Pyrimidines and methods of use thereof

Abstract

Disclosed are compounds and pharmaceutical compositions that contain pyrimidinyl cores that are useful for the treatment of neurological disorders.The compounds described herein can be used alone or in combination with other pharmacoactive agents to treat or prevent nervous system diseases, including FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer's disease, LATE or frontotemporal lobar degeneration.The present invention relates to heteroarenes and their use for the therapeutic treatment of neurological disorders in patients, such as human patients.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to 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.

[0004] In an aspect, the present disclosure provides a compound of Formula I: [ka] or a pharmaceutically acceptable salt thereof. (In the formula, V is -NH-, -NR 5 -, -CH2NH-, -CH2NR 5 -, -O-, -CO- or -CHOH-, R 1 is optionally substituted morpholin-4-yl, pyridin-4-yl, pyridin-3-yl, optionally substituted 2-oxo-pyrrolidin-1-yl, optionally substituted piperidin-1-yl or optionally substituted pyridiazin-4-yl; R 2 is a halogen, -(CH2) n OH, optionally substituted C 1~6 Alkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted 2-oxo-pyrrolidin-1-yl, -(CO)NR 7a R 7b , -P(O)R 7c R 7dor -S(O) k R 7e and R 3 is optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridazin-3-yl, optionally substituted pyrimidin-4-yl or optionally substituted C6-C 10 aryl or R 2 and R 3 together with the ring to which they are attached, form an optionally substituted C4-C 12 forming a heteroaryl, n is 1, 2, 3, 4, 5 or 6; k is 0, 1 or 2; R 4 is optionally substituted pyridin-4-yl, optionally substituted 1-methylpyridin-1-ium-4-yl, optionally substituted pyridin-3-yl, optionally substituted 1-methylpiperidin-3-yl, optionally substituted pyridazin-3-yl or -NHR 8 and R 5 is an optionally substituted C1-C6 alkyl; R 6 is H or optionally substituted C1-C6 alkyl, R 7a and R 7b are each independently H or optionally substituted C1-C6 alkyl, or R 7a and R 7b together with the nitrogen atom to which they are attached form an optionally substituted C2-C9 heterocyclyl; R 7c , R 7d and R 7e are each independently an optionally substituted C 1~6Alkyl, optionally substituted C 1~6 is alkoxy or hydroxyl, R 8 is optionally substituted phenyl or optionally substituted C3-C6 cycloalkyl).

[0005] In some embodiments, R 1 is optionally substituted morpholin-4-yl. In some embodiments, R 1 is optionally substituted pyridin-4-yl. In some embodiments, R 1 is an optionally substituted pyridin-3-yl.

[0006] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is morpholin-4-yl. In some embodiments, R 1 is optionally substituted piperidin-1-yl. In some embodiments, R 1 teeth, [ka] is.

[0007] In some embodiments, V is -NH-. In some embodiments, V is -CHNH-. In some embodiments, V is -O-. In some embodiments, V is -CO-. In some embodiments, V is -CHOH-. In some embodiments, V is -NR 5 In some embodiments, V is —CH NR 5 -It is.

[0008] In some embodiments, R 4 is optionally substituted pyridin-4-yl, optionally substituted 1-methylpyridin-1-ium-4-yl, optionally substituted pyridin-3-yl, optionally substituted 1-methylpiperidin-3-yl, or optionally substituted pyridazin-3-yl. 4 is optionally substituted pyridin-4-yl, optionally substituted pyridin-3-yl, optionally substituted 1-methylpiperidin-3-yl, or optionally substituted pyridazin-3-yl. 4 is optionally substituted pyridin-4-yl or optionally substituted pyridin-3-yl. In some embodiments, R 4 is pyridin-4-yl or pyridin-3-yl.

[0009] In some embodiments, R 2 and R 3 together with the ring to which they are attached, form an optionally substituted C4-C 12 In some embodiments, R 2 and R 3 taken together with the ring to which they are attached form an optionally substituted C4-C9 heteroaryl.

[0010] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, R 2 is a halogen, -(CH2) n OH, optionally substituted C 1~6Alkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted 2-oxo-pyrrolidin-1-yl, -(CO)NR 7a R 7b , -P(O)R 7c R 7d or -S(O) k R 7e In some embodiments, R 2 is replaced as necessary 1~6 Alkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted 2-oxo-pyrrolidin-1-yl, -(CO)NR 7a R 7b , -P(O)R 7c R 7d or -S(O) k R 7e is.

[0012] In some embodiments, R 2 is replaced as necessary 1~6 In some embodiments, R 2 is -OCH3.

[0013] In some embodiments, R 2 is -(CO)NR 7a R 7b In some embodiments, R 7a and R 7b Each is independently an optionally substituted C1-C6 alkyl. In some embodiments, R 7a and R 7b Each R is methyl. 7a and R 7b taken together with the nitrogen atom to which they are attached form an optionally substituted C2-C9 heterocyclyl. In some embodiments, -(CO)NR 7a R 7b teeth, [ka] is.

[0014] In some embodiments, R 2 is -P(O)R 7c R 7d or -S(O) k R 7e In some embodiments, R 2 teeth, [ka] is.

[0015] In some embodiments, R 2 is an optionally substituted C2-C9 heteroaryl. In some embodiments, R 2 teeth, [ka] is.

[0016] In some embodiments, R 2 is a halogen. In some embodiments, R 2 is Cl.

[0017] In some embodiments, R 2 is -(CH2) n In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1.

[0018] In some embodiments, R 3 is optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridazin-3-yl, optionally substituted pyrimidin-4-yl or optionally substituted C6-C 10 It is aryl.

[0019] In some embodiments, R 3is an optionally substituted pyridin-3-yl, an optionally substituted pyridin-4-yl or an optionally substituted C6-C 10 It is aryl.

[0020] In some embodiments, R 3 is an optionally substituted C aryl. In some embodiments, R 3 teeth, [ka] is.

[0021] In some embodiments, R 3 is optionally substituted pyridin-3-yl or optionally substituted pyridin-4-yl. In some embodiments, R 3 teeth, [ka] is.

[0022] In some embodiments, R 3 is optionally substituted pyridin-2-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridazin-3-yl, or optionally substituted pyrimidin-4-yl. 3 teeth, [ka] is.

[0023] In an aspect, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 9is optionally substituted morpholin-4-yl, optionally substituted morpholin-3-ylalkoxy, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted 1-methylpiperazin-2-yl or optionally substituted C-C 10 is aryl, R 10 is replaced as necessary 1~6 Alkoxy, -(CO)NR 7a R 7b , -P(O)R 7c R 7d or -S(O) k R 7e and R 7a and R 7b are each independently H or optionally substituted C1-C6 alkyl, or R 7a and R 7b together with the nitrogen atom to which they are attached form an optionally substituted C2-C9 heterocyclyl; R 7c , R 7d and R 7e are each independently an optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 is alkoxy or hydroxyl, k is 0, 1 or 2; R 11 is optionally substituted morpholin-4-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-4-yl, optionally substituted 1H-imidazol-2-yl, optionally substituted quinolin-6-yl or optionally substituted C6-C 10 is aryl, R 12is optionally substituted 1-methylpiperazin-2-onyl, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted N-(pyridin-3-ylmethyl)amine, optionally substituted N-(pyridin-4-yl)amine or optionally substituted C-C 10 (aryl).

[0024] In some embodiments, R 9 is morpholin-4-yl.

[0025] In some embodiments, R 9 is optionally substituted morpholin-3-ylalkoxy. In some embodiments, R 9 teeth, [ka] is.

[0026] In some embodiments, R 9 is optionally substituted 2-(pyridin-2-yl)alkoxy. In some embodiments, R 9 teeth, [ka] is.

[0027] In some embodiments, R 9 is optionally substituted 1-methylpiperazin-2-yl. In some embodiments, R 9 teeth, [ka] is.

[0028] In some embodiments, R 9 is optionally substituted C6 to C 10 In some embodiments, R 9 teeth, [ka] is.

[0029] In some embodiments, R 10 is replaced as necessary 1~6 In some embodiments, R 10 is methoxy.

[0030] In some embodiments, R 11 is optionally substituted morpholin-4-yl. In some embodiments, R 11 is morpholin-4-yl. In some embodiments, R 11 is optionally substituted pyridin-4-yl. In some embodiments, R 11 is pyridin-4-yl.

[0031] In some embodiments, R 11 is optionally substituted pyrazol-4-yl. In some embodiments, R 11 teeth, [ka] is.

[0032] In some embodiments, R 11 is optionally substituted 1H-imidazol-2-yl. In some embodiments, R 11 teeth, [ka] is.

[0033] In some embodiments, R 11 is optionally substituted quinolin-6-yl. In some embodiments, R 11 teeth, [ka] is.

[0034] In some embodiments, R 11 is optionally substituted C6 to C 10 In some embodiments, R 11 teeth, [ka] is.

[0035] In some embodiments, R 12 is optionally substituted 1-methylpiperazin-2-onyl (only). In some embodiments, R 12 teeth, [ka] is.

[0036] In some embodiments, R 12 is optionally substituted 2-(pyridin-2-yl)alkoxy. In some embodiments, R 12 teeth, [ka] is.

[0037] In some embodiments, R 12 is optionally substituted N-(pyridin-3-ylmethyl)amine. In some embodiments, R 12 teeth, [ka] is.

[0038] In some embodiments, R 12 is an optionally substituted N-(pyridin-4-yl)amine. In some embodiments, R 12 teeth, [ka] is.

[0039] In some embodiments, R 12 is optionally substituted C6 to C 10 In some embodiments, R 12 teeth, [ka] is.

[0040] In some embodiments, the compound has the structure of any one of compounds 1-78 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds 1-3, 6-29, 31-36, 38-41, 43-51, 53-57, 59, 62, and 64-78 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of any one of compounds 4, 5, 30, 37, 42, 52, 58, 60, 61, and 63 in Table 1, or a pharmaceutically acceptable salt thereof.

[0041] In embodiments, the compound has the structure of any one of compounds 1-78 in Table 1, or a pharmaceutically acceptable salt thereof.

[0042] In embodiments, the compound has the structure of any one of compounds 1-3, 6-29, 31-36, 38-41, 43-51, 53-57, 59, 62, and 64-78 in Table 1, or a pharmaceutically acceptable salt thereof.

[0043] In embodiments, the compound has the structure of any one of compounds 4, 5, 30, 37, 42, 52, 58, 60, 61, and 63 in Table 1, or a pharmaceutically acceptable salt thereof.

[0044] In embodiments, the compound has the structure of any one of compounds 66 and 34 in Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0045] In aspects, the present invention provides intermediates in the synthesis of some compounds of the invention. Non-limiting examples of intermediates include compounds i-1 through i-4 in Table 2.

[0046] [Table 2]

[0047] In an aspect, the invention features a pharmaceutical composition including any of the compounds described above and a pharmaceutically acceptable excipient.

[0048] 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.

[0049] 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.

[0050] 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 I or a pharmaceutically acceptable salt thereof (e.g., a compound having the structure of any one of compounds 1-3, 6-29, 31-36, 38-41, 43-51, 53-57, 59, 62, and 64-78 in Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof (e.g., a compound having the structure of any one of compounds 4, 5, 30, 37, 42, 52, 58, 60, 61, and 63 in Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a compound having the structure of any one of compounds 1-78 in Table 1, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the invention features a method of inhibiting PIKfyve. The method includes contacting a cell with an effective amount of any of the compounds or pharmaceutical compositions described above. In some embodiments, the method includes administering to a subject in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., a compound having the structure of any one of compounds 1-3, 6-29, 31-36, 38-41, 43-51, 53-57, 59, 62, and 64-78 in Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes administering to a subject in need thereof an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof (e.g., a compound having the structure of any one of compounds 4, 5, 30, 37, 42, 52, 58, 60, 61, and 63 in Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes administering to a subject in need thereof an effective amount of a compound having the structure of any one of compounds 1-78 in Table 1, or a pharmaceutically acceptable salt thereof.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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

[0060] 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.

[0061] 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.

[0062] 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]

[0063] 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.

[0064] 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.

[0065] In some embodiments, the compounds described and / or illustrated herein may be provided and / or utilized in salt form.

[0066] In certain embodiments, the compounds described and / or illustrated herein may be supplied and / or utilized in hydrated or solvated forms.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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).

[0072] 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).

[0073] 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).

[0074] 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.

[0075] The term "arylalkyl," as used herein, refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7-30 carbon (e.g., C1-C6 alkylC), such as benzyl and phenethyl. 6~10 Aryl, C1-C 10 Alkyl C 6~10 Aryl or C1-C 20 Alkyl C 6~10 In some embodiments, alkyl and aryl may each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0076] The term "azido" as used herein refers to the group -N3.

[0077] The term "cyano" as used herein refers to the group CN.

[0078] 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.

[0079] 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.

[0080] The term "halo," as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring and containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrazolyl (e.g., pyrazol-1-yl and pyrazol-3-yl), pyrimidinyl (e.g., pyrimidin-4-yl), pyridazinyl (e.g., pyridazin-3-yl), benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0085] 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., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 Alkyl C2-C9 heteroaryl or C1-C 20 and 7-16 or 7-20 carbons, such as alkyl C2-C9 heteroaryl. In some embodiments, alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0086] The term "heterocyclyl," as used herein, refers to a non-aromatic monocyclic or polycyclic radical having 3 to 12 atoms and at least one ring containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S. Examples of heterocyclyl groups include, but are not limited to, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl, furyl, piperazinyl, piperidinyl (e.g., piperidin-1-yl), pyranyl, pyrrolidinyl (e.g., pyrrolidin-1-yl), tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. Heterocyclyl groups may be aromatic or non-aromatic. Aromatic heterocyclyls are also referred to as heteroaryls.

[0087] 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., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 Alkyl C2-C9 heterocyclyl or C1-C 20and 7-16 or 7-20 carbons, such as alkyl C2-C9 heterocyclyl. In some embodiments, the alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0088] The term "hydroxyl" as used herein refers to an --OH group.

[0089] 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).

[0090] The term "nitro" as used herein refers to the NO2 group.

[0091] The term "oxyheteroaryl," as used herein, refers to a heteroaryl group having at least one ring oxygen atom.

[0092] The term "oxyheterocyclyl," as used herein, refers to a heterocyclyl group having at least one ring oxygen atom.

[0093] The term "thiol" as used herein refers to an --SH group.

[0094] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. If substituted, there will generally be 1 to 4 substituents unless otherwise specified. Substituents include, for example, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), 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).

[0095] 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

[0096] 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 "comprising" 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.

[0097] 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.

[0098] 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.

[0099] 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).

[0100] 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).

[0101] 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

[0102] 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.

[0103] 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).

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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).

[0116] 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.

[0117] 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.

[0118] 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]

[0119] [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.

[0120] [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.

[0121] [Figure 3] FIG. 3 is a histogram generated from a flow cytometry-based viability assay of FAB1 TDP-43.

[0122] [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).

[0123] [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.

[0124] [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.

[0125] [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

[0126] 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 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] PIKfyve inhibitors Exemplary PIKfyve inhibitors described herein include compounds of Formula I: [ka] or a pharmaceutically acceptable salt thereof (In the formula, V is -NH-, -NR 5 -, -CH2NH-, -CH2NR 5 -, -O-, -CO- or -CHOH-, R 1 is optionally substituted morpholin-4-yl, pyridin-4-yl, pyridin-3-yl, optionally substituted 2-oxo-pyrrolidin-1-yl, optionally substituted piperidin-1-yl or optionally substituted pyridiazin-4-yl; R 2 is a halogen, -(CH2) n OH, optionally substituted C 1~6 Alkoxy, optionally substituted C2-C9 heteroaryl, optionally substituted 2-oxo-pyrrolidin-1-yl, -(CO)NR 7a R 7b , -P(O)R 7c R 7d or -S(O) k R 7e and R 3 is optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridazin-3-yl, optionally substituted pyrimidin-4-yl or optionally substituted C6-C 10 aryl or R 2 and R 3 together with the ring to which they are attached, form an optionally substituted C4-C 12 forming a heteroaryl, n is 1, 2, 3, 4, 5 or 6; k is 0, 1 or 2; R 4 is optionally substituted pyridin-4-yl, optionally substituted 1-methylpyridin-1-ium-4-yl, optionally substituted pyridin-3-yl, optionally substituted 1-methylpiperidin-3-yl, optionally substituted pyridazin-3-yl or -NHR 8 and R 5 is an optionally substituted C1-C6 alkyl; R 6 is H or optionally substituted C1-C6 alkyl, R 7a and R 7b are each independently H or optionally substituted C1-C6 alkyl, or R 7a and R 7b together with the nitrogen atom to which they are attached form an optionally substituted C2-C9 heterocyclyl; R 7c , R 7d and R 7e are each independently an optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 is alkoxy or hydroxyl, R 8 is optionally substituted phenyl or optionally substituted C3-C6 cycloalkyl).

[0131] Exemplary PIKfyve inhibitors described herein also include compounds of Formula II: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 9is optionally substituted morpholin-4-yl, optionally substituted morpholin-3-ylalkoxy, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted 1-methylpiperazin-2-yl or optionally substituted C-C 10 is aryl, R 10 is replaced as necessary 1~6 Alkoxy, -(CO)NR 7a R 7b , -P(O)R 7c R 7d or -S(O) k R 7e and R 7a and R 7b are each independently H or optionally substituted C1-C6 alkyl, or R 7a and R 7b together with the nitrogen atom to which they are attached form an optionally substituted C2-C9 heterocyclyl; R 7c , R 7d and R 7e are each independently an optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 is alkoxy or hydroxyl, k is 0, 1 or 2; R 11 is optionally substituted morpholin-4-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-4-yl, optionally substituted 1H-imidazol-2-yl, optionally substituted quinolin-6-yl or optionally substituted C6-C 10 is aryl, R 12is optionally substituted 1-methylpiperazin-2-onyl, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted N-(pyridin-3-ylmethyl)amine, optionally substituted N-(pyridin-4-yl)amine or optionally substituted C-C 10 (aryl). Treatment method Inhibition of PIKfyve activity and TDP-43 aggregation to treat neurological disorders

[0132] 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.

[0133] 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.

[0134] 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

[0135] 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

[0136] 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

[0137] 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

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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

[0146] 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.

[0147] 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.

[0148] The following examples are intended to illustrate the invention. They are not intended to limit the invention in any way. [Example]

[0149] [Table 4-1] [Table 4-2] Example 1 Synthesis of 5-methoxy-2-morpholino-N-phenyl-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide (compound 1): [ka]

[0150] Step 1: Synthesis of 5-methoxy-2-morpholinopyrimidine-4,6-diol.

[0151] To a solution of morpholine-4-carboximidamide hydrochloride (2 g, 12.1 mmol) and dimethyl 2-methoxymalonate (1.95 g, 12.1 mmol) in MeOH (35 mL) was added MeONa (30% solution in MeOH, 6.8 mL, 36.3 mmol). After the addition, the reaction mixture was stirred at 80° C. for 17 hours and then concentrated to give 5-methoxy-2-morpholinopyrimidine-4,6-diol (2.5 g, 91%) as a brown solid, which was used directly in the next step without further purification.

[0152] Step 2: Synthesis of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine.

[0153] A mixture of 5-methoxy-2-morpholinopyrimidine-4,6-diol (2.5 g, 11 mmol) and phosphorus oxychloride (25 mL) was stirred at 110° C. for 16 hours and then concentrated. The resulting residue was diluted with ethyl acetate / water (20 mL / 20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (Biotage, 40 g silica gel, eluted with 20% to 40% ethyl acetate in petroleum ether) to give 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (1.5 g, 51.6%) as a pale yellow solid. LCMS (ESI) m / z: 264.1 [M+H] + .

[0154] Step 3: Synthesis of 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-4-ol.

[0155] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.14 g, 0.53 mmol), 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.16 g, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (49 mg, 0.053 mmol), tricyclohexylphosphine (30 mg, 0.1 mmol), and cesium carbonate (0.34 g, 1.06 mmol) in dimethyl sulfoxide (20 mL) was stirred at 130° C. under a nitrogen atmosphere for 16 hours. The reaction was cooled, and the mixture was diluted with ethyl acetate (20 mL) and filtered through a pad of Celite. The filtrate was extracted with water (40 mL) and the aqueous phase was lyophilized to give 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-4-ol (0.15 g, 80%) as a white solid. LCMS (ESI) m / z: 354.1 [M+H] + .

[0156] Step 4: Synthesis of 4-(4-chloro-5-methoxy-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-2-yl)morpholine.

[0157] A mixture of 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-4-ol (0.15 g, 0.42 mmol) and phosphorus oxychloride (8 mL) was stirred at 110° C. for 16 hours. The mixture was concentrated, and the residue was diluted with ethyl acetate / water (20 mL / 20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (Biotage, 40 g silica gel, eluted with 20% to 40% ethyl acetate in petroleum ether) to give 4-(4-chloro-5-methoxy-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-2-yl)morpholine (0.11 g, 70.6%) as a white solid. LCMS (ESI) m / z: 372.1 [M+H] + .

[0158] Step 5: Synthesis of methyl 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylate.

[0159] A solution of 4-(4-chloro-5-methoxy-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-2-yl)morpholine (100 mg, 0.27 mmol), triethylamine (82 mg, 0.81 mmol), palladium(II) acetate (6 mg, 0.03 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (30 mg, 0.06 mmol) in methanol (4 mL) and dimethyl sulfoxide (6 mL) was stirred at 80° C. under a carbon monoxide atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was diluted with ethyl acetate (30 mL), washed with water (20 mL×3) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give methyl 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylate (25 mg, 23.4%) as a white solid. LCMS (ESI) m / z: 396.1 [M+H] + .

[0160] Step 6: Synthesis of 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylic acid.

