetyl, propionyl, cyclopropylcarbonyl, etc. When R is alkyl, the group is also referred to herein as alkylcarbonyl.

[0106] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of 3 to 10 carbon atoms, in which one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0107] "Carboxy" means --COOH.

[0108] "Halo" refers to fluoro, chloro, bromo, or iodo; in one embodiment, fluoro or chloro.

[0109] "Haloalkyl" means an alkyl group as defined above substituted with 1 or 1 to 5 halogen atoms (in one embodiment, fluorine or chlorine), including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl is substituted with only fluoro, it may be referred to as fluoroalkyl in the present disclosure.

[0110] "Haloalkoxy" means an -OR group where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl and the alkyl is substituted with only fluoro, it may be referred to in the present disclosure as fluoroalkoxy.

[0111] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both 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. Further examples include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0112] "Heterocyclyl" refers to a heterocyclic group in which one or two ring atoms are N, O, and S(O). nwhere n is an integer from 0 to 2, and the remaining ring atoms are C. Furthermore, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group. More specifically, the term heterocyclyl 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)-on-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-on-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]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and the like. If the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic.

[0113] "Heterocyclylalkyl" or "heterocycloalkyl" means a -(alkylene)-R radical where R is a heterocyclyl ring as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0114] "Heterocycloamino" refers to a heterocyclic group in which one or two ring atoms are N, O, or S(O). n where n is an integer from 0 to 2, and the remaining ring atoms are C, with the proviso that at least one of the ring atoms is N. Furthermore, one or two ring carbon atoms in the heterocycloamino ring may optionally be replaced by a -CO- group. When the heterocycloamino ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic.

[0115] "Heterocycloaminoalkyl" means a -(alkylene)-R radical where R is heterocycloamino as defined above.

[0116] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms in which one or more (in one embodiment 1, 2, or 3) ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0117] As used herein, "mammal" refers to domestic animals (such as dogs, cats, and horses) and humans. In one embodiment, the mammal is a human.

[0118] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic 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, and the like. The organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium and magnesium salts.It is understood that pharmaceutically acceptable salts are non-toxic.Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0119] "Oxo" means the =(O) group and "carbonyl" means the >C(O) group.

[0120] "Optional" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that alkyl may be present but need not be present, and that the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with an alkyl group.

[0121] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes 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, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0122] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0123] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to 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 harmful to the patient. Some examples of materials that can serve 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) oils, 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) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0124] "Treating" or "treatment" of a disease means (1) To prevent disease, e.g., to prevent the development of clinical symptoms of disease in a mammal that may be exposed to or predisposed to the disease but that has not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, e.g., arresting or reducing the onset of the disease or its clinical symptoms; or (3) alleviating the disease, e.g., causing regression of the disease or its clinical symptoms Includes.

[0125] "Therapeutically effective amount" means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein) that, when administered to a mammal for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0126] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, and racemic forms, both individually and as mixtures thereof, are within the scope of the present disclosure. Compounds of the present disclosure containing asymmetrically substituted atoms can be isolated in optically active, optically enriched, optically pure, or racemic forms. Methods for preparing optically active forms, for example, by resolution of materials, are well known in the art. Separation of stereoisomers can be carried out by chromatography, or by forming diastereomers and separating them 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, incorporated herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0127] Certain compounds of formula (I) (or any of the embodiments thereof described herein) and / or pharmaceutically acceptable salts thereof may exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of the present disclosure. For example, the pyrazole tautomers shown below are equivalent structures. The depiction of one such structure encompasses both structures.

[0128] [ka]

[0129] Furthermore, as used herein, the term alkyl includes all possible isomeric forms of said alkyl groups, although only a few examples are given. Furthermore, when cyclic groups such as heteroaryl, heterocyclyl, etc. are substituted, they include all positional isomers.

[0130] Pharmaceutically acceptable salts of the compounds of formula (I) (or any of the embodiments thereof described herein) are within the scope of this disclosure. Additionally, the compounds described herein include hydrates and solvates of the compounds or their pharmaceutically acceptable salts.

[0131] The present disclosure also includes prodrugs of the compounds of Formula (I) (or any of the embodiments thereof described herein) and / or pharmaceutically acceptable salts thereof. The term prodrug is intended to refer to covalently bonded carriers that can release the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. 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 regenerate the original functional groups in vivo or by routine manipulation. Prodrugs of the compounds of Formula (I) (or any of the embodiments thereof described herein) include compounds in which hydroxy, amino, carboxylic acid, or similar groups have been modified. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate), carbamates (e.g., N,N-dimethylaminocarbonyl), amides (e.g., trifluoroacetylamino, acetylamino, etc.) of hydroxy or amino functional groups in the compounds of formula (I). Prodrugs of the compounds of formula (I) (or any of the embodiments thereof described herein) and / or pharmaceutically acceptable salts thereof are also within the scope of this disclosure.

[0132] The present disclosure also includes polymorphic forms (amorphous and crystalline) and deuterated forms of the compound of formula (I) (or any of the embodiments thereof described herein) and / or its pharmaceutically acceptable salts.

[0133] The compounds disclosed herein may, in some embodiments, be used in a variety of applications, e.g. 2 H, 3 H, 11 C. 13 C and / or 14 The compound is used in various enriched isotopic forms, enriched in 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.

[0134] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C or 14 Compounds having this structure except for substitution by a C-enriched carbon are within the scope of this disclosure.

[0135] The compounds of the present disclosure may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes containing, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with an isotope such as C. 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 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0136] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 is replaced with an H atom. Synthetic methods for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0137] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in 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, 110 pp; 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.

[0138] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical distributors such as Aldrich Chemical Co.

[0139] One embodiment is a compound of formula (I):

[0140] [ka] (In the formula, X is N or CH and Y is N or CR a where, if X is N, then Y is CR a and when Y is N, X is CH; R a and R 1 one of which is H and the other is optionally one, two or three R d phenyl or heteroaryl substituted with a substituent; Each R d The substituents are independently: C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, -OC 1~4 Alkyl, halo, cyano, nitro, azido, halo-C 1~4 Alkyl, -OC 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 , =NSO2R 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)2R 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 heterocycloalkyl, or monocyclic heteroaryl; R dEach phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl optionally contains one, two, or three substituents R e is replaced by; Each R e The substituents are independently: C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, halo, cyano, nitro, azido, -OH, halo-C 1~4 Alkyl, -OC 1~4 Alkyl, or -OC 1~4 -haloalkyl; R g and R h are each independently H or C 1~4 is alkyl; or R g and R h together with the atoms to which they are attached, and sometimes C 1~4 forming a monocyclic cycloalkyl or heterocycloalkyl substituted with alkyl; R 2 and R 3 Each of is H, or C 1~4 Alkyl, cycloalkyl, C 1~4 alkylcycloalkyl, heterocyclyl, heterocycloalkyl, or R 2 and R 3 together with the nitrogen to which they are attached, optionally one, two or three R j forming a monocyclic heterocyclyl substituted by a substituent; Each R j The substituents are independently: C 1~4 Alkyl, oxo, -OH, -NR k R l , Halo, Halo-C 1~4 Alkyl, -OC 1~4 Alkyl, or -OC 1~4 -haloalkyl; R k and R l are each independently H or C 1~4 is alkyl; R4 is -C(O)NR x R y or optionally one, two or three R z phenyl or heteroaryl substituted with a substituent; R x is H or C 1~4 alkyl, and R y is H, and optionally one, two or three R o C substituted with a substituent 1~4 Alkyl, -OC 1~4 Alkyl, -SO2-C 1~4 Alkyl, C 1~4 Alkyl-SO2-R r , monocyclic cycloalkyl, -C 1~4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, -O-monocyclic heterocyclyl, or monocyclic heterocycloalkyl; or R x and R y together with the nitrogen to which they are attached, and sometimes C 1~4 forming an alkyl-substituted heterocyclyl or monocyclic heterocycloalkyl; Each R r is C 1~4 Alkyl or -NR p R q and; Each R z The substituents are independently: C 1~4 Alkyl, halo, -OH, or -OC 1~4 Alkyl, C 1~4 Alkyl NR m R n , C(O)NHC 1~4 Alkyl-NR m R n , or -NR m R n and; R m and R n are independently H, C 1~4 Alkyl or C 1~4 Alkyl NR p R q or Rm and R n together with the nitrogen to which they are attached, optionally one or two R o forming a substituted heterocyclyl or monocyclic heterocycloalkyl; Each R o The substituents are independently: C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, halo, cyano, or -NR p R q and; 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 heterocyclyl; R 5 is H, C 1~4 Alkyl, halo, -OH, or -OC 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0141] 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. a is H or methyl. In some embodiments, R a is H.

[0142] In some embodiments, R a or R 1 is 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 1is 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. 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 Sometimes one or two R d It is substituted with a substituent.

[0143] In some embodiments, each R d The substituents are independently C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, -OC 1~4 Alkyl, halo, cyano, nitro, azido, halo-C 1~4 Alkyl, -OC 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 , =NSO2R 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)2R 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 heterocycloalkyl, or monocyclic heteroaryl, and R d The phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl, and monocyclic heteroaryl of each optionally contain one or two substituents R e In some embodiments, each R d The substituents are independently C 1~4 Alkyl, Halo-C 1~4 Alkyl, phenyl, -C 1~4 Alkynyl-phenyl, pyridyl, thiophenyl, cycloalkyl, or -C 1~4 alkyl-cycloalkyl, where phenyl, pyridyl, and thiophenyl each optionally contain one or two substituents R e In some embodiments, each R d The substituents are independently methyl, ethyl, isopropyl, -CF3, -OCH3, -OCF3, phenyl, pyridyl, thiophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; R d wherein the phenyl, cycloalkyl, and heteroaryl each optionally contain one or two substituents R e In some embodiments, each R d But C1~4 In some embodiments, R is independently selected from alkyl, —CF, fluoro, chloro, —OCH, and —OCF. a or R 1 is one R d is substituted with R d C 1~4 In some embodiments, R a or R 1 is one R d is substituted with R d is methyl. In some embodiments, R a or R 1 However, depending on the case, C 1~4 In some embodiments, R is phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF, fluoro, chloro, -OCH, and -OCF. 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.

[0144] In some embodiments, each R e The substituents are independently C 1~4 Alkyl, Halo, Halo-C 1~4 Alkyl, -OC 1~4 Alkyl, or -OC 1~4 -haloalkyl. In some embodiments, each R e The substituents are independently methyl, -CF, fluoro, chloro, -OCH, or -OCF. In some embodiments, each R d The substituents are independently methyl, ethyl, isopropyl, -CF3, phenyl, pyridyl, thiophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, and each R eare independently methyl, -CF3, fluoro, chloro, -OCH3, or -OCF3.

[0145] In some embodiments, R g and R h are each independently H or methyl.

[0146] In some embodiments, R 2 and R 3 together with the nitrogen to which they are attached, may each optionally contain one, two or three R j In some embodiments, R forms a substituted pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide. 2 and R 3 together with the nitrogen to which they are attached, may optionally be one or two R j A substituted morpholine is formed.

[0147] In some embodiments, each R j The substituents are independently methyl, hydroxy, -OCH3, halo, -CF3, or -OCF3.

[0148] In some embodiments, R k and R l are each independently H or methyl.

[0149] In some embodiments, R 4 is 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. 4is an optionally substituted pyrazole, pyridine, or pyrimidine. 4 is an optionally substituted pyridine. In some embodiments, R 4 is pyridine. In some embodiments, R 4 is 4-pyridyl. In some embodiments, R 4 Sometimes one or two R z In some embodiments, R 4 However, depending on the case, C 1~4 It is phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3.

[0150] In some embodiments, R 4 -C(O)NR x R y In some embodiments, R x is H. In some embodiments, R x But sometimes one, two or three R o In some embodiments, R is methyl or ethyl substituted with a substituent. x is methyl. In some embodiments, R y is H. In some embodiments, R y But sometimes one, two or three R o C substituted with a substituent 1~4 Alkyl, -C 1~4 Alkyl (monocyclic cycloalkyl), monocyclic cycloalkyl, monocyclic heterocycloalkyl, monocyclic heterocyclyl, -O-monocyclic heterocyclyl, -OC 1~4 Alkyl, -SO2-C 1~4 In some embodiments, R y But sometimes one, two or three R o C substituted with a substituent 1~4 In some embodiments, R y However, depending on the case, one, two or three R oIn some embodiments, R is methyl, ethyl, propyl, or isopropyl substituted with a substituent. y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl. y is methoxy. In some embodiments, R y is -SO2-methyl.

[0151] In some embodiments, R y However, depending on the case, one, two or three R o Substituted monocyclic cycloalkyl or -C 1~2 alkyl(monocyclic cycloalkyl). In some embodiments, R y But sometimes one, two or three R o In some embodiments, R is a monocyclic cycloalkyl substituted with a substituent. y However, depending on the case, one, two or three R o In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with a substituent. 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. y But sometimes one, two or three R o In some embodiments, R is a monocyclic heterocyclyl substituted with a substituent or -O-monocyclic heterocyclyl. y is optionally substituted tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy.

