LRRK2 inhibitors and uses thereof

Abstract

The present invention provides compounds that modulate the activity of protein kinases associated with human diseases, disorders, and conditions. In particular, the compounds of the present invention inhibit LRRK2. In another aspect, the present invention provides a method for modulating the activity of a kinase by contacting a cell containing the kinase with one or more compounds of the present invention, such as any of those described above. The compounds can inhibit the activity of the kinase. The compounds can increase the activity of the kinase. The kinase can be LRRK2.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds capable of inhibiting one or more kinases, more particularly LRRK2, which have application in the treatment of a variety of disorders, including cancer and neurodegenerative diseases such as Parkinson's disease. [Background technology]

[0002] background A variety of medical conditions that affect millions of people are caused or aggravated by the unregulated activity of protein kinase.For example, abnormality in kinase activity is related to autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, cardiovascular disease, allergy, asthma, Alzheimer's disease, Parkinson's disease, skin disorder, eye disease, infectious disease and hormone-related disease.However, for many of these disorders, there is no effective inhibitor or activator for the specific kinase that causes the disorder or its symptoms.Therefore, patients continue to suffer from many disorders because there is no suitable drug for these conditions. Parkinson's disease affects approximately 1-2% of the population over the age of 60 (Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet. 2009;373(9680):2055-66. hereafter referred to as Lees 2009). It is a progressively disabling and ultimately fatal disease characterized by motor symptoms of tremor, rigidity, bradykinesia, and postural instability, and non-motor features including agnosia, depression, constipation, pain, olfactory deficits, and sleep disturbances (Macleod AD, Taylor KS, Counsell CE. Mortality in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1615-22.) (Lees 2009; Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol. 2006;5(3):235-45.) Hallmark neuropathological signs of Parkinson's disease include loss of dopaminergic neurons in the substantia nigra, decreased dopamine neurotransmission, and the presence of Lewy body inclusions in neuronal cells (Lees 2009). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet. 2009;373(9680):2055-66 [Non-patent document 2] Macleod AD, Taylor KS, Counsell CE. Mortality in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1615-22 [Non-patent document 3] Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol. 2006;5(3):235-45 Summary of the Invention [Means for solving the problem]

[0004] overview Inhibitors of leucine-rich repeat kinase 2 (LRRK2) can be effective in treating Parkinson's disease (PD). The present invention provides LRRK2 inhibitors for treating PD. In one aspect, the present invention provides a compound of formula (I): [ka] or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof. (In the formula, n is 1, 2 or 3; Y1 and Y2 are independently N or C; Z1, Z2, and Z3 are independently selected from H, —OH, halo, cyano, amino, C1-C6 alkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; X is H, halo, cyano, C1-C6 alkyl, optionally deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, -CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; R1, R2, and R4 are independently selected from H, halo, cyano, C1-C6 alkyl, optionally deuterated C1-C6 alkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, -CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy, provided that substitution is allowed according to valence; W is H or C1-C4 substituted or unsubstituted alkyl, and W may optionally form a ring with Y2 when Y2 is C; L is a linker, L is a single bond, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, and one or more heteroatoms are selected from O, S, or N; A is a 4-8 membered substituted or unsubstituted heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, wherein one or more heteroatoms are selected from the group consisting of O, S, or N; Substituents include substituted or unsubstituted 3- to 7-membered heterocycles, -CH2-cycloalkyl, -CF2-cycloalky, -C(=O)-O-alkyl, halo, deuterium, cyano, cyanoalkyl, -CF3, mono-, di-, or trihaloalkyl, CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -COOH (and esters and carboxamides thereof), -C(=O)-morpholine, -C(=O)-heterocycle, -C(-CH3)2-OH, -CH2-C(=O)-NH2; -hydroxy, alkylhybrid. and wherein the heterocyclic ring is a substituted or unsubstituted 3-7 membered cycloalkyl or heterocyclic ring, and the 3-7 membered cycloalkyl or heterocyclic ring is optionally fused to another 3-7 membered cycloalkyl or heterocyclic ring, and the ring is spiro, bridged bicyclic, or spiro, and at least one heteroatom in the heterocyclic ring is independently selected from O, S, and N; one or more hydrogen atoms are optionally deuterium).

[0005] In another embodiment, Y 1 is N and Y 2 is C.

[0006] In another embodiment, Y 1 is C and Y 2 is N.

[0007] In another embodiment, Y 1 is C and Y 2 is C.

[0008] In another embodiment, X is selected from the group consisting of -CH3, -CH2-CH3, -CD3, H, and F.

[0009] In another embodiment, Z1, Z2 and Z3 are independently selected from H, F or Cl.

[0010] In another embodiment, Z 1 is F and Z 2 is F.

[0011] In another embodiment, Z3 is H.

[0012] In another embodiment, Z3 is F.

[0013] In another embodiment, R1 is selected from H, F, -CH3, -CH2-CH3, -CF3, or -CHF2.

[0014] In another embodiment, R2 is selected from the group consisting of H or F.

[0015] In another embodiment, R2 is F.

[0016] In another embodiment, R4 is H.

[0017] In another embodiment, L is a single bond.

[0018] In another embodiment, L is alkyl.

[0019] In another embodiment, L is -C≡C-.

[0020] In another embodiment, L is -NH-CH2-.

[0021] In another embodiment, A is not a substituted or unsubstituted 1,2,3,6-tetrahydropyridine.

[0022] In another embodiment, A is [ka] [ka] [ka]

[0023] is selected from.

[0024] In another embodiment, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0025] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) above, and a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0026] In one embodiment, the present invention provides compounds of formula (I) above and pharmaceutically acceptable salts thereof for use in therapy.

[0027] In one embodiment, the present invention provides a compound of formula (I) above and a pharmaceutically acceptable salt thereof for use in a method of treating a disease associated with LRRK2.

[0028] In one embodiment, the present invention relates to the use of the compounds of formula (I) above and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in the treatment of a disease associated with LRRK2.

[0029] In one embodiment, the present invention relates to a method for the treatment of LRRK2-related diseases, including PD, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula A above, and pharmaceutically acceptable salts thereof.

[0030] In another aspect, the present invention provides a method for modulating the activity of a kinase by contacting a cell containing the kinase with one or more compounds of the present invention, such as any of those described above. The compound can inhibit the activity of the kinase. The compound can increase the activity of the kinase. The kinase can be LRRK2.

[0031] In an embodiment of use, the condition treated by the compounds of the invention is an autoimmune disease, an inflammatory disease, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, an allergy, asthma, Alzheimer's disease, Parkinson's disease, a skin disorder, an eye disease, an infectious disease or a hormone-related disease.

[0032] In another embodiment, the compounds of the present invention are particularly advantageous because they are useful in treating disorders related to the central nervous system (CNS). In particular, the compounds of the present invention cross the blood-brain barrier. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description LRRK2 gene and Parkinson's disease: Although the majority of Parkinson's disease cases are of unknown cause (termed sporadic or idiopathic), approximately 5-10% are due to genetic mutations. Mutations in the LRRK2 gene are the most common cause of both autosomal dominant and sporadic Parkinson's disease (Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord. 2013;28(1):14-23.), accounting for approximately 5-13% of familial and 1-5% of sporadic Parkinson's cases (Kumari U, Tan EK. LRRK2 in Parkinson's disease: genetic and clinical studies from patients. FEBS J. 2009;276(22):6455-63.). On an individual basis, the clinical manifestations of LRRK2 Parkinson's disease are considered indistinguishable from those of idiopathic Parkinson's disease in terms of signs, symptoms, and response to levodopa, although some data suggest that patients with LRRK2 Parkinson's disease may have fewer non-motor symptoms and a somewhat slower rate of progression than patients with sporadic Parkinson's disease (Kestenbaum M, Alcalay RN. Clinical features of LRRK2 carriers with Parkinson's disease. Adv Neurobiol., 2017, 14, 31-48; Hernandez D, Paisan Ruiz C, Crawley A, Malkani R, Werner J, Gwinn-Hardy K, et al. The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases. Neurosci Lett., 2005, 389(3), 137-139).Neuropathological findings in LRRK2 Parkinson's disease patients typically include α-synuclein-containing Lewy bodies within degenerating neurons in the substantia nigra pars compacta, but may also include tau pathology (neurofibrillary tangles) or nigral neuron loss in the absence of detectable neuronal inclusions (Loeffler DA, Aasly JO, LeWitt PA, Coffey MP. What have we learned from cerebrospinal fluid studies about biomarkers for detecting LRRK2 Parkinson's disease patients and healthy subjects with Parkinson's-associated LRRK2 mutations? J Parkinsons Dis. 2019;9(3):467-88.).

[0034] The LRRK2 gene encodes a 286-kDa multidomain peptide whose functions include neurite outgrowth, cytoskeletal maintenance, vesicle trafficking, regulation of autophagy, and immune function (Cookson MR. LRRK2 pathways leading to neurodegeneration. Curr Neurol Neurosci Rep. 2015;15(7):42.; Wallings R, Manzoni C, Bandopadhyay R. Cellular processes associated with LRRK2 function and dysfunction. FEBS J. 2015;282(15):2806-26.). Over 100 LRRK2 gene variants have been described, but the significance of most is unknown. Mutations in the LRRK2 kinase, Ras complex protein (ROC), and Ras C-terminal (COR) domains, including the G2019S, G2385R, A419V, R1441C / G / H, and R1628P LRRK2 mutations, are associated with increased risk of Parkinson's disease (Shu L, Zhang Y, Sun Q, Pan H, Tang B. A comprehensive analysis of population differences in LRRK2 variant distribution in Parkinson's disease. Front Aging Neurosci., 2019, 11, 13.).G2019S is the most common Parkinson's disease-associated mutation (found in 4% of familial and 1% of idiopathic Parkinson's disease cases worldwide), with the highest frequencies found in North African Arabs (36% hereditary, 39% sporadic) and Ashkenazi Jews (28% hereditary, 10% sporadic) (Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, et al; International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol., 2008, 7(7), 583-590).

[0035] Extensive independent studies have demonstrated that Parkinson's disease-associated mutations in LRRK2 confer a toxic gain of function in its kinase activity (West AB. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson's disease. Exp Neurol. 2017;298(Pt B):236-45. West 2017), leading to increased LRRK2 autophosphorylation (Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, Dominguez SL, et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med. 2012;4(164):164ra161.) and phosphorylation of downstream substrates such as Ras-family Rab GTPases (Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, et al. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5:e12813. Furthermore, pathways downstream of overactive LRRK2 mutants are associated with a host of pathological pathways that have been shown to lead to neurodegeneration, including autophagy, mitochondrial function, protein clearance, and neuritogenesis. Taken together, these findings suggest that LRRK2 inhibitors may be useful for treating LRRK2-associated Parkinson's disease. chemistry definition

[0036] The term alkyl refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1~12 In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common alkyl abbreviations include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0037] The term heteroalkyl refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, heteroalkyl groups are groups having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 alkyl).

[0038] The term alkenyl refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds) ("C 2~20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0039] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2~10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroalkenyl"). 2~6 alkenyl).

[0040] The term cycloalkyl refers to saturated or partially unsaturated (e.g., cycloalkenyl) cyclic groups containing one or more rings, for example, two or three rings, and containing 3 to 14 ring carbon atoms, such as 3 to 10 (e.g., 3, 4, 5, 6, or 7) ring carbon atoms. The term cycloalkyl further refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups, i.e., for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone, or cyclopentanone. Further specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl groups.

[0041] The term cycloheteroalkyl or heterocycle refers to a cycloalkyl group as defined above in which one or more (e.g., one, two, or three) ring carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. A cycloheteroalkyl or heterocycle group may have one or two rings containing 3 to 10 (e.g., three, four, five, six, or seven) ring atoms (e.g., C, O, N, or S). A cycloheteroalkyl or heterocycle group includes a cycloheteroalkenyl group or a heterocycloalkenyl group. The term cycloheteroalkyl or heterocycle further refers to groups substituted by a fluorine, chlorine, bromine, or iodine atom, or by an OH, ═O, SH, ═S, NH, ═NH, N, or NO group. Examples are piperidinyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl groups, and also lactams, lactones, cyclic imides and cyclic anhydrides.

[0042] The expression alkylcycloalkyl refers to groups containing both cycloalkyl, and also alkyl, alkenyl or alkynyl groups, in accordance with the above definition, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Alkylcycloalkyl groups preferably include cycloalkyl groups containing one or two rings with 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl or alkynyl groups with 1 or 2 to 6 carbon atoms.

[0043] The term "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above in which one or more (e.g., one, two, or three) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 3 to 10 (e.g., three, four, five, six, or seven) ring atoms and one or two alkyl, alkenyl, alkynyl, or heteroalkyl groups with one or two to six carbon atoms. Examples of such groups are alkylheterocycles, alkylheterocycloalkenyls, alkenylheterocycles, alkynylheterocycles, heteroalkylcycloalkyls, heteroalkylheterocycles, and heteroalkylheterocycloalkenyls, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated.

[0044] The term "aryl" refers to an aromatic group containing one or more rings, for example, two or three rings, containing 6 to 14 ring carbon atoms, such as 6 to 10 ring carbon atoms. The term "aryl" also refers to groups substituted with fluorine, chlorine, bromine, or iodine atoms, or with CH, OH, SH, NH, N, or NO groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl, or 4-hydroxyphenyl groups.

[0045] The term heteroaryl refers to an aromatic group containing one or more rings, e.g., two or three rings, containing 5 to 14 ring atoms, such as 5 to 10 ring atoms, and containing one or more (e.g., 1, 2, 3, or 4) oxygen, nitrogen, phosphorus, or sulfur ring atoms. The term heteroaryl further refers to groups substituted by fluorine, chlorine, bromine, or iodine atoms, or by CH3, OH, SH, N3, NH2, or NO2 groups. Examples are pyridyl (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3′-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl groups.

[0046] The term "aralkyl" refers to a group containing both an aryl and an alkyl, alkenyl, alkynyl, and / or cycloalkyl group, as defined above, such as an arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl group. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene, and indane. The aralkyl group preferably contains one or two aromatic ring systems containing 6 to 10 carbon atoms and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0047] The term heteroaralkyl refers to an aralkyl group as defined above, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, boron, or sulfur atoms, i.e., a group containing both an aryl or heteroaryl, respectively, and an alkyl, alkenyl, alkynyl, and / or heteroalkyl and / or cycloalkyl and / or heterocyclic group, according to the above definitions. Heteroaralkyl groups preferably contain one or two aromatic ring systems containing 5 or 6 to 10 ring carbon atoms, and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or a cycloalkyl group containing 5 or 6 ring carbon atoms, in which one, two, three, or four of these carbon atoms are replaced by oxygen, sulfur, or nitrogen atoms.

[0048] Examples are arylheteroalkyl, arylheterocycle, arylheterocycloalkenyl, arylalkylheterocycle, arylalkenylheterocycle, arylalkynylheterocycle, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycle, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, where the cyclic groups are saturated or mono-, di- or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl groups.

[0049] As noted above, the terms cycloalkyl, cycloheteroalkyl, heterocycle, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups substituted by fluorine, chlorine, bromine or iodine atoms or by CH, OH, ═O, SH, ═S, NH, ═NH, N or NO groups.

[0050] The term carbocyclyl or carbocyclic refers to a non-aromatic ring system containing 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 10"). 3~8 In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3~8 Carbocyclyl groups include, but are not limited to, those described above as C 3~6 Included are carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (G), and the like. Exemplary C 3~10 Carbocyclyl groups include, but are not limited to, the Gs carbocyclyl groups described above, as well as cyclononyl (C), cyclononenyl (C), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10) and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to designate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0051] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0052] The terms heterocyclyl or heterocyclic refer to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, if valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such situations, the number of ring members refers to the continuing number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is a 3- to 10-membered unsubstituted heterocyclyl. In certain embodiments, the heterocyclyl group is a 3- to 10-membered substituted heterocyclyl.

[0053] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0054] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0055] The phrase "optionally substituted" means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen may have substituents, such as any suitable substituents described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0056] For example, and without limitation, optional substituents include fluorine, chlorine, bromine, and iodine atoms, as well as CF, CN, OH, ═O, SH, ═S, NH, ═NH, N, and NO groups. Optional substituents also include C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Heteroalkyl, C3-C 16 Cycloalkyl, C2-C 17 Heterocycle, C4~C 20 Alkylcycloalkyl, C2-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C 1~17 Heteroaryl, C7-C 20 Aralkyl or C2-C 19 Heteroaralkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C2-C9 heterocycle, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Aralkyl, C2-C 11 Heteroaralkyl and C1-C 10 Contains haloalkyl groups.

[0057] Exemplary substituents are F, Cl, Br, OH, SH, ═O, NH, amino, C 1~4 Alkyl, C 1~4Heteroalkyl cyclopropyl, SF5, NO, NO2.

[0058] Other exemplary substituents are F, Cl, Br, OH, SH, ═O, NH, C 1~4 alkyl (e.g., methyl, ethyl, t-butyl), NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3.

[0059] Other exemplary substituents are F, Cl, Br, Me, OMe, CN, or CF3.

[0060] The term halogen preferably refers to F, Cl, Br or I.

[0061] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycle, aralkyl, or heteroaralkyl group contains more than one ring, the rings may be joined to each other via single or double bonds, or the rings may be cyclized.

[0062] According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycle, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, and heteroaralkyl groups described herein may be optionally substituted.

[0063] Other optional substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(Rbb ) 3 + X - 、 -N(OR cc ) R bb 、 -SH、 -SR aa 、 -SSR CC 、 -C(O) R aa 、 -CO2H、 -CHO、 -C(OR cc ) 2、 -CO2R aa 、 -OC(O) R aa 、 -OCO2R aa 、 -C(O) N(R bb ) 2、 -C(O) N(R aa )(R bb 、 -OC(O) N(R bb ) 2、 -NR bb C(O) R aa 、 -NR bb CO2R<000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, -C(S)SR aa , -SC(S)SR aa , -SC(O)SR aa , -OC(O)SR aa , -SC(O)OR aa , -SC(O)R aa , -P(O)2R aa , -OP(O)2R aa , -P(O)(R aa )2, -OP(O)(R aa )2, -OP(O)(OR cc )2, -P(O)2N(R bb )2, -OP(O)2N(R bb )2, -P(O)(NR bb )2, -OP(O)(NR bb )2, -NR bb P(O)(OR cc )2, -NR bb P(O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl each have 0, 1, 2, 3, 4 or 5 R dd groups, or the two geminal hydrogens on the carbon atom are independently replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(O)R aa , =NNR bb C(O)OR aa , =NNR bb S(O)2R aa , =NR bb or =NORcc is replaced by, where: R aa For each case, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloheteroalkyl, C 3~10 Cycloalkenyl, C 3~10 Cycloheteroalkenyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa and the groups taken together form a 3- to 14-membered cycloalkyl, 3- to 14-membered cycloheteroalkyl, 3- to 14-membered heterocyclyl, or 5- to 14-membered heteroaryl ring, and the alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each contain zero, one, two, three, four, or five R dd and are independently substituted by groups, R bb In each case, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(O)R aa , -C(O)N(R cc )2, -CO2R aa , -SO2R aa , -C(NR cc ) OR aa , -C(NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(S)N(R cc )2, -C(O)SR cc , -C(S)SR cc , -P(O)2R aa , -P(O)(R aa )2, -P(O)2N(Rcc )2, -P(O)(NR cc )2, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloheteroalkyl, C 3~10 Cycloalkenyl, C 3~10 Cycloheteroalkenyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each of the alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd and are independently substituted by groups, R cc In each case, hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa The groups, taken together, form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and the alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each have 0, 1, 2, 3, 4, or 5 R dd and are independently substituted by groups, R dd In each case, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(Rn);CX~, -N(ORee )R ff , -SH, -SR ee , -SSR ee , -C(O)R ee , -CO2H, -CO2R ee , -OC(O)R ee , -OCO2R ee , -C(O)N(R ff )2, -OC(O)N(R ff )2, -NR ff C(O)R ee , -NR ff CO2R ee , -NR ff C(O)N(R ff )2, -C(NR ff ) OR ee , -OC(NR ff )R ee , -OC(NR ff ) OR ee , -C(NR ff )N(R ff )2, -OC(NR ff )N(R ff )2, -NR ff C(NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(O)R ee , e.g., -S(O)R cc , -Si(R ee )3, -OSi(R ee )3, -C(S)N(R ff )2, -C(O)SR ee , -C(S)SR ee , -SC(S)SR ee , -P(O)2R ee , -P(O)(R ee )2, -OP(O)(R ee )2, -OP(O)(OR ee )2, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 1~6 Haloalkyl, C2~6 Alkenyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, each of alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl having 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd the substituents together can form =O or =S; R ee For each case, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5-10 membered heteroaryl, each of alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl having 0, 1, 2, 3, 4, or 5 R gg and are independently substituted by groups, R ff In each case, hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or two R ff The groups, taken together, form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and the alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each have 0, 1, 2, 3, 4, or 5 R gg and are independently substituted by groups, R gg In each case, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 - X - , -NH2(C 1~6 alkyl) + X - -MR + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(O)NH2, -C(O)N(C 1~6 alkyl)2, -OC(O)NH(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(O)N(C 1~6 alkyl)2, -NHC(O)NH(C 1~6 alkyl), -NHC(O)NH2, -C(NH)O(C 1~6 alkyl), -OC(NH)(C 1~6 alkyl), -OC(NH)OC 1~6 Alkyl, -C(NH)N(C 1~6 alkyl)2, -C(NH)NH(C 1~6 alkyl), -C(NH)NH2, -OC(NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(S)N(C 1~6 alkyl)2, C(S)NH(C 1~6 alkyl), C(S)NH2, -C(O)S(C 1~6 alkyl), -C(S)SC 1~6 Alkyl, -SC(S)SC 1~6 Alkyl, -P(O)2(C 1~6 alkyl), -P(O)(C 1~6 alkyl)2, -OP(O)(C 1~6 alkyl)2, -OP(O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, C 3~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents together can form =O or =S, and X - is the counter ion.

[0064] compound In one aspect, the present invention provides a compound of formula (I): [ka] or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof. (In the formula, n is 1, 2 or 3; Y1 and Y2 are independently N or C; Z1, Z2 and Z3 are independently selected from H, —OH, halo, cyano, amino, C1-C6 alkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl or hydroxyalkoxy; X is H, halo, cyano, C1-C6 alkyl, optionally deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, -CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; R1, R2, and R4 are independently selected from H, halo, cyano, C1-C6 alkyl, optionally deuterated C1-C6 alkyl, C1-C6 heteroalkyl, haloalkyl, alkoxy, haloalkoxy, -CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy, provided that substitution is allowed according to valence; W is H or C1-C4 substituted or unsubstituted alkyl, and W may optionally form a ring with Y2 when Y2 is C; L is a linker, L is a single bond, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, and one or more heteroatoms are selected from O, S, or N; A is a 4-8 membered substituted or unsubstituted heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, wherein one or more heteroatoms are selected from the group consisting of O, S, or N; Substituents include substituted or unsubstituted 3- to 7-membered heterocycle, -CH2-cycloalkyl, -CF2-cycloalkyl, -C(=O)-O-alkyl, halo, deuterium, cyano, cyanoalkyl, -CF3, mono-, di-, or trihaloalkyl, CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -COOH (and esters and carboxamides thereof), -C(=O)-morpholine, -C(=O)-heterocycle, -C(-CH3)2-OH, -CH2-C(=O)-NH2; -hydroxy, alkylhydroxy, aryl. and wherein the heterocyclic ring is a substituted or unsubstituted 3-7 membered cycloalkyl or heterocyclic ring, and the 3-7 membered cycloalkyl or heterocyclic ring is optionally fused to another 3-7 membered cycloalkyl or heterocyclic ring, and the ring is spiro, bridged bicyclic, or spiro, and at least one heteroatom in the heterocyclic ring is independently selected from O, S, and N; One or more of the hydrogen atoms is optionally deuterium).

[0065] In another embodiment, Y 1 is N and Y 2 is C.

[0066] In another embodiment, Y 1 is C and Y 2 is N.

[0067] In another embodiment, Y 1 is C and Y 2 is C.

[0068] In another embodiment, X is selected from the group consisting of -CH3, -CH2-CH3, -CD3, H and fluoro.

[0069] In another embodiment, Z1, Z2 and Z3 are independently selected from H, F or Cl.

[0070] In another embodiment, Z 1 is F and Z 2 is F.

[0071] In another embodiment, Z3 is H.

[0072] In another embodiment, Z3 is F.

[0073] In another embodiment, R1 is selected from H, F, -CH3, -CH2-CH3, -CF3, or -CHF2.

[0074] In another embodiment, R2 is selected from the group consisting of H or F.

[0075] In another embodiment, R2 is F.

[0076] In another embodiment, R4 is H.

[0077] In another embodiment, L is a single bond.

[0078] In another embodiment, L is alkyl.

[0079] In another embodiment, L is -C≡C-.

[0080] In another embodiment, L is -NH-CH2-.

[0081] In another embodiment, A is not a substituted or unsubstituted 1,2,3,6-tetrahydropyridine.

[0082] In another embodiment, A is [ka] [ka] [ka] is selected from.

[0083] In another embodiment, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0084] In another embodiment, the compounds of the present invention are particularly advantageous because they are useful for treating disorders related to the central nervous system (CNS). A common problem in treating disorders related to the CNS is that therapeutic agents treating the CNS cannot cross the blood-brain barrier (BBB). The BBB limits the transport of drugs from the blood to the brain. This barrier consists of a continuous layer of unique endothelial cells joined by tight junctions. Advantageously, in some embodiments, the compounds of the present invention cross the blood-brain barrier, as evidenced by the data disclosed in Table 2. Because the compounds of the present invention can cross the BBB, these compounds are particularly effective in treating disorders related to the CNS, including Alzheimer's disease. Pharmaceutical Composition

[0085] The present invention provides pharmaceutical compositions containing one or more of the compounds described above, or pharmaceutically acceptable esters, prodrugs, hydrates, solvates or salts of such compounds, optionally in combination with a pharmaceutically acceptable carrier.The present invention further provides such compounds for the preparation of medicaments for treating one or more of the diseases specified herein.

[0086] Pharmaceutical compositions may contain one or more therapeutically effective amounts of the compounds of the present invention.The therapeutically effective amount of a compound according to the present invention means the amount of compound that is effective for preventing disease, alleviating or alleviating its symptoms, or prolonging the life of the subject being treated.Determining a therapeutically effective amount is within the skill of the art.

[0087] The therapeutically effective amount or dosage of the compounds according to the invention can vary within wide limits and can be determined by methods known in the art. Such dosage can be adjusted to the individual requirements in each particular case, including the specific compound administered, the route of administration, the condition being treated, and the patient being treated.

[0088] The compositions of the present invention may include a vehicle for delivery of one or more compounds of the present invention. For example, the compositions may contain particles such as nanoparticles, microparticles, liposomes, micelles, and viral particles.

[0089] Examples of pharmacologically acceptable salts of sufficiently basic compounds of the present invention include salts of physiologically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid, and salicylic acid. Furthermore, sufficiently acidic compounds of the present invention can form alkali metal salts or alkaline earth metal salts, such as sodium, potassium, lithium, calcium, or magnesium salts; ammonium salts; or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine, or arginine salts, all of which are further examples of salts of the present invention. The compounds of the present invention may be solvated, particularly hydrated. Hydration / wetting may occur during the process of producing a compound of the present invention that does not initially contain water, or as a result of its hygroscopic nature. The solvates and / or hydrates may, for example, exist in solid or liquid form.

[0090] It should be recognized that certain compounds of the present invention may have tautomeric forms (only one of which may be specifically specified or illustrated in the following description), different geometric isomers (usually designated as cis / trans isomers or, more commonly, as (E) and (Z) isomers), or different optical isomers (usually designated in the Cahn-Ingold-Prelog or R / S system) as a result of one or more chiral carbon atoms. All of these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphs are included in the present invention. Because the compounds of the present invention may contain asymmetric C atoms, they may exist as achiral compounds, mixtures of diastereomers, mixtures of enantiomers, or optically pure compounds. The present invention includes both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any ratio.

[0091] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of drugs with little or no change in their inherent pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites, and / or increases the formation of desired active metabolites. Therefore, the present invention also encompasses partially and fully deuterated compounds of the present invention. The term hydrogen also encompasses deuterium.

[0092] The therapeutic use of the compounds according to the invention, their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also fall within the scope of the present invention. Pharmaceutical compositions according to the present invention may comprise at least one compound of the present invention as an active ingredient, and, if necessary, carrier materials and / or adjuvants.

[0093] The present invention also relates to prodrugs composed of a compound of the present invention and at least one pharmacologically acceptable protecting group, which is cleaved under physiological conditions to yield a prodrug, such as an alkoxy, arylalkyloxy, acyl, acyloxymethyl group (e.g., pivaloyloxymethyl), a 2-alkyl, 2-aryl, or 2-arylalkyloxycarbonyl-2-alkylideneethyl group, or an acyloxy group, as defined herein, such as ethoxy, benzyloxy, acetyl, or acetyloxy, or, in the case of a compound of the present invention possessing a hydroxy group (-OH), a sulfate, phosphate (-OPO or -OCHOPO) or an ester of an amino acid, among others. For example, the composition may contain a prodrug of a hydroxy group of a compound of the present invention.

[0094] As used herein, the term "pharmaceutically acceptable ester" particularly refers to esters that undergo hydrolysis in vivo, including those that are easily decomposed in the human body, leaving behind the parent compound or its salt.Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acid, alkenoic acid, cycloalkanoic acid and alkanedioic acid, where the alkyl or alkenyl moiety advantageously has 6 or less carbon atoms.Specific examples of esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate and ethylsuccinate.

[0095] The present invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable ethers, physiologically functional group derivatives, atropisomers or in vivo hydrolyzable precursors, diastereomers or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of the present invention.