[0161] To a solution of methyl 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylate (20 mg, 0.05 mmol) in tetrahydrofuran / methanol / water (4 mL / 1 mL / 1 mL) was added lithium hydroxide monohydrate (4 mg, 0.1 mmol), and the reaction mixture was stirred at room temperature for 2 hours. It was concentrated, and the residue was diluted with water (5 mL). The pH was adjusted to 3-4 with 2N aqueous HCl and extracted twice with ethyl acetate (10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylic acid (15 mg, 78.7%) as a white solid. LCMS (ESI) m / z: 382.2 [M+H] + .

[0162] Step 7: Synthesis of 5-methoxy-2-morpholino-N-phenyl-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide.

[0163] To a solution of 5-methoxy-2-morpholino-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxylic acid (15 mg, 0.039 mmol) and aniline (4 mg, 0.039 mmol) in N,N-dimethylformamide (5 mL) was added HATU (15 mg, 0.047 mmol) and DIPEA (10 mg, 0.08 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC to give 5-methoxy-2-morpholino-N-phenyl-6-(1-phenyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide (4.3 mg, 24.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.68 (d, J=2.6Hz, 1H), 7.97 (d, J=7.7 Hz, 2H), 7.73 (d, J=7.6 Hz, 2H), 7.56 (t, J=8.0 Hz, 2H), 7.38 (t, J=7.8 Hz, 3H), 7.22 (d, J=2.5 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 3.84 (s, 3H), 3.76 (d, J= 5 Hz, 4H), 3.71(d, J=4.9 Hz, 4H); LCMS (ESI) m / z: 457.1 [M+H] + . Example 2 Synthesis of 4-(5-methoxy-4-(4-phenyl-1H-pyrazol-1-yl)-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine (compound 2): [ka]

[0164] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine.

[0165] To a solution of pyridin-3-ol (0.18 g, 1.9 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60% in mineral oil, 0.11 g, 2.85 mmol) in portions at 0° C. After the addition, the mixture was warmed and stirred at room temperature for 20 minutes. A solution of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.5 g, 1.9 mmol) in tetrahydrofuran (10 mL) was then added. The resulting mixture was heated to reflux with stirring for 16 hours. It was cooled, diluted with ethyl acetate / water (20 mL / 20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash chromatography (Biotage, 40 g silica gel, eluting with 50% to 70% ethyl acetate in petroleum ether) to give 4-(4-chloro-5-methoxy-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine (0.46 g, 75.4%) as a white solid. LCMS (ESI) m / z: 323.1 [M+H] + .

[0166] Step 2: Synthesis of 4-(5-methoxy-4-(4-phenyl-1H-pyrazol-1-yl)-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine.

[0167] A mixture of 4-(4-chloro-5-methoxy-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine (40 mg, 0.12 mmol), 4-phenyl-1H-pyrazole (18 mg, 0.12 mmol), and cesium carbonate (80 mg, 0.24 mmol) in N,N-dimethylacetamide (6 mL) was stirred at 100° C. for 4 hours. The resulting mixture was filtered through a pad of Celite and concentrated. The residue was subjected to preparative HPLC to give 4-(5-methoxy-4-(4-phenyl-1H-pyrazol-1-yl)-6-(pyridin-3-yloxy)pyrimidin-2-yl)morpholine (12.5 mg, 23.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.60 (d, J=2.7Hz, 1H), 8.50 (dd, J=4.7, 1.3Hz, 1H), 8.39 (s, 1H), 7.85-7.73 (m, 3H), 7.54 (d, LCMS(ESI)m / z:431.1[M+H] + . Example 3 Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 3): [ka]

[0168] Step 1: Preparation of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine.

[0169] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.2 g, 0.76 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.21 g, 0.76 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (62 mg, 0.075 mmol), and cesium carbonate (0.62 g, 1.89 mmol) in 1,4-dioxane / water (20 mL / 4 mL) was stirred at 95 °C under an argon atmosphere for 3 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash chromatography (Biotage, 40 g silica gel, eluting with 20% to 40% petroleum ether in ethyl acetate) to give 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (0.15 g, 51.3%) as a white solid. LCMS (ESI) m / z: 385.8 / 387.8 [M+H] + .

[0170] Step 2: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0171] A mixture of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (80 mg, 0.21 mmol), pyridin-4-amine (20 mg, 0.21 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), XPhos (20 mg, 0.04 mmol), and cesium carbonate (0.17 g, 0.52 mmol) in toluene (15 mL) was stirred at 95 °C under an argon atmosphere for 16 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (17.8 mg, 19%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.44-8.42 (m, 3H), 7.91-7.86 (m, 4H), 7.77 (d, J=2.2Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 6.71 (d, LCMS (ESI) m / z: 443.9 [M] + . Example 4 Synthesis of 4-(5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (compound 4): [ka]

[0172] Step 1: Synthesis of 4-(2,6-dichloro-5-methoxypyrimidin-4-yl)morpholine.

[0173] To a solution of 2,4,6-trichloro-5-methoxypyrimidine (0.4 g, 1.88 mmol) and morpholine (0.16 g, 1.88 mmol) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (0.48 g, 3.77 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the resulting crude product was purified by column chromatography (silica gel) to give 4-(2,6-dichloro-5-methoxypyrimidin-4-yl)morpholine (0.49 g, 98%) as a white solid. LCMS (ESI) m / z: 264.0 [M+H] + .

[0174] Step 2: Synthesis of 4-(2-chloro-5-methoxy-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine.

[0175] To a solution of 2-(pyridin-2-yl)ethan-1-ol (0.19 g, 1.52 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60%, 91 mg, 2.28 mmol) portionwise at 0° C. After the addition, the mixture was stirred at 0° C. for 30 minutes, followed by the dropwise addition of 4-(2,6-dichloro-5-methoxypyrimidin-4-yl)morpholine (0.4 g, 1.52 mmol) in tetrahydrofuran (4 mL) at the same temperature. The resulting mixture was warmed and stirred at room temperature for 4 hours, then diluted with ethyl acetate / water (20 mL / 20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash chromatography (Biotage, 40 g silica gel, eluting with 20% to 40% 7N ammonia methanol in DCM) to give 4-(2-chloro-5-methoxy-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (0.26 g, 48.9%) as a white solid. LCMS (ESI) m / z: 351.1 [M+H] + . (Rt:1.81 min)

[0176] The regioisomer 4-(6-chloro-5-methoxy-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (0.14 g, 26.3%) was also obtained as a white solid. LCMS (ESI) m / z: 351.1 [M+H] + (Rt=1.68 min). Two isomers were confirmed by NOESY.

[0177] Step 3: Synthesis of 4-(5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine.

[0178] A mixture of 4-(2-chloro-5-methoxy-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (0.1 g, 0.28 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (81 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium (33 mg, 0.03 mmol), and cesium carbonate (0.23 g, 0.71 mmol) in dioxane / water (20 mL / 4 mL) was stirred at 90° C. for 16 hours. The resulting mixture was filtered and concentrated. The residue was subjected to preparative HPLC to give 4-(5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (28.7 mg, 21.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J = 1.6 Hz, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.25 (dt, J = 4.0, 1.6Hz, 1H), 7.88 (dt, J = 4.0, 1.6Hz, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (t, J = 8Hz, 1H), 7.41 (d, J = 1.6Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.0, 5.4 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 4.93 (t, J = 6.6 Hz, 2H), 3.98 (s, 3H), 3.83 (s, 8H), 3.59 (s, 3H), 3.37 (t, J = 6.6 Hz, 2H); LCMS (ESI) m / z: 473.3 [M+H] + . Example 5 Synthesis of 4-(5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (compound 5): Following the protocol described above in Example 4, the following compounds were synthesized: [Table 5]

[0179] Example 6 Synthesis of N-cyclopropyl-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxamide (compound 6): [ka]

[0180] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine.

[0181] To a solution of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.26 g, 0.984 mmol) and 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.28 g, 0.984 mmol) in dioxane / water (10 mL / 2 mL) was added cesium carbonate (0.64 g, 1.97 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.073 g, 0.1 mmol). The resulting mixture was stirred at 90 °C for 2 h, then poured into ice water and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine, dried, and evaporated to dryness. The crude product was chromatographed on silica gel (petroleum ether / ethyl acetate=20:1) to give the target product (200 mg, 53%) as a yellow solid. LCMS (ESI) m / z: 385.8 / 387.8 [M] + .

[0182] Step 2: Synthesis of methyl 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxylate.

[0183] A mixture of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (0.2 g, 0.52 mmol), triethylamine (0.16 g, 1.56 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.04 g, 0.05 mmol) in methanol / dimethyl sulfoxide (10 mL / 5 mL) was stirred under carbon monoxide at 75°C for 16 hours. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (silica gel using petroleum ether / ethyl acetate = 2:1) to give the target product as a yellow solid (0.12 g, 56%). LCMS (ESI) m / z: 410.1 [M+H] + .

[0184] Step 3: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxylic acid.

[0185] A mixture of methyl 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxylate (0.12 g, 0.29 mmol) and lithium hydroxide hydrate (0.025 g, 0.58 mmol) in water (1 mL) / tetrahydrofuran (4 mL) was stirred at 25° C. for 5 hours. It was concentrated to give the target product (0.1 g, 86%) as a yellow solid. LCMS (ESI) m / z: 396.1 [M+H] + .

[0186] Step 4: Synthesis of N-cyclopropyl-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxamide.

[0187] A solution of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidine-4-carboxylic acid (120 mg, 0.3 mmol), cyclopropanamine (52 mg, 0.91 mmol), N,N-diisopropylethylamine (120 mg, 0.91 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (171 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 hours. The resulting mixture was filtered and concentrated. The residue was subjected to 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 target product as a white solid (42.6 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 4.5Hz, 1H), 8.41 (t, J = 1.5Hz, 1H), 7.97 - 7.86 (m, 2H), 7.77 (d, J = 2.2Hz, 1H), 7.53 (t, J = 7.8Hz, 1H), 6.73 (d, J = 2.2Hz, 1H), 3.90 (s, 3H), 3.70 (d, J = 3.6Hz, 8H), 3.48 (d, J = 6.2Hz, 3H), 2.83 (pent, J = 4.1Hz, 1H), 0.76 - 0.69 (m, 2H), 0.59 - 0.49 (m, 2H); LCMS (ESI) m / z: 435.1 [M+H] + . Example 7 Synthesis of 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 7): [ka]

[0188] Step 1: Synthesis of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0189] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.5 g, 1.89 mmol), pyridin-4-amine (0.16 g, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol), X-Phos (0.18 g, 0.38 mmol), and cesium carbonate (1.54 g, 4.73 mmol) in toluene (25 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash chromatography (eluting with 30% to 60% petroleum ether in ethyl acetate) to give 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.2 g, 36.7%) as a white solid. LCMS (ESI) m / z: 321.8 [M] + .

[0190] Step 2: Synthesis of 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0191] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (80 mg, 0.25 mmol), (5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)boronic acid (60.7 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 0.025 mmol), and cesium carbonate (0.2 g, 0.62 mmol) in 1,4-dioxane / water (15 mL / 3 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, followed by the addition of water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC to give 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (45 mg, 40.5%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.07 - 9.06 (m, 2H), 8.69 (s, 1H), 8.43 (d, J = 6.1 Hz, 2H), 7.89 (d, J = 6.2 Hz, 2H), 7.83 (d, J LCMS (ESI) m / z: 444.8 [M] + . Example 8 Synthesis of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 8): [ka]

[0192] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (40 mg, 0.12 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (33.6 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol), and cesium carbonate (0.1 g, 0.31 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 95° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to give 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (17.8 mg, 33.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 6.1 Hz, 2H), 7.99 - 7.86 (m, 4H), 7.79 (d, J = 1.6 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 6.62 - 6.55 (m, 1H), 3.71 (s, 8H), 3.48 (s, 3H); LCMS (ESI) m / z: 430.2 [M+H] + . Example 9 Synthesis of 5-methoxy-6-(3-(3-methyl-1H-pyrazol-1-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 9): [ka]

[0193] A solution of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.28 mmol), 3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (48 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.0028 mmol), and cesium carbonate (209 mg, 0.84 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried and concentrated to give the crude product. It was then purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give 4-(3-(3-(1H-pyrazol-1-yl)phenyl)-7-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)morpholine (23.4 mg, 34%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.42 (dd, J = 4.6, 2.8Hz, 4H), 7.94 - 7.85 (m, 4H), 7.59 (t, J = 7.9Hz, 1H), 3.71 (s, 8H), 3.47 (s, 3H), 2.29 (s, 3H); LCMS (ESI) m / z: 443.9 [M] + .

[0194] Example 10 Synthesis of 5-methoxy-2-morpholino-6-(3-(pyridazin-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (compound 10), 3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-N,N-dimethylbenzamide (compound 11) and 6-(5,6-dimethoxypyridin-3-yl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 12):

[0195] Following the protocol described above in Example 9, the following compounds were synthesized: [Table 6]

[0196] Example 11 Synthesis of 6-(3,4-dimethoxyphenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 13): [ka]

[0197] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (55 mg, 0.17 mmol), (3,4-dimethoxyphenyl)boronic acid (37.6 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.017 mmol), and cesium carbonate (0.14 g, 0.43 mmol) in 1,4-dioxane / water (10 mL / 2 mL) was stirred at 95 °C for 16 hours under an argon atmosphere. The reaction mixture was concentrated, diluted with water (15 mL), and extracted with ethyl acetate (15 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to give 6-(3,4-dimethoxyphenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (63.9 mg, 88.9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.40 (d, J = 6.3Hz, 2H), 7.87 (dd, J = 4.9, 1.4Hz, 2H), 7.78 (s, 2H), 7.09 (d, J = 9.1Hz, 1H), 3.82 (d, J = 6.7Hz, 6H), 3.70 (d, J = 3.0Hz, 8H), 3.49 (s, 3H); LCMS (ESI) m / z: 424.6 [M+H] + . Example 12 Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 14): [ka]

[0198] Step 1: Synthesis of 4-bromo-2-(1-methyl-1H-pyrazol-3-yl)pyridine.

[0199] A mixture of 2,4-dibromopyridine (472 mg, 2 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (416 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol), and cesium carbonate (1.956 g, 6 mmol) in water (3 mL) and dioxane (30 mL) was stirred at 80 °C for 16 h under an argon atmosphere. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0% to 3%) to give 4-bromo-2-(1-methyl-1H-pyrazol-3-yl)pyridine (450 mg, 61%) as a yellow oil. LCMS (ESI) m / z: 238.0 [M+H] + .

[0200] Step 2: Synthesis of 2-(1-methyl-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[0201] A mixture of 4-bromo-2-(1-methyl-1H-pyrazol-3-yl)pyridine (95 mg, 0.4 mmol), bis(pinacolato)diboron (122 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (33 mg, 0.04 mmol), and potassium acetate (118 mg, 1.2 mmol) in dioxane (10 mL) was stirred at 90 °C for 16 h. The resulting mixture was used directly in the next step. LCMS (ESI) m / z: 286.2 [M+H] + .

[0202] Step 3: Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0203] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (128 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol), cesium carbonate (391 mg, 1.2 mmol), and water (0.5 mL) was added to the reaction mixture from the previous step, and the resulting mixture was stirred at 95 °C under argon for 16 hours. This was concentrated and purified by preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120 A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (76.1 mg, 34%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 9.43 (bs, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.52 (s, 1H), 8.43 (d, J = 6.3Hz, 2H), 7.87 (d, J = 6.4Hz, 1H) 7.80 (d, J = LCMS (ESI) m / z: 445.2 [M+H] + . Example 13 Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one (compound 15): [ka]

[0204] Step 1: Synthesis of 4-(3-bromophenyl)-1-methylpiperazin-2-one.

[0205] A mixture of 1-methylpiperazin-2-one (1 g, 8.76 mmol), 1,3-dibromobenzene (6.2 g, 26.28 mmol), cesium carbonate (11.42 g, 35.04 mmol), palladium(II) acetate (0.39 g, 1.75 mmol), and 1,1'-binaphthyl-2,2'-diphenylphosphine (1.64 g, 2.63 mmol) in toluene (25 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 4-(3-bromophenyl)-1-methylpiperazin-2-one (1.5 g, 64%) as a yellow solid. LCMS (ESI) m / z: 269.1 [M+H] + .

[0206] Step 2: Synthesis of 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one.

[0207] A mixture of 4-(3-bromophenyl)-1-methylpiperazin-2-one (0.4 g, 1.49 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.57 g, 2.23 mmol), potassium acetate (0.37 g, 3.72 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.14 g, 0.15 mmol), and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.11 g, 0.23 mmol) in 1,4-dioxane (15 mL) was stirred at 85° C. for 4 hours. The reaction mixture was then filtered, the filtrate was concentrated, and the crude product thus obtained was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one (0.3 g, 64%) as a yellow solid. LCMS (ESI) m / z: 317.1 [M+H] + .

[0208] Step 3: Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one.

[0209] To a solution of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.1 g, 0.31 mmol) and 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one (0.14 g, 0.44 mmol) in dioxane / water (5 mL / 1 mL) was added cesium carbonate (0.2 g, 0.62 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.022 g, 0.03 mmol). The resulting mixture was stirred at 90 °C for 2 hours and poured into ice water. The aqueous medium was extracted with ethyl acetate (15 mL × 3), and the combined organic layers were washed with brine, dried, and concentrated. The resulting crude product was purified by preparative HPLC (SunFire C18, 4.6 x 50 mm, 3.5 um column. The elution system used was a 5% to 95% gradient over 1.5 minutes at 2 ml / min, and the solvent was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give 4-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one (51.3 mg, 35%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.41 (d, J = 6.2Hz, 2H), 7.88 (d, J = 6.4Hz, 2H), 7.56 (s, 1H), 7.47 (d, J = 7.6Hz, 1H), 7.37 (t, J = 7.9Hz, 1H), 7.09 (d, J = 8.2Hz, 1H), 3.80 (s, 2H), 3.69 (d, J = 3.3Hz, 8H), 3.54 (t, J = 8Hz, 2H), 3.46 (s, 2H), 3.45 (s, 3H), 2.91 (s, 3H). LCMS (ESI) m / z: 475.8 [M] + . Example 14 Synthesis of 5-methoxy-2-morpholino-N-(pyridin-4-yl)-6-(3-(pyrimidin-2-yl)phenyl)pyrimidin-4-amine (compound 16): [ka]

[0210] Step 1: Synthesis of 2-(3-bromophenyl)pyrimidine.

[0211] A solution of 2-bromopyrimidine (300 mg, 2.0 mmol), (3-bromophenyl)boronic acid (400 mg, 2.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (240 mg, 0.28 mmol), and cesium carbonate (1960 mg, 6.0 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried and concentrated. The crude product thus obtained was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to give 2-(3-bromophenyl)pyrimidine (210 mg, 47%) as a yellow oil. LCMS (ESI) m / z: 234.8 [M+H] +

[0212] Step 2: Synthesis of 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine.

[0213] To a solution of 2-(3-bromophenyl)pyrimidine (200 mg, 0.9 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (300 mg, 1.2 mmol), [1'1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (82 mg, 0.09 mmol), and potassium acetate (877 mg, 2.7 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours and then concentrated. The resulting residue was subjected to silica gel column chromatography (2% methanol in dichloromethane) to give 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine (180 mg, 71.0%) as a white solid. LCMS (ESI) m / z: 283.2 [M+H] + .

[0214] Step 3: Synthesis of 5-methoxy-2-morpholino-N-(pyridin-4-yl)-6-(3-(pyrimidin-2-yl)phenyl)pyrimidin-4-amine.

[0215] A solution of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.28 mmol), 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine (48 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.0028 mmol), and cesium carbonate (209 mg, 0.84 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100° C. for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL×3). The organic layer was dried and concentrated, and the resulting crude product was purified by preparative TLC (petroleum ether:ethyl acetate 50:1 to 10:1) to afford 5-methoxy-2-morpholino-N-(pyridin-4-yl)-6-(3-(pyrimidin-2-yl)phenyl)pyrimidin-4-amine (13.4 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.13 (s, 1H), 8.95 (d, J = 4.8Hz, 2H), 8.52-8.42 (m, 3H), 8.16 (d, J = 7.9Hz, 1H), 7.90 (d, J = 7.68 (t, J = 7.8Hz, 1H), 7.49 (t, J = 4.8Hz, 1H), 3.72 (s, 8H), 3.47 (s, 3H). LCMS (ESI) m / z: 441.8 [M] + . Example 15 Synthesis of 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridazin-3-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine (compound 17): [ka]

[0216] Step 1: Synthesis of 6-chloro-5-methoxy-2-morpholino-N-(p-tolyl)pyrimidin-4-amine.

[0217] To a solution of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (530 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added p-toluidine (214 mg, 2.0 mmol) and potassium carbonate (556 mg, 4.0 mmol). The mixture was stirred at 100° C. for 20 hours, then quenched with water (15 mL) and extracted with ethyl acetate (20 mL×3). 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 6-chloro-5-methoxy-2-morpholino-N-(p-tolyl)pyrimidin-4-amine as a yellow solid (340 mg, 50.5%). LCMS (ESI) m / z: 335.1 [M+H] + .

[0218] Step 2: Synthesis of 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridazin-3-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine.

[0219] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(p-tolyl)pyrimidin-4-amine (0.1 g, 0.3 mmol), 3-chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridazine (0.1 g, 0.51 mmol), hexamethyldistannane (0.17 g, 0.51 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.03 g, 0.06 mmol) in 1,4-dioxane (4 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was concentrated and the residue was subjected to preparative HPLC (SunFire C18, 4.6 x 50 mm, 3.5 um column. The elution system used was a 5% to 95% gradient over 1.5 minutes at 2 ml / min, and the solvent was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridazin-3-yl)-2-morpholino-N-(p-tolyl)pyrimidin-4-amine as a yellow solid (3.4 mg, 2.5%). 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (d, J = 2.1Hz, 1H), 8.45 (d, J = 2.1Hz, 1H), 7.76 (d, J = 2.4Hz, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.16 (d, J = LCMS (ESI) m / z: 459.1 [M+H] + . Example 16 Synthesis of 6-(5,6-dimethoxypyridin-3-yl)-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 18): [ka]

[0220] Step 1: Synthesis of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0221] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.5 g, 1.89 mmol), pyridin-3-amine (0.16 g, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.18 g, 0.38 mmol), and cesium carbonate (1.54 g, 4.73 mmol) in toluene (25 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to flash chromatography (eluting with 30% to 60% petroleum ether in ethyl acetate) to give 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (0.2 g, 36.7%) as a white solid. LCMS (ESI) m / z: 321.8 [M] + .