[0152] In some embodiments, R yis oxetanyl, or oxetanyloxy. In some embodiments, R y But sometimes one, two or three R o In some embodiments, R is a monocyclic heterocycloalkyl substituted with a substituent. 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.

[0153] In some embodiments, R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 In some embodiments, R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 In some embodiments, 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.

[0154] In some embodiments, each R z independently, C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, C 1~4 Alkyl NR m R n or -NR m R n and each alkyl is optionally —NR m R n In some embodiments, each R zis independently methyl, —OH, halo, or —OCH. In some embodiments, R z Ga-NR m R n C replaced with 2~3 It is alkyl.

[0155] In some embodiments, R m and R n are each independently H or C 1~4 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, may optionally be one or two R o In some embodiments, R m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o In some embodiments, R forms a substituted pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide. m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o This forms a substituted pyrrolidine, piperidine, piperazine, or morpholine.

[0156] In some embodiments, each R o Substituent is C 1~4 In some embodiments, each R o The substituent is methyl. In some embodiments, each R o 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.

[0157] In some embodiments, R p and R q together with the nitrogen to which they are attached form a heterocyclyl. p and R q together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0158] In some embodiments, R 5 is H, methyl, ethyl, chloro, bromo, fluoro, —OH, or —OCH. In some embodiments, R 5 is H.

[0159] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

[0160] [ka] (In the formula, R 1a are C depending on the case 1~4 Alkyl, CO2R p , -C(O)NR p R q phenyl or pyridyl substituted with one or two substituents selected from fluoro, chloro, bromo, NH2, and —OCH3; R 4a is -C(O)NR x R y or C, respectively 1~4 phenyl or pyridyl substituted with one or two substituents selected from alkyl, -CF3, fluoro, chloro, -OCH3, and -OCF3; R x is H or C 1~4 alkyl, and R y is H, and in some cases C1~4 Alkyl, -OH, -OC 1~4 Alkyl, halo, or cyano or -NR p R q C substituted with one or two substituents selected from 1~4 Alkyl, -OC 1~4 Alkyl, -SO2-C 1~4 Alkyl, C 1~4 Alkyl-SO2-R r , monocyclic cycloalkyl, -C 1~4 alkyl(monocyclic cycloalkyl), monocyclic heterocyclyl, -O-monocyclic heterocyclyl, or monocyclic heterocycloalkyl; Each R r is C 1~4 Alkyl or -NR p R q and; R p and R q are each independently H or C 1~4 is alkyl, or R x and R y together with the nitrogen to which they are attached, and sometimes C 1~4 forming a monocyclic heterocyclyl substituted with alkyl or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, R 1a is phenyl or pyridyl, each optionally substituted with methyl or —CF. 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 with methyl or —CF. 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.

[0162] In some embodiments, the compound of formula (I):

[0163] [ka] Medium, R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as described herein, or Compounds of formula (II):

[0164] [ka] Medium, R 1a and R 4a is as described herein; One or more hydrogen atoms bonded to a carbon atom of the compound are replaced by deuterium atoms.

[0165] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 1a or R 4a One or more hydrogen atoms bonded to the carbon atom of is replaced by a deuterium atom.

[0166] In some embodiments, 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 zIn some embodiments, one or more hydrogen atoms bonded to a carbon atom of R are replaced by deuterium atoms. 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 C in which one or more hydrogen atoms attached to a carbon atom are replaced by deuterium atoms. 1~4 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 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 -CD3.

[0167] In some embodiments, the compound of Formula (I) or Formula (II) includes at least one -D in place of -H or at least one -CD3 in place of CH3 substituent.

[0168] 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 phenyl 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 with a -CD3 group.

[0169] In some embodiments, the compound is

[0170] [Table 1-1]

[0171] [Table 1-2]

[0172] [Table 1-3]

[0173] [Table 1-4]

[0174] [Table 1-5]

[0175] [Table 1-6]

[0176]

Table 1-7

[0177]

Table 1-8

[0178]

Table 1-9

[0179]

Table 1-10

[0180]

Table 1-11

[0181]

Table 1-12

[0182]

Table 1-13

[0183]

Table 1-14

[0184]

Table 1-15

[0185]

Table 1-16

[0186] [Table 1-17]

[0187] [Table 1-18]

[0188] [Table 1-19] and pharmaceutically acceptable salts thereof.

[0189] Methods of Treatment, Administration, and Pharmaceutical Compositions In general, compounds of the present disclosure are administered in therapeutically effective amounts by any of the accepted modes of administration for agents that provide similar utilities. Therapeutically effective amounts of compounds of Formula (I) can range from about 0.01 to about 500 mg / kg of patient body weight per day, and can be administered in single or multiple doses. In one embodiment, dosage levels will be from about 0.1 to about 250 mg / kg per day. In another embodiment, dosage levels will be from about 0.5 to about 100 mg / kg per day. Suitable dosage levels can be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, dosages can be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing about 1.0 to about 1000 milligrams of active ingredient, particularly 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 active ingredient. The actual amount of a compound of the present disclosure, i.e., active ingredient, will depend on numerous factors, such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound utilized, the route and form of administration, and other factors.

[0190] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred method of administration is oral, using a convenient once-daily dosing regimen, which can be adjusted according to the severity of the pain. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0191] Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers, including excipients and auxiliary agents.Preparation can be modified according to the selected route of administration.Pharmaceutical compositions can also include the compound described herein in free base form or pharmaceutically acceptable salt form.

[0192] A method for formulating a pharmaceutical composition can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules, and capsules, and in some embodiments, solid compositions further contain non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and other pharmaceutically acceptable additives. Alternatively, the compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, before use. The active ingredient can be entrapped in microcapsules, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions, prepared, for example, by coacervation techniques or interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively).

[0193] Pharmaceutical compositions and formulations can be sterilized, which can be achieved by filtration via sterile filtration.

[0194] The pharmaceutical compositions described herein can be formulated for administration as injection.Non-limiting examples of injection preparations can include sterile suspensions, solutions, or emulsions in oily or aqueous vehicles.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.Suspensions can also contain suitable stabilizers.Injections can be formulated for bolus injection or continuous infusion.

[0195] For parenteral administration, the compound can be formulated into a unit-dose injection form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles are essentially non-toxic and non-therapeutic. Vehicles 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. Vehicles can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0196] Sustained-release preparations can also be prepared. Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0197] Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing the compound with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be non-toxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, 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 glycol.

[0198] The compounds of the present disclosure may be used in treatment methods in combination with one or more other concomitant medications (e.g., one, two, or three other drugs) used to prevent, treat, manage, ameliorate, or reduce the risk of a disease or condition for which the compounds of the present disclosure are useful. In some embodiments, the combination of drugs together is safer or more effective than either drug alone. In some embodiments, the compounds disclosed herein and the one or more concomitant medications have complementary activities that do not adversely affect each other. Such molecules may be present in the combination in amounts useful for the intended purpose. Such other drug(s) may therefore be administered simultaneously or sequentially with the compounds of the present disclosure by a route and in an amount commonly used. When a compound of the present disclosure is used simultaneously with one or more other drugs, in some embodiments, the drugs are administered together in a single pharmaceutical composition in unit dosage form. Thus, pharmaceutical compositions of the present disclosure also include those containing one or more other active ingredients in addition to the compounds of the present disclosure. The weight ratio of the compound of the present disclosure to the second active agent may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. In some embodiments, the combination therapy includes a therapy in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more drugs are administered on different, overlapping schedules.It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present disclosure and the other active ingredients may be used at lower doses than when each is used alone.In some embodiments, the combination drug is a drug for reducing the symptoms of ALS.In some embodiments, the combination drug is a drug for reducing the symptoms of ALS.In some embodiments, the combination drug is a drug for reducing the symptoms of ALS, such as NAD supplements (nicotinamide riboside, available under the trade names Basis® or Tru Niagen®), vitamin B 12 (oral or injectable), glycopyrrolate, atropine, scopolamine, baclofen, tizanidine, mexiletine, SSRIs, benzodiazepines, Neudexta, riluzole, and edaravone, and combinations thereof.

[0199] The compounds, pharmaceutical compositions, and methods of the present disclosure may be useful for treating subjects such as, but not limited to, mammals, humans, non-human mammals, domestic animals (e.g., laboratory animals, household pets, or livestock), non-domestic animals (e.g., wildlife), dogs, cats, rodents, mice, hamsters, cows, birds, chickens, fish, pigs, horses, goats, sheep, or rabbits. In preferred embodiments, the compounds, pharmaceutical compositions, and methods of the present disclosure are used to treat humans.

[0200] The compounds, pharmaceutical compositions and methods described herein can be useful as treatments, for example, can be administered to a subject in need thereof.The therapeutic effect can be achieved in a subject by reducing, suppressing, alleviating or eradicating disease state, including but not limited to its symptoms.The therapeutic effect in a subject who has a disease or condition, or who is predisposed to have a disease or condition, or who is beginning to have a disease or condition, can be achieved by reducing, suppressing, preventing, alleviating or eradicating condition or disease, or pre-condition or pre-disease condition.

[0201] In carrying out 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, often to treat and / or prevent the condition or its progression.The pharmaceutical composition can affect the subject's physiology, such as the immune system, inflammatory response, or other physiological effects.The therapeutically effective amount can vary widely depending on the severity of the disease, the subject's age and relative health, the potency of the compound used, and other factors.

[0202] Treat and / or treating can refer to any indication of successful treatment or improvement of a disease or condition. Treatment can include, for example, reducing, delaying, or improving the severity of one or more symptoms of a disease or condition, or treatment can include reducing the frequency with which a symptom of a disease, defect, disorder, or adverse condition is experienced by a patient. Treating can be used herein to refer to a method that brings about some level of treatment or improvement of a disease or condition, and can contemplate a range of results toward that goal, including, but not limited to, prevention of the condition altogether.

[0203] Prevent, preventing, etc. can refer to the prevention of a disease or condition in a patient. For example, if an individual at risk of contracting a disease is treated with a method of the present disclosure and does not later contract the disease, the disease has been prevented in that individual for at least some period of time.

[0204] A therapeutically effective amount can be the amount of a compound or pharmaceutical composition or its active ingredient that is sufficient to produce a beneficial effect or reduce adverse, non-beneficial events in an individual to whom the composition is administered.A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, and such administration can be performed one or more times over a given period of time.The exact dose depends on the purpose of treatment and can be ascertained by those skilled in the art using known techniques.

[0205] The compounds or pharmaceutical compositions described herein that can be used for treatment can be formulated and dosages can be established in a manner consistent with good clinical practice, 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 experts.The compounds or pharmaceutical compositions can be prepared according to the preparation instructions described herein.

[0206] Those skilled 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 will depend on several factors, including, but not limited to, the health of the subject, the patient's particular disease or condition, the grade or level of the patient's particular disease or condition, additional treatments that are or have been administered to the subject, etc.

[0207] The method, compound and pharmaceutical composition described herein can be for administration to a subject in need thereof.Often, the administration of compound or pharmaceutical composition can include an administration route, and non-limiting examples of administration route include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral or intraperitoneal.In addition, pharmaceutical composition or compound can be administered to a subject by additional administration route, for example, by inhalation, oral, transdermal, intranasal or intrathecal administration.

[0208] The pharmaceutical composition or compound of the present disclosure may be administered to a subject in need thereof in a first administration and one or more additional administrations. The one or more additional administrations may be administered to a subject in need thereof minutes, hours, days, weeks, or months after the first administration. Any one of the additional administrations may be administered to a subject in need thereof less than 21 days, or less than 14 days, or less than 10 days, or less than 7 days, or less than 4 days, or less than 1 day after the first administration. The one or more administrations may be administered more than once daily, more than once weekly, or more than once monthly. The compound or pharmaceutical composition may be administered to a subject in need thereof in a daily cycle over 21, 14, 10, 7, 4, or 1-7 days.

[0209] The compounds, pharmaceutical compositions and methods provided herein can be useful for treating a variety of diseases or conditions, or for preventing disease or conditions in a subject, or for other therapeutic applications for 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, comprising administering to the subject an effective amount of the compound or pharmaceutical composition described herein.In some embodiments, the disease is associated with FIG4 deficiency.

[0210] In some embodiments, the neurological disease is selected from the group consisting of 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 epileptic seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, polyglutamine neuronal nuclear and intranuclear inclusion disease, Marinesco and Hirano body disease, tauopathy, Alzheimer's disease, and neurodegenerative diseases. The neuropathies include: encephalopathy, spongiform degeneration, 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 disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV; neuropathy; Huntington's disease; psychiatric disorders; ADHD; schizophrenia; mood disorders; major depressive disorder; depression; bipolar disorder type I; or bipolar disorder type II.

[0211] 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.

[0212] 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.

[0213] In some embodiments, the neurological disease is a lysosomal storage disease, such as Fabry disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, or mucolipidosis type IV.

[0214] In some embodiments, the neurological disease is a psychiatric disorder such as ADHD, schizophrenia, or a mood disorder such as major depressive disorder, depression, bipolar disorder I, or bipolar disorder II.

