Imidazole macrocycles for the treatment of autoimmune disease The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to antagonist of STING useful for treating autoimmune diseases. FIELD OF THE INVENTION Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), refer to a spectrum of conditions where the immune system mistakenly attacks one's own body, leading to unresolved and inappropriately activated inflammation that become pathogenic. Many of the autoimmune diseases are poorly managed by existing treatments that provide only symptomatic relief. Steroid and broad immunosuppressant drugs (e.g. mycophenolate and cyclophosphamide) constitute the stand of care, but are associated with significant treatment-related toxicity. Pathway selective agents such as Adalizumab (anti-TNF antibody, for RA and IBD) occasionally resulting in infection or insufficient tumor surveillance. And Belimumab (anti-BAFF antibody, the only FDA-approved new drug for SLE) shows a slow onset of remission with modest efficacy in the clinic. In addition, the heterogeneity of many autoimmune diseases with no-existing treatment illustrates the difficulty in finding efficacy through the blockade of one immune pathway. Thus, currently available treatments fail to fulfill a greater unmet needs of autoimmune inflammatory diseases with limited remission, severe side effects, opportunistic infection, and poor quality of life with chronic inflammation. Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-located transmembrane protein that is pivotal in mediating the host's innate sensing of pathogen-/ damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic-GMP-AMP synthase (cGAS)-STING pathway has emerged as a critical mechanism for coupling cytosolic DNA recognition to the induction of type-I interferon (IFN) and broader immune defense programs. The binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic site, leading to the production of 2'3'- cyclic GMP-AMP (cGAMP), a secondary messenger molecule that is agonistic to STING. Upon activation, STING translocates from ER to Golgi and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB) to initiate the expression of type-I IFN and a myriad of pro-inflammatory cytokines (e.g., IL-6 and TNFα), respectively. Besides 2'3'-cGAMP, STING can be activated by other types of cyclic-di-nucleotides (CDNs), such as c-di-AMP, c-di- GMP, and 3’,3’-cGAMP from bacteria. Following the signal transduction, STING is rapidly degraded to prevent it from constitutive signaling of the inflammatory responses. While eliciting robust host defense responses, aberrant STING signaling fuels dysregulated immune responses associated with many pathologies. Gain-of-function (GoF) human STING mutations are the root cause of STING-associated vasculopathy with onset in infancy (SAVI), a monogenic disease characterized by the onset of auto-inflammation conditions called type I interferonopathies. Mechanistically, the disease-causing substitutions trigger ligand-independent, constitutive STING activation. Besides, STING is implicated in DNA-driven inflammations, such as Aicardi-Goutières Syndrome (AGS) and genetic forms of lupus. Unlike SAVI, the STING mediated continuous innate immune activation in AGS is caused by deficiencies in self- DNA clearance and metabolisms due to mutations in endonuclease gene TREX1 and/or DNASE2. Consistently, genetic and pharmacological inhibition of STING ameliorates systemic inflammation and morbidity in the Trex1-/- mouse model. Apart from genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role of STING in a range of inflammation-associated disorders such as SLE and RA. A direct link between the cGAS-STING pathway and SLE was established by observing that PBMC from a subset of SLE patients has elevated cytosolic cGAMP than healthy controls. In addition, membrane vesicles from apoptotic cells in SLE sera have high ISGs-stimulating activities dependent on cGAS-STING. And that disrupting STING signaling ameliorated the development of lupus-like phenotypes in FcγrIIb-/- mice. Furthermore, multiple recent studies associate STING with distinct types of neurodegeneration. Taking Parkinson's disease as an example, missense mutations in PARKIN and PINK resulted in the accumulation of mitochondrial DNA that triggers neuronal inflammation in a cGAS-STING dependent manner. The absence of STING rescued the motor deficit and neuronal cell loss in the mouse disease model. Finally, STING also mediates tumorigenic DNA responses caused by chromosomal instability during cancer metastasis, and that STING-deficiency confers protection against colorectal and skin cancer in the mouse. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (Ia),

wherein M ¹ is heteroarylene optionally substituted by R ¹ ; wherein R ¹ is deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R) ₂ N, RCO, RSO ₂ , RNHSO ₂ , R ₂ NSO ₂ , RSO(NR), R ₃ Si, ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R) ₂ NC _1-6 alkyl, RSO ₂ C _1-6 alkyl, RNHSO ₂ C _1-6 alkyl, R ₂ NSO ₂ C _1-6 alkyl, RSO(NR)C _1-6 alkyl or R ₃ SiC _1-6 alkyl; wherein R is H, R ^a , R ^b or R ^c ; R ^a is C _1-6 alkyl optionally substituted by R ^b or R ^c ; R ^b is C _3-7 cycloalkyl, heterocyclyl, heteroaryl or aryl, said C _3-7 cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or R ^c ; R ^c is selected from deuterio, C _1-6 alkyl, (C _1-6 alkyl) ₃ Si, haloC _1-6 alkyl, deuterioC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, deuterioC _1-6 alkoxy, C _2-6 alkenyl, haloC _2-6 alkenyl, deuterioC _2-6 alkenyl, C _2-6 alkynyl, haloC _2-6 alkynyl, deuterioC _2-6 alkynyl, C _{3- 7} cycloalkyl, haloC _3-7 cycloalkyl, deuterioC _3-7 cycloalkyl, amino, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, haloC _1-6 alkylamino, haloC _{1- 6} alkylcarbonylamino, (haloC _1-6 alkyl) ₂ amino, C _3-7 cycloalkylamino, C _{3- 7} cycloalkylcarbonylamino, (C _3-7 cycloalkyl) ₂ amino, haloC _3-7 cycloalkylamino, (haloC _3-7 cycloalkyl) ₂ amino, C _3-7 cycloalkyl(C _1-6 alkyl)amino, haloC _{3- 7} cycloalkyl(C _1-6 alkyl)amino, C _1-6 alkylsulfonylamino, haloC _{1- 6} alkylsulfonylamino, C _1-6 alkoxyC _1-6 alkyl, (haloC _1-6 alkoxy)C _1-6 alkyl, C _{1- 6} alkoxy(halo)C _1-6 alkyl, C _3-7 cycloalkylC _1-6 alkyl, C _3-7 cycloalkylhaloC _1-6 alkyl, C _1-6 alkylcarbonyl, haloC _1-6 alkylcarbonyl, C3-7cycloalkylcarbonyl, haloC3- 7cycloalkylcarbonyl, C _1-6 alkoxycarbonyl, haloC _1-6 alkoxycarbonyl, C _{3- 7} cycloalkoxycarbonyl, haloC _3-7 cycloalkoxycarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _3-7 cycloalkylaminocarbonyl, (C _{3- 7} cycloalkyl) ₂ aminocarbonyl, C _1-6 alkylC _3-7 cycloalkylaminocarbonyl, haloC _{1- 6} alkylaminocarbonyl, halo(C _1-6 alkyl) ₂ aminocarbonyl, haloC _{3- 7} cycloalkylaminocarbonyl, halo(C _3-7 cycloalkyl) ₂ aminocarbonyl, haloC _{1- 6} alkylC _3-7 cycloalkylaminocarbonyl, C _1-6 alkylhaloC _3-7 cycloalkylaminocarbonyl, (C _1-6 alkyl) ₃ ammonio, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _{3- 7} cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, haloC _{1- 6} alkylsulfanyl, haloC _1-6 alkylsulfinyl, haloC _1-6 alkylsulfonyl, haloC _{3- 7} cycloalkylsulfanyl, haloC _3-7 cycloalkylsulfinyl, haloC _3-7 cycloalkylsulfonyl, haloC _1-6 alkoxysulfonyl, C _1-6 alkylaminosulfonyl, (haloC _1-6 alkylamino)sulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl, (haloC _1-6 alkyl) ₂ aminosulfonyl, (C _{1- 6} alkyl) ₂ phosphoryl, (C _1-6 alkoxy) ₂ phosphoryl, hydroxy(C _1-6 alkoxy)phosphoryl, C _1-6 alkoxyphosphoryl, hydroxy, hydroxyC _1-6 alkyl, hydroxyhaloC _1-6 alkyl, hydroxyC _1-6 alkoxy, hydroxylhaloC _1-6 alkoxy, hydroxyC _3-7 cycloalkyl, hydroxyhaloC _3-7 cycloalkyl and sulfonimidoyl optionally substituted by H, C _{1- 6} alkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocyclyl; M ² is arylene, heterocyclylene or heteroarylene, said arylene, heterocyclylene or heteroarylene being optionally substituted by R ¹ ; M ³ is heterocyclylene which is unsubstituted or optionally substituted by R ³ ; R ² is deuterio, R, ROC _1-6 alkyl, RSC _1-6 alkyl, RSO ₂ C _1-6 alkyl, RNHC _1-6 alkyl or (R) ₂ NC _{1- 6} alkyl; R ³ is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, said heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl and arylcarbonyl being unsubstituted or optionally substituted by R ¹ ; Q ¹ is -M-, -M-O-M-, -M-S-M-, -M-SO ₂ -M-, -M-SO(NH)-M-, -M-SO(NR)-M-, -M-SiR ₂ - M- or -M-N(R)-M-; wherein M is C _1-6 alkylene unsubstituted or optionally substituted by the substituents independently selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R ₂ N, RSO ₂ , ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R) ₂ NC _1-6 alkyl and RSO ₂ C _1-6 alkyl; Q ² is NH, O, S, SO, SO ₂ , P(O)R, PO(NR), Se, N(R), SiR ₂ , heterocyclyl, heteroaryl or aryl; or a pharmaceutically acceptable salt thereof. Another object of the present invention is related to novel compounds of formula (I) or (Ia). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or (Ia) as STING antagonist, and for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, or selective types of cancers where overexpression or activation of STING is implicated. The compounds of formula (I) or (Ia) show superior STING antagonism activity. In addition, the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, human microsome stability and SDPK profiles, as well as low CYP inhibition. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “deuterio” or “deuterium” denotes the isotope of hydrogen that has a single neutron as well as a proton in the nucleus. The term “C _1-6 alkyl” denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C _1-6 alkyl” groups are methyl, ethyl and n-propyl. The term “C _1-6 alkylene” denotes a linear or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of C _1-6 alkylene groups include methylene, ethylene, propylene, 2- methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C _1-6 alkoxy” denotes C _1-6 alkyl-O-. The term “trideuterioC _1-6 alkyl” denotes a C _1-6 alkyl group wherein three of the hydrogen atoms of the C _1-6 alkyl group has been replaced by deuterium. Example of trideuterioC _1-6 alkyl includes trideuteriomethyl. The term “C _2-6 alkenyl” denotes a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of C _2-6 alkenyl include ethenyl (or vinyl), propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl. The term “C _2-6 alkynyl” denotes a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms with at least one triple bond. In particular embodiments, alkynyl has 2 to 4 carbon atoms with at least one triple bond. Examples of C _2-6 alkynyl include ethynyl (–C{CH), prop-1-ynyl (–C{CCH ₃ ), prop-2-ynyl (propargyl, –CH ₂ C{CH), but-1-ynyl, but-2-ynyl, and but- 3-ynyl.The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. The term “haloC _1-6 alkyl” denotes a C _1-6 alkyl group wherein at least one of the hydrogen atoms of the C _1-6 alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “haloC _1-6 alkoxy” denotes haloC _1-6 alkyl-O-. The term “haloazetidinyl” denotes an azetidinyl group wherein at least one of the hydrogen atoms of the azetidinyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of halopiperidinyl include fluoroazetidinyl and difluoroazetidinyl. The term “pyrimidinyloxy” denotes pyrimidinyl-O-. The term “trideuterioC _1-6 alkoxy” denotes trideuterioC _1-6 alkyl-O-. The term “carboxy” denotes -COOH. The term “C _3-7 cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl. The term “haloC _3-7 cycloalkyl” denotes a C _3-7 cycloalkyl group wherein at least one of the hydrogen atoms of the C _3-7 cycloalkyl group has been replaced by same or different halogen atoms, particularly fluoro atom. The term “halo-1,2,3,5,6,7-hexahydropyrrolizinyl” denotes a 1,2,3,5,6,7- hexahydropyrrolizinyl group wherein at least one of the hydrogen atoms of the C _3-7 cycloalkyl group has been replaced by same or different halogen atoms, particularly fluoro atom. The term “C _3-7 cycloalkoxy” denotes C _3-7 cycloalkyl-O-. The term “oxetanyloxy” denotes oxetanyl-O-. The term “azetidinyloxy” denotes azetidinyl-O-. The term “C _1-6 alkylcarbonyloxy” denotes C _1-6 alkyl-C(O)-O-. The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO ₂ ), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR ₄ ] ⁺ Cl-, [NR ₄ ] ⁺ OH-). Examples of heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8- azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7- oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1- azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, and 2,3,4a,5,7,7a- hexahydro-[1,4]dioxino[2,3-c]pyrrolyl. Particularly, heterocyclyl herein can be The term “heterocyclylene” denotes a divalent heterocyclyl group. The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. The term “arylene” denotes a divalent aryl group. The term “heteroaryl” refers to any mono-, bi-, or tricyclic aromatic ring system containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13 ^th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. In one embodiment, heteroaryl includes 7-12 membered bicyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2- a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyridazine, imidazo[1,5- a]pyrazine, imidazo[5,1-f][1,2,4]triazine, [1,2,4]triazolo[4,3-a]pyrazine, 1H-pyrazolo[3,4- c]pyridazine, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4- c]pyridine, 1H-pyrazolo[4,3-c]pyridine and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl. Particularly, heteroaryl herein can be The term “heteroarylene” denotes a divalent heteroaryl group. In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring. In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. The term “optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents. In one embodiment, the skill in the art can understand the keto‑enol tautomerism exists for certain structures as illustrated below: The term “RSO(NR)” denotes . The term “SO ₂ ” or “sulfonyl” denotes . The term “sulfonimidoyl” denotes . The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practit ioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. ANTAGONIST OF STING The present invention relates to (i) a compound of formula (Ia), wherein M ¹ is heteroarylene optionally substituted by R ¹ ; wherein R ¹ is deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R) ₂ N, RCO, RSO ₂ , RNHSO ₂ , R ₂ NSO ₂ , RSO(NR), R ₃ Si, ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R) ₂ NC _1-6 alkyl, RSO ₂ C _1-6 alkyl, RNHSO ₂ C _1-6 alkyl, R ₂ NSO ₂ C _1-6 alkyl, RSO(NR)C _1-6 alkyl or R ₃ SiC _1-6 alkyl; wherein R is H, R ^a , R ^b or R ^c ; R ^a is C _1-6 alkyl optionally substituted by R ^b or R ^c ; R ^b is C _3-7 cycloalkyl, heterocyclyl, heteroaryl or aryl, said C _3-7 cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or R ^c ; R ^c is selected from deuterio, C _1-6 alkyl, (C _1-6 alkyl) ₃ Si, haloC _1-6 alkyl, deuterioC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, deuterioC _1-6 alkoxy, C _2-6 alkenyl, haloC _2-6 alkenyl, deuterioC _2-6 alkenyl, C _2-6 alkynyl, haloC _2-6 alkynyl, deuterioC _2-6 alkynyl, C _{3- 7} cycloalkyl, haloC _3-7 cycloalkyl, deuterioC _3-7 cycloalkyl, amino, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, haloC _1-6 alkylamino, haloC _{1- 6} alkylcarbonylamino, (haloC _1-6 alkyl) ₂ amino, C _3-7 cycloalkylamino, C _{3- 7} cycloalkylcarbonylamino, (C _3-7 cycloalkyl) ₂ amino, haloC _3-7 cycloalkylamino, (haloC _3-7 cycloalkyl) ₂ amino, C _3-7 cycloalkyl(C _1-6 alkyl)amino, haloC _{3- 7} cycloalkyl(C _1-6 alkyl)amino, C _1-6 alkylsulfonylamino, haloC _{1- 6} alkylsulfonylamino, C _1-6 alkoxyC _1-6 alkyl, (haloC _1-6 alkoxy)C _1-6 alkyl, C _{1- 6} alkoxy(halo)C _1-6 alkyl, C _3-7 cycloalkylC _1-6 alkyl, C _3-7 cycloalkylhaloC _1-6 alkyl, C _1-6 alkylcarbonyl, haloC _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, haloC _{3- 7} cycloalkylcarbonyl, C _1-6 alkoxycarbonyl, haloC _1-6 alkoxycarbonyl, C _{3- 7} cycloalkoxycarbonyl, haloC _3-7 cycloalkoxycarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _3-7 cycloalkylaminocarbonyl, (C _{3- 7} cycloalkyl) ₂ aminocarbonyl, C _1-6 alkylC _3-7 cycloalkylaminocarbonyl, haloC _{1- 6} alkylaminocarbonyl, halo(C _1-6 alkyl) ₂ aminocarbonyl, haloC _{3- 7} cycloalkylaminocarbonyl, halo(C _3-7 cycloalkyl) ₂ aminocarbonyl, haloC _{1- 6} alkylC _3-7 cycloalkylaminocarbonyl, C _1-6 alkylhaloC _3-7 cycloalkylaminocarbonyl, (C _1-6 alkyl) ₃ ammonio, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _{3- 7} cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, haloC _{1- 6} alkylsulfanyl, haloC _1-6 alkylsulfinyl, haloC _1-6 alkylsulfonyl, haloC _{3- 7} cycloalkylsulfanyl, haloC _3-7 cycloalkylsulfinyl, haloC _3-7 cycloalkylsulfonyl, haloC _1-6 alkoxysulfonyl, C _1-6 alkylaminosulfonyl, (haloC _1-6 alkylamino)sulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl, (haloC _1-6 alkyl) ₂ aminosulfonyl, (C _{1- 6} alkyl) ₂ phosphoryl, (C _1-6 alkoxy) ₂ phosphoryl, hydroxy(C _1-6 alkoxy)phosphoryl, C _1-6 alkoxyphosphoryl, hydroxy, hydroxyC _1-6 alkyl, hydroxyhaloC _1-6 alkyl, hydroxyC _1-6 alkoxy, hydroxylhaloC _1-6 alkoxy, hydroxyC _3-7 cycloalkyl, hydroxyhaloC _3-7 cycloalkyl and sulfonimidoyl optionally substituted by H, C _{1- 6} alkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocyclyl; M ² is arylene, heterocyclylene or heteroarylene, said arylene, heterocyclylene or heteroarylene being optionally substituted by R ¹ ; M ³ is heterocyclylene which is unsubstituted or optionally substituted by R ³ ; R ² is deuterio, R, ROC _1-6 alkyl, RSC _1-6 alkyl, RSO ₂ C _1-6 alkyl, RNHC _1-6 alkyl or (R) ₂ NC _{1- 6} alkyl; R ³ is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, said heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl and arylcarbonyl being unsubstituted or optionally substituted by R ¹ ; Q ¹ is -M-, -M-O-M-, -M-S-M-, -M-SO ₂ -M-, -M-SO(NH)-M-, -M-SO(NR)-M-, -M-SiR ₂ - M- or -M-N(R)-M-; wherein M is C _1-6 alkylene unsubstituted or optionally substituted by the substituents independently selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R ₂ N, RSO ₂ , ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R) ₂ NC _1-6 alkyl and RSO ₂ C _1-6 alkyl; Q ² is NH, O, S, SO, SO ₂ , P(O)R, PO(NR), Se, N(R), SiR ₂ , heterocyclyl, heteroaryl or aryl; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (I), wherein R ¹ is deuterio, H, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, (C _{1- 6} alkylsulfonylpiperazinyl)C _1-6 alkyl, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _{1- 6} alkoxycarbonyl, C _1-6 alkyl, C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _{3- 7} cycloalkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, hydroxy, pyrazolylC _1-6 alkyl or triazolylC _1-6 alkyl; R ² is H, (2-oxa-5-azabicyclo[2.2.1]heptanyl)C _1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptanyl)C _{1- 6} alkyl, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, ((C _{1- 6} alkyl) ₃ ammonio)C _1-6 alkyl, (C _1-6 alkylsulfonylpiperazinyl)C _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _{1- 6} alkyl, morpholinylC _1-6 alkyl, phenylC _1-6 alkyl, pyrimidinyloxyC _1-6 alkyl, tetrazolylC _{1- 6} alkyl or trideuterioC _1-6 alkyl; wherein R ⁴ is H, (C _1-6 alkyl) ₂ amino, (C _1-6 alkyl) ₂ aminocarbonyl, (C _1-6 alkyl) ₂ phosphoryl, 1,1-dioxothianyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolyl substituted by C _1-6 alkyl, 1,6-diazaspiro[3.3]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 1,7-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl or oxetanyl, 2,2-dioxo-2λ⁶-thia-6-azaspiro[3.3]heptanyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C _1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C _1-6 alkyl, haloC _1-6 alkyl or oxetanyl, 2-azaspiro[3.3]heptanyl once or twice substituted by substituents independently selected from haloC _1-6 alkyl and hydroxy, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylcarbonyl, cyanoC _1-6 alkyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, haloC _3-7 cycloalkyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3,6-diazabicyclo[3.2.0]heptanyl substituted by oxetanyl, 3,7-diazabicyclo[4.2.0]octanyl substituted by oxetanyl, 3,8-diazabicyclo[3.2.1]octanyl substituted by haloC _1-6 alkyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 4,7-diazaspiro[2.5]octanyl unsubstituted or substituted by C _1-6 alkyl, 4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl, 6,6-dioxo-6λ⁶-thia-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, amino, aminocarbonyl, azetidinyl unsubstituted or once or twice substituted by substituents independently selected from (C _1-6 alkyl) ₂ amino, (C _1-6 alkyl) ₂ aminoC _1-6 alkyl, amino, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylC _1-6 alkyl, C _3-7 cycloalkyl, cyano, cyanoC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinyl and morpholinylC _1-6 alkyl, azetidinyloxy substituted by haloC _1-6 alkyl or C _3-7 cycloalkyl, C _1-6 alkoxy unsubstituted or substituted by (haloC _1-6 alkylcarbonyl)azetidinyl, C _{1- 6} alkylazetidinyl, C _1-6 alkylpiperazinyl, C _1-6 alkylpyrrolidinyl, halo-1,2,3,5,6,7- hexahydropyrrolizinyl, haloC _1-6 alkylazetidinyl, morpholinyl, oxetanyl or tetrahydrofuranyl, C _1-6 alkoxyC _1-6 alkylamino, C _1-6 alkoxycarbonyl, C _1-6 alkyl unsubstituted or once or twice substituted by substituents independently selected from (C _1-6 alkoxyC _1-6 alkylcarbonyl)azetidinyl, (haloC _{1- 6} alkylcarbonyl)pyrrolidinyl, 1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4,7-diazaspiro[2.5]octanyl, C _1-6 alkoxy, C _{1- 6} alkylcarbonylazetidinyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylpyrrolidinyl, C _1-6 alkylsulfonylazetidinyl, C _1-6 alkylsulfonylpyrrolidinyl, C _{3- 7} cycloalkylsulfonylazetidinyl, cyano, haloC _1-6 alkylazetidinyl, hydroxy, hydroxyC _1-6 alkyl, morpholinyl and oxetanyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl unsubstituted or substituted by 1,1-dioxothietanyl, C _1-6 alkylsulfonyl, C _3-7 cycloalkyl unsubstituted or substituted by C _1-6 alkoxy or hydroxy, carboxy, cyano, haloC _1-6 alkoxy, haloC _1-6 alkyl substituted by hydroxy, hydroxy, hydroxyC _1-6 alkylcarbamoyl, imidazolyl, morpholinyl, morpholinylcarbonyl, oxetanyl, oxomorpholinyl, oxooxazolidinyl, oxopiperazinyl substituted by C _1-6 alkyl, oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy, piperazinyl once or twice substituted by substituents independently selected from C _{1- 6} alkyl, carboxy, oxetanyl and phenylC _1-6 alkyl, piperidinyl substituted by C _1-6 alkyl, 2H-tetrazolyl or oxazolyl, pyrrolidinyl once or twice substituted by substituents independently selected from amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, cyano, haloC _1-6 alkylcarbonyl and halogen, pyrrolidinylcarbonyl, tetrahydrofuranyl, or tetrahydropyranyl; R ⁵ is 1,3-dihydroisobenzofuranyl, 1H-indazolyl substituted by halogen, C _2-6 alkynyl, thienyl, bicyclo[1.1.1]pentanyl unsubstituted or substituted by halogen or C _1-6 alkyl, phenyl substituted once, twice or three times by the substituents independently selected from (C _1-6 alkoxyC _1-6 alkyl)C _3-7 cycloalkyloxy, (C _1-6 alkyl) ₂ phosphoryl, (C _1-6 alkylmorpholinyl)C _1-6 alkoxy, (C _1-6 alkylsulfonylazetidinyl)C _1-6 alkoxy, 2- oxa-6-azaspiro[3.3]heptanyl, azetidinyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _{1- 6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _2-6 alkynyl, C _1-6 alkoxyC _3-7 cycloalkyloxy, C _{1- 6} alkoxypyrrolidinyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _{1- 6} alkylsulfinyl, C _1-6 alkylsulfonyl, C _2-6 alkenyl, C _3-7 cycloalkyl, C _3-7 cycloalkyloxy, carboxy, cyano, cyanoC _1-6 alkoxy, haloC _1-6 alkoxy, haloC _1-6 alkyl, halogen, hydroxy, morpholinyl, morpholinylC _1-6 alkoxy, oxetanylC _1-6 alkoxy, oxetanyloxy, oxopyrrolidinyl, phenyl, tetrahydrofuranyl, tetrahydrofuranyloxy and trideuterioC _1-6 alkoxy, pyridinyl unsubstituted or substituted once or twice by the substituents independently selected from halogen, hydroxy, C _1-6 alkylsulfanyl and C _1-6 alkoxy, or pyrimidinyl unsubstituted or substituted by halogen; R ⁶ is H or C _1-6 alkyl; R ⁷ is C _1-6 alkyl; R ^7a is C _1-6 alkyl, C _3-7 cycloalkyl or C _1-6 alkoxyC _1-6 alkyl; R ^7b is H, C _1-6 alkoxy or phenylC _1-6 alkoxy; R ^7c is H or C _1-6 alkoxy; R ^7d is C _1-6 alkyl, C _3-7 cycloalkylC _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl; R ^7e is H, amino, phenylC _1-6 alkylamino or morpholinylC _1-6 alkylamino; R ^7f is C _1-6 alkyl, phenylC _1-6 alkyl or oxetanyl; R ^7g is H or C _1-6 alkoxyC _1-6 alkyl; Q ¹ is C _1-6 alkylene unsubstituted or substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkyl, C _{1- 6} alkylcarbonyloxy, carboxy, hydroxy, hydroxyC _1-6 alkoxy, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkoxy and trideuterioC _1-6 alkoxy, or -M-O-M-, wherein M is C _1-6 alkylene; Q ² is NH, O or S; A ¹ is CH or N; A ² is CH, CR ^7h or N; wherein R ^7h is C _1-6 alkyl; A ³ is CR ⁸ or N, wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkoxy, C _3-7 cycloalkoxyamino, cyano, haloazetidinylC _1-6 alkyl, haloC _1-6 alkoxy, halogen, morpholinylC _1-6 alkyl or oxetanyl; A ⁴ is CR ⁹ or N, wherein R ⁹ is H; or R ⁸ and R ⁹ together with the atoms that they are attached to form a heterocyclyl; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ or N, wherein R ¹¹ is H, deuterio, halogen, C _1-6 alkyl or C _1-6 alkoxy; A ⁷ is CR ¹² or N, wherein R ¹² is H or halogen; provided that no more than two of A ¹ , A ² , A ³ and A ⁴ are N simultaneously; and no more than one of A ⁵ , A ⁶ and A ⁷ is N; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (iii) a compound of formula (Ib),

wherein R ¹ is deuterio, H, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, (C _{1- 6} alkylsulfonylpiperazinyl)C _1-6 alkyl, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _{1- 6} alkoxycarbonyl, C _1-6 alkyl, C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _{3- 7} cycloalkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, hydroxy, pyrazolylC _1-6 alkyl or triazolylC _1-6 alkyl; R ² is H, (2-oxa-5-azabicyclo[2.2.1]heptanyl)C _1-6 alkyl, (2-oxa-6-azaspiro[3.3]heptanyl)C _{1- 6} alkyl, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, ((C _{1- 6} alkyl) ₃ ammonio)C _1-6 alkyl, (C _1-6 alkylsulfonylpiperazinyl)C _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _{1- 6} alkyl, morpholinylC _1-6 alkyl, phenylC _1-6 alkyl, pyrimidinyloxyC _1-6 alkyl, tetrazolylC _{1- 6} alkyl or trideuterioC _1-6 alkyl;

wherein R ⁴ is H, (C _1-6 alkyl) ₂ amino, (C _1-6 alkyl) ₂ aminocarbonyl, (C _1-6 alkyl) ₂ phosphoryl, 1,1-dioxothianyl, 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolyl substituted by C _1-6 alkyl, 1,6-diazaspiro[3.3]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 1,7-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl or oxetanyl, 2,2-dioxo-2λ⁶-thia-6-azaspiro[3.3]heptanyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C _1-6 alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C _1-6 alkyl, haloC _1-6 alkyl or oxetanyl, 2-azaspiro[3.3]heptanyl once or twice substituted by substituents independently selected from haloC _1-6 alkyl and hydroxy, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C _1-6 alkyl, C _1-6 alkoxyC _{1- 6} alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylcarbonyl, cyanoC _1-6 alkyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, haloC _3-7 cycloalkyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3,6-diazabicyclo[3.2.0]heptanyl substituted by oxetanyl, 3,7-diazabicyclo[4.2.0]octanyl substituted by oxetanyl, 3,8-diazabicyclo[3.2.1]octanyl substituted by haloC _1-6 alkyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 4,7-diazaspiro[2.5]octanyl unsubstituted or substituted by C _1-6 alkyl, 4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, 5-oxa-2,8-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl, 6,6-dioxo-6λ⁶-thia-1-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl substituted by haloC _1-6 alkyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, amino, aminocarbonyl, azetidinyl unsubstituted or once or twice substituted by substituents independently selected from (C _1-6 alkyl) ₂ amino, (C _1-6 alkyl) ₂ aminoC _1-6 alkyl, amino, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylC _1-6 alkyl, C _3-7 cycloalkyl, cyano, cyanoC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinyl and morpholinylC _1-6 alkyl, azetidinyloxy substituted by haloC _1-6 alkyl or C _3-7 cycloalkyl, C _1-6 alkoxy unsubstituted or substituted by (haloC _1-6 alkylcarbonyl)azetidinyl, C _{1- 6} alkylazetidinyl, C _1-6 alkylpiperazinyl, C _1-6 alkylpyrrolidinyl, halo-1,2,3,5,6,7- hexahydropyrrolizinyl, haloC _1-6 alkylazetidinyl, morpholinyl, oxetanyl or tetrahydrofuranyl, C _1-6 alkoxyC _1-6 alkylamino, C _1-6 alkoxycarbonyl, C _1-6 alkyl unsubstituted or once or twice substituted by substituents independently selected from (C _1-6 alkoxyC _1-6 alkylcarbonyl)azetidinyl, (haloC _{1- 6} alkylcarbonyl)pyrrolidinyl, 1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4,7-diazaspiro[2.5]octanyl, C _1-6 alkoxy, C _{1- 6} alkylcarbonylazetidinyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylpyrrolidinyl, C _1-6 alkylsulfonylazetidinyl, C _1-6 alkylsulfonylpyrrolidinyl, C _{3- 7} cycloalkylsulfonylazetidinyl, cyano, haloC _1-6 alkylazetidinyl, hydroxy, hydroxyC _1-6 alkyl, morpholinyl and oxetanyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl unsubstituted or substituted by 1,1-dioxothietanyl, C _1-6 alkylsulfonyl, C _3-7 cycloalkyl unsubstituted or substituted by C _1-6 alkoxy or hydroxy, carboxy, cyano, haloC _1-6 alkoxy, haloC _1-6 alkyl substituted by hydroxy, hydroxy, hydroxyC _1-6 alkylcarbamoyl, imidazolyl, morpholinyl, morpholinylcarbonyl, oxetanyl, oxomorpholinyl, oxooxazolidinyl, oxopiperazinyl substituted by C _1-6 alkyl, oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy, piperazinyl once or twice substituted by substituents independently selected from C _{1- 6} alkyl, carboxy, oxetanyl and phenylC _1-6 alkyl, piperidinyl substituted by C _1-6 alkyl, 2H-tetrazolyl or oxazolyl, pyrrolidinyl once or twice substituted by substituents independently selected from amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, cyano, haloC _1-6 alkylcarbonyl and halogen, pyrrolidinylcarbonyl, tetrahydrofuranyl, or tetrahydropyranyl; R ⁵ is 1,3-dihydroisobenzofuranyl, 1H-indazolyl substituted by halogen, C _2-6 alkynyl, thienyl, bicyclo[1.1.1]pentanyl unsubstituted or substituted by halogen or C _1-6 alkyl, phenyl substituted once, twice or three times by the substituents independently selected from (C _1-6 alkoxyC _1-6 alkyl)C _3-7 cycloalkyloxy, (C _1-6 alkyl) ₂ phosphoryl, (C _1-6 alkylmorpholinyl)C _1-6 alkoxy, (C _1-6 alkylsulfonylazetidinyl)C _1-6 alkoxy, 2- oxa-6-azaspiro[3.3]heptanyl, azetidinyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _{1- 6} alkoxyC _1-6 alkyl, C _1-6 alkoxyC _2-6 alkynyl, C _1-6 alkoxyC _3-7 cycloalkyloxy, C _{1- 6} alkoxypyrrolidinyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _{1- 6} alkylsulfinyl, C _1-6 alkylsulfonyl, C _2-6 alkenyl, C _3-7 cycloalkyl, C _3-7 cycloalkyloxy, carboxy, cyano, cyanoC _1-6 alkoxy, haloC _1-6 alkoxy, haloC _1-6 alkyl, halogen, hydroxy, morpholinyl, morpholinylC _1-6 alkoxy, oxetanylC _1-6 alkoxy, oxetanyloxy, oxopyrrolidinyl, phenyl, tetrahydrofuranyl, tetrahydrofuranyloxy and trideuterioC _1-6 alkoxy, pyridinyl unsubstituted or substituted once or twice by the substituents independently selected from halogen, hydroxy, C _1-6 alkylsulfanyl and C _1-6 alkoxy, or pyrimidinyl unsubstituted or substituted by halogen; R ⁶ is H or C _1-6 alkyl; R ⁷ is C _1-6 alkyl; R ^7a is C _1-6 alkyl, C _3-7 cycloalkyl or C _1-6 alkoxyC _1-6 alkyl; R ^7b is H, C _1-6 alkoxy or phenylC _1-6 alkoxy; R ^7c is H or C _1-6 alkoxy; R ^7d is C _1-6 alkyl, C _3-7 cycloalkylC _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl; R ^7e is H, amino, phenylC _1-6 alkylamino or morpholinylC _1-6 alkylamino; R ^7f is C _1-6 alkyl, phenylC _1-6 alkyl or oxetanyl; R ^7g is H or C _1-6 alkoxyC _1-6 alkyl; Q ¹ is C _1-6 alkylene unsubstituted or substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkyl, C _{1- 6} alkylcarbonyloxy, carboxy, hydroxy, hydroxyC _1-6 alkoxy, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkoxy and trideuterioC _1-6 alkoxy, or -M-O-M-, wherein M is C _1-6 alkylene; Q ² is NH, O or S; A ¹ is CH or N; A ² is CH, CR ^7h or N; wherein R ^7h is C _1-6 alkyl; A ³ is CR ⁸ or N, wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkoxy, C _3-7 cycloalkoxyamino, cyano, haloazetidinylC _1-6 alkyl, haloC _1-6 alkoxy, halogen, morpholinylC _1-6 alkyl or oxetanyl; A ⁴ is CR ⁹ or N, wherein R ⁹ is H; or R ⁸ and R ⁹ together with the atoms that they are attached to form a heterocyclyl; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ or N, wherein R ¹¹ is H, deuterio, halogen, C _1-6 alkyl or C _1-6 alkoxy; A ⁷ is CR ¹² or N, wherein R ¹² is H or halogen; provided that no more than two of A ¹ , A ² , A ³ and A ⁴ are N simultaneously; and no more than one of A ⁵ , A ⁶ and A ⁷ is N; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (iv) a compound of formula (I) or (Ia) according to (i) or (iii), or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or C _{1- 6} alkyl. A further embodiment of present invention is (v) a compound of formula (I) or (Ia), according to any one of (i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or methyl. A further embodiment of present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), wherein R ² is C _1-6 alkyl or trideuterioC _1-6 alkyl. A further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), wherein R ² is methyl, ethyl or trideuteriomethyl. A further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R ³

wherein R ⁴ is H, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkylcarbonyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, amino, azetidinyl substituted by C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl or cyano, C _1-6 alkoxy, C _1-6 alkyl unsubstituted or substituted by C _1-6 alkoxy, C _1-6 alkylcarbonylazetidinyl, C _{1- 6} alkylsulfonylazetidinyl, C _3-7 cycloalkylsulfonylazetidinyl, haloC _1-6 alkylazetidinyl, hydroxy, morpholinyl or oxetanyl, oxetanyl, oxooxazolidinyl, or oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkyloxy, cyano, haloC _1-6 alkoxy, halogen, hydroxy and trideuterioC _1-6 alkoxy, pyridinyl twice substituted by halogen, or pyrimidinyl substituted by halogen; R ⁶ is H; R ^7a is C _1-6 alkyl; R ^7e is amino; R ^7f is C _1-6 alkyl; R ^7g is H or C _1-6 alkoxyC _1-6 alkyl. A further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein R ³ R ⁴ is H, R ⁴ is H, (1-acetylazetidin-3-yl)methyl, (1-cyclopropylsulfonylazetidin-3-yl)methyl, (1- ethylsulfonylazetidin-3-yl)methyl, (1-methylsulfonylazetidin-3-yl)methyl, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 1-acetylazetidin-3-yl, 1-methylsulfonylazetidin-3-yl, 2- oxooxazolidin-3-yl, 2-oxopyrrolidin-1-yl, 3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-hydroxycyclopropanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2- hydroxy-2-methyl-propanoyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-hydroxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-hydroxy-2-oxo-pyrrolidin-1-yl, 3- methyl-2-oxo-pyrrolidin-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5- (2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, 9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl, amino, azetidin-1-yl, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl, morpholinylmethyl, oxetan-2-ylmethyl or oxetan-3-yl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from ethoxy, methoxy, cyclopropoxy, cyano, difluoromethoxy, fluoro, hydroxy and trideuteriomethoxy, pyridinyl twice substituted by fluoro, or pyrimidinyl substituted by fluoro; R ⁶ is H; R ^7a is methyl; R ^7e is amino; R ^7f is methyl; R ^7g is H or methoxymethyl. A further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R ³ is ; wherein R ⁴ is H, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkylcarbonyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, amino, azetidinyl substituted by C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl or cyano, C _1-6 alkoxy, C _1-6 alkyl unsubstituted or substituted by C _1-6 alkoxy, C _1-6 alkylcarbonylazetidinyl, C _{1- 6} alkylsulfonylazetidinyl, C _3-7 cycloalkylsulfonylazetidinyl, haloC _1-6 alkylazetidinyl, hydroxy, morpholinyl or oxetanyl, oxetanyl, oxooxazolidinyl, or oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkyloxy, cyano, haloC _1-6 alkoxy, halogen, hydroxy and trideuterioC _1-6 alkoxy, pyridinyl twice substituted by halogen, or pyrimidinyl substituted by halogen; R ⁶ is H. A further embodiment of present invention is (xi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R ³ is ; wherein R ⁴ is H, (1-acetylazetidin-3-yl)methyl, (1-cyclopropylsulfonylazetidin-3-yl)methyl, (1- ethylsulfonylazetidin-3-yl)methyl, (1-methylsulfonylazetidin-3-yl)methyl, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 1-acetylazetidin-3-yl, 1-methylsulfonylazetidin-3-yl, 2- oxooxazolidin-3-yl, 2-oxopyrrolidin-1-yl, 3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-hydroxycyclopropanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2- hydroxy-2-methyl-propanoyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-hydroxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-hydroxy-2-oxo-pyrrolidin-1-yl, 3- methyl-2-oxo-pyrrolidin-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5- (2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, 9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl, amino, azetidin-1-yl, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl, morpholinylmethyl, oxetan-2-ylmethyl or oxetan-3-yl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from ethoxy, methoxy, cyclopropoxy, cyano, difluoromethoxy, fluoro, hydroxy and trideuteriomethoxy, pyridinyl twice substituted by fluoro, or pyrimidinyl substituted by fluoro; R ⁶ is H. A further embodiment of present invention is (xii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein Q ¹ is C _{1- 6} alkylene substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkylcarbonyloxy, hydroxy, C _1-6 alkyl and trideuterioC _1-6 alkoxy. A further embodiment of present invention is (xiii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein Q ¹ is propylene substituted once or twice by the substituents independently selected from ethoxy, methoxy, hydroxy, methyl, acetoxy and trideuteriomethoxy. A further embodiment of present invention is (xiv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xiii), wherein Q ¹ is C _{1- 6} alkylene substituted by C _1-6 alkoxy. A further embodiment of present invention is (xv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xiv), wherein Q ¹ is propylene substituted by methoxy or ethoxy. A further embodiment of present invention is (xvi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xv), wherein Q ² is NH or O. A further embodiment of present invention is (xvii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xvi), wherein A ¹ is N. A further embodiment of present invention is (xviii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xvii), wherein A ³ is CR ⁸ , wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkoxy, haloC _1-6 alkoxy or halogen. A further embodiment of present invention is (xix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xviii), wherein A ³ is CR ⁸ , wherein R ⁸ is H, methoxy, methyl, cyclopropoxy, difluoromethoxy or fluoro. A further embodiment of present invention is (xx) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xix), wherein A ³ is CR ⁸ , wherein R ⁸ is H. A further embodiment of present invention is (xxi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xx), wherein A ⁴ is CR ⁹ , wherein R ⁹ is H. A further embodiment of present invention is (xxii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxi), wherein A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or fluoro. A further embodiment of present invention is (xxiii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxii), wherein A ⁵ is CR ¹⁰ , wherein R ¹⁰ is H. A further embodiment of present invention is (xxiv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxiii), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is H or halogen. A further embodiment of present invention is (xxv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxiv), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is H or fluoro. A further embodiment of present invention is (xxvi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxv), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is halogen. A further embodiment of present invention is (xxvii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxvi), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is fluoro. A further embodiment of present invention is (xxviii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxvii), wherein A ⁷ is CR ¹² , wherein R ¹² is H or halogen. A further embodiment of present invention is (xxix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxviii), wherein A ⁷ is CR ¹² , wherein R ¹² is H or fluoro. A further embodiment of present invention is (xxx) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xxix), wherein A ⁷ is CR ¹² , wherein R ¹² is H. A further embodiment of present invention is (xxxi) a compound of formula (I) or (Ia), according to any one of (i) or (ii) or (iii), wherein R ¹ is H or C _1-6 alkyl; R ² is C _1-6 alkyl or trideuterioC _1-6 alkyl; wherein R ⁴ is H, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkylcarbonyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, amino, azetidinyl substituted by C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl or cyano, C _1-6 alkoxy, C _1-6 alkyl unsubstituted or substituted by C _1-6 alkoxy, C _1-6 alkylcarbonylazetidinyl, C _{1- 6} alkylsulfonylazetidinyl, C _3-7 cycloalkylsulfonylazetidinyl, haloC _1-6 alkylazetidinyl, hydroxy, morpholinyl or oxetanyl, oxetanyl, oxooxazolidinyl, oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkyloxy, cyano, haloC _1-6 alkoxy, halogen, hydroxy and trideuterioC _1-6 alkoxy, pyridinyl twice substituted by halogen, or pyrimidinyl substituted by halogen; R ⁶ is H; R ^7a is C _1-6 alkyl; R ^7e is amino; R ^7f is C _1-6 alkyl; R ^7g is H or C _1-6 alkoxyC _1-6 alkyl; Q ¹ is C _1-6 alkylene substituted once or twice by the substituents independently selected from C _{1- 6} alkoxy, C _1-6 alkylcarbonyloxy, hydroxy, C _1-6 alkyl and trideuterioC _1-6 alkoxy; Q ² is NH or O; A ¹ is N; A ² is CH, CR ^7h or N; wherein R ^7h is C _1-6 alkyl; A ³ is CR ⁸ , wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkoxy, haloC _1-6 alkoxy or halogen; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ , wherein R ¹¹ is H or halogen; A ⁷ is CR ¹² , wherein R ¹² is H or halogen; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxii) a compound of formula (I) or (Ia), according to (xxxi), wherein R ¹ is H or methyl; R ² is methyl, ethyl or trideuteriomethyl; ; wherein R ⁴ is H, R ⁴ is H, (1-acetylazetidin-3-yl)methyl, (1-cyclopropylsulfonylazetidin-3-yl)methyl, (1- ethylsulfonylazetidin-3-yl)methyl, (1-methylsulfonylazetidin-3-yl)methyl, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 1-acetylazetidin-3-yl, 1-methylsulfonylazetidin-3-yl, 2- oxooxazolidin-3-yl, 2-oxopyrrolidin-1-yl, 3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-hydroxycyclopropanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2- hydroxy-2-methyl-propanoyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-hydroxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-hydroxy-2-oxo-pyrrolidin-1-yl, 3- methyl-2-oxo-pyrrolidin-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5- (2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, 9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl, amino, azetidin-1-yl, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl, morpholinylmethyl, oxetan-2-ylmethyl or oxetan-3-yl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from ethoxy, methoxy, cyclopropoxy, cyano, difluoromethoxy, fluoro, hydroxy and trideuteriomethoxy, pyridinyl twice substituted by fluoro, or pyrimidinyl substituted by fluoro; R ⁶ is H; R ^7a is methyl; R ^7e is amino; R ^7f is methyl; R ^7g is H or methoxymethyl; Q ¹ is propylene substituted once or twice by the substituents independently selected from ethoxy, methoxy, hydroxy, methyl, acetoxy and trideuteriomethoxy; Q ² is NH or O; A ¹ is N; A ² is CH, CR ^7h or N; wherein R ^7h is methyl; A ³ is CR ⁸ , wherein R ⁸ is H, methoxy, methyl, cyclopropoxy, difluoromethoxy or fluoro; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or fluoro; A ⁶ is CR ¹¹ , wherein R ¹¹ is H or fluoro; A ⁷ is CR ¹² , wherein R ¹² is H or fluoro; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxiii) a compound of formula (I) or (Ia), according to (xxxii), wherein R ¹ is C _1-6 alkyl; R ² is C _1-6 alkyl; R ³ is ; wherein R ⁴ is H, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC _1-6 alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkylcarbonyl, haloC _1-6 alkyl, haloC _1-6 alkylcarbonyl, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkylcarbonyl, hydroxyC _3-7 cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by C _1-6 alkyl, amino, azetidinyl substituted by C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl or cyano, C _1-6 alkoxy, C _1-6 alkyl unsubstituted or substituted by C _1-6 alkoxy, C _1-6 alkylcarbonylazetidinyl, C _{1- 6} alkylsulfonylazetidinyl, C _3-7 cycloalkylsulfonylazetidinyl, haloC _1-6 alkylazetidinyl, hydroxy, morpholinyl or oxetanyl, oxetanyl, oxooxazolidinyl, oxopyrrolidinyl unsubstituted or substituted by C _1-6 alkyl or hydroxy; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkyloxy, cyano, haloC _1-6 alkoxy, halogen, hydroxy and trideuterioC _1-6 alkoxy, pyridinyl twice substituted by halogen, or pyrimidinyl substituted by halogen; R ⁶ is H; Q ¹ is C _1-6 alkylene substituted by C _1-6 alkoxy; Q ² is NH or O; A ¹ is N; A ² is CH or N; A ³ is CR ⁸ , wherein R ⁸ is H; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H; A ⁶ is CR ¹¹ , wherein R ¹¹ is halogen; A ⁷ is CR ¹² , wherein R ¹² is H; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxiv) a compound of formula (I) or (Ia), according to (xxxiii), wherein R ¹ is methyl; R ² is methyl; R ³ is ; wherein R ⁴ is H, (1-acetylazetidin-3-yl)methyl, (1-cyclopropylsulfonylazetidin-3-yl)methyl, (1- ethylsulfonylazetidin-3-yl)methyl, (1-methylsulfonylazetidin-3-yl)methyl, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 1-acetylazetidin-3-yl, 1-methylsulfonylazetidin-3-yl, 2- oxooxazolidin-3-yl, 2-oxopyrrolidin-1-yl, 3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-hydroxycyclopropanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2- hydroxy-2-methyl-propanoyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-hydroxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-hydroxy-2-oxo-pyrrolidin-1-yl, 3- methyl-2-oxo-pyrrolidin-1-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5- (2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl, 9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl, amino, azetidin-1-yl, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl, morpholinylmethyl, oxetan-2-ylmethyl or oxetan-3-yl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from ethoxy, methoxy, cyclopropoxy, cyano, difluoromethoxy, fluoro, hydroxy and trideuteriomethoxy, pyridinyl twice substituted by fluoro, or pyrimidinyl substituted by fluoro; R ⁶ is H; Q ¹ is propylene substituted by methoxy or ethoxy; Q ² is NH or O; A ¹ is N; A ² is CH or N; A ³ is CR ⁸ , wherein R ⁸ is H; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H; A ⁶ is CR ¹¹ , wherein R ¹¹ is fluoro; A ⁷ is CR ¹² , wherein R ¹² is H; or a pharmaceutically acceptable salt thereof. The present invention relates to (i’) a compound of formula (Ia), wherein M ¹ is heteroarylene optionally substituted by R ¹ ; wherein R ¹ is deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R) ₂ N, RCO, RSO ₂ , RNHSO ₂ , R ₂ NSO ₂ , RSO(NR), ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R)2NC _1-6 alkyl, RSO2C _1-6 alkyl, RNHSO2C _1-6 alkyl, R2NSO2C _1-6 alkyl or RSO(NR)C _1-6 alkyl; wherein R is H, R ^a , R ^b or R ^c ; R ^a is C _1-6 alkyl optionally substituted by R ^b or R ^c ; R ^b is C _3-7 cycloalkyl, heterocyclyl, heteroaryl or aryl, said C _3-7 cycloalkyl,heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by halogen or R ^c ; R ^c is selected from C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, haloC _2-6 alkenyl, C _2-6 alkynyl, haloC _2-6 alkynyl, C _3-7 cycloalkyl, haloC _3-7 cycloalkyl, amino, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, haloC _1-6 alkylamino, halo(C _1-6 alkyl) ₂ amino, C _{3- 7} cycloalkylamino, (C _3-7 cycloalkyl) ₂ amino, haloC _3-7 cycloalkylamino, (haloC _{3- 7} cycloalkyl) ₂ amino, C _3-7 cycloalkyl(C _1-6 alkyl)amino, haloC _3-7 cycloalkyl(C _{1- 6} alkyl)amino, C _1-6 alkoxyC _1-6 alkyl, (haloC _1-6 alkoxy)C _1-6 alkyl, C _{1- 6} alkoxy(halo)C _1-6 alkyl, C _3-7 cycloalkylC _1-6 alkyl, C _3-7 cycloalkylhaloC _1-6 alkyl, C _1-6 alkylcarbonyl, haloC _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, haloC _{3- 7} cycloalkylcarbonyl, C _1-6 alkoxycarbonyl, haloC _1-6 alkoxycarbonyl, C _{3- 7} cycloalkoxycarbonyl, haloC _3-7 cycloalkoxycarbonyl, haloC _1-6 alkoxycarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _{3- 7} cycloalkylaminocarbonyl, (C _3-7 cycloalkyl) ₂ aminocarbonyl, C _1-6 alkylC _{3- 7} cycloalkylaminocarbonyl, haloC _1-6 alkylaminocarbonyl, halo(C _{1- 6} alkyl) ₂ aminocarbonyl, haloC _3-7 cycloalkylaminocarbonyl, halo(C _{3- 7} cycloalkyl) ₂ aminocarbonyl, haloC _1-6 alkylC _3-7 cycloalkylaminocarbonyl, C _{1- 6} alkylhaloC _3-7 cycloalkylaminocarbonyl, (C _1-6 alkyl) ₃ ammonio, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _3-7 cycloalkylsulfanyl, C _{3- 7} cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, haloC _1-6 alkylsulfanyl, haloC _{1- 6} alkylsulfinyl, haloC _1-6 alkylsulfonyl, haloC _3-7 cycloalkylsulfanyl, haloC _{3- 7} cycloalkylsulfinyl, haloC _3-7 cycloalkylsulfonyl, haloC _1-6 alkoxysulfonyl, C _{1- 6} alkylaminosulfonyl, (haloC _1-6 alkylamino)sulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl, (haloC _1-6 alkyl) ₂ aminosulfonyl, (C _1-6 alkyl) ₂ phosphoryl, (C _1-6 alkoxy) ₂ phosphoryl, hydroxy(C _1-6 alkoxy)phosphoryl, C _1-6 alkoxyphosphoryl, hydroxy, hydroxyC _{1- 6} alkyl, hydroxyhaloC _1-6 alkyl, hydroxyC _1-6 alkoxy, hydroxylhaloC _1-6 alkoxy, hydroxyC _3-7 cycloalkyl, hydroxyhaloC _3-7 cycloalkyl and sulfonimidoyl optionally substituted by H, C _1-6 alkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocyclyl; M ² is arylene, heterocyclylene or heteroarylene, said arylene, heterocyclylene or heteroarylene being optionally substituted by R ¹ ; M ³ is heterocyclylene which is unsubstituted or optionally substituted by R ³ ; R ² is deuterio, R, ROC _1-6 alkyl, RSC _1-6 alkyl, RSO ₂ C _1-6 alkyl, RNHC _1-6 alkyl or (R) ₂ NC _{1- 6} alkyl; R ³ is heteroaryl, aryl, heteroarylcarbonyl or arylcarbonyl, said heteroaryl and aryl being optionally substituted by R ¹ ; Q ¹ is -M-, -M-O-M-, -M-S-M-, -M-N(R)-M-; wherein M is C _1-6 alkylene unsubstituted or optionally substituted by the substituents independently selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R ₂ N, RSO ₂ , ROC _1-6 alkyl, RSC _1-6 alkyl, RNHC _1-6 alkyl, (R) ₂ NC _1-6 alkyl and RSO ₂ C _1-6 alkyl; Q ² is NH, O or S; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii’) a compound of formula (I), wherein R ¹ is deuterio, H, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, (C _{1- 6} alkylsulfonylpiperazinyl)C _1-6 alkyl, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _{1- 6} alkoxycarbonyl, C _1-6 alkyl, C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _{3- 7} cycloalkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, hydroxy, pyrazolylC _1-6 alkyl or triazolylC _1-6 alkyl; R ² is H, ((C _1-6 alkyl)3ammonio)C _1-6 alkyl, (C _1-6 alkylsulfonylpiperazinyl)C _1-6 alkyl, C1- 6alkoxyC _1-6 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, phenylC _1-6 alkyl, pyrimidinyloxyC _1-6 alkyl, tetrazolylC _1-6 alkyl or trideuterioC _1-6 alkyl; R ³ is , ; wherein R ⁴ is H, (C _1-6 alkyl) ₂ aminocarbonyl, (C _1-6 alkyl) ₂ phosphoryl, amino, aminocarbonyl, C _{1- 6} alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkylamino, C _1-6 alkoxycarbonyl, C _{1- 6} alkyl, C _1-6 alkylamino, C _3-7 cycloalkyl, carboxy, cyano, hydroxy, hydroxyC _1-6 alkyl, morpholinyl, morpholinylC _1-6 alkoxy or morpholinylC _1-6 alkyl; R ⁵ is thienyl, bicyclo[1.1.1]pentanyl unsubstituted or substituted by halogen or C _1-6 alkyl, phenyl substituted once, twice or three times by the substituents independently selected from (C _1-6 alkyl) ₂ phosphoryl, (C _1-6 alkylmorpholinyl)C _1-6 alkoxy, C _{1- 6} alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _2-6 alkenyl, C _{3- 7} cycloalkoxy, C _3-7 cycloalkyl, carboxy, cyano, haloC _1-6 alkoxy, haloC _1-6 alkyl, halogen, hydroxy, morpholinylC _1-6 alkoxy, oxetanylC _1-6 alkoxy, oxetanyloxy, oxopyrrolidinyl, phenyl, tetrahydrofuranyl and trideuterioC _1-6 alkoxy, pyridinyl unsubstituted or substituted once or twice by the substituents independently selected from halogen, hydroxy and C _1-6 alkoxy, or pyrimidinyl unsubstituted or substituted by halogen; R ⁶ is H or C _1-6 alkyl; R ⁷ is C _1-6 alkyl; Q ¹ is C _1-6 alkylene unsubstituted or substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkyl, C _{1- 6} alkylcarbonyloxy, carboxy, hydroxy, hydroxyC _1-6 alkoxy, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkoxy and trideuterioC _1-6 alkoxy, or -M-O-M-, wherein M is C _1-6 alkylene; Q ² is NH, O or S; A ¹ is CH or N; A ² is CH or N; A ³ is CR ⁸ or N, wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkoxy, cyano, haloazetidinylC _1-6 alkyl, haloC _1-6 alkoxy, morpholinylC _1-6 alkyl or oxetanyl; A ⁴ is CR ⁹ or N, wherein R ⁹ is H; or R ⁸ and R ⁹ together with the atoms that they are attached to form a heterocyclyl; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ or N, wherein R ¹¹ is H, deuterio, halogen, C _1-6 alkyl or C _1-6 alkoxy; A ⁷ is CR ¹² or N, wherein R ¹² is H or halogen; provided that no more than two of A ¹ , A ² , A ³ and A ⁴ are N simultaneously; and no more than one of A ⁵ , A ⁶ and A ⁷ is N; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (iii’) a compound of formula (Ib), wherein R ¹ is deuterio, H, (2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl)C _1-6 alkyl, (C _{1- 6} alkylsulfonylpiperazinyl)C _1-6 alkyl, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _{1- 6} alkoxycarbonyl, C _1-6 alkyl, C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _{3- 7} cycloalkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, hydroxy, pyrazolylC _1-6 alkyl or triazolylC _1-6 alkyl; R ² is H, ((C _1-6 alkyl) ₃ ammonio)C _1-6 alkyl, (C _1-6 alkylsulfonylpiperazinyl)C _1-6 alkyl, C _{1- 6} alkoxyC _1-6 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylC _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkyl, phenylC _1-6 alkyl, pyrimidinyloxyC _1-6 alkyl, tetrazolylC _1-6 alkyl or trideuterioC _1-6 alkyl; R ³ is , ; wherein R ⁴ is H, (C _1-6 alkyl) ₂ aminocarbonyl, (C _1-6 alkyl) ₂ phosphoryl, amino, aminocarbonyl, C _{1- 6} alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkylamino, C _1-6 alkoxycarbonyl, C _{1- 6} alkyl, C _1-6 alkylamino, C _3-7 cycloalkyl, carboxy, cyano, hydroxy, hydroxyC _1-6 alkyl, morpholinyl, morpholinylC _1-6 alkoxy or morpholinylC _1-6 alkyl; R ⁵ is thienyl, bicyclo[1.1.1]pentanyl unsubstituted or substituted by halogen or C _1-6 alkyl, phenyl substituted once, twice or three times by the substituents independently selected from (C _1-6 alkyl) ₂ phosphoryl, (C _1-6 alkylmorpholinyl)C _1-6 alkoxy, C _{1- 6} alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _2-6 alkenyl, C _{3- 7} cycloalkoxy, C _3-7 cycloalkyl, carboxy, cyano, haloC _1-6 alkoxy, haloC _1-6 alkyl, halogen, hydroxy, morpholinylC _1-6 alkoxy, oxetanylC _1-6 alkoxy, oxetanyloxy, oxopyrrolidinyl, phenyl, tetrahydrofuranyl and trideuterioC _1-6 alkoxy, pyridinyl unsubstituted or substituted once or twice by the substituents independently selected from halogen, hydroxy and C _1-6 alkoxy, or pyrimidinyl unsubstituted or substituted by halogen; R ⁶ is H or C _1-6 alkyl; R ⁷ is C _1-6 alkyl; Q ¹ is C _1-6 alkylene unsubstituted or substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy, C _1-6 alkyl, C _{1- 6} alkylcarbonyloxy, carboxy, hydroxy, hydroxyC _1-6 alkoxy, hydroxyC _1-6 alkyl, morpholinylC _1-6 alkoxy and trideuterioC _1-6 alkoxy, or -M-O-M-, wherein M is C _1-6 alkylene; Q ² is NH, O or S; A ¹ is CH or N; A ² is CH or N; A ³ is CR ⁸ or N, wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, C _{3- 7} cycloalkoxy, cyano, haloazetidinylC _1-6 alkyl, haloC _1-6 alkoxy, morpholinylC _1-6 alkyl or oxetanyl; A ⁴ is CR ⁹ or N, wherein R ⁹ is H; or R ⁸ and R ⁹ together with the atoms that they are attached to form a heterocyclyl; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ or N, wherein R ¹¹ is H, deuterio, halogen, C _1-6 alkyl or C _1-6 alkoxy; A ⁷ is CR ¹² or N, wherein R ¹² is H or halogen; provided that no more than two of A ¹ , A ² , A ³ and A ⁴ are N simultaneously; and no more than one of A ⁵ , A ⁶ and A ⁷ is N; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (iv’) a compound of formula (I) or (Ia) according to (i’) or (iii’), or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or C _{1- 6} alkyl. A further embodiment of present invention is (v’) a compound of formula (I) or (Ia), according to any one of (i’) to (iv’), or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or methyl. A further embodiment of present invention is (vi’) a compound of formula (I) or (Ia) according to any one of (i’) to (v’), wherein R ² is H or C _1-6 alkyl. A further embodiment of present invention is (vii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (vi’), wherein R ² is H, methyl or ethyl. A further embodiment of present invention is (viii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (vii’), wherein R ³ is ; wherein R ⁴ is H, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, hydroxyC _1-6 alkyl or morpholinylC _{1- 6} alkyl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkoxy, haloC _1-6 alkoxy, halogen, hydroxy and trideuterioC _{1- 6} alkoxy; R ⁶ is H. A further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (viii’), wherein R ³ is ; wherein R ⁴ is H, amino, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl or morpholinylmethyl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from fluoro, methoxy, trideuteriomethoxy, difluoromethoxy, ethoxy, cyclopropoxy and hydroxy; R ⁶ is H. A further embodiment of present invention is (x’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (ix’), wherein R ³ is ; wherein R ⁴ is H or C _1-6 alkoxyC _1-6 alkyl; R ⁵ is phenyl substituted twice or three times by the substituents independently selected from C _{1- 6} alkoxy and halogen; R ⁶ is H. A further embodiment of present invention is (xi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (x’), wherein R ³ is ; wherein R ⁴ is H or methoxymethyl; R ⁵ is phenyl substituted twice or three times by the substituents independently selected from methoxy and fluoro; R ⁶ is H. A further embodiment of present invention is (xii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xi’), wherein Q ¹ is C _{1- 6} alkylene substituted once or twice by the substituents independently selected from C _1-6 alkoxy, C _1-6 alkylcarbonyloxy, hydroxy and C _1-6 alkyl. A further embodiment of present invention is (xiii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xii’), wherein Q ¹ is propylene substituted once or twice by the substituents independently selected from ethoxy, methoxy, hydroxy, methyl and acetoxy. A further embodiment of present invention is (xiv’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xiii’), wherein Q ¹ is C _{1- 6} alkylene substituted by C _1-6 alkoxy. A further embodiment of present invention is (xv’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xiv’), wherein Q ¹ is propylene substituted by methoxy or ethoxy. A further embodiment of present invention is (xvi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xv’), wherein Q ² is NH or O. A further embodiment of present invention is (xvii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xvi’), wherein A ¹ is N. A further embodiment of present invention is (xviii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xvii’), wherein A ³ is CR ⁸ , wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkoxy or haloC _1-6 alkoxy. A further embodiment of present invention is (xix’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xviii’), wherein A ³ is CR ⁸ , wherein R ⁸ is H, methoxy, methyl, cyclopropoxy or difluoromethoxy. A further embodiment of present invention is (xx’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xix’), wherein A ³ is CR ⁸ , wherein R ⁸ is H. A further embodiment of present invention is (xxi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xx’), wherein A ⁴ is CR ⁹ , wherein R ⁹ is H. A further embodiment of present invention is (xxii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxi’), wherein A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or fluoro. A further embodiment of present invention is (xxiii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxii’), wherein A ⁵ is CR ¹⁰ , wherein R ¹⁰ is H. A further embodiment of present invention is (xxiv’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxiii’), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is H or halogen. A further embodiment of present invention is (xxv’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxiv’), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is H or fluoro. A further embodiment of present invention is (xxvi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxv’), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is halogen. A further embodiment of present invention is (xxvii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxvi’), wherein A ⁶ is CR ¹¹ , wherein R ¹¹ is fluoro. A further embodiment of present invention is (xxviii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxvii’), wherein A ⁷ is CR ¹² , wherein R ¹² is H or halogen. A further embodiment of present invention is (xxix’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxviii’), wherein A ⁷ is CR ¹² , wherein R ¹² is H or fluoro. A further embodiment of present invention is (xxx’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i’) to (xxix’), wherein A ⁷ is CR ¹² , wherein R ¹² is H. A further embodiment of present invention is (xxxi’) a compound of formula (I) or (Ia), according to any one of (i’) or (ii’) or (iii’), wherein R ¹ is H or C _1-6 alkyl; R ² is H or C _1-6 alkyl; R ³ is ; wherein R ⁴ is H, amino, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkyl, hydroxyC _1-6 alkyl or morpholinylC _{1- 6} alkyl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from C _1-6 alkoxy, C _3-7 cycloalkoxy, haloC _1-6 alkoxy, halogen, hydroxy, and trideuterioC _{1- 6} alkoxy; R ⁶ is H; Q ¹ is C _1-6 alkylene substituted once or twice by the substituents independently selected from C _{1- 6} alkoxy, C _1-6 alkylcarbonyloxy, hydroxy and C _1-6 alkyl; Q ² is NH or O; A ¹ is CH or N; A ² is CH or N; A ³ is CR ⁸ , wherein R ⁸ is H, C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkoxy or haloC _1-6 alkoxy; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or halogen; A ⁶ is CR ¹¹ , wherein R ¹¹ is H or halogen; A ⁷ is CR ¹² , wherein R ¹² is H or halogen; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxii’) a compound of formula (I) or (Ia), according to (xxxi’), wherein R ¹ is H or methyl; R ² is H, methyl or ethyl; R ³ is ; wherein R ⁴ is H, amino, ethoxy, hydroxymethyl, methoxy, methoxymethyl, methyl, morpholinylmethyl; R ⁵ is phenyl substituted once, twice or three times by the substituents independently selected from fluoro, methoxy, trideuteriomethoxy, difluoromethoxy, ethoxy, cyclopropoxy and hydroxy; R ⁶ is H; Q ¹ is propylene substituted once or twice by the substituents independently selected from ethoxy, methoxy, hydroxy, methyl and acetoxy; Q ² is NH or O; A ¹ is CH or N; A ² is CH or N; A ³ is CR ⁸ , wherein R ⁸ is H, methoxy, methyl, cyclopropoxy or difluoromethoxy; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H or fluoro; A ⁶ is CR ¹¹ , wherein R ¹¹ is H or fluoro; A ⁷ is CR ¹² , wherein R ¹² is H or fluoro; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxiii’) a compound of formula (I) or (Ia), according to (xxxi’), wherein R ¹ is C _1-6 alkyl; R ² is C _1-6 alkyl; R ³ is ; wherein R ⁴ is H or C _1-6 alkoxyC _1-6 alkyl; R ⁵ is phenyl substituted twice or three times by the substituents independently selected from C _{1- 6} alkoxy and halogen; R ⁶ is H; Q ¹ is C _1-6 alkylene substituted by C _1-6 alkoxy; Q ² is NH or O; A ¹ is N; A ² is CH or N; A ³ is CR ⁸ , wherein R ⁸ is H; A ⁴ is CR ⁹ , wherein R ⁹ is H; A ⁵ is CR ¹⁰ or N, wherein R ¹⁰ is H; A ⁶ is CR ¹¹ , wherein R ¹¹ is halogen; A ⁷ is CR ¹² , wherein R ¹² is H; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxiv’) a compound of formula (I) or (Ia), according to (xxxiii’), wherein R ¹ is methyl; R ² is methyl,

R ³ is ; wherein

R ⁴ is H or methoxy methyl;

R ⁵ is phenyl substituted twice or three times by the substituents independently selected from methoxy and fluoro;

R ⁶ is H;

Q ¹ is propylene substituted by methoxy or ethoxy;

Q ' is NH or O;

A ¹ is N;

A ² is CH orN;

A ³ is CR ⁸ , wherein R ⁸ is H;

A ⁴ is CR ⁹ , wherein R ⁹ is H;

A ³ is CR ¹⁰ or N, wherein R ¹⁰ is H,

A ⁰ is CR ^U , wherein R ¹¹ is fluoro;

A ⁷ is CR ¹² , wherein R ¹² is H; or a pharmaceutically acceptable salt thereof.