[0222] Step 2: Synthesis of 6-(5,6-dimethoxypyridin-3-yl)-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0223] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (80 mg, 0.25 mmol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (79.5 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 0.025 mmol), and cesium carbonate (0.2 g, 0.62 mmol) in 1,4-dioxane / water (15 mL / 3 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated, and the residue was diluted with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to preparative HPLC to give 6-(5,6-dimethoxypyridin-3-yl)-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (27.6 mg, 26%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.98 (d, J = 2.6Hz, 1H), 8.47 (d, J = 1.8Hz, 1H), 8.22 (d, J = 4.7Hz, 1H), 8.18 (d, J = 9.2Hz, 1H), 7.89 (d, J = 1.8Hz, 1H), 7.36 (dd, J = 8.3, 4.6Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.66 (d, J = 5.8Hz, 8H), 3.54 (s, 3H). LCMS (ESI) m / z: 424.8 [M] + . Example 17 Synthesis of compounds 19-24

[0224] The following compounds were synthesized according to the protocol described above in Example 16: 5-methoxy-6-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 19), 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 20), 5-methoxy-2-morpholino-6-(3-(pyridazin-3-yl)phenyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 21). (3,4-dimethoxyphenyl)-N-(pyridin-3-yl)pyrimidin-4-amine (Compound 21), 6-(3,4-dimethoxyphenyl)-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (Compound 22), 3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)benzonitrile (Compound 23), and 3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)-N,N-dimethylbenzamide (Compound 24). [Table 7]

[0225] Example 18 Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 25): [ka]

[0226] Step 1: Synthesis of 2-(1-methyl-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[0227] A mixture of 4-bromo-2-(1-methyl-1H-pyrazol-3-yl)pyridine (71 mg, 0.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (91 mg, 0.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (24 mg, 0.03 mmol), and potassium acetate (88 mg, 0.9 mmol) in 1,4-dioxane (8 mL) was stirred at 90 °C for 16 h. The reaction mixture was cooled and used directly in the next step. LCMS (ESI) m / z: 279.1 [M-4]. + .

[0228] Step 2: Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0229] To the mixture from Step 1, 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (96 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), cesium carbonate (293 mg, 0.9 mmol), and water (1 mL) were added, and the resulting mixture was stirred at 95° C. under an argon atmosphere for 16 hours. It was then concentrated and subjected to preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120 A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (34.6 mg, 19%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.99 (d, J = 2.4Hz, 1H), 8.69 (d, J = 5.2Hz, 1H), 8.52 (s, 1H), 8.25 (dd, J = 4.6, 1.3Hz, 1H), 8.20 (ddd, J = 8.4, 2.3, 1.5Hz, 1H), 7.82 (dd, J = 5.2, 1.6Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.3, 4.7 Hz, 1H), 6.85 (d, J = 2.2Hz, 1H), 3.94 (s, 3H), 3.67 (d, J = 4.5Hz, 8H), 3.52 (s, 3H). LCMS (ESI) m / z: 444.8 [M] + . Example 19 Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-3-ol (compound 26): [ka]

[0230] Step 1: Synthesis of 1-(3-bromophenyl)pyrrolidin-3-ol.

[0231] A mixture of 1,3-dibromobenzene (2.34 g, 10.0 mmol), pyrrolidin-3-ol (870 mg, 10.0 mmol), tris(dibenzylideneacetone)-dipalladium(0) (458 mg, 0.5 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (622 mg, 1.0 mmol), and potassium tert-butoxide (2.24 g, 20.0 mmol) in 1,4-dioxane (40 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then poured into water and extracted with dichloromethane (200 mL × 2). The combined organic phase was concentrated, and the resulting residue was subjected to silica gel column chromatography (70% ethyl acetate in petroleum ether) to give 1-(3-bromophenyl)pyrrolidin-3-ol (1.3 g, 46%) as a gray solid. LCMS(ESI)m / z:241.6 / 243.8[M+H] + .

[0232] Step 2: Synthesis of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-ol.

[0233] A mixture of 1-(3-bromophenyl)pyrrolidin-3-ol (1.2 g, 5.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.54 g, 10.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (408 mg, 0.5 mmol), and potassium acetate (980 mg, 10.0 mmol) in 1,4-dioxane (40 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was poured into water and extracted with ethyl acetate (150 mL × 2). The combined organic phase was concentrated and subjected to silica gel column chromatography (60% ethyl acetate in petroleum ether) to give 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-ol (1.4 g, 97%) as a brown oil. LCMS (ESI) m / z: 289.9 [M] + .

[0234] Step 3: Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-3-ol.

[0235] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (100 mg, 0.38 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-ol (136 mg, 0.47 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (201 mg, 0.62 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was then poured into water and extracted with ethyl acetate (100 mL × 2). The combined organic phases were concentrated and subjected to silica gel column chromatography (15% methanol in dichloromethane) followed 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 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-3-ol (60.3 mg, 42%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.99 (d, J = 1.9 Hz, 1H), 8.20 (t, J = 5.9 Hz, 2H), 7.36 (dd, J = 8.2, 4.7 Hz, 1H), 7.26 (d, J = 5.5 Hz, 2H), 7.19 (s, 1H), 6.60 (d, J = 3.4 Hz, 1H), 4.97 (d, J = 3.6 Hz, 1H), 4.43 (s, 1H), 3.65 (d, J = 9.8 Hz, 8H), 3.49 - 3.42 (m, 4H), 3.37 (d, J = 7.5 Hz, 2H), 3.11 (d, J = 9.1 Hz, 1H), 2.10 - 2.03 (m, 1H), 1.93 (d, J = 3.5 Hz, 1H); LCMS (ESI) m / z: 448.8 [M] + . Example 20 Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one (compound 27): [ka]

[0236] Step 1: Synthesis of 4-(3-bromophenyl)-1-methylpiperazin-2-one.

[0237] A mixture of 1,3-dibromobenzene (1000 mg, 4.24 mmol), 1-methylpiperazin-2-one (320.2 mg, 2.82 mmol), tris(dibenzylideneacetone)dipalladium (250 mg, 0.28 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (260 mg, 0.56 mmol), and cesium carbonate (2700 mg, 8.46 mmol) in 1,4-dioxane (10 mL) was stirred at 85 °C for 16 h under an argon atmosphere. The mixture was then filtered, and the filtrate was concentrated. The residue was subjected to preparative TLC (dichloromethane / methanol = 10 / 1) to give 4-(3-bromophenyl)-1-methylpiperazin-2-one (550 mg, 50%) as a white solid. LCMS(ESI)m / z:271.0[M+H] + .

[0238] Step 2: Synthesis of 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one.

[0239] A mixture of 4-(3-bromophenyl)-1-methylpiperazin-2-one (230 mg, 0.85 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (324 mg, 1.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.08 mmol), and potassium carbonate (351 mg, 2.55 mmol) in 1,4-dioxane (5 mL) was stirred at 85 °C under an argon atmosphere for 16 hours. The resulting mixture was filtered, and the filtrate was concentrated. The residue was subjected to preparative TLC (dichloromethane / methanol=10 / 1) to give 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one (150 mg, 55%) as a white solid. LCMS (ESI) m / z: 317.2 [M+H] + .

[0240] Step 3: Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one.

[0241] A mixture of 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one (95 mg, 0.3 mmol), 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (100 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.03 mmol), and cesium carbonate (195 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 85 °C for 16 hours under an argon atmosphere. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried and concentrated. The resulting residue was subjected to preparative HPLC to afford 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one (18 mg, 13%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 9.00 (s, 1H), 8.20 (d, J = 9.4Hz, 2H), 7.56 (s, 1H), 7.47 (d, J = 7.2Hz, 1H), 7.36 (t, J = 7.8Hz, LCMS (ESI) m / z: 475.8 [M] + . Example 21 Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)morpholin-3-one (compound 28): [ka]

[0242] Step 1: Synthesis of 4-(3-bromophenyl)morpholin-3-one.

[0243] A mixture of 1,3-dibromobenzene (1.4 g, 5.94 mmol), morpholin-3-one (500 mg, 4.95 mmol), cuprous iodide (95 mg, 0.5 mmol), and potassium carbonate (1.4 g, 9.9 mmol) in DMF (8 mL) was stirred at 130 °C for 2 hours under microwave irradiation. The resulting mixture was filtered, and the filtrate was concentrated. The residue was then subjected to preparative TLC (dichloromethane / methanol = 10 / 1) to give 4-(3-bromophenyl)morpholin-3-one (800 mg, 53%) as a colorless oil. LCMS (ESI) m / z: 258.0 [M+H] + .

[0244] Step 2: Synthesis of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one.

[0245] A mixture of 4-(3-bromophenyl)morpholin-3-one (330 mg, 1.28 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (489 mg, 1.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95 mg, 0.13 mmol), and potassium carbonate (529 mg, 3.84 mmol) in dioxane (5 mL) was stirred at 85 °C under an argon atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated. The residue was subjected to preparative TLC (dichloromethane / methanol=10 / 1) to give 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (250 mg, 64%) as a white solid. LCMS (ESI) m / z: 304.3 [M+H] + .

[0246] Step 3: Synthesis of 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)morpholin-3-one.

[0247] A mixture of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (91 mg, 0.3 mmol), 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (100 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.03 mmol), and cesium carbonate (195 mg, 0.6 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 85 °C for 16 hours under an argon atmosphere. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried and concentrated. The crude product thus obtained was purified by preparative HPLC to afford 4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)morpholin-3-one (32 mg, 23%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.98 (d, J = 2.3Hz, 1H), 8.20 (dd, J = 14.7, 6.9Hz, 2H), 8.05 (s, 1H), 7.94 (d, J = 7.4Hz, 1H), 7.57 - 7.47 (m, 2H), 7.37 (dd, J = 8.3, 4.6Hz, 1H), 4.24 (s, 2H), 4.05 - 3.98 (m, 2H), 3.83 - 3.78 (m, 2H), 3.65 (d, J = 7.6Hz, 8H), 3.50 (s, 3H). LCMS (ESI) m / z: 462.8 [M] + . Example 22 Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one (compound 29): [ka]

[0248] Step 1: Synthesis of 1-(3-bromophenyl)pyrrolidin-2-one.

[0249] A mixture of 1,3-dibromobenzene (2.34 g, 10.0 mmol), pyrrolidin-2-one (850 mg, 10.0 mmol), palladium acetate (112 mg, 0.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (578 mg, 1.0 mmol), and cesium carbonate (6.5 g, 20.0 mmol) in dioxane (40 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with dichloromethane (200 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (70% ethyl acetate in petroleum ether) to give 1-(3-bromophenyl)pyrrolidin-2-one (1.1 g, 46%) as a gray solid. LCMS(ESI)m / z:240.8 / 242.8[M+H] + .

[0250] Step 2: Synthesis of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one.

[0251] A mixture of 1-(3-bromophenyl)pyrrolidin-2-one (1.0 g, 4.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.0 g, 8.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (334 mg, 0.41 mmol), and potassium acetate (804 mg, 8.2 mmol) in dioxane (40 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was poured into water and extracted with ethyl acetate (150 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (50% ethyl acetate in petroleum ether) to give 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (1.2 g) as a pale yellow solid. LCMS (ESI) m / z: 287.9 ​​[M+H] + .

[0252] Step 3: Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one.

[0253] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (100 mg, 0.38 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (135 mg, 0.47 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), cesium carbonate (201 mg, 0.62 mmol), dioxane (5 mL), and water (0.5 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (100 mL × 2). The combined organic phases were concentrated, and the residue was first subjected to silica gel column chromatography (15% methanol in dichloromethane) and then preparative HPLC (column Xbridge 21.2 × 250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile) to give 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one (36.4 mg, 26.1%) as a grey solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.99 (d, J = 2.1Hz, 1H), 8.40 (s, 1H), 8.25 - 8.17 (m, 2H), 7.80 (d, J = 7.7Hz, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.49 (t, J = 8.0Hz, 1H), 7.37 (dd, J = 8.3, 4.7Hz, 1H), 3.89 (t, J = 7.0Hz, 2H), 3.65 (d, J = 7.8Hz, 8H), 3.49 (s, 3H), 2.54 (d, J = 8.0Hz, 2H), 2.13 - 2.05 (m, 2H); LCMS (ESI) m / z: 446.9 [M+H] + . Example 23 Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine (compound 30): [ka]

[0254] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine.

[0255] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.45 g, 1.70 mmol), pyridin-4-ylboronic acid (0.21 g, 1.70 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.14 g, 0.17 mmol), and cesium carbonate (1.39 g, 4.26 mmol) in 1,4-dioxane / water (20 mL / 3 mL) was stirred at 95 °C under a nitrogen atmosphere for 16 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (eluting with 30% to 60% petroleum ether in ethyl acetate) to give 4-(4-chloro-5-methoxy-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine (0.2 g, 38.4%) as a pale yellow solid. LCMS (ESI) m / z: 307.1 [M+H] + .

[0256] Step 2: Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine.

[0257] A mixture of 4-(4-chloro-5-methoxy-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine (100 mg, 0.33 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (92.8 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (27 mg, 0.033 mmol), and cesium carbonate (0.27 g, 0.82 mmol) in 1,4-dioxane / water (8 mL / 1 mL) was stirred at 95° C. for 16 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (base) to give 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-yl)pyrimidin-2-yl)morpholine (40.8 mg, 28.9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 5.8Hz, 2H), 8.43 (s, 1H), 8.00 (d, J = 6.0Hz, 2H), 7.92 (dd, J = 7.8, 1.6Hz, 2H), 7.77 (d, J = 2.1Hz, 1H), 7.55 (t, J = 7.8Hz, 1H), 6.74 (d, J = 2.2Hz, 1H), 3.91 (s, 3H), 3.78 (d, J = 5.0Hz, 4H), 3.72 (d, J = 4.8Hz, 4H), 3.28 (s, 3H).LCMS (ESI) m / z: 429.3 [M+H] + . Example 24 Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridazin-3-ylmethyl)pyrimidin-4-amine (compound 31): [ka]

[0258] A mixture of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (150 mg, 0.390 mmol), pyridazin-3-ylmethanamine·2HCl (71 mg, 0.390 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.05 mmol), X-Phos (56 mg, 0.06 mmol), and sodium tert-butoxide (75 mg, 0.780 mmol) in toluene (5 mL) was stirred at 110 °C under a nitrogen atmosphere for 16 h. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridazin-3-ylmethyl)pyrimidin-4-amine (25.3 mg, 14.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (dd, J = 4.7, 1.6 Hz, 1H), 8.37 (s, 1H), 7.88-7.74 (m, 4H), 7.62 (ddd, J = 10.1, 8.5, 3.2 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 4.84 (d, J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.53 (d, J = 4Hz, 4H), 3.49 (d, J = 4Hz, 4H), 3.45 (s, 3H); LCMS (ESI) m / z: 459.0 [M+H]+. Example 25 Synthesis of (5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)(pyridin-4-yl)methanol (compound 32): [ka]

[0259] Step 1: Synthesis of 4-(4-iodo-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine.

[0260] A solution of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (0.3 g, 0.78 mmol) in hydrogen iodide (5 mL) was stirred at 25° C. under an argon atmosphere for 2 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (25 mL×3). The combined organic layer was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give 4-(4-iodo-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-pyrimidin-2-yl)morpholine (0.3 g, 54%) as a yellow solid. LCMS (ESI) m / z: 477.1 [M+H] + .

[0261] Step 2: Synthesis of (5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)(pyridin-4-yl)methanol.

[0262] Isopropylmagnesium chloride (1.3 M in tetrahydrofuran, 0.65 mL, 0.84 mmol) was added to a solution of 4-(4-iodo-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (100 mg, 0.21 mmol) in anhydrous tetrahydrofuran (3 mL) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 minutes, followed by the addition of isonicotinaldehyde (90 mg, 0.84 mmol) in tetrahydrofuran (1.0 mL) at the same temperature. The reaction mixture was warmed and stirred at room temperature for 2 hours. It was then quenched with aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. This was then 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 elution system used was a 5% to 95% gradient over 1.5 minutes at 2 ml / min, and the solvent was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give (5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)(pyridin-4-yl)methanol (34.3 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.5, 1.6 Hz, 2H), 8.37 (t, J = 1.5 Hz, 1H), 7.93 - 7.82 (m, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.49 - 7.44 (m, 2H), 6.72 (d, J = 2.3 Hz, 1H), 6.11 (bs, 1H), 5.97 (s, 1H), 3.89 (d, J = 8.1 Hz, 3H), 3.74 - 3.63 (m, 8H), 3.36 (s, 3H); LCMS (ESI) m / z: 458.5 [M] + . Example 26 Synthesis of N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxamide (compound 33): [ka]

[0263] Step 1: Synthesis of ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate.

[0264] A solution of LDA (2.0 M in THF, 1.92 mL) was added dropwise to a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (750 mg, 3.20 mmol) in anhydrous THF (10 mL) at −70° C., and the resulting mixture was stirred for 1 h under a nitrogen atmosphere. Ethyl carbonochloridate (670 mg, 6.17 mmol) was then added via syringe, and the mixture was stirred for an additional 2 h at −70° C. and 30 min at 20° C. The reaction mixture was poured into ice-water (15 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. This was purified by flash column (ISCO 20 g silica, 0-20% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate (900 mg, 92%) as a white solid.

[0265] Step 2: Synthesis of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0266] To a solution of pyridin-4-amine (120 mg, 1.28 mmol) in DMSO (10 mL) was added NaH (131 mg, 3.27 mmol) at 0 °C. The mixture was warmed and stirred at 20 °C for 0.5 h, and recooled to 0 °C. A solution of ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate (500 mg, 1.63 mmol) in DMSO (5 mL) was added, and the mixture was warmed and stirred at 20 °C for 2 h. The mixture was then poured into saturated aqueous NH Cl (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated to give ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (500 mg, 84%) as a yellow solid.

[0267] Step 3: Synthesis of ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0268] To a solution of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (400 mg, 1.10 mmol) in dioxane (8 mL) and HO (1.4 mL) was added 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (297 mg, 1.10 mmol), CsCO (1.07 g, 3.30 mmol), and Pd(dppf)Cl (80 mg, 110 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours, then cooled to 15 °C and poured into ice water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. This was then purified by flash column chromatography (ISCO 40 g silica, 0 to 80% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate (300 mg, 58%) as a yellow solid.

[0269] Step 4: Synthesis of 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylic acid.

[0270] To a solution of ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate (250 mg, 530 mmol) in MeOH (0.5 mL), THF (1 mL), and HO (0.5 mL) was added LiOH·HO (67 mg, 1.59 mmol). The mixture was stirred at 20 °C for 12 hours and concentrated. It was then diluted with water (1 mL), and the aqueous phase was extracted with ethyl acetate (1 mL × 3). The pH of the aqueous phase was then adjusted to approximately 5 with saturated citric acid, and the resulting precipitate was collected by filtration and dried to give 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (130 mg, 55%) as a pale yellow solid.

[0271] Step 5: Synthesis of N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxamide.

[0272] To a solution of 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (80 mg, 180 μmol) in DMF (1 mL) was added N-methylmethanamine (2.0 M, 90 μL), HATU (69 mg, 180 μmol), and DIPEA (70 mg, 541 μmol), and the resulting mixture was stirred at 20° C. for 2 hours. The crude product from DMF was isolated by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 um column; 10-50% acetonitrile in 0.05% ammonia solution in water and 10 mM ammonium bicarbonate solution, 8 minute gradient) to give N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(4-pyridylamino)pyrimidine-5-carboxamide (31 mg, 36%) as a pale yellow solid. 1 H NMR (400MHz, chloroform-d) δ 9.15 (bs, 1H), 8.49 (d, J = 6.3 Hz, 2H), 8.11 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.66 (bs, 2H), 7.60 - 7.46 (m, 2H), 6.52 (t, J = 1.9 Hz, 1H), 3.94 (s, 4H), 3.84 (t, J = 4.8Hz, 4H), 2.88 (s, 3H), 2.42 (s, 3H).LCMS (ESI for C25H26N8O2) [M+H] + : 471.1. Example 27 Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-yl)-2-(pyridin-4-yl)pyrimidin-4-amine (compound 34): [ka]

[0273] Step 1: Synthesis of 5-methoxy-2-(pyridin-4-yl)pyrimidine-4,6-diol.

[0274] A mixture of isonicotinimidamide hydrochloride (2 g, 12.7 mmol), methanol (10 mL), and sodium methoxide in methanol (25 wt%, 4.6 mL, 25.4 mmol) was heated to reflux for 30 minutes, followed by the addition of diethyl 2-methoxymalonate (2.4 g, 12.7 mmol). The resulting mixture was refluxed for an additional 5 hours. The reaction mixture was then cooled, poured onto ice / water (approximately 50 mL), and acidified using 2N HCl to give a precipitate, which was collected by filtration and air-dried to give 5-methoxy-2-(pyridin-4-yl)pyrimidine-4,6-diol (1.5 g, 54%) as a yellow solid. LCMS (ESI) m / z: 220.1 [M+H] + .

[0275] Step 2: Synthesis of 4,6-dichloro-5-methoxy-2-(pyridin-4-yl)pyrimidine.