[0096] As mentioned above, therapeutically useful agents containing the compounds of the present invention, their solvates, salts or formulations are also included within the scope of the present invention. Generally, the compounds of the present invention are administered by using accepted modes known in the art, either alone or in combination with any other therapeutic agent.

[0097] For oral administration, such therapeutically useful agents may be administered by one of the following routes: orally, for example, as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, e.g., soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenterally, including intravenous, intramuscular and subcutaneous injection, for example, as injectable solutions or suspensions; rectally as a suppository; by inhalation or insufflation, for example, as a powder formulation, as microcrystals or as a spray (e.g., liquid aerosol); transdermally, for example, by a transdermal delivery system (TDS), such as a plaster containing the active ingredient, or intranasally. For the preparation of such tablets, pills, semisolids, coated tablets, dragees, and hard, e.g., gelatin capsules, the therapeutically useful product may be mixed with pharmaceutically inert inorganic or organic excipients such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, dried skim milk powder, etc. For the preparation of soft capsules, excipients such as vegetable oils, petroleum, animal oils, or synthetic oils, waxes, fats, and polyols may be used. For the preparation of liquid solutions, emulsions, suspensions, or syrups, excipients such as water, alcohol, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum, animal oils, or synthetic oils may be used. In particular, lipids such as phospholipids (e.g., of natural origin and / or with a particle size between 300 and 350 nm) in phosphate-buffered saline (pH = 7-8, e.g., 7.4) are useful. For suppositories, excipients such as vegetable oils, petroleum, animal oils, or synthetic oils, waxes, fats, and polyols may be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, may be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavoring agents, salts for changing osmotic pressure, buffers, coating additives, and antioxidants.

[0098] Generally, for oral or parenteral administration to an adult human weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg or about 20 mg to about 1,000 mg should be appropriate, although the upper limit may be exceeded if indicated. The daily dosage may be administered as a single dose or in divided doses, or, for parenteral administration, may be given as continuous infusion or subcutaneous injection. Methods for making compounds

[0099] The present invention also provides methods of making the compounds of the invention, such as those described above. Synthetic schemes for making specific compounds of Formula (I) are provided in the Examples below. How to Treat the Condition

[0100] The compounds and compositions of the present invention modulate the activity of one or more protein kinases.The compounds and compositions can inhibit, activate, or otherwise modify kinase activity.Therefore, the compounds and compositions can be used to diagnose, treat, or prevent conditions, such as diseases, disorders, or other conditions, in which modulating kinase activity provides therapeutic benefits.

[0101] Diseases, disorders, and conditions that can be diagnosed and / or treated using the compositions and methods of the present invention include those associated with abnormal activity, e.g., increased or decreased activity, of one or more kinases. The disease, disorder, or condition may be associated with abnormal LRRK2 activity, such as Alzheimer's disease, Crohn's disease, inflammatory bowel disease, inflammatory disease, leprosy, neurodegenerative disease, non-skin cancer, or Parkinson's disease (including familial Parkinson's disease, sporadic Parkinson's disease, late-onset Parkinson's disease (PD), and Parkinson's disease type 8).

[0102] The disease, disorder or condition may be rhinorrhea, tracheal stenosis, airway constriction, acute, allergic, atrophic or chronic rhinitis (such as caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, or rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupus, fibrinous rhinitis, and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including neurogenic rhinitis (hay fever) and vasomotor rhinitis), hay fever, asthma (bronchial, atopic, allergic, endogenous, extrinsic, exercise-induced, cold-induced, occupational, bacterial infection-induced, and dust-induced asthma, particularly chronic or habitual asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis (chronic bronchitis, acute bronchitis, arachidonic bronchitis, catarrhal asthma), and the like. bronchitis, croupy bronchitis, tuberculous bronchitis, and eosinophilic bronchitis), cardiobronchitis, pneumoconiosis, chronic inflammatory diseases of the lung (leading to interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis or other autoimmune conditions)), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway, or lung disease (such as CORD, COAD, COLD, or COPD (irreversible COPD)), chronic sinusitis, conjunctivitis (e.g., allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (such as farmer's lung and related diseases), pulmonary fibrosis lung), hypersensitivity lung disease, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyps, otitis media and cough (chronic cough associated with inflammation or iatrogen-induced), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, pulmonary fibrosisThe allergic reaction may be or may include airway / obstructive airway diseases or disorders such as pulmonary fibrosis (including fibrosing alveolitis of unknown etiology, fibrosis complicating antineoplastic therapy), chronic infections (including tuberculosis and aspergillosis and other fungal infections), vasculitic and thrombotic disorders of the pulmonary vasculature, and pulmonary hypertension, acute viral infections (including the common cold and infections with respiratory syncytial viruses, influenza, coronaviruses (including SARS), and adenoviruses), allergic bronchopulmonary mycosis, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and food-related allergies that may have effects away from the gastrointestinal tract (such as migraine, rhinitis, and eczema), anaphylactic shock, or vasospasm.

[0103] The diseases, disorders or conditions include osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, and malignant), seronegative spondyloarthropathy (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Behcet's disease, Marie-Strümpel arthritis, inflammatory bowel disease arthritis, and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthritis (both primary and secondary to, for example, congenital hip dysplasia), cervical and lumbar spondylitis, and low back and neck pain, Still's disease, reactive arthritis, and untreated idiopathic arthritis. Differentiated spondyloarthropathy, septic arthritis, and other infection-related arthropathies and bone disorders (tuberculosis, including Pott's disease and Ponset syndrome), acute and chronic crystal-induced synovitis (including urate gout, calcium pyrophosphate crystal deposition disease, and calcium apatite-associated tendon, bursar, and synovial inflammation), primary and secondary Sjogren's syndrome, systemic sclerosis and morphea, mixed connective tissue disease, and undifferentiated connective tissue disease, inflammatory myopathies (polymyalgia rheumatica, etc.), and inflammatory myopathies (polymyalgia rheumatica, etc.). rheumatica), juvenile arthritis (including idiopathic inflammatory arthritis of any joint distribution and related syndromes), other joint diseases (such as intervertebral disc degeneration or temporomandibular joint degeneration), rheumatic fever and its systemic complications, vasculitis (including giant cell myocarditis, Takayasu's arteritis, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infections), hypersensitivity reactions, cryoglobulins, paraproteins, low back pain, familial Mediterranean fever, Muckle-Wells syndrome, and familial Irish (Hibenian) fever, Kikuchi disease, drug-induced It may be or include a disease or disorder related to bones and joints, such as arthalgias, tendonitis, polychondritis and myopathy, osteoporosis, osteomalacia (such as osteoporosis, osteopenia), osteogenesis imperfecta, osteopetrosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, loosening of artificial joint implants, muscle or joint sprains or strains, tendinitis, fasciitis, periarthritis of the shoulder, cervicobrachial syndrome or tenosynovitis.

[0104] Diseases, disorders, or conditions include glaucoma, ocular hypertension, cataracts, retinal detachment, psoriasis (including plaque psoriasis, pustular psoriasis, arthritic psoriasis, and erythrodermic psoriasis), palmoplantar pustulosis, xerodoma, eczematous diseases (such as atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis, and seborrheic dermatitis), plant dermatitis, photodermatitis, cutaneous eosinophilia, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis (including sensitivity to poison ivy, sumac, or oak), and eosinophilic folliculitis (Ofuji disease), pruritus, drug rash, urticaria (acute or chronic, allergic or non-allergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus et atrophicus atrophica), pyoderma gangrenosum, cutaneous sarcoid, pemphigus, ocular pemphigoid, pemphigoid, epidermolysis bullosa, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, Sweet's syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis (both infectious and non-infectious), panniculitis, cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmia (sympathetic ophthalmia, sarcoid) The skin or eye disease or disorder may be or include skin or eye-related diseases or disorders such as corneal ulcers, dry eye, dry skin infections (including viral, fungal and bacterial), allergic conjunctivitis, increasing fibrosis, keloids, scar formation, post-surgical scarring, epidermolysis bullosa, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis and giant papillary conjunctivitis, intraocular neovascularization, corneal damage and scarring, all types of macular degeneration, macular edema, macular dystrophy, abnormalities of wound healing, scleritis, episcleritis, scleroderma, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; keratoconus, dystorphia epithelialis comeae, or severe intraocular inflammation.

[0105] The disease, disorder, or condition may be celiac / coeliac disease (e.g., celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen-induced diarrhea, gastroenteropathy associated with seronegative arthropathy, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, intestinal ischemia, glossitis, gingivitis, periodontitis, esophagitis (including reflex), proctitis, hepatic fibrosis and cirrhosis, pancreatitis ( The disease or disorder may be or include: pancreatic fibrosis, pancreatic cirrhosis, pancreatic lithiasis, liver cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupus, steatohepatitis, and chronic viral), fatty liver, primary biliary cirrhosis, hepatic porphyria and gastrointestinal tract-related allergic disorders, spastic colon, diverticulitis, gastrointestinal bleeding, Behcet's disease; diseases or disorders related to the gastrointestinal tract and abdomen, such as partial hepatectomy, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, or anoxic conditions), or hemolytic uremic syndrome.

[0106] The disease, disorder or condition can be or include a hematological disease or disorder such as anemia, coagulation, a myeloproliferative disorder, a bleeding disorder, leukopenia, an eosinophilic disorder, leukemia (e.g., myeloid), lymphoma, a plasma cell dyscrasia, a disorder of the spleen, band disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0107] The disease, disorder, or condition may be obesity, amyloidosis, disorders of amino and acid metabolism (such as branched chain diseases), hyperaminoacidemia, hyperaminoaciduria, disorders of urea metabolism, hyperammonemia, mucopolysaccharidoses, e.g., Maroteaux-Lamy syndrome, storage diseases (such as glycogen storage diseases and lipid storage diseases, glycogen storage disease I diseases such as Cori's disease), malabsorption diseases (such as intestinal carbohydrate malabsorption), oligosaccharidase deficiency, The metabolic disease or disorder may be or include a metabolic disease or disorder such as a deficiency (such as maltase, lactase, sucrase deficiency), a disorder of fructose metabolism, a disorder of galactose metabolism, galactosemia, a disorder of carbohydrate utilization (such as diabetes, hypoglycemia), a disorder of pyruvate metabolism, hypolipidemia, hypolipidemia, hyperlipidemia, hyperlipoproteinemia, a carnitine or carnitine acyltransferase deficiency, a disorder of porphyrin metabolism, a disorder of porphyrin, purine metabolism, a lysosomal disease, a metabolic disease of the nerves and nervous system (such as gangliosidoses, sphingolipidoses, sulfatidoses), leucodystrophy, or Lesch-Nyhan syndrome.

[0108] The disease, disorder, or condition may be dementia, Alzheimer's disease, Huntington's chorea, Parkinson's disease, Pick's disease, toxic encephalopathy, demyelinating polyneuropathy, or the like. neuropathies (such as inflammatory neuropathies), Guillain-Barré syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormonal deficiencies (such as any disorder resulting from either hyperfunction or hypofunction of one hormone-secreting endocrine gland and any combination thereof), Sipple's syndrome, pituitary insufficiency and its effects on other endocrine glands (such as the thyroid, adrenal glands, ovaries and testes), acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroid syndrome, thyroiditis and thyroid cancer, over- or under-production of adrenal steroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary hyperaldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disorders caused by insufficiency of the parathyroid glands, pancreatic islet cell dysfunction, diabetes mellitus, the female endocrine system disorders (such as estrogen deficiency, resistant ovary syndrome); muscle weakness, myotonia, Duchenne and other muscular dystrophies, Steinert's myotonic dystrophy, mitochondrial myopathies (such as disorders of catabolic metabolism in muscle), carbohydrate and lipid storage myopathies, glycogen storage diseases, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, polymyositis, primary cardiac myopathy, cardiomyopathies; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis nodosa, Louis-Barr syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; male and female sexual dysfunction; confusional states and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, cerebellar dysfunction or disorders of cerebral metabolism such as Liddle syndrome, Bartter syndrome, Fanconi I syndrome or renal electrolyte wasting.

[0109] The disease, disorder or condition can be or include acute and chronic allograft rejection after solid organ transplantation, e.g., kidney, heart, liver, lung and corneal transplants, chronic graft-versus-host disease, skin graft rejection and bone marrow graft rejection, or transplant rejection-related conditions such as immunosuppression.

[0110] The disease, disorder or condition can be or include urogenital related conditions such as nephritis (interstitial, acute interstitial (allergic) and glomerulonephritis), nephrotic syndrome, cystitis (including acute and chronic (interstitial) cystitis) and Hannah's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, vulvovaginal candidiasis, Peyronie's disease and erectile dysfunction, kidney disease, renal fibrosis, pyelonephritis, secondary atrophic kidney, steroid-dependent and steroid-resistant nephrosis, or Goodpasture's syndrome.

[0111] Diseases, disorders or conditions include neurodegenerative diseases, Alzheimer's disease and other cementing disorders (including CJD and nvCJD), amyloidosis and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic such pain (acute, intermittent or persistent, whether of central or peripheral origin) (including post-operative, visceral pain, headache, migraine, neuralgia (including trigeminal neuralgia), atypical facial pain, joint and bone pain), pain due to cancer and tumor invasion, neuropathic pain syndromes (including diabetic, post-herpetic and HIV-associated neuropathies), neurosarcoidosis in response to brain injury, cerebrovascular disease and its consequences, Parkinson's disease, corticobasal degeneration "CNS disorder" means a condition that is a CNS disorder that affects the nervous system, including, but not limited to, encephalopathy ... Central and peripheral nervous system complications of malignant, infectious or autoimmune processes, pain, cerebral infarction, seizures, cerebral ischemia, head trauma, spinal cord injury, myelogenous muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe dementia, acute anterior spinal cord hornitis (poliomyelitis), anterior hornitis neuropathy, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathy, Creutzfeldt-Jakob disease, kuru, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, bipolar disorder, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome or Machado-Joseph disease.

[0112] The diseases, disorders or conditions include general inflammation (of the eyes, nose, lungs and gastrointestinal tract), mastocytosis / mast cell disorders (cutaneous, systemic, mast cell activation syndrome and childhood mastocytosis), mastitis (breast), vaginitis, vasculitis (e.g., necrotizing, cutaneous and hypersensitivity vasculitis), Wegener's granulomatosis, myositis (including polymyositis, dermatomyositis), basophil-associated disorders (including basophilic leukemia and basophilia) and eosinophil-associated disorders (such as Churg-Strauss syndrome, eosinophilic granuloma), lupus erythematosus (systemic erythematosus), The disease or disorder may be or include an inflammatory or immunological disease or disorder such as thyroiditis, chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, type 1 diabetes, complications due to diabetes mellitus, other immune disorders, eosinophilic fasciitis, hyper-IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency disorders, acquired immunodeficiency syndrome (AIDS), leprosy, Sézary syndrome, paraneoplastic syndromes and other autoimmune disorders, fever, myositis, neurological disorders (selected from polymyositis), bursitis, Evans' syndrome, leukotriene B4-mediated disease, idiopathic hypoparathyroidism, nephrotic syndrome, lupus, or immunosuppression.

[0113] The disease, disorder or condition can be or include cardiovascular diseases or disorders such as congestive heart failure, myocardial infarction, ischemic disease of the heart, all types of atrial and ventricular arrhythmias, hypertension, cerebral trauma, occlusive vascular disease, stroke, cerebrovascular accidents, atherosclerosis, restenosis, those affecting the coronary arteries and peripheral circulation, pericarditis, myocarditis, inflammatory and autoimmune cardiomyopathy (including myocardial sarcoid), endocarditis, valvulitis and aortitis (including infectious (e.g., syphilitic)), hypertensive vascular disease, peripheral vascular disease and atherosclerosis, vasculitis, disorders of the proximal and peripheral veins (including phlebitis) and thrombosis (including deep vein thrombosis and complications of varicose veins of the legs), aortic aneurism, periarteritis nodosa, myocardial fibrosis, post-myocardial infarction, idiopathic cardiomyopathy or angioplasty.

[0114] The diseases, disorders or conditions include common cancers (prostate, breast, lung, ovarian, pancreatic, intestinal and colon, abdominal, stomach (and any other digestive system cancer), liver, pancreas, peritoneal, endocrine glands (adrenal, parathyroid, pituitary, testes, ovaries, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvic, skin, bone, soft tissue, spleen, thoracic, genitourinary and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, malignancies affecting the bone marrow (including leukemia) and lymphoproliferative system (Hodgkin's and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, etc.), metastatic disease and tumor recurrence and paraneoplastic syndromes, and hypergammaglobulinemia. The tumor may be or include neoplastic diseases or disorders such as erythrombocytosis, lymphoproliferative diseases, disorders and / or conditions, paraproteinemia, purpura (including idiopathic thrombocytopenic purpura), Waldenstrom's macroglobulinemia, Gaucher's disease, histiocytosis, retinoblastoma and any other hyperproliferative disease, sarcoma, cachexia, tumor growth, tumor invasion, metastasis, AIDS-related lymphoma, malignant immunoproliferative disorders, multiple myeloma and malignant plasmacytoma, lymphocytic leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specific cell types, leukemias of non-specific cell types, other and non-specific malignant neoplasms of lymphocytes, hematopoietic tissues and related tissues, e.g., diffuse large cell lymphoma, T-cell lymphoma, or cutaneous T-cell lymphoma. Myeloid cancers include, e.g., acute or chronic myeloid leukemia, or corneal leukemia.

[0115] The diseases, disorders or conditions include pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenia purpura, postoperative adhesions, flushing, ischemic / reperfusion injury in the heart, brain or peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxic shock, septic shock, heat regulation (including fever), Raynaud's disease, gangrene, diseases requiring anticoagulation therapy, congestive heart failure, impaired mucus secretion, pulmonary hypotension, prostanoid-induced smooth muscle contraction associated with dysmenorrhea and preterm labor, preterm labor, reperfusion injury, burns, thermal injury, hemorrhagic or traumatic shock, menstrual pain, menstrual cramps, dysmenorrhea, periodontitis, rickettsial infections, protozoal diseases, reproductive disorders It may be or include another disease or disorder such as a pulmonary edema, toothache, post-tooth extraction pain, shingles, herpes simplex, retroperitoneal fibrosis, or various radiation injuries.

[0116] In certain embodiments, the disease is selected from the group consisting of inflammatory diseases, autoimmune diseases, allergic disorders, and ocular disorders, hi certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, and uveitis.

[0117] The method can include modulating the activity of one or more kinases in a subject, such as any of the kinases described above. The method can include inhibiting the kinase. The method can include activating, e.g., stimulating or enhancing, the activity of the kinase. The method can include modulating the activity of a single kinase, or preferentially modulating the activity of a particular kinase over other kinases. The method can include modulating the activity of multiple kinases, or even preferentially modulating the activity of two particular kinases over other kinases.

[0118] The method can include providing a compound of the invention.The method can include providing a plurality of compounds of the invention.

[0119] The method can include contacting a cell containing a kinase with one or more compounds of the present invention. For example, and without limitation, contacting a cell with a compound can include exposing the cell to a compound, such as any of those described above in a formulation, delivering the compound to the interior of the cell, providing the compound to a subject, and allowing the cell in the subject to be exposed to the compound. The contact can be performed in vivo or in vitro. In vitro contact can include exposing cells or tissues isolated from a subject. The method can include contacting the cell with a single compound of the present invention. The method can include contacting the cell with multiple compounds of the present invention.

[0120] The brain is protected from potentially toxic substances by the presence of two barrier systems: the blood-brain barrier (BBB) ​​and the blood-cerebrospinal fluid barrier (BCSFB). The BBB restricts drug transport from the blood to the brain. This barrier consists of a continuous layer of unique endothelial cells joined by tight junctions. Brain capillaries, which constitute more than 95% of the total surface area of ​​the BBB, are the primary route for entry of most solutes and drugs into the central nervous system. Therefore, the BBB is a major obstacle to the treatment of CNS diseases, as many drugs cannot reach this organ at therapeutic concentrations. The BBB is considered the primary route for the uptake of serum ligands because its surface area is approximately 5,000 times greater than that of the BCSFB. The brain endothelium, which constitutes the BBB, is a major obstacle to the use of potential drugs for many CNS disorders. The compounds of the present invention are particularly advantageous because they are useful for the treatment of disorders related to the central nervous system (CNS) by crossing the BBB. The compounds of the present invention cross the BBB, thus making them effective in treating disorders related to the CNS, including Alzheimer's disease.

[0121] The method can include administering a composition to a subject. The composition can be provided by any suitable route of administration. For example, and without limitation, the composition can be administered orally, by injection, cutaneously, intestinally, intraarterially, intravenously, intranasally (e.g., by inhalation), intraocularly, orally, parenterally, pulmonary, rectally, subcutaneously, systemically, topically (e.g., to the skin or eye), transdermally, or by or on an implanted medical device (e.g., a stent or a drug-eluting stent or balloon equivalent). The methods can include using the compositions of the invention to diagnose a disease, disorder, or condition in a subject. For example, radiolabeled forms of the compounds can be used as tracers in positron emission tomography (PET) to identify locations in the body where kinase activity is abnormal. PET is known in the art, see, for example, Wadsak Wolfgang, Mitterhauser Markus (2010), "Basics and principles of radiopharmaceuticals for PET / CT", European Journal of Radiology, 73 (3): 461-469. doi:10.1016 / j.ejrad.2009.12.022; Bailey, DL; DW Townsend; PE Valk; MN Maisey (2005), Positron Emission Tomography: Basic Sciences. Secaucus, NJ: Springer-Verlag, ISBN 1-85233-798-2; and Carlson, Neil (January 22, 2012). Physiology of Behavior. Methods and Strategies of Research, 11th edition, Pearson, p. 151, ISBN 0205239390. The present invention can involve administering one or more compositions of the present invention for both diagnostic and therapeutic purposes. [Example]

[0122] General synthetic scheme The compounds of the present disclosure can be made by the methods illustrated in the reaction schemes shown below. The starting materials and reagents used in the preparation of these compounds are either available from commercial suppliers such as Sigma-Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics, Bachem (Torrance, Calif.), Oakwood Chemicals, Matrix Chemicals, or are prepared by methods known to those skilled in the art according to procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0123] The general schemes are merely illustrative of some of the methods by which the compounds of the present disclosure and their pharmaceutically acceptable salts may be synthesized, and various modifications to these schemes may be made and will be suggested to those skilled in the art upon reading this disclosure. The starting materials, intermediates, and final products of the reaction(s) may, if desired, be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0124] Unless specified to the contrary, reactions described herein are carried out at atmospheric pressure over a temperature range of about -78°C to about 200°C, such as about 0°C to about 125°C, and even about room temperature (or ambient temperature), e.g., about 20°C. The routes shown and described herein are merely exemplary, and they are not intended to, and should not be construed to, limit the scope of the claims in any way. Those of skill in the art will recognize modifications of the disclosed syntheses and will be able to devise alternative routes, based on the disclosure herein, and such modifications and alternative routes will be within the scope of the claims.

[0125] The compounds of the present invention can be synthesized by the methods illustrated in the general reaction schemes shown below.

[0126] The following general scheme I illustrates the synthesis of compounds of the present invention, i.e., compounds of formula (A), (B), (C), (D), and (E), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X and Y are as defined above. General Scheme I [ka]

[0127] In general scheme I, compounds (I), (II_a) and (II_b) are purchased from commercial sources or prepared according to literature methods.

[0128] CH activation between compound (I) and compound (II_a) gives compound (III_a), which is then halogenated to give compound (IV_a), which is reduced to compound (V_a) and then deprotected to give compound (VI_a). Ring closure between compound (VI_a) and an aldehyde gives compound (VII_a), which is converted to compound (VIII_a) by cross-coupling. Deprotection of compound (VIII_a) gives compound of formula (A). Compound (VIII_a) can be converted to compound (VIII_b) by cross-coupling, which is deprotected to give compound of formula (B).

[0129] CH activation with compound (I) and compound (II_b) gives compound (IV_b), which is then reduced to give compound (V_b). Direct deprotection gives compound (VI_b), which can be used in a ring closure reaction to give compound (VIII_a).

[0130] Substitution of compound (VIII_a) gives compound (VIII_c), which is deprotected to give compound of formula (C).

[0131] Carbonylation of compound (VII_a) gives compound (VII_d), which is hydrolyzed to give compound (VIII_d). Deprotection of compound (VIII_d) gives compound of formula (D), which can be used in acid-amine coupling to give compound of formula (E). General Scheme II [ka]

[0132] In general Scheme II, compounds (I), (II_a) and (II_b) are purchased from commercial sources or prepared according to literature methods.

[0133] CH activation between compound (I) and compound (II_a) gives compound (III_a), which is then reduced to give compound (IV_a), which is deprotected to give compound (V_a). Ring closure between compound (V_a) and an aldehyde gives compound (VI_a), which is converted to compound (VII_a) by cross-coupling. Deprotection of compound (VII_a) gives compound of formula (A). Compound (VII_a) can be converted to compound (VII_b) by cross-coupling, which is deprotected to give compound of formula (B).

[0134] CH activation with compounds (I) and (II_b) gives compound (III_b), which is then reduced to give compound (IV_b). Direct deprotection gives compound (V_b), which can be used in a ring closure reaction to give compound (VII_a). Synthesis Examples

[0135] In order that those skilled in the art may more clearly understand and practice the present disclosure, the following preparations of intermediates, reference compounds and / or compounds of formula (I) are set forth which are not to be construed as limiting the scope of the disclosure, but merely as illustrative and representative thereof. Key intermediates used in the synthetic preparation of the compounds described herein are presented below: [ka] [ka] [ka]

[0136] Example (A1-1) Synthesis of 3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate A1-1) [ka]

[0137] To a solution of 3-methyl-4-nitro-1H-pyrazole (25 g, 0.197 mol, 1.0 equiv.) in THF (400 mL) was added NaH (11.8 g, 0.295 mol, 60% (wt %) in mineral oil, 1.5 equiv.) in small portions at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 30 min. SEM-Cl (42.0 mL, 0.237 mol, 1.2 equiv.) was added dropwise at 0° C. After the addition, the mixture was warmed to 20° C. and stirred at 20° C. for 1 h. The reaction was slowly quenched with HO (100 mL) under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-5% EtOAc in petroleum ether as eluent to give the title compound as a yellow oil (41 g, 81%, containing some isomers). LCMS (ESI) m / z: 257.9 [M+H] + . Example (A1-2) Synthesis of 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate A1-2) [ka]

[0138] Step 1: Synthesis of 2-[(5-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane [ka]

[0139] To a mixture of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (12.5 g, 51.3 mmol, 1.0 equiv) in THF (100 mL) was added 1 M LiHMDS in THF (77.0 mL, 77 mmol, 1.5 equiv) dropwise at −78° C. After the addition, the resulting solution was stirred at this temperature for 30 min, and then NCS (8.23 g, 61.6 mmol) was added. The reaction mixture was stirred under N atmosphere at −78° C. for 2 h, diluted with HO (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 330 g SepaFlash® silica flash column, 0-2% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 mn) to give the title compound as a yellow oil (12.2 g, 85%). LCMS (ESI) m / z: 278.1 [M+H] + . Step 2: Synthesis of 5-chloro-4-nitro-1H-pyrazole [ka]

[0140] A mixture of 2-[(5-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (24 g, 86.4 mmol, 1.0 equiv) in 4 N HCl in MeOH (200 mL) was stirred for 2 hours at 20° C. The reaction mixture was concentrated under reduced pressure to give crude 5-chloro-4-nitro-1H-pyrazole as a white solid (13 g). Step 3: Synthesis of 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane [ka]

[0141] A mixture of 3-chloro-4-nitro-1H-pyrazole (12 g, 81.3 mmol, 1.0 equiv), SEM-Cl (14.9 g, 89.4 mmol, 1.1 equiv), and CsCO (79.5 g, 0.244 mol, 3.0 equiv) in THF (200 mL) was stirred for 2 h at 20° C. Then, the reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-1.5% petroleum ether / EtOAc at 35 mL / min) to give the pure product, 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane, as a white solid (14 g, 30.9%). LCMS (ESI) m / z: 278.1 [M+H] + . Example (A1-3) Synthesis of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate A1-3) [ka]

[0142] To a solution of 4-nitro-1H-pyrazole (10 g, 88.4 mmol) in THF (200 mL) was added NaH (5.31 g, 0.132 mol, 60% (wt%) in mineral oil, 1.5 equiv.) in small portions at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. SEM-Cl (16.2 g, 97.2 mmol, 1.2 equiv.) was added dropwise at 0 °C. After the addition, the mixture was warmed to 20 °C and stirred at 20 °C for 1 h. The reaction was slowly quenched with HO (100 mL) under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-5% EtOAc in petroleum ether as eluent to give the title compound as a yellow oil (20 g, 93%). LCMS (ESI) m / z: 244.1 [M+H] + . Example (A1-4) Synthesis of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate A1-4) [ka]

[0143] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (10 g, 58.4 mmol, 1 equiv.) in THF (250 mL) was added NaH (3.51 g, 87.7 mmol, 60% purity, 1.5 equiv.) in small portions at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes. SEM-Cl (11.68 g, 70.1 mmol, 1.2 equiv.) was added dropwise at 0° C. After the addition, the mixture was warmed to 20° C. and stirred at 20° C. for 1 hour. The reaction was slowly quenched with HO (100 mL) under a nitrogen atmosphere. The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220 g AgelaFlash® silica flash column, 0-10% MeOH in DCM / MeOH, flow rate = 100 mL / min, 254 nm) to give methyl 4-nitro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (15.37 g, 87.3%) as a yellow oil. LCMS (ESI) m / z: 302.1 [M+H] + . Example (A2-1) Synthesis of 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole (Intermediate A2-1) [ka]