Another embodiment of present in vention (xxxv) is a compound of formula. (I) or (la) selected from the following:

(8S, 11 S)- 10-[ 1 -(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa- 10, 13, 17, 19 2,6 8, 11 20,24 tetrazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa-l(23),2(26),3,5,18,20(24),21-heptaen-12-one;

(8 S, 11 S)- 10-[2-(2,4-difluorophenyl)-3 -methyl-imidazole-4-carbonyl]-7-oxa- 10, 13 , 17, 19- 2,6 8,11 20,24 tetrazapentacyclo [15.6.1. 1 .1 .0 ]hexacosa-l(23),2,4,6(26),18,20(24),21-heptaen-12-one;

(8S, 11 S)-10-[l -(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-10 ,13,16, 18- 2,6 8,11 19,23 tetrazapentacyclo[14.6.1.1 .1 .0 ]pentacosa- 1(22), 2, 4,6(25),! 7,19(23), 20-heptaen- 12-one; (8S, 11 S)-10-[l-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 13-(2-hydroxyethyl)- 2,6 8,11 20,24

7-oxa-10, 13, 17, 19-tetrazapentacyclo[15.6.1.1 .1 .0' ]hexacosa- 1 (23), 2(26), 3, 5, 18, 20(24), 21 -heptaen- 12-one; (8S,11S)-13-benzyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(2-methoxyethyl)- 2,6 8,11 20,24 7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18, 20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3- 2,6 8,11 20,24 morpholinopropyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1 .1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimid in-4-yl]-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-13-yl]propyl-trimethyl-ammonium; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[1 5.6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[1 5.6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(4-fluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl ]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-13-methyl-10-[3-(3-pyridyl)imidazo[1,5-a]pyrazin-8- yl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]tria zin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl] -15-(2- 2,6 8,11 20,24 methoxyethoxy)-13-methyl-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl] -15-(2- 2,6 8,11 20,24 methoxyethoxy)-13-methyl-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15- (2- 2,6 8,11 20,24 methoxyethoxy)-13-methyl-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-4-(oxetan-3-yl)-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(2-fluorophenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(2-fluorophenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-m ethyl-pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-m ethyl-pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3, 4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy )phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(1-bicyclo[1.1.1]pentanyl)pyrazolo[3,4-d] pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-[1,2,4]triazolo[4,3- a]pyrazin-8-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(3,4-difluoro-2-methoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[1-(3-me thyl-1- bicyclo[1.1.1]pentanyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(3-fluoro-1-bicyclo[1.1.1]penta nyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 5-fluoro-2-[4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimet hyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile; [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-4- carbonitrile; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-4- carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 15-ethoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentacy clo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(cyclopropoxy) -4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentacycl o[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18, 20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-4,10,13,17,19,26-hexazapentacycl o[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-4,10,13,17,19,26-hexazapentacycl o[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-4,10,13,17,19,26-hexa zapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-4,10,13,17,19,26-hexa zapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-4,5,10,13,17,19-hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-4,5,10,13,17,19-hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18, 20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)-6-methyl- pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-4,5,10,1 3,17,19-hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)-6-methyl- pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-4,5,10,1 3,17,19-hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- (hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- (hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 1-(4-fluoro-2-methoxy-phenyl)-4-[(8S,11S)-22-fluoro-15-metho xy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxamide; 1-(4-fluoro-2-methoxy-phenyl)-N,N-dimethyl-4-[(8S,11S)-22-fl uoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7-oxa-10,13,17,19,26-pentazapentacyclo[15.6. 1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxamide; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methylamino)pyrazolo[ 3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentaz apentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-methoxy-pyrazolo[3,4-d ]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentac yclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-hydroxy-pyrazolo[3,4-d ]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentac yclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 8S,11S)-10-[1-(2,4-difluorophenyl)-6-ethoxy-pyrazolo[3,4-d]p yrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentac yclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(2-methoxyethylamino)p yrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26 - 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pen tazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(2-morpholinoethoxy)py razolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26 -pentazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-10-[1-(4-fluoro-2-methylsulfanyl-phen yl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)-6-m ethyl-pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19, 26 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacycl o[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacycl o[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(6-fluoro-2-hydroxy-3-pyridyl)imidazo[1,5-a]p yrazin-8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[3-(2,6-difluoro-3-pyridyl)imidazo[1,5-a]pyrazin -8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-13-methyl-10-[3-(2-thienyl)imidazo[1,5-a]pyrazin-8- yl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(5-fluoro-3-methoxy-2-pyridyl)pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(3-fluoro-5-methoxy-2-pyridyl)pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[3-(3,5-difluoro-2-pyridyl)imidazo[1,5-a]pyrazin -8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[2-(2-chloro-4-fluoro-phenyl)pyrimidin-5-yl]-13- methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(methylamino)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,22,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)py razolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(2-morpholinoethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(2-morpholinoethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(2-methoxyethoxy)phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[2-fluoro-4-(2-methoxyethoxy)phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(oxetan-3-ylmethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(oxetan-3-yloxy)phenyl]pyrazolo[3 ,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[2-fluoro-4-(oxetan-3-yloxy)phenyl]pyrazolo[3 ,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-[(4-methylmorpholin-2-yl)methoxy] phenyl]pyrazolo[3,4- 2,6 8,11 20,24 d]pyrimidin-4-yl]-13-methyl-7,10,13,17,19,26-hexazapentacycl o[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-18-(2-methoxyethyl)-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-18-(2-morpholinoethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-(2-hydroxyethyl)- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-18-[2-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxi no[2,3-c]pyrrol-6-yl]ethyl]- 10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13- methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-[2-(4- methylsulfonylpiperazin-1-yl)ethyl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-[2- 2,6 8,11 20,24 (1,2,4-triazol-1-yl)ethyl]-7,10,13,17,19,26-hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-(2- 2,6 8,11 20,24 pyrazol-1-ylethyl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-23-fluoro-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 22,26 7,10,13,19,21,28-hexazapentacyclo[17.6.1.1 .1 .0 ]octacosa-1(25),2(28),3,5,20,22(26),23- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-3-methyl-pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 5-fluoro-2-[4-[(8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile; 5-fluoro-2-[4-[(8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzoic acid; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-ethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-13-ethyl-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(2-methoxyethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-(2-morpholinoethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3-hydroxypropyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(tetrazol-2- 2,6 8,11 20,24 yl)propyl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(tetrazol-1- 2,6 8,11 20,24 yl)propyl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(4- methylsulfonylpiperazin-1-yl)propyl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-(2- hydroxyethoxy)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-(2- hydroxyethoxy)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 15-(2-morpholinoethoxy)-7,10,13,17,19,26-hexazapentacyclo[15 .6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 15-(2-morpholinoethoxy)-7,10,13,17,19,26-hexazapentacyclo[15 .6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-18,22-dideuterio-10-[1-(2,4-difluorophenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-15-hydroxy-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-hydroxy- 2,6 8,11 20,24 13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-hydroxy- 2,6 8,11 20,24 13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 hydroxy-13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 hydroxy-13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; [(8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-dimethylphosphoryl-pyr azolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacy clo[15.6.1.1 .1 .0 ]- hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidine-6-carboxylic acid; 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidine-6-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyrida zin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyrida zin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-b]pyridi n-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-b]pyridi n-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-b ]pyridin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-b ]pyridin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-23-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(hydroxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]- hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-morpholino-pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; Ethyl 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-carboxylate; (8S,11S)-10-[1-(4-fluoro-2-methylsulfanyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methylsulfinyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methylsulfonyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-dimethylphosphoryl-4-fluoro-phenyl)pyrazol o[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]- hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-4-[(3,3-difluoroazetidin-1-yl)methyl]-10-[1-(4-fluo ro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimet hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 13,18-dimethyl-4-(morpholinomethyl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-4,15-dimethoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-4,15-dimethoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-4,13-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-4,13-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-amino-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22- 2,6 8,11 20,24 fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapent acyclo[15.6.1.1 .1 .0 ]- hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[6-amino-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)py razolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-22-fluoro-15-hydroxy-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-vinyl-phenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S)-10-[1-(2-cyclopropyl-4-fluoro-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S)-10-[1-(2-bromo-4-fluoro-phenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyri midin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-methoxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13,22- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-methyl-pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-4-(difluoromethoxy)-10-[1-(2,4-difluorophenyl)pyraz olo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-4-(cyclopropoxy)-10-[1-(2,4-difluorophenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-13-cyclopropyl-10-[1-(2,4-difluorophenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15- (trideuteriomethoxy)-13-(trideuteriomethyl)-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-[2-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)-1H-pyrazolo[4,3-d]pyrimi din-7-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-ethyl-15-methoxy- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-18-ethyl-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-(hydroxymethyl)- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[6-cyclobutyl-1-(2,4-difluorophenyl)pyrazolo[3,4 -d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4,5-difluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyri midin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo [3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-[2-fluoro-4-(trifluoromethoxy)phenyl]pyrazolo [3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-15-methoxy-10-[1-(2-methoxyphenyl)pyrazolo[3,4-d]py rimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-chloro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(5-chloro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-4- (methoxymethyl)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-4-carbonitrile; (8S,11S)-10-[1-[4-fluoro-2-(trifluoromethoxy)phenyl]pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methyl-phenyl)pyrazolo[3,4-d]pyri midin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18- 2,6 8,11 20,24 (trifluoromethyl)-5,7,10,13,17,19,26-heptazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-4,13-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13- 2,6 8,11 20,24 ethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13- 2,6 8,11 20,24 ethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methy l-pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-5,7,10,13,17,19, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-m ethyl-pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-5,7,10,13,17,19, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-m ethyl-pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-5,7,10,13,17,19, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyri midin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 4,13-dimethyl-3,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-methyl- 2,6 8,11 20,24 3,5,7,10,13,17,19-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-thia-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13 ,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)triazolo[4,5-c]pyridi n-4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2- (methoxymethyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-d imethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(5-fluoropyrimidin-2-yl)pyrazol o[4,3-c]pyridin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-3,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-3,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-3,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]- 15-ethoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-4,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-4,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-4,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-5,7,10,13,17,19-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(1-bicyclo[1.1.1]pentanyl)pyrazolo[3,4-d]pyri midin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(5-fluoropyrimidin-2-yl)pyrazol o[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-fluoro-4-phenyl-phenyl)pyrazolo[3,4-d]pyri midin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(4,4,4- 2,6 8,11 20,24 trifluorobutyl)-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl ]-22-fluoro-13-(3- 2,6 8,11 20,24 pyrimidin-2-yloxypropyl)-4,7,10,13,17,19,26-heptazapentacycl o[15.6.1.1 .1 .0 ]- hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-22-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-21-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21-fluoro-15- 2,6 8,11 20,24 methoxy-13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]py rimidin-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]py rimidin-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-methyl- 2,6 8,11 20,24 4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3- 2,6 8,11 20,24 methoxypropyl)-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-16-oxa- 2,6 8,11 22,26 7,10,13,19,21,28-hexazapentacyclo[17.6.1.1 .1 .0 ]octacosa-1(25),2(28),3,5,20,22(26),23- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(1-pyrim idin-5-ylpyrazolo[3,4- 2,6 8,11 20,24 d]pyrimidin-4-yl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (11S,14S,18R)-13-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-25-fluoro-18- methoxy-16,21-dimethyl-5-oxa-10,13,16,20,22,29- 2,9 11,14 3,7 23,27 hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa-1(26),2(29),3(7),8,21,23(27),24-heptaen- 15-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[1-methy l-6-(3- thienyl)pyrazolo[4,3-c]pyridin-3-yl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4, 3-c]pyridin-3-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-21,23-difluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyr azolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S)-10-[2-(2,4-difluorophenoxy)-4-pyridyl]-15-ethoxy-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (8S,11S)-15-ethoxy-10-[1-[4-fluoro-2-(2-oxopyrrolidin-1-yl)p henyl]pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,15,18- 2,6 8,11 20,24 trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,15,18- 2,6 8,11 20,24 trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]- 2,6 8,11 20,24 13,15,18-trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-13,15,18- 2,6 8,11 20,24 trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21-fluoro-18-hydroxy- 2,6 8,11 20,24 13-methyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaene-14-carboxylic acid; (8S,11S,15R)-10-[6-ethoxy-1-(4-fluoro-2-methoxy-phenyl)pyraz olo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methoxy-pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-ethoxy-pyrazolo[3, 4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(morpholinomethyl) pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-isopropyl-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; methyl (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-12- 2,6 8,11 20,24 oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-18-carboxylate; (8S,11S)-18-(chloromethyl)-10-[1-(2,4-difluorophenyl)pyrazol o[3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-hydroxy-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-18-amino-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]p yrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-N,13-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-18-carboxamide; (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; N-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimid in-4-yl]-13-methyl-12-oxo- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-18-yl]acetamide; (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-18-cyclopropyl-10-[1-(2,4-difluorophenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2-fluoro-4-tetrahydrofuran-3-yl-phenyl)pyraz olo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22,23-difluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S)-10-[1-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]pyra zolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-18- methyl-15-(trideuteriomethoxy)-13-(trideuteriomethyl)-7-oxa- 5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyraz olo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-tetrahydrofuran-3- yl-pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-tetrahydropyran-4- yl-pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-ylmethyl )pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-2-ylmethyl )pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylsulfonyl azetidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(1-acetylazetidin-3-yl)methyl]-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyraz olo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-hydroxy-1- (hydroxymethyl)ethyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethox y-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(hydroxymethyl) -2-methoxy- ethyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13, 18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methylsulfonyla zetidin-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(1-acetylazetidin-3-yl)-1-(2,4-difluoroph enyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methylsulfonylp yrrolidin-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2,2,2-trifluor oacetyl)pyrrolidin-3- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(1-acetylpyrrolidin-3-yl)-1-(2,4-difluoro phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylsulfonyl pyrrolidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[1-(2,2,2-trifluo roacetyl)pyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(1-acetylpyrrolidin-3-yl)methyl]-1-(2,4- difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methyl-4-piperi dyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl- 2,6 8,11 20,24 13-(3-morpholinopropyl)-7,10,13,17,19,26-hexazapentacyclo[15 .6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl- 13-[3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl]-7,10,13, 17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl- 13-[3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl]-7,10,13,17,1 9,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-13-[3-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxi no[2,3-c]pyrrol-6-yl]propyl]- 10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-18-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-ethylsulfonyla zetidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,18-dim ethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1-cyclopropylsulfonylazetidin-3-yl)meth yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,1 8-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[1-(2,2,2-trifluo roethyl)azetidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,18-dim ethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(pyrrolidine-1-carbony l)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-(2,4-difluorophenyl)-4-[(8S,11S)-22-fluoro-13,18-dimethyl- 12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- N-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidine-6-carboxamide; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(morpholine-4-carbonyl )pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-(methoxymethyl)pyr azolo[4,3-c]pyridin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-5,13,18-trimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(1,3-dihydroisobenzofuran-4-yl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methyl-6-oxo-pyraz olo[3,4-b]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1 -hydroxy-ethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[7-cyclopropyl-1-(2,4-difluorophenyl)-6-oxo- pyrazolo[3,4-b]pyridin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-(2-methoxyethyl)-6 -oxo-pyrazolo[3,4- b]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3 ,4-c]pyridin-4-yl]-22- 2,6 8,11 20,24 fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3 ,4-c]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methoxycyclopro pyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-hydroxycyclopro pyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-[2-(azetidin-1-yl)-4-fluoro-phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-morpholino-phenyl)p yrazolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacy clo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-morpholino-phenyl)p yrazolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-[4-fluor-2-(2-oxa-6-azaspiro[3. 3]heptan-6- yl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6-(methox ymethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(3-methoxycyclobuto xy)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 -hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-[1-(methoxymethyl)c yclopropoxy]phenyl] pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,1 0,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(hydroxymethyl)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-4,22-difluoro-10-[1-(4-fluoro-2-methoxy-phenyl) pyrazolo[3,4-d]pyrimidin- 2,6 8,11 20,24 4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapenta cyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2-dioxo-2λ⁶- thia-6-azaspiro[3.3]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl) azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-6-azaspiro[ 3.3]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxy-1-me thyl-ethyl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl ]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(dimethylamino )methyl]azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyla zetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(tetrahydrofuran-3 -ylmethoxy)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(1-cyclopropylazetidin-3-yl)oxy-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(4-methylpipera zin-1- yl)ethoxy]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[[1-(2,2-difluoroacetyl)azetidin-3-yl]met hoxy]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methylpiperazin -1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylazetidin -3-yl)methoxy]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylpyrrolid in-3- yl)methoxy]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-metho xy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-fluoroethyl) azetidin-3-yl]oxy- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-ylmethox y)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-y l]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(dimethylamino) azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(3-amino-3-methyl-azetidin-1-yl)-1-(2,4-d ifluorophenyl)pyrazolo [3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[1-(2,2-difluoroethyl)azetidin-3-yl]oxy-1 -(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-morpholinoazeti din-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[[1-(2,2-difluoroethyl)azetidin-3-yl]meth oxy]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[1-(2,2-difluoroethyl)azetidin-3-yl]-1-(2 ,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]ethyl acetate; (8S,11S,15R)-22-fluoro-10-[1-(5-fluoro-3-methylsulfanyl-2-py ridyl)-6-methylsulfanyl- pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,1 0,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R)-1-hydroxyeth yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S)-1-hydroxyeth yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-6-azaspiro[ 3.3]heptan-6- ylmethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(morpholinometh yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]acetonitrile; (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-1-( 2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[4-(oxetan-3-yl)pi perazin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-yl)-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[4-(2H-tetrazol-5- yl)-1-piperidyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methyl-4,7-diaz aspiro[2.5]octan-7- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(3,5-difluoro-2-pyridyl)-6-(3-morpholinoa zetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7,10,13 ,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-3,6-diaz abicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a] pyrazin-2-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[(2R,8S)-2-fluoro -1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahyd ropyrrolo[3,4-c]pyrrol-5- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-cyclopentyl-1-(3,5-difluoro-2-pyridyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- ylmethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(4aR,7aR)-4-methy l-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]pyrazolo[3,4-d]pyrim idin-4-yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-benzyl-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro -15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]piperazine-2- carboxylic acid; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(9-methyl-3-oxa-7, 9-diazabicyclo[3.3.1]nonan- 7-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-oxazol-5-yl-1-p iperidyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-methylsulfonyl-pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(3-prop- 1-ynylimidazo[1,5- a]pyrazin-8-yl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ^2,6 .1 ^8,11 .0 ^20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methylsulfanyl-pyr azolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6-[[1-(2- methoxyacetyl)azetidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro -13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(3-methox y-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7- oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(3-methox ypyrrolidin-1- yl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-ox a-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluoro-6-tetrahydrofuran-3-yloxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[2-[4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12- oxo-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-1-yl]-3,5-difluoro-ph enoxy]acetonitrile; (8S,11S,15S)-10-[1-[2,4-difluoro-6-[(1-methylsulfonylazetidi n-3- yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-4-(cyclopropylamino)-10-[1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19 ,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(6-fluoro-1H-indazol- 5-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)indazol-4-yl]-15-etho xy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(trideute riomethoxy)phenyl]-6- (oxetan-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5 ,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(trideute riomethoxy)phenyl]-6-[3- oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methyl-7-oxo-pyraz olo[3,4-c]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-methoxyethyl)-7 -oxo-pyrazolo[3,4- c]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[7-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[ 3,4-c]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(cyclopropylmethyl)-1-(2,4-difluorophenyl )-7-oxo-pyrazolo[3,4- c]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3-yl)methyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15S)-22-fluoro-15-me thoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimi din-6-yl]azetidin-1-yl]acetonitrile; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothian-4- yl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(methylsulfonyl methyl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[6-(1-cyclopropylazetidin-3-yl)-1-(2,4-diflu orophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3- yl)methylsulfanyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy )phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-(azetidin-1-yl)-1-[4-fluoro-2-(trideuteri omethoxy)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10 ,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-(azetidin-1-yl)-1-(2,4-difluorophenyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(dimethylamino)pyr azolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hex azapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-5-azabicycl o[2.2.1]heptan-5- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-oxa-3-azabicycl o[3.2.1]octan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-8-azabicycl o[3.2.1]octan-8- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-imidazol-1-yl-pyra zolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2,2-trifluoroet hoxy)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-(oxetan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,1 7,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (3S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]pyrrolidine-3- carbonitrile; 8-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]-6,7,9,9a-tetrahydro- 1H-pyrazino[2,1-c][1,4]oxazin-4-one; (8S,11S,15R)-10-[6-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c ][1,4]oxazin-8-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-oxa-6-azabicycl o[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-oxa-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,1 8-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(2- methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3, 4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[6-[3-(2-fluoroethyl)-3, 6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[8-(2-fluoroethyl) -5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[8-(2-methoxyethyl )-5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[5-(2-fluoroethyl) -8-oxa-2,5- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-py rrolidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,8-diazabicyclo[3.2.1]octan- 8-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-5-(3-phenylpropylami no)pyrazole-4-carbonyl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5S)-3-cyclopropyl-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxopyrrolidin-1 -yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6-oxa-3-azabicycl o[3.1.1]heptan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxeta n-3-yl)methyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxeta n-3-yl)methyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-hydroxy-6-(trif luoromethyl)-2- azaspiro[3.3]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-f luoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6-oxa-1-azaspiro[ 3.3]heptan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(2-fluoroethyl) -1,6-diazaspiro[3.3]heptan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-( 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,1 8-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-d iazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5 ,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-hydroxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6 -diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5 ,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimi din-6-yl]azetidin-1-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimi din-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; (8S,11S,15R)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy -22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro -15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro -15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-5-(2-morpholinoethyl amino)pyrazole-4- carbonyl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19, 26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[11-benzyl-3-(2,4-difluorophenyl)-3,4,8,11- 2,6 tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-11-methyl-3,4,8,11-t etrazatricyclo[7.3.0.0 ^2,6 ]dodeca- 1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13,18-dimet hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[5-amino-1-(2,4-difluorophenyl)pyrazole-4-ca rbonyl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(methoxyme thyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3-carb onitrile; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(2-methoxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(2-fluoroethyl) -1,7-diazaspiro[3.5]nonan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-1 ,7-diazaspiro[3.5]nonan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(oxetan-3-yl)-1 ,6-diazaspiro[3.3]heptan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6,6-dioxo-6λ⁶- thia-1-azaspiro[3.3]heptan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,7-diazabicyclo[4.2.0]octan- 7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-11-(oxetan-3-yl)-3,4 ,8,11- 2,6 tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(oxetan -3-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(2-methoxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(4-fluoro- 2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15 -methoxy-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[6-[3-(2-fluoroethyl)-3, 6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(4-fluoro- 2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22 -fluoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(2- methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3, 4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(oxetan-3-yl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-2-oxo-p yrrolidin-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxopyrrolidin-1 -yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10, 13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxazolidin-2-one ; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxazolidin-2-one ; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methyl-2-oxo-pi perazin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-[6-[3-(2-fluoroethyl)-3,6-diazabic yclo[3.1.1]heptan-6-yl]-1-(4- fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-me thoxy-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-hydroxy-2-me thyl-propanoyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclo propanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclo butanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicycl o[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one;and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-fluorocyclob utyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; orapharmaceuticallyacceptablesaltthereof. Anotherembodimentofpresentinvention(xxxvi)isaprocessforthepr eparationofa compoundaccordingtoanyoneof(i)to(xxxv)comprisinganyofthefoll owingsteps: a)theformationofcompoundofformula(I), (I), via nucleophilic substitution between compound of formula (VIII), (VIII), and R ³ X, in the presence of a base; b) the formation of compound of formula (I) via Buchwald-Hartwig reaction between compound of formula (VIII) and R ³ X, in the presence of a catalyst; c) the formation of compound of formula (I) via condensation reaction between compound of formula (VIII) and R ³ OH, in the presence of coupling reagent; d) the formation of compound of formula (I) via cyclization reaction between compound of formula (XVIII) , (XVIII), and regents; e) the formation of compound of formula (XXI), (XXI), via nucleophilic substitution between compound of formula (XX), (XX), and R ³ X in the presence of a base;

f) the formation of compound of formula (XXII), via reaction between compound of formula (Ic) , and alcohols or amines (R ⁴ -X) in the presence of a base; g) the amino group of compound of formula (XXIV), , reacts with halide via nucleophilic substitution or with ketone via reductive amination to provide final compound of formula (XXII); wherein in step a) and e) , the base is DIEA; in step b), the catalyst is Pd ₂ (dba) ₃ ; in step c), the coupling reagent is HATU; in step d), the regents is CDI, BrCN or R ¹ (OCH ₃ ) ₃ ; in step e), the base is DIEA; in step f), the base is DIPEA, K ₂ CO ₃ or NaH; X is halogen; R ¹³ is R ^a , R ^b or R ^c ; M is C _1-6 alkylene; R ^e is a substituent bearing primary or secondary amino groups; R ¹ to R ⁷ , Q ¹ , Q ² , A ¹ to A ⁷ are as defined as in any one of (i) to (xxxv) or (i’) to (xxxiv’). Another embodiment of present invention (xxxvii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxxv) or (i’) to (xxxiv’) for use as therapeutically active substance. Another embodiment of present invention (xxxviii) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xxxv) or (i’) to (xxxiv’) and a therapeutically inert carrier. Another embodiment of present invention (xxxix) is related to the use of a compound according to any one of (i) to (xxxv) or (i’) to (xxxiv’) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. Another embodiment of present invention (xl) is related to the use of a compound according to any one of (i) to (xxxv) or (i’) to (xxxiv’) for the treatment to subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root- cause of disease pathologies. Another embodiment of present invention (xli) is related to the use of a compound according to any one of (i) to (xxxv) or (i’) to (xxxiv’) for the inhibition of STING. Another embodiment of present invention (xlii) is related to the use of a compound according to any one of (i) to (xxxv) or (i’) to (xxxiv’) for the preparation of a medicament for the inhibition of STING. Another embodiment of present invention (xliii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxxv) or (i’) to (xxxiv’), when manufactured according to a process of (xxxvi). Another embodiment of present invention (xliv) is related to a method for the treatment or prophylaxis of autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound as defined in any one of (i) to (xxxv) or (i’) to (xxxiv’). PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit STING interaction with IRF3, NF-kB, NLRP3 etc., for blocking downstream type I IFN and pro-inflammatory cytokine (e.g. IL-6, TNFa, ISGs) production, cellular responses/conditions (e.g. autophagy, apoptosis, cell senescence). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg/kg, alternatively about 0.1 to 1000 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.1 to 1000 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the invention compounded with about 0.1 to 1000 mg anhydrous lactose, about 0.1 to 1000 mg sodium croscarmellose, about 0.1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 0.1 to 1000 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathies, autoimmune and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infection or selective type of cancer. The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compounds of the invention inhibit STING, including its signaling and activities. Accordingly, the compounds of the invention are useful for infection, inflammation, auto- immune, degenerative diseases and cancer therapy. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of autoimmune diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of inflammatory diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of neurological disorders diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of cardiovascular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of ocular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of selective types of cancers where overexpression or activation of STING is implicated. Alternatively, compounds of the invention are useful for the treatment of subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. More broadly, the compounds can be used for the treatment of all pathological cellular processes which are STING dependent. Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R ¹ to R ⁷ , Q ¹ , Q ² , A ¹ to A ⁷ are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the compound of the invention are shown in following schemes. Scheme 1

Wherein R ^d is H or PG, wherein PG can be, for example, Boc or Cbz; X is halogen. As depicted in Scheme 1, the synthesis of compounds of the present invention started from bronic ester compound of formula (II) or halide (III). Suzuki coupling between compound of formula (II) and compound of formula (IIb) with a catalyst, such as Pd(dppf)Cl ₂ , and a base, such as K ₂ CO ₃ , provides compound of formula (V), which can also be obtained via the Suzuki coupling between bronic ester compound of formula (IIIb) and halide (III). On the other hand, Suzuki coupling between compound of formula (II) and halide (IIa) or between compound of formula (IIIa) and halide (III) provides an intermediate of formula (IV), which is reacted with compound of formula (IVa) via Buchwald-Hartwig amination or nucleophilic substitution to give compound of formula (V). Compound of formula (V) is hydrolyzed in the presence of LiOH directly and followed by appropriate deprotection to give compound of formula (VI) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd/C or Pd(OH) ₂ /C under H ₂ ). Compound of formula (VI) can be cyclized to give compound of formula (VII) in the presence of a coupling reagent, such as HATU, and a base, such as DIPEA. The following Boc deprotection in acidic condition (HCl in dioxane or TFA in DCM) or Cbz deprotection by catalytic hydrogenation (Pd/C or Pd(OH) ₂ /C under H ₂ ) or in acidic condition (TFA) to give compound of formula (VIII). Compound of formula (I) can be obtained by the reaction between compound of formula (VIII) and R ³ X via nucleophilic substitution in the presence of a base, such as DIEA, or via Buchwald-Hartwig reaction in the presence of a catalyst, such as Pd ₂ (dba) ₃ . On the other hand, compound of formula (IX) can also be obtained via condensation reaction between compound of formula (VIII) and R ³ OH in the presence of coupling reagent, such as HATU. Scheme 2

As depicted in Scheme 2, Suzuki coupling between halide (IIb) and bronic ester compound of formula (X) provides compound of formula (XI), which reacts with compound of formula (XII) via nucleophilic substitution in the presence of a base, such as DIPEA, K ₂ CO ₃ to give compound of formula (XIII). The preparation of compounds of formula (XIV), (XV), (XVI), (XVII) are in analogy to the preparation of compounds of formula (VI), (VII), (VIII), (IX) that described above in scheme 1. Compound of formula (XVII) is hydrogenated in the presence of zinc and ammonium chloride to give compound of formula (XVIII), which reacts with CDI, BrCN or R ¹ (OCH ₃ ) ₃ to give compound of formula (I). General synthetic routes for preparing the compound of formula (XXI) is shown below. Wherein R ¹³ is R ^a , R ^b or R ^c . As depicted in Scheme 3, compound of formula (VIIa) is presented when R ¹ in formula (VII) is hydroxyC _1-6 alkyl. Compound of formula (VIIa) reacts with methanesulfonic anhydride or methanesulfonyl chloride in the presence of a base, such as DIPEA or TEA to give a methanesulfonate ester intermediate, which was treated with amine to provide compound of formula (XIX). The preparation of compounds of formula (XX) is in analogy to the preparation of compounds of formula (VIII) in scheme 1. Compound of formula (XXI) can be obtained via nucleophilic substitution between compound of formula (XX) and R ³ X in the presence of a base, such as DIEA. General synthetic routes for preparing the compound of formula (XXII) is shown below.

Wherein X is OH, NH, SH or halogen; R ^e is a substituent bearing primary or secondary amino groups. As depicted in Scheme 4, compound of formula (Ic) is presented when R ³ in formula (I) is . Compound of formula (Ic) reacts ⁴ with alcohols or amines (R -X) in the presence of a base, such as DIPEA, K ₂ CO ₃ or NaH to directly give compound of formula (XXII) or give intermediate compound of formula (XXIII), which was then deprotected in acidic condition to give compound of formula (XXIV). The amino group of compound of formula (XXIV) reacts with halide via nucleophilic substitution or with ketone via reductive amination to provide final compound of formula (XXII). On the other hand, photoredox coupling between compound of formula (Ic) and alkyl halide (R ⁴ X) in the presence of a catalyst, such as Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ to directly give compound of formula (XXII) or give Boc-protected compound of formula (XXIII), which was then deprotected in acidic condition to give compound of formula (XXIV). Nucleophilic substitution with halide or reductive amination with ketone of compound of formula (XXIV) to provide final compound of formula (XXII). Thirdly, Buchwald coupling between compound of formula (Ic) and lactams (such as pyrrolidin-2-one, morpholin-3-one) in the presence of a catalyst, such as Pd ₂ dba ₃ to give compound of formula (XXII). Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. This invention also relates to a process for the preparation of a compound of formula (I) or (I) comprising any of the following steps: a) the formation of compound of formula (I), via nucleophilic substitution between compound of formula (VIII), and R ³ X, in the presence of a base; b) the formation of compound of formula (I) via Buchwald-Hartwig reaction between compound of formula (VIII) and R ³ X, in the presence of a catalyst; c) the formation of compound of formula (I) via condensation reaction between compound of formula (VIII) and R ³ OH, in the presence of coupling reagent; d) the formation of compound of formula (I) via cyclization reaction between compound of formula (XVIII), , and regents; e) the formation of compound of formula (XXI), , via nucleophilic substitution between compound of formula (XX), , and R ³ X in the presence of a base;

f) the formation of compound of formula (XXII), via reaction between compound of formula (Ic), , and alcohols or amines (R ⁴ -X) in the presence of a base; g) the amino group of compound of formula (XXIV), reacts with halide via nucleophilic substitution or with ketone via reductive amination to provide final compound of formula (XXII); wherein in step a) and e) , the base can be, for example, DIEA; in step b), the catalyst can be, for example, Pd ₂ (dba) ₃ ; in step c), the coupling reagent can be, for example, HATU; in step d), the regents can be, for example, CDI, BrCN or R ¹ (OCH ₃ ) ₃ ; in step e), the base can be, for example, DIEA; in step f), the base can be, for example, DIPEA, K ₂ CO ₃ or NaH; X is halogen; R ¹³ is R ^a , R ^b or R ^c ; M is C _1-6 alkylene; R ^e is a substituent bearing primary or secondary amino groups. A compound of formula (I) or (Ia) when manufactured according to the above process is also an object of the invention. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: ACN: acetonitrile Boc ₂ O: di-tert butyl dicarbonate BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-dinaphthalene DCM: dichloromethane DCE: dichloroethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: diisobutylaluminium hydride DIAD: diisopropyl azodicarboxylate DMA: N,N-Dimethylacetylamine DMAP: 4-dimethylaminopyridine DMF: N,N-Dimethylformamide DMSO: dimethyl sulfoxide DPPP: 1,3-Bis(diphenylphosphino)propane EA or EtOAc: ethyl acetate FA: formic acid HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate h(s) or hr(s): hour (s) hPBMC: human peripheral blood mononuclear cells IC ₅₀ : half inhibition concentration Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ): [4,4’-Bis(1,1-dimethylethyl)-2,2’-bipyridine- N1,N1’]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl -N]phenyl-C]Iridium(III) hexafluorophosphate IPA: isopropanol LCMS: liquid chromatography-mass spectrometry mCPBA: meta-chloroperoxybenzoic acid min(s): minute(s) MS: mass spectrometry MsCl: methanesulfonyl chloride Ms ₂ O: methanesulfonic anhydride NBS: N-bromosuccinimide NIS: N-iodosuccinimide NMP: N-Methylpyrrolidone NiCl ₂ .dtbbpy: [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride PE: petroleum ether prep-HPLC: preparative high performance liquid chromatography prep-TLC: preparative thin layer chromatography PyBOP/BOP : (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylphosphorus hexafluorophosphate PPh ₃ : triphenylphosphine Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium(0) (R)-binap : (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Rf: retention factor rt, r.t: room temperature RT: retention time RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’ - biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) 2nd generation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: supercritical fluid chromatography S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBSCl: tert-butyldimethylsilyl chloride t-BuXPhos: 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl tBuXPhos Pd G3: Methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl -1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) tBu ₃ P-Pd-G2 Chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2- yl)palladium(II) T ₃ P: Propylphosphonic anhydride TEA: trimethylamine TFA: trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: tetrahydrofuran TLC: thin layer chromatography XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) v/v volume ratio GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge ^TM Prep-C18 (5 μm, OBDTM 30 × 100 mm) column, SunFire ^TM Prep-C18 (5 μm, OBD ^TM 30 × 100 mm) column, Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO ₂ and IPA (0.5% TEA in IPA) or CO ₂ and MeOH (0.1% NH ₃ ∙H ₂ O in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm. LC/MS spectra of compounds were obtained using a LC/MS (Waters ^TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H ₂ O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H ₂ O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH ₃ ·H ₂ O in H ₂ O; B: acetonitrile; Basic condition II: A: 0.025% NH ₃ ·H ₂ O in H ₂ O; B: acetonitrile; Neutral condition: A: H ₂ O; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH) ⁺ . NMR Spectra were obtained using Bruker Avance 400 MHz, 500 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. PREPARATIVE EXAMPLES The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: Intermediate A1 tert-butyl N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxab orolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound A1-b) To a solution of 1,3-diamino-2-propanol (35.64 g, 395.45 mmol, as the “AMINE” in table 1) in ACN was added 3-bromo-2-fluoronitrobenzene (compound A1-a, 43.5 g, 197.73 mmol, as the “ARYL FLUORIDE” in table 1) slowly at 25 °C. After being stirred at 20 °C for 0.5 hours, the mixture was filtered, and the filtered cake was collected and dissolved in methanol. Then tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (106.8 g, 489.47 mmol) and DIPEA (63.26 g, 489.47 mmol) was added. After being stirred at 20 °C for 1 h, the mixture was concentrated, the residue was purified prep-HPLC to afford compound A1-b (51.5 g). LCMS (M-56+H) ⁺ :336. Step 2: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)-2-hydroxy- propyl]carbamate (compound A1-c) To a solution of tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxy-propyl]carbamate (compound A1-b, 50.5 g, 129.41 mmol) in methanol (846 mL) was added Raney Ni (30.38 g, 517.64 mmol) and hydrazine hydrate (34.79 g, 694.97 mmol). After being stirred at 25 °C for 1 h, the mixture was filtered and concentrated. The crude product was dissolved in DCM (500 mL), washed with water (300 mL). The organic layer was dried and concentrated to give compound A1-c (43 g). LCMS (M+H) ⁺ : 360. Step 3: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- hydroxy-propyl] carbamate (compound A1-d) To a solution of tert-butyl N-[3-(2-amino-6-bromo-anilino)-2-hydroxy-propyl]carbamate (compound A1-c, 37.5 g, 104.09 mmol) in anhydrous THF (496 mL) was added trimethyl orthoacetate (45 mL, as the “SOLVENT” in table 1) and pyridinium p-toluenesulfonate (3.75 g, 14.92 mmol). After being stirred for 1 h at 20 °C, the mixture was concentrated and the residue was triturated by PE/EA(1/1, 150 mL) to give compound A1-d (39 g). LCMS (M+H) ⁺ : 384. Step 4: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- methoxy-propyl]-N-methyl-carbamate (compound A1-e) To a solution of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-hydroxy- propyl]carbamate (compound A1-d, 10.0 g, 26.02 mmol) in DMF (200 mL) was added CH ₃ I (11.08 g, 78.07 mmol, as the “ALKYL IODIDE” in table 1) at -10 °C under N ₂ , then NaH (2.6 g, 65.06 mmol) was added slowly in portions. The mixture was stirred at -10 °C for 5 hours. The mixture was then stirred at 20 °C for another 12 h. The reaction was quenched with ice cold NH ₄ Cl solution and extracted with EA twice, the organic layer was dried and concentrated to afford compound A1-e (11.7 g). LCMS (M+H) ⁺ : 412. Step 5: preparation of tert-butyl N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-c arbamate (Intermediate A1) To a mixture of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-methoxy- propyl]-N-methyl-carbamate (compound A1-e, 10.5 g, 25.47 mmol) in DMSO (150 mL) was added potassium acetate (5.0 g, 50.93 mmol), bis(triphenylphosphine)palladium(II) chloride (2.68 g, 3.82 mmol) and BUTYLDI-1-ADAMANTYLPHOSPHINE (2.74 g, 7.64 mmol). The mixture was degassed with N ₂ for three times and stirred at 130 °C for 2 hours. The reaction mixture was poured into water (1000 mL) and extracted with EA (300 mL) twice. The organic phase was washed with brine (300 mL), dried and concentrated, the residue was purified by silica gel to afford Intermediate A1 (8.8 g). LCMS (M+H) ⁺ : 460. The following intermediates in Table 1 were prepared in analogy to Intermediate A1 by replacing compound A1-a with the “ARYL FLUORIDE” and 1,3-diamino-2-propanol with the “AMINE” in step 1, trimethyl orthoacetate with the “SOLVENT” in step 3, CH ₃ I with the “ALKYL IODIDE” in step 4 by the reagents indicated in Table 1. Table 1. Compound synthesis and characterization Intermediate A6 tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate The title compound was prepared according to the following scheme: The title compound was prepared in analogy to the preparation of Intermediate A1 by using compound A7-d instead of compound A1-d. LCMS (M+H) ⁺ : 478. Intermediate A7 tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbama te The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-anilino)-2- hydroxy-propyl]carbamate (compound A7-b) To a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxy-propyl]carbamate (59.59 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitro-benzene (71.0 g, 298.33 mmol) in ACN (710 mL) was added potassium carbonate (82.46 g, 596.66 mmol). After being stirred at 50 °C for 2 hours, the mixture was filtered and the filtrate was concentrated to give compound A7-b (131 g). LCMS (M+H) ⁺ : 352. Step 2: preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoro-anilino)-2- hydroxy-propyl]carbamate (compound A7-c) To a solution of compound A7-b (63.0 g, 154.33 mmol) in methanol (1000 mL) was added Raney Ni (36.23 g, 617.31 mmol) and hydrazine hydrate (29.19 g, 583.1 mmol). After being stirred at 25 °C for 1 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM, washed with water and brine. The organic layer was dried and concentrated to give compound A7-c (128 g). LCMS (M+H) ⁺ : 378. Step 3: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]carbamate (compound A7-d) To a solution of compound A7-c (123.0 g, 325.19 mmol) in anhydrous THF (1500 mL) was added trimethyl orthoacetate (136.74 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.71 g, 46.62 mmol). The reaction was stirred for 1 h at 20 °C. The mixture was concentrated under reduced pressure to give compound A7-d (160 g). LCMS (M+H) ⁺ : 400. Step 4: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]carbamate (compound A7-e) To a solution of compound A7-d (80.0 g, 198.88 mmol) and imidazole (40.62 g, 596.63 mmol) in DMF (765 mL) was added tert-butyldimethylchlorosilane (59.95 g, 397.75 mmol), then the mixture was stirred for 18 hours at 30 °C. The mixture was poured into ice-aq.NH ₄ Cl (2000 mL), extracted with EtOAc (800 mL) twice. The organic layer was dried and concentrated to give compound A7-e (94 g). LCMS (M+H) ⁺ : 518. Step 5: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carb amate (compound A7-f) To a solution of compound A7-e (82.0 g, 158.75 mmol) in DMF (800 mL) was added sodium hydride (60% in oil, 15.87 g, 396.89 mmol) at 0°C and then stirred at 0 °C for 1 h. Iodomethane (90.13 g, 635.02 mmol) was then added at 0°C and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA. The organic layer was dried and concentrated, the crude product was purified by column chromatography to give compound A7-f (44.4 g). LCMS (M+H-56) ⁺ : 530. Step 6: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]-N-methyl-carbamate (compound A7-g) A mixture of compound A7-f (39.8 g, 75.02 mmol) and TBAF/THF (1M, 150.0 mL, 150 mmol) was stirred at 20 °C for 2 hours. Then the mixture was concentrated and the crude product was diluted with EtOAc (600mL), washed with water and brine. The organic layer was dried and concentrated to give compound A7-g (39.4 g). LCMS(M+H) ⁺ : 416. Step 7: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound A7-h) To a solution of compound A7-g (17.4 g, 41.8 mmol) and iodoethane (5.01 mL, 62.7 mmol) in DMF (174 mL) was added sodium hydride (2.17 g, 54.34 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction was then quenched with water, and the mixture was extracted with EA. The organic layer was dried and concentrated to give compound A7-h (20.4 g). LCMS (M+H) ⁺ : 444. Step 8: preparation of tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl ]-N-methyl-carbamate (Intermediate A7) To a mixture of compound A7-h (19.4 g, 43.66 mmol) and bis(pinacolato)diboron (27.72 g, 109.15 mmol) in DMSO (194 mL) was added potassium acetate (8.57 g, 87.32 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.55 mmol) and butyldi-1- adamantylphospine (4.7 g, 13.1 mmol). The mixture was degassed with N ₂ for three times, and then stirred at 130 °C for 2 hours. The reaction mixture was then poured into water (1000 mL) and extracted with EA (500 mL). The organic layer was dried and concentrated, the crude product was purified by column chromatography to give Intermediate A7 (15 g). LCMS (M+H) ⁺ : 478. Intermediate A8 tert-butyl N-[(2R)-2-ethoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate The title compound was prepared in analogy to the preparation of Intermediate A7 by using 3-bromo-2-fluoronitrobenzene instead of 1-bromo-2,5-difluoro-3-nitro-benzene. LCMS (M+H) ⁺ : 474. Intermediate A9 tert-butyl N-[2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan- 2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate

The title compound was prepared in analogy to the preparation of Intermediate A7 by using tert-butyl N-[(3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate. LCMS (M+H) ⁺ : 492. Intermediate A10 tert-butyl N-[2-ethoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate The title compound was prepared in analogy to the preparation of Intermediate A7 by using tert-butyl N-[(3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate and 3-bromo-2-fluoronitrobenzene instead of 1-bromo-2,5- difluoro-3-nitro-benzene. LCMS (M+H) ⁺ : 474. Intermediate A15 tert-butyl N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimi dazol-1- yl]propyl] carbamate The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]carbamate (intermediate A15-a) To a microwave tube was added 1-bromo-2-fluoro-3-nitro-benzene (2.7 g, 12.3 mmol, as the “ARYL FLUORIDE” in table 2), tert-butyl N-(3-aminopropyl)carbamate (2.14 g, 12.3 mmol, as the “AMINE” in table 2), K ₂ CO ₃ (1.7 g, 12.3 mmol) and acetonitrile (15 mL). The tube was sealed and heated to 90 °C for 3 hrs. The mixture was cooled and filtered, the filtrate was concentrated and the residue was purified by silica gel to give intermediate A15-a (4.8 g). LCMS (M+H ⁺ ): 374. Step 2: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]carbamate (intermediate A15-b) To a flask was added nickel (2.9 g, 49.4 mmol), MeOH (100mL) and tert-butyl N-[3-(2- bromo-6-nitro-anilino)propyl]carbamate (intermediate A15-a, 5 g, 13.4 mmol), the suspension was stirred vigorously and hydrazine (8.56 g, 8.32 mL, 134 mmol) was then added. After being stirred at r.t. for 1 hr, the mixture was filtered and filtrate was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to give intermediate A15-b (4.6 g), LCMS (M+H ⁺ ): 344. Step 3: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (intermediate A15-c) To a flask containing tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]carbamate (intermediate A15-b, 3.5 g, 10.2 mmol) was added trimethyl orthoformate (9.7 g, 10 mL, 91.4 mmol, as the “SOLVENT” in table 2) and p-toluenesulfonic acid monohydrate (387 mg, 2.03 mmol), a light yellow solution formed. The mixture was stirred at r.t. for 5 hrs. The mixture was concentrated and the residue was purified by silica gel to give intermediate A15-c (3.2 g). LCMS (M+H ⁺ ): 354. Step 4: preparation of tert-butyl N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl]carbamate (intermediate A15) To a tube was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (intermediate A15-c, 2.7 g, 7.62 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (4.84 g, 19.1 mmol), potassium acetate (1.5 g, 15.2 mmol) and DMSO (12 mL). The solution was bubbled with N ₂ for 5 mins and then Butyldi-1-adamantylphosphine (820 mg, 2.29 mmol) and bis(triphenylphosphine)palladium(II) dichloride (802 mg, 1.14 mmol) were added. The tube was sealed, and heated to 130 °C for 4 hrs. The mixture was diluted with water and then it was extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel to give intermediate A15 (2.1 g). LCMS (M+H ⁺ ): 402. The following intermediates in Table 2 were prepared in analogy to Intermediate A15 by replacing 1-bromo-2-fluoro-3-nitro-benzene with the “ARYL FLUORIDE” and tert-butyl N- (3-aminopropyl)carbamate with the “AMINE” in step 1, trimethyl orthoformate with the “SOLVENT” in step 3 by the reagents indicated in Table 2. Table 2. Compound synthesis and characterization Intermediate A17 tert-butyl N-[2-ethoxy-3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)benzimidazol- 1-yl]propyl]-N-methyl-carbamate The title compound was prepared in analogy to the preparation of intermediate A7 by using tert-butyl N-[(3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate, trimethoxymethane instead of 1,1,1-trimethoxyethane and 3- bromo-2-fluoronitrobenzene instead of 1-bromo-2,5-difluoro-3-nitro-benzene. LCMS (M+H) ⁺ : 474. Intermediate A18 tert-butyl N-[3-[2-(2-morpholinoethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2- yl)benzimidazol-1-yl]propyl]carbamate The title compound was prepared according to the following scheme: Step 1: preparation of 3-[7-bromo-2-(2-morpholinoethyl)benzimidazol-1-yl]propan-1- amine (Intermediate A18-a) A mixture of tert-butyl N-[3-(2-amino-6-bromo-anilino) propyl]carbamate (compound A15-b 4.5 g, 13.07 mmol) and 3-morpholinopropanoic acid (2.08 g, 13.07 mmol) in con.HCl (45.0 mL, 13.07 mmol) and water (45 mL) was stirred at 100 °C for 40 h. After adjusting the reaction mixture’s pH to 8~10 with NaOH (20%), the reaction mixture was extracted with DCM, the organic layer was dried concentrated to give compound A18-a (3.7 g). LCMS (M+H ⁺ ): 367. Step 2: preparation of tert-butyl N-[3-[7-bromo-2-(2-morpholinoethyl)benzimidazol-1- yl]propyl]carbamate (Intermediate A18-b) A mixture of compound A18-a (3.7g, 10.21 mmol) and di-t-butyldicarbonate (3.34 g, 15.32 mmol) in methanol was stirred at 20 °C for 16 hr. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give intermediate A18-b (1 g). LCMS (M+H ⁺ ): 467. Step 3: preparation of tert-butyl N-[3-[2-(2-morpholinoethyl)-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (Intermediate A18) To a tube was added tert-butyl N-[3-[7-bromo-2-(2-morpholinoethyl)benzimidazol-1- yl]propyl]carbamate (Intermediate A18-b, 560 mg, 1.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1,3,2-dioxaborolane) (700 mg, 2.76 mmol), potassium acetate (235 mg, 2.4 mmol), and DMSO (6 mL). The solution was bubbled with N ₂ for 5 mins and then butyldi-1- adamantylphosphine (85.9 mg, 240 μmol) and bis(triphenylphosphine)palladium(II) dichloride (84.1 mg, 120 μmol) were added. The tube was heated to 130 °C for about 6 hrs. The mixture was diluted with water and then extracted with EA, the organic layer was dried and concentrated. The residue was purified by silica gel to give Intermediate A18 (180 mg). LCMS (M+H ⁺ ): 515. Intermediate A19 tert-butyl N-methyl-N-[3-[5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)benzimidazol-1-yl]propyl]carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-methyl-N-[3-(4-methyl-2-nitro- anilino)propyl]carbamate (compound A19-a) To a mixture of 4-fluoro-3-nitrotoluene (5.0 g, 32 mmol) and potassium carbonate (8.9 g, 64 mmol) in ACN (100 mL) was added N-(3-aminopropyl)-N-methylcarbamic acid tert- butylester (6.7 g, 35.5 mmol) slowly at 25 °C. After being stirred at 85 °C for 2 hours, the mixture was filtered and concentrated to afford compound A19-a (11.6 g). LCMS (M+H) ⁺ : 324. Step 2: preparation of tert-butyl N-[3-(2-bromo-4-methyl-6-nitro-anilino)propyl]-N- methyl-carbamate (compound A19-b) A mixture of compound A19-a (10.0 g, 31 mmol) and NBS (6.73 g, 37.82 mmol) in ACN (100 mL) was stirred at 85 °C for 12 hours. Then the reaction was concentrated and the residue was purified by flash chromatography to give compound A19-b (4.75 g). LCMS (M+H) ⁺ : 402. Step 3~5: preparation of tert-butyl N-methyl-N-[3-[5-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (intermediate A19) The title compound was prepared in analogy to the preparation of intermediate A15 by using compound A19-b instead of compound A15-a. LCMS (M+H) ⁺ : 430. Intermediate A20 tert-butyl N-cyclopropyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)benzimidazol-1-yl]propyl]carbamate The title compound was prepared according to the following scheme: Step 1~3: preparation of 3-(7-bromobenzimidazol-1-yl)propan-1-ol (compound A20-c) Compound A20-c was prepared in analogy to the preparation of intermediate A15-c by using 3-aminopropan-1-ol instead of tert-butyl N-(3-aminopropyl)carbamate, LCMS (M+H) ⁺ : 255. Step 4: preparation of 7-bromo-1-(3-chloropropyl)benzimidazole (compound A20-d) A mixture of compound A20-c (10 g, 39 mmol) in SOCl ₂ (40 mL) was stirred at 80 °C for 1 h. Then the mixture was concentrated, the residue was dissolved in EtOAc, washed with 5% NaHCO ₃ and brine (50.0mL). The organic layer was dried and concentrated to give compound A20-d (7.0 g). LCMS (M+H) ⁺ : 273. Step 5: preparation of N-[3-(7-bromobenzimidazol-1-yl)propyl]cyclopropanamine (compound A20-e) A mixture of compound A20-d (1.6 g, 5.85 mmol), cyclopropylamine (1.6 g, 28.03 mmol), DIPEA (1.6 g, 12.38 mmol) in NMP (10.0 mL) was stirred for 12 hours at 110 °C. Then the mixture was diluted with DCM, washed with water and brine. The organic layer was dried and concentrated to give the crude compound A20-e (560 mg). LCMS (M+H) ⁺ : 295. Step 6: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N- cyclopropyl-carbamate (compound A20-f) A mixture of compound A20-e (500 mg, 1.7 mmol) and di-t-butyldicarbonate (500 mg, 2.29 mmol) in DCM (10 mL) was stirred for 1 h at 20 °C. The mixture was concentrated and the residue was purified by prep-TLC to give compound A20-f (560 mg), which was used in next step directly. LCMS (M+H) ⁺ : 396. Step 7: preparation of tert-butyl N-cyclopropyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (Intermediate A20) The title compound was prepared in analogy to the preparation of intermediate A15 by using compound A20-f instead of compound A15-c. LCMS (M+H) ⁺ : 442. Intermediate A22 tert-butyl N-[3-[2-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzimidazol- 1-yl]-2-methoxy-propyl]-N-methyl-carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-2-ethyl-benzimidazol-1-yl)-2- hydroxy-propyl]carbamate (compound A22-a) To a solution of compound A1-c (7.3 g, 20 mmol) in water (8 mL) and DMF (80 mL) was added oxone (3.41 g, 20.26 mmol), propionaldehyde (1.35 g, 23.3 mmol) in turns at 0 °C and then stirred at 20 °C for 12 hours. The reaction was quenched with saturated ammonium chloride solution (500 mL), extracted with EA (1000 mL). The organic layer was dried and concentrated; the residue was purified by column chromatography to give compound A22-a (2.5 g). LCMS (M+H) ⁺ : 398. Step 2~3: tert-butyl N-[3-[2-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (intermediate A22) The title compound was prepared in analogy to the preparation of intermediate A1 by using compound A22-a instead of compound A1-d. LCMS(M+H) ⁺ : 474. Intermediate A23 tert-butyl N-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-[2-methyl-7-(4 ,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl ]-N-methyl-carbamate The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 3-(benzylamino)-2-[(benzylamino)methyl]propanoate (compound A23-a) To a mixture of benzylamine (7.97 mL, 73.01 mmol) and DIPEA (12.72 mL, 73.01 mmol) in ACN (80 mL) was added ethyl-3-bromo-2-(bromomethyl)propionate (10 g, 36.5 mmol) in ACN (20 mL) slowly at 80 °C in 1 h. Then the mixture was stirred at 80 °C for 6 hours. The reaction was concentrated and the residue was purified by flash chromatography to give compound A23-a (5.9 g). LCMS (M+H ⁺ ): 327. Step 2: preparation of 3-(benzylamino)-2-[(benzylamino)methyl]propan-1-ol (compound A23-b) To a solution of compound A23-a (8.7 g, 26.65 mmol) in THF (120 mL) was added LiAlH ₄ (1.2 g, 32 mmol) at 0 °C, then the mixture was stirred at 0 °C for 2 hours. The reaction was quenched with H ₂ O (1.2 mL), 10% aq.NaOH(3.6 mL). Then the mixture was diluted with EA (100 mL), dried over anhydrous magnesium sulfate. The organic layer was concentrated to give compound A23-b (6.1 g). LCMS (M+H) ⁺ : 285. Step 3: preparation of 3-amino-2-(aminomethyl)propan-1-ol (compound A23-c) To a solution of compound A23-b (11 g, 38.68 mmol ) in methanol (80 mL) and acetic acid (10 mL) was added Pd(OH) ₂ /C (2.2 g) under N ₂ . The mixture was stirred under hydrogen at 60 °C for 48 hours. The reaction mixture was filtered and concentrated to give compound A23-c (5 g). LCMS (M+H) ⁺ : 105. Step 4~7: preparation of tert-butyl N-[2-[(7-bromo-2-methyl-benzimidazol-1- yl)methyl]-3-hydroxy-propyl]carbamate (compound A23-g) Compound A23-g was prepared in analogy to the preparation of intermediate A1-d by using compound A23-c instead of 1,3-diamino-2-propanol, LCMS (M+H) ⁺ : 398. Step 8~9: preparation of tert-butyl N-[2-[(7-bromo-2-methyl-benzimidazol-1- yl)methyl]-3-[tert-butyl(dimethyl)silyl]oxy-propyl]carbamate (compound A23-i) Compound A23-i was prepared in analogy to the preparation of intermediate A7-f by using compound A23-g instead of compound A7-d. LCMS (M+H ⁺ ): 526. Step 10: preparation of tert-butyl N-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-[2- methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzim idazol-1-yl]propyl]-N-methyl- carbamate (intermediate A23) The title compound was prepared in analogy to the preparation of intermediate A1 by using compound A23-i instead of compound A1-e. LCMS (M+H ⁺ ): 574. Intermediate A24 tert-butyl N-[2-(2-methoxyethoxy)-3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate The title compound was prepared in analogy to the preparation of Intermediate A7 by using tert-butyl N-[(3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate, 3-bromo-2-fluoronitrobenzene instead of 1-bromo-2,5-difluoro-3- nitro-benzene, trimethoxymethane instead of trimethoxymethane and 1-bromo-2-methoxy-ethane instead of ethyl iodide. LCMS (M+H) ⁺ : 490. Intermediate A25 tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)-2- (trifluoromethyl)benzimidazol-1-yl]propyl]carbamate The title compound was prepared according to the following scheme: Step 1: preparation of 3-[7-bromo-2-(trifluoromethyl)benzimidazol-1-yl]-N-methyl- propan-1-amine (compound A25-b) A mixture of compound A26-a (7.65 g, 21.35 mmol) and con.HCl (1 mL) in TFA (70.0 mL) was stirred at 70 °C for 12 h. The mixture was concentrated to give compound A25-b (6.6 g). LCMS(M+H) ⁺ : 336 Step 2: preparation of 3-[7-bromo-2-(trifluoromethyl)benzimidazol-1-yl]-N-methyl- propan-1-amine (compound A25-c) A mixture of compound A25-b (3.25 g, 9.67 mmol), Boc ₂ O (4.36 g, 20 mmol) and DIPEA (3.37 mL, 19.34 mmol) in methanol (30 mL) was stirred at 20 °C for 1 h. Then the mixture was concentrated, the residue was purified by silica gel to give compound A25-c (3.25 g). LCMS(M+H) ⁺ : 436. Step 3: preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-(trifluoromethyl)benzimidazol-1-yl]prop yl]carbamate (intermediate A25) To a mixture of compound A25-c (3.2 g, 7.33 mmol) and bis(pinacolato)diboron (4.66 g, 18.34 mmol) in DMSO (44.73 mL) was added potassium acetate (1.44 g, 14.67 mmol), bis(triphenylphosphine)palladium(II) chloride (0.77 g, 1.1 mmol) and butyldi-1- adamantylphosphine(0.79 g, 2.2 mmol). The mixture was degassed with N ₂ for three times and stirred at 130 °C for 2 h. The reaction mixture was poured into water and extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel to give intermediate A25 (1.46 g). LCMS (M+H) ⁺ : 484. Intermediate A26 tert-butyl N-[3-[2-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-2-methoxy-benzimidazol-1-yl)propyl]- N-methyl-carbamate (compound A26-b) To a solution of compound A26-a (9.0 g, 26.1 mmol, the synthesis was refer to A15-b) in methanol (50 mL) was added tetramethoxymethane (7.1 g, 52.2 mmol) and TsOH•pyridine (1.3 g, 5.2 mmol). After being stirred at 60 °C for 12 h, the mixture was concentrated and then purified by prep-HPLC to give compound A26-b (4.0 g). LCMS (M+H ⁺ ): 454. Step 2: preparation of tert-butyl N-[3-[2-methoxy-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbama te (Intermediate A26) To a mixture of compound A26-b (2.0 g, 5.0 mmol) and bis(pinacolato)diboron (1.9 g, 7.5 mmol) in 1,4-dioxane (20 mL) was added potassium acetate (1.0 g, 10.04 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.6 g, 0.7 mmol). After being stirred at 100 °C for 2 h under N ₂ atmosphere, the mixture was poured into water (20.0 mL), extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by prep- HPLC to give Intermediate A26 (0.5 g). LCMS (M+H ⁺ ): 446. Intermediate A27 tert-butyl N-methyl-N-[5-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]pentyl]carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[5-(2-bromo-6-nitro-anilino)pentyl]carbamate (compound A27-a) A mixture of 1-bromo-2-fluoro-3-nitro-benzene (660 mg, 3 mmol), tert-butyl N-(5- aminopentyl)carbamate (667 mg, 3.3 mmol), K ₂ CO ₃ (622 mg, 4.5 mmol) in acetonitrile (10 mL) was heated to 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer were extracted with DCM, the combined organic layer was washed with brine, dried and concentrated to give crude compound A27-a (1.43 g), which was directly used for next step without purification. LCMS (M+H ⁺ ): 302. Step 2: preparation of tert-butyl N-[5-(2-amino-6-bromo-anilino)pentyl]carbamate (compound A27-b) To a mixture of tert-butyl N-[5-(2-bromo-6-nitro-anilino)pentyl]carbamate (compound A27-a, 1.43 g, 3.0 mmol) and Raney-nickel (197 mg, 3.0 mmol) in methanol (10 mL) was added hydrazine hydrate (698 mg, 9.0 mmol) dropwise, after 30 minutes later (no more bubbles), the reaction mixture was filtered carefully. The filtrate was concentrated, the residue was dissolved in EtOAc, then washed with water and brine, the organic layer was dried and concentrated to afford crude compound A27-b (1.54 g), which was directly used for next step without purification. LCMS (M+H ⁺ ): 372. Step 3: preparation of tert-butyl N-[5-(7-bromobenzimidazol-1-yl)pentyl]carbamate (compound A27-c) A mixture of tert-butyl N-[5-(7-bromobenzimidazol-1-yl)pentyl]carbamate (A27-b, 1.54 g, 2.9 mmol), trimethyl orthoformate (922 mg, 8.7 mmol) and p-toluenesulfonic acid monohydrate (55 mg, 0.29 mmol) in anhydrous THF was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give some oil; the oil was dissolved in DCM and then washed with sat.aq.NaHCO ₃ , and brine. The organic layer was dried and concentrated to afford crude compound A27-c (1.59 g), which was directly used for next step without purification. LCMS (M+H ⁺ ): 382. Step 4: preparation of tert-butyl N-[5-(7-bromobenzimidazol-1-yl)pentyl]-N-methyl- carbamate (compound A27-d) To a mixture of tert-butyl N-[5-(7-bromobenzimidazol-1-yl)pentyl]-N-methyl-carbamate (A27-c, 1.59 g, 2.08 mmol) and iodomethane (886 mg, 6.24 mmol) in anhydrous DMF (8 mL) was added NaH (333 mg, 8.32 mmol) in one portion, the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water, and then extracted with EtOAc. The separated organic layer was washed with water and brine, the organic layer was dried and concentrated and the residue was purified by flash column to afford compound A27-d (595 mg). LCMS (M+H ⁺ ): 396. Step 5: preparation of tert-butyl N-methyl-N-[5-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]pentyl]carbamate (intermediate A27) A mixture of tert-butyl N-[5-(7-bromobenzimidazol-1-yl)pentyl]-N-methyl-carbamate (compound A27-d, 595 mg, 1.13 mmol), bis(pinacolato)diboron (572 mg, 2.25 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (47 mg, 0.056 mmol) and potassium acetate (332 mg, 3.38 mmol ) in anhydrous 1,4-dioxane (10 mL) was heated at 110 °C for 16 hours under nitrogen with conventional heating. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted with DCM, the combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , and then concentrated. The residue was purified by flash chromatography to afford crude Intermediate A27 (429 mg). LCMS (M+H ⁺ ): 444. Intermediate A28 tert-butyl N-methyl-N-[2-[2-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2- yl)benzimidazol-1-yl]ethoxy]ethyl]carbamate The title Intermediate A28 was prepared in analogy to the preparation of Intermediate A27 by replacing tert-butyl N-(5-aminopentyl)carbamate with tert-butyl N-[2-(2- aminoethoxy)ethyl]carbamate. LCMS (M+H ⁺ ): 446. Intermediate A30 tert-butyl N-[(2S)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate The title compound was prepared according to the following scheme:

Step 1~3: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)-2-hydroxy-propyl]carbamate (compound A30-d) The title compound was prepared in analogy to the preparation of compound A7-d by using tert-butyl N-[(2S)-3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3- amino-2-hydroxy-propyl]carbamate, LCMS (M+H) ⁺ : 400. Step 4~5: preparation of tert-butyl N-[(2S)-3-[5-fluoro-2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]-2-met hoxy-propyl]-N-methyl- carbamate (Intermediate A30) The title compound was prepared in analogy to the preparation of Intermediate A1 by using compound A30-d instead of compound A1-d. LCMS (M+H) ⁺ : 478. Intermediate B1 and B2 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B1) and O1-tert-butyl O2-methyl (2S,4S)-4-[(2- chloropyrimidin-4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B2) The title compound was prepared according to the following scheme: A mixture of 2,4-dichloropyrimidine (19.21 g, 128.94 mmol), 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (21 g, 85.96 mmol) and K ₂ CO ₃ (35.64 g, 257.89 mmol) in DMF (100 mL) was stirred at 80 °C for 16 hours. Then the reaction was diluted with EtOAc, washed with water and brine, the organic layer was concentrated, the residue was purified by silica gel (eluting with 10%-30% PE in EtOAc) to give intermediate B1 (faster eluted, 5 g), LCMS (M+H ⁺ ): 357; and intermediate B2 (slower eluted, 25 g), LCMS (M+H ⁺ ): 357. Intermediate B3 and B4 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloro-6-methyl-pyrimidin-2- yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B3) and O1-tert-butyl O2-methyl (2S,4S)-4-[(2-chloro-6-methyl-pyrimidin-4-yl)amino]pyrrolidi ne-1,2-dicarboxylate (Intermediate B4) The title compound was prepared according to the following scheme: A mixture of 2,4-dichloro-6-methyl-pyrimidine (1.2 g, 7.37 mmol),1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (1.2 g, 4.91 mmol), DIPEA (634.85 mg, 4.91 mmol) and K ₂ CO ₃ (2.04 g, 14.74 mmol) in acetonitrile (24 mL) was stirred at 80 °C for 16 hours. Then the reaction was filtered and concentrated, the residue was purified by silica gel (eluting with 10%-30% PE in EtOAc) to give intermediate B3 (faster eluted, 300 mg), LCMS (M+H ⁺ ): 371; and intermediate B4 (slower eluted, 700 mg), LCMS (M+H ⁺ ): 371. Intermediate B5 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloropyrimidin-4-yl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: A mixture of 4,6-dichloropyrimidine (2.29 g, 15.35 mmol), 1-(tert-butyl) 2-methyl (2S,4S)- 4-aminopyrrolidine-1,2-dicarboxylate (2.5 g, 10.23 mmol, 1 eq) and K ₂ CO ₃ (4.24 g, 30.7 mmol) in acetonitrile (50 mL) was stirred at 80 °C for 16 hours. Then the reaction was filtered and concentrated, the residue was purified by silica gel to give intermediate B5 (3.5 g), LCMS (M+H ⁺ ): 357. Intermediate B6 and B7 O1-benzyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B6) and O1-benzyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin- 4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B7) The title compound was prepared according to the following scheme A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K ₂ CO ₃ (4.97 g, 35.9 mmol) and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at rt for 48 hours. Then the reaction was filtered and concentrated, the residue was purified by silica gel (eluting with 10%-30% PE in EtOAc) to give intermediate B6 (faster eluted, 1 g), LCMS (M+H ⁺ ): 391; and intermediate B7 (slower eluted, 6 g), LCMS (M+H ⁺ ): 391. Intermediate B8 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: A mixture of 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28.0 g, 99.73 mmol), DIPEA (69.49 mL, 398.93 mmol) and 2-bromo-6-fluoropyridine (21.06 g, 119.68 mmol) in DMSO (140 mL) was heated to 110 °C for 16 hours. The mixture was diluted with water and extracted with EA, the organic layer was concentrated to give intermediate B8 (34 g), LCMS (M+H ⁺ ): 400. Intermediate B9 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl- amino]pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme:

A mixture of intermediate B8 (12.0 g, 29.98 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-t-butyldicarbonate (19.63 g, 89.94 mmol) and triethylamine (10.45 mL, 74.95 mmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give intermediate B9 (11.8 g), LCMS (M+H ⁺ ): 500. Intermediate B10 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2- dicarboxylate;hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol) and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was concentrated, the residue was purified by prep-HPLC to give intermediate B10 (5.1 g), LCMS (M+H+): 434. Intermediate B11 O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme: To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (2 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.79 g, 8.15 mmol) and Ph ₃ P (2.46 g, 9.38 mmol) in THF (50 mL) was added DIAD (1.9 g, 9.38 mmol) in THF (10 mL) dropwise at 0 °C. After being stirred at 20 °C overnight, the reaction mixture was concentrated, and the residue was s purified by silica gel to give intermediate B11, LCMS: (M+H) ⁺ : 448. Intermediate B12 O1-benzyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-1,2-dicarboxylate The title compound was prepared in analogy to the preparation of intermediate B11 by using 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate instead of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate. LCMS: (M+H) ⁺ : 482. Intermediate B13 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromopyrazin-2-yl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: A mixture of 2-bromo-6-fluoro-pyrazine (3.12 g, 17.63 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (4.5 g, 16.03 mmol) and DIPEA (6.21 g, 8.4mL, 48.09 mmol) in DMSO was heated to 110 °C for 12 hrs. The mixture was diluted with EA, washed with water, the organic layer was dried and concentrated to give intermediate B13 (7 g), LCMS (M+H ⁺ ): 401. Intermediate B14 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromopyrazin-2-yl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: A mixture of 2-bromo-6-fluoro-pyrazine (1.05 g, 5.72 mmol), O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (1.5 g, 4.77 mmol) and DIPEA (1.85 g, 2.5mL, 14.3 mmol) in DMSO was heated to 110 °C for 12 hrs. The mixture was diluted with EA, washed with water, the organic layer was dried and concentrated to give intermediate B14 (2.4 g), LCMS (M+H ⁺ ): 435. Intermediate B15 O1-benzyl O2-methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: To a mixture of O1-benzyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.0 g, 107.4 mmol) and 4-chloro-2-methylsulfonyl-pyrimidine (20.0 g, 103.8 mmol) in anhydrous THF (340 mL) was added sodium hydride (60% in oil, 4.4 g, 110 mmol) in portions at room temperature under nitrogen, the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into aq.NH ₄ Cl (200 mL) and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product, which was purified by silica gel to give Intermediate B15 (27.0 g). LCMS (M+H) ⁺ : 392. Intermediate B16 O1-tert-butyl O2-methyl (2S,4S)-4-(4-bromopyrimidin-2-yl)oxypyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.0 g, 20.4 mmol), potassium carbonate (8.45 g, 61.2 mmol) in acetonitrile (100 mL) was added 4-bromo-2-chloropyrimidine (3.94 g, 20.4 mmol) and then stirred at 80℃ for 16 hours. The reaction mixture was poured into aq.NH ₄ Cl (200 mL) and then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to afford crude product. The crude product was purified by column chromatography to afford Intermediate B16 (2.69 g). LCMS (M-100+H) ⁺ : 302. Intermediate B20 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-bromo-2-pyridyl)oxy]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: To a mixture of 4-bromo-2-hydroxypyridine (10.64 g, 61.16 mmol), O1-tert-butyl O2- methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.77 mmol) and PPh ₃ (16.04 g, 61.16 mmol) in Toluene (100 mL) was added DIAD (12.37 g, 61.16 mmol) at 0 °C under N ₂ , then the mixture was stirred at 100 °C for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to afford intermediate B20 (12.5 g). LCMS (M-56+H) ⁺ : 345. Intermediate B21 O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4-(difluoromethoxy)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme: Step 1: preparation of 2,6-dibromo-4-(difluoromethoxy)pyridine (compound B21-a) To a stirred solution of 2,6-dibromopyridin-4-ol (2.0 g, 7.91 mmol) and potassium carbonate (2.19 g, 15.82 mmol) in DMF (20 mL) was added ethyl bromodifluoroacetate (4.82 g, 23.73 mmol) at 25°C. After being stirred for 16 h at 80 °C, the reaction mixture was poured into water and extracted with EA. The organic phase was concentrated and the residue was purified by silica gel to afford compound B21-a (2.7 g), LCMS (M+H) ⁺ : 304. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4- (difluoromethoxy)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxyl ate (Intermediate B21) To a solution of compound B21 (1186.79 mg, 3.92 mmol) in 1,4-dioxane (20 mL) was added O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (1 g, 3.56 mmol), cesium carbonate (3481.6 mg, 10.69 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (343.5 mg, 0.590 mmol) and tris(dibenzylideneacetone)dipalladium (0) (400.0 mg, 0.440 mmol). The reaction was stirred at 85 °C for 12 h under N ₂ . The reaction mixture was filtered and concentrated, the residue was purified by prep-HPLC to give intermediate B21 (200 mg), LCMS (M+H) ⁺ : 466. Intermediate B22 O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4-(cyclopropoxy)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme: Step 1: preparation of 2,6-dibromo-4-(cyclopropoxy)pyridine (compound B22-a) To a solution of 2,6-dibromo-4-chloro-pyridine (5.0 g, 18.4 mmol) in DMF (40 mL) was added NaH (0.88 g, 22 mmol, 60%) at 0 °C, then cyclopropanol (1.28 g, 22 mmol) was added and stirred at 0 °C for 1 h. The reaction was quenched with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give compound B22-a (2.6 g). LCMS (M+H) ⁺ : 294. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4-(cyclopropoxy)- 2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (intermediate B22) To a solution of compound B21-a (1.1 g, 3.7 mmol) in 1,4-dioxane (18 mL) was added O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (0.9 g, 3.2 mmol), cesium carbonate (3.1 g, 9.6 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (309 mg, 0.5 mmol) and Pd(OAc) ₂ (120 mg, 0.5 mmol). The reaction was stirred at 90 °C for 12 h under N ₂ . The reaction mixture was concentrated, the residue was purified by silica gel to give intermediate B22 (550 mg). LCMS (M+H) ⁺ : 456. Intermediate B23 O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4-(methoxymethyl)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme: Step 1: preparation of (2,6-dibromo-4-pyridyl)methanol (compound B23-a) To a solution of methyl 2,6-dibromopyridine-4-carboxylate (2.5 g, 8.5 mmol) in methanol (30 mL) was added sodium borohydride (1.3 g, 34 mmol) at 0 °C, and then the solution was stirred at 65 °C for 3 hours. The reaction mixture was poured into ice water and adjusted the pH around 7 by adding 1 N aq. HCl solution. The mixture was extracted with EtOAc, and then the organic layer was dried and concentrated to give compound B23-a (2.3 g). LCMS (M+H) ⁺ : 268. Step 2: preparation of 2,6-dibromo-4-(methoxymethyl)pyridine (compound B23-b) To a solution of compound B23-a (2.1 mg, 7.9 mmol) in THF (20 mL) was added sodium hydride (378 mg, 9.4 mmol) at 0 °C slowly, after being stirred at 0 °C for 20 mins, iodomethane (0.54 mL, 8.65 mmol) was added. After stirring at 0 °C for 2 hours, the reaction was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by flash chromatography to give compound B23-b (1.75 g). LCMS (M+H) ⁺ : 282. Step 3: : preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4- (methoxymethyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylat e (Intermediate B23) To a solution of compound B23-b (1 g, 3.56 mmol) in 1,4-dioxane (20 mL) was added O1- tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (700 mg, 2.5 mmol), cesium carbonate (3.48 g, 10.7 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (345 mg, 0.6 mmol) and tris(dibenzylideneacetone)dipalladium (0) (391 mg, 0.43 mmol). The reaction was stirred at 85 °C for 16 hs under N ₂ . The reaction mixture was poured into water, and extracted with EA, the organic layer was dried and concentrated. The residue was purified by flash chromatography to give intermediate B23 (500 mg). LCMS (M+H) ⁺ : 444. Intermediate B24 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloro-4-cyano-2-pyridyl)amino]pyrrolidine- 1,2-dicarboxylate The title compounds were prepared in analogy to the preparation of Intermediate B8 by using 2,6-dichloroisonicotinonitrile instead of 2-bromo-6-fluoropyridine, LCMS (M+H) ⁺ : 381. Intermediate B25 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)sulfanyl]pyrrolidine-1,2- dicarboxylate The title compound was prepared according to the following scheme: Step 1: preparation of 6-bromopyridine-2-thiol (compound B25-a) A mixture of 2,6-dibromopyridine (10 g, 42 mmol), MeONa (5.7 g, 105 mmol) and methyl 3-mercaptopropionate (11 mL, 97 mmol) in DMF (100 mL) was stirred at 70 °C for 12 hours. Then the reaction was concentrated, methanol (100 mL) and MeONa (5.7 g, 105 mmol) was added to the residue, the resulted mixture was heated at 70 °C for 4 hours. The mixture was concentrated and the residue was dissolved in water (100 mL), after adjusting the solution pH to 5 with FA, a solid precipitated, which was collected by filtration to give compound B25-a (1.9 g). LCMS (M+H) ⁺ : 190. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4R)-4- methylsulfonyloxypyrrolidine-1,2-dicarboxylate (compound B25-b) To a solution of O1-tert-butyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (15 g, 61 mmol) and TEA (18.5 g, 183.5 mmol) in anhydrous THF (100 mL) was added Ms2O (13.85 g, 79.5 mmol) in THF (30 mL) dropwise, then the reaction mixture was stirred for 4 h at 50 °C. The reaction mixture was quenched with NaHCO ₃ , extracted with EA, the organic phase was dried and concentrated to give compound B25-b (18 g). LCMS (M+H) ⁺ : 324. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2- pyridyl)sulfanyl]pyrrolidine-1,2-dicarboxylate (Intermediate B25) A mixture of compound B25-a (1.9 g, 10 mmol), K ₂ CO ₃ (2.1 g, 15 mmol) and compound B25-b (3.9 mg, 12 mmol) in anhydrous DMF (15 mL) was stirred at 70 °C for 12 hours. The reaction mixture was poured into water and then extracted with EA. The combined organic layer was dried and concentrated, the residue was purified by column chromatography to give intermediate B25 (1.9 g). LCMS (M-Boc+H) ⁺ : 317. Intermediate B26 O1-benzyl O2-methyl (2S,4S)-4-[[6-chloro-4-(oxetan-3-yl)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (intermediate B26) The title compound was prepared according to the following scheme: Step 1: preparation of 2,6-dichloro-4-(oxetan-3-yl)pyridine (compound B26-a) To a 15 mL vial was added 4-bromo-2,6-dichloro-pyridine (500.0 mg, 2.2 mmol), 3- bromooxetane (392.42 mg, 2.86 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (24.72 mg, 0.020 mmol), NiCl ₂ .dtbbpy (4.39 mg, 0.010 mmol), TTMSS (547.97 mg, 2.2 mmol), Na ₂ CO ₃ (467.19 mg, 4.41 mmol) in 1,2-dimethoxyethane (22.04 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 h (Three batch, total 1.5 g ). Then the mixture was concentrated, the residue was purified by prep-HPLC to give compound B26-a (280 mg). LCMS (M+H) ⁺ : 204. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-chloro-4-(oxetan-3-yl)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (intermediate B26) To a mixture of compound B26-a (225 mg, 1.1 mmol) in 1,4-dioxane (6 mL) was added O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (300.0 mg, 0.950 mmol), cesium carbonate (931.62 mg, 2.86 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (91.92 mg, 0.160 mmol) and Pd(OAc) ₂ (35.58 mg, 0.160 mmol). The reaction was stirred at 85 °C for 12 h under N ₂ . The reaction mixture was purified by silica gel to give intermediate B26 (210 mg). LCMS (M+H) ⁺ : 446. Intermediate B30 O1-tert-butyl O2-methyl (2S,4S)-4-[(2-bromo-4-pyridyl)oxy]pyrrolidine-1,2- dicarboxylate The title compound was prepared in the analogy to the preparation of intermediate B20 by using 2-bromo-4-hydroxypyridine instead of 4-bromo-2-hydroxypyridine. LCMS (M+H ⁺ ): 401. Intermediate B31 O1-tert-butyl O2-methyl (2S,4S)-4-[(5-bromo-3-pyridyl)oxy]pyrrolidine-1,2- dicarboxylate The title compound was prepared in the analogy to the preparation of intermediate B20 by using 3-bromo-5-hydroxypyridine instead of 4-bromo-2-hydroxypyridine. LCMS (M+H ⁺ ): 401. Intermediate B32 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate The title compound was prepared in the analogy to the preparation of intermediate B8 by using 4-bromo-2-fluoropyridine instead of 2-bromo-6-fluoropyridine. LCMS (M+H ⁺ ): 400. Intermediate B33 O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme:

To a mixture of 3-bromophenol (4.23 g, 24.5 mmol), O1-tert-butyl O2-methyl (2S,4R)-4- hydroxypyrrolidine-1,2-dicarboxylate (4 g, 16.3 mmol), triphenylphosphine (6.42 g, 24.5 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (4.95 g, 24.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 4 hours, then concentrated and the residue was purified by flash chromatography to afford Intermediate B33 (5.5 g). LCMS (M+H) ⁺ : 400. Intermediate B34 O1-tert-butyl O2-methyl (2S,4S)-4-[4-chloro-6-(cyclopropylamino)pyrimidin-2- yl]oxypyrrolidine-1,2-dicarboxylate The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-(4,6-dichloropyrimidin-2- yl)oxypyrrolidine-1,2-dicarboxylate (compound B34-a) A mixture of 4,6-dichloro-2-methylsulfonyl-pyrimidine (2.0 g, 8.81 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.2 g, 8.81 mmol) and potassium carbonate (3.6 g, 26.42 mmol) in acetonitrile (20 mL) was stirred at room temperature for 1 hr. The reaction was quenched by water, then the mixture was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography to afford compound B34-a (1.0 g) as a colorless oil. LCMS (M+H) ⁺ : 392. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[4-chloro-6- (cyclopropylamino)pyrimidin-2-yl]oxypyrrolidine-1,2-dicarbox ylate (Intermediate B34) To a mixture of O1-tert-butyl O2-methyl (2S,4S)-4-(4,6-dichloropyrimidin-2- yl)oxypyrrolidine-1,2-dicarboxylate (1.0 g, 2.55 mmol) and cyclopropylamine (0.18 mL, 2.55 mmol) in acetonitrile (1 mL) was added potassium carbonate (1.06 g, 7.65 mmol), the resulting mixture was stirred at 90 °C for 1 hr. The reaction was quenched by water, then the mixture was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give desired Intermediate B34 (0.83 g) as a light yellow oil. LCMS (M+H) ⁺ : 413. Intermediate C1 4-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. Step 1: preparation of (3,5-difluoro-2-pyridyl)hydrazine (compound C1-b) To a solution of 2,3,5-trifluoropyridine (compound C1-a, 6.0 g, 45 mmol) in ethanol (60 mL) was added hydrazine hydrate (21.87 mL, 450 mmol). After being stirred at 65 °C for 16 h, the reaction mixture was concentrated to afford compound C1-b (6.5 g). LCMS (M+H) ⁺ : 146. Step 2: preparation of 5-amino-1-(3,5-difluoro-2-pyridyl)pyrazole-4-carbonitrile (compound C1-c) A mixture of (3,5-difluoro-2-pyridyl)hydrazine (compound C1-b, 6.5 g, 45 mmol), DIEA (11.74 mL, 67.39 mmol) and ethoxymethylenemalononitrile (6.05 g, 50 mmol) in ethanol (65 mL) was stirred at 80 °C for 16 hrs. After cooling the reaction mixture to 0 °C, solid precipitated, which was collected and dried to afford compound C1-c (3.8 g). LCMS (M+H) ⁺ : 222. Step 3: preparation of 1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C1-d) A solution of 5-amino-1-(3,5-difluoro-2-pyridyl)pyrazole-4-carbonitrile (compound C1-c, 3.8 g, 17.18 mmol) in formic acid (38.0 mL, 17.18 mmol) was stirred at 100 °C for 16 hrs. The reaction was concentrated and the solid was washed with MeCN to afford compound C1-d (2.9 g). LCMS (M+H) ⁺ : 250. Step 4: preparation of 4-chloro-1-(3,5-difluoro-2-pyridyl) pyrazolo[3,4-d] pyrimidine (Intermediate C1) To a solution of 1-(3,5-difluoro-2-pyridyl) pyrazolo[3,4-d]pyrimidin-4-ol (compound C1-d, 1.8 g, 7.22 mmol) was added phosphorus oxychloride (19.29 mL, 206.91 mmol) and then stirred at 100 °C for 1 h. The reaction mixture was concentrated and the residue was diluted with DCM (10 mL). The mixture was concentrated and the residual solid was washed with DCM to give intermediate C1 (1.33 g). LCMS (M+H) ⁺ : 268. Intermediate C2 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. Step 1: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b) A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.91 g, 137.95 mmol) and potassium carbonate (21.17 g, 153.21 mmol) in DCM (400 mL) was stirred at 20 °C for 12 h. Then the mixture was washed with water and brine, the organic layer was dried and concentrated to give the crude compound C2-b (34.5 g). LCMS (M+H) ⁺ : 303. Step 2: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2) To a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b,18.5 g, 61.04 mmol) in NMP (185 mL) was added 4A molecular sieve (2 g). The mixture was stirred at 110 °C for 40 h. The reaction was cooled and 300 mL of water was added into the reaction mixture within 20 min. The precipitate was collected and dried to give intermediate C2 (8.5 g). LCMS (M+H) ⁺ : 267. Intermediate C3 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine The title compound was prepared according to the following scheme:. Step 1: preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (compound C3-b) To a mixture of 2,4-difluorobenzoic acid (compound C3-a, 8 g, 50.6 mmol) in DCM (100 mL) was added thionyl chloride (260 mL) at 25 °C. After being stirred at 80 °C for 2 h, the mixture was concentrated and diluted with DCM. Then to the reaction mixture was added (3- chloropyrazin-2-yl)methanamine hydrochloride (9.12 g, 50.66 mmol) and triethylamine (14.33 mL, 102.78 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was concentrated, the residue was diluted with DCM (400 mL), washed with water (500 mL) and brine. The organic layer was dried and concentrated to afford compound C3-b (7620 mg). LCMS (M+H) ⁺ : 284. Step 2: preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3) To a solution of compound C3-b (16.2 g, 57.11 mmol) in toluene (320 mL) was added phosphorus oxychloride (26.62 mL, 285.55 mmol). The mixture was stirred at 110 °C for 16 h. Then mixture was concentrated, the residue was added to a vigorous stirring mixture of EA (300 mL, contained 10 mL of triethylamine) and 50 g NaHCO ₃ in 300 mL water at 0 °C. The organic layer was separated, dried and concentrated to give intermediate C3 (15.4 g). LCMS (M+H) ⁺ : 266. Intermediate C4 4-chloro-1-(2-fluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 5-amino-1-(2-fluorophenyl)pyrazole-4-carbonitrile (compound C4-b) To a solution of ethoxymethylenemalononitrile (11.27 g, 92.26 mmol) in ethanol (70 mL) was added 2-fluorophenylhydrazine hydrochloride (compound C4-a, 15.0 g, 92.26 mmol) and DIEA (49.27 mL, 276.77 mmol). The mixture was stirred at 25 °C for 1 h and then at 80 °C for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography to give compound C4-b (17.8 g). LCMS (M+H ⁺ ): 202. Step 2: preparation of 1-(2-fluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C4-c) A solution of 5-amino-1-(2-fluorophenyl)pyrazole-4-carbonitrile (compound C4-b, 5.0 g, 24.73 mmol) in formic acid (25.0 mL, 24.73 mmol) was stirred at 100 °C for 16 h. Then the mixture was concentrated, the crude product was recrystallized in MeOH to give compound C4- c (3.5 g), LCMS (M+H ⁺ ): 231. Step 3: preparation of 4-chloro-1-(2-fluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C4) A mixture of phosphorus oxychloride (10.0 mL, 107.28 mmol) and 1-(2- fluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (C4-c, 1.5 g, 6.52 mmol) was stirred at 100 °C for 3 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give intermediate C4 (1.4 g), LCMS (M+H ⁺ ): 248. Intermediate C5 4-chloro-1-(4-fluorophenyl)pyrazolo[3,4-d]pyrimidine 4 The title compound was prepared in analogy to the preparation of intermediate C4 by using 4-fluorophenylhydrazine hydrochloride instead of 2-fluorophenylhydrazine hydrochloride. LCMS (M+H ⁺ ): 248. Intermediate C6 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyridazine The title compound was prepared according to the following scheme:

Step 1: preparation of (2E)-2-(ethoxymethylene)-3-oxo-butanenitrile (compound C6- b) A mixture of triethyl orthoformate (90.08 mL, 541.58 mmol) and 3-oxobutanenitrile (compound C6-a15.0 g, 180.53 mmol) in acetic anhydride (18.4 g, 180.53 mmol) was stirred at 130 °C for 4 h under N ₂ atmosphere. The reaction was concentrated to give the crude product compound C6-b (25 g), LCMS (M+H ⁺ ): 140. Step 2: preparation of 1-[5-amino-1-(2,4-difluorophenyl)pyrazol-4-yl]ethanone (compound C6-c) To a solution of (2E)-2-(ethoxymethylene)-3-oxo-butanenitrile (compound C6-b, 25.0 g, 89.83 mmol) in ethanol (80 mL) was added triethylamine (25.04 mL, 179.66 mmol) at 0 °C, then the mixture was stirred at 0 °C for 30 mins, then 2,4-difluorophenylhydrazine hydrochloride (16221.7 mg, 89.83 mmol) was added slowly (about 30 min) at 0 °C. The reaction mixture was stirred at 90 °C for 18 h and then concentrated; the residue was purified by flash chromatography to give compound C6-c (5 g), LCMS (M+H ⁺ ): 238. Step 3: preparation of 1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyridazin-4-ol (compound C6-d) A mixture of 1-[5-amino-1-(2,4-difluorophenyl)pyrazol-4-yl]ethanone (compound C6-c, 4 g, 16.86 mmol) in hydrochloride acid (50 mL) and water (25 mL) was stirred at -5 °C for 1 h. Then sodium nitrite (2560 mg, 37 mmol) in water (25 mL) was added, the mixture was stirred at -5°C for 1 h and 25 °C for 1 h. After heating at 65°C for 4 h, the reaction mixture was adjusted pH to 7 using aq.NaHCO ₃ solution at 0 °C. Then the mixture was extracted with EtOAc, dried and concentrated to give compound C6-d (4 g), LCMS (M+H ⁺ ): 248. Step 4: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyridazine (Intermediate C6) A mixture of 1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyridazin-4-ol (compound C6-d, 5 g, 20.15 mmol) and DIPEA (7.02 mL, 40.29 mmol) in phosphorus oxychloride (50.0 mL) was heated to 110 °C for 3 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give the crude product, which was purified by flash chromatography to give intermediate C6 (395 mg), LCMS (M+H ⁺ ): 266. Intermediate C7 4-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. Step 1: preparation of ethyl (2Z)-2-(dimethylaminomethylene)-4,4-diethoxy-3-oxo- butanoate (compound C7-b) A mixture of ethyl 4,4-diethoxy-3-oxo-butanoate (2.0 g, 9.16 mmol) and DMF dimethyl acetal (1.31 g, 11 mmol) in toluene (20 mL) was stirred at 110 °C for 2 h. The reaction mixture was concentrated to give compound C7-b (2.45 g). LCMS (M+H) ⁺ : 274. Step 2: preparation of ethyl 5-(diethoxymethyl)-1-(2,4-difluorophenyl)pyrazole-4- carboxylate (compound C7-c) A mixture of ethyl (2Z)-2-(dimethylaminomethylene)-4,4-diethoxy-3-oxo-butanoate (compound C7-b, 1.95 g, 7.13 mmol) and 2,4-difluorophenylhydrazine hydrochloride (1.42 g, 7.85 mmol) in ethanol (20 mL) was stirred at 80 °C for 1 h. Then the reaction was concentrated, the residue was diluted with EA, washed with water and brine. The organic layer was dried and concentrated; the residue was purified by flash column chromatography to give compound C7-c (2 g). LCMS (M+H) ⁺ : 355. Step 3: preparation of 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazin-4-ol (compound C7-d) To a solution of ethyl-5-(diethoxymethyl)-1-(2,4-difluorophenyl)pyrazole-4-ca rboxylate (compound C7-c, 1.0 g, 2.82 mmol) in Acetic acid (10 mL) was added hydrazine hydrate (0.28 g, 5.64 mmol). The reaction was stirred at 90 °C for 12 h. Then hydrazine hydrate (0.28 g, 5.64 mmol, 2 eq) was added and the reaction was stirred at 120 °C for 12 h. After cooling to 0°C, a solid precipitated, which was collected and dried in vacuo to give compound C7-d (500 mg). LCMS (M+H) ⁺ : 249. Step 4: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine (Intermediate C7) A solution of 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazin-4-ol (C7-d, 100.0 mg, 0.400 mmol) in phosphoryl trichloride (1.06 mL, 11.35 mmol) was stirred at 100 °C for 12 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated, the crude compound was purified by pre-TLC to give intermediate C7 (50 mg). LCMS (M+H) ⁺ : 267. Intermediate C8 4-bromo-1-(2,4-difluorophenyl)pyrazolo[3,4-b]pyridine The title compound was prepared according to the following scheme:

Step 1: preparation of N-[(4-bromo-2-fluoro-3-pyridyl)methyleneamino]-2,4-difluoro- aniline (compound C8-b) A mixture of 4-bromo-2-fluoro-pyridine-3-carbaldehyde (1.5 g, 7.35 mmol), 2,4- difluorophenylhydrazine hydrochloride (1.5 g, 8.31 mmol) and potassium carbonate (1.2 g, 8.68 mmol) in DCM (30 mL) was stirred at 25 °C for 16 h. The mixture was diluted with EA (50 mL), washed with water (100 mL) and brine (100 mL). The organic layer was dried and concentrated, the residue was purified by silica gel to afford compound C8-b (2.35 g). LCMS (M+H) ⁺ : 330. Step 2: preparation of 4-bromo-1-(2,4-difluorophenyl)pyrazolo[3,4-b]pyridine (Intermediate C8) A mixture of compound C8-b (2.25 g, 6.82 mmol) and DIPEA (2.4 mL, 14.51 mmol) in anhydrous NMP (40 mL) was stirred for 16 h at 120 °C. The mixture was diluted with EA (50 mL), washed with water (100 mL) and brine (100 mL). The organic layer was dried and concentrated; the residue was purified by silica gel to afford intermediate C8 (644 mg). LCMS (M+H) ⁺ : 310. Intermediate C9 4-bromo-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-b]pyridine The title compound was prepared according to the following scheme: Step 1: preparation of N-[(4-bromo-2-fluoro-3-pyridyl)methyleneamino]-4-fluoro-2- methoxy-aniline (compound C9-b) A mixture of 4-bromo-2-fluoro-pyridine-3-carbaldehyde (3.0 g, 14.71 mmol), (4-fluoro-2- methoxy-phenyl)hydrazine hydrochloride (compound C9-a, 3.5 g, 14.9 mmol) and potassium carbonate (2.4 g, 17.37 mmol) in DCM (30 mL) was stirred at 25 °C for 16 h. The mixture was diluted with EtOAc (150 mL), washed with water and brine. The organic layer was dried and concentrated to give compound C9-b (4.2 g). LCMS (M+H) ⁺ : 342. Step 2: preparation of 4-bromo-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- b]pyridine (Intermediate C9) A mixture of N-[ (4-bromo-2-fluoro-3-pyridyl)methyleneamino]-4-fluoro-2-metho xy- aniline (compound C9-b, 4.2 g, 12.28 mmol) and DIPEA (4.32 mL, 26.13 mmol) in anhydrous NMP (60 mL) was stirred for 72 h at 130 °C. The reaction was poured into water (200 mL) and extracted with EtOAc (150 mL). The organic phase dried and concentrated, the residue was purified by prep-HPLC to afford intermediate C9 (1066 mg). LCMS (M+H) ⁺ : 310. Intermediate C10 4-chloro-1-(2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. Step 1: preparation of 4-chloro-6-(2-methoxyanilino)pyrimidine-5-carbaldehyde (compound C10-b) A mixture of O-anisidine (5.0 g, 40.6 mmol), TEA (8.2 g, 81.2 mmol) and 4,6-dichloro-5- pyrimidinecarbaldehyde (C10-a 7.19 g, 40.6 mmol) in chloroform (20 mL) was stirred at 20 °C for 12 h. To the mixture was added water (50 mL) and EtOAc(50 mL), the mixture was filtered and the filter cake was collected to give compound C10-b (8.1 g). LCMS (M+H) ⁺ : 264. Step 2: preparation of 1-(2-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C10-c) To a solution of 4-chloro-6-(2-methoxyanilino)pyrimidine-5-carbaldehyde (C10-b ,1.0 g, 3.79 mmol) in ACN (20 mL) was added hydroxylamine-o-sulfonic acid (2.57 g, 22.75 mmol), and the reaction mixture was stirred at 20 °C for 12 h. Then aq. NaOH (1N, 16 mL) was added and the reaction mixture was stirred at 20 °C for another 4 h. The reaction mixture was poured into water (100 mL), extracted with EA (150 mL), the organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound C10-c (102 mg). LCMS (M+H) ⁺ : 244. Step 3: preparation of 4-chloro-1-(2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C10) A solution of compound C10-c (102 mg, 0.42 mmol) in POCl ₃ (5.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give intermediate C10 (80 mg). LCMS (M+H) ⁺ : 261. Intermediate C11 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimid ine The title compound was prepared according to the following scheme:

Step 1: preparation of N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (compound C11-c) A solution of 2-bromo-5-fluoroanisole (compound C11-a, 10.0 g, 48.78 mmol), benzophenone hydrazone (compound C11-b, 10.0 g, 50.96 mmol), palladium (II) acetate (200.0 mg, 0.89 mmol), xant-phos (400.0 mg, 0.69 mmol) and sodium tert-butoxide (6.7 g, 69.72 mmol) in anhydrous toluene (150.0 mL) was stirred for 12 h at 100 °C under N ₂ . The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated to give crude product, which was recrystallized from PE (200 mL) to give compound C11-c (12 g), used in next step directly. LCMS (M+H) ⁺ : 321. Step 2: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C11-d) A mixture of compound C11-c (11.0 g, 34.34 mmol) in ethanol (100.0 mL) and con. HCl (10.0 mL, 120 mmol) was stirred for 12 h at 60 °C. The mixture was concentrated, and then EtOAc (100 mL) was added. After stirring for 5 mins, the mixture was filtered, the filter cake was washed with PE (50 mL) and dried to give compound C11-d (4.5 g), which was used in next step directly. LCMS (M+H) ⁺ : 141. Step 3: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2- methoxy-aniline (compound C11-f) A mixture of compound C11-d (4.3 g, 22.32 mmol), 4,6-dichloro-5- pyrimidinecarbaldehyde (compound C11-e, 4.3 g, 24.3 mmol) and triethylamine (3.5 g, 34.59 mmol) in anhydrous THF (100.0 mL) was stirred for 12 h at 20 °C. The reaction solution was diluted with EtOAc (100.0 mL), washed with water and brine. The organic layer was dried and concentrated to give crude compound C11-f (5.2 g), used in next step directly. LCMS (M+H) ⁺ : 315. Step 4: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C11) A mixture of N-[(E)-(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro- 2-methoxy- aniline (compound C11-f, 4.0 g, 12.69 mmol) and 4A MS (1.0 g) in anhydrous DMF (10.0 mL) was stirred for 12 h at 100 °C. The mixture was diluted with EtOAc (200.0 mL), washed with water and brine. The organic layer was dried and concentrated to give crude product, which was purified by prep-TLC to give intermediate C11 (747 mg). LCMS (M+H) ⁺ : 279. Intermediate C12 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4 -d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of ((4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C12-b) To a stirring solution of 4-fluoro-2-methoxy-aniline (compound C12-a, 30.0 g, 212.55 mmol) in HCl/water (297.58 mL, 1488 mmol) was added a solution of NaNO ₂ (22.0 g, 318.9 mmol) in water (300 mL) at 0 °C. After stirring for 30 mins, a solution of tin (II) chloride dihydrate (119.92 g, 531.45 mmol) in conc. HCl (53.14 mL, 637.65 mmol) was added dropwise. The mixture was stirred at 15 °C for 12 h. The mixture was adjusted to pH 10-12 with 20% aqueous sodium hydroxide, and then extracted with EA. The organic phase were dried and concentrated. The residue was acidified with HCl in dioxane to pH 3~4, then the solid was collected and dried to give compound C12-b (26 g). LCMS (M+H) ⁺ : 157. Step 2: preparation of (5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4- carbonitrile (compound C12-c) To a solution of (4-fluoro-2-methoxy-phenyl)hydrazine;hydrochloride (compound C12-b, 11.5 g, 59.7 mmol) in ethanol (10 mL) was added ethoxymethylenemalononitrile (7.29 g, 59.7 mmol) and DIEA (31.88 mL, 179.11 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and the residue was diluted with EA. The organic layer was washed with water and brine (100 mL), and then concentrated, the residue was purified by column chromatography to give compound C12-c (5.2 g). LCMS (M+H) ⁺ : 233. Step 3: preparation of (N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3- yl]acetamide (compound C12-d) A solution of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carbonitrile (compound C12-c, 5.2 g, 22.39 mmol) in acetic anhydride (2286.13 mg, 22.39 mmol) was stirred at 100 °C for 12 h. The reaction was quenched with aq. NaOH (1 M, 30 mL) at 0~20 °C and then stirred at 100°C for 1 h. The reaction mixture was diluted with water, extracted with EA, the organic layer was concentrated and the residue was recrystallized (PE:EA=3:1) to give compound C12-d (3.9 g). LCMS (M+H) ⁺ : 275. Step 4: preparation of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-ol (compound C12-e) To a solution of N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3-yl]acetami de (C12-d, 1300.0 mg, 4.74 mmol) in acetic acid (13 mL) was added phosphorus oxychloride (1.3 mL, 13.95 mmol), then the reaction was stirred at 110 °C for 2 h. The reaction mixture was poured into water (100 mL), the solid was collected and dried to give compound C12-e (1.1 g). LCMS (M+H) ⁺ : 275. Step 5: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-methyl- pyrazolo[3,4-d]pyrimidine (Intermediate C12) A mixture of 1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimi din-4-ol (compound C12-e, 1100 mg, 4 mmol) in phosphorus oxychloride (11 mL) was stirred at 100 °C for 12 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give intermediate C12 (1.1 g). LCMS (M+H) ⁺ : 293. Intermediate C13 4-chloro-1-(2-ethoxyphenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 5-amino-1-(2-ethoxyphenyl)pyrazole-4-carbonitrile (compound C13-b) To a solution of ethoxymethylenemalononitrile (compound C13-a, 8.42 g, 68.91 mmol) in ethanol (70 mL) was added (2-ethoxyphenyl)hydrazine; hydrochloride (13.0 g, 68.91 mmol) and DIEA (36.8 mL, 206.73 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated and the residue was purified by silica gel to give compound C13-b (15 g). LCMS (M+H) ⁺ : 229. Step 2: preparation of 1-(2-ethoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C13-c) A mixture of 5-amino-1-(2-ethoxyphenyl)pyrazole-4-carbonitrile (compound C13-b, 5.0 g, 21.91 mmol) in formic acid (50 mL) was stirred at 100 °C for 16 h. The mixture was concentrated and the residue was recrystallized in MeOH (12 mL) to give compound C13-c (4.5 g). LCMS (M+H) ⁺ : 257. Step 3: preparation of 4-chloro-1-(2-ethoxyphenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C13) A mixture of 1-(2-ethoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C13-c, 4.5 g, 17.56 mmol) in phosphorus oxychloride (50 mL) was stirred at 100 °C for 12 h. The reaction mixture was added into ice-NaHCO ₃ solution slowly, and then extracted with DCM (50 mL) twice. The organic layer was dried and concentrated to give intermediate C13 (4.44 g). LCMS (M+H) ⁺ : 275. Intermediate C14 8-chloro-3-(3-pyridyl)imidazo[1,5-a]pyrazine The title compound was prepared in analogy to the preparation of intermediate C3 by using nicotinic acid instead of 2,4-difluorobenzoic acid. LCMS (M+H ⁺ ): 231. Intermediate C15 4-chloro-1-(2,4-difluorophenyl)-6-methyl-1H-pyrazolo[3,4-d]p yrimidine The title compound was prepared according to the following scheme:.

Step 1: preparation of 5-amino-1-(2,4-difluorophenyl)-1H-pyrazole-4-carbonitrile (compound C15-c) To a solution of 2,4-difluorophenylhydrazine hydrochloride (compound C15-a, 5.0 g, 27.69 mmol) in ethanol (80 mL) was added ethoxymethylenemalononitrile (compound C15-b, 3.38 g, 27.69 mmol) and triethylamine (7.72 mL, 55.38 mmol). The mixture was stirred at 25 °C for 0.5 hours, and then heated to 80 °C for 1 h. The mixture was concentrated, the residue was dissolved in EA, washed with water and brine. The organic layer was dried and concentrated to give compound C15-c (5.5 g). LCMS (M+H) ⁺ : 221. Step 2: preparation of 5-amino-1-(2,4-difluorophenyl)-1H-pyrazole-4-carboxamide (compound C15-d) 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carbonitrile (compound C15-c, 4.5 g, 20.44 mmol) was added to ice-cold sulfuric acid (50.0 g, 509.79 mmol). After stirring at 25 °C for 2 h, the mixture was poured into ice-water, and then basified with ammonia. The precipitate was collected and then dissolved in 60 mL of 6 M HCl solution and basified with 10 M NaOH solution to pH 8~9. The precipitate was collected and dried to give compound C15-d (4.5 g). LCMS (M+H) ⁺ : 239. Step 3: preparation of 1-(2,4-difluorophenyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-ol (compound C15-f) A mixture of 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxamide (compound C15-d, 1.0 g, 4.2 mmol) in trimethyl orthoacetate (compound C15-e, 5.0 mL, 8.4 mmol) was stirred at 120 °C for 40 h. Then the reaction mixture was concentrated, the residue was purified by prep- HPLC to give compound C15-f (80 mg). LCMS (M+H) ⁺ : 263. Step 4: preparation of 4-chloro-1-(2,4-difluorophenyl)-6-methyl-1H-pyrazolo[3,4- d]pyrimidine (Intermediate C15) A mixture of 1-(2,4-difluorophenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4-o l (compound C15-f, 70.0 mg, 0.270 mmol) in phosphorus oxychloride (2.0 mL) was stirred at 110 °C for 16 h under N ₂ . The mixture was quenched with 100 mL of NaHCO ₃ and extracted with EA (50 mL). The organic layer was dried and concentrated to give intermediate C15 (35 mg). LCMS (M+H) ⁺ : 281. Intermediate C16 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylate (compound C16-a) A mixture of 2-chloro-4-fluorophenylhydrazine hydrochloride (6 g, 30.5 mmol) and ethyl 2-formyl-3-oxopropanoate (4.4 g, 30.5 mmol) in ethanol (120 mL) and was stirred for 16 hs at 25 °C. Then the mixture was diluted with DCM and adjusted to pH=3 with aq. HCl (1 M). The organic layer was separated; dried and concentrated to give the crude compound C16-a (8.18 g). LCMS (M+H) ⁺ : 269. Step 2: preparation of 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (Intermediate C16) A mixture of compound C16-a (8.18 g, 30.5 mmol) and lithium hydroxide monohydrate (3.8 g, 91 mmol) in ethanol (100 mL) was stirred at 45 °C for 4 hrs. The mixture was concentrated to about 20 mL and diluted with 80 mL of water, acidified to pH 3~4 with 1 M HCl solution. The solid was filtered and the filter cake was dried to give intermediate C16 (6.2 g). LCMS (M+H) ⁺ : 241. Intermediate C17 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d] pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 2-(cyclopropoxy)-4-fluoro-1-nitro-benzene (compound C17-a) A mixture of 2,4-difluoro-1-nitro-benzene (10.0 g, 62.86 mmol), cyclopropanol (5.0 g, 86.09 mmol) and sodium tert-butoxide (12.1 g, 0.12 mol) in THF (0.2 L) was stirred at 50 °C for 1 h. The mixture was poured into water (0.2 L) and extracted with EtOAc (0.2 L twice). The combined organic layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography to give compound C17-a (8.0 g). Step 2~6: preparation of 4-chloro-1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4- d]pyrimidine (Intermediate C17) The title compound was prepared in analogy to the preparation of intermediate C18 by using compound C17-a instead of compound C18-a. LCMS (M+H) ⁺ : 305. Intermediate C18 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidi ne The title compound was prepared according to the following scheme: Step 1: preparation of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a) A mixture of 5-fluoro-2-nitro-phenol (1.0 g, 6.4 mmol), potassium carbonate (1.7 g, 12.7 mmol) and iodoethane (0.6 mL, 7.64 mmol, 1.2 eq) in DMF (10.0 mL) was stirred at 30 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to give compound C18-a (1.0 g). Step 2: preparation of 2-ethoxy-4-fluoro-aniline (compound C18-b) To the mixture of 2-ethoxy-4-fluoro-1-nitro-benzene (compound C18-a, 1.0 g, 5.4 mmol) in methanol (10.0 mL) was added Pd/C (0.1 g) and the mixture was stirred at 20 °C for 4 h under H ₂ atmosphere. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL twice). The organic layer was concentrated, the residue was purified by flash chromatography column to give compound C18-b, (0.8 g). LCMS (M+H ⁺ ): 156. Step 3: preparation of 4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidine-5- carbaldehyde (compound C18-c) To a mixture of 4,6-dichloropyrimidine-5-carbaldehyde (0.8 g, 4.51 mmol) and TEA (0.9 g, 9.0 mmol) in chloroform (20.0 mL) was added 2-ethoxy-4-fluoro-aniline (compound C18-b, 0.7 g, 4.5 mmol) dropwise and the mixture was stirred at 0 °C for 1 h. The mixture was washed with water, the organic layer was concentrated, and the residue was purified by silica gel to give compound C18-c (0.1 g). LCMS (M+H ⁺ ): 296. Step 4: preparation of [[4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidin-5- yl]methyleneamino] hydrogen sulfate (compound C18-d) A mixture of amino hydrogen sulfate (0.2 g, 1.7 mmol) and 4-chloro-6-(2-ethoxy-4-fluoro- anilino)pyrimidine-5-carbaldehyde (compound C18-c, 0.1 g, 0.34 mmol) in MeCN (5.0 mL) was stirred at 20 °C for 16 h. The mixture was used in next step directly. LCMS (M+H ⁺ ): 311. Step 5: preparation of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18-e) To the mixture of compound C18-d (0.1 g, 0.3 mmol) in ACN (5.0 mL) was added NaOH a.q (2.0 mL, 1M) and the reaction mixture was stirred at 25 °C for 2 h under N ₂ . The mixture was purified by prep-HPLC to give compound C18-e (30.0 mg). LCMS (M+H ⁺ ): 275. Step 6: preparation of 4-chloro-1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C18-f) A solution of 1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C18- e, 20.0 mg, 0.07 mmol) in POCl ₃ (1.0 mL) was stirred at 100 °C for 1 h. The mixture was concentrated to give intermediate C18 (20.0 mg). LCMS (M+H ⁺ ): 293. Intermediate C19 4-chloro-1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4 -d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 2-(difluoromethoxy)-4-fluoro-1-nitro-benzene (C19-a) To a solution of 5-fluoro-2-nitro-phenol (5.0 g, 31.83 mmol) and sodium chlorodifluoroacetate (5.8 g, 38.2mmol) in DMF (60.0 mL) was added Na ₂ CO ₃ (6.75 g, 63.65 mmol). The mixture was stirred at 100 °C for 2 h, and then poured into water (200.0 mL). The resulting mixture was extracted with EtOAc, and the organic layer was washed with brine, dried and concentrated to give compound C19-a (5.0 g). Step 2-6: preparation of 4-chloro-1-[2-(difluoromethoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidine (Intermediate C19) The title compound was prepared in analogy to the preparation of intermediate C18 by using compound C19-a instead of compound C18-a. LCMS (M+H) ⁺ : 315. Intermediate C20 2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-benzonitr ile The title compound was prepared according to the following scheme: Step 1~3: preparation of 1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C20-d) Compound C20-d was prepared in analogy to the preparation of intermediate C43 by using 4-fluoro-2-iodo-aniline instead of 2-bromo-4-fluoro-aniline. LCMS (M+H) ⁺ : 356. Step 4: preparation of 4-chloro-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimidine (compound C20-e) A solution of 4-chloro-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimidine (compound C20-d, 5 g, 14.0 mmol) in POCl ₃ (15 mL) was stirred at 80 °C for 2 hours. Then the reaction mixture was concentrated, the residue was diluted with EtOAc (100 mL), and poured into aq.NaHCO ₃ . The organic layer was separated and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated to give compound C20-e (4.5 g). LCMS (M+H) ⁺ : 375. Step 5: preparation of 2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro- benzonitrile (Intermediate C20) To a solution of 4-chloro-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimidine (compound C20-e, 2 g, 5.3 mmol) in DMF (50 mL) was added cuprous cyanide (1.0 g, 5.9 mmol) under nitrogen at room temperature. The reaction mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was poured into water (200 mL), and extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated to get crude product, which was purified by column chromatography to give Intermediate C20 (0.8 g). LCMS (M+H) ⁺ : 274. Intermediate C21 [2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenyl]m ethanol The title compound was prepared according to the following scheme: Step 1: preparation of (5-fluoro-2-hydrazino-phenyl)methanol;hydrochloride (compound C21-b) To a solution of 5-fluoro-2-hydrazino-benzoic acid hydrochloride (compound C21-a, 1.24 g, 6 mmol) in anhydrous THF (15 mL) was added 1M borane tetrahydrofuran complex (30 mL, 30 mmol) at 0 °C, the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was carefully quenched by adding MeOH, then 4M HCl in 1,4-dioxane solution was added and stirred for 1 h. The white suspension was concentrated in vacuo to give crude compound C21-b (1.12 g). Step 2: preparation of [2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro- phenyl]methanol (Intermediate C21) To a mixture of (5-fluoro-2-hydrazino-phenyl)methanol hydrochloride (compound C21-b, 930 mg, 4.8 mmol) in DCM (12 mL) was added Et ₃ N (2.44 g, 24.14 mmol), then 4,6- dichloropyrimidine-5-carbaldehyde (854.54 mg, 4.83 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and DCM, the separated aqueous layer was extracted with DCM. The combined organic layer was dried and concentrated, the residue was purified by flash chromatography to afford Intermediate C21 (270 mg). LCMS (M+H) ⁺ : 279. Intermediate C22 2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: preparation of methyl 2-bromo-3-methyl-imidazole-4-carboxylate (compound C22-a) To a solution of methyl 3-methylimidazole-4-carboxylate (5.0 g, 35.6 mmol) in carbon tetrachloride (300.0 mL) was added NBS (12.7 g, 71.4 mmol) and 2,2'-azobis(2- methylpropionitrile) (0.3 g, 1.8 mmol). The mixture was stirred at 60 °C for 12 h and then concentrated. The residue was purified by silica gel to give compound C22-a (1.5 g). LCMS (M+H) ⁺ : 219. Step 2: preparation of methyl 2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carboxylate (compound C22-b) A solution of 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola ne (1.2 g, 5.1 mmol), compound C22-a (1.0 g, 4.6 mmol), Pd-Ad ₂ nBuP Biphenyl (0.3 g, 0.46 mmol) and K ₃ PO4 (2.9 g, 13.7 mmol) in THF (10.0 mL) and water (1.0 mL) was stirred at 80 °C for 2 h under N ₂ . The mixture was quenched with water (20.0 mL) and then extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound C22-b (0.7 g) as a white solid. LCMS (M+H) ⁺ : 253. Step 3: preparation of 2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carboxylic acid (Intermediate C22) A solution of compound C22-b (0.7 g, 2.78 mmol) and LiOH•H ₂ O (0.35 g, 8.33 mmol) in methanol (15.0 mL) and water (2.0 mL) was stirred at 20 °C for 12 h. The mixture was concentrated, the residue was dissolved in water (20 mL) and acidified with HCl (1M) to pH=4. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give Intermediate C22 (0.6 g). LCMS (M+H) ⁺ : 238. Intermediate C23 [4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-y l]amine The title compound was prepared in analogy to the preparation of intermediate C2 by using 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde instead of 4,6-dichloro-5- pyrimidinecarbaldehyde (compound C2-a). LCMS (M+H ⁺ ): 282. Intermediate C24 [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimi din-6-yl]amine The title compound was prepared in analogy to the preparation of intermediate C2 by using 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde and (4-fluoro-2-methoxy- phenyl)hydrazine;hydrochloride (C9-a) instead of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a) and 2,4-difluorophenylhydrazine hydrochloride. LCMS (M+H ⁺ ): 294. Intermediate C25 [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimi din-6-yl]amine The title compound was prepared according to the following scheme: Bromotrimethylsilane (2.45 g, 2.07 mL, 15.98 mmol) was added dropwise to a stirred solution of [4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-y l]amine (compound C23, 500 mg, 1.78 mmol) in dibromomethane (54 mL) under N ₂ atmosphere. Then tert-butyl nitrite (4.21 mL, 35.51 mmol) was added dropwise, and stirring was continued at ambient temperature for 1 h. The mixture was cooled for 15 min and added dropwise to a cold, vigorously stirred mixture of saturated NaHCO ₃ /H ₂ O (50 mL)/CH ₂ Cl ₂ (50 mL). The aqueous layer was extracted with DCM (30 mL, twice) and the combined organic phase was washed with water (20 mL) and brine (20 mL), dried (MgSO ₄ ) and concentrated. The resulting residue was purified by silica gel to afford intermediate C25 (450 mg). LCMS (M+H ⁺ ): 346. Intermediate C27 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-c arbonitrile

The title compound was prepared according to the following scheme: Step 1: preparation of 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylic acid ethyl ester (compound C27-a) A solution of 2-cyano-3-ethoxy-acrylic acid ethyl ester (507 mg, 3 mmol), (2,4- difluorophenyl)hydrazine;hydrochloride (540 mg, 3 mmol) and Et ₃ N (836 μL, 6 mmol) in ethanol (10 mL) was stirred at 90 °C for 12 hours. The solvent was removed by reduce pressure and then purified by silica gel to afford compound C27-a (635 mg), LCMS (M+H ⁺ ): 268. Step 2: preparation of 1-(2,4-difluorophenyl)-4-keto-5H-pyrazolo[3,4-d]pyrimidine-6 - carboxylic acid ethyl ester (compound C27-b) To a suspension of compound C27-a (635 mg, 2.38 mmol) in 4 M HCl in dioxane (12 mL) was added cyanoformic acid ethyl ester (470 mg, 4.75 mmol). The mixture was stirred at 100 °C for 14 hours and then was cooled to room temperature. After 1,4-dioxane was removed in vacuo, the residue was partitioned between methylene chloride and water. The organic layer was dried and concentrated, the residue was purified by silica gel to afford compound C27-b (700 mg), LCMS (M+H ⁺ ): 321. Step 3: preparation of 1-(2,4-difluorophenyl)-4-keto-5H-pyrazolo[3,4-d]pyrimidine-6 - carboxamide (compound C27-c) A suspension of compound C27-b (260 mg, 0.812 mmol) in 7 M ammonia in MeOH (4 mL) was stirred at room temperature for 12 hours. The mixture was concentrated to afford compound C27-c, (220 mg). Step 4: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6- carbonitrile (Intermediate C27) A suspension of compound C27-c (160 mg, 0.522 mmol) in phosphorus oxychloride (2 mL) was stirred at 90 °C for 2 hours. The mixture was concentrated and the residue was purified by silica gel to afford intermediate C27 (123 mg), LCMS (M+H ⁺ ): 292. Intermediate C28 [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimi din-6-yl]amine The title compound was prepared according to the following scheme: A suspension of compound C28-a (200 mg, 0.684 mmol, the synthesis refer to C27-b by using 2-methoxyacetonitrile instead of cyanoformic acid ethyl ester in step 2) in phosphorus oxychloride (mL, 21.46 mmol) was stirred at 90 °C for 0.5 hours. Then the reaction mixture was concentrated to give an oil, which was purified by silica gel to give intermediate C28 (182 mg) as white solid. LCMS (M+H ⁺ ): 311. Intermediate C30 4-chloro-6-cyclobutyl-1-(2,4-difluorophenyl)pyrazolo[3,4-d]p yrimidine

The title compound was prepared according to the following scheme: Step 1: preparation of 6-cyclobutyl-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- ol (compound C30-a) To a solution of intermediate C2 (50 mg, 0.19 mmol) in acetonitrile (1 mL) was added cyclobutanecarboxylic acid (56.0 mg, 0.56 mmol), silver nitrate (255 mg, 1.5 mmol). The reaction mixture was heated at 60 °C for 2 hours, and then a solution of ammonium persulfate (214 mg, 0.94 mmol) in water (1 mL) was added. After being stirred at 60 °C for another 2 hours, the mixture was concentrated and the residue was purified by prep-HPLC to afford compound C30-a (15 mg). LCMS (M+H) ⁺ : 357. Step 2: preparation of 4-chloro-6-cyclobutyl-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (intermediate C30) A solution of compound C30-a (15.0 mg, 0.050 mmol) in phosphorus oxychloride (0.5 mL, 5.36 mmol) was stirred at 80 °C for 2 hrs. The reaction mixture was cooled to 0 °C and then diluted with EA. The mixture was quenched with sat.NaHCO ₃ (30 mL) at 0 °C. The organic phase was separated, dried and concentrated to afford intermediate C30 (15 mg). LCMS (M+H) ⁺ : 321. Intermediate C31 4-chloro-1-(4,5-difluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidine The title compounds were prepared in analogy to the preparation of intermediate C10 by using 4,5-difluoro-2-methoxy-aniline instead of O-anisidine, LCMS (M+H) ⁺ : 297. Intermediate C32 4-chloro-1-(4-chloro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimid ine The title compounds were prepared in analogy to the preparation of intermediate C10 by using 4-chloro-2-methoxyaniline instead of O-anisidine, LCMS (M+H) ⁺ : 295. Intermediate C33 4-chloro-1-(5-chloro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimid ine The title compounds were prepared in analogy to the preparation of intermediate C10 by using 5-chloro-2-methoxyaniline instead of O-anisidine, LCMS (M+H) ⁺ : 295. Intermediate C34 4-chloro-7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazine The title compound was prepared according to the following scheme:

Step 1: preparation of ethyl 3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropanoate (compound C34-a) To a solution of ethyl 2,3-epoxypropanoate (10.0 g, 86.12 mmol) in DMF (200 mL) was added phthalimide (11.0 g, 74.76 mmol) and potassium phthalimide (2 g, 10.8 mmol), the mixture was stirred at 90 °C for 5 hours. The mixture was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound C34-a (19 g). LCMS (M+H) ⁺ : 264. Step 2: preparation of ethyl 3-(1,3-dioxoisoindolin-2-yl)-2-oxopropanoate (compound C34-b) To a solution of compound C34-a (18.0 g, 68.38 mmol) in DCM (200 mL) was added Dess-Martin periodinane (43.5 g, 102.56 mmol) at 0 °C. The mixture was stirred at 20 °C for 3 h. The mixture was filtered through celite and the filtrate was concentrated to give compound C34-b (14 g). LCMS (M+H) ⁺ : 262. Step 3: preparation of 2-((5-hydroxy-3-mercapto-1,2,4-triazin-6- yl)methyl)isoindoline-1,3-dione (compound C34-c) A slurry of compound C34-b (10.0 g, 38.28 mmol) in anhydrous ethanol (200 mL) was charged with thiosemicarbazide (3.49 g, 38.28 mmol) in one portion and heated to 80 °C for 2 h. The reaction mixture was charged with DIPEA (6.67 mL, 38.28 mmol) and heated to 40 °C for 16 hours. The mixture was concentrated, and the residue was dissolved in acetonitrile (80 mL). After water (300 mL) was added to the solution, solid precipitated, which was collected by filtration to give compound C34-c (5.6 g). LCMS (M+H) ⁺ : 289. Step 4: preparation of 2-((5-hydroxy-1,2,4-triazin-6-yl)methyl)isoindoline-1,3-dion e (compound C34-d) A mixture of compound C34-c (4.6 g, 15.96 mmol), Et ₃ SiH (3.6 g) and Raney Ni (6.0 g, 15.96 mmol) in ethanol (130 mL) was stirred at 80 °C for 12 hours. Then the mixture was filtered through celite and the filtrate was concentrated to give compound C34-d (2.8 g). LCMS (M+H) ⁺ : 257. Step 5: preparation of 6-(aminomethyl)-1,2,4-triazin-5-ol (compound C34-e) To a solution of compound C34-d (100 mg) in ethanol (1 mL) was added methylamine (1.0 mL, 2 M in EtOH) at 20 °C, then the mixture was stirred at 60 °C for 1 h. The reaction solution was concentrated to give compound C34-e. LCMS (M+H) ⁺ : 127. Step 6~7: preparation of 4-chloro-7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazine (intermediate C34) The title compound was prepared in analogy to the preparation of intermediate C3 by using compound C34-e instead of (3-chloropyrazin-2-yl)methanamine hydrochloride. LCMS (M+H) ⁺ : 267. Intermediate C41 7-chloro-3-(2,4-difluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-ol (compound C41-a) A mixture of 1H-pyrazolo[4,3-d]pyrimidin-7-ol (0.3 g, 2.2 mmol) and NIS (0.8 g, 4.4 mmol) in DMF (10.0 mL) was stirred at 60 °C for 1 h, and then the mixture was concentrated , the residue was triturated in MeOH (5.0 mL) to give compound C41-a, (0.5 g). LCMS (M+H ⁺ ): 262. Step 2: preparation of 3-(2,4-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrimidin-7 - one (compound C41-b) To a mixture of (2,4-difluorophenyl)boronic acid (0.7 g, 4.6 mmol) and 3-iodo-1H- pyrazolo[4,3-d]pyrimidin-7-ol (compound C41-a, 0.5 g, 2.3 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (170.1 mg, 0.2 mmol) and potassium carbonate (1.0 g, 7.0 mmol) under N ₂ atmosphere. The mixture was stirred at 80 °C for 2 h under N ₂ atmosphere and then filtered. The filter cake was washed with ACN (20.0 mL) and MeOH (20.0 mL). The solid was dried to give compound C41-b (0.2 g). LCMS (M+H ⁺ ): 249. Step 3: preparation of 7-chloro-3-(2,4-difluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine (Intermediate C41) A mixture of 3-(2,4-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrimidin-7 -one (C41-b, 0.1 g, 0.4 mmol) in POCl ₃ (5.0 mL) was stirred at 80 °C for 2 h. The mixture was then concentrated under reduce pressure and the residue was partitioned between EtOAc (20.0 mL) and aqueous solution of NaHCO ₃ (20.0 mL). The organic layer was separated, dried and concentrated to give intermediate C41 (60.0 mg). LCMS (M+H ⁺ ): 267. Intermediate C42 4-chloro-1-(4-fluoro-2-methyl-phenyl)pyrazolo[3,4-d]pyrimidi ne The title compound was prepared in analogy to the preparation of intermediate C18 by using (4-fluoro-2-methyl-phenyl)hydrazine hydrochloride instead of compound C2-a. LCMS (M+H ⁺ ): 263. Intermediate C43 1-(2-bromo-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol The title compound was prepared according to the following scheme: Step 1: preparation of (2-bromo-4-fluoro-phenyl)hydrazine (compound C43-a) To a solution of 2-bromo-4-fluoro-aniline (5.0 g, 26.3 mmol) in hydrochloric acid (12 M) (50.0 mL) and water (25.0 mL) was added a solution of sodium nitrite (2.0 g, 28.9 mmol) in water (3.0 mL) dropwise at -5 °C. After addition, the reaction mixture was stirred at -5 °C for 0.5 h. Then a solution of tin(II) chloride dihydrate (17.8 g, 78.9 mmol) in hydrochloric acid (12 M) (50.0 mL) was added into this mixture at -5 °C drop wise. The mixture was stirred for additional 2 hours and then filtered. This filter cake was washed with cold brine and dried to give compound C43-a (5.0 g). Step 2: Preparation of 5-amino-1-(2-bromo-4-fluoro-phenyl)pyrazole-4-carbonitrile (compound C43-b) A mixture of compound 43-a (4.0 g, 19.5 mmol), 2-(ethoxymethylene)propanedinitrile (2.4 g, 19.5 mmol) and DIEA (7.5 g, 58.5 mmol, 3.0 eq) in ethanol (0.1 L) was stirred at 80 °C for 2 h. The mixture was poured into waster (0.1 L) and extracted with EtOAc (0.1 L twice). The combined organic layer was dried and concentrated to give compound C43-b (4.5 g). LCMS (M+H ⁺ ): 281. Step 3: preparation of 1-(2-bromo-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate C43) A solution of compound C43-b (4.0 g, 14.23 mmol) in formic acid (20.0 mL) was stirred at 80 °C for 1 h. The mixture was concentrated and the residue was recrystallized in MeOH to give intermediate C43 (2.0 g). LCMS (M+H ⁺ ): 309. Intermediate C44 1-(4-fluoro-2-vinyl-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol The title compound was prepared according to the following scheme: To a mixture of intermediate C43 (0.5 g, 1.6 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (0.37 g, 1.6 mmol) and potassium carbonate (0.7 g, 4.85 mmol) in 1,4-dioxane (10.0 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride toluene (0.13 g, 0.16 mmol, 0.1 eq). The mixture was stirred at 100 °C for 12 h under N ₂ . The mixture was filtered and the filtrate was concentrated, the residue was purified by chromatography column to give intermediate C44 (0.2 g). LCMS (M+H ⁺ ): 257. Intermediate C45 1-(2-cyclopropyl-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4- ol The title compound was prepared according to the following scheme:

Step 1: preparation of 1-(2-bromo-4-fluoro-phenyl)-4-chloro-pyrazolo[3,4- d]pyrimidine (compound C45-a) A solution of intermediate C43 (4.5 g, 14.5 mmol) in POCl ₃ (50.0 mL) was stirred at 100 °C for 2 h. The mixture was concentrated and the residue was dissolved in EtOAc (0.3 L). The solution was poured into aq. NaHCO ₃ (0.3 L). The organic phase was separated, washed with brine, dried and concentrated to compound C45-a (4.0 g). LCMS (M+H ⁺ ): 327. Step 2: preparation of 4-benzyloxy-1-(2-bromo-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C45-b) A mixture of compound C45-a (4.0 g, 12.2 mmol), benzyl alcohol (1.1 mL, 14.6 mmol) and t-BuOK (24.4 mL, 24.4 mmol) in THF (50.0 mL) was stirred at 20 °C for 1 h. The mixture was poured into water (50.0 mL) and extracted with EtOAc (50 mL twice). The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound C45-b (3.1 g). LCMS (M+H ⁺ ): 399. Step 3: preparation of 4-benzyloxy-1-(2-cyclopropyl-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C45-c) To a mixture of compound C45-b (1.0 g), potassium cyclopropyltrifluoroborate (0.7 g, 5.0 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in 1,4-dioxane (20.0 mL) and water (2.0 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride toluene (0.21 g, 0.25 mmol). The mixture was stirred at 100 °C for 16 h under N ₂ . After cooled to r.t., the mixture was poured into brine (20.0 mL) and extracted with EtOAc (20.0 mL twice). The combined organic layer was dried and concentrated, the residue was purified by pre-TLC to compound C45-c (50.0 mg). LCMS (M+H ⁺ ): 361. Step 4: preparation of 1-(2-cyclopropyl-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4- ol (Intermediate C45) To a mixture of compound C45-c (50.0 mg, 0.14 mmol) in DCM (3.0 mL) was added BBr ₃ (34.3 mg, 0.14 mmol) at -78 °C dropwise and the mixture was stirred at -78 °C for 1 h under N ₂ . The reaction was quenched water (3.0 mL) and then concentrated, the residue was purified by prep-HPLC to give intermediate C45 (25.0 mg). LCMS (M+H ⁺ ): 271. Intermediate C46A and C46B 4-chloro-1-[4-fluoro-2-(trifluoromethoxy)phenyl]pyrazolo[3,4 -d]pyrimidine (Intermediate C46A) and 4-chloro-1-[2-fluoro-4-(trifluoromethoxy)phenyl]pyrazolo[3,4 -d]pyrimidine (Intermediate C46B) The title compounds were prepared according to the following scheme: Step 1: preparation of 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene (compound C46A-a) and 2-fluoro-1-nitro-4-(trifluoromethoxy)benzene (compound C46B-a) 1-fluoro-3-(trifluoromethoxy)benzene (10.0 g, 55.5 mmol) was dissolved in H ₂ SO ₄ (40.0 mL) and the mixture was cooled to 0 °C in ice bath. Then to the mixture was added KNO ₃ (1.4 g, 13.86 mmol) portion-wise with internal temperature below 5 °C. Upon completion of the addition, the mixture was stirred at 0 °C for 1 h. The mixture was poured into ice (200.0 g) and extracted with EtOAc (100.0 mL twice). The mixture was dried and concentrated to give a mixture of compound C46A-a and C46B-a (1.5 g). Step 2: preparation of 4-fluoro-2-(trifluoromethoxy)aniline (C46A-b) and 2-fluoro-4- (trifluoromethoxy)aniline (C46B-b) To a mixture of Pd/C (0.3 g) in methanol (10.0 mL) was added a mixture of compound C46A-a and C46B-a (1.5 g, 6.6 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The mixture was filtered and the filtrate was concentrated to give a mixture of compound C46A- b and C46B-b (0.6 g). LCMS (M+H ⁺ ): 196. Step 3: preparation of 4-chloro-6-[4-fluoro-2-(trifluoromethoxy)anilino]pyrimidine- 5- carbaldehyde (compound C46A-c) and 4-chloro-6-((2-fluoro-4- (trifluoromethoxy)phenyl)amino)pyrimidine-5-carbaldehyde (compound C46B-c) To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.3 g, 7.3 mmol) and TEA (2.2 g, 22.04 mmol) in chloroform (20.0 mL) was added a mixture of compound C46A-b and C46B-b (0.6 g, 3.1 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1h and then stirred at 20 °C for another 16 h. The mixture was poured into water (30.0 mL), and the organic layer was separated, dried and concentrated. The residue was purified by TLC to give a mixture of compound C46A-c and C46B-c (250 mg). LCMS (M+H ⁺ ): 336. Step 4: preparation of [(E)-[4-chloro-6-[4-fluoro-2- (trifluoromethoxy)anilino]pyrimidin-5-yl]methyleneamino] hydrogen sulfate (compound C46A-d) and [(E)-[4-chloro-6-[2-fluoro-4-(trifluoromethoxy)anilino]pyrim idin-5- yl]methyleneamino] hydrogen sulfate (compound C46B-d) To a solution of amino hydrogen sulfate (0.5 g, 4.5 mmol) in ACN (20.0 mL) was added a mixture of compound C46A-c and C46B-c (0.25 g, 0.7 mmol). The reaction mixture was stirred at 20 °C for 16 h under N ₂ . Then the mixture containing compound C46A-d and C46B-d was used in next step directly. LCMS (M+H ⁺ ): 351. Step 5: preparation of 1-[4-fluoro-2-(trifluoromethoxy)phenyl]pyrazolo[3,4- d]pyrimidin-4-ol (compound C46A-e) and 1-[2-fluoro-4- (trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-ol (compound C46B-e) To a solution of NaOH/H ₂ O (1.2 mL,1.0 M) in ACN (10.0 mL) was added the mixture of compound C46A-d and C46B-d in step 4 and the resulting mixture was stirred at 25 °C for 1 h under N ₂ . The mixture was purified by prep-HPLC to give compound C46A-e (faster eluted, 50.0 mg) and C46B-e (slower eluted, 30.0 mg). LCMS (M+H ⁺ ): 315. Step 6: preparation of 4-chloro-1-[4-fluoro-2-(trifluoromethoxy)phenyl]pyrazolo[3,4 - d]pyrimidine (Intermediate C46A) A solution of compound C46A-e (20.0 mg, 0.06 mmol) in POCl ₃ (1.0 mL) was stirred at 80 °C for 1 h. The mixture was poured into a mixture of saturated aqueous NaHCO ₃ solution (20.0 mL) and EtOAc (20.0 mL). The organic layer was washed with water, dried and concentrated to give intermediate C46A (8.0 mg). LCMS (M+H ⁺ ): 333. Step 7: Preparation of 4-chloro-1-[2-fluoro-4-(trifluoromethoxy)phenyl]pyrazolo[3,4 - d]pyrimidine (Intermediate C46B) The title compound was prepared in analogy to the preparation of intermediate C46A by using compound C46B-e instead of compound C46A-e. LCMS (M+H ⁺ ): 333. Intermediate C47 4-chloro-1-[2-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4- d]pyrimidine The title compound was prepared in analogy to the preparation of intermediate C2 by using [2-(difluoromethyl)-4-fluoro-phenyl]hydrazine hydrochloride instead of compound C2-a. LCMS (M+H ⁺ ): 299. Intermediate C50 2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenol The title compound was prepared according to the following scheme:. To a solution of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimid ine (200.0 mg, 0.72 mmol, Intermediate C11) in DCM (5 mL) was added BCl ₃ /DCM (2.15 mL, 2.15 mmol) at -78 °C. After being stirred at 20 °C for 2 h, the reaction mixture was poured into ice- water and extracted with EA, the organic layer was dried and concentrated to give intermediate C50 (190 mg). LCMS (M+H) ⁺ : 265. Intermediate C51 4-chloro-1-(3,4-difluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidine The title compound was prepared according to the following scheme:.

Step 1~2: preparation of (3,4-difluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C51-c) Compound C51-c was prepared in analogy to the preparation of compound C11-d by using compound C51-a instead of compound C11-a. LCMS (M+H) ⁺ : 158. Step 3~5: preparation of 4-chloro-1-(3,4-difluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C51) Intermediate C51 was prepared in analogy to the preparation of Intermediate C4 by using compound C51-c instead of compound C4-a. LCMS (M+H) ⁺ : 297. Intermediate C52 4-chloro-1-[4-fluoro-2-(methoxymethyl)phenyl]pyrazolo[3,4-d] pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 1-bromo-4-fluoro-2-(methoxymethyl)benzene (compound C52- b) To a solution of 2-bromo-5-fluorobenzyl alcohol (compound C52-a, 3 g, 14.63 mmol) and iodomethane (4.2 g, 29.27 mmol) in THF (30 mL) was added NaH (1.2 g, 29.27 mmol) at 0 °C, and then the mixture was stirred at 20 °C for 2 hours. The reaction was quenched with water and extracted with EA, the organic layer was dried and concentrated to give compound C52-b (3.4 g). Step 2: preparation of N-[4-fluoro-2-(methoxymethyl)phenyl]-1,1-diphenyl- methanimine (compound C52-c) A mixture of compound C52-b (1 g, 4.57 mmol), diphenylmethanimine (0.92 mL, 5.48 mmol), (R)-binap (625 mg, 1 mmol), tris(dibenzylideneacetone)dipalladium (418 mg, 0.46 mmol) and cesium carbonate (2231 mg, 6.85 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 12 hours under N ₂ . The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel to give compound C52-c (1.4 g). LCMS (M+H) ⁺ : 320. Step 3: preparation of 4-fluoro-2-(methoxymethyl)aniline (compound C52-d) A mixture of compound C52-c (1.4 g, 2.76 mmol), sodium acetate (0.5 mL, 6.63 mmol) and NH ₂ OH•HCl (0.38 g, 5.52 mmol) in methanol (8 mL) was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the filtrate was poured into water, acidified pH to 1~2 with HCl (1 M). The resulting solution was extracted with EA to remove organic impurity, the aqueous layer was then basified pH to 8~9 with NaOH (1 M) and extracted with EA. The organic layer was dried and concentrated to give compound C52-d (230 mg). Step 4: preparation of [4-fluoro-2-(methoxymethyl)phenyl]hydrazine (compound C52-e) To a stirring solution of 4-fluoro-2-(methoxymethyl)aniline (compound C52-d 230 mg, 1.48 mmol) in HCl/water (2.08 mL, 10.38 mmol) was added a solution of NaNO ₂ (0.15 g, 2.22 mmol) in water (2 mL) at 0 °C. After stirring for 30 mins, a solution of tin(II) chloride dihydrate (0.84 g, 3.71 mmol) in conc. HCl (0.37 mL, 4.45 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hours and then adjusted pH to 10~12 with 20% aqueous sodium hydroxide. The resulting solution was extracted with EA, the organic layer was added HCl in dioxane (4 M) while white solid precipitated, which was collected by filtration to give compound C52-e (130 mg). LCMS (M-NH ₂ +H) ⁺ : 154. Step 5~7: preparation of 4-chloro-1-[4-fluoro-2-(methoxymethyl)phenyl]pyrazolo[3,4- d]pyrimidine (Intermediate C52) Intermediate C52 was prepared in analogy to the preparation of Intermediate C4 by using compound C52-e instead of compound C4-a. LCMS (M+H) ⁺ : 293. Intermediate C53 4-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. To a stirred solution of 2-chloro-5-fluoropyrimidine (compound C53-a, 60 mg, 0.45 mmol) and cesium fluoride (100 mg, 0.66 mmol) in acetonitrile (3 mL) was added 4-chloro-1H- pyrazolo[4,3-c]pyridine (50 mg, 0.33 mmol) at 40 °C, and the reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was concentrated and the residue was purified by prep- TLC to afford intermediate C53 (60 mg). LCMS (M+H) ⁺ : 250. Intermediate C54 4-chloro-1-(5-fluoropyrimidin-2-yl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of (5-fluoropyrimidin-2-yl)hydrazine (compound C54-b) To a stirred solution of 2-chloro-5-fluoropyrimidine (compound C54-a, 2.0 g, 15.09 mmol) in ethanol (12 mL) was added hydrazine hydrate (3.66 mL, 75.46 mmol), then the mixture was stirred at 25 °C for 1 h. The reaction was concentrated to afford compound C54-b (1.9 g). LCMS (M+H) ⁺ : 129. Step 2~4: preparation of 4-chloro-1-(5-fluoropyrimidin-2-yl)pyrazolo[3,4-d] pyrimidine (Intermediate C54) Intermediate C54 was prepared in analogy to the preparation of Intermediate C4 by using compound C54-b instead of compound C4-a. LCMS (M+H) ⁺ : 251. Intermediate C56 1-(1-bicyclo[1.1.1]pentanyl)-4-chloro-pyrazolo[3,4-d]pyrimid ine The title compounds were prepared in analogy to the preparation of intermediate C10 by using bicyclo[1.1.1]pentan-1-amine instead of O-anisidine, LCMS (M+H) ⁺ : 211. Intermediate C57 4-chloro-1-(3-methyl-1-bicyclo[1.1.1]pentanyl)pyrazolo[3,4-d ]pyrimidine The title compound was prepared in analogy to the preparation of intermediate C10 by using 3-methylbicyclo[1.1.1]pentan-1-amine instead of O-anisidine, LCMS (M+H) ⁺ : 235. Intermediate C58 4-chloro-1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazolo[3,4-d ]pyrimidine The title compound was prepared in analogy to the preparation of intermediate C10 by using 3-fluorobicyclo[1.1.1]pentan-1-amine instead of O-anisidine. LCMS (M+H) ⁺ : 239. Intermediate C59 4-chloro-1-(2-ethoxyphenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 6-bromo-1-methyl-pyrazolo [4,3-c]pyridine (compound C59-b) A solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (compound C59-a, 4.0 g, 20.2 mmol) in DMFDMA (15.0 mL) was stirred at 120 °C for 12 h. The reaction mixture was concentrated and the residue was purified by silica gel to give compound C59-b (2.3 g). LCMS (M+H) ⁺ : 212. Step 2: preparation of 3-bromo-6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4,3- c]pyridine (compound C59-c) To a solution of compound C59-b (300 mg, 1.22 mmol) in DMF (6.2 mL) was added NBS (435 mg, 2.45 mmol) and then stirred at 80 °C for 2 hours. The reaction mixture was quenched with water, extracted with EA, the organic layer was dried and concentrated. The residue was purified by silica gel to afford compound C59 c (140 mg). LCMS (M+H) ⁺ : 292. Step 3: preparation of 3-bromo-1-methyl-6-(3-thienyl)-pyrazolo-[4,3-c]pyridine (intermediate C59) To a solution of compound C59-c (100 mg, 0.34 mmol) in THF (2 mL) and water (2 mL) was added tetrakis (triphenylphosphine) palladium (40 mg, 0.03 mmol), thiophene-2- boronic acid (66 mg, 0.52 mmol) and Na ₂ CO ₃ (108 mg, 0.86 mmol). After stirring at 85 °C for 16 hours, the mixture was concentrated and the residue was purified by pre-TLC to afford intermediate C59 (60 mg). LCMS (M+H) ⁺ : 296. Intermediate C60 3-bromo-6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4,3-c]pyrid ine The title compound was prepared according to the following scheme:

Step 1: preparation of 6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4,3-c]pyridine (compound C60-b) To a solution of compound C59-b (500 mg, 2.36 mmol), 2,4-difluorobenzeneboronic acid (447 mg, 2.83 mmol,) and potassium carbonate (652 mg, 4.72 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (173 mg, 0.240 mmol) under N ₂ , and the mixture was stirred at 90 °C for 3 h under N ₂ . The mixture was concentrated and the residue was purified by silica gel to give compound C60-b (540 mg). LCMS (M+H) ⁺ :246. Step 2: preparation of 3-bromo-6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4,3- c]pyridine (intermediated C60) To a solution of compound C60-b (300 mg) in DMF (6 mL) was added NBS (435 mg, 2.45 mmol) and then stirred at 80 °C for 2 hours. The reaction mixture was quenched with water, extracted with EA, the organic layer was dried and concentrated. The residue was purified by silica gel to give intermediate C60 (80 mg). LCMS (M+H) ⁺ : 324. Intermediate C61 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyr imidine The title compound was prepared according to the following scheme:

Step 1: preparation of 1,5-difluoro-3-methoxy-2-nitro-benzene (compound C61-b) A mixture of 3,5-difluoro-2-nitro-phenol (compound C61-a, 9.5 g, 54.3 mmol), iodomethane (10.0 g, 70.5 mmol) and potassium carbonate (10.0 g, 72.4 mmol) in anhydrous DMF (250 mL) was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc (500 mL), and washed with water (200 mL) and brine (200 mL). The organic layer was dried and concentrated to give the crude product, which was purified by flash chromatography to give compound C61-b (10.0 g). LCMS (M+H) ⁺ : 190. Step 2: preparation of 2,4-difluoro-6-methoxy-aniline (compound C61-c) To a mixture of 1,5-difluoro-3-methoxy-2-nitro-benzene (compound C61-b, 10.0 g, 52.9 mmol) in anhydrous EtOAc (200 mL) was added Pd/C (1.0 g) and the reaction mixture was stirred at room temperature for 12 h under hydrogen. The mixture was filtered, the filtrate was concentrated to give compound C61-c (7.5 g). LCMS (M+H) ⁺ : 160. Step 3~5: preparation of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound C61-f) Compound C61-f was prepared in analogy to the preparation of intermediate C43 by using 2,4-difluoro-6-methoxy-aniline instead of 2-bromo-4-fluoro-aniline. LCMS (M+H) ⁺ : 279. Step 6: preparation of 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C61) A mixture of 1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- ol (compound C61-f, 4.6 g, 16.5 mmol) in POCl ₃ (18 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, the residue was taken in EtOAc (100 mL) and poured into aq.NaHCO ₃ (100 mL). The separated organic layer was washed with brine, dried and concentrated to give Intermediate C61 (4.14 g). LCMS (M+H) ⁺ : 297. Intermediate C62 4-chloro-1-[4-fluoro-2-(trideuteriomethoxy)phenyl]pyrazolo[3 ,4-d]pyrimidine The title compound was prepared according to the following scheme: To a mixture of intermediate C50 (100 mg, 0.38 mmol), trideuterio(deuteriooxy)methane (40.89 mg, 1.13 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in THF (1 mL) was added DIAD (153 mg, 0.76 mmol) in one portion. The mixture was stirred at rt for 1 h and then concentrated, the residue was purified by silica gel to give intermediate C62 (50 mg), LCMS: (M+H) ⁺ : 282. Intermediate C63 8-chloro-3-(2,4-difluorophenyl)-[1,2,4]triazolo[4,3-a]pyrazi ne The title compound was prepared according to the following scheme: Step 1: preparation of N'-(3-chloropyrazin-2-yl)-2,4-difluoro-benzohydrazide (compound C63-a) A mixture of 2,3-dichloropyrazine (1 g, 6.71 mmol), 2,4-difluorobenzohydrazide (1.16 g, 6.71 mmol), and Cs ₂ CO ₃ (4.37 g, 13.42 mmol) in DMF was stirred at 100 °C for 2 hours, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound C63-a (1.5 g). LCMS: (M+H) ⁺ : 285. Step 2: preparation of 8-chloro-3-(2,4-difluorophenyl)-[1,2,4]triazolo[4,3-a]pyrazi ne (Intermediate C63) A mixture of compound C63-a(1.5 g, 5.27 mmol) in phosphorus oxychloride (10 mL ) was stirred at 100 °C for 16 hours, then the reaction was diluted with EA, quench by adding to NaHCO ₃ (5%, 100 mL). The organic layer was separated and concentrated, the residue was purified by flash preparation to give Intermediate C63 (300 mg). LCMS: (M+H) ⁺ : 267. Intermediate C64 4-chloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1~2: preparation of 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C64-c) Compound C64-c was prepared in analogy to the preparation of intermediate C43 by using 2,6-difluoro-aniline instead of 2-bromo-4-fluoro-aniline. LCMS (M+H) ⁺ : 249. Step 3: preparation of 4-chloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C64) A mixture of 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C64-c, 3.7 g, 14.9 mmol) in POCl ₃ (18 mL) was stirred at 100 °C for 4 h. The mixture was concentrated, the residue was diluted with EtOAc (200 mL) and poured into aq.NaHCO ₃ (200 mL). The separated organic layer was washed with brine, dried and concentrated to give Intermediate C64 (3.7 g). LCMS (M+H) ⁺ : 267. Intermediate C65 1-(2,4-difluorophenyl)-3-methyl-pyrazolo[3,4-d]pyrimidin-4-o l The title compound was prepared according to the following scheme: A mixture of 5-amino-1-(2,4-difluorophenyl)-3-methyl-pyrazole-4-carbonitr ile (compound C65-a, 234 mg, 1 mmol) in formic acid (3 mL) was stirred at 120 °C for 2 h under microwave irritation. After removing excess formic acid in vacuo, the residue formed a slurry in EtOAc/hexane, then filtered. The filter cake was collected and dried to give Intermediate C65 (241 mg). LCMS (M+H) ⁺ : 263. Intermediate C66 2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-benzoic acid The title compound was prepared according to the following scheme:

A mixture of 5-fluoro-2-hydrazino-benzoic acid hydrochloride (620 mg, 3 mmol ), 4,6- dichloropyrimidine-5-carbaldehyde (531 mg, 3 mmol ) and Et ₃ N (911 mg, 9 mmol) in anhydrous 1,2-dichloroethane (8 mL) was stirred at room temperature for 3 h. After removing solvent in vacuo, the residue formed a slurry in EtOAc/hexane, then filtered. The filtrate was concentrated and the residue was purified by flash chromatography to afford Intermediate C66 (404 mg). LCMS (M+H) ⁺ : 293. Intermediate C67 4-chloro-2-(2,4-difluorophenoxy)pyridine The title compound was prepared according to the following scheme: A mixture of 4-chloro-2-fluoropyridine (2.0 g, 15.2 mmol), 2,4-difluorophenol (2.2 g, 16.7 mmol) and potassium carbonate (4.2 g, 30.4 mmol) in DMF (60 mL) was stirred at 80 °C for 12 hours. After being cooled to room temperature, the reaction mixture was diluted with EtOAc (200 mL), washed with water and brine, the organic layer was dried and concentrated. The residue was purified by column chromatography to afford Intermediate C67 (2.9 g). LCMS (M+H) ⁺ : 242. Intermediate C68 1-[2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenyl ]pyrrolidin-2-one The title compound was prepared according to the following scheme: To a solution of compound C20-e (0.5 g, 1.1 mmol), 2-pyrrolidone (0.11 mL, 1.5 mmol), CuI (0.1 g, 0.5 mmol) and 1,10-phenanthroline (0.1 g, 0.55 mmol) in 1,4-dioxane (20 mL) was added potassium phosphate (283.0 mg, 1.3 mmol, 1.0 eq) and the reaction mixture was stirred at 75 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to get crude product, which was purified by column chromatography to afford Intermediate C68 (0.1 g). LCMS (M+H) ⁺ : 332. Intermediate C69 4-chloro-1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrazolo[3,4- d]pyrimidine The title compound was prepared in analogy to the preparation of Intermediate C2 by using [4-fluoro-2-(trifluoromethyl)phenyl]hydrazine hydrochloride instead of 2,4- difluorophenylhydrazine hydrochloride. LCMS (M+H ⁺ ): 317. Intermediate C71 4-chloro-1-(2-fluoro-4-phenyl-phenyl)pyrazolo[3,4-d]pyrimidi ne The title compound was prepared according to the following scheme: Step 1: preparation of 5-amino-1-(4-bromo-2-fluoro-phenyl)pyrazole-4-carbonitrile (compound C71-a) A mixture of 2-(methoxymethylene)propanedinitrile (2.5 g, 20.7 mmol), DIEA (8.0 g, 62.1 mmol) and (4-bromo-2-fluoro-phenyl)hydrazine hydrochloride (5.0 g, 20.7 mmol) in ethanol (150 mL) was stirred at 60 °C for 2 hours. The mixture was poured into water (200 mL) and extracted with EtOAc (200 mL twice). The combined organic layer was dried and concentrated to give compound C71-a (5.5 g). LCMS (M+H ⁺ ): 281. Step 2: preparation of 1-(4-bromo-2-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C71-b) A mixture of compound C71-a (5.5 g, 19.6 mmol) in formic acid (20.0 mL) was stirred at 120 °C for 12 hours. The mixture was concentrated, and the residue was triturated in MeOH (0.1 L) to give compound C71-b (5.0 g). LCMS (M+H ⁺ ): 309. Step 3: preparation of 1-(4-bromo-2-fluoro-phenyl)-4-chloro-pyrazolo[3,4- d]pyrimidine (compound C71-c) The mixture of compound C71-b (4.0 g, 12.9 mmol) in POCl ₃ (10.0 mL) was stirred at 100 °C for 2 hours. The mixture was concentrated. The residue was triturated in MeOH (0.1 L) to give compound C71-c (4.0 g) as a yellow solid. LCMS (M+H ⁺ ): 327. Step 4: preparation of 4-benzyloxy-1-(4-bromo-2-fluoro-phenyl)pyrazolo[3,4- d]pyrimidine (compound C71-d) A mixture of compound C71-c (1.0 g, 3.0 mmol), benzyl alcohol (0.4 g, 3.9 mmol) and t- BuOK (0.6 g, 6.0 mmol) in THF (5 mL) was stirred at 0 °C for 1 h. The mixture was poured into water (20 mL) and extracted with EA (20 mL twice). The combined organic layer was dried and concentrated to give compound C71-d (0.3 g). LCMS (M+H ⁺ ): 399. Step 5: preparation of 4-benzyloxy-1-[4-(4-chlorophenyl)-2-fluoro- phenyl]pyrazolo[3,4-d]pyrimidine (compound C71-e) To a mixture of compound C71-d (0.2 g, 0.5 mmol) and Na ₂ CO ₃ (0.1 g, 1.0 mmol) in 1,4- dioxane (2 mL) and water (0.4 mL) was added (4-chlorophenyl)boronic acid (131.4 mg, 0.6mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and toluene (41.21 mg, 0.05 mmol). Then the mixture was stirred at 50 °C for 12 hours under N ₂ . The mixture was filtered and concentrated, the residue was purified by pre-HPLC to compound C71-e (0.2 g). LCMS (M+H ⁺ ): 431. Step 6: preparation of 1-(2-fluoro-4-phenyl-phenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C71-f) To a mixture of compound C71-e (0.1 g, 0.2 mmol) in methanol (1 mL) was added Pd/C (20 mg) and the mixture was stirred at 20 °C for 2 hours under H ₂ . The mixture was filtered and concentrated to give crude compound C71-f (30 mg). LCMS (M+H ⁺ ): 307. Step 6: preparation of 4-chloro-1-(2-fluoro-4-phenyl-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C71) A mixture of crude compound C71-f (30.0 mg) in POCl ₃ (1.0 mL) was stirred at 100 °C for 2 hours. The mixture was partitioned between NaHCO ₃ a.q. (30 mL) and EA (30 mL). The organic layer was dried and concentrated to give crude Intermediate C71 (30 mg). LCMS (M+H ⁺ ): 325. Intermediate C72 1-(2-fluoro-4-tetrahydrofuran-3-yl-phenyl)pyrazolo[3,4-d]pyr imidin-4-ol The title compound was prepared according to the following scheme: Step 1: preparation of 4-benzyloxy-1-[4-(2,5-dihydrofuran-3-yl)-2-fluoro- phenyl]pyrazolo[3,4-d]pyrimidine (compound C72-a) To a mixture of compound C71-d (0.2 g, 0.5 mmol) and K3PO4 (0.2 g, 1 mmol) in 1,4- dioxane (5 mL) and water (1 mL) was added 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.1 g, 0.6 mmol) and Pd-Ad ₂ nBuP Biphenyl Precat (G1) (33.4 mg, 0.05 mmol). Then the mixture was stirred at 60 °C for 1 h under N ₂ . The mixture was filtered and the filtrate was concentrated, the residue was purified by pre-HPLC to give compound C72-a (120 mg). LCMS (M+H ⁺ ): 389. Step 2: preparation of 1-(2-fluoro-4-tetrahydrofuran-3-yl-phenyl)pyrazolo[3,4- d]pyrimidin-4-ol (Intermediate C72) To a mixture of compound C72-a (0.1 g, 0.3 mmol) in MeOH (5 mL) was added Pd/C (50 mg) and then the mixture was stirred at 20 °C for 1 h under H ₂ . The mixture was filtered and the filtrate was concentrated to give intermediate C72 (70.0 mg). LCMS (M+H ⁺ ): 301. Intermediate C73 1-[4-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoro-phenyl ]pyrrolidin-2-one The title compound was prepared according to the following scheme: Step 1: preparation of 1-[3-fluoro-4-(4-hydroxypyrazolo[3,4-d]pyrimidin-1- yl)phenyl]pyrrolidin-2-one (compound C73-a) To a mixture of pyrrolidin-2-one (1.0 mL, 12.9 mmol), compound C71-b (1.0 g, 3.24 mmol) and TMEDA (0.4 g, 6.5 mmol) in DMF (10 mL) was added K ₂ CO ₃ (1.4 g, 9.7 mmol) and CuI (1.2 g, 6.4 mmol). After being stirred at 120 °C for 2 h, the mixture was filtered and the filtrate was concentrated, the residue was purified by pre-HPLC to give compound C73-a (0.1 g). LCMS (M+H ⁺ ): 314. Step 2: preparation of 1-[4-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoro- phenyl]pyrrolidin-2-one (Intermediate C73) A mixture of compound C73-a (20.0 mg, 0.06 mmol) in POCl ₃ (1.0 mL) was stirred at 100 °C for 1 h, and then poured into a mixture of NaHCO ₃ a.q. (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine and concentrated to give Intermediate C73 (15 mg). LCMS (M+H ⁺ ): 332. Intermediate C74 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared in analogy to the preparation of Intermediate C1 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5- carbaldehyde. LCMS (M+H ⁺ ): 301. Intermediate C75 4,6-dichloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidine The title compound was prepared in analogy to the preparation of Intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5- carbaldehyde and compound C11-d instead of compound C2-a. LCMS (M+H ⁺ ): 313. Intermediate C76 4,6-dichloro-1-[4-fluoro-2-(trideuteriomethoxy)phenyl]pyrazo lo[3,4-d]pyrimidine The title compound was prepared according to the following scheme: Step 1: preparation of 2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-pheno l (compound C76-a) To a solution of intermediate C75 (2.0 g, 6.39 mmol) in DCM (40 mL) was added BCl ₃ /THF (31.94 mL, 31.94 mmol) at -78 °C and the reaction mixture was stirred at 25 °C for 12 hours, then poured into ice-water (100 mL), extracted with DCM. The organic layer was dried and concentrated to give compound C76-a (1.51 g), LCMS (M+H ⁺ ): 299. Step 2: preparation of 4,6-dichloro-1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d] pyrimidine (Intermediate C76) To a mixture of compound C76-a (1 g, 3.34 mmol), trideuterio(deuteriooxy) methane (350 mg, 10.92 mmol) and TPP (1.3 g, 5 mmol) in toluene (15 mL) was added DEAD (873 mg, 5 mmol) at 0 °C under N ₂ , then the mixture was stirred at 50 °C for 1 h under N ₂ . The reaction was quenched with water (100 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by column chromatography to Intermediate C76 (800 mg). LCMS (M+H ⁺ ): 316. Intermediate C77 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimi dine The title compound was prepared in analogy to the preparation of Intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5- carbaldehyde and compound C1-b instead of compound C2-a. LCMS (M+H ⁺ ): 302. Intermediate C78 methyl 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-c arboxylate The title compound was prepared according to the following scheme: Step 1 : preparation of methyl 2-[[4-cyano-2-(2,4-difluorophenyl)pyrazol-3-yl]amino]- 2-oxo-acetate (compound C78-b) To a solution of compound C4-b (5.0 g, 22.71 mmol) in sulfolane (50 mL) at 10 °C was added methyl oxalyl chloride (3.07 mL, 34.06 mmol) slowly (about 30 min). Then the mixture was stirred at 110 °C for 16 h. The mixture was cooled to 25 °C and poured into a stirred ice water (500 mL) and EtOAc (100 mL). The organic layer was separated, dried and concentrated, the residue was purified by silica gel and prep-HPLC to give compound C78-b (5 g). LCMS (M+H ⁺ ): 307. Step 2 : preparation of methyl 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine-6-carboxylate (Intermediate C78) To the compound C78-b (2.2 g, 7.18 mmol) was added POCl ₃ (30 mL) at 0 °C. After being stirred at 110 °C for 36 hours, the mixture was concentrated to give the crude product, which was diluted with DCM (30 mL) and then poured into ice-NaHCO ₃ . Then the mixture was extracted with DCM, the organic layer was dried and concentrated, the residue was purified by flash chromatography to give Intermediate C78 (1.5 g). LCMS (M+H ⁺ ): 325 Intermediate C79 4,6-dichloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidine The title compound was prepared in analogy to the preparation of Intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5- carbaldehyde and compound C61-d instead of compound C2-a. LCMS (M+H ⁺ ): 331. Intermediate C80 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo [3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxyla te (compound C80-a) To a solution of compound 431a (1.25 g, 3.35 mmol), tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate (731.32 mg, 3.69 mmol) in DMSO (20 mL) was added N,N-diisopropylethylamine (1.75 mL, 10 mmol) and then stirred at 100 °C for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to give compound C80-a (2.0 g) as a brow oil. LCMS (M+H ⁺ ):535. Step 2: preparation of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C80-b) To a solution of compound C80-a (4.0 g, 7.48 mmol) in DCM (20 mL) was added TFA at 0 °C and then stirred at 25 °C for 2 hrs. The reaction mixture was concentrated and the residue was diluted with water (50 mL), which was lyophilized to give compound C80-b (2.5 g) as a yellow solid. LCMS (M+H ⁺ ):345. Step 3: preparation of 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (intermediate C80) To a solution of compound C80-b (500.0 mg, 1.09 mmol), 1-fluoro-2-iodoethane (1.90 g, 10.91 mmol) in ACN (20 mL) was added triethylamine (1.52 mL, 10.91 mmol) and then the mixture was stirred at 80 °C for 12 hrs. The reaction was quenched with water (200 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash- HPLC (TFA as additive) to give intermediate C80 (300.0 mg) as a yellow solid. LCMS (M+H ⁺ ):391. Intermediate C81 6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl] -1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C81 was prepared in analogy to the preparation of Intermediate C80 by using 2,2-difluoroethyl methanesulfonate instead of 1-fluoro-2-iodoethane. LCMS (M+H ⁺ ):409. Intermediate C82 1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluoroethyl)-3,6-diaza bicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C82 was prepared in analogy to the preparation of Intermediate C80 by using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of 1-fluoro-2-iodoethane. LCMS (M+H ⁺ ):427. Intermediate C83 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diaz abicyclo[2.2.1]heptan-2- yl]pyrazolo[3,4-d]pyrimidin-4-ol

Intermediate C83 was prepared in analogy to the preparation of Intermediate C80 by using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ):391. Intermediate C84 6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]hept an-2-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C84 was prepared in analogy to the preparation of Intermediate C80 by using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate and 2,2-difluoroethyl methanesulfonate instead of 1- fluoro-2-iodoethane. LCMS (M+H ⁺ ):409. Intermediate C85 1-(2,4-difluorophenyl)-6-[6-(2-fluoroethyl)-3,6-diazabicyclo [3.1.1]heptan-3- yl]pyrazolo[3,4-d]pyrimidin-4-ol

Intermediate C85 was prepared in analogy to the preparation of Intermediate C80 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ):391. Intermediate C86 1-(2,4-difluorophenyl)-6-[3-(2-hydroxyethyl)-3,6-diazabicycl o[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C86 was prepared in analogy to the preparation of Intermediate C80 by using ethylene oxide instead of 1-fluoro-2-iodoethane. LCMS (M+H ⁺ ):389. Intermediate C87 1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicycl o[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol

Intermediate C87 was prepared in analogy to the preparation of Intermediate C80 by using 1-iodo-2-methoxy-ethane instead of 1-fluoro-2-iodoethane. LCMS (M+H ⁺ ):403. Intermediate C88 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl]pyrazolo[3,4-d]pyrimidin-4-ol The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl (1R,4R)-5-[4-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2,5-diazabicyc lo[2.2.1]heptane-2- carboxylate (compound C88-a) To a solution of compound 431a (1.0 g, 2.68 mmol) and tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (585 mg, 2.95 mmol) in DMSO (16 mL) was added N,N-diisopropylethylamine (1.4 mL, 8.05 mmol) and then stirred at 90 °C for 1 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give compound C88-a (3.5 g) as a brown oil. LCMS (M+H ⁺ ): 535. Step 2: preparation of 6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound C88-b) To a solution of compound C88-a (650 mg, 1.22 mmol) in DCM (10 mL) was added TFA (3.04 mL, 12.16 mmol) at 0 °C and then stirred at 25 °C for 1 h. The reaction mixture was concentrated to give compound c88-b (1500 mg) as a yellow oil. LCMS (M+H ⁺ ): 345. Step 3: preparation of 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate C88) To a solution of compound C88-b (450.0 mg, 0.98 mmol), 3-oxetanone (720.0 mg, 9.99 mmol) in DCE (9 mL) was added sodium triacetoxyborohydride (1.04 g, 4.91 mmol) at 0 °C and then stirred at 25 °C for 1 h. The mixture was diluted with H ₂ O (30 mL) and extracted with EA (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate C88 (200.0) as a brown solid. LCMS (M+H ⁺ ): 401. Intermediate C89 1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3 .1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C89 was prepared in analogy to the preparation of Intermediate C88 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. LCMS (M+H ⁺ ): 401. Intermediate C90 1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-3, 6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol

Intermediate C90 was prepared in analogy to the preparation of Intermediate C88 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 3-fluorooxetane-3-carbaldehyde instead of cyclobutanone. LCMS (M+H ⁺ ): 433. Intermediate C91 6-[3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C91 was prepared in analogy to the preparation of Intermediate C88 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and (1-ethoxycyclopropoxy)trimethylsilane instead of cyclobutanone. LCMS (M+H ⁺ ): 385. Intermediate C92 1-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimi din-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]-2,2,2-trifluoro-ethanone

To a solution of compound C80-b (100.0 mg, 0.22 mmol), triethylamine (0.09 mL, 0.65 mmol) in DCM (2 mL) was added trifluoroacetic anhydride (0.05 mL, 0.33 mmol) at 0 °C and then stirred at 25 °C for 1 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (20mL). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , and concentrated to give intermediate C92 (100.0 mg) as a white solid. LCMS (M+H ⁺ ): 441. Intermediate C93 1-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimi din-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]-2,2-difluoro-ethanone Intermediate C93 was prepared in analogy to the preparation of Intermediate C92 by using (2,2-difluoroacetyl) 2,2-difluoroacetate instead of trifluoroacetic anhydride. LCMS (M+H ⁺ ): 423. Intermediate C94 3-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimi din-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile

Intermediate C94 was prepared in analogy to the preparation of Intermediate C80 by using 3-bromopropionitrile instead of 1-fluoro-2-iodoethane. LCMS (M+H ⁺ ):398. Intermediate C95 1-(2,4-difluorophenyl)-6-[3-(3-fluorocyclobutyl)-3,6-diazabi cyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-ol Intermediate C95 was prepared in analogy to the preparation of Intermediate C88 by using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 3-fluorocyclobutanone instead of cyclobutanone. LCMS (M+H ⁺ ): 417. Example 1 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one

The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[3-[3-[3-(tert- butoxycarbonylamino)propyl]benzimidazol-4-yl]phenoxy]pyrroli dine-1,2-dicarboxylate (compound 1a) To a flask was added O1-benzyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (compound B12, 1.63 g, 3.39 mmol) , tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (compound A15-c, 1 g, 2.82 mmol,), K ₂ CO ₃ (780 mg, 5.65 mmol), 1,4-dioxane (15mL) and water (0.5mL), the suspension was bubbled with N2 for 5 mins and PdCl2(DPPF)-CH ₂ Cl ₂ adduct (207 mg, 282 μmol) was added. The mixture was heated to 100 °C for 2 hrs. The mixture was diluted with 40 mL water and then it was extracted with EA three times, the organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel to give compound 1a (688 mg), LCMS (M+H ⁺ ): 629. Step 2: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)benzimidazol-4-yl]phenoxy]-1- benzyloxycarbonyl-pyrrolidine-2-carboxylic acid;hydrochloride (compound 1b) To the flask containing O1-benzyl O2-methyl (2S,4S)-4-[3-[3-[3-(tert- butoxycarbonylamino)propyl]benzimidazol-4-yl]phenoxy]pyrroli dine-1,2-dicarboxylate (compound 1a, 866 mg, 1.38 mmol) was added THF (8mL) and 2 N aqueous solution of LiOH (4mL, 8 mmol). The mixture was stirred at r.t. for 3 hrs. To the mixture was added 20 mL DCM and then it was acidified with 1 N aqueous solution of HCl (pH ~ 5). The mixture was separated, the organic layer was dried concentrated to give (2S,4S)-1-benzyloxycarbonyl-4-[3-[3-[3-(tert- butoxycarbonylamino) propyl]benzimidazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid which was obtained as brown oil, then dissolved in EtOAc (2mL) and HCl 4 N in dioxane (4.8 g, 4mL, 16 mmol) was added. The mixture was stirred at r.t. for 3 hrs. The mixture was concentrated directly to give compound 1b (650 mg), LCMS (M+H ⁺ ): 515. Step 3: preparation of benzyl (8S,11S)-12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 1c) To a 1000 mL flask was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (720 mg, 1.89 mmol), DIPEA (408 mg, 552 μL, 3.16 mmol) and acetonitrile (325mL), the solution was cooled with ice bath and then a solution of (2S,4S)-4-(3-(1-(3-aminopropyl)-1H-benzo[d]imidazol-7-yl)phe noxy)-1-((benzyloxy) carbonyl)pyrrolidine-2-carboxylic acid (compound 1b, 650 mg, 1.26 mmol) in DMF (65mL) was added via dropping funnel for about 20 min. The mixture was concentrated to remove the ACN, the residue was poured into 200 mL water and extracted with EA/MeOH=50:1 (150 mL for 3 times), the organic layer was dried over Na ₂ SO ₄ and concentrated to give an oil, which was dried to give compound 1c (440 mg), LCMS (M+H ⁺ ): 497. Step 4: preparation of (8S,11S)-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (compound 1d) The benzyl (8S,11S)-12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxyla te (compound 1c, 440 mg, 0.88 mmol) was dissolved in MeOH (50mL) and then Pd(OH) ₂ (20% on carbon with 50% H ₂ O) (177 mg, 1.26 mmol) was added. The mixture was purged with H ₂ for 5 times. The mixture was heated to 60 °C and stirred under H ₂ balloon for about 16 hrs. The mixture was concentrated to give compound 1d (~800 mg, containing some DMF), LCMS (M+H ⁺ ): 363. Step 5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- 2,6 8,11 20,24 yl]-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (example 1) To a microwave tube was added (8S,11S)-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 1d, 30 mg, 82.8 μmol), 4-chloro-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4- d]pyrimidine (compound C2, 22.1 mg, 82.8 μmol,), DIPEA (32.1 mg, 43.4 μL, 248 μmol) and acetonitrile (2mL). The mixture was heated to 90 °C and stirred for about 1 hr, then concentrated to give an oil which was purified via prep-HPLC to give Example 1 (3.7 mg), LCMS (M+H ⁺ ): 593. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.31 - 7.94 (m, 2H), 7.70 - 7.59 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.23 - 7.18 (m, 1H), 7.18 - 7.12 (m, 2H), 7.09 (br s, 1H), 7.00 (d, J = 7.7 Hz, 1H), 5.53 - 5.33 (m, 1H), 5.06 (br d, J = 9.7 Hz, 1H), 4.54 (br d, J = 11.4 Hz, 1H), 4.42 - 4.28 (m, 1H), 4.23 - 4.07 (m, 1H), 4.05 - 3.91 (m, 1H), 3.52 - 3.37 (m, 1H), 3.20 - 3.08 (m, 1H), 2.86 (br d, J = 14.2 Hz, 1H), 2.76 - 2.50 (m, 1H), 2.29 - 2.13 (m, 1H), 2.03 - 1.86 (m, 1H). Example 2 (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-car bonyl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme: To a microwave tube was added 2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carboxylic acid (compound C22, 65.7 mg, 276 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (157 mg, 414 μmol,), DIPEA (107 mg, 145 μL, 828 μmol) and DCM (2mL), the suspension was stirred for a while and a solution of (8S,11S)-7- 2,6 8,11 20,24 oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21- heptaen-12-one (compound 1d, 100 mg, 276 μmol) in DMF (0.5mL) was added. After being stirred at r.t. for 16 hrs, the mixture was filtered, the filtrate was concentrated to give an oil which was purified via prep-HPLC to give Example 2 (23 mg), LCMS (M+H ⁺ ): 583. ¹ H NMR (400 MHz, METHANOL-d4) δ = 9.50 - 9.38 (m, 1H), 8.10 - 8.01 (m, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.69 - 7.63 (m, 1H), 7.60 - 7.54 (m, 1H), 7.51 - 7.45 (m, 1H), 7.37 - 7.23 (m, 3H), 7.11 - 7.01 (m, 2H), 5.43 - 5.35 (m, 1H), 4.96 - 4.91 (m, 1H), 4.17 - 4.00 (m, 2H), 3.94 - 3.87 (m, 3H), 3.87 - 3.83 (m, 2H), 3.56 - 3.39 (m, 1H), 3.10 - 2.88 (m, 1H), 2.86 - 2.72 (m, 1H), 2.71 - 2.47 (m, 1H), 2.45 - 2.20 (m, 1H), 2.05 - 1.74 (m, 1H). Example 3 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-7-oxa-10,13,16,18- 2,6 8,11 19,23 tetrazapentacyclo[14.6.1.1 .1 .0 ]pentacosa-1(22),2,4,6(25),17,19(23),20-heptaen-12- one The title compound was prepared according to the following scheme: To a microwave tube was added (8S,11S)-7-oxa-10,13,16,18-tetrazapentacyclo 2,6 8,11 19,23 [14.6.1.1 .1 .0 ]pentacosa-1(22),2,4,6(25),17,19(23),20-heptaen-12-one (compound 3a, 40 mg, 115 μmol, the synthesis refers to compound 1d by using tert-butyl N-(2- aminoethyl)carbamate instead of tert-butyl N-(3-aminopropyl)carbamate), 4-chloro-1-(2,4- difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C2, 36.7 mg, 138 μmol, Eq: 1.2), DIPEA (59.4 mg, 80.2 μL, 459 μmol) and acetonitrile (4 mL), a yellow solution formed. The mixture was heated to 90 °C for 2 hrs, then the mixture was concentrated to give an oil, which was purified via prep-HPLC to give the Example 3 (9 mg), LCMS (M+H ⁺ ): 579. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.33 (s, 1H), 8.59 - 8.36 (m, 1H), 8.27 - 7.95 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.32 - 7.25 (m, 1H), 7.24 - 7.16 (m, 1H), 7.04 (br d, J = 7.5 Hz, 1H), 7.01 - 6.96 (m, 1H), 5.66 - 5.50 (m, 1H), 5.12 - 5.02 (m, 1H), 4.62 - 4.45 (m, 2H), 4.39 (br dd, J = 3.7, 11.2 Hz, 1H), 3.80 - 3.68 (m, 1H), 3.62 - 3.51 (m, 2H), 2.79 - 2.67 (m, 1H), 2.63 - 2.50 (m, 1H). Example 4 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(2-hydroxyethyl)-7- 2,6 8,11 20,24 oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of example 1 by using compound 4f instead of intermediate A15-c. Example 4 (6.4 mg), LCMS (M+H ⁺ ): 637. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.49 - 9.41 (m, 1H), 8.58 - 8.47 (m, 1H), 8.38 - 8.22 (m, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.72 - 7.60 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.24 - 7.16 (m, 1H), 7.09 - 6.99 (m, 2H), 5.64 - 5.45 (m, 2H), 4.41 - 4.28 (m, 1H), 4.26 - 4.17 (m, 1H), 4.17 - 3.99 (m, 2H), 3.84 - 3.72 (m, 1H), 3.71 - 3.58 (m, 2H), 3.46 - 3.40 (m, 1H), 3.18 - 3.10 (m, 1H), 3.09 - 3.00 (m, 1H), 2.97 - 2.86 (m, 1H), 2.83 - 2.64 (m, 2H), 1.85 - 1.72 (m, 1H). The compound 4f was prepared according to the following scheme:

Step 1 ~ 2: preparation of tert-butyl N-[3-(benzyloxycarbonylamino)propyl]-N-(2- hydroxyethyl)carbamate (compound 4b) To a flask was added benzyl (3-oxopropyl)carbamate (2 g, 9.65 mmol), 2-aminoethan-1-ol (1.18 g, 19.3 mmol), EtOH (50mL) and 5 drops of AcOH. The mixture was heated to 60 °C for about 30 mins and then sodium triacetoxyborohydride (3.07 g, 14.5 mmol) was added. The mixture was stirred at the same temperature for about 16 hrs. The mixture was concentrated to give compound 4a, then DCM (30mL), TEA (4.89 g, 6.73mL, 48.3 mmol) and Boc2O (7.38 g, 7.85mL, 33.8 mmol) were added. After being stirred at r.t. for 2 hrs, the mixture was filtered through celite, the filtrate was concentrated to give an oil, which was purified by silica gel to give compound 4b (1.95 g), LCMS (M+H ⁺ ): 353. Step 3: preparation of tert-butyl N-(3-aminopropyl)-N-(2-hydroxyethyl)carbamate (compound 4c) To a flask was added tert-butyl N-[3-(benzyloxycarbonylamino)propyl]-N-(2- hydroxyethyl)carbamate (4b, 1.95 g, 5.53 mmol), Pd(OH) ₂ 20% on carbon with 50% H ₂ O (200 mg, 1.42 mmol) and MeOH (50 mL), the suspension was purged with H ₂ for 5 times. After being stirred at r.t. for 2 hrs, the mixture was filtered, the filtrate was concentrated to give compound 4c (1.2 g), LCMS (M+H ⁺ ): 219. Step 4: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]-N-(2- hydroxyethyl)carbamate (compound 4d) To a microwave tube was added 1-bromo-2-fluoro-3-nitrobenzene (1.45 g, 6.6 mmol), tert- butyl N-(3-aminopropyl)-N-(2-hydroxyethyl)carbamate (compound 4c, 1.2 g, 5.5 mmol), K ₂ CO ₃ (1.52 g, 11 mmol) and acetonitrile (30 mL). The tube was sealed and heated to 90 °C for 2 hrs. The mixture was cooled and filtered, the filtrate was concentrated to give an oil. The oil was purified by silica gel to give compound 4d (1.78 g), LCMS (M+H ⁺ ): 418. Step 5: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]-N-(2- hydroxyethyl)carbamate (compound 4e) To a flask was added: nickel (1 g, 17 mmol), MeOH (50mL), tert-butyl N-[3-(2-bromo-6- nitro-anilino)propyl]-N-(2-hydroxyethyl)carbamate (compound 4d, 1.7 g, 4.06 mmol), the suspension was stirred vigorously and hydrazine monohydrate (1.02 g, 1.02mL, 20 mmol) was added. After being stirred at r.t. for 1 hr, the mixture was filtered through celite, the filtrate was concentrated to give an oil. The oil was dissolved in 40 mL DCM and washed with 20 mL water for three times. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 4e (1 g), LCMS (M+H ⁺ ): 388. Step 6: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-(2- hydroxyethyl)carbamate (compound 4f) To the flask containing the tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]-N-(2- hydroxyethyl)carbamate (4e, 1 g, 2.58 mmol) was added trimethyl orthoformate (2.91 g, 3mL, 27.4 mmol) and 4-methylbenzenesulfonic acid hydrate (98 mg, 515 μmol2), a light yellow solution formed. After being stirred at r.t. for 16 hrs, the mixture was concentrated to give an oil. The oil was purified by silica gel to give compound 4f (367 mg), LCMS (M+H ⁺ ): 398. Example 5 (8S,11S)-13-benzyl-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d] pyrimidin-4-yl]-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one The title compound was prepared according to the following scheme: To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one (Example 1, 130 mg, 219 μmol) in DMF (2mL) was added NaH (35.1 mg, 877 μmol) slowly. The mixture was stirred for about 10 mins and (bromomethyl)benzene (75 mg, 52.1 μL, 439 μmol) was added. After being stirred at 40 °C for 16 hrs, the mixture was quenched with 2 mL water and then it was purified via prep-HPLC to give Example 5 (28.6 mg), LCMS (M+H ⁺ ): 683. ¹ H NMR (400 MHz, METHANOL-d4) δ = 9.37 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.86 - 7.80 (m, 1H), 7.72 - 7.60 (m, 3H), 7.49 - 7.42 (m, 1H), 7.41 - 7.33 (m, 3H), 7.33 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.07 (s, 1H), 5.68 (br s, 1H), 5.61 (d, J = 9.4 Hz, 1H), 4.65 (d, J = 16.0 Hz, 1H), 4.59 - 4.52 (m, 2H), 4.51 - 4.39 (m, 1H), 4.01 - 3.87 (m, 2H), 3.78 - 3.66 (m, 1H), 2.93 (br d, J = 14.4 Hz, 1H), 2.84 - 2.61 (m, 3H), 1.77 - 1.63 (m, 1H). Example 7 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(2-methoxyethyl)-7- 2,6 8,11 20,24 oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18, 20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: To a tube was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]- 2,6 8,11 20,24 13-(2-hydroxyethyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 4, 25 mg, 39.3 μmol) and DMF (1 mL), the solution was cooled with ice bath and NaH (7.85 mg, 196 μmol) was added. The mixture was stirred for a while and iodomethane (27.9 mg, 18.2 μL, 196 μmol) was added. The mixture was heated to 50 °C and stirred for 4 hrs. The mixture solution was purified via prep-HPLC directly to give Example 7 (2.3 mg), LCMS (M+H ⁺ ): 651. Example 9 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3- 2,6 8,11 20,24 morpholinopropyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1 .1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: The title compound was prepared in analogy to example 5 by using 4-(3- bromopropyl)morpholine hydrobromide instead of (bromomethyl)benzene. Example 9, LCMS (M+H ⁺ ): 720. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.69 - 7.61 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.23 - 7.16 (m, 2H), 7.08 (dd, J = 0.9, 7.3 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.66 - 5.58 (m, 2H), 4.59 - 4.46 (m, 2H), 4.02 (dt, J = 3.3, 13.0 Hz, 1H), 3.97 - 3.90 (m, 1H), 3.82 (dt, J = 6.1, 12.8 Hz, 1H), 3.77 - 3.66 (m, 4H), 3.52 - 3.40 (m, 1H), 3.34 - 3.31 (m, 1H), 3.23 - 3.14 (m, 1H), 2.99 - 2.87 (m, 1H), 2.71 (br d, J = 3.1 Hz, 2H), 2.62 - 2.50 (m, 4H), 2.50 - 2.33 (m, 2H), 1.92 - 1.80 (m, 1H), 1.76 - 1.57 (m, 2H). Example 11 3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimid in-4-yl]-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-13-yl]propyl-trimethyl-ammonium The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- yl]-13-[3-(dimethylamino)propyl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (compound 11a) To a microwave tube was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- 2,6 8,11 20,24 d]pyrimidin-4-yl]-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1 .1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (example 1, 40 mg, 67.5 μmol), 3-bromo-N,N- dimethylpropan-1-amine hydrobromide (33.3 mg, 135 μmol) and DMF (0.5mL), a light yellow solution formed, and then NaH (21.6 mg, 540 μmol) was added in one portion. After being stirred at r.t. for 1 hr, the mixture was quenched with 10 mL water and neutralized with 1 N HCl aq., then it was extracted with 15 mL DCM twice, the organic layer was dried over Na ₂ OS ₄ and concentrated, the residue was purified by silica gel to give compound 11a (22 mg), LCMS (M+H ⁺ ): 678. Step 2: preparation of 3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimid in 2,6 8,11 20,24 -4-yl]-12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23), 2(26),3,5,18,20(24), 21-heptaen-13-yl]propyl-trimethyl-ammonium (Example 11) To a tube was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]- 13-[3-(dimethylamino)propyl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 11a, 22 mg, 31.8 μmol), DMF (0.5mL) and methyl iodide (45.1 mg, 19.9 μL, 318 μmol). The mixture was stirred at r.t. for 2 hrs and then it was purified via prep-HPLC directly to give example 11 (9.9 mg), LCMS (M ⁺ ): 692. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.47 (br s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.70 - 7.61 (m, 2H), 7.51 (t, J = 7.9 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.24 - 7.17 (m, 2H), 7.10 (dd, J = 0.8, 7.3 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.68 - 5.62 (m, 1H), 5.47 (br d, J = 8.7 Hz, 1H), 4.55 - 4.49 (m, 2H), 4.08 - 3.93 (m, 2H), 3.91 - 3.78 (m, 1H), 3.57 (td, J = 7.4, 15.2 Hz, 1H), 3.49 - 3.40 (m, 2H), 3.20 (s, 9H), 3.17 - 3.13 (m, 1H), 3.06 - 2.93 (m, 1H), 2.78 - 2.62 (m, 3H), 2.34 - 2.18 (m, 1H), 2.12 - 2.00 (m, 1H), 1.69 - 1.56 (m, 1H). Example 12 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(methyl)amino]propyl]benzimidazol-4-yl]-2-pyri dyl]amino]pyrrolidine-1,2- dicarboxylate (compound 12a) To a tube was added O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino] pyrrolidine-1,2-dicarboxylate (intermediate B10, 750 mg, 1.73 mmol, as the “HALIDE 1” in table 3), tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)benzimidazol- 1-yl]propyl]carbamate (intermediate A11, 500 mg, 1.2 mmol, as the “BORONIC REAGENT” in table 3), K ₂ CO ₃ (333 mg, 2.41 mmol), water (0.5mL) and 1,4-dioxane (15mL), the suspension was bubbled with N ₂ for 5 mins. Then PdCl ₂ (DPPF)-CH ₂ Cl ₂ adduct (88.1 mg, 120 μmol) was added and the mixture was heated to 100 °C for 3 hrs. The mixture was diluted with EA and filtered, the filtrate was concentrated to give an oil, which was purified by silica gel to give compound 12a (860 mg), LCMS (M+H ⁺ ): 643. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[3- (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrro lidine-2-carboxylic acid (compound 12b) A mixture of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(methyl)amino]propyl]benzimidazol-4-yl]-2-pyri dyl]amino]pyrrolidine-1,2- dicarboxylate (compound 12a, 977 mg, 1.52 mmol) and LiOH (6 mL, 2 N) in THF (2 mL) and MeOH (4 mL) was stirred at rt for 2 hrs. The mixture was diluted with 30 mL DCM and adjusted pH to 4, the mixture was extracted with DCM, the organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in EA (3 mL) and then treated with 4 N HCl in dioxane (3 mL). After being stirred at r.t. for 4 hrs, the mixture was concentrated, the residue was purified via prep- HPLC to give compound 12b (684 mg), LCMS (M+H ⁺ ): 529. Step 3: preparation of benzyl (8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 12c) To a solution of HATU (1.08 g, 2.84 mmol) and DIPEA (611 mg, 826 μL, 4.73 mmol) in DMF (20 mL) was added a solution of compound (compound 12b, 500 mg, 946 μmol) in DMF (20 mL) and acetonitrile (200 mL) dropwise in 1 hr. After being stirred at r.t. for16 hrs, the mixture was concentrated, the residue was purified by silica gel to give compound 12c (480 mg), LCMS (M+H ⁺ ): 511. Step 4: preparation of (8S,11S)-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 12d) A mixture of compound 1c (480 mg, 940 μmol) and Pd(OH) ₂ 20% on carbon with 50% H ₂ O (132 mg, 940 μmol) in MeOH (50 mL) was purged with H ₂ for three times. After being stirred at 65 °C for 2 hrs, the mixture was cooled and filtered, the filtrate was concentrated to give compound 12d (410 mg), LCMS (M+H ⁺ ): 377. Step 5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- 2,6 8,11 20,24 yl]-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 12) To a microwave tube was added (8S,11S)-13-methyl-7,10,13,17,19,26- 2,6 1 20,24 hexazapentacyclo[15.6.1.1 . .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 6d, 50 mg, 133 μmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 39 mg, 146 μmol, as the “HALIDE 2” in table 3), DIPEA (51.5 mg, 69.6 μL, 398 μmol) and acetonitrile (3 mL). After being stirred at 85 °C for 2 hrs, the mixture was concentrated to give an oil, which was purified via prep-HPLC to give Example 12 (23.3 mg), LCMS (M+H ⁺ ): 607. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.52 (s, 1H), 8.34 - 8.28 (m, 1H), 8.22 (s, 1H), 7.82 - 7.76 (m, 1H), 7.72 (dd, J = 1.5, 7.6 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.40 - 7.35 (m, 1H), 7.35 - 7.31 (m, 1H), 7.28 (ddd, J = 2.7, 8.8, 10.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 5.50 (d, J = 8.4 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.75 - 4.68 (m, 1H), 4.55 (dd, J = 6.5, 11.4 Hz, 1H), 4.37 - 4.24 (m, 1H), 4.19 - 4.05 (m, 2H), 3.04 (s, 3H), 2.92 - 2.83 (m, 1H), 2.68 - 2.61 (m, 1H), 2.60 - 2.52 (m, 1H), 2.20 - 1.95 (m, 1H), 1.59 - 1.40 (m, 1H). The following examples in Table 3 were prepared in analogy to Example 12, replacing Intermediate A11 with the “BORONIC REAGENT” in step 1, Intermediate B10 with the “HALIDE 1” in step 1, Intermediate C2 with the “HALIDE 2” in step 5 by the reagents indicated in Table 3. Table 3. Compound synthesis and characterization