[0276] To a mixture of 5-methoxy-2-(pyridin-4-yl)pyrimidine-4,6-diol (1 g, 4.56 mmol) in phosphorus oxychloride (30 mL) was added N,N-diisopropylethylamine (2.0 mL). The resulting mixture was stirred at 90° C. for 5 hours. The volatiles were evaporated and further azeotroped with toluene (2×100 mL). The resulting residue was subjected to flash chromatography (petroleum ether / ethyl acetate=2:1) ​​to afford 4,6-dichloro-5-methoxy-2-(pyridin-4-yl)pyrimidine (0.2 g, 17%) as a yellow solid. LCMS (ESI) m / z: 256.1 [M+H] + .

[0277] Step 3: Synthesis of 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(pyridin-4-yl)pyrimidine.

[0278] To a solution of 4,6-dichloro-5-methoxy-2-(pyridin-4-yl)pyrimidine (0.2 g, 0.78 mmol) and 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.2 g, 0.7 mmol) in dioxane / water (5 mL / 1.5 mL), cesium carbonate (0.51 g, 1.56 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.058 g, 0.08 mmol) were added, and the resulting mixture was stirred at 90° C. for 2 hours. The mixture was then poured into ice water and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine, dried, and concentrated. The resulting crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate=10:1) to give 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(pyridin-4-yl)pyrimidine (100 mg, 34%) as a yellow solid. LCMS (ESI) m / z: 378.1 [M+H] + .

[0279] Step 4: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-yl)-2-(pyridin-4-yl)pyrimidin-4-amine formate.

[0280] A mixture of 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(pyridin-4-yl)pyrimidine (0.08 g, 0.2 mmol), pyridin-3-amine (0.04 g, 0.42 mmol), cesium carbonate (0.21 g, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (0.015 g, 0.03 mmol) in toluene (4 mL) was stirred at 100°C for 4 hours. This was concentrated and the crude product was dissolved in DMF and subjected to preparative HPLC (SunFire C18, 4.6 x 50 mm, 3.5 um column. The elution system used was a 5% to 95% gradient over 1.5 minutes at 2 ml / min, and the solvent was acetonitrile / 0.01% aqueous ammonium bicarbonate) to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-yl)-2-(pyridin-4-yl)pyrimidin-4-amine as a yellow solid (38.6 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.11 (d, J = 2.4Hz, 1H), 8.76 (dd, J = 4.5, 1.5Hz, 2H), 8.54 (t, J = 1.5Hz, 1H), 8.36-8.33 (m, 3H), 8.20 (dd, J = 4.5, 1.6Hz, 2H), 8.04 - 8.02 (m, 1H), 7.95 - 7.93 (m, 1H), 7.79 (d, J = 2.2Hz, 1H), 7.61 (t, J = 7.8Hz, 1H), 7.49 (dd, J = 8.2, 4.7Hz, 1H), 6.78 (d, J = 2.2Hz, 1H), 3.93 (d, J = 6.6Hz, 3H), 3.63 (s, 3H). LCMS (ESI) m / z: 435.8 [M+H] + . Example 28 Synthesis of 4-((1-methylpiperidin-3-yl)oxy)-2-morpholino-8-phenyl-6H-pyrazolo[1,5-d]pyrimido[5,4-b][1,4]oxazine (compound 35): [ka]

[0281] Step 1a: Synthesis of 1-phenyl-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-one.

[0282] A mixture of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (1.0 g, 7.13 mmol), benzoyl chloride (1.0 g, 7.13 mmol), cuprous iodide (67 mg, 0.36 mmol), and bis(triphenylphosphine)palladium(II) chloride (50 mg, 0.07 mmol) in triethylamine (15 mL) was stirred at 25° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (1.2 g, 69%) as a yellow solid. LCMS (ESI) m / z: 245.0 [M+H] + .

[0283] Step 1b: Synthesis of 3-phenyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole.

[0284] A mixture of 1-phenyl-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-one (1 g, 4.1 mmol) and hydrazine hydrate (1 mL) in methanol (15 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give the title compound (0.6 g, 57%) as a yellow solid. LCMS (ESI) m / z: 259.0 [M+H] + .

[0285] Step 1: Synthesis of 4-(4,5,6-trichloropyrimidin-2-yl)morpholine.

[0286] To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (5 g, 21.3 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was added N-chlorosuccinimide (5.7 g, 42.7 mmol) portionwise at room temperature. The resulting mixture was stirred at 60 °C for 16 hours. After cooling, the mixture was diluted with ethyl acetate / water (20 mL / 20 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (Biotage, 40 g silica gel, eluted with 20% to 30% ethyl acetate in petroleum ether) to give 4-(4,5,6-trichloropyrimidin-2-yl)morpholine (5.1 g, 89.7%) as an off-white solid.

[0287] Step 2: Synthesis of 4-(4,5-dichloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-2-yl)morpholine.

[0288] To a solution of 1-methylpiperidin-3-ol (0.45 g, 3.91 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60%, 0.23 g, 5.87 mmol) portionwise at 0° C. After the addition, the reaction mixture was stirred at 0° C. for 30 minutes, followed by the dropwise addition of a solution of 4-(4,5,6-trichloropyrimidin-2-yl)morpholine (1 g, 3.91 mmol) in tetrahydrofuran (10 mL). The resulting mixture was warmed and stirred at room temperature for 16 hours. It was then diluted with ethyl acetate / water (20 mL / 20 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude product thus obtained was purified by flash chromatography (Biotage, 40 g silica gel, eluting with 20% to 40% ethyl acetate in petroleum ether) to give 4-(4,5-dichloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-2-yl)morpholine (1.2 g, 88.7%) as a white solid. LCMS (ESI) m / z: 347.1 [M+H] + .

[0289] Step 3: Synthesis of 4-(5-chloro-4-((1-methylpiperidin-3-yl)oxy)-6-(3-phenyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)morpholine.

[0290] A mixture of 4-(4,5-dichloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-2-yl)morpholine (0.5 g, 1.45 mmol), 3-phenyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (0.37 g, 1.45 mmol), and cesium carbonate (0.94 g, 2.89 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 95° C. for 16 hours. The reaction was cooled, the mixture was diluted with ethyl acetate / water (20 mL / 20 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (Biotage, 40 g silica gel, eluting with 1:10 methanol:dichloromethane 15% to 30% in dichloromethane) to give 4-(5-chloro-4-((1-methylpiperidin-3-yl)oxy)-6-(3-phenyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)morpholine (0.4 g, 48.6%) as a white solid. LCMS (ESI) m / z: 569.2 [M+H] + .

[0291] Step 4: Synthesis of (1-(5-chloro-6-((1-methylpiperidin-3-yl)oxy)-2-morpholinopyrimidin-4-yl)-3-phenyl-1H-pyrazol-5-yl)methanol.

[0292] To a solution of 4-(5-chloro-4-((1-methylpiperidin-3-yl)oxy)-6-(3-phenyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)morpholine (0.4 g, 0.7 mmol) in methanol (20 mL) was added hydrochloric acid (3.0 M in methanol, 2 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the residue was diluted with dichloromethane (10 mL), and the pH of the medium was increased above 7 using sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give (1-(5-chloro-6-((1-methylpiperidin-3-yl)oxy)-2-morpholinopyrimidin-4-yl)-3-phenyl-1H-pyrazol-5-yl)methanol (0.28 g, 82.6%) as a white foam. LCMS (ESI) m / z: 485.1 [M+H] + .

[0293] Step 5: Synthesis of 4-((1-methylpiperidin-3-yl)oxy)-2-morpholino-8-phenyl-6H-pyrazolo[1,5-d]pyrimido[5,4-b][1,4]oxazine.

[0294] A mixture of (1-(5-chloro-6-((1-methylpiperidin-3-yl)oxy)-2-morpholinopyrimidin-4-yl)-3-phenyl-1H-pyrazol-5-yl)methanol (0.11 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.46 mmol) in NMP (3 mL) was stirred at 125° C. for 5 hours. The resulting reaction mixture was filtered, and the filtrate was subjected to preparative HPLC (BOSTON pHlex ODS 10 μm 21.2×250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give the target compound (1.1 mg, 1%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 7.1 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 6.49 (s, 1H), 5.47 (bs, 1H), 5.40 (s, LCMS (ESI) m / z: 448.8 [M] + .

[0295] Example 29 Synthesis of 4-[5-methoxy-6-morpholino-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]-1-methyl-piperazin-2-one (compound 36) and 4-[5-methoxy-4-morpholino-6-(3-pyrazol-1-ylphenyl)pyrimidin-2-yl]-1-methyl-piperazin-2-one (compound 37): [ka]

[0296] Step 1: Synthesis of 4-[2-chloro-5-methoxy-6-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]morpholine and 4-[6-chloro-5-methoxy-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]morpholine.

[0297] To a solution of 4-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)morpholine (500 mg, 1.89 mmol) in dioxane (1 mL) and HO (0.1 mL) was added 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (511 mg, 1.89 mmol), NaCO (2 M, 2.84 mL), and Pd(PPh) (219 mg, 189 μmol) under a nitrogen atmosphere, and the resulting mixture was stirred at 100 °C for 24 h. The mixture was then filtered, and the filtrate was subjected to preparative HPLC (Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um column; 30-70% acetonitrile in 0.04% ammonia solution in water, 8 min gradient) to give 4-[2-chloro-5-methoxy-6-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]morpholine (170 mg) and 4-[6-chloro-5-methoxy-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]morpholine (40 mg) as yellow solids. LCMS (ESI) m / z: 372.1 [M+H] + (both isomers).

[0298] Step 2: Synthesis of 4-[5-methoxy-6-morpholino-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]-1-methyl-piperazin-2-one (compound 37).

[0299] To a solution of 4-[6-chloro-5-methoxy-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]morpholine (170 mg, 457 μmol) in DMSO (3 mL) was added 1-methylpiperazin-2-one (157 mg, 1.37 mmol) and DIPEA (177 mg, 1.37 mmol). The resulting mixture was stirred at 110° C. for 12 hours. Water (5 mL) was then added to the reaction mixture, which was then extracted with ethyl acetate (3 mL × 2). The combined organic layer was washed with brine (5 mL) and dried over Na2SO4. Concentration followed by preparative HPLC of the residue (Waters Xbridge BEH C18 100 x 25 mm x 5 um column; 40-75% acetonitrile in 10 mM ammonium bicarbonate solution in water, 10 min gradient) gave 4-[5-methoxy-6-morpholino-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]-1-methyl-piperazin-2-one (86 mg, 42%) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.57 (s, 1H), 8.27 (d, J = 7.9Hz, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.82 - 7.73 (m, 2H), 7.51 (t, J = 8Hz, 1H), 6.51 (t, J = 2.1Hz, 1H), 4.41 (s, 2H), 4.02 (t, J = 5.3Hz, 2H), 3.89 - 3.72 (m, 8H), 3.65 (s, 3H), 3.52 (t, J = 5.4Hz, 2H), 3.04 (s, 3H). LCMS (ESI) [M+H] for (C23H27N7O3). + : 450.1 Step 3: Synthesis of 4-[5-methoxy-4-morpholino-6-(3-pyrazol-1-ylphenyl)pyrimidin-2-yl]-1-methyl-piperazin-2-one (compound 38):

[0300] Compound 38 was synthesized according to the protocol described for compound 37 and isolated as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.31 (t, J = 2.0 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 6.49 (t, J = 2.1 Hz, 1H), 4.41 (s, 2H), 4.09 (bs, 2H), 3.82 (m, 8H), 3.46 (t, J = 5.2 Hz, 2H), 3.42 (s, 3H), 3.05 (s, 3H). LCMS (ESI) [M+H] for (C23H27N7O3). + : 450.2. Example 30 Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[4',3':4,5]pyrano[3,2-d]pyrimidin-4-amine (compound 38): [ka]

[0301] Step 1: Synthesis of ethyl 4-chloro-6-(1-methyl-1H-pyrazol-3-yl)nicotinate.

[0302] To a mixture of ethyl 4,6-dichloronicotinate (3 g, 13.63 mmol) in 1,4-dioxane / water (50 mL / 10 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.84 g, 13.63 mmol), cesium carbonate (8.88 g, 27.27 mmol), and tetrakis(triphenylphosphine)palladium (0.95 g, 0.82 mmol). The reaction mixture was stirred at 100 °C under argon for 4 hours. It was then filtered, diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layer was concentrated and loaded onto a silica gel column (petroleum ether:ethyl acetate = 2:1) to give ethyl 4-chloro-6-(1-methyl-1H-pyrazol-3-yl)nicotinate (2 g, 55%) as a yellow solid. LCMS(ESI)m / z:266.1[M+H] + .

[0303] Step 2: Synthesis of (5-(ethoxycarbonyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)boronic acid and ethyl 6-(1-methyl-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate.

[0304] A mixture of ethyl 4-chloro-6-(1-methyl-1H-pyrazol-3-yl)nicotinate (1.28 g, 4.82 mmol), 4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.12 g, 24.09 mmol), potassium acetate (1.28 g, 13.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.44 g, 0.48 mmol), and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.34 g, 0.72 mmol) in 1,4-dioxane (15 mL) was stirred at 100° C. for 4 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to give a mixture of (5-(ethoxycarbonyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)boronic acid and ethyl 6-(1-methyl-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.9 g, 68%) as a yellow solid. LCMS (ESI) m / z: 276.1 [M+H] + , 358.1[M+H] + .

[0305] Step 3: Synthesis of ethyl 4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinate.

[0306] To a solution of 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.3 g, 0.72 mmol) and the mixture from Step 2 [(5-(ethoxycarbonyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)boronic acid and ethyl 6-(1-methyl-1H-pyrazol-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate] (0.69 g, 2.51 mmol) in N,N-dimethylformamide (10 mL) was added potassium phosphate tribasic acid (0.56 g, 2.51 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 g, 0.07 mmol). The resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was concentrated, and the residue was subjected to flash chromatography on silica gel (dichloromethane:methanol=10:1) to give ethyl 4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinate as a yellow solid (0.13 g, 35%). LCMS (ESI) m / z: 521.3 [M+H] + .

[0307] Step 4: Synthesis of (4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol.

[0308] Lithium aluminum hydride (1.0 M in THF, 2.56 mL, 2.56 mmol) was added to a solution of ethyl 4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinate (130 mg, 0.25 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. under a nitrogen atmosphere. The mixture was then warmed and stirred at 25° C. for 1.5 hours. The reaction was then quenched by carefully adding sodium sulfate decahydrate while cooling in an ice bath. Tetrahydrofuran (50 mL) was added to the reaction mixture, which was stirred for 15 minutes, and the resulting solid was filtered off. The filtrate was concentrated, and the resulting residue was subjected to flash chromatography on silica gel (dichloromethane:methanol=10:1) to give (4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol (50 mg, 80%) as a yellow solid. LCMS (ESI) m / z: 479.3 [M+H] + .

[0309] Step 5: Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[4',3':4,5]pyrano[3,2-d]pyrimidin-4-amine.

[0310] To a mixture of ((4-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol (0.06 g, 0.13 mmol) in toluene (2.5 mL) was added cesium carbonate (0.08 g, 0.25 mmol), palladium(II) acetate (0.006 g, 0.03 mmol), and racemic-2-di-t-butylphosphino-1,1'-binaphthyl (0.026 g, 0.06 mmol). The reaction mixture was stirred at 110°C under an argon atmosphere for 5 hours. The resulting mixture was filtered to remove solids, and the filtrate was concentrated. The residue was purified by preparative HPLC (BOSTON pHlex ODS 10 um 21.2 x 250 mm). 120A, using the mobile phase acetonitrile / 0.1% ammonium bicarbonate) to give 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[4',3':4,5]pyrano[3,2-d]pyrimidin-4-amine as an off-white solid (4.0 mg, 7%). 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.58 (s, 1H), 8.41 (d, J = 6.1Hz, 2H), 8.35 (s, 1H), 7.87 (d, J = 6.2Hz, 2H), 7.80 (d, J = 2.2Hz, 1H), 6.84 (d, J = 2.1Hz, 1H), 5.37 (s, 2H), 3.96 (s, 3H), 3.73 (d, J = 8.5Hz, 8H). LCMS (ESI) m / z: 443.3 [M+H] + . Example 31 Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-N,2-di(pyridin-4-yl)pyrimidin-4-amine (compound 39): [ka]

[0311] Step 1: Synthesis of 6-chloro-5-methoxy-N,2-di(pyridin-4-yl)pyrimidin-4-amine.

[0312] A mixture of pyridin-4-amine (0.11 g, 1.2 mmol) and sodium hydride (0.06 g, 2.4 mmol) in dimethyl sulfoxide was stirred at 25° C. for 0.5 hours. 4,6-Dichloro-5-methoxy-2-(pyridin-4-yl)pyrimidine (0.31 g, 1.2 mmol) was added to the mixture, and the reaction mixture was stirred at 25° C. for an additional 2 hours. The mixture was then poured into ice water and extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (dichloromethane:methanol=20:1) to give 6-chloro-5-methoxy-N,2-di(pyridin-4-yl)pyrimidin-4-amine (70 mg, 18%) as a yellow solid. LCMS (ESI) m / z: 314.1 [M+H] + .

[0313] Step 2: Synthesis of (2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)boronic acid.

[0314] To a solution of 4-bromo-2-(1-methyl-1H-pyrazol-3-yl)pyridine (0.08 g, 0.34 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.11 g, 0.44 mmol) in 1,4-dioxane (7 mL) was added potassium acetate (0.067 g, 0.68 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.025 g, 0.034 mmol). The resulting mixture was stirred at 90 °C for 16 h and cooled. This reaction mixture was used directly in the next step without further purification. LCMS (ESI) m / z: 204.1 [M+H] + .

[0315] Step 3: Synthesis of 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-N,2-di(pyridin-4-yl)pyrimidin-4-amine.

[0316] To the mixture from Step 2 was added 5 mL of 1,4-dioxane / water (4 mL / 1 mL), followed by 6-chloro-5-methoxy-N,2-di(pyridin-4-yl)pyrimidin-4-amine (0.08 g, 0.25 mmol), cesium carbonate (0.16 g, 0.5 mmol), and tetrakis(triphenylphosphine)palladium (0.03 g, 0.025 mmol). The resulting reaction mixture was stirred at 90° C. under an argon atmosphere for 16 hours and concentrated. The residue was then subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A, using a mobile phase of acetonitrile / 0.1% ammonium bicarbonate) to give 5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-N,2-di(pyridin-4-yl)pyrimidin-4-amine as an off-white solid (3.7 mg, 3%). 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.80 (dd, J = 8.3, 3.7Hz, 3H), 8.61 (s, 1H), 8.55 (d, J = 6.3Hz, 2H), 8.26 (dd, J = 4.5, 1.5Hz, 2H), 8.05 (dd, J = 4.9, 1.5Hz, 2H), 7.96 (dd, J = 5.1, 1.7Hz, 1H), 7.83 (d, J = 2.2Hz, 1H), 6.89 (d, J = 2.2Hz, 1H), 3.96 (s, 3H), 3.67 (s, 3H). LCMS (ESI) m / z: 437.3 [M+H] + . Example 32 Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[3',2':4,5]pyrano[3,2-d]pyrimidin-4-amine (compound 40): [ka]

[0317] Step 1: Synthesis of ethyl 5-bromo-3-chloropicolinate.

[0318] To a solution of 5-bromo-3-chloropicolinic acid (5 g, 21.2 mmol) in ethanol (50 mL) was added sulfuric acid (0.1 mL). The reaction mixture was stirred at 80° C. for 16 hours and concentrated. The residue was dissolved in ethyl acetate (100 mL), filtered, and concentrated to give ethyl 5-bromo-3-chloropicolinate as a yellow oil (3.5 g, 63%). LCMS (ESI) m / z: 264.1 [M+H] + .

[0319] Step 2: Synthesis of ethyl 3-chloro-5-(1-methyl-1H-pyrazol-3-yl)picolinate.

[0320] To a mixture of ethyl 5-bromo-3-chloropicolinate (1.5 g, 5.67 mmol) in N,N-dimethylformamide (25 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.10 mmol), potassium phosphate tribasic (0.66 g, 0.57 mmol), and tetrakis(triphenylphosphine)palladium (0.66 g, 0.57 mmol). The resulting reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 4 hours. The reaction mixture was then cooled, filtered, and the filtrate was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give ethyl 3-chloro-5-(1-methyl-1H-pyrazol-3-yl)picolinate as a yellow solid (1 g, 66%). LCMS (ESI) m / z: 266.1 [M+H] + .

[0321] Step 3: Synthesis of ethyl 5-(1-methyl-1H-pyrazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate.

[0322] A mixture of ethyl 3-chloro-5-(1-methyl-1H-pyrazol-3-yl)picolinate (1.28 g, 4.82 mmol), 4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.12 g, 24.09 mmol), potassium acetate (1.28 g, 13.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.44 g, 0.48 mmol), and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.34 g, 0.72 mmol) in 1,4-dioxane (15 mL) was stirred at 85° C. for 4 hours. The resulting mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to give ethyl 5-(1-methyl-1H-pyrazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate as a yellow solid (0.9 g, 68%). LCMS (ESI) m / z: 276.1 [M+H] + .

[0323] Step 4: Synthesis of ethyl 3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)picolinate.

[0324] To a solution of 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.3 g, 0.72 mmol) and ethyl 5-(1-methyl-1H-pyrazol-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (0.9 g, 2.51 mmol) in N,N-dimethylformamide (10 mL) was added potassium phosphate tribasic acid (0.53 g, 2.51 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 g, 0.07 mmol). The resulting mixture was stirred at 100 °C for 3 hours and cooled. The mixture was filtered to remove solids, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated, and the residue was subjected to flash chromatography on silica gel (dichloromethane:methanol=10:1) to give ethyl 3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)picolinate as a yellow solid (0.11 g, 29%). LCMS (ESI) m / z: 521.3 [M+H] + .

[0325] Step 5: Synthesis of (3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)methanol.

