Purines and methods of use thereof

Abstract

Purine-containing bicyclic heteroarene compounds are disclosed as PIKfyve inhibitors useful for treating neurological / neurodegenerative disorders associated with TDP-43, such as frontotemporal dementia, ALS and Alzheimer's disease.The compounds described herein can be used alone or in combination with other pharmacoactive agents to treat or prevent such neurological / neurodegenerative diseases.The present invention relates to bicyclic heteroarene and its use for therapeutic treatment of neurological disorders in patients, such as human patients.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to bicyclic heteroarenes and their use for the therapeutic treatment of neurological disorders in patients, such as human patients. [Background technology]

[0002] background The incomplete understanding of the molecular perturbations that cause disease and the limited availability of solid model systems have contributed to the inability to produce successful disease-modifying therapies for common progressive neurological disorders such as ALS and FTD.In order to find drugs that can prevent the progression of these disorders, progress has been made in many frontier fields.However, most, if not all, of the current treatments for these diseases only bring about very little relief.Therefore, there is a need to develop therapies that can change the course of neurodegenerative diseases.More generally, there is a need for better methods and compositions for treating neurodegenerative diseases in order to improve the quality of life of people who suffer from such diseases. Summary of the Invention [Means for solving the problem]

[0003] Abstract TDP-43 is a nuclear DNA / RNA-binding protein involved in RNA splicing. Under pathological cellular stress, TDP-43 translocates to the cytoplasm and aggregates into stress granules and associated protein inclusions. These phenotypes are hallmarks of degenerating motor neurons and are observed in 97% of all ALS cases. The high penetrance of this pathology indicates that TDP-43 is broadly involved in both familial and sporadic ALS. Furthermore, aggregation-promoting TDP-43 mutations are linked to a higher risk of developing ALS, suggesting that protein misfolding and aggregation act as drivers of toxicity. TDP-43 toxicity can be recapitulated in yeast models, where the protein causes viability deficits and localizes to stress granules. In an aspect, the present invention provides a compound of formula (1) [ka] or a pharmaceutically acceptable salt thereof. (In the formula, X is NR A and Y is CR A or N, R 1 are substituted as necessary C1 to C 10Heteroaryl (including a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core); 4,5-dihydropyrazol-1-yl substituted by phenyl; optionally substituted pyrimidin-2-yl, optionally substituted pyridazin-6-yl, optionally substituted pyrimidin-4-yl; pyridin-3-yl optionally substituted by methoxy; optionally substituted indazol-1-yl; optionally substituted indazol-2-yl; optionally substituted indazol-7-yl; optionally substituted isoindolin-6-yl; optionally substituted pyridazin-5-yl; optionally substituted pyrrolidin-1-yl; optionally substituted pyrimidin-6-yl; optionally substituted piperazinyl; phenyl (methoxy, optionally substituted C1-C6 alkyl, hydroxyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 substituted by aryl, optionally substituted C2-C9 heterocyclyl or C3-C8 cycloalkoxy); optionally substituted C3 carbocyclyl; optionally substituted morpholin-1-yl; optionally substituted benzodioxolyl; optionally substituted benzopyrrolidonyl; optionally substituted tetrahydroquinoline; optionally substituted monoalkylamino; optionally substituted dialkylamino; amino monosubstituted by optionally substituted C2-C9 heteroaryl; halo; optionally substituted C2-C9 heterocycle-C1 alkyl; optionally substituted C2-C9 heteroaryl-C1 alkyl; optionally substituted benzodioxanyl; -NHNHR 1A ;-N(R 1A )N=C(R 1B )2;-C(R 1A )=NN(R 1B )2;-C(R 1A )=NOR 1A ; or -Q 1 -N(R 1C )2, Q1 is a bond, CH or CO, R 1A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl or optionally substituted C6-C 10 aryl C1-C6 alkyl, R 1B one of which is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl, R 1B the remainder being optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; R 1C are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heteroaryl, or R 1C together with the nitrogen atom to which they are attached form a C2-C9 heterocyclyl or a C2-C9 heteroaryl; R 2 is H, halogen, optionally substituted C6-C 10 Aryl; optionally substituted C 1~9Heterocyclyl; -O-pyridin-3-yl; optionally substituted C3-C8 cycloalkyl; optionally substituted C3-C8 cycloalkenyl, C1-C2 alkyl (optionally substituted with hydroxy, methoxy, -CH2OH, pyridin-4-yl, 4-pyridon-1-yl, -O-pyridin-4-yl, oxo, or dialkylamino); C1 alkyl (optionally substituted with deuterium, oxo, hydroxy, halo, or amino (substituted with C3 cycloalkyl)); C3 alkyl (substituted with hydroxy, oxo, or dialkylamino); C4 alkyl; optionally substituted C2-C9 heteroaryl; -QN(R 1C )2;-S(O) r -R 1A ; or -P(O)(R 1A )2 and R A are each independently H, C1-C2 alkyl (hydroxyl or -S(O) r -(optionally substituted C1-C6 alkyl), C3 alkyl, C4-C5 alkyl (substituted by hydroxyl), optionally substituted C2-C9 heteroarylC1-C6 alkyl; optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkylC1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl, or R 2 and R A together with the atoms to which they are attached form an optionally substituted C3-C4 heterocyclic ring, and R A The remainder, if present, is H, C1-C2 alkyl (hydroxyl or -S(O) r-(optionally substituted C1-C6 alkyl), C3 alkyl, C4-C5 alkyl (substituted by hydroxyl), optionally substituted C2-C9 heteroarylC1-C6 alkyl; optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkylC1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; r is 0, 1 or 2; R 3 teeth, [ka] (It is).

[0004] In some embodiments, X is NR A In some embodiments, Y is N. In some embodiments, R 3 teeth, [ka] is.

[0005] In some embodiments, R 3 teeth, [ka] is.

[0006] In some embodiments, the compound is Formula 1a: [ka] or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, R Ais C1-C2 alkyl (optionally substituted with hydroxyl or -S(O)CH3), C3 alkyl, C4-C5 alkyl (substituted with hydroxyl). In some embodiments, R A is H. In some embodiments, R 1 is an optionally substituted C2-C9 heteroaryl and comprises a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core. 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted 1,2,3-triazol-1-yl, optionally substituted 1,2,3-triazol-2-yl, optionally substituted benzotriazol-1-yl, optionally substituted 1,2,4-triazol-3-yl, optionally substituted 1,2,4-oxadiazol-3-yl, or optionally substituted 1,2,4-oxadizol-2-yl. In some embodiments, R 1 is pyrazol-1-yl substituted at the 3-position. In some embodiments, R 1 is pyrazol-1-yl substituted at the 4-position. In some embodiments, R 1 is optionally substituted C6 to C 10 Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 1~9 Heterocyclyl, optionally substituted C2-C9 heteroaryl or optionally substituted C 3~8 Optionally substituted with cycloalkyl, or halo (e.g., chloro, fluoro, bromo, iodo). 1 teeth, [ka] [ka] [ka] is.

[0008] In some embodiments, R 1 is optionally substituted pyrazol-3-yl. In some embodiments, R 1 is pyrazol-3-yl substituted at the 1-position. In some embodiments, R 1 is optionally substituted C6 to C 10 Aryl, optionally substituted C 1~9 Heterocyclyl, optionally substituted C2-C9 heteroaryl or optionally substituted C 3~8 In some embodiments, R 1 teeth, [ka] is.

[0009] In some embodiments, R 1 is optionally substituted pyrimidin-6-yl. In some embodiments, R 1 is optionally substituted pyrimidin-4-yl. In some embodiments, R 1 teeth, [ka] is.

[0010] In some embodiments, R 1 is methoxy, optionally substituted C1-C6 alkyl, hydroxyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or phenyl substituted with C3-C8 cycloalkoxy. 1is substituted with C2-C9 heteroaryl. 1 teeth, [ka] is.

[0011] In some embodiments, R 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 2 is optionally substituted pyridyl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is optionally substituted tetrahydropyranyl, optionally substituted dihydropyranyl, optionally substituted piperidinyl, or optionally substituted azetidinyl. 2 is optionally substituted tetrahydropyran-4-yl, optionally substituted 5,6-dihydro-2H-pyran-4-yl, optionally substituted piperidin-4-yl or optionally substituted piperidin-3-yl.

[0012] In some embodiments, R 1A is substituted by oxo. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, phenyl (substituted with optionally substituted C2-C9 heteroaryl) or optionally substituted pyridimin-4-yl; R 4 and R 5 are each independently hydroxyl or methoxy).

[0013] In some embodiments, R 4 and R 5 is hydroxyl. In some embodiments, R 4 and R 5 is methoxy. In some embodiments, R 4 is hydroxyl and R 5 is methoxy. In some embodiments, R 4 is methoxy and R 5 is hydroxyl. In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] is.

[0014] In some embodiments, R 1 is phenyl substituted with an optionally substituted C2-C9 heteroaryl. 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyridin-4-yl. In some embodiments, R 1 teeth, [ka] is. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is optionally substituted pyrazol-1-yl, phenyl (substituted by optionally substituted heteroaryl), optionally substituted indazol-1-yl or optionally substituted indazol-2-yl; R 4 is hydroxyl, 4-pyridinon-1-yl, -O-pyridin-3-yl or CHOH, R 3 is pyridin-4-yl or morpholin-1-yl).

[0015] In some embodiments, R 4 is hydroxyl. In some embodiments, R 4 is 4-pyridinon-1-yl. In some embodiments, R 4 is -O-pyridin-3-yl. In some embodiments, R 4 is CHOH. In some embodiments, R 3 is pyridin-4-yl. In some embodiments, R 3 is morpholin-1-yl. In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is phenyl substituted with optionally substituted heteroaryl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted indazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R1 is optionally substituted indazol-2-yl. In some embodiments, R 1 teeth, [ka] is.

[0016] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is phenyl (optionally substituted with methoxy or optionally substituted heteroaryl) or optionally substituted pyrazol-1-yl; R 3 is morpholin-1-yl or piperidin-1-yl, R 2 teeth, [ka] and R A is ethyl, 2-hydroxy-ethyl or [ka] (It is).

[0017] In some embodiments, R 3 is morpholin-1-yl. In some embodiments, R 3 is piperidin-1-yl. In some embodiments, R 1 is phenyl optionally substituted with methoxy or optionally substituted heteroaryl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] is.

[0018] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 6 is hydrogen or methyl, R 7 is optionally substituted phenoxy, optionally substituted benzyloxy or optionally substituted amine).

[0019] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is methyl. In some embodiments, R 7 is optionally substituted phenoxy. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is optionally substituted benzyloxy. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is an optionally substituted amine. In some embodiments, R 7 teeth, [ka] is.

[0020] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or -N(R 1A )N=C(R 1B )2).

[0021] In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -N(R 1A )N=C(R 1B )2. In some embodiments, R 1 teeth, [ka] is.

[0022] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 8 is hydrogen or methoxy, R 9 is hydrogen or phenyl, R 10 is hydrogen or phenyl).

[0023] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methoxy. In some embodiments, R 9 is hydrogen. In some embodiments, R 9is phenyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is phenyl.

[0024] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 11 is hydrogen or phenyl).

[0025] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is phenyl.

[0026] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 12 is hydrogen, methoxy or CH2OH, R 13 is hydrogen, methoxy, C3 cycloalkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C6 alkyl; R 14 is hydrogen or C3 cycloalkoxy or optionally substituted C2-C9 heteroaryl; R 15 is hydrogen or hydroxyl, R 2 is hydrogen, pyridin-4-yl, [ka] and R 3 teeth, [ka] (It is).

[0027] In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is hydroxyl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is methoxy. In some embodiments, R 12 is CHOH. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is C cycloalkoxy. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is methoxy. In some embodiments, R 13 is C cycloalkoxy. In some embodiments, R 13 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 13 is pyrazol-1-yl, 1-methyl-pyrazol-3-yl, pyridazin-3-yl, or 4-bromo-1-methyl-pyrazol-3-yl. 13 is optionally substituted C2-C9 heterocyclyl. In some embodiments, R 13 teeth, [ka] In some embodiments, R 13 is optionally substituted C1-C6 alkyl. In some embodiments, R 13 is CH2OH or [ka] is.

[0028] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] and R 16 is hydrogen or pyridin-3-yl, R 2 is pyridin-4-yl or hydrogen).

[0029] In some embodiments, R 16 is hydrogen. In some embodiments, R 16 is pyridin-3-yl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is hydrogen. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X 1 is O or CH2, R 1 is -N(R 1A )N=C(R 1B )2).

[0030] In some embodiments, R 1 teeth, [ka] is.

[0031] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is).

[0032] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -N(R 1A )N=C(R 1B )2).

[0033] In some embodiments, R 1 teeth, [ka] is.

[0034] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 17 is optionally substituted C6 to C 10 Aryl C1-C6 alkyl; optionally substituted C6-C 10 heteroarylC1-C6 alkyl; -NH2, optionally substituted C3-C8 cycloalkyl; or optionally substituted C2-C9 heteroaryl (C2-C9heterlaryl); R 18 is hydrogen or optionally substituted C1-C6 alkyl, R A is methyl or ethyl, R 2 is pyridin-4-yl or hydrogen).

[0035] In some embodiments, R 18is hydrogen. In some embodiments, R 18 is optionally substituted C1-C6 alkyl. In some embodiments, R 18 is methyl. In some embodiments, R 18 is ethyl. In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is hydrogen. In some embodiments, R 17 is optionally substituted C6 to C 10 arylC1-C6 alkyl. In some embodiments, R 17 teeth, [ka] In some embodiments, R 17 is optionally substituted C6 to C 10 heteroarylC1-C6 alkyl. In some embodiments, R 17 teeth, [ka] In some embodiments, R 17 is -NH. In some embodiments, R 17 is optionally substituted C-C cycloalkyl. In some embodiments, R 17 teeth, [ka] In some embodiments, R 17 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 17 teeth, [ka] is.

[0036] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 19 is an optionally substituted amino, an optionally substituted C2-C9 heterocycle, or an optionally substituted C2-C9 heteroaryl; R H and R 20 together with the atom to which they are attached to form oxo, R 20 is hydrogen or R 20 and R H together with the atom to which they are attached to form oxo, R A is ethyl or cyclopropyl).

[0037] In some embodiments, R A is ethyl. In some embodiments, R A is cyclopropyl. In some embodiments, R 20 is hydrogen. In some embodiments, R 20 and R H together with the atoms to which they are attached form oxo. In some embodiments, R 19 is optionally substituted amino. In some embodiments, R 19 teeth, [ka] In some embodiments, R 19 is an optionally substituted C2-C9 heterocycle. 19 teeth, [ka] In some embodiments, R 19 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R19 teeth, [ka] In some embodiments, R 19 is optionally substituted C6 to C 10 It is aryl. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 21 is hydrogen or R 21 and R H1 together with the atom to which they are attached to form oxo, R H1 is hydrogen or R H1 and R 21 together with the atom to which they are attached to form an oxo).

[0038] In some embodiments, R 21 and R H1 together with the atoms to which they are attached form oxo. In some embodiments, R 21 is hydrogen.

[0039] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted C6 to C 10 pyrazol-1-yl disubstituted by aryl; optionally substituted C1-C6 heteroalkyl; optionally substituted C1-C6 alkyl; optionally substituted C2-C9 heteroaryl, halo, hydroxy, optionally substituted C3-C8 cycloalkyl or optionally substituted C1-C6 alkyl; R3 teeth, [ka] and R A is ethyl, 2-hydroxy-ethyl, methyl, [ka] and R 2 is hydrogen, methyl, ethyl, halo, pyridin-3-yl, pyridin-4-yl, cyclopropyl, [ka] or R 2 and R A together with the atoms to which they are attached form an optionally substituted C4 heterocyclyl). R 1 teeth, [ka] is.

[0040] In some embodiments, the compound has the structure: [ka] have (In the formula, R 1 is an optionally substituted triazolyl; R A is methyl, ethyl or cyclopropyl).

[0041] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R A is cyclopropyl. In some embodiments, R 1 teeth, [ka] is.

[0042] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted indazolyl or optionally substituted 4,5,6,7-tetrahydrotriazaindenyl).

[0043] In some embodiments, R is optionally substituted indazolyl. 1 teeth, [ka] In some embodiments, R 1 is optionally substituted 4,5,6,7-tetrahydrotriazaindenyl. In some embodiments, R 1 teeth, [ka] is. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (wherein X is S or NR A and R 22 is hydrogen or phenyl, R 23 is hydrogen or methyl, R 2 is pyrazol-3-yl, pyridin-4-yl or 4-phenyl-pyrazol-1-yl, R A is methyl).

[0044] In some embodiments, X is S. In some embodiments, X is NRA In some embodiments, R 23 is hydrogen. In some embodiments, R 23 is methyl. In some embodiments, R 2 is pyrazol-3-yl. In some embodiments, R 2 is pyrazol-4-yl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is 4-phenyl-pyrazol-1yl.

[0045] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 22 is phenyl, pyridin-2-yl, or R 22 and R H2 together with the atom to which they are attached to form oxo, R H2 is hydrogen or R H2 and R 22 together with the atom to which they are attached to form oxo, R 23 is hydrogen or R 23 and R H3 together with the atom to which they are attached to form oxo, R H3 is hydrogen or R H3 and R 23 together with the atom to which they are attached to form an oxo).

[0046] In some embodiments, R 23 is hydrogen. In some embodiments, R 23 and R H3 together with the atom to which they are attached to form an oxo.

[0047] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is). In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is). In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 24 is methoxy, methyl or hydroxyl, R A is methyl or ethyl).

[0048] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazolyl, optionally substituted pyrimidin-3-yl or optionally substituted pyridin-4-yl; R Ais methyl or ethyl, R 2 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C1-C9 heterocyclyl; R 3 teeth, [ka] (It is).

[0049] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R 1 is optionally substituted pyrazolyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrimidin-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyridin-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 2 is pyridin-4-yl or 1-methyl-pyrazol-5-yl. In some embodiments, R 2 is optionally substituted C1-C9 heterocyclyl. 2 teeth, [ka] is.

[0050] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or phenyl substituted with an optionally substituted C2-C9 heteroaryl; R 25 and R 26 together with the atoms to which they are attached form a C3-C5 heterocyclyl substituted by hydroxyl).

[0051] In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is phenyl substituted with an optionally substituted C2-C9 heteroaryl. 1 teeth, [ka] In some embodiments, R 25 , R 26 and the heterocycle formed by the combination of the atoms to which they are attached is [ka] is.

[0052] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-5-yl, or phenyl (substituted with methoxy or C3-C8 cycloalkoxy).

[0053] In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 is optionally substituted pyrazol-5-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is phenyl substituted with methoxy or C-C cycloalkoxy. 1 teeth, [ka] is.

[0054] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl). In some embodiments, R 1 teeth, [ka] is. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl or optionally substituted pyrazol-5-yl; R 3 is morpholin-1-yl or piperidin-1-yl, R A is methyl or ethyl, R 2 teeth, [ka] (It is).

[0055] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] [ka] is.

[0056] In some embodiments, R 1 is optionally substituted pyrazol-3-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrazol-5-yl. In some embodiments, R 1 teeth, [ka] is.

[0057] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted C2-C9 heterocyclyl or C6-C 10 and pyrazolyl monosubstituted by aryl.

[0058] In some embodiments, R 1 teeth, [ka] is.

[0059] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or an optionally substituted pyrimidin-4-yl optionally substituted with an optionally substituted C1-C6 alkyl; R A is methyl or difluoromethyl, R 2 is pyridin-4-yl or [ka] (It is).

[0060] In some embodiments, R A is methyl. In some embodiments, R A is difluoromethyl. In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrimidin-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R A teeth, [ka] (It is). In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is). In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 27 is hydrogen, tetrahydropyran-3-yl or tetrahydropyran-4-yl, R 28 is hydrogen, methoxy, phenyl, methyl, difluoromethyl, optionally substituted cyclobutyl; R 15 is hydrogen or methoxy, R 2 is pyridin-4-yl or -O-pyridin-4-yl).

[0061] In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is methoxy. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is -O-pyridin-4-yl. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 29 is an optionally substituted C2-C9 heterocyclyl or an optionally substituted C6-C 10 (aryl).

[0062] In some embodiments, R 29 is optionally substituted C2-C9 heterocyclyl. In some embodiments, R 29 is tetrahydropyran-4-yl. In some embodiments, R 29 is optionally substituted C6 to C 10 In some embodiments, R 29 is phenyl.

[0063] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is optionally substituted 4,5-dihydro-pyrazol-1-yl, optionally substituted imidazol-2-yl, optionally substituted piperidin-1-yl or optionally substituted 1,2,4-triazol-3-yl, optionally substituted pyrazol-4-yl, optionally substituted 1,3,4-oxadiazol-2-yl or optionally substituted pyridin-3-yl, R A is methyl or ethyl).

[0064] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R 1 is optionally substituted 4,5-dihydro-pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted 1,2,3,4-tetrahydroquinolin-7-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted imidazol-2-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted piperidin-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1is optionally substituted 1,2,4-triazol-3-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrazol-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted 1,3,4-oxadiazol-2-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyridin-3-yl. In some embodiments, R 1 teeth, [ka] is.

[0065] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 C2-C9 heteroaryl, C6-C 10 pyrazol-5-yl optionally substituted with aryl, C3-C8 cycloalkyl, or C3-C8 cycloalkylC1-C6 alkyl; R A is methyl or ethyl).

[0066] In some embodiments, R 1 teeth, [ka] is.

[0067] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted C2-C9 heteroaryl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C2 alkyl or an optionally substituted C6-C 10 pyrazol-3-yl substituted by aryl C1-C6 alkyl; R A is methyl or ethyl).

[0068] In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R 1 teeth, [ka] is.

[0069] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is C1-C6 alkyl or C6-C 10 aryl-disubstituted pyrazol-3-yl).

[0070] In some embodiments, R 1 teeth, [ka] is.

[0071] In an aspect, the present invention provides a compound of formula (40) [ka] or a pharmaceutically acceptable salt thereof. wherein Y is CH or N; X is O or S; R 1 is an optionally substituted morpholin-1-yl, an optionally substituted pyrimidin-4-yl, -N(R 1A )N=C(R 1B ) 2, optionally substituted pyrazol-3-yl or optionally substituted indazol-4-yl; R 2 is hydrogen or methyl, R 30 is optionally substituted pyridin-4-yl, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-1-yl or C2-C9 heterocyclylC1-C6 alkyl (substituted by —S(O)2CH3).

[0072] In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 1 is optionally substituted morpholin-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrimidin-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -N(R 1A )N=C(R 1B )2. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrazol-3-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is optionally substituted indazol-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 30 is optionally substituted pyridin-4-yl. In some embodiments, R 30 is pyridin-4-yl. In some embodiments, R 30 is optionally substituted pyrazol-3-yl. In some embodiments, R 30 is pyrazol-3-yl. In some embodiments, R 30 is optionally substituted pyrazol-1-yl. In some embodiments, R 30 teeth, [ka] In some embodiments, R 30 is a C2-C9 heterocycle C1-C6 alkyl substituted with -S(O)2CH3. 30 teeth, [ka] is.

[0073] In an aspect, the present invention provides a compound of formula (41) [ka] or a pharmaceutically acceptable salt thereof. (wherein Y is S or NR A and R 1 is an optionally substituted pyrimidin-4-yl; R A is optionally substituted C1-C6 alkyl).

[0074] In some embodiments, Y is S. In some embodiments, Y is N-CH. In some embodiments, R 1 teeth, [ka] is.

[0075] In an aspect, the present invention provides a compound of formula (42) [ka] or (oa) a pharmaceutically acceptable salt thereof. (In the formula, X 2 and X 3 are each independently N or CR 32 and R 31 is an optionally substituted C2-C9 heteroaryl; R 32 is an optionally substituted C2-C9 heteroaryl).

[0076] In some embodiments, X 2 is N and X 3 is CR 32 In some embodiments, X 2 is CR 32 and X3 is N. In some embodiments, R 31 is optionally substituted pyraozl-1-yl. In some embodiments, R 31 teeth, [ka] In some embodiments, R 32 is optionally substituted pyridin-4-yl. In some embodiments, R 32 is pyridin-4-yl.

[0077] In an aspect, the present invention provides a compound of formula (43) [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 33 is an optionally substituted amino; R 34 is an optionally substituted C2-C9 heteroaryl).

[0078] In some embodiments, R 33 teeth, [ka] In some embodiments, R 34 is optionally substituted pyrazol-1-yl. In some embodiments, R 34 teeth, [ka] is.

[0079] In an aspect, the present invention provides a compound of formula (44) [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 35 and R36 are each independently an optionally substituted C2-C9 heteroaryl).

[0080] In some embodiments, R 35 is optionally substituted pyridin-4-yl. In some embodiments, R 35 is pyridin-4-yl. In some embodiments, R 36 is optionally substituted pyrazol-1-yl. In some embodiments, R 36 teeth, [ka] is.

[0081] In an embodiment, the present invention provides a compound of formula (45) [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 37 is an optionally substituted C2-C9 heteroaryl).

[0082] In some embodiments, R 37 is optionally substituted pyrazol-1-yl. In some embodiments, R 37 teeth, [ka] is.

[0083] In an embodiment, the present invention provides a compound of formula (46) [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 38 is optionally substituted C6 to C 10 is aryl, R 39is optionally substituted C2-C9 heteroaryl C1-C6 alkyl).

[0084] In some embodiments, R 38 is phenyl. In some embodiments, R 39 teeth, [ka] is. In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is hydrogen, optionally substituted C2-C9 heteroaryl; optionally substituted C2-C9 heterocyclyl or C1-C3 alkyl (optionally substituted by hydroxyl, oxo or dialkylamino); R 1 is an optionally substituted pyrazol-1-yl, phenyl (optionally substituted C2-C9 heteroaryl or optionally substituted C6-C 10 optionally substituted with aryl) or -N(R 1A )N=C(R 1B )2, R 3 teeth, [ka] (It is).

[0085] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 2 is optionally substituted C2-C9 heterocyclyl. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is C1-C3 alkyl optionally substituted with hydroxyl, oxo, or dialkylamino. 2 teeth, [ka] In some embodiments, R 1 is optionally substituted pyrazol-1-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C6-C 10 In some embodiments, R is phenyl optionally substituted with aryl. 1 teeth, [ka] In some embodiments, R 1 is -N(R 1A )N=C(R 1B )2. In some embodiments, R1 teeth, [ka] In some embodiments, the compound has the structure: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound has the structure: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is an optionally substituted C2-C9 heteroaryl; R 1 is -N(R 1A )N=C(R 1B )2).

[0087] In some embodiments, R 2 is optionally substituted pyridin-4-yl. In some embodiments, R 2 is pyridin-4-yl. In some embodiments, R 1 teeth, [ka] In some embodiments, the compound has the structure: [ka] It has.

[0088] In some embodiments, the compound has the structure of any one of compounds 1, 2, 14-22, 31, 44-46, 48-52, 56, 57, 60, 76-82, 93-96, 98, 108, 109, 116, 126, 133-139, 147-149, 157-163, 165-169, 171-180, 186, 195-197, 262, 286, 287, 291, 292, 294-299, 325, 329, 464, 465, and 467-473 in Table 1, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound has the structure of any one of compounds 3-13, 24-30, 32-43, 47, 53-55, 58, 59, 61-75, 83-92, 97, 99-107, 110-115, 117-125, 127-132, 140-146, 450-156, 181-185, 187-194, 198-261, 263-285, 288-290, 293, 300-324, 326-328, 330-390, 392-463, and 466 in Table 1, or a pharmaceutically acceptable salt thereof.

[0090] In an aspect, the present invention provides a compound having the structure [ka] or a pharmaceutically acceptable salt thereof.

[0091] In an aspect, the invention features a pharmaceutical composition including any of the compounds described above and a pharmaceutically acceptable excipient.

[0092] In aspects, the invention features a method of treating a neurological disorder (e.g., frontotemporal dementia-TDP (FTLD-TDP), chronic traumatic encephalopathy, ALS, Alzheimer's disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), or frontotemporal lobar degeneration) in a subject in need thereof, the method comprising administering an effective amount of any of the compounds or pharmaceutical compositions described above.

[0093] In aspects, the invention features a method of inhibiting toxicity in a cell (e.g., a mammalian neuronal cell) associated with a protein (e.g., TDP-43 or C9orf72), the method comprising administering an effective amount of any of the compounds or pharmaceutical compositions described above.