[0144] A mixture of 3-methyl-4-nitro-1H-pyrazole (50.6 g, 0.398 mmol, 1.0 equiv), K2CO3 (82.5 g, 0.60 mol, 1.5 equiv), and 1-(chloromethyl)-4-methoxybenzene (68.6 g, 0.438 mol, 1.1 equiv) in MeCN (500 mL) was heated to 55 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and then poured into HO (200 mL) and extracted with EtOAc (300 mL × 2). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give the title compound as a light yellow solid (90 g, 91.5%). 1 H NMR (400 MHz, CDCl3) δ ppm 3.84 (s, 3 H), 5.26 (s, 2 H), 6.93 (d, J = 8.4 Hz, 2 H), 6.93-6.98 (m, 1 H), 7.27 (d, J = 8.4 Hz, 2 H), 8.02 (s, 1 H), 8.10 (s, 1 H). Example (A2-2) Synthesis of 3-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (Intermediate A2-2) [ka]

[0145] A mixture of 3-chloro-4-nitro-1H-pyrazole (10 g, 67.7 mmol, 1.0 equiv), KCO (28.1 g, 0.203 mol, 3.0 equiv), and PMB-Cl (11.6 g, 74.5 mmol, 1.1 equiv) in DMF (200 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0–20% petroleum ether / EtOAc at 35 mL / min) to give the title compound as a light yellow solid (18 g, 50%). 1 H NMR (400MHz, DMSO-d6) δ ppm 3.74 (s, 3 H), 5.28 (s, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 2 H), 9.17-9.06 (m, 1 H). Example (A2-3) Synthesis of 3-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (Intermediate A2-3) [ka]

[0146] A mixture of 4-nitro-1H-pyrazole (45 g, 0.398 mol, 1.0 equiv.), K2CO3 (82.5 g, 0.60 mol), and 1-(chloromethyl)-4-methoxybenzene (68.56 g, 0.438 mol) in MeCN (500 mL) was stirred at 55 °C for 4 h. The reaction was cooled to room temperature and then poured into 200 mL of HO and extracted with EtOAc (200 mL × 2). The combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to afford the title compound as a light yellow solid (90 g, 97.0%). 1 H NMR (400 MHz, CDCl3) δ ppm 3.84 (s, 3 H), 5.26 (s, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.93 (m, 1 H), 7.27 (d, J = 8.4 Hz, 2 H), 8.02 (s, 1 H), 8.10 (s, 1 H). Example (A2-4) Synthesis of 1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (Intermediate A2-4) [ka]

[0147] Step 1: 4-Nitro-3-(trifluoromethyl)-1H-pyrazole [ka]

[0148] To a solution of 3-(trifluoromethyl)-1H-pyrazole (5 g, 36.74 mmol, 1.0 equiv) in HSO (20 mL) was added concentrated HNO (2.68 g, 40.4 mmol, 1.1 equiv) dropwise at 0 °C. The mixture was then stirred at 80 °C for 2 h. The reaction mixture was diluted with ice water (10 mL) and then filtered to give 4-nitro-3-(trifluoromethyl)-1H-pyrazole as a white solid (6.8 g, 51.1%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 1H). Step 2: 1-(4-Methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole [ka]

[0149] To a solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (6.5 g, 35.9 mmol, 1.0 equiv) in MeCN (130 mL) was added KCO (14.9 g, 0.108 mol, 3.0 equiv) and PMB-Cl (6.18 g, 39.5 mmol, 1.1 equiv). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–10% EtOAc in petroleum ether as eluent to give 1-[(4-methoxyphenyl)methyl]-4-nitro-3-(trifluoromethyl)pyrazole as a white solid (16.3 g, 75.4%). Example (A2-5) Synthesis of 4-[4-amino-5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-bromopyridin-3-amine (A-5) [ka]

[0150] To a solution of methyl 4-nitro-1H-pyrazole-5-carboxylate (5 g, 29.2 mmol, 1 equiv.) in DMF (200 mL) was added K2CO3 (8.08 g, 58.4 mmol, 2 equiv.) and PMB-Cl (5.03 g, 32.1 mmol, 1.1 equiv.). The mixture was stirred at 25 °C for 2 h. HO (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as the eluent to give methyl 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-carboxylate as a yellow oil (6.5 g, 76.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.67-3.77 (m, 3 H), 3.81-3.93 (m, 3 H), 5.25-5.54 (m, 2 H), 6.83-7.03 (m, 2 H), 7.23-7.44 (m, 2 H), 8.96-9.23 (m, 1 H). Example (B1-1) Synthesis of 5-(2-amino-5-bromophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (Intermediate B1-1) [ka]

[0151] Step 1: tert-Butyl N-(2-bromophenyl)carbamate [ka]

[0152] A mixture of 2-bromoaniline (60.0 g, 0.349 mol, 1 equiv.) and BocO (115 g, 0.527 mol, 1.5 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 100 °C for 48 h under N2 atmosphere until the starting material was completely consumed and cooled to room temperature. The resulting mixture was quenched at 25 °C by adding HO (100 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–15% EtOAc in petroleum ether as the eluent to give tert-butyl N-(2-bromophenyl)carbamate as a yellow oil (87.0 g, 85.8%). LCMS(ESI)m / z:271.7[M+H] + . Step 2: tert-butyl (2-(3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phenyl)carbamate [ka]

[0153] A mixture of tert-butyl N-(2-bromophenyl)carbamate (A1-1) (10 g, 36.8 mmol, 1 equiv.), trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (19.0 g, 73.8 mmol, 2 equiv.), Pd(OAc) (825 mg, 3.67 mmol, 0.1 equiv.), XPhos (5.26 g, 11.0 mmol, 0.3 equiv.), and CsCO (24.0 g, 73.7 mmol, 2 equiv.), 2,2-dimethylpropanoic acid (7.51 g, 73.5 mmol, 2 equiv.) in toluene (200 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under N atmosphere for 16 h. The reaction mixture was quenched at 25° C. by adding HO (100 mL) and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate as a brown oil (22.5 g, 41.0%). LCMS (ESI) m / z: 449.1 [M+H] + . Step 3: tert-butyl (4-bromo-2-(3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phenyl)carbamate [ka]

[0154] A mixture of tert-butyl N-[2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate (30.0 g, 66.9 mmol, 1 equiv.), NBS (12.0 g, 67.4 mmol, 1 equiv.) in MeCN (150 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 20 °C for 48 h. The residue was filtered and concentrated under reduced pressure to give crude tert-butyl N-[4-bromo-2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate as a brown oil (45.0 g). LCMS (ESI) m / z: 529.1 [M+H] + . Step 4: tert-butyl (2-(4-amino-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-bromophenyl)carbamate [ka]

[0155] A mixture of tert-butyl N-[4-bromo-2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate (40.0 g, 37.9 mmol, 1 equiv.), Fe (10.6 g, 0.190 mol, 5 equiv.), and NH4Cl (10.2 g, 0.190 mol, 5 equiv.) in EtOH / HO (1:1, 200 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 80 °C for 2 h. The resulting mixture was quenched at 25 °C by the addition of HO (50 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-15% EtOAc in petroleum ether as eluent to give tert-butyl N-[2-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-bromophenyl]carbamate as a red oil (3.0 g, 15.9%). LCMS (ESI) m / z: 499.2 [M+H] + . Step 5: 5-(2-amino-5-bromophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine [ka]

[0156] To a solution of tert-butyl N-[2-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-bromophenyl]carbamate (7.86 g, 15.8 mmol, 1 equiv.) in DCM (80 mL) at room temperature was added ZnBr (7.15 g, 31.7 mmol, 2 equiv.), and the mixture was stirred at 40 °C under a N atmosphere for 12 h. The reaction mixture was diluted with THF (20 mL), added with anhydrous NaSO, filtered, and concentrated under reduced pressure at low temperature to give crude 5-(2-amino-5-bromophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine as a brown oil (8 g). LCMS (ESI) m / z: 399.2 [M+H] + . Example (B1-2) Synthesis of 5-(2-amino-5-bromophenyl)-3-chloro-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-2) [ka]

[0157] Step 1: 2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline [ka]

[0158] A mixture of 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (Intermediate A1-2) (10 g, 36 mmol, 1 equiv.), 2-iodoaniline (7.88 g, 36 mmol, 1 equiv.), Pd(PPh3)4 (4.16 g, 3.6 mmol, 0.1 equiv.), CuI (686 mg, 3.60 mmol, 0.1 equiv.), and Cs2CO3 (17.6 g, 54.0 mmol, 1.5 equiv.) in dioxane (100 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-40% petroleum ether / EtOAc at 45 mL / min) to give 2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (6.6 g, 46.7%) as a dark green liquid. LCMS (ESI) m / z: 369.1 [M+H] + . Step 2: 4-Bromo-2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline [ka]

[0159] A mixture of 2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (8.1 g, 21.9 mmol, 1 equiv.) and NBS (3.91 g, 21.9 mmol, 1 equiv.) in MeCN (80 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–30% petroleum ether / EtOAc at 35 mL / min) to give 4-bromo-2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (6.30 g, 63.4%) as a yellow solid. LCMS(ESI)m / z:449.1[M+H] + . Step 3: 5-(2-amino-5-bromophenyl)-3-chloro-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine [ka]

[0160] To a solution of 4-bromo-2-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (5.8 g, 12.9 mmol, 1 equiv.) in EtOH (60 mL) and HO (20 mL) was added Fe (4.34 g, 77.7 mmol, 6 equiv.) and NHCl (4.16 g, 77.7 mmol, 6 equiv.). The mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-30% petroleum ether / EtOAc at 35 mL / min) to afford 5-(2-amino-5-bromophenyl)-3-chloro-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (4.80 g, 81.6%) as a yellow solid. LCMS (ESI) m / z: 419.1 [M+H] + . Example (B1-3) Synthesis of 5-(2-amino-5-bromo-3-methylphenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-3) [ka]

[0161] Step 1: 2-Methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline [ka]

[0162] To a solution of 2-bromo-6-methylaniline (5 g, 26.9 mmol, 1 equiv.) in dioxane (150 mL) was added trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (11.5 g, 26.9 mmol, 60% purity, 1 equiv.), CsCO (13.1 g, 40.3 mmol, 1.5 equiv.), Pd(OAc) (603 mg, 2.69 mmol, 0.1 equiv.), XPhos (2.56 g, 5.37 mmol, 0.2 equiv.), and CsOPiv (6.92 g, 29.6 mmol, 1.1 equiv.). The mixture was degassed and purged with N three times. The mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (300 mL) and extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-15% EtOAc in petroleum ether as eluent to give 2-methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline as a black oil (8.5 g, 29.1%). LCMS (ESI) m / z: 363.2 [M+H] + . Step 2: 4-Bromo-2-methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline [ka]

[0163] To a solution of 2-methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (4.25 g, 11.7 mmol, 1 equiv.) in MeCN (50 mL) was added NBS (2.30 g, 12.9 mmol, 1.1 equiv.). The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure. The residue was diluted with HO (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, 4-bromo-2-methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline, as a black oil (10.1 g). LCMS(ESI)m / z:441.1[M+H] + . Step 3: 2-Methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline [ka]

[0164] To a solution of 4-bromo-2-methyl-6-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]aniline (5 g, 11.3 mmol, 1 equiv.) in EtOH / HO (3:1, 130 mL) was added NH4Cl (3.03 g, 56.6 mmol, 5 equiv.) and Fe (3.16 g, 56.6 mmol, 5 equiv.). The mixture was stirred at 80 °C for 3 h, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was diluted with HO (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 5-(2-amino-5-bromo-3-methylphenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine as a black oil (8.1 g, 69.5%, 80% purity). LCMS (ESI) m / z: 412.9 [M+H] + . Example (B1-7) Synthesis of methyl 4-amino-3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate [ka]

[0165] Step 1: Methyl 4-(tert-butoxycarbonylamino)-3-iodobenzoate [ka]

[0166] To a solution of methyl 4-amino-3-iodobenzoate (20 g, 72.1 mmol, 1.0 equiv.) in THF (400 mL) was added 1 M NaHMDS in THF (158 mL, 0.158 mol, 2.2 equiv.) dropwise over 30 min at 0 °C under a N atmosphere, followed by (Boc) O (16.5 g, 75.8 mmol, 1.05 equiv.). The reaction mixture was warmed to 25 °C and stirred for 16 h, then poured into ice-water (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO®; 220 g SepaFlash® silica flash column, 0–20% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 mn) to give 4-(tert-butoxycarbonylamino)-3-iodobenzoate as a yellow solid (21.5 g, 78.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.56 (m, 9 H), 3.79-3.91 (m, 3 H), 7.67 (d, J = 8.56 Hz, 1 H), 7.93 (dd, J = 8.44, 1.96 Hz, 1 H), 8.34 (d, J = 2.08 Hz, 1 H), 8.45-8.57 (m, 1 H); LCMS(ESI)m / z:378.0[M+H] + . Step 2: Methyl 4-(tert-butoxycarbonylamino)-3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate [ka]

[0167] Methyl 4-(tert-butoxycarbonylamino)-3-iodobenzoate (2.0 g, 5.30 mmol, 1.0 equiv.), 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (Intermediate A1-2) (1.47 g, 5.30 mmol, 1.0 equiv.), Pd(OAc) (119 mg, 0.530 mmol), in toluene (50 mL). A mixture of CsCO (2.59 g, 7.95 mmol, 1.5 equiv), XPhos (1.26 g, 2.65 mmol, 0.5 equiv), and CsCO (2.59 g, 7.95 mmol, 1.5 equiv), cesium 2,2-dimethylpropanoate (1.37 g, 5.83 mmol, 1.1 equiv) was degassed and purged with N three times, and then the mixture was stirred under N at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–20% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn) to give methyl 4-(tert-butoxycarbonylamino)-3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate as a white solid (1.1 g, 39.3% yield). 1 H NMR (400 MHz, CD3OD) δ ppm 0.06 (s, 9 H), 0.87-1.05 (m, 2 H), 1.26-1.29 (m, 9 H), 2.13-2.38 (m, 2 H), 2.53 (s, 3 H), 3.60-3.92 (m, 3 H), 4.13-4.21 (m, 1 H), 4.28 (t, J = 6.36 Hz, 2 H), 5.33 (s, 2 H), 7.67-7.87 (m, 1 H); LCMS(ESI)m / z:549.1[M+H] + . Step 3: Methyl 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate [ka]

[0168] A mixture of methyl 4-(tert-butoxycarbonylamino)-3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate (250 mg, 0.474 mmol, 1.0 equiv.), Zn (310 mg, 4.74 mmol, 10.0 equiv.), and NHCl (253 mg, 4.74 mmol, 10.0 equiv.) in EtOH / HO (3:1, 8 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 50° C. for 16 h. The reaction mixture was filtered and concentrated to remove the solvent. The residue was then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO and concentrated to give methyl 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate as a white solid (200 mg, 84.8%). LCMS (ESI) m / z: 519.2 [M+H] + . Step 4: Methyl 4-amino-3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate [ka]

[0169] A mixture of methyl 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate (300 mg, 0.603 mmol) in 4 N HCl in MeOH (2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was quenched with NaHCO / HO (20 mL) and extracted with EtOAc (25 mL × 2). The extract was dried over NaSO and concentrated to give methyl 4-amino-3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]benzoate as a yellow solid (200 mg), which was used directly in the next step without any further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 0.04 (s, 9 H), 0.83-0.95 (m, 2 H), 3.51-3.66 (m, 2 H), 3.87-3.90 (m, 3 H), 5.22 (br d, J = 17.4 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 1 H), 7.92 - 8.03 (m, 2 H); LCMS(ESI)m / z:419.1[M+H] + . Example (B1-8) Synthesis of 5-(2,6-difluorophenyl)-1-(4-methoxybenzyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (Intermediate B1-8) [ka]

[0170] Step 1: Methyl 4-(tert-butoxycarbonylamino)-3-iodobenzoate [ka]

[0171] To a solution of methyl 4-amino-3-iodobenzoate (50 g, 0.180 mol, 1.0 equiv.) in THF (500 mL), 1 M NaHMDS in THF (397 mL, 0.397 mol, 2.2 equiv.) was added dropwise, and the resulting mixture was stirred at 0 °C for 30 min. Next, BocO (41.4 g, 0.189 mol, 1.05 equiv.) was added, and the reaction was stirred at 25 °C for an additional 2 h. The reaction mixture was concentrated to remove most of the THF, dissolved in EtOAc (1 L), and washed with brine (200 mL × 3). The organic layer was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (using 0–20% EtOAc in petroleum ether as eluent) to give methyl 4-(tert-butoxycarbonylamino)-3-iodobenzoate as a white solid (19.0 g, 27.9%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.48 (s, 9 H), 3.84 (s, 3 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.92 (dd, J = 8.5, 1.9 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 8.51 (s, 1 H); LCMS(ESI)m / z:321.9[M+H] + . Step 2: Methyl 4-(tert-butoxycarbonylamino)-3-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]benzoate [ka]

[0172] A mixture of methyl 4-(tert-butoxycarbonylamino)-3-iodobenzoate (10.0 g, 26.5 mmol, 1.0 equiv), 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole (Intermediate A2-3) (6.18 g, 26.5 mmol, 1.0 equiv), Pd(OAc) (595 mg, 2.65 mmol, 0.2 equiv), XPhos (6.32 g, 13.3 mmol, 0.5 equiv), and CsCO (12.9 g, 39.7 mmol, 1.5 equiv), 2,2-dimethylpropanoate (6.82 g, 29.1 mmol, 1.1 equiv) in toluene (300 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under N for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash chromatography on a silica gel column using 0–50% EtOAc in petroleum ether as eluent to give methyl 4-(tert-butoxycarbonylamino)-3-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]benzoate as a white solid (6.30 g, 49.2%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H), 3.72-3.73 (m, 3 H), 3.80 (s, 3 H), 4.88 (d, J = 15.13 Hz, 1 H), 5.10 (d, J = 15.26 Hz, 1 H), 6.84 (d, J = 8.76 Hz, 2 H), 7.02 (d, J = 8.63 Hz, 2 H), 7.62 (d, J = 2.00 Hz, 1 H), 7.81 (d, J = 8.63 Hz, 1H), 8.07 (dd, J = 8.63, 2.00 Hz, 1 H), 8.36-8.46 (m, 1 H), 9.28 (s, 1 H); LCMS(ESI)m / z:505.2[M+H] + . Step 3: Methyl 3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate [ka]

[0173] To methyl 4-(tert-butoxycarbonylamino)-3-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]benzoate (5.80 g, 12.0 mmol, 1.0 equiv.) in EtOH / HO (1:1, 70 mL) was added Zn (7.86 g, 0.120 mol, 10.0 equiv.) and NH4Cl (6.43 g, 0.120 mol, 10.0 equiv.). The mixture was stirred at 50 °C for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (100 mL × 2) and saturated brine (100 mL × 2). The organic layer was concentrated in vacuo to remove the solvent. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent gradient of 0 to 60% EtOAc / petroleum ether at 50 mL / min) to give methyl 3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate as a purple oil (1.90 g, 34.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 9 H), 3.73 (s, 3 H), 3.87 (s, 3 H), 4.12 (q, J = 7.13 Hz, 3 H), 5.00 (d, J = 13.63 Hz, 2 H), 6.72 (d, J = 8.63 Hz, 2 H), 6.87 (d, J = 8.63 Hz, 3 H), 7.79 (d, J = 2.00 Hz, 1 H), 8.07 (dd, J = 8.76, 2.00 Hz, 1 H), 8.25 (d, J = 8.88 Hz, 1 H); LCMS(ESI)m / z:475.2[M+H] + . Step 4: Methyl 4-amino-3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]benzoate [ka]

[0174] Methyl 3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate (300 mg, 663 μmol, 1.0 equiv) in 4 N HCl in MeOH (5 mL) was stirred for 1 hour at 25° C. The mixture was concentrated in vacuo to give methyl 4-amino-3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]benzoate as a yellow solid (300 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 3.83 (s, 5 H), 4.59 (s, 2 H), 6.91 (d, J = 8.6 Hz, 3 H), 7.34 (d, J = 8.6 Hz, 3 H); LCMS(ESI)m / z:352.7[M+H] + . Example (B1-10) Synthesis of 5-(2-amino-5-bromophenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-10) [ka]

[0175] Step 1: tert-Butyl N-(2-bromophenyl)carbamate [ka]

[0176] A solution of 2-bromoaniline (10 g, 58.1 mmol, 1 equiv.) in BocO (38.1 g, 0.174 mol, 3 equiv.) was stirred at 100° C. for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (1000 mL) and extracted with EtOAc (1500 mL × 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, tert-butyl N-(2-bromophenyl)carbamate, as a yellow oil (156 g). 1 H NMR (400 MHz, CDCl3) δ ppm 1.52-1.57 (m, 9 H), 6.82-6.94 (m, 1 H), 7.01 (brs, 1 H), 7.25-7.32 (m, 1 H), 7.50 (dd, J = 7.9, 1.1 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H). Step 2: tert-butyl (2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phenyl)carbamate [ka]

[0177] To a solution of tert-butyl N-(2-bromophenyl)carbamate (5 g, 18.4 mmol, 1 equiv.) in toluene (50 mL) was added trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-3) (4.69 g, 19.3 mmol, 1.05 equiv.), CsCO (12.0 g, 36.8 mmol, 2 equiv.), 2,2-dimethylpropanoic acid (3.75 g, 36.8 mmol, 2 equiv.), Pd(OAc) (412 mg, 1.84 mmol, 0.1 equiv.), and XPhos (2.63 g, 5.51 mmol, 0.3 equiv.). The mixture was degassed and purged with N three times. The mixture was stirred under N at 100 °C for 3 h and then concentrated under reduced pressure. The residue was diluted with HO (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude tert-butyl N-[2-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate as a brown oil (40 g). Step 3: tert-butyl N-[4-bromo-2-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate [ka]

[0178] To a solution of tert-butyl N-[2-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate (8 g, 18.4 mmol, 1 equiv.) in MeCN (300 mL) was added NBS (3.60 g, 20.3 mmol, 1.1 equiv.), and the mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[4-bromo-2-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate as a brown oil (26 g, 55.0%). Step 4: tert-butyl N-[2-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-bromophenyl]carbamate [ka]

[0179] To a solution of tert-butyl N-[4-bromo-2-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]carbamate (26 g, 50.6 mmol, 1 equiv.) in EtOH / HO (1:1, 200 mL) was added NH4Cl (19.0 g, 0.354 mol, 7 equiv.) and Fe (19.8 g, 0.354 mol, 7 equiv.). The mixture was stirred at 80 °C for 3 h. The solution was filtered and the collected solution was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-50% EtOAc in petroleum ether as eluent to give tert-butyl N-[2-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-bromophenyl]carbamate as a red oil (10.1 g, 40.0%). LCMS (ESI) m / z: 483.1 [M+H] + . Step 5: 5-(2-amino-5-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine [ka]

[0180] To a solution of tert-butyl N-[2-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-bromophenyl]carbamate (5 g, 10.3 mmol, 1 equiv.) in DCM (40 mL) was added ZnBr (4.66 g, 20.7 mmol, 2 equiv.). The mixture was stirred at 40 °C for 12 h. The mixture was filtered and the solid was collected. The solid was dissolved in EtOAc (200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product 5-(2-amino-5-bromophenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine as a red solid (7.35 g). LCMS (ESI) m / z: 383.0 [M+H] + . Example (B1-12) Synthesis of 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (Intermediate B1-12) [ka]

[0181] Step 1: Methyl 4-amino-2-fluoro-5-iodobenzoate [ka]

[0182] A mixture of methyl 4-amino-2-fluorobenzoate (5 g, 29.5 mmol, 1.0 equiv), ICl (5.28 g, 32.5 mmol, 1.1 equiv), CaCO (5.92 g, 59.1 mmol) in DCM / MeOH (60 mL, v / v=1 / 1) was degassed and purged with N three times, and then the mixture was stirred at 25 °C for 2 h. The reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn / I2) to give methyl 4-amino-2-fluoro-5-iodobenzoate as a white solid (2.5 g, 28.6% yield). 1 LCMS(ESI)m / z:296.1[M+H] + . Step 2: Methyl 4-(tert-butoxycarbonylamino)-2-fluoro-5-iodobenzoate [ka]

[0183] To a solution of methyl 4-amino-2-fluoro-5-iodobenzoate (2.5 g, 8.47 mmol, 1.0 equiv) in THF (30 mL) was added 1 M LiHMDS / THF (16.9 mL, 2.0 equiv) dropwise over 30 min at 0 °C. After the addition, the mixture was stirred at 0 °C for 30 min. Then, BocO (2.22 g, 2.34 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding HO (50 mL) at 0 °C and then extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure to remove the solvent, and the residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–20% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn / I2) to give methyl 4-(tert-butoxycarbonylamino)-2-fluoro-5-iodobenzoate as a white solid (2.3 g, 68.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 9 H), 3.79-3.93 (m, 3 H), 7.44-7.71 (m, 1 H), 8.13-8.34 (m, 1 H), 8.43 (br d, J = 9.66 Hz, 1 H); LCMS(ESI)m / z:396.1[M+H] + . Step 3: Methyl 4-amino-5-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate [ka]

[0184] A mixture of methyl 4-(tert-butoxycarbonylamino)-2-fluoro-5-iodobenzoate (2.3 g, 5.82 mmol, 1.0 equiv), 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (1.62 g, 5.82 mmol, 1.0 equiv), Pd(OAc) (392 mg, 1.75 mmol, 0.3 equiv), XPhos (1.39 g, 2.91 mmol, 0.5 equiv), CsCO (2.84 g, 8.73 mmol, 1.5 equiv), and cesium 2,2-dimethylpropanoate (1.50 g, 6.40 mmol, 1.1 equiv) in toluene (50 mL) was degassed and purged with N three times, then stirred at 100 °C under N for 16 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn) to give methyl 4-amino-5-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate as a white solid (1.2 g, 46.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.06 (s, 9 H), 0.73-0.81 (m, 2 H), 3.44 (td, J = 8.3, 3.6 Hz, 2 H), 3.73 (s, 3 H), 5.09-5.31 (m, 2 H), 6.44-6.50 (m, 2 H), 6.50-6.57 (m, 1 H), 7.73 (d, J = 8.2 Hz, 1 H). Step 4: Methyl 4-amino-5-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate [ka]

[0185] A mixture of methyl 4-amino-5-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate (1.2 g, 2.70 mmol, 1.0 equiv.), Fe (1.51 g, 26.9 mmol, 10.0 equiv.), and NHCl (1.44 g, 26.9 mmol, 10.0 equiv.) in EtOH / HO (v / v=5 / 1, 30 mL) was stirred at 50° C. for 2 hours. The reaction mixture was extracted with EtOAc (50 mL×2). The combined organic layers were concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn) to give methyl 4-amino-5-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate as a white solid (600 mg, 53.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (m, 9 H), 0.74 (br dd, J = 8.38, 5.32 Hz, 2 H), 3.33 (br s, 2 H), 3.74 (s, 3 H), 3.85 (s, 2 H), 4.81-5.27 (m, 2 H), 6.09 (s, 2 H), 6.54 (d, J = 13.82 Hz, 1 H), 7.63 (d, J = 8.44 Hz, 1 H). Example (B2-1) Synthesis of 4-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-1) [ka]

[0186] Step 1: 6-chloro-4-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine [ka]

[0187] A mixture of 6-chloro-4-iodopyridin-3-amine (2 g, 7.86 mmol, 1 equiv.), trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-3) (2.11 g, 8.65 mmol, 1.1 equiv.), Pd(PPh3)4 (0.91 g, 0.79 mmol, 0.1 equiv.), Cs2CO3 (7.68 g, 23.6 mmol, 3.0 equiv.), and CuI (299 mg, 2.36 mmol, 0.3 equiv.) in dioxane (20 mL) was degassed and purged with N2 three times, then stirred under N2 atmosphere at 80 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–27% EtOAc in petroleum ether as eluent to give 6-chloro-4-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine as a yellow solid (1.2 g, 37.2%). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.04-0.09 (m, 9 H), 0.80-0.72 (m, 2 H), 3.47-3.41 (m, 2 H), 5.19 (d, J = 11.3 Hz, 1 H), 5.35 (d, J = 11.0 Hz, 1 H), 5.73 (s, 2 H), 7.27 (s, 1 H), 7.94 (s, 1 H), 8.48 (s, 1H); LCMS(ESI)m / z:370.2,[M+H] + . Step 2: 4-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (B2-1) [ka]

[0188] A mixture of 6-chloro-4-[4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine (1.2 g, 3.24 mmol, 1 equiv.), Fe (1.45 g, 26.0 mmol, 8 equiv.), and NHCl (1.39 g, 26.0 mmol, 8 equiv.) in EtOH / HO (2:1, 12 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 60 °C for 3 h. The reaction mixture was filtered and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-56% EtOAc in petroleum ether as eluent to give 4-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine as a yellow oil (1.0 g, 88.0%). LCMS (ESI) m / z: 340.1 [M+H] + . Example (B2-2) Synthesis of 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-2) [ka]

[0189] Step 1: 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine [ka]

[0190] To a mixture of 6-chloro-4-iodopyridin-3-amine (30 g, 0.118 mol, 1 equiv.), trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (75.9 g, 0.295 mol, 2.5 equiv.), CuI (26.9 g, 0.141 mol, 1.2 equiv.), CsCO (96.0 g, 0.295 mol, 2.5 equiv.), and 2,2-dimethylpropanoic acid (30.6 g, 0.299 mol, 2.5 equiv.) in dioxane (50 mL) was added Pd(PPh) (20.4 g, 17.7 mmol, 0.15 equiv.). The system was purged with nitrogen three times. The mixture was heated to 100 °C and stirred under nitrogen for 12 h. The reaction was slowly quenched with HO (100 mL) under a nitrogen atmosphere and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-16% EtOAc in petroleum ether as eluent to give 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine as a yellow solid (31.5 g, 64.0%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.00 (s, 9 H), 0.84-1.00 (m, 2 H), 2.62 (s, 3 H), 3.59-3.67 (m, 2 H), 3.83 (s, 2 H), 5.12-5.31 (m, 2 H), 7.05-7.16 (m, 1 H), 8.05 (s, 1 H); LCMS(ESI)m / z:384.2[M+H] + . Step 2: 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (B2-2) [ka]