[0215] The present disclosure further provides any compound disclosed herein for use in a method of treating the human or animal body by therapy. The treatment can be by any of the mechanisms disclosed herein, such as inhibiting, reducing, or diminishing the progression of a disease disclosed herein. The present disclosure further provides any compound disclosed herein for the prevention or treatment of any condition disclosed herein. The present disclosure also provides any compound disclosed herein or a pharmaceutical composition thereof for achieving any clinical outcome disclosed herein for any condition 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 condition disclosed herein. [Example]

[0216] In order to enable those skilled in the art to more clearly understand and to practice the present disclosure, the following preparations of compounds of formula (I) and intermediates are given, which should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0217] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri), or are prepared by methods known to those skilled in the art according to procedures set forth in references 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 Supplementals (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 are merely illustrative of some of the methods by which the compounds of the present disclosure may be synthesized, and various modifications to these schemes will occur and be suggested to those skilled in the art in view of this disclosure. The starting materials and intermediates of the reactions, as well as the final products, can be isolated and purified, if desired, using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0218] Unless otherwise specified, reactions described herein are carried out over a temperature range of about −78° C. to about 150° C., or about 0° C. to about 125° C., or at about room temperature (or ambient temperature), e.g., about 20° C., at atmospheric pressure.

[0219] Compounds of formula (I) and subformulas and species described herein, including those in which the substituents are as defined herein, can be prepared as illustrated and described below.

[0220] Unless otherwise noted, all reagents were used without further purification. 1 H NMR spectra were obtained on a Bruker 300 MHz instrument at room temperature in CDCl3, DMSO-d6, or CD3OD. When more than one conformer was detected, the chemical shifts of the most abundant one are reported. 1 Chemical shifts for H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad. LC-MS conditions are described below:

[0221] LCMS column: Agilent Zorbax XDB C18 4.6 x 50 mm, 3.5 μm a. Mobile phase, Solvent A: Water (+0.1% formic acid); Solvent B: MeOH b.Flow rate: 1.0mL / min c. Run time: 2 min gradient (20% to 90% B), then 3 min at 90% B d.Temperature: 30℃

[0222] HPLC column: Agilent SB-C18 4.6 x 150 mm, 3.5 μm a. Mobile phase, Solvent A: Water (+0.02% TFA); Solvent B: MeOH b.Flow rate: 1.0mL / min c. Run time: 0.5 min at 10% B, 9.5 min gradient (10% to 90% B), then 10 min at 90% B d.Temperature: 30℃

[0223] Preparative LC column: Phenomenex Luna 5u 100A, 21.2 x 250mm, 5µm a. Mobile phase, Solvent A: Water; Solvent B: MeOH b.Flow rate: 10mL / min c. Run time: 20% B for 1 min, 30 min gradient (20% to 80%), then 90% B for 10 min d. Temperature: Ambient

[0224] The following abbreviations are used in the text: PE = petroleum ether, EA or EtOAc = ethyl acetate, DMSO = dimethyl sulfoxide, DMF = N,N-dimethylacetamide, MeOH = methanol, EtOH = ethanol, EtO = 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) = bis(pinacolato)diboron, HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol, DIBAL-H = diisobutylaluminum hydride, MeI = iodomethane, he x = hexane, n-Hex = n-hexane, DCE = 1,2-dichloroethane, TBSCl = tert-butyldimethylsilyl chloride, TfO = trifluoromethanesulfonic anhydride, n-BuLi = n-butyllithium, DMAP = 4-dimethylaminopyridine, KOAc = potassium acetate, NaOAc = sodium acetate, TFAA = trifluoroacetic anhydride, m-CPBA = meta-chloroperbenzoic 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 = hours, hrs = hours.

[0225] Intermediate A: 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0226] [ka]

[0227] Preparation of A.2: To a solution of A.1 (200.0 g, 1.46 mol, 172.4 mL, 1.0 equiv.) in toluene (1800 mL) was added NaH (116.6 g, 2.92 mol, 60% purity, 2.0 equiv.) at 25° C. The mixture was heated to 90° C., and then MeCN (280.1 g, 6.83 mol, 359.2 mL, 4.68 equiv.) was added dropwise. The mixture was stirred at 90° C. for 8 hours, after which an assay by 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 the yellow solid filter cake was then 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, then the organic layer was separated, and the aqueous layer 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.

[0228] Preparation of A.3: To a solution of A.2 (150.0 g, 1.03 mol, 1.0 equiv.) in EtOH (800 mL) was added NHNH-H0 (78.6 g, 1.54 mol, 76.3 mL, 98% purity, 1.5 equiv.). The mixture was stirred at 90 °C. TLC (dichloromethane / methanol = 10 / 1, R f =0.3) indicated that most of the starting material had been consumed after 2 h. The reaction mixture was concentrated to give the crude product, which was then crystallized from ethyl alcohol (200 mL) to give a yellow solid. After isolation of the yellow solid, it was kept 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).

[0229] Preparation of A.4: To a solution of A.3 (80.0 g, 499.4 mmol, 1.0 equiv.) and diethyl malonate (80.0 g, 499.4 mmol, 75.4 mL, 1.0 equiv.) in EtOH (480 mL) was added sodium ethoxide (84.9 g, 1.25 mol, 2.5 equiv.) at 25° C. The mixture was stirred at 90° C. for 8 h, and TLC (dichloromethane / methanol=10 / 1, R f =0.3) indicated that the starting material had been consumed. Filtration of the mixture gave A.4 (80.0 g, crude) as a yellow solid; LC-MS (ESI+): m / z 229 (MH + ).

[0230] Preparation of A.5: To a solution of A.4 (20.0 g, 87.6 mmol, 1.0 equiv.) in POCl3 (322.5 g, 2.10 mol, 195.4 mL, 24.0 equiv.) at 25 °C, N,N-dimethylaniline (13.8 g, 113.9 mmol, 14.4 mL, 1.3 equiv.) was added. The mixture was heated with stirring at 110 °C. TLC (dichloromethane / methanol = 10 / 1, R f =0.8), indicating that the starting material was 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 (14.0 g) as a yellow solid; LC-MS (ESI+): m / z 265 / 267 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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.

[0231] Intermediate A: To a solution of A.5 (2.0 g, 7.54 mmol, 1.0 equiv) in EtN (1.53 g, 15.0 mmol, 2.10 mL, 2.0 equiv) and 1,4-dioxane (12 mL) at 25 °C, morpholine (1.31 g, 15.0 mmol, 1.33 mL, 2.0 equiv) was added. The mixture was stirred at 25 °C; after 3 h, TLC (petroleum ether / ethyl acetate = 1 / 1, Rf =0.5), indicating that the starting material had been consumed. 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, CDCl3) 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.

[0232] Intermediate B: 5-amino-N,N-dimethyl-3-(4-methylphenyl)-1H-pyrazole-1-sulfonamide

[0233] [ka]

[0234] To a solution of 3-(4-methylphenyl)-1H-pyrazolo-5-amine (250 mg, 1.57 mmol) in THF (5 mL) at 0° C. was added NaH (94 mg, 2.35 mmol). After stirring at 0° C. for 1 hour, dimethylsulfamoyl chloride (270 mg, 1.88 mmol) was added to the solution. The reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with gradient elution using 20% ​​EtOAc / PE to 33% EtOAc / PE to give 5-amino-N,N-dimethyl-3-phenyl-1H-pyrazole-1-sulfonamide (Intermediate B, 212 mg, 0.79 mmol); LC-MS: m / z 281 (MH + ).1 HNMR (300 MHz, DMSO-d6) 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.

[0235] [Example 1] 7-Morpholino-2-(pyridin-4-yl)-N-(3-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-amine, hydrochloride salt

[0236] 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

[0237] [ka]

[0238] 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), CsCO (142 mg, 0.44 mmol), Pd(OAc) (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 directly concentrated, and the resulting residue was purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 3% MeOH / DCM to give 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 (50 mg, 0.09 mmol) as a yellow solid; LC-MS (ESI + ): m / z 560 (MH + ).

[0239] 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 salt

[0240] [ka]

[0241] 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 / EtO (1 mL). The reaction was stirred at ambient temperature for 2 hours. A large amount of solid precipitated. After concentration, the residue was triturated in MeOH / EtO (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 salt (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-d6) 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.

[0242] [Example 2] 7-Morpholino-N-(5-phenyl-1H-pyrazol-3-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine

[0243] [ka]

[0244] Compound 2 was prepared from intermediate A and a protected pyrazole following the same two-step procedure used in Example 1. The protected pyrazole was prepared from 3-phenyl-1H-pyrazol-5-amine following the procedure used to prepare 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-d6) 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.

[0245] [Example 3] 7-Morpholino-N-[5-(o-tolyl)-1H-pyrazol-3-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine

[0246] [ka]

[0247] Compound 3 was prepared from intermediate A and a protected pyrazole following the same two-step procedure used in Example 1. The protected pyrazole was prepared from 3-(2-methylphenyl)-1H-pyrazol-5-amine following the procedure used to prepare 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 + ). 1HNMR (300 MHz, CD3OD) 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.

[0248] [Example 4] 7-Morpholino-N-[3-(m-tolyl)-1H-pyrazol-5-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine, hydrochloride salt

[0249] [ka]

[0250] Compound 4 was prepared from intermediate A and a protected pyrazole following the same two-step procedure used in Example 1. The protected pyrazole was prepared from 3-(3-methylphenyl)-1H-pyrazol-5-amine following the procedure used to prepare 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 salt, was obtained; LC-MS (ESI+): m / z 453 (MH + ). 1HNMR (300 MHz, DMSO-d6) 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.

[0251] [Example 5] N-(5-methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine

[0252] [ka]

[0253] Compound 5 was prepared from intermediate A and a protected pyrazole following the same two-step procedure used in Example 1. The protected pyrazole was prepared from 3-(3-methyl)-1H-pyrazol-5-amine following the procedure used to prepare intermediate B. Compound 5, N-(5-methyl-1H-pyrazol-3-yl)-7-morpholino-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine, was obtained; LC-MS (ESI+): m / z 377 (MH + ). 1 HNMR (300 MHz, CD3OD) 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.

[0254] [Example 6] 7-Morpholino-2-(4-pyridyl)-N-[5-(4-pyridyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine

[0255] [ka]

[0256] Compound 6 was prepared from intermediate A and a protected pyrazole following the same two-step procedure used in Example 1. The protected pyrazole was prepared from 3-(pyrid-4-yl)-1H-pyrazol-5-amine following the procedure used to prepare intermediate B. Compound 6, 7-morpholino-2-(4-pyridyl)-N-[5-(4-pyridyl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-5-amine, was obtained: LC-MS (ESI+): m / z 440 (MH + ). 1 HNMR (300 MHz, CD3OD) 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.

[0257] [Example 7] 1-(7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine

[0258] [ka]

[0259] 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 t-butoxide (18.3 mg, 0.191 mmol), Pd(dba) (4.2 mg, 0.005 mmol) and Xantphos (2.1 mg, 0.005 mmol) in DMF (3 mL) was heated to 110 °C under microwave conditions for 30 min. The reaction mixture was directly concentrated and purified by silica gel column chromatography eluting with a gradient of 2% MeOH / DCM to 3% MeOH / DCM to give 1-(7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-phenyl-1H-pyrazol-5-amine (compound 7, 14.2 mg, 0.03 mmol) as a white solid; LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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.

[0260] [Example 8] 1-(7-morpholino-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-(o-tolyl)-1H-pyrazol-5-amine

[0261] [ka]

[0262] Compound 8 was prepared from intermediate A and 3-(2-methylphenyl)-1H-pyrazol-5-amine according to the procedure used in Example 7; LC-MS (ESI+): m / z 453 (MH + ). 1 HNMR (300 MHz, CDCl3) 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.

[0263] [Example 9] 4-[5-(4-phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0264] [ka]

[0265] 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 (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated 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 give 4-[5-(4-phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine (compound 9, 17.5 mg, 0.04 mmol) as an off-white solid; LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl3) 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.

[0266] Intermediate C

[0267] Step 1: Synthesis of tert-butyl 4-(3-methylphenyl)-1H-pyrazole-1-carboxylate

[0268] [ka]

[0269] 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), and Pd(PPh)Cl (392 mg, 0.34 mmol) in 1,4-dioxane / HO (30 mL, 2 / 1) was heated to 80 °C overnight. Completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution from 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, CDCl3) 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.

[0270] Step 2: Synthesis of 4-(3-methylphenyl)-1H-pyrazole hydrochloride, intermediate C

[0271] [ka]

[0272] To a solution of tert-butyl 4-(3-methylphenyl)-1H-pyrazole-1-carboxylate (117 mg, 0.45 mmol) in DCM was added HCl / EtO (1 mL). The reaction was stirred overnight at ambient temperature. A large amount of solid precipitated. After concentration, the residue was triturated in MeOH / EtO (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, CDCl3) δ: 8.13 (s, 2H), 7.38-7.20 (m, 4H) and 2.42 (s, 3H) ppm.