[0094] In aspects, the invention features a method of treating a TDP-43- or C9orf72-associated disorder (e.g., FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer's disease, LATE, or frontotemporal lobar degeneration) in a subject in need thereof. The method includes administering to the subject an effective amount of a compound described herein or a pharmaceutical composition containing one or more compounds described herein. In some embodiments, the method includes administering to a subject in need thereof an effective amount of a compound of Formula 49 [ka] or a pharmaceutically acceptable salt thereof (In the formula, X is NR A , S or O, Y is CR A or N, Z is CR 2 or N, R 1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C9 heterocyclyl, optionally substituted amino, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclylC1-C6 alkyl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl; -NHNHR 1A ;-N(R 1A )N=C(R 1B )2;-C(R 1A )=NN(R 1B )2;-C(R1A )=NOR 1A ; or -Q 1 -N(R 1C )2, Q 1 is a bond, CH or CO, R 1A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl or optionally substituted C6-C 10 aryl C1-C6 alkyl, R 1B one of which is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl, R 1B the remainder being optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; R 1C are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heteroaryl, or R 1C together with the nitrogen atom to which they are attached form a C2-C9 heterocyclyl or a C2-C9 heteroaryl; R 2 is an optionally substituted C1-C6 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heteroaryloxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl or optionally substituted C2-C9 heteroaryl, -QN(R 1C )2;-S(O) r -R1A ; or -P(O)(R 1A )2 and R A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or R 2 and R A together with the atoms to which they are attached form an optionally substituted C3-C4 heterocyclic ring, and R A the remainder, if present, is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl; r is 0, 1 or 2; R 3 teeth, [ka] is) The method includes administering

[0095] In some embodiments, the compound has formula 49a: [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, R A is optionally substituted C1-C6 alkyl. In some embodiments, R A is H. In some embodiments, the compound has formula 49b: [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound has formula 49c: [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound has formula 49d: [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, R 1 is an optionally substituted C2-C9 heteroaryl containing a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core.

[0100] In some embodiments, R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted 1,2,3-triazol-1-yl, optionally substituted 1,2,3-triazol-2-yl, optionally substituted benzotriazol-1-yl, optionally substituted 1,2,4-triazol-3-yl, optionally substituted 1,2,4-oxadiazol-3-yl, optionally substituted 1,2,4-oxadizol-2-yl. In some embodiments, R 1 is a pyrazol-1-yl substituted at the 3- or 4-position. In some embodiments, the pyrazol-1-yl is an optionally substituted C6-C 10 Aryl, optionally substituted C 1~9 Heterocyclyl, optionally substituted C2-C9 heteroaryl, optionally substituted C 3~8Optionally substituted with cycloalkyl or halo (e.g., fluoro, chloro, bromo). 1 is optionally substituted pyrazol-3-yl. In some embodiments, R 1 is a pyrazol-3-yl substituted at the 1-position.

[0101] In some embodiments, the optionally substituted pyrazol-1-yl is [ka] [ka] [ka] is.

[0102] In some embodiments, the pyrazol-3-yl is an optionally substituted C6-C 10 Aryl, optionally substituted C 1~9 Heterocyclyl, optionally substituted C2-C9 heteroaryl or optionally substituted C 3~8 In some embodiments, the pyrazol-3-yl is substituted by: [ka] [ka] is.

[0103] In some embodiments, R 1 is optionally substituted pyrimidin-6-yl or optionally substituted pyrimidin-4-yl. In some embodiments, R 1 teeth, [ka] is.

[0104] In some embodiments, R 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 2 is optionally substituted pyridyl. In some embodiments, R 2 is optionally substituted tetrahydropyranyl, optionally substituted dihydropyranyl, optionally substituted piperidinyl, or optionally substituted azetidinyl. 2 is optionally substituted tetrahydropyran-4-yl, optionally substituted 5,6-dihydro-2H-pyran-4-yl, optionally substituted piperidin-4-yl or optionally substituted piperidin-3-yl.

[0105] In some embodiments, R 1 is methoxy, optionally substituted C1-C6 alkyl, hydroxyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 In some embodiments, R is substituted with an optionally substituted C2-C9 heterocyclyl or C3-C8 cycloalkoxy. In some embodiments, R is substituted with a C2-C9 heteroaryl. 1 teeth, [ka] [ka] is.

[0106] In aspects, the invention features a method of inhibiting PIKfyve, the method including contacting a cell with an effective amount of any of the compounds or pharmaceutical compositions described above.

[0107] In another aspect, the present invention features a method for treating a neurological disorder in a patient, such as a human patient, identified based on TDP-43 toxicity as likely to benefit from treatment with a compound of the present invention. In this aspect, the method can include (i) determining that the patient exhibits or is prone to developing TDP-43 toxicity, and (ii) providing the patient with a therapeutically effective amount of a compound of the present invention. In some embodiments, the patient has previously been determined to exhibit or be prone to developing TDP-43 toxicity, and the method includes providing the patient with a therapeutically effective amount of a compound of the present invention. The patient's susceptibility to developing TDP-43 aggregation can be determined, for example, by determining whether the patient expresses a mutant isoform of TDP-43 containing a mutation associated with TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. This can be done, for example, by determining the amino acid sequence of a TDP-43 isoform isolated from a sample obtained from the patient, or by determining the nucleic acid sequence of a TDP-43 gene isolated from a sample obtained from the patient. In some embodiments, the method includes obtaining a sample from the patient.

[0108] In a further aspect, the invention features a method for treating a neurological disorder in a patient, such as a human patient, identified based on TDP-43 expression as likely to benefit from treatment with a compound of the invention. In this aspect, the method includes (i) determining that the patient expresses a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation (e.g., a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D), and (ii) providing the patient with a therapeutically effective amount of a compound of the invention. In some embodiments, the patient has previously been determined to express a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation, such as a Q331K, M337V, Q343R, N345K, R361S, or N390D mutation, and the method includes providing the patient with a therapeutically effective amount of a compound of the invention.

[0109] In another aspect, the invention features a method for determining whether a patient (e.g., a human patient) with a neurological disorder is likely to benefit from treatment with a compound of the invention by (i) determining whether the patient exhibits or is prone to developing TDP-43 aggregation, and (ii) identifying the patient as likely to benefit from treatment with a compound of the invention if the patient exhibits or is prone to developing TDP-43 aggregation. In some embodiments, the method further includes (iii) notifying the patient whether the patient is likely to benefit from treatment with a compound of the invention. A patient's susceptibility to developing TDP-43 aggregation can be determined, for example, by determining whether the patient expresses a mutant isoform of TDP-43 containing a mutation associated with TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. This can be done, for example, by determining the amino acid sequence of a TDP-43 isoform isolated from a sample obtained from the patient, or by determining the nucleic acid sequence of a TDP-43 gene isolated from a sample obtained from the patient. In some embodiments, the method includes obtaining a sample from the patient.

[0110] In another aspect, the invention features a method for determining whether a patient (e.g., a human patient) with a neurological disorder is likely to benefit from treatment with a compound of the invention by (i) determining whether the patient expresses a TDP-43 mutant having a mutation associated with TDP-43 aggregation (e.g., a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D), and (ii) identifying the patient as likely to benefit from treatment with a compound of the invention if the patient expresses a TDP-43 mutant. In some embodiments, the method further includes (iii) notifying the patient whether the patient is likely to benefit from treatment with a compound of the invention. The TDP-43 isoform expressed by a patient can be assessed, for example, by isolating TDP-43 protein from a sample obtained from the patient and sequencing the protein using molecular biology techniques described herein or known in the art. In some embodiments, the TDP-43 isoform expressed by the patient is determined by analyzing the patient's genotype at the TDP-43 locus, for example, by determining the sequence of the TDP-43 gene in a sample obtained from the patient. In some embodiments, the method includes obtaining a sample from the patient.

[0111] In some embodiments of any of the above aspects, the compound of the invention is provided to a patient by administering a compound of the invention to the patient, hi some embodiments, the compound of the invention is provided to a patient by administering a prodrug that is converted in vivo to the compound of the invention.

[0112] In some embodiments of any of the above aspects, the neurological disorder is a neuromuscular disorder, such as a neuromuscular disorder selected from amyotrophic lateral sclerosis, congenital myasthenic syndromes, congenital myopathies, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaacs syndrome, Kearns-Sayre syndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal-bulbar muscular atrophy, spinal muscular atrophy, stiff-person syndrome, Troyer syndrome, and Guillain-Barré syndrome. In some embodiments, the neurological disorder is amyotrophic lateral sclerosis.

[0113] In some embodiments of any of the above aspects, the neurological disorder is selected from frontotemporal degeneration (also referred to as frontotemporal lobar degeneration and frontotemporal dementia), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism-ALS complex, Huntington's disease, early-onset Paget's disease and inclusion body myopathy with frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy.

[0114] In some embodiments, the neurological disorder is amyotrophic lateral sclerosis, and after administration of a compound of the invention to the patient, the patient exhibits one or more, or all of the following responses: (i) an improvement in a condition as assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) or Revised ALSFRS (ALSFRS-R), such as an improvement in a patient's ALSFRS or Revised ALSFRS (ALSFRS-R) score within one day or more days, weeks, or months after administration of a compound of the invention (e.g., within about one day to about 48 weeks (e.g., within about two days to about 36 weeks, about four weeks to about 24 weeks, about eight weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the patient, e.g., within one day, two days, three days, four days, five days, or more after initial administration of a compound of the invention to the patient). improvement in the patient's ALSFRS or ALSFRS-R score within 1 week, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more (ii) an improvement in slow vital capacity, such as an improvement in a patient's slow vital capacity within one or more days, weeks, or months after administration of a compound of the invention (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks Improvement in the patient's normal vital capacity within 1 week, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more (iii) a reduction in the response exhibited by the patient upon repeated nerve stimulation, such as a reduction observed within one day or more days, weeks, or months after administration of a compound of the invention (e.g., within about one day to about 48 weeks (e.g., within about two days to about 36 weeks, about four weeks to about 24 weeks, about eight weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks after initial administration of a compound of the invention to the patient). , a decrease observed within 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more), (iv) an improvement in muscle strength as assessed, for example, by the British Medical Research Council Muscle Testing Scale (which relates to measuring patient response to treatment of a nervous system disorder and is described, for example, in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference), such as an improvement observed within one day or more days, weeks, or months after administration of a compound of the invention (e.g., within about one day to about 48 weeks (e.g., about two days to about 36 weeks, about four weeks to about 24 weeks, about eight weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks after initial administration of a compound of the invention to the patient). , improvement observed within 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more), (v) an improvement in quality of life, such as an improvement in the patient's quality of life, observed within one day or more days, weeks, or months after administration of a compound of the invention, e.g., an improvement in quality of life as assessed using an amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, or more after initial administration of a compound of the invention to the patient). an improvement in the subject's quality of life observed within 1 day, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more; (vi) a reduction in the frequency and / or severity of muscle cramps, such as a reduction in cramp frequency and / or severity within 1 day or more days, weeks, or months after administration of a compound of the invention (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks after initial administration of a compound of the invention to a patient). , 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more), and / or a decrease in seizure frequency and / or severity within (vii) a reduction in TDP-43 aggregation, such as a reduction in TDP-43 aggregation within 1 day or more days, weeks, or months after administration of a compound of the invention (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks after initial administration of a compound of the invention to a patient). , 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more). chemical terms

[0115] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0116] Those of skill in the art will recognize that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, tautomers) and / or isotopic (e.g., one or more atoms replaced by a different isotope of that atom, such as hydrogen being replaced by deuterium) forms. Unless otherwise indicated or apparent from the context, it will be understood that the depicted structures represent all such isomeric or isotopic forms individually or in combination.

[0117] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms.Unless otherwise expressly excluded, when the context is clear, when describing such compounds, all of these tautomeric forms are included.In some embodiments, tautomeric forms result from the exchange of a single bond with an adjacent double bond and the simultaneous migration of a proton.In certain embodiments, tautomeric forms may be prototropic tautomers, which are isomeric protonation states that have the same empirical formula and total charge as the reference form. Examples of moieties that contain prototropic tautomeric forms include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and ring forms in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.In some embodiments, tautomeric forms can be in equilibrium, or can be sterically fixed into one form by appropriate substitution.In certain embodiments, tautomeric forms result from acetal interconversion, for example, the interconversion illustrated in the following scheme: [ka]

[0118] Those skilled in the art will recognize that in some embodiments, isotopes of the compounds described herein can be prepared and / or utilized by the present invention. "Isotopes" refer to atoms that have the same atomic number but different mass numbers due to the different number of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, isotope substitution (e.g., substitution of hydrogen with deuterium) can alter the physicochemical properties of a molecule, such as the rate of metabolism and / or racemization of a chiral center.

[0119] As is known in the art, many chemical entities (particularly many organic molecules and / or many small molecules) can exist in a variety of different solid forms, such as, for example, amorphous and / or crystalline forms (e.g., polymorphs, hydrates, solvates, etc.). In some embodiments, such entities may be utilized in any form, including all solid forms. In some embodiments, such entities are utilized in a particular form, e.g., a particular solid form.

[0120] In some embodiments, the compounds described and / or illustrated herein may be provided and / or utilized in salt form.

[0121] In certain embodiments, the compounds described and / or illustrated herein may be supplied and / or utilized in hydrated or solvated forms.

[0122] Substituents for compounds of the present disclosure are disclosed herein in groups or ranges at various positions. It is specifically intended that the present disclosure include all individual subcombinations of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound includes multiple positions where a substituent is disclosed in a group or range, unless otherwise indicated, the disclosure is intended to encompass individual compounds and groups (e.g., classes and subclasses) of compounds, including all individual subcombinations of the members at each position.

[0123] As used herein, phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) are intended to be equivalent to "X, where X is optionally substituted, X" (e.g., "alkyl, where the alkyl is optionally substituted, alkyl"). The feature "X" (e.g., alkyl) is not itself intended to imply optionality.

[0124] The term "acyl," as used herein, refers to a hydrogen or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0125] The term "alkyl," as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). Alkylene is a divalent alkyl group.

[0126] The term "alkenyl," as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0127] The term "alkynyl," as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0128] The term "amino" as used herein refers to -N(R N1 )2, and R N1 are each independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these described R N1 Each group may be optionally substituted, or two R N1 together form an alkylene or heteroalkylene, and R N2 are each independently H, alkyl, or aryl. The amino group of the present invention can be an unsubstituted amino (i.e., —NH) or a substituted amino (i.e., —N(R N1 )2) can be one R 1 is H and the other R N1 The amino group that R has as a non-H group is sometimes called a monosubstituted amino. N1 One of them is H and the other is R N1 When R is an optionally substituted alkyl, the resulting amino group is an optionally substituted monoalkylamino. N1 When both of the groups are independently optionally substituted alkyl, the resulting amino group is an optionally substituted dialkylamino.

[0129] The term "aryl," as used herein, refers to an aromatic carbomonocyclic or polycyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0130] The term "arylalkyl," as used herein, refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are those containing 7 to 30 carbons (e.g., C6-C6), such as benzyl and phenethyl. 10 Aryl C1-C6 alkyl, C6-C 10 Aryl C1-C 10 Alkyl or C6-C 10 Aryl C1-C20 In some embodiments, alkyl and aryl may each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0131] The term "aryloxy," as used herein, refers to an oxygen atom substituted with an aryl group, as defined herein, for example, --O-phenyl or --O-naphthyl.

[0132] The term "azido" as used herein refers to the group -N3.

[0133] The term "cyano" as used herein refers to the group CN.

[0134] The term "carbocyclyl," as used herein, refers to a non-aromatic C-C ring in which the ring is formed by carbon atoms. 12 It refers to a monocyclic, bicyclic, or tricyclic structure. The carbocyclyl structure comprises a cycloalkyl group and an unsaturated carbocyclyl radical.

[0135] The term "cycloalkenyl," as used herein, refers to a non-aromatic, monovalent, carbocyclic or polycyclic radical of 3 to 10, preferably 3 to 6, carbon atoms and one or two endocyclic carbon-carbon double bonds. This term is further exemplified by radicals such as cycloheptenyl, cyclohexenyl, and cyclopentenyl. Polycyclic cycloalkenyls may be fused, bridged, or spirocycloalkenyl.

[0136] The term "cycloalkyl," as used herein, refers to a saturated, non-aromatic, monovalent, carbocyclic, or polycyclic radical of 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. Polycyclic cycloalkyls may be fused, bridged, or spirocycloalkyls.

[0137] The term "cycloalkoxy," as used herein, refers to an oxygen atom substituted by a cycloalkyl group, as defined herein, e.g., -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl.

[0138] The term "halo," as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0139] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with one, two, three, or four substituents as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group.

[0140] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, in which one or more constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, heteroalkenyl groups can be further substituted with one, two, three, or four substituents described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy," which, as used herein, refers to alkenyl-O-. Heteroalkenylene is a divalent heteroalkenyl group.

[0141] The term "heteroalkynyl" as used herein refers to an alkynyl group, as defined herein, in which one or more constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with one, two, three, or four substituents as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy," which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0142] The term "heteroaryl," as used herein, refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring and containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0143] The term "heteroarylalkyl," as used herein, refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., C2-C9 heteroaryl C1-C6 alkyl C2-C9, C2-C9 heteroaryl C1-C 10 Alkyl C2-C9 or C2-C9 heteroaryl C1-C 20 alkyl (7-16 or 7-20 carbons, such as C2-C9). In some embodiments, alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0144] The term "heteroaryloxy," as used herein, refers to an oxygen atom substituted by a heteroaryl group, as defined herein, for example, --O-pyridinyl or --O-thiazolyl.

[0145] The term "heterocyclyl," as used herein, refers to a monocyclic or polycyclic radical having 3 to 12 atoms, with at least one ring containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, and none of the rings being aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. Heterocyclyl groups may be aromatic or non-aromatic. Aromatic heterocyclyls are also referred to as heteroaryls. Polycyclic heterocyclyls may be fused, bridged, or spiroheterocyclyls.

[0146] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., C2-C9 heterocyclylC1-C6 alkylC2-C9, C2-C9 heterocyclylC1-C 10Alkyl C2-C9 or C2-C9 heterocyclyl C1-C 20 and 7-16 or 7-20 carbons, such as alkyl C2-C9. In some embodiments, alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0147] The term "hydroxyl" as used herein refers to an --OH group.

[0148] The term "N-protecting group," as used herein, refers to a group intended to protect an amino group from undesired reactions during synthetic procedures. Commonly used N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis," 3 rdEdition (John Wiley & Sons, New York, 1999). N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D-, L-, or D,L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 2,5 ... oxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl carbamate-forming groups such as phenyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl.Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0149] The term "nitro" as used herein refers to the NO2 group.

[0150] The term "oxyheteroaryl," as used herein, refers to a heteroaryl group having at least one ring oxygen atom.

[0151] The term "oxyheterocyclyl," as used herein, refers to a heterocyclyl group having at least one ring oxygen atom.

[0152] The term "thiol" as used herein refers to an --SH group.

[0153] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. If substituted, one to four substituents are typically present unless otherwise specified. Substituents include, for example, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), cycloalkoxy, halo (e.g., fluoro), heteroaryloxy, hydroxyl, oxo, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl, such as unsubstituted and substituted arylalkyl (e.g., substituted and unsubstituted benzyl).

[0154] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g., racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemic diastereoisomers, or racemic mixtures of diastereoisomers. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis, or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers, most commonly those whose mirror images are non-superimposable because they contain asymmetrically substituted carbon atoms that act as chiral centers. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are non-superimposable. Diastereomers are stereoisomers that are not mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more asymmetric carbon atoms. Enantiomers of a compound can be prepared, for example, by separating one enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating one enantiomer of a compound described herein from a racemic mixture can be readily determined by those skilled in the art. A "racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such a mixture does not exhibit optical activity, i.e., they do not rotate the plane of polarized light. A "geometric isomer" refers to an isomer that differs in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents pointing to the same side) configuration. * "," "R*"," "E," "Z," "cis," and "trans" indicate configurations relative to the core molecule. Certain disclosed compounds may exist in the form of atropisomers. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is sufficiently high to allow isolation of the conformers. The compounds of the present invention can be prepared as individual isomers either by isomer-specific synthesis or by resolution from an isomeric mixture. Conventional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either the starting materials or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is depicted by name or structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomer. When a single enantiomer is depicted by name or structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is depicted by name or structure, the named or depicted diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity is the ratio of the weight of an enantiomer, or the weight of an enantiomer, to the sum of the weights of its enantiomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. Where the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure on a mole fraction basis relative to other stereoisomers.When a single enantiomer is depicted by name or structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a mole fraction basis. When a single diastereomer is depicted by name or structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure on a mole fraction basis. Percent purity on a mole fraction basis is the ratio of moles of an enantiomer, or moles of an enantiomer, to the sum of moles of its optical isomer. Similarly, percent purity on a mole fraction basis is the ratio of moles of a diastereomer, or moles of a diastereomer, to the sum of moles of its optical isomer. When a disclosed compound is depicted by a name or structure without indicating stereochemistry and the compound has at least one chiral center, it should be understood that the name or structure encompasses either an enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is depicted by a name or structure without indicating stereochemistry and the compound has two or more chiral centers, it should be understood that the name or structure encompasses diastereomers free from other diastereomers, several diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms. definition

[0155] In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," (iii) the terms "including" and "including" may be understood to encompass the listed components or steps, whether presented alone or together with one or more additional components or steps, (iv) the terms "about" and "approximately" may be understood to allow for standard deviation, as understood by one of ordinary skill in the art, and (v) when ranges are presented, the endpoints are included.

[0156] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound, a conjugate, or a preparation comprising a compound or conjugate described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), oral, intraintestinal, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intramucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including by intratracheal instillation), transdermal, intravaginal, and intravitreal.

[0157] As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, a cow, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0158] As used herein, the terms "approximately" and "about" are intended to encompass normal statistical variations, as would be understood by one of ordinary skill in the art, where appropriate in the relevant context. In certain embodiments, the terms "approximately" or "about" refer to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated value, unless otherwise specified or otherwise evident from the context (e.g., when such a number exceeds 100% of the possible values).

[0159] As used herein, the term associated refers to two events or entities being "associated" with one another if the presence, level, and / or form of one correlates with that of the other. For example, a particular entity (e.g., a polypeptide) is considered to be associated with a particular disease, disorder, or condition if its presence, level, and / or form correlates with the incidence and / or susceptibility of the disease, disorder, or condition (e.g., across a relevant population).

[0160] As used herein, the terms "benefit" and "response" are used interchangeably in the context of a subject, such as a human subject undergoing therapy to treat neurological disorders, for example, amyotrophic lateral sclerosis, frontotemporal degeneration (also referred to as frontotemporal lobar degeneration and frontotemporal dementia), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism ALS complex, Huntington's disease, early-onset Paget's disease and inclusion body myopathy with frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander's disease and hereditary inclusion body myopathy.The terms "benefit" and "response" refer to any clinical improvement in the condition of the subject. Exemplary benefits in the context of a subject undergoing treatment for a neurological disorder using the compositions and methods described herein (e.g., in the context of a human subject undergoing treatment for a neurological disorder described herein, such as amyotrophic lateral sclerosis, with a FYVE-type zinc finger-containing phosphoinositide kinase (PIKfyve) inhibitor described herein, such as an inhibitory small molecule, antibody, antigen-binding fragment thereof, or interfering RNA molecule) include slowing and halting disease progression, and suppression of one or more symptoms associated with the disease. In particular, examples of clinical "benefit" and "response" in the context of a patient (e.g., a human patient) undergoing treatment for amyotrophic lateral sclerosis with a compound of the invention include (i) an improvement in the subject's Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) or Revised ALSFRS (ALSFRS-R) score within one or more days, weeks, or months after administration of a compound of the invention, as assessed using the ALSFRS or ALSFRS-R following administration of a compound of the invention. Improvement in the subject's condition (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or within more weeks after initial administration of a compound of the invention to the subject, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,(ii) an improvement in a subject's ALSFRS or ALSFRS-R score within 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more; (iii) an improvement in a subject's ALSFRS or ALSFRS-R score within 1 day or more after administration of a compound of the invention; An improvement in a subject's normal lung capacity after administration of a compound of the invention, such as an improvement in the subject's normal lung capacity within a number of days, weeks, or months (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the subject, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more); (iii) an improvement in a subject's normal vital capacity within 1 day or more of administration of a compound of the invention upon repeated nerve stimulation; A reduction in the reduction response exhibited by the subject, such as a reduction observed within a longer number of days, weeks, or months (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the subject, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,(iv) a reduction observed within 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more after administration of a compound of the invention), e.g., an improvement observed within one or more days, weeks, or months after administration of a compound of the invention, e.g., using the British Medical Research Council Muscle Testing Scale (related to measuring patient response to treatment of nervous system disorders, the disclosure of which is incorporated herein by reference, e.g., Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014)) (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the present invention to the subject, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, (v) an improvement in a subject's quality of life, such as an improvement observed within 1 day or more days, weeks, or months after administration of a compound of the invention, as assessed, for example, using an amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire (e.g., an improvement observed within about 1 day to about 48 weeks (e.g., within about 1 day to about 48 weeks after the subject's first administration of a compound of the invention), (vi) an improvement in a subject's quality of life, such as an improvement observed within 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more weeks after administration of a compound of the invention); (vi) an improvement in a subject's quality of life, such as an improvement observed within 1 day or more days, weeks, or months after administration of a compound of the invention, as assessed, for example, using an amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire (e.g., an improvement observed within about 1 day to about 48 weeks (e.g., within about 1 day to about 48 weeks after the subject's first administration of a compound of the invention),Within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 8 (vi) an improvement in the subject's quality of life observed within 1 week, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more after administration of a compound of the invention); and (vi) an improvement in the frequency and / or severity of seizures exhibited by the subject within 1 day or more days, weeks or months after administration of a compound of the invention. a reduction in the frequency and / or severity of muscle spasms, such as a reduction in the severity of the spasms (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a compound of the invention to the subject, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 7 a reduction in seizure frequency and / or severity within 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more

[0161] As used herein, the term "dosage form" refers to a physically discrete unit of active compound (e.g., a therapeutic or diagnostic agent) for administration to a subject. Each unit contains a predetermined amount of active agent. In some embodiments, such amount is a unit dosage (or a whole fraction thereof) suitable for administration according to a dosing regimen (i.e., a therapeutic dosing regimen) determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will recognize that the total amount of a therapeutic composition or compound to be administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0162] As used herein, the term "dosing regimen" refers to a set of unit doses (usually more than one) administered individually to a subject, usually separated by a period of time. In some embodiments, a given therapeutic compound has a recommended dosing regimen that can include one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated from the other by a period of the same length. In some embodiments, a dosing regimen includes multiple doses and at least two different periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose amount. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first administration at a first dosage amount, followed by one or more additional administrations at a second dosage amount that is different from the first dosage amount. In some embodiments, a dosing regimen includes a first administration at a first dosage amount, followed by one or more additional administrations at a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to an entire relevant population (ie, is a therapeutic dosing regimen).

[0163] In practicing the methods of this invention, an "effective amount" of any one of the compounds of this invention, or any combination of compounds of this invention or pharmaceutically acceptable salts thereof, either alone or in combination, is administered by any of the conventional and accepted methods known in the art.

[0164] The term "pharmaceutical composition" as used herein refers to a composition containing a compound described herein, which is formulated with pharmaceutically acceptable additives and manufactured or sold under the approval of a government regulatory agency as part of a therapeutic regimen for treating disease in a mammal.The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gel cap or syrup), for topical administration (e.g., cream, gel, lotion or ointment), for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use, without particulate obstruction), or in any other pharmaceutically acceptable formulation.

[0165] As used herein, the term "pharmaceutically acceptable additive" refers to any component other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound), which has substantially non-toxic and non-inflammatory properties in patients. Additives can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and wetting water. Exemplary additives may include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0166] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of the compound of formula (I). For example, any pharmaceutically acceptable salt of the compounds described herein includes salts that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared separately during the final isolation and purification of the compounds described herein, or in situ by reacting the free base group with a suitable organic acid.

[0167] The compounds of the present invention can have ionizable groups so that they can be prepared as pharmaceutically acceptable salts.These salts can be acid addition salts, including inorganic or organic acids, or salts can be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form.In many cases, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.Suitable pharmaceutically acceptable acids and bases, and methods for preparing suitable salts, are well known in the art.Salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and inorganic and organic bases.

[0168] The terms "PIKfyve" and "FYVE-type zinc finger-containing phosphoinositide kinase" are used interchangeably herein and refer to an enzyme that catalyzes the phosphorylation of phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate, for example, in a human subject. The terms "PIKfyve" and "FYVE-type zinc finger-containing phosphoinositide kinase" refer not only to the wild-type form of PIKfyve, but also to variants of the wild-type PIKfyve protein and nucleic acids encoding same. The gene encoding PIKfyve can be found under NCBI reference sequence number NG_021188.1. Exemplary transcript sequences of the wild-type form of human PIKfyve can be found under NCBI reference sequence numbers NM_015040.4, NM_152671.3, and NM_001178000.1. Exemplary protein sequences for the wild-type form of human PIKfyve are available at NCBI reference sequence numbers NP_055855.2, NP_689884.1, and NP_001171471.1.

[0169] As used herein, the term "PIKfyve inhibitor" refers to a substance such as a compound of Formula I. This type of inhibitor can competitively inhibit PIKfyve activity, for example, by specifically binding to the PIKfyve enzyme (e.g., due to the inhibitor's affinity for the PIKfyve active site), thereby disabling, hindering, or stopping the entry of one or more endogenous substrates of PIKfyve into the enzyme active site. Additional examples of PIKfyve inhibitors that suppress the activity of the PIKfyve enzyme include substances that can bind to PIKfyve at a site distal to the active site and weaken the binding of endogenous substrates to the PIKfyve active site by changing the spatial conformation of the enzyme due to inhibitor binding. The term "PIKfyve inhibitor" includes substances that modulate PIKfyve activity, as well as substances that reduce the concentration and / or stability of PIKfyve mRNA transcripts in vivo and substances that suppress the translation of functional PIKfyve enzyme.