[0191] To a solution of 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine (11.6 g, 30.2 mmol, 1 equiv.) in EtOH / HO (3:1, 120 mL) was added Fe (10.1 g, 0.181 mol, 6 equiv.) and NH4Cl (9.70 g, 0.181 mol, 6 equiv.), and the mixture was stirred at 80 °C for 6 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine as a gray solid (9.6 g). 1 H NMR (400 MHz, CDCl3) δ ppm -0.05-0.03 (m, 9 H), 0.91 (dd, J = 9.0, 7.6 Hz, 2 H), 1.19-1.31 (m, 1 H), 2.24 (s, 3 H), 3.60 (br t, J = 8.3 Hz, 2 LCMS(ESI)m / z:354.3[M+H] + . Example (B2-3) Synthesis of 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-3) [ka]

[0192] Step 1: 6-Bromo-4-iodopyridine-3-carboxylic acid [ka]

[0193] To a solution of TMP (4.20 g, 29.7 mmol, 3 equiv.) in THF (20 mL) was added dropwise 2.5 M n-BuLi (11.9 mL, 29.7 mmol, 3 equiv.) in n-hexane at −78° C. The mixture was stirred at −78° C. for 30 min. Next, 6-bromopyridine-3-carboxylic acid (2.0 g, 9.9 mmol, 1 equiv.) was added to the above solution, and the mixture was stirred at −78° C. for 2 h. To this solution was added I2 (7.54 g, 29.7 mmol, 3 equiv.) at −78° C. The mixture was stirred at 25° C. for 12 h. The reaction solvent was removed under vacuum, and the residue was suspended in water (50 mL) and then washed with DCM (100 mL × 2). The aqueous layer was acidified to pH ∼2 by adding 12 N concentrated HCl in HO, and the precipitate was collected by filtration, washed with water (30 mL), and then dried under vacuum to give 6-bromo-4-iodopyridine-3-carboxylic acid as a light yellow solid (2.7 g, 83.2%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1 H), 8.62 (s, 1 H), 13.83 (br s, 1 H). Step 2: tert-Butyl N-(6-bromo-4-iodo-3-pyridyl)carbamate [ka]

[0194] 6-Bromo-4-iodopyridine-3-carboxylic acid (1.00 g, 3.05 mmol, 1 equiv.) tTo a solution of BuOH / toluene (1:1, 10 mL) was added DPPA (1.26 g, 4.57 mmol, 1.5 equiv.) and TEA (926 mg, 9.15 mmol, 3 equiv.). The mixture was stirred at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-20% EtOAc in petroleum ether as eluent to give tert-butyl N-(6-bromo-4-iodo-3-pyridyl)carbamate as a white solid (250 mg, 20.3%). LCMS (ESI) m / z 398.7 [M+H] + . Step 3: 6-Bromo-4-iodopyridin-3-amine [ka]

[0195] To a solution of tert-butyl N-(6-bromo-4-iodo-3-pyridyl)carbamate (6.50 g, 16.3 mmol, 1 equiv.) in DCM (50 mL) was added TFA (36.8 g, 0.323 mol, 20 equiv.). The mixture was stirred at 25 °C under N atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-30% EtOAc in petroleum ether as the eluent to give 6-bromo-4-iodopyridin-3-amine as a white solid (4.2 g, 36.2%). LCMS (ESI) m / z: 298.7 [M+H] + . Step 4: 6-Bromo-4-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine [ka]

[0196] To a solution of 6-bromo-4-iodopyridin-3-amine (3.0 g, 10.0 mmol, 1 equiv.) in dioxane (30 mL), Pd(PPh3)4 (1.16 g, 1.00 mmol, 0.1 equiv.), CuI (382 mg, 2.01 mmol, 0.2 equiv.), Cs2CO3 (9.81 g, 30.1 mmol, 3 equiv.), and 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (Intermediate A1-2) (3.07 g, 11.0 mmol, 1.1 equiv.) were added. The mixture was degassed and purged with N2 three times. The mixture was stirred under N2 atmosphere at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-30% EtOAc in petroleum ether as eluent to give 6-bromo-4-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine as a yellow solid (1.4 g, 29.8%). LCMS (ESI) m / z: 449.9 [M+H] + . Step 5: 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (B2-3) [ka]

[0197] A solution of 6-bromo-4-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine (1.20 g, 2.67 mmol, 1 equiv.) in THF (10 mL) was added at 0 °C with NaBH4 (405 mg, 10.7 mmol, 4 equiv.), NiCl 2·6H2O (2.54 g, 10.7 mmol, 4 equiv.) was added. The mixture was degassed and purged with N2 three times. The mixture was stirred under N2 atmosphere at 0 °C for 1 h. The solution was quenched at 0 °C by the addition of ammonium chloride (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were then washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-30% EtOAc in petroleum ether as eluent to afford 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine as a yellow solid (500 mg, 44.6%). LCMS (ESI) m / z 420.0 [M+H] + . Example (B2-4) Synthesis of 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (Intermediate B2-4) [ka]

[0198] Step 1: 4-Bromo-6-chloro-2-methylpyridin-3-amine [ka]

[0199] To a solution of 6-chloro-2-methylpyridin-3-amine (20 g, 0.140 mol, 1 equiv.) in MeCN (300 mL) was added NBS (25.0 g, 0.140 mol, 1 equiv.) at 0 °C. The mixture was stirred at 25 °C under a N atmosphere for 16 h. The solution was concentrated under reduced pressure and treated with saturated aqueous NaHCO (200 mL). The resulting mixture was extracted with EtOAc (200 mL × 2), washed with brine (200 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to afford 4-bromo-6-chloro-2-methylpyridin-3-amine as a yellow solid (7.5 g, 24.1% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 2.44 (s, 3 H), 3.95-4.27 (m, 2 H), 7.28 (s, 1 H). Step 2: 6-chloro-2-methyl-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine [ka]

[0200] To a solution of 4-bromo-6-chloro-2-methylpyridin-3-amine (11 g, 49.7 mmol, 1 equiv.) and trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (38.4 g, 0.149 mol, 3 equiv.) in dioxane (400 mL) was added CsCO (48.6 g, 0.149 mol, 3 equiv.), Pd(PPh) (5.74 g, 4.97 mmol, 0.1 equiv.), and CuI (1.89 g, 9.93 mmol, 0.2 equiv.). The mixture was stirred at 100 °C under a N atmosphere for 16 h. The solution was filtered and concentrated. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give 6-chloro-2-methyl-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine as a yellow solid (6 g, 30.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.06 (s, 9 H), 0.64-0.84 (m, 2 H), 2.35 (s, 3 H), 2.49-2.51 (m, 3 H), 3.36-3.52 (m, 2 H), 4.92-5.30 (m, 2 H), 5.38 (s, 2 H), 7.09 (s, 1 H). Step 3: 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (B2-4) [ka]

[0201] To a solution of 6-chloro-2-methyl-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-amine (6 g, 15.1 mmol, 1 equiv.) in EtOH / HO (3:1, 120 mL) was added Fe (8.42 g, 0.151 mol, 10 equiv.) and NH4Cl (8.07 g, 0.151 mol, 10 equiv.). The mixture was stirred at 50 °C under a N2 atmosphere for 16 h. The solution was filtered and extracted with saturated aqueous NaHCO3 (200 mL) and EtOAc (200 mL × 2), washed with brine (200 mL), and dried over anhydrous Na2SO4. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine as a yellow oil (5 g, 90.1%). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.07 (s, 9 H), 0.76 (br t, J = 8.0 Hz, 2 H), 2.12 (s, 3 H), 2.35 (s, 3 H), 3.96 (br s, 2 H), 4.97-5.17 (m, 4 H), 7.12 (s, 1 H). Example (B2-6) Synthesis of 4-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (Intermediate B2-6) [ka]

[0202] Step 1: 4-Bromo-6-chloro-2-methylpyridin-3-amine [ka]

[0203] To a solution of 6-chloro-2-methylpyridin-3-amine (30 g, 0.210 mol, 1 equiv.) in MeOH (200 mL) and AcOH (25.3 g, 0.421 mol, 2 equiv.) at 0 °C was added Br (60.5 g, 0.379 mol, 1.8 equiv.). The mixture was stirred at 25 °C under a N atmosphere for 16 h. The solution was quenched with aqueous NaHSO (50 mL), and NaHCO was added until the pH reached approximately 7. The solution was extracted with EtOAc (200 mL × 2), washed with brine (200 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–20% EtOAc in petroleum ether as the eluent to give 4-bromo-6-chloro-2-methylpyridin-3-amine as a brown solid (30 g, 64.4%). 1 H NMR (400 MHz, CDCl3) δ ppm 2.33-2.49 (m, 3 H), 7.12-7.41 (m, 1 H). Step 2: 6-chloro-4-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]-2-methylpyridin-3-amine [ka]

[0204] To a solution of 4-bromo-6-chloro-2-methylpyridin-3-amine (20 g, 90.3 mmol, 1 equiv.) and 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole (Intermediate A2-3) (31.6 g, 0.136 mol, 1.5 equiv.) in dioxane (400 mL) was added CsCO (88.3 g, 0.271 mol, 3.0 equiv.), Pd(PPh) (10.4 g, 9.03 mmol, 0.1 equiv.), and CuI (3.44 g, 18.1 mmol, 0.2 equiv.). The mixture was stirred at 100 °C under a N atmosphere for 16 h. The solution was filtered and concentrated. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give 6-chloro-4-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]-2-methylpyridin-3-amine as a yellow oil (20 g, 59.3%). 1 H NMR (400 MHz, CDCl3) δ ppm 2.36 (s, 3 H), 3.49 (s, 2 H), 3.69 (s, 3 H), 4.85-5.09 (m, 2 H), 6.65-6.75 (m, 3 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.18-7.31 (m, 1 H), 8.14 (s, 1 H). Step 3: 4-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (B2-6) [ka]

[0205] To a solution of 6-chloro-4-[2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]-2-methylpyridin-3-amine (20 g, 53.5 mmol, 1 equiv.) in EtOH / HO (3:1, 400 mL) was added Fe (29.9 g, 0.535 mol, 10 equiv.) and NH4Cl (28.6 g, 0.535 mol, 10 equiv.). The mixture was stirred at 50 °C under a N2 atmosphere for 5 h. The solution was filtered and concentrated under reduced pressure. The residue was extracted with EtOAc (400 mL × 2), washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–100% EtOAc in petroleum ether as eluent to give 4-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine as a yellow solid (14 g, 68.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 3.69 (s, 3 H), 4.03 (br d, J = 6.9 Hz, 2 H), 4.82-5.18 (m, 4 H), 6.81 (d, J = 9.8 Hz, 5 H), 7.13-7.23 (m, 1 H). Example (B2-14) Synthesis of 3-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine (Intermediate B2-14) [ka]

[0206] Step 1: 3-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine [ka]

[0207] A mixture of 3-iodo-5-(trifluoromethyl)pyridin-2-amine (3 g, 10.4 mmol, 1 equiv.), trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (2.68 g, 10.4 mmol, 1 equiv.), Pd(PPh) (1.20 g, 1.04 mmol, 0.1 equiv.), KCO (2.16 g, 15.6 mmol, 1.5 equiv.), and CuI (595 mg, 3.12 mmol, 0.3 equiv.) in DMF (30 mL) was degassed and purged with N three times, then stirred under N atmosphere at 90 °C for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-20% EtOAc in petroleum ether as eluent to give 3-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine as a brown oil (1.7 g, 35.1%). LCMS (ESI) m / z: 418.1 [M+H] + . Step 2: 3-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine (B2-14) [ka]

[0208] To a solution of 3-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine (1 g, 2.40 mmol, 1 equiv.) in EtOH / HO (2:1, 15 mL) was added NHCl (640 mg, 11.9 mmol, 2 equiv.) and Fe (1.34 g, 24.0 mmol, 10 equiv.). The mixture was stirred at 70 °C for 4 h, then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–40% EtOAc in petroleum ether as eluent to give 3-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-(trifluoromethyl)pyridin-2-amine as a brown oil (703 mg, 70.4%). LCMS(ESI)m / z:388.1[M+H] + . Example (B2-17) Synthesis of 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (Intermediate B2-17) [ka]

[0209] Step 1: 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine [ka]

[0210] A mixture of 4-iodo-6-(trifluoromethyl)pyridin-3-amine (1 g, 3.47 mmol, 1 equiv.), 1-[(4-methoxyphenyl)methyl]-3-methyl-4-nitropyrazole (Intermediate A2-1) (858 mg, 3.47 mmol, 1 equiv.), Pd(PPh3)4 (401 mg, 0.347 mmol, 0.1 equiv.), K2CO3 (719 mg, 5.21 mmol, 1.5 equiv.), and CuI (198 mg, 1.04 mmol, 0.3 equiv.) in DMF (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 90 °C for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-60% EtOAc in petroleum ether as eluent to give 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine as a brown oil (620 mg, 38.5%). No mass signal. Step 2: 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (B2-17) [ka]

[0211] To a solution of 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (620 mg, 1.52 mmol, 1 equiv.) in EtOH / HO (3:1, 32 mL) was added NH4Cl (407 mg, 7.61 mmol) and Fe (850 mg, 15.2 mmol, 10 equiv.). The mixture was stirred at 70 °C for 4 h, then diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-80% EtOAc in petroleum ether as eluent to give 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine as a brown oil (320 mg, 51.2%). LCMS (ESI) m / z: 378.1 [M+H] + . Example (B2-18) Synthesis of 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (Intermediate B2-18) [ka]

[0212] Step 1: 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine [ka]

[0213] A mixture of 4-iodo-6-(trifluoromethyl)pyridin-3-amine (1.3 g, 4.51 mmol, 1 equiv.), 1-[(4-methoxyphenyl)methyl]-3-methyl-4-nitropyrazole (Intermediate A1-3) (1.12 g, 4.51 mmol, 1 equiv.), Pd(PPh3)4 (521 mg, 0.451 mmol, 0.1 equiv.), K2CO3 (935 mg, 6.77 mmol, 1.5 equiv.), and CuI (257 mg, 1.35 mmol, 0.3 equiv.) in DMF (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 90 °C for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-60% EtOAc in petroleum ether as eluent to give 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine as a brown oil (1 g, 32.6%). No mass signal. Step 2: 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (B2-18) [ka]

[0214] To a solution of 4-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine (1 g, 2.45 mmol, 1 equiv.) in EtOH / HO (5:2, 7 mL) was added NHCl (656 mg, 12.2 mmol, 5 equiv.) and Fe (1.37 g, 24.5 mmol, 10 equiv.). The mixture was stirred at 70 °C for 4 h, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–40% EtOAc in petroleum ether as eluent to give 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-(trifluoromethyl)pyridin-3-amine as a brown oil (300 mg, 27.5%). No mass signal was observed. Example (B2-19) Synthesis of 4-(4-amino-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-6-bromopyridin-3-amine (Intermediate B2-19) [ka]

[0215] Step 1: 6-Bromo-4-[2-[(4-methoxyphenyl)methyl]-4-nitro-5-(trifluoromethyl)pyrazol-3-yl]pyridin-3-amine [ka]

[0216] A mixture of 1-[(4-methoxyphenyl)methyl]-4-nitro-3-(trifluoromethyl)pyrazole (Intermediate A2-4) (1 g, 3.32 mmol, 1.0 equiv), 6-bromo-4-iodopyridin-3-amine (1.19 g, 3.98 mmol, 1.2 equiv), CsCO (3.24 g, 9.96 mmol, 3.0 equiv), CuI (126 mg, 0.663 mmol, 0.2 equiv), and Pd(PPh) (384 mg, 0.331 mmol, 0.1 equiv) in dioxane (20 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 70 °C for 16 h. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give 6-bromo-4-[2-[(4-methoxyphenyl)methyl]-4-nitro-5-(trifluoromethyl)pyrazol-3-yl]pyridin-3-amine as a yellow oil (2 g, 52.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H), 5.05 (d, J = 15.1 Hz, 1 H), 5.22 (d, J = 15.1 Hz, 1 H), 5.93 (s, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 2 H), 7.34 (s, 1 H), 7.95 (s, 1 H). Step 2: 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl]-6-bromopyridin-3-amine [ka]

[0217] A mixture of 6-bromo-4-[2-[(4-methoxyphenyl)methyl]-4-nitro-5-(trifluoromethyl)pyrazol-3-yl]pyridin-3-amine (2 g, 4.24 mmol, 1.0 equiv.) and NiCl-6H0 (6.04 g, 25.4 mmol, 6.0 equiv.) in THF (20 mL) was stirred at 25 °C for 10 min. Then, NaBH (480 mg, 12.7 mmol, 3.0 equiv.) was added to the mixture at 0 °C, and the mixture was stirred for 10 min. The reaction mixture was diluted with H0 (20 mL), filtered, and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 0-30% EtOAc in petroleum ether as eluent to give 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl]-6-bromopyridin-3-amine as a yellow solid (1.04 g, 53.8%). LCMS (ESI) m / z: 442.0 [M+H] + . Example (B2-20) Synthesis of 4-[4-amino-5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-bromopyridin-3-amine (B2-20) [ka]

[0218] Step 1: [1-[(4-Methoxyphenyl)methyl]-4-nitropyrazol-3-yl]methanol [ka]

[0219] To a solution of methyl 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-carboxylate (Intermediate A2-5) (6.5 g, 22.3 mmol, 1 equiv.) in THF (100 mL) was added dropwise 1 M DIBAL-H in toluene (44.6 mL, 44.6 mmol, 2 equiv.) at −78 °C. The mixture was stirred at 25 °C for 16 h. HO (50 mL) was added to the reaction mixture, which was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product [1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-yl]methanol as a yellow solid (5.8 g, crude), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H), 4.63 (d, J = 6.02 Hz, 2 H), 5.20 (t, J = 5.90 Hz, 1 H), 5.26 (s, 2 H), 6.93 (d, J = 8.53 Hz, 2 H), 7.31 (d, J = 8.53 Hz, 2 H), 8.81-9.01 (m, 1 H). Step 2: 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-carbaldehyde [ka]

[0220] To a solution of [1-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]methanol (5.8 g, 22.0 mmol, 1 equiv.) in DCM (100 mL) was added DMP (28.0 g, 66.1 mmol, 3 equiv.). The mixture was stirred at 25 °C for 16 h. HO (40 mL) was added to the reaction mixture, which was then extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–60% EtOAc in petroleum ether as the eluent to give 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-carbaldehyde as a white solid (4.95 g, 86.1%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3 H), 5.40 (s, 2 H), 6.93-6.95 (m, 2 H), 7.34-7.37 (m, 2 H), 9.12 (s, 1 H), 10.19 (s, 1 H). Step 3: 3-(Difluoromethyl)-1-[(4-methoxyphenyl)methyl]-4-nitropyrazole [ka]

[0221] To a solution of 1-[(4-methoxyphenyl)methyl]-4-nitropyrazole-3-carbaldehyde (6.5 g, 24.8 mmol, 1 equiv.) in DCM (100 mL) was added DAST (8.02 g, 49.7 mmol, 2 equiv.) at 0 °C, and the reaction was stirred at 25 °C for 16 h. The reaction mixture was diluted with HO (40 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as eluent to give 3-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-4-nitropyrazole as a yellow solid (4.15 g, 58.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3 H), 5.36 (s, 2 H), 6.92-6.96 (m, 2 H), 7.15 (s, 1 H), 7.28 (s, 1 H), 7.32-7.37 (m, 2 H), 7.41 (s, 1 H), 9.14 (s, 1 H), 19 F NMR (377 MHz, DMSO-d6) δ ppm -117.49. Step 4: 6-Bromo-4-[5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]pyridin-3-amine [ka]

[0222] To a solution of 3-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-4-nitropyrazole (2 g, 7.06 mmol) and 6-bromo-4-iodopyridin-3-amine (2.11 g, 7.06 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (816 mg, 0.706 mmol), Cs2CO3 (6.90 g, 21.2 mmol), and CuI (403 mg, 2.12 mmol). The mixture was stirred at 90 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 35 mL / min, 254 nm) to afford 6-bromo-4-[5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]pyridin-3-amine (1.61 g, 47.9%) as a yellow solid. LCMS (ESI) m / z: 456.1 [M+H] + . Step 5: 4-[4-amino-5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-bromopyridin-3-amine (B2-20) [ka]

[0223] To a solution of 6-bromo-4-[5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]pyridin-3-amine (1.6 g, 3.52 mmol) in HO (7 mL) and EtOH (21 mL) was added Fe (1.97 g, 35.2 mmol) and NH4Cl (1.88 g, 35.2 mmol). The mixture was stirred at 50 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 nm) to afford 4-[4-amino-5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-bromopyridin-3-amine (1.01 g, 66.8%) as a white solid. LCMS (ESI) m / z: 426.1 [M+H] + . Example (B2-21) Synthesis of methyl 4-amino-5-(5-amino-2-chloro-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (B2-21) [ka]

[0224] Step 1: Methyl 5-(5-amino-2-chloro-4-pyridyl)-4-nitro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate [ka]

[0225] To a solution of 6-chloro-4-iodopyridin-3-amine (5 g, 19.6 mmol) in dioxane (250 mL), CsCO (16.0 g, 49.1 mmol), 2,2-dimethylpropanoic acid (5.02 g, 49.1 mmol), CuI (4.49 g, 23.5 mmol), methyl 4-nitro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (Intermediate A1-4) (7.11 g, 23.5 mmol), and Pd(PPh) (4.54 g, 3.93 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, flow rate = 80 mL / min, 254 nm) to give methyl 5-(5-amino-2-chloro-4-pyridyl)-4-nitro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (7.26 g, 65.6%) as a yellow oil. LCMS (ESI) m / z: 428.0 [M+H] + . Step 2: Methyl 4-amino-5-(5-amino-2-chloro-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (B2-21) [ka]

[0226] To a solution of methyl 5-(5-amino-2-chloro-4-pyridyl)-4-nitro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (7.26 g, 16.9 mmol) in MeOH (150 mL) and HO (50 mL) was added Fe (4.74 g, 84.8 mmol) and NHCl (4.54 g, 84.8 mmol). The mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The mixture was cooled to 20 °C and filtered through Celite, rinsing with MeOH (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, flow rate = 80 mL / min, 254 nm) to give methyl 4-amino-5-(5-amino-2-chloro-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.8 g, 60.2%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 0.00 (s, 9 H), 0.86-0.95 (m, 2 H), 3.57-3.74 (m, 2 H), 3.98 (s, 3 H), 5.35 (br d, J = 13.30 Hz, 2 H), 7.41 (s, 1 H), 8.01 (s, 1 H); LCMS(ESI)m / z:398.0[M+H] + . Example (B2-22) Synthesis of methyl 4-amino-5-(5-amino-2-chloro-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (B2-22) [ka]

[0227] Step 1: 4-Bromo-6-chloro-2-(trifluoromethyl)pyridin-3-amine [ka]

[0228] To a solution of 6-chloro-2-(trifluoromethyl)pyridin-3-amine (2 g, 10.18 mmol, 1 equiv.) in MeOH (30 mL) and AcOH (3 mL) was added Br (2.93 g, 18.3 mmol, 1.8 equiv.) dropwise at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was evaporated in vacuo. The residue was diluted with water (30 mL), adjusted to pH 7 with solid NaHCO, and extracted with a mixture of EtOAc and petroleum ether (2 / 1, 40 mL × 2). The combined organic layers were washed with brine (40 mL), water (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; Agela® flash column silica-CS (40 g), eluent petroleum ether to 5% EtoAc in petroleum ether, gradient at 65 mL / min) to give 4-bromo-6-chloro-2-(trifluoromethyl)pyridin-3-amine (2.48 g, 78.3%) as a yellow solid. LCMS (ESI) m / z: 274.9 [M+H] + . Step 2: 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-(trifluoromethyl)pyridin-3-amine [ka]

[0229] To a mixture of 4-bromo-6-chloro-2-(trifluoromethyl)pyridin-3-amine (2.6 g, 8.50 mmol, 1 equiv.) and trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (6.90 g, 16.1 mmol, 60% purity, 1.89 equiv.) in dioxane (100 mL), Pd(PPh3)4 (984 mg, 0.852 mmol, 0.1 equiv.), CuI (324 mg, 1.70 mmol, 0.2 equiv.), and Cs2CO3 (8.30 g, 25.5 mmol, 3 equiv.) were added. The reaction mixture was stirred at 100 °C under N2 for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage®; 220 g Agela silica flash column, eluent of 0-25% EtOAc / petroleum ether, gradient at 100 mL / min) to afford 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-(trifluoromethyl)pyridin-3-amine (1.7 g, 39.9%) as a gray oil. LCMS (ESI) m / z: 452.0 [M+H] + . Step 3: 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-(trifluoromethyl)pyridin-3-amine (B2-22) [ka]

[0230] To a mixture of 6-chloro-4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-(trifluoromethyl)pyridin-3-amine (1.1 g, 2.19 mmol, 90% purity, 1 equiv.) in EtOH (16 mL) and HO (4 mL) was added Fe (1.23 g, 22.0 mmol, 10.04 equiv.) and NH4Cl (1.18 g, 22.1 mmol, 10.08 equiv.). The mixture was stirred at 50 °C under a N2 atmosphere for 16 h. The combined reaction mixture was filtered. To the filtrate was added saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 20 g Agela silica flash column, eluent of 0-35% EtOAc / petroleum ether, gradient at 70 mL / min) to afford 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-(trifluoromethyl)pyridin-3-amine (970 mg, 64.5%) as a brown solid. LCMS (ESI) m / z: 422.1 [M+H] - . Example (C1-1) Synthesis of 5-(2-amino-5-morpholinophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (Intermediate C1-1) [ka]

[0231] Step 1: Synthesis of 4-(3-bromo-4-nitrophenyl)morpholine [ka]

[0232] A mixture of 2-bromo-4-fluoro-1-nitrobenzene (10 g, 45.5 mmol, 1.0 equiv.), morpholine (5.1 g, 59.1 mmol, 1.3 equiv.), and KCO (12.6 g, 90.9 mmol, 2.0 equiv.) in DMF (200 mL) was stirred at 20 °C for 2 h. The reaction mixture was then diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, 4-(3-bromo-4-nitrophenyl)morpholine, as a white solid (14 g, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.47 (m, 4 H), 3.64-3.76 (m, 1 H), 3.64-3.76 (m, 4 H), 7.03 (d, J = 2.8 Hz, 1 H), 7.27 (d, J = 2.8 Hz, 1 H), 8.02 (d, J = 9.4 Hz, 1 H). Step 2: Synthesis of 2-bromo-4-morpholinoaniline [ka]

[0233] To a solution of 4-(3-bromo-4-nitrophenyl)morpholine (5 g, 17.41 mmol, 1.0 equiv.) in EtOH (75 mL) and HO (25 mL) was added NHCl (4.66 g, 87.07 mmol, 5.0 equiv.) and Zn (5.69 g, 87.1 mmol, 5.0 equiv.). The mixture was stirred at 50 °C for 1 h and then filtered to remove insoluble material. The combined filtrate was dried over sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 70 mL / min, 254 nm) to give 2-bromo-4-morpholinoaniline as a yellow solid (12 g, 65.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78-2.98 (m, 4 H), 3.59-3.79 (m, 4 H), 3.63-3.79 (m, 1 H), 3.63-3.79 (m, 1 H), 4.79 (s, 2 H), 6.64-6.83 (m, 2 H), 6.92 (d, J = 2.5 Hz, 1 H). Step 3: tert-butyl N-(2-bromo-4-morpholinophenyl)carbamate [ka]

[0234] To a solution of 2-bromo-4-morpholinoaniline (5.5 g, 21.4 mmol, 1 equiv.) in THF (200 mL) was added 1 M NaHMDS in THF (32 mL, 32 mmol, 1.5 equiv.) and BocO (5.14 g, 23.5 mmol, 1.1 equiv.) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by adding NH Cl / HO (20 mL) at 0 °C and then extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, 0–10% EtOAc in petroleum ether / EtOAc, 85 mL / min, 254 nm) to give tert-butyl N-(2-bromo-4-morpholinophenyl)carbamate as a white solid (6.3 g, 41.2%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H), 3.00-3.15 (m, 4 H), 3.63-3.80 (m, 4 H), 6.91 (dd, J = 9.0, 2.7 Hz, 1 H), 7.11 (d, J = 2.7 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 8.36 (s, 1 H); LCMS(ESI)m / z 356.9[M+H]+ . Step 4: tert-butyl N-[2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-morpholinophenyl]carbamate [ka]

[0235] A mixture of tert-butyl N-(2-bromo-4-morpholinophenyl)carbamate (1.41 g, 3.95 mmol, 1.0 equiv), trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (1.02 g, 3.95 mmol, 1.0 equiv), CsCO (1.93 g, 5.92 mmol, 1.5 equiv), cesium(I) 2,2-dimethylpropanoate (1.02 g, 4.34 mmol, 1.1 equiv), Pd(OAc) (265.8 mg, 1.18 mmol, 0.3 equiv), and XPhos (940.8 mg, 1.97 mmol, 0.5 equiv) in toluene (50 mL) was stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 nm) to give tert-butyl N-[2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-morpholinophenyl]carbamate as a yellow solid (1.3 g, 49%). LCMS (ESI) 534.2, [M+H] + . Step 5: tert-butyl N-[2-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-morpholinophenyl]carbamate [ka]