[0326] A solution of lithium aluminum hydride (1.0 M in THF, 2.56 mL, 2.56 mmol) was added to a solution of ethyl 3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)picolinate (130 mg, 0.25 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred at 25° C. under a nitrogen atmosphere for 1.5 hours. The reaction mixture was then quenched by the careful addition of sodium sulfate decahydrate while cooling in an ice bath. This was further diluted with THF (50 mL), stirred for 15 minutes, filtered, and the filtrate was collected. Concentration followed by flash chromatography of the residue on silica gel (dichloromethane:methanol=10:1) afforded (3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)methanol (60 mg, 50%) as a yellow solid. LCMS (ESI) m / z: 479.3 [M+H] + .

[0327] Step 6: Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[3',2':4,5]pyrano[3,2-d]pyrimidin-4-amine.

[0328] To a mixture of (3-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)methanol (0.045 g, 0.09 mmol) in toluene (2.5 mL) was added cesium carbonate (0.06 g, 0.19 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), and racemic-2-di-t-butylphosphino-1,1'-binaphthyl (0.019 g, 0.05 mmol). The mixture was stirred at 110° C. under an argon atmosphere for 5 hours. The mixture was then filtered, and the filtrate was concentrated. The residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120A, using acetonitrile / 0.1% ammonium bicarbonate as the mobile phase) to give 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-pyrido[3′,2′:4,5]pyrano[3,2-d]pyrimidin-4-amine as an off-white solid (10.0 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.01 (d, J = 2.1Hz, 1H), 8.60 (d, J = 2.1Hz, 1H), 8.40 (d, J = 6.2Hz, 2H), 7.87 (d, J = 6.4Hz, 2H), 7.83 (d, J = 2.2Hz, 1H), 6.93 (d, J = 2.3Hz, 1H), 5.35 (s, 2H), 3.94 (s, 3H), 3.73 (d, J = 4.0Hz, 8H). LCMS (ESI) m / z: 443.3 [M+H] + . Example 33 Synthesis of 6-(3-(1,4-dimethyl-1H-pyrazol-3-yl)phenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 41): [ka]

[0329] Step 1: Synthesis of 3-bromo-1,4-dimethyl-1H-pyrazole.

[0330] To a solution of 3-bromo-4-methyl-1H-pyrazole (800 mg, 5 mmol) and potassium carbonate (1.3 g, 10 mmol) in tetrahydrofuran (25 mL) was added iodomethane (710 mg, 5 mmol) dropwise at 0° C., and the resulting reaction mixture was stirred at 0° C. for 0.5 hours. It was then filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (petroleum ether:acetic acid ester=1:4) to give 3-bromo-1,4-dimethyl-1H-pyrazole (700 mg, 80%) as a white solid. LCMS (ESI) m / z: 175.1 [M+H] + .

[0331] Step 2: Synthesis of 3-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole.

[0332] A mixture of 3-bromo-1,4-dimethyl-1H-pyrazole (194 mg, 0.82 mmol), (3-bromophenyl)boronic acid (165 mg, 0.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (66 mg, 0.082 mmol), and cesium carbonate (668 mg, 2.05 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 90 °C for 16 h under an argon atmosphere. The mixture was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:acetic acid ester = 10:1) to give 3-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole as a white solid (140 mg, 64%). LCMS (ESI) m / z: 251.1 [M+H] + .

[0333] Step 3: Synthesis of 1,4-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

[0334] A mixture of 3-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole (140 mg, 0.52 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (21 mg, 0.026 mmol), potassium acetate (153 mg, 1.56 mmol), and bis(pinacolato)diboron (172 mg, 3.7 mmol) in 1,4-dioxane (5 mL) was stirred at 110° C. for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:acetic acid ester=4:1) to give 1,4-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole as a gray-yellow oil (100 mg, 61%). LCMS(ESI)m / z:299.3[M+H] + .

[0335] Step 4: Synthesis of 6-(3-(1,4-dimethyl-1H-pyrazol-3-yl)phenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0336] A mixture of 1,4-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (100 mg, 0.31 mmol), 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (245 mg, 0.75 mmol) in 1,4-dioxane (5 mL) containing water (1 mL) was stirred at 90° C. under an argon atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using a mobile phase of acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 6-(3-(1,4-dimethyl-1H-pyrazol-3-yl)phenyl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (20.0 mg, 14%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.41 (s, 2H), 8.37 (s, 1H), 7.96 (d, J = 7.3Hz, 1H), 7.90 (s, 2H), 7.77 (d, J = 7.6Hz, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 3.84 (s, 3H), 3.70 (s, 8H), 3.48 (s, 3H), 2.23 (s, 3H). LCMS (ESI) m / z: 458.1 [M+H] + . Example 34 Synthesis of (R)-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(morpholin-3-ylmethoxy)-N-(pyridin-4-yl)pyrimidin-4-amine (compound 42): [ka]

[0337] A mixture of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (60 mg, 0.14 mmol), (S)-morpholin-3-ylmethanol (97 mg, 0.82 mmol), and cesium fluoride (63 mg, 0.41 mmol) in dry acetonitrile (4 ml) was stirred in a sealed tube at 120° C. for 16 hours. The reaction mixture was filtered, 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 (R)-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(morpholin-3-ylmethoxy)-N-(pyridin-4-yl)pyrimidin-4-amine (17.2 mg, 0.036 mmol, yield: 26%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.52-8.40 (m, 3H), 7.98-7.87 (m, 4H), 7.78 (d, J = 2.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 4.21 (d, J = 5.9 Hz, 2H), 3.91 (s, 3H), 3.84 (dd, J = 10.8, 2.8 Hz, 1H), 3.68 (d, J = 10.9 Hz, 1H), 3.51 (s, 3H), 3.40 (dd, J = 14.0, 6.7 Hz, 1H), 3.26 (d, J = 10.2 Hz, 1H), 3.15 (s, 1H), 2.79 (d, J = 13.1 Hz, 2H). LCMS (ESI) m / z: 474.1 [M+H] + . Example 35 Synthesis of (R)-(4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)morpholin-3-yl)methanol (compound 43): [ka]

[0338] Step 1: Synthesis of 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)pyrimidine.

[0339] A mixture of 4,6-dichloro-5-methoxy-2-(methylthio)pyrimidine (1 g, 4.46 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (1.26 g, 4.44 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.36 g, 0.44 mmol), and cesium carbonate (3.6 g, 11 mmol) in 1,4-dioxane / water (40 mL / 4 mL) was stirred at 95° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was subjected to silica gel chromatography (eluting with 20% to 40% ethyl acetate in petroleum ether) to give 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)pyrimidine (0.75 g, 48.6%) as a white solid. LCMS (ESI) m / z: 347.0 [M+H] + .

[0340] Step 2: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0341] A mixture of 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)pyrimidine (0.66 g, 1.91 mmol), pyridin-4-amine (0.18 g, 1.91 mmol), tris(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.18 g, 0.38 mmol) and cesium carbonate (1.55 g, 4.77 mmol) in dry 1,4-dioxane (40 mL) was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated, and the residue was subjected to silica gel chromatography (eluting with 20% to 40% 7N ammonia methanol in dichloromethane) to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine (0.6 g, 78.2%) as a white solid. LCMS (ESI) m / z: 405.1 [M+H] + .

[0342] Step 3: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0343] To a solution of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine (0.53 g, 1.31 mmol) in methanol (15 mL) was added dropwise a solution of oxone (1.61 g, 2.62 mmol) in water (7.5 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 3 hours, and the resulting precipitate was collected by filtration. The solid was further dispersed in aqueous sodium bicarbonate solution and stirred at room temperature for 20 minutes. The resulting solid was again collected by filtration, washed with water, and dried in vacuo to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (0.4 g, 70%) as a white solid. LCMS(ESI)m / z:437.1[M+H]+ .

[0344] Step 4: Synthesis of (R)-(4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)morpholin-3-yl)methanol.

[0345] A mixture of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (50 mg, 0.11 mmol), (R)-morpholin-3-ylmethanol (80 mg, 0.69 mmol), and cesium fluoride (52 mg, 0.34 mmol) in dry acetonitrile (2 mL) was stirred in a sealed tube at 120° C. for 16 hours. The reaction mixture was filtered to remove solids, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give (R)-(4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)morpholin-3-yl)methanol (4 mg, 7.7%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.45 (s, 1H), 8.38(d, J = 6.2Hz, 2H), 7.93-7.81 (m, 4H), 7.77 (d, J = 2.1Hz, 1H), 7.52 (t, J = 7.7Hz, 1H), 6.71 (d, J = 2.2Hz, 1H), 4.91 (t, J = 5.1Hz, 1H), 4.39 (s, 1H), 4.26 (d, J = 13.8Hz, 1H), 4.11 (d, J = 11.2Hz, 1H), 4.00-3.90 (m, 4H), 3.79 (d, J = 5.7Hz, 1H), 3.57 - 3.40 (m, 6H), 3.16 (t, J = 16.3Hz, 1H). LCMS (ESI) m / z: 474.2 [M+H] + . Example 36 Synthesis of 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)pyrrolidin-2-one (compound 44): [ka]

[0346] Step 1: Synthesis of 5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-ol.

[0347] A solution of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (180 mg, 0.413 mmol) in 2.0 M sodium hydroxide (5 mL) was stirred at room temperature under a nitrogen atmosphere for 6 hours. The mixture was triturated with water, and the resulting precipitate was collected by filtration and dried in vacuo to give 5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-ol (152 mg, 88.64%) as a white solid. LCMS (ESI) m / z: 375.0 [M+H] + .

[0348] Step 2: Synthesis of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0349] A solution of 5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-ol (132 mg, 0.353 mmol) in phosphorus oxychloride (4 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel chromatography eluting with a linear gradient of 0% to 63% ethyl acetate in petroleum ether to give 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (40 mg, 25.95%) as a white solid. LCMS(ESI)m / z:393.0[M+H] + .

[0350] Step 3: Synthesis of 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)pyrrolidin-2-one.

[0351] A mixture of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (40 mg, 0.102 mmol), pyrrolidin-2-one (13 mg, 0.153 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (9 mg, 0.02 mmol) and potassium carbonate (84 mg, 0.255 mmol) in dry 1,4-dioxane (6 ml) was stirred at 90°C under a nitrogen atmosphere for 16 hours. The mixture was filtered to remove solids, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)pyrrolidin-2-one (8.1 mg, 18.04%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.64 (s, 2H), 8.54 (d, J = 6.4Hz, 2H), 8.51 (s, 1H), 7.94 (dd, J = 15.3, 7.8Hz, 2H), 7.78 (d, J = 2.2Hz, 1H), 7.58 (t, J = 7.8Hz, 1H), 6.74 (d, J = 2.2Hz, 1H), 4.08 (t, J = 7.0Hz, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 2.61 (t, J = 8.0Hz, 2H), 2.10 - 2.04 (m, 2H). LCMS (ESI) m / z: 442.0 [M+H] + . Example 37 Synthesis of dimethyl(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-5-yl)phosphine oxide (compound 45): [ka]

[0352] Step 1: Synthesis of 5-bromo-6-iodo-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0353] To a mixture of pyridin-3-amine (376 mg, 4.0 mmol) in dimethyl sulfoxide (15 mL) was added sodium hydride (320 mg, 8.0 mmol) at 0° C. The mixture was warmed and stirred at 28° C. for 20 minutes, followed by the addition of 4-(5-bromo-4,6-diiodopyrimidin-2-yl)morpholine (2.0 g, 4.0 mmol). Stirring was continued at 28° C. for an additional 30 minutes, and then the mixture was poured into dilute hydrochloric acid (cooled with crushed ice). The formed precipitate was collected by filtration and dried in vacuo to give 5-bromo-6-iodo-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (500 mg, 24.2%) as a gray solid. LCMS (ESI) m / z: 461.9 / 464.9 [M+H] + .

[0354] Step 2: Synthesis of 5-bromo-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0355] To a mixture of 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.28 g, 0.97 mmol) in acetonitrile / water (15 mL / 3 mL) was added 5-bromo-6-iodo-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (0.5 g, 1.1 mmol), potassium carbonate (0.37 g, 2.71 mmol), and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol). The resulting reaction mixture was stirred at 85° C. under argon for 3 hours and then cooled. The solid was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=15:1) to give 5-bromo-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine as a yellow solid (0.12 g, 23%). LCMS (ESI) m / z: 492.1 [M+H] + .

[0356] Step 3: Synthesis of dimethyl(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-5-yl)phosphine oxide.

[0357] To a mixture of dimethylphosphine oxide (0.023 g, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added 5-bromo-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (0.12 g, 0.24 mmol), potassium phosphate tribasic (0.062 g, 0.29 mmol), palladium(II) acetate (0.006 g, 0.024 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.028 g, 0.048 mmol). The resulting mixture was stirred at 150 °C under argon for 3 h and then cooled. The mixture was filtered to remove solids, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A, using mobile phase acetonitrile / 0.1% ammonium bicarbonate) to give dimethyl(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-5-yl)phosphine oxide (2.6 mg, 2%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.71 (d, J = 2.4Hz, 1H), 8.24 (d, J = 4.7Hz, 1H), 7.99 (d, J = 8.5Hz, 1H), 7.90 (d, J = 7.9Hz, 1H), 7.75 (d, J = 1.9Hz, 2H), 7.48 (t, J = 7.7Hz, 1H), 7.39 (dd, J = 8.2, 4.7Hz, 1H), 7.28 (d, J = 7.6Hz, 1H), 6.77 (d, J = 2.2Hz, 1H), 3.88 (s, 3H), 3.70 (d, J = 4.7Hz, 4H), 3.64 (s, 4H), 1.36 (s, 3H), 1.33 (s, 3H). LCMS (ESI) m / z: 490.2 [M+H] + . Example 38 Synthesis of 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)piperidin-4-ol (compound 46): [ka]

[0358] Step 1: Synthesis of 6-hydroxy-5-methoxy-2-thioxo-2,5-dihydropyrimidin-4(3H)-one.

[0359] To a solution of thiourea (4.7 g, 61.7 mmol) and dimethyl 2-methoxymalonate (10 g, 61.7 mmol) in methanol (50 mL) was added sodium methoxide solution (30% solution in methanol, 11.6 mL, 61.7 mmol). After the addition, the reaction mixture was stirred at 80° C. for 20 hours. It was cooled and used directly in the next step without further purification. LCMS (ESI) 174.7 [M+H] + .

[0360] Step 2: Synthesis of 5-methoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione.

[0361] To the reaction mixture from the above step, iodomethane (10.5 g, 74 mmol) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 20 hours and concentrated. The residue was triturated with water (30 mL), the precipitate was collected by filtration, the solid was washed with water (30 mL), and dried in vacuo to give 5-methoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione (7.5 g, 64.7% over two steps) as a white solid. LCMS (ESI) 188.7 [M+H] + .

[0362] Step 3: Synthesis of 4,6-dichloro-5-methoxy-2-(methylthio)pyrimidine.

[0363] A mixture of 5-methoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione (7 g, 37.2 mmol) and phosphorus oxychloride (50 mL) was stirred at 110° C. for 3 hours and concentrated. The residue was slowly poured into warm water (approximately 40° C.) with vigorous stirring. After addition, the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (eluted with 20% to 40% ethyl acetate in petroleum ether) to give 4,6-dichloro-5-methoxy-2-(methylthio)pyrimidine (7 g, 84%) as a white solid. LCMS (ESI) m / z: 224.9 [M+H] + .

[0364] Step 4: Synthesis of 6-chloro-5-methoxy-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0365] To a solution of pyridin-4-amine (0.28 g, 3 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 0.18 g, 4.5 mmol) portionwise at 0° C. After the addition, the mixture was stirred at room temperature for 30 minutes and recooled to 0° C. Then, a solution of 4,6-dichloro-5-methoxy-2-(methylthio)pyrimidine (0.7 g, 3.13 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. It was diluted with ethyl acetate and water (20 mL / 20 mL), the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (20 mL). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (eluting with 5% to 15% 7N ammonia methanol in dichloromethane) to give 6-chloro-5-methoxy-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine (0.4 g, 47.3%) as a brown solid. LCMS (ESI) m / z: 282.8 [M+H] + .

[0366] Step 5: Synthesis of 6-chloro-5-methoxy-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0367] To a solution of 6-chloro-5-methoxy-2-(methylthio)-N-(pyridin-4-yl)pyrimidin-4-amine (0.4 g, 1.42 mmol) in methanol (15 mL) was added dropwise a solution of oxone (1.74 g, 2.8 mmol) in water (8 mL) at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then neutralized to pH 7-8 with aqueous sodium bicarbonate, and the resulting solid was collected by filtration, washed with water, and dried under vacuum to give 6-chloro-5-methoxy-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (0.25 g, 56.3%) as a brown solid. LCMS (ESI) m / z: 314.7 [M+H] + .

[0368] Step 6: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0369] A mixture of 6-chloro-5-methoxy-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (0.25 g, 0.8 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.23 g, 0.8 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (65 mg, 0.08 mmol), and cesium carbonate (0.65 g, 2 mmol) in 1,4-dioxane / water (25 mL / 4 mL) was stirred at 95° C. for 16 hours under a nitrogen atmosphere. The resulting reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (eluting with 5% to 15% 7N ammonia methanol in dichloromethane) to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (0.18 g, 51.6%) as a yellow solid. LCMS (ESI) m / z: 437.1 [M+H] + .

[0370] Step 7: Synthesis of 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)piperidin-4-ol.

[0371] A mixture of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(methylsulfonyl)-N-(pyridin-4-yl)pyrimidin-4-amine (80 mg, 0.18 mmol), piperidin-4-ol (37 mg, 0.36 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. for 64 hours. The reaction mixture was concentrated, and the residue was subjected to preparative HPLC (base) to give 1-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(pyridin-4-ylamino)pyrimidin-2-yl)piperidin-4-ol (6.5 mg, 8%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.47-8.35 (m, 3H), 7.87 (dt, J = 7.0, 5.0Hz, 4H), 7.77(d, J = 2.2Hz, 1H), 7.52 (t, J = 7.8Hz, 1H), 6.70 (d, J = 2.2Hz, 1H), 4.72 (d, J = 4.3Hz, 1H), 4.28 (d, J = 13.6Hz, 2H), 3.90 (s, 3H), 3.73 (s, 1H), 3.44 (s, 3H), 3.26 (t, J = 10.2Hz, 2H), 1.82 (s, 2H), 1.39 (d, J = 9.5Hz, 2H). LCMS (ESI) m / z: 458.3 [M+H] + . Example 39 Synthesis of 5-methoxy-6-(3-(4-methoxy-1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 47): [ka]

[0372] Step 1: Synthesis of 3-iodo-4-methoxy-1H-pyrazole.

[0373] A mixture of 4-methoxy-1H-pyrazole (600 mg, 6.0 mmol) and N-iodosuccinimide (1.08 g, 4.8 mmol) in N,N-dimethylformamide (50 mL) was stirred at 25° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=12:78) to give 3-iodo-4-methoxy-1H-pyrazole (800 mg, 60%) as a white solid. LCMS (ESI) m / z: 225.1 [M+H] + .

[0374] Step 2: Synthesis of 3-iodo-4-methoxy-1-methyl-1H-pyrazole.

[0375] To a solution of 3-iodo-4-methoxy-1H-pyrazole (800 mg, 3.57 mmol) in tetrahydrofuran (25 mL) was added sodium hydride (60%, 171.36 mg, 4.28 mmol) portionwise at 0° C. After the addition, the mixture was stirred for another 30 minutes. It was then filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=1:4) to give 3-iodo-4-methoxy-1-methyl-1H-pyrazole (194 mg, 19%) as a white solid. LCMS (ESI) m / z: 239.1 [M+H] + .

[0376] Step 3: Synthesis of 3-(3-bromophenyl)-4-methoxy-1-methyl-1H-pyrazole.

[0377] A mixture of 3-iodo-4-methoxy-1-methyl-1H-pyrazole (194 mg, 0.82 mmol), (3-bromophenyl)boronic acid (165 mg, 0.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (66 mg, 0.082 mmol), and cesium carbonate (668 mg, 2.05 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 90 °C for 16 h under an argon atmosphere. The mixture was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-(3-bromophenyl)-4-methoxy-1-methyl-1H-pyrazole (140 mg, 64%) as a white solid. LCMS (ESI) m / z: 269.0 [M+H] + .

[0378] Step 4: Synthesis of 4-methoxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

[0379] A mixture of 3-(3-bromophenyl)-4-methoxy-1-methyl-1H-pyrazole (140 mg, 0.52 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (21 mg, 0.026 mmol), potassium acetate (153 mg, 1.56 mmol), and bis(pinacolato)diboron (172 mg, 3.7 mmol) in 1,4-dioxane (5 mL) was stirred at 110° C. for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give 4-methoxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole as a pale yellow oil (100 mg, 61%). LCMS(ESI)m / z:315.3[M+H] + .

[0380] Step 5: Synthesis of 5-methoxy-6-(3-(4-methoxy-1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0381] A mixture of 4-methoxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (100 mg, 0.31 mmol), 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (245 mg, 0.75 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under an argon atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 5-methoxy-6-(3-(4-methoxy-1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (58.8 mg, 40%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.63 (s, 1H), 8.41 (d, J = 6.2Hz, 2H), 7.91 (t, J = 7.6Hz, 2H), 7.88 (d, J = 6.3Hz, 2H), 7.63 (s, 1H), 7.50 (t, J = 7.8Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (d, J = 1.8Hz, 8H), 3.47 (s, 3H). LCMS (ESI) m / z: 474.2 [M+H] + . Example 40 Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol (compound 48): [ka]

[0382] Step 1: Synthesis of 1-(3-bromophenyl)piperidin-4-ol.