[0170] The term "pure" means substantially pure or free from undesired components (e.g., other compounds and / or other components of a cell lysate), contaminants, impurities, or imperfections.

[0171] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobacillus acid salts, and benzoates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0172] Various clinical indicators can be used to identify patients as "at risk" for developing specific neurological disorders, including amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism-ALS complex, Huntington's disease, early-onset Paget's disease and inclusion body myopathy with frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy. Examples of patients (e.g., human patients) "at risk" of developing a neurological disorder such as amyotrophic lateral sclerosis include (i) subjects who exhibit or are prone to exhibit TAR-DNA binding protein (TDP)-43 aggregation, and (ii) subjects who express mutant forms of TDP-43 containing mutations associated with TDP-43 aggregation and toxicity, such as mutations selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. A subject "at risk" of developing amyotrophic lateral sclerosis may exhibit one or both of these characteristics, for example, prior to initial administration of a PIKfyve inhibitor according to the compositions and methods described herein.

[0173] As used herein, the terms "TAR-DNA binding protein-43" and "TDP-43" are used interchangeably and refer to a transcriptional repressor protein involved in the modulation of HIV-1 transcription and the alternative splicing of the pre-mRNA transcript of cystic fibrosis transmembrane conductance regulator (CFTR), for example, in human subjects.The terms "TAR-DNA binding protein-43" and "TDP-43" refer not only to the wild-type form of TDP-43, but also to the variant of wild-type TDP-43 protein and the nucleic acid encoding it.The amino acid sequence of the wild-type form of human TDP-43 and the corresponding mRNA sequence are provided in NCBI reference sequence numbers NM_007375.3 and NP_031401.1, respectively.

[0174] The terms "TAR-DNA binding protein-43" and "TDP-43," as used herein, include, for example, forms of the human TDP-43 protein having an amino acid sequence at least 85% identical to the amino acid sequence of NCBI Reference SEQ ID NO: NP_031401.1 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or 100% identical to the amino acid sequence of NCBI Reference SEQ ID NO: NP_031401.1), and / or forms of the human TDP-43 protein that include one or more substitutions, insertions and / or deletions (e.g., one or more conservative and / or non-conservative amino acid substitutions, such as up to 5, 10, 15, 20, 25 or more conservative or non-conservative amino acid substitutions) relative to the wild-type TDP-43 protein. Patients who can be treated for neurological disorders described herein, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism-ALS complex, Huntington's disease, early-onset Paget's disease and inclusion body myopathy with frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander's disease, and hereditary inclusion body myopathy, include human patients who express forms of TDP-43 with mutations associated with increased TDP-43 aggregation and toxicity, such as mutations selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. Similarly, the terms "TAR-DNA binding protein-43" and "TDP-43," as used herein, include forms of the human TDP-43 gene that encode an mRNA transcript having a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of, for example, NCBI Reference SEQ ID NO: NM_007375.3 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or 100% identical to the amino acid sequence of NCBI Reference SEQ ID NO: NM_007375.3).

[0175] As used herein, the term "subject" refers to any living organism to which a composition according to the present invention may be administered, for example, for experimental, diagnostic, preventive and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal that may seek or require treatment, may request treatment, may currently be undergoing treatment, may be likely to undergo treatment in the future, or may be under the supervision of a trained professional for a particular disease or condition.

[0176] A "therapeutic regimen" refers to a dosing regimen, the administration of which to a relevant population as a whole correlates with a desired or beneficial therapeutic outcome.

[0177] The term "therapeutically effective amount" refers to an amount that, when administered to a population suffering from or susceptible to a disease, disorder, and / or condition according to a therapeutic dosing regimen, is sufficient to treat the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of a disease, disorder, and / or condition and / or delays the onset of one or more symptoms thereof. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not, in fact, require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to patients in need of such treatment, results in a particular desired pharmacological response in a significant number of subjects. It is specifically understood that certain subjects may, in fact, be "refractory" to a "therapeutically effective amount." By way of example, a refractory subject may have low bioavailability such that clinical efficacy cannot be achieved. In some embodiments, reference to a therapeutically effective amount may be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of skill in the art will understand that in some embodiments, a therapeutically effective amount may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated and / or administered in multiple doses, for example, as part of a dosing regimen. [Brief explanation of the drawings]

[0178] [Figure 1] Figure 1 shows a scheme for generating a control TDP-43 yeast model (FAB1 TDP-43). The control yeast TDP-43 model was generated by integrating the human TDP-43 gene and the GAL1 promoter into the yeast genome. The yeast ortholog of human PIKFYVE is FAB1.

[0179] [Figure 2]Figure 2 is a scheme illustrating the approach for generating the humanized PIKFYVE TDP-43 yeast model (PIKFYVE TDP-43). The FAB1 gene was transfected by homologous recombination with a G418 resistance cassette (fab1::G418R) (Figure 2). PIKFYVE was cloned downstream of the GPD promoter harbored in a URA3-containing plasmid and introduced into the fab1::G418R ura3 strain. The pGAL1-TDP-43 construct was then introduced into the "humanized" yeast strain to assess cytotoxicity.

[0180] [Figure 3] FIG. 3 is a histogram generated from a flow cytometry-based viability assay of FAB1 TDP-43.

[0181] [Figure 4] Figure 4 shows a histogram generated from a flow cytometry-based viability assay of PIKFYVE TDP-43. Upon TDP-43 induction, there was a significant increase in nonviable cells (right-most population), with a more pronounced effect for PIKFYVE TDP-43 than for the FAB1 TDP-43 strain (see Figure 3).

[0182] [Figure 5] FIG. 5 is an overlay of histograms generated from a flow cytometry-based viability assay of FAB1 TDP-43 in the presence of APY0201.

[0183] [Figure 6] FIG. 6 is an overlay of histograms generated from a flow cytometry-based viability assay of PIKFYVE TDP-43 in the presence of APY0201.

[0184] [Figure 7] FIG. 7 is a scatter plot comparing the PIKFYVE TDP-43 cytoprotective efficacy and PIKfyve inhibitory activity of test compounds. DETAILED DESCRIPTION OF THE INVENTION

[0185] Detailed Description The present invention features compositions and methods for treating neurological disorders such as amyotrophic lateral sclerosis and other neuromuscular disorders, as well as frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism-ALS complex, Huntington's disease, early-onset Paget's disease and inclusion body myopathy with frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander's disease, and hereditary inclusion body myopathy, among others. In particular, the present invention provides inhibitors of FYVE-type zinc finger-containing phosphoinositide kinases (PIKfyve) that can be administered to patients (e.g., human patients) to treat or prevent neurological disorders, such as one or more of the above-mentioned conditions. In the context of therapeutic treatment, a PIKfyve inhibitor can be administered to a patient to alleviate one or more symptoms of a disorder, such as to inhibit or prevent aggregation of TAR-DNA binding protein (TDP)-43, and / or to treat the underlying molecular pathology associated with the disease.

[0186] The disclosure herein is based in part on the discovery that PIKfyve inhibition modulates TDP-43 aggregation in cells.Suppressing TDP-43 aggregation exerts beneficial effects in patients suffering from neurological disorders.Many pathological conditions are correlated with TDP-43-promoted aggregation and toxicity, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism ALS complex, Huntington's disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander's disease and hereditary inclusion body myopathy. Without being limited by mechanism, for example, by administering an inhibitor of PIKfyve, TDP-43 aggregation induced by the PIKfyve inhibitor is suppressed, and thus patients suffering from diseases associated with TDP-43 aggregation and toxicity can be treated.

[0187] Patients likely to respond to PIKfyve inhibition described herein include patients who have developed or are at risk of developing TDP-43 aggregation, such as patients who express mutant forms of TDP-43 associated with TDP-43 aggregation and toxicity in vivo. Examples of such mutations in TDP-43 that correlate with increased TDP-43 aggregation and toxicity include, among others, Q331K, M337V, Q343R, N345K, R361S, and N390D. Thus, the compositions and methods described herein provide the additional clinical benefit of identifying patients likely to respond to PIKfyve inhibitor therapy, and therefore, providing a process for treating these patients.

[0188] The following section provides a description of exemplary PIKfyve inhibitors that can be used in conjunction with the compositions and methods disclosed herein. The following section also provides a description of various exemplary administration routes and pharmaceutical compositions that can be used to deliver these substances for treating neurological disorders.

[0189] PIKfyve inhibitors The PIKfyve inhibitors described herein include compounds of Formula 1: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X is NR A and Y is CR A or N, R 1 are substituted as necessary C1 to C 10 Heteroaryl (including a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core); 4,5-dihydropyrazol-1-yl substituted by phenyl; optionally substituted pyrimidin-2-yl, optionally substituted pyridazin-6-yl, optionally substituted pyrimidin-4-yl; pyridin-3-yl optionally substituted by methoxy; optionally substituted indazol-1-yl; optionally substituted indazol-2-yl; optionally substituted indazol-7-yl; optionally substituted isoindolin-6-yl; optionally substituted pyridazin-5-yl; optionally substituted pyrrolidin-1-yl; optionally substituted pyrimidin-6-yl; optionally substituted piperazinyl; phenyl (methoxy, optionally substituted C1-C6 alkyl, hydroxyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10substituted by aryl, optionally substituted C2-C9 heterocyclyl or C3-C8 cycloalkoxy); optionally substituted C3 carbocyclyl; optionally substituted morpholin-1-yl; optionally substituted benzodioxolyl; optionally substituted benzopyrrolidonyl; optionally substituted tetrahydroquinoline; optionally substituted monoalkylamino; optionally substituted dialkylamino; amino monosubstituted by optionally substituted C2-C9 heteroaryl; halo; optionally substituted C2-C9 heterocycle-C1 alkyl; optionally substituted C2-C9 heteroaryl-C1 alkyl; optionally substituted benzodioxanyl; -NHNHR 1A ;-N(R 1A )N=C(R 1B )2;-C(R 1A )=NN(R 1B )2;-C(R 1A )=NOR 1A ; or -Q 1 -N(R 1C )2, Q 1 is a bond, CH or CO, R 1A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl or optionally substituted C6-C 10 aryl C1-C6 alkyl, R 1B one of which is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl, R 1B the remainder being optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; R 1Care each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heteroaryl, or R 1C together with the nitrogen atom to which they are attached form a C2-C9 heterocyclyl or a C2-C9 heteroaryl; R 2 is H, halogen, optionally substituted C6-C 10 Aryl; optionally substituted C 1~9 Heterocyclyl; -O-pyridin-3-yl; optionally substituted C3-C8 cycloalkyl; optionally substituted C3-C8 cycloalkenyl, C1-C2 alkyl (optionally substituted with hydroxy, methoxy, -CH2OH, pyridin-4-yl, 4-pyridon-1-yl, -O-pyridin-4-yl, oxo, or dialkylamino); C1 alkyl (optionally substituted with deuterium, oxo, hydroxy, halo, or amino (substituted with C3 cycloalkyl)); C3 alkyl (substituted with hydroxy, oxo, or dialkylamino); C4 alkyl; optionally substituted C2-C9 heteroaryl; -QN(R 1C )2;-S(O) r -R 1A ; or -P(O)(R 1A )2 and R A are each independently H, C1-C2 alkyl (hydroxyl or -S(O) r -(optionally substituted C1-C6 alkyl), C3 alkyl, C4-C5 alkyl (substituted by hydroxyl), optionally substituted C2-C9 heteroarylC1-C6 alkyl; optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkylC1-C6 alkyl, optionally substituted C6-C 10aryl or optionally substituted C2-C9 heteroaryl, or R 2 and R A together with the atoms to which they are attached form an optionally substituted C3-C4 heterocyclic ring, and R A The remainder, if present, is H, C1-C2 alkyl (hydroxyl or -S(O) r -(optionally substituted C1-C6 alkyl), C3 alkyl, C4-C5 alkyl (substituted by hydroxyl), optionally substituted C2-C9 heteroarylC1-C6 alkyl; optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkylC1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; R is 0, 1 or 2; R 3 teeth, [ka] (It is). The PIKfyve inhibitors described herein also include compounds of Formula 2: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, phenyl (substituted with optionally substituted C2-C9 heteroaryl) or optionally substituted pyridimin-4-yl; R 4 and R 5 are each independently hydroxyl or methoxy). The PIKfyve inhibitors described herein also include compounds of Formula 3: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, phenyl (substituted by optionally substituted heteroaryl), optionally substituted indazol-1-yl or optionally substituted indazol-2-yl; R 4 is hydroxyl, 4-pyridinon-1-yl, -O-pyridin-3-yl or CHOH, R 3 is pyridin-4-yl or morpholin-1-yl). The PIKfyve inhibitors described herein also include compounds of Formula 4: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is phenyl (optionally substituted with methoxy or optionally substituted heteroaryl) or optionally substituted pyrazol-1-yl; R 3 is morpholin-1-yl or piperidin-1-yl, R 2 teeth, [ka] and R A is ethyl, 2-hydroxy-ethyl or [ka] (It is). The PIKfyve inhibitors described herein also include compounds of Formula 5: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 6 is hydrogen or methyl, R 7 is optionally substituted phenoxy, optionally substituted benzyloxy or optionally substituted amine).

[0190] The PIKfyve inhibitors described herein also include compounds of Formula 6: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or -N(R 1A )N=C(R 1B )2). The PIKfyve inhibitors described herein also include compounds of Formula 7: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 8 is hydrogen or methoxy, R 9 is hydrogen or phenyl, R 10 is hydrogen or phenyl).

[0191] The PIKfyve inhibitors described herein also include compounds of Formula 8: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 11 is hydrogen or phenyl).

[0192] The PIKfyve inhibitors described herein also include compounds of formula 9: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R12 is hydrogen, methoxy or CH2OH, R 13 is hydrogen, methoxy, C3 cycloalkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C6 alkyl; R 14 is hydrogen or C3 cycloalkoxy or optionally substituted C2-C9 heteroaryl; R 15 is hydrogen or hydroxyl, R 2 is hydrogen, pyridin-4-yl, [ka] and R 3 teeth, [ka] (It is).

[0193] The PIKfyve inhibitors described herein also include compounds of formula 10: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] and R 16 is hydrogen or pyridin-3-yl, R 2 is pyridin-4-yl or hydrogen).

[0194] The PIKfyve inhibitors described herein also include compounds of formula 11: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X 1 is O or CH2, R 1 is -N(R 1A )N=C(R 1B )2).

[0195] The PIKfyve inhibitors described herein also include compounds of formula 12: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is).

[0196] Exemplary PIKfyve inhibitors described herein also include compounds of Formula 13: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is -N(R 1A )N=C(R 1B )2).

[0197] The PIKfyve inhibitors described herein also include compounds of formula 14: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 17 is optionally substituted C6 to C 10 Aryl C1-C6 alkyl; optionally substituted C6-C 10 heteroaryl C1-C6 alkyl; -NH2, optionally substituted C3-C8 cycloalkyl; or optionally substituted C2-C9 heteroaryl; R18 is hydrogen or optionally substituted C1-C6 alkyl, R A is methyl or ethyl, R 2 is pyridin-4-yl or hydrogen).

[0198] The PIKfyve inhibitors described herein also include compounds of formula 15: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 19 is an optionally substituted amino, an optionally substituted C2-C9 heterocycle, or an optionally substituted C2-C9 heteroaryl; R H and R 20 together with the atom to which they are attached to form oxo, R 20 is hydrogen or R 20 and R H together with the atom to which they are attached to form an oxo).

[0199] The PIKfyve inhibitors described herein also include compounds of formula 16: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 21 is hydrogen or R 21 and R H1 together with the atom to which they are attached to form oxo, R H1 is hydrogen or R H1 and R 21 together with the atom to which they are attached to form an oxo).

[0200] The PIKfyve inhibitors described herein also include compounds of formula 17: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted C6 to C 10 pyrazol-1-yl disubstituted by aryl; optionally substituted C1-C6 heteroalkyl; optionally substituted C1-C6 alkyl; optionally substituted C2-C9 heteroaryl, halo, hydroxy, optionally substituted C3-C8 cycloalkyl or optionally substituted C1-C6 alkyl; R 3 teeth, [ka] and R A is ethyl, 2-hydroxy-ethyl, methyl, [ka] and R 2 is hydrogen, methyl, ethyl, halo, pyridin-3-yl, pyridin-4-yl, cyclopropyl, [ka] or R 2 and R A together with the atoms to which they are attached form an optionally substituted C4 heterocyclyl).

[0201] The PIKfyve inhibitors described herein also include compounds of formula 18: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted triazolyl; R Ais methyl, ethyl or cyclopropyl).

[0202] The PIKfyve inhibitors described herein also include compounds of formula 19: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted indazolyl or optionally substituted 4,5,6,7-tetrahydrotriazaindenyl).

[0203] The PIKfyve inhibitors described herein also include compounds of formula 20: [ka] or a pharmaceutically acceptable salt thereof (wherein X is S or NR A and R 22 is hydrogen or phenyl, R 23 is hydrogen or methyl, R 2 is pyrazol-3-yl, pyridin-4-yl or 4-phenyl-pyrazol-1-yl, R A is methyl).

[0204] The PIKfyve inhibitors described herein also include compounds of formula 21: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 22 is phenyl, pyridin-2-yl, or R 22 and R H2 together with the atom to which they are attached to form oxo, R H2 is hydrogen or R H2and R 22 together with the atom to which they are attached to form oxo, R 23 is hydrogen or R 23 and R H3 together with the atom to which they are attached to form oxo, R H3 is hydrogen or R H3 and R 23 together with the atom to which they are attached to form an oxo).

[0205] The PIKfyve inhibitors described herein also include compounds of formula 22: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is).

[0206] The PIKfyve inhibitors described herein also include compounds of formula 23: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is).

[0207] The PIKfyve inhibitors described herein also include compounds of Formula 24: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 24 is methoxy, methyl or hydroxyl, RA is methyl or ethyl).

[0208] The PIKfyve inhibitors described herein also include compounds of formula 25: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazolyl, optionally substituted pyrimidin-3-yl or optionally substituted pyridin-4-yl; R A is methyl or ethyl, R 2 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C1-C9 heterocyclyl; R 3 teeth, [ka] (It is).

[0209] The PIKfyve inhibitors described herein also include compounds of formula 26: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or phenyl substituted with an optionally substituted C2-C9 heteroaryl; R 25 and R 26 together with the atoms to which they are attached form a C3-C5 heterocyclyl substituted by hydroxyl).

[0210] The PIKfyve inhibitors described herein also include compounds of formula 27: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-5-yl, or phenyl (substituted with methoxy or C3-C8 cycloalkoxy).

[0211] The PIKfyve inhibitors described herein also include compounds of formula 28: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl). The PIKfyve inhibitors described herein also include compounds of formula 29: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl or optionally substituted pyrazol-5-yl; R 3 is morpholin-1-yl or piperidin-1-yl, R A is methyl or ethyl, R 2 teeth, [ka] (It is).

[0212] The PIKfyve inhibitors described herein also include compounds of formula 30: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted C2-C9 heterocyclyl or C6-C 10 and pyrazolyl monosubstituted by aryl.

[0213] The PIKfyve inhibitors described herein also include compounds of formula 31: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted pyrazol-1-yl or pyrimidin-4-yl optionally substituted with an optionally substituted C1-C6 alkyl; R A is methyl or difluoromethyl, R 2 is pyridin-4-yl or [ka] (It is).

[0214] The PIKfyve inhibitors described herein also include compounds of formula 32: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R A teeth, [ka] (It is).

[0215] The PIKfyve inhibitors described herein also include compounds of formula 33: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] (It is).

[0216] The PIKfyve inhibitors described herein also include compounds of formula 34: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 27 is hydrogen, tetrahydropyran-3-yl or tetrahydropyran-4-yl, R 28 is hydrogen, methoxy, phenyl, methyl, difluoromethyl, optionally substituted cyclobutyl; R 15 is hydrogen or methoxy, R 2 is pyridin-4-yl or -O-pyridin-4-yl).

[0217] The PIKfyve inhibitors described herein also include compounds of formula 35: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 79 is an optionally substituted C2-C9 heterocyclyl or an optionally substituted C6-C 10 (aryl).

[0218] The PIKfyve inhibitors described herein also include compounds of formula 36: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is optionally substituted 4,5-dihydro-pyrazol-1-yl, optionally substituted benzopiperidin-7-yl, optionally substituted 1,2,3,4-tetrahydroquinolin-7-yl, optionally substituted imidazol-2-yl, optionally substituted piperidin-1-yl or optionally substituted 1,2,4-triazol-3-yl, optionally substituted pyrazol-4-yl, optionally substituted 1,3,4-oxadiazol-2-yl or optionally substituted pyridin-3-yl, R A is methyl or ethyl).

[0219] The PIKfyve inhibitors described herein also include compounds of formula 37: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 C2-C9 heteroaryl, C6-C 10 pyrazol-5-yl optionally substituted with aryl, C3-C8 cycloalkyl, or C3-C8 cycloalkylC1-C6 alkyl; R A is methyl or ethyl).

[0220] The PIKfyve inhibitors described herein also include compounds of formula 38: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is an optionally substituted C2-C9 heteroaryl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C2 alkyl or an optionally substituted C6-C 10 pyrazol-3-yl substituted by aryl C1-C6 alkyl; RA is methyl or ethyl).

[0221] The PIKfyve inhibitors described herein also include compounds of formula 39: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is C1-C6 alkyl or C6-C 10 aryl-disubstituted pyrazol-3-yl).

[0222] The PIKfyve inhibitors described herein also include compounds of formula 40: [ka] or a pharmaceutically acceptable salt thereof wherein Y is CH or N; X is O or S; R 1 is an optionally substituted morpholin-1-yl, an optionally substituted pyrimidin-4-yl, -N(R 1A )N=C(R 1B ) 2, optionally substituted pyrazol-3-yl or optionally substituted indazol-4-yl; R 2 is hydrogen or methyl, R 30 is optionally substituted pyridin-4-yl, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-1-yl or C2-C9 heterocyclylC1-C6 alkyl (substituted by —S(O)2CH3).

[0223] The PIKfyve inhibitors described herein also include compounds of formula 41: [ka] or a pharmaceutically acceptable salt thereof (wherein Y is S or NR A and R 1 is an optionally substituted pyrimidin-4-yl; R A is optionally substituted C1-C6 alkyl).

[0224] The PIKfyve inhibitors described herein also include compounds of formula 42: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X 2 and X 3 are each independently N or CR 32 and R 31 is an optionally substituted C2-C9 heteroaryl; R 32 is an optionally substituted C2-C9 heteroaryl).

[0225] The PIKfyve inhibitors described herein also include compounds of formula 43: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 33 is an optionally substituted amino; R 34 is an optionally substituted C2-C9 heteroaryl).

[0226] The PIKfyve inhibitors described herein also include compounds of formula 44: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 35 and R36 are each independently an optionally substituted C2-C9 heteroaryl).

[0227] The PIKfyve inhibitors described herein also include compounds of formula 45: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 37 is an optionally substituted C2-C9 heteroaryl).

[0228] The PIKfyve inhibitors described herein also include compounds of formula 46: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 38 is optionally substituted C6 to C 10 is aryl, R 39 is optionally substituted C2-C9 heteroaryl C1-C6 alkyl).

[0229] The PIKfyve inhibitors described herein also include compounds of formula 47: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is hydrogen, optionally substituted C2-C9 heteroaryl; optionally substituted C2-C9 heterocyclyl or C1-C3 alkyl (optionally substituted with hydroxyl, oxo or dialkylamino); R 1 is an optionally substituted pyrazol-1-yl, phenyl (optionally substituted C2-C9 heteroaryl or optionally substituted C6-C 10optionally substituted with aryl) or -N(R 1A )N=C(R 1B )2, R 3 teeth, [ka] (It is).

[0230] The PIKfyve inhibitors described herein also include compounds of formula 48: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is an optionally substituted C2-C9 heteroaryl; R 1 is -N(R 1A )N=C(R 1B )2).

[0231] The PIKfyve inhibitors described herein also include compounds of formula 49: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X is NR A , S or O, Y is CR A or N, Z is CR 2 or N, R 1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C9 heterocyclyl, optionally substituted amino, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclylC1-C6 alkyl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl; -NHNHR 1A ;-N(R 1A )N=C(R 1B )2;-C(R 1A )=NN(R 1B )2;-C(R 1A )=NOR 1A ; or -Q 1 -N(R 1C )2, Q 1 is a bond, CH or CO, R 1A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl or optionally substituted C6-C 10 aryl C1-C6 alkyl, R 1B one of which is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl, R 1B the remainder being optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; R 1C are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C2-C9 heteroaryl, or R 1Ctogether with the nitrogen atom to which they are attached form a C2-C9 heterocyclyl or a C2-C9 heteroaryl; R 2 is an optionally substituted C1-C6 alkyl, an optionally substituted C6-C 10 Aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heteroaryloxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl or optionally substituted C2-C9 heteroaryl, -QN(R 1C )2;-S(O) r -R 1A ; or -P(O)(R 1A )2 and R A are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or R 2 and R A together with the atoms to which they are attached form an optionally substituted C3-C4 heterocyclic ring, and R A the remainder, if present, is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl; r is 0, 1 or 2; R 3 teeth, [ka] (It is).

[0232] In some preferred embodiments, R 1is optionally substituted C2-C9 heteroaryl (including a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core), optionally substituted pyrimidin-6-yl, or optionally substituted benzodioxanyl. In some preferred embodiments, R 2 is optionally substituted C6 to C 10 Aryl, optionally substituted C 1~9 Heterocyclyl or optionally substituted C 1~9 In some preferred embodiments, Z is CR 2 is.

[0233] Exemplary PIKfyve inhibitors described herein also include any one of the compounds in Table 1.

[0234] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

[0235] Using the compositions and methods described herein, a patient suffering from a neurological disorder can be administered a PIKfyve inhibitor, such as a small molecule described herein, to treat the disorder and / or suppress one or more symptoms associated with the disorder. Exemplary neurological disorders that can be treated using the compositions and methods described herein include, but are not limited to, amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Guam dementia-parkinsonism-ALS complex, Huntington's disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease and hereditary inclusion body myopathy, and congenital myasthenia gravis. Neuromuscular diseases include: congenital myopathies, twitch-fasciculations syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaacs syndrome, Kearns-Sayre syndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophies, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal-bulbar muscular atrophy, spinal muscular atrophy, stiff-person syndrome, Troyer syndrome, and Guillain-Barré syndrome.

[0236] The present disclosure is based in part on the discovery that PIKfyve inhibitors, such as the agents described herein, can attenuate TDP-43 toxicity. TDP-43-promoted toxicity is associated with various neurological disorders. The discovery that PIKfyve inhibitors modulate TDP-43 aggregation provides important therapeutic benefits. Using PIKfyve inhibitors, such as those described herein, patients suffering from or at risk of developing neurological disorders can be treated in a manner that addresses the underlying molecular pathogenesis of the disease. Without being limited by mechanism, the compositions and methods described herein can be used to treat or prevent such neurological conditions, for example, by inhibiting pathology-promoting TDP-43 aggregation.