[0236] To a solution of tert-butyl N-[2-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)-pyrazol-3-yl]-4-morpholinophenyl]carbamate (1.3 g, 1.95 mmol, 1.0 equiv.) in EtOH (3 mL) and HO (0.6 mL) was added NH4Cl (1.04 g, 19.5 mmol, 10.0 equiv.) and Zn (1.27 g, 19.5 mmol, 10.0 equiv.). The mixture was stirred under a N2 atmosphere at 50 °C for 16 hours and filtered to remove insoluble material. The combined filtrate was dried over sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 70 mL / min, 254 nm) to afford tert-butyl N-[2-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-morpholinophenyl]carbamate as a yellow solid (800 mg, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.06 (s, 9 H), 0.76 (t, J = 8.3 Hz, 2 H), 1.38 (s, 9 H), 2.12 (s, 3 H), 3.07 (br d, J = 5.0 Hz, 4 H), 3.73 (t, J = 4.7 Hz, 4 H), 3.84 (br s, 2 H), 4.83-5.21 (m, 2 H), 6.92 (d, J = 2.8 Hz, 1 H), 7.02 (dd, J = 9.1, 2.8 Hz, 1 H), 7.55 (br d, J = 8.0 Hz, 1 H), 8.44 (s, 1 H); LCMS(ESI)504.2[M+H] + . Step 6: 5-(2-amino-5-morpholinophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (C1-1) [ka]

[0237] To a solution of tert-butyl N-[2-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-morpholinophenyl]carbamate (200 mg, 0.397 mmol, 1.0 equiv) in DCM (2 mL) was added ZnBr (268 mg, 1.19 mmol, 3.0 equiv). The mixture was stirred at 40 °C under a N atmosphere for 16 h. The reaction mixture was quenched with water (1 mL), extracted with EtOAc (10 mL), dried over NaSO, and concentrated to give 5-(2-amino-5-morpholinophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine as a yellow solid (160 mg), which was used directly in the next step without any further purification. Example (C1-2) Synthesis of 5-(2-amino-5-morpholinophenyl)-3-chloro-1-(4-methoxybenzyl)-1H-pyrazol-4-amine (Intermediate C1-2) [ka]

[0238] Step 1: tert-butyl (2-(3-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate [ka]

[0239] A mixture of tert-butyl N-(2-bromo-4-morpholinophenyl)carbamate (1.5 g, 4.20 mmol, 1.0 equiv.), 3-chloro-1-[(4-methoxyphenyl)methyl]-4-nitropyrazole (Intermediate A2-2) (1.12 g, 4.20 mmol, 1.0 equiv.), CsCO (2.05 g, 6.30 mmol), and 100 mL of dioxane (15 mL) was added. A mixture of 2,2-dimethylpropanoate (1.08 g, 4.62 mmol, 1.1 equiv.), Pd(OAc) (282.8 mg, 1.26 mmol, 0.3 equiv.), and XPhos (1.0 g, 2.10 mmol, 0.5 equiv.) was degassed and purged with N three times, then the mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 nm) to give tert-butyl N-[2-[5-chloro-2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate as a brown oil (2.9 g, 55.2%). LCMS (ESI) 544.2 [M+H] + . Step 2: tert-butyl (2-(4-amino-3-chloro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate [ka]

[0240] A solution of tert-butyl N-[2-[5-chloro-2-[(4-methoxyphenyl)methyl]-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate (1.4 g, 2.57 mmol, 1.0 equiv.) in THF (20 mL) was treated with NaBH4 (584.2 mg, 15.44 mmol, 7.0 equiv.) and NiCl at 0 °C. 2·6HO (1.84 g, 7.72 mmol, 3.0 equiv.) was added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 40 mL / min, 254 nm) to afford tert-butyl N-[2-[4-amino-5-chloro-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-morpholinophenyl]carbamate as a white solid (800 mg, 58.6%). LCMS (ESI) 514.2 [M+H] + . Step 3: 5-(2-amino-5-morpholinophenyl)-3-chloro-1-(4-methoxybenzyl)-1H-pyrazol-4-amine (C1-2) [ka]

[0241] A solution of tert-butyl N-[2-[4-amino-5-chloro-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-morpholinophenyl]carbamate (1.5 g, 2.92 mmol, 1.0 equiv) in 4 N HCl (15 mL) in MeOH was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give 5-(2-amino-5-morpholinophenyl)-3-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-amine as a white solid (1.4 g, 96.3%). LCMS (ESI) 414.1 [M+H] + . Example (C1-3) Synthesis of 5-(2-amino-4-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine (Intermediate C1-3) [ka]

[0242] Step 1: 4-(5-bromo-2-fluoro-4-nitrophenyl)morpholine [ka]

[0243] To a solution of 1-bromo-4,5-difluoro-2-nitrobenzene (20.0 g, 84.0 mmol, 1 equiv.) in DMF (360 mL) was added K2CO3 (13.9 g, 0.101 mol, 1.2 equiv.) and morpholine (8.05 g, 92.4 mmol, 1.1 equiv.). The mixture was stirred at 25 °C for 1 h. To the solution was added HO (1200 mL). A large amount of solid precipitated. This was extracted with EtOAc (500 mL × 3), washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–60% EtOAc in petroleum ether as the eluent to give 4-(5-bromo-2-fluoro-4-nitrophenyl)morpholine as a yellow solid (20 g, 78.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 4 H), 3.67-3.78 (m, 4 H), 7.35 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 13.4 Hz, 1 H). Step 2: 2-Bromo-5-fluoro-4-morpholinoaniline [ka]

[0244] A mixture of 4-(5-bromo-2-fluoro-4-nitrophenyl)morpholine (20.0 g, 65.6 mmol, 1 equiv), Zn (42.9 g, 0.656 mol, 10 equiv), and NHCl (35.1 g, 0.656 mol, 10 equiv) in EtOH / HO (5:1, 24 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 50° C. for 2 h. The mixture was filtered and concentrated to give 2-bromo-5-fluoro-4-morpholinoaniline as a white solid (16.0 g, 87.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.77-2.89 (m, 4 H), 3.62-3.75 (m, 4 H), 5.19 (s, 2 H), 6.62 (d, J = 14.1 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H). Step 3: tert-butyl N-(2-bromo-5-fluoro-4-morpholinophenyl)carbamate [ka]

[0245] To a solution of 2-bromo-5-fluoro-4-morpholinoaniline (16.0 g, 58.2 mmol, 1 equiv.) in THF (400 mL) was added 1 M LiHMDS in THF (128 mL, 0.128 mol, 2.2 equiv.) dropwise at 0 °C. After the addition, the mixture was stirred at this temperature for 30 min, and then BocO (13.3 g, 61.1 mmol, 1.05 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 16 h, then diluted with HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–60% EtOAc in petroleum ether as eluent to give tert-butyl N-(2-bromo-5-fluoro-4-morpholinophenyl)carbamate as a white solid (18.0 g, 80.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.48 (m, 9 H), 2.86-2.98 (m, 4 H), 3.59-3.71 (m, 4 H), 7.11 (d, J = 9.0 Hz, 1 H), 7.26 (d, J = 14.0 Hz, 1 H), 8.45 (s, 1 H). Step 4: tert-butyl N-[5-fluoro-2-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate [ka]

[0246] A solution of tert-butyl N-(2-bromo-5-fluoro-4-morpholinophenyl)carbamate (1 g, 2.67 mmol, 1 equiv.), 1-[(4-methoxyphenyl)methyl]-3-methyl-4-nitropyrazole (Intermediate A2-1) (725 mg, 2.93 mmol, 1.1 equiv.), XPhos (508 mg, 1.07 mmol, 0.4 equiv.), CsCO (1.30 g, 4.00 mmol, 1.5 equiv.), and CsOPiv (686 mg, 2.93 mmol, 1.1 equiv.) in toluene (10 mL) was degassed and Pd(OAc) (120 mg, 0.533 mmol, 0.2 equiv.) was added. The mixture was stirred at 100 °C under a N atmosphere for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–20% EtOAc in petroleum ether as eluent to give tert-butyl N-[5-fluoro-2-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate as a yellow oil (680 mg, 47.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 2.48 (s, 3 H), 2.62-2.73 (m, 2 H), 2.76-2.85 (m, 2 H), 3.65 (t, J = 4.6 Hz, 4 H), 3.72 (s, 3 H), 4.80 (d, J = 15.4 Hz, 1 H), 5.08 (d, J = 15.3 Hz, 1 H), 6.55 (d, J = 9.5 Hz, 1 H), 6.80-6.88 (m, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 7.33 (d, J = 14.4 Hz, 1 H), 8.90 (s, 1 H). Step 5: tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-5-fluoro-4-morpholinophenyl]carbamate [ka]

[0247] To a solution of tert-butyl N-[5-fluoro-2-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate (680 mg, 1.26 mmol, 1 equiv.) in EtOH / HO (3:1, 12 mL) was added NH4Cl (672 mg, 12.6 mmol, 10 equiv.) and Fe (701 mg, 12.6 mmol, 10 equiv.). The mixture was stirred at 50 °C under a N2 atmosphere for 16 h. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–100% EtOAc in petroleum ether as eluent to give tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-5-fluoro-4-morpholinophenyl]carbamate as a yellow solid (250 mg, 38.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.47 (m, 9 H), 2.13 (s, 3 H), 2.59-2.84 (m, 4 H), 3.64 (t, J = 4.5 Hz, 4 H), 3.69 (s, 3 H), 3.87 (br s, 2 H), 4.76-4.87 (m, 1 H), 4.99-5.11 (m, 1 H), 6.56 (d, J = 9.7 Hz, 1 H), 6.72-6.89 (m, 4 H), 7.40-7.60 (m, 1 H), 8.45 (s, 1 H); LCMS(ESI)m / z 312.3[M+H] + . Step 6: 5-(2-amino-4-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine (C1-3) [ka]

[0248] A solution of tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-5-fluoro-4-morpholinophenyl]carbamate (250 mg, 0.489 mmol, 1 equiv) in 4 N HCl (10 mL) in MeOH was stirred for 2 h at 25° C. The solution was concentrated to give 5-(2-amino-4-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine as a yellow solid (220 mg, 92.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H), 2.73-2.81 (m, 1 H), 2.84-2.93 (m, 2 H), 3.66-3.75 (m, 7 H), 4.85 (br d, J = 15.3 Hz, 1 H), 5.08 (d, J = 15.4 Hz, 1 H), 6.52 (br d, J = 9.1 Hz, 1 H), 6.75-6.94 (m, 5 H); LCMS(ESI)m / z 412.2[M+H]+ . Example (C1-4) Synthesis of 5-(2-amino-3-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine (Intermediate C1-4) [ka]

[0249] Step 1: 4-(3-bromo-5-fluoro-4-nitrophenyl)morpholine [ka]

[0250] A mixture of 1-bromo-3,5-difluoro-2-nitrobenzene (20 g, 84.0 mmol, 1 equiv.) and morpholine (7.32 g, 84.0 mmol, 1 equiv.) in DMF (200 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 25 °C for 1 h. To the solution was added HO (600 mL). The solution was extracted with EtOAc (200 mL × 3), and the combined organic layer was washed with 5 wt% LiCl in HO (300 mL × 2) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-20% EtOAc in petroleum ether as eluent to give 4-(3-bromo-5-fluoro-4-nitrophenyl)morpholine as a yellow solid (8.8 g, 34.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.35-3.43 (m, 4 H), 3.66-3.75 (m, 4 H), 7.06 (dd, J = 14.6, 2.3 Hz, 1 H), 7.14 (d, J = 1.0 Hz, 1 H). Step 2: 2-Bromo-6-fluoro-4-morpholinoaniline [ka]

[0251] A mixture of 4-(3-bromo-5-fluoro-4-nitrophenyl)morpholine (8.8 g, 28.8 mmol, 1 equiv.), Zn (18.7 g, 0.288 mol, 10 equiv.), and NHCl (15.4 g, 0.288 mol, 10 equiv.) in EtOH / HO (3:1, 160 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 50 °C for 1 h. The reaction mixture was filtered, and the filtrate was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–30% EtOAc in petroleum ether as the eluent to give 2-bromo-6-fluoro-4-morpholinoaniline as a colorless oil (7.5 g, 94.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.88-2.98 (m, 4 H), 3.62-3.71 (m, 4 H), 4.69 (s, 2 H), 6.78-6.84 (m, 2 H). Step 3: tert-butyl N-(2-bromo-6-fluoro-4-morpholinophenyl)carbamate [ka]

[0252] To a solution of 2-bromo-6-fluoro-4-morpholinoaniline (6.6 g, 23.9 mmol, 1 equiv.) in THF (70 mL) was added dropwise 1 M NaHMDS in THF (47.9 mL, 47.9 mmol, 2 equiv.) under N2 at 0 °C for 30 min. Then, Boc2O (7.85 g, 35.9 mmol, 1.5 equiv.) in THF (70 mL) was added dropwise at 0 °C. The resulting mixture was stirred under N2 atmosphere at 20 °C for 16 h. An aqueous solution of NH4Cl (70 mL) was added at 0 °C to quench the reaction. The mixture was extracted with EtOAc (100 mL × 2), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 0–20% EtOAc in petroleum ether as eluent to give tert-butyl N-(2-bromo-6-fluoro-4-morpholinophenyl)carbamate as a white solid (4.1 g, 45.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.48 (m, 9 H), 3.12-3.17 (m, 5 H), 3.68-3.73 (m, 5 H), 6.86 (dd, J = 13.0, 2.6 Hz, 1 H), 6.99 (s, 1 H), 8.48 (br s, 1 H). Step 4: tert-butyl N-[2-fluoro-6-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate [ka]

[0253] To a stirred solution of tert-butyl N-(2-bromo-6-fluoro-4-morpholinophenyl)carbamate (1 g, 2.67 mmol, 1 equiv.), 1-[(4-methoxyphenyl)methyl]-3-methyl-4-nitropyrazole (Intermediate A2-1) (658 mg, 2.67 mmol, 1 equiv.) in toluene (30 mL) was added Pd(OAc) (59.8 mg, 0.266 mmol, 0.1 equiv.), XPhos (381 mg, 0.799 mmol, 0.3 equiv.), CsOPiv (686 mg, 2.93 mmol, 1.1 equiv.), and CsCO (1.30 g, 4.00 mmol, 1.5 equiv.). The mixture was purged and degassed with N three times and then stirred at 100 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0 to 20% EtOAc in petroleum ether as eluent to give tert-butyl N-[2-fluoro-6-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate as a dark brown oil (580 mg, 40.32%). 1 H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 11 H), 2.61 (s, 3 H), 2.80-2.99 (m, 5 H), 3.67-3.84 (m, 8 H), 4.97-5.24 (m, 2 H), 6.12 (d, J = 1.8 Hz, LCMS(ESI)m / z 542.3[M+H + . Step 5: tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-fluoro-4-morpholinophenyl]carbamate [ka]

[0254] A stirred solution of tert-butyl N-[2-fluoro-6-[2-[(4-methoxyphenyl)methyl]-5-methyl-4-nitropyrazol-3-yl]-4-morpholinophenyl]carbamate (580 mg, 1.07 mmol, 1 equiv.), Zn (700 mg, 10.7 mmol, 10 equiv.), and NHCl (572 mg, 10.7 mmol, 10 equiv.) in EtOH / HO (1:1, 30 mL) was stirred at 50° C. for 1 h. To the reaction mixture was added EtOAc (50 mL) and HO (50 mL), and the mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 0–60% EtOAc in petroleum ether as eluent to give tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-fluoro-4-morpholinophenyl]carbamate as a brown solid (280 mg, 51.1%). 1 H NMR (500 MHz, CDCl3) δ ppm 1.33-1.47 (m, 9 H), 2.19-2.31 (m, 3 H), 2.84-3.01 (m, 5 H), 3.69-3.81 (m, 7 H), 4.91-5.01 (m, 1 H), 5.13 (d, J = 15.7 Hz, 1 H), 6.27-6.38 (m, 2 H), 6.66 (dd, J = 12.7, 2.7 Hz, 1 H), 6.73-6.81 (m, 2 H), 6.92 (d, J = 8.5 Hz, 2 H). Step 6: 5-(2-amino-3-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine (C1-4) [ka]

[0255] To a stirred solution of tert-butyl N-[2-[4-amino-2-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-yl]-6-fluoro-4-morpholinophenyl]carbamate (280 mg, 0.547 mmol, 1 equiv.) in MeOH (1 mL) was added 4 N HCl in MeOH (3.00 mL, 12 mmol, 22 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give 5-(2-amino-3-fluoro-5-morpholinophenyl)-1-[(4-methoxyphenyl)methyl]-3-methylpyrazol-4-amine as a dark brown solid (220 mg, 97.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H), 3.16 (s, 3 H), 3.63-3.72 (m, 4 H), 3.87 (br s, 6 H), 4.78-5.21 (m, 2 H), 6.79 (d, J = 8.6 Hz, 3 H), 6.84-6.95 (m, 2 H), 7.28-7.61 (m, 1 H). Example (C1-5) Synthesis of 5-(2-amino-5-morpholinophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-amine (Intermediate C1-5) [ka]

[0256] Step 1: 4-(3-bromo-4-nitrophenyl)morpholine [ka]

[0257] To a solution of 2-bromo-4-fluoro-1-nitrobenzene (650 g, 2.87 mol, 1.0 equiv.) in DMAc (3.25 L) was added TEA (145 g, 1.43 mol, 0.5 equiv.), and then morpholine (274 g, 3.15 mol, 1.1 equiv.) was added to the mixture at 20° C. The mixture was stirred at 30° C. for 12 hours. The reaction mixture was poured into water (6 L) at 30° C. and maintained stirring at 30° C. for 15 minutes. The suspension was filtered, and the filter cake was washed with water (500 mL) and dissolved in DCM (2.00 L). The combined organic layer was dried over anhydrous NaSO and filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether (9 L) at 20° C. for 2 hours, then the mixture was filtered and the filter cake was dried under reduced pressure to give 4-(3-bromo-4-nitrophenyl)morpholine as a yellow solid (2.30 kg, 92.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.40 (t, J = 4.8 Hz, 4 H), 3.72 (t, J = 4.8 Hz, 4 H), 7.03 (dd, J = 2.8, 9.2 Hz, 1 H), 7.26 (d, J = 2.8 Hz, 1 H), 8.00 (d, J = 9.2 Hz, 1 H). Step 2: 2-Bromo-4-morpholinoaniline [ka]

[0258] To a solution of 4-(3-bromo-4-nitrophenyl)morpholine (180 g, 0.626 mol, 1.0 equiv) in EtOH (2:1, 4.0 L) was added NHCl (168 g, 3.14 mol, 5.0 equiv) at 20° C., and then Fe (175 g, 3.13 mol, 5.0 equiv) was added to the mixture at 20° C. under a N atmosphere. The mixture was stirred at 40° C. under a N atmosphere for 3 hours. The reaction mixture was cooled to 20° C. and filtered, and the filtrate was concentrated under reduced pressure to remove most of the EtOH. The residue was diluted with water and extracted with EtOAc (2.00 L), and the combined organic phases were washed with brine (1.00 L × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-bromo-4-morpholinoaniline as a dark brown solid (1.75 kg, 89.8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.89 (t, J = 4.8 Hz, 4 H), 3.69 (t, J = 4.8 Hz, 4 H), 4.79 (s, 2 H), 6.71-6.82 (m, 2 H), 6.92 (d, J = 2.4 Hz, 1 H). Step 3: tert-butyl (2-bromo-4-morpholinophenyl)carbamate [ka]

[0259] A 10 mL reaction tube was charged with 2-bromo-4-morpholinoaniline (300 mg, 1.17 mmol, 1.0 equiv), THF (3 mL), NH4Cl (2 mg, 37.4 μmol, 0.03 equiv), and HO (126 mg, 6.99 mmol, 6.0 equiv) at 25 °C. Then, Boc2O (382 mg, 1.75 mmol, 1.5 equiv) in THF (1 mL) was added at 60 °C. The reaction mixture was stirred at 60 °C for 16 h and cooled to 25 °C. The mixture was purified by column chromatography (silica gel, petroleum ether / EtOAc = 40 / 1 to 5 / 1) to give tert-butyl (2-bromo-4-morpholinophenyl)carbamate as a white solid (340 mg, 78.8%).1 H NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 9 H), 2.97-3.19 (m, 4 H), 3.76-3.95 (m, 4 H), 6.73 (s, 1 H), 6.82-6.91 (m, 1 H), 7.05 (d, J = 2.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H); LCMS(ESI)m / z 357.1[M+H] + . Step 4: tert-butyl (2-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate [ka]

[0260] To a 1 L reaction vessel was added tert-butyl (2-bromo-4-morpholinophenyl)carbamate (22.0 g, 61.6 mmol, 1 equiv.), 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (Intermediate A2-3) (15.8 g, 67.7 mmol, 1.1 equiv.), XPhos (8.81 g, 18.5 mmol, 0.3 equiv.), CsCO (30.1 g, 92.4 mmol, 1.5 equiv.), CsOPiv (15.8 g, 67.7 mmol, 1.1 equiv.), and toluene (440 mL) at 25 °C. The reaction mixture was degassed and purged with nitrogen three times. Pd(OAc) (1.38 g, 6.16 mmol, 0.1 equiv.) was then added at 25 °C. The reaction mixture was purged with nitrogen three times and stirred under nitrogen at 100°C for 16 hours. The reaction mixture was cooled to 25°C and quenched with water (400 mL). The mixture was extracted with EtOAc (450 mL x 2). The combined organic phases were washed with brine (300 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / EtOAc = 20 / 1 to 3 / 1) to give tert-butyl (2-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate as a brown solid (22.0 g, 67.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 9 H), 2.81-2.97 (m, 4 H), 3.60-3.69 (m, 4 H), 3.71 (s, 3 H), 4.89 (d, J = 15.2 Hz, 1 H), 5.12 (d, J = 15.2 Hz, 1 H), 6.54 (d, J = 2.8 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 7.00 (d, J = 8.4 Hz, 2 H), 7.04-7.14 (m, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 8.35 (s, 1 H), 8.71 (s, 1 H); LCMS(ESI) m / z 510.3[M+H] + . Step 5: tert-butyl (2-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate [ka]

[0261] To a solution of tert-butyl (2-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate (20.0 g, 39.2 mmol, 1.0 equiv) in EtOH / HO (2:1, 450 mL) was added Fe (11.2 g, 0.20 mol, 5.1 equiv) and NHCl (10.6 g, 0.20 mol, 5.1 equiv) at 25 °C. After the addition, the solution was stirred at 80 °C under nitrogen for 2 h. The reaction mixture was cooled to 25 °C and filtered through a Celite pad. The filter cake was washed with EtOH (300 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL) and water (200 mL) with stirring. The aqueous phase was then extracted with EtOAc (200 mL × 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / EtOAc = 5 / 1 to 1 / 1). The residue was triturated with petroleum ether / EtOAc (100 mL, petroleum ether / EtOAc = 1 / 1). The precipitate was filtered and dried under reduced pressure to give tert-butyl (2-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate as a light yellow solid (11.9 g, 62.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H), 2.73-2.83 (m, 2 H), 2.84-2.93 (m, 2 H), 3.64 (t, J = 4.4 Hz, 4 H), 3.68 (s, 3 H), 4.03 (s, 2 H), 4.90 (d, J = 15.6 Hz, 1 H), 5.15 (d, J = 16.0 Hz, 1 H), 6.51 (d, J = 2.8 Hz, 1 H), 6.74-6.89 (m, 4 H), 6.92-7.07 (m, 1 H), 7.18 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 8.39 (s, 1H); LCMS(ESI)m / z 480.3[M+H] + . Step 6: 5-(2-amino-5-morpholinophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-amine (C1-5) [ka]

[0262] To a 250 mL reaction vessel was added tert-butyl (2-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-4-morpholinophenyl)carbamate (11.9 g, 24.8 mmol, 1.0 equiv) and 4 N HCl in EtOAc (100 mL) at 25° C. and stirred for 2 hours at 25° C. The precipitate was collected. The solid was dissolved in water (200 mL). The pH of the mixture was adjusted to 8 with solid sodium carbonate. A white precipitate formed, which was collected and dried under reduced pressure to give 5-(2-amino-5-morpholinophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-amine as a light yellow solid (7.70 g, 79.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64-2.83 (m, 4 H), 3.63 (t, J = 4.4 Hz, 4 H), 3.67-3.84 (m, 5 H), 4.49 (s, 2 H), 4.88 (d, J = 15.6 Hz, 1 H), 5.12 (d, J = 15.6 Hz, 1 H), 6.38 (d, J = 2.4 Hz, 1 H), 6.69-6.76 (m, 1 H), 6.76-6.91 (m, 5 H), 7.12 (s, 1 H); LCMS(ESI)m / z 380.2[M+H] + . Example (C2-1) Synthesis of 4-(4-amino-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-morpholinopyridin-3-amine (Intermediate C2-1) [ka]

[0263] Step 1: 4-(5-nitropyridin-2-yl)morpholine [ka]

[0264] A solution of 2-chloro-5-nitropyridine (15 g, 94.6 mmol, 1.0 equiv.), morpholine (12.36 g, 0.142 mol, 1.5 equiv.), and EtN (28.72 g, 0.284 mol, 3.0 equiv.) in CHCl (50 mL) was stirred under N atmosphere at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H0 (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 4-(5-nitro-2-pyridyl)morpholine as a yellow solid (130 g, crude), which was used directly without further purification. LCMS (ESI) 210.1 [M+H] + . Step 2: 6-Morpholinopyridin-3-amine [ka]

[0265] To a solution of 4-(5-nitro-2-pyridyl)morpholine (10 g, 47.8 mmol, 1.0 equiv) in EtOH (100 mL) was added wet Pd / C (5.09 g, 10 wt% Pd with 50 wt% water). The mixture was degassed and purged with H 3 times. The mixture was stirred under H 2 atmosphere at 20 °C for 12 h. The solid was filtered off and washed with MeOH (10 mL × 2). The organic layers were combined. The organic solvent was removed under reduced pressure to give the crude product, 6-morpholinopyridin-3-amine, as a light blue solid (103 g, crude). Step 3: 2,2-Dimethyl-N-(6-morpholino-3-pyridyl)propanamide [ka]

[0266] To a solution of 6-morpholinopyridin-3-amine (10 g, 46.4 mmol, 1.0 equiv.) in THF (150 mL) was added TEA (7.04 g, 69.6 mmol, 1.5 equiv.) and 2,2-dimethylpropanoyl chloride (8.39 g, 69.6 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred under a N atmosphere at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (300 mL) and extracted with EtOAc (350 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2,2-dimethyl-N-(6-morpholino-3-pyridyl)propanamide as a white solid (20 g, 73.7%). Step 4: N-(4-iodo-6-morpholinopyridin-3-yl)pivalamide [ka]

[0267] To a solution of 2,2-dimethyl-N-(6-morpholino-3-pyridyl)propanamide (6 g, 22.8 mmol, 1.0 equiv.) in THF (40 mL) was added TMEDA (7.94 g, 68.4 mmol, 3.0 equiv.). The mixture was stirred at −78° C. for 1 h under a N atmosphere. Next, n-BuLi (2.5 M, 27.3 mL) was added to the above solution, and the mixture was stirred at −35° C. for 2 h. To the mixture was added I (7.52 g, 29.6 mmol, 1.3 equiv.) in THF (20 mL), and the mixture was stirred at 25° C. for 12 h. The solution was quenched with NH4Cl / HO (100 mL) at 0° C. and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 nm) to give N-(4-iodo-6-morpholino-3-pyridyl)-2,2-dimethylpropanamide as a brown solid (4.3 g, 20.6%). LCMS (ESI) m / z 389.9 [M+H] + . Step 5: 4-Iodo-6-morpholinopyridin-3-amine [ka]

[0268] To a solution of concentrated H2SO4 (18.4 g, 0.188 mol) in HO (30 mL) was carefully added N-(4-iodo-6-morpholino-3-pyridyl)-2,2-dimethylpropanamide (4 g, 10.3 mmol, 1 equiv.). The mixture was stirred at 100 °C for 4 h. The mixture was basified with 2 N NaOH in HO at 0 °C until the pH reached 7-8 and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75 × 40 mm × 3 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-MeCN]; B%: 14% to 45% in 9.5 min, as additive) to give 4-iodo-6-morpholinopyridin-3-amine as a purple solid (1.2 g, 37.8%). LCMS (ESI) m / z: 305.9 [M+H] + . Step 6: tert-butyl (4-iodo-6-morpholinopyridin-3-yl)carbamate [ka]

[0269] A solution of 4-iodo-6-morpholinopyridin-3-amine (1.2 g, 3.93 mmol, 1.0 equiv) and BocO (8.58 g, 39.3 mmol, 10.0 equiv) in THF (15 mL) was stirred at 70 °C for 8 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 40 mL / min, 254 nm) to give tert-butyl N-(4-iodo-6-morpholino-3-pyridyl)carbamate as a white solid (1.42 g, 85.5%). LCMS (ESI) m / z 406.0 [M+H] + . Step 7: tert-butyl (4-(3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-morpholinopyridin-3-yl)carbamate [ka]

[0270] tert-Butyl N-(4-iodo-6-morpholino-3-pyridyl)carbamate (1.4 g, 3.45 mmol, 1.0 equiv.), trimethyl-[2-[(3-methyl-4-nitropyrazol-1-yl)methoxy]ethyl]silane (Intermediate A1-1) (1.48 g, 3.45 mmol, 1.0 equiv.), CsCO(1 A mixture of XPhos (658.8 mg, 1.38 mmol, 0.3 equiv.), Pd(OAc) (155.1 mg, 0.691 mmol, 0.2 equiv.), and cesium 2,2-dimethylpropanoate (889.4 mg, 3.80 mmol, 1.1 equiv.) was stirred under a N atmosphere at 100° C. for 16 hours. The solid was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-25% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 nm) to give tert-butyl N-[4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-morpholino-3-pyridyl]carbamate as a brown oil (880 mg, 31.4%). LCMS (ESI) m / z 535.2 [M+H] + . Step 8: tert-butyl (4-(4-amino-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-morpholinopyridin-3-yl)carbamate [ka]