[0273] [Example 10] 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0274] [ka]

[0275] 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 minutes. 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 reaction was determined to be complete by TLC. The reaction mixture was quenched with water (10 mL), and the aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution from 30% EtOAc / PE to EtOAc to give 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine (compound 10, 15.5 mg, 0.035 mmol) as an off-white solid; LC-MS (ESI+): m / z 438 (MH + ). 1 HNMR (300 MHz, CDCl3) 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.

[0276] [Example 11] 4-[2-(4-pyridyl)-5-[4-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0277] [ka]

[0278] Compound 11 was prepared by the reaction of intermediate A with 4-(4-pyridyl)-1H-pyrazole according to the conditions used in Examples 9 and 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, CDCl3) 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.

[0279] [Example 12] 4-[5-(4-methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0280] [ka]

[0281] Compound 12 was prepared by the reaction of intermediate A with 4-methylpyrazole according to the conditions used in Examples 9 and 10. Compound 12, 4-[5-(4-methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine, was obtained; LC-MS (ESI+): m / z 362 (MH + ). 1HNMR (300 MHz, DMSO-d6) 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.

[0282] [Example 13] 4-[5-(3-phenylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0283] [ka]

[0284] 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. To the mixture was added 4-(5-chloro-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (Intermediate A, 62 mg, 0.19 mmol). 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 (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated 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 give 4-[5-(3-phenylpyrazol-1-yl)-2-(4-pyridyl)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 + ). 1HNMR (300 MHz, CDCl3) 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.

[0285] [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

[0286] [ka]

[0287] Compound 14 was prepared by the reaction of intermediate A with 3-(3-methylphenyl)pyrazole according to the conditions used in Example 13. 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 HNMR (300 MHz, CDCl3) 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.

[0288] [Example 15] 4-[2-(4-pyridyl)-5-[3-(4-pyridyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0289] [ka]

[0290] Compound 15 was prepared by the reaction of intermediate A with 3-(4-pyridyl)pyrazole according to the conditions used in Example 13. 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, CDCl3) 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.

[0291] [Example 16] 4-[5-(3-methylpyrazol-1-yl)-2-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0292] [ka]

[0293] Compound 16 was prepared by the reaction of intermediate A with 3-(4-pyridyl)pyrazole according to the conditions used in Example 13. 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, CDCl3) 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.

[0294] Intermediate D: 4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0295] [ka]

[0296] D.2: Synthesis of 3-(pyridin-2-yl)-1H-pyrazol-5-amine

[0297] [ka]

[0298] To a solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (2.5 g, 17.1 mmol) in EtOH (75 mL) was added NH2NH2.HO (1.71 g, 34.2 mmol). The reaction mixture was heated to reflux overnight. Upon completion of the reaction as indicated by TLC analysis, the reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 1% MeOH / DCM to 3% MeOH / DCM to afford 3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.34 g, 8.37 mmol) as a brown solid. LC-MS (ESI+): m / z 161 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0299] D.3: Synthesis of 2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

[0300] [ka]

[0301] To a solution of anhydrous EtOH (10 mL) was carefully added small pieces of sodium (580 mg, 25.2 mmol) at ambient temperature. After all of the sodium had dissolved, the solution was concentrated to give fresh NaOEt as a white solid. 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 that 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 diethyl ether to give crude 2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (3.89 g, 17.1 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI+): 229 (MH + ).

[0302] D.4: Synthesis of 5,7-dichloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

[0303] [ka]

[0304] A solution of crude 2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (3.89 g, 17.1 mmol) in phenylphosphonic acid dichloride (20 mL) was heated to 110° C. overnight. The reaction mixture was quenched with saturated NaHCO solution and basified to pH 8. The aqueous solution was extracted with DCM / MeOH (15:1, 6×50 mL). The combined organic phases were dried over anhydrous NaSO, 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 + ).

[0305] Intermediate D: Synthesis of 4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0306] [ka]

[0307] 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 directly concentrated and purified by silica gel column chromatography with a gradient elution 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 (400 mg, 1.27 mmol) as a yellow solid. LC-MS (ESI+): m / z 316 / 318 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0308] Intermediate E: 4-(5-chloro-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0309] [ka]

[0310] Intermediate E was prepared by the same method used to prepare 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.

[0311] [Example 17] 4-(2-(pyridin-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine.

[0312] [ka]

[0313] Compound 17 was prepared by the reaction of intermediate E with 3-(m-tolyl)-1H-pyrazole according to the conditions used in Example 18. LC-MS (ESI + ): m / z 438 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0314] [Example 18] 4-(2-(pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine.

[0315] [ka]

[0316] 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), CsCO (312 mg, 0.96 mmol), and CuI (18 mg, 0.014 mmol) in DMF (10 mL) was heated to 120 °C overnight. Upon 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 × 20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution from 1% MeOH / DCM to 5% MeOH / DCM to give 4-(2-(pyridin-2-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (compound 18, 40.6 mg, 0.093 mmol) as a white solid. LC-MS (ESI+): m / z 438 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0317] Intermediate F: 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0318] [ka]

[0319] F.2: Ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0320] [ka]

[0321] To a solution of anhydrous EtOH (10 mL) was carefully added small pieces of sodium (890 mg, 38.7 mmol) at ambient temperature. After all of the sodium had dissolved, the solution was concentrated to give fresh NaOEt as a white solid. 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 that 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 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 + ).

[0322] F.3 Synthesis of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0323] [ka]

[0324] A solution of crude ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate (5.92 g, 26.5 mmol) in phenylphosphonic acid dichloride (15 mL) was heated to 120 °C overnight. The reaction mixture was quenched with saturated NaHCO solution until basic (pH 8). The aqueous solution was extracted with DCM / MeOH (15:1, 6 × 40 mL). The combined organic phases were dried over anhydrous NaSO, 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+).

[0325] F.4) Synthesis of ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate

[0326] [ka]

[0327] 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) was added morpholine (3.2 g, 37.3 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 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, CDCl3) 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).

[0328] F.5: Ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

[0329] [ka]

[0330] A suspension of 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), CsCO (6.9 g, 21.3 mmol), and CuI (400 mg, 2.1 mmol) in DMF (120 mL) was heated to 110 °C overnight. Upon 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 × 30 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution from 1% MeOH / DCM to 5% MeOH / DCM to give 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, CDCl3) 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).

[0331] Intermediate F: 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0332] [ka]

[0333] 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 N aqueous NaOH (30 mL). The reaction was heated to 40 °C for 3 h. Upon completion of the reaction, as indicated by TLC analysis, 1 M aqueous HCl was added to the reaction mixture until the pH reached 4. The resulting solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (Intermediate F, 3.5 g, 8.7 mmol) as a white solid. LC-MS (ESI+): m / z 405 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0334] [Example 19] N-Ethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0335] [ka]

[0336] 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), ethanamine 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 at ambient temperature overnight. Upon completion of the reaction as indicated by TLC analysis, 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 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, CDCl3) δ 8.64 (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).

[0337] [Example 20] N-Cyclopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0338] [ka]

[0339] Compound 20 was prepared from intermediate F and aminocyclopropane according to the method used in Example 19. LC-MS (ESI+): m / z 444 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.64 (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).

[0340] [Example 21] (R)-N-(1-cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0341] [ka]

[0342] Compound 21 was prepared from intermediate F and (R)-1-cyclopropylethylamine according to the procedure used in Example 19. LC-MS (ESI+): m / z 472 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.64 (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).

[0343] [Example 22] (S)-N-(1-cyclopropylethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0344] [ka]

[0345] Compound 22 was prepared from intermediate F and (S)-1-cyclopropylethylamine according to the procedure used in Example 19. LC-MS (ESI+): m / z 472 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.64 (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).

[0346] [Example 23] N-(2-Methoxyethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0347] [ka]

[0348] Compound 23 was prepared from intermediate F and 3-(methoxy)ethylamine according to the procedure used in Example 19. LC-MS (ESI+): m / z 462 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0349] [Example 24] N,N-Dimethyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0350] [ka]

[0351] Compound 24 was prepared from intermediate F and dimethylamine according to the procedure used in Example 19. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0352] [Example 25] N-Ethyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0353] [ka]

[0354] Compound 25 was prepared by N-methylation of compound 19 according to the procedure used in Example 37. LC-MS (ESI+): m / z 446 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0355] [Example 26] N-Cyclopropyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0356] [ka]

[0357] Compound 26 was prepared from intermediate F and N-methyl(cyclopropyl)amine according to the method used in Example 19. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0358] [Example 27] N-(cyclopropylmethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0359] [ka]

[0360] Compound 27 was prepared by the reaction of intermediate F with N-(cyclopropylmethyl)amine following the coupling procedure used in Example 19. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.64 (d, J = 2.7 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), 7.08-7.06 (m, 1H), 7.02 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.05-4.03 (m, 4H), 3.88-3.85 (m, 4H), 3.37 (t, J = 6.6 HZ, 1H), 2.45 (s, 3H), 1.11-1.09 (m, 1H), 0.59-0.57 (m, 2H), 0.33-0.31 (m, 2H).

[0361] [Example 28] Azetidin-1-yl(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone

[0362] [ka]

[0363] Compound 28 was prepared from azetidine and intermediate F according to the coupling procedure used in Example 19. LC-MS (ESI+): m / z 444 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.64 (d, J = 2.7 Hz, 1H), 7.83-7.66 (m, 2H), 7.35 (t, J = 7.5 HZ, 1H), 7.22-7.20 (m, 1H), 7.13 (s, 1H), 6.98 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 4.65 (t, J = 7.5 HZ, 2H), 4.28 (t, J = 7.5 HZ, 1H), 4.01-3.98 (m, 4H), 3.88-3.85 (m, 4H), 2.45-2.37 (m, 5H).

[0364] [Example 29] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(pyrrolidin-1-yl)methanone

[0365] [ka]

[0366] Compound 29 was prepared by the reaction of intermediate F with pyrrolidine using the same procedure as used in Example 19. LC-MS (ESI+): m / z 458 (MH + ). 1 HNMR (300 MHz, CDCl3) 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), 7.12 (s, 1H), 6.94 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 4.00-3.88 (m, 10H), 3.76-3.71 (m, 2H), 2.45 (s, 3H), 1.98-1.94 (m, 4H).

[0367] [Example 30] (7-Morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone

[0368] [ka]

[0369] Compound 30 was prepared by the reaction of intermediate F with piperidine using the same procedure as used in Example 19. LC-MS (ESI+): m / z 472 (MH + ). 1 HNMR (300 MHz, CDCl3) 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 (t, J = 7.5 HZ, 1H), 7.10 (s, 1H), 6.82 (d, J = 2.4 Hz, 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).

[0370] [Example 31] Morpholino(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone

[0371] [ka]

[0372] Compound 31 was prepared by the reaction of intermediate F with morpholine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 474 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.4 Hz, 1H), 7.76-7.71 (m, 2H), 7.36 (t, J = 7.5 HZ, 1H), 7.23-7.20 (m, 1H), 7.13 (s, 1H), 6.83 (d, J = 2.4 Hz, 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).

[0373] [Example 32] (4-Methylpiperazin-1-yl)(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone

[0374] [ka]

[0375] Compound 32 was prepared by the reaction of intermediate F with N-(methyl)piperidine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 487 (MH + ). 1 HNMR (300 MHz, CDCl3) 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 (t, J = 7.5 HZ, 1H), 7.11 (s, 1H), 6.83 (d, J = 2.4 Hz, 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).

[0376] [Example 33] N-Methoxy-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0377] [ka]

[0378] Compound 33 was prepared by the reaction of intermediate F with N-methoxy-N-methylamine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 448 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.7 Hz, 1H), 7.76-7.71 (m, 2H), 7.36 (t, J = 7.5 HZ, 1H), 7.21 (t, J = 7.2 HZ, 1H), 7.14 (s, 1H), 6.92 (s, 1H), 6.82 (d, J = 2.7 Hz, 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).

[0379] [Example 34] N-Methoxy-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0380] [ka]

[0381] Compound 34 was prepared by the reaction of intermediate F with N-methoxylamine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 434 (MH + ). 1HNMR (300 MHz, CDCl3) δ 9.39 (s, 1H), 8.64 (d, J = 2.7 Hz, 1H), 7.76-7.71 (m, 2H), 7.36 (t, J = 7.5 HZ, 1H), 7.23-7.19 (m, 2H), 7.04 (s, 1H), 6.83 (d, J = 2.4 Hz, 1H), 4.05-4.02 (m, 4H), 3.96 (s, 3H), 3.84-3.83 (m, 4H), 2.45 (s, 3H).

[0382] [Example 35] N-(Methylsulfonyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0383] [ka]

[0384] Compound 35 was prepared by the reaction of intermediate F with methylsulfonamide by the same procedure as used in Example 19. LC-MS (ESI+): m / z 482 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0385] [Example 36] N-Cyclopentyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0386] [ka]

[0387] Compound 36 was prepared by the reaction of intermediate F with cyclopentylamine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 472 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0388] [Example 37] N-Cyclopentyl-N-methyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0389] [ka]

[0390] 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) at 0 °C was added NaH (10 mg, 0.24 mmol). After stirring at that temperature for 0.5 h, iodomethane (25 mg, 0.17 mmol) was added to the solution. Upon 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 × 10 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution from 1% MeOH / DCM to 5% MeOH / DCM to give 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, CDCl3) 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).