[0237] Furthermore, the compositions and methods described herein provide the beneficial feature of enabling the identification and treatment of patients likely to respond to PIKfyve inhibitor therapy. For example, in some embodiments, a patient (e.g., a human patient suffering from or at risk of developing a nervous system disease described herein, such as amyotrophic lateral sclerosis) is administered a PIKfyve inhibitor if the patient is identified as likely to respond to such a form of treatment. Thus, a patient can be identified, for example, based on susceptibility to TDP-43 aggregation. In some embodiments, a patient is identified as likely to respond to PIKfyve inhibitor treatment based on the TDP-43 isoform expressed by the patient. For example, patients expressing TDP-43 isoforms with mutations selected from, among others, Q331K, M337V, Q343R, N345K, R361S, and N390D are more likely to develop TDP-43-promoted aggregation and toxicity than patients who do not express such isoforms of TDP-43. Using the compositions and methods described herein, patients can be identified as likely to respond to PIKfyve inhibitor therapy based on their expression of such isoforms of TDP-43, and can subsequently be administered a PIKfyve inhibitor to treat or prevent one or more neurological disorders, such as one or more neurological disorders described herein. Assessment of patient response

[0238] Various methods known in the art and described herein can be used to determine whether patients with neurological disorders (e.g., patients at risk of developing TDP-43 aggregation, such as patients who express mutant forms of TDP-43 with mutations associated with increased TDP-43 aggregation and toxicity, for example, mutations selected from Q331K, M337V, Q343R, N345K, R361S and N390D) will respond favorably to PIKfyve inhibition.For example, the success of treating patients with nervous system diseases, such as amyotrophic lateral sclerosis, with PIKfyve inhibitors as described herein can be predicted by: (i) An improvement in a condition assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) or Revised ALSFRS (ALSFRS-R), such as an improvement in a patient's ALSFRS or Revised ALSFRS (ALSFRS-R) score within one day or more days, weeks, or months after administration of a PIKfyve inhibitor (e.g., within about one day to about 48 weeks (e.g., within about two days to about 36 weeks, about four weeks to about 24 weeks, about eight weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the patient's first administration of a PIKfyve inhibitor, e.g., within one day, two days, three days, four days, or more after the patient's first administration of a PIKfyve inhibitor). improvement in the patient's ALSFRS or ALSFRS-R score within 1, 5, 6, 7, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 weeks or more; (ii) an improvement in normal lung capacity, such as an improvement in normal lung capacity within 1 day or more days, weeks, or months after administration of a PIKfyve inhibitor (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the first administration of a PIKfyve inhibitor to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, Improvement in the patient's normal vital capacity within 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, or more (iii) A reduction in the response exhibited by the patient upon repeated nerve stimulation, such as a reduction observed within 1 day or more days, weeks, or months after administration of the PIKfyve inhibitor (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the initial administration of the PIKfyve inhibitor to the patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks after the initial administration of the PIKfyve inhibitor to the patient). , a decrease observed within 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 weeks or more), (iv) an improvement in muscle strength as assessed, for example, by the British Medical Research Council Muscle Testing Scale (related to measuring patient response to treatment of a nervous system disease, as described, for example, in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference), such as an improvement observed within 1 day or more days, weeks, or months after administration of a PIKfyve inhibitor (e.g., within about 1 day to about 48 weeks (e.g., about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the patient's first administration of a PIKfyve inhibitor, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, improvement observed within 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 weeks or more) (v) An improvement in quality of life, such as an improvement in a patient's quality of life, observed within one day or more days, weeks, or months after administration of a PIKfyve inhibitor, as assessed, for example, using an amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire (e.g., within about one day to about 48 weeks (e.g., within about two days to about 36 weeks, about four weeks to about 24 weeks, about eight weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the patient's first administration of a PIKfyve inhibitor, e.g., within one day, two days, three days, four days, or more weeks after the patient's first administration of a PIKfyve inhibitor). an improvement in the subject's quality of life observed within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 weeks or more; (vi) a reduction in the frequency and / or severity of muscle spasms, such as a reduction in spasm frequency and / or severity within 1 day or more days, weeks, or months after administration of a PIKfyve inhibitor (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after the initial administration of a PIKfyve inhibitor to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks after the initial administration of a PIKfyve inhibitor to a patient). , 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks or more), and / or a decrease in seizure frequency and / or severity within (vii) a reduction in TDP-43 aggregation, such as a reduction in TDP-43 aggregation within 1 day or more days, weeks, or months after administration of a PIKfyve inhibitor (e.g., within about 1 day to about 48 weeks (e.g., within about 2 days to about 36 weeks, about 4 weeks to about 24 weeks, about 8 weeks to about 20 weeks, or about 12 weeks to about 16 weeks) or more weeks after initial administration of a PIKfyve inhibitor to a patient, e.g., within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks after initial administration of a PIKfyve inhibitor to a patient). reduction in TDP-43 aggregation within 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 weeks or more). Combination preparations and their uses

[0239] The compounds of the present invention can be combined with one or more therapeutic agents, particularly those that treat or prophylactically treat any of the neurological disorders described herein. Combination therapy

[0240] The compounds of the present invention can be used alone or in combination with other drugs that treat neuropathy or symptoms related to neuropathy, or in combination with other types of treatments that treat, prevent, and / or reduce the risk of any neuropathy.In combined treatment, the dosage of one or more therapeutic compounds may be reduced from the standard dosage when administered alone.For example, dosage may be empirically determined from the combination and sequence of drugs, or may be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005).In this case, the dosage of the compounds when combined should produce therapeutic effect. Pharmaceutical Composition

[0241] The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Thus, in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0242] The compounds of the present invention may be used in the form of free base, salt, solvate, and prodrug.All forms are within the scope of the present invention.According to the method of the present invention, the described compounds or salts, solvates, or their prodrugs may be administered to patients in various forms depending on the selected administration route, as will be understood by those skilled in the art.The compounds of the present invention can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via patch, pump, or transdermal administration, and by pharmaceutical compositions formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration.Parenteral administration can be by continuous infusion over a selected period of time.

[0243] The compounds of the present invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly into the food of the diet. For oral therapeutic administration, the compounds of the present invention may be incorporated into excipients and used in the form of ingestible tablets, lozenges, capsules, elixirs, suspensions, syrups, and wafers.

[0244] The compounds of the present invention may also be administered parenterally. Solutions of the compounds of the present invention may be prepared in water suitably mixed with a surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof, with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003, 20 th ed.), and The National Formulary, published in 1999 (USP 24 NF19).

[0245] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy administration by syringe is possible.

[0246] Compositions for nasal administration can be conveniently formulated as aerosols, droplets, gels and powders.Aerosol formulations usually comprise a solution or fine suspension of an active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single-dose or multi-dose amounts in a sterile form in a sealed container, which can be in the form of a cartridge or refill for use in a spray device.Alternatively, the sealed container can be an integrated dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended to be discarded after use.When the dosage form comprises an aerosol dispenser, the dispenser contains a propellant, which can be compressed air or a compressed gas, such as an organic propellant, such as fluorochlorohydrocarbon.Aerosol dosage forms can also be in the form of a pump-action atomizer.

[0247] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0248] The compounds of the present invention can be administered to animals, e.g., humans, alone or in combination with pharmaceutically acceptable carriers described herein, the proportions of which will depend on the solubility and chemical nature of the compounds, the chosen route of administration, and standard pharmaceutical practice. Dosage

[0249] The dosage of the compounds of the present invention and / or compositions containing the compounds of the present invention can vary depending on numerous factors, including the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of symptoms, the frequency of treatment and type of concurrent treatment (if any), and the clearance rate of the compound in the treated animal. Those skilled in the art will be able to determine the appropriate dosage based on the above factors. The compounds of the present invention may be administered initially at a suitable dosage, which can be adjusted, if necessary, depending on the clinical response. In general, satisfactory results can be obtained when the compounds of the present invention are administered to humans at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as solid form). Dose ranges include, for example, between 10 and 1000 mg.

[0250] Alternatively, the dosage can be calculated using the patient's body weight. For example, the dose of the compound or pharmaceutical composition thereof administered to the patient may range from 0.1 to 50 mg / kg.

[0251] The following examples are intended to illustrate the invention. They are not intended to limit the invention in any way. [Example]

[0252] [Table 2-1] [Table 2-2] Example 1 Preparation of compounds General Scheme 1 [ka]

[0253] The appropriately substituted aryl chloride I is reacted with a appropriately substituted amine II under basic conditions (e.g., N,N-diisopropylethylamine) to give the appropriately substituted aryl chloride III. The aryl chloride III is halogenated with a bromine or iodine source (e.g., N-bromosuccinimide) to give the appropriately substituted aryl halide IV. The aryl halide IV is reacted with a appropriately substituted boronic acid V in the presence of a palladium source (e.g., 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)) to give the appropriately substituted aryl chloride VI. The aryl chloride VI is coupled with 1,1,1,2,2,2-hexamethyldistannane in the presence of a palladium source (e.g., bis(triphenylphosphine)palladium(II) dichloride) to give the appropriately substituted organostannane VII. Coupling of organostannane VII with an appropriately substituted aryl chloride VIII in the presence of a palladium source (eg, tetrakis(triphenylphosphine)palladium(0)) affords the desired purine IX. General Scheme 2 [ka]

[0254] The appropriately substituted aryl chloride I is reacted with a appropriately substituted amine II under basic conditions (e.g., triethylamine) to give the appropriately substituted aryl chloride III. The aryl chloride III is halogenated with a bromine or iodine source (e.g., N-bromosuccinimide) to give the appropriately substituted aryl halide IV. The aryl halide IV is reacted with a appropriately substituted boronic acid V in the presence of a palladium source (e.g., 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)) to give the appropriately substituted aryl chloride VI. The aryl chloride VI is coupled with a appropriately substituted pyrazole VII under basic conditions (e.g., cesium carbonate) to give the desired purine VIII. General Scheme 3 [ka]

[0255] An appropriately substituted aryl chloride I is coupled with zinc cyanide in the presence of a palladium source (e.g., tetrakis(triphenylphosphine)palladium(0)) to give an appropriately substituted aryl nitrile II. The aryl nitrile II is coupled with hydroxylamine to give an appropriately substituted oxime III. The oxime III is reacted with an appropriately substituted carboxylic acid IV in the presence of a coupling agent (e.g., HATU) to give the desired purine V. General Scheme 4 [ka]

[0256] An appropriately substituted methyl ketone I is coupled with N,N-dimethylformamide dimethyl acetal by heating to give the appropriately substituted enone II. Condensation of the enone II with hydrazine monohydrate gives the appropriately substituted pyrazole III. Reaction of the pyrazole III with an appropriately substituted aryl chloride IV under basic conditions (e.g., cesium carbonate) and / or in the presence of a palladium source (e.g., tris(dibenzylideneacetone)dipalladium) gives the desired purine V. General Scheme 5 [ka]

[0257] An appropriately substituted aryl chloride I is reacted with an appropriately substituted boronic acid or ester II in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride) to give the desired purine III. General Scheme 6 [ka]

[0258] An appropriately substituted aryl chloride I is reacted with hydrazine hydrate under heating to give the appropriately substituted hydrazine II. The hydrazine II is reacted with an appropriately substituted α-keto acid III under acidic conditions (e.g., hydrochloric acid) to give the appropriately substituted hydrazone IV. The hydrazone IV is condensed with diphenylphosphoryl azide under basic conditions (e.g., triethylamine) to give the desired purine V. Synthesis of 4-(9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 1): [ka]

[0259] Step 1: Synthesis of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine.

[0260] A solution of 2,6-dichloro-9-methyl-9H-purine (2 g, 9.85 mmol), morpholine (0.86 g, 9.85 mmol), and N,N-diisopropylethylamine (2.54 g, 19.7 mmol) in isopropanol (80 mL) was stirred at 75° C. for 16 hours. The mixture was filtered to give 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (2 g, 80%) as a white solid. LCMS (ESI) m / z: 254.1 [M+H] + .

[0261] Step 2: Synthesis of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine.

[0262] A solution of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (2 g, 7.88 mmol) and N-bromosuccinimide (2.1 g, 11.82 mmol) in DMF (40 mL) was stirred at 75° C. for 6 hours. The mixture was cooled to 20° C. and filtered. The solid was washed with ethyl acetate to give 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.75 g, 29%) as a white solid. LCMS (ESI) m / z: 332.0 / 334.0 [M+H] + .

[0263] Step 3: Synthesis of 4-(9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0264] A solution of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.75 g, 2.25 mmol), pyridin-4-ylboronic acid (0.28 g, 2.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.17 g, 0.23 mmol), and cesium carbonate (1.47 g, 4.5 mmol) in water (2 mL) and dioxane (10 mL) was stirred under argon at 80° C. for 1 hour. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was concentrated and purified by preparative HPLC (Boston C18 21 × 250 mm 10 μm column. The mobile phase was acetonitrile / 0.01% aqueous trifluoroacetic acid) to give 4-(9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (0.03 g, 5%) as a white solid.

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.9 Hz, 2H), 8.32 - 8.23 ​​(m, 3H), 4.32 (s, 4H), 3.83 (s, 3H), 3.77 (t, J = 4.8Hz, 4H). LCMS (ESI) m / z: 297.1 [M+H] + . Preparation of 7-methyl-6-(morpholin-4-yl)-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-7H-purine (compound 2): [ka]

[0266] Step 1: Preparation of 4-(2-chloro-7-methyl-7H-purin-6-yl)morpholine.

[0267] To a solution of 2,6-dichloro-7-methyl-7H-purine (4.80 g, 24 mmol) and morpholine (2.27 g, 26 mmol) in ethanol (100 mL) was added DIPEA (3.06 g, 24 mmol), and the reaction mixture was stirred at room temperature for 16 h. The formed precipitate was collected by filtration, washed with ethanol, and dried in vacuo to give 4-(2-chloro-7-methyl-7H-purin-6-yl)morpholine (5.00 g, 20 mmol, 83%) as a white solid. 1 H NMR (500 MHz, chloroform-d) δ 7.97 (s, 1H), 4.01 (s, 3H), 3.93 - 3.83 (m, 4H), 3.58 - 3.48 (m, 4H); LCMS (ESI) m / z: 254.1 [M+H] + .

[0268] Step 2: Preparation of 4-(2-chloro-8-iodo-7-methyl-7H-purin-6-yl)morpholine.

[0269] To a solution of 4-(2-chloro-7-methyl-7H-purin-6-yl)morpholine (4.50 g, 18 mmol) in tetrahydrofuran (270 mL) was added a 2.5 M solution of n-butyllithium in hexane (8.5 mL, 21 mmol) at −78° C., and the resulting mixture was stirred at −78° C. for 30 minutes. A solution of iodine (6.75 g, 27 mmol) in tetrahydrofuran (30 mL) was then added to the reaction mixture, which was warmed to −60° C. with stirring over 2 hours. A solution of saturated sodium thiosulfate (200 mL) was added to the reaction vial at −60° C., and the mixture was then extracted with ethyl acetate (2×500 mL). The organic layers were pooled, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel using a gradient of 0-5% methanol in dichloromethane to give 4-(2-chloro-8-iodo-7-methyl-7H-purin-6-yl)morpholine (2.30 g, 6.1 mmol, 34%) as a yellow solid. LCMS (ESI) m / z: 216.1 [M+H] + .

[0270] Step 3: Preparation of 4-(2-chloro-7-methyl-8-(pyridin-4-yl)-7H-purin-6-yl)morpholine.

[0271] To a solution of 4-(2-chloro-8-iodo-7-methyl-7H-purin-6-yl)morpholine (2.30 g, 6.1 mmol) in dioxane (120 mL) and water (30 mL) was added pyridin-4-ylboronic acid (0.372 g, 3.0 mmol), cesium carbonate (0.197 g, 0.61 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.219 g, 0.30 mmol), and the mixture was stirred at 100 °C under argon for 2 h. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 500 mL). The organic layers were pooled, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography through silica gel using a gradient of 0–10% methanol in dichloromethane. The product 4-(2-chloro-7-methyl-8-(pyridin-4-yl)-7H-purin-6-yl)morpholine (0.750 g, 75%) was obtained as a yellow solid. LCMS (ESI) m / z: 331.0 [M+H] + .

[0272] Step 4: Preparation of 4-(7-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-7H-purin-6-yl)morpholine.

[0273] To a solution of 4-(2-chloro-7-methyl-8-(pyridin-4-yl)-7H-purin-6-yl)morpholine (281 mg, 0.85 mmol) in dioxane (10 mL) was added 1,1,1,2,2,2-hexamethyldistannane (557 mg, 1.7 mmol) and bis(triphenylphosphine)palladium(II) dichloride (91.0 mg, 0.13 mmol). The reaction mixture was stirred at 100° C. for 2 hours, cooled to room temperature, and then a 4 M aqueous solution of potassium fluoride (50 mL) was added. The resulting reaction mixture was stirred for 30 minutes and filtered through Celite. The filtrate was extracted with dichloromethane (2×60 mL), washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product 4-(7-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-7H-purin-6-yl)morpholine (390 mg, 0.85 mmol, 100%) was obtained as a brown solid and used in the next step without further purification. LCMS (ESI) m / z: 459.0 [M+H] + .

[0274] Step 5: Preparation of 4-(7-methyl-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-7H-purin-6-yl)morpholine.

[0275] To a mixture of 4-(7-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-7H-purin-6-yl)morpholine (390 mg, 0.85 mmol), 4-chloro-2-phenylpyrimidine (194 mg, 1.0 mmol), and lithium chloride (89.0 mg, 2.13 mmol) in dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (98.0 mg, 0.085 mmol). The reaction mixture was stirred at 100° C. under argon for 16 hours. The reaction mixture was cooled to room temperature and then filtered through Celite, washing with ethyl acetate (2×30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (unless otherwise stated, crude samples were purified after dissolving in N,N-dimethylformamide. Boston pHlex ODS 10 um 21.2 × 250 mm 120A. Mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give the product 4-(7-methyl-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-7H-purin-6-yl)morpholine (14.1 mg, 0.031 mmol, 3.3%) as a white solid.

[0276] 1 H NMR (500 MHz, chloroform-d) δ 8.98 (d, J = 5.1 Hz, 1H), 8.88 (d, J = 5.1 Hz, 2H), 8.69 - 8.62 (m, 2H), 8.37 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 5.2 Hz, 2H), 7.56 - 7.48 (m, 3H), 4.12 (s, 3H), 4.05 - 3.98 (m, 4H), 3.75 (t, J = 4.6 Hz, 4H). LCMS (ESI) m / z: 451.0 [M+H] + . Synthesis of 4-(2-(2-(furan-3-yl)pyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 3): [ka]

[0277] Step 1: Synthesis of 2-(furan-3-yl)-4-methoxypyrimidine.

[0278] To a solution of furan-3-ylboronic acid (560 mg, 5 mmol), 2-chloro-4-methoxypyrimidine (725 mg, 5 mmol), and potassium carbonate (2.07 mg, 15 mmol) in dioxane (20 mL) and water (10 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (409 mg, 0.5 mmol), and the resulting mixture was stirred under argon at 100°C for 4 hours. The mixture was then concentrated and purified by flash chromatography (Biotage, 40 g silica gel, dichloromethane = 1) to give 2-(furan-3-yl)-4-methoxypyrimidine as a white solid (700 mg, 66%); LCMS: [M+H] + =177.1.

[0279] Step 2: Synthesis of 2-(furan-3-yl)pyrimidin-4-ol hydrochloride.

[0280] A mixture of 2-(furan-3-yl)-4-methoxypyrimidine (524 mg, 3.0 mmol) and hydrochloric acid (6 N, 5 mL) was stirred at 100° C. for 2 hours. The mixture was concentrated to give 2-(furan-3-yl)pyrimidin-4-ol hydrochloride (790 mg, crude) as a yellow solid. LCMS: [M+H] + =163.1.

[0281] Step 3: Synthesis of 4-chloro-2-(furan-3-yl)pyrimidine.

[0282] A mixture of 2-(furan-3-yl)pyrimidin-4-ol hydrochloride (590 mg, 3.0 mmol) in phosphorus oxychloride (5 mL) was stirred at 120 °C for 2 hours. The mixture was concentrated, and the residue was diluted with water (50 mL) and neutralized with sodium bicarbonate to pH = 8-9. The mixture was then extracted with ethyl acetate (100 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-chloro-2-(furan-3-yl)pyrimidine (600 mg, crude) as a yellow solid. LCMS: [M+H] + 180.1.

[0283] Step 4: Synthesis of 2-(furan-3-yl)-4-(trimethylstannyl)pyrimidine.

[0284] A mixture of 4-chloro-2-(furan-2-yl)pyrimidine (180 mg, 1.0 mmol), hexamethyldistannane (490 mg, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (71 mg, 0.1 mmol), and dioxane (10 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was poured into dichloromethane (200 mL), and the organic phase was washed successively with saturated aqueous potassium fluoride (100 mL), brine, and concentrated to give crude 2-(furan-2-yl)-4-(trimethylstannyl)pyrimidine (250 mg, crude) as a brown oil. LCMS: [M+H] + 310.8.

[0285] Step 5: Synthesis of 4-(2-(2-(furan-3-yl)pyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0286] To a solution of 2-(furan-3-yl)-4-(trimethylstannyl)pyrimidine (280 mg, 0.9 mmol) and 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (298 mg, 0.9 mmol) in dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol). The mixture was stirred under argon at 100° C. for 2 hours and concentrated. The resulting crude product was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% formic acid), and then further purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(2-(2-(furan-3-yl)pyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (14.2 mg, 3.2%).

[0287] 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 5.1 Hz, 1H), 8.81 (d, J = 6.0 Hz, 2H), 8.50 (s, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 6.0 Hz, 2H), 7.86 (s, 1H), 7.14 (s, 1H), 4.40 (s, 4H), 4.05 (s, 3H), 3.85 - 3.79 (m, 4H); LCMS: [M+H]+ 441.1.

[0288] Synthesis of 4-(9-ethyl-2-(5-methoxy-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 4) and 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-2-phenylpyrimidin-5-ol (compound 5): [ka]

[0289] Step 1: 4-(9-ethyl-2-(5-methoxy-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0290] A mixture of 4-chloro-5-methoxy-2-phenylpyrimidine (320 mg, 1.45 mmol), hexamethyldistannane (720 mg, 2.2 mmol), bis(triphenylphosphine)palladium(II) chloride (71 mg, 0.1 mmol), and dioxane (10 mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hours. The mixture was poured into dichloromethane (200 mL), and the organic phase was washed successively with saturated aqueous potassium fluoride (100 mL), brine, and concentrated to give crude 5-methoxy-2-phenyl-4-(trimethylstannyl)pyrimidine (500 mg) as a brown oil. 100 mg of this product was mixed with 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (80 mg, 0.23 mmol) and bis(tri-tert-butylphosphine)palladium (52 ​​mg, 0.1 mmol) in dioxane (5 mL), stirred at 100° C. for an additional 6 hours, and concentrated. The crude product thus obtained was purified by silica gel column chromatography to give 4-(9-ethyl-2-(5-methoxy-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (180 mg, 82% purity) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.85 - 8.77 (m, 2H), 8.62 (s, 1H), 8.40 (dd, J = 7.8, 1.5 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.50 - 7.41 (m, 3H), 4.49 (q, J = 7.2Hz, 2H), 4.41 (bs, 4H), 3.98 (s, 3H), 3.90 - 3.83 (m, 4H), 1.48 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 494.8 [M+H] + .

[0291] Step 2: Synthesis of 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-2-phenylpyrimidin-5-ol.

[0292] A mixture of 4-(9-ethyl-2-(5-methoxy-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (100 mg, 0.2 mmol) in hydrobromic acid (45% in acetic acid, 6 mL) was stirred for 4 hours at 100° C. The formed precipitate was collected by filtration and purified by preparative HPLC (column Xbridge 21.2×250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-2-phenylpyrimidin-5-ol (28.4 mg, 60%) as a pale yellow solid.

[0293] 1 H NMR (400 MHz, CDCl3) δ 13.43 (s, 1H), 8.85 (dd, J = 4.5, 1.6Hz, 2H), 8.71 (s, 1H), 8.55 - 8.47 (m, 2H), 7.72 (dd, J = 4.5, 1.6 Hz, 2H), 7.55 - 7.42 (m, 3H), 4.72 - 4.30 (m, 6H), 4.04 - 3.88 (m, 4H), 1.60 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 480.8 [M+H] + . Synthesis of 4-(9-ethyl-8-(1-methyl-1H-pyrazol-5-yl)-2-(2-phenylpyrimidin-4-yl)-9H-purin-6-yl)-3-methylmorpholine (compound 6): [ka]

[0294] Step 1: 4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine.

[0295] A mixture of 2,6-dichloro-9H-purine (5 g, 24.6 mmol) and 3-methylmorpholine (4 g, 39.7 mmol) in methanol (50 mL) was stirred at room temperature for 16 hours. The mixture was evaporated, and water (100 mL) was added. The aqueous layer was extracted with ethyl acetate (100 mL x 4), which was dried and concentrated to give the target compound (0.6 g, 9%) as a white solid. LCMS (ESI) m / z: 254.1 [M+H] + .

[0296] Step 2: 4-(8-Bromo-2-chloro-9H-purin-6-yl)-3-methylmorpholine.

[0297] A mixture of 4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (612 mg, 2.4 mmol) and N-bromosuccinimide (861 mg, 4.8 mmol) in acetonitrile (6 mL) was stirred at 65° C. for 16 hours. The mixture was filtered, and the filtrate was triturated with acetonitrile to give the target compound (0.5 g, 62%) as a white solid. LCMS (ESI) m / z: 334.0 [M+H] + .

[0298] Step 3: 4-(8-Bromo-2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine.

[0299] To a solution of 4-(8-bromo-2-chloro-9H-purin-6-yl)-3-methylmorpholine (440 mg, 1.32 mmol) and sodium hydride (58 mg, 1.45 mmol) in N,N-dimethylformamide (5 mL) was added iodoethane (413 mg, 2.65 mmol) under ice cooling, and the mixture was stirred at 0-25°C for 2.0 hours. The mixture was then extracted with ethyl acetate (20 mL x 2) and washed with water (10 mL x 2). The organic layer was dried over sodium sulfate and concentrated. The crude product thus obtained was purified by silica gel column chromatography (10% methanol in dichloromethane) to give the title compound (450 mg, 94%) as a white solid. LCMS (ESI) m / z: 360.0 [M+H] + .

[0300] Step 4: 4-(2-chloro-9-ethyl-8-(1-methyl-1H-pyrazol-5-yl)-9H-purin-6-yl)-3-methylmorpholine.

[0301] A mixture of 4-(8-bromo-2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine (150 mg, 0.42 mmol), potassium carbonate (86 mg, 0.625 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.042 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (173 mg, 0.83 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 16 h under nitrogen. The mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (10% methanol in dichloromethane) to give the title product as a white solid (110 mg, 72%). LCMS (ESI) m / z: 361.8 [M+H] + .

[0302] Step 4a: 2-phenyl-4-(trimethylstannyl)pyrimidine.

[0303] To a solution of 4-chloro-2-phenylpyrimidine (1 g, 5.26 mmol) in dioxane (10 mL) at 25 °C, 1,1,1,2,2,2-hexamethyldistannane (3.4 g, 10.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (370 mg, 0.52 mmol) were added, and the reaction was stirred at 100 °C for 5 hours under a full argon atmosphere. An aqueous solution of potassium fluoride (500 mL) was added, stirred, and the mixture was filtered. The filtrate was then extracted with dichloromethane (100 mL x 3). The organic layer was dried and concentrated to give the title product (1.6 g, 99%) as a brown oil. LCMS (ESI) m / z: 320.9 [M+H] + .

[0304] Step 5: 4-(9-ethyl-8-(1-methyl-1H-pyrazol-5-yl)-2-(2-phenylpyrimidin-4-yl)-9H-purin-6-yl)-3-methylmorpholine.

[0305] A mixture of 4-(2-chloro-9-ethyl-8-(1-methyl-1H-pyrazol-5-yl)-9H-purin-6-yl)-3-methylmorpholine (110 mg, 0.3 mmol), 2-phenyl-4-(trimethylstannyl)pyrimidine (145 mg, 3.3 mmol), and tetratriphenylphosphonium palladium (34 mg, 0.03 mmol) in dioxane (2 mL) was stirred under nitrogen protection at 100° C. for 16 hours. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate 20:1→10:1→5:1) to give 4-(9-ethyl-8-(1-methyl-1H-pyrazol-5-yl)-2-(2-phenylpyrimidin-4-yl)-9H-purin-6-yl)-3-methylmorpholine (30.5 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 5.1 Hz, 1H), 8.55 (dd, J = 7.2, 2.3 Hz, 2H), 8.30 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.66 - 7.50 (m, 3H), 6.93 (d, J = 2.0 Hz, 1H), 5.57 (bs, 1H), 5.17 (bs, 1H), 4.43 (q, J = 7.3 Hz, 2H), 4.25-4.05 (m, 4H), 3.84 (d, J = 7.2 Hz, 1H), 3.78 (d, J = LCMS (ESI) m / z: 482.0 [M+H] + .

[0306] Following the protocol described above, the following compounds were synthesized: [Table 3]

[0307] Synthesis of 4-(9-methyl-2-(5-methyl-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 9): [ka]

[0308] Step 1: 4-(2-(2-chloro-5-methylpyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0309] To a solution of 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (30 mg, 0.06 mmol) in dioxane (5 mL) was added 2,4-dichloro-5-methylpyrimidine (100 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium (1 mg, 0.006 mmol) at 25° C. The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 17 hours. The reaction mixture was then diluted with water (30 mL), and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the desired product (50 mg, 99%). LCMS (ESI) m / z: 423.7 [M+H] + .

[0310] Step 2: 4-(9-methyl-2-(5-methyl-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0311] A mixture of 4-(2-(2-chloro-5-methylpyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (50 mg, 0.12 mmol), phenylboronic acid (21 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (96 mg, 0.3 mmol) and cesium carbonate (96 mg, 2.5 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 85°C under an argon atmosphere for 16 hours. The mixture was concentrated and the crude product was chromatographed on silica gel (petroleum ether / ethyl acetate 20:1 → 10:1 → 5:1) to give 4-(9-methyl-2-(5-methyl-2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (40 mg, 72%) as a white solid.

[0312] 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.81 (d, J = 6.1 Hz, 2H), 8.41 (dd, J = 6.6, 3.2 Hz, 2H), 7.95 (d, J = 6.1 Hz, 2H), 7.53 (d, J = LCMS (ESI) m / z: 465.7 [M+H]+ Following the protocol described above, the following compounds were prepared: [Table 4]

[0313] The following compounds were synthesized according to the protocol described for Compound 2. [Table 5-1] [Table 5-2]

[0314] Synthesis of 4-(2-(2-cyclopropylpyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 20): [ka]

[0315] Step 1: Synthesis of 4-chloro-2-cyclopropylpyrimidine.