[0271] A mixture of tert-butyl N-[4-[5-methyl-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-morpholino-3-pyridyl]carbamate (880 mg, 1.65 mmol, 1.0 equiv) and wet Pd / C (300 mg, 10 wt% Pd with 50 wt% water) in MeOH (10 mL) was stirred under H (15 psi) at 25° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-70% EtOAc in petroleum ether / EtOAc, 40 mL / min, 254 nm) to give tert-butyl N-[4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-morpholino-3-pyridyl]carbamate as a white solid (600 mg, 71.5%). LCMS (ESI) m / z 505.2 [M+H] + . Step 9: 4-(4-amino-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-morpholinopyridin-3-amine (C2-1) [ka]

[0272] A mixture of tert-butyl N-[4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-morpholino-3-pyridyl]carbamate (600 mg, 1.19 mmol, 1.0 equiv) and ZnBr (1.61 g, 7.13 mmol, 6.0 equiv) in DCM (10 mL) was stirred at 40 °C for 16 h. HO (10 mL) was added to the reaction mixture, and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (550 mg, 83.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.04 (m, 9 H), 0.74 (t, J = 8.16 Hz, 2 H), 2.10 (s, 3 H), 3.22 (br d, J = 2.76 Hz, 4 H), 3.41 (br s, 2 H), 3.67-3.73 (m, 6 H), 4.67 (br s, 2 H), 5.12 (br s, 2 H), 6.63-6.75 (m, 1 H), 7.85 (s, 1 H); LCMS(ESI)m / z 405.1[M+H] + . Example (C2-3) Synthesis of 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine (C2-3) [ka]

[0273] Step 1: Ethyl N-(5-bromo-3-pyridyl)carbamate [ka]

[0274] To a solution of 5-bromopyridin-3-amine (30 g, 0.173 mmol, 1 equiv.) in DCM (400 mL) were added pyridine (41.15 g, 0.520 mol, 3 equiv.) and ethyl chloroformate (18.82 g, 0.173 mmol, 1 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with DCM (300 mL). The solution was quenched at 0 °C by the addition of HO (300 mL) and extracted with DCM (300 mL × 3). The combined organic layer was then washed with 10 wt% CuSO / HO (300 mL) and saturated aqueous NaHCO (300 mL), brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 120 g SepaFlash® silica flash column, 0–50% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 mn) to give ethyl N-(5-bromo-3-pyridyl)carbamate (29 g, 68.2%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.33 (t, J = 7.1 Hz, 3H), 4.26 (q, J = 7.1 Hz, 2H), 7.48 (br s, 1H), 8.27-8.44 (m, 3H); LCMS(ESI)m / z:246.7[M+H] + . Step 2: Ethyl N-(5-bromo-2-nitro-3-pyridyl)carbamate [ka]

[0275] To a solution of ethyl N-(5-bromo-3-pyridyl)carbamate (6 g, 24.4 mmol, 1 equiv.) in HSO (18 mL) was added HNO (15.43 g, 0.245 mol, 10 equiv.) dropwise at 0 °C. After the addition of nitric acid, the reaction mixture was gradually warmed to 0 °C for 30 min and then stirred at 25 °C for 15.5 h. The reaction mixture was poured into ice water (500 g) and then quenched with 3 N NaOH in HO, and the pH was adjusted to 7. The aqueous phase was extracted with DCM (100 mL × 3) to give ethyl N-(5-bromo-2-nitro-3-pyridyl)carbamate (25 g, 87.1%) as a white solid. 1 LCMS(ESI)m / z:289.9[M+H] + . Step 3: 5-Bromo-2-nitropyridin-3-amine [ka]

[0276] To a solution of ethyl N-(5-bromo-2-nitro-3-pyridyl)carbamate (12.5 g, 43.0 mmol, 1 equiv) in EtOH (15 mL) was added KOH (6.47 g, 0.115 mol, 2.6 equiv) in HO (75 mL). The mixture was stirred at 90 °C for 16 h. HO (200 mL) was added, and a precipitate formed which was collected by filtration, washed with water, and dried under reduced pressure to give 5-bromo-2-nitropyridin-3-amine (15 g, 76.6%) as a green solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (br s, 2 H), 7.76 (d, J = 2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1 H); LCMS(ESI)m / z:219.6[M+H] + . Step 4: 5-Morpholino-2-nitropyridin-3-amine [ka]

[0277] A solution of 5-bromo-2-nitropyridin-3-amine (3 g, 13.7 mmol, 1 equiv.) in morpholine (6.4 g, 73.4 mmol, 5.3 equiv.) was stirred at 140° C. for 3 h. This solution was added to HO (20 mL) and the solid was then collected by filtration. The residue was triturated with EtOH (10 mL) to give 5-morpholino-2-nitropyridin-3-amine (3 g, 95.2%) as a yellow solid. LCMS (ESI) m / z: 224.9 [M+H] + . Step 5: 4-(5-iodo-6-nitro-3-pyridyl)morpholine [ka]

[0278] To a solution of CuI (5.10 g, 26.7 mmol, 2 equiv.) in MeCN (20 mL) was added isopentyl nitrite (7.84 g, 66.9 mmol, 5 equiv.) dropwise at 50° C. The reaction mixture was stirred at 80° C. for 1 h, and then a solution of 5-morpholino-2-nitropyridin-3-amine (3 g, 13.3 mmol, 1 equiv.) in MeCN (10 mL) was added in small portions (nitrogen gas evolution was observed). The reaction mixture was stirred at 80° C. for 15 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 nm) to give 4-(5-iodo-6-nitro-3-pyridyl)morpholine (1.3 g, 27.2%) as a yellow solid. LCMS (ESI) m / z: 335.8 [M+H] + . Step 6: 3-Iodo-5-morpholinopyridin-2-amine [ka]

[0279] To a solution of 4-(5-iodo-6-nitro-3-pyridyl)morpholine (1.3 g, 3.88 mmol, 1 equiv.) in EtOH (90 mL) under a N atmosphere, tin(II) chloride (5.88 g, 31.0 mmol, 8 equiv.) and HO (1 mL) were added sequentially. The mixture was degassed and purged with N three times. The mixture was stirred under a N atmosphere at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was basified with 2 N NaOH in HO at 0 °C to adjust the pH to 11 and extracted with DCM (50 mL × 3). The combined organic layers were then washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, 50 mL / min, 254 mn) to give 3-iodo-5-morpholinopyridin-2-amine (650 mg, 54.9%) as a gray solid. LCMS (ESI) m / z: 305.8 [M+H] + . Step 7: 3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine [ka]

[0280] To a solution of 3-iodo-5-morpholinopyridin-2-amine (650 mg, 2.13 mmol, 1 equiv.) in DMF (8 mL) was added CuI (81.14 mg, 0.426 mmol, 0.2 equiv.), Pd(PPh3)4 (246.17 mg, 0.213 mmol, 0.1 equiv.), K2CO3 (883.3 mg, 6.39 mmol, 3 equiv.), and 2-[(3-chloro-4-nitropyrazol-1-yl)methoxy]ethyltrimethylsilane (Intermediate A1-1) (710.1 mg, 2.56 mmol, 1.2 equiv.). The mixture was degassed and purged with N2 three times. The mixture was stirred under N2 atmosphere at 90 °C for 16 h. The residue was diluted with HO (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 mn) to afford 3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine (990 mg, 61.2%) as a yellow oil. LCMS (ESI) m / z: 455.1 [M+H] + . Step 8: 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine (C2-3) [ka]

[0281] A solution of 3-[5-chloro-4-nitro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine (990 mg, 1.31 mmol, 1 equiv.) in THF (5 mL) was added at 0 °C with NaBH4 (197.5 mg, 5.22 mmol, 4 equiv.), NiCl 2·6HO (1.24 g, 5.22 mmol, 4 equiv.) was added. The mixture was degassed and purged with N three times. The mixture was stirred under N at 0 °C for 1 h. The solution was quenched at 0 °C by the addition of ammonium chloride (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were then washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0–50% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 mn) to afford 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-morpholinopyridin-2-amine (130 mg, 16.4%) as a black solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.08 (s, 9 H), 0.70-0.75 (m, 2 H), 2.98 (br s, 4 H), 3.38 (br t, J = 8.16 Hz, 2 H), 3.68-3.72 (m, 4 H), 4.16 (s, 2H), 4.98-5.24 (m, 2 H), 6.11 (s, 2 H), 7.65 (br d, J = 4.02 Hz, 2 H); LCMS(ESI)m / z:425.0[M+H] + . Example (D1-1) Synthesis of 9-bromo-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (Intermediate D1-1) [ka]

[0282] Step 1: 9-Bromo-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine [ka]

[0283] 5-(2-amino-5-bromophenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-10) (6.30 g, 16.4 mmol, 1 equiv.) t To a solution of BuOH (60 mL) was added 2,6-difluorobenzaldehyde (2.34 g, 16.4 mmol, 1 equiv.), Y(OTf) (440 mg, 0.82 mmol, 0.05 equiv.), and KCO (6.81 g, 49.3 mmol, 3 equiv.). The mixture was stirred at 70 °C for 30 min. Crude 2-[[9-bromo-5-(2,6-difluorophenyl)-5,6-dihydro-4H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (8.3 g, crude) was obtained as a yellow oil, which was used in the next step without further purification. Step 2: 9-Bromo-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (D1-1) [ka]

[0284] 2-[[9-bromo-5-(2,6-difluorophenyl)-5,6-dihydro-4H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (6.3 g, 12.4 mmol, 1 equiv.) tTo a solution of BuOH (60 mL) was added DDQ (3.38 g, 14.9 mmol, 1.2 equiv.), and the mixture was stirred at 70 °C for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–21% EtOAc in petroleum ether as the eluent to give the compound 2-[[9-bromo-5-(2,6-difluorophenyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane as a red solid (4.05 g, 64.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.01 (s, 9 H), 0.80-1.01 (m, 2 H), 3.72 (t, J = 8.0 Hz, 2 H), 5.40 (s, 2 H), 6.73 (d, J = 8.5 Hz, 1 H), 7.19 (br t, J = 8.2 Hz, 2 H), 7.31 (s, 1 H), 7.44 (dd, J = 8.5, 2.3 Hz, 1 H), 7.49-7.61 (m, 1 H), 7.74 (d, J = 2.3 Hz, 1 H), 8.40 (s, 1 H). Example (D1-2) Synthesis of 9-bromo-3-chloro-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (Intermediate D1-2) [ka]

[0285] A mixture of 5-(2-amino-5-bromophenyl)-3-chloro-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-2) (4.8 g, 11.5 mmol, 1 equiv.), 2,6-difluorobenzaldehyde (1.63 g, 11.5 mmol, 1 equiv.) in t-BuOH (24 mL) and THF (24 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 16 h. DDQ (2.76 g, 12.2 mmol, 1.1 equiv.) was then added to the mixture, which was purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 1 h. The residue was diluted with NaHCO / HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30% petroleum ether / EtOAc at 35 mL / min) to afford 2-[[9-bromo-3-chloro-5-(2,6-difluorophenyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (5 g, 76.9%) as a yellow solid. LCMS (ESI) m / z: 541.2 [M+H] + . Example (D1-3) Synthesis of 9-bromo-5-(2,6-difluorophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (Intermediate D1-3) [ka]

[0286] 5-(2-amino-5-bromophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-1) (880 mg, 2.21 mmol, 1 equiv.) and 2,6-difluorobenzaldehyde (630 mg, 4.43 mmol, 2 equiv.) t To a solution of BuOH (20 mL) and THF (4 mL) was added K2CO3 (1.22 g, 8.86 mmol, 4 equiv.) at 25 °C for 2 h, followed by the addition of I2 (1.12 g, 4.43 mmol, 2 equiv.). The resulting mixture was stirred under a N2 atmosphere at 25 °C for 1 h. The reaction mixture was quenched by the addition of HO (50 mL) at 25 °C and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0–10% EtOAc in petroleum ether / EtOAc, flow rate: 40 mL / min, 254 nm) to give 2-[[9-bromo-5-(2,6-difluorophenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane as a brown solid (670 mg, 58.2%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.02 (s, 9 H), 0.97-1.04 (m, 2 H), 2.25 (s, 3 H), 3.77-3.84 (m, 2 H), 5.38 (s, 2 H), 6.52 (d, J = 8.3 Hz, 1 H), 6.98 (t, J = 8.2 Hz, 2 H), 7.32-7.43 (m, 2 H), 7.94 (d, J = 2.3 Hz, 1 H), 19 F NMR (377 MHz, CDCl3) δ ppm -111.51; LCMS(ESI)m / z:521.2[M+H] + . Example (D1-4) Synthesis of 2-[[9-bromo-5-(2-chloro-6-fluorophenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (Intermediate D1-4) [ka]

[0287] To a solution of 5-(2-amino-5-bromophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-1) (500 mg, 1.26 mmol) and 2-chloro-6-fluorobenzaldehyde (400 mg, 2.52 mmol) in t-BuOH (15 mL) and THF (3 mL) was added KCO (696 mg, 5.04 mmol) at 25 °C for 2 hours, followed by the addition of I (640 mg, 2.52 mmol). The resulting mixture was stirred under a N atmosphere at 25 °C for 1 hour. The reaction mixture was quenched at 25 °C by the addition of HO (50 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-20% EtOAc in petroleum ether / EtOAc, flow rate: 40 mL / min, 254 nm) to give 2-[[9-bromo-5-(2-chloro-6-fluorophenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (330 mg, 48.9%) as a yellow solid. LCMS (ESI) m / z: 537.2 [M+H] + . Example (D1-5) Synthesis of 2-[[9-bromo-5-(2,6-difluoro-4-methylphenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (D1-5) [ka]

[0288] To a solution of 5-(2-amino-5-bromophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate B1-1) (400 mg, 1.01 mmol, 1 equiv.), 2,6-difluoro-4-methylbenzaldehyde (320 mg, 2.05 mmol, 2.04 equiv.) in t-BuOH (10 mL) and THF (2 mL) was added KCO (560 mg, 4.05 mmol, 4.03 equiv.) at 25 °C for 3 h, followed by the addition of I (510 mg, 2.01 mmol, 2 equiv.). The resulting mixture was stirred under a N atmosphere at 25 °C for 1 h. The reaction mixture was quenched by the addition of HO (50 mL) at 25 °C and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0-5% EtOAc in petroleum ether / EtOAc, flow rate: 40 mL / min, 254 nm) to give 2-[[9-bromo-5-(2,6-difluoro-4-methylphenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (310 mg, 57.7%) as a yellow solid. LCMS (ESI) m / z: 534.1 [M+H] + . Example (D2-1) Synthesis of 9-chloro-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (Intermediate D2-1) [ka]

[0289] 4-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-1) (5 g, 14.7 mmol, 1 equivalent) t To a solution of BuOH (40 mL) and THF (20 mL) was added K2CO3 (6.10 g, 44.1 mmol, 3 equiv), Y(OTf)3 (394.3 mg, 0.735 mmol, 0.05 equiv), and 2,6-difluorobenzaldehyde (2.09 g, 14.7 mmol, 1 equiv). The mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered. To the solution was added DDQ (3.33 g, 14.7 mmol, 1 equiv). The mixture was stirred at 25 °C for 3 h. The mixture was diluted with EtOAc (300 mL) and washed with NaHCO3 / H2O (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0–30% EtOAc in petroleum ether / EtOAc, 60 mL / min, 254 nm) to give 2-[[13-chloro-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a yellow solid (5.6 g, 82.7%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.03 (s, 9 H), 0.90 (t, J = 7.91 Hz, 2 H), 3.69 (t, J = 7.91 Hz, 2 H), 5.50 (s, 2 H), 7.22 (br t, J = 8.03 Hz, 2 H), 7.37 (br s, 1 H), 7.49-7.65 (m, 2 H), 7.73 (br s, 1 H), 8.70 (br s, 1 H); 19 F NMR (377 MHz, CD3OD) δ ppm -113.44; LCMS(ESI)m / z:462.1[M+H] + . Example (D2-2) Synthesis of 9-bromo-3-chloro-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (Intermediate D2-2) [ka]

[0290] 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-3) (500 mg, 1.19 mmol, 1 equiv.) t To a solution of BuOH (5 mL) and THF (1 mL) was added 2,6-difluorobenzaldehyde (169.7 mg, 1.19 mmol, 1 equiv.). The mixture was stirred at 25 °C under a N atmosphere for 16 h. MnO (518.9 mg, 5.97 mmol, 5 equiv.) was then added, and the mixture was stirred at 25 °C under a N atmosphere for an additional 5 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–30% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 mn) to give 2-[[13-bromo-5-chloro-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0]]. 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane was obtained as a yellow solid (250 mg, 32.9%). 1H NMR (400 MHz, CDCl3) δ ppm 0.04 (s, 9 H), 0.95-1.04 (m, 2 H), 3.78-3.85 (m, 2 H), 5.43 (s, 2 H), 5.77 (s, 1 H), 7.02 (t, J = 8.19 Hz, 2 H), 7.37-7.48 (m, 1 H), 7.70 (s, 1 H), 7.94 (s, 1 H); LCMS(ESI)m / z:542.0[M+H] + . Example (D2-3) Synthesis of 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (Intermediate D2-3) [ka]

[0291] 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-2) (3.3 g, 9.32 mmol, 1 equiv.), 2,6-difluorobenzaldehyde (1.99 g, 13.9 mmol, 1.5 equiv.), KCO (3.87 g, 28.0 mmol, 3 equiv.), I (3.55 g, 13.9 mmol, 1.5 equiv.) tThe BuOH (50 mL) solution was degassed and purged with N three times. The mixture was stirred under N at 60 °C for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0–50% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 mn) to give 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (2 g, 45.1%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.05-0.00 (m, 9 H), 0.83-0.95 (m, 2 H), 2.51-2.53 (m, 3 H), 3.69 (t, J = 7.8 Hz, 2 H), 5.43 (s, 2 H), 7.23 (t, J = 8.1 Hz, 2 H), 7.51-7.64 (m, 2 H), 7.73 (s, 1 H); LCMS(ESI)m / z:476.1[M+H] + . Example (D2-4) Synthesis of 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (Intermediate D2-4) [ka]

[0292] Step 1: tert-butyl-[(2,4-difluorophenyl)methoxy]dimethylsilane [ka]

[0293] To a solution of (2,4-difluorophenyl)methanol (5 g, 34.7 mmol, 1 equiv.) in DMF (50 mL) was added TBSCl (6.27 g, 41.6 mmol, 1.2 equiv.) and imidazole (5.90 g, 86.7 mmol, 2.5 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0–5% EtOAc in petroleum ether / EtOAc, 30 mL / min, 254 mn) to give tert-butyl-[(2,4-difluorophenyl)methoxy]dimethylsilane (7.8 g, 87.0%) as a colorless oil. Step 2: tert-butyl-[(2,4-difluorophenyl)methoxy]dimethylsilane [ka]

[0294] To a solution of tert-butyl-[(2,4-difluorophenyl)methoxy]dimethylsilane (4 g, 15.5 mmol, 1 equiv.) in THF (40 mL) was added dropwise 2 M LDA (9.3 mL, 18.6 mmol, 1.2 equiv.) in THF at −30° C., and the mixture was stirred at −30° C. for 30 min. Next, to the above solution was added dropwise DMF (1.36 g, 18.6 mmol, 1.2 equiv.) in THF (5 mL) at 0° C., and the mixture was stirred at −30° C. for 30 min. The solution was quenched by adding ammonium chloride at 0° C. and extracted with EtOAc (40 mL×3). The combined organic layers were then washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorobenzaldehyde (4.01 g, 90.5%) as a yellow oil. Step 3: 9-Bromo-5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-difluorophenyl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine [ka]

[0295] To a solution of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorobenzaldehyde (410.3 mg, 1.43 mmol) in MeOH (8 mL) was added 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-3) (500 mg, 1.19 mmol). The reaction mixture was stirred at 40° C. for 30 minutes, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (100 mL) to give 2-[[13-bromo-8-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-pentaazatricyclo[8.4.0.0] 2,6 ]tetradec-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (730 mg, 80.1%) was obtained as an off-white solid. Step 4: 9-Bromo-5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-difluorophenyl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (D2-4) [ka]

[0296] 2-[[13-bromo-8-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 To a solution of ]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (730 mg, 1.06 mmol) in DCM (10 mL) was added DDQ (289.4 mg, 1.27 mmol). The reaction mixture was stirred at 25 °C for 24 h and then triturated with petroleum ether (20 mL) to give 2-[[13-bromo-8-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-pentaazatricyclo[8.4.0.0] 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (520 mg, 71.4%) was obtained as a yellow solid. Example (D2-5)

[0297] 2-[[13-bromo-8-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-petroleum ethertroleum etherntazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane Synthesis of etherntazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyl-trimethyl-silane) (Intermediate D2-5) [ka]

[0298] Step 1: tert-butyl-[(3,5-difluorophenyl)methoxy]dimethylsilane [ka]

[0299] A mixture of (3,5-difluorophenyl)methanol (5 g, 34.69 mmol), TBSCl (5.1 mL, 41.6 mmol), and imidazole (5.90 g, 86.7 mmol) in DMF (50 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 25 °C for 16 h. The reaction mixture was quenched with HO (60 mL) and then extracted with EtOAc (40 mL × 2). The combined organic phase was washed with HO (20 mL × 3), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0–10% petroleum ether / EtOAc at 60 mL / min) to afford tert-butyl-[(3,5-difluorophenyl)methoxy]dimethylsilane (7 g, 78.1%) as a white oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6 H), 0.96 (s, 9 H), 4.72 (s, 2 H), 6.67 (tt, J = 8.94, 2.35 Hz, 1 H), 6.82-6.89 (m, 2 H). Step 2: 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorobenzaldehyde [ka]

[0300] To a mixture of tert-butyl-[(3,5-difluorophenyl)methoxy]dimethylsilane (3 g, 11.61 mmol) in THF (30 mL) was added dropwise 2 M LDA (5.8 mL) in THF at −30° C. under N. The mixture was stirred at −30° C. for 1 h, and DMF (1.1 mL, 13.9 mmol) was added and stirred at −30° C. for 1 h. The solution was quenched by adding HO (10 mL) at 0° C. and extracted with EtOAc (20 mL × 3). The combined organic layers were then washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0–10% petroleum ether / EtOAc, flow rate: 60 mL / min) to afford 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorobenzaldehyde (2 g, 60.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.10 (s, 6 H), 0.91 (s, 9 H), 4.79 (s, 2 H), 7.14 (d, J = 10.04 Hz, 2 H), 10.18 (s, 1 H). Step 3: 9-Bromo-5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-difluorophenyl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine [ka]

[0301] A mixture of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorobenzaldehyde (341.9 mg, 1.19 mmol, 1 equiv.), 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-3) (500 mg, 1.19 mmol, 1 equiv.) in MeOH (20 mL) was degassed and purged with N three times and stirred under N atmosphere at 45° C. for 30 min. The reaction mixture was then concentrated under reduced pressure. The residue was triturated with petroleum ether (5 mL) to give 9-bromo-5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-difluorophenyl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (580 mg, crude) as a white solid.

[0302] Step 4: 2-[[13-bromo-8-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-petroleum ethertroleum etherntazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-5) [ka]

[0303] A mixture of 9-bromo-5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-difluorophenyl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (580 mg, 0.84 mmol), DDQ (191.6 mg, 0.84 mmol) in DCM (1 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25 °C for 16 h. The residue was diluted with NaHCO / H0 (20 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (10 mL) to give 2-[[13-bromo-8-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6-difluorophenyl]-5-chloro-3,4,7,9,12-petroleumethertroleumetherntazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (542 mg, 87.2% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.02 (s, 9 H), 0.11 (s, 6 H), 0.87-0.90 (m, 2 H), 0.92 (s, 9 H), 3.70 (br t, J = 7.78 Hz, 2 H), 4.77 (s, 2 H), 5.46 (s, 2 H), 7.12 (br d, J = 8.78 Hz, 2 H), 7.66-7.74 (m, 2 H), 8.87 (br s, 1 H); LCMS(ESI)m / z:686.1[M+H] + . Example (D2-6) Synthesis of 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-6) [ka]

[0304] Step 1: 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0305] To a solution of 4-[4-amino-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-1) (1 g, 2.94 mmol, 1 equiv.) and 2-chloro-6-fluorobenzaldehyde (466.2 mg, 2.94 mmol, 1 equiv.) in t-BuOH (10 mL) and THF (5 mL) was added yttrium(III) trifluoromethanesulfonate (78.86 mg, 0.14 mmol, 0.05 equiv.) and KCO (1.22 g, 8.82 mmol, 3 equiv.). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. Crude 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (1.4 g) was obtained as a black oil, which was used directly in the next step. Step 2: 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-6) [ka]

[0306] To a solution of 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (1.4 g, 2.91 mmol) in THF (5 mL) and t-BuOH (10 mL) was added DDQ (661.5 mg, 2.91 mmol). The mixture was stirred at 25 °C for 3 h. The residue was diluted with EtOAc (30 mL) and washed with NaHCO / HO. The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–30% EtOAc in petroleum ether / EtOAc, 60 mL / min, 254 nm) to afford 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (1.2 g, 85.1%) as a yellow solid. LCMS (ESI) m / z: 478.0 [M+H] + . Example (D2-7) Synthesis of 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-7) [ka]

[0307] Step 1: 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0308] A mixture of 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloropyridin-3-amine (Intermediate B2-2) (1.75 g, 4.94 mmol, 1 equiv), 2-chloro-6-fluorobenzaldehyde (784.0 mg, 4.94 mmol, 1 equiv), KCO (2.05 g, 14.8 mmol, 3 equiv), yttrium(III) trifluoromethanesulfonate (132.5 mg, 0.24 mmol, 0.05 equiv) in THF (6 mL) and t-BuOH (14 mL) was degassed and purged with N three times, then the mixture was stirred at 50 °C under N atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (2.2 g, 89.9%) as a yellow solid. Step 2: 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-7) [ka]

[0309] To a solution of 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (2.2 g, 4.45 mmol, 1 equiv.) in THF (12 mL) and t-BuOH (4 mL) was added DDQ (1.01 g, 4.45 mmol, 1 equiv.). The mixture was stirred at 25 °C for 2 h. HO (16 mL) was added to the reaction mixture, which was then extracted with EtOAc (16 mL × 3). The combined organic layer was washed with aqueous NaHCO (16 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent gradient of 0 to 20% EtOAc / petroleum ether at 30 mL / min) to afford 2-[[13-chloro-8-(2-chloro-6-fluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (1.51 g, 66.0%) as a yellow solid. LCMS (ESI) m / z: 492.1 [M+H] + . Example (D2-8) 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 Synthesis of ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-8) [ka]

[0310] Step 1: 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0311] A mixture of 2-chloro-6-fluorobenzaldehyde (389 mg, 2.45 mmol, 1 equiv.), 4-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-3) (1 g, 2.45 mmol, 1 equiv.) in THF (10 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0]phenyl]]. 2,6 ]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (1.37 g, crude) was obtained as a yellow solid. LCMS (ESI) m / z: 560.1 [M+H] + . Step 2: 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D2-8) [ka]

[0312] 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6 A mixture of ]tetradeca-1(10),2(6),4,11,13-pentaen-3-yl]methoxy]ethyltrimethylsilane (1.32 g, 2.36 mmol, 1 equiv.), DDQ (643 mg, 2.83 mmol, 1.2 equiv.) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 20 °C for 16 h. The reaction mixture was diluted with aqueous NaHCO3 (20 mL), extracted with EtOAc (30 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0–15% EtOAc in petroleum ether / EtOAc, 30 mL / min, 254 nm) to give 2-[[13-bromo-5-chloro-8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0] 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (1.18 g, 90.0%) was obtained as a yellow solid. LCMS (ESI) m / z: 560.1 [M+H] + . Example (D3-1) Synthesis of 13-bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene (D3-1) [ka]

[0313] Step 1: 13-Bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene [ka]

[0314] A mixture of 4-[4-amino-2-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-19) (800 mg, 1.81 mmol, 1 equiv) and 2,6-difluorobenzaldehyde (257.0 mg, 1.81 mmol, 1 equiv) in THF (1 mL) was stirred for 16 h at 25° C. The reaction mixture was concentrated in vacuo. The crude product, 13-bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene (1 g, crude) was obtained as a yellow oil, which was used in the next step without further purification. Step 2: 13-Bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene (D3-1) [ka]

[0315] A mixture of 13-bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene (1 g, 1.77 mmol), MnO (1.54 g, 17.7 mmol, 10 equiv.) in THF (10 mL) was stirred under a N atmosphere at 25 °C for 16 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (ISCO®; 24 g SepaFlash® silica flash column, 0–30% EtOAc in petroleum ether / EtOAc, 100 mL / min, 254 mn) to give 13-bromo-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene as a yellow solid (800 mg, 80.2%). LCMS (ESI) m / z: 566.0 [M+H] + . Example (D3-4) Synthesis of 13-bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene [ka]

[0316] Step 1: 13-Bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene [ka]

[0317] A solution of 4-[4-amino-5-(difluoromethyl)-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-bromopyridin-3-amine (Intermediate B2-20) (500 mg, 1.18 mmol) and 2,6-difluorobenzaldehyde (167 mg, 1.18 mmol) in THF (7 mL) was stirred for 16 hours at 25° C. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, 0–40% EtOAc in petroleum ether / EtOAc, 30 mL / min, 254 nm) to afford 13-bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene (534 mg, 82.1% yield) as a yellow solid. LCMS (ESI) m / z: 550.1 [M+H] + . Step 2: 13-Bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene (D3-4) [ka]