16 16

Example 15 and Example 16 [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21-heptaen-15-yl] acetate and [(8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl -12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21-heptaen-15-yl] acetate

The title compound was prepared according to the following scheme: Step 1: preparation of [1-[(7-bromo-2-methyl-benzimidazol-1-yl)methyl]-2-[tert- butoxycarbonyl(methyl)amino]ethyl] acetate (compound 15a) A mixture of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-hydroxy-propyl]- N- methyl-carbamate (intermediate A10-g, 1.1 g, 2.76 mmol, the synthesis refers to intermediate A7-g) and Ac ₂ O (4.33 g, 4 mL, 42.39 mmol) in THF (4 mL) was heated to 70 °C for 16 hrs. The mixture was concentrated, the residue was purified by silica gel to give compound 17a (1.3 g), LCMS (M+H ⁺ ): 440. Step 2~4: preparation of benzyl (8S,11S)-15-hydroxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaene-10-carboxylate (compound 15d) Compound 15d was prepared in analogy to the preparation of compound 1c by using compound 15a instead of intermediate A15-c. LCMS (M+H ⁺ ): 541. Step 5: preparation of benzyl (8S,11S)-15-acetoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaene-10-carboxylate (compound 15e) To a microwave tube was added (8S,11S)-15-hydroxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-10-carboxylate (15d , 594.67 mg, 1.1 mmol) and Ac ₂ O (12.87 g, 11.89 mL, 126.05 mmol), a brown suspension formed. Then it was reacted under microwave at 90 °C for 150 mins. The mixture was concentrated, the residue was dissolved in 100 mL DCM and washed with brine, the organic layer was dried and concentrated. The crude product was purified by silica gel to give compound 15e (550 mg), LCMS (M+H ⁺ ): 583. Step 6: preparation of [(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (compound 15f) Compound 15f was prepared in analogy to step 4 in the preparation of Example 1 by using compound 15e) instead of compound 1c. LCMS (M+H ⁺ ): 449. Step 7: preparation of [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19-te trazapentacyclo[15.6.1.12,6. 18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-1 5-yl] acetate and [(8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24), 21-heptaen-15-yl] acetate (Example 15 & 16) Example 15 & 16 were prepared in analogy to step 5 in the preparation of Example 1 by using compound 15f instead of compound 1d. The mixture was purified via prep-HPLC and SFC. (SFC condition: Instrument: SFC 80; Column: Pyridine, 250×30 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O); Gradient: B 35%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 35℃) Example 15, faster eluted, LCMS (M+H ⁺ ): 679. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.56 (s, 1H), 8.21 (s, 1H), 7.70 - 7.63 (m, 1H), 7.56 (dd, J = 1.1, 8.1 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.32 - 7.25 (m, 2H), 7.24 - 7.22 (m, 1H), 7.21 - 7.16 (m, 2H), 7.08 - 7.01 (m, 1H), 6.96 - 6.87 (m, 1H), 5.61 - 5.56 (m, 1H), 5.48 (d, J = 9.5 Hz, 1H), 4.73 - 4.58 (m, 1H), 4.55 - 4.48 (m, 2H), 4.34 - 4.20 (m, 2H), 3.14 - 3.00 (m, 4H), 2.96 - 2.89 (m, 1H), 2.71 - 2.66 (m, 1H), 2.66 - 2.57 (m, 4H), 1.64 (s, 3H). Example 16, slower eluted, LCMS (M+H ⁺ ): 679. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.54 (s, 1H), 8.19 (s, 1H), 7.70 - 7.63 (m, 1H), 7.53 - 7.50 (m, 1H), 7.50 - 7.44 (m, 1H), 7.31 - 7.25 (m, 1H), 7.23 - 7.16 (m, 4H), 7.00 - 6.95 (m, 1H), 6.86 - 6.79 (m, 1H), 5.62 - 5.57 (m, 1H), 5.51 - 5.39 (m, 2H), 4.56 - 4.40 (m, 2H), 4.31 - 4.22 (m, 1H), 4.08 - 3.99 (m, 1H), 3.71 (dd, J = 3.9, 14.9 Hz, 1H), 3.15 - 2.99 (m, 4H), 2.95 - 2.88 (m, 1H), 2.68 - 2.63 (m, 1H), 2.61 (s, 3H), 1.65 (s, 3H). Example 17 and Example 18 [(8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate and [(8S,11S,15S)-10-[1-(4-fluoro-2- methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl -12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate The title compounds were prepared in analogy to the preparation of Example 15 and Example 16 by using intermediate C11 instead of intermediate C2. (SFC condition: Instrument: SFC 80; Column: Pyridine, 250×30 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O); Gradient: B 35%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 35℃) Example 17, faster eluted, LCMS (M+H ⁺ ): 691. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.50 (s, 1H), 8.15 (s, 1H), 7.56 (dd, J = 1.1, 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.45 (dd, J = 6.0, 8.6 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.19 (dd, J = 2.2, 8.2 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.94 - 6.85 (m, 2H), 5.60 - 5.56 (m, 1H), 5.47 (d, J = 9.6 Hz, 1H), 4.59 - 4.47 (m, 3H), 4.33 - 4.21 (m, 2H), 3.77 - 3.75 (m, 1H), 3.75 (s, 3H), 3.14 - 3.00 (m, 4H), 2.92 (br d, J = 13.6 Hz, 1H), 2.70 - 2.65 (m, 1H), 2.65 - 2.63 (m, 3H), 1.64 (s, 3H). Example 18, slower eluted, LCMS (M+H ⁺ ): 691. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.54 (s, 1H), 8.14 (s, 1H), 7.59 (br d, J = 8.1 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.44 (dd, J = 6.3, 8.7 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.19 (dd, J = 2.7, 11.0 Hz, 1H), 7.09 - 7.01 (m, 1H), 7.00 - 6.92 (m, 2H), 6.87 - 6.82 (m, 1H), 5.59 (t, J = 4.3 Hz, 1H), 5.43 - 5.38 (m, 1H), 5.28 - 5.18 (m, 1H), 4.48 - 4.41 (m, 1H), 4.35 (br d, J = 11.7 Hz, 1H), 4.20 - 4.16 (m, 1H), 3.93 - 3.84 (m, 1H), 3.73 - 3.72 (m, 5H), 3.03 - 2.90 (m, 4H), 2.66 - 2.63 (m, 3H), 2.63 - 2.57 (m, 1H), 1.64 - 1.58 (m, 3H). Example 21 and Example 22 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-4- carbonitrile and (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-10, 13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-4- carbonitrile The title compounds were prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-(3-bromo-5-cyano- phenoxy)pyrrolidine-1,2-dicarboxylate (compound 21a) To a flask was added 3-bromo-5-hydroxy-benzonitrile (4.17 g, 21.05 mmol, as the “ArOH” in table 4), O1-benzyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.6 g, 20.05 mmol), THF (25 mL) and triphenylphosphine (6.31 g, 24.06 mmol). And then to the solution was added DIAD (5.27 g, 26.07 mmol) dropwise. After being stirred at r.t. for 3 hrs, the mixture was concentrated, the residue was purified by silica gel to give compound 21a (13.8 g), LCMS (M+H ⁺ ): 459. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[3-[3-[3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-me thyl-benzimidazol-4-yl]-5- cyano-phenoxy]pyrrolidine-1,2-dicarboxylate (compound 21b) To a flask was added tert-butyl N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-met hyl-carbamate(intermediate A2, 2 g, 4.19 mmol, as the “BORONIC REAGENT” in table 4), compound 21a (3.21 g, 4.19 mmol ), K ₂ CO ₃ (1.16 g, 8.38 mmol), 1,4-dioxane (20 mL) and water (1 mL). The suspension was bubbled with N ₂ for 5 mins, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), dichloromethane adduct (342.13 mg, 0.419 mmol) was added. After being heated to 90 °C for 16 hrs, the mixture was diluted with 200 mL water and extracted with 50 mL EA for three times. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 21b (1.9 g), LCMS (M+H ⁺ ): 730. Step 3: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[3-cyano-5-[6-fluoro-3-[2- methoxy-3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]ph enoxy]pyrrolidine-2- carboxylic acid (compound 21c) A mixture of compound 21b (1.9 g, 2.6 mmol) and LiOH (2 N, 3 mL ) in THF (2 mL) and methanol (2 mL) was stirred at rt for 2 hrs. The mixture was diluted with 20 mL water and adjusted pH to about 4 with 2 N aq. solution of HCl, then it was extracted with 30 mL DCM for three times. The organic layer was dried and concentrated, the residue was dissolved in DCM (5 mL) and TFA (5 mL), the mixture was stirred at r.t. for 1 hr and then concentrated. The crude product was purified via prep-HPLC to give compound 21c (1.47 g), LCMS (M+H ⁺ ): 616. Step 4: preparation of benzyl (8S,11S)-4-cyano-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26), 3,5,18,20(24),21-heptaene-10-carboxylate (compound 21d) To a solution of HATU (1.66 g, 4.36 mmol) and DIEA (1.8 g, 13.94 mmol) in acetonitrile (400 mL) was added another solution of compound 21c (1.47 g, 1.74 mmol) in acetonitrile (350 mL) dropwise in 3 hrs. The mixture was concentrated and the residue was dissolved in 150 mL EA, which was washed with water and brine, the organic layer was dried and concentrated, the residue was purified via prep-HPLC to give compound 21d (850 mg, LCMS (M+H ⁺ ): 598. Step 5: preparation of (8S,11S)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaene-4-carbonitrile (compound 21e) To a microwave tube was added compound 21d (450 mg, 0.670 mmol) and TFA (1 mL). The mixture was reacted under microwave at 100 °C for 10 mins, and then the mixture was concentrated to give compound 21d (700 mg), LCMS (M+H ⁺ ): 464. Step 6: preparation of (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimet hyl-12-oxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21 - heptaene-4-carbonitrile and (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl) pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-12- oxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21 -heptaene-4- carbonitrile (Example 21 & 22) To a flask was added compound 21e (103.96 mg, 0.180 mmol), intermediate C11 (47.99 mg, 0.180 mmol as “HALIDE” in table 4), DIEA (93.05 mg, 125.75 μL, 0.720 mmol) and acetonitrile (4.69 mL). The mixture was heated to 85 °C for 1 hr, then the mixture was concentrated and the residue was purified by silica gel and SFC (as “SFC condition” in table 4) to give Example 21 and Example 22. (SFC condition: Instrument: SFC 80; Column: IA, 250×30 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O); Gradient: B 40%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 35℃) Example 21 (77.3 mg), faster eluted, LCMS (M+H ⁺ ): 706. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 8.17 (s, 1H), 7.67 (s, 1H), 7.44 (dd, J = 6.0, 8.6 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.26 - 7.22 (m, 1H), 7.05 (dd, J = 2.7, 10.7 Hz, 1H), 6.88 (dt, J = 2.6, 8.4 Hz, 1H), 6.81 (dd, J = 2.4, 9.6 Hz, 1H), 5.67 - 5.63 (m, 1H), 5.45 (d, J = 9.3 Hz, 1H), 4.57 - 4.40 (m, 2H), 4.17 - 4.10 (m, 1H), 4.07 - 3.98 (m, 1H), 3.76 - 3.71 (m, 3H), 3.64 - 3.56 (m, 1H), 3.49 - 3.42 (m, 1H), 3.15 - 2.99 (m, 3H), 2.84 - 2.81 (m, 3H), 2.79 (br d, J = 14.6 Hz, 1H), 2.72 - 2.60 (m, 2H), 2.56 (s, 3H). Example 22 (7 mg), slower eluted, LCMS (M+H ⁺ ): 706. NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 8.17 (s, 1H), 7.68 - 7.57 (m, 2H), 7.44 (dd, J = 6.0, 8.6 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.32 (dd, J = 2.4, 8.5 Hz, 1H), 7.05 (dd, J = 2.6, 10.7 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.90 - 6.84 (m, 1H), 5.69 - 5.59 (m, 1H), 5.52 (d, J = 9.5 Hz, 1H), 4.58 - 4.37 (m, 3H), 4.32 - 4.19 (m, 1H), 4.14 - 4.01 (m, 1H), 3.75 (s, 3H), 3.16 - 3.04 (m, 3H), 3.03 - 2.96 (m, 3H), 2.96 - 2.78 (m, 3H), 2.75 - 2.67 (m, 1H), 2.66 - 2.57 (m, 3H). The following examples in Table 4 were prepared in analogy to Example 21 & 22, replacing 3-bromo-5-hydroxy-benzonitrile with “ArOH” in step 1, Intermediate A2 with the “BORONIC REAGENT” in step 2, Intermediate C11 with the “HALIDE” in step 6 by the reagents indicated in Table 4. Table 4. Compound synthesis and characterization Example 34 and Example 35 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-( hydroxymethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,1 9,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- (hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

E ^{xample 34 and 35} Step 1: preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]methanol (compound 34a) NaBH ₄ (13 mg, 0.342 mmol) was added to a solution of compound 36j (100 mg, 0.285 mmol) in THF (4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture was added methanol (4 mL) and NaBH ₄ (13 mg, 0.342 mmol) , and stirred for another 4 hours. Saturated NH ₄ Cl solution was added to quenched the reaction and then the solution was extracted with DCM (20 mL). The organic layer was dried and concentrated, the residue was by silica gel to afford compound 34a (35 mg, 37.78%). LCMS (M+H ⁺ ): 309. Step 2: preparation of (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6- (hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 34) and (8S,11S,15S)-22-fluoro-10-[1- (4-fluoro-2-methoxy-phenyl)-6-(hydroxymethyl)pyrazolo[3,4-d] pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 35) A suspension of compound 36f (47 mg, 0.108 mmol), [4-chloro-1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]methanol (compound 34a, 35 mg, 0.108 mmol) and DIEA (56 μL, 0.323 mmol ) in acetonitrile (1 mL) was stirred at 70 °C for 0.5 hours. The reaction was concentrated and the residue was purified by reversed-phase Chromatography to afford product (54 mg), which was separated via SFC to give example 34 and 35. SFC conditions: Instrument: SFC 80; Column: OD, 250×20 mm I.D., 5μm.; Mobile phase: A for CO ₂ and B for ethanol (0.1% NH ₃ H ₂ O); Gradient: B 35%; Flow rate: 40 mL /min; Back pressure: 100bar; Column temperature: 35℃. Example 34 (24 mg), faster eluted, LCMS (M+H ⁺ ): 712. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.44 - 8.37 (m, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.31 (dd, J = 2.5, 8.5 Hz, 1H), 7.15 (br d, J = 9.9 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.74 (d, J = 9.3 Hz, 1H), 5.58 (br t, J = 4.0 Hz, 1H), 5.47 - 5.40 (m, 1H), 4.59 - 4.49 (m, 2H), 4.49 - 4.46 (m, 1H), 4.45 - 4.35 (m, 1H), 4.08 (br dd, J = 3.3, 14.3 Hz, 2H), 3.74 (s, 3H), 3.58 - 3.47 (m, 1H), 3.17 - 3.09 (m, 1H), 3.06 - 2.96 (m, 3H), 2.81 (d, J = 2.3 Hz, 4H), 2.74 - 2.65 (m, 1H), 2.60 - 2.54 (m, 3H). Example 35 (7 mg), slower eluted LCMS (M+H ⁺ ): 712. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.47 - 8.38 (m, 1H), 8.09 - 7.96 (m, 1H), 7.59 - 7.52 (m, 1H), 7.46 - 7.23 (m, 3H), 7.13 - 7.01 (m, 2H), 6.89 - 6.82 (m, 1H), 5.91 - 5.71 (m, 2H), 5.60 - 5.41 (m, 1H), 4.60 - 4.39 (m, 4H), 4.19 - 4.08 (m, 1H), 4.01 - 3.91 (m, 1H), 3.79 - 3.72 (m, 3H), 3.10 - 3.04 (m, 1H), 3.01 - 2.89 (m, 3H), 2.86 - 2.78 (m, 4H), 2.72 - 2.65 (m, 1H), 2.63 - 2.46 (m, 5H). Example 36 1-(4-fluoro-2-methoxy-phenyl)-4-[(8S,11S)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxamide The title compound was prepared according to the following scheme: Step 1: preparation of (2S, 4S)-4-[(6-bromo-2-pyridyl)oxy]pyrrolidine-1,2- dicarboxylic acid O1-benzyl ester O2-methyl ester (compound 36a) To a flask was added 6-bromopyridin-2-ol (6.04 g, 34.7 mmol), (2S,4R)-4- hydroxypyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester (9.41 g, 33.69 mmol, 1 eq), THF (37.64 mL) and triphenylphosphine (17.67 g, 67.39 mmol), a brown solution formed. To the solution was added DIAD (10.22 g, 9.92 mL, 50.54 mmol) dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was purified by silica gel and prep-HPLC to afford compound 36a (13.6 g). LCMS (M+H ⁺ ): 435. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-me thyl-benzimidazol-4-yl]- 2-pyridyl]oxy]pyrrolidine-1,2-dicarboxylate (compound 36b) To a flask was added intermediate A2 (28.77 g, 18.38 mmol), compound 36a (8 g, 18.38 mmol), K ₂ CO ₃ (5.08 g, 36.76 mmol), 1,4-dioxane (80 mL) and water (4 mL), the suspension was bubbled with N ₂ for 5 mins and 1,1’-bis(diphenylphosphino)ferrocene-palladium(II)dichlori de dichloromethane complex (1.5 g, 1.84 mmol) was added. After being heated to 90 °C for 2 hours, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel to afford compound 36b (12.46 g). LCMS (M+H ⁺ ): 706. Step 3: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-me thyl-benzimidazol-4-yl]- 2-pyridyl]oxy]pyrrolidine-2-carboxylic acid (compound 36c) To a solution of compound 36b (6.9 g, 9.78 mmol) in THF (60 mL)/water (60 mL) was added hydroxylithium (468 mg, 19.55 mmol ), the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and adjusted pH to about 4 with HCl (1 M), then it was extracted with DCM. The organic layer was dried and concentrated to afford compound 36c (6.6 g). LCMS (M+H ⁺ ): 692. Step 4: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[2-methoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]o xy]pyrrolidine-2-carboxylic acid;2,2,2-trifluoroacetic acid (compound 36d) A mixture of compound 36c (6.6 g, 9.54 mmol) in DCM (10 mL) and TFA (12 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to afford compound 36d (8.9 g). LCMS (M+H ⁺ ): 592. Step 5: preparation of benzyl (8S,11S)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7-oxa-10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 36e) To a solution of HATU (5.75 g, 15.13 mmol) and DIEA (15.0 mL, 85.79 mmol) in acetonitrile (1200 mL) was added another solution of compound 36d (8.9 g, 9.53 mmol) in acetonitrile (1180 mL) dropwise in 2 hours. The mixture was concentrated and the residue was purified via reversed phase chromatography to afford compound 36e (2200 mg). LCMS (M+H ⁺ ): 574. Step 6: preparation of (8S,11S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19,26-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 36f) A mixture of compound 36e (2200 mg, 3.84 mmol) and palladium hydroxide (20% on carbon with 50% H ₂ O) (440 mg, 3.13 mmol) in methanol (263 mL) was purged with H ₂ for 3 times. After being heated to 50 °C for 3 hours, the mixture was filtered, the filtrate was concentrated to afford compound 36f (1570 mg). LCMS (M+H ⁺ ): 440. Step 7: preparation of ethyl 1-(4-fluoro-2-methoxy-phenyl)-4-[(8S,11S)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19,26-pentazape ntacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazol o[3,4- d]pyrimidine-6-carboxylate (compound 36k) A suspension of compound 36f (40 mg, 0.091 mmol), compound 36j (35 mg, 0.100 mmol) and DIEA (32 μL, 0.182 mmol) in acetonitrile (1 mL) was stirred at 70 °C for 0.5 hours. The mixture was concentrated and the residue was purified by reversed-phase chromatography to afford compound 36k (60 mg). LCMS (M+H ⁺ ): 754. Step 8: preparation of 1-(4-fluoro-2-methoxy-phenyl)-4-[(8S,11S)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19,26-pentazape ntacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazol o[3,4- d]pyrimidine-6-carboxamide (Example 36) A solution of compound 36k (20 mg, 0.027 mmol) in 7 M ammonia (7M in MeOH, 1 mL, 7 mmol) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was purified by reversed-phase chromatography to afford Example 36 (8 mg), LCMS (M+H ⁺ ): 725. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.51 (m, 1H), 8.18 - 8.02 (m, 1H), 7.69 - 7.53 (m, 2H), 7.51 - 7.38 (m, 2H), 7.27 - 7.14 (m, 1H), 7.08 - 7.02 (m, 1H), 6.92 - 6.83 (m, 1H), 6.25 - 5.90 (m, 1H), 5.67 - 5.48 (m, 1H), 4.64 - 4.42 (m, 3H), 4.34 - 4.19 (m, 1H), 4.16 - 3.93 (m, 1H), 3.84 - 3.73 (m, 3H), 3.67 - 3.58 (m, 1H), 3.17 - 3.02 (m, 4H), 2.96 - 2.88 (m, 4H), 2.86 - 2.80 (m, 3H), 2.79 - 2.69 (m, 1H). The preparation of compound 36j was prepared according to the following scheme:

Step 1: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine (compound 36g) To a stirring solution of (4-fluoro-2-methoxy-phenyl)amine (3 g, 21.26 mmol) in 5 M HCl (30 mL) was added a solution of sodium nitrite (2.2 g, 31.87 mmol) in water (30 mL) at 0° C. After stirring for 30 mins, a solution of tin (II) chloride (10 g, 53.14 mmol, ) in Conc. HCl (12 N, 6 mL) was added dropwise to the mixture. Then the mixture was stirred at room temperature overnight. After being adjusted pH to 10-12 with 20% aqueous sodium hydroxide, the mixture was extracted with CH2Cl2. The organic layer was dried and concentrated to afford compound 36g (3 g). LCMS (M+H ⁺ ): 157. Step 2: preparation of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carboxylic acid ethyl ester (compound 36h) A solution of compound 36g (1.5 g, 9.61 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (1.63 g, 9.61 mmol) and Et ₃ N (2.68 mL, 19.21 mmol) in ethanol (20 mL) was stirred at 90 °C for 12 hours. The mixture was concentrated, and the residue was purified by silica gel to afford compound 36h (1.91 g). LCMS (M+H ⁺ ): 280. Step 3: preparation of 1-(4-fluoro-2-methoxy-phenyl)-4-keto-5H-pyrazolo[3,4- d]pyrimidine-6-carboxylic acid ethyl ester (compound 36i) To a solution of compound 36h (1.91 g, 6.84 mmol) in 4 M HCl in dioxane) (15 mL) at room temperature was added cyanoformic acid ethyl ester (1.36 g, 13.68 mmol). The mixture was stirred at 100 °C for 14 hours and then was cooled to room temperature. The reaction mixture was concentrated and the residue was purified by silica gel to afford compound 36i (763 mg). LCMS (M+H ⁺ ): 333. Step 4: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine-6-carboxylic acid ethyl ester (compound 36j) A suspension of compound 36i (300 mg, 0.858 mmol) in phosphorus oxychloride (6.58 g, 4 mL, 42.91 mmol) was stirred at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and then poured into the saturated NaHCO ₃ (30 mL) at 0°C. The mixture was adjusted pH to 8 and extracted with EtOAc (50 mL, three times). The organic layer was dried and concentrated, the residue was purified by silica gel to afford compound 36j (250 mg). LCMS (M+H ⁺ ): 351. Example 37 1-(4-fluoro-2-methoxy-phenyl)-N,N-dimethyl-4-[(8S,11S)-22-fl uoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7-oxa-10,13,17,19,26-pentazapentacyclo[15.6. 1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxamide The title compounds were prepared according to the following scheme: Step 1: preparation of 1-(4-fluoro-2-methoxy-phenyl)-4-[(8S,11S)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19,26-pentazape ntacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazol o[3,4- d]pyrimidine-6-carboxylic acid (compound 37a) A mixture of compound 36k (40 mg, 0.054 mmol) and hydroxylithium (5 mg, 0.212 mmol) in THF (4 mL)/water (4 mL) was stirred at room temperature for 0.5 hours. After adjusting the pH to 5, the reaction mixture was extracted with EtOAc (20 mL, three times). The combined organic layer was dried and concentrated to afford compound 37a (37 mg). LCMS (M+H ⁺ ): 726. Step 2: preparation of 1-(4-fluoro-2-methoxy-phenyl)-N,N-dimethyl-4-[(8S,11S)-22- fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-10,13,17,19,26 - 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]-hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (Example 37) A suspension of compound 37a (20 mg, 0.028 mmol), HATU (14 mg, 0.036 mmol) and DIEA (10 μL, 0.055 mmol) in DMF (2 mL) was stirred at room temperature for 0.5 hours. 2 M dimethylamine (28 μL, 0.055 mmol) was added and the reaction mixture was stirred at room temperature for another 15 mins. The reaction mixture was directly purified by reversed-phase chromatography to afford Example 37 (7 mg), LCMS (M+H ⁺ ): 753. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.52 (s, 1H), 8.16 - 8.04 (m, 1H), 7.68 - 7.52 (m, 2H), 7.50 - 7.36 (m, 2H), 7.24 - 7.13 (m, 1H), 7.08 - 6.99 (m, 1H), 6.90 - 6.83 (m, 1H), 6.21 (br dd, J = 4.1, 15.6 Hz, 1H), 5.70 - 5.47 (m, 2H), 4.63 - 4.53 (m, 1H), 4.41 - 4.19 (m, 2H), 4.14 - 3.92 (m, 1H), 3.77 - 3.71 (m, 3H), 3.67 - 3.56 (m, 1H), 3.18 - 2.80 (m, 18H). Example 38 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methylamino)pyrazolo[ 3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentaz apentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-10-[6-bromo-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa- 10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (compound 38a) A suspension of intermediate C25 (100 mg, 0.256 mmol), compound 36f (113 mg, 0.256 mmol) and DIEA (90 μL, 0.513 mmol) in ethanol (5 mL) was stirred at room temperature for 12 hours. The solvent was removed under reduce pressure and then the residue was purified by reversed-phase chromatography to afford compound 38a (157 mg). LCMS (M+H ⁺ ): 748. Step 2: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methylamino)- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7-oxa-10,13,17,19,26- 2,6 8,11 20,24 pentazapentacyclo-[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 38) A suspension of compound 38a (20 mg, 0.027 mmol), 2 M methylamine (2 mL, 4 mmol) and K ₂ CO ₃ (7 mg, 0.053 mmol) was microwaved at 120 °C for 3 hours. The suspension was filtered and the filtrate was concentrated. The residue was purified by reversed-phase chromatography to afford Example 38 (12 mg), LCMS (M+H ⁺ ): 699. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.37 - 8.31 (m, 1H), 8.17 - 8.04 (m, 1H), 7.70 - 7.59 (m, 2H), 7.59 - 7.45 (m, 2H), 7.32 - 7.25 (m, 1H), 7.24 - 7.12 (m, 2H), 6.24 - 6.01 (m, 1H), 5.64 - 5.59 (m, 1H), 5.51 - 5.46 (m, 1H), 4.59 - 4.48 (m, 2H), 4.42 - 4.36 (m, 1H), 4.31 - 4.23 (m, 1H), 4.09 (br dd, J = 4.6, 14.5 Hz, 1H), 3.98 - 3.90 (m, 1H), 3.67 - 3.59 (m, 1H), 3.13 - 3.08 (m, 1H), 3.05 - 2.98 (m, 3H), 2.94 - 2.80 (m, 8H), 2.79 - 2.71 (m, 1H). Example 40 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-methoxy-pyrazolo[3,4-d ]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentac yclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

A suspension of compound 38a (20 mg, 0.027 mmol), 5 M Sodium methoxide (11 μL, 0.053 mmol) in methanol (64 μL) was stirred at room temperature for 0.5 hours. After being stirred at 40 °C for 2 hours, the reaction mixture was concentrated and the residue was purified by reversed-phase chromatography to afford Example 40 (10 mg), LCMS (M+H ⁺ ): 700. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.45 - 8.40 (m, 1H), 8.16 - 8.04 (m, 1H), 7.73 - 7.46 (m, 4H), 7.30 - 7.14 (m, 3H), 6.25 - 6.08 (m, 1H), 5.65 - 5.55 (m, 2H), 4.58 - 4.55 (m, 1H), 4.50 (br d, J = 11.4 Hz, 1H), 4.40 - 4.29 (m, 2H), 4.12 - 4.06 (m, 1H), 3.97 (s, 1H), 3.87 - 3.85 (m, 2H), 3.15 - 3.12 (m, 1H), 3.04 (s, 2H), 2.95 - 2.89 (m, 4H), 2.85 - 2.81 (m, 4H), 2.79 - 2.73 (m, 1H). Example 41 and Example 42 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-hydroxy-pyrazolo[3,4-d ]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentac yclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10- [1-(2,4-difluorophenyl)-6-ethoxy-pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-10,13,17,19,26-pentazapentacyclo-[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

A suspension of compound 38a ( 20 mg, 0.027 mmol) in 2 M sodium hydroxide (2 mL, 4 mmol)/ethanol (2 mL) was stirred at room temperature for 0.5 hours. After being stirred at 70 °C for 12 hours, the reaction mixture was concentrated. The residue was purified by reversed-phase chromatography to afford example 41 (3 mg) and example 42 (12 mg). Example 41, LCMS (M+H ⁺ ): 686. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.39 - 8.33 (m, 1H), 8.16 - 8.02 (m, 1H), 7.72 (br d, J = 2.6 Hz, 2H), 7.56 - 7.41 (m, 2H), 7.34 - 7.11 (m, 3H), 5.62 - 5.47 (m, 2H), 4.58 (br dd, J = 5.0, 12.2 Hz, 2H), 4.53 - 4.50 (m, 1H), 4.38 - 4.32 (m, 1H), 4.11 (br d, J = 14.2 Hz, 1H), 3.67 - 3.61 (m, 2H), 3.18 - 3.06 (m, 2H), 3.02 - 2.96 (m, 3H), 2.93 - 2.87 (m, 4H), 2.84 - 2.77 (m, 3H). Example 42, LCMS (M+H ⁺ ): 714. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.40 (s, 1H), 8.16 - 8.03 (m, 1H), 7.70 - 7.43 (m, 4H), 7.29 - 7.12 (m, 3H), 6.25 - 5.87 (m, 1H), 5.66 - 5.43 (m, 2H), 4.59 - 4.39 (m, 2H), 4.39 - 4.20 (m, 3H), 4.14 - 3.90 (m, 1H), 3.71 - 3.53 (m, 1H), 3.34 (s, 1H), 3.18 - 3.06 (m, 2H), 3.05 - 3.00 (m, 2H), 2.95 - 2.88 (m, 3H), 2.85 - 2.70 (m, 4H), 1.38 (t, J = 7.1 Hz, 1H), 1.34 - 1.29 (m, 2H). Example 43 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(2-methoxyethylamino)p yrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26 - 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared in analogy to the preparation of Example 38 by using 2- methoxyethylamine instead of methylamine. LCMS (M+H ⁺ ): 743. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.23 - 8.17 (m, 1H), 8.05 - 7.94 (m, 1H), 7.58 - 7.36 (m, 4H), 7.20 - 7.03 (m, 3H), 5.56 - 5.47 (m, 1H), 5.40 - 5.33 (m, 1H), 4.47 - 4.36 (m, 2H), 4.29 - 4.24 (m, 1H), 4.21 - 4.13 (m, 1H), 4.03 - 3.95 (m, 1H), 3.57 - 3.47 (m, 3H), 3.42 - 3.31 (m, 5H), 3.07 - 3.02 (m, 2H), 2.96 - 2.92 (m, 2H), 2.81 (s, 3H), 2.75 - 2.67 (m, 4H). Example 44 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pentaz apentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 36 by using 2- methoxyacetonitrile (step 9) instead of cyanoformic acid ethyl ester. LCMS (M+H ⁺ ): 714. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.45 - 8.37 (m, 1H), 8.09 - 7.93 (m, 1H), 7.60 - 7.33 (m, 4H), 7.27 - 7.02 (m, 3H), 6.17 - 5.84 (m, 1H), 5.66 - 5.37 (m, 2H), 4.52 - 4.26 (m, 4H), 4.25 - 4.12 (m, 1H), 4.02 - 3.75 (m, 2H), 3.59 - 3.44 (m, 1H), 3.42 - 3.36 (m, 1H), 3.34 - 3.28 (m, 2H), 3.07 - 2.89 (m, 4H), 2.85 - 2.78 (m, 3H), 2.76 - 2.71 (m, 3H), 2.66 - 2.46 (m, 1H). Example 45 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(2-morpholinoethoxy)py razolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-10,13,17,19,26-pen tazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 40 by using 2- morpholinoethanol and sodium hydride instead of sodium methoxide. LCMS (M+H ⁺ ): 799. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.38 - 8.32 (m, 1H), 8.10 - 7.91 (m, 1H), 7.60 - 7.33 (m, 4H), 7.21 - 7.03 (m, 3H), 6.15 - 5.63 (m, 1H), 5.56 - 5.36 (m, 2H), 4.69 - 4.67 (m, 1H), 4.55 - 4.50 (m, 2H), 4.48 - 4.41 (m, 2H), 4.33 - 4.23 (m, 2H), 4.18 - 4.13 (m, 1H), 4.03 - 3.94 (m, 2H), 3.89 - 3.81 (m, 2H), 3.75 - 3.69 (m, 1H), 3.56 - 3.53 (m, 1H), 3.47 (br s, 1H), 3.07 - 2.98 (m, 3H), 2.97 - 2.89 (m, 3H), 2.86 - 2.78 (m, 4H), 2.76 - 2.69 (m, 4H). Example 53 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of example 289 by using Intermediate B16 instead of Intermediate B1 and Intermediate C2 instead of Intermediate C11. LCMS (M+H ⁺ ): 623. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.85 - 8.75 (m, 1H), 8.66 - 8.33 (m, 1H), 8.28 - 7.86 (m, 1H), 7.79 - 7.67 (m, 2H), 7.65 - 7.54 (m, 2H), 7.47 - 7.38 (m, 1H), 7.36 - 7.18 (m, 2H), 5.85 - 5.65 (m, 1H), 5.58 - 5.40 (m, 1H), 5.23 - 5.04 (m, 1H), 4.55 - 4.12 (m, 2H), 4.04 - 3.88 (m, 2H), 2.99 - 2.93 (m, 1H), 2.87 (s, 2H), 2.84 - 2.74 (m, 1H), 2.73 - 2.59 (m, 2H), 2.57 (s, 3H), 1.83 - 1.59 (m, 1H), 1.20 - 1.09 (m, 1H). Example 54 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of example 289 by using Intermediate B16 instead of Intermediate B1. LCMS (M+H ⁺ ): 635. ¹ H NMR (500 MHz, DMSO-d6) δ = 8.87 - 8.73 (m, 1H), 8.57 - 7.76 (m, 2H), 7.73 - 7.66 (m, 1H), 7.60 - 7.52 (m, 1H), 7.49 - 7.37 (m, 2H), 7.31 - 7.24 (m, 1H), 7.23 - 7.15 (m, 1H), 6.98 - 6.88 (m, 1H), 5.86 - 5.42 (m, 2H), 5.25 - 5.03 (m, 1H), 4.56 - 4.10 (m, 2H), 4.05 - 3.87 (m, 2H), 3.74 (s, 3H), 2.99 - 2.84 (m, 3H), 2.83 - 2.74 (m, 1H), 2.72 - 2.65 (m, 1H), 2.59 (br d, J = 15.3 Hz, 1H), 2.57 (s, 3H), 1.75 (br dd, J = 4.0, 8.2 Hz, 1H), 1.15 (br dd, J = 8.2, 12.8 Hz, 1H). Example 63 and Example 64 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,1 8-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-[3-[3-[tert- butoxycarbonyl(methyl)amino]-2-ethoxy-propyl]-2-methyl-benzi midazol-4-yl]pyrimidin-2- yl]oxypyrrolidine-1,2-dicarboxylate (compound 63a) A mixture of K ₂ CO ₃ (2.96 g, 21.44 mmol), intermediate A10 (3.38 g, 7.15 mmol), intermediate B15 (3.50 g, 7.15 mmol) and PdCl ₂ (dppf) DCM(261.45 mg, 0.357 mmol) in 1,4- dioxane (30 mL) and water (3 mL) was heated to 100°C for 12 hours under N ₂ atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 63a (4.0 g). LCMS (M+H ⁺ ): 703. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[4-[3-[2-ethoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]pyrimidin-2- yl]oxy-pyrrolidine-2- carboxylic acid (compound 63b) A mixture of compound 63a (3.60 g, 5.12 mmol) and LiOH.H ₂ O (2.15 g, 51.22 mmol) in tetrahydrofuran (15 mL) and water (3 mL) was stirred at 25 °C for 12 hours. The reaction mixture was adjusted PH = 5 with HCl (1 M) and extracted with MeOH/DCM. The organic layer was dried and concentrated, the residue was dissolved in 1,4-dioxane (5 mL) and TFA (5 mL). After stirred at 25 °C for 4 hours, the mixture was concentrated to give crude compound 63b (3.2 g). LCMS (M+H ⁺ ): 589. Step 3: preparation of benzyl (8S,11S,15R)-15-ethoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate and benzyl (8S,11S,15S)-15-ethoxy- 13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 63c-1&63c-2) To a solution of HATU (4.13 g, 10.87 mmol) and DIPEA (3.51 g, 27.18 mmol) in acetonitrile (800 mL) was added a solution of compound 63b (3.2 g, 5.44 mmol) in acetonitrile (2400 mL) dropwise at rt. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, the residue was diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated, the residue was purified by SFC (Instrument: SFC 80, Column: IA, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 50%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃) to give faster eluted compound 63c-1 (500 mg) and slower eluted compound 63c-2(400 mg), LCMS (M+H ⁺ ): 571. Step 4: preparation of (8S,11S,15R)-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one(compound 63d-1&63d-2) A mixture of compound 63c-1 (500 mg, 0.876 mmol) in TFA (2.0 mL) was stirred for 100 °C for 10 mins under microwave. The reaction mixture was concentrated to give compound 63d- 1 (380 mg). LCMS (M+H ⁺ ): 437. A mixture of compound 63c-2 (400 mg, 0.701 mmol) in TFA (2.0 mL) was stirred for 100 °C for 10 mins under microwave. The reaction mixture was concentrated to give compound 63d- 2 (300 mg). LCMS (M+H ⁺ ): 437. Step 5: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17, 19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one(example 63&64) A mixture of compound 63d-1 (50 mg, 0.115 mmol), DIPEA (44 mg, 0.344 mmol) and intermediate C2 (30 mg, 0.115 mmol, as the “HALIDE 1” in table 5) in DMSO (1 mL) was stirred for 1 hour at 80 °C. The reaction mixture was purified by prep-HPLC to give Example 63 (9.3 mg). LCMS (M+H ⁺ ): 667. ¹ H NMR (500 MHz, DMSO-d6) δ = 8.87 - 8.76 (m, 1H), 8.68 - 8.35 (m, 1H), 8.29 - 7.87 (m, 1H), 7.80 - 7.68 (m, 3H), 7.65 - 7.53 (m, 2H), 7.39 - 7.26 (m, 2H), 5.76 - 5.47 (m, 3H), 4.51 - 4.38 (m, 1H), 4.37 - 4.15 (m, 1H), 4.11 - 3.99 (m, 1H), 3.94 - 3.80 (m, 1H), 3.20 - 3.10 (m, 1H), 3.00 - 2.86 (m, 3H), 2.84 - 2.75 (m, 1H), 2.75 - 2.66 (m, 2H), 2.55 - 2.53 (m, 3H), 2.48 - 2.39 (m, 2H), 0.45 - 0.35 (m, 3H). A mixture of compound 63d-2 (50 mg, 0.115 mmol), DIPEA (44 mg, 0.344 mmol) and intermediate C2 (30 mg, 0.115 mmol, as the “HALIDE 2” in table 5) in DMSO (1 mL) was stirred for 1 hour at 80 °C. The reaction mixture was purified by prep-HPLC to give Example 64 (7.0 mg). LCMS (M+H ⁺ ): 667. ¹ H NMR (500 MHz, DMSO-d6) δ = 8.81 - 8.70 (m, 1H), 8.68 - 8.34 (m, 1H), 8.28 - 7.84 (m, 1H), 7.79 - 7.71 (m, 1H), 7.70 - 7.66 (m, 1H), 7.64 - 7.56 (m, 1H), 7.54 - 7.42 (m, 2H), 7.37 - 7.30 (m, 1H), 7.29 - 7.20 (m, 1H), 5.82 - 5.47 (m, 3H), 4.51 - 4.36 (m, 1H), 4.25 - 4.14 (m, 1H), 4.07 - 3.85 (m, 2H), 3.51 - 3.39 (m, 1H), 3.29 (br s, 1H), 3.18 - 3.09 (m, 1H), 3.03 - 2.89 (m, 3H), 2.85 (br s, 1H), 2.78 - 2.66 (m, 1H), 2.64 - 2.56 (m, 1H), 2.54 (d, J = 2.9 Hz, 3H), 0.47 - 0.40 (m, 3H). The following examples in Table 5 were prepared in analogy to Example 63 & 64 by replacing Intermediate C2 with the “HALIDE” in step 5 by the reagents indicated in Table 5. Table 5. Compound synthesis and characterization

Example 66 and Example 67 (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-[3-[3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-2-methyl-benz imidazol-4-yl]pyrimidin- 2-yl]oxypyrrolidine-1,2-dicarboxylate (compound 66a) A mixture of K ₂ CO ₃ (619.07 mg, 4.48 mmol), Intermediate A1 (754.49 mg, 1.64 mmol) intermediate B15 (900 mg, 1.49 mmol) and Pd(dppf)Cl ₂ DCM(54.62 mg, 0.075 mmol) in dioxane (20 mL) and water (2 mL) was heated to 100°C for 12 h under N ₂ atmosphere. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 66a (680 mg), LCMS (M+H ⁺ ): 689. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[4-[3-[2-methoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]pyrimidin-2- yl]oxy-pyrrolidine-2- carboxylic acid (compound 66b) A mixture of compound 66a (680 mg, 0.987 mmol) and lithium hydroxide monohydrate (207.13 mg, 4.94 mmol) in tetrahydrofuran (8 mL) and water (2 mL) was stirred at 25 °C for 12 hours. The reaction mixture was adjusted pH = 5 with HCl (1M), then extracted with MeOH/DCM. The organic layer was dried and concentrated, the residue was dissolved in dichloromethane (6 mL) and 4 M HCl in dioxane (2 mL). After being stirred at 25 °C for 3 hours, the reaction mixture was concentrated to give crude compound 66b (740 mg), LCMS (M+H ⁺ ): 575. Step 3: preparation of benzyl (8S,11S)-15-methoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 66c) To a mixture of HATU (992.54 mg, 2.61 mmol) and DIEA (843.41 mg, 6.53 mmol) in DMF (10 mL) and acetonitrile (60 mL) was added a solution of compound 66b (750 mg, 1.31 mmol) in DMF (30 mL) and acetonitrile (600 mL) dropwise at rt. After being stirred at room temperature for 1 hour, the reaction mixture was concentrated, the residue was diluted with EtOAc. The organic layer was washed with water and brine, then it was dried and concentrated, further purified by silica gel to give compound 66c (560 mg), LCMS (M+H ⁺ ): 557. Step 4: preparation of tert-butyl (8S,11S)-15-methoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 66d) To a flask containing compound 66c (560 mg, 1.01 mmol) was added methanol (50 mL) and palladium hydroxide (20% on carbon with 50% H ₂ O) (114.02 mg, 0.812 mmol). The suspension was purged with H ₂ for 3 times. After heated to 60 °C for 1.5 hrs, the mixture was filtered and the filtrate was concentrated to give compound 66d, used in the next step directly. LCMS (M+H ⁺ ): 423. Step 5: preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17 ,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 66e) Compound 66d (151.61 mg, 0.36 mmol) and DIEA (183.54 mg, 1.42 mmol) were dissolved in dimethyl sulfoxide (4 mL) and Intermediate C11 (100 mg, 0.36 mmol) was added. The mixture was stirred for 1 hours at 80 °C. The reaction mixture was concentrated, the residue was purified by prep-HPLC to give compound 66e (200 mg), LCMS (M+H ⁺ ): 665. Step 6: preparation of (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17 ,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one(Example 66&67) Compound 66e was separated by SFC (Instrument: SFC 80, Column: Pyridine, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 35%, Flow rate: 60 mL /min, Back pressure: 100 bar, Column temperature: 35℃) to give Example 66 (slower eluted) and Example 67 (faster eluted). Example 66 (44 mg, slower eluted), LCMS (M+H ⁺ ): 665. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.84 - 8.77 (m, 1H), 8.68 - 7.88 (m, 2H), 7.80 - 7.67 (m, 3H), 7.65 - 7.51 (m, 2H), 7.40 - 7.24 (m, 2H), 5.76 - 5.32 (m, 3H), 4.53 - 4.16 (m, 2H), 4.11 - 3.99 (m, 1H), 3.94 - 3.77 (m, 1H), 3.33 - 3.33 (m, 3H), 3.01 - 2.89 (m, 3H), 2.89 - 2.81 (m, 1H), 2.79 - 2.74 (m, 1H), 2.69 - 2.66 (m, 3H), 2.51 (s, 3H), 2.45 - 2.37 (m, 1H), 2.04 - 1.94 (m, 1H). Example 67 (47 mg, faster eluted), LCMS (M+H ⁺ ): 665. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.82 - 8.66 (m, 1H), 8.59 - 7.73 (m, 2H), 7.71 - 7.64 (m, 1H), 7.56 - 7.36 (m, 3H), 7.33 - 7.11 (m, 2H), 7.03 - 6.88 (m, 1H), 5.86 - 5.38 (m, 3H), 4.54 - 4.19 (m, 2H), 4.14 - 4.01 (m, 1H), 3.99 - 3.88 (m, 1H), 3.74 (d, J = 2.4 Hz, 3H), 3.55 - 3.46 (m, 1H), 3.20 - 3.09 (m, 1H), 3.04 - 2.91 (m, 3H), 2.89 - 2.79 (m, 1H), 2.79 - 2.71 (m, 1H), 2.69 (br d, J = 4.4 Hz, 3H), 2.53 (s, 3H). Example 69 and Example 70 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: The title compounds were prepared in analogy to the preparation of Example 66 and Example 67 by using Intermediate C2 instead of Intermediate C11. Compound 69a was separated by SFC (Instrument: SFC 80, Column: Pyridine, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 35%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃) to give Example 69 and Example 70. Example 69 (slower eluted), LCMS (M+H ⁺ ): 653. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.89 - 8.78 (m, 1H), 8.67 - 8.28 (m, 1H), 8.27 - 7.80 (m, 1H), 7.78 - 7.52 (m, 4H), 7.50 - 7.25 (m, 2H), 7.23 - 6.90 (m, 1H), 5.77 - 5.37 (m, 3H), 4.52 - 4.16 (m, 2H), 4.13 - 3.99 (m, 1H), 3.93 - 3.79 (m, 1H), 3.78 - 3.68 (m, 1H), 3.02 - 2.88 (m, 3H), 2.87 - 2.73 (m, 2H), 2.72 - 2.66 (m, 3H), 2.51 (br s, 3H), 2.46 - 2.34 (m, 1H). Example 70 (faster eluted), LCMS (M+H ⁺ ): 653. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.78 - 8.69 (m, 1H), 8.67 - 7.81 (m, 2H), 7.79 - 7.70 (m, 1H), 7.70 - 7.65 (m, 1H), 7.64 - 7.56 (m, 1H), 7.54 - 7.48 (m, 1H), 7.47 - 7.39 (m, 1H), 7.37 - 7.29 (m, 1H), 7.28 - 7.20 (m, 1H), 5.84 - 5.45 (m, 3H), 5.38 - 5.26 (m, 1H), 4.51 - 4.18 (m, 2H), 4.09 - 4.00 (m, 1H), 3.98 - 3.88 (m, 1H), 3.04 - 2.91 (m, 3H), 2.90 - 2.83 (m, 1H), 2.77 - 2.71 (m, 1H), 2.69 (d, J = 3.4 Hz, 3H), 2.53 (d, J = 2.9 Hz, 3H), 1.99 - 1.93 (m, 1H). Example 72 and Example 73 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

The title compounds were prepared in analogy to the preparation of Example 66 and Example 67 by using Intermediate A2 instead of Intermediate A1. SFC condition of compound 72e: Instrument: SFC 80, Column: Pyridine, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 50%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃. Example 72 (faster eluted), LCMS (M+H ⁺ ): 671. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.82 - 8.70 (m, 1H), 8.67 - 7.82 (m, 2H), 7.79 - 7.69 (m, 1H), 7.65 - 7.54 (m, 2H), 7.50 (td, J = 2.8, 8.9 Hz, 1H), 7.42 - 7.27 (m, 2H), 5.80 - 5.45 (m, 3H), 4.52 - 4.14 (m, 2H), 4.09 - 3.84 (m, 2H), 3.43 - 3.33 (m, 1H), 3.19 - 3.03 (m, 1H), 3.03 - 2.90 (m, 3H), 2.89 - 2.82 (m, 1H), 2.73 (br d, J = 4.0 Hz, 1H), 2.70 (d, J = 3.7 Hz, 3H), 2.56 - 2.52 (m, 3H). Example 73 (slower eluted), LCMS (M+H ⁺ ): 671. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.90 - 8.80 (m, 1H), 8.67 - 7.90 (m, 2H), 7.80 - 7.68 (m, 2H), 7.64 - 7.54 (m, 2H), 7.53 - 7.44 (m, 1H), 7.38 - 7.27 (m, 1H), 5.78 - 5.43 (m, 3H), 4.53 - 4.20 (m, 2H), 4.19 - 3.90 (m, 2H), 3.88 - 3.72 (m, 1H), 3.01 - 2.88 (m, 3H), 2.86 - 2.73 (m, 2H), 2.70 - 2.68 (m, 3H), 2.51 (br s, 3H), 2.42 - 2.34 (m, 1H). Example 75 and Example 76 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4- yl]-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared in analogy to the preparation of Example 72 and Example 73 by using Intermediate C11 instead of Intermediate C2. SFC condition of compound 72e: Instrument: SFC 80, Column: Pyridine, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 50%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃. Example 75 (faster eluted), LCMS (M+H ⁺ ): 683. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.80 - 8.72 (m, 1H), 8.56 - 7.70 (m, 2H), 7.56 (t, J = 4.5 Hz, 1H), 7.51 (td, J = 2.6, 8.9 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.34 (br dd, J = 2.0, 6.3 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.99 - 6.91 (m, 1H), 5.80 - 5.32 (m, 3H), 4.51 - 4.17 (m, 2H), 4.07 - 3.85 (m, 2H), 3.74 (d, J = 2.0 Hz, 3H), 3.42 - 3.34 (m, 1H), 3.05 - 2.92 (m, 3H), 2.88 - 2.81 (m, 1H), 2.70 (d, J = 4.9 Hz, 3H), 2.69 - 2.61 (m, 1H), 2.54 (s, 3H), 2.07 - 1.92 (m, 1H). Example 76 (slower eluted), LCMS (M+H+): 683. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.88 - 8.81 (m, 1H), 8.56 - 7.80 (m, 2H), 7.79 - 7.75 (m, 1H), 7.61 - 7.54 (m, 1H), 7.52 - 7.38 (m, 2H), 7.20 (dd, J = 2.7, 11.1 Hz, 1H), 7.00 - 6.92 (m, 1H), 5.81 - 5.35 (m, 3H), 4.52 - 3.94 (m, 4H), 3.90 - 3.77 (m, 1H), 3.76 - 3.70 (m, 3H), 3.02 - 2.89 (m, 3H), 2.88 - 2.72 (m, 2H), 2.71 - 2.66 (m, 3H), 2.51 (d, J = 1.4 Hz, 3H), 2.43 - 2.36 (m, 1H). Example 77 and Example 78 (8S,11S,15S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