[0316] A solution of 2,4-dichloropyrimidine (500 mg, 3.355 mmol), cyclopropylboronic acid (288 mg, 3.355 mmol), tetrakis(triphenylphosphine)palladium (352 mg, 0.3355 mmol), and potassium carbonate (1389 mg, 10.065 mmol) in dioxane (30 mL) was stirred at 100° C. for 16 hours. Water was then added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried and concentrated, and the crude product was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give 4-chloro-2-cyclopropylpyrimidine (310 mg, 60%) as a yellow solid. LC-MS: m / z=155 (M+H). + .

[0317] Step 2: Synthesis of 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine.

[0318] A solution of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (600 mg, 1.812 mmol), 1,1,1,2,2,2-hexamethyldistannane (1185 mg, 3.625 mmol), bis(triphenylphosphine)palladium(II) dichloride (127 mg, 0.181 mmol) in dioxane (25 mL) was stirred at 100° C. for 1 hour. To the resulting mixture was added 4-chloro-2-cyclopropylpyrimidine (250 mg, 1.623 mmol), tetrakis(triphenylphosphine)palladium (170 mg, 0.162 mmol), and lithium chloride (136 mg, 3.246 mmol) in dioxane (30 mL), and the resulting mixture was stirred at 100° C. for 16 hours. It was concentrated, and the crude product was purified by silica gel column (dichloromethane:methanol 100:1 to 10:1) to give 4-(2-(2-cyclopropylpyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (6.3 mg, 1%) as a white solid.

[0319] 1 H NMR (400 MHz, CD3OD) δ 8.79-8.76 (m, 3H), 8.24(d, J = 5.2Hz, 1H), 8.02 (d, J = 4.8, 1.4Hz, 2H), 4.48(bs, 4H), 4.14(s, 3H), 3.91-3.88(m, 4H), 2.50-2.42 (m, 1H), 1.26-1.24 (m, 2H), 1.17-1.15(m, 2H); LC-MS: m / z=415.2 (M+H) + . Synthesis of 4-(9-methyl-2-(2-(piperidin-3-yl)pyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 21): [ka]

[0320] Step 1: Preparation of tert-butyl 5-(4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyrimidin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate.

[0321] A mixture of 4-(2-(2-chloropyrimidin-4-yl)-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (75 mg, 0.18 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (62 mg, 0.20 mmol), NaCO (58 mg, 0.55 mmol), and Pd(dppf)Cl (15 mg, 0.2 mmol) in DMF (8 mL) and HO (1 mL) was stirred at 80 °C for 2 h under nitrogen protection. The mixture was concentrated and purified by column chromatography (20% EA in PE) to give tert-butyl 5-(4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyrimidin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a white solid (60 mg, 59%). LCMS (ESI) m / z: 556 [M+H] + .

[0322] Step 2: Preparation of tert-butyl 3-(4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyrimidin-2-yl)piperidine-1-carboxylate.

[0323] A mixture of tert-butyl 5-(4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyrimidin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (70 mg, 0.14 mmol) and 10% Pd / C (70 mg) in MeOH (5 mL) and ethyl acetate (5 mL) was stirred at 80° C. under an atmosphere of H for 16 hours. The mixture was filtered and concentrated to give the desired product as a white solid (60 mg, 85%). LCMS (ESI) m / z: 558 [M+H] +.

[0324] Step 3: Preparation of 4-(9-methyl-2-(2-(piperidin-3-yl)pyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0325] To a solution of tert-butyl 3-(4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyrimidin-2-yl)piperidine-1-carboxylate (50 mg, 0.11 mmol) in DCM (5 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by preparative HPLC to give 4-(9-methyl-2-(2-(piperidin-3-yl)pyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (2.3 mg, 4%) as a white solid.

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 5.2 Hz, 1H), 8.81 (d, J = 5.6 Hz, 2H), 8.22 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 6.0 Hz, 2H), 4.43-4.31 (m, 4H), 4.02 (s, 3H), 3.81-3.77 (m, 4H), 3.40-3.35 (m, 1H), 3.11-2.92 (m, 3H), 2.89-2.60 (m, 1H), 2.44-2.15 (m, 1H), 2.11-1.54 (m, 3H); LCMS (ESI) m / z: 458.2 [M +H] + . Synthesis of 4-(9-(difluoromethyl)-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 22): [ka]

[0327] Step 1: Synthesis of 4-(2-chloro-9-(difluoromethyl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0328] A solution of 4-(8-bromo-2-chloro-9-(difluoromethyl)-9H-purin-6-yl)morpholine (300 mg, 0.8 mmol), pyridin-4-ylboronic acid (108 mg, 0.88 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (65 mg, 0.08 mmol), and potassium carbonate (330 mg, 2.4 mmol) in water (1.5 mL) and dioxane (15 mL) was stirred at 90° C. under argon for 16 hours. The reaction mixture was cooled and concentrated. The crude product was purified by flash chromatography (Biotage, 80 g silica gel, methanol / dichloromethane = 3% to 4%) to give the desired product 4-(2-chloro-9-(difluoromethyl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (240 mg, 73%) as a yellow solid. LCMS: (ESI) m / z 366.8 [M+H] + .

[0329] Step 2: Synthesis of 4-(9-(difluoromethyl)-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0330] To a solution of 4-chloro-2-phenylpyrimidine (92 mg, 0.5 mmol) in dioxane (10 mL), hexamethyldistannane (196 mg, 0.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol) were added. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled, and 4-(2-chloro-9-(difluoromethyl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (92 mg, 0.25 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were added to the reaction mixture, and stirring was continued at 100° C. for 16 hours. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(9-(difluoromethyl)-2-(2-phenylpyrimidin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (23.3 mg, 13%) as a white solid.

[0331] 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 5.1 Hz, 1H), 8.85 (d, J = 6.0 Hz, 2H), 8.57 (dd, J = 6.7, 3.0 Hz, 2H), 8.33 (d, J = 5.2Hz, 1H), 8.26 (t, J = 58Hz, 1H), 7.87 (d, J = 6.0 Hz, 2H), 7.66 - 7.52 (m, 3H), 4.41 (s, 4H), 3.89 - 3.74 (m, 4H); LCMS: (ESI) m / z 486.8 [M+H]+. Synthesis of 4-(9-ethyl-2-(6-methoxy-5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 24): [ka]

[0332] A solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (93 mg, 0.27 mmol), 6-chloro-3-methoxy-4-phenylpyridazine (50 mg, 0.22 mmol), bis(triphenylphosphine)palladium(II) chloride (15 mg, 0.02 mmol), and hexamethyldistannane (143 mg, 0.44 mmol) in dioxane (5 mL) was stirred at 100° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, treated with aqueous potassium fluoride (500 mL), stirred for 10 minutes, and filtered. The filtrate was extracted with dichloromethane (100 mL × 3), and the combined organic layers were concentrated. The residue was purified by flash chromatography (dichloromethane / methanol 20:1→10:1→5:1) to give 4-(9-ethyl-2-(6-methoxy-5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (5.7 mg, 5%) as a white solid.

[0333] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 6.0 Hz, 2H), 8.40 (s, 1H), 7.88 (d, J = 6.1 Hz, 2H), 7.75 (d, J = 6.4 Hz, 2H), 7.58 - 7.50 (m, 3H), 4.45 (q, J =7.2Hz, 6H), 4.35 (bs, 4H), 4.17 (s, 3H), 3.79 (s, 4H), 1.37 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 495.1 [M+H] + . Synthesis of 4-(9-ethyl-2-(4-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 25): [ka]

[0334] Step 1: Synthesis of 4-phenylpyridazin-3-ol.

[0335] To a solution of 4-chloropyridazin-3-ol (0.6 g, 4.6 mmol) and phenylboronic acid (0.56 g, 4.6 mmol) in dioxane / water (10 mL / 3 mL) was added cesium carbonate (3 g, 9.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.34 g, 0.46 mmol), and the resulting mixture was stirred at 100 °C for 2 h. The mixture was poured into ice water and extracted with ethyl acetate (15 mL × 3). The organic layer was washed with brine, dried, and evaporated to dryness. The crude product was chromatographed on silica gel (dichloromethane / methanol 10:1) to give the desired product (400 mg, 51%) as a brown solid. LCMS (ESI) m / z: 173.1 [M+H] + .

[0336] Step 2: Synthesis of 3-chloro-4-phenylpyridazine.

[0337] A solution of 4-phenylpyridazin-3-ol (0.4 g, 2.0 mmol) in phosphorus oxychloride (10 mL) was stirred at 100° C. under argon protection for 2 hours. The reaction was cooled, quenched with water (60 mL), adjusted to pH 7 with potassium carbonate, and extracted with ethyl acetate (100 mL×5). The organics were combined and concentrated to give the product as a brown solid (0.2 g, 45%). LCMS (ESI) m / z: 191.1 [M+H] + .

[0338] Step 3: Synthesis of 4-(9-ethyl-2-(4-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0339] To a solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (0.18 g, 0.52 mmol) in dioxane (7 mL) at 25° C. was added hexamethyldistannane (0.24 g, 0.73 mmol) and tetrakis(triphenylphosphine)palladium (0.06 g, 0.052 mmol), and the reaction was stirred at 100° C. under argon protection for 3 hours. The reaction mixture was cooled to 25 °C, followed by the addition of bis(tri-tert-butylphosphine)palladium(0) (0.027 g, 0.052 mmol), cesium fluoride (0.16 g, 1.4 mmol), cuprous iodide (0.01 g, 0.052 mmol), and 3-chloro-4-phenylpyridazine (0.12 g, 0.63 mmol). The resulting mixture was stirred at 100 °C under argon for an additional 16 h. The entire mixture was concentrated, and the resulting crude product was purified by preparative HPLC (SunFire C18, 4.6 × 50 mm, 3.5 μm column; Xbridge C18 3.5 μm 4.6 × 50 mm column. The mobile phase was acetonitrile / 0.1% aqueous ammonium bicarbonate) to give the desired product as an off-white solid (28.6 mg, 11.8%). 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 5.3 Hz, 1H), 8.79 (dd, J = 4.5, 1.5 Hz, 2H), 7.88 - 7.77 (m, 3H), 7.38 - 7.31 (m, 3H), 7.29 - 7.21 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.98 (s, 4H), 3.55 (s, 4H), 1.18 (t, J = 7.2Hz, 3H); LCMS (ESI) m / z: 465.1 [M+H] + . Synthesis of 4-(9-ethyl-2-(6-methyl-5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 26): [ka]

[0340] Step 1: Synthesis of 6-chloro-3-methyl-4-phenylpyridazine.

[0341] A mixture of 4,6-dichloro-3-methylpyridazine (486 mg, 3.0 mmol), phenylboronic acid (440 mg, 3.6 mmol), palladium(II) acetate (34 mg, 0.15 mmol), potassium fluoride (174 mg, 3.0 mmol), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (213 mg, 0.3 mmol), and diacetoxypalladium (70 mg, 0.10 mmol) in toluene (10 mL) and water (2 mL) was stirred at 110°C under a nitrogen atmosphere for 3 hours. The reaction mixture was then concentrated and the residue was purified by flash chromatography on silica gel (10% ethyl acetate in petroleum ether) and further by preparative HPLC (column Xbridge 21.2 x 250 mm C18, 10 um, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 6-chloro-3-methyl-4-phenylpyridazine (160 mg, 26%) as a white solid. LCMS (ESI) m / z: 204.9 / 206.9 [M+H] + .

[0342] Step 2: Synthesis of 4-(9-ethyl-2-(6-methyl-5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0343] A mixture of 4-(9-ethyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (474 ​​mg, 1.0 mmol), 6-chloro-3-methyl-4-phenylpyridazine (102 mg, 0.5 mmol) and bis(tri-tert-butylphosphine)palladium (10 mg, 0.02 mmol) in dioxane (5 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated and the crude product was purified by silica gel column chromatography (20% dichloromethane in methanol) to give 200 mg of a brown oil, which was further purified by preparative HPLC (column Xbridge 21.2 × 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-2-(6-methyl-5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (36.9 mg, 15.4%) as an off-white solid.

[0344] 1 H NMR (400 MHz, CDCl3) δ 8.82 (dd, J = 4.5, 1.5 Hz, 2H), 8.33 (s, 1H), 7.73 (dd, J = 4.5, 1.6 Hz, 2H), 7.57 - 7.49 (m, 3H), 7.48 - 7.43 (m, LCMS (ESI) m / z: 478.8 [M] + . Synthesis of 4-(9-ethyl-2-(5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 27): [ka]

[0345] Step 1: Preparation of 3-chloro-5-phenylpyridazine.

[0346] To a solution of 3,5-dichloropyridazine (600 mg, 1.0 equiv.) in toluene (10 mL) and water (5 mL), phenylboronic acid (589 mg, 1.2 equiv.), potassium fluoride (467 mg, 8.054 mmol, 2.0 equiv.), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (70 mg, 0.10 mmol), and diacetoxypalladium (70 mg, 0.10 mmol) were added. The mixture was stirred at 110 °C for 2 hours and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 5:95) to give the product as a white solid (450 mg, 74.2%).

[0347] Step 2: Preparation of 4-(9-ethyl-2-(5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0348] To a solution of 4-(9-ethyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (300 mg) in dioxane (10 mL) was added 3-chloro-5-phenylpyridazine (400 mg, 1.0 equiv.) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). The mixture was stirred at 100° C. for 16 hours and concentrated. The crude product was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2×250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(9-ethyl-2-(5-phenylpyridazin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (4 mg, 2.3%) as a white solid.

[0349] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, J = 2.2 Hz, 1H), 8.83 (s, 2H), 8.70 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 6.8 Hz, 2H), 7.90 (d, J = 5.0 Hz, LCMS (ESI) m / z: 464.9[M+H] + . Synthesis of 4-(9-ethyl-2-(6-phenylpyridazin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 28): [ka]

[0350] Step 1: Synthesis of 5-chloro-3-phenylpyridazine.

[0351] A solution of 3,5-dichloropyridazine (600 mg, 4 mmol), phenylboronic acid (488 mg, 4 mmol), palladium(II) acetate (90 mg, 0.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene (222 mg, 0.4 mmol), and cesium carbonate (3.91 g, 12 mmol) in water (3 mL) and dioxane (30 mL) was stirred under argon at 70 °C for 20 h. The resulting mixture was concentrated and purified by flash chromatography (dichloromethane / methanol = 20:1) to give 5-chloro-3-phenylpyridazine (450 mg, 47%) as a white solid. LCMS: (ESI) m / z: 190.9 [M+H] + .

[0352] Step 2: Synthesis of 4-(9-ethyl-2-(6-phenylpyridazin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0353] To a solution of 5-chloro-3-phenylpyridazine (38 mg, 0.2 mmol) and bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.04 mmol) in dioxane (10 mL) was added hexamethyldistannane (157 mg, 0.48 mmol), and the mixture was stirred at 100° C. for 4 hours and then cooled to room temperature. 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (69 mg, 0.2 mmol) and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were then added to the reaction mixture, and stirring was continued at 100° C. for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(9-ethyl-2-(6-phenylpyridazin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (49.6 mg, 36%) as a yellow solid.

[0354] 1H NMR (400MHz, DMSO-d6) δ 10.05 (s, 1H), 8.88 - 8.74 (m, 3H), 8.23 ​​(d, J = 7.6Hz, 2H), 7.87 (d, J = 4.8Hz, 2H), 7.65 - 7.56 (m, 3H), 4.54 (q, J = 7.2Hz, 2H), 4.39 (bs, 4H), 3.86 - 3.76 (m, 4H), 1.40 (t, J = 7.2 Hz,3H); LCMS: (ESI) m / z 464.8 [M+] + . Synthesis of 2-methoxy-4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)phenol (compound 29): [ka]

[0355] A mixture of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (165 mg, 0.5 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (41 mg, 0.05 mmol), and cesium carbonate (325 mg, 1.0 mmol) in water (1 mL) and dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (20% dichloromethane in methanol) and further washed with methanol (15 mL) to give 2-methoxy-4-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)phenol (116.0 mg, 0.28 mmol, 56%) as a gray solid.

[0356] 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.79 (s, 2H), 8.01 (d, J = 1.8 Hz, 1H), 7.96 - 7.88 (m, 3H), 6.87 (d, J = 8.3 Hz, 1H), 4.33 (s, 4H), 3.98 (s, 3H), 3.88 (s, 3H), 3.82 - 3.75 (m, 4H); LCMS (ESI) m / z: 418.8 [M+H] + . Following the protocol described above, the following compounds were synthesized: [Table 6-1] [Table 6-2] [Table 6-3]

[0357] Synthesis of 4-[9-ethyl-2-(1H-indazol-4-yl)-8-(4-pyridyl)purin-6-yl]morpholine (compound 43): [ka]

[0358] To a mixture of 4-[2-chloro-9-ethyl-8-(4-pyridyl)purin-6-yl]morpholine (150 mg, 435 μmol) in DMAc (2 mL) was added 1H-indazol-4-ylboronic acid (106 mg, 653 μmol), Na2CO3 (1 M in water, 1.31 mL), and Pd(PPh3)4 (50 mg, 44 μmol) under a nitrogen atmosphere, and the resulting mixture was heated at 120 °C under microwave irradiation for 30 min. After aqueous workup and extraction with ethyl acetate, the resulting crude product was purified by preparative HPLC (Phenomenex luna C18 80 x 40 mm x 3 um column; 25-43% acetonitrile in 0.04% HCl in water, 7 min gradient) to afford 4-[9-ethyl-2-(1H-indazol-4-yl)-8-(4-pyridyl)purin-6-yl]morpholine (85 mg, 46%) as a yellow solid.

[0359] 1 H NMR (400MHz, METHANOL-d4) δ 9.05 (s, 1H), 8.97 (d, J = 6.9 Hz, 2H), 8.60 (d, J = 6.8 Hz, 2H), 8.37 (d, J = 7.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.62 - 7.48 (m, 1H), 4.80 - 4.76 (m, 2H), 4.51 (bs, 4H), 3.98 - 3.84 (m, 4H), 1.65 (t, J = 7.2 Hz, 3H). LCMS (ESI for C23H22N8O) [M+H] + : 427.1. Following the protocol described above, the following compounds were synthesized: [Table 7-1] [Table 7-2]

[0360] Synthesis of 2-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)isoindolin-1-one (compound 52): [ka]

[0361] Step 1: Synthesis of 6-bromo-2-methylisoindolin-1-one.

[0362] A mixture of 6-bromoisoindolin-1-one (100 mg, 0.47 mmol), MeSO (0.1 mL, 0.71 mmol), NaOH (45% aqueous solution) (419 mg, 4.72 mmol), and BuNCl (26 mg, 0.09 mmol) in toluene (5 mL) was stirred at 80 °C for 12 min. The mixture was concentrated and purified by column chromatography (50% EA in PE) to give the desired compound as a white solid (30 mg, 60%). LCMS (ESI) m / z: 226 [M+H] + .

[0363] Step 2: Synthesis of 2-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)isoindolin-1-one.

[0364] To a solution of 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (80 mg, 0.17 mmol), 6-bromo-2-methylisoindolin-1-one (47 mg, 0.21 mmol), and LiCl (26 mg, 0.51 mmol) in dioxane (10 mL) was added Pd(PPh) (25 mg, 0.02 mmol), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was then concentrated and purified by preparative HPLC to give the desired product (6 mg, 10%) as a yellow solid.

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 5.2 Hz, 1H), 8.70-8.66 (m, 2H), 7.93 (d, J = 5.6 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 4.53 (s, 2H), 4.40-4.33 (m, 4H), 4.03 (s, 3H), 4.02-3.82 (m, 4H), 3.11 (s, 3H); LCMS (ESI) m / z: 442.2 [M +H] + . Synthesis of 4-(9-ethyl-2-(pyridazin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 53): [ka]

[0366] A mixture of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (86 mg, 0.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (60 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), tricyclohexylphosphine (14 mg, 0.05 mmol), and cesium carbonate (163 mg, 0.5 mmol) in dimethyl sulfoxide (4 mL) was stirred at 100° C. under a nitrogen atmosphere for 6 hours. The mixture was purified by preparative HPLC (column Xbridge 21.2 × 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-2-(pyridazin-4-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (21.0 mg, 21.6) as a grey solid.

[0367] 1H NMR (400 MHz, CDCl3) δ 10.17 (dd, J = 2.1, 1.3 Hz, 1H), 9.32 (dd, J = 5.3, 1.2 Hz, 1H), 8.83 (dd, J = 4.5, 1.6 Hz, 2H), 8.42 (dd, J = 5.3, 2.2 LCMS (ESI) m / z: 388.9 [M+H] + . Synthesis of 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine (compound 54): [ka]

[0368] Step 1: Preparation of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate.

[0369] To a solution of tert-butyl 7-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (622 mg, 2 mmol) in dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (765 mg, 3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol), and potassium acetate (588 mg, 6 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 16 h under nitrogen protection. The mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (petroleum ether / acetic acid ester = 10:1 to 3:1) to give tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate as a white solid (610 mg, 84.9%). LCMS (ESI) m / z: 304.2 [M + -55] + .

[0370] Step 2: Preparation of 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine.

[0371] To a solution of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (300 mg, 0.83 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (132 mg, 0.4 mmol), palladium(II) acetate (20 mg, 0.08 mmol), and sodium carbonate (124 mg, 1.2 mmol) at 25 °C. The sealed vial was stirred at 120 °C under microwave irradiation for 2 hours. The mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue (50 mg, 0.1 mmol) was mixed with dichloromethane (5 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120 A. The mobile phase was dimethyl sulfoxide / 0.1% ammonium bicarbonate) to give 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine as a white solid (17.3 mg, 13.3%).

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.6 Hz, 2H), 7.91 (d, J = 5.6 Hz, 2H), 7.62 - 7.49 (m, 2H), 6.92 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 4.34 (s, 4H), 3.96 (s, 3H), 3.79 (s, 4H), 3.21 (s, 2H), 2.71 (t, J = 5.9 Hz, 2H), 1.82 (s, 2H); LCMS (ESI) m / z: 428.0 [M+H] + . Synthesis of (5-(9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxyphenyl)methanol (compound 55): [ka]

[0373] Step 1: Synthesis of methyl 5-(9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxybenzoate.

[0374] A solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)-3-methylmorpholine (200 mg, 0.55 mmol), (4-methoxy-3-(methoxycarbonyl)phenyl)boronic acid (175 mg, 0.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.055 mmol), and cesium carbonate (357 mg, 1.1 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 80° C. under nitrogen for 16 hours. Water was then added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried and concentrated. The crude residue was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give methyl 5-(9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxybenzoate (250 mg, 92%) as a white solid. LCMS (ESI) m / z: 489.3 [M+H] + .

[0375] Step 2: Synthesis of (5-(9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxyphenyl)methanol.

[0376] To a suspension of LiAlH4 (1 mol / L in tetrahydrofuran, 0.5 mol, 0.5 mL) in tetrahydrofuran (1.5 mL) at 0 °C, a solution of methyl 5-(9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxybenzoate (50 mg, 0.1 mol) in tetrahydrofuran (0.5 mL) was carefully added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0 °C and quenched with water (0.1 mL) and aqueous sodium hydroxide solution (1 N, 0.2 mL). The reaction was allowed to warm to room temperature and stirred for 1 hour. Dichloromethane (10 mL) was then added, and the salts were filtered. The filtrate was treated with brine (5 mL) and extracted with dichloromethane (20 mL × 3). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol 20:1→10:1) to give 9-ethyl-6-(3-methylmorpholino)-8-(pyridin-4-yl)-9H-purin-2-yl)-2-methoxyphenyl)methanol (29 mg, 66%) as a white solid.

[0377] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 5.4 Hz, 2H), 8.48 (s, 1H), 8.32 (d, J = 6.7 Hz, 1H), 7.85 (d, J = 5.6 Hz, 2H), 7.05 (d, J = 8.7 Hz, 1H), 5.5 (bs, 1H), 5.12 (bs, 2H), 4.56 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 9.4 Hz, 1H), 3.95-3.70 (m, 4H), 3.74 (d, J = 9.0 Hz, 1H), 3.63 - 3.46 (m, 2H), 1.40-1.25 (m, 6H); LCMS (ESI) m / z: 461.3 [M+H] + . Synthesis of 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-8-(piperidin-4-yl)-9H-purin-6-yl)morpholine (compound 56): [ka]

[0378] Step 1: Synthesis of tert-butyl 4-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0379] A mixture of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (120 mg, 0.36 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (112 mg, 0.36 mmol), NaCO (115 mg, 1.08 mmol), and Pd(dppf)Cl (26 mg, 0.04 mmol) in dioxane (8 mL) and HO (1 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was then concentrated, and the crude product was purified by column chromatography (30% EA in PE) to give the desired compound as a white solid (100 mg, 64%). LCMS (ESI) m / z: 435 [M+H] + .

[0380] Step 2: Synthesis of tert-butyl 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-6-morpholino-9H-purin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0381] A mixture of tert-butyl 4-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.23 mmol), 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121 mg, 0.46 mmol), NaCO (73 mg, 0.69 mmol), and Pd(dppf)Cl (17 mg, 0.02 mmol) in dioxane (8 mL) and HO (1 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated, and the crude product was purified by column chromatography (30% EA in PE) to give the desired product as a white solid (80 mg, 65%). LCMS(ESI)m / z:535[M+H] + .

[0382] Step 3: Synthesis of tert-butyl 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidine-1-carboxylate.

[0383] A suspension of tert-butyl 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-6-morpholino-9H-purin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.10 mmol) and 10% Pd / C (25 mg) in MeOH (5 mL) and EA (5 mL) was stirred under a hydrogen atmosphere at 80° C. for 16 h. The mixture was then filtered and concentrated to give the desired product as a white solid (30 mg, 60%). LCMS (ESI) m / z: 537 [M+H] + .

[0384] Step 4: Synthesis of 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-8-(piperidin-4-yl)-9H-purin-6-yl)morpholine.

[0385] To a solution of tert-butyl 4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidine-1-carboxylate (30 mg, 0.10 mmol) in DCM (5 mL), TFA (2 mL) was added and the mixture was stirred at room temperature for 1 hour. It was concentrated and the crude product was purified by preparative HPLC to give the desired product as a white solid (3.6 mg, 9%).

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.86 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.30-4.25 (m, 8H), 3.77-3.75 (m, 7H), 3.33-3.30 (m, 3H), 2.97-3.00 (m, 2H), 2.04-1.93 (m, 4H); LCMS (ESI) m / z: 437.3 [M +H] + . Synthesis of 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine (compound 57): [ka]

[0387] Step 1: Preparation of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate.

[0388] To a solution of tert-butyl 7-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (622 mg, 2 mmol) in dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (765 mg, 3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol), and potassium acetate (588 mg, 6 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 16 h under nitrogen protection. The mixture was then extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (petroleum ether / acetic acid ester = 10:1 to 3:1) to give crude tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate as a white solid (610 mg, 84.9%). LCMS (ESI) m / z: 304.2 [M-55] + .

[0389] Step 2: Preparation of 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine.

[0390] To a solution of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (300 mg, 0.83 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (132 mg, 0.4 mmol), palladium(II) acetate (20 mg, 0.08 mmol), and sodium carbonate (124 mg, 1.2 mmol) at 25 °C. The sealed vial was stirred at 120 °C under microwave irradiation for 2 hours, and the resulting mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue (50 mg, 0.1 mmol) was mixed with dichloromethane (5 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120 A. The mobile phase was dimethyl sulfoxide / 0.1% ammonium bicarbonate) to give 4-(9-methyl-8-(pyridin-4-yl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)-9H-purin-6-yl)morpholine as a white solid (17.3 mg, 13.3%).

[0391] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.6 Hz, 2H), 7.91 (d, J = 5.6 Hz, 2H), 7.62 - 7.49 (m, 2H), 6.92 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 4.34 (s, 4H), 3.96 (s, 3H), 3.79 (s, 4H), 3.21 (s, 2H), 2.71 (t, J = 5.9 Hz, 2H), 1.82 (s, 2H); LCMS (ESI) m / z: 428.0 [M+H] + . Synthesis of (4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol (compound 58): [ka]

[0392] Step 1: Synthesis of methyl 3-chloro-4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)benzoate.

[0393] A solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (344 mg, 1 mmol), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (214 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and potassium carbonate (73 mg, 0.1 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 80°C under nitrogen for 16 hours. Water was then added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was dried and concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 20:1 to 3:1) to give methyl 3-chloro-4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)benzoate (280 mg, 58%) as a white solid. LCMS (ESI) m / z: 479.1 [M+H] + .

[0394] Step 2: Synthesis of methyl 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)benzoate.

[0395] A solution of methyl 3-chloro-4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)benzoate (478 mg, 1 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (312 mg, 1.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and potassium carbonate (27 mg, 2 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 80 °C under nitrogen for 16 hours. Water was then added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was dried and concentrated. The crude residue was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give methyl 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)benzoate (450 mg, 85%) as a white solid. LCMS (ESI) m / z: 525.4 [M+H] + .

[0396] Step 3: Synthesis of (4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol.