[0391] [Example 38] N-Isopropyl-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0392] [ka]

[0393] Compound 38 was prepared by the reaction of intermediate F with isopropylamine using the same procedure as used in Example 19. LC-MS (ESI+): m / z 446 (MH + ). 1 HNMR (300 MHz, CDCl3) 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), 7.01 (s, 1H), 6.83 (d, J = 2.7 Hz, 1H), 6.75 (d, J = 8.1 Hz, 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 = 6.6 Hz, 6H).

[0394] [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

[0395] [ka]

[0396] Compound 39 was prepared by the reaction of intermediate F with N-(1,3-dimethoxypropan-2-yl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 506 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.64 (d, J = 2.7 Hz, 1H), 7.76-7.71 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.22-7.20 (m, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.83 (d, J = 2.4 Hz, 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).

[0397] [Example 40] N-(2-(dimethylamino)ethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0398] [ka]

[0399] Compound 40 was prepared by the reaction of intermediate F with N-(2-(dimethylamino)ethyl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 475 (MH + ). 1 HNMR (300 MHz, CD3OD) 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).

[0400] [Example 41] N-(4-(dimethylamino)butyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0401] [ka]

[0402] Compound 41 was prepared by the reaction of intermediate F with N-(4-(dimethylamino)butyl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 503 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0403] [Example 42] 7-Morpholino-N-(oxetan-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0404] [ka]

[0405] Compound 42 was prepared by the reaction of intermediate F with N-(oxetan-3-yl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 460 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.7 Hz, 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 = 2.4 Hz, 1H), 5.36-5.26 (m, 1H), 5.06 (t, J = 7.2 Hz, 2H), 4.68 (t, J = 6.6 Hz, 2H), 4.07-4.04 (m, 4H), 3.86-3.85 (m, 4H), 2.45 (s, 3H).

[0406] [Example 43] 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0407] [ka]

[0408] Compound 43 was prepared by the reaction of intermediate F with N-(oxetan-3-ylmethyl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 474 (MH + ). 1HNMR (300 MHz, CDCl3) 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, 3H), 7.01 (s, 1H), 6.83 (d, 4.87 (t, J = 7.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.03-4.01 (m, 4H), 3.85-3.78 (m, 6H), 3.40-3.30 (m, 1H), 2.45 (s, 3H).

[0409] [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

[0410] [ka]

[0411] Compound 44 was prepared by the reaction of intermediate F with N-((3-(hydroxymethyl)oxetan-3-yl)methyl)amine by the same procedure as used in Example 19. LC-MS (ESI+): m / z 504 (MH + ). 1HNMR (300 MHz, DMSO-d6) δ 8.73 (d, J = 2.7 Hz, 1H), 8.67-8.64 (m, 1H), 7.83-7.80 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 5.12 (t, J = 7.8 HZ, 1H), 4.42 (d, J = 5.7 Hz, 2H), 4.30 (d, J = 6.0 Hz, 2H), 3.89 (s, 8H), 3.68 (d, J = 5.1 Hz, 2H), 3.60 (d, J = 5.4 Hz, 2H), 2.40 (s, 3H).

[0412] [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

[0413] [ka]

[0414] Compound 45 was prepared by the reaction of intermediate F with 2-oxa-6-azaspiro[3.3]heptane using the same procedure as used in Example 19. LC-MS (ESI+): m / z 486 (MH + ). 1HNMR (300 MHz, CDCl3) 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), 6.97 (s, 1H), 6.83 (d, J = 2.4 Hz, 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).

[0415] [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

[0416] [ka]

[0417] Compound 46 was prepared by the reaction of intermediate F with 6-oxa-1-azaspiro[3.3]heptane using the same procedure as used in Example 19. LC-MS (ESI+): m / z 486 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0418] [Example 47] 7-Morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0419] [ka]

[0420] Synthesis of 2-(oxetan-3-yloxy)isoindoline-1,3-dione

[0421] [ka]

[0422] To a solution of 2-hydroxyisoindoline-1,3-dione (4.84 g, 27 mmol) in THF (120 mL) at 0 °C, PPh3 (8.5 g, 32.4 mmol), DEAD (6.56 g, 32.4 mmol), and oxetan-3-ol (2 g, 29.7 mmol) were added. The reaction was heated to 30 °C overnight. Upon completion of the reaction, as indicated by TLC analysis, the reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3 × 30 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 with a gradient elution from 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 approximately 10%. LC-MS (ESI+): m / z 220 (MH + ).

[0423] Synthesis of O-(oxetan-3-yl)hydroxylamine

[0424] [ka]

[0425] To a solution of impure 2-(oxetan-3-yloxy)isoindoline-1,3-dione (1 g, 0.5 mmol) in MeOH (75 mL) was added NHNH.HO (229 mg, 4.58 mmol). The reaction mixture was heated to 65 °C and stirred at that temperature for 1.5 h. The reaction mixture was directly concentrated. EtOAc (10 mL) was added to the residue, causing a large amount of solid to precipitate. After filtration, the filtrate was concentrated to give crude O-(oxetan-3-yl)hydroxylamine (400 mg, 4.49 mmol). The crude product was used directly in the next step without further purification.

[0426] Synthesis of 7-morpholino-N-(oxetan-3-yloxy)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0427] [ka]

[0428] A solution of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (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 at room temperature overnight. Upon completion of the reaction as indicated by TLC analysis, 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 give 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-d6) 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).

[0429] General Procedure 1

[0430] Compound 48: N-[(3S)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0431] [ka]

[0432] Synthesis of ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0433] [ka]

[0434] To a solution of anhydrous EtOH (10 mL) was carefully added small pieces of sodium (890 mg, 38.7 mmol) at room temperature. After all the sodium was dissolved, the solution was concentrated to give fresh NaOEt as a white solid. 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 that 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 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 + ).

[0435] Synthesis of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0436] [ka]

[0437] A solution of crude ethyl 5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate (5.92 g, 26.5 mmol) in phenylphosphonic acid dichloride (15 mL) was heated to 120° C. overnight. The reaction mixture was quenched with saturated NaHCO solution until pH=8. The aqueous solution was extracted with DCM / MeOH (15:1, 6×40 mL). The combined organic phases were dried over anhydrous NaSO, 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 + ).

[0438] Synthesis of ethyl 5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidine-2-carboxylate

[0439] [ka]

[0440] 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) was added morpholine (3.2 g, 37.3 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 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, CDCl3) 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).

[0441] Synthesis of ethyl 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

[0442] [ka]

[0443] A suspension of 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), CsCO (6.9 g, 21.3 mmol), and CuI (400 mg, 2.1 mmol) in DMF (120 mL) was heated to 110 °C overnight. 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 × 30 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution from 1% MeOH / DCM to 5% MeOH / DCM to give 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, CDCl3) 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).

[0444] Synthesis of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0445] [ka]

[0446] 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 (30 mL). The reaction was heated for 3 h at 40°C. Completion of the reaction was monitored by TLC. 1 M 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 NaSO, filtered, and concentrated under reduced pressure to give 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (3.5 g, 8.7 mmol) as a white solid. LC-MS (ESI+): m / z 405 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0447] 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

[0448] [ka]

[0449] 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 at room temperature overnight. 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 from 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 (compound 48, 32 mg, 0.07 mmol) as a white solid. LC-MS (ESI+): m / z 487 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0450] General Procedure 2

[0451] 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]ethanamine

[0452] [ka]

[0453] Synthesis of 2-bromopyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

[0454] [ka]

[0455] To a solution of diethyl malonate (50 mL) and 3-bromo-1H-pyrazol-5-amine (5 g, 30.86 mmol), NaOEt (20% in absolute EtOH, 26 g) was added. The mixture was heated to 120 °C to remove EtOH using a Dean-Stark trap. The reaction mixture was then stirred at that 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 (13.5 g, 59.2 mmol) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 230 / 232 (MH + ).

[0456] Synthesis of 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine

[0457] [ka]

[0458] A solution of crude 2-bromopyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (13.8 g, 56.7 mmol) in phenylphosphonic acid dichloride (100 mL) was heated to 120 °C overnight. The reaction mixture was quenched with saturated NaHCO solution in an ice bath until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 6 × 40 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 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 + ).

[0459] Synthesis of 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0460] [ka]

[0461] 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) was added morpholine (6.58 g, 75.6 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 3% MeOH / DCM to afford 4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)morpholine (8.6 g, 27.2 mmol) as a yellow solid. LC-MS (ESI+): m / z 317 / 319 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 6.52 (s, 1H), 6.08 (s, 1H), 3.98-3.93 (m, 4H), 3.82-3.76 (m, 4H).

[0462] Synthesis of 4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0463] [ka]

[0464] 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 minutes. 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 hours. The completion of the reaction was monitored by TLC. Water (200 mL) was added to the above solution, causing a large amount of solid to precipitate. After filtration, the filter cake was washed twice with ether to give 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, CDCl3) 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).

[0465] Synthesis of tert-butyl 3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazole-1-carboxylate

[0466] [ka]

[0467] 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)Cl (1.35 g, 1.92 mmol), and CsF (8.77 g, 57.7 mmol) in 1,4-dioxane / HO (330 mL, 10:1) was heated to 95 °C overnight. The reaction was monitored for completion by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with gradient elution from 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 + ). 1 HNMR (300 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 7.39-7.32 (m, 3 H), 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).

[0468] Synthesis of 4-(5-(benzyloxy)-2-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0469] [ka]

[0470] 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 hours. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO solution until pH = 8. A large amount of solid precipitated. After filtration, the filter cake was washed twice with ether to give 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) as a white solid. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 391 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 7.39-7.32 (m, 3 H), 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).

[0471] Synthesis of 2-(3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine and 2-(5-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine

[0472] [ka]

[0473] 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 CsCO (11.28 g, 34.62 mmol) and 2-chloro-N,N-dimethylethanamine 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 × 70 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution from 5% MeOH / DCM to 10% MeOH / DCM to give 2-(5-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (top 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-dimethylethanamine (bottom spot, 0.6 g, 1.3 mmol) as white solids.

[0474] 2-(5-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (top spot). LC-MS (ESI+): m / z 462 (MH + ). 1HNMR (300 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 7.39-7.32 (m, 3 H), 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-dimethylethanamine (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, 3 H), 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).

[0475] Synthesis of 2-(1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrazol-3-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-5-ol

[0476] [ka]

[0477] To a solution of 2-(3-(5-(benzyloxy)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (0.6 g, 1.3 mmol) in MeOH, Pd / C was added under a H balloon at room temperature for 4 h. The reaction was monitored for completion by TLC. After filtration, the filtrate was directly concentrated to give 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 + ).

[0478] Synthesis of 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine

[0479] [ka]

[0480] 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 acid dichloride (15 mL) was heated to 110° C. for 4 h. The reaction mixture was quenched with saturated NaHCO solution until pH=8. The aqueous solution was extracted with DCM / MeOH (15:1, 2×30 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC to give 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (250 mg, 0.64 mmol) as a white solid. LC-MS (ESI+): m / z 390 / 392 (MH + ).

[0481] 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)ethanamine

[0482] [ka]

[0483] A suspension of 2-(3-(5-chloro-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylethanamine (39 mg, 0.10 mmol), 4-(m-tolyl)-1H-pyrazole (17 mg, 0.11 mmol), CsCO (65 mg, 0.20 mmol), and CuO (2.8 mg, 0.02 mmol) in DMF (5 mL) was heated to 110 °C overnight. The reaction was monitored for completion by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 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)ethanamine (compound 91, 9 mg, 0.018 mmol) as a white solid. LC-MS (ESI+): m / z 512 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0484] General Procedure 3

[0485] Compound 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-ethanamine

[0486] [ka]

[0487] Synthesis of 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0488] [ka]

[0489] 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 (225 mg, 0.30 mmol) in 1,4-dioxane / HO (44 mL, 10:1) was heated to 60 °C overnight. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 10% EtOAc / Hex to 20% EtOAc / Hex to give 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 + ).

[0490] Synthesis of 3-(3-chlorophenyl)-1H-pyrazole

[0491] [ka]

[0492] To a solution of impure 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (377 mg, 1.44 mmol) in DCM was added TFA (3 mL). The reaction was stirred at room temperature for 2 hours. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO3 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI+): m / z 179 / 181 (MH + ).

[0493] 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-dimethylethanamine

[0494] [ka]

[0495] 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-dimethylethanamine (40 mg, 0.10 mmol), CsCO (68 mg, 0.20 mmol), and CuO (3 mg, 0.02 mmol) in DMF (10 mL) was heated to 110 °C overnight. The reaction was monitored for completion by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 3% MeOH / DCM to give 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-dimethylethanamine (compound 97 15.2 mg, 0.03 mmol) as a white solid. LC-MS (ESI+): m / z 532 / 534 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0496] General Procedure 4

[0497] Compound 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]ethanamine

[0498] [ka]

[0499] Synthesis of (E)-3-(dimethylamino)-1-(2-methylpyridin-4-yl)prop-2-en-1-one

[0500] [ka]

[0501] 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. 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 from 2% MeOH / DCM to 3% MeOH / DCM to give (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 HNMR (300 MHz, CDCl3) 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).