T he title compounds were prepared according to the following scheme: The title compounds were prepared in analogy to the preparation of Example 63 and Example 64 by using intermediate C17 instead of Intermediate C2, and intermediate A2 instead of intermediate A10. SFC preparation (Instrument: SFC 80, Column: IA, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH _3˖ H ₂ O), Gradient: B 50%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃) to give faster eluted compound 78c-1 and slower eluted compound 78c-2. Example 77, LCMS (M+H ⁺ ): 709. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.82 - 8.74 (m, 1H), 8.54 - 7.72 (m, 2H), 7.61 - 7.54 (m, 2H), 7.47 - 7.35 (m, 3H), 7.02 - 6.94 (m, 1H), 5.80 - 5.41 (m, 3H), 4.49 - 4.14 (m, 2H), 4.12 - 4.02 (m, 1H), 4.00 - 3.88 (m, 2H), 3.52 (br d, J = 11.4 Hz, 1H), 3.18 - 3.04 (m, 1H), 3.03 - 2.91 (m, 3H), 2.88 - 2.82 (m, 1H), 2.73 - 2.70 (m, 3H), 2.70 - 2.63 (m, 1H), 2.62 - 2.56 (m, 3H), 0.79 - 0.68 (m, 2H), 0.58 - 0.46 (m, 2H) Example 78, LCMS (M+H ⁺ ): 709. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.92 - 8.82 (m, 1H), 8.53 - 7.80 (m, 2H), 7.80 - 7.77 (m, 1H), 7.65 - 7.60 (m, 1H), 7.57 - 7.50 (m, 1H), 7.47 - 7.36 (m, 2H), 7.04 - 6.95 (m, 1H), 5.76 - 5.45 (m, 3H), 4.48 - 4.16 (m, 2H), 4.15 - 4.05 (m, 1H), 4.00 - 3.93 (m, 1H), 3.90 - 3.79 (m, 1H), 3.01 - 2.89 (m, 3H), 2.88 - 2.82 (m, 1H), 2.82 - 2.74 (m, 1H), 2.73 - 2.71 (m, 3H), 2.70 - 2.62 (m, 1H), 2.57 - 2.53 (m, 3H), 2.44 - 2.37 (m, 1H), 0.78 - 0.70 (m, 2H), 0.58 - 0.49 (m, 2H). Example 79 and Example 80 (8S,11S,15S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyra zolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19, 26 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared in analogy to the preparation of Example 77 and Example 78 by using intermediate C19 instead of intermediate C17. Example 79 (prepared in analogy to Example 77), LCMS (M+H ⁺ ): 719. ¹ H NMR (500 MHz, DMSO-d6) δ = 8.86 - 8.73 (m, 1H), 8.67 - 7.80 (m, 2H), 7.73 - 7.64 (m, 1H), 7.62 - 7.52 (m, 2H), 7.48 - 7.39 (m, 2H), 7.38 - 7.31 (m, 1H), 7.30 - 7.09 (m, 1H), 5.80 - 5.43 (m, 3H), 4.51 - 4.17 (m, 2H), 4.14 - 4.01 (m, 1H), 4.00 - 3.86 (m, 1H), 3.51 - 3.45 (m, 1H), 3.17 - 3.04 (m, 1H), 3.04 - 2.91 (m, 3H), 2.91 - 2.80 (m, 1H), 2.71 (d, J = 4.4 Hz, 3H), 2.71 - 2.65 (m, 1H), 2.59 (s, 3H). Example 80 (prepared in analogy to Example 78), LCMS (M+H ⁺ ): 719. ¹ H NMR (500 MHz, DMSO-d6) δ = 8.91 - 8.79 (m, 1H), 8.64 - 7.85 (m, 2H), 7.82 - 7.76 (m, 1H), 7.72 - 7.64 (m, 1H), 7.61 (br d, J = 8.5 Hz, 1H), 7.54 (br d, J = 9.5 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.38 - 7.31 (m, 1H), 7.30 - 7.06 (m, 1H), 5.78 - 5.44 (m, 3H), 4.50 - 4.17 (m, 2H), 4.13 - 4.02 (m, 1H), 3.90 - 3.79 (m, 1H), 3.02 - 2.88 (m, 3H), 2.87 - 2.82 (m, 1H), 2.81 - 2.75 (m, 1H), 2.73 (br s, 1H), 2.72 - 2.66 (m, 3H), 2.57 - 2.53 (m, 3H), 2.45 - 2.38 (m, 1H). Example 81 and Example 82 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: The title compounds were prepared in analogy to the preparation of Example 63 and Example 64 by using Intermediate A7 instead of Intermediate A8 to give compound 81c-1 (faster eluted) and compound 81c-2 (slower eluted). SFC condition of compound 81c: Instrument: SFC 80, Column: Pyridine, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 50%, Flow rate: 60 mL /min, Back pressure: 100bar, Column temperature: 35℃. Example 81, LCMS (M+H ⁺ ): 685. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ =1H NMR (500 MHz, DMSO-d6) δ = 8.88 - 8.80 (m, 1H), 8.68 - 7.88 (m, 2H), 7.82 - 7.69 (m, 2H), 7.65 - 7.55 (m, 2H), 7.54 - 7.46 (m, 1H), 7.38 - 7.28 (m, 1H), 5.79 - 5.43 (m, 3H), 4.51 - 4.17 (m, 2H), 4.11 - 3.80 (m, 2H), 3.53 - 3.42 (m, 1H), 3.22 - 3.11 (m, 1H), 2.98 - 2.86 (m, 3H), 2.85 - 2.77 (m, 1H), 2.75 - 2.64 (m, 2H), 2.57 - 2.52 (m, 3H), 2.49 - 2.44 (m, 1H), 0.45 - 0.36 (m, 3H). Example 82, LCMS (M+H ⁺ ): 685. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ =1H NMR (500 MHz, DMSO-d6) δ = 8.80 - 8.73 (m, 1H), 8.68 - 7.83 (m, 2H), 7.80 - 7.69 (m, 1H), 7.64 - 7.56 (m, 2H), 7.56 - 7.49 (m, 1H), 7.47 - 7.37 (m, 1H), 7.37 - 7.27 (m, 1H), 5.82 - 5.44 (m, 3H), 4.53 - 4.15 (m, 2H), 4.08 - 3.85 (m, 2H), 3.51 - 3.43 (m, 1H), 3.21 - 3.10 (m, 1H), 3.04 - 2.91 (m, 3H), 2.89 - 2.79 (m, 1H), 2.77 - 2.69 (m, 1H), 2.68 - 2.58 (m, 2H), 2.58 - 2.53 (m, 3H), 0.46 (dt, J = 4.3, 6.9 Hz, 3H). Example 83 and Example 84 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared in analogy to the preparation of Example 81 and Example 82 by using Intermediate C11 instead of Intermediate C2. Example 83 (prepared in analogy to Example 81), LCMS (M+H ⁺ ): 697. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.90 - 8.83 (m, 1H), 8.55 - 7.79 (m, 2H), 7.79 - 7.76 (m, 1H), 7.62 - 7.57 (m, 1H), 7.55 - 7.48 (m, 1H), 7.47 - 7.39 (m, 1H), 7.20 (dd, J = 2.6, 11.0 Hz, 1H), 6.99 - 6.92 (m, 1H), 5.75 - 5.46 (m, 3H), 4.49 - 4.16 (m, 2H), 4.09 - 3.99 (m, 1H), 3.91 - 3.79 (m, 1H), 3.75 (s, 3H), 3.33 - 3.28 (m, 1H), 3.21 - 3.14 (m, 1H), 2.99 - 2.87 (m, 3H), 2.84 - 2.75 (m, 1H), 2.74 - 2.64 (m, 2H), 2.55 (s, 3H), 2.47 (br d, J = 7.0 Hz, 1H), 0.45 - 0.37 (m, 3H). Example 84 (prepared in analogy to Example 82), LCMS (M+H ⁺ ): 697. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.79 - 8.72 (m, 1H), 8.58 - 7.71 (m, 2H), 7.63 - 7.50 (m, 2H), 7.49 - 7.36 (m, 2H), 7.20 (dd, J = 2.6, 11.0 Hz, 1H), 6.99 - 6.91 (m, 1H), 5.84 - 5.46 (m, 3H), 4.55 - 4.16 (m, 2H), 4.09 - 3.86 (m, 2H), 3.74 (s, 3H), 3.49 - 3.43 (m, 1H), 3.20 - 3.06 (m, 2H), 3.03 - 2.91 (m, 3H), 2.86 - 2.80 (m, 1H), 2.76 - 2.61 (m, 2H), 2.56 (s, 3H), 0.48 - 0.40 (m, 3H). Example 95 (8S,11S)-10-[3-(6-fluoro-2-hydroxy-3-pyridyl)imidazo[1,5-a]p yrazin-8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-10-(3-bromoimidazo[1,5-a]pyrazin-8-yl)-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 95a) To a flask was added (8S,11S)-13-methyl-7,10,13,17,19,26-hexazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 12d, 100 mg, 239 μmol), 3-bromo-8-chloro-imidazo[1,5-a]pyrazine (100 mg, 478 μmol), CsF (181 mg, 1.2 mmol), DIPEA (155 mg, 208 μL, 1.2 mmol), DMSO (2 mL). The mixture was heated to 90 °C for 12 hrs. The mixture was diluted with 40 mL EA and then it was washed with water 25 mL for three times, the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel to give compound 95a (69 mg), LCMS (M+H ⁺ ): 579. Step 2: preparation of (8S,11S)-10-[3-(6-fluoro-2-hydroxy-3-pyridyl)imidazo[1,5- 2,6 8,11 20,24 a]pyrazin-8-yl]-13-methyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]- hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 95) To a microwave tube was added (8S,11S)-10-(3-bromoimidazo[1,5-a]pyrazin-8-yl)-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 95a, 10 mg, 17 μmol), 6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (12.6 mg, 52 μmol), Cs ₂ CO ₃ (22.8 mg, 70 μmol), 1,4-dioxane (1 mL) and Water (0.4 mL). The suspension was bubbled with N ₂ for 5 mins and PdCl ₂ (DPPF)-CH ₂ Cl ₂ adduct (5.1 mg, 7 μmol) was added. The mixture was heated to 110 °C for 16 hrs. The mixture was concentrated and purified by prep-HPLC to give Example 95 (2 mg). LCMS (M+H ⁺ ): 605. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.53 - 8.40 (m, 1H), 8.10 - 8.02 (m, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.72 (br d, J = 7.3 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.24 - 7.17 (m, 1H), 7.12 - 7.02 (m, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.83 - 6.79 (m, 1H), 6.79 - 6.76 (m, 1H), 6.74 - 6.69 (m, 1H), 6.55 - 6.49 (m, 1H), 5.73 - 5.49 (m, 1H), 5.46 - 5.28 (m, 1H), 4.94 - 4.76 (m, 1H), 4.67 - 4.51 (m, 2H), 4.11 - 4.03 (m, 2H), 4.01 - 3.92 (m, 2H), 2.97 (br s, 3H), 2.86 - 2.75 (m, 2H), 2.09 - 1.89 (m, 1H), 1.45 - 1.29 (m, 1H). Example 96 (8S,11S)-10-[3-(2,6-difluoro-3-pyridyl)imidazo[1,5-a]pyrazin -8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one Example 96 was prepared in analogy to the preparation of Example 95 by using 2,6- difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine instead of 6-fluoro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol. LCMS (M+H ⁺ ): 607. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.52 - 8.41 (m, 1H), 8.31 – 8.28 (m, 2H), 7.79 - 7.73 (m, 1H), 7.68 (dd, J = 1.8, 7.2 Hz, 1H), 7.42 (dd, J = 2.0, 8.2 Hz, 2H), 7.27 - 7.21 (m, 2H), 7.18 - 7.09 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.54 - 5.35 (m, 2H), 4.88 - 4.72 (m, 1H), 4.64 - 4.53 (m, 2H), 4.07 - 3.91 (m, 4H), 2.98 (br s, 3H), 2.87 - 2.77 (m, 2H), 2.12 - 1.95 (m, 1H), 1.45 - 1.32 (m, 1H). Example 97 (8S,11S)-13-methyl-10-[3-(2-thienyl)imidazo[1,5-a]pyrazin-8- yl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one Example 97 was prepared in analogy to the preparation of Example 95 by using 4,4,5,5- tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane instead of 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-ol. Example 97 (1.5 mg) was obtained. LCMS (M+H ⁺ ): 576. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.92 - 7.86 (m, 1H), 7.82 - 7.75 (m, 6H), 7.44 - 7.37 (m, 3H), 7.28 (dd, J = 4.0, 5.0 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.81 - 5.61 (m, 1H), 5.45 - 5.31 (m, 1H), 4.95-4.81 (m, 1H), 4.65 - 4.53 (m, 2H), 4.16 - 4.07 (m, 2H), 4.03 - 3.93 (m, 2H), 2.97 (br s, 3H), 2.85 - 2.79 (m, 2H), 2.05 - 1.89 (m, 1H), 1.46 - 1.31 (m, 1H). Exemple 98 & 99 (8S,11S)-10-[1-(5-fluoro-3-methoxy-2-pyridyl)pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-(3-fluoro-5-methoxy-2- pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,13,17, 19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-10-[1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 98a) A mixture of intermediate C1 (38 mg, 0.1 mmol), compound 12d (36 mg, 0.1 mmol) and DIPEA (0.05 mL, 0.29 mmol) in ACN (1.5 mL) was stirred at 85 °C for 2 h. The mixture was concentrated to give crude compound 98a (60 mg). LCMS (M+H) ⁺ : 608. Step 2: preparation of 8S,11S)-10-[1-(5-fluoro-3-methoxy-2-pyridyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-(3-fluoro-5-methoxy-2-pyridyl)pyrazolo[3,4-d] pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 98 & 99) To a solution of compound 98a (60 mg, 0.1 mmol) in methanol (1.5 mL) was added MeONa (1.5 mL, 5 M in MeOH) at 25 °C, then the mixture was stirred at 25 °C for 4 hours. The mixture was quenched with sat. NH ₄ Cl (10 mL), extracted with EtOAc (10 mL). The organic layer was concentrated and the residue was purified by prep-HPLC to give Example 98 (9 mg) and Example 99 (1.6 mg). Example 98: LCMS(M+H) ⁺ : 620, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.44 - 9.31 (m, 1H), 8.54 - 8.46 (m, 1H), 8.25 - 8.22 (m, 1H), 8.20 - 8.15 (m, 1H), 7.92 - 7.80 (m, 3H), 7.62 - 7.52 (m, 2H), 7.03 (br d, J =7.21 Hz, 1H), 6.85 - 6.72 (m, 1H), 5.85 - 5.69 (m, 1H), 5.51 - 5.37 (m, 1H), 5.11 – 4.83 (m, 1H), 4.73 - 4.61 (m, 1H), 4.51 - 4.42 (m, 1H), 4.28 - 4.13 (m, 3H), 4.05 - 3.94 (m, 1H), 3.80 - 3.78 (m, 3H), 3.04 (s, 1H), 2.96 (s, 2H), 2.89 - 2.78 (m, 1H), 2.70 - 2.57 (m, 1H), 2.41 - 2.29 (m, 1H). Example 99: LCMS(M+H) ⁺ : 620, ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.28 - 8.16 (m, 3H), 7.84 - 7.76 (m, 1H), 7.71 (br d, J=7.46 Hz, 1H), 7.60 (dd, J=10.94, 2.26 Hz, 1H), 7.39 - 7.28 (m, 2H), 6.99 (br d, J=7.21 Hz, 1H), 6.78 - 6.69 (m, 1H), 5.54 - 5.41 (m, 1H), 4.77 - 4.69 (m, 1H), 4.66 (br s, 2H), 4.58 - 4.52 (m, 2H), 4.30 (br d, J=12.47 Hz, 1H), 4.20 - 4.06 (m, 2H), 4.00 (s, 3H), 3.18 - 3.00 (m, 3H), 2.96 - 2.83 (m, 1H), 2.75 - 2.51 (m, 2H). Example 100 (8S,11S)-10-[3-(3,5-difluoro-2-pyridyl)imidazo[1,5-a]pyrazin -8-yl]-13-methyl- 2,6 8,11 20 24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one Example 100 was prepared in analogy to the preparation of Example 95 by using 3,5- difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine instead of 6-fluoro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol. LCMS (M+H ⁺ ): 607. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.81 (br s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.20 (ddd, J = 2.4, 8.8, 10.8 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.79 - 7.77 (m, 1H), 7.77 - 7.75 (m, 1H), 7.46 - 7.36 (m, 2H), 7.21 (br s, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.86 - 5.58 (m, 1H), 5.54 - 5.26 (m, 1H), 4.99 - 4.78 (m, 1H), 4.71 - 4.48 (m, 2H), 4.19 - 4.06 (m, 2H), 4.02 – 3.97 (m, 2H), 2.98 (br s, 3H), 2.85 – 2.80 (m, 2H), 1.99 (br s, 1H), 1.40 (br s, 1H). Example 102 (8S,11S)-10-[2-(2-chloro-4-fluoro-phenyl)pyrimidin-5-yl]-13- methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 5-bromo-2-(2-chloro-4-fluoro-phenyl)pyrimidine (compound 102a) A solution of 5-bromo-2-iodopyrimidine (1.7 g, 5.97 mmol), PdCl ₂ (dppf) (487 mg, 597 μmol), (2-chloro-4-fluorophenyl)boronic acid (1.04 g, 5.97 mmol and K ₂ CO ₃ (2.47 g, 17.9 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 120 °C for 16 hrs. The mixture was cooled and diluted with EA (20 mL), and then it was washed with brine (20 mL). The organic layer was dried and concentrated. The crude product was purified by silica gel to give the compound 102a (420 mg), LCMS (M+H ⁺ ): 287. Step 2: preparation of (8S,11S)-10-[2-(2-chloro-4-fluoro-phenyl)pyrimidin-5-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19-pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20 (24),21-heptaen-12-one (example 102) To a solution of (8S,11S)-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (12d, 50 mg, 133 μmol) in 1,4-dioxane (3 mL) was added 5-bromo-2-(2-chloro-4- fluorophenyl)pyrimidine (102a, 57.3 mg, 199 μmol), 2,2'-bis(diphenylphosphaneyl)-1,1'- binaphthalene (33.1 mg, 53.1 μmol), Pd ₂ (dba) ₃ (24.3 mg, 26.6 μmol) and Cs ₂ CO ₃ (108 mg, 332 μmol). The reaction mixture was bubbled with N ₂ for 5 mins and then heated to 110 °C for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to give Example 102 (7.3 mg), LCMS (M+H ⁺ ): 584. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.47 (s, 1H), 8.19 (s, 2H), 7.89 (dd, J = 2.0, 5.1 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.73 - 7.68 (m, 2H), 7.67 - 7.62 (m, 1H), 7.34 (dd, J = 2.6, 8.8 Hz, 1H), 7.19 (dt, J = 2.6, 8.4 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.25 - 5.15 (m, 1H), 4.93 (d, J = 8.8 Hz, 1H), 4.64 - 4.58 (m, 1H), 4.41 - 4.31 (m, 1H), 4.22 (dd, J = 10.7, 13.8 Hz, 1H), 4.01 (dd, J = 5.7, 10.6 Hz, 1H), 3.82 (d, J = 10.6 Hz, 1H), 3.04 (s, 3H), 2.96 - 2.87 (m, 1H), 2.77 - 2.68 (m, 1H), 2.66 - 2.56 (m, 1H), 2.08 - 1.95 (m, 1H), 1.68 - 1.53 (m, 1H). Example 104 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: To a tube was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]- 2,6 8,11 20,24 13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 12, 33 mg, 54.4 μmol), MeOH (2mL) and sodium methanolate (4 N in methanol) (3mL, 12 mmol), a suspension formed. The mixture was heated to 70 °C for 16 hrs. The mixture was concentrated and then it was purified via prep- HPLC to give the Example 104 (6.6 mg). LCMS (M+H ⁺ ) 619. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.48 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.47 - 7.40 (m, 1H), 7.29 - 7.22 (m, 2H), 7.22 - 7.16 (m, 1H), 6.99 - 6.91 (m, 2H), 6.79 - 6.67 (m, 1H), 5.54 (br d, J = 8.4 Hz, 1H), 5.44 (d, J = 8.6 Hz, 1H), 4.96 - 4.76 (m, 1H), 4.72 - 4.60 (m, 1H), 4.55 - 4.43 (m, 1H), 4.28 - 4.14 (m, 1H), 4.09 - 3.89 (m, 3H), 3.73 (s, 3H), 2.95 (s, 3H), 2.90 - 2.75 (m, 1H), 2.41 - 2.34 (m, 1H), 2.09 - 1.83 (m, 1H), 1.45 - 1.24 (m, 1H) Example 106 (8S,11S)-10-[1-[4-fluoro-2-(methylamino)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 104 by using the reaction condition with methanamine (33% in ethanol) instead of NaOMe and MeOH. LCMS (M+H ⁺ ) 618. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.83 - 7.76 (m, 1H), 7.71 (dd, J = 1.7, 7.5 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.19 - 7.11 (m, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.77 - 6.71 (m, 1H), 6.54 (dd, J = 2.7, 11.6 Hz, 1H), 6.45 (dt, J = 2.8, 8.4 Hz, 1H), 5.50 (d, J = 8.6 Hz, 1H), 4.78 - 4.72 (m, 1H), 4.57 - 4.53 (m, 2H), 4.29 (d, J = 11.7 Hz, 1H), 4.20 - 4.04 (m, 2H), 3.05 (s, 3H), 2.96 - 2.84 (m, 1H), 2.75 (s, 3H), 2.68 - 2.62 (m, 1H), 2.62 - 2.53 (m, 1H), 2.23 - 2.00 (m, 1H), 1.61 - 1.41 (m, 1H). Example 111 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,22,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 7-bromo-1-(3-chloropropyl)imidazo[4,5-c]pyridine (compound 111a) To a flask was added 7-bromo-1H-imidazo[4,5-c]pyridine (2 g, 10.1 mmol), 1-chloro-3- iodo-propane (2.68 g, 1.41mL, 13.13 mmol), Cs ₂ CO ₃ (6.58 g, 20.2 mmol), DMF (15 mL). The mixture was heated to 55 °C for 3 hrs. The mixture was diluted with 40 mL EA, which was washed with water 25 mL for three times, the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel to give compound 111a (470 mg), LCMS (M+H ⁺ ): 274. Step 2: preparation of 3-(7-bromoimidazo[4,5-c]pyridin-1-yl)-N-methyl-propan-1- amine (compound 111b) To a flask was added 7-bromo-1-(3-chloropropyl)imidazo[4,5-c]pyridine (compound 111a, 470 mg, 1.71 mmol), DIPEA (442 mg, 598 μL, 3.42 mmol), 33% MeNH ₂ in EtOH (6 mL), The mixture was heated to 90 °C for 16 hrs, then the mixture was concentrated to give compound 111b (500 mg), LCMS (M+H ⁺ ): 269. Step 3: preparation of tert-butyl N-[3-(7-bromoimidazo[4,5-c]pyridin-1-yl)propyl]-N- methyl-carbamate (compound 111c) To a flask was added 3-(7-bromoimidazo[4,5-c]pyridin-1-yl)-N-methyl-propan-1-amin e (compound 111b, 460 mg, 1.71 mmol), DIPEA (663 mg, 895 μL, 5.13 mmol), tert- butoxycarbonyl tert-butyl carbonate (448 mg, 2.05 mmol), DCM (6 mL), the suspension was stirred at room temperature for 1 hr. Then the mixture was concentrated, the crude product was purified by silica gel to give compound 111c (430 mg), LCMS (M+H ⁺ ): 369. Step 4: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[1-[3-[tert- butoxycarbonyl(methyl)amino]propyl]imidazo[4,5-c]pyridin-7-y l]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 111d) To a flask was added O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2- pyridyl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B10, 1 g, 2.3 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.17 g, 4.6 mmol), KOAc (452 mg, 4.6 mmol) and 1,4-dioxane (8 mL). The suspension was bubbled with N ₂ for 5 mins, then Pd(OAc) ₂ (103 mg, 461 μmol) and dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (439 mg, 921 μmol) were added. The mixture was heated to 80 °C for 12 hrs, then the mixture was filtered, tert-butyl N-[3-(7-bromoimidazo[4,5- c]pyridin-1-yl)propyl]-N-methyl-carbamate (compound 111c, 425 mg, 1.15 mmol), K ₂ CO ₃ (477 mg, 3.45 mmol), and water (1 mL) were added into the filtrate. The suspension was bubbled with N ₂ for 5 mins and PdCl ₂ (DPPF)-CH ₂ Cl ₂ adduct (207 mg, 282 μmol) was added. After being heated to 90 °C for 2 hrs, the mixture was diluted with 40 mL water and extracted with EA 25 mL for three times, the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel to give compound 111d (460 mg), LCMS (M+H ⁺ ): 644. Step 5~8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-7,10,13,17,19,22,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 111) Example 111 was prepared in analogy to the preparation of Example 1 by using compound 111d instead of compound 1a. LCMS (M+H ⁺ ): 608. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.93 (s, 1H), 8.53 (s, 1H), 8.46 - 8.40 (m, 2H), 8.24 - 8.21 (m, 1H), 7.89 - 7.79 (m, 1H), 7.71 - 7.59 (m, 1H), 7.33 - 7.24 (m, 1H), 7.23 - 7.14 (m, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.84 - 6.76 (m, 1H), 5.55 - 5.41 (m, 1H), 5.41 - 5.20 (m, 1H), 4.62 - 4.50 (m, 3H), 4.39 - 4.20 (m, 2H), 4.15 - 4.03 (m, 1H), 3.13 (s, 1H), 3.04 (s, 2H), 2.94 - 2.82 (m, 1H), 2.63 - 2.58 (m, 1H), 2.11 - 1.89 (m, 1H), 1.62 - 1.41 (m, 1H). Example 112 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 112 was prepared in analogy to the preparation of Example 111 by using 4- chloro-3H-imidazo[4,5-c]pyridine instead of 7-bromo-1H-imidazo[4,5-c]pyridine. Example 112 (7 mg) was obtained. LCMS (M+H ⁺ ): 608. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.61 - 8.47 (m, 2H), 8.38 (d, J = 3.2 Hz, 1H), 8.37 - 8.25 (m, 1H), 7.86 - 7.80 (m, 1H), 7.78 - 7.71 (m, 1H), 7.71 - 7.69 (m, 1H), 7.64 - 7.57 (m, 1H), 7.43 - 7.38 (m, 1H), 7.37 - 7.30 (m, 1H), 6.83 - 6.73 (m, 1H), 5.59 (br d, J = 8.6 Hz, 1H), 5.48 (d, J = 8.7 Hz, 1H), 5.43 - 5.31 (m, 1H), 4.76 - 4.67 (m, 1H), 4.55 – 4.49 (m, 1H), 4.30 - 4.20 (m, 2H), 4.21 - 4.08 (m, 1H), 3.98 - 3.90 (m, 1H), 3.02 (s, 1H), 2.93 (s, 2H), 2.90 - 2.75 (m, 1H), 2.64 - 2.35 (m, 1H), 1.82 - 1.56 (m, 1H), 1.46 - 1.25 (m, 1H). Example 113 (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)py razolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(4-chloroimidazo[4,5-c]pyridin-3- yl)propyl]carbamate (compound 113a) The mixture of 4-chloro-3H-imidazo[4,5-c]pyridine (6.0 g, 39.07 mmol), 3-(BOC- amino)propyl bromide (10.23 g, 42.98 mmol) and cesium carbonate (19.09 g, 58.61 mmol) in ACN (50 mL) was stirred at 90 °C for 2 h. The mixture was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to give compound 113a (3.5 g), LCMS (M+H) ⁺ : 311. Step 2: preparation of tert-butyl N-[3-(4-chloroimidazo[4,5-c]pyridin-3-yl)propyl]-N- (cyclopropylmethyl)carbamate (compound 113b) To a solution of compound 113a (3.4 g, 11 mmol) in DMF (30 mL) was added sodium hydride, 60% in oil (880. mg, 22 mmol) at -10 °C. The mixture was stirred at -10 °C for 0.5 h. Then (bromomethyl)cyclopropane (1.17 mL, 12 mmol) was added and then stirred at 25 °C for 16 hours. The reaction was quenched with aq. NH ₄ Cl solution, the mixture was extracted with EA, the organic layer was dried and concentrated, the residue was purified by silica gel to give compound 113b (3.5 g), LCMS (M+H) ⁺ : 365. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(cyclopropylmethyl)amino]propyl]imidazo[4,5-c] pyridin-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 113c) To a mixture of compound 113b (420 mg, 1.15 mmol), intermediate B10 (500 mg, 1.15 mmol), Zn (301.1 mg, 4.61 mmol) in DMA (8 mL) was added pyridine-2-carboximindamide hydrochloride (54.43 mg, 0.350 mmol), Nickel chloride dimethoxyethane adduct (75.89 mg, 0.350 mmol) at 25 °C under N ₂ atmosphere. The reaction was stirred at 25 °C for 15 hours. Then the reaction was filtered and the filtrate was concentrated, the residue was purified by flash chromatography column to give compound 113c (155 mg), LCMS (M+H) ⁺ : 684. Step 4~8: preparation of (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,17,19, 23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (Example 113) The title compound was prepared in analogy to the preparation of Example 12 by using compound 113c instead of compound 12a. LCMS (M+H) ⁺ : 648. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.98 - 9.95 (m, 1H), 8.56 (s, 1H), 8.53 - 8.51 (m, 1H), 8.39 - 8.25 (m, 1H), 8.20 - 8.19 (m, 1H), 7.98 - 7.83 (m, 1H), 7.83 - 7.68 (m, 1H), 7.34 -7.20 (m, 3H), 7.06 - 7.04 (m, 1H), 5.60 - 5.51 (m, 2H), 4.82 - 4.80 (m, 2H), 4.61 - 4.58 (m, 1H), 4.46 - 4.33 (m, 2H), 4.11 - 3.98 (m, 1H), 3.60 - 3.55 (m, 1H), 3.33 - 3.32 (m, 1H), 3.15 - 3.10 (m, 1H), 2.68 - 2.66 (m, 1H), 2.15 - 1.90 (m, 1H), 1.62 - 1.59 (m, 1H), 0.64 - 0.26 (m, 5H). Example 114 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 114 was prepared in analogy to the preparation of Example 111 by using 7- chloro-1H-imidazo[4,5-b]pyridine instead of 7-bromo-1H-imidazo[4,5-c]pyridine. LCMS (M+H ⁺ ): 608. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.62 - 8.51 (m, 2H), 8.44 (d, J = 4.9 Hz, 1H), 8.38 - 8.22 (m, 1H), 7.87 - 7.79 (m, 1H), 7.78 - 7.69 (m, 1H), 7.60 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 6.86 - 6.75 (m, 1H), 5.70 – 5.67 (m, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.17 - 4.98 (m, 1H), 4.75 - 4.65 (m, 1H), 4.52 - 4.47 (m, 1H), 4.28 - 4.18 (m, 2H), 4.17 - 4.05 (m, 1H), 3.97 – 3.90 (m, 1H), 3.03 (s, 1H), 2.94 (s, 2H), 2.90 - 2.61 (m, 1H), 2.61 - 2.34 (m, 1H), 1.99 - 1.74 (m, 1H), 1.43 - 1.21 (m, 1H). Exemple 115 & 116 (8S,11S)-10-[1-[4-fluoro-2-(2-morpholinoethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-[4-fluoro-2-(2- morpholinoethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13-me thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one To a solution of 2-morpholinoethanol (86.49 mg, 0.660 mmol) in DMF (1 mL) was added NaH (21.1 mg, 0.530 mmol) at 0°C and the mixture was stirred at 0°C for 30 mins, Example 12 (40 mg, 0.07 mmol) in DMF (0.5 mL) was added at 0 °C. The mixture was stirred at 80 °C for 2 h, then the mixture was quenched with water, the solution was purified by prep-HPLC to afford Example 115 (3.8 mg) and Example 116 (3 mg). Example 115: LCMS (M+H) ⁺ : 718. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.52 - 9.44 (m, 1H), 8.58 - 8.51 (m, 1H), 8.25 (s, 1H), 7.94 - 7.84 (m, 2H), 7.72 - 7.68 (m, 2H), 7.55 - 7.46 (m, 1H), 7.22 - 7.17 (m, 1H), 7.13 - 7.09 (m, 1H), 7.04 - 6.95 (m, 1H), 6.89 - 6.84 (m, 1H), 5.54 - 5.44 (m, 1H), 5.17 – 5.01 (m, 2H), 4.65 - 4.55 (m, 2H), 4.50 - 4.44 (m, 2H), 4.37 - 4.31 (m, 2H), 4.28 - 4.13 (m, 2H), 3.96 - 3.72 (m, 4H), 3.48 - 3.43 (m, 2H), 3.09 - 3.06 (m, 3H), 2.98 - 2.88 (m, 2H), 2.68 - 2.59 (m, 2H), 2.24 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H), 1.76 - 1.63 (m, 1H). Example 116: LCMS (M+H) ⁺ : 718. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.37 - 9.15 (m, 1H), 8.17 - 7.98 (m, 1H), 7.93 - 7.76 (m, 3H), 7.74 - 7.57 (m, 3H), 7.09 - 7.03 (m, 1H), 7.01 - 6.93 (m, 1H), 6.86 - 6.75 (m, 2H), 5.57 - 5.39 (m, 1H), 4.75 - 4.55 (m, 3H), 4.49 - 4.44 (m, 2H), 4.35 - 4.24 (m, 2H), 4.21 - 4.10 (m, 2H), 4.01 - 3.81 (m, 4H), 3.67 - 3.59 (m, 2H), 3.46 - 3.37 (m, 2H), 3.05 - 2.99 (m, 3H), 2.97 - 2.80 (m, 1H), 2.80 - 2.59 (m, 1H), 2.55 - 2.41 (m, 1H), 2.26 - 2.14 (m, 1H), 2.07 - 2.02 (m, 1H), 1.75 - 1.52 (m, 1H). Example 118 & 119 (8S,11S)-10-[1-[4-fluoro-2-(2-methoxyethoxy)phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-[2-fluoro-4-(2- methoxyethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13-methy l-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one Example 118 & 119 were prepared in analogy to the preparation of Example 115 & 116 by using 2-methoxyethanol instead of 2-morpholinoethanol. Example 118: LCMS (M+H) ⁺ : 663. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 8.27 - 8.22 (m, 1H), 8.18 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.45 (br dd, J = 6.1, 8.7 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.08 (dd, J = 2.3, 10.7 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.89 (dt, J = 2.4, 8.3 Hz, 1H), 6.78 - 6.70 (m, 1H), 5.49 (br d, J = 8.6 Hz, 1H), 4.77 - 4.70 (m, 2H), 4.30 (br d, J = 11.4 Hz, 1H), 4.22 - 4.10 (m, 4H), 3.53 - 3.46 (m, 2H), 3.14 (s, 3H), 3.05 (s, 3H), 2.88 (br dd, J = 6.9, 13.8 Hz, 1H), 2.69 - 2.54 (m, 2H), 2.20 - 2.12(m, 1H), 1.73 - 1.44 (m, 2H). Example 119: LCMS (M+H) ⁺ : 663. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 (s, 1H), 8.35 - 8.20 (m, 2H), 7.84 - 7.77 (m, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.53 - 7.43 (m, 1H), 7.39 - 7.28 (m, 2H), 7.04 - 6.95 (m, 3H), 6.75 (br d, J = 8.3 Hz, 1H), 5.50 (br d, J = 8.9 Hz, 1H), 4.76 - 4.72 (m, 2H), 4.33 - 4.27 (m, 1H), 4.25 - 4.20 (m, 2H), 4.18 - 4.08 (m, 2H), 3.82 - 3.77 (m, 2H), 3.45 (s, 3H), 3.05 (s, 3H), 2.94 - 2.84 (m, 1H), 2.72 - 2.57 (m, 2H), 2.25 - 2.17 (m, 1H), 1.75 - 1.46 (m, 2H). Example 120 & 121 (8S,11S)-10-[1-[4-fluoro-2-(oxetan-3-ylmethoxy)phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-[2-fluoro-4-(oxetan-3- ylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7, 10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 120 & 121 were prepared in analogy to the preparation of Example 115 & 116 by using oxetan-3-ylmethanol instead of 2-morpholinoethanol. Example 120: LCMS (M+H) ⁺ : 675. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.5 - 8.45 (m, 1H), 8.30 – 8.25 (m, 1H), 8.17 (s, 1H), 7.78 - 7.67 (m, 2H), 7.55 - 7.51 (m, 1H), 7.31 – 7.27 (m, 2H), 7.20 – 7.15 (m, 1H), 7.05 – 6.95 (m, 1H), 6.9 – 6.8 (m, 1H), 6.85 – 6.75 (m, 1H), 5.63 - 5.44 (m, 1H), 4.55 – 4.61 (m, 10H), 4.35 - 4.25 (m, 2H), 4.23 - 4.05 (m, 4H), 3.05 (s, 3H), 2.95 - 2.75 (m, 1H), 2.68 - 2.55 (m, 1H). Example 121: LCMS (M+H) ⁺ : 675. ¹ H NMR (400 MHz, METHANOL-d ₄₎ δ = 9.01 - 8.55 (m, 1H), 8.26 (s, 1H), 8.15 – 7.95 (m, 1H), 7.75 – 7.65 (m, 2H), 7.26 – 7.2 (m, 3H), 6.95 – 6.90 (m, 2H), 6.85 – 6.75 (m, 1H), 6.65 - 6.60 (m, 1H), 5.63 - 5.44 (m, 1H), 5.43 - 5.29 (m, 1H), 4.88 - 4.56 (m, 4H), 4.53 - 4.30 (m, 4H), 4.22 (br d, J = 6.8 Hz, 2H), 4.18 - 3.89 (m, 4H), 2.88 (s, 3H), 2.80 - 2.71 (m, 1H), 2.03 - 1.94 (m, 2H). Example 122 & 123 (8S,11S)-10-[1-[4-fluoro-2-(oxetan-3-yloxy)phenyl]pyrazolo[3 ,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-[2-fluoro-4-(oxetan-3- yloxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 122 & 123 were prepared in analogy to the preparation of Example 115 & 116 by using oxetan-3-ol instead of 2-morpholinoethanol. Example 122: LCMS(M+H) ⁺ : 661. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.52 - 8.3 (m, 1H), 8.34 - 8.28 (m, 1H), 8.27 - 8.16 (m, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.68 (br d, J = 7.3 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.29 - 7.20 (m, 2H), 7.00 (dt, J = 2.3, 8.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.76 - 6.65 (m, 1H), 5.62 - 5.49 (m, 1H), 5.45 (br d, J = 8.7 Hz, 1H), 5.36 (td, J = 5.4, 11.1 Hz, 1H), 4.99 - 4.79 (m, 2H), 4.72 - 4.55 (m, 1H), 4.53 - 4.44 (m, 1H), 4.36 - 4.26 (m, 2H), 4.26 - 4.18 (m, 1H), 4.12 - 3.91 (m, 2H), 3.32 - 3.23 (m, 2H), 2.94 (s, 3H), 2.90 - 2.74 (m, 1H), 2.71 - 2.57 (m, 1H), 2.41 - 2.30 (m, 1H). Example 123: LCMS(M+H) ⁺ : 661. ¹ H NMR (400 MHz, DMSO--d6) δ = 8.55 - 8.41 (m, 1H), 8.35 - 8.27 (m, 1H), 8.27 - 8.20 (m, 1H), 7.80 - 7.73 (m, 1H), 7.68 (br d, J = 7.5 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.30 - 7.20 (m, 2H), 7.03 - 6.91 (m, 2H), 6.85 (br d, J = 8.6 Hz, 1H), 6.76 - 6.64 (m, 1H), 5.59 - 5.49 (m, 1H), 5.47 - 5.36 (m, 2H), 4.97 (br t, J = 6.7 Hz, 2H), 4.72 - 4.63 (m, 1H), 4.59 (dd, J = 5.2, 6.9 Hz, 2H), 4.53 - 4.43 (m, 1H), 4.19 (br d, J = 11.5 Hz, 1H), 4.05 - 3.93 (m, 2H), 3.32 - 3.26 (m, 2H), 3.02 (s, 3H), 2.87 - 2.74 (m, 1H), 2.70 - 2.61 (m, 1H), 2.41 - 2.30 (m, 1H). Example 124 (8S,11S)-10-[1-[4-fluoro-2-[(4-methylmorpholin-2-yl)methoxy] phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 124 were prepared in analogy to the preparation of Example 115 & 116 by using (4-methylmorpholin-2-yl)methanol instead of 2-morpholinoethanol. LCMS( M+H) ⁺ : 718. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.58 - 8.48 (m, 1H), 8.38 - 8.13 (m, 2H), 7.80 - 7.72 (m, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.56 - 7.40 (m, 1H), 7.30 - 7.10 (m, 3H), 7.01 - 6.89 (m, 2H), 6.76 - 6.64 (m, 1H), 5.61 - 5.48 (m, 1H), 5.44 (br dd, J = 5.4, 8.3 Hz, 1H), 4.98 - 4.76 (m, 1H), 4.74 - 4.61 (m, 1H), 4.55 - 4.41 (m, 1H), 4.21 (br dd, J = 6.2, 10.9 Hz, 1H), 4.12 - 3.86 (m, 4H), 3.85 - 3.79 (m, 1H), 3.73 - 3.63 (m, 1H), 3.60 - 3.53 (m, 1H), 2.95 (s, 3H), 2.90 - 2.75 (m, 2H), 2.69 - 2.56 (m, 2H), 2.43 - 2.30 (m, 2H), 2.21 (s, 1H), 2.09 - 1.99 (m, 3H), 1.93 - 1.81 (m, 1H). Example 126 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-18-(2-methoxyethyl)-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using 126c instead of Intermediate A11 in step one. LCMS (M+H ⁺ ) 665. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.22 (s, 1H), 7.82 - 7.75 (m, 1H), 7.70 - 7.59 (m, 2H), 7.32 - 7.23 (m, 3H), 7.22 - 7.15 (m, 1H), 6.90 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.49 (d, J = 8.7 Hz, 1H), 4.75 - 4.72 (m, 1H), 4.59 - 4.54 (m, 2H), 4.32 - 4.23 (m, 1H), 4.08 - 3.94 (m, 2H), 3.92 - 3.81 (m, 2H), 3.34 - 3.32 (m, 3H), 3.19 (t, J = 6.3 Hz, 2H), 3.04 (s, 3H), 2.98 - 2.83 (m, 1H), 2.75 - 2.68 (m, 1H), 2.62 - 2.49 (m, 1H), 2.23 - 1.99 (m, 1H), 1.38 - 1.23 (m, 1H). The compound 126c was prepared according to the following scheme: The compound 126c was prepared in analogy to the preparation of intermediate A18 by using 3-methoxypropanoic acid instead of 3-morpholinopropanoic acid in step one. LCMS (M+H ⁺ ) 474. Example 127 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-18-(2-morpholinoethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using Intermediate A18 instead of Intermediate A11 in step one. LCMS (M+H ⁺ ) 706. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.41 - 8.25 (m, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.32 - 7.24 (m, 3H), 7.23 - 7.17 (m, 1H), 6.90 (br d, J = 7.5 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.17 - 5.07 (m, 1H), 5.03 - 4.92 (m, 1H), 4.67 - 4.52 (m, 3H), 4.39 - 4.30 (m, 1H), 4.27 - 4.15 (m, 1H), 4.14 - 4.03 (m, 1H), 3.70 (br t, J = 4.2 Hz, 4H), 3.17 - 3.09 (m, 2H), 2.99 - 2.87 (m, 3H), 2.67 - 2.59 (m, 4H), 2.58 - 2.37 (m, 1H), 1.87 - 1.63 (m, 1H), 1.45 - 1.25 (m, 1H). Example 129 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-(2-hydroxyethyl)-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-[2-(2-benzyloxyethyl)-7-bromo-benzimidazol-1- yl]propyl]-N-methyl-carbamate (compound 129b) To a solution of tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]-N-methyl-carbamate (compound A26-a, 19 g, 53.03 mmol) in methanol (558.24 mL) was added 3-benzyloxypropanal (9578.75 mg, 58.34 mmol) and 4A MS (38 g). After being stirred at 70 °C for 48 hrs, the mixture was filtered, the filtrate was concentrated and the residue was purified by flash-HPLC to give compound 129b (12.9 g), LCMS (M+H ⁺ ): 502. Step 2: preparation of tert-butyl N-[3-[2-(2-benzyloxyethyl)-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-c arbamate (compound 129c) To a solution of compound 129b (12.7 g, 25.28 mmol) in 1,4-dioxane (127 mL) was added bis(pinacolato)diboron (12837.5 mg, 50.55 mmol), catacxium a-Pd-G2 (1.35 mg, 2.02 mmol) and K ₃ PO ₄ (4.19 mL, 50.55 mmol) under Ar. The mixture was stirred at 110 °C for 16 hrs, then the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel to give compound 129c (6.7 g), LCMS (M+H ⁺ ): 550. Step 3: preparation of 3-[2-(2-benzyloxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]-N-methyl-propan-1-amine (compound 129d) To a solution of compound 129c (3.7 g, 6.73 mmol) in DCM (20 mL) was added HCl/dioxane (20.0 mL, 4 M) at 0°C. The reaction was stirred at 25°C for 2 hrs, then the mixture was concentrated to give compound 129d (3.7 g), LCMS (M+H ⁺ ): 450. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-(2-benzyloxyethyl)-3- [3-(methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]-tert-bu toxycarbonyl- amino]pyrrolidine-1,2-dicarboxylate (compound 129e) To a solution of compound 129d (3.5 g, 7.2 mmol), intermediate B9 (3.6 g, 7.2 mmol), Pd(dppf)Cl ₂ (510 mg, 0.7 mmol) in 1,4-dioxane (35 mL) and water (4 mL) was added Na ₂ CO ₃ (2.2 g, 21 mmol) in glovebox under Ar. The reaction solution was stirred at 85 °C for 12 hrs. The mixture was poured into 100 mL water, and then it was extracted with EtOAc. The organic layer was dried and concentrated to give crude compound 129e (7.6 g), which was used in next step directly, LCMS (M+H ⁺ ): 743. Step 5: preparation of (2S,4S)-4-[[6-[2-(2-benzyloxyethyl)-3-[3- (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]-tert-butox ycarbonyl-amino]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 129f) To a solution of compound 129e (7.45 g, 10.03 mmol) in the mixture solvent of methanol (16 mL) and THF (50 mL) was added a solution of Lithium hydroxide (30.08 mL, 1 M) in water (30.81 mL) at 0 °C. The solution was stirred at 15 °C for 18 hrs, then the reaction mixture was acidified with 5% citric acid to pH=4~5, the mixture solution was directly purified by prep- HPLC to give compound 129f (1.5 g), LCMS (M+H ⁺ ): 729. Step 6: preparation of ditert-butyl (8S,11S)-18-(2-benzyloxyethyl)-13-methyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-7,10-dicarboxylate (compound 129g) To a solution of DIPEA (0.6 mL, 3.43 mmol) and HATU (782.5 mg, 2.06 mmol) in DMF (68.6 mL) was added a solution of compound 129f (1.0 g, 1.37 mmol) in THF (200 mL) dropwise in 1 h at 0 °C. The mixture was concentrated to give an oil and then it was purified by Flash-HPLC to give the compound 129g (800 mg), LCMS (M+H ⁺ ): 711. Step 7: preparation of ditert-butyl (8S,11S)-18-(2-hydroxyethyl)-13-methyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-7,10-dicarboxylate (compound 129h) To a solution of compound 129g (900.0 mg, 1.27 mmol) in methanol (50 mL) was added Pd(OH) ₂ /C (900.0 mg, 6.96 mmol). The reaction was stirred at 20°C for 72 hrs under H ₂ . The mixture was filtered and the filtrate was concentrated to give compound 129h (605 mg), LCMS (M+H ⁺ ): 621. Step 8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- yl]-18-(2-hydroxyethyl)-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 129) A mixture of compound 129h (500 mg, 0.805 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at r.t. for 1 hr. The mixture was concentrated, the residue was dissolved in acetonitrile (8 mL) and then DIPEA (832.86 mg, 1.13 mL, 6.44 mmol), intermediate C2 (236.25 mg, 0.886 mmol) was added. The mixture was heated to 85 °C for 2 hrs and then concentrated. The residue was purified via prep-HPLC to give compound 129 (64 mg). LCMS (M+H ⁺ ) 651. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.61 (s, 1H), 8.26 - 8.11 (m, 1H), 7.81 - 7.68 (m, 2H), 7.66 - 7.55 (m, 2H), 7.38 - 7.28 (m, 1H), 7.28 - 7.13 (m, 2H), 6.92 - 6.84 (m, 1H), 6.78 - 6.65 (m, 1H), 5.55 - 5.41 (m, 2H), 5.21 - 4.97 (m, 1H), 4.95 - 4.77 (m, 1H), 4.73 - 4.64 (m, 1H), 4.56 - 4.45 (m, 1H), 4.26 - 4.07 (m, 1H), 3.97 - 3.80 (m, 4H), 3.08 - 2.99 (m, 3H), 2.97 - 2.90 (m, 2H), 2.89 - 2.69 (m, 1H), 2.63 - 2.53 (m, 1H), 2.48 - 2.40 (m, 1H), 2.10 - 1.80 (m, 1H), 1.22 - 1.07 (m, 1H). Example 130 (8S,11S)-18-[2-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxi no[2,3-c]pyrrol-6-yl]ethyl]-10- [1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-met hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-18-(2-chloroethyl)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7,10 ,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 130a) To a tube was added Example 129 (200 mg, 0.307 mmol), DIPEA (79.45 mg, 107.37 μL, 0.615 mmol) and DCM (10 mL), the white suspension was stirred at r.t. and SOCl ₂ (731.29 mg, 448.64 μL, 6.15 mmol) was added. After being stirred at r.t. for 5 hrs, the mixture was quenched with water and then it was adjusted pH to 7, the mixture was extracted with 10 mL DCM twice, the organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 130a. LCMS (M+H ⁺ ): 669. Step 2: preparation of (8S,11S)-18-[2-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro- [1,4]dioxino[2,3-c]pyrrol-6-yl]ethyl]-10-[1-(2,4-difluorophe nyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 130) To a microwave tube was added compound 130a (50 mg, 0.044 mmol), sodium iodide (26.19 mg, 0.175 mmol), (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrr ole hydrochloride (14.47 mg, 0.087 mmol), DIPEA (28.22 mg, 38.14 μL, 0.218 mmol) and DMF (0.860 mL), the mixture was stirred at 70 °C for 16 hrs. The mixture was diluted with 10 mL DCM and washed with 10 mL sat. NH ₄ Cl for 3 times. The organic layer was concentrated, the residue was purified via prep-HPLC to give Example 130 (12.4 mg). LCMS (M+H ⁺ ) 762. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.22 (s, 1H), 7.82 - 7.75 (m, 1H), 7.70 - 7.59 (m, 2H), 7.32 - 7.16 (m, 4H), 6.95 - 6.87 (m, 1H), 6.78 - 6.69 (m, 1H), 5.53 - 5.41 (m, 1H), 5.16 - 5.01 (m, 1H), 4.75 - 4.69 (m, 1H), 4.67 - 4.49 (m, 3H), 4.36 - 4.17 (m, 2H), 4.17 - 4.09 (m, 2H), 4.09 - 4.02 (m, 1H), 4.01 - 3.89 (m, 1H), 3.83 - 3.71 (m, 2H), 3.58 - 3.47 (m, 2H), 3.18 - 3.01 (m, 6H), 3.00 - 2.85 (m, 3H), 2.75 - 2.64 (m, 1H), 2.63 - 2.50 (m, 1H), 2.25 - 1.91 (m, 1H), 1.38 - 1.23 (m, 1H). Example 131 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-[2-(4- methylsulfonylpiperazin-1-yl)ethyl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 130 by using 1-mesylpiperazine instead of (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrr ole in step two. LCMS (M+H ⁺ ) 797. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.58 (s, 1H), 8.25 (s, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.71 - 7.59 (m, 1H), 7.55 - 7.46 (m, 2H), 7.34 - 7.26 (m, 1H), 7.25 - 7.17 (m, 1H), 7.06 - 6.99 (m, 1H), 6.90 - 6.83 (m, 1H), 5.53 - 5.45 (m, 1H), 5.43 - 5.31 (m, 1H), 4.79 - 4.75 (m, 1H), 4.64 - 4.55 (m, 1H), 4.40 - 4.26 (m, 1H), 4.14 - 4.01 (m, 2H), 3.62 - 3.44 (m, 8H), 3.39 - 3.32 (m, 3H), 3.05 (s, 3H), 3.04 - 2.91 (m, 2H), 2.91 - 2.86 (m, 3H), 2.80 - 2.71 (m, 1H), 2.66 - 2.55 (m, 1H), 2.14 - 2.03 (m, 1H), 1.43 - 1.28 (m, 1H). Example 132 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-[2-(1,2,4- 2,6 8,11 20,24 triazol-1-yl)ethyl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1 .1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 130 by using 1,2,4-triazole instead of (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrr ole in step two. LCMS (M+H ⁺ ): 702. Example 133 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-18-(2- 2,6 8,11 20,24 pyrazol-1-ylethyl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 130 by using 1H-pyrazole instead of (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrr ole in step two. LCMS (M+H ⁺ ) 701. Example 135 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-23-fluoro-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-6-fluoro-benzimidazol-1-yl)propyl]- N-methyl-carbamate (compound 135b) To a flask was added tert-butyl N-[3-(7-bromo-6-fluoro-benzimidazol-1- yl)propyl]carbamate (compound 135a, 520 mg, 1.4 mmol, the synthesis refers to the intermediate 15A-c by using 2-bromo-1,3-difluoro-4-nitro-benzene instead of 1-bromo-2- fluoro-3-nitro-benzene in step 1), MeI (594.86 mg, 262.05 μL, 4.19 mmol) and DMF (6 mL). The solution was stirred at r.t. and then NaH (223.5 mg, 5.59 mmol) was added in one portion. After being stirred at rt for 1 hour, the mixture was poured into 50 mL water and then extracted with 15 mL EA for three times. The organic layer was dried and concentrated, the crude product was purified by silica gel to give compound 135b (574 mg), LCMS (M+H ⁺ ): 386. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(methyl)amino]propyl]-5-fluoro-benzimidazol-4- yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 135c) To a microwave tube was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (761.82 mg, 3 mmol), O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine- 1,2-dicarboxylate (compound B10, 651.4 mg, 1.5 mmol), potassium acetate (294.4 mg, 3 mmol) and 1,4-dioxane (7 mL). The suspension was bubbled with N ₂ for 5 mins and then dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-3-yl)phos phane (143.0 mg, 0.300 mmol) & Pd(OAc) ₂ (33.7 mg, 0.150 mmol) were added. After being heated 85 °C for 16 hrs, to the mixture was added compound 135b (270.0 mg, 0.7 mmol), K ₂ CO ₃ (193.5 mg, 1.4 mmol), 1,4- dioxane (2 mL) and water (1 mL), the suspension was bubbled with N ₂ for 5 mins and then PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (51.2 mg, 0.070 mmol) was added. The mixture was stirred at 100 °C for 4 hrs, and then diluted with water, extracted with EA. The organic layer was dried and concentrated, the crude product was purified by silica gel to give compound 135c (320 mg), LCMS (M+H ⁺ ): 661. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-1-benzyloxycarbonyl-4-[[6-[5- fluoro-3-[3-(methylamino)propyl]benzimidazol-4-yl]-2-pyridyl ]amino]pyrrolidine-2- carboxylic acid (compound 135d) A mixture of compound 135c (320 mg, 0.315 mmol) and LiOH (1.39 mL, 2 N ) was stirred at r.t. for 2 hrs. The mixture was diluted with water and adjusted pH to 4, then it was extracted with DCM twice. The organic layer was dried and concentrated, the residue was dissolved in DCM (2 mL) and TFA (2 mL). After being stirred at r.t. for 1 hr, the mixture was concentrated and the residue was purified via prep-HPLC to give compound 135d (110 mg), LCMS (M+H ⁺ ): 547. Step 4: preparation of benzyl (8S,11S)-23-fluoro-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 135e) To a solution of HATU (126.6 mg, 0.333 mmol), DIEA (129.1 mg, 174 μL, 0.999 mmol) in DMF (2 mL) and acetonitrile (30 mL) was added another suspension of compound 135d (110 mg, 0.167 mmol) in DMF (2 mL) and acetonitrile (30 mL) dropwise in 1 hr. Then the mixture was concentrated, the residue was purified by silica gel to give compound 135e (120 mg), LCMS (M+H ⁺ ): 529. Step 5: preparation of (8S,11S)-23-fluoro-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 135f) To a 100 mL flask was added compound 135e (80 mg, 0.151 mmol), palladium hydroxide (20% on carbon with 50% H ₂ O) (16 mg, 0.023 mmol) and MeOH (20 mL), the suspension was purged with H ₂ for 3 times. The mixture was heated to 65 °C and stirred for about 2 hrs. The mixture was filtered, the filtrate was concentrated to compound 135f (91 mg), LCMS (M+H ⁺ ): 395. Step 6: preparation of (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8- 2,6 8,11 20,24 yl]-23-fluoro-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15 .6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 135) To a microwave tube was added compound 135f (19.72 mg, 0.050 mmol), intermediate C3 (17.27 mg, 0.065 mmol), cesium fluoride (15.19 mg, 0.100 mmol), DIPEA (12.92 mg, 17.47 μL, 0.100 mmol) and DMSO (1 mL). The brown suspension was heated to 90 °C and stirred for about 16 hrs. The mixture was concentrated, the residue was purified via prep-HPLC to give Example 135 (8.7 mg), LCMS (M+H ⁺ ): 624. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.30 (s, 1H), 8.24 - 7.91 (m, 1H), 7.78 - 7.69 (m, 2H), 7.67 (dd, J = 4.8, 8.9 Hz, 1H), 7.53 (ddd, J = 2.4, 9.4, 10.5 Hz, 1H), 7.32 (dt, J = 2.4, 8.3 Hz, 1H), 7.24 (br s, 1H), 7.18 - 7.03 (m, 2H), 6.81 (dd, J = 1.4, 7.3 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.63 - 5.24 (m, 2H), 4.69 - 4.44 (m, 1H), 4.42 - 4.07 (m, 2H), 4.04 - 3.92 (m, 1H), 3.70 - 3.55 (m, 1H), 3.31 - 3.23 (m, 2H), 3.01 (br s, 3H), 2.84 - 2.73 (m, 1H), 2.45 - 2.23 (m, 2H), 1.45 - 1.31 (m, 1H). Example 139 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl- 2,6 8,11 22,26 7,10,13,19,21,28-hexazapentacyclo[17.6.1.1 .1 .0 ]octacosa- 1(25),2(28),3,5,20,22(26),23-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using Intermediate A27 instead of Intermediate A12. Example 139 was obtained. LCMS (M+H ⁺ ): 635. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.56 - 8.16 (m, 3H), 7.78 - 7.57 (m, 3H), 7.36 - 7.13 (m, 4H), 6.88 (d, J = 7.3 Hz, 1H), 6.77 - 6.65 (m, 1H), 5.60 - 5.31 (m, 1H), 4.73 - 4.46 (m, 3H), 4.38 - 3.88 (m, 5H), 3.27 - 3.14 (m, 3H), 2.81 - 2.65 (m, 2H), 1.88 - 1.44 (m, 5H). Example 141 (8S,11S)-10-[1-(2,4-difluorophenyl)-3-methyl-pyrazolo[3,4-d] pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: A mixture of Intermediate C65 (26 mg, 0.1 mmol), benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (53 mg, 0.12 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (23 mg, 0.15 mmol ) in anhydrous N,N-dimethylformamide (1 mL) was stirred at room temperature for 15 mins, then compound 12d (38 mg, 0.1 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was directly purified by prep-HPLC to afford Example 141 (19 mg). LCMS (M+H ⁺ ): 621. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.44 - 8.09 (m, 2H), 7.87 - 7.68 (m, 2H), 7.65 - 7.56 (m, 1H), 7.40 - 7.30 (m, 2H), 7.29 - 7.22 (m, 1H), 7.17 (br t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.71 (br d, J = 8.4 Hz, 1H), 5.62 (br d, J = 6.1 Hz, 1H), 5.00 - 4.75 (m, 1H), 4.72 - 4.49 (m, 2H), 4.35 - 4.06 (m, 3H), 3.05 (s, 3H), 2.94 - 2.71 (m, 4H), 2.67 - 2.44 (m, 2H), 2.23 - 2.06 (m, 1H), 1.53 (br s, 1H). Example 146 (8S,11S)-10-[1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrazolo[ 3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 146 was prepared in analogy to the preparation of Example 12 by using intermediate C69 instead of intermediate C2., LCMS (M+H ⁺ ): 657. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.58 (s, 1H), 8.34 - 8.17 (m, 2H), 8.01 - 7.91 (m, 1H), 7.82 - 7.72 (m, 3H), 7.71 - 7.64 (m, 1H), 7.30 - 7.18 (m, 2H), 6.98 - 6.87 (m, 1H), 6.76 - 6.63 (m, 1H), 5.65 - 5.34 (m, 2H), 5.00 - 4.77 (m, 1H), 4.74 - 4.57 (m, 1H), 4.54 - 4.41 (m, 1H), 4.26 - 4.15 (m, 1H), 4.09 - 3.93 (m, 2H), 3.05 - 2.88 (m, 3H), 2.86 - 2.74 (m, 1H), 2.39 - 2.30 (m, 1H), 2.07 - 1.90 (m, 1H), 1.89 - 1.18 (m, 2H). Example 147 5-fluoro-2-[4-[(8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-13-methyl-10-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 147-a) A mixture of (8S,11S)-13-methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 12d, 92 mg, 0.25 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (38 mg, 0.25 mmol, ) and N,N-diisopropylethylamine (95 mg, 0.73 mmol) in anhydrous acetonitrile and N,N- dimethylformamide (1 mL) was stirred at room temperature for 1 h. The reaction mixture was partitioned between water and EtOAc, the organic layer was separated and the aqueous layer was further extracted with EtOAc for three times. The organic layer was washed with brine, dried and concentrated. The residue was purified by precipitation from EtOAc/PE, the solid was collected to afford compound 147-a (65 mg). LCMS (M+H) ⁺ : 495. Step 2: preparation of 5-fluoro-2-[4-[(8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile (Example 147) A mixture of (8S,11S)-13-methyl-10-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one (compound 147-a, 65 mg, 0.13 mmol), 2,5-difluorobenzonitrile (55 mg, 0.39 mmol) and cesium carbonate (86 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL) was heated at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to afford Example 147 (10 mg). LCMS (M+H) ⁺ : 614. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.61 - 8.20 (m, 3H), 7.92 - 7.77 (m, 3H), 7.75 - 7.64 (m, 2H), 7.39 - 7.26 (m, 2H), 7.04 - 6.94 (m, 1H), 6.77 - 6.69 (m, 1H), 5.55 - 5.42 (m, 1H), 4.62 - 4.53 (m, 2H), 4.34 - 4.08 (m, 3H), 3.15 - 3.03 (m, 3H), 2.89 (td, J = 6.8, 13.7 Hz, 1H), 2.69 - 2.50 (m, 2H), 2.16 - 1.97 (m, 2H), 1.65 - 1.54 (m, 1H). Example 148 5-fluoro-2-[4-[(8S,11S)-13-methyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]benzoic acid The title compound was prepared in analogy to the preparation of Example 12 by using Intermediate C66 instead of Intermediate C2. Example 148 was obtained. LCMS (M+H ⁺ ): 633. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.52 - 8.14 (m, 3H), 7.86 - 7.73 (m, 3H), 7.68 - 7.61 (m, 1H), 7.53 (dt, J = 2.6, 8.2 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.01 (d, J = 7.5 Hz, 1H), 6.79 - 6.71 (m, 1H), 5.53 - 5.40 (m, 1H), 4.78 - 4.69 (m, 1H), 4.60 - 4.26 (m, 1H), 4.38 - 4.26 (m, 1H), 4.24 - 4.08 (m, 2H), 3.18 - 3.01 (m, 3H), 2.89 (br dd, J = 7.6, 14.0 Hz, 1H), 2.69 - 2.52 (m, 2H), 2.16 - 1.96 (m, 2H), 1.65 - 1.44 (m, 1H). Example 150 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-ethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using compound 150b instead of intermediate A11. LCMS (M+H ⁺ ): 621. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.52 (s, 1H), 8.28 - 8.18 (m, 2H), 7.83 - 7.76 (m, 1H), 7.71 (br d, J = 7.5 Hz, 1H), 7.66 (dt, J = 6.0, 8.6 Hz, 1H), 7.41 - 7.24 (m, 4H), 7.19 (br t, J = 8.3 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.51 (br d, J = 6.2 Hz, 1H), 5.04 - 4.93 (m, 1H), 4.78 - 4.66 (m, 1H), 4.60 - 4.49 (m, 1H), 4.34 - 4.27 (m, 1H), 4.18 - 4.08 (m, 1H), 4.02 - 3.87 (m, 1H), 3.45 - 3.34 (m, 2H), 2.98 - 2.83 (m, 1H), 2.62 - 2.55 (m, 1H), 2.23 - 2.06 (m, 1H), 1.55 - 1.38 (m, 1H), 1.15 - 0.99 (m, 3H). The compound 150b was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-ethyl- carbamate (compound 150a) To a flask was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (compound A15-c, 4 g, 11.29 mmol), ethyl iodide (4.4 g, 2.28 mL, 28.23 mmol) and DMF (40 mL), the solution was stirred at r.t. and then NaH (903.26 mg, 22.58 mmol) was added in one portion. After being stirred at rt for 1 h, the mixture was poured into water and then extracted with EA for three times. The organic layer was dried and concentrated, the crude product was purified by silica gel to give compound 150a (3.85 g), LCMS (M+H ⁺ ): 383. Step 2: preparation of tert-butyl N-ethyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (compound 150b) To a seal tube was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-ethyl- carbamate (compound 150a, 1.47 g, 3.85 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.96 g, 7.7 mmol), potassium acetate (755.7 mg, 7.7 mmol), DMSO (30 mL). The solution was bubbled with N ₂ for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (270.23 mg, 0.385 mmol) & Butyldi-1-adamantylphosphine (276.08 mg, 0.770 mmol) were added. The tube was heated to 130 °C and stirred for about 16 hrs. The mixture was diluted with 200 mL water and then it was extracted with 50 mL EA for 3 times. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 150b (1.42g), LCMS (M+H ⁺ ): 430. Example 151 (8S,11S)-13-ethyl-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-4-yl]- 2,6 8,11 20 24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 12 by using compound 150b instead of intermediate A11 in step 1 and using intermediate C11 instead of intermediate C2 in step 5. LCMS (M+H ⁺ ) 633. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.46 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.82 - 7.77 (m, 1H), 7.73 - 7.68 (m, 1H), 7.46 - 7.41 (m, 1H), 7.39 - 7.34 (m, 1H), 7.34 - 7.29 (m, 1H), 7.05 (dd, J = 2.4, 10.7 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.87 (dt, J = 2.4, 8.3 Hz, 1H), 6.75 - 6.69 (m, 1H), 5.50 (br d, J = 7.3 Hz, 1H), 5.04 - 4.95 (m, 1H), 4.74 - 4.67 (m, 1H), 4.56 - 4.48 (m, 1H), 4.29 (br d, J = 11.3 Hz, 1H), 4.18 - 4.09 (m, 1H), 4.00 - 3.89 (m, 1H), 3.75 (s, 3H), 3.44 - 3.33 (m, 2H), 3.03 - 2.89 (m, 1H), 2.63 - 2.50 (m, 2H), 2.20 - 2.08 (m, 1H), 1.53 - 1.41 (m, 1H), 1.11 (br t, J = 6.9 Hz, 3H). Example 153 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(2-methoxyethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using compound 153b instead of intermediate A11 in step 1. LCMS (M+H ⁺ ) 651. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 - 8.50 (m, 1H), 8.36 - 8.31 (m, 1H), 8.29 - 8.19 (m, 1H), 7.85 - 7.78 (m, 1H), 7.72 (br d, J = 7.6 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.40 - 7.31 (m, 2H), 7.31 - 7.25 (m, 1H), 7.23 - 7.14 (m, 1H), 7.00 (dd, J = 2.4, 7.3 Hz, 1H), 6.77 - 6.68 (m, 1H), 5.62 - 5.42 (m, 1H), 5.15 - 4.95 (m, 1H), 4.74 - 4.67 (m, 1H), 4.58 - 4.50 (m, 1H), 4.36 - 4.26 (m, 1H), 4.25 - 4.10 (m, 1H), 4.04 - 3.80 (m, 1H), 3.76 - 3.57 (m, 1H), 3.55 - 3.38 (m, 2H), 3.38 (s, 1H), 3.18 (s, 2H), 3.17 - 3.01 (m, 1H), 2.99 - 2.78 (m, 1H), 2.78 - 2.46 (m, 1H), 2.32 - 1.95 (m, 1H), 1.60 - 1.34 (m, 1H). The compound 153b was prepared according to the following scheme: To a tube was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-(2- methoxyethyl)carbamate (compound 153a, 720 mg, 1.75 mmol, the synthesis refer to the preparation of compound 4f by using 2-methoxyethanamine instead of 2-aminoethan-1-ol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.1 g, 4.33 mmol), potassium acetate (343 mg, 3.49 mmol), DMSO (15 mL). The mixture was bubbled with N ₂ for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (123 mg, 175 μmol) and butyldi-1- adamantylphosphine (125 mg, 349 μmol) were added. After being heated to 130 °C for 5 hrs, the mixture was diluted with water and extracted with EA for 3 times. The organic layer was dried over and concentrated, the residue was purified by silica gel to give compound 153b (540 mg), LCMS (M+H ⁺ ): 460. Example 155 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-(2-morpholinoethyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 12 by using compound 155b instead of intermediate A11 in step 1 and intermediate C3 instead of intermediate C2 in step 5. LCMS (M+H ⁺ ) 705. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.23 (s, 1H), 8.12 - 7.91 (m, 1H), 7.83 - 7.75 (m, 1H), 7.73 - 7.64 (m, 2H), 7.38 - 7.34 (m, 1H), 7.34 - 7.28 (m, 1H), 7.28 - 7.17 (m, 3H), 7.09 (br d, J = 4.2 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 5.47 (br s, 1H), 5.12 - 4.94 (m, 1H), 4.68 - 4.50 (m, 2H), 4.44 - 4.27 (m, 1H), 4.23 - 4.12 (m, 1H), 4.07 - 3.89 (m, 1H), 3.73 - 3.60 (m, 4H), 3.54 - 3.44 (m, 2H), 3.00 (br dd, J = 6.8, 13.7 Hz, 1H), 2.70 - 2.42 (m, 7H), 2.39 - 2.24 (m, 1H), 2.16 - 2.00 (m, 1H), 1.53 - 1.39 (m, 1H). Compound 155b was prepared in analogy to the preparation of compound 153b by using compound 155a (the synthesis refer to the preparation of compound 4f by using 2- morpholinoethanamine instead of 2-aminoethan-1-ol) instead of compound 153a according to the following scheme. LCMS (M+H ⁺ ): 515. Example 156 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3-hydroxypropyl)- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-[3-[tert- butyl(dimethyl)silyl]oxypropyl]carbamate (compound 156a) To a flask was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (A15-c, 2.3 g, 6.49 mmol), (3-bromopropoxy)(tert-butyl)dimethylsilane (3.29 g, 13 mmol) and DMF (15 mL), the solution was stirred at r.t. and then NaH (623 mg, 26 mmol) was added in one portion. The mixture was poured into 50 mL water and then extracted with 15 mL EA for three times. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 156a (2.7 g). LCMS (M+H ⁺ ): 484. Step 2: preparation of tert-butyl N-(3-hydroxypropyl)-N-[3-[7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (compound 156b) To a tube was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-[3-[tert- butyl(dimethyl)silyl]oxypropyl]carbamate (compound 156a, 1 g, 1.9 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (964.49 mg, 3.8 mmol), potassium acetate (372.75 mg, 3.8 mmol), DMSO (15 mL). The mixture was bubbled with N ₂ for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (133.29 mg, 0.190 mmol) & Butyldi-1- adamantylphosphine (136.18 mg, 0.380 mmol) were added. After being heated to 130 °C for 4 hrs, the mixture was diluted with water and then it was extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 156b (364 mg) and TBS-compound 156b (470 mg). LCMS (M+H ⁺ ): 460 and LCMS (M+H ⁺ ): 574. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(3-hydroxypropyl)amino]propyl]benzimidazol-4-y l]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 156c) To a flask was added K ₂ CO ₃ (782.19 mg, 5.66 mmol), compound 156b (1.3 g, 2.83 mmol), Intermediate B10 (1.23 g, 2.83 mmol), 1,4-dioxane (10 mL) and water (0.200 mL), the suspension was bubbled with N ₂ for 5 mins and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (207.06 mg, 0.283 mmol) was added. After being heated to 90 °C for 3 hrs, then the mixture was diluted water and extracted with EA. The organic layer was dried concentrated the residue was purified by silica gel to give compound 156c (1 g). LCMS (M+H ⁺ ): 687. Step 4: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[3-(3- hydroxypropylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino ]pyrrolidine-2-carboxylic acid (compound 156d) A mixture of compound 156c (500 mg, 0.728 mmol) and hydroxylithium (3 mL, 2 N) in THF (1.5 mL) and methanol (1.5 mL) was stirred at rt for 2 hrs. The mixture was diluted with 5 mL water and adjusted pH to about 4, then it was extracted with 100 mL DCM twice. The organic layer was dried and concentrated, the residue was dissolved in 1,4-dioxane (1 mL), and then it was treated with 4 N HCl in dioxane) (1 mL). The mixture was stirred at r.t. for 4 hrs and then concentrated to give compound 156d (500 mg). LCMS (M+H ⁺ ): 573. Step 5: preparation of benzyl (8S,11S)-13-(3-hydroxypropyl)-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 156e) To a solution of HATU (557.49 mg, 1.47 mmol), DIEA (568.47 mg, 768.2 μL, 4.4 mmol), in DMF (20 mL) and acetonitrile (130 mL) was added another suspension of compound 156d (500 mg, 0.733 mmol) in DMF (20 mL) and acetonitrile (130 mL) dropwise in 2 hrs. The mixture was concentrated, the residue was purified by silica gel to give compound 156e (270 mg). LCMS (M+H ⁺ ): 555. Step 6: preparation of (8S,11S)-13-(3-hydroxypropyl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 156f) To a 100 mL flask was added (8S,11S)-13-(3-hydroxypropyl)-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (156e, 270 mg, 0.487 mmol), palladium hydroxide on carbon (49.48 mg, 0.352 mmol) and MeOH (40 mL), the suspension was purged with H ₂ for 5 times. The mixture was heated to 65 °C and stirred for about 4 hrs. The mixture was filtered, the filtrate was concentrated to give compound 156e (400 mg). LCMS (M+H ⁺ ): 421. Step 7: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- 2,6 8,11 20,24 yl]-13-(3-hydroxypropyl)-7,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ] hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 156) To a microwave tube was added (8S,11S)-13-(3-hydroxypropyl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (156f, 126.15 mg, 0.300 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2, 103.99 mg, 0.390 mmol), DIPEA (77.55 mg, 104.79 μL, 0.600 mmol), acetonitrile (5 mL), a yellow solution formed. The mixture was heated to 86 °C and stirred for about 2 hrs. The mixture was concentrated to give an oil and then purified via flash column (EA/PE=0~100% & MeOH/EA=10% & MeOH/DCM=20%), the elution was concentrated to give Example 156 (6.6 mg). LCMS (M+H ⁺ ): 651. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.61 (s, 1H), 8.53 - 8.42 (m, 1H), 8.23 (s, 1H), 7.81 - 7.68 (m, 3H), 7.60 (ddd, J = 2.8, 9.1, 10.3 Hz, 1H), 7.39 - 7.26 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 5.58 (br d, J = 8.4 Hz, 1H), 5.44 (d, J = 8.6 Hz, 1H), 4.91 (dt, J = 4.6, 12.6 Hz, 1H), 4.73 - 4.65 (m, 1H), 4.64 - 4.44 (m, 2H), 4.22 (br d, J = 11.7 Hz, 1H), 4.18 - 4.03 (m, 2H), 3.85 - 3.72 (m, 2H), 3.49 - 3.45 (m, 2H), 2.94 - 2.83 (m, 1H), 2.40 - 2.34 (m, 1H), 2.11 - 2.00 (m, 1H), 1.84 - 1.64 (m, 1H), 1.63 - 1.42 (m, 1H), 1.40 - 1.27 (m, 1H), 1.27 - 1.10 (m, 1H). Example 157 and Example 158 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(tetrazol-2- 2,6 8,11 20,24 yl)propyl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-[3-(tetrazo l-1-yl)propyl]- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme: Step 1: preparation of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,17,19, 26-hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 157a) To a tube was added (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]- 2,6 8,11 20,24 13-(3-hydroxypropyl)-7,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 156, 169 mg, 0.260 mmol), DIPEA (67.14 mg, 90.73 μL, 0.519 mmol) and DCM (2 mL). Then SOCl ₂ (308.97 mg, 189.55 μL, 2.6 mmol) was added and the mixture kept stirring at r.t. for 5 hrs. The mixture was quenched with water and then it was adjusted pH to about 7, the mixture was extracted with 10 mL DCM twice, the organic layer was dried and concentrated to give compound 157a (65 mg). LCMS (M+H ⁺ ): 669. Step 2: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- yl]-13-[3-(tetrazol-2-yl)propyl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(tetrazol-1- 2,6 8,11 20,24 yl)propyl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 157 & 158) To a tube was added (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,17,19, 26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (157a, 33. mg, 0.049 mmol), 2H-tetrazole (6.91 mg, 0.099 mmol), DIEA (19.12 mg, 25.84 μL, 0.148 mmol), sodium iodide (14.78 mg, 0.099 mmol), and DMF (0.262 mL). The mixture was heated to 70 °C for 16 hrs and then the reaction mixture was purified by prep-HPLC to give Example 157 (faster eluted) and Example 158 (slower eluted). Example 157 (5.6 mg), LCMS (M+H ⁺ ): 703. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.45 (s, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.76 - 7.66 (m, 3H), 7.64 - 7.54 (m, 1H), 7.36 - 7.29 (m, 1H), 7.29 - 7.20 (m, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.57 (d, J = 8.4 Hz, 1H), 5.35 (d, J = 8.8 Hz, 1H), 4.92 - 4.80 (m, 1H), 4.71 - 4.63 (m, 1H), 4.62 - 4.46 (m, 3H), 4.45 - 4.35 (m, 1H), 4.22 (br d, J = 11.5 Hz, 1H), 4.11 - 3.98 (m, 1H), 3.78 (br dd, J = 10.2, 13.1 Hz, 1H), 2.87 (br dd, J = 7.9, 13.0 Hz, 1H), 2.40 - 2.34 (m, 1H), 2.22 - 2.13 (m, 2H), 2.05 - 1.93 (m, 1H), 1.91 - 1.80 (m, 1H), 1.38 - 1.22 (m, 1H). Example 158 (10.6 mg), LCMS (M+H ⁺ ): 703. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.01 (s, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.77 - 7.66 (m, 3H), 7.59 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.37 - 7.29 (m, 1H), 7.29 - 7.20 (m, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.57 (br d, J = 8.8 Hz, 1H), 5.35 (br d, J = 8.9 Hz, 1H), 4.89 - 4.74 (m, 3H), 4.70 - 4.62 (m, 1H), 4.52 - 4.44 (m, 1H), 4.22 (br d, J = 11.5 Hz, 1H), 4.16 - 4.09 (m, 1H), 4.08 - 4.02 (m, 1H), 3.87 - 3.80 (m, 1H), 2.91 (br dd, J = 7.6, 13.4 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.30 - 2.22 (m, 1H), 2.19 (br d, J = 13.3 Hz, 1H), 2.06 - 1.90 (m, 2H), 1.39 - 1.24 (m, 1H). Example 159 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-[3-(4- methylsulfonylpiperazin-1-yl)propyl]-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 157 by using 1-methylsulfonylpiperazine instead of 2H-tetrazole in step 2. LCMS (M+H ⁺ ): 797, ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.83 - 7.75 (m, 1H), 7.71 (dd, J = 1.3, 7.8 Hz, 1H), 7.66 (dt, J = 5.8, 8.6 Hz, 1H), 7.37 - 7.34 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.23 - 7.16 (m, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.61 (br d, J = 7.9 Hz, 1H), 4.77 - 4.71 (m, 1H), 4.64 - 4.49 (m, 6H), 4.31 (d, J = 11.4 Hz, 1H), 4.19 - 4.07 (m, 1H), 3.95 (dd, J = 8.9, 14.2 Hz, 1H), 3.52 - 3.41 (m, 1H), 3.28 - 3.17 (m, 4H), 3.01 (br dd, J = 7.3, 13.9 Hz, 1H), 2.83 (s, 3H), 2.65 - 2.48 (m, 6H), 2.48 - 2.38 (m, 1H), 2.24 - 1.78 (m, 1H), 1.70 - 1.39 (m, 1H). Example 161 and Example 162 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-(2- hydroxyethoxy)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-(2- hydroxyethoxy)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-[2- [tert-butyl(dimethyl)silyl]oxyethoxy]propyl]-N-methyl-carbam ate (compound 161a) To a mixture of intermediate A10-g (2.5 g, 6.28 mmol, the synthesis refer to intermediate A7-g) and (2-bromoethoxy)-tert-butyldimethylsilane (3 g, 12.55 mmol) in dry DMF(20 mL) was added NaH (502 mg, 12.55 mmol) at 0 °C in portions. The mixture was stirred at rt for 1 hour. The mixture was poured into 100 mL water and extracted with 100 mL EA. The organic layer was dried and concentrated; the crude oil was purified by silica gel to give compound 161a (1.5 g). LCMS (M+H ⁺ ): 556. Step 2: preparation of tert-butyl N-[2-(2-hydroxyethoxy)-3-[2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl ]-N-methyl-carbamate (compound 161b) A mixture of compound 161a (1.5 g, 1.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (2.05 g, 8.08 mmol), potassium acetate (397 mg, 4 mmol) in DMSO (35 mL) was bubbled with N ₂ for 5 mins. Then Pd(PPh ₃ ) ₂ Cl ₂ (94.6 mg, 0.135 mmol) and Butyl di-1- adamantylphosphine (96.6 mg, 0.269 mmol) were added and stirred at 130 °C for about 4 hours. The mixture was diluted with water and extracted with EA. The organic layer was dried and concentrated to give crude compound 161b (1.72 g). LCMS (M+H ⁺ ): 490. Step 3: preparation of [3-[2-(2-hydroxyethoxy)-3-(methylamino)propyl]-2-methyl- benzimidazol-4-yl]boronic acid (compound 161c) A mixture of compound 161b (1.72 g, 1.53 mmol) in HCl in Dioxane (4 M, 7.66 mL, 30.65 mmol) and DCM (15 mL) was stirred at rt for 2 hours. Then the reaction was concentrated, 1 M HCl (10 mL) was added, the aqueous phase was washed with EA and then lyophilized to give compound 161c (1 g). LCMS (M+H ⁺ ): 308. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-[ 2- (2-hydroxyethoxy)-3-(methylamino)propyl]-2-methyl-benzimidaz ol-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 161d) A mixture of K ₂ CO ₃ (6.56 g, 47.49 mmol), compound 161c (1.17 g, 3.8 mmol), intermediate B8 (4.75 g, 9.5 mmol) and PdCl ₂ (DPPF)DCM (775.7 mg, 0.950 mmol) in Dioxane/ H ₂ O (10:1, 50 mL) was stirred at 90 °C for 2 hours. Then mixture was filtered and concentrated, the residue was dissolved in THF/MeOH (2:1, 10 mL), 2 M LiOH (2.93 mL, 5.86 mmol) was added and stirred at rt for 4 hours. The reaction was adjusted to pH=5, and then the mixture was concentrated to remove most organic solvent, the residue was purified by flash preparation (MeCN/ TFA in water) to give compound 161d (1 g). LCMS (M+H ⁺ ): 569. Step 5: preparation of ditert-butyl (8S,11S,15R)-15-(2-hydroxyethoxy)-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-7,10-dicarboxylate and ditert-butyl (8S,11S,15S)-15- (2-hydroxyethoxy)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-7,10- dicarboxylate (compound 161e-1 & 161e-2) To a mixture of DIPEA (1.16 g, 1.57 mL, 8.97 mmol) and HATU (1.36 g, 3.59 mmol) in acetonitrile (90 mL) was added a solution of compound 161d (1.2 g, 0.897 mmol) in acetonitrile (90 mL) dropwise in 2 hours. Then the reaction was stirred at rt for 1 hour. The reaction was concentrated; the residue was purified by silica gel and SFC to give compound 161e-1 (40 mg, faster eluted) and 161e-2 (40 mg, slower eluted). LCMS (M+H ⁺ ): 551 SFC condition: instrument: SFC 80. Column: IA, 250×30 mm I.D., 5μm. Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O). Gradient: B 25%. Flow rate: 60 mL /min. Backpressure: 100bar. Step 6: preparation of (8S,11S,15R)-15-(2-hydroxyethoxy)-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-15-(2-hydroxyethoxy)-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 161f-1 & 161f-2) A mixture of compound 161e-1 (40 mg, 0.061 mmol) and 4 M HCl in dioxane (1 mL) in DCM (2 mL) was stirred at rt for 4 hours, then the reaction was concentrated to give compound 161f-1 (40 mg). LCMS (M+H ⁺ ): 451. A mixture of compound 161e-2 (40 mg, 0.061 mmol ) and 4 M HCl in dioxane (1 mL) in DCM (2 mL) was stirred at rt for 4 hours, then the reaction was concentrated to give compound 161f-2 (40 mg). LCMS (M+H ⁺ ): 451. Step 7: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-(2-hydroxyethoxy)-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-(2- hydroxyethoxy)-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 161 & 162) A mixture of compound 161f-1 (40 mg, 0.09 mmol), intermediate C2 (24 mg, 0.09 mmol) and DIPEA (57 mg, 0.44 mmol ) in acetonitrile (2 mL) was stirred at 80 °C for 2 hours, then the reaction was concentrated, the residue was purified by HPLC to give Example 161 (15 mg). LCMS (M+H ⁺ ): 681. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.59 - 8.36 (m, 1H), 8.27 - 7.80 (m, 2H), 7.75 - 7.61 (m, 2H), 7.44 - 7.18 (m, 4H), 7.18 - 7.08 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.86 - 5.68 (m, 1H), 5.54 - 5.38 (m, 1H), 4.72 - 4.52 (m, 2H), 4.39 - 4.29 (m, 1H), 4.25 - 4.14 (m, 1H), 4.05 - 3.99 (m, 2H), 3.06 (s, 6H), 3.00 - 2.93 (m, 1H), 2.79 - 2.59 (m, 6H). A mixture of compound 161f-2 (40 mg, 0.09 mmol), intermediate C2 (24 mg, 0.09 mmol) and DIPEA (57 mg, 0.44 mmol ) in acetonitrile (2 mL) was stirred at 80 °C for 2 hours, then the reaction was concentrated, the residue was purified by HPLC to give Example 162 (15 mg). LCMS (M+H ⁺ ): 681. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.50 - 8.23 (m, 1H), 8.17 - 7.64 (m, 2H), 7.62 - 7.42 (m, 2H), 7.26 - 7.04 (m, 4H), 6.80 (br s, 1H), 6.65 - 6.54 (m, 1H), 5.48 - 5.31 (m, 1H), 4.68 - 4.62 (m, 1H), 4.53 - 4.44 (m, 1H), 4.31 - 4.17 (m, 1H), 4.15 - 3.98 (m, 1H), 3.96 - 3.75 (m, 2H), 3.11 - 2.98 (m, 7H), 2.94 - 2.84 (m, 1H), 2.76 - 2.58 (m, 2H), 2.56 - 2.44 (m, 4H). Example 163 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,18-dimethyl-15- 2,6 8,11 20,24 (2-morpholinoethoxy)-7,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: To a mixture of Example 161 (15 mg, 0.022 mmol) and DIPEA (14 mg, 0.110 mmol) in DCM (2 mL) was added methanesulfonic anhydride (7.7 mg, 0.044 mmol) and stirred at rt for 1 hour. Then the reaction was concentrated, the residue was dissolved in acetonitrile (2 mL), DIPEA (14 mg, 0.11 mmol), sodium iodide (3 mg, 0.02 mmol) and morpholine (19 mg, 0.220 mmol) was added and stirred at 80 °C for 30 mins. The reaction was concentrated and the residue was purified by HPLC to Example 163 (4 mg). LCMS (M+H ⁺ ): 750. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 - 8.23 (m, 1H), 8.18 - 7.67 (m, 2H), 7.62 - 7.47 (m, 2H), 7.33 - 7.06 (m, 4H), 7.04 - 6.95 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.76 - 5.51 (m, 1H), 5.44 - 5.23 (m, 1H), 4.63 - 4.51 (m, 1H), 4.46 - 4.36 (m, 1H), 4.28 - 4.02 (m, 2H), 3.86 (br dd, J = 9.2, 14.3 Hz, 1H), 3.51 - 3.23 (m, 5H), 3.09 - 2.78 (m, 5H), 2.73 - 2.64 (m, 1H), 2.60 - 2.35 (m, 5H), 2.10 - 1.98 (m, 1H), 1.97 - 1.82 (m, 3H), 1.80 - 1.70 (m, 2H). Example 164 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,18-dimethyl-15- 2,6 8,11 20,24 (2-morpholinoethoxy)-7,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of example 163 by using example 162 instead of example 161. LCMS (M+H ⁺ ): 750. ¹ H NMR (500 MHz, METHANOL- d ₄ ) δ = 8.49 - 8.22 (m, 1H), 8.18 - 7.62 (m, 2H), 7.50 (br d, J = 9.0 Hz, 2H), 7.27 - 7.04 (m, 4H), 6.82 (br s, 1H), 6.61 (br d, J = 8.4 Hz, 1H), 5.53 - 5.26 (m, 1H), 4.68 - 4.60 (m, 1H), 4.52 - 4.42 (m, 1H), 4.29 - 4.17 (m, 1H), 4.01 (br d, J = 14.5 Hz, 3H), 3.38 - 3.25 (m, 5H), 3.13 - 2.82 (m, 6H), 2.66 - 2.41 (m, 5H), 2.03 - 1.80 (m, 6H). Example 170 (8S,11S)-18,22-dideuterio-10-[1-(2,4-difluorophenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13-methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 1-amino-3-(4-chloro-2-nitro-anilino)propan-2-ol (compound 170b) To a mixture of 5-chloro-2-fluoronitrobenzene (10.0 g, 56.97 mmol) and in acetonitrile (200 mL) was added 1,3-diamino-2-propanol (20.54 g, 227.87 mmol) slowly at 25 °C. After being stirred at 70 °C for 0.5 h, the mixture was filtered and concentrated to afford compound 170b (14 g). LCMS (M+H) ⁺ : 246. Step 2: preparation of tert-butyl N-[3-(4-chloro-2-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 170c) To a mixture of compound 170b (14 g, 57 mmol) and DIPEA (11 g, 85 mmol) in methanol (150 mL) was added di-t-butyldicarbonate (15 g, 69 mmol) slowly at 25 °C. After being stirred at 20 °C for 1 h, tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (60.0 mL, 284.95 mmol) was added and the mixture was stirred at 20 °C for another 1 h. Then the mixture was concentrated and the residue was purified by silica gel to give compound 170c (27 g). LCMS (M+H) ⁺ : 368. Step 3: preparation of tert-butyl N-[3-(2-bromo-4-chloro-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 170d) A mixture of compound 170c (27.0 g, 78.08 mmol) and NBS (15.29 g, 85.89 mmol) in acetonitrile (270 mL) was stirred at 85 °C for 12 h. Then the mixture was diluted with EA, washed with water and brine. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 170d (7.5 g), LCMS (M+H) ⁺ : 448. Step 4: preparation of tert-butyl N-[3-(2-amino-6-bromo-4-chloro-anilino)-2-hydroxy- propyl]carbamate (compound 170e) A mixture of compound 170d (7.0 g, 16.48 mmol) and Pt/C (1.4 g, 25 mmol) in EA (82.42 mL) was stirred for 2 h at 20 °C under H ₂ balloon. The mixture was filtered and the filtrate was concentrated to give compound 170e (7 g) LCMS (M+H) ⁺ : 396. Step 5-7: preparation of tert-butyl N-[3-[5-chloro-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (compound 170h) Compound 170h was prepared in analogy to the preparation of Intermediate A1 by using compound 170e instead of compound A1-c and trimethoxymethane instead of trimethyl orthoacetate. LCMS (M+H) ⁺ : 480. Step 8-11: preparation of tert-butyl (8S,11S)-22-chloro-15-methoxy-13-methyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 170l) Compound 170l was prepared in analogy to the preparation of compound 289c by using compound 170h instead of intermediate A12 and intermediate B8 instead of intermediate B1. LCMS (M+H) ⁺ : 541. Step 12: preparation of tert-butyl (8S,11S)-18,22-dideuterio-15-methoxy-13-methyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 170m) To a mixture of triethylamine (0.01 mL, 0.06 mmol) and compound 170l (20.0 mg, 0.04 mmol) in trideuterio(deuteriooxy)methane (2 mL) was added Pd/C (2 mg, washed with deuterium oxide) under N ₂ . The mixture was stirred at 20 °C for 4 h under deuterium balloon. Then the reaction mixture was filtered, the filtrate was concentrated to give compound 170m (14 mg). LCMS (M+H) ⁺ : 509. Step 13-14: preparation of (8S,11S)-18,22-dideuterio-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13- methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 170) Example 170 was prepared in analogy to the preparation of Example 289 by using compound 170m instead of compound 289c. LCMS (M+H) ⁺ : 639. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.45 - 9.28 (m, 0.5H), 8.60 - 8.22 (m, 2H), 7.94 - 7.60 (m, 4H), 7.35 - 7.27 (m, 1H), 7.24 - 7.04 (m, 2H), 6.79 (t, J = 8.4 Hz, 1H), 6.14 - 5.99 (m, 1H), 5.58 - 5.37 (m, 1H), 4.79 - 4.70 (m, 1H), 4.60 - 4.06 (m, 4H), 3.99 - 3.79 (m, 1H), 3.23 - 2.94 (m, 8H), 2.76 - 2.51 (m, 2H). Example 172 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-15-hydroxy-13- 2,6 8,11 20,24 methyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: To a flask was added ditert-butyl (8S,11S)-15-hydroxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-7,10-dicarboxylate (compound 192e, 30.0 mg, 0.05 mmol), DCM (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol), the mixture was stirred at r.t. for 1 hr. The mixture was concentrated to give an oil. The oil was dissolved in dimethyl sulfoxide (1 mL), and then 8- chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3, 19.9 mg, 0.075 mmol), DIPEA (25. mg, 35 μL, 0.200 mmol) and cesium fluoride (15.19 mg, 0.100 mmol) were added. The mixture was heated to 90 °C and stirred for about 16 hrs. The mixture was purified via prep- HPLC to give Example 172 (4.8 mg). LCMS (M+H ⁺ ): 622, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (s, 1H), 8.02 (s, 1H), 7.79 - 7.71 (m, 2H), 7.68 (dt, J = 1.5, 6.7 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.44 - 7.27 (m, 2H), 7.27 - 7.21 (m, 2H), 7.20 - 7.07 (m, 1H), 7.07 - 6.86 (m, 1H), 6.75 - 6.58 (m, 1H), 5.60 - 5.46 (m, 1H), 5.45 - 5.24 (m, 1H), 4.88 - 4.75 (m, 1H), 4.73 - 4.51 (m, 1H), 4.32 - 4.20 (m, 1H), 4.13 (br d, J = 14.9 Hz, 1H), 4.07 - 3.94 (m, 1H), 3.25 - 3.02 (m, 4H), 3.00 - 2.84 (m, 2H), 2.83 - 2.69 (m, 1H), 2.46 - 2.35 (m, 1H), 2.29 - 2.10 (m, 1H). Example 179 and Example 180 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13, 18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