[0383] A mixture of 1,3-dibromobenzene (2.34 g, 10.0 mmol), piperidin-4-ol (870 mg, 10.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (458 mg, 0.5 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (622 mg, 1.0 mmol), and potassium tert-butoxide (2.24 g, 20.0 mmol) in 1,4-dioxane (40 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was poured into water and extracted with dichloromethane (200 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (10% methanol in dichloromethane) to give 1-(3-bromophenyl)piperidin-4-ol (300 mg, 12%) as a red oil. LCMS(ESI)m / z:255.9 / 257.9[M+H] + .

[0384] Step 2: Synthesis of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol.

[0385] A mixture of 1-(3-bromophenyl)piperidin-4-ol (275 mg, 1.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (559 mg, 2.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (90 mg, 0.11 mmol), and potassium acetate (216 mg, 2.2 mmol) in dioxane (10 mL) was stirred at 100° C. under a nitrogen atmosphere for 4 hours. The mixture was poured into water and extracted with ethyl acetate (150 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (5% methanol in dichloromethane) to give 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (250 mg, 74.5%) as a brown oil. LCMS (ESI) m / z: 304.2 [M+H] + .

[0386] Step 3: Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol.

[0387] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (160 mg, 0.5 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (227 mg, 0.75 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 dioxane (6 mL) and water (0.6 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was poured into water and extracted with dichloromethane (100 mL × 2). The combined organic phase was concentrated and the residue was subjected to silica gel column chromatography (15% methanol in dichloromethane) and preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 1-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol (45.5 mg, 19.6%) as a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.40 (d, J = 6.3Hz, 2H), 7.87 (d, J = 6.4Hz, 2H), 7.58 (s, 1H), 7.39 (d, J = 7.7Hz, 1H), 7.31 (t, J = 7.9Hz, 1H), 7.06 (dd, J = 8.2, 2.0Hz, 1H), 4.69 (d, J = 4.3Hz, 1H), 3.70-3.67 (m, 9H), 3.58 - 3.53 (m, 2H), 3.44 (s, 3H), 2.93 - 2.86 (m, 2H), 1.86 - 1.81 (m, 2H), 1.53 - 1.44 (m, 2H); LCMS (ESI) m / z: 463.2 [M+H] + . Example 41 Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-isochromeno[4,3-d]pyrimidin-4-amine (compound 49): [ka]

[0388] Step 1: Synthesis of ethyl 2-bromo-4-iodobenzoate.

[0389] To a solution of 2-bromo-4-iodobenzoic acid (5 g, 15.3 mmol) in ethanol (100 mL) was added sulfuric acid (5 mL), and the reaction mixture was stirred at 80° C. for 16 hours. The mixture was concentrated, and the residue was subjected to column chromatography on silica gel (5% to 10% ethyl acetate in petroleum ether) to give ethyl 2-bromo-4-iodobenzoate (5.3 g, 97.8%) as a yellow oil. LCMS (ESI) m / z: 355.0, 357.0 [M+H] + .

[0390] Step 2: Synthesis of ethyl 2-bromo-4-(1-methyl-1H-pyrazol-3-yl)benzoate.

[0391] A mixture of ethyl 2-bromo-4-iodobenzoate (2 g, 5.63 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.46 g, 0.56 mmol), and cesium carbonate (4.6 g, 14.1 mmol) in 1,4-dioxane / water (50 mL / 5 mL) was stirred at 85 °C for 16 hours under an argon atmosphere. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (eluting with 30% to 60% ethyl acetate in petroleum ether) to give ethyl 2-bromo-4-(1-methyl-1H-pyrazol-3-yl)benzoate (1.45 g, 83.6%) as a white solid. LCMS (ESI) m / z: 310.6 [M+H] + .

[0392] Step 3: Synthesis of ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

[0393] A mixture of ethyl 2-bromo-4-(1-methyl-1H-pyrazol-3-yl)benzoate (1.1 g, 3.57 mmol), bis(pinacolato)diboron (1.36 g, 5.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.29 g, 0.36 mmol) and potassium acetate (0.87 g, 8.92 mmol) in 1,4-dioxane (25 mL) was stirred at 90°C for 16 hours. The mixture was then concentrated and the residue was subjected to flash chromatography (eluting with 30% to 60% ethyl acetate in petroleum ether) to give ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1 g, 78.7%) as a white solid. LCMS (ESI) m / z: 357.1 [M+H] + .

[0394] Step 4: Synthesis of ethyl 2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)benzoate.

[0395] To a solution of 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.26 g, 0.62 mmol) and ethyl 4-(1-methyl-1H-pyrazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.27 g, 0.75 mmol) in 1,4-dioxane / water (7 mL / 2 mL) was added cesium carbonate (0.41 g, 1.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.044 g, 0.06 mmol). The mixture was stirred at 90 °C under an argon atmosphere for 2 hours and then cooled. The mixture was poured into ice water and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (dichloromethane:methanol=10:1) to give ethyl 2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)benzoate (0.19 g, 59%) as a yellow solid. LCMS (ESI) m / z: 520.3 [M+H] + .

[0396] Step 5: Synthesis of (2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol.

[0397] A solution of lithium aluminum hydride (1.0 M in THF, 2.56 mL, 2.56 mmol) was added to a solution of ethyl 2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)benzoate (190 mg, 0.37 mmol) in anhydrous tetrahydrofuran (8 mL) at 0° C., and the resulting mixture was warmed and stirred at 25° C. under nitrogen for 1.5 hours. The reaction was then quenched by the careful addition of sodium sulfate decahydrate while cooling in an ice bath. Tetrahydrofuran (50 mL) was added to the reaction mixture, which was stirred for 15 minutes, filtered, the solid washed with tetrahydrofuran (50 mL), and the filtrate was collected. The combined filtrate was concentrated to give (2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol (140 mg, 80%) as a yellow solid. LCMS (ESI) m / z: 478.3 [M+H] + .

[0398] Step 6: Synthesis of 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-isochromeno[4,3-d]pyrimidin-4-amine.

[0399] A mixture of (2-(5-chloro-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)-4-(1-methyl-1H-pyrazol-3-yl)phenyl)methanol (0.11 g, 0.23 mmol) and potassium tert-butoxide (0.92 mL, 0.92 mmol) in tetrahydrofuran in dimethyl sulfoxide (6 mL) was stirred at 100° C. for 4 hours. The mixture was then filtered, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A, using a mobile phase of acetonitrile / 0.1% ammonium bicarbonate) to give 9-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-6H-isochromeno[4,3-d]pyrimidin-4-amine (12.7 mg, 13%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.39 (d, J = 6.1Hz, 3H), 7.88 (dd, J = 9.1, 3.2Hz, 3H), 7.77 (d, J = 2.1Hz, 1H), 7.38 (d, J = 7.9Hz, 1H), 6.78 (d, J = 2.2Hz, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 3.75 (d, J = 4.6Hz, 4H), 3.72 (d, J = 4.7Hz, 4H). LCMS (ESI) m / z: 442.3 [M+H] + . Example 42 Synthesis of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-chloro-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 50): [ka]

[0400] Step 1: Synthesis of 4-(4,6-diiodopyrimidin-2-yl)morpholine.

[0401] A mixture of 4-(4,6-dichloropyrimidin-2-yl)morpholine (3 g, 12.8 mmol) and hydroiodic acid (30 mL) was stirred at 25° C. for 24 hours. The reaction mixture was filtered, and the solid was dissolved in dichloromethane and ethyl acetate, washed with water, and concentrated. The residue was subjected to silica gel column chromatography (eluted with dichloromethane:methanol=10:1) to give 4-(4,6-diiodopyrimidin-2-yl)morpholine as a yellow solid (2.5 g, 47%). LCMS (ESI) m / z: 418.1 [M+H] + .

[0402] Step 2: Synthesis of 4-(5-chloro-4,6-diiodopyrimidin-2-yl)morpholine.

[0403] To a solution of 4-(4,6-diiodopyrimidin-2-yl)morpholine (2.5 g, 6 mmol) in 1-methyl-2-pyrrolidinone (40 mL) was added N-chlorosuccinimide (1.6 g, 12 mmol) in portions. After the addition, the reaction mixture was stirred at 25 °C for 16 hours. It was diluted with ethyl acetate / water (20 mL / 20 mL), the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography (Biotage, 40 g silica gel, eluted with 20% to 30% ethyl acetate in petroleum ether) to give 4-(5-chloro-4,6-diiodopyrimidin-2-yl)morpholine (1.8 g, 67%) as an off-white solid. LCMS (ESI) m / z: 452.1 [M+H] + .

[0404] Step 3: Synthesis of 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0405] A mixture of pyridin-4-amine (0.21 g, 2.22 mmol) and sodium hydride (0.177 g, 4.43 mmol) in dimethyl sulfoxide (5 mL) was stirred at 25 °C for 0.5 hours. 4-(5-chloro-4,6-diiodopyrimidin-2-yl)morpholine (1 g, 2.22 mmol) was added to the resulting mixture, and stirring was continued for another 2 hours. The mixture was then poured into ice water and extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (dichloromethane:methanol = 20:1) to give 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (400 mg, 43%) as a yellow solid. LCMS (ESI) m / z: 418.1 [M+H] + .

[0406] Step 4: Synthesis of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-chloro-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0407] To a solution of 5-chloro-6-iodo-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (0.05 g, 0.12 mmol) and 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (0.035 g, 0.13 mmol) in 1,4-dioxane / water (1.5 mL / 0.4 mL) was added cesium carbonate (0.078 g, 0.24 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.007 g, 0.01 mmol) at room temperature. The resulting mixture was heated and stirred at 90°C for 2 hours. This was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A, using acetonitrile / 0.1% ammonium bicarbonate as the mobile phase) to give 6-(3-(1H-pyrazol-1-yl)phenyl)-5-chloro-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine as a yellow solid (28.3 mg, 54%). 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.57 (d, J = 2.5Hz, 1H), 8.46 (d, J = 6.3Hz, 2H), 8.13 (s, 1H), 7.96 (dt, J = 7.3, 2.1Hz, 1H), 7.83 - 7.79 (m, 2H), 7.78 (d, J = 1.6Hz, 1H), 7.64 - 7.59 (m, 2H), 6.59 - 6.56 (m, 1H), 3.68 (s, 8H). LCMS (ESI) m / z: 434.3 [M+H] + . Example 43 Synthesis of 6-(5,6-dimethoxypyridin-2-yl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (compound 51): [ka]

[0408] Step 1: Synthesis of 2-bromo-6-iodo-3-methoxypyridine.

[0409] A solution of 2-bromo-6-iodopyridin-3-ol (1 g, 3.36 mmol), iodomethane (955 mg, 6.72 mmol), and potassium carbonate (464 mg, 3.36 mmol) in DMF (40 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, treated with water (30 mL), and stirred for 0.5 hours. The resulting precipitate was isolated by filtration and dried to give 2-bromo-6-iodo-3-methoxypyridine (0.92 g, 87.5%) as a brown solid. LCMS (ESI) m / z: 313.9 [M+H] + .

[0410] Step 2: Synthesis of 6-iodo-2,3-dimethoxypyridine.

[0411] A solution of 2-bromo-6-iodo-3-methoxypyridine (0.92 g, 2.94 mmol), sodium methanolate (320 mg, 5.9 mmol) in dry methanol (30 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography eluting with a linear gradient of 0% to 10% ethyl acetate in petroleum ether to give 6-iodo-2,3-dimethoxypyridine (664 mg, 85.1%) as a brown solid. LCMS (ESI) m / z: 266.0 [M+H] + .

[0412] Step 3: Synthesis of 3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[0413] A solution of 6-iodo-2,3-dimethoxypyridine (200 mg, 0.75 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (230 mg, 0.9 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (61 mg, 0.075 mmol), and potassium acetate (180 mg, 1.5 mmol) in dry 1,4-dioxane (10 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction mixture was used directly in the next step without further purification. LCMS (ESI) m / z: 266.0 [M+H] + .

[0414] Step 4: Synthesis of 6-(5,6-dimethoxypyridin-2-yl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine.

[0415] To the reaction mixture from the previous step, 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (50 mg, 0.156 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride:dichloromethane complex (12 mg, 0.015 mmol), potassium carbonate (146 mg, 0.45 mmol), and water (1 mL) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. It was then filtered to remove solids, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 6-(5,6-dimethoxypyridin-2-yl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (20.6 mg, 31.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.40 (s, 2H), 7.88 (d, J = 4.6 Hz, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.69 (d, J = 6.4 Hz, 8H), 3.65 (s, 3H). LCMS (ESI) m / z: 425.2 [M+H] + . Example 44 Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine (compound 52): [ka]

[0416] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine.

[0417] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (90 mg, 0.341 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (88 mg, 0.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (245 mg, 0.75 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 90° C. under an argon atmosphere for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:acetic acid ester=3:1) to give 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (80 mg, 61%) as a white solid. LCMS (ESI) m / z: 386.2 [M+H] + .

[0418] Step 2: Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine.

[0419] A mixture of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (118 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (245 mg, 0.75 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 90° C. under an argon atmosphere for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine (15.3 mg, 12%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.89 (d, J = 7.8Hz, 2H), 7.77 (d, J = 2.2Hz, 1H), 7.53 (t, J = 7.8Hz, LCMS (ESI) m / z: 432.2 [M+H] + . Example 45 Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N,2-di(pyridin-4-yl)pyrimidin-4-amine (compound 53): [ka]

[0420] A mixture of 4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(pyridin-4-yl)pyrimidine (0.08 g, 0.2 mmol), pyridin-4-amine (0.04 g, 0.42 mmol), cesium carbonate (0.21 g, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (0.015 g, 0.03 mmol) in toluene (4 mL) was stirred at 100°C for 4 hours. The reaction mixture was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A, using acetonitrile / 0.1% ammonium bicarbonate as the mobile phase) to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N,2-di(pyridin-4-yl)pyrimidin-4-amine as a yellow solid (8.8 mg, 10%). 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (dd, J = 4.5, 1.5 Hz, 2H), 8.54 (t, J = 1.9 Hz, 2H), 8.53 (d, J = 1.4 Hz, 1H), 8.27 (dd, J = 4.5, 1.6 Hz, 2H), 8.05 (dd, J = 4.8, 1.5 Hz, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.07 (s, 1H), 3.92 (s, 3H), 3.62 (s, 3H). LCMS (ESI) m / z: 435.8 [M+H] + . Example 46 Synthesis of 5-methoxy-2-morpholino-6-(3-(oxazol-2-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (compound 54): [ka]

[0421] Step 1: Synthesis of 2-(3-bromophenyl)oxazole.

[0422] A mixture of 1-bromo-3-iodobenzene (0.5 g, 1.77 mmol), oxazole (0.12 g, 1.77 mmol), palladium acetate (0.04 g, 0.18 mmol), and copper(I) iodide (0.068 g, 0.36 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 140 °C for 16 h under an argon atmosphere. The reaction mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (eluting with 30% to 60% petroleum ether in ethyl acetate) to give 2-(3-bromophenyl)oxazole (0.3 g, 76.7%) as an oil. LCMS (ESI) m / z: 223.8 [M+H] + .

[0423] Step 2: Synthesis of 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole.

[0424] A mixture of 2-(3-bromophenyl)oxazole (250 mg, 1.12 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (320 mg, 1.12 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (92 mg, 0.112 mmol), and cesium carbonate (1.08 g, 3.36 mmol) in 1,4-dioxane / water (10 mL / 2 mL) was stirred at 100 °C under an argon atmosphere for 3 h. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (base) to give 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (180 mg, 59%) as a white solid. LCMS (ESI) m / z: 271.9 [M+H] + .

[0425] Step 3: Synthesis of 5-methoxy-2-morpholino-6-(3-(oxazol-2-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine.

[0426] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.31 mmol), 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (84 mg, 0.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.031 mmol), and cesium carbonate (0.3 g, 0.93 mmol) in 1,4-dioxane / water (15 mL / 3 mL) was stirred at 100 °C under an argon atmosphere for 3 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC (base) to afford 5-methoxy-2-morpholino-6-(3-(oxazol-2-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine (23.4 mg, 17%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.67 (s, 1H), 8.42 (s, 2H), 8.27 (s, 1H), 8.17 (d, J = 7.7Hz, 1H), 8.09 (d, J = 7.6Hz, 1H), 7.89 (s, 2H), 7.69 (t, J = 7.7Hz, 1H), 7.43 (s, 1H), 3.71 (s, 8H), 3.48 (s, 3H). LCMS (ESI) m / z: 430.8 [M+H] + . Example 47 Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol (compound 55): [ka]

[0427] Step 1: Synthesis of 1-(3-bromophenyl)piperidin-4-ol.

[0428] A mixture of 1,3-dibromobenzene (2.34 g, 10.0 mmol), piperidin-4-ol (870 mg, 10.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (458 mg, 0.5 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (622 mg, 1.0 mmol), and potassium tert-butoxide (2.24 g, 20.0 mmol) in 1,4-dioxane (40 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was then poured into water and extracted with dichloromethane (200 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (10% methanol in dichloromethane) to give 1-(3-bromophenyl)piperidin-4-ol (300 mg, 12%) as a red oil. LCMS(ESI)m / z:255.9 / 257.9[M+H] + .

[0429] Step 2: Synthesis of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol.

[0430] A mixture of 1-(3-bromophenyl)piperidin-4-ol (275 mg, 1.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (559 mg, 2.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (90 mg, 0.11 mmol), and potassium acetate (216 mg, 2.2 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under a nitrogen atmosphere for 4 hours. The mixture was then poured into water and extracted with ethyl acetate (150 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (5% methanol in dichloromethane) to give 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (250 mg, 74.5%) as a brown oil. LCMS (ESI) m / z: 304.2 [M+H] + .

[0431] Step 3: Synthesis of 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol.

[0432] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (100 mg, 0.38 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (136 mg, 0.47 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol), and cesium carbonate (201 mg, 0.62 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was then poured into water and extracted with dichloromethane (100 mL × 2). The combined organic phase was concentrated and the residue was subjected to silica gel column chromatography (15% methanol in dichloromethane) to give an impure product, which was further subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol (23.5 mg, 16%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.99 (s, 1H), 8.34 - 8.16 (m, 2H), 7.58 (s, 1H), 7.35 (m, 3H), 7.05 (d, J = 7.9Hz, 1H), 4.71 LCMS (ESI) m / z: 463.2 [M+H]+ . Example 48 Synthesis of 5-methoxy-2'-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-4,4'-bipyrimidin-6-amine (compound 56): [ka]

[0433] Step 1: Synthesis of 4-methoxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine.

[0434] A mixture of 2-chloro-4-methoxypyrimidine (1.44 g, 10.0 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.08 g, 10.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (163 mg, 0.2 mmol), and cesium carbonate (6.5 g, 20.0 mmol) in dioxane / water (50 mL / 6.0 mL) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was poured into water and extracted with ethyl acetate (200 mL × 2). The combined organic phase was concentrated, and the residue was subjected to silica gel column chromatography (50% ethyl acetate in petroleum ether) to give 4-methoxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine (1.2 g, 63%) as a viscous liquid. LCMS (ESI) m / z: 191.1 [M+H] + .

[0435] Step 2: Synthesis of 2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-ol.

[0436] A mixture of 4-methoxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine (1 g, 5.2 mmol) and concentrated hydrochloric acid (10.0 mL) was stirred at 65° C. for 2 hours. The mixture was poured into crushed ice, basified with solid sodium bicarbonate, and extracted with dichloromethane (150 mL×5). The combined organic phases were concentrated, and the residue was subjected to silica gel column chromatography (20% methanol in dichloromethane) to give 2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-ol (650 mg, 54.7%) as a gray solid. LCMS (ESI) m / z: 177.0 [M+H] + .

[0437] Step 3: Synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine.

[0438] A mixture of 2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-ol (600 mg, 3.4 mmol) and phosphorus oxychloride (10.0 mL) was stirred at 100° C. for 2 hours. The mixture was concentrated, and the residue was poured into crushed ice and extracted with dichloromethane (200 mL×3). The combined organic phases were concentrated, and the residue was subjected to silica gel column chromatography (5% methanol in dichloromethane) to give 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine (450 mg, 58.1%) as a gray solid. LCMS (ESI) m / z: 194.9 / 196.9 [M+H] + .

[0439] Step 4: Synthesis of 5-methoxy-2'-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-4,4'-bipyrimidin-6-amine.

[0440] A mixture of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (150 mg, 0.46 mmol), 1,1,1,2,2,2-hexamethyldistannane (229 mg, 0.7 mmol), and bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.04 mmol) in dioxane (6 mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hours. To the resulting mixture, 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine (90 mg, 0.46 mmol) and bis(tri-tert-butylphosphine)palladium (20 mg, 0.04 mmol) were added, and stirring was continued at 100° C. for an additional 2 hours. It was concentrated, and the residue was subjected to silica gel column chromatography (10% methanol in dichloromethane) followed by preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 5-methoxy-2'-(1-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-4,4'-bipyrimidin-6-amine (9.5 mg, 4.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.97 (d, J = 5.1Hz, 1H), 8.44 (d, J = 6.3Hz, 2H), 7.92 - 7.88 (m, 2H), 7.83 (m, 2H), 6.95 (d, J = 2.2Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 3.69 (s, 8H); LCMS (ESI) m / z: 445.8 [M+H] + .