[0502] Synthesis of 2-methyl-4-(1H-pyrazol-3-yl)pyridine

[0503] [ka]

[0504] 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) was added hydrazine (0.3 mL). The reaction mixture was heated to 60° C. for 30 minutes. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-methyl-4-(1H-pyrazol-3-yl)pyridine (109 mg, 0.68 mmol) as a yellow solid. LC-MS (ESI+): m / z 160 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0505] 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

[0506] [ka]

[0507] 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), CsCO (68 mg, 0.20 mmol), and CuO (2 mg, 0.01 mmol) in DMF (4 mL) was heated to 110 °C overnight. The reaction was monitored for completion by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 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 (compound 96 15.6 mg, 0.03 mmol) as a white solid. LC-MS (ESI+): m / z 513 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.70 (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).

[0508] General Procedure 5

[0509] 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

[0510] Compound 87: 4-[2-(1,5-dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0511] [ka]

[0512] Synthesis of 4-(2-bromo-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0513] [ka]

[0514] 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), CsCO (10.3 g, 31.6 mmol), and CuO (453 mg, 3.2 mmol) in DMF (80 mL) was heated to 110 °C overnight. 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 from 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 + ). 1HNMR (300 MHz, 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).

[0515] 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

[0516] [ka]

[0517] 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 (32 mg, 0.05 mmol) in 1,4-dioxane / HO (22 mL, 10:1) was heated to 100 °C for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 20% EtOAc / Hex to 33% EtOAc / Hex to afford 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 + ).

[0518] 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

[0519] [ka]

[0520] 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 / EtO solution (2 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO solution until pH = 8. The aqueous solution was extracted with DCM / MeOH (15:1, 2 × 20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-(2-(5-methyl-1H-pyrazol-3-yl)-5-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (138 mg, 0.31 mmol) as a pale yellow solid. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0521] 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

[0522] [ka]

[0523] 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 CsCO (222 mg, 0.68 mmol) in DMF (5 mL) at room temperature was added CHI (48 mg, 0.34 mmol). The reaction was monitored for completion by TLC. The reaction was quenched with water (50 ml), and the solution was extracted with DCM (3 × 20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of 5% MeOH / DCM to 8% MeOH / DCM to give 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, bottom 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, top spot, 42 mg, 0.092 mmol).

[0524] 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, bottom spot). LC-MS (ESI+): m / z 455 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0525] 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, CDCl3) 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).

[0526] General Procedure 6

[0527] Compound 57: 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0528] [ka]

[0529] Synthesis of 4-(2-bromo-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0530] [ka]

[0531] 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), CsCO (6.16 g, 18.9 mmol), and CuO (135 mg, 0.945 mmol) in DMF (150 mL) was heated to 110 °C overnight. The reaction was monitored for completion by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 3% MeOH / DCM to give 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, CDCl3) 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).

[0532] Synthesis of 4-(2-(pyrimidin-4-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0533] [ka]

[0534] A suspension of 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)Cl in DMF (3 mL) was heated to 100 °C under N for 3 h. The reaction completion was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 3% MeOH / DCM to give 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, CDCl3) 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).

[0535] General Procedure 7

[0536] Compound 58: 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0537] [ka]

[0538] Synthesis of 4-(2-(pyrimidin-5-yl)-5-(4-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine

[0539] [ka]

[0540] A suspension of 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)Cl (16 mg, 0.023 mmol) in 1,4-dioxane / HO (7.5 mL, 2:1) was heated to 80 °C overnight. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 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 (compound 58, 21 mg, 0.048 mmol) as a yellow solid. LC-MS (ESI+): m / z 439 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0541] General Procedure 8

[0542] Compound 89: Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate

[0543] [ka]

[0544] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0545] [ka]

[0546] 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 carbonochloridate (107 mg, 1.12 mmol). The mixture was stirred at room temperature for 10 minutes, and then ammonium hydroxide (143 mg, 1.44 mmol) was added to the mixture. 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 from 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-d6) 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).

[0547] Synthesis of (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanamine

[0548] [ka]

[0549] 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. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with 1 M aqueous HCl, and then the pH was adjusted to 8 using NaHCO solution. The aqueous solution was extracted with DCM / MeOH (10:1, 3 × 20 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with a gradient elution from 2% MeOH / DCM to 5% MeOH / DCM to give (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 + ).

[0550] Synthesis of methyl ((7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methyl)carbamate

[0551] [ka]

[0552] 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 carbonochloridate (13.8 mg, 0.016 mmol). The mixture was stirred at room temperature for 10 minutes, and then EtN (22 mg, 0.026 mmol) was added to the mixture. 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 from 2% MeOH / DCM to 10% MeOH / DCM to afford methyl ((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, CDCl3) 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).

[0553] [Example 48] N-[(3S)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0554] [ka]

[0555] Compound 48 was prepared by general procedure 1. LC-MS (ESI+): m / z 487 (MH + ).1 HNMR (300 MHz, DMSO-d6) 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).

[0556] [Example 49] N-[(3R)-1-Methylpyrrolidin-3-yl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0557] [ka]

[0558] Compound 49 was prepared by general procedure 1. LC-MS (ESI+): m / z 487 (MH + ). 1HNMR (300 MHz, DMSO-d6) 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).

[0559] [Example 50] 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0560] [ka]

[0561] Compound 50 was prepared by general procedure 1. LC-MS (ESI+): m / z 474 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0562] [Example 51] 7-Morpholino-5-[3-(m-tolyl)pyrazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0563] [ka]

[0564] Compound 51 was prepared by general procedure 1. LC-MS (ESI+): m / z 474 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0565] [Example 52] N-[(3R)-1-Methyl-3-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0566] [ka]

[0567] Compound 52 was prepared by general procedure 1. LC-MS (ESI+): m / z 501 (MH+). 1HNMR (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).

[0568] [Example 53] N-[(3S)-1-Methyl-3-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0569] [ka]

[0570] Compound 53 was prepared by general procedure 1. LC-MS (ESI+): m / z 501 (MH + ). 1HNMR (300 MHz, DMSO-d6) 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).

[0571] [Example 54] N-(1-methyl-4-piperidyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0572] [ka]

[0573] Compound 54 was prepared by general procedure 1. LC-MS (ESI+): m / z 501 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0574] [Example 55] N-(1-methyl-4-piperidyl)-7-morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0575] [ka]

[0576] Compound 55 was prepared by general procedure 1. LC-MS (ESI+): m / z 501 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0577] [Example 56] 7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]-N-tetrahydropyran-4-yl-pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0578] [ka]

[0579] Compound 56 was prepared by general procedure 1. LC-MS (ESI+): m / z 488 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0580] [Example 57] 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0581] [ka]

[0582] Compound 57 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0583] [Example 58] 4-[5-[4-(m-tolyl)pyrazol-1-yl]-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0584] [ka]

[0585] Compound 58 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0586] [Example 59] 3-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0587] [ka]

[0588] Compound 59 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 453 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0589] [Example 60] 5-[7-Morpholino-5-[4-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine

[0590] [ka]

[0591] Compound 60 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 454 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0592] [Example 61] 4-[2-(1-methylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0593] [ka]

[0594] Compound 61 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 441 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0595] [Example 62] 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0596] [ka]

[0597] Compound 62 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ). 1 HNMR (300 MHz, DMSO-d6+D2O) 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).

[0598] [Example 63] 4-[5-(3-phenylpyrazol-1-yl)-2-pyrimidin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0599] [ka]

[0600] Compound 63 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0601] [Example 64] 4-[5-(3-phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0602] [ka]

[0603] Compound 64 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0604] [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

[0605] [ka]

[0606] Compound 65 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0607] [Example 66] 4-[2-(1-methylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0608] [ka]

[0609] Compound 66 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.66 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.48-7.32 (m, 4H), 7.05 (s, 1H), 6.82 (s, 2H), 6.73 (d, J = 2.1 Hz, 1H), 4.15-4.05 (m, 4H), 4.02 (s, 3H), 3.95-3.88 (m, 4H).

[0610] [Example 67] 4-[5-(3-phenylpyrazol-1-yl)-2-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0611] [ka]

[0612] Compound 67 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 413 (MH + ). 1 HNMR (300 MHz, DMSO-d6+D2O) δ 8.73 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.78 (d, J = 2.1 Hz, 1H), 7.53-7.40 (m, 3H), 7.15 (d, J = 2.7 Hz, 1H), 6.99 (s, 1H), 6.80-6.78 (m, 2H), 3.92 (s, 8H).

[0613] [Example 68] 4-[5-(3-phenylpyrazol-1-yl)-2-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0614] [ka]

[0615] Compound 68 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0616] [Example 69] 4-[5-(3-phenylpyrazol-1-yl)-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0617] [ka]

[0618] Compound 69 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0619] [Example 70] 3-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0620] [ka]

[0621] Compound 70 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (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).

[0622] [Example 71] 5-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine

[0623] [ka]

[0624] Compound 71 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 440 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0625] [Example 72] 4-[5-(3-phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0626] [ka]

[0627] Compound 72 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0628] [Example 73] N-Isopropyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0629] [ka]

[0630] Compound 73 was prepared by general procedure 1. LC-MS (ESI+): m / z 432 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0631] [Example 74] N-[(1R)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0632] [ka]

[0633] Compound 74 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 = 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).

[0634] [Example 75] N-[(1S)-1-Cyclopropylethyl]-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0635] [ka]

[0636] Compound 75 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 = 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).

[0637] [Example 76] 7-Morpholino-N-(oxetan-3-ylmethyl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0638] [ka]

[0639] Compound 76 was prepared by general procedure 1. LC-MS (ESI+): m / z 460 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0640] [Example 77] N-Cyclopentyl-7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0641] [ka]

[0642] 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).

[0643] [Example 78] 4-[5-(4-phenylpyrazol-1-yl)-2-(2-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0644] [ka]

[0645] Compound 78 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 424 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0646] [Example 79] 4-[5-(4-phenylpyrazol-1-yl)-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0647] [ka]

[0648] Compound 79 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 424 (MH + ). 1HNMR (300 MHz, DMSO-d6) 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).

[0649] [Example 80] N-Isopropyl-7-morpholino-5-(4-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0650] [ka]

[0651] Compound 80 was prepared by general procedure 1. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0652] [Example 81] 4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0653] [ka]

[0654] Compound 81 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 427 (MH + ). 1 HNMR (300 MHz, DMSO-d6+D2O) 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).

[0655] [Example 82] 4-[5-(3-phenylpyrazol-1-yl)-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0656] [ka]

[0657] Compound 82 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 440 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0658] [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]ethanamine

[0659] [ka]

[0660] Compound 83 was prepared by general procedure 2. LC-MS (ESI+): m / z 512 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0661] [Example 84] 4-[2-(2,5-dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0662] [ka]

[0663] Compound 84 was prepared by general procedures 2 and 5. LC-MS (ESI+): m / z 455 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0664] [Example 85] 4-[2-(2,5-dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0665] [ka]

[0666] Compound 85 was prepared by general procedures 2 and 5. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0667] [Example 86] 4-[2-(1,5-dimethylpyrazol-3-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0668] [ka]

[0669] Compound 86 was prepared by general procedures 2 and 5. LC-MS (ESI+): m / z 441 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.49-7.35 (m, 3H), 7.04 (s, 1H), 6.79 (d, J = 3.9 Hz, 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).

[0670] [Example 87] 4-[2-(1,5-dimethylpyrazol-3-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0671] [ka]

[0672] Compound 87 was prepared by general procedures 2 and 5. LC-MS (ESI+): m / z 455 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0673] [Example 88] 4-[5-(3-phenylpyrazol-1-yl)-2-pyridazin-3-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0674] [ka]

[0675] Compound 88 was prepared by general procedures 2 and 6. LC-MS (ESI+): m / z 425 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 9.21 (d, J = 3.3 Hz, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 4.5 Hz, 1H), 7.50-7.37 (m, 4H), 7.15 (s, 1H), 6.85 (d, J = 2.7 Hz, 1H), 4.11-4.02 (m, 4H), 3.96-3.85 (m, 4H).

[0676] [Example 89] Methyl N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]carbamate

[0677] [ka]

[0678] Compound 89 was prepared by general procedure 8. LC-MS (ESI+): m / z 434 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0679] [Example 90] N-[[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]methyl]propenamide

[0680] [ka]

[0681] Compound 90 was prepared by general procedure 8. LC-MS (ESI+): m / z 432 (MH + ). 1 HNMR (300 MHz, CDCl3) 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, 2 H), 1.16 (t, J = 7.5Hz, 3H).