[0397] To a solution of methyl 4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)benzoate (150 mg, 0.28 mmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (1 mol / L in tetrahydrofuran, 0.56 mL, 0.56 mmol) slowly at 0° C. After the addition, the mixture was warmed to room temperature and stirred for 2 hours. Water was then added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried and concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give (4-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol (103.2 mg, 74%) as a white solid.

[0398] 1H NMR (400 MHz, DMSO-d6) δ 8.79 (dd, J = 4.5, 1.6 Hz, 2H), 7.82 (dd, J = 4.5, 1.6 Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 7.9, 1.6 Hz, 1H), 5.66 (d, J = 2.2 Hz, 1H), 5.29 (s, 1H), 4.59 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.27 - 3.80 (m, 4H), 3.79 (s, 3H), 3.64 (s, 4H), 1.25 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 497.3 [M+H] + . Synthesis of 2-(3-(1H-pyrazol-1-yl)phenyl)-9-ethyl-6,8-di(pyridin-4-yl)-9H-purine (compound 59): [ka]

[0399] Step 1: Preparation of 2-chloro-9-ethyl-6-(4-pyridyl)purine.

[0400] To a solution of 2,6-dichloro-9-ethyl-purine (9.3 g, 42.85 mmol) and 4-pyridylboronic acid (5.27 g, 42.85 mmol) in dioxane (75 mL) and HO (25 mL) was added KCO (17.76 g, 128.54 mmol) and Pd(dppf)Cl (1.57 g, 2.14 mmol, 0.05 equiv). The reaction mixture was stirred at 100 °C under nitrogen for 5 hours. The reaction mixture was then cooled to room temperature, quenched with water (75 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (75 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by flash column (ISCO 80 g silica, 0-10% methanol in dichloromethane, gradient over 20 min) to give 2-chloro-9-ethyl-6-(4-pyridyl)purine (4.89 g, 40%) as a purple solid. LCMS (ESI) m / z: 260.2 [M+H] + .

[0401] Step 2: Preparation of 2-chloro-9-ethyl-8-iodo-6-(4-pyridyl)purine.

[0402] To a solution of 2-chloro-9-ethyl-6-(4-pyridyl)purine (4.3 g, 16.56 mmol) in THF (160 mL) was added dropwise LDA (2 M, 16.56 mL) at -70 to -60 °C under nitrogen. The resulting mixture was stirred at -60 °C for 1 hour. Iodine monochloride (13.44 g, 82.79 mmol) dissolved in THF (83 mL) was then added dropwise to the above solution. The resulting reaction mixture was stirred at 20 °C for 2 hours, then quenched with 100 mL of saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was washed with saturated aqueous NaHCO (150 mL), water, and brine, then dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (ISCO 40 g silica, 50-100% ethyl acetate in petroleum ether, gradient over 20 min) to give 2-chloro-9-ethyl-8-iodo-6-(4-pyridyl)purine (2.45 g, 38%) as a brown solid. LCMS (ESI) m / z: 385.9 [M+H] + .

[0403] Step 3: Preparation of 2-chloro-9-ethyl-6,8-bis(4-pyridyl)purine.

[0404] To a solution of 2-chloro-9-ethyl-8-iodo-6-(4-pyridyl)purine (2.3 g, 5.96 mmol) in dioxane (18 mL) and HO (6 mL) was added 4-pyridylboronic acid (769 mg, 6.26 mmol), KCO (2.47 g, 17.89 mmol), and Pd(dppf)Cl (218 mg, 298 mmol). The reaction mixture was stirred at 100 °C under nitrogen for 5 h. It was cooled to room temperature, quenched with water (15 mL), and extracted with ethyl acetate (20 mL × 2). The combined organics were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ISCO 20 g silica, 0 to 10% methanol in dichloromethane, gradient over 20 min) to give 2-chloro-9-ethyl-6,8-bis(4-pyridyl)purine (1.6 g, 72%) as a yellow solid.

[0405] 1 H NMR (400 MHz, chloroform-d) δ 8.93 (br d, J = 4.6 Hz, 2H), 8.88 (br s, 2H), 8.72 (d, J = 5.5 Hz, 2H), 7.79 (d, J = 5.7 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H).

[0406] Step 4: 9-Ethyl-2-(3-pyrazol-1-ylphenyl)-6,8-bis(4-pyridyl)purine.

[0407] To a solution of 2-chloro-9-ethyl-6,8-bis(4-pyridyl)purine (120 mg, 0.36 mmol) in dioxane (10 mL) was added 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (96 mg, 0.36 mmol), Pd(PPh) (41 mg, 0.04 mmol), HO (1 mL), and KCO (148 mg, 1.07 mmol). The mixture was stirred at 80 °C for 2 h and then concentrated. The crude product was purified by preparative HPLC (Agela Durashell C18 150 × 40 10 u column; 30–60% acetonitrile in 0.05% ammonia solution in water, 8 min gradient) to give 9-ethyl-2-(3-pyrazol-1-ylphenyl)-6,8-bis(4-pyridyl)purine (52 mg, 0.12 mmol, 33%) as a pale yellow solid.

[0408] 1H NMR (400MHz, chloroform-d) δ 9.00 (s, 1H), 8.92 - 8.84 (m, 6H), 8.66 (d, J = 7.8 Hz, 1H), 8.57 - 8.55 (m, 1H), 8.02 - 7.98 (m, 3H), 7.73 (s, 1H), 7.73 - 7.69 (m, 1H), 6.63 (s, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). LCMS (ESI [M+H] for CHN) + : 445.2. Synthesis of 4-(9-methyl-2-(6-(2-methylpiperidin-4-yl)pyridin-2-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 60): [ka]

[0409] Step 1: Preparation of tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[0410] To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.5 g, 7 mmol) in tetrahydrofuran (20 mL) was slowly added lithium bis(trimethylsilyl)amide (7.7 mL, 7.7 mmol) at −70° C. The mixture was stirred at −70° C. for 0.5 hours, followed by the slow addition of a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.76 g, 7.7 mmol) in tetrahydrofuran (12 mL) at −70° C. The mixture was warmed and stirred at 20° C. for 16 hours. Ethyl acetate (50 mL) was added to the reaction mixture, which was washed with aqueous ammonium chloride (20 mL), brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography (petroleum ether / acetic acid ester=20:1) to give tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 58%) as a pale yellow oil. LCMS (ESI) m / z: 290.1 ​​[M+H-56] + .

[0411] Step 2: Preparation of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0412] To a solution of tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.45 g, 4.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.17 g, 4.62 mmol) in dioxane (25 mL) was added potassium acetate (0.82 g, 8.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.31 g, 0.42 mmol), and the resulting mixture was stirred at 100°C under nitrogen for 3 hours. The mixture was then concentrated and purified with (petroleum ether:ethyl acetate=10:1) to give tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 48%) as a white solid. LCMS (ESI) m / z: 268.2 [M+H-56] + .

[0413] Step 3: Preparation of tert-butyl 6-bromo-2'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and tert-butyl 6-bromo-6'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate.

[0414] To a solution of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.5 g, 1.55 mmol) and 2,6-dibromopyridine (0.5 g, 2.1 mmol) in DMSO / water (17 mL / 1.8 mL) was added potassium carbonate (0.64 g, 4.64 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.117 g, 0.16 mmol), and the reaction mixture was stirred at 85° C. under nitrogen for 0.5 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 2), and the organics were concentrated. The crude product was purified by SGC (petroleum ether:ethyl acetate = 10:1) to give tert-butyl 6-bromo-2'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and tert-butyl 6-bromo-6'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (410 mg, 75%) as a pale yellow oil. LCMS (ESI) m / z: 297.1 [M+H-56] + .

[0415] Step 4: Preparation of tert-butyl 6'-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and tert-butyl 2'-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate.

[0416] To a solution of tert-butyl 6-bromo-6'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and tert-butyl 6-bromo-2'-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (0.33 g, 0.72 mmol) in dioxane (8 mL) was added lithium chloride (0.06 g, 1.4 mmol), 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (0.3 g, 0.86 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.08 g, 0.072 mmol) and the reaction was stirred at 100°C under nitrogen for 4 hours. The reaction was quenched with aqueous potassium fluoride (15 mL), filtered, and extracted with dichloromethane (20 mL × 3). The pooled organic layers were concentrated, and the resulting crude product was purified by SGC (petroleum ether:ethyl acetate = 2:1) to give a mixture of tert-butyl 2'-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and tert-butyl 6'-methyl-6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (100 mg, 24%) as a yellow solid. LCMS(ESI)m / z:569.3[M+H] + .

[0417] Step 5: Preparation of tert-butyl 2-methyl-4-(6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyridin-2-yl)piperidine-1-carboxylate.

[0418] A mixture of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.085 g, 0.15 mmol) and palladium on activated carbon (10% Pd, 0.07 g) in methanol / ethyl acetate (4 mL / 4 mL) was stirred under hydrogen at 45° C. for 6 hours. The reaction was filtered and concentrated to give tert-butyl 2-methyl-4-(6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyridin-2-yl)piperidine-1-carboxylate (40 mg, 47%) as a pale yellow solid. LCMS (ESI) m / z: 571.3 [M+H] + .

[0419] Step 6: Preparation of 4-(9-methyl-2-(6-(2-methylpiperidin-4-yl)pyridin-2-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0420] A mixture of tert-butyl 2-methyl-4-(6-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)pyridin-2-yl)piperidine-1-carboxylate (40 mg, 0.07 mmol), hydrochloric acid / dioxane (4 mL), and methanol (1 mL) was stirred at 25° C. for 1 hour. The mixture was filtered and purified by preparative HPLC (SunFire C18, 4.6 × 50 mm, 3.5 μm column, Xbridge C18 3.5 μm 4.6 × 50 mm column. The mobile phase was acetonitrile / 10 mM aqueous ammonium bicarbonate) to give 4-(9-methyl-2-(6-(2-methylpiperidin-4-yl)pyridin-2-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (5.2 mg, 16%).

[0421] 1H NMR (400 MHz, DMSO) δ 8.80 (d, J = 5.6 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 5.4 Hz, 2H), 7.86 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 4.36 (s, 4H), 4.01 (s, 3H), 3.80 (s, 4H), 3.14 (d, J = 10.1 Hz, 1H), 2.93 (s, 1H), 2.79 (d, J = 11.7 Hz, 1H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 1H), 1.40-1.30 (m, 1H), 1.10-1.05 (m, 3H); LCMS (ESI) m / z: 471.3 [M+H] + . Synthesis of 8-(2-methoxypyridin-4-yl)-9-methyl-6-(piperidin-1-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-9H-purine (compound 61): [ka]

[0422] Step 1a: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole.

[0423] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194 mg, 1 mmol) in N,N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (696 mg, 1 mmol) and potassium t-butoxide (22 mg, 0.1 mmol) at 25 °C. The resulting reaction mixture was stirred at room temperature for 1 hour, then diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (250 mg, 90.5%). LCMS(ESI)m / z:277.0[M+H] + .

[0424] Step 1b: Synthesis of 4-(2-chloro-8-(2-methoxypyridin-4-yl)-9-methyl-9H-purin-6-yl)morpholine.

[0425] To a solution of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (330 mg, 1 mmol) in dioxane (9 mL) and water (1 mL) was added (2-methoxypyridin-4-yl)boronic acid (150 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and potassium carbonate (414 mg, 3 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 3 hours under an argon atmosphere. The product was then extracted with ethyl acetate (20 mL × 2), washed with water (10 mL × 2), dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (petroleum ether / acetic acid ester 3:1→1:1) to give 4-(2-chloro-8-(2-methoxypyridin-4-yl)-9-methyl-9H-purin-6-yl)morpholine as a white solid (110 mg, 30.6%). LCMS (ESI) m / z: 361.1 [M+H] + .

[0426] Step 2: Synthesis of 8-(2-methoxypyridin-4-yl)-9-methyl-6-(piperidin-1-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-9H-purine.

[0427] To a solution of 4-(2-chloro-8-(2-methoxypyridin-4-yl)-9-methyl-9H-purin-6-yl)morpholine (83 mg, 0.3 mmol) in dioxane (9 mL) and water (1 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (110 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.03 mmol), and potassium carbonate (124 mg, 0.9 mmol) at 25 °C. The resulting mixture was stirred at 100 °C for 3 hours under an argon atmosphere. The product was extracted with ethyl acetate (20 mL × 2), washed with water (10 mL × 2), dried, and concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2×250 mm 120A. The mobile phase was acetonitrile / 0.1% formic acid) to give 8-(2-methoxypyridin-4-yl)-9-methyl-6-(piperidin-1-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-9H-purine as a yellow solid (15.0 mg, 10.5%). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 5.3, 1H), 7.31 (s, 1H), 7.02 (d, J = 2.3 Hz, LCMS (ESI) m / z: 475.1 [M+H] + . Synthesis of 3-methyl-4-(9-methyl-2-(1-phenyl-1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 62): [ka]

[0428] A mixture of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)-3-methylmorpholine (200 mg, 0.58 mmol), 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (187 mg, 0.69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0.058 mmol), and potassium carbonate (473 mg, 1.45 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 85 °C for 3 hours under nitrogen protection. The mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified by preparative HPLC to give the target compound (159 mg, 60%) as a white solid.

[0429] 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 6.1 Hz, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 6.9 Hz, 2H), 7.79 (d, J = 4Hz, 2H), 7.49 (dd, J = 15.3, 7.8 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.98 - 5.43 (m, 1H), 5.46 - 4.73 (m, 1H), 4.10 (d, J = 8.1 Hz, 1H), 4.08 (s, 3H), 3.88 (s, 2H), 3.73 (t, J = 10.5 Hz, 1H), 3.61 (s, 1H), 1.49 (d, J = 6.8 Hz, 3H); LCMS (ESI) m / z: 453.1 [M+H] + . Synthesis of 4-(2-(1-(cyclobutylmethyl)-1H-pyrazol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 63): [ka]

[0430] Step 1: Synthesis of 1-(cyclobutylmethyl)-1H-pyrazole.

[0431] A mixture of 1H-pyrazole (1.36 g, 20 mmol), (bromomethyl)cyclobutane (3.576 g, 24 mmol), and cesium carbonate (13.04 g, 40 mmol) in acetonitrile (40 mL) was stirred at 90° C. for 2 hours. The reaction mixture was concentrated, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a linear gradient of 0% to 30% ethyl acetate in petroleum ether to give (2.6 g, 91%) as a yellow oil. LCMS: [M+H] + =137.3.

[0432] Step 2: Synthesis of 1-(cyclobutylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0433] To a solution of 1-(cyclobutylmethyl)-1H-pyrazole (1.36 g, 10 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (2.5 M in tetrahydrofuran, 4.4 mL, 11 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour and then cooled to −78° C. To the resulting mixture was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.23 g, 12 mmol), and the mixture was stirred at −78° C. for 15 minutes. The reaction mixture was then warmed to 0° C. over 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane (80 mL×2). The organic fraction was washed with water (50 mL x 2), dried over sodium sulfate, and concentrated in vacuo to give the product 1-(cyclobutylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.2 g, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS: [M+H] + =263.3.

[0434] Step 3: Synthesis of 4-(2-(1-(cyclobutylmethyl)-1H-pyrazol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0435] A solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (69 mg, 0.2 mmol), 1-(cyclobutylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (157 mg, 0.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (16 mg, 0.02 mmol), and cesium carbonate (261 mg, 0.8 mmol) in water (1 mL) and dioxane (10 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(2-(1-(cyclobutylmethyl)-1H-pyrazol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (36.1 mg, 32.5%) as a white solid.

[0436] 1H NMR (400MHz, DMSO-d6) δ 8.80 (d, J = 5.9Hz, 2H), 7.83 (d, J = 6.0Hz, 2H), 7.47 (d, J = 1.8Hz, 1H), 6.97 (d, J = 1.8Hz, 1H), 4.86 (d, J = 7.2Hz, 2H), 4.40 (q, J = 7.2Hz, 2H), 4.29 (bs, 4H), 3.84 - 3.72 (m, 4H), 2.85 (dd, J = 15.0, 7.4Hz, 1H), 1.95 - 1.78 (m, 6H), 1.39 (t, J = 7.1 Hz, 3H); LCMS: (ESI) m / z: 445.2 [M+H] + . Following the protocol described above, the following compounds were synthesized: [Table 8-1] [Table 8-2] [Table 8-3]

[0437] Preparation of 9-methyl-6-(morpholin-4-yl)-2-(1-phenyl-1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purine (compound 77): [ka]

[0438] A mixture of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (100 mg, 0.30 mmol), 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (105 mg, 0.39 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (49.0 mg, 0.060 mmol), and cesium carbonate (293 mg, 0.90 mmol) in water (2 mL) and DMSO (8 mL) was stirred at 130 °C under argon for 3 hours. The mixture was filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was further diluted with water (50 mL), and the layers were separated. The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Boston pHlex ODS 10 μm 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 9-methyl-6-(morpholin-4-yl)-2-(1-phenyl-1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purine (64.5 mg, 0.15 mmol, 30%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.83 - 8.76 (m, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.79 - 7.74 (m, 2H), 7.53 - 7.44 (m, 2H), 7.35 - 7.29 (m, 1H), 7.23 (d, J = 2.5 Hz, 1H), 4.47 (s, 4H), 4.07 (s, 3H), 3.96 - 3.84 (m, 4H); LCMS (ESI) m / z: 439.2 [M+H] + .

[0439] Following the protocol described above, the following compounds were synthesized: [Table 9]

[0440] Synthesis of 4-(9-ethyl-2-(5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 83): [ka]

[0441] Step 1: Synthesis of tert-butyl 3-(hydroxymethylene)-4-oxopiperidine-1-carboxylate.

[0442] To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (700 mg, 3.5 mmol) in toluene (10 mL) was added potassium 2-methylpropan-2-olate (784 mg, 7.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of ethyl formate (260 mg, 3.5 mmol). The resulting mixture was stirred for an additional 16 hours, diluted with water, and extracted with ethyl acetate (150 mL × 2). The combined organic phases were dried and concentrated to give tert-butyl 3-(hydroxymethylene)-4-oxopiperidine-1-carboxylate (700 mg, crude) as an orange oil. LCMS (ESI) m / z: 249.9.2 [M+Na] + .

[0443] Step 2: Synthesis of tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.

[0444] A mixture of tert-butyl 3-(hydroxymethylene)-4-oxopiperidine-1-carboxylate (600 mg, 1.0 mmol), hydrazine hydrate (98%, 1.0 mL), and ethanol (10 mL) was stirred at 90° C. for 2 hours and then concentrated. The residue was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to give tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (200 mg, 0.9 mmol) as an off-white solid. LCMS (ESI) m / z: 223.9 [M+H] + .

[0445] Step 3: Synthesis of tert-butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.

[0446] To a suspension of sodium hydride (72 mg, 1.8 mmol) in tetrahydrofuran (5 mL) was added a solution of tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (200 mg, 0.9 mmol) in tetrahydrofuran (5 mL) at 0 °C under a nitrogen atmosphere. After stirring for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (166 mg, 1.0 mmol) was added and stirred for another 2 hours. The mixture was poured into crushed ice and extracted with ethyl acetate (100 mL × 2). The combined organic phase was concentrated. The residue was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give tert-butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (200 mg, 62.2%) as a pale yellow solid. LCMS (ESI) m / z: 354.0 [M+H] + .

[0447] Step 4: Synthesis of 5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylboronic acid.

[0448] To a solution of tert-butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (200 mg, 0.56 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of butyllithium (2.5 mol / L in tetrahydrofuran, 0.5 mL) at −78° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at this temperature for an additional 30 minutes, followed by the addition of trimethyl borate (88 mg, 0.84 mmol). The resulting mixture was stirred for an additional 1 hour at −78° C. The reaction was quenched with aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried and concentrated to give 5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylboronic acid (180 mg, crude) as a yellow oil. LCMS (ESI) m / z: 397.9 [M+H] + .

[0449] Step 5: Synthesis of tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.

[0450] A mixture of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (60 mg, 0.17 mmol), 5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylboronic acid (150 mg), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (28 mg, 0.034 mmol), water (0.5 mL), and dioxane (6 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was poured into water and extracted with dichloromethane (100 mL × 2). The combined organic phases were concentrated, and the residue was purified by silica gel column chromatography (10% dichloromethane in methanol) to give tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (160 mg, purity 64%) as a pale yellow oil. LCMS (ESI) m / z: 661.8 [M+H] + .

[0451] Step 6: Synthesis of 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-9H-purin-6-yl)morpholine.

[0452] A mixture of tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (100 mg), HCl (4 M in dioxane, 2 mL), and dichloromethane (10 mL) was stirred at 20 °C for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (50 mL × 2). The organic phase was concentrated to give 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-9H-purin-6-yl)morpholine (50 mg) as a pale yellow solid. LCMS(ESI)m / z:431.9[M+H] + .

[0453] Step 7: Synthesis of 4-(9-ethyl-2-(5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0454] A mixture of 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-9H-purin-6-yl)morpholine (40 mg), formaldehyde (40% in water, 2 mL), acetic acid (0.05 mL), and methanol (5 mL) was stirred at 20° C. for 30 minutes, followed by the addition of sodium cyanoborohydride (63 mg, 1.0 mmol). The mixture was stirred at 20° C. for an additional 30 minutes and concentrated. The crude product was purified by preparative HPLC (column Xbridge 21.2 × 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-2-(5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (13.1 mg, 0.029 mmol) as a white solid.

[0455] 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 6.0 Hz, 2H), 7.69 (dd, J = 4.5, 1.5 Hz, 2H), 4.50-4.30 (m, 6H), 3.98 (s, 2H), 3.93 - 3.81 (m, 4H), 2.95 (s, 2H), 2.87 (s, 2H), 2.60 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 445.8 [M+H] + .

[0456] Synthesis of 4-(2-(1-cyclopropyl-1H-pyrazol-3-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 84) and 4-(2-(1-cyclopropyl-1H-pyrazol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 85): [ka]

[0457] Step 1: Preparation of 4-(9-ethyl-2-(1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0458] To a solution of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (300 mg, 0.9 mmol) in dioxane (5 mL) and water (1 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (262 mg, 1.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.8 mg, 0.09 mmol), and potassium carbonate (373 mg, 2.7 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 2 hours under N protection. The mixture was extracted with dichloromethane (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (5% methanol in dichloromethane) to give 4-(9-ethyl-2-(1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (290 mg, 73.8%). LCMS (ESI) m / z: 377.0 [M+H] + .

[0459] Step 2: Preparation of 4-(2-(1-cyclopropyl-1H-pyrazol-3-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0460] To a solution of 4-(9-ethyl-2-(1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (200.0 mg, 0.52 mmol) in toluene (15 mL) was added cyclopropylboronic acid (91.4 mg, 1.06 mmol), cupric acetate (99.9 mg, 0.52 mmol), DMAP (194.9 mg, 1.59 mmol), and sodium bis(trimethylsilyl)amide (0.53 mL) at 25 °C. The reaction mixture was heated to 95 °C and stirred for 48 hours under N protection. The mixture was extracted with dichloromethane (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was DMSO / 0.1% ammonium bicarbonate) to give 4-(2-(1-cyclopropyl-1H-pyrazol-3-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (22.3 mg, 20.6%) and 4-(2-(1-cyclopropyl-1H-pyrazol-5-yl)-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (81.1 mg, 75.1%).

[0461] Compound 84: 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 7.85 (d, J = 5.4 Hz, 2H), 7.80 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 4.43 (q, J = 7.2Hz, LCMS (ESI) m / z: 417.0 [M+H] + . Compound 85: 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 5.4 Hz, 2H), 7.85 (d, J = 6.0 Hz, 2H), 7.43 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 4.69 - 4.62 (m, 1H), 4.42 (q, J = 7.1Hz, 2), 4.39 (bs, 4H), 3.83 - 3.72 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H), 1.16 - 1.10 (m, 2H), 1.05 - 0.97 (m, 2H); LCMS (ESI) m / z: 417.0 [M+H] + . Synthesis of 4-(9-ethyl-2-(3-phenyl-1H-pyrazol-5-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 86): [ka]

[0462] Step 1: Preparation of (E)-3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-phenylprop-2-en-1-one.

[0463] Acetophenone (44.3 mg, 0.37 mmol) was added to a solution of 9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purine-2-carbaldehyde (150.0 mg, 0.45 mmol) in ethanol (20 mL) while cooling in an ice bath. The mixture was slowly warmed to 24 °C and stirred for 2.0 hours. The resulting mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (5% methanol in dichloromethane) to give (E)-3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-phenylprop-2-en-1-one as a white solid (100 mg, 61.3%). LCMS(ESI)m / z:441.8[M+H]+ .

[0464] Step 2: Preparation of 4-(9-ethyl-2-(3-phenyl-1H-pyrazol-5-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0465] A mixture of (E)-3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1-phenylprop-2-en-1-one (135.0 mg, 0.3 mmol) and hydrazine hydrate (46.1 mg, 0.9 mol) in acetic acid (20 mL) was stirred at reflux for 2 hours. Hydrochloric acid (20 mL) was then added, and the mixture was stirred at reflux for 16 hours. The resulting mixture was extracted with ethyl acetate (20 mL × 2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (5% methanol in dichloromethane) to give 4-(9-ethyl-2-(3-phenyl-1H-pyrazol-5-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (15.5 mg, 11.4%).

[0466] 1 H NMR (500 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.80 (s, 2H), 7.93 (d, J = 7.7 Hz, 2H), 7.87 (d, J = 5.3 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.36 - 7.30 (m, 2H), 4.48 (q, J = 7.2Hz, 2H), 4.46 (bs, 4H), 3.83 - 3.74 (m, 4H), 1.36 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 453.0 [M+H] + . Synthesis of 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-9H-purin-6-yl)morpholine (compound 87): [ka]

[0467] Step 1: Synthesis of tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate.

[0468] A mixture of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (34 mg, 0.1 mmol), 1,1,1,2,2,2-hexamethyldistannane (65 mg, 0.2 mmol), and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) in dioxane (2 mL) was stirred at 100° C. for 2 hours. The mixture was cooled, and tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (30 mg, 0.1 mmol) and bis(tri-tert-butylphosphine)palladium (11 mg, 0.02 mmol) were added to the reaction mixture. The mixture was stirred for an additional 4 hours and concentrated. The resulting residue was purified by silica gel column chromatography (15% methanol in dichloromethane) and preparative HPLC (column Xbridge 21.2 x 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (25 mg, 9.4%) as a white solid. LCMS (ESI) m / z: 531.8 [M+H] + .

[0469] Step 2: Synthesis of 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-9H-purin-6-yl)morpholine.

[0470] A mixture of tert-butyl 3-(9-ethyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (20 mg, 0.037 mmol) and hydrochloric acid (4 M in dioxane, 2 mL) in dichloromethane (5 mL) was stirred for 2 hours at 30° C. The mixture was quenched with ammonium chloride in methanol (7.0 M, 10 mL) and concentrated. The residue was purified by silica gel column chromatography (30% dichloromethane in methanol) and preparative HPLC (column Xbridge 21.2 × 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-8-(pyridin-4-yl)-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-9H-purin-6-yl)morpholine (9.1 mg, 56.7%) as a white solid.

[0471] 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 2H), 8.18 (s, 1H), 7.69 (d, J = 5.8 Hz, 2H), 4.58 (s, 2H), 4.45-4.25 (m, 6H), 4.20 (t, J = 5.4 Hz, 2H), 3.91 - 3.83 (m, 4H), 3.36 (s, 2H), 1.49 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 431.9 [M+H] + . Synthesis of 4-(9-methyl-2-(4-methyl-1-phenyl-1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 88): [ka]

[0472] Step 1: 3-Bromo-4-methyl-1-phenyl-1H-pyrazole.

[0473] A mixture of phenylboronic acid (300 mg, 2.48 mmol), pyridine (300 mg, 3.73 mmol), copper acetate (500 mg, 2.48 mmol), and 3-bromo-4-methyl-1H-pyrazole (200 mg, 0.61 mmol) in dichloromethane (10 mL) was stirred under oxygen at 45 °C for 24 hours. The reaction mixture was diluted with water (30 mL), and the resulting mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (v / v) 5 / 1 to give the desired product as a yellow liquid (120 mg, 41%). LCMS (ESI) m / z: 238.1 / 239.0 [M+H] + .

[0474] Step 2: 4-(9-methyl-2-(4-methyl-1-phenyl-1H-pyrazol-3-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0475] To a solution of 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (30 mg, 0.06 mmol) in dioxane (5 mL) was added 3-bromo-4-methyl-1-phenyl-1H-pyrazole (16 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium (1 mg, 0.006 mmol) at 25° C. The reaction mixture was stirred at 100° C. for 17 hours under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (20 mL×2), washed with water (10 mL×2), dried, and concentrated. The crude product was purified by flash chromatography on silica gel (dichloromethane / methanol 10:1) to give the desired product (5 mg, 18.5%).