Compound 179c (The compound was prepared in analogy to the preparation of compound 189c by using Intermediate B8 instead of Intermediate B1 in step 2)) was separated via SFC to give the compound 179c-1 and 179c-2. (SFC condition: Instrument: SFC 80; Column: IA, 250×30 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O); Gradient: B 35%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 35℃) Step 1: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 - 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 179 and Example 180) To a flask was added tert-butyl (8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-10-carboxylate (179c-1, 120 mg, 0.230 mmol), dichloromethane (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol), the yellow solution was stirred at r.t. for 1 hr. The mixture was concentrated to give an oil, some of the oil (32 mg, 0.060 mmol) was dissolved in acetonitrile (0.8 mL), and then 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2, 16 mg, 0.060 mmol), DIEA (46 mg, 63 μL, 0.36 mmol) was added. The mixture was heated to 85 °C for 1 hr, then the mixture was concentrated and purified via prep-HPLC, Example 179 (27.4 mg) was obtained. LCMS (M+H ⁺ ): 651, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.57 (s, 1H), 8.25 (s, 1H), 7.90 - 7.84 (m, 1H), 7.81 (dd, J = 0.9, 8.1 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.70 - 7.61 (m, 2H), 7.30 (ddd, J = 2.6, 8.8, 10.1 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.18 - 7.14 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.17 (dd, J = 4.6, 15.4 Hz, 1H), 5.49 (d, J = 9.0 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.57 - 4.50 (m, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.33 - 4.27 (m, 1H), 4.00 - 3.91 (m, 1H), 3.17 - 3.06 (m, 3H), 2.98 (dd, J = 1.5, 14.3 Hz, 1H), 2.96 (s, 3H), 2.92 (br d, J = 13.6 Hz, 1H), 2.86 - 2.79 (m, 3H), 2.64 - 2.51 (m, 2H). To a flask was added tert-butyl (8S,11S,15S)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-10-carboxylate (179c-2, 120 mg, 0.230 mmol), dichloromethane (1 mL) and TFA (1.48 g, 1.0 mL, 12.98 mmol), the yellow solution was stirred at r.t. for 1 hr. The mixture was concentrated to give an oil, some of the oil (32 mg, 0.06 mmol) was dissolved in acetonitrile (0.800 mL), and then 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2, 16. mg, 0.060 mmol), DIEA (46 mg, 63 μL, 0.360 mmol) was added. The mixture was heated to 85 °C for 1 hr, then the mixture was concentrated and purified via prep-HPLC, Example 180 (34.4 mg) was obtained. LCMS (M+H ⁺ ): 651, ¹ H NMR (500 MHz, METHANOL- d ₄ ) δ = 8.57 (s, 1H), 8.24 (s, 1H), 7.85 - 7.81 (m, 1H), 7.80 - 7.76 (m, 1H), 7.70 - 7.66 (m, 1H), 7.65 - 7.59 (m, 2H), 7.30 (ddd, J = 2.7, 8.9, 10.1 Hz, 1H), 7.25 - 7.16 (m, 1H), 6.99 (br d, J = 7.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 5.94 - 5.58 (m, 1H), 5.55 - 5.46 (m, 1H), 4.77 - 4.73 (m, 1H), 4.58 (dd, J = 6.4, 11.6 Hz, 1H), 4.37 - 4.31 (m, 1H), 4.28 - 4.16 (m, 1H), 4.15 - 4.06 (m, 1H), 3.88 - 3.72 (m, 1H), 3.22 - 3.19 (m, 1H), 3.10 (s, 3H), 2.97 - 2.92 (m, 3H), 2.88 - 2.82 (m, 3H), 2.78 (br d, J = 13.6 Hz, 1H), 2.62 - 2.55 (m, 1H). Example 183 and Example 184 (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimet hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The compounds were prepared analogy to the preparation of Example 179 and Example 180 by using intermediate C11 instead of intermediate C2 in step 1. Example 183, LCMS (M+H ⁺ ): 663, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.56 (s, 1H), 8.24 (s, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.76 - 7.72 (m, 1H), 7.69 - 7.63 (m, 1H), 7.47 (dd, J = 6.0, 8.6 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.08 (dd, J = 2.6, 10.7 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.16 (dd, J = 4.4, 15.4 Hz, 1H), 5.49 (d, J = 8.9 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.55 (dd, J = 5.9, 11.5 Hz, 1H), 4.40 (d, J = 11.7 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.01 - 3.90 (m, 1H), 3.80 - 3.74 (m, 3H), 3.19 - 3.14 (m, 1H), 3.14 - 3.03 (m, 3H), 3.00 (br d, J = 1.4 Hz, 1H), 2.96 (s, 3H), 2.85 (s, 3H), 2.64 - 2.53 (m, 2H). Example 184, LCMS (M+H ⁺ ): 663, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.23 (s, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.68 - 7.58 (m, 2H), 7.47 (dd, J = 6.0, 8.7 Hz, 1H), 7.08 (dd, J = 2.6, 10.7 Hz, 1H), 6.99 (br d, J = 6.9 Hz, 1H), 6.93 - 6.85 (m, 1H), 6.81 - 6.72 (m, 1H), 6.06 - 5.57 (m, 1H), 5.53 (d, J = 9.0 Hz, 1H), 4.78 - 4.74 (m, 1H), 4.59 (dd, J = 6.3, 11.6 Hz, 1H), 4.36 (br d, J = 11.4 Hz, 1H), 4.28 - 4.15 (m, 1H), 4.14 - 4.07 (m, 1H), 3.88 - 3.78 (m, 1H), 3.78 - 3.73 (m, 3H), 3.22 - 3.08 (m, 4H), 2.98 - 2.94 (m, 3H), 2.87 (s, 3H), 2.80 (br d, J = 13.4 Hz, 1H), 2.64 - 2.56 (m, 1H). Example 187 and Example 188 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-hydroxy- 2,6 8,11 20,24 13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-hydroxy-13, 15,18-trimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The compounds were prepared analogy to the preparation of Example 12 by using compound 187f instead of intermediate A11 in step 1. The mixture of Example 187 (faster eluted) and Example 188 (slower eluted) was separated via prep-HPLC. Example 187, LCMS (M+H ⁺ ): 651, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.54 (s, 1H), 8.22 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.67 (dt, J = 6.0, 8.6 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.45 - 7.40 (m, 1H), 7.32 - 7.24 (m, 2H), 7.23 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 6.58 (d, J = 8.2 Hz, 1H), 5.84 - 5.72 (m, 1H), 5.52 - 5.39 (m, 1H), 4.68 (br t, J = 5.1 Hz, 1H), 4.55 - 4.49 (m, 1H), 4.31 (br d, J = 11.1 Hz, 1H), 4.23 - 4.12 (m, 1H), 4.08 (br d, J = 14.2 Hz, 1H), 3.17 - 3.04 (m, 3H), 2.99 (br d, J = 13.6 Hz, 1H), 2.65 (br d, J = 14.0 Hz, 1H), 2.60 - 2.56 (m, 3H), 2.55 - 2.48 (m, 1H), 0.79 (s, 3H). Example 188, LCMS (M+H ⁺ ): 651, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.54 (s, 1H), 8.24 (s, 1H), 7.81 - 7.74 (m, 1H), 7.67 (dt, J = 5.8, 8.5 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.68 - 5.58 (m, 1H), 5.49 (d, J = 9.0 Hz, 1H), 4.72 - 4.68 (m, 1H), 4.54 (dd, J = 6.3, 11.3 Hz, 1H), 4.34 (d, J = 11.4 Hz, 1H), 4.25 (br d, J = 15.3 Hz, 1H), 4.16 - 4.10 (m, 1H), 3.23 - 3.09 (m, 3H), 2.77 - 2.71 (m, 1H), 2.70 - 2.66 (m, 3H), 2.65 (br d, J = 13.9 Hz, 1H), 2.58 (ddd, J = 4.4, 9.1, 13.6 Hz, 1H), 0.48 - 0.39 (m, 3H). The compound 187f was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-oxo- propyl]-N-methyl-carbamate (compound 187a) To a microwave tube was added tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- hydroxy-propyl]-N-methyl-carbamate (Intermediate A10-g, 1.9 g, 4.77 mmol), 1,1,1- tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (2.63 g, 6.2 mmol) and DCM(19 mL). The mixture was stirred at r.t. for 2 hrs and then quenched with aqueous solution of NaHSO ₃ . The mixture was neutralized with aqueous solution of NaHCO ₃ and separated, the water layer was extracted with another 30 mL DCM. The organic layer was dried over Na2SO4 and concentrated to give compound 187a (2.2 g). LCMS (M+H ⁺ ): 396. Step 2: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- hydroxy-2-methyl-propyl]-N-methyl-carbamate (compound 187b) To a flask which contain tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-oxo- propyl]-N-methyl-carbamate (187a, 1.78 g, 4.5 mmol) was added 1 M methylmagnesium bromide (11.25 mL, 11.25 mmol). The mixture was stirred at r.t. for about 2 hrs. The mixture was quenched with 50 mL sat. NH ₄ Cl and then extracted with 20 mL EA twice, the organic layer was dried over Na ₂ SO ₄ and concentrated, a yellow oil was obtained. The final oil was purified by silica gel to give compound 187b (830 mg).LCMS (M+H ⁺ ): 412. Step 3: preparation of tert-butyl N-[2-hydroxy-2-methyl-3-[2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl ]-N-methyl-carbamate (compound 187c) To a microwave tube was added compound 187b (830 mg, 2.01 mmol), potassium acetate (395 mg, 4.03 mmol) and DMSO (12 mL), the solution was bubbled with N ₂ for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (141 mg, 0.201 mmol) & bis(1-adamantyl)- butyl-phosphine (144 mg, 0.403 mmol) were added. The tube was heated to 130 °C and stirred for about 5hrs. The mixture was diluted with 100mL water and then extracted with 25 mL EA for 3 times. The organic layer was dried over Na ₂ SO ₄ and concentrated, the residue was purified by silica gel to give compound 187c (830 mg). LCMS (M+H ⁺ ): 460. Example 189 and Example 190 (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15-hydroxy- 2,6 8,11 20,24 13,15,18-trimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-hydroxy-13,15,18-tr imethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The compounds were prepared analogy to the preparation of Example 12 by using compound 187f instead of intermediate A11 in step 1 and using intermediate C11 instead of intermediate C2 in step 5. The mixture of Example 189 (faster eluted) and Example 190 (Slower eluted) was separated via prep-HPLC. Example 189, LCMS (M+H ⁺ ): 663, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 8.20 - 8.15 (m, 1H), 7.76 - 7.69 (m, 1H), 7.61 (br d, J = 7.8 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.26 (br t, J = 7.7 Hz, 1H), 7.16 - 7.09 (m, 1H), 7.08 - 7.01 (m, 1H), 6.92 - 6.82 (m, 1H), 6.58 (br d, J = 8.2 Hz, 1H), 5.80 (br d, J = 15.7 Hz, 1H), 5.49 (br d, J = 9.2 Hz, 1H), 4.68 (br t, J = 4.9 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.31 (br d, J = 11.1 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.79 - 3.72 (m, 4H), 3.16 - 3.03 (m, 3H), 2.67 - 2.62 (m, 1H), 2.61 - 2.56 (m, 3H), 2.55 - 2.48 (m, 1H), 0.79 (s, 3H). Example 190, LCMS (M+H ⁺ ): 663, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 8.18 (s, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.06 (dd, J = 2.6, 10.7 Hz, 1H), 6.88 (dt, J = 2.7, 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 15.4 Hz, 1H), 5.48 (d, J = 9.0 Hz, 1H), 4.70 (t, J = 5.2 Hz, 1H), 4.54 (dd, J = 6.2, 11.4 Hz, 1H), 4.33 (d, J = 11.4 Hz, 1H), 4.26 (br d, J = 15.4 Hz, 1H), 4.14 (d, J = 13.9 Hz, 1H), 3.78 - 3.74 (m, 3H), 3.11 (s, 3H), 2.76 - 2.71 (m, 1H), 2.70 - 2.67 (m, 3H), 2.65 (d, J = 13.9 Hz, 1H), 2.61 - 2.53 (m, 1H), 0.47 - 0.40 (m, 3H). Example 192 and Example 193 [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate and [(8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate The title compounds were prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-[tert- butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate (compound 192a) A mixture of intermediate A10-g, (3 g, 7.53 mmol), imidazole (5.12 g, 75.3 mmol) and TBDMS-Cl (5.67 g, 37.6 mmol) in DMF (95 mL) was stirred at r.t. for 16 hrs, then the reaction was diluted with EA, washed with water and brine. The organic layer was concentrated and the residue was purified by silica gel to give compound 192a. LCMS (M+H ⁺ ): 512. Step 2~5: preparation of ditert-butyl (8S,11S,15R)-15-hydroxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-7,10-dicarboxylate and ditert-butyl (8S,11S,15S)-15- hydroxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-7,10- dicarboxylate (compound 192e-1 and 192e-2) The preparation of compound 192e was in analogy to the preparation of compound 161e by using compound 192a instead of compound 161a. LCMS: LCMS (M+H ⁺ ): 607. Compound 192e was separated by SFC to give compound 192e-1 (faster eluted) and 192e-2 (slower eluted). SFC condition: Instrument: SFC 80. Column: IA, 250×30 mm I.D., 5μm. Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O). Gradient: B 25%. Flow rate: 60 mL /min. Backpressure: 100bar. Step 6: preparation of [(8S,11S,15R)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (compound 192f-1) and [(8S,11S,15S)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (compound 192f-2) To a tube was added ditert-butyl (8S,11S,15R)-15-hydroxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-7,10-dicarboxylate (compound 192e-1, 130 mg, 0.214 mmol) and Ac ₂ O (1.08 g, 1 mL, 10.6 mmol), the solution was heated to 80 °C and stirred for about 16 hrs. The mixture was concentrated directly to give an oil (140 mg). Then it was dissolved in dichloromethane (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol), the solution was stirred at r.t. for 1 hr. The mixture was concentrated directly to give compound 192f-1 (160 mg). LCMS (M+H ⁺ ): 449. To a tube was added ditert-butyl (8S,11S,15S)-15-hydroxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaene-7,10-dicarboxylate (compound 192e-2, 130 mg, 0.214 mmol) and Ac ₂ O (1.08 g, 1 mL, 10.6 mmol), the solution was heated to 80 °C and stirred for about 16 hrs. The mixture was concentrated directly to give an oil (135 mg). Then it was dissolved in dichloromethane (1 mL) and TFA (1.48 g, 1.0 mL, 12.98 mmol), the solution was stirred at r.t. for 1 hr. The mixture was concentrated directly to give compound 192f-2 (150 mg). LCMS (M+H ⁺ ): 449. Step 7: preparation of [(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate and [(8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (Example 192 and Example 193) To a microwave tube was added [(8S,11S,15R)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (compound 192f-1, 28.13 mg, 0.050 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 13.3 mg, 0.050 mmol), DIEA (38.8 mg, 52.4 μL, 0.300 mmol) and acetonitrile (0.667 mL), a yellow solution formed. The mixture was heated to 85 °C and stirred for about 1 hr. The mixture was concentrated to give an oil and then it was purified via prep-HPLC to give Example 192. LCMS (M+H ⁺ ): 679. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.22 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.67 (dt, J = 5.9, 8.6 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.54 - 7.48 (m, 1H), 7.32 - 7.25 (m, 1H), 7.24 - 7.17 (m, 1H), 7.13 - 7.08 (m, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.20 (dd, J = 4.0, 15.3 Hz, 1H), 5.47 (d, J = 8.9 Hz, 1H), 4.69 (t, J = 4.9 Hz, 1H), 4.57 - 4.49 (m, 1H), 4.49 - 4.40 (m, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.04 (s, 3H), 2.98 - 2.92 (m, 1H), 2.87 (d, J = 12.4 Hz, 1H), 2.83 (s, 3H), 2.58 - 2.48 (m, 1H), 1.73 (s, 3H). To a microwave tube was added [(8S,11S,15S)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate (28.1 mg, 0.050 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 13.3 mg, 0.050 mmol), DIEA (64.6 mg, 87.3 μL, 0.500 mmol) and acetonitrile (0.667 mL), a yellow solution formed. The mixture was heated to 85 °C and stirred for about 1 hr. The mixture was concentrated to give an oil and then it was purified via prep-HPLC to give Example 193. LCMS (M+H ⁺ ): 679. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.22 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.32 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.51 - 6.34 (m, 1H), 5.51 (d, J = 9.2 Hz, 1H), 5.23 (br dd, J = 5.0, 10.9 Hz, 1H), 4.77 - 4.74 (m, 1H), 4.62 - 4.54 (m, 1H), 4.46 (br d, J = 16.0 Hz, 1H), 4.35 (d, J = 11.6 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.19 (dd, J = 5.4, 14.9 Hz, 1H), 3.05 (s, 3H), 2.79 (s, 3H), 2.76 - 2.72 (m, 1H), 2.65 - 2.57 (m, 1H), 1.57 (s, 3H). Example 194 and Example 195 [(8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate and [(8S,11S,15S)-10-[1-(4-fluoro-2- methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-15-yl] acetate