[0682] [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]ethanamine

[0683] [ka]

[0684] Compound 91 was prepared by general procedure 2. LC-MS (ESI+): m / z 512 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0685] [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

[0686] [ka]

[0687] Compound 92 was prepared by general procedure 2. LC-MS (ESI+): m / z 499 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0688] [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

[0689] [ka]

[0690] Compound 93 was prepared by general procedure 2. LC-MS (ESI+): m / z 499 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.72-8.69 (m, 3H), 7.81 (d, J = 6.0 Hz, 2H), 7.00 (s, 1H), 6.90 (d, J = 6.6 Hz, 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).

[0691] [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]ethanamine

[0692] [ka]

[0693] Compound 94 was prepared by general procedure 2. LC-MS (ESI+): m / z 513 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.67 (t, J = 7.5 Hz, 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).

[0694] [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]ethanamine

[0695] [ka]

[0696] Compound 95 was prepared by general procedures 2 and 4. LC-MS (ESI+): m / z 513 (MH + ). 1HNMR (300 MHz, CDCl3) δ 8.69 (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).

[0697] [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]ethanamine

[0698] [ka]

[0699] Compound 96 was prepared by general procedures 2 and 4. LC-MS (ESI+): m / z 513 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.70 (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).

[0700] [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-ethanamine

[0701] [ka]

[0702] Compound 97 was prepared by general procedures 2 and 3. LC-MS (ESI+): m / z 532 / 534 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0703] [Example 98] 5-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0704] [ka]

[0705] Compound 98 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 432 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0706] [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]ethanamine

[0707] [ka]

[0708] Compound 99 was prepared by general procedure 2. LC-MS (ESI+): m / z 498 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.66 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 2H), 7.49-7.38 (m, 3H), 7.04 (s, 1H), 6.81 (d, J = 2.7 Hz, 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).

[0709] [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-ethanamine

[0710] [ka]

[0711] Compound 100 was prepared by general procedure 2. LC-MS (ESI+): m / z 528 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.65 (d, J = 2.7 Hz, 1H), 7.61-7.52 (m, 2H), 7.37 (t, J = 8.1 Hz, 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).

[0712] [Example 101] 4-[5-[3-(3-chlorophenyl)pyrazol-1-yl]-2-(1-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0713] [ka]

[0714] Compound 101 was prepared by general procedures 2 and 3. LC-MS (ESI+): m / z 461 / 463 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0715] [Example 102] 4-[5-[3-(5-methyl-3-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0716] [ka]

[0717] Compound 102 was prepared by general procedure 2. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0718] [Example 103] 4-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0719] [ka]

[0720] Compound 103 was prepared by general procedures 2 and 4. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.98 (s, 1H), 8.72 (d, J = 2.7 Hz, 1H), 8.66-8.64 (m, 1H), 8.25 (d, J = 7.8 Hz, 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).

[0721] [Example 104] 4-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyrimidin-2-amine

[0722] [ka]

[0723] Compound 104 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 440 (MH + ). 1 HNMR (300 MHz, CDCl3) δ 8.67 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 5.4 Hz, 1H), 7.95 (d, J = 6.9 Hz, 2H), 7.49-7.36 (m, 4H), 7.14 (s, 1H), 7.11 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 5.32 (brs, 2H), 4.10-4.01 (m, 4H), 3.95-3.85 (m, 4H).

[0724] [Example 105] 4-[5-[3-(3-chlorophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0725] [ka]

[0726] Compound 105 was prepared by general procedures 2 and 3. LC-MS (ESI+): m / z 458 / 460 (MH + ). 1 HNMR (300 MHz, DMSO-d6) 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).

[0727] [Example 106] 4-[5-[3-(3-bromophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0728] [ka]

[0729] Compound 106 was prepared by general procedures 2 and 7. LC-MS (ESI+): m / z 502 / 504 (MH + ). 1HNMR (300 MHz, CDCl3) 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).

[0730] [Example 107] 4-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0731] [ka]

[0732] Compound 107 was prepared by general procedures 2 and 3. LC-MS (ESI+): m / z 454 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0733] [Example 108] 4-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0734] [ka]

[0735] Compound 108 was prepared by general procedure 2. LC-MS (ESI+): m / z 439 (MH + ). 1 HNMR (300 MHz, CDCl3) 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).

[0736] [Example 109] 6-[7-morpholino-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]pyridin-2-amine

[0737] [ka]

[0738] Compound 109 was prepared by the method described above. LC-MS (ESI+): m / z 438 (MH + ).

[0739] [Example 110] 4-[2-(3-methylisoxazol-5-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0740] [ka]

[0741] Compound 110 was prepared by the method described above. LC-MS (ESI+): m / z 441 (MH + ).

[0742] [Example 111] 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0743] [ka]

[0744] Compound 111 was prepared by the method described above. LC-MS (ESI+): m / z 443 (MH + ).

[0745] [Example 112] 4-[2-(1-methylpyrazol-4-yl)-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0746] [ka]

[0747] Compound 112 was prepared by the method described above. LC-MS (ESI+): m / z 440 (MH + ).

[0748] [Example 113] 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0749] [ka]

[0750] Compound 113 was prepared by the method described above. LC-MS (ESI+): m / z 426 (MH + ).

[0751] [Example 114] 4-[5-(3-phenylpyrazol-1-yl)-2-thiazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0752] [ka]

[0753] Compound 114 was prepared by the method described above. LC-MS (ESI+): m / z 429 (MH + ).

[0754] [Example 115] 4-[2-(1-methylpyrazol-4-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0755] [ka]

[0756] Compound 115 was prepared by the method described above. LC-MS (ESI+): m / z 426 (MH + ).

[0757] [Example 116] 4-[5-(3-phenylpyrazol-1-yl)-2-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0758] [ka]

[0759] Compound 116 was prepared by the method described above. LC-MS (ESI+): m / z 412 (MH + ).

[0760] [Example 117] Methyl 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate

[0761] [ka]

[0762] Compound 117 was prepared by the method described above. LC-MS (ESI+): m / z 481 (MH + ).

[0763] [Example 118] 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide

[0764] [ka]

[0765] Compound 118 was prepared by the method described above. LC-MS (ESI+): m / z 482 (MH + ).

[0766] [Example 119] 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzonitrile

[0767] [ka]

[0768] Compound 119 was prepared by the method described above. LC-MS (ESI+): m / z 448 (MH+ ).

[0769] [Example 120] 4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0770] [ka]

[0771] Compound 120 was prepared by the method described above. LC-MS (ESI+): m / z 427 (MH + ).

[0772] [Example 121] 4-[2-(3-methylisoxazol-5-yl)-5-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0773] [ka]

[0774] Compound 121 was prepared by the method described above. LC-MS (ESI+): m / z 427 (MH + ).

[0775] [Example 122] 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoic acid

[0776] [ka]

[0777] Compound 122 was prepared by the method described above. LC-MS (ESI+): m / z 467 (MH + ).

[0778] [Example 123] 4-[2-(1-methylpyrazol-3-yl)-5-[3-[3-(trideuteriomethyl)phenyl]pyrazol-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]morpholine

[0779] [ka]

[0780] Compound 123 was prepared by the method described above. LC-MS (ESI+): m / z 443.

[0781] Biological Example 1: Inhibition of PIKfyve

[0782] Full-length human recombinant PIKFYVE expressed in a baculovirus expression system as an N-terminal GST fusion protein (265 kDa) was obtained from Carna Biosciences (Kobe, Japan). Kinase substrates were prepared by mixing and sonicating fluorescently labeled phosphatidylinositol 3-phosphate (PI3P) and phospho-L-serine (PS) at a 1:10 ratio in 50 mM HEPES buffer, pH 7.5.

[0783] Kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows: Kinase proteins were prediluted in assay buffer containing 25 mM HEPES, pH 7.5, 1 mM DTT, 2.5 mM MgCl2, and 2.5 mM MnCl2, and 0.005% Triton X-100, and dispensed into 384-well plates (10 μL / well). Test compounds were serially prediluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). The DMSO concentration was equilibrated to 1% in all samples. All test compounds were tested at 12 concentrations. Aprimod was used as a reference compound and tested in an identical manner in each assay plate. Control samples (0% inhibition, no inhibitor, DMSO only) and 100% inhibition (absence of enzyme) were assembled in quadruplicate and used to calculate % inhibition in the presence of compound. The reaction was initiated by adding 10 μL of 2×PI3P / PS substrate supplemented with ATP. The final enzyme concentration was 2 nM, the final ATP concentration was 10 mM, and the final PI3P / PS substrate concentration was 1 μM (PI3P). The kinase reaction proceeded for 3 hours at room temperature. After incubation, the reaction was quenched by adding 50 mL of termination buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100, 20 mM EDTA). The terminated plate was analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000, Caliper Life Sciences / Perkin Elmer). The change in relative fluorescence intensity of the PI(3)P substrate and PI(3,5)P product peaks was measured. The activity of each test sample was determined as the product-to-total ratio (PSR): P / (S+P), where P is the product peak height and S is the substrate peak height. The following formula was used to calculate percent inhibition (P inh ) was decided: P inh =(PSR 0%inh -PSR 化合物 ) / (PSR 0%inh -PSR 100%inh ) * 100 (In the formula, PSR 化合物is the product / total ratio in the presence of the compound, and PSR 0%inh is the product / total ratio in the absence of compound, and PSR 100%inh is the product / total ratio in the absence of enzyme). IC of the test compound 50 The %inh c data (P ) were fitted with a four-parameter sigmoidal dose-response model using XLfit software (IDBS) to determine the 50% inhibition. inh The concentration of the compound was applied.

[0784] IC for certain compounds of the present disclosure 50 The values ​​are provided in Table 1 below.

[0785] [Table 2]

[0786] Biological Example 2: Cellular Data HEK / TDP Survival Assay: Immortalized human embryonic kidney 293T (HEK 293T) cells were transfected with a plasmid containing the TDP-43 Q331K mutation to obtain increased cell death biologically relevant to ALS patients. Cell death is measured as a decrease in the amount of ATP, an indicator of metabolically active cells, quantified by the luminescent Cell-Titer-Glo® (CTG) reagent. Compounds are evaluated in this model for changes in CTG compared to the untreated group. An increased signal indicates improved survival (rescue), and a decreased signal indicates decreased survival.

[0787] Cell rescue was measured in a 96-well format using eight different concentrations of test compound in sextuplicate over 48 hours. ATP, an indicator of metabolically active cells, was quantified using the Promega Cell-Titer-Glo® Luminescent Cell Viability Assay (see protocol: https: / / www.promega.com / - / media / files / resources / protocols / technical-manuals / 101 / celltiterglo-2-0-assay-protocol.pdf?la=en). Luminescent signals were detected using a PerkinElmer En Vision or Molecular Devices SpectraMax.

[0788] A three-step procedure was used to determine the effect of a given dose of compound on cell viability. First, Hedges' g was calculated for Cell Titer-Glo luminescence values, using six untreated wells from all plates as controls. Second, because multiple experimental trials of each compound-dose pair were performed, these results were meta-analyzed to obtain a single estimate of effect size. Finally, values ​​from all compound-dose pairs were corrected for multiple hypothesis testing using Stephens, M.'s Empirical Bayesian framework (False discovery rates: a new deal, Biostatistics, 18 [2], 2017, 275-294) to obtain a credible interval for the measured effect and associated s value.

[0789] Briefly, this method calculates a local false sign 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 the sign of each effect (rather than the confidence that each effect is non-zero). The s-value reported in the previous figure is the expected percentage error when estimating the signs of all effects at a larger absolute local false sign rate, defined similarly to Storey, JD's q-value (The positive false discovery rate: a Bayesian interpretation and the q-value, Ann. Statist. 31 [6] 2003, 2013-2035).

[0790] Drugs that produced a signed log s value greater than 3 were considered hits. This threshold was determined by a separate calibration experiment in which Cell Titer-Glo® was specified with a blank plate consisting of untreated cells to assess the noise inherent in the assay. Data are presented as the maximum effect of rescue obtained from the dose-response curve.

[0791] iPSC MN survival assay: Fibroblasts derived 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, ALS patient-derived motor neurons exhibit increased mortality under stressful conditions (nutrient starvation medium, Hank's Buffered Salt Solution - HBSS) compared to motor neurons derived from healthy individuals. The SOD1 survival defect is relevant to a subset of ALS patient biology and serves as a suitable cell-based model for measuring compound-induced survival rescue.

[0792] Cell rescue was measured following three or more different concentrations of each compound over six days in quadruplicate in a 96-well format to ensure a power of >0.8. Cells were transfected with a GFP reporter and imaged daily to track survival. A broad-spectrum caspase inhibitor served as a positive control. Microscopic image-based readout: Cells are transfected with a GFP reporter and imaged once a day with a blue laser to track survival. Imagers used include Biotek Cytation 5 and Thermo Fisher EVOS Auto FL2. All images undergo uniform processing consisting of rolling hat background subtraction and contrast adjustment.