[0476] 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 6.2 Hz, 2H), 8.14 (d, J = 6.4 Hz, 2H), 7.87 - 7.76 (m, 3H), 7.48 (dd, J = 18.3, 10.6 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 4.47 (s, 4H), 4.15 (s, 3H), 3.98 - 3.85 (m, 4H), 2.55 (s, 3H); LCMS (ESI) m / z: 453.7 [M+H]+. Following the protocol described above, the following compounds were synthesized: [Table 10]

[0477] Synthesis of 1-methyl-4-(3-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one (compound 90) and 1-methyl-4-(5-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one (compound 91): [ka]

[0478] Step 1: Synthesis of 4-(5-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (Step 1PA) and 4-(3-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (Step 1PB).

[0479] To a solution of 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid (400 mg, 2.6 mmol), 3-bromo-1H-pyrazole (382 mg, 2.6 mmol) in dichloromethane (10 mL) was added cupric acetate (946 mg, 5.2 mmol) and pyridine (616 mg, 7.8 mmol). The reaction mixture was stirred under oxygen at 45° C. for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give two products as green solids: 4-(5-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (50 mg, 7%) and 4-(3-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (200 mg, 28%) were isolated.

[0480] Step 1PA: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 7.3, 2.4 Hz, 1H), 3.48 (s, 3H); LCMS: [M+H]+ = 254.

[0481] Step 1PB: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 5.5, 2.8 Hz, 3H), 3.44 (s, 3H); LCMS: [M+H]+ = 254.

[0482] Step 2: Synthesis of 1-methyl-4-(3-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one (compound 90).

[0483] To a solution of 4-(3-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (80 mg, 0.315 mmol) and 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (217 mg, 0.472 mmol) in dioxane (5 mL) was added Pd(PPh3)4 (36 mg, 0.0315 mmol), and the resulting mixture was stirred at 100 °C under argon for 16 h. The crude product formed was purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2×250 mm 120A. The mobile phase was acetonitrile / 0.1% formic acid) to give 1-methyl-4-(3-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one as a white solid (12.4 mg, 6.4%). 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 3.6 Hz, 2H), 8.70 (d, J = 2.6 Hz, 1H), 7.93 (d, J = 5.7 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 7.3, 2.4 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 4.36 (s, 4H), 3.99 (s, 3H), 3.84 - 3.74 (m, 4H), 3.47 (s, 3H); LCMS: [M+H]+ = 470.1.

[0484] Step 3: Synthesis of 1-methyl-4-(5-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one (compound 91).

[0485] To a solution of 4-(5-bromo-1H-pyrazol-1-yl)-1-methylpyridin-2(1H)-one (40 mg, 0.157 mmol) and 4-(9-methyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (109 mg, 0.236 mmol) in dry NMP (4 mL) was added Pd(PPh3)4 (18 mg, 0.0157 mmol), and the resulting mixture was stirred at 135 °C under argon for 16 h. It was concentrated and the product was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% formic acid) to give 1-methyl-4-(5-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one as a white solid (4.3 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 8.79 (d, J = 5.7 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.82 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.07 (d, LCMS [M+H]+ = 470.1. Synthesis of 4-(9-ethyl-8-(pyridin-4-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-9H-purin-6-yl)morpholine (compound 92): [ka]

[0486] Step 1: Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-4-methoxypyrimidine.

[0487] To a solution of 2-chloro-4-methoxypyrimidine (870 mg, 6.041 mmol) in dioxane (10 mL) and water (5 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 7.25 mmol), potassium carbonate (1.6 g, 12.08 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (70 mg, 0.10 mmol). The resulting mixture was stirred at 110°C for 2.0 hours. It was then cooled and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 5:95) to give the desired product as a yellow solid (860 mg, 74.2%).

[0488] Step 2: Preparation of 4-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine.

[0489] A solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4-methoxypyrimidine (860 mg, 4.42 mmol), palladium (10% on carbon, 30 mg) in methanol (10 mL) was stirred under a hydrogen atmosphere at 30° C. for 2.5 hours. The mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=75:25) to give the desired product as a yellow oil (750 mg, 87.5%).

[0490] Step 3: Preparation of 2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol.

[0491] To a solution of 4-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (750 mg, 3.86 mmol) in water (10 mL) was added hydrochloric acid (6 M, 10 mL). The reaction mixture was stirred at 100° C. for 3 hours and concentrated. The residue was diluted with water (20 mL), and then the pH was adjusted to about 4 with NaHCO. The aqueous phase was extracted with ethyl acetate (20 ml × 3). The organic layer was washed with water (20 mL) and brine (20 mL), dried over NaSO, and concentrated to give the target compound as a brown solid (500 mg).

[0492] Step 4: Preparation of 4-chloro-2-(tetrahydro-2H-pyran-4-yl)pyrimidine.

[0493] A mixture of 2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol (500 mg, 2.78 mmol) and phosphoryl trichloride (10 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated and diluted with water (20 mL). The pH was then adjusted to about 7 with 2 M NaHCO3, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 75:25) to give the desired product as a white solid (550 mg, 100%).

[0494] Step 5: Preparation of 4-(9-ethyl-8-(pyridin-4-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-9H-purin-6-yl)morpholine.

[0495] To a solution of 4-(9-ethyl-8-(pyridin-4-yl)-2-(trimethylstannyl)-9H-purin-6-yl)morpholine (150 mg) in dioxane (10 mL) was added 4-chloro-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (200 mg, 1.01 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). The mixture was stirred at 100° C. for 16 hours. It was concentrated and the crude product thus obtained was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4-(9-ethyl-8-(pyridin-4-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-9H-purin-6-yl)morpholine (32 mg, 6.7%) as a white solid.

[0496] 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 5.1 Hz, 1H), 8.82 (d, J = 6.0 Hz, 2H), 8.21 (d, J = 5.1 Hz, 1H), 7.87 (dd, J = 4.5, 1.6 Hz, 2H), 4.49 (q, J = 7.2 Hz, 2H), 4.37 (bs, 4H), 3.98 (d, J = 11.2 Hz, 2H), 3.87 - 3.77 (m, 4H), 3.52 (td, J = 11.3, 3.0 Hz, 2H), 3.20 (dt, J = 9.6, 5.5 Hz, 1H), 2.00 - 1.86 (m, 4H), 1.36 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 472.8[M+H]+. Synthesis of 9-phenyl-2,6-di(pyridin-4-yl)-9H-purine (compound 93): [ka]

[0497] To a solution of 2,6-dichloro-9-phenyl-9H-purine (264 mg, 1 mmol) in dioxane (10 mL) and water (2 mL) was added pyridin-4-ylboronic acid (123 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg, 0.1 mmol), and potassium carbonate (414 mg, 3 mmol) at 25° C. The resulting mixture was stirred under argon protection at 90° C. for 16 hours. It was then extracted with ethyl acetate (20 mL × 3) and washed with water (20 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 9-phenyl-2,6-di(pyridin-4-yl)-9H-purine (13 mg, 4%) as a yellow solid. (2-Chloro-9-phenyl-6-(pyridin-4-yl)-9H-purine was also isolated as a major product.)

[0498] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.88-8.94 (m, 4H), 8.81 (d, J = 6.0 Hz, 2H), 8.46 (d, J = 6.0 Hz, 2H), 8.06 (d, J = 7.6 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6Hz, 1H); LCMS (ESI) m / z: 351.1 [M+H]+. Synthesis of 9-methyl-6-(morpholin-4-yl)-2-[3-(pyridin-3-yl)-1H-pyrazol-1-yl]-8-(pyridin-4-yl)-9H-purine (compound 94): [ka]

[0499] Step 1: Preparation of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine.

[0500] A mixture of 2,6-dichloro-9-methyl-9H-purine (6.00 g, 30 mmol) and morpholine (6.50 g, 74 mmol) in methanol (300 mL) was stirred at room temperature for 16 hours. The mixture was filtered, and the residue was triturated with methanol. The product, 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (7.00 g, 28 mmol, 93%), was obtained as a white solid and used in the next step without further purification. LCMS (ESI) m / z: 254.1 [M+H] + .

[0501] Step 2: Preparation of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine.

[0502] A mixture of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (7.00 g, 28 mmol) and N-bromosuccinimide (8.80 g, 50 mmol) in acetonitrile (500 mL) was stirred at 65° C. for 16 hours. The mixture was filtered, and the residue was triturated with acetonitrile. The product, 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (8.00 g, 24 mmol, 87%), was isolated as a pale yellow solid and used in the next step without further purification. LCMS (ESI) m / z: 332.3 [M+H] + .

[0503] Step 3: Preparation of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0504] A mixture of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.00 mmol), pyridin-4-ylboronic acid (2.20 g, 18 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.10 g, 1.5 mmol), and potassium carbonate (5.20 g, 38 mmol) in dioxane (50 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 3 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate (3×25 mL). The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by flash column chromatography through silica gel using a gradient of 0 to 5% methanol in dichloromethane to give 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (3.00 g, 9.1 mmol, 60%) as a pale yellow solid. LCMS (ESI) m / z: 331.1 [M+H] + .

[0505] Step 4: Preparation of 4-(9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0506] A mixture of 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (100 mg, 0.30 mmol), 3-(1H-pyrazol-3-yl)pyridine (58.0 mg, 0.40 mmol), and cesium carbonate (196 mg, 0.60 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 120° C. for 16 hours. The mixture was cooled, quenched with water (10 mL), and extracted with ethyl acetate (3×10 mL). The organic layers were pooled, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Boston C18 21×250 mm 10 μm column. The mobile phase was acetonitrile / 0.01% aqueous ammonium bicarbonate). The product 4-(9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (25.6 mg, 0.058 mmol, 19%) was obtained as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.17 (d, J = 2.3 Hz, 1H), 8.82 (d, J = 2.7 Hz, 1H), 8.80 - 8.76 (m, 2H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (dt, J = 7.9, 1.9 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 4.23 (bs, 4H), 3.97 (s, 3H), 3.80 (t, J = 4.8 Hz, 4H); LCMS (ESI) m / z: 440.2 [M+H] + .

[0507] Synthesis of 4-(8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (compound 95) and 4-(9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-8-(tetrahydro-2H-pyran-4-yl)-9H-purin-6-yl)morpholine (compound 96): [ka]

[0508] Step 1: Synthesis of 4-(8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine.

[0509] A mixture of 4-(2-chloro-8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-9H-purin-6-yl)morpholine (200 mg, 0.60 mmol), 3-(1H-pyrazol-3-yl)pyridine (110 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium (56 mg, 0.06 mmol), [1,1'-biphenyl]-2-yldi-tert-butylphosphane (36 mg, 0.12 mmol), and potassium tert-butoxide (134 mg, 1.2 mmol) in dry toluene (8 mL) was stirred at 110 °C for 16 h under nitrogen protection. The mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative HPLC (crude sample was purified after dissolving in methanol as described elsewhere. Boston C18 21 × 250 mm 10 μm column. Mobile phase was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give the target compound (70 mg, 20.7%) as a white solid.

[0510] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 2.3 Hz, 1H), 8.80 (d, J = 2.7 Hz, 1H), 8.58 (dd, J = 4.8, 1.7 Hz, 1H), 8.32 (dt, J = 8.0, 2.0 Hz, 1H), 7.51 (dd, J = 8.0, 4.7 Hz, 1H), 7.16 (d, J = 2.7 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 4.50-4.30 (m, 6H), 3.90 - 3.82 (m, 5H), 3.77 (t, J = 4.8 Hz, 4H), 2.64 - 2.58 (m, 2H); LCMS (ESI) m / z: 445.1 [M+H] + .

[0511] Step 2: Synthesis of 4-(9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-8-(tetrahydro-2H-pyran-4-yl)-9H-purin-6-yl)morpholine.

[0512] A mixture of 4-(8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-2-(3-(pyridin-3-yl)-1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (30 mg, 0.067 mmol) and Pd / C (10 mg) in methanol (5 mL) and ethyl acetate (2 mL) was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC (purified after dissolving the crude sample in methanol as described elsewhere. Boston C18 21 × 250 mm 10 μm column. The mobile phase was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give the target compound (11.7 mg, 39.2%) as a white solid.

[0513] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.7 Hz, 1H), 8.58 (dd, J = 4.8, 1.7 Hz, 1H), 8.32 (dt, J = 8.0, 2.0 Hz, 1H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 4.30 (bs, 4H), 3.97 (dt, J = 11.4, 3.2 Hz, 2H), 3.82 - 3.72 (m, 7H), 3.51 (td, J = 11.2, 3.4 Hz, 2H), 3.29 - 3.25 (m, 1H), 1.93 - 1.77 (m, 4H); LCMS (ESI) m / z: 447 [M+H] + . Following the protocol described above, the following compounds were synthesized: [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0514] Synthesis of 4-(9-cyclopropyl-2-(5-cyclopropyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 115): [ka]

[0515] Step 1a: Preparation of (E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one.

[0516] A solution of 1-cyclopropylethan-1-one (840 mg, 10 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated to give the desired product (400 mg, 28%) as a yellow oil, which was used directly in Step 2.

[0517] Step 1: Synthesis of 4-(9-cyclopropyl-2-hydrazinyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0518] A mixture of 4-(2-chloro-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (200 mg, 0.561 mmol) and hydrazine hydrate (5 mL) in ethanol (20 mL) was stirred at 85° C. for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the desired product (180 mg, 91%) as a yellow solid.

[0519] Step 2: Preparation of 4-(9-cyclopropyl-2-(5-cyclopropyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0520] A mixture of 4-(9-cyclopropyl-2-hydrazinyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (45 mg, 0.128 mmol) and (£)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (400 mg, crude) in methanol (5 mL) and acetic acid (5 mL) was stirred at 85° C. for 16 hours. The reaction mixture was filtered and purified by preparative HPLC (SunFire C18, 4.6 × 50 mm, 3.5 μm column, Xbridge C18 3.5 μm 4.6 × 50 mm column. The mobile phase was acetonitrile / 10 mM aqueous ammonium bicarbonate) to give the desired product as an off-white solid (17.2 mg, 31%).

[0521] 1H NMR (400 MHz, CDCl3) δ 8.79 (dd, J = 4.6, 1.4 Hz, 2H), 7.89 (dd, J = 4.6, 1.5 Hz, 2H), 7.62 (d, J = 1.6 Hz, 1H), 6.02 (d, J = 1.1 Hz, 1H), 4.41 (bs, 4H), 3.93 - 3.75 (m, 4H), 3.59 - 3.49 (m, 1H), 2.79 - 2.65 (m, 1H), 1.22 (q, J = 6.9 Hz, 2H), 1.04 - 0.85 (m, 4H), 0.80 - 0.68 (m, 2H). LCMS (ESI) m / z: 429.1 [M+H] + . Synthesis of 1-methyl-5-(1-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-3-yl)piperidin-2-one (compound 116): [ka]

[0522] Step 1: Preparation of N-methoxy-N,1-dimethyl-6-oxopiperidine-3-carboxamide.

[0523] A mixture of 1-methyl-6-oxopiperidine-3-carboxylic acid (300 mg, 1.91 mmol), DIPEA (1.26 mL, 7.64 mmol), and HATU (1.1 g, 2.86 mmol) in THF (10 mL) was stirred at room temperature for 30 minutes, and then N,O-dimethylhydroxylamine hydrochloride (279 mg, 2.86 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography (5% MeOH in DCM) to give N-methoxy-N,1-dimethyl-6-oxopiperidine-3-carboxamide as a white solid (350 mg, 92%). LCMS (ESI) m / z: 201 [M+H] + .

[0524] Step 2: Preparation of 5-acetyl-1-methylpiperidin-2-one.

[0525] To a solution of N-methoxy-N,1-dimethyl-6-oxopiperidine-3-carboxamide (300 mg, 1.5 mmol) in THF (8 mL) was slowly added methylmagnesium bromide (0.65 mL, 1.95 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was warmed and stirred at room temperature for 16 hours. Saturated NH4Cl (3 mL) solution was added to the mixture, which was then concentrated. The crude product was purified by column chromatography (5% MeOH in DCM) to give 5-acetyl-1-methylpiperidin-2-one as a colorless oil (150 mg, 65%). LCMS (ESI) m / z: 156 [M+H] + .

[0526] Step 3: Preparation of (E)-5-(3-(dimethylamino)acryloyl)-1-methylpiperidin-2-one.

[0527] A mixture of 5-acetyl-1-methylpiperidin-2-one (80 mg, 0.52 mmol) in DMF-DMA (5 mL) was stirred at 110° C. for 16 minutes and then concentrated. The crude product thus obtained was purified by column chromatography (8% MeOH in DCM) to give (E)-5-(3-(dimethylamino)acryloyl)-1-methylpiperidin-2-one as a white solid (80 mg, 65%). LCMS (ESI) m / z: 311 [M+H] + .

[0528] Step 4: Preparation of 1-methyl-5-(1H-pyrazol-3-yl)piperidin-2-one.

[0529] A mixture of (E)-5-(3-(dimethylamino)acryloyl)-1-methylpiperidin-2-one (80 mg, 0.38 mmol) and NHNHOH (5 mL) in EtOH (5 mL) was stirred at 80° C. under a nitrogen atmosphere for 6 hours. The mixture was concentrated to give 1-methyl-5-(1H-pyrazol-3-yl)piperidin-2-one as a white solid (60 mg, 88%). LCMS (ESI) m / z: 180 [M+H] + .

[0530] Step 5: Preparation of 1-methyl-5-(1-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-3-yl)piperidin-2-one.

[0531] A mixture of 1-methyl-5-(1H-pyrazol-3-yl)piperidin-2-one (50 mg, 0.15 mmol), 4-(2-chloro-9-methyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (33 mg, 0.18 mmol) and CsCO (148 mg, 0.45 mmol) in DMAc (5 mL) was stirred at 120° C. for 16 hours. The resulting mixture was purified by preparative HPLC to give 1-methyl-5-(1-(9-methyl-6-morpholino-8-(pyridin-4-yl)-9H-purin-2-yl)-1H-pyrazol-3-yl)piperidin-2-one as a white solid (21.7 mg, 40%).

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 8.79-8.78 (m, 2H), 8.65 (d, J = 2.0 Hz, 1H), 7.91-7.90 (m, 2H), 6.50 (d, J = 2.0 Hz, 1H), 4.41-4.24 (m, 4H), 3.93(s, 3H), 3.79-3.77 (m, 4H), 3.60-3.47 (m, 2H), 3.29-3.25 (m, 1H), 2.87 (s, 3H), 2.45-2.29(m, 2H), 2.12-1.88 (m, 2H); LCMS (ESI) m / z: 474.3 [M+H] + . Synthesis of 4-(9-cyclopropyl-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 117): [ka]

[0533] Step 1: Preparation of 4-(2-chloro-9-cyclopropyl-9H-purin-6-yl)morpholine.

[0534] To a solution of 4-(2-chloro-9H-purin-6-yl)morpholine (1.0 mg, 4.18 mmol) in toluene (15 mL) was added cyclopropylboronic acid (718.1 mg, 8.37 mmol), cupric acetate (784.1 mg, 4.18 mmol), 4-dimethylaminepyridine (1.53 g, 12.54 mmol), and sodium bis(trimethylsilyl)amide (4.18 mL) at 25° C. The resulting mixture was stirred at 95° C. for 48 hours under nitrogen protection. The mixture was then extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to give 4-(2-chloro-9-cyclopropyl-9H-purin-6-yl)morpholine as a white solid (600.0 mg, 51.5%). LCMS (ESI) m / z: 280.0 [M+H] + .

[0535] Step 2: Preparation of 4-(2-chloro-9-cyclopropyl-8-iodo-9H-purin-6-yl)morpholine.

[0536] A mixture of 4-(2-chloro-9-cyclopropyl-9H-purin-6-yl)morpholine (500 mg, 1.79 mmol) and n-butyllithium (1.0 mL, 2.33 mmol) in tetrahydrofuran (10 mL) was stirred at −78° C. for 1 hour. Iodine (1.25 g, 5.37 mmol) was then added, and the mixture was warmed and stirred at 25° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (21% ethyl acetate in petroleum ether) to give 4-(2-chloro-9-cyclopropyl-8-iodo-9H-purin-6-yl)morpholine as a white solid (360.0 mg, 49.7%). LCMS (ESI) m / z: 405.8 [M+H] + .

[0537] Step 3: Preparation of 4-(2-chloro-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0538] To a solution of 4-(2-chloro-9-cyclopropyl-8-iodo-9H-purin-6-yl)morpholine (360 mg, 0.9 mmol) in dioxane (6 mL) and water (1 mL) was added pyridin-4-ylboronic acid (71.9 mg, 123.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47.5 mg, 0.09 mmol), and potassium carbonate (269.5 mg, 2.7 mmol) at 25°C. The resulting mixture was stirred at 90°C under nitrogen for 16 hours. The mixture was then extracted with dichloromethane (20 mL x 2) and washed with water (10 mL x 2). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (3% methanol in dichloromethane) to give 4-(2-chloro-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (250 mg, 78.1%). LCMS (ESI) m / z: 357.0 [M+H] + .

[0539] Step 4: Preparation of 4-(9-cyclopropyl-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine hydrochloride.

[0540] To a solution of 4-(2-chloro-9-cyclopropyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (100.0 mg, 0.28 mmol) in N,N-dimethylformamide (2 mL) was added 1H-pyrazole (28.5 mg, 0.42 mmol) and cesium carbonate (273.0 mg, 0.84 mmol), and the resulting mixture was stirred at 90° C. for 2 hours. It was then extracted with dichloromethane (20 mL×2) and washed with water (10 mL×2). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (the crude sample was purified after dissolving in N,N-dimethylformamide as described elsewhere. BOSTON pHlex ODS 10 μm 21.2×250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give the product as a white solid. The white solid was added with hydrochloric acid (3 M, 0.5 mL), recrystallized from water, and dried by lyophilization to give the product 4-(9-cyclopropyl-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine hydrochloride as a yellow solid (44.4 mg, 40.8%).

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 8.69 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 4.0 Hz, 2H), 7.80 (s, 1H), 6.56 (s, 1H), 4.34 - 3.93 (m, LCMS (ESI) m / z: 389.0 [M+H] + . Synthesis of Preparation of 4-(9-ethyl-2-(4-methyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (Compound 118): [ka]

[0542] A mixture of 4-(2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (100 mg, 0.29 mmol), 4-methyl-1H-pyrazole (30 mg, 0.37 mmol), and cesium carbonate (293 mg, 0.87 mmol) in N,N-dimethylacetamide (3 mL) was stirred at 120° C. under a nitrogen atmosphere for 16 hours. The mixture was filtered and purified by preparative HPLC (Xbridge 21.2×250 mm C18 column, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 4-(9-ethyl-2-(4-methyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine as a white solid (69.1 mg, 61.03%).

[0543] 1H NMR (400MHz, DMSO-d6) δ 8.79 (dd, J = 4.5, 1.5 Hz, 2H), 8.47 (s, 1H), 7.84 (dd, J = 4.5, 1.6 Hz,2H), 7.60 (s, 1H), 4.40 (q, J = 7.2 Hz, 6H), 3.81 - 3.73 (m, 4H), 2.11 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z: 391.0. [M+H]+. Following the protocol described above, the following compounds were synthesized: [Table 12-1] [Table 12-2]

[0544] Preparation of (S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2-(4-phenyl-1H-pyrazol-1-yl)thiazolo[5,4-d]pyrimidin-5-yl)morpholine (compound 127): [ka]

[0545] Step 1: Preparation of (R)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine.

[0546] To a stirred solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (2.00 g, 9.71 mmol) and DIPEA (3.40 mL, 19.4 mmol) in isopropanol (2.9 mL) was added (R)-3-methylmorpholine (1.08 g, 10.7 mmol) dropwise, and the resulting mixture was stirred at 25° C. for 1.5 hours. It was concentrated, the residue was triturated with water, and the solid formed was collected by filtration and dried under high vacuum to give the product (2.10 g, 80%) as a brown solid. LCMS (ESI) m / z: 271.1 [M+H] + .

[0547] Step 2: Preparation of (R)-4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine.

[0548] To a solution of (R)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine (1.2 g, 4.43 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (3.4 mL, 8.5 mmol) at −78° C. and stirred at −78° C. for 0.5 h. A solution of iodine (2.25 g, 8.86 mmol) in tetrahydrofuran (10 mL) was then added to the reaction mixture, which was stirred at −78° C. to 25° C. for an additional 2 h. The reaction mixture was then quenched with a saturated solution of sodium thiosulfate and extracted with ethyl acetate (100 mL × 2). The pooled organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated. The residue was slurried in a mixture of EA:DCM (15 mL, v / v=10:1) to give the desired compound (R)-4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine as a yellow solid (1 g, 2.52 mmol, 57%). LCMS (ESI) m / z: 397.0 [M+H] + .

[0549] Step 3: Preparation of (R)-4-(2-iodo-5-((S)-3-methylmorpholino)thiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine.

[0550] To a solution of (R)-4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholine (0.5 g, 1.26 mmol) in 1-methyl-2-pyrrolidinone (7 mL) at 25 °C, (S)-3-methylmorpholine (0.63 g, 6.3 mmol) was added, and the reaction was stirred at 90 °C for 16 h under Ar protection. The mixture was filtered and purified by preparative HPLC (SunFire C18, 4.6 x 50 mm, 3.5 µm column, Xbridge C18 3.5 µm 4.6 x 50 mm column. The mobile phase was acetonitrile / 10 mM aqueous formic acid) to give the desired product as a white solid (120 mg, 23%). LCMS (ESI) m / z: 462.2 [M+H] + .

[0551] Step 4: Preparation of (S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2-(4-phenyl-1H-pyrazol-1-yl)thiazolo[5,4-d]pyrimidin-5-yl)morpholine.

[0552] To a solution of (R)-4-(2-iodo-5-((S)-3-methylmorpholino)thiazolo[5,4-d]pyrimidin-7-yl)-3-methylmorpholino (0.08 g, 0.17 mmol) and 4-phenyl-1H-pyrazole (0.038 g, 0.26 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added potassium carbonate (0.06 g, 0.46 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.013 g, 0.09 mmol) and cuprous iodide (0.01 g, 0.05 mmol), and the resulting mixture was irradiated with stirring in a microwave at 110 °C for 1 h. The mixture was filtered and the crude product was purified by preparative HPLC (SunFire C18, 4.6 x 50 mm, 3.5 um column Xbridge C18 3.5 μm 4.6 x 50 mm column. The mobile phase was acetonitrile / 10 mM aqueous formic acid) to give the desired product (0.0128 g, 16%) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.39 (s, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 5.24 (s, 2H), 4.57 (s, 1H), 4.19 (d, J = 12.1 Hz, 1H), 3.99 (d, J = 7.9 Hz, 1H), 3.90 (d, J = 9.2 Hz, 1H), 3.81 - 3.69 (m, 3H), 3.58 (s, 2H), 3.46 - 3.37 (m, 2H), 3.14 (t, J = 11.1 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H); LCMS (ESI) m / z: 478.2 [M+H] + . Synthesis of 4-(9-((methylsulfonyl)methyl)-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 128): [ka]

[0553] Step 1: Preparation of 4-(8-bromo-2-chloro-9-((methylthio)methyl)-9H-purin-6-yl)morpholine.

[0554] To a solution of 4-(8-bromo-2-chloro-9H-purin-6-yl)morpholine (400 mg, 1.26 mmol) in acetonitrile (10 mL) was added (chloromethyl)(methyl)sulfane (183 mg, 1.89 mmol) and cesium carbonate (821 mg, 2.52 mmol). The mixture was stirred at 30° C. for 8 hours, quenched with water (15 mL), and extracted with ethyl acetate (20×3 mL). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=75:25) to give the desired product as a yellow oil (550 mg, 100%). LCMS (ESI) m / z: 377.7 / 379.6 [M+H] + .

[0555] Step 2: Preparation of 4-(8-bromo-2-chloro-9-((methylsulfonyl)methyl)-9H-purin-6-yl)morpholine.

[0556] To a solution of 4-(8-bromo-2-chloro-9-((methylthio)methyl)-9H-purin-6-yl)morpholine (550 mg, 1.45 mmol, 1.0 equiv) in ethoxyethane (10 mL) was added hydrogen peroxide in ethoxyethane (10 mL). The mixture was stirred at 50° C. for 8 hours. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (20×3 mL). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=75:25) to give the product as a white solid. (450 mg, 100%)

[0557] Step 3: Preparation of 4-(2-chloro-9-((methylsulfonyl)methyl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0558] To a solution of 4-(8-bromo-2-chloro-9-((methylsulfonyl)methyl)-9H-purin-6-yl)morpholine (450 mg, 1.10 mmol) in dioxane (10 mL) was added pyridin-4-ylboronic acid (202 mg, 1.65 mmol, 1.5 equiv), potassium carbonate (305 mg, 2.20 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (50 mg, 0.196 mmol). The resulting mixture was stirred at 90°C for 3 hours. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (20 x 3 mL). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=75:25) to give the product as a yellow oil (160 mg, 35.6%). LCMS (ESI) m / z: 408.8 [M+H] + .

[0559] Step 4: Preparation of 4-(9-((methylsulfonyl)methyl)-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine.

[0560] To a solution of 4-(2-chloro-9-((methylsulfonyl)methyl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (160 mg, 0.392 mmol) in N,N-dimethylformamide (10 mL) was added 1H-pyrazole (266 mg, 3.92 mmol) and potassium carbonate (109 mg, 0.784 mmol). The mixture was stirred at 120 °C for 3 hours and concentrated. The residue was purified by preparative HPLC (0.05% NH4HCO3 / HO:CH3CN = 5% to 95%) to give 4-(9-((methylsulfonyl)methyl)-2-(1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (57.6 mg, 35.6%) as a white solid.