[0441] Example 49 Synthesis of 5-methoxy-2-morpholino-6-(5-(pyridazin-3-yl)pyridin-3-yl)-N-(pyridin-4-yl)pyrimidin-4-amine (compound 57). [ka]

[0442] A solution of 6-chloro-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.31 mmol), 3-(5-chloropyridin-3-yl)pyridazine (70 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.06 mmol), bis(tri-tert-butylphosphine)palladium(0) (30 mg, 0.03 mmol) and hexamethyldistannane (153 mg, 0.46 mmol) in dry 1,4-dioxane (10 mL) was stirred at 100° C. under an argon atmosphere for 16 hours. The resulting mixture was filtered, the filtrate was concentrated, and the residue was subjected to preparative HPLC (BOSTON pHlex ODS 10 um 21.2 × 250 mm 120A. The mobile phase was acetonitrile / 0.1% ammonium bicarbonate) to give 5-methoxy-2-morpholino-6-(5-(pyridazin-3-yl)pyridin-3-yl)-N-(pyridin-4-yl)pyrimidin-4-amine (12.7 mg, 9.26%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.39 (d, J = 2.2Hz, 1H), 9.32 (dd, J = 4.0, 1.8Hz, 2H), 9.09 (t, J = 2.1Hz, 1H), 8.42 (dd, J = 10.3, 3.2Hz, 3H), 7.89 (dd, J = 7.7, 5.8Hz, 3H), 3.72 (s, 8H), 3.53 (s, 3H). LCMS (ESI) m / z: 443.1 [M+H] + . Example 50 Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine (compound 58): [ka]

[0443] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine.

[0444] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (0.4 g, 1.70 mmol), quinolin-6-ylboronic acid (0.29 g, 1.70 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.14 g, 0.17 mmol), and cesium carbonate (1.39 g, 4.26 mmol) in 1,4-dioxane / water (20 mL / 3 mL) was stirred at 100 °C for 2 hours. The reaction mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (eluting with 30% to 60% petroleum ether in ethyl acetate) to give 4-(4-chloro-5-methoxy-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine (0.2 g, 33.1%) as a pale yellow solid. LCMS (ESI) m / z: 356.8 [M+H] + .

[0445] Step 2: Synthesis of 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine.

[0446] A mixture of 4-(4-chloro-5-methoxy-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine (200 mg, 0.56 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (160 mg, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (46 mg, 0.056 mmol), and cesium carbonate (0.54 g, 1.68 mmol) in 1,4-dioxane / water (10 mL / 2 mL) was stirred at 100° C. for 32 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC (base) to give 4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine (59.6 mg, 22.3%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 4.1Hz, 1H), 8.76 (s, 1H), 8.57 (d, J = 8.0Hz, 1H), 8.48 (s, 1H), 8.44 (m, 1H), 8.15 (d, J = 8.9Hz, 1H), 7.98-7.91 (m, 2H), 7.78 (d, J = 2.0Hz, 1H), 7.56 (t, J = 7.7Hz, 1H), 6.76 (d, J = 2.1Hz, 1H), 3.92 (s, 3H), 3.81 (d, J = 4.1Hz, 4H), 3.75 (d, J = 4.0Hz, 4H), 3.27 (s, 3H). LCMS (ESI) m / z: 478.6 [M+H] + . Example 51 Synthesis of 6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (compound 59): [ka]

[0447] Step 1: Synthesis of 4-(4,6-dichloro-5-(methylthio)pyrimidin-2-yl)morpholine.

[0448] To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (2.4 g, 10.2 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (8 mL, 20.4 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour, followed by the addition of 1,2-dimethyldisulfane (964 mg, 10.2 mmol), which was stirred at −78° C. for an additional 1 hour. The reaction was then quenched with water (15 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography on silica gel (petroleum ether:ethyl acetate = 75:25) to give 4-(4,6-dichloro-5-(methylthio)pyrimidin-2-yl)morpholine as a yellow oil (1.2 g, 42.5%). LCMS(ESI)m / z:279.9[M+H] + .

[0449] Step 2: Synthesis of 4-(4,6-dichloro-5-(methylsulfinyl)pyrimidin-2-yl)morpholine.

[0450] To a solution of 4-(4,6-dichloro-5-(methylthio)pyrimidin-2-yl)morpholine (250 mg, 0.896 mmol) in dichloromethane (10 mL) was added 3-chlorobenzoperoxoic acid (154 mg, 0.89 mmol), and the resulting mixture was stirred at room temperature for 8 hours. The reaction was then quenched with water (15 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography on silica gel (petroleum ether:ethyl acetate = 75:25) to give 4-(4,6-dichloro-5-(methylsulfinyl)pyrimidin-2-yl)morpholine as a yellow solid (215 mg, 81.1%). LCMS (ESI) m / z: 296.0 [M+H] + .

[0451] Step 3: Synthesis of 6-chloro-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0452] A mixture of 4-(4,6-dichloro-5-(methylsulfinyl)pyrimidin-2-yl)morpholine (215 mg, 0.726 mmol), pyridin-3-amine (68 mg, 0.726 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.05 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (56 mg, 0.06 mmol), and potassium carbonate (201 mg, 1.45 mmol) in toluene (10 mL) was stirred at 85°C for 16 hours. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography on silica gel (petroleum ether:ethyl acetate=75:25) to give 6-chloro-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine as a yellow solid (180 mg, 70.3%). LCMS (ESI) m / z: 354.0 [M+H]+ .

[0453] Step 4: Synthesis of 6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine.

[0454] To a solution of 6-chloro-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (180 mg, 0.508 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was added 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (224 mg, 0.792 mmol), potassium carbonate (147 mg, 1.05 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 2 hours. The resulting mixture was filtered, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC (0.05% ammonium bicarbonate:acetonitrile = 5% to 95%) to give 6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-5-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine (26.6 mg, 28.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.78 (d, J = 2.4Hz, 1H), 8.31 (dd, J = 4.6, 1.2Hz, 1H), 8.04 (ddd, J = 8.3, 2.6, 1.5Hz, 1H), 7.92 - 7.81 (m, 2H), 7.76 (d, J = 2.2Hz, 1H), 7.52 - 7.33 (m, 3H), 6.76 (d, J = 2.3Hz, 1H), 3.90 (s, 3H), 3.74 (s, 4H), 3.67 (s, 4H), 2.98 (s, 3H). LCMS (ESI) m / z: 475.6[M+H] + . Example 52 Synthesis of 4-(5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)-1-methylpiperazin-2-one (compound 60): [ka]

[0455] Step 1: Synthesis of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine.

[0456] A mixture of 4-(4,6-dichloro-5-methoxypyrimidin-2-yl)morpholine (782 mg, 3 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (852 mg, 3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (245 mg, 0.3 mmol), and cesium carbonate (2445 mg, 7.5 mmol) in 1,4-dioxane / water (20 mL / 4 mL) was stirred at 90°C under an argon atmosphere for 16 hours. The reaction mixture was filtered to remove solids, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:acetic acid ester=3:1) to give 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (523 mg, 45%) as a white solid. LCMS (ESI) m / z: 386.2 [M+H] + .

[0457] Step 2: Synthesis of 4-(5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)-1-methylpiperazin-2-one.

[0458] A mixture of 4-(4-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-2-yl)morpholine (153.5 mg, 0.4 mmol), 1-methylpiperazin-2-one (45 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (37 mg, 0.08 mmol), and sodium tert-butoxide (115 mg, 4.14 mmol) in toluene (10 mL) was stirred at 85°C under an argon atmosphere for 16 hours. The reaction mixture was filtered to remove solids, the filtrate was concentrated, and the residue was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using mobile phase acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 4-(5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)-1-methylpiperazin-2-one (64 mg, 34.5%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.84 - 7.74 (m, 3H), 7.47 (t, J = 7.7 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 4.26 (s, 2H), 4.00 (t, J LCMS (ESI) m / z: 464.4 [M+H]+. Example 53 Synthesis of 4-(4-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-6-(4-phenyl-1H-imidazol-2-yl)pyrimidin-2-yl)morpholine (compound 61): [ka]

[0459] Step 1: Synthesis of methyl 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylate.

[0460] To a solution of 4-(4-(3-(1H-pyrazol-1-yl)phenyl)-6-chloro-5-methoxypyrimidin-2-yl)morpholine (400 mg, 1.08 mmol) in dimethyl sulfoxide (8 mL) and methanol (10 mL) was added palladium(II) acetate (20 mg, 0.088 mmol), 1,1'-bis(diphenylphosphino)ferrocene (244 mg, 0.44 mmol), and triethylamine (266 mg, 2.64 mmol), and the reaction mixture was stirred at 85°C under a carbon monoxide atmosphere for 16 hours. The mixture was extracted with dichloromethane (20 mL x 2) and washed with water (10 mL x 2). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was then subjected to silica gel column chromatography (3% methanol in dichloromethane) to give methyl 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylate (130 mg, 30%). LCMS (ESI) m / z: 395.9 [M+H] + .

[0461] Step 2: Synthesis of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylic acid.

[0462] To a solution of methyl 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylate (130 mg, 0.3 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (25 mg, 0.6 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then quenched by adding water (10 mL), and the mixture was then filtered to remove solids. The filtrate was extracted with dichloromethane (10 mL × 3), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (methanol:dichloromethane = 1:8) to give 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylic acid (110 mg, 90%) as a yellow solid. LCMS(ESI)m / z:381.8[M+H] + .

[0463] Step 3: Synthesis of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholino-N-(2-oxo-2-phenylethyl)pyrimidine-4-carboxamide.

[0464] To a stirred solution of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholinopyrimidine-4-carboxylic acid (110 mg, 0.27 mmol) and 2-amino-1-phenylethan-1-one (40 mg, 0.30 mmol) in N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetraethyluronium hexafluorophosphate (150 mg, 0.4 mmol) and N,N-diisopropylethylamine (130 mg, 1 mmol). The resulting mixture was stirred at 20 °C for 16 h and concentrated. The residue was subjected to flash chromatography (dichloromethane:methanol=50:1) to give 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholino-N-(2-oxo-2-phenylethyl)pyrimidine-4-carboxamide (125 mg, 90%) as a white solid. LCMS (ESI) m / z: 498.7 [M+H] + .

[0465] Step 4: Synthesis of 4-(4-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-6-(4-phenyl-1H-imidazol-2-yl)pyrimidin-2-yl)morpholine.

[0466] A solution of 6-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-2-morpholino-N-(2-oxo-2-phenylethyl)pyrimidine-4-carboxamide (125 mg, 0.24 mmol) and ammonium acetate (500 mg, 5.5 mmol) was stirred at 180° C. under an argon atmosphere for 2 hours. The mixture was cooled, diluted with ethyl acetate (25 mL), and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give 4-(4-(3-(1H-pyrazol-1-yl)phenyl)-5-methoxy-6-(4-phenyl-1H-imidazol-2-yl)pyrimidin-2-yl)morpholine (4.3 mg, 4%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.59 (d, J = 2.4Hz, 1H), 8.52 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 8.0Hz, 3H), 7.80 (s, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.41 (t, J = 7.6Hz, 2H), 7.26 (s, 1H), 6.59 (s, 1H), 3.86 (s, 4H), 3.74 (d, J = 4.6Hz, 4H), 3.70 (s, 3H). LCMS (ESI) m / z: 479.7 [M+H] + . Example 53 Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-2-(pyridin-4-yl)pyrimidin-4-amine (compound 62): [ka]

[0467] Step 1: Synthesis of 2,6-dichloro-5-methoxy-N-(pyridin-3-ylmethyl)pyrimidin-4-amine.

[0468] A mixture of 2,4,6-trichloro-5-methoxypyrimidine (0.45 g, 2.11 mmol), pyridin-3-ylmethanamine (0.23 g, 2.11 mmol), and N,N-diisopropylethylamine (0.55 g, 4.22 mmol) in tert-butanol (15 mL) was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was subjected to column chromatography (Biotage, 40 g silica gel, eluted with 5% to 15% 7N ammonia methanol in dichloromethane) to give 2,6-dichloro-5-methoxy-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (0.39 g, 65%) as a brown solid. LCMS (ESI) m / z: 284.8 [M+H] + .

[0469] Step 2: Synthesis of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine and 6-chloro-5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine.

[0470] A mixture of 2,6-dichloro-5-methoxy-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (0.35 g, 1.23 mmol), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (314 mg, 1.1 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (100 mg, 0.12 mmol), and cesium carbonate (1 g, 3.07 mmol) in 1,4-dioxane / water (25 mL / 4 mL) was stirred at 95° C. for 16 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to preparative HPLC (base) to give 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (50 mg, 11.2%) and 6-chloro-5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (100 mg, 22.4%) as white solids. LCMS (ESI) m / z: 407.1 [M+H] + .

[0471] Step 3: Synthesis of 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-2-(pyridin-4-yl)pyrimidin-4-amine.

[0472] A mixture of 2-chloro-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (40 mg, 0.098 mmol), pyridin-4-ylboronic acid (15 mg, 0.12 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (10 mg, 0.01 mmol) and cesium carbonate (0.08 g, 0.25 mmol) in 1,4-dioxane / water (5 mL / 1 mL) was stirred at 95°C for 16 hours. The mixture was concentrated and the residue was subjected to preparative HPLC (base) to give 5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-2-(pyridin-4-yl)pyrimidin-4-amine (5.9 mg, 13.4%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.77-8.66 (m, 3H), 8.62-8.54 (m, 1H), 8.48 (t, J = 1.6Hz, 1H), 8.28 (dd, J = 4.5, 1.6Hz, 2H), 8.04-7.99 (m, 1H), 7.93 (dd, J = 7.8, 1.4Hz, 1H), 7.78 (d, J = 7.8, 1Hz, 1H), 7.53 (t, J = 7.8Hz, 1H), 7.42 (d, J = 2.2Hz, 1H), 7.31 (dd, J = 7.8, 4.8Hz, 1H), 6.63 (d, J = 2.3Hz, 1H), 5.95 (t, J = 6.0Hz, 1H), 4.89 (d, J = 6.0Hz, 2H), 3.98 (s, 3H), 3.57 (s, 3H). LCMS (ESI) m / z: 450.1 [M+H] + . Example 54 Synthesis of 5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-6-(pyridin-4-yl)pyrimidin-4-amine (compound 63): [ka]

[0473] A mixture of 6-chloro-5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (70 mg, 0.17 mmol), pyridin-4-ylboronic acid (25 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (14 mg, 0.02 mmol) and cesium carbonate (0.14 g, 0.43 mmol) in 1,4-dioxane / water (8 mL / 1 mL) was stirred at 95°C for 16 hours. The mixture was concentrated and the residue was subjected to preparative HPLC (base) to give 5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-6-(pyridin-4-yl)pyrimidin-4-amine (22.9 mg, 30%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.80-8.73 (m, 3H), 8.70 (s, 1H), 8.44 (dd, J = 4.8, 1.5 Hz, 1H), 8.33 (t, J = 6.1 Hz, 1H), 8.23 ​​(d, J = 7.8 Hz, 1H), 8.04 (dd, J = 4.6, 1.5 Hz, 2H), 7.90 (d, J = 7.9, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 2.2Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.37 (dd, J = 7.8, 4.8 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.60 (s, 3H).LCMS (ESI) m / z: 450.1 [M+H] + .

[0474] Example 55 Synthesis of 2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)-6H-pyrimido[5,4-c]quinolin-5-one (compound 64) and 6-methyl-2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)pyrimido[5,4-c]quinolin-5-one (compound 65): [ka]

[0475] Step 1: Synthesis of 1-(3-bromo-4-nitro-phenyl)pyrazole.

[0476] To a solution of 2-bromo-4-fluoro-1-nitrobenzene (2 g, 9.09 mmol) in DMF (20 mL) was added 1H-pyrazole (619 mg, 9.09 mmol) and Na2CO3 (2.41 g, 22.73 mmol). The resulting mixture was stirred at 100 °C for 12 h, then cooled to 15 °C and poured into ice-water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ISCO 40 g silica, 0–30% ethyl acetate in petroleum ether, gradient over 20 min) to afford 1-(3-bromo-4-nitrophenyl)pyrazole (1.3 g, 53%) as a yellow solid.

[0477] Step 2: Synthesis of 1-[4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole.

[0478] To a solution of 1-(3-bromo-4-nitrophenyl)pyrazole (1.15 g, 4.29 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.31 g, 5.15 mmol), Pd(dppf)Cl (314 mg, 429 mmol), and KOAc (1.26 g, 12.87 mmol) were added. The resulting mixture was stirred at 80 °C for 12 hours. It was then filtered to remove solids, and the filtrate was concentrated to give the crude product. This was purified by flash column chromatography (ISCO 40 g silica, 0 to 50% ethyl acetate in petroleum ether, gradient over 20 min) to give 1-[4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (1 g, 74%) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ 8.29 (d, J = 8.8Hz, 1H), 8.05 (d, J = 2.6Hz, 1H), 7.91–7.76 (m, 3H), 6.59–6.52 (m, 1H), 1.28 (s, 12H)

[0479] Step 3: Synthesis of ethyl 2-morpholino-4-(2-nitro-5-pyrazol-1-yl-phenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0480] To a solution of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (200 mg, 550 μmol) in THF (5 mL) was added 1-[4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (208 mg, 660 μmol), KPO (350 mg, 1.65 mmol), and [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (43 mg, 55 μmol) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 4 hours, then cooled to 15° C. and poured into ice water (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was subjected to flash column chromatography (ISCO 10 g silica, 0–100% ethyl acetate in petroleum ether, gradient over 20 min) to afford ethyl 2-morpholino-4-(2-nitro-5-pyrazol-1-yl-phenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate (340 mg, 60%) as a yellow solid.

[0481] Step 4: Synthesis of 2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)-6H-pyrimido[5,4-c]quinolin-5-one.

[0482] To a solution of ethyl 2-morpholino-4-(2-nitro-5-pyrazol-1-yl-phenyl)-6-(4-pyridylamino)pyrimidine-5-carboxylate (230 mg, 445 μmol) in EtOH (3 mL) and HO (1 mL) was added Fe (249 mg, 4.45 mmol) and NHCl (238 mg, 4.45 mmol). The mixture was stirred at 80 °C for 8 h, and the iron powder was removed by filtration. The filtrate was then concentrated to give 2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)-6H-pyrimido[5,4-c]quinolin-5-one (crude, 150 mg) as a black solid. The crude product (30 mg) was purified by preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using a mobile phase of acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give 2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)-6H-pyrimido[5,4-c]quinolin-5-one (2 mg, 4.75 μmol) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 12.34 (s, 1H), 8.75 (d, J = 2.4Hz, 1H), 8.58 (d, J = 2.4Hz, 1H), 8.50 (d, J = 5.4Hz, 2H), 8.13 (dd, J = 8.9, 2.6Hz, 1H), 7.81 - 7.66 (m, 3H), 7.48 (d, J = 8.7Hz, 1H), 6.59 (s, 1H), 3.80 - 3.79 (m, 4H), 3.78 (d, J = 4.4Hz, 4H). LCMS (ESI for C23H20N8O2) [M+H] + : 441.1.

[0483] Step 5: Synthesis of 6-methyl-2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)pyrimido[5,4-c]quinolin-5-one.

[0484] To a solution of 2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)-6H-pyrimido[5,4-c]quinolin-5-one (100 mg, 227 μmol) in DMF (1 mL) was added NaH (18 mg, 454 μmol, 60% suspension in oil) at 0° C. The mixture was warmed and stirred at 25° C. for 0.5 h. Iodomethane (32 mg, 227 μmol) was then added to the mixture, which was stirred at 25° C. for an additional 2 h. The mixture was then poured into ice water (2 mL) at 0° C., filtered, and the filtrate was concentrated to give the crude product. This was then dissolved in DMF (1 mL), which was allowed to stand for 1 day, and then the solid that formed was removed by filtration, washed with HO (1 mL × 2), and the combined filtrate was concentrated to give 6-methyl-2-morpholino-9-pyrazol-1-yl-4-(4-pyridylamino)pyrimido[5,4-c]quinolin-5-one (9 mg, 8%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 12.21 (bs, 1H), 8.68 (bs, 1H), 8.56 - 8.33 (m, 3H), 8.09 - 7.95 (m, 1H), 7.80 (s, 1H), 7.61 (bs, 2H), 7.48 (bs, 1H), 6.58 (bs, 1H), 4.08 - 3.38 (m, 11H). LCMS (ESI for C24H22N8O2) [M+H] + : 455.1. Example 56 Synthesis of N,N-dimethyl-4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide (compound 66): [ka]

[0485] Step 1: Synthesis of ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate.

[0486] A solution of LDA (2 M in THF, 17.94 mL) was added dropwise to a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (7 g, 29.90 mmol) in anhydrous THF (70 mL) at -70 to -60 °C under a nitrogen atmosphere, and the mixture was stirred for 1 h. Ethyl carbonochloridate (8.68 g, 79.98 mmol) was then added via syringe, and the mixture was stirred for an additional 2 h at -70 to -60 °C. The contents were warmed to 25 °C and stirred for an additional 0.5 h. It was then poured into ice-water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ISCO 40 g silica, 0-20% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate (8.4 g, 92%) as a white solid.

[0487] Step 2: Synthesis of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0488] To a solution of pyridin-4-amine (0.96 g, 10.20 mmol) in DMSO (15 mL) was added NaH (392 mg, 9.80 mmol, 60% suspension) at 0 °C. The mixture was stirred at 20 °C for 0.5 h and re-cooled to 0 °C, followed by the addition of ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate (1.5 g, 4.90 mmol). The mixture was further stirred at 20 °C for an additional 2 h and then poured into ice water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ISCO 20 g silica, 0-100% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (850 mg) as a pale yellow solid. LCMS (ESI) m / z: 364.0 [M+H] +

[0489] Step 3: Synthesis of ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0490] To a solution of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (500 mg, 1.37 mmol) in dioxane (7 mL) and HO (0.7 mL) was added 1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (586 mg, 2.06 mmol), KCO (570 mg, 4.12 mmol), and Pd(PPh) (159 mg, 137 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. To the residue was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, and concentrated. The residue was subjected to flash column chromatography (ISCO 20 g silica, 0 to 87% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (520 mg, 78%) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 6.3Hz, 2H), 7.93 - 7.80 (m, 2H), 7.69 - 7.61 (m, 2H), 7.49 - 7.33 (m, 3H), 6.56 (d, J = 2.3Hz, 1H), 4.04 - 3.86 (m, 9H), 3.80 (bs, 4H), 0.76 (t, J = 7.2Hz, 3H); LCMS (ESI) m / z: 486.3 [M+H] + .