[0318] To a solution of 13-bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene (Intermediate B2-20) (500 mg, 0.911 mmol) in CHCl (8 mL) was added DDQ (227 mg, 1.00 mmol). The mixture was stirred at 25 °C for 16 hours. NaHCO / H O (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0–30% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 nm) to afford 13-bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene (450 mg, 83.4% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H), 5.55 (s, 2 H), 6.74 (s, 1 H), 6.88 (s, 1 H), 6.94 (d, J = 8.75 Hz, 2 H), 7.01 (s, 1 H), 7.09 (d, LCMS(ESI)m / z:546.1[M+H] + . Example (D3-5) Synthesis of 13-bromo-5-(difluoromethyl)-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene [ka]

[0319] Step 1: Methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxylate [ka]

[0320] A mixture of methyl 4-amino-5-(5-amino-2-chloro-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (Intermediate B-21) (4.80 g, 12.0 mmol) and 2,6-difluorobenzaldehyde (3.43 g, 24.1 mmol) in t-BuOH (80 mL) and THF (80 mL) was stirred at 20° C. for 16 hours. The mixture was filtered and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® silica flash column, 0-35% EtOAc in petroleum ether / EtOAc, flow rate = 55 mL / min, 254 nm) to give methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxylate (3.13 g, 29.3% yield) as a light yellow solid. LCMS (ESI) m / z: 522.1 [M+H] + . Step 2: Methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene-5-carboxylate [ka]

[0321] Methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxylate (3.13 g, 6.00 mmol), methyl 13-chloro-8-(2,6-difluorophenyl)-3-( To a solution of (2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxylate (3.13 g, 6.00 mmol) in THF (160 mL) was added DDQ (2.72 g, 11.9 mmol) and KCO (1.66 g, 11.9 mmol). The mixture was stirred under a nitrogen atmosphere at 20 °C for 16 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® silica flash column, 0-15% EtOAc in petroleum ether / EtOAc, flow rate = 50 mL / min, 254 nm) to give methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene-5-carboxylate (1.4 g, 44.9%) as a yellow solid. LCMS (ESI) m / z: 520.0 [M+H] + . Step 3: [13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-5-yl]methanol [ka]

[0322] To a solution of methyl 13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene-5-carboxylate (300 mg, 0.577 mmol) in EtOH (8 mL) and THF (8 mL) was added NaBH (66.0 mg, 1.74 mmol) and CaCl (192.0 mg, 1.73 mmol) under nitrogen at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was slowly quenched with water (30 mL) at 0 °C and stirred for 15 min. The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, flow rate = 35 mL / min, 254 nm) to afford [13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-5-yl]methanol (259 mg, 91.2%) as a yellow solid. LCMS (ESI) m / z: 492.1 [M+H] + . Step 4: tert-butyl-[[13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-5-yl]methoxy]dimethylsilane (D3-5) [ka]

[0323] To a solution of [13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-5-yl]methanol (259 mg, 0.526 mmol) in DMF (10 mL) was added imidazole (286 mg, 4.20 mmol) at 0° C. under nitrogen, followed by TBSCl (238 mg, 1.58 mmol). The mixture was stirred at 60° C. for 3 hours. The reaction was slowly quenched with water (30 mL) at 0° C. and stirred for 15 minutes. The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® silica flash column, 0–50% EtOAc in petroleum ether / EtOAc, flow rate = 35 mL / min, 254 nm) to afford tert-butyl-[[13-chloro-8-(2,6-difluorophenyl)-3-(2-trimethylsilylethoxymethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-5-yl]methoxy]dimethylsilane (227 mg, 69.5%) as a yellow solid. LCMS (ESI) m / z: 606.2 [M+H] + . Example (D4-1) Synthesis of 9-chloro-5-(2,6-difluorophenyl)-3,7-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (Intermediate D4-1) [ka]

[0324] 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (Intermediate B2-4) (3.5 g, 9.51 mmol, 1 equiv.) and 2,6-difluorobenzaldehyde (1.35 g, 9.51 mmol, 1.02 mL, 1 equiv.) t To a solution of BuOH (5 mL) and THF (1 mL) was added KCO (3.94 g, 28.5 mmol, 3 equiv.) at 25 °C. After the addition, the mixture was stirred at this temperature for 30 min, and then DDQ (4.32 g, 19.0 mmol, 2 equiv.) was added. The resulting mixture was stirred at 25 °C for 4 h under a N atmosphere and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 0% to 30%) to give 2-[[13-chloro-8-(2,6-difluorophenyl)-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a yellow solid (3 g, 64.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm -0.03 (s, 9 H), 0.81-0.95 (m, 2 H), 2.01-2.08 (m, 3 H), 2.26-2.34 (m, 3 H), 3.64-3.76 (m, 2 H), 5.41 (s, 1 LCMS(ESI)m / z:490.1[M+H] + . Example (D4-2) Synthesis of 9-chloro-5-(2,6-difluorophenyl)-1-(4-methoxybenzyl)-7-methyl-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine (Intermediate D4-2) [ka]

[0325] 4-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-chloro-2-methylpyridin-3-amine (Intermediate B2-6) (14 g, 40.7 mmol, 1 equiv.) and 2,6-difluorobenzaldehyde (5.79 g, 40.7 mmol, 1 equiv.) t To a solution of BuOH (300 mL) was added K2CO3 (16.88 g, 0.122 mmol, 3 equiv.) and I2 (20.67 g, 81.4 mmol, 2 equiv.) at 25 °C. After the addition, the mixture was stirred at this temperature for 30 min, and then MnO2 (35.4 g, 0.407 mol, 10 equiv.) was added. The resulting mixture was stirred at 60 °C under a N2 atmosphere for 2 h and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: EtOAc = 0% to 50%) and preparative HPLC (column: Kromasil Eternity XT 150 × 30 mm × 10 μm; mobile phase: [water (NH₃H₂O + NH₄HCO₃)-MeCN]; B%: 18% to 58% in 9 min) to give 13-chloro-8-(2,6-difluorophenyl)-3-[(4-methoxyphenyl)methyl]-11-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene (3.5 g, 18.4%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3 H), 3.73 (s, 3 H), 5.45 (br s, 2 H), 6.92 (d, J = 8.5 Hz, 3 H), 7.08 (d, J = 8.5 Hz, 3 H), 7.22 (t, J = 8.2 Hz, 2 H), 7.57 (quin, J = 7.5 Hz, 1 H); LCMS(ESI)m / z:478.0[M+H] + . Example (D7-1) Synthesis of 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-11-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (D7-1) [ka]

[0326] To a mixture of 4-[4-amino-5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-6-chloro-2-(trifluoromethyl)pyridin-3-amine (Intermediate B2-22) (300 mg, 0.676 μmol, 1 equiv.) and 2,6-difluorobenzaldehyde (97 mg, 0.683 mmol, 1.01 equiv.) in t-BuOH (4 mL) and THF (0.8 mL) was added KCO (282 mg, 2.04 mmol, 3.02 equiv.). The mixture was stirred at 25° C. for 30 minutes. To the above mixture was added DDQ (308 mg, 1.36 mmol, 2.01 equiv.). The reaction mixture was stirred at 25° C. for 4 hours under N. The mixture was combined with another batch and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage®; 40 g Agela silica flash column, eluent: 0-13% EtOAc / petroleum ether, gradient at 60 mL / min). 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-11-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (802 mg, 68.2%) was obtained as a yellow solid. LCMS (ESI) m / z: 544.3 [M+H] + . Example (E1-1) Synthesis of 3-chloro-5-(2,6-difluorophenyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (intermediate E1-1) [ka]

[0327] Step 1: Methyl 3-chloro-5-(2,6-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate [ka]

[0328] A mixture of methyl 3-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-(tert-butoxycarbonylamino)benzoate (Intermediate B1-7) (200 mg, 0.402 mmol, 1.0 equiv), 2,6-difluorobenzaldehyde (57.1 mg, 0.402 mmol, 1.0 equiv), KCO (166 mg, 1.21 mmol, 3.0 equiv) in t-BuOH / THF (1:1, 3 mL) was stirred for 30 min, then I (153 mg, 0.603 mmol, 1.5 equiv) was added and the mixture was stirred at 25 °C for 2 h. The t-BuOH / THF was evaporated and the residue purified by column chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-50% EtOAc in petroleum ether / EtOAc, 20 mL / min, 254 mn) to give methyl 3-chloro-5-(2,6-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate as a white solid (40 mg, 19.1%). LCMS (ESI) m / z: 519.1 [M+H] + . Step 2: 3-chloro-5-(2,6-difluorophenyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (E1-1) [ka]

[0329] A mixture of methyl 3-chloro-5-(2,6-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate (40 mg, 0.077 mmol, 1.0 equiv.) and LiOH·HO (6.47 mg, 0.154 mmol, 2.0 equiv.) in THF / HO (3:1, 2 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated and neutralized with 1 N HCl in HO until the pH reached 1. A precipitate formed and was collected by filtration and air-dried to give 3-chloro-5-(2,6-difluorophenyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as a white solid (30 mg), which was used directly in the next step. 1 H NMR (400 MHz, CD3OD) δ ppm 6.84 (d, J = 8.31 Hz, 1 H), 7.08-7.25 (m, 2 H), 7.44-7.62 (m, 1 H), 7.88-8.04 (m, 1 H), 8.39 (d, J = 1.83 Hz, 1 H); LCMS(ESI)m / z:375.1[M+H] + . Example (E2-1) Synthesis of methyl 5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate [ka]

[0330] Step 1: Methyl 5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate [ka]

[0331] A mixture of methyl 4-amino-3-[4-amino-2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]benzoate (Intermediate B1-8) (230 mg, 0.652 mmol, 1.0 equiv), 2,6-difluorobenzaldehyde (231 mg, 1.63 mmol), KCO (270 mg, 1.96 mmol), and I (497 mg, 1.96 mmol) in t-BuOH / THF (4:1, 5 mL) was stirred for 2 h at 20 °C. The mixture was quenched with NaSO / HO (30 mL) and extracted with EtOAc (50 mL × 2). The extract was concentrated in vacuo and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0 to 100% EtOAc / petroleum ether, gradient at 20 mL / min) to give methyl 5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate as a dark brown oil (210 mg, 67.8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (d, J = 4.63 Hz, 7 H) 3.94-4.13 (m, 2 H), 5.34 (s, 2 H), 6.84 (d, J = 8.38 Hz, 1 H), 6.94 (d, J = 8.76 Hz, 2 H), 7.09-7.24 (m, 5 H), 7.35 (s, 1 H), 7.50-7.59 (m, 1 H), 7.64 (d, J = 1.88 Hz, 1 H), 7.75 (dd, J = 8.38, 1.88 Hz, 1 H), 8.60 (s, 1 H); LCMS(ESI)m / z:475.1[M+H] + . Step 2: Methyl 5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylic acid (E2-1) [ka]

[0332] Methyl 5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate (210 mg, 0.442 mmol, 1.0 equiv.) and LiOH·HO (185 mg, 4.43 mmol, 10.0 equiv.) in THF / HO (3:1, 4 mL) were stirred at 25 °C for 8 h. The mixture was neutralized with 1 M HCl (5 mL) to pH = 7. The mixture was extracted with EtOAc (10 mL × 3). The extract was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluting with a gradient of 0 to 10% MeOH / DCM at 12 mL / min) to afford the title compound as a yellow solid (90.0 mg, 44.2%). 1 H NMR (400 MHz, CDCl3) δ ppm 3.69-3.88 (m, 4 H), 4.13 (q, J = 7.17 Hz, 1 H), 5.45 (s, 2 H), 5.79 (s, 1 H), 6.65 (d, J = 8.24 Hz, 1 H), 6.85-6.92 (m, 2 H), 6.99 (t, J = 8.16 Hz, 2 H), 7.24 (d, J = 8.70 Hz, 2 H), 7.35-7.43 (m, 1 H), 7.53 (s, 1 H), 7.86-7.99 (m, 2 H); LCMS(ESI)m / z:461.7[M+H] + . Example (E2-5) Synthesis of 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (E2-5) [ka]

[0333] Step 1: Methyl 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate [ka]

[0334] A mixture of methyl 4-amino-5-[4-amino-5-chloro-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-2-fluorobenzoate (100 mg, 0.241 mmol, 1.0 equiv.), 2,6-difluorobenzaldehyde (68.4 mg, 0.482 mmol, 2.0 equiv.), and K2CO3 (66.6 mg, 0.482 mmol, 2.0 equiv.) in t-BuOH (3 mL) was stirred for 30 min, and then I2 (91.7 mg, 0.361 mmol, 1.5 equiv.) was added, and the mixture was stirred at 60 °C for 2 h. The solid was filtered off and washed with MeOH (4 mL × 2). The organic layers were combined. Removal of the organic solvent under reduced pressure gave the crude product, which was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-40% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 mn) to give methyl 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate as a white solid (90 mg, 69.5%). LCMS (ESI) m / z: 537.1, [M+H] + . Step 2: Synthesis of 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (E2-5) [ka]

[0335] A mixture of methyl 3-chloro-5-(2,6-difluorophenyl)-8-fluoro-1-(2-trimethylsilylethoxymethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepine-9-carboxylate (90 mg, 0.167 mmol, 1.0 equiv.) and LiOH·HO (21.1 mg, 0.502 mmol, 3.0 equiv.) in THF / HO (3:1, 4 mL) was stirred at 25 °C for 16 h. The THF was evaporated and acidified with 12 N HCl in HO until a pH of 1 was reached. The reaction mixture was extracted with EtOAc (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-40% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 mn) to give the title compound as a white solid (30 mg, 45%). LCMS (ESI) m / z: 393.1 [M+H] + . Example (Int-1) Synthesis of 4-[8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0336] Step 1: 2-[[8-(2,6-difluorophenyl)-5-methyl-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0337] 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (Intermediate D2-3) (160 mg, 0.336 mmol) in dioxane (5 mL) A mixture of Pd(dba) (154 mg, 0.168 mmol, 0.5 equiv.), morpholine (29.3 mg, 0.336 mmol, 1.0 equiv.), DavePhos (132 mg, 0.336 mmol, 1.0 equiv.), Pd(dba) (154 mg, 0.168 mmol, 0.5 equiv.), and t-BuONa (96.9 mg, 1.01 mmol, 3.0 equiv.) was stirred at 100 °C under a N atmosphere for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-100% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 nm) to give 2-[[8-(2,6-difluorophenyl)-5-methyl-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a red oil (70 mg, 27.7%). LCMS (ESI) m / z: 527.2 [M+H] + . Step 2: 4-[8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0338] A solution of 2-[[8-(2,6-difluorophenyl)-5-methyl-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (70 mg, 0.133 mmol) in 4 N HCl (2 mL) in MeOH was stirred at 25° C. for 2 hours. The resulting mixture was cooled to 0° C. The precipitate was collected by filtration to give the title compound as a yellow solid (30 mg, 54.1%). 1 H NMR (400 MHz, CD3OD) δ ppm 2.26 (s, 3 H), 3.58-3.68 (m, 4 H), 3.77-3.87 (m, 4 H), 7.31 (t, J = 8.6 Hz, 2 H), 7.47 (s, 1 H), 7.63 (s, 1 H), 7.76-7.89 (m, 1 H); LCMS(ESI)m / z 397.2[M+H] + . Example (Int-2) 4-[5-cyclopropyl-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 Synthesis of ]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0339] Step 1: 2-[[5-cyclopropyl-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 Synthesis of ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0340] 2-[[5-chloro-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0] in dioxane / H2O (2:1, 1.5 mL) 2,6 A mixture of [tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (Int-3 below) (150 mg, 0.213 mmol, 1 equiv.), cyclopropylboronic acid (22.0 mg, 0.256 mmol, 1.2 equiv.), CsCO (209 mg, 0.641 mmol, 3 equiv.), and BrettPhos-Pd-G (39.4 mg, 42.7 μmol, 0.2 equiv.) was degassed and purged with N three times, then stirred under N at 100 °C for 16 h. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-20% EtOAc in petroleum ether as eluent to give 2-[[5-cyclopropyl-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0] 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane was obtained as a yellow oil (50 mg, 42.3%). Step 2: 4-[5-cyclopropyl-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 Synthesis of ]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0341] 2-[[5-cyclopropyl-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0] in 4N HCl in MeOH (1.0 mL) 2,6 A mixture of [tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (50 mg, 90.4 μmol, 1 equiv.) and EtSiH (28.9 μL, 0.180 mmol, 2 equiv.) was stirred at 25 °C for 1 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure, and then the mixture was diluted with HO (2 mL), and the pH of the mixture was adjusted to 7 with saturated NaHCO solution. This mixture was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–50% EtOAc in petroleum ether as eluent to give 4-[5-cyclopropyl-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradec-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine was obtained as a yellow solid (20.2 mg, 52.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.87-0.78 (m, 4 H), 1.77-1.67 (m, 1 H), 3.28-3.24 (m, 4 H), 3.69-3.64 (m, 4 H), 3.69-3.68 (m, 1 H), 6.81 LCMS(ESI)m / z 423.1[M+H] + . Example (Int-3) Synthesis of 4-(3-chloro-5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepin-9-yl)morpholine [ka]

[0342] Step 1: 2-[[5-chloro-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0343] The title compound was prepared from intermediate D2-2 following a similar synthetic procedure as described in the synthesis of Int-1 (above); the reaction was carried out in dioxane at 100° C. for 12 hours. Purification of the crude product by preparative TLC (silica, petroleum ether / EtOAc = 3 / 1, 254 nm) gave 2-[[5-chloro-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0] 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane was obtained as a yellow solid (30 mg, 17.4%). LCMS (ESI) m / z: 547.1, [M+H] + . Step 2: 4-[5-chloro-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0344] 2-[[5-chloro-8-(2,6-difluorophenyl)-13-morpholino-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6To a solution of 4N HCl (1 mL) in MeOH was added triethylsilane (19.1 mg, 0.16 mmol, 3 equiv.) containing tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (30 mg, 0.05 mmol, 1 equiv.). The mixture was stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure. The residue was diluted with NaHCO (2 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica, petroleum ether / EtOAc = 1 / 1, 254 nm) to give compound 4-[5-chloro-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]tetradec-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine was obtained as a yellow solid (10.3 mg, 45.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (br d, J = 5.77 Hz, 4 H), 3.65-3.70 (m, 4 H), 6.71 (br s, 1 H), 7.18 (t, J = 8.00 Hz, 2 H), 7.35 (br s, 1 H), 7.46-7.58 (m, 1 H), 8.40 (br s, 1 H), 13.25 (brs, 1 H); LCMS(ESI)m / z:417.0[M+H] + . Example (Int-4) 13-[1-(2,2-difluoroethyl)pyrazol-4-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0345] Step 1: 2-[[13-[1-(2,2-difluoroethyl)pyrazol-4-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0346] 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane intermediate D2-3 (200 mg, 0.420 mmol, 1.0 equiv.), 1- A mixture of (2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (108 mg, 0.420 mmol, 1.0 equiv), NaCO (134 mg, 1.26 mmol, 3.0 equiv), and Pd(dppf)Cl (92.2 mg, 0.126 mmol, 0.3 equiv) was stirred under a N atmosphere at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0–50% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 nm) to give 2-[[13-[1-(2,2-difluoroethyl)pyrazol-4-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a brown oil (100 mg, 41.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm -0.03 (s, 9 H), 0.90-0.97 (m, 2 H), 2.04 (s, 3 H), 3.66-3.77 (m, 2 H), 4.66-4.75 (m, 2 H), 5.49 (s, 2 H), 6.22-6.57 (m, 1 H), 7.23 (t, J = 8.2 Hz, 2 H), 7.53-7.63 (m, 1 H), 7.74-7.77 (m, 1 H), 7.90 (d, J = 2.5 Hz, 2 H), 8.18 (s, 1 H), 8.52 (s, 1 H). Step 2: 13-[1-(2,2-difluoroethyl)pyrazol-4-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0347] A solution of 2-[[13-[1-(2,2-difluoroethyl)pyrazol-4-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (100 mg, 0.175 mmol) in 4 N HCl (2 mL) in MeOH was stirred at 20° C. for 5 hours. The resulting mixture was cooled to 0° C. The precipitated solid was collected by filtration to give the title compound as a yellow solid (43.0 mg, 55.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3 H), 4.71 (td, J = 15.1, 3.1 Hz, 2 H), 6.09-6.62 (m, 1 H), 7.24-7.37 (m, 2 H), 7.66 (br s, 1 H), 7.80 (s, 1 H), 7.89 (br s, 1 H), 8.23 ​​(s, 1 H), 8.57 (br s, 1 H); LCMS(ESI)m / z:441.1[M+H] + . Example (Int-5) Synthesis of 4-[5-(3-chloro-2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine [ka]

[0348] Step 1: Synthesis of 2-[[5-(3-chloro-2,6-difluorophenyl)-3-methyl-9-morpholino-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane [ka]

[0349] To a solution of 5-(2-amino-5-morpholinophenyl)-3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-amine (Intermediate C1-1) (150 mg, 0.372 mmol, 1 equiv.) and 3-chloro-2,6-difluorobenzaldehyde (65.6 mg, 0.372 mmol, 1 equiv.) in t-BuOH / THF (5:1, 6 mL) was added KCO (154 mg, 1.11 mmol, 3 equiv.). The reaction mixture was stirred for 30 minutes, and then I (142 mg, 0.558 mmol, 1.5 equiv.) was added. The mixture was stirred at 70 °C under N for 30 minutes, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-27% EtOAc in petroleum ether as eluent to give 2-[[5-(3-chloro-2,6-difluorophenyl)-3-methyl-9-morpholino-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (40.0 mg, 11.5%) as a yellow oil. LCMS (ESI) m / z: 560.1 [M+H] + . Step 2: Synthesis of 4-[5-(3-chloro-2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine [ka]

[0350] To a solution of 2-[[5-(3-chloro-2,6-difluorophenyl)-3-methyl-9-morpholino-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (40.0 mg, 0.0429 mmol, 1 equiv.) in 4 N HCl (2 mL) in MeOH was added EtSiH (9.96 mg, 0.0857 mmol, 2 equiv.). The mixture was stirred at 20 °C under a N atmosphere for 16 h. The solution was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 4% to 44% in 9 min), and the fractions were lyophilized to give 4-[5-(3-chloro-2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine as a white solid (4.3 mg, 23.4%). 1 H NMR (400 MHz, CD3OD) δ ppm 2.12-2.23 (m, 3 H), 3.31 (br d, J = 4.6 Hz, 4 H), 3.82-3.94 (m, 4 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.90-7.02 (m, 1 LCMS(ESI)m / z:429.2[M+H] + . Example (Int-6) Synthesis of 4-(3-chloro-5-(2,6-difluorophenyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepin-9-yl)morpholine [ka]

[0351] Step 1: Synthesis of 4-[3-chloro-5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine [ka]

[0352] A mixture of 5-(2-amino-5-morpholinophenyl)-3-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-amine (Intermediate C1-2) (600 mg, 1.33 mmol, 1 equiv.), KCO (552 mg, 4.00 mmol, 3 equiv.), and 2,6-difluorobenzaldehyde (208 mg, 1.47 mmol, 1.1 equiv.) in toluene (30 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled to 25° C., filtered, and concentrated under reduced pressure. Next, diluted with DCM (30 mL), DDQ (302 mg, 1.33 mmol, 1 equiv.) was added to the reaction mixture, and the reaction mixture was stirred at 25° C. for 1 hour. The residue was diluted with HO (10 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-40% EtOAc in petroleum ether as eluent to give 4-[3-chloro-5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine as a yellow solid (450 mg, 26.1%). LCMS (ESI) m / z: 536.2 [M+H] + . Step 2: Synthesis of 4-(3-chloro-5-(2,6-difluorophenyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepin-9-yl)morpholine [ka]

[0353] A solution of 4-[3-chloro-5-(2,6-difluorophenyl)-1-[(4-methoxyphenyl)methyl]-6H-pyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine (400 mg, 0.746 mmol) in TFA (10 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and then washed with saturated aqueous NaHCO until the pH was approximately 7. The residue was purified by flash chromatography on a silica gel column using 0 to 50% EtOAc in petroleum ether as eluent to give 4-[3-chloro-5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]morpholine as a yellow solid (222 mg, 70.7%). 1 H NMR (400 MHz, CD3OD) δ ppm 3.04-3.13 (m, 4 H), 3.75-3.88 (m, 4 H), 6.47 (d, J = 8.8 Hz, 1 H), 6.72 (dd, J = 8.8, 2.63 Hz, 1 H), 6.82 (d, J = 2.6 Hz, 1 H), 7.05 (t, J = 8.1 Hz, 2 H), 7.41-7.53 (m, 1 H); 19 F NMR (376 MHz, CD3OD) δ ppm -115.10; LCMS(ESI)m / z:416.0[M+H] + . Example (Int-7) Synthesis of (S)-4-(3-chloro-5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepin-9-yl)-2-methylmorpholine [ka]

[0354] The title compound was prepared from intermediate D2-2 following a similar synthetic procedure described in the synthesis of Example 18 (above), except that (S)-2-methylmorpholine was used instead of 1-(2-fluoroethyl)-3-methylpiperazine, and the reaction was carried out in dioxane for 1 hour at 100° C. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0–60% EtOAc in petroleum ether / EtOAc, 30 mL / min, 254 mn) to afford (S)-4-(3-chloro-5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepin-9-yl)-2-methylmorpholine as a yellow solid (23.4 mg, 53.7%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J = 6.3 Hz, 3 H), 2.41 (br dd, J = 12.0, 10.5 Hz, 1 H), 2.65-2.78 (m, 1 H), 3.47-3.61 (m, 2 H), 3.77-3.95 (m, 3 H), 6.69 (s, 1 H), 7.11-7.25 (m, 2 H), 7.33 (s, 1 H), 7.47-7.55 (m, 1 H), 8.38 (s, 1 H), 13.21 (s, 1 H); LCMS(ESI)m / z:429.9[M+H] + .