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.7 Hz, 3H), 7.88 (dd, J = 4.5, 1.5 Hz, 2H), 7.80 (d, J = 0.8 Hz, 1H), 6.56 (dd, J = 2.6, 1.6 Hz, 1H), 5.88 (s, 2H), 4.75-4.00 (m, 4H), 3.80 (t, J = 4Hz, 4H), 3.23 (s, 3H); LCMS (ESI) m / z: 441.0[M+H]+. Following the protocol described above, the following compounds were synthesized: [Table 13]

[0562] Synthesis of 4-(8-(cyclohex-1-en-1-yl)-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (Compound 131) and 4-(8-cyclohexyl-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (Compound 132). [ka]

[0563] Step 1: 4-(2-chloro-8-(cyclohex-1-en-1-yl)-9-methyl-9H-purin-6-yl)morpholine.

[0564] A mixture of 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1 g, 3 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (688 mg, 3.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200 mg, 0.3 mmol), and potassium carbonate (1.1 g, 2.5 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 85°C under a nitrogen atmosphere for 16 hours. The crude product thus obtained was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate 20:1 → 10:1 → 5:1) to give 4-(2-chloro-8-(cyclohex-1-en-1-yl)-9-methyl-9H-purin-6-yl)morpholine (600 mg, 60%) as a white solid. LCMS (ESI) m / z: 333.9 [M+H] + .

[0565] Step 2: 4-(8-(cyclohex-1-en-1-yl)-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine.

[0566] A mixture of 4-(2-chloro-8-(cyclohex-1-en-1-yl)-9-methyl-9H-purin-6-yl)morpholine (70 mg, 0.21 mmol), 1H-pyrazole (28.5 mg, 0.42 mmol), and cesium carbonate (205.4 mg, 0.63 mmol) in N,N-dimethylacetamide (1 mL) was stirred for 16 hours at 140° C. The crude product was purified by flash chromatography on silica gel (dichloromethane / methanol 20:1 to 10:1) to give 4-(8-(cyclohex-1-en-1-yl)-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (25 mg, 35%) as a white solid.

[0567] 1H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 6.58 - 6.44 (m, 1H), 6.36 (dd, J = 3.8, 1.9 Hz, 1H), 4.35 (s, 4H), 3.85 - 3.80 (m, 7H), 2.52 (d, J = 2.1 Hz, 2H), 2.33 (dd, J = 6.2, 2.7 Hz, 2H), 1.88 - 1.65 (m, 4H); LCMS (ESI) m / z: 366.1 [M+H] + .

[0568] Step 3: 4-(8-cyclohexyl-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine.

[0569] A mixture of 4-(8-(cyclohex-1-en-1-yl)-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (0.1 g, 0.3 mmol), palladium on carbon (10 mg, 10%) in methanol (10 mL) was stirred under hydrogen at 85° C. for 16 hours. The crude product was purified by flash chromatography on silica gel (dichloromethane / methanol 20:1 to 10:1) to give 4-(8-cyclohexyl-9-methyl-2-(1H-pyrazol-1-yl)-9H-purin-6-yl)morpholine (64 mg, 64%) as a white solid.

[0570] 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.77 (d, J = 1.0 Hz, 1H), 6.51 (dd, J = 2.6, 1.7 Hz, 1H), 4.34 (s, 4H), 3.92 - 3.80 (m, 4H), 3.78 (s, 3H), 3.03 - 2.84 (m, 1H), 1.98 (d, J = 13.4 Hz, 2H), 1.93 - 1.84 (m, 2H), 1.78 (d, J = 12.6 Hz, 1H), 1.74 - 1.60 (m, 2H), 1.56 - 1.42 (m, 2H), 1.38 - 1.29 (m, 1H); LCMS (ESI) m / z: 368.0 M+H] + . Preparation of 3-{1-[8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-6-(morpholin-4-yl)-9H-purin-2-yl]-1H-pyrazol-3-yl}benzonitrile (compound 133): [ka]

[0571] Step 1: Preparation of (E)-3-(3-(dimethylamino)acryloyl)benzonitrile.

[0572] A mixture of 3-acetylbenzonitrile (1.50 g, 10 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred at 110° C. for 16 hours. The resulting mixture was concentrated to give (£)-3-(3-(dimethylamino)acryloyl)benzonitrile (2.00 g, 10 mmol, 100%) as a pale yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z: 201 [M+H] + .

[0573] Step 2: Preparation of 3-(1H-pyrazol-3-yl)benzonitrile.

[0574] A mixture of (E)-3-(3-(dimethylamino)acryloyl)benzonitrile (2.00 g, 10 mmol) and hydrazine monohydrate (1.50 g, 30 mmol) in ethanol (20 mL) was stirred at 80 °C for 3 h. The resulting mixture was concentrated, and the residue was purified by flash column chromatography through silica gel using a gradient of 0 to 30% ethyl acetate in petroleum ether to give 3-(1H-pyrazol-3-yl)benzonitrile (1.40 g, 8.3 mmol, 83%) as a pale yellow solid. LCMS (ESI) m / z: 170 [M+H] + .

[0575] Step 3: Preparation of 3-(1-(8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-6-morpholino-9H-purin-2-yl)-1H-pyrazol-3-yl)benzonitrile.

[0576] A mixture of 4-(2-chloro-8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-9H-purin-6-yl)morpholine (200 mg, 0.60 mmol), 3-(1H-pyrazol-3-yl)benzonitrile (128 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium (56.0 mg, 0.060 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (56.0 mg, 0.12 mmol), and cesium carbonate (392 mg, 1.2 mmol) in N,N-dimethylacetamide (8 mL) was stirred at 130 °C under nitrogen for 16 h. The mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layers were pooled, washed with water and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Boston C18 21 × 250 mm 10 μm column. The mobile phase was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give 3-(1-(8-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-6-morpholino-9H-purin-2-yl)-1H-pyrazol-3-yl)benzonitrile (80.0 mg, 0.17 mmol, 29%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.78 (d, J = 2.7 Hz, 1H), 8.38 (t, J = 1.7 Hz, 1H), 8.32 (dt, J = 8.0, 1.4 Hz, 1H), 7.85 (dt, J = 7.7, 1.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 6.57 (dd, J = 6.3, 2.1 Hz, 1H), 4.88 (q, J = 3.2 Hz, 1H), 4.47–4.15 (m, 4H), 4.10–4.03 (m, 1H). 3.98 - 3.91 (m, 1H), 3.83 - 3.71 (m, 7H), 3.31 (s, 1H), 2.22 - 2.12 (m, 2H); LCMS (ESI) m / z: 469 [M+H]+.

[0577] Following the protocol described above, the following compounds were synthesized: [Table 14-1] [Table 14-2]

[0578] Synthesis of 4,4'-(9-ethyl-2-(4-phenyl-1H-pyrazol-1-yl)-9H-purine-6,8-diyl)dimorpholine (compound 140): [ka]

[0579] Step 1: Preparation of 4-(8-bromo-2-chloro-9-ethyl-9H-purin-6-yl)morpholine.

[0580] To a solution of 4-(8-bromo-2-chloro-9H-purin-6-yl)morpholine (318 mg, 1.0 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (522 mg, 2.0 mmol). A solution of iodoethane (172 mg, 1.1 mmol) was then added, and the reaction mixture was stirred overnight. Water (10 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (36% acetic acid ester in petroleum ether) to give 4-(8-bromo-2-chloro-9-ethyl-9H-purin-6-yl)morpholine as a white solid (150 mg, 73.5%). LCMS (ESI) m / z: 348.0 [M+H] + .

[0581] Step 2: Preparation of 4,4'-(2-chloro-9-ethyl-9H-purine-6,8-diyl)dimorpholine.

[0582] To a solution of 4-(8-bromo-2-chloro-9-ethyl-9H-purin-6-yl)morpholine (640 mg, 1.86 mmol) in N,N-dimethylformamide (10 mL) was added morpholine (324 mg, 3.72 mmol) and potassium carbonate (770 mg, 5.58 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. The mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (50% acetic acid ester in petroleum ether) to give 4,4'-(2-chloro-9-ethyl-9H-purine-6,8-diyl)dimorpholine as a white solid (250 mg, 0.39%). LCMS (ESI) m / z: 353.0 [M+H] + .

[0583] Step 3: Preparation of 4,4'-(9-ethyl-2-(4-phenyl-1H-pyrazol-1-yl)-9H-purine-6,8-diyl)dimorpholine.

[0584] To a solution of 4,4'-(2-chloro-9-ethyl-9H-purine-6,8-diyl)dimorpholine (160 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was added 4-phenyl-1H-pyrazole (78 mg, 0.54 mmol) and cesium carbonate (439 mg, 1.35 mmol) at 25 °C, and the reaction mixture was stirred at 90 °C for 2 hours. The resulting mixture was extracted with ethyl acetate (20 mL × 2) and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 4,4′-(9-ethyl-2-(4-phenyl-1H-pyrazol-1-yl)-9H-purine-6,8-diyl)dimorpholine as a white solid (18.6 mg, 8.9%).

[0585] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.21 (d, J = 0.7 Hz, 1H), 7.78 (d, J=12 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.27 (s, 1H), 4.24 (s, 4H), 4.14 (d, J = 7.2 Hz, 2H), 3.83 - 3.72 (m, 8H), 3.25 - 3.18 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z: 461.0 [M+H] + .

[0586] Synthesis of 4-(9-(difluoromethyl)-2-(4-phenyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 141) and 4-(2-(4-phenyl-1H-pyrazol-1-yl)-8-(pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 142): [ka]

[0587] Step 1: Synthesis of 4-(8-bromo-2-chloro-9-(difluoromethyl)-9H-purin-6-yl)morpholine.

[0588] A mixture of potassium fluoride (174 mg, 3 mmol), 4-(8-bromo-2-chloro-9H-purin-6-yl)morpholi...

Claims

1. Compound of formula (1): 【Chemical 501】 or a pharmaceutically acceptable salt thereof [In the formula, X is NR Ａ and Y is CR Ａ or N, R １ is an optionally substituted C containing a 5-membered ring with a nitrogen atom at the 2-position relative to the bond to the core １ ~C １０ Heteroaryl; 4,5-dihydropyrazol-1-yl substituted by phenyl; optionally substituted pyrimidin-2-yl, optionally substituted pyridazin-6-yl, optionally substituted pyrimidin-4-yl; pyridin-3-yl optionally substituted by methoxy; optionally substituted indazol-1-yl; optionally substituted indazol-2-yl; optionally substituted indazol-7-yl; optionally substituted isoindolin-6-yl; optionally substituted pyridazin-5-yl; optionally substituted pyrrolidin-1-yl; optionally substituted pyrimidin-6-yl; optionally substituted piperazinyl; methoxy, optionally substituted C １ ~C ６ Alkyl, hydroxyl, optionally substituted C ２ ~C ９ Heteroaryl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ２ ~C ９ Heterocyclyl or C ３ ~C ８ phenyl substituted by cycloalkoxy; optionally substituted C ３ Carbocyclyl; optionally substituted morpholin-1-yl; optionally substituted benzodioxolyl; optionally substituted benzopyrrolidonyl; optionally substituted tetrahydroquinoline; optionally substituted monoalkylamino; optionally substituted dialkylamino; optionally substituted C ２ ~C ９ Amino monosubstituted with heteroaryl; halo; optionally substituted C ２ ~C ９ Heterocycle C １ alkyl; optionally substituted C ２ ~C ９ Heteroaryl C １ alkyl; optionally substituted benzodioxanyl; -NHNHR １Ａ ; -N(R １Ａ ) N=C(R １Ｂ ) ２ ; -C(R １Ａ ) = N-N(R １Ｂ ) ２ ; -C(R １Ａ ) = NOR １Ａ or -Q １ -N(R １Ｃ ) ２ and Q １ is a bond, CH ２ or CO, R １Ａ each independently represents H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl or optionally substituted C ６ ~C １０ Aryl C １ ~C ６ is alkyl, R １Ｂ one of which is independently H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl or optionally substituted C ２ ~C ９ heteroaryl, and R １Ｂ The remainder is optionally substituted C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl or optionally substituted C ２ ~C ９ is heteroaryl, R １Ｃ each independently represents H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C ８ Cycloalkyl or optionally substituted C ２ ~C ９ heteroaryl, or R １Ｃ together with the nitrogen atom to which they are attached, form C ２ ~C ９ Heterocyclyl or C ２ ~C ９ forming a heteroaryl, R ２ is H, halogen, optionally substituted C ６ ~C １０ Aryl; optionally substituted C １～９ Heterocyclyl; -O-pyridin-3-yl; optionally substituted C ３ ~C ８ Cycloalkyl; optionally substituted C ３ ~C ８ Cycloalkenyl; hydroxy, methoxy, —CH ２ C optionally substituted by OH, pyridin-4-yl, 4-pyridon-1-yl, -O-pyridin-4-yl, oxo or dialkylamino １ ~C ２ Alkyl; deuterium, oxo, hydroxy, halo or amino (C ３ C optionally substituted by cycloalkyl １ alkyl; C substituted by hydroxy, oxo or dialkylamino ３ Alkyl; C ４ alkyl; optionally substituted C ２ ~C ９ Heteroaryl; -Q-N(R １Ｃ ) ２ -S(O) ｒ -R １Ａ or -P(O)(R １Ａ ) ２ and R Ａ are each independently H; hydroxyl or —S(O) ｒ -(optionally substituted C １ ~C ６ C optionally substituted with alkyl １ ~C ２ Alkyl; C ３ C substituted by alkyl, hydroxyl ４ ~C ５ Alkyl, optionally substituted C ２ ~C ９ Heteroaryl C １ ~C ６ alkyl; optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ３ ~C ８ Cycloalkyl C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl or optionally substituted C ２ ~C ９ heteroaryl, or R ２ and R Ａ together with the atoms to which they are attached, optionally substituted C ３ ~C ４ form a heterocyclic ring, and R Ａ The remainder, if present, is H; hydroxyl or -S(O) ｒ -(optionally substituted C １ ~C ６ C optionally substituted with alkyl １ ~C ２ Alkyl; C ３ C substituted by alkyl, hydroxyl ４ ~C ５ Alkyl, optionally substituted C ２ ~C ９ Heteroaryl C １ ~C ６ alkyl; optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ３ ~C ８ Cycloalkyl C １ ~C ６ Alkyl, optionally substituted C ６ ~C １０ Aryl or optionally substituted C ２ ~C ９ is heteroaryl, r is 0, 1 or 2; R ３ teeth, 【Chemical 502】 is.

2. The compound of claim 1 wherein Y is N.

3. R Ａ is H; hydroxyl or —S(O)CH ３ C optionally substituted with １ ~C ２ Alkyl; C ３ Alkyl; C substituted by hydroxyl ４ ~C ５ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

4. R １ is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted 1,2,3-triazol-1-yl, optionally substituted 1,2,3-triazol-2-yl, optionally substituted benzotriazol-1-yl, optionally substituted 1,2,4-triazol-3-yl, optionally substituted 1,2,4-oxadiazol-3-yl or optionally substituted 1,2,4-oxadiazol-2-yl.

5. R １ but, 【Chemical 663】 【Chemical 664】 【Chemical 665】 2. The compound of claim 1, wherein:

6. R １ but, 【Chemical 666】 【Chemical 667】 2. The compound of claim 1, wherein:

7. R ２ is optionally substituted C ２ ~C ９ The compound of claim 1 which is heteroaryl.

8. R ２ 2. The compound of claim 1, wherein is optionally substituted pyridyl.

9. R ２ is optionally substituted tetrahydropyranyl, optionally substituted dihydropyranyl, optionally substituted piperidinyl or optionally substituted azetidinyl.

10. R1 Ａ 10. The compound of claim 1, wherein is substituted by oxo.

11. The compound of formula 1a: 【Chemical 505】 or a pharmaceutically acceptable salt thereof; The compound has the structure: 【Chemical 513】 or a pharmaceutically acceptable salt thereof [In the formula, R １ is optionally substituted pyrazol-1-yl, optionally substituted C ２ ~C ９ phenyl substituted by heteroaryl or optionally substituted pyridin-4-yl; R ４ and R ５ are each independently hydroxyl or methoxy. or The compound has the structure: 【Chemical 517】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl, phenyl substituted with optionally substituted heteroaryl, optionally substituted indazol-1-yl or optionally substituted indazol-2-yl; R 4 is hydroxyl, 4-pyridinon-1-yl, —O-pyridin-3-yl or CH 2 OH; R 3 is pyridin-4-yl or morpholin-1-yl. or The compound has the structure: 【Chemical Formula 522】 or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl optionally substituted with methoxy or optionally substituted heteroaryl, or is optionally substituted pyrazol-1-yl; R 3 is morpholin-1-yl or piperidin-1-yl; R 2 is 【Chemical 523】 and R A is ethyl, 2-hydroxy-ethyl or 【Chemical 524】 is] or The compound has the structure: 【Chemical 527】 or a pharmaceutically acceptable salt thereof wherein R 6 is hydrogen or methyl; R 7 is optionally substituted phenoxy, optionally substituted benzyloxy, or optionally substituted amine. or The compound has the structure: 【Chemistry 531】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl or —N(R 1A )N═C(R 1B ) 2 . or The compound has the structure: 【Chemistry 534】 or a pharmaceutically acceptable salt thereof wherein R 8 is hydrogen or methoxy; R 9 is hydrogen or phenyl; R 10 is hydrogen or phenyl. or The compound has the structure: 【Chemical 535】 or a pharmaceutically acceptable salt thereof wherein R 11 is hydrogen or phenyl. or The compound has the structure: 【Chemical 536】 or a pharmaceutically acceptable salt thereof wherein R 12 is hydrogen, methoxy or CH 2 OH; R 13 is hydrogen, methoxy, C 3 cycloalkoxy, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 9 heterocyclyl or optionally substituted C 1 -C 6 alkyl; R 14 is hydrogen or C 3 cycloalkoxy or optionally substituted C 2 -C 9 heteroaryl; R 15 is hydrogen or hydroxyl; R 2 is hydrogen, pyridin-4-yl, 【Chemical 537】 and R 3 is 【Chemical 538】 is] or The compound has the structure: 【Chemistry 541】 or a pharmaceutically acceptable salt thereof wherein R 1 is 【Chemistry 542】 and R 16 is hydrogen or pyridin-3-yl; R 2 is pyridin-4-yl or hydrogen. or The compound has the structure: 【Chemistry 543】 or a pharmaceutically acceptable salt thereof wherein X 1 is O or CH 2 ; R 1 is —N(R 1A )N═C(R 1B ) 2 . or The compound has the structure: 【Chemical 545】 or a pharmaceutically acceptable salt thereof wherein R 1 is 【Chemical Formula 546】 is] or The compound has the structure: 【Chemical 547】 or a pharmaceutically acceptable salt thereof wherein R 1 is —N(R 1A )N═C(R 1B ) 2 . or The compound has the structure: 【Chemistry 549】 or a pharmaceutically acceptable salt thereof wherein R 17 is optionally substituted C 6 -C 10 arylC 1 -C 6 alkyl, optionally substituted C 6 -C 10 heteroarylC 1 -C 6 alkyl, —NH 2 , optionally substituted C 3 -C 8 cycloalkyl or optionally substituted C 2 -C 9 heteroaryl; R 18 is hydrogen or optionally substituted C 1 -C 6 alkyl; R A is methyl or ethyl; R 2 is pyridin-4-yl or hydrogen. or The compound has the structure: 【Chemical Formula 554】 or a pharmaceutically acceptable salt thereof wherein R 19 is optionally substituted amino, optionally substituted C 2 -C 9 heterocycle, optionally substituted C 2 -C 9 heteroaryl; R H and R 20 together with the atom to which they are attached form oxo; R 20 is hydrogen, or R 20 and R H together with the atom to which they are attached form oxo; R A is ethyl or cyclopropyl. or The compound has the structure: 【Chemical 558】 or a pharmaceutically acceptable salt thereof wherein R 21 is hydrogen, or R 21 and R H1 together with the atom to which they are attached form oxo; R H1 is hydrogen, or R H1 and R 21 together with the atom to which they are attached form an oxo. or The compound has the structure: 【Chemical 559】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted C 6 -C 10 aryl; optionally substituted C 1 -C 6 heteroalkyl; optionally substituted C 1 -C 6 alkyl; pyrazol-1-yl disubstituted by optionally substituted C 2 -C 9 heteroaryl, halo, hydroxy, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted C 1 -C 6 alkyl; R 3 is 【Chemical Formula 560】 and R A is ethyl, 2-hydroxy-ethyl, methyl, 【Chemical 666】 and 【Chemical 561】 and R 2 is hydrogen, methyl, ethyl, halo, pyridin-3-yl, pyridin-4-yl, cyclopropyl, 【Chemical Formula 562】 or R 2 and R A together with the atoms to which they are attached form an optionally substituted C 4 heterocyclyl. or The compound has the structure: 【Chemical 565】 or a pharmaceutically acceptable salt thereof wherein R 1 is an optionally substituted triazolyl; R A is methyl, ethyl or cyclopropyl. or The compound has the structure: 【Chemical 567】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted indazolyl or optionally substituted 4,5,6,7-tetrahydrotriazaindenyl. or The compound has the structure: 【Chemical 570】 or a pharmaceutically acceptable salt thereof wherein X is S or NR A ; R 22 is hydrogen or phenyl; R 23 is hydrogen or methyl; R 2 is pyrazol-3-yl, pyridin-4-yl or 4-phenyl-pyrazol-1-yl; R A is methyl. or The compound has the structure: 【Chemistry 571】 or a pharmaceutically acceptable salt thereof wherein R 22 is phenyl, pyridin-2-yl, or R 22 and R H2 together with the atom to which they are attached form oxo; R H2 is hydrogen or R H2 and R 22 together with the atom to which they are attached form oxo; R 23 is hydrogen, or R 23 and R H3 together with the atom to which they are attached form oxo; R H3 is hydrogen, or R H3 and R 23 together with the atom to which they are attached form an oxo. or The compound has the structure: 【Chemistry 572】 or a pharmaceutically acceptable salt thereof wherein R 1 is 【Chemistry 573】 is] or The compound has the structure: 【Chemistry 574】 or a pharmaceutically acceptable salt thereof wherein R 1 is 【Chemical 575】 is] or The compound has the structure: 【Chemical 576】 or a pharmaceutically acceptable salt thereof wherein R 24 is methoxy, methyl or hydroxyl; R A is methyl or ethyl. or The compound has the structure: 【Chemical 577】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazolyl, optionally substituted pyrimidin-3-yl or optionally substituted pyridin-4-yl; R A is methyl or ethyl; R 2 is optionally substituted C 2 -C 9 heteroaryl or optionally substituted C1-C9 heterocyclyl; R 3 is 【Chemical 578】 is] or The compound has the structure: 【Chemical 583】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl or phenyl substituted with optionally substituted C 2 -C 9 heteroaryl; R 25 and R 26 together with the atoms to which they are attached form a C 3 -C 5 heterocyclyl substituted by hydroxyl. or The compound has the structure: 【Chemical 587】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-5-yl, or phenyl substituted by methoxy or C 3 -C 8 cycloalkoxy. or The compound has the structure: 【Chemical 590】 or a pharmaceutically acceptable salt thereof wherein R 1 is an optionally substituted pyrazol-1-yl. or The compound has the structure: 【Chem.592】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl or optionally substituted pyrazol-5-yl; R 3 is morpholin-1-yl or piperidin-1-yl; R A is methyl or ethyl; R 2 is 【Chem.593】 is] or The compound has the structure: 【Chemistry 597】 or a pharmaceutically acceptable salt thereof wherein R 1 is an optionally substituted C 2 -C 9 heterocyclyl or pyrazolyl monosubstituted with C 6 -C 10 aryl. or The compound has the structure: 【Chemical 599】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted pyrazol-1-yl or pyrimidin-4-yl optionally substituted with optionally substituted C 1 -C 6 alkyl; R A is methyl or difluoromethyl; R 2 is pyridin-4-yl or 【Chemical 600】 is] or The compound has the structure: 【Chemical 603】 or a pharmaceutically acceptable salt thereof [In the formula, R A is 【Chemical 604】 is] or The compound has the structure: 【Chemical 605】 or a pharmaceutically acceptable salt thereof wherein R 1 is 【Chemical 606】 is] or The compound has the structure: 【Chemical 607】 or a pharmaceutically acceptable salt thereof wherein R 27 is hydrogen, tetrahydropyran-3-yl or tetrahydropyran-4-yl; R 28 is hydrogen, methoxy, phenyl, methyl, difluoromethyl, optionally substituted cyclobutyl; R 15 is hydrogen or methoxy; R 2 is pyridin-4-yl or —O-pyridin-4-yl. or The compound has the structure: 【Chemical 608】 or a pharmaceutically acceptable salt thereof wherein R 29 is optionally substituted C 2 -C 9 heterocyclyl or optionally substituted C 6 -C 10 aryl. or The compound has the structure: 【Chemical 609】 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted 4,5-dihydro-pyrazol-1-yl, optionally substituted imidazol-2-yl, optionally substituted piperidin-1-yl or optionally substituted 1,2,4-triazol-3-yl, optionally substituted pyrazol-4-yl, optionally substituted 1,3,4-oxadiazol-2-yl or optionally substituted pyridin-3-yl; R A is methyl or ethyl. or The compound has the structure: 【Chemical 618】 or a pharmaceutically acceptable salt thereof wherein R 1 is pyrazol-5-yl optionally substituted with C 2 -C 9 heteroaryl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkylC 1 -C 6 alkyl; R A is methyl or ethyl. or The compound has the structure: 【Chemical 620】 or a pharmaceutically acceptable salt thereof wherein R 1 is pyrazol-3-yl substituted by optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 alkyl or optionally substituted C 6 -C 10 arylC 1 -C 6 alkyl; R A is methyl or ethyl. or The compound has the structure: 【Chemical Formula 622】 or a pharmaceutically acceptable salt thereof wherein R 1 is pyrazol-3-yl disubstituted by C 1 -C 6 alkyl or C 6 -C 10 aryl. or The compound has the structure: 【Chemistry 645】 or a pharmaceutically acceptable salt thereof wherein R 2 is hydrogen, optionally substituted C 2 -C 9 heteroaryl; optionally substituted C 2 -C 9 heterocyclyl; or C 1 -C 3 alkyl optionally substituted with hydroxyl, oxo, or dialkylamino; R 1 is optionally substituted pyrazol-1-yl; phenyl optionally substituted with optionally substituted C 2 -C 9 heteroaryl or optionally substituted C 6 -C 10 aryl; or —N(R 1A )N═C(R 1B ) 2 ; R 3 is 【Chemical 646】 is] or The compound has the structure: 【Chemical Formula 657】 or a pharmaceutically acceptable salt thereof wherein R 2 is an optionally substituted C 2 -C 9 heteroaryl; R 1 is —N(R 1A )N═C(R 1B ) 2 .

2. The compound of claim 1 having the formula:

12. structure: 【Chemical Formula 624】 or a pharmaceutically acceptable salt thereof wherein Y is CH or N; X is O or S; R １ is an optionally substituted morpholin-1-yl, an optionally substituted pyrimidin-4-yl, —N(R １Ａ ) N=C(R １Ｂ ) ２ , optionally substituted pyrazol-3-yl or optionally substituted indazol-4-yl; R ２ is hydrogen or methyl, R ３０ is optionally substituted pyridin-4-yl, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-1-yl, or —S(O) ２ CH ３ C substituted by ２ ~C ９ Heterocycle C １ ~C ６ alkyl; or structure: 【Chemical 632】 or a pharmaceutically acceptable salt thereof wherein Y is S or NR A ; R 1 is optionally substituted pyrimidin-4-yl; R A is optionally substituted C 1 -C 6 alkyl; or structure: 【Transformation 634】 or a pharmaceutically acceptable salt thereof wherein X 2 and X 3 are each independently N or CR 32 ; R 31 is an optionally substituted C 2 -C 9 heteroaryl; R 32 is an optionally substituted C 2 -C 9 heteroaryl; or structure: 【Chemical 636】 or a pharmaceutically acceptable salt thereof wherein R 33 is optionally substituted amino; R 34 is an optionally substituted C 2 -C 9 heteroaryl; or structure: 【Chemistry 639】 or a pharmaceutically acceptable salt thereof wherein R 35 and R 36 are each independently an optionally substituted C 2 -C 9 heteroaryl; or structure: 【Chemistry 641】 or a pharmaceutically acceptable salt thereof wherein R 37 is an optionally substituted C 2 -C 9 heteroaryl; or structure: 【Chemistry 643】 or a pharmaceutically acceptable salt thereof wherein R 38 is an optionally substituted C 6 -C 10 aryl; R 39 is optionally substituted C 2 -C 9 heteroarylC 1 -C 6 alkyl. A compound having the formula:

13. A compound having the structure of any one of compounds 1 to 476 in Table 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition for use in the treatment of neurological disorders, comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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