[0491] Step 4: Synthesis of 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid.

[0492] To a solution of ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (500 mg, 1.03 mmol) in THF (4 mL), MeOH (2 mL), and HO (2 mL) was added LiOH·HO (129 mg, 3.09 mmol). The mixture was stirred at 25 °C for 12 h and concentrated. The residue was diluted with HO (5 mL), and saturated aqueous citric acid was added to the mixture at 0 °C until the pH reached 3–4. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (450 mg, 96%) as a yellow solid. LCMS (ESI) m / z: 458.2 [M+H] +

[0493] Step 5: Synthesis of N,N-dimethyl-4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide.

[0494] To a mixture of 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (120 mg, 262 μmol) and N,N-dimethylamine (2 M in THF, 1 mL), HATU (120 mg, 315 μmol) and DIPEA (102 mg, 787 μmol) were added. The mixture was stirred at 20°C for 2 hours, followed by the addition of 1 mL of water. The mixture was extracted with ethyl acetate (3 mL × 2), and the combined organic layers were washed with brine (1 mL), dried over Na2SO4, and concentrated. The residue was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using a mobile phase of acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give N,N-dimethyl-4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide (51 mg, 40%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.47 (d, J = 5.8Hz, 2H), 8.14 - 8.09 (m, 1H), 7.97 (d, J = 7.8Hz, 1H), 7.77 - 7.66 (m, 2H), 7.61 (d, J = 7.8Hz, 1H), 7.51 - 7.44 (m, 1H), 7.42 (d, J = 2.1Hz, 1H), 6.59 (d, J = 2.3Hz, 1H), 4.06 - 3.89 (m, 7H), 3.88 - 3.79 (m, 4H), 2.85 (s, 3H), 2.37 (s, 3H). LCMS (ESI) [M+H] for (C26H28N8O2) + : 485.3. Example 57 Synthesis of 4-(3-cyanophenyl)-N,N-dimethyl-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide (compound 67): [ka]

[0495] Step 1: Synthesis of ethyl 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0496] To a solution of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (400 mg, 1.10 mmol) in dioxane (5 mL) and HO (0.5 mL) was added (3-cyanophenyl)boronic acid (242 mg, 1.65 mmol), KCO (456 mg, 3.30 mmol), and Pd(PPh) (127 mg, 110 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. It was then filtered, the filtrate was concentrated, and the residue was diluted with 5 mL of water. The aqueous phase was extracted with ethyl acetate (5 mL × 2), and the combined organic layers were washed with brine (5 mL), dried over NaSO, and concentrated. The residue was subjected to flash column chromatography (ISCO 20 g silica, 0-80% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (250 mg, 53%) as a yellow solid. LCMS (ESI) m / z: 431.1 [M+H] +

[0497] Step 2: Synthesis of 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid.

[0498] To a solution of ethyl 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (240 mg, 558 μmol) in THF (2 mL), MeOH (1 mL), and HO (1 mL) was added LiOH·HO (70 mg, 1.67 mmol). The mixture was stirred at 25 °C for 12 h and concentrated. To the residue was added 3 mL of water and saturated aqueous citric acid at 0 °C until pH = 4. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (220 mg, 98%) as a yellow solid. LCMS (ESI) m / z: 403.1 [M+H] +

[0499] Step 3: Synthesis of 4-(3-cyanophenyl)-N,N-dimethyl-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide.

[0500] To a mixture of 4-(3-cyanophenyl)-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (110 mg, 273 μmol) and N,N-dimethylamine (2 M in THF, 1 mL), HATU (125 mg, 328 μmol) and DIPEA (106 mg, 820 μmol) were added. The mixture was stirred at 25 °C for 2 h and concentrated. The residue was subjected to preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm column; 10–55% acetonitrile in 10 mM ammonium hydroxide solution in water, 8 min gradient) to afford 4-(3-cyanophenyl)-N,N-dimethyl-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxamide (8 mg, 7%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.77 (s, 1H), 8.50 (d, J = 5.8Hz, 2H), 8.11 (t, J = 1.5Hz, 1H), 7.87 (td, J = 8.2, 1.4Hz, 1H), 7.77 (td, J = 7.8, 1.4Hz, 1H), 7.57 - 7.51 (m, 3H), 3.93 (bs, 4H), 3.86 - 3.81 (m, 4H), 2.89 (s, 3H), 2.38 (s, 3H). LCMS (ESI) [M+H]+ for (C23H23N7O2): 430.3. Example 58 Synthesis of azetidin-1-yl-[4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidin-5-yl]methanone (compound 68): [ka]

[0501] Step 1: Synthesis of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0502] To a solution of pyridin-4-amine (154 mg, 1.63 mmol) in DMSO (30 mL) was added NaH (131 mg, 3.27 mmol, 60% suspension) portionwise at 0 °C. The mixture was then stirred at 25 °C for 0.5 h, and then ethyl 4,6-dichloro-2-morpholino-pyrimidine-5-carboxylate (500 mg, 1.63 mmol) was added to the above mixture at 0 °C. The resulting mixture was stirred at 25 °C for 2 h, and then poured into saturated aqueous NH Cl solution (30 mL) at 0 °C, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na SO and concentrated. The residue was subjected to flash chromatography (ISCO 40 g silica, 0 to 56% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (1.66 g, 28%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 10.82 (s, 1H), 8.46 (d, J = 6.1Hz, 2H), 7.49 (d, J = 6.2Hz, 2H), 4.36 (q, J = 7.1Hz, 2H), 3.86 - 3.72 (m, 8H), 1.39 (t, J = 7.2Hz, 3H).

[0503] Step 2: Synthesis of ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate.

[0504] To a solution of ethyl 4-chloro-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (1 g, 2.06 mmol) in dioxane (15 mL) and HO (1.5 mL) was added 1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (879 mg, 2.47 mmol), KCO (855 mg, 6.18 mmol), and Pd(PPh) (238 mg, 206 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction mixture was then diluted with water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated. The residue was subjected to flash chromatography (ISCO 20 g silica, 0-77% ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (600 mg, 60%) as a pale yellow solid. LCMS (ESI) m / z: 486.3 [M+H] +

[0505] Step 3: Synthesis of 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid.

[0506] To a solution of ethyl 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylate (200 mg, umol) in THF (4 mL), MeOH (2 mL), and HO (2 mL) was added LiOH·HO (52 mg, 1.24 mmol). The mixture was stirred at 25 °C for 12 h and concentrated. The residue was diluted with HO (5 mL), and saturated aqueous citric acid was added to the mixture at 0 °C until the pH reached 5–6. The resulting precipitate was filtered and dried in vacuo to give the crude product (300 mg). 150 mg of this product was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; 5-45% acetonitrile in 10 mM ammonium bicarbonate solution in water, 8 min gradient) to give the compound 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (78 mg, 41%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 - 10.64 (m, 1H), 8.50 - 8.42 (m, 2H), 7.84 (s, 1H), 7.81 (td, J = 1.5, 7.4Hz, 1H), 7.74 (d, J = 2.1Hz, 1H), 7.72 - 7.67 (m, 2H), 7.45 - 7.35 (m, 2H), 6.71 (d, J = 2.3Hz, 1H), 3.88 (s, 3H), 3.85 - 3.78 (m, 4H), 3.71 (d, J = 4.1Hz, 4H). LCMS(ESI) for (C24H23N7O3) [M+H] + : 458.1

[0507] Step 4: Synthesis of azetidin-1-yl(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-5-yl)methanone.

[0508] To a solution of 4-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholino-6-(4-pyridylamino)pyrimidine-5-carboxylic acid (150 mg, 327.88 umol) in DMF (2 mL) was added azetidine (423 mg, 7.41 mmol), HATU (150 mg, 393 umol) and DIPEA (127 mg, 984 umol). The mixture was stirred at 25°C for 2 hours and the entire mixture was subjected to preparative HPLC (Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um column; 25-55% acetonitrile in 10 mM ammonium hydroxide solution in water, 8 minute gradient) to give azetidin-1-yl(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-5-yl)methanone (78 mg, 48%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 9.79 (s, 1H), 8.48 (d, J = 6.3Hz, 2H), 8.18 (t, J = 1.6Hz, 1H), 7.99 (td, J = 7.8, 1.3Hz, 1H), 7.73 - 7.60 (m, 3H), 7.52 - 7.45 (m, 1H), 7.42 (d, J = 2.3Hz, 1H), 6.61 (d, J = 2.3Hz, 1H), 4.04 - 3.93 (m, 8H), 3.90 - 3.73 (m, 5H), 3.42 - 3.27 (m, 2H), 2.07 - 1.99 (m, 2H). LCMS (ESI) [M+H] for (C27H28N8O2) + : 497.3 Example 59 Synthesis of N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxamide (compound 69): [ka]

[0509] Step 1: Synthesis of ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylate.

[0510] To a solution of ethyl 4-chloro-2-morpholino-6-(3-pyridylamino)pyrimidine-5-carboxylate (500 mg, 1.37 mmol) in dioxane (5 mL) and HO (0.5 mL) was added 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole (371 mg, 1.37 mmol), Pd(PPh) (159 mg, 137 mmol), and KCO (570 mg, 4.12 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h, then diluted with 10 mL of water, and the aqueous mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over NaSO and concentrated. The residue was subjected to flash column chromatography (ISCO 12 g silica, 0-60% ethyl acetate in petroleum ether, gradient over 30 min) to give ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylate (500 mg, 46%) as a yellow oil. [M+H] + LCMS(ESI):472.2

[0511] Step 2: Synthesis of 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylic acid.

[0512] To a solution of ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylate (500 mg, 530 mmol) in THF (4 mL) and MeOH (2 mL) was added a solution of LiOH·HO (67 mg, 1.59 mmol) in HO (2 mL) at 0 °C. The mixture was then warmed, stirred at 20 °C for 3 h, and concentrated. It was then diluted with 8 mL of water, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was discarded, and the aqueous phase was treated with saturated aqueous citric acid under ice-bath conditions until pH = 5. The solid formed was collected by filtration and dried under reduced pressure to give 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylic acid (150 mg, 64%) as a yellow solid. [M+H] + LCMS(ESI):444.1

[0513] Step 3: Synthesis of N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxamide.

[0514] To a solution of 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylic acid (120 mg, 271 μmol) in DMF (2 mL) was added N-methylmethanamine (2 M, 406 μL), HATU (123 mg, 325 μmol), and DIPEA (105 mg, 812 μmol). The mixture was stirred at 20° C. for 14 hours and concentrated. The residue was subjected to preparative HPLC [Welch Xtimate C18 21.2 × 250 mm, 10 μm, using a mobile phase of acetonitrile / water (10 mM NH4HCO3 and NH3·H2O)] to give N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxamide (82 mg, 65%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.95 (d, J = 2.4Hz, 1H), 8.56 (s, 1H), 8.32 (d, 1H, J = 3.6 Hz), 8.09 (s, 1H), 7.99 (s, 1H), 7.84 (q, J = 1.4 Hz, 2H), 7.58 (s, 1H), 7.53 - 7.52 (m, 1H), 7.52 - 7.51 (m, 1H), 7.29 - 7.28 (m, 1H), 6.51 (s, 1H), 3.89 (s, 4H), 3.80 - 3.78 (m, 4H), 2.88 (s, 3H), 2.45 (s, 3H). LCMS (ESI for C25H26N8O2) [M+H] + : 471.2

[0515] Example 60 Synthesis of [2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidin-5-yl]methanol (Compound 70). [ka]

[0516] To a solution of ethyl 2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-5-carboxylate (210 mg, 445 μmol) in THF (3 mL) was added LiAlH (34 mg, 891 μmol) portionwise at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. The reaction was then quenched with NaSO·10H O (2 equiv.) at 0 °C, and the mixture was warmed and stirred at 20 °C for 30 min. The resulting heterogeneous mixture was filtered to remove solids, and the filtrate was concentrated. The residue was then subjected to preparative HPLC (Phenomenex luna C18 80 x 40 mm x 3 um column; 8 to 28% acetonitrile in 0.04% hydrochloric acid in water, 7 minute gradient) and then again to additional preparative HPLC conditions (Phenomenex luna C18 80 x 40 mm x 3 um column; 18 to 33% acetonitrile in 0.04% hydrochloric acid in water, 6 minute gradient) to give [2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidin-5-yl]methanol (17 mg, 8%) as a pale yellow viscous liquid. 1 H NMR (400 MHz, METHANOL-d) δ = 9.37 (d, J = 1.6Hz, 1H), 8.80 (d, J = 8.4Hz, 1H), 8.71 (d, J = 5.6Hz, 1H), 8.38 (s, 1H), 8.11 - 8.05 (m, 3H), 7.82 (d, J = 1.6Hz, 1H), 7.76 - 7.74 (m, 1H), 7.62 - 7.60 (m, 1H), 6.62 (t, J = 2.0Hz, 1H), 4.62 (s, 2H), 3.83 - 3.79 (m, 8H). LCMS (ESI for C23H23N7O2) [M+H] + : 430.0. Example 61 Synthesis of 6-methyl-9-(1-methylpyrazol-3-yl)-2-morpholino-4-(4-pyridylamino)pyrimido[5,4-c]quinolin-5-one (compound 71): [ka]

[0517] Step 1: Synthesis of tert-butyl N-(2-bromo-4-iodo-phenyl)carbamate.

[0518] To a solution of 2-bromo-4-iodoaniline (4 g, 13.43 mmol) in THF (40 mL) was added 1 M NaHMDS (20.14 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, and then a solution of BocO (3.22 g, 14.77 mmol) in THF (10 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 h, and a saturated aqueous solution of NH Cl (80 mL) was carefully added to the flask. The resulting mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with brine (15 mL), dried over Na SO , and concentrated. The residue was subjected to flash column chromatography (ISCO 20 g silica, 0–3% ethyl acetate in petroleum ether, gradient over 10 min) to afford tert-butyl N-(2-bromo-4-iodophenyl)carbamate (3 g, 56%) as a yellow solid. LCMS(ESI)m / z:397.1[M+H] + .

[0519] Step 2: Synthesis of tert-butyl N-(2-bromo-4-iodo-phenyl)-N-methylcarbamate.

[0520] To a solution of tert-butyl N-(2-bromo-4-iodo-phenyl)carbamate (3 g, 7.54 mmol) in THF (40 mL) was added NaH (361 mg, 9.04 mmol, 60% suspension in oil) portionwise at 0 °C. The resulting heterogeneous mixture was stirred at 0 °C for 30 min, followed by the addition of CHI (2.14 g, 15.07 mmol). The mixture was warmed and stirred at 25 °C for 2 h, followed by the addition of 50 mL of saturated aqueous NH Cl. The resulting mixture was then extracted with ethyl acetate (30 mL × 2), and the combined organic layers were washed with brine (3 mL), dried over Na SO , and concentrated to give tert-butyl N-(2-bromo-4-iodo-phenyl)-N-methylcarbamate (3 g, 96%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.95 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.13 (s, 3H), 1.36 (s, 9H).

[0521] Step 3: Synthesis of tert-butyl N-[2-bromo-4-(1-methylpyrazol-3-yl)phenyl]-N-methylcarbamate.

[0522] To a solution of tert-butyl N-(2-bromo-4-iodo-phenyl)-N-methylcarbamate (1.7 g, 4.13 mmol) in dioxane (20 mL) and HO (2 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (858 mg, 4.13 mmol), CsCO (2.69 g, 8.25 mmol), and Pd(dppf)Cl (301 mg, 412 mmol). The resulting mixture was stirred at 80 °C under an argon atmosphere for 5 hours. It was then diluted with 40 mL of water, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over NaSO, and concentrated. The residue was subjected to flash column chromatography (ISCO 20 g silica, 0 to 30% ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl N-[2-bromo-4-(1-methylpyrazol-3-yl)phenyl]-N-methylcarbamate (900 mg, 59%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.70 (dd, J = 8.1, 1.6Hz, 1H), 7.38–7.26 (m, 1H), 7.22 (d, J = 8.1Hz, 1H), 6.53 (d, J = 2.0Hz, 1H), 3.96 (s, 3H), 3.17 (s, 3H), 1.35 (s, 9H).

[0523] Step 4: Synthesis of 2-bromo-N-methyl-4-(1-methylpyrazol-3-yl)aniline.

[0524] A solution of tert-butyl N-[2-bromo-4-(1-methylpyrazol-3-yl)phenyl]-N-methylcarbamate (850 mg, 2.32 mmol) in HCl / EtOAc (4 M, 580 μL) was stirred at 25° C. for 2 hours and concentrated. The residue was dissolved in water (5 mL) and then basified with saturated aqueous NaHCO at 0° C. The resulting mixture was extracted with ethyl acetate (10 mL×2), and the combined organic layers were washed with brine (5 mL), dried over NaSO, and concentrated to give 2-bromo-N-methyl-4-(1-methylpyrazol-3-yl)aniline (600 mg, 97%) as a yellow oil. LCMS (ESI) m / z: 266.2 [M+H] +

[0525] Step 5: Synthesis of N-methyl-4-(1-methylpyrazol-3-yl)-2-(4,4,5,5-t...

Claims

1. Compounds of Formula I: 【Chemistry 92】 or a pharmaceutically acceptable salt thereof [In the formula, V is -NH-, -NR ５ -, -CH ２ NH-, -CH ２ NR ５ -, -O-, -CO- or -CHOH-; R １ is optionally substituted morpholin-4-yl, pyridin-4-yl, pyridin-3-yl, optionally substituted 2-oxo-pyrrolidin-1-yl, optionally substituted piperidin-1-yl or optionally substituted pyridazin-4-yl; R ２ is a halogen, -(CH ２ ) ｎ OH, optionally substituted C １～６ Alkoxy, optionally substituted C ２ ~C ９ Heteroaryl, optionally substituted 2-oxo-pyrrolidin-1-yl, —(CO)NR ７ａ R ７ｂ , -P(O)R ７ｃ R ７ｄ or -S(O) ｋ R ７ｅ and R ３ is optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridazin-3-yl, optionally substituted pyrimidin-4-yl or optionally substituted C ６ ~C １０ aryl or R ２ and R ３ together with the ring to which they are attached, optionally substituted C ４ ~C １２ forming a heteroaryl, n is 1, 2, 3, 4, 5 or 6; k is 0, 1 or 2; R ４ is optionally substituted pyridin-4-yl, optionally substituted 1-methylpyridin-1-ium-4-yl, optionally substituted pyridin-3-yl, optionally substituted 1-methylpiperidin-3-yl, optionally substituted pyridazin-3-yl or -NHR ８ and R ５ is an optionally substituted C １ ~C ６ is alkyl, R ６ is H or optionally substituted C １ ~C ６ is alkyl, R ７ａ and R ７ｂ each independently represents H or optionally substituted C １ ~C ６ alkyl or R ７ａ and R ７ｂ together with the nitrogen atom to which they are attached, optionally substituted C ２ ~C ９ forming a heterocyclyl, R ７ｃ , R ７ｄ and R ７ｅ each independently represents an optionally substituted C １～６ Alkyl, optionally substituted C １～６ is alkoxy or hydroxyl, R ８ is optionally substituted phenyl or optionally substituted C ３ ~C ６ is cycloalkyl.

2. R １ but 【Chemistry 131】 2. The compound of claim 1, wherein:

3. R ８ 3. The compound of claim 1 or 2, wherein is cyclopropyl or phenyl.

4. R ４ The compound of claim 1, wherein is pyridin-4-yl or pyridin-3-yl.

5. The compound has the following structure: 【Chemistry 96】 2. The compound of claim 1, wherein

6. R ２ が-OCH ３ 、-(CO)(CH 3 ) 2 、 【Chemistry 133】 , Cl, -(CH 2 )OH.

7. R ３ but, 【Chemistry 134】 2. The compound of claim 1, wherein:

8. Compound of Formula II: 【Chemistry 103】 or a pharmaceutically acceptable salt thereof [In the formula, R ９ is optionally substituted morpholin-4-yl, optionally substituted morpholin-3-ylalkoxy, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted 1-methylpiperazin-2-yl or optionally substituted C ６ ~C １０ is aryl, R １０ is an optionally substituted C １～６ Alkoxy, —(CO)NR ７ａ R ７ｂ , -P(O)R ７ｃ R ７ｄ or -S(O) ｋ R ７ｅ and R ７ａ and R ７ｂ each independently represents H or optionally substituted C １ ~C ６ alkyl or R ７ａ and R ７ｂ together with the nitrogen atom to which they are attached, optionally substituted C ２ ~C ９ forming a heterocyclyl, R ７ｃ , R ７ｄ and R ７ｅ each independently represents an optionally substituted C １～６ Alkyl, optionally substituted C １～６ is alkoxy or hydroxyl, k is 0, 1 or 2; R １１ is optionally substituted morpholin-4-yl, optionally substituted pyridin-4-yl, optionally substituted pyrazol-4-yl, optionally substituted 1H-imidazol-2-yl, optionally substituted quinolin-6-yl or optionally substituted C ６ ~C １０ is aryl, R １２ is optionally substituted 1-methylpiperazin-2-onyl, optionally substituted 2-(pyridin-2-yl)alkoxy, optionally substituted N-(pyridin-3-ylmethyl)amine, optionally substituted N-(pyridin-4-yl)amine or optionally substituted C ６ ~C １０ is aryl].

9. R ９ but 【Chemistry 135】 9. The compound of claim 8, wherein:

10. R １１ The compound according to claim 8 or 9, wherein is pyridin-4-yl.

11. R １１ but, 【Transformation 136】 9. The compound of claim 8, wherein:

12. R １２ but 【Chemistry 137】 9. The compound of claim 8, wherein:

13. The following structure: 【Chemistry 141】 【Chemistry 142】 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 【Chemistry 148】 【Chemistry 149】 or a pharmaceutically acceptable salt of any of the foregoing.

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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