[0355] Representative compounds of formula (I) or salts thereof are disclosed in Table 1. While Table 1 may show specific salts of compounds of formula (I), one of ordinary skill in the art will be able to recognize other salts, such as the parent compound (a "parent compound" is a compound that does not contain any salt moieties present), and pharmaceutically acceptable salts of those compounds in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0356] Example 1 9-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine [ka]

[0357] The title compound was prepared from intermediate D2-3 following a similar synthetic procedure described in the synthesis of Int-1 (above), except that 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole was used instead of morpholine, 10% Pd(dppf)Cl was employed as the catalyst, and the reaction was carried out in dioxane at 110° C. for 16 hours. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure. The crude product was triturated with MeOH at 25° C. for 0.5 hours to afford the title compound (41.4 mg, 45.0%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (br s, 3 H), 7.31 (br t, J = 8.07 Hz, 2 H), 7.62-7.73 (m, 1 H), 7.84 (br d, J = 13.57 Hz, 2 H), 7.90-8.02 (m, 1 H), 8.34 (s, 1 H), 8.89 (s, 1 H); LCMS(ESI)m / z 428.1[M+H] + . Example 2 13-(3,3-Difluoroazetidin-1-yl)-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0358] The title compound was prepared from intermediate D2-3 following a similar synthetic procedure described in the synthesis of Int-1 (above), except that 3,3-difluoroazetidine was used instead of morpholine, 10% Pd(dba) was employed as the catalyst, and the reaction was carried out in dioxane at 100 °C for 12 h. The crude product was treated with 30% TFA in CHCl for 3 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (Kromasil Eternity XT 150 × 30 mm × 10 μm; mobile phase: [water (NHH0 + NHHCO)-ACN]; B%: 10% to 50% in 9 min) to afford the title compound as a yellow solid (27.7 mg, 19.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H), 4.24-4.31 (m, 4 H), 6.59 (s, 1 H), 7.14-7.21 (m, 2 H), 7.43 (s, 1 H), 7.45-7.54 (m, 1 H), 8.28-8.32 (m, 1 H), 12.49 (s, 1 H); LCMS(ESI)m / z:403.0[M+H] + . Example 3 8-(2,6-Difluorophenyl)-13-(4-fluoro-1-piperidyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0359] The title compound was prepared from intermediate D2-3 following a similar synthetic procedure to that described in the synthesis of Example 5 (below), except that 4-fluoropiperidine was used instead of morpholine, 10% Pd2(dba)3 was employed as the catalyst, and the reaction was carried out in dioxane for 12 hours at 100 °C. The reaction was purified by flash chromatography (ISCO®; 20 g AgelaFlash® silica flash column, 0 to 100% EtOAc in petroleum ether / EtOAc, flow rate = 30 mL / min, 254 nm), and then the SEM protecting group was removed with 4 N HCl in MeOH to give the title compound as a yellow solid (28 mg, 30.7%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.93-2.21 (m, 4 H), 2.26-2.42 (m, 3 H), 3.73-3.92 (m, 4 H), 7.34 (t, J = 8.6 Hz, 2 H), 7.64 (d, J = 15.0 Hz, 2 H), 7.78-7.93 (m, 1 H); LCMS(ESI)m / z:413.4[M+H] + . Example 4 Synthesis of 4-[8-(2,6-difluorophenyl)-5-methyl-11-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0360] The title compound was prepared from intermediate D7-1 following a similar synthetic procedure as described in the synthesis of Int-1 (above); the reaction was carried out in dioxane at 100° C. for 3 hours. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by trituration with petroleum ether (20 mL) to give 4-[8-(2,6-difluorophenyl)-5-methyl-11-(trifluoromethyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine as a yellow solid (38.4 mg, 64.7%, HCl salt). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s, 3 H), 3.37-3.40 (m, 4 H), 3.63-3.70 (m, 4 H), 7.03 (s, 1H), 7.14 (t, J = 8.0 Hz, 2 H), 7.43-7.49 (m, 1H); LCMS(ESI)m / z:465.3[M+H] + . Example 5 Synthesis of 5-(2,6-difluorophenyl)-9-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3,7-dimethyl-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine [ka]

[0361] Step 1: tert-Butyl 4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate [ka]

[0362] To a mixture of tert-butyl piperazine-1-carboxylate (5 g, 26.9 mmol, 1.0 equiv.) and 2,2-dimethyloxirane (1.94 g, 26.9 mmol, 1.0 equiv.) in DMF (40 mL) was added K2CO3 (11.2 g, 81.0 mmol, 3.0 equiv.). The reaction mixture was stirred at 130 °C for 2 hours. Water (100 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 80 g Agela silica flash column, eluent of 0 to 100% ethyl acetate / petroleum ether, gradient at 100 mL / min) to give tert-butyl 4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate as a colorless oil (1.12 g, 15.3%). Step 2: tert-Butyl 4-(2-fluoro-2-methylpropyl)piperazine-1-carboxylate [ka]

[0363] To a mixture of tert-butyl 4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate (1 g, 3.68 mmol, 95% purity, 1.0 equiv.) in DCM (10 mL) was added DAST (1.78 g, 11.1 mmol, 3.0 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The solution was concentrated, and the mixture was poured into saturated aqueous NaHCO (30 mL) at 0 °C. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Biotage®; 20 g Agela silica flash column, eluent of 0 to 25% ethyl acetate / petroleum ether, gradient at 60 mL / min) to afford tert-butyl 4-(2-fluoro-2-methylpropyl)piperazine-1-carboxylate as a colorless oil (660 mg, 62.1%). Step 3: 1-(2-fluoro-2-methylpropyl)piperazine [ka]

[0364] To a solution of tert-butyl 4-(2-fluoro-2-methylpropyl)piperazine-1-carboxylate (660 mg, 2.28 mmol, 90% purity, 1 equiv.) in DCM (8 mL) was added TFA (2.31 g, 20.3 mmol, 8.9 equiv.) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The yellow oil was dissolved in MeCN (3 mL) and water (20 mL) to give a yellow solution. The solution was lyophilized to dryness. The product was then dissolved in water (20 mL) at 25° C., the pH was adjusted to approximately 13 with saturated aqueous KCO (6 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 1-(2-fluoro-2-methylpropyl)piperazine as a yellow oil (360 mg, 93.8%). Step 4: 8-(2,6-difluorophenyl)-13-[4-(2-fluoro-2-methylpropyl)piperazin-1-yl]-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0365] The title compound was prepared from intermediate D4-1 following a similar synthetic procedure described in the synthesis of Int-1 (above), except that 1-(2-fluoro-2-methylpropyl)piperazine was used instead of morpholine, and the reaction was carried out in dioxane at 100 °C for 3 h. The resulting crude product was treated with 4 N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-MeCN]; B%: 0% to 90% in 36 min). The eluent was concentrated to remove the organic solvent, and the remaining aqueous solution was lyophilized to give 8-(2,6-difluorophenyl)-13-[4-(2-fluoro-2-methylpropyl)piperazin-1-yl]-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene as a yellow solid (71 mg, 47.3%, HCl salt). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.57 (m, 6 H), 2.21 (br s, 3 H), 2.38 (s, 3 H), 3.18 (m, 2 H), 3.45-3.71 (m, 6 H), 4.29 (d, J = 13.3 Hz, LCMS(ESI)m / z:484.2[M+H] + . Example 6 Synthesis of 5-(2,6-difluorophenyl)-3-methyl-9-[4-methyl-3-(trifluoromethyl)piperazin-1-yl]-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine [ka]

[0366] The title compound was prepared from intermediate D1-3 following a similar synthetic procedure as described in the synthesis of Int-1 (above), except that tert-butyl 2-(trifluoromethyl)piperazine-1-carboxylate was used instead of morpholine, and the reaction was carried out in dioxane for 12 hours at 100° C. The resulting crude product was treated with 4 N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparative HPLC (instrument: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector; column: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water(FA)-ACN]; B%: 4% to 44% over 8 min, hold at 100% B for 2 min; flow rate: 25 mL / min; column temperature: 30 °C; wavelength: 220 nm) to give 5-(2,6-difluorophenyl)-3-methyl-9-[4-methyl-3-(trifluoromethyl)piperazin-1-yl]-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine as a yellow solid (22 mg, 46.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (br s, 3 H), 2.44 (s, 3 H), 2.56 (br s, 2 H), 2.95 (m, 3 H), 3.19 (m, 2 H), 6.49 (br s, 1 H), 6.59 (br d, J = 7.3 Hz, 1 H), 7.06 (br s, 1 H), 7.16 (br s, 2 H), 7.49 (br s, 1 H), 8.01 (br s, 1 H), 12.16 (br s, 1 H); LCMS(ESI)m / z:477.1[M+H]+ . Example 7 Synthesis of (R)-4-(5-(2,6-difluorophenyl)-3-methyl-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepin-9-yl)-2-methylmorpholine [ka]

[0367] The title compound was prepared from intermediate D1-3 following a similar synthetic procedure as described in the synthesis of Int-1 (above), except that (2R)-2-methylmorpholine was used instead of morpholine, and the reaction was carried out in dioxane for 12 hours at 100° C. The resulting crude product was treated with 4 N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Welch Xtimate C18 150 × 25 mm × 5 μm; Mobile Phase A: H2O containing 0.05% NH3-H2O (v%); Mobile Phase B: ACN; Gradient: 70% to 100% B in 7.8 min, hold at 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm). The fractions were concentrated under reduced pressure and then lyophilized overnight. The residue was purified by chiral SFC (instrument: Berger, MULTIGR AM-II; column: Chiralpak AD 250 × 30 mm ID 3 μm; mobile phase: supercritical CO / EtOH (0.05% NH -H O, v%) = 60 / 40; flow rate: 2.8 mL / min; column temperature: 35 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm). The fractions were concentrated under reduced pressure and then lyophilized overnight to give (2R)-4-[5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]-2-methylmorpholine as a yellow solid (57 mg, 37.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J = 6.0 Hz, 3 H), 2.00 (br s, 3 H), 2.27 (br t, J = 10.7 Hz, 1 H), 2.57-2.70 (m, 1 H), 3.44-3.67 (m, 4 H), 3.89 (br d, J = 9.5 Hz, 1 H), 6.49-6.70 (m, 2 H), 6.99 - 7.14 (m, 1 H), 7.17-7.33 (m, 2 H), 7.47-7.69 (m, 1 H), 11.93-12.84 (m, 1 H); 19 F NMR (376 MHz, DMSO-d6) δ ppm -73.54; LCMS(ESI)m / z:410.1[M+H] + . Example 8 Synthesis of 4-[8-(2,6-difluorophenyl)-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0368] The title compound was prepared from intermediate D4-1 following a similar synthetic procedure as described for the synthesis of Int-1 (above), except that 2,5-dioxa-8-azaspiro[3.5]nonane was used instead of morpholine and the reaction was carried out in dioxane at 100 °C for 12 h. The resulting crude product was treated with 4 N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by filtration to give 4-[8-(2,6-difluorophenyl)-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine as a yellow solid (50 mg, 30.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3 H), 2.38 (s, 3 H), 3.55 (br d, J = 4.3 Hz, 4 H), 3.65-3.76 (m, 4 H), 7.00 (s, 1 H), 7.35 (br t, J = 8.5 Hz, 2 H), 7.76 (br s, 1 H); LCMS(ESI)m / z:411.3[M+H] + . Example 9 Synthesis of 8-(2,6-difluorophenyl)-13-[4-(2-fluoroethyl)piperazin-1-yl]-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0369] The title compound was prepared from intermediate D4-1 following a similar synthetic procedure as described in the synthesis of Int-1 (above), except that 1-(2-fluoroethyl)piperazine was used instead of morpholine, and the reaction was carried out in dioxane at 110° C. for 3 hours. The SEM protecting group of the resulting crude product was removed with 4N HCl in MeOH. The residue was purified by reverse-phase HPLC (YMC-Actus Triart C18 150 × 30 mm × 5 μm column; mobile phase: [water (HCl)-ACN]; B%: 0% to 35% in 9 min). The fractions were lyophilized to give 8-(2,6-difluorophenyl)-13-[4-(2-fluoroethyl)piperazin-1-yl]-5,11-dimethyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene as a yellow solid (24.1 mg, 31.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (br s, 3 H), 2.35 (br s, 3 H), 3.17 (br s, 2 H), 3.40 (br d, J = 11.8 Hz, 4 H), 3.51 (br s, 2 H), 4.38 (br d, J = 13.1 Hz, 2 H), 4.87-5.05 (m, 2 H), 7.01 (br s, 1 H), 7.34 (br d, J = 9.5 Hz, 2 H), 7.77 (br s, 1 H), 11.66 (br s, 1 H); 19 F NMR (377 MHz, DMSO-d6) δ ppm -115.39, -220.21; LCMS(ESI)m / z:456.1[M+H] + . Example 10 Synthesis of 4-[5-(difluoromethyl)-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0370] The title compound was prepared from intermediate D3-4 following a similar synthetic procedure as described in the synthesis of Int-1 (above); the reaction was carried out in dioxane at 100° C. for 2 hours. The PMB protecting group of the resulting crude product was removed with TFA and then purified by flash chromatography on a silica gel column using 0–35% EtOAc in petroleum ether as the eluent to give 4-[5-(difluoromethyl)-8-(2,6-difluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine as a yellow solid (77.5 mg, 48.5%). 1H NMR (400 MHz, CD3OD) δ ppm 3.18-3.26 (m, 4 H), 3.63-3.75 (m, 4 H), 6.45-6.81 (m, 1 H), 6.90-7.04 (m, 3 H), 7.25-7.37 (m, 1 H), 7.34-7.47 (m, 1H), 19 F NMR (376 MHz, CD3OD) δ ppm -115.30, -115.68, -116.31, -117.25; LCMS(ESI)m / z:433.2[M+H] + . Example 11 Synthesis of (2R)-4-[5-(2,6-difluorophenyl)-3-(trideuteriomethyl)-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]-2-methylmorpholine [ka]

[0371] Step 1: (2R)-4-(3-chloro-5-(2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepin-9-yl)-2-methylmorpholine [ka]

[0372] The title compound was prepared from intermediate D1-2 following a similar synthetic procedure described in the synthesis of Int-1 (above), except that (2R)-2-methylmorpholine was used instead of morpholine, and the reaction was carried out in dioxane at 100 °C for 2 h. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-40% petroleum ether / EtOAc, flow rate: 40 mL / min) to afford 2-[[3-chloro-5-(2,6-difluorophenyl)-9-[(2R)-2-methylmorpholin-4-yl]-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane as a yellow solid (520 mg, 45.1%). LCMS (ESI) m / z: 560.2 [M+H] + . Step 2: 2-[[5-(2,6-difluorophenyl)-9-[(2R)-2-methylmorpholin-4-yl]-3-(trideuteriomethyl)-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane [ka]

[0373] The title compound was prepared from 2-[[3-chloro-5-(2,6-difluorophenyl)-9-[(2R)-2-methylmorpholin-4-yl]-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane according to a similar synthetic procedure described in the synthesis of compound Int-2 (below), except that trideuteriomethylboronic acid was used instead of cyclopropylboronic acid, and the reaction was carried out in dioxane and water at 100 °C for 16 hours. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MeCN (5 mL) to give (2R)-4-[5-(2,6-difluorophenyl)-3-(trideuteriomethyl)-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepin-9-yl]-2-methylmorpholine as a yellow solid (90.52 mg, 46.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J = 6.27 Hz, 3 H), 2.25-2.41 (m, 1 H), 2.62-2.74 (m, 1 H), 3.47 (br d, J = 12.6 Hz, 4 H), 3.85-3.96 (m, 1 H), 6.76 (br d, J = 8.5 Hz, 1 H), 6.83-6.95 (m, 1 H), 7.21 (br s, 1 H), 7.40 (br t, J = 8.8 Hz, 2 H), 7.74-7.89 (m, 1 H), 11.23 (br s, 1 H), 11.54-11.93 (m, 1 H); LCMS(ESI)m / z 413.2[M+H] + . Example 12 13-[1-(Difluoromethyl)pyrazol-3-yl]-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0374] The title compound was prepared from intermediate D2-3 following a similar synthetic procedure to that described in the synthesis of Int-4 (below), except that 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole was used instead of 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, 10% Pd(dppf)Cl was employed as the catalyst, and the reaction was carried out in dioxane / HO (5:1) solvent at 100 °C for 12 hours. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (instrument: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector; column: ACE 5 C18-AR 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 23% to 53% in 9.5 min; flow rate: 25 mL / min; column temperature: 30 °C; wavelength: 220 nm) to give the title compound as a yellow solid (34.6 mg, 50.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (s, 3 H), 2.01 (s, 6 H), 7.19 (t, J = 7.9 Hz, 2 H), 7.47-7.54 (m, 1 H), 7.60 (s, 1 H), 7.74 (s, 1 H), 8.01-8.06 (m, 1 H), 8.45-8.53 (m, 2 H), 12.51 (s, 1 H); LCMS(ESI)m / z:428.1[M+H] + . Example 13 Synthesis of 9-[1-(difluoromethyl)pyrazol-4-yl]-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine [ka]

[0375] The title compound was prepared from intermediate D1-3 following a similar synthetic procedure as described in the synthesis of Int-4 (above), except that 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole was used instead of 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, and the reaction was carried out in dioxane / HO (5:1) solvent at 100° C. for 12 hours. The resulting crude product was treated with 4N HCl in MeOH to remove the SEM protecting group. The resulting mixture was concentrated under reduced pressure and TES and purified by reverse-phase HPLC (instrument: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector; column: ACE 5 C18-AR 150 × 30 mm × 5 μm; mobile phase: [water(FA)-ACN]; B%: 0% to 60% in 7.8 min, hold at 100% B for 3 min; flow rate: 30 mL / min; column temperature: 30 °C; wavelength: 220 nm) to give 9-[1-(difluoromethyl)pyrazol-4-yl]-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine as a yellow solid (63.7 mg, 54.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (br s, 3 H), 6.84 (br s, 1 H), 7.35 (m, 3 H), 7.80 (m, 3 H), 8.19 (s, 1 H), 8.67 (br s, 1 H); 19 F NMR (377 MHz, DMSO-d6) δ ppm -94.09; LCMS(ESI)m / z:427.1[M+H] + . Example 14 Synthesis of 9-[1-(difluoromethyl)pyrazol-3-yl]-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine [ka]

[0376] To a solution of 2-[[9-bromo-5-(2,6-difluorophenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (Intermediate D1-3) (200 mg, 0.385 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (400 mg, 1.64 mmol), KPO (160 mg, 0.754 mmol), and XPhos (20.0 mg, 42.0 μmol) in dioxane (10 mL) and HO (2 mL) was added Pd(dba) (30.0 mg, 52.2 μmol). The mixture was stirred at 100 °C for 12 h. The residue was purified by flash chromatography (ISCO@; 20 g SepaFlash@ silica flash column, 0–20% EtOAc in petroleum ether / EtOAc, flow rate: 30 mL / min, 254 nm) to give 2-[[9-[1-(difluoromethyl)pyrazol-3-yl]-5-(2,6-difluorophenyl)-3-methyl-6H-pyrazolo[4,3-d][1,3]benzodiazepin-1-yl]methoxy]ethyltrimethylsilane (250 mg, 51.3%) as a yellow solid. The SEM protecting group of the product was removed with 4N HCl in MeOH and purified by reverse-phase preparative HPLC (instrument: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector; column: ACE 5 C18-AR 150 × 30 mm × 5 μm; mobile phase: [water(FA)-ACN]; B%: 35% to 65% in 7.8 min, hold at 100% B for 2 min; flow rate: 25 mL / min; column temperature: 30 °C; wavelength: 220 nm) to give 9-[1-(difluoromethyl)pyrazol-3-yl]-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d][1,3]benzodiazepine as a yellow solid (54.4 mg, 31.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H), 6.62 (d, J = 8.25 Hz, 1 H), 6.87 (d, J = 2.63 Hz, 1 H), 7.17 (br t, J = 7.94 Hz, 2 H), 7.40 (dd, J = 8.25, 1.88 Hz, 1 H), 7.50 (quin, J = 7.47 Hz, 1 H), 7.76 (m, 1 H), 7.96 (s, 1 H), 8.23 ​​(d, J = 2.63 Hz, 1 H), 8.36 (br s, 1 H), 12.33 (br s, 1 H); 19 F NMR (377 MHz, DMSO-d6) δ ppm -94.03, -114.06; LCMS(ESI)m / z 427.0[M+H] + . Example 15 Synthesis of 8-(2,6-difluorophenyl)-5-methyl-13-[3-(trifluoromethyl)pyrazol-1-yl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0377] Step 1: 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[3-(trifluoromethyl)pyrazol-1-yl]-3,4,7,9,12 pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a yellow solid [ka]

[0378] A mixture of 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane intermediate D2-2 (200 mg, 0.420 mmol), 3-(trifluoromethyl)-1H-pyrazole (85.7 mg, 0.630 mmol), RockPhos-Pd-G3 (70.4 mg, 0.084 mmol), and CsCO3 (410 mg, 1.26 mmol) in dioxane (10 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-100% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 mn) to give 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[3-(trifluoromethyl)pyrazol-1-yl]-3,4,7,9,12 pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a yellow solid (100 mg, 41.4%). LCMS (ESI) m / z 576.2 [M+H] + .

[0379] Step 2: 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[3-(trifluoromethyl)pyrazol-1-yl]-3,4,7,9,12 pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a yellow solid [ka]

[0380] A solution of 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[3-(trifluoromethyl)pyrazol-1-yl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (100 mg, 0.173 mmol) in 4 N HCl (2 mL) in MeOH was stirred at 20° C. for 2 hours. The reaction was concentrated under reduced pressure. The solid was triturated with EtOAc (2 mL) to afford the title compound as a yellow solid (70 mg, 83.6%). 1 H NMR (400 MHz, CD3OD) δ ppm 2.16 (s, 3 H), 6.81 (d, J = 2.5 Hz, 1 H), 7.19 (t, J = 8.4 Hz, 2 H), 7.58-7.70 (m, 1 H), 7.76 (s, 1 H), 8.14 (s, 1 H), 8.57 (s, 1 H); LCMS(ESI)m / z:446.3[M+H] + . Example 16 N-(2,4-Difluorobenzyl)-5-(2,6-difluorophenyl)-3-methyl-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepin-9-amine [ka]

[0381] The title compound was prepared from intermediate D2-2 according to a similar synthetic procedure described in the synthesis of Example 15 (above), except that 2-fluoroaniline was used instead of 3-(trifluoromethyl)-1H-pyrazole, 10% Pd(dba) / DavePhos was employed as the catalyst, and the reaction was carried out in dioxane at 100° C. for 16 hours. The SEM protecting group of the resulting crude product was removed with 4N HCl in MeOH and purified by reverse-phase preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [water(HCl)-ACN]; B%: 20% to 60% in 9 min) to give the title compound as a yellow solid (64.7 mg, 78.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3 H), 7.08 (br d, J = 5.8 Hz, 1 H), 7.13-7.19 (m, 1 H), 7.22-7.29 (m, 1 H), 7.33 (s, 1 H), 7.39 (br t, LCMS(ESI)m / z:421.2[M+H] + . Example 17 Synthesis of 8-(2,6-difluorophenyl)-5-methyl-13-[2-(4-methyltetrahydropyran-4-yl)ethynyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0382] Step 1: 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[2-(4-methyltetrahydropyran-4-yl)ethynyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane [ka]

[0383] 2-[[13-chloro-8-(2,6-difluorophenyl)-5-methyl-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (50 mg, 105 umol, 1.0 equiv.), 4-ethynyl-4-methyltetrahydropyran in DMF (2 mL) A mixture of Pd(t-BuP) (13.0 mg, 0.105 mmol, 1.0 equiv), CuI (4.00 mg, 21.0 μmol, 0.05 equiv), Pd(t-BuP) (10.7 mg, 21.0 μmol, 0.05 equiv), and CsCO (102 mg, 0.315 mmol, 3.0 equiv) was degassed and purged with N three times, then the mixture was stirred under N at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, 0-100% EtOAc in petroleum ether / EtOAc, 12 mL / min, 254 mn) to give 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[2-(4-methyltetrahydropyran-4-yl)ethynyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane as a brown solid (50 mg). LCMS (ESI) m / z: 564.2 [M+H] + . Step 2: 8-(2,6-difluorophenyl)-5-methyl-13-[2-(4-methyltetrahydropyran-4-yl)ethynyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaene [ka]

[0384] A mixture of 2-[[8-(2,6-difluorophenyl)-5-methyl-13-[2-(4-methyltetrahydropyran-4-yl)ethynyl]-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-3-yl]methoxy]ethyltrimethylsilane (50 mg, 88.7 μmol) in 4 N HCl in MeOH (2 mL) was stirred for 2 hours at 25° C. The reaction was concentrated under reduced pressure to give the title compound as a yellow solid (9.4 mg, 24.4%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.41 (s, 3 H), 1.65-1.73 (m, 2 H), 1.78-1.85 (m, 2 H), 2.24 (s, 3 H), 3.76-3.83 (m, 2 H), 3.87-3.93 (m, 2 H), 7.33 (t, J = 8.5 Hz, 2 H), 7.78-7.89 (m, 2 H), 7.95 (s, 1 H); LCMS(ESI)m / z 434.5[M+H] + . Example 18 Synthesis of 4-[8-(2-chloro-6-fluorophenyl)-3,4,7,9,12-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,7,11,13-hexaen-13-yl]morpholine [ka]

[0385] Step 1: O1-Benzyl O4-tert-butyl 2-methylpiperazine-1,4-dicarboxylate [ka]

[0386] To a solution of tert-butyl 3-methylpiperazine-1-carboxylate (5 g, 24.9 mmol) in THF (50 mL) were added CbzCl (5.11 g, 29.9 mmol) and CsCO (24.4 g, 74.9 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (30 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-40% petroleum ether / EtOAc at 45 mL / min) to afford 1-benzyl 4-tert-butyl 2-methylpiperazine-1,4-dicarboxylate (2.6 g, 30.5%, 98% purity) as a colorless oil. ...

Claims

1. Compounds of formula (I): 【Chemistry 378】 or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof [In the formula, n is 1, 2 or 3; Y １ and Y ２ are independently N or C; Z １ , Z ２ and Z ３ is H, —OH, halo, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ independently selected from heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; X is H, halo, cyano, C １ ~C ６ Alkyl, optionally deuterated C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; R １ , R ２ and R ４ H, halo, cyano, C １ ~C ６ Alkyl, optionally deuterated C １ ~C ６ Alkyl, C １ ~C ６ independently selected from heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy, provided that such substitution is allowed according to valence; W is H or C １ ~C ４ is a substituted or unsubstituted alkyl; W is Y ２ If is C, then Y ２ and optionally forming a ring, L is a linker, and L is a single bond, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ４ heteroalkyl, wherein one or more heteroatoms are selected from O, S, or N; A is a 4-8 membered substituted or unsubstituted heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, wherein one or more heteroatoms are selected from the group consisting of O, S, or N; The substituents are substituted or unsubstituted 3- to 7-membered heterocycles, —CH ２ -cycloalkyl, -CF ２ -cycloalkyl, -C(=O)-O-alkyl, halo, deuterium, cyano, cyanoalkyl, -CF ３ , mono-, di- or trihaloalkyl, CH(CH ３ )-cycloalkyl, —CH ２ -aryl, -CF ２ -aryl, -CH(-CH ３ )-aryl, C(=O)-alkyl, —C(=O)cycloalkyl, —C(=O)-NH-alkyl, —COOH (and its esters and carboxamides), —C(=O)-morpholine, —C(=O)-heterocycle, —C(—CH ３ ) ２ —OH, —CH ２ —C(═O)—NH ２ -hydroxy, alkylhydroxy, alkyl-COOH (and esters and carboxamides thereof), amino, -NHC(=O)alkyl, -N(alkyl)C(=O)alkyl, -NHC(=O)aryl, -N(alkyl)C(=O)aryl, substituted or unsubstituted morpholine, 3-7 membered heterocycle, any of which may bear one or more substituents, a 3-7 membered cycloalkyl or heterocycle, said 3-7 membered cycloalkyl or heterocycle optionally fused to another 3-7 membered cycloalkyl or heterocycle, said ring being spiro, bridged bicyclic or spiro, and said at least one heteroatom in said heterocycle being independently selected from O, S and N; one or more hydrogen atoms are optionally deuterium].

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

3. Y １ is C and Y ２ The compound of claim 1 , wherein is N.

4. Y １ is C and Y ２ The compound of claim 1 , wherein

5. X is -CH ３ , -CH ２ -CH ３ , -CD ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of , H and F.

6. Z １ , Z ２ and Z ３ is independently selected from H, F, or Cl.

7. Z １ is F and Z ２ The compound of claim 1 , wherein is F.

8. Z ３ The compound of claim 1 , wherein is H.

9. Z ３ The compound of claim 1 , wherein is F.

10. R １ is H, fluoro, -CH ３ , -CH ２ -CH ３ , -CF ３ or -CHF ２ 2. The compound of claim 1 selected from:

11. R ２ The compound of claim 1 , wherein is selected from the group consisting of H or F.

12. R ２ The compound of claim 1 , wherein is F.

13. R ４ The compound of claim 1 , wherein is H.

14. A is, 【Chemistry 379】 【Chemical 380】 【Chemistry 381】 2. The compound of claim 1 selected from:

15. The compound of formula (I) 【Chem.382】 【Chemistry 383】 【Chemical 384】 【Chem.385】 【Chemical 386】 【Chemistry 387】 【Chemical Formula 388】 2. The compound of claim 1 selected from:

16. 1. A method of treating a patient suffering from a neurological condition, comprising: a therapeutically effective amount of a compound of formula (I): 【Chem.389】 or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof [In the formula, n is 1, 2 or 3; Y １ and Y ２ are independently N or C; Z １ , Z ２ and Z ３ is H, —OH, halo, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ independently selected from heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; X is H, halo, cyano, C １ ~C ６ Alkyl, optionally deuterated C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy; R １ , R ２ and R ４ H, halo, cyano, C １ ~C ６ Alkyl, optionally deuterated C １ ~C ６ Alkyl, C １ ~C ６ independently selected from heteroalkyl, haloalkyl, alkoxy, haloalkoxy, —CH(OH)-alkyl, hydroxyalkyl, or hydroxyalkoxy, provided that such substitution is allowed according to valence; W is H or C １ ~C ４ is a substituted or unsubstituted alkyl; W is Y ２ If is C, then Y ２ and optionally forming a ring, L is a linker, and L is a single bond, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ４ heteroalkyl, wherein one or more heteroatoms are selected from O, S, or N; A is a 4-8 membered substituted or unsubstituted heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, wherein one or more heteroatoms are selected from the group consisting of O, S, or N; The substituents are substituted or unsubstituted 3- to 7-membered heterocycles, —CH ２ -cycloalkyl, -CF ２ -cycloalkyl, -C(=O)-O-alkyl, halo, deuterium, cyano, cyanoalkyl, -CF ３ , mono-, di- or trihaloalkyl, CH(CH ３ )-cycloalkyl, —CH ２ -aryl, -CF ２ -aryl, -CH(-CH ３ )-aryl, C(=O)-alkyl, —C(=O)cycloalkyl, —C(=O)-NH-alkyl, —COOH (and its esters and carboxamides), —C(=O)-morpholine, —C(=O)-heterocycle, —C(—CH ３ ) ２ —OH, —CH ２ —C(═O)—NH ２ -hydroxy, alkylhydroxy, alkyl-COOH (and esters and carboxamides thereof), amino, -NHC(=O)alkyl, -N(alkyl)C(=O)alkyl, -NHC(=O)aryl, -N(alkyl)C(=O)aryl, substituted or unsubstituted morpholine, 3-7 membered heterocycle, any of which may bear one or more substituents, a 3-7 membered cycloalkyl or heterocycle, said 3-7 membered cycloalkyl or heterocycle optionally fused to another 3-7 membered cycloalkyl or heterocycle, said ring being spiro, bridged bicyclic or spiro, and said at least one heteroatom in said heterocycle being independently selected from O, S and N; one or more hydrogen atoms are optionally deuterium. The method of claim 1, further comprising administering

17. Y １ is N and Y ２ The method of claim 16, wherein is C.

18. Y １ is C and Y ２ The method of claim 16 , wherein is N.

19. Y １ is C and Y ２ The method of claim 16, wherein is C.

20. X is -CH ３ , -CH ２ -CH ３ , -CD ３ 17. The method of claim 16, wherein the aryl group is selected from the group consisting of , H and F.

21. Z １ , Z ２ and Z ３ 17. The method of claim 16, wherein is independently selected from H, F, or Cl.

22. Z １ is F and Z ２ The method of claim 16 , wherein is F.

23. Z ３ The method of claim 16 , wherein is H.

24. Z ３ The method of claim 16 , wherein is F.

25. R １ is H, F, -CH ３ , -CH ２ -CH ３ , -CF ３ or -CHF ２ 17. The method of claim 16, wherein the compound is selected from the group consisting of:

26. R ２ 17. The method of claim 16, wherein is selected from the group consisting of H or F.

27. R ２ The method of claim 16 , wherein is F.

28. R ４ The method of claim 16 , wherein is H.

29. A is, 【Chemical 390】 【Chemistry 391】 【Chemistry 392】 17. The method of claim 16, wherein the compound is selected from the group consisting of:

30. The compound of formula (I) 【Chemistry 393】 【Chem. 394】 【Chemical 395】 【Chemistry 396】 【Chemistry 397】 【Chem.398】 【Chem.399】 17. The method of claim 16, wherein the compound is selected from the group consisting of:

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