[0793] Cells are identified by their shape, and each cell is tracked across images and time points for each well. Survival is visually assessed from Kaplan-Meier curves. Cell survival is modeled and tested using mixed-effects Cox regression (each well is modeled as a random effect and group (control / treatment) is modeled as a fixed effect). Hazard ratios between treatment and control are estimated within Cox regression (a value of 1.0 represents no change, values ​​above 1.0 indicate decreased survival in response to treatment, and values ​​below 1.0 indicate increased survival in response to treatment). Data are presented as the maximum decrease in hazard ratio score measured at various concentrations.

[0794] [Table 3]

[0795] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It is therefore to be understood that the foregoing description is intended to be illustrative and not restrictive. The scope of the present disclosure should, therefore, be determined not with reference to the above description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. The following aspects may be included. [1] A compound of formula (I):

change

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

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

[12] R a or R 1 is one R d and Rd C 1~4 The compound according to the above [1], wherein the aryl group is alkyl or halo.

[13] R a or R 1 is one R d and R d is methyl, NH 2 , fluoro, chloro, or bromo.

[14] R a or R 1 However, depending on the case, C 1~4 Alkyl, -CF 3 , fluoro, chloro, bromo, -OCH 3 , and -OCF 3 The compound according to [1] above, wherein the compound is phenyl or pyridyl substituted with one or two substituents selected from:

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

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

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

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

[19] R 2 and R 3 together with the nitrogen to which they are attached, may each optionally contain one, two or three R j The compound according to [1] above, which forms a pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, or 2-oxa-6-azaspiro[3.3]heptane substituted with a substituent.

[20] R 2 and R 3 together with the nitrogen to which they are attached, may optionally be one or two R j The compound according to the above [1], which forms a morpholine substituted with a substituent.

[21] Each R j The substituents are independently methyl, hydroxy, -OCH 3 , oxo, halo, -CF 3 , or -OCF 3 The compound according to [1] above,

[22] R k and R l are each independently H or methyl.

[23] R 4 The compound according to the above [1], wherein is optionally substituted phenyl.

[24] R 4 is an optionally substituted heteroaryl.

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

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

[27] R 4 The compound according to the above [1], wherein is pyridine.

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

[29] R 4 Sometimes one or two R z The compound according to the above [1], which is substituted with a substituent.

[30] R 4 However, depending on the case, C 1~4 Alkyl, -CF 3 , fluoro, chloro, -OCH 3 , and -OCF 3 The compound according to [1] above, wherein the compound is phenyl or pyridyl substituted with one or two substituents selected from:

[31] R 4 -C(O)NR x R y The compound according to [1] above,

[32] R x The compound according to the above [1], wherein is H.

[33] R x But sometimes one, two or three R o The compound according to the above [1], which is methyl or ethyl substituted with a substituent.

[34] R x is methyl.

[35] R y The compound according to the above [1], wherein is H.

[36] R y But sometimes one, two or three R o C substituted with a substituent 1~4 Alkyl, -C 1~4 Alkyl (monocyclic cycloalkyl), monocyclic cycloalkyl, monocyclic heterocycloalkyl, monocyclic heterocyclyl, -O-monocyclic heterocyclyl, -OC 1~4 Alkyl, -SO 2 -C 1~4 The compound according to the above [1], wherein the alkyl is alkyl.

[37] R y But sometimes one, two or three R o C substituted with a substituent 1~4 The compound according to the above [1], wherein the alkyl is alkyl.

[38] R y However, depending on the case, one, two or three R o The compound according to [1] above, which is methyl, ethyl, propyl, or isopropyl substituted with a substituent.

[39] R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.

[40] R y The compound according to the above [1], wherein is methoxy.

[41] R y -SO 2 -methyl.

[42] R y However, depending on the case, one, two or three R o Substituted monocyclic cycloalkyl or -C 1~2 The compound according to the above [1], which is alkyl(monocyclic cycloalkyl).

[43] R y But sometimes one, two or three R o The compound according to the above [1], which is a monocyclic cycloalkyl substituted with a substituent.

[44] R y However, depending on the case, one, two or three R o The compound according to [1] above, which is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with a substituent.

[45] R y The compound according to the above [1], wherein is cyclopropyl.

[46] R y The compound according to the above [1], wherein is cyclopentyl.

[47] R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.

[48] R y But sometimes one, two or three R o The compound according to the above [1], which is a monocyclic heterocyclyl or -O-monocyclic heterocyclyl substituted with a substituent.

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

[50] Ry is oxetanyl or oxetanyloxy.

[51] R y But sometimes one, two or three R o The compound according to the above [1], which is a monocyclic heterocycloalkyl substituted with a substituent.

[52] R y Sometimes one or two R o is substituted with a substituent, R o is methyl.

[53] R x is methyl and R y is methyl, ethyl, cyclopropyl, methoxy, or cyclopentyl.

[54] R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 The compound according to the above [1], which forms a monocyclic heterocycloalkyl substituted with alkyl.

[55] R x and R y However, together with the nitrogen to which they are attached, they can sometimes form C 1~4 The compound according to the above [1], which forms a monocyclic heterocyclyl substituted with alkyl.

[56] R x and R y are taken together with the nitrogen to which they are attached to 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.

[57] Each R z independently, C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, C 1~4 Alkyl NR m R n or -NR m R n The compound according to [1] above,

[58] Each R z are independently methyl, -OH, halo, or -OCH 3 The compound according to [1] above,

[59] R z Ga-NR m R n C replaced with 2~3 The compound according to the above [1], wherein the alkyl is alkyl.

[60] R m and R n are each independently H or C 1~4 The compound according to the above [1], wherein the alkyl is alkyl.

[61] R m and R n and each is methyl.

[62] R m and R n together with the nitrogen to which they are attached, may optionally be one or two R o The compound according to the above [1], which forms a monocyclic heterocyclyl substituted with a substituent.

[63] R m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o The compound according to the above [1], which forms a pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or thiomorpholine-1,1-dioxide substituted with a substituent.

[64] R m and R n together with the nitrogen to which they are attached, each optionally containing one or two R o The compound according to [1] above, which forms a pyrrolidine, piperidine, piperazine, or morpholine substituted with a substituent.

[65] Each R o Substituent is C 1~4 The compound according to the above [1], wherein the alkyl is alkyl.

[66] Each R o The compound according to the above [1], wherein the substituent is —OH.

[67] Each R o The substituent is -NR p R q The compound according to [1] above,

[68] R p and R q are each independently H or methyl.

[69] R p and R q are taken together with the nitrogen to which they are attached to form a heterocyclyl.

[70] R p and R q are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[71] R 5 is H, methyl, ethyl, chloro, bromo, fluoro, -OH, or -OCH 3 The compound according to [1] above,

[72] R 5 The compound according to the above [1], wherein is H.

[73] Compound of formula (II):

change

[74] 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-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3S)-1-Methyl-3-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-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-pyridyl)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]ethanamine; 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]ethanamine; 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; 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; 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]ethanamine; 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]ethanamine; 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]ethanamine; 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-ethanamine; 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]ethanamine; 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; 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-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-bromophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate; 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide; 3-[1-[7-morpholino-2-(3-pyridyl)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 A compound selected from:

[75] A pharmaceutical composition comprising the compound and / or pharmaceutically acceptable salt according to any one of [1] to

[74] or

[87] above, and a pharmaceutically acceptable excipient.

[76] A method for inhibiting PIKfyve kinase in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of [1] to

[74] or

[87] above, or a pharmaceutical composition described in

[75] above.

[77] A method for treating a neurological disease associated with PIKfyve activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of [1] to

[74] or

[87] above, or a pharmaceutical composition described in

[75] above.

[78] The neurological disease 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 epileptic seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, polyglutamine neuronal inclusions and intranuclear inclusion disease, Marinesco and Hirano body disease, tauopathy, Alzheimer's disease, neurodegenerative diseases, and neurodegenerative diseases. 77. The method according to claim 77, wherein the neurological disorder is selected from the group consisting of neuropathies, 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 disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, and mucolipidosis type IV, neurological disorders, Huntington's disease, psychiatric disorders, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder type I, and bipolar disorder type II.

[79] The method according to

[78] above, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT.

[80] The method according to

[79] above, wherein the disease is ALS.

[81] The method according to

[78] above, wherein the disease is a tauopathy such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.

[82] The method according to

[78] above, wherein the disease is a lysosomal storage disease such as Fabry disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, or mucolipidosis type IV.

[83] The method according to

[78] above, wherein the disease is a psychiatric disorder such as ADHD, schizophrenia, or a mood disorder such as major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

[84] A compound according to any one of [1] to

[74] or

[87] above for use as a pharmaceutical.

[85] The compound according to

[84] above, for use in treating a neurological disease treatable by inhibition of PIKfyve kinase.

[86] Use of a compound described in any one of [1] to

[74] or

[87] above 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 neurological disease.

[87] A compound and / or a pharmaceutically acceptable salt thereof according to any one of [1] to

[74] above, wherein one or more hydrogen atoms bonded to a carbon atom of the compound are replaced by deuterium atoms.

Claims

1. Compound of formula (II): 【Chemical 1】 (In the formula, R １ａ are C depending on the case １～４ Alkyl, CO ２ R ｐ , —C(O)NR ｐ R ｑ , Fluoro, Chloro, Bromo, NH ２ , and -OCH ３ is phenyl or pyridyl substituted by one or two substituents selected from R ４ａ -C(O)NR ｘ R ｙ or each optionally C １～４ Alkyl, —CF ３ , fluoro, chloro, -OCH ３ , and -OCF ３ phenyl, pyrazolyl or pyridyl substituted by one or two substituents selected from R ｘ is H or C １～４ alkyl, and R ｙ is H, and in some cases C １～４ Alkyl, —OH, —OC １～４ Alkyl, halo, or cyano or —NR ｐ R ｑ C substituted with one or two substituents selected from 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 heterocyclyl, -O-monocyclic heterocyclyl, or monocyclic heterocycloalkyl; Each R ｒ Ha-C １～４ Alkyl or -NR ｐ R ｑ and R ｐ and R ｑ are each independently H or C １～４ is alkyl, or R ｘ and R ｙ together with the nitrogen to which they are attached, optionally C １～４ forming an alkyl-substituted heterocyclyl or a pharmaceutically acceptable salt thereof.

2. 1. The compound having the structure: 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

3. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound 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 a pharmaceutically acceptable salt thereof.

4. 2. The compound of 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.

5. 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-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-[(3S)-1-methyl-3-piperidyl]-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-7-morpholino-5-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine-2-carboxamide; N-(1-methyl-4-piperidyl)-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-pyridyl)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]ethanamine; 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]ethanamine; 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; 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; 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]ethanamine; 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]ethanamine; 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]ethanamine; 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-ethanamine; 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]ethanamine; 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; 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-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(2-methyl-4-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-bromophenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(3-methoxyphenyl)pyrazol-1-yl]-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]morpholine; 4-[5-[3-(6-methyl-2-pyridyl)pyrazol-1-yl]-2-(3-pyridyl)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-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzoate; 3-[1-[7-morpholino-2-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrazol-3-yl]benzamide; 3-[1-[7-morpholino-2-(3-pyridyl)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 or a pharmaceutically acceptable salt thereof.

6. 6. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein one or more hydrogen atoms bonded to a carbon atom of the compound are replaced by a deuterium atom.

7. 10. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. 10. A pharmaceutical composition for use in a method of inhibiting PIKfyve kinase in a subject in need thereof, comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 6, said method comprising administering to said subject an effective amount of said compound or pharmaceutically acceptable salt.

9. 10. A pharmaceutical composition for use in a method for treating a neurological disease associated with PIKfyve kinase activity in a subject in need thereof, comprising a compound or pharmaceutically acceptable salt of any one of claims 1 to 6, said method comprising administering to said subject an effective amount of said compound or pharmaceutically acceptable salt.

10. The neurological disease may be amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth disease (CMT; including type 4J (CMT4J)), Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with epileptic seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, neuronal nuclear and intranuclear polyglutamine inclusion disease, Marinesco and Hirano body disease, tauopathy, Alzheimer's disease, neurodegenerative diseases, 10. The pharmaceutical composition of claim 9, wherein the disease is one of: 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 disease, Gaucher disease, Niemann-Pick disease type C, Tay-Sachs disease, mucolipidosis type IV, neurological disorders, Huntington's disease, psychiatric disorders, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder type I, or bipolar disorder type II.

11. 11. The pharmaceutical composition of claim 10, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT.

12. The pharmaceutical composition of claim 11, wherein the disease is ALS.

13. 11. The pharmaceutical composition of claim 10, wherein the disease is a tauopathy selected from Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and chronic traumatic encephalopathy.

14. 14. The pharmaceutical composition of any one of claims 8 to 13, wherein the compound or pharmaceutically acceptable salt 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 a pharmaceutically acceptable salt thereof.

15. 10. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 for use as a medicament.

16. 16. The pharmaceutical composition of claim 15 for use in treating a neurological disease treatable by inhibition of PIKfyve kinase.

17. 16. The pharmaceutical composition of claim 15 for use in treating ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT.

18. 18. The pharmaceutical composition of any one of claims 15 to 17, wherein the compound or pharmaceutically acceptable salt 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 a pharmaceutically acceptable salt thereof.

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