The title compounds were preparation in analogy to the preparation of Example 192 and Example 193 by using Intermediate C11 instead of Intermediate C2 in step 7. Example 194, LCMS (M+H ⁺ ): 691, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 8.16 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.12 - 7.09 (m, 1H), 7.06 (dd, J = 2.5, 10.6 Hz, 1H), 6.92 - 6.85 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.16 (dd, J = 3.8, 15.3 Hz, 1H), 5.46 (d, J = 8.9 Hz, 1H), 4.68 (t, J = 4.9 Hz, 1H), 4.55 - 4.49 (m, 1H), 4.47 - 4.40 (m, 1H), 4.37 - 4.26 (m, 1H), 4.23 - 4.11 (m, 2H), 3.79 - 3.74 (m, 3H), 3.14 - 3.02 (m, 3H), 2.93 (br d, J = 13.9 Hz, 1H), 2.85 (d, J = 12.5 Hz, 1H), 2.81 - 2.75 (m, 3H), 2.57 - 2.49 (m, 1H), 1.73 - 1.67 (m, 3H). Example 195, LCMS (M+H ⁺ ): 691, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.22 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.32 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.51 - 6.34 (m, 1H), 5.51 (d, J = 9.2 Hz, 1H), 5.23 (br dd, J = 5.0, 10.9 Hz, 1H), 4.77 - 4.74 (m, 1H), 4.62 - 4.54 (m, 1H), 4.46 (br d, J = 16.0 Hz, 1H), 4.35 (d, J = 11.6 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.19 (dd, J = 5.4, 14.9 Hz, 1H), 3.16 - 3.04 (m, 3H), 2.81 - 2.77 (m, 3H), 2.76 (s, 1H), 2.65 - 2.57 (m, 1H), 1.60 - 1.54 (m, 3H). Example 197 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-dimethylphosphoryl-pyr azolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]- hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 4-chloro-1-(2,4-difluorophenyl)-6-iodo-pyrazolo[3,4- d]pyrimidine (compound 197a) To a suspension of Intermediate C23 (700 mg, 2.49 mmol), diiodomethane (3.33 g, 1.0 mL, 12.43 mmol) and copper (I) iodide (946 mg, 4.97 mmol) in extra dry tetrahydrofuran (40 mL) was added isoamyl nitrite (998 μL, 7.46 mmol) dropwise under nitrogen atmosphere. After the addition, the reaction mixture was stirred at 90°C for 3 hours. The mixture was cooled to the room temperature, EtOAc (60 mL) was added to dilute the solution, Na ₂ S ₂ O ₃ (saturated solution, 30 mL) was added and the organic layer was washed with water (twice, 50 mL). The organic layer was dried and concentrated, the crude product was purified by silica gel to afford compound 197a (420 mg). LCMS (M+H ⁺ ): 393. Step 2: preparation of 1-(2,4-difluorophenyl)-6-dimethylphosphoryl-pyrazolo[3,4- d]pyrimidin-4-ol (compound 197b) To a mixture of compound 197a (120 mg, 0.284 mmol) in extra dry 1,4-dioxane (6 mL) was added methylphosphonoylmethane (24 mg, 0.313 mmol), Pd ₂ (dba) ₃ (26 mg, 0.028 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (33 mg, 0.057 mmol), cesium carbonate (185 mg, 0.569 mmol). The resulting mixture was stirred at 90 °C overnight. The mixture was concentrated and the residue was purified by silica gel to afford compound 197b (80 mg). LCMS (M+H ⁺ ): 325. Step 3: preparation of 4-chloro-1-(2,4-difluorophenyl)-6-dimethylphosphoryl- pyrazolo[3,4-d]pyrimidine (compound 197c) A suspension of compound 197c (80 mg, 0.247 mmol) in phosphorus oxychloride (1 mL, 10.73 mmol) was stirred at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and then removed the solvent. The resulting residue was purified by silica gel to afford compound 197c (64 mg). LCMS (M+H ⁺ ): 343. Step 4: preparation of (8S,11S)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 197d) A solution of compound 179c (972 mg, 1.49 mmol) in dichloromethane (10 mL) was added a HCl solution(4M in dioxane, 5 mL, 20 mmol) at 0 °C and then stirred at room temperature for 4 hours. The solvent was removed to afford crude product compound 197d (954 mg). LCMS (M+H ⁺ ): 421. Step 5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)-6-dimethylphosphoryl- pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,1 0,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 197) A solution of compound 197c (22 mg, 0.064 mmol), compound 197d (45 mg, 0.064 mmol ) and DIEA (33 μL, 0.193 mmol) in 1,4-dioxane (2 mL) was stirred at 70 °C for 1 hour. The solvent was removed and purified by prep-HPLC to afford Example 197 (12.6 mg). LCMS (M+H ⁺ ): 727. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.51 - 8.45 (m, 1H), 7.79 - 7.66 (m, 1H), 7.64 - 7.53 (m, 2H), 7.41 - 7.16 (m, 3H), 7.14 - 7.00 (m, 2H), 6.85 - 6.58 (m, 1H), 5.87 - 5.68 (m, 1H), 5.53 - 5.21 (m, 1H), 4.68 - 4.58 (m, 1H), 4.52 - 4.42 (m, 1H), 4.29 - 4.16 (m, 1H), 4.13 - 4.05 (m, 1H), 4.00 - 3.89 (m, 1H), 3.87 - 3.76 (m, 1H), 3.10 - 2.94 (m, 3H), 2.89 - 2.81 (m, 1H), 2.79 - 2.75 (m, 3H), 2.64 - 2.52 (m, 4H), 2.50 - 2.41 (m, 1H), 1.81 - 1.62 (m, 6H). Example 198 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidine-6-carboxylic acid The title compound was prepared in analogy to the preparation of Example 37 by using Example 214 instead of compound 37a. Example 198 (13 mg) was obtained. LCMS (M+H ⁺ ): 695. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.54 - 8.46 (m, 1H), 7.81 - 7.53 (m, 5H), 7.24 - 7.14 (m, 1H), 7.13 - 7.02 (m, 2H), 6.71 - 6.63 (m, 1H), 6.09 - 5.95 (m, 1H), 5.68 - 5.34 (m, 1H), 4.67 - 4.57 (m, 1H), 4.53 - 4.42 (m, 1H), 4.32 - 4.17 (m, 2H), 4.11 - 3.96 (m, 1H), 3.90 - 3.81 (m, 1H), 3.12 - 2.95 (m, 4H), 2.91 - 2.80 (m, 4H), 2.77 - 2.67 (m, 3H), 2.52 - 2.40 (m, 2H). Example 199 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidine-6-carbonitrile The title compound was prepared in analogy to the preparation of Example 214 by using 4- intermediate C27 instead of compound 214c. Example 199 (7 mg) was obtained. LCMS (M+H ⁺ ): 676. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.70 - 8.50 (m, 1H), 7.93 - 7.59 (m, 3H), 7.47 - 7.08 (m, 5H), 6.97 - 6.59 (m, 1H), 5.86 - 5.68 (m, 1H), 5.54 - 5.41 (m, 1H), 4.69 - 4.47 (m, 3H), 4.39 - 3.86 (m, 4H), 3.17 - 3.04 (m, 3H), 3.00 - 2.91 (m, 1H), 2.88 - 2.80 (m, 3H), 2.65 - 2.58 (m, 3H), 2.56 - 2.48 (m, 1H). Example 200 and Example 201 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-c]pyrida zin-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-c]pyridazin-4-yl]-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The compounds were prepared analogy to the preparation of Example 179 and Example 180 by using intermediate C6 instead of intermediate C2. Example 200, LCMS (M+H ⁺ ): 651. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.70 - 8.50 (m, 1H), 8.21 - 7.91 (m, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.67 (dd, J = 0.8, 8.0 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.32 - 7.26 (m, 1H), 7.21 (br t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.78 (br d, J = 15.0 Hz, 1H), 5.47 - 5.22 (m, 1H), 4.67 - 4.45 (m, 2H), 4.36 (br d, J = 10.8 Hz, 1H), 4.28 - 4.07 (m, 2H), 4.05 - 3.85 (m, 1H), 3.16 - 3.12 (m, 1H), 3.12 - 3.02 (m, 3H), 2.85 (s, 3H), 2.63 (br s, 3H), 2.61 - 2.49 (m, 2H). Example 201, LCMS (M+H ⁺ ): 651. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.72 - 8.51 (m, 1H), 8.16 - 7.88 (m, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.71 (br s, 1H), 7.67 - 7.62 (m, 1H), 7.39 - 7.33 (m, 2H), 7.30 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.95 (br d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.57 - 5.39 (m, 1H), 5.36 - 5.17 (m, 1H), 4.73 - 4.63 (m, 1H), 4.41 - 4.25 (m, 1H), 4.21 - 3.99 (m, 3H), 3.76 - 3.64 (m, 1H), 3.23 - 3.18 (m, 1H), 3.17 - 3.05 (m, 3H), 3.01 - 2.88 (m, 1H), 2.87 (s, 3H), 2.65 (br s, 3H), 2.64 - 2.58 (m, 1H). Example 202 and Example 203 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-b]pyridi n-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-b]pyridin-4-yl]-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The compounds were prepared analogy to the preparation of Example 179 and Example 180 by using Intermediate C8 instead of Intermediate C2 (Reaction condition: using Pd ₂ (dba) ₃ , BINAP, Cs ₂ CO ₃ , dioxane 100°C instead of DIPEA, CAN 85°C). Example 202, LCMS (M+H ⁺ ): 650, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.71 - 8.34 (m, 1H), 8.15 - 7.95 (m, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.64 (br d, J = 7.5 Hz, 2H), 7.58 - 7.53 (m, 1H), 7.31 - 7.24 (m, 1H), 7.20 (br t, J = 8.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.57 - 6.08 (m, 1H), 6.02 (dd, J = 4.3, 15.4 Hz, 1H), 5.55 - 5.02 (m, 1H), 4.66 - 4.38 (m, 2H), 4.33 - 4.06 (m, 2H), 3.97 (br dd, J = 9.4, 14.1 Hz, 1H), 3.11 (br s, 3H), 3.06 - 2.96 (m, 2H), 2.92 (s, 3H), 2.76 (s, 3H), 2.67 - 2.51 (m, 2H). Example 203, LCMS (M+H ⁺ ): 650, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.83 - 8.68 (m, 1H), 8.18 - 7.87 (m, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.76 - 7.68 (m, 1H), 7.63 (br d, J = 4.7 Hz, 2H), 7.42 - 7.33 (m, 1H), 7.27 (br t, J = 7.6 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.76 (br d, J = 8.4 Hz, 1H), 6.73 - 6.29 (m, 1H), 5.72 - 5.51 (m, 1H), 5.42 - 5.23 (m, 1H), 4.77 - 4.63 (m, 1H), 4.53 - 4.27 (m, 1H), 4.24 - 4.04 (m, 2H), 3.87 - 3.73 (m, 1H), 3.29 - 3.25 (m, 1H), 3.23 - 3.07 (m, 4H), 3.03 - 2.96 (m, 1H), 2.95 (s, 3H), 2.85 (s, 3H), 2.77 - 2.64 (m, 1H). Example 204 and Example 205 (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-b ]pyridin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-b]pyridin-4-yl]-15-methoxy-13,18-dimethy l-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The compounds were prepared analogy to the preparation of Example 179 and Example 180 by using Intermediate C9 instead of Intermediate C2 (Reaction condition: using Pd ₂ (dba) ₃ , BINAP, Cs ₂ CO ₃ , dioxane 100°C instead of DIPEA, CAN 85°C). Example 204, LCMS (M+H ⁺ ): 662, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.76 - 8.35 (m, 1H), 8.14 - 7.90 (m, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.46 (br t, J = 7.8 Hz, 2H), 7.13 (d, J = 7.5 Hz, 1H), 7.07 (dd, J = 2.4, 10.6 Hz, 1H), 6.89 (dt, J = 2.4, 8.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.56 - 6.06 (m, 1H), 5.91 (br dd, J = 4.0, 15.3 Hz, 1H), 5.58 - 5.07 (m, 1H), 4.67 - 4.48 (m, 2H), 4.23 (br dd, J = 11.1, 15.3 Hz, 2H), 3.97 (br dd, J = 9.5, 14.0 Hz, 1H), 3.77 (s, 3H), 3.18 - 2.93 (m, 5H), 2.88 (s, 3H), 2.69 (s, 3H), 2.65 - 2.48 (m, 2H). Example 205, LCMS (M+H ⁺ ): 662, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.74 - 8.46 (m, 1H), 8.07 - 7.86 (m, 1H), 7.79 (dd, J = 7.6, 8.2 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.51 - 7.36 (m, 3H), 7.07 (dd, J = 2.6, 10.7 Hz, 1H), 6.95 (br d, J = 7.2 Hz, 1H), 6.89 (dt, J = 2.6, 8.3 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.59 - 6.02 (m, 1H), 5.68 - 5.10 (m, 2H), 4.73 - 4.55 (m, 2H), 4.17 - 4.03 (m, 2H), 3.76 (s, 3H), 3.75 (br s, 1H), 3.23 - 3.06 (m, 4H), 2.94 - 2.90 (m, 1H), 2.89 (s, 3H), 2.88 - 2.83 (m, 1H), 2.71 (s, 3H), 2.67 (br d, J = 15.1 Hz, 1H). Example 209 (8S,11S)-23-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 2-bromo-1,3-dichloro-4-nitro-benzene (compound 209a) In a 100.0 mL round-bottom flask was added H ₂ SO ₄ (20.0 mL) and to the mixture was added HNO ₃ (6.0 g, 66.67 mmol) dropwise over 15 minutes. Then a solution of 1-bromo-2,6- dichlorobenzene (10.0 g, 44.27 mmol) in dichloromethane (10.0 mL) was added to the mixture dropwise and the mixture was stirred at 20 °C for 12 h. The mixture was poured into ice (100.0 g) and extracted with EtOAc (50.0 mL twice). The combined organic layer was washed with NaHCO ₃ aqueous solution and brine (50.0 mL), dried and concentrated to give compound 209a (10.0 g). LCMS (M+H ⁺ ): 271. Step 2: preparation of tert-butyl N-[3-(2-bromo-3-chloro-6-nitro-anilino)propyl]-N- methyl-carbamate (compound 209b) To a mixture of 2-bromo-1,3-dichloro-4-nitro-benzene (209a, 10.0 g, 36.91 mmol) in DMF (100.0 mL) was added a solution of N-(3-aminopropyl)-N-methylcarbamic acid tert-butylester (10.4 g, 55.37 mmol) in DMF (100.0 mL). The mixture was stirred at 20 °C for 16 h. To the mixture was added 2-bromo-1,3-dichloro-4-nitro-benzene (10.0 g, 36.91 mmol) and the resulting mixture was stirred at 20 °C for 2 h. The mixture was poured into water (200.0 mL) and extracted with EtOAc (200.0 mL for 3 times). The combined organic layer was washed with water (200.0 mL for 5 times), dried and concentrated. The residue was purified by flash chromatography column to give compound 209b (13.0 g). LCMS (M+H ⁺ ): 422. Step 3: preparation of tert-butyl N-[3-(6-amino-2-bromo-3-chloro-anilino)propyl]-N- methyl-carbamate (compound 209c) To a mixture of tert-butyl N-[3-(2-bromo-3-chloro-6-nitro-anilino)propyl]-N-methyl- carbamate (209b, 13.0 g, 30.75 mmol) in methanol (100.0 mL) was added Raney Ni (15.0 g) under N ₂ . Then N ₂ H ₄ •H ₂ O (15.0 g, 312.50 mmol) was added dropwise at 20 °C over 0.5 h. The resulting mixture was stirred at 20 °C for 0.5 h, and then filtered. The filtrate was concentrated and the residue was taken in DCM (300.0 mL) and washed with water (100.0 mL for 3 times). The organic layer was dried and concentrated to give compound 209c (10.0 g). LCMS (M+H ⁺ ): 394. Step 4: preparation of tert-butyl N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazol-1- yl)propyl]-N-methyl-carbamate (compound 209d) To a solution of tert-butyl N-[3-(6-amino-2-bromo-3-chloro-anilino)propyl]-N-methyl- carbamate (209c, 10.0 g, 7.64 mmol) in THF (100 mL) was added trimethyl orthoacetate (2.8 g, 22.92 mmol). The mixture was stirred at 20 °C for 12 h under N ₂ and then concentrated. The residue was taken in EtOAc (200.0 mL) and washed with brine (100.0 mL twice). The organic layer was dried and concentrated, the residue was purified by flash chromatography column to give compound 209d (2.5 g). LCMS (M+H ⁺ ): 420. Step 5: preparation of 3-(7-bromo-6-chloro-2-methyl-benzimidazol-1-yl)-N-methyl- propan-1-amine (compound 209e) To a solution of tert-butyl N-[3-(7-bromo-6-chloro-2-methyl-benzimidazol-1-yl)propyl]-N- methyl-carbamate (209d, 2.5 g, 6.00 mmol) in DCM (10.0 mL) was added TFA (3.0 mL) and the mixture was stirred at 20 °C for 12 h under N ₂ . The mixture was concentrated to give compound 209e (1.8 g). LCMS (M+H ⁺ ): 320. Step 6: preparation of 2-trimethylsilylethyl N-[3-(7-bromo-6-chloro-2-methyl- benzimidazol-1-yl)propyl]-N-methyl-carbamate (compound 209f) To a solution of 3-(7-bromo-6-chloro-2-methyl-benzimidazol-1-yl)-N-methyl-pro pan-1- amine (209e, 1.2 g, 3.79 mmol) and 2,5-dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate (1.5 g, 5.69 mmol) in THF (50.0 mL) was added saturated aqueous solution of NaHCO ₃ (50.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 1 h, and then adjusted to pH=7 by saturated aq. NH ₄ Cl. The mixture was extracted with EtOAc (100.0 mL twice) and the combined organic layer was washed with brine (100.0 mL twice), dried and concentrated. The residue was purified by reversed phase flash chromatography to give compound 209f (1400 mg). LCMS (M+H ⁺ ): 462. Step 7: preparation of 2-trimethylsilylethyl N-[3-[6-chloro-7-(6-chloro-2-pyridyl)-2- methyl-benzimidazol-1-yl]propyl]-N-methyl-carbamate (compound 209g) To a solution of compound 209f (1.7 g, 3.82 mmol) in 1,4-dioxane (40.0 mL) and water (4.0 mL) was added 6-chloropyridine-2-boronic acid pinacol ester (1.4 g, 5.73 mmol), chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl )]palladium(II) (200.0 mg), phosphoric acid and potassium salt (0.6 mL, 7.64 mmol) under Ar, and the mixture was stirred at 80 °C for 4 h. The mixture was diluted with EtOAc (100.0 mL) and then washed with brine (100.0 mL twice), dried and concentrated. The residue was purified by reversed phase flash chromatography to give compound 209g (1.5 g). LCMS (M+H ⁺ ): 493. Step 8: Preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[5-chloro-2-methyl-3-[3- [methyl(2-trimethylsilylethoxycarbonyl)amino]propyl]benzimid azol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 209h) To a solution of compound 209g, (1.3 g, 2.63 mmol) in 1,4-dioxane (20.0 mL) was added O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (1.5 g, 5.27 mmol), cesium carbonate (2.6 g, 7.90 mmol), SPhos (200.0 mg) and Pd ₂ (dba) ₃ (200.0 mg) under Ar. The mixture was stirred at 90 °C for 12 h. After cooled to r.t., the reaction mixture was diluted with EtOAc (200.0 mL) and poured into water (200.0 mL). The aqueous layer was extracted with EtOAc (200.0 mL twice). The combined organic layer was washed with brine (200.0 mL twice), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by prep-HPLC to give compound 209h (800.0 mg). LCMS (M+H ⁺ ): 701. Step 9: preparation of tert-butyl (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[5-chloro-2- methyl-3-[3-[methyl(2-trimethylsilylethoxycarbonyl)amino]pro pyl]benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 209i) A solution of compound 209h (400.0 mg, 0.57 mmol) and lithium hydroxide hydrate (136.6 mg, 5.70 mmol) in methanol (5.0 mL) and water (1.0 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with EtOAc (100.0 mL) and poured into water (100.0 mL). The resulting mixture was extracted with EtOAc (100.0 mL twice). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by reversed phase flash chromatography to give compound 209i (250.0 mg). LCMS (M+H ⁺ ): 687. Step 10: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[5-chloro-2-methyl-3-[3- (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrro lidine-2-carboxylic acid (compound 209j) To a solution of TBAF in THF (5.0 mL, 5.00 mmol) was added of compound 209i (250.0 mg, 0.36 mmol). The mixture was stirred at 25 °C for 12 h and then partitioned between EtOAc (100.0 mL) and water (100.0 mL). The aqueous layer was extracted with EtOAc (100.0 mL twice). The combined organic layer was washed with brine (100.0 mL twice), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by reversed phase flash chromatography to give compound 209j (200.0 mg). LCMS (M+H ⁺ ): 543. Step 11: preparation of tert-butyl (8S,11S)-23-chloro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaene-10-carboxylate (compound 209k) A solution of HATU (93.6 mg, 0.40 mmol), DIEA (64.3 mg, 0.50 mmol) in DMF (250.0 mL) was stirred at 0 °C for 0.5 h. Then compound 209j (180.0 mg, 0.33 mmol) in DMF (250.0 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h, and then concentrated. The residue was purified by reversed phase flash chromatography to give compound 209k (160.0 mg). LCMS (M+H ⁺ ): 525. Step 12 : preparation of (8S,11S)-23-chloro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 209m) A solution of compound 209k (160.0 mg, 0.3 mmol) in trifluoroacetic acid (3.0 mL, 38.94 mmol) was stirred at 25°C for 1h. The mixture was concentrated under reduced pressure to give compound 209m (150.0 mg) as a light yellow solid, which was used in next step directly. LCMS (M+H ⁺ ): 425. Step 13: preparation of (8S,11S)-23-chloro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13 ,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 209) To a solution of compound 209m (91.5 mg, 0.22 mmol) and DIEA (34.7 mg, 0.27 mmol) in NMP (3.0 mL) was added 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimid ine (50.0 mg, 0.18 mmol). The reaction mixture was stirred at 80 °C for 1 h, and then purified by prep-HPLC to give Example 209 (43.1 mg). LCMS (M+H ⁺ ): 667. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 - 8.46 (m, 1H), 8.12 (m, 1H), 7.80 (m, 1H), 7.54 (m, 1H), 7.47 - 7.41 (m, 1H), 7.29 (s, 1H), 7.07 - 7.03 (m, 1H), 6.89 - 6.81 (m, 2H), 6.65 (m, 1H), 5.52 - 5.46 (m, 1H), 4.80 - 4.72 (m, 1H), 4.63 - 4.57 (m, 2H), 4.27 (m, 1H), 4.07 - 3.98 (m, 2H), 3.76 - 3.74 (m, 3H), 3.43 - 3.37 (m, 1H), 3.19 (s, 1H), 3.09 (s, 3H), 2.82 (m, 1H), 2.69 - 2.62 (m, 1H), 2.58 (s, 3H), 1.19 - 1.11 (m, 1H). Example 211 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(hydroxymethyl)pyrazol o[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 34 by using Example 214 instead of compound 36j. LCMS (M+H ⁺ ): 681. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 7.84 - 7.72 (m, 1H), 7.70 - 7.58 (m, 2H), 7.38 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.18 (br t, J = 7.7 Hz, 1H), 7.13 - 7.08 (m, 1H), 6.71 - 6.62 (m, 1H), 5.82 - 5.68 (m, 1H), 5.67 - 5.58 (m, 1H), 5.45 - 5.32 (m, 1H), 4.68 - 4.47 (m, 4H), 4.35 - 4.22 (m, 1H), 4.18 - 4.06 (m, 1H), 4.00 - 3.90 (m, 1H), 3.19 - 3.08 (m, 2H), 3.04 (s, 1H), 2.98 - 2.88 (m, 1H), 2.86 - 2.79 (m, 3H), 2.74 - 2.60 (m, 1H), 2.59 - 2.54 (m, 3H), 2.51 (dt, J = 4.4, 9.5 Hz, 1H). Example 213 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-morpholino-pyrazol o[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4 - d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 213a) A mixture of compound 370b (0.90 g, 2.05 mmol), intermediate C74 (618.0 mg, 2.05 mmol) and DIPEA (1.33 g, 10.26 mmol) in acetonitrile (60 mL) was stirred at 45 °C for 3 hours, then the reaction was concentrated and the residue was purified by silica gel to give compound 213a (1 g), LCMS (M+H ⁺ ): 703. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-morpholino- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 213) A mixture of compound 213a (15 mg, 0.021 mmol), morpholine (9.3 mg, 9.3 μL, 0.107 mmol) and DIPEA (27.6 mg, 0.213 mmol) in acetonitrile (1 mL) was stirred at 80 °C for 3 hours, then the reaction was purified by prep-HPLC to give example 213 (15 mg). LCMS (M+H ⁺ ): 754. 1H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.14 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.48 - 7.42 (m, 1H), 7.39 (dd, J = 2.3, 10.2 Hz, 1H), 7.20 - 6.95 (m, 3H), 6.67 (d, J = 8.3 Hz, 1H), 6.15 - 5.89 (m, 1H), 5.36 - 5.13 (m, 1H), 4.59 - 4.09 (m, 4H), 3.89 - 3.74 (m, 1H), 3.74 - 3.48 (m, 8H), 3.17 - 3.09 (m, 1H), 3.06 - 2.95 (m, 3H), 2.93 - 2.82 (m, 4H), 2.74 - 2.59 (m, 3H), 2.58 - 2.35 (m, 2H). Example 214 Ethyl 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18-dimethyl -12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxylate The title compound was prepared according to the following scheme: Step 1: preparation of 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylic acid ethyl ester (compound 214a) A solution of 2-cyano-3-ethoxy-acrylic acid ethyl ester (507 mg, 3 mmol), (2,4- difluorophenyl)hydrazine;hydrochloride (54 mg, 3 mmol) and Et ₃ N (836 μL, 6 mmol) in ethanol (10 mL) was stirred at 90 °C for 12 hours. The mixture was concentrated and the residue was purified by silica gel to afford compound 198a (635 mg), LCMS (M+H ⁺ ): 268. Step 2: preparation of 1-(2,4-difluorophenyl)-4-keto-5H-pyrazolo[3,4-d]pyrimidine-6 - carboxylic acid ethyl ester (compound 214b) To a suspension of compound 214a (635 mg, 2.38 mmol) and a HCl solution (4 M in dioxane, 12 mL, 48 mmol) at room temperature was added cyanoformic acid ethyl ester (470 mg, 469 μL, 4.75 mmol). The mixture was stirred at 100 °C for 14 hours and then was cooled to room temperature. After 1,4-dioxane was removed in vacuo, the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and concentrated, the residue was purified by silica gel to afford compound 214b (700 mg), LCMS (M+H ⁺ ): 321. Step 3: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6- carboxylic acid ethyl ester (compound 214c) A solution of compound 214b (120 mg, 0.375 mmol) in phosphorus oxychloride (2.0 mL, 21.46 mmol) was stirred at 90 °C for 4 hours. The cooled solution was poured into cooled saturated NaHCO ₃ solution and then extracted with EtOAc (10 mL, three times). The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel o afford compound 214c (80 mg), LCMS (M+H ⁺ ): 339. Step 4: preparation of Ethyl 1-(2,4-difluorophenyl)-4-[(8S,11S)-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxylate (Example 214) A suspension of compound 214c (50 mg, 0.140 mmol), compound 197d (98 mg, 0.140 mmol) and DIEA (74 μL, 0.421 mmol) in acetonitrile (1 mL) was stirred at 70 °C for 0.5 hour. The solvent was removed by reduce pressure and then purified by prep-HPLC to afford Example 214 (33.8 mg), LCMS (M+H ⁺ ): 723. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 7.80 - 7.66 (m, 1H), 7.65 - 7.45 (m, 3H), 7.43 - 7.32 (m, 1H), 7.23 - 7.14 (m, 1H), 7.13 - 6.81 (m, 2H), 6.66 - 6.57 (m, 1H), 5.98 - 5.76 (m, 1H), 5.58 - 5.34 (m, 1H), 4.66 - 4.56 (m, 1H), 4.50 - 4.18 (m, 5H), 4.18 - 4.08 (m, 1H), 4.05 - 3.93 (m, 1H), 3.89 - 3.80 (m, 1H), 3.09 - 2.90 (m, 4H), 2.86 - 2.76 (m, 4H), 2.66 - 2.57 (m, 3H), 2.51 - 2.40 (m, 1H), 1.33 - 1.20 (m, 3H). Example 219 (8S,11S)-10-[1-(4-fluoro-2-methylsulfanyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of 4-fluoro-2-(methylthio)-1-nitro-benzene (compound 219a) To a mixture of 2,4-difluoro-1-nitro-benzene (4.0 g, 25.1 mmol), pyridine (4 mL, 49.5 mmol) in methanol (20 mL) was added the solution of sodium thiomethoxide (1.76 g, 25.1 mmol) in methanol (20 mL) dropwise at 0 ^° C. The mixture was stirred for 1 hour and then diluted with dichloromethane. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was recrystallized from EA/PE to afford compound 219a (2.3 g), LCMS (M+H ⁺ ): 188. Step 2: preparation of [4-fluoro-2-(methylthio)phenyl]amine (compound 219b) To a flask was added nickel (721 mg, 12.29 mmol), methanol (40 mL), compound 219a (2.3 g, 12.29 mmol), the suspension was stirred vigorously and hydrazine;hydrate (615.09 mg, 12.29 mmol) was added. After being stirred at room temperature for 1 hr, the mixture was filtered through celite, the filtrate was concentrated to give an oil. The oil was dissolved in 40 mL DCM and washed with 20 mL water for three times. The organic layer was dried over Na ₂ SO ₄ and concentrated to afford compound 219b (731 mg), LCMS (M+H ⁺ ): 158. Step 3: preparation of [4-fluoro-2-(methylthio)phenyl]hydrazine (compound 219c) To a stirring solution of compound 219b (731 mg, 4.65 mmol) in 5 M HCl (6.7 mL, 33.5 mmol) at 0 °C was added a solution of sodium nitrite (481 mg, 6.97 mmol) in water (4 mL) below 0 °C. The reaction mixture was stirred at 0 ºC for another 30 mins and a solution of tin (II) chloride (1.32 g, 6.97 mmol) dissolved in conc. HCl (2 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. Then the mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide and extracted with EA. The organic layer was dried and concentrated to afford compound 219c (499 mg), LCMS (M-NH ₃ +H ⁺ ): 156. Step 4: preparation of [(Z)-(4,6-dichloropyrimidin-5-yl)methyleneamino]-[4-fluoro-2 - (methylthio)phenyl]amine (compound 219d) A suspension of compound 219c (499 mg, 2.9 mmol) and 4,6-dichloropyrimidine-5- carbaldehyde (513 mg, 2.9 mmol) in acetonitrile (15 mL) was stirred at room temperature for 12 hours. The mixture was concentrated and the residue was purified by silica gel to afford compound 219d (900 mg). LCMS (M+H ⁺ ): 331. Step 5: preparation of [(Z)-(4,6-dichloropyrimidin-5-yl)methyleneamino]-[4-fluoro-2 - (methylthio)phenyl]amine (compound 219e) A suspension of compound 219d (900 mg, 2.72 mmol) in extra dry acetonitrile (20 mL) was microwaved at 180 °C for 1 hour. Then the solvent was removed and the resulting residue was purified by silica gel to afford compound 219e, (430 mg), LCMS (M+H ⁺ ): 295. Step 6: preparation of (8S,11S)-10-[1-(4-fluoro-2-methylsulfanyl-phenyl)pyrazolo[3, 4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 -hexazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]-hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 219) A solution of compound 197d (50 mg, 0.071 mmol), compound 219e ( 23. mg, 0.078 mmol) and DIEA (49 μL, 0.284 mmol) in acetonitrile (2 mL) was stirred at 70 °C for 1 hour. The solvent was removed and the resulting residue was purified by prep-HPLC to afford Example 219 (6 mg), LCMS (M+H ⁺ ): 679. ¹ H NMR (500 MHz, METHANOL-d4) δ = 8.54 - 8.49 (m, 1H), 8.33 - 8.13 (m, 1H), 7.84 - 7.74 (m, 1H), 7.67 - 7.60 (m, 1H), 7.45 - 7.24 (m, 4H), 7.13 - 7.05 (m, 2H), 6.95 - 6.88 (m, 1H), 6.72 - 6.65 (m, 1H), 5.86 - 5.74 (m, 1H), 5.52 - 5.40 (m, 1H), 4.75 - 4.65 (m, 1H), 4.61 - 4.50 (m, 2H), 4.37 - 4.27 (m, 1H), 4.25 - 4.14 (m, 1H), 4.11 - 3.90 (m, 1H), 3.19 - 3.01 (m, 3H), 2.94 - 2.88 (m, 1H), 2.86 - 2.82 (m, 3H), 2.64 - 2.59 (m, 3H), 2.56 - 2.49 (m, 1H), 2.43 - 2.38 (m, 3H). Example 220 (8S,11S)-10-[1-(4-fluoro-2-methylsulfinyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 4-chloro-1-(4-fluoro-2-methylsulfinyl-phenyl)pyrazolo[3,4- d]pyrimidine (compound 220a) To a solution of compound 219e (300 mg, 1.02 mmol) in dichloromethane (30 mL) was added 3-chloroperoxybenzoic acid (175 mg, 1.02 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture was quenched with saturated NaHCO ₃ solution (20 mL) and then extracted with DCM (three times, 40 mL). The combined organic layer was washed with brine (30 mL) and then concentrated. The residue was purified by silica gel to afford compound 220a (230 mg), LCMS (M+H ⁺ ): 311. Step 2: preparation of (8S,11S)-10-[1-(4-fluoro-2-methylsulfinyl-phenyl)pyrazolo[3, 4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 -hexazapentacyclo- 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]-hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 220) A solution of compound 197d (50 mg, 0.071 mmol), compound 220a (22 mg, 0.071 mmol) and DIEA (49 μL, 0.284 mmol) in 1,4-dioxane (1 mL) was stirred at 70°C for 1 hour. The solvent was removed and the residue was purified by prep-HPLC to afford Example 220 (16.1 mg), LCMS (M+H ⁺ ): 695. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.50 (m, 1H), 8.43 - 8.24 (m, 1H), 8.03 - 7.94 (m, 1H), 7.92 - 7.86 (m, 1H), 7.83 - 7.73 (m, 1H), 7.68 - 7.60 (m, 1H), 7.54 - 7.47 (m, 1H), 7.44 - 7.39 (m, 1H), 7.37 - 7.28 (m, 1H), 7.14 - 6.88 (m, 1H), 6.71 - 6.61 (m, 1H), 5.87 - 5.64 (m, 1H), 5.53 - 5.41 (m, 1H), 4.74 - 4.45 (m, 3H), 4.36 - 4.26 (m, 1H), 4.23 - 3.90 (m, 2H), 3.18 - 3.01 (m, 4H), 2.95 - 2.87 (m, 4H), 2.86 - 2.81 (m, 3H), 2.65 - 2.57 (m, 3H), 2.55 - 2.47 (m, 1H). Example 221 (8S,11S)-10-[1-(4-fluoro-2-methylsulfonyl-phenyl)pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 219 by using (4-fluoro-2-mesyl-phenyl)amine instead of [4-fluoro-2-(methylthio)phenyl]amine (compound 219b). LCMS (M+H ⁺ ): 711. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.19 (s, 1H), 8.04 - 7.96 (m, 1H), 7.84 - 7.58 (m, 5H), 7.41 - 7.36 (m, 1H), 7.32 - 7.23 (m, 1H), 7.14 - 6.88 (m, 1H), 6.72 - 6.63 (m, 1H), 5.82 - 5.69 (m, 1H), 5.53 - 5.38 (m, 1H), 4.73 - 4.64 (m, 1H), 4.62 - 4.51 (m, 4H), 4.38 - 3.91 (m, 4H), 3.15 - 3.01 (m, 3H), 2.95 - 2.87 (m, 1H), 2.85 - 2.80 (m, 3H), 2.61 - 2.57 (m, 3H), 2.54 - 2.48 (m, 1H). Example 222 (8S,11S)-10-[1-(2-dimethylphosphoryl-4-fluoro-phenyl)pyrazol o[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]-hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 219 by using compound 222a instead of compound 219b in step 3. LCMS (M+H ⁺ ): 709. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.62 - 8.56 (m, 1H), 8.37 - 8.21 (m, 1H), 7.91 - 7.70 (m, 3H), 7.67 - 7.58 (m, 1H), 7.57 - 7.40 (m, 3H), 7.14 - 6.93 (m, 1H), 6.76 - 6.65 (m, 1H), 5.90 - 5.71 (m, 1H), 5.51 - 5.38 (m, 1H), 4.71 - 4.56 (m, 1H), 4.52 - 4.41 (m, 1H), 4.35 - 4.09 (m, 2H), 4.00 - 3.82 (m, 1H), 3.11 - 2.97 (m, 2H), 2.96 - 2.88 (m, 2H), 2.81 - 2.76 (m, 3H), 2.74 - 2.62 (m, 4H), 2.03 - 1.94 (m, 1H), 1.58 - 1.49 (m, 1H), 1.48 - 1.39 (m, 4H), 1.29 - 1.20 (m, 3H). The compound 222a was prepared according to the following scheme: A suspension of 4-fluoro-2-iodoaniline (1.19 g, 5.0 mmol), methylphosphonoylmethane (429 mg, 5.5 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (578 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (457 mg, 0.50 mmol) and cesium carbonate (3.26 g, 10.0 mmol) in 1,4-dioxane (2.5 mL) was stirred at 100 °C for 12 hour. The solvent was removed and the residue was purified by reversed-phase chromatography to afford compound 222a (690 mg), LCMS (M+H ⁺ ): 188. Example 226 (8S,11S)-4-[(3,3-difluoroazetidin-1-yl)methyl]-10-[1-(4-fluo ro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimet hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of (2,6-dibromo-4-pyridyl)methanol (compound 226b) To a solution of methyl 2,6-dibromopyridine-4-carboxylate (10. g, 33.91 mmol) in methanol (100 mL) was added sodium borohydride (5.13 g, 135.63 mmol) at 0 °C. After being heated to 65 °C for 3 h, the reaction mixture was cooled and poured into ice water. Then the mixture was adjusted to pH around 7 and extracted with EA, the organic layer was dried and concentrated to give the crude compound 226b (8.5 g) LCMS (M+H) ⁺ : 268. Step 2: preparation of tert-butyl-[(2,6-dibromo-4-pyridyl)methoxy]-dimethyl-silane (compound 226c) To a mixture of triethylamine (1.31 mL, 9.37 mmol) and compound 226b (1 g, 3.75 mmol) in DCM (10 mL) was added tert-butyldimethylsiyl triflate (1.3 g, 4.9 mmol) dropwise at 0 °C. After being stirred at 0 °C for 2 h, the reaction was quenched with water and then extracted with DCM, the organic layer was dried and concentrated to give compound 226c (1.3 g). LCMS (M+H) ⁺ : 379. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-bromo-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]amino]pyrrolidine- 1,2-dicarboxylate (compound 226d) A mixture of compound 226c (3.93 g, 10.3 mmol), O1-tert-butyl O2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate;hydrochloride (2.5 g, 8.9 mmol), Cs ₂ CO ₃ (8.7 g, 26.71 mmol), Pd(OAc) ₂ (0.33 g, 1.48 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.86 g, 1.48 mmol) in 1,4-dioxane (60 mL) was stirred at 85 °C for 12 h under N ₂ . The reaction mixture was concentrated and the residue was purified by silica gel to give compound 226d (2.3 g). LCMS (M+H) ⁺ : 544. Step 4-9: preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-4-(hydroxymethyl)-15-methoxy-13,18-dimethy l-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 226i) Compound 226i was prepared in analogy to the preparation of compound 289 by using compound 226d instead of intermediate B1, intermediate A1 instead of intermediate A12. LCMS (M+H) ⁺ : 693. Step 10-11: preparation of (8S,11S)-4-[(3,3-difluoroazetidin-1-yl)methyl]-10-[1-(4- fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-me thoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one;2,2,2-trifluoroa cetic acid (Example 226) To a mixture of compound 226i (25.0 mg, 0.03 mmol) and DIPEA (17.5 μL, 0.110 mmol) in DCM (1 mL) was added Ms ₂ O (18.86 mg, 0.11 mmol) at 0 °C. After being stirred at rt for 1 h, 3,3-difluoroazetidine hydrochloride (21.01 mg, 0.160 mmol) was added and the mixture was stirred at rt for 12 h. Then the mixture was concentrated, the residue was purified by prep-HPLC to give Example 226 (2.3 mg). LCMS (M+H) ⁺ : 768. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.37 - 8.18 (m, 1H), 7.92 - 7.63 (m, 3H), 7.52 - 7.37 (m, 1H), 7.25 - 7.02 (m, 2H), 6.96 - 6.68 (m, 2H), 6.27 - 6.04 (m, 1H), 5.57 - 5.37 (m, 1H), 4.79 - 4.70 (m, 1H), 4.60 - 4.52 (m, 1H), 4.47 - 4.15 (m, 7H), 4.04 - 3.73 (m, 5H), 3.23 - 2.94 (m, 8H), 2.88 - 2.82 (m, 3H), 2.72 - 2.53 (m, 2H). Example 230 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-15-methoxy- 13,18-dimethyl-4-(morpholinomethyl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 226 by using morpholine instead of 3,3-difluoroazetidine hydrochloride. LCMS (M+H) ⁺ : 762. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.56 (s, 1H), 8.39 - 8.21 (m, 1H), 7.88 - 7.73 (m, 2H), 7.71 - 7.62 (m, 1H), 7.50 - 7.38 (m, 1H), 7.35 - 7.14 (m, 1H), 7.08 (dd, J = 2.4, 10.4 Hz, 1H), 6.93 - 6.84 (m, 2H), 6.19 - 5.45 (m, 2H), 4.80 - 4.69 (m, 1H), 4.64 - 4.55 (m, 1H), 4.51 - 4.22 (m, 5H), 4.13 - 3.87 (m, 5H), 3.77 (s, 3H), 3.46 - 3.36 (m, 3H), 3.23 - 3.03 (m, 4H), 3.01 - 2.75 (m, 8H), 2.67 - 2.58 (m, 1H). Example 231 and Example 232 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-4,15-dimethoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4,15-dimethoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared in analogy to the preparation of Example 129 by using Intermediate A1 instead of compound 129c in step 2 and compound 231a instead of Intermediate B9 in step 3. The mixture Example 231 (Faster eluted) and Example 232 (Slower eluted) was separated via prep-HPLC. Example 231, LCMS (M+H ⁺ ): 681, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.22 (s, 1H), 7.69 - 7.61 (m, 1H), 7.61 - 7.57 (m, 1H), 7.31 - 7.16 (m, 4H), 6.53 - 6.45 (m, 1H), 6.21 - 6.15 (m, 1H), 5.50 (d, J = 9.0 Hz, 1H), 5.13 - 4.96 (m, 1H), 4.71 (t, J = 5.3 Hz, 1H), 4.56 (dd, J = 6.5, 11.5 Hz, 1H), 4.27 (d, J = 11.4 Hz, 1H), 4.13 - 4.05 (m, 1H), 4.02 - 3.94 (m, 1H), 3.94 - 3.91 (m, 3H), 3.86 - 3.74 (m, 1H), 3.12 (s, 3H), 3.02 - 2.93 (m, 1H), 2.86 (s, 3H), 2.76 (d, J = 13.4 Hz, 1H), 2.60 - 2.57 (m, 3H), 2.54 (td, J = 4.5, 9.1 Hz, 1H). Example 232, LCMS (M+H ⁺ ): 681, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.22 (s, 1H), 7.67 (dt, J = 6.0, 8.5 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.32 - 7.25 (m, 2H), 7.20 (br t, J = 8.4 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 6.14 (s, 1H), 5.85 - 5.70 (m, 1H), 5.50 - 5.39 (m, 1H), 4.67 - 4.57 (m, 1H), 4.53 - 4.46 (m, 1H), 4.31 (br d, J = 11.3 Hz, 1H), 4.27 - 4.20 (m, 1H), 4.18 - 4.09 (m, 1H), 3.98 (s, 3H), 3.96 - 3.91 (m, 1H), 3.08 (s, 3H), 2.98 - 2.87 (m, 2H), 2.85 (s, 3H), 2.67 - 2.59 (m, 1H), 2.59 - 2.55 (m, 3H). The compound 231a was prepared according to the following scheme: To a solution of 2,6-dibromo-4-methoxy-pyridine (1000 mg, 3.74 mmol) in 1,4-dioxane (20 mL) was added O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (1052 mg, 3.74 mmol), cesium carbonate (3652 mg, 11.24 mmol), 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene (343 mg, 0.75 mmol) and tris(dibenzylideneacetone) dipalladium (0) (400.0 mg, 0.375 mmol). The reaction was stirred at 85 °C for 12 hrs under N ₂ . The reaction mixture was filtered and concentrated, the residue was purified by flash-HPLC to give compound 231a (600 mg), LCMS (M+H) ⁺ : 431. Example 250 & 251 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-4,13-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-4,13-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compounds were prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-4-methyl-2- pyridyl)amino]pyrrolidine-1,2-dicarboxylate (compound 250a) To a flask was added 2-bromo-6-fluoro-4-methyl-pyridine (372 mg, 1.96 mmol), O1-tert- butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (500 mg, 1.78 mmol), DIPEA (690 mg, 933 μL, 5.34 mmol), DMSO (10mL). The mixture was heated to 110 °C for 12 hrs. The mixture was diluted with 40 mL EA and then it was washed with water 25 mL for three times, the organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel to give compound 250a (390 mg), LCMS (M+H ⁺ ): 414. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[6-fluoro-3-[2-methoxy- 3-(methylamino)propyl]benzimidazol-4-yl]-4-methyl-2-pyridyl] amino]pyrrolidine-1,2- dicarboxylate (compound 250b) To a flask was added tert-butyl N-[3-[5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (Intermediate A4, 800 mg, 1.38 mmol), 1,4-dioxane (3 mL). Then HCl in dioxane (4 N, 3 mL) was added to the suspension dropwise. The suspension was stirred at room temperature for 1 hr. Then the mixture was concentrated and the residue was dissolved in 1,4-dioxane (5 mL), compound 250a (390 mg, 0.94 mmol), K ₂ CO ₃ (650 mg, 4.71 mmol) and water (1mL) were added. The suspension was bubbled with N ₂ for 5 mins and PdCl ₂ (DPPF)-CH ₂ Cl ₂ adduct (69 mg, 94 μmol) was added. The mixture was heated to 90 °C for 1 hr, then filtered, the filtrate was diluted with water and then it was extracted with EA for three times, the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel to give compound 250b (270 mg), LCMS (M+H ⁺ ): 571. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[6-fluoro-3-[2-methoxy-3 - (methylamino)propyl]benzimidazol-4-yl]-4-methyl-2-pyridyl]am ino]pyrrolidine-2- carboxylic acid (compound 250c) To the flask containing O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[6-fluoro-3-[2-methoxy-3- (methylamino)propyl]benzimidazol-4-yl]-4-methyl-2-pyridyl]am ino]pyrrolidine-1,2- dicarboxylate (compound 250b, 177 mg, 0.31 mmol) was added MeOH (2 mL) and 2 N aqueous solution of LiOH (2 mL, 4 mmol). The mixture was stirred at room temperature for 30 mins, then the mixture was acidified to pH = 5 with 1 N HCl. The mixture was concentrated, the residue was purified by flash preparation to give compound 250c (220 mg), LCMS (M+H ⁺ ): 557. Step 4: preparation of tert-butyl (8S,11S)-22-fluoro-15-methoxy-4,13-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 250d) To a 250 mL flask was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (451 mg, 1.19 mmol), DIPEA (511 mg, 690 μL, 3.95 mmol) and acetonitrile (60 mL). Then a solution of compound 250c (220 mg, 0.39 mmol) in acetonitrile (60 mL) was added dropwise in 20 mins. The mixture was concentrated, the residue was purified via flash preparation to give compound 250d (200 mg), LCMS (M+H ⁺ ): 539. Step 5: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-4,13-dimethyl-7,10,13 ,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-4,13-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (example 250 & 251) To a microwave tube was added tert-butyl (8S,11S)-22-fluoro-15-methoxy-4,13-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 250d, 200 mg, 0.362 mmol), 4-chloro-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C2, 116 mg, 0.434 mmol), DIPEA (468 mg, 632 μL, 3.62 mmol) and acetonitrile (4 mL). The mixture was heated to 80 °C and stirred for about 30 mins. The mixture was filtered and concentrated, then it was purified via prep-HPLC and SFC to obtain example 250 and example 251. SFC conditions: Instrument: SFC 80; Column: TCI Chiral MB-S 250×30 mm I.D., 5μm. Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 20%. Flow rate: 60 mL /min. Back pressure: 100 bar. Column temperature: 35℃. Example 250 (faster eluted, 44 mg), LCMS (M+H ⁺ ): 669. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.59 - 8.34 (m, 1H), 8.27 - 7.81 (m, 2H), 7.79 - 7.70 (m, 1H), 7.60 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.37 - 7.30 (m, 1H), 7.29 - 7.23 (m, 1H), 7.04 - 6.96 (m, 1H), 6.56 - 6.46 (m, 1H), 5.73 - 5.60 (m, 1H), 5.60 - 5.43 (m, 2H), 4.64 - 4.56 (m, 1H), 4.50 - 4.38 (m, 1H), 4.28 (br d, J = 11.5 Hz, 1H), 4.19 - 4.05 (m, 2H), 3.85 - 3.70 (m, 1H), 3.04 (s, 1H), 2.95 (s, 2H), 2.92 - 2.85 (m, 1H), 2.82 (br d, J = 12.8 Hz, 1H), 2.75 (s, 2H), 2.73 (s, 1H), 2.63 (br d, J = 13.4 Hz, 1H), 2.40 (s, 3H). Example 251 (slower eluted, 96 mg), LCMS (M+H ⁺ ): 669. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.62 (s, 1H), 8.55 - 8.47 (m, 1H), 8.39 - 8.25 (m, 1H), 7.77 - 7.69 (m, 1H), 7.60 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.53 (dd, J = 2.6, 8.8 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.22 (dd, J = 2.4, 10.4 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.69 - 6.56 (m, 1H), 5.56 - 5.44 (m, 1H), 5.41 - 5.31 (m, 1H), 4.99 - 4.83 (m, 1H), 4.77 - 4.69 (m, 1H), 4.57 - 4.49 (m, 1H), 4.26 - 4.16 (m, 2H), 4.05 - 3.96 (m, 1H), 3.91 (br dd, J = 5.0, 10.5 Hz, 1H), 3.24 - 3.15 (m, 1H), 3.13 (s, 1H), 3.03 (s, 2H), 2.92 (s, 2H), 2.88 (s, 1H), 2.59 - 2.53 (m, 1H), 2.38 (s, 3H), 2.34 - 2.27 (m, 1H). Example 269 and Example 270 (8S,11S,15R)-10-[6-amino-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]- hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[6-amino-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compounds were prepared in analogy to the preparation of Example 12 by using intermediate A2 and instead of Intermediate A11 andIntermediate C23 instead of Intermediate C2. The example 269 and 270 were separated via SFC. SFC conditions: Instrument: SFC 80; Column: OD, 250×20 mm I.D., 5μm.; Mobile phase: A for CO ₂ and B for ethanol (0.1% NH _3· H ₂ O); Gradient: B 35%; Flow rate: 40 mL /min; Back pressure: 100bar; Column temperature: 35℃ Example 269, faster eluted, LCMS (M+H ⁺ ): 684. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.21 - 8.10 (m, 1H), 7.79 - 7.67 (m, 1H), 7.55 - 7.32 (m, 2H), 7.30 - 7.21 (m, 1H), 7.19 - 7.11 (m, 2H), 7.10 - 7.04 (m, 1H), 7.03 - 6.97 (m, 1H), 6.65 - 6.55 (m, 1H), 5.82 - 5.64 (m, 1H), 5.36 - 5.20 (m, 1H), 4.57 - 4.49 (m, 1H), 4.40 - 4.30 (m, 1H), 4.18 - 3.96 (m, 3H), 3.88 - 3.78 (m, 1H), 3.07 - 2.98 (m, 1H), 2.93 (s, 2H), 2.79 - 2.75 (m, 3H), 2.57 - 2.51 (m, 3H), 2.45 - 2.32 (m, 2H). Example 270, slower eluted, LCMS (M+H ⁺ ): 684. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.20 - 8.11 (m, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.24 (dd, J = 2.5, 8.3 Hz, 1H), 7.18 - 7.11 (m, 1H), 7.09 - 6.99 (m, 2H), 6.86 - 6.79 (m, 1H), 6.61 (br d, J = 8.4 Hz, 1H), 5.36 (d, J = 9.0 Hz, 1H), 5.28 - 5.16 (m, 1H), 4.61 - 4.54 (m, 1H), 4.44 - 4.34 (m, 1H), 4.17 - 4.09 (m, 1H), 4.03 - 3.90 (m, 2H), 3.68 - 3.54 (m, 1H), 3.09 - 3.04 (m, 1H), 2.96 (s, 2H), 2.93 - 2.87 (m, 1H), 2.77 (s, 3H), 2.61 - 2.48 (m, 4H), 2.39 (ddd, J = 4.6, 9.0, 13.5 Hz, 1H). Example 279 (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4-difluorophenyl)py razolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 22-fluoro-15-hydroxy-7,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1~5: preparation of tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl)-2-[tert- butyl(dimethyl)silyl]oxy-propyl]-N-(cyclopropylmethyl)carbam ate (compound 279a) The compound 279a was prepared in analogy to the preparation of intermediate A7-f by using tert-butyl N-[(3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate, trimethoxymethane instead of 1,1,1-trimethoxyethane and bromomethylcyclopropane instead of methyl iodide. LCMS (M+H) ⁺ : 556. Step 6: preparation of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxy-3-[5-fluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1- yl]propyl]-N- (cyclopropylmethyl)carbamate (compound 279b) The compound 279b was prepared in analogy to the preparation of intermediate A7 by using compound 279a instead of intermediate A7-h. LCMS (M+H) ⁺ : 604. Step 7~11: preparation of (8S,11S)-13-(cyclopropylmethyl)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-h ydroxy-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 279) The title compound was prepared in analogy to the preparation of Example 289 by using compound 279b instead of intermediate A12, intermediate B9 instead of intermediate B1 and intermediate C2 instead of intermediate C11. LCMS (M+H) ⁺ : 681. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.59 - 8.33 (m, 1H), 8.33 - 7.84 (m, 2H), 7.80 - 7.54 (m, 2H), 7.46 - 7.01 (m, 4H), 6.94 - 6.63 (m, 1H), 5.82 - 5.41 (m, 1H), 4.79 - 4.67 (m, 1H), 4.62 - 3.88 (m, 7H), 3.57 - 3.44 (m, 1H), 3.26 - 3.08 (m, 2H), 3.00 - 2.76 (m, 1H), 2.69 - 2.56 (m, 1H), 1.10 - 0.96 (m, 1H), 0.74 - 0.11 (m, 4H). Example 283 (8S,11S)-10-[1-(4-fluoro-2-vinyl-phenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one The title compound was prepared according to the following scheme: To the solution of Intermediate C44 (15.0 mg, 0.06 mmol) in DMF (1.0 mL) was added PyBOP (28.5 mg, 0.06 mmol) and DIEA (15.1 mg, 0.12 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. Then compound 283a (22.1 mg, 0.06 mmol, the preparation was refer to compound 289d by using Intermediate A11 instead of Intermediate A12) was added and the mixture was stirred at 20 °C for additional 2 h. The mixture was purified by prep-HPLC to give Example 283 (5.2 mg). LCMS (M+H) ⁺ : 616. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.15 - 9.22 (m, 1H), 8.64 (d, J=5.26 Hz, 1H), 8.56 (s, 1H), 8.20 - 8.35 (m, 1H), 7.95 (d, J=7.46 Hz, 1H), 7.60 - 7.85 (m, 3H), 7.47 (dd, J=8.68, 5.14 Hz, 1H), 7.23 - 7.30 (m, 1H), 7.15 (d, J=5.26 Hz, 1H), 6.17 - 6.27 (m, 1H), 5.81 - 5.89 (m, 1H), 5.38 - 5.54 (m, 2H), 5.29 (d, J=11.25 Hz, 1H), 4.49 - 4.57 (m, 1H), 4.38 - 4.47 (m, 2H), 4.08 - 4.18 (m, 1H), 3.05 - 3.22 (m, 4H), 2.89 - 2.97 (m, 2H), 2.57 - 2.66 (m, 1H), 1.89 - 2.01 (m, 1H), 1.45 - 1.57 (m, 1H). Example 284 (8S,11S)-10-[1-(2-cyclopropyl-4-fluoro-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one The title compound was prepared in analogy to the preparation of Example 283 by using Intermediate C45 instead of Intermediate C44. LCMS (M+H) ⁺ : 630. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 - 8.65 (m, 2H), 8.18 - 8.35 (m, 2H), 7.82 (d, J=8.44 Hz, 1H), 7.52 (br d, J=7.46 Hz, 1H), 7.35 - 7.44 (m, 2H), 7.05 - 7.17 (m, 2H), 6.94 (dd, J=9.96, 2.87 Hz, 1H), 5.49 (d, J=8.68 Hz, 1H), 5.16 - 5.31 (m, 1H), 4.51 (s, 1H), 4.25 - 4.39 (m, 2H), 4.12 (br d, J=4.16 Hz, 1H), 2.77 - 3.27 (m, 6H), 2.52 - 2.73 (m, 1H), 1.75 - 1.95 (m, 1H), 1.39 - 1.58 (m, 2H), 0.63 - 0.77 (m, 4H). Example 286 (8S,11S)-10-[1-(2-bromo-4-fluoro-phenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-13-methyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 283 by using Intermediate C43 instead of Intermediate C44. LCMS (M+H) ⁺ : 668. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.78 - 8.87 (m, 1H), 8.61 (d, J=5.14 Hz, 1H), 8.56 (s, 1H), 8.21 - 8.38 (m, 1H), 7.90 (d, J=8.44 Hz, 1H), 7.66 - 7.74 (m, 2H), 7.54 - 7.64 (m, 2H), 7.40 (td, J=8.41, 2.87 Hz, 1H), 7.13 (d, J=5.14 Hz, 1H), 5.51 (d, J=8.93 Hz, 1H), 5.31 - 5.39 (m, 1H), 4.47 - 4.58 (m, 1H), 4.31 - 4.43 (m, 2H), 4.05 - 4.19 (m, 1H), 3.04 - 3.18 (m, 4H), 2.83 - 2.97 (m, 2H), 2.60 (s, 1H), 1.94 - 2.07 (m, 1H), 1.50 - 1.67 (m, 1H). Example 289 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyr imidin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propan-1-amine (compound 289a) A mixture of N-methyl-N-[3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)benzimidazol-1-yl]propyl]carbamic acid tert-butyl ester (compound A12, 500 mg, 1.16 mmol, as the “BORONIC REAGENT” in table 6) in DCM (5 mL) and HCl in Dioxane (4 M, 2 mL, ) was stirred at rt for 4 hours, then the reaction was filtered to give compound 289a (400 mg). LCMS (M+H ⁺ ): 330. Step 2: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2-methyl-3-[3- (methylamino)propyl]benzimidazol-4-yl]pyrimidin-2-yl]amino]p yrrolidine-2-carboxylic acid (compound 289b) A mixture of K ₂ CO ₃ (968.36 mg, 7.01 mmol), N-methyl-3-[2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propan -1-amine (compound 289a, 580 mg, 1.68 mmol), intermediate B1 (500 mg, 1.4 mmol, as the “HALIDE 1” in table 6) and PdDCl ₂ (DPPF) (114.4 mg, 0.14 mmol) in Dioxane/ H ₂ O (10:1, 20 mL) was stirred at 90 °C for 2 hours. Then the reaction mixture was concentrated, the residue was dissolved in THF/MeOH (15 mL, 2:1), 2 M LiOH (3.87 mL, 7.73 mmol ) was added and stirred at rt for 4 hours. The reaction was adjusted to pH=5, then the reaction was concentrated to remove most organic solvent, the residue was purified by flash preparation (MeCN/ TFA in water) to give compound 289b (600mg). LCMS (M+H ⁺ ): 510. Step 3~4: preparation of (8S,11S)-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (compound 289d) To a mixture of HATU (1.23 g, 3.23 mmol) and DIPEA (1.04 g, 8.07 mmol) in acetonitrile (150 mL) was added (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2-methyl-3-[3- (methylamino)propyl]benzimidazol-4-yl]pyrimidin-2-yl]amino]p yrrolidine-2-carboxylic acid (289b, 800 mg, 1.61 mmol ) in acetonitrile (150 mL) dropwise in 2 hours. Then the reaction was concentrated, the residue was purified by flash preparation (MeCN/ TFA in water) to give a light yellow solid, which was dissolved in dichloromethane (10 mL) and 4 M HCl in dioxane (4.04 mL, 16.14 mmol) and stirred at rt for 4 hours. The reaction was concentrated to give compound 289d (400 mg). LCMS (M+H ⁺ ): 392. Step 5: preparation of (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (Example 289) A mixture of ((8S,11S)-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 289d, 100 mg, 0.255 mmol), 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (intermediate C11, 71 mg, 0.255 mmol, as the “HALIDE 2” in table 6) and DIPEA (165 mg, 1.28 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 2 hours. Then the reaction was concentrated, the residue was purified by HPLC to give Example 289 (70 mg). LCMS (M+H ⁺ ): 634. ¹ H NMR (500 MHz, METHANOL-d4) δ = 8.55 (d, J = 5.2 Hz, 1H), 8.49 - 8.24 (m, 1H), 8.20 - 7.65 (m, 2H), 7.50 - 7.32 (m, 3H), 7.12 - 6.95 (m, 2H), 6.87 (dt, J = 2.7, 8.4 Hz, 1H), 5.54 - 5.19 (m, 2H), 4.66 (br d, J = 3.5 Hz, 1H), 4.47 (dd, J = 6.3, 11.4 Hz, 1H), 4.36 - 4.19 (m, 1H), 4.13 - 3.99 (m, 2H), 3.84 - 3.69 (m, 3H), 3.11 (s, 1H), 3.03 (s, 2H), 2.99 - 2.82 (m, 2H), 2.72 - 2.49 (m, 3H), 2.55 (ddd, J = 4.6, 9.0, 13.6 Hz, 1H), 2.04 - 1.75 (m, 1H), 1.44 - 1.24 (m, 1H). The following examples in Table 6 were prepared in analogy to Example 289, replacing Intermediate A12 with the “BORONIC REAGENT” in step 1, Intermediate B1 with the “HALIDE 1” in step 2, Intermediate C11 with the “HALIDE 2” in step 5 by the reagents indicated in Table 6. Table 6. Compound synthesis and characterization Example 292 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(4,4,4-trifluorobutyl)- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1~2: preparation of tert-butyl N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl]-N-(4,4,4-trifluorobutyl)carbama te (compound 292b) Compound 292b was prepared in analogy to the preparation of compound 340b and by using 1,1,1-trifluoro-4-iodo-butane instead of 1-bromo-3-methoxy-propane. LCMS (M+H) ⁺ : 512. Step 3~7: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-(4,4,4-trifluorobutyl)-5,7,10,13,17,19, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (Example 292) The title compounds were prepared in analogy to the preparation of Example 289 by using compound 292b instead of Intermediate A12 and Intermediate C2 instead of Intermediate C11. LCMS (M+H) ⁺ : 704. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.58 - 9.33 (m, 1H), 8.69 - 8.34 (m, 2H), 8.29 - 7.92 (m, 2H), 7.88 - 7.54 (m, 3H), 7.40 - 7.09 (m, 3H), 5.66 - 5.39 (m, 2H), 4.99 - 4.91 (m, 1H), 4.58 - 4.16 (m, 3H), 3.95 (br dd, J = 10.0, 14.4 Hz, 1H), 3.57 - 3.33 (m, 2H), 3.15 - 2.96 (m, 1H), 2.86 - 2.75 (m, 1H), 2.74 - 2.56 (m, 1H), 2.43 - 2.10 (m, 2H), 2.06 - 1.71 (m, 2H), 1.63 - 1.21 (m, 2H). Example 294 (8S,11S)-10-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl ]-22-fluoro-13-(3-pyrimidin- 2,6 8,11 20,24 2-yloxypropyl)-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]-hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl) propyl] carbamate (compound 294a) Compound 294a was prepared in analogy to the preparation of Intermediate A15-c by using 1-bromo-2,5-difluoro-3-nitro-benzene instead of 1-bromo-2-fluoro-3-nitro-benzene. LCMS (M+H ⁺ ): 372. Step 2: preparation of tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl)propyl]- N-(3-hydroxypropyl]carbamate (compound 294b) To a flask was added 3-bromopropoxy-tert-butyl-dimethyl-silane (2.04 g, 8.06 mmol), DMF (30mL), NaH (60% purity, 645 mg, 16.12 mmol). The solution was stirred at room temperature for 10 mins, then tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl) propyl] carbamate (compound 294a, 3 g, 8.06 mmol) was added. The mixture was stirred at room temperature for 2 hrs, then NaH (60% purity, 645 mg, 16.12 mmol) and tert-butyl N-[3-(7- bromo-5-fluoro-benzimidazol-1-yl) propyl] carbamate (compound 294a, 3 g, 8.06 mmol) were added again. The mixture was stirred at room temperature for 12 hrs, and then it was quenched with water. The mixture was poured into 150 mL EA, and then washed with 50 mL water for three times. The organic layer was dried and concentrated, the residue was dissolved in THF (40 mL), then TBAF (1 M, 33.4 mL, 33.4 mmol) was added. After being stirred at room temperature for 1 hr, the mixture was concentrated and the residue was purified by silica gel to give compound 294b (3.34 g), LCMS (M+H ⁺ ): 430. Step 3: preparation of tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl)propyl]-N- (3-pyrimidin-2-yloxypropyl]carbamate (compound 294c) A mixture of tert-butyl N-[3-(7-bromo-5-fluoro-benzimidazol-1-yl)propyl]-N-(3- hydroxypropyl]carbamate (compound 294b, 3.34 g, 7.76 mmol), 2-fluoropyrimidine (1.52 g, 15.52 mmol), and Cs ₂ CO ₃ (7.59 g, 23.29 mmol) in DMF (60 mL) was heated to 100 °C for 12 hrs. The mixture was poured into 150 mL EA, and then washed with 50 mL water for three times. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 294c (3.2 g), LCMS (M+H ⁺ ): 508. Step 4: preparation of tert-butyl N-[3-[5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-(3-pyrimidin-2 -yloxypropyl)carbamate (compound 294d) To a flask was added compound 294c (3.2 g, 6.29 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.2 g, 12.59 mmol), KOAc (1.24 g, 12.59 mmol) and DMSO (30mL), the suspension was bubbled with N ₂ for 5 mins, then Pd(PPh ₃ ) ₂ Cl ₂ (441.8 mg, 629 μmol) and bis(1-adamantyl)-butylphosphane (451.4 mg, 1.26 mmol) were added. The mixture was heated to 130 °C for 12 hrs. The mixture was poured into 150 mL EA, and then washed with 50 mL water for three times. The organic layer was dried and concentrated; the residue was purified by silica gel to give compound 294d (1.6 g), LCMS (M+H ⁺ ): 556. Step 5~7: preparation of tert-butyl (8S,11S)-22-fluoro-12-oxo-13-(3-pyrimidin-2- 2,6 8,11 20,24 yloxypropyl)-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaene-10-carboxylate (compound 294g) Compound 294g was prepared in analogy to the preparation of compound 289c by using compound 294d instead of intermediate A12 and Intermediate B13 instead of intermediate B2. LCMS (M+H ⁺ ): 618. Step 8: preparation of (8S,11S)-10-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl ]- 22-fluoro-13-(3-pyrimidin-2-yloxypropyl)-4,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (Example 294) To a mixture of 294g (200 mg, 0.324 mmol) in 1,4-dioxane (2 mL) was added HCl in dioxane (4 N, 2 mL) dropwise. The suspension was stirred at room temperature for 2 hrs. Then the mixture was concentrated, and 30 mg of the crude was dissolved in DMF (2mL), to the mixture was added intermediate C16 (16.7 mg, 70 μmol), HATU (66.1 mg, 174 μmol) and DIPEA (74.9 mg, 101 μL, 0.58 mmol). The mixture was stirred at room temperature for 2 hrs. The mixture was filtered and the filtrated was purified by prep-HPLC to give Example 294 (2 mg), LCMS (M+H ⁺ ): 740. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.65 (s, 1H), 8.60 (d, J = 4.8 Hz, 2H), 8.58 (d, J = 4.8 Hz, 1H), 8.26 - 8.11 (m, 3H), 7.81 - 7.71 (m, 2H), 7.61 - 7.54 (m, 1H), 7.49 - 7.36 (m, 1H), 7.33 - 7.24 (m, 1H), 7.16 - 7.11 (m, 1H), 5.21 – 5.04 (m, 1H), 4.86 - 4.64 (m, 1H), 4.36 - 4.27 (m, 3H), 4.20 - 3.96 (m, 4H), 3.88 - 3.71 (m, 1H), 2.97 - 2.78 (m, 1H), 2.46 - 2.38 (m, 2H), 2.23 – 2.20 (m, 1H), 2.11 - 1.90 (m, 2H), 1.85 - 1.64 (m, 2H), 1.50 - 1.21 (m, 1H). Example 295 (8S,11S)-22-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(4-chloro-2-nitro-anilino)propyl]-N-methyl- carbamate (compound 295a) To a solution of 4-chloro-1-fluoro-2-nitro-benzene (5.0 g, 28.4 mmol) and tert-butyl N-(3- aminopropyl)-N-methyl-carbamate (3.56 mL, 28.4 mmol) in ACN (50.0 mL) was added potassium carbonate (11.8 g, 85.4 mmol), and the mixture was stirred at 20 °C for 12 h under N ₂ . The reaction mixture was filtered and the filtrate was concentrated to give compound 295a (9.7 g) which was used in next step directly. LCMS (M+H) ⁺ : 244. Step 2: preparation of tert-butyl N-[3-(2-bromo-4-chloro-6-nitro-anilino)propyl]-N- methyl-carbamate (compound 295b) To a solution of tert-butyl N-[3-(4-chloro-2-nitro-anilino)propyl]-N-methyl-carbamate (compound 295a, 9.5 g, 27.63 mmol) in ACN (50.0 mL) was added NBS (9.7 g, 55.26 mmol), and the mixture was stirred at 80 °C for 12 h under N ₂ . The mixture was concentrated the residue was purified by column chromatography to give compound 295b (1.5 g). LCMS (M+H) ⁺ : 321. Step 3: preparation of tert-butyl N-[3-(2-amino-6-bromo-4-chloro-anilino)propyl]-N- methyl-carbamate (compound 295c) To a mixture of Raney Ni (2.0 g) and compound 295b (1.5 g, 3.55 mmol) in methanol (20.0 mL) was added NH ₂ NH ₂ •H ₂ O (0.96 g) dropwise below 20 °C over 0.5 h. After being stirred at 20 °C for 0.5 h, the mixture was filtered and the filtrate was concentrated, the residue was dissolved in DCM (0.5 L) and washed with brine (0.2 L for 3 times). The organic layer was dried and concentrated to give compound 295c (1.0 g). LCMS (M+H) ⁺ : 392. Step 4: preparation of tert-butyl N-[3-(7-bromo-5-chloro-benzimidazol-1-yl)propyl]- N-methyl-carbamate (compound 295d) To a solution of compound 295c (1.0 g, 2.55 mmol) in anhydrous THF (20.0 mL) was added trimethoxymethane (0.84 mL, 7.64 mmol) and pyridinium p-toluenesulfonate (0.32 g, 1.27 mmol). The mixture was stirred at 20 °C for 16 h, and then partitioned between EtOAc (0.5 L) and water (0.1 L). The organic layer was washed with brine (0.1 L), dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 295d (0.9 g). LCMS (M+H) ⁺ : 368. Step 5: preparation of 3-(7-bromo-5-chloro-benzimidazol-1-yl)-N-methyl-propan-1- amine (compound 295e) To a mixture of compound 295d (0.85 g, 2.12 mmol) in anhydrous DCM (2.0 mL) was added TFA (0.2 mL). The mixture was stirred at 20 °C for 16 h, and then concentrated to give compound 295e (0.5 g). LCMS (M+H) ⁺ : 301. Step 6: preparation of benzyl N-[3-(7-bromo-5-chloro-benzimidazol-1-yl)propyl]-N- methyl-carbamate (compound 295f) To a solution of compound 295e (0.5 g, 1.65 mmol) in THF (10.0 mL) and was added sodium hydrogen carbonate (0.7 g, 8.26 mmol) and benzyl carbonochloridate (1.1 g, 6.61 mmol). After being stirred 25 °C for 2 h, the mixture was concentrated; the residue was dissolved in EtOAc (0.1 L) and washed with water and brine. The organic layer was dried and concentrated, the residue was purified by flash column chromatography to give compound 295f (0.7 g). LCMS (M+H) ⁺ : 436. Step 7: preparation of benzyl N-[3-[5-chloro-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbama te (compound 295g) To a mixture of compound 295f (0.4 g, 0.92 mmol) in 1,4-dioxane (5.0 mL) was added potassium acetate (179.8 mg, 1.83 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (67.0 mg, 0.09 mmol). The mixture was stirred at 100 °C for 4 h under N ₂ , and then the mixture was used directly in next step without purification. LCMS (M+H) ⁺ : 484. Step 8: preparation of benzyl N-[3-[5-chloro-7-(2-chloropyrimidin-4-yl)benzimidazol- 1-yl]propyl]-N-methyl-carbamate (compound 295h) To a mixture of 2,4-dichloropyrimidine (138.6 mg, 0.93 mmol) and benzyl N-[3-[5-chloro- 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol- 1-yl]propyl]-N-methyl-carbamate (compound 295g, 0.5 g, 0.62 mmol) in 1,4-dioxane (5.0 mL) and H ₂ O (0.5 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (453.7 mg, 0.62 mmol) and potassium carbonate (85.7 mg, 0.62 mmol). The mixture was stirred at 130 °C for 4 h under N ₂ . After cooled to room temperature, the mixture was poured into water (0.1 L) and extracted with EtOAc (0.1 L twice). The combined organic layer was concentrated and the residue was purified by prep-HPLC to give compound 295h (200.0 mg). LCMS (M+H) ⁺ : 470. Step 9: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[4-[3-[3- [benzyloxycarbonyl(methyl)amino]propyl]-6-chloro-benzimidazo l-4-yl]pyrimidin-2- yl]amino]pyrrolidine-1,2-dicarboxylate (compound 295i) A mixture of compound 295h (190.0 mg, 0.40 mmol), DIEA (260.5 mg, 2.02 mmol) and O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (170.1 mg, 0.61 mmol) in NMP (5.0 mL) was stirred at 110 °C for 16 h. The mixture was purified by prep-HPLC to give compound 295i (150.0 mg). LCMS (M+H) ⁺ : 678. Step 10: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[4-[6-chloro-3-[3- (methylamino)propyl]benzimidazol-4-yl]pyrimidin-2-yl]amino]p yrrolidine-1,2- dicarboxylate (compound 295j) A mixture of compound 295i (120.0 mg, 0.18 mmol) in formic acid (10.0 mL) and methanol (10.0 mL) was added Pd/C (240.0 mg). The mixture was stirred at 20 °C for 0.25 h. The mixture was filtered and concentrated to give compound 295j (85.0 mg) as a yellow oil. LCMS (M+H) ⁺ : 544. Step 11: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[6-chloro-3-[3- (methylamino)propyl]benzimidazol-4-yl]pyrimidin-2-yl]amino]p yrrolidine-2-carboxylic acid (compound 295k) A mixture of compound 295j (85.0 mg, 0.16 mmol) and LiOH (32.0 mg, 0.78 mmol) in methanol (5.0 mL) and water (0.5 mL) was stirred at 20 °C for 12 h. The mixture was adjusted to pH=5, and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 295k (60.0 mg). LCMS (M+H) ⁺ : 530. Step 12: preparation of tert-butyl (8S,11S)-22-chloro-13-methyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaene-10-carboxylate (compound 295m) To a mixture of HATU (35.8 mg, 0.09 mmol) and DIPEA (0.03 mL, 0.19 mmol) in DMF (20.0 mL) was added compound 295k (50.0 mg, 0.09 mmol). The mixture was stirred at 20 °C for 1 h under N ₂ , and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 295m (30.0 mg). LCMS (M+H) ⁺ : 512. Step 13: preparation of (8S,11S)-22-chloro-13-methyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 295n) To a mixture of compound 295m (30.0 mg, 0.06 mmol) in DCM (1.0 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 4 h and then concentrated to give compound 295n (20.0 mg). LCMS (M+H) ⁺ : 412. Step 14: preparation (8S,11S)-22-chloro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-5,7,10,13,17 ,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 295) A mixture of compound 295n (20.0 mg, 0.04 mmol), intermediate C11 (20.3 mg, 0.06 mmol) and DIPEA (0.02 mL, 0.08 mmol) in NMP (1.0 mL) was stirred at 100 °C for 2 h. The mixture was concentrated and the residue was purified by prep-HPLC to give example 295 (14 mg). LCMS (M+H) ⁺ : 654. ¹ H NMR (DMSO-d ₆ ) δ = 8.58-8.64 (m, 1H), 8.37-8.49 (m, 2H), 8.15- 8.31 (m, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.38-7.49 (m, 2H), 7.20 (dd, J=11.3, 2.8 Hz, 1H), 7.08- 7.12 (m, 1H), 6.92-7.00 (m, 1H), 6.50-6.66 (m, 1H), 5.36-5.45 (m, 1H), 4.86-5.02 (m, 1H), 4.52- 4.81 (m, 1H), 4.05-4.46 (m, 3H), 3.87-4.00 (m, 1H), 3.74 (s, 3H), 2.93-3.06 (m, 3H), 2.73-2.91 (m, 1H), 2.59-2.70 (m, 1H), 2.53-2.58 (m, 1H), 1.68-1.90 (m, 1H), 1.24 (br s, 1H). Example 296 (8S,11S)-21-chloro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo [3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 4-bromo-3-fluoro-2-nitro-aniline (compound 296a) To a mixture of 3-fluoro-2-nitro-aniline (10.0 g, 64.06 mmol) in DMF (10.1L) was added NBS (11.4 g, 64.1 mmol) at 0°C. The mixture was stirred at 20 °C for 2 h and then concentrated. The residue was dissolved in EtOAc (0.5 L). The resulting organic solution was washed with water and brine, dried over anhydrous Na ₂ SO ₄ ^{and concentration to give compound 296a (11.0} g). LCMS (M+H) ⁺ : 235. Step 2: preparation of 1-bromo-4-chloro-2-fluoro-3-nitro-benzene (compound 296b) To a mixture of compound 296a (5.0 g, 21.3 mmol) in hydrochloric acid (2 M) (122.3 mL, 244.73 mmol) was added a solution of sodium nitrite (1.6 g, 23.4 mmol) in water (50.0 mL) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 2 h. Then a solution of copper (I) chloride (2.1 g, 21.3 mmol) in water (10.0 mL) was added into this mixture at 0 °C. The resulting mixture was stirred at 90 °C for 2 h. This mixture was extracted by EtOAc (0.1 L twice). The combined organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 296b (4.5 g). Step 3: preparation of tert-butyl N-[3-(6-bromo-3-chloro-2-nitro-anilino)propyl]-N- methyl-carbamate (compound 296c) A mixture of tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (3.7 g, 19.45 mmol), compound 296b (4.5 g, 17.69 mmol) and potassium carbonate (4.9 g, 35.37 mmol) in MeCN (0.1 L) was stirred at 85 °C for 12 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (0.2 L). The organic solution washed with water and brine, dried over anhydrous MgSO ₄ and concentration. The residue was purified by flash column chromatography to give compound 296c (3.5 g). LCMS (M+H) ⁺ : 322. Step 4: preparation of tert-butyl N-[3-(2-amino-6-bromo-3-chloro-anilino)propyl]-N- methyl-carbamate (compound 296d) A mixture of compound 296c (3.5 g, 8.56 mmol) and Pt/C (1.04 g, 18.56 mmol) in EA (80.0 mL) was stirred at 20 °C for 4 h under H ₂ ballnoon. The mixture was filtered through celite and the filtrate was concentrated to compound 296d (2.8 g) as a colorless oil. LCMS (M+H) ⁺ : 392. Step 5~15: preparation of (8S,11S)-21-chloro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-5,7,10,13,17 ,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 296) The title compound was prepared in analogy to the preparation of Example 295 (Step 4~14) by using compound 296d instead of compound 295c. LCMS (M+H) ⁺ : 654. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.57-8.65 (m, 1H), 8.39-8.49 (m, 2H), 8.15-8.31 (m, 1H), 7.40-7.47 (m, 3H), 7.20 (dd, J=11.3, 2.8 Hz, 1H), 7.03-7.09 (m, 1H), 6.90-7.00 (m, 1H), 6.46-6.66 (m, 1H), 5.33-5.48 (m, 1H), 4.92-5.08 (m, 1H), 4.51-4.81 (m, 1H), 4.36-4.45 (m, 1H), 4.14-4.34 (m, 2H), 3.94 (br dd, J=14.3, 9.3 Hz, 1H), 3.75 (s, 3H), 2.93-3.05 (m, 3H), 2.76-2.86 (m, 1H), 2.61-2.66 (m, 1H), 2.40-2.46 (m, 1H), 1.71-1.88 (m, 1H), 1.25-1.33 (m, 1H). Example 318 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21-fluoro-15-methoxy- 2,6 8,11 20,24 13-methyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of 1-bromo-2,4-difluoro-3-nitro-benzene (compound 318a) To a mixture of 1,3-difluoro-2-nitro-benzene (20.0 g, 0.12 mol) in sulfuric acid (40.0 mL) and trifluoroacetic acid (80.0 mL) was added NBS (26.8 g, 0.15 mol). The mixture was stirred at 80 °C for 12 hrs. The mixture was poured into ice water (0.1 L) and extracted with EtOAc (0.1 L twice). The combined organic layer was washed with NaHCO ₃ aq. (0.1 L) and brine (0.1 L), and then the organic layer was dried and concentrated, the residue was purified by flash chromatography to give compound 318a (22.0 g). Step 2: preparation of benzyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 318b) To a mixture of compound 318a (22.0 g, 0.1 mol) and DIEA (23.8 g, 0.2 mol, 2.0 eq) in DMF (0.1 L) was added a solution of benzyl N-(3-amino-2-hydroxy-propyl)carbamate (20.7 g, 0.1 mol) in DMF (0.2 L) dropwise over 0.5 h. The mixture was stirred at 20 °C for 1 h and then poured into ice water (0.5 L). The resulting mixture was extracted with EtOAc (0.5 L twice). The combined organic layer was washed with NaHCO ₃ aq. (0.1 L) followed by brine (0.1 L), dried and concentrated. The residue was purified by flash chromatography to give compound 318b (20.0 g). Step 3: preparation of benzyl N-[3-(2-amino-6-bromo-3-fluoro-anilino)-2-hydroxy- propyl]carbamate (compound 318c) To a mixture of Raney Ni (11.0 g) and compound 318b (10.0 g, 22.61 mmol) in methanol (0.3 L) was added N ₂ H ₄ •H ₂ O (11.0 g) dropwise and the mixture was stirred at 20 °C for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (0.3 L) and the solution was washed with brine (0.1 L twice). The organic layer was dried and concentrated to give compound 318c (8.0 g). LCMS (M+H) ⁺ : 412. Step 4: preparation of benzyl N-[3-(7-bromo-4-fluoro-benzimidazol-1-yl)-2-hydroxy- propyl]carbamate (compound 318d) To a solution of compound 318c (8.0 g) in anhydrous THF (0.1 L) was added trimethyl orthoformate (6.37 mL, 58.2 mmol) and pyridinium p-toluenesulfonate (1.0 g, 3.9 mmol). The mixture was stirred at 20 °C for 2 h, and then diluted with EtOAc (0.1 L). The resulting mixture was partitioned between water (0.1L) and EtOAc (0.1 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by prep-HPLC to give compound 318d (5.0 g). LCMS (M+H) ⁺ : 422. Step 5: preparation of benzyl N-[3-(7-bromo-4-fluoro-benzimidazol-1-yl)-2-methoxy- propyl]-N-methyl-carbamate (compound 318e) To a mixture of compound 318d (3.0 g, 7.1 mmol) and iodomethane (5.0 g, 35.5 mmol) in DMF (20.0 mL) was added sodium hydride (60% in oil, 1.4 g, 35.5 mmol) at -10 °C. The mixture was stirred at -10 °C for 2 h, and then poured into a.q. NH ₄ Cl (30.0 mL). The resulting mixture was extracted with EtOAc (30.0 mL twice). Then the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography to give compound 318e (1.5 g). LCMS (M+H) ⁺ : 450. Step 6~8: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[4-[3-[3- [benzyloxycarbonyl(methyl)amino]-2-methoxy-propyl]-7-fluoro- benzimidazol-4- yl]pyrimidin-2-yl]amino]pyrrolidine-1,2-dicarboxylate (compound 318h) The title compound was prepared in analogy to the preparation of Example 295 (Step 7~9) by using compound 318e instead of compound 295f. Compound 318h (0.2g) was obtained. LCMS (M+H) ⁺ : 692. Step 9: preparation of (2S,4S)-4-[[4-[3-[3-[benzyloxycarbonyl(methyl)amino]-2- methoxy-propyl]-7-fluoro-benzimidazol-4-yl]pyrimidin-2-yl]am ino]-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 318i) To a mixture of compound 318h (180.0 mg, 0.26 mmol) in water (5.0 mL) was added LiOH•H ₂ O (32.8 mg, 0.78 mmol) and the mixture was stirred at 20 °C for 12 h. The mixture was acidified with HCl (1M) to pH=4~5, and then extracted with EtOAc (20 mL twice). The combined organic layer was washed with brine, dried and concentrated to give compound 318i (150.0 mg). LCMS (M+H) ⁺ : 678. Step 10: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[7-fluoro-3-[2-methoxy-3 - (methylamino)propyl]benzimidazol-4-yl]pyrimidin-2-yl]amino]p yrrolidine-2-carboxylic acid (compound 318j) To the solution of compound 318i (150.0 mg, 0.22 mmol) in IPA (10.0 mL) was added Pd/C (150.0 mg) and the mixture was stirred at 80 °C for 12 h under H ₂ . The mixture was filtered and the filtrate was concentrated to give compound 318j (70.0 mg). LCMS (M+H) ⁺ : 544. Step 11~13: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-21-fluoro-15-methoxy-13-methyl-5,7,10,13,1 7,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 318) The title compound was prepared in analogy to the preparation of Example 295 (Step 12~14) by using compound 318j instead of compound 295k, and intermediate C2 instead of intermediate C11. LCMS (M+H) ⁺ : 656. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.42 - 8.60 (m, 2H), 8.08 - 8.37 (m, 2H), 7.48 - 7.87 (m, 2H), 7.00 - 7.36 (m, 4H), 5.36 - 5.69 (m, 2H), 3.86 - 4.70 (m, 5H), 2.97 - 3.30 (m, 5H), 2.80 - 2.93 (m, 4H), 2.52 - 2.65 (m, 1H). Example 326 and Example 327 (8S,11S,15R)-10-[1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]py rimidin-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(3,5-difluoro-2- pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-1 3,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

The title compounds were prepared in analogy to the preparation of Example 161 and Example 162 by using Intermediate A9 instead of compound 161b and Intermediate C1 instead of Intermediate C2. SFC condition of compound 326c: Instrument SFC 80. Column: IA, 250×30 mm I.D., 5μm. Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O). Gradient: B 40%. Flow rate: 60 mL /min. Backpressure: 100 bar. Column temperature: 35 °C. Compound 326c-1 (faster eluted), compound 326c-2 (slower eluted). Example 326, LCMS (M+H) ⁺ : 685. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.73 - 8.33 (m, 3H), 8.31 - 7.82 (m, 2H), 7.75 - 7.62 (m, 2H), 7.25 - 7.08 (m, 1H), 5.95 - 5.73 (m, 1H), 5.55 - 5.35 (m, 1H), 4.81 - 4.55 (m, 1H), 4.52 - 4.16 (m, 3H), 4.07 - 3.90 (m, 1H), 3.55 - 3.38 (m, 1H), 3.19 - 2.98 (m, 4H), 2.95 - 2.75 (m, 5H), 2.75 - 2.63 (m, 1H), 2.55 (ddd, J = 4.3, 9.1, 13.7 Hz, 1H), 0.73 - 0.54 (m, 3H). Example 327, LCMS (M+H) ⁺ : 685. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.67 - 8.35 (m, 3H), 8.30 - 7.79 (m, 2H), 7.72 - 7.55 (m, 2H), 7.09 (br s, 1H), 6.21 - 5.85 (m, 1H), 5.57 - 5.37 (m, 1H), 4.70 (br s, 1H), 4.50 (dd, J = 6.1, 11.6 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.31 - 4.23 (m, 1H), 4.07 (br d, J = 14.8 Hz, 1H), 3.82 - 3.66 (m, 1H), 3.45 - 3.36 (m, 1H), 3.21 - 3.04 (m, 4H), 2.98 - 2.80 (m, 5H), 2.74 - 2.50 (m, 1H), 0.73 - 0.54 (m, 3H). Example 330 and Example 331 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-22- 2,6 8,11 20,24 fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared in analogy to the preparation of Example 161 and Example 162 by using compound 326d-1 instead of compound 161e-1 and compound 326d-2 instead of compound 161e-2. Example 330, LCMS (M+H) ⁺ : 684. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.64 (d, J = 5.2 Hz, 1H), 8.57 - 8.32 (m, 1H), 8.27 - 7.79 (m, 1H), 7.74 - 7.58 (m, 3H), 7.39 - 7.05 (m, 3H), 5.94 - 5.67 (m, 1H), 5.53 - 5.33 (m, 1H), 4.81 - 4.58 (m, 1H), 4.51 - 4.16 (m, 3H), 3.99 (dd, J = 9.5, 14.3 Hz, 1H), 3.49 - 3.38 (m, 1H), 3.20 - 3.00 (m, 4H), 2.97 - 2.64 (m, 6H), 2.59 - 2.45 (m, 1H), 0.69 - 0.56 (m, 3H). Example 331, LCMS (M+H) ⁺ : 684. ¹ H NMR (500 MHz, METHANOL-d4) δ = 8.53 - 8.24 (m, 2H), 8.18 - 7.67 (m, 1H), 7.65 - 7.39 (m, 3H), 7.28 - 6.92 (m, 3H), 6.12 - 5.73 (m, 1H), 5.49 - 5.26 (m, 1H), 4.71 - 4.55 (m, 1H), 4.46 - 4.13 (m, 3H), 4.03 - 3.86 (m, 1H), 3.75 - 3.57 (m, 1H), 3.39 - 3.27 (m, 1H), 3.15 - 2.97 (m, 4H), 2.89 - 2.70 (m, 5H), 2.68 - 2.46 (m, 1H), 0.62 - 0.47 (m, 3H). Example 332 and Example 333 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15S)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-methoxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compounds were prepared in analogy to the preparation of Example 161 and Example 162 by using compound 326d-1 instead of compound 161e-1; compound 326d-2 instead of compound 161e-2 and Intermediate C11 instead of Intermediate C2. Example 332, LCMS (M+H) ⁺ : 696. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.65 (d, J = 5.2 Hz, 1H), 8.59 - 8.29 (m, 1H), 8.25 - 7.76 (m, 1H), 7.74 - 7.64 (m, 2H), 7.51 - 7.35 (m, 1H), 7.24 - 7.12 (m, 1H), 7.08 (dd, J = 2.6, 10.7 Hz, 1H), 6.96 - 6.81 (m, 1H), 5.95 - 5.70 (m, 1H), 5.53 - 5.37 (m, 1H), 4.81 - 4.59 (m, 1H), 4.53 - 4.18 (m, 3H), 4.05 - 3.94 (m, 1H), 3.83 - 3.70 (m, 3H), 3.51 - 3.36 (m, 1H), 3.19 - 3.01 (m, 4H), 2.95 - 2.64 (m, 6H), 2.62 - 2.42 (m, 1H), 0.69 - 0.53 (m, 3H). Example 333, LCMS (M+H) ⁺ : 696. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.64 - 8.29 (m, 2H), 8.25 - 7.71 (m, 1H), 7.64 (br dd, J = 2.4, 7.5 Hz, 2H), 7.51 - 7.33 (m, 1H), 7.07 (dd, J = 2.6, 10.7 Hz, 2H), 6.96 - 6.77 (m, 1H), 6.19 - 5.79 (m, 1H), 5.58 - 5.40 (m, 1H), 4.81 - 4.68 (m, 1H), 4.57 - 4.18 (m, 3H), 4.14 - 4.01 (m, 1H), 3.83 - 3.65 (m, 4H), 3.48 - 3.35 (m, 1H), 3.23 - 3.04 (m, 4H), 2.97 - 2.78 (m, 5H), 2.76 - 2.52 (m, 1H), 0.71 - 0.58 (m, 3H). Example 338 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-13-methyl- 2,6 8,11 20,24 4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1~4: preparation of (8S,11S)-13-methyl-4,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (compound 338d) Compound 338d was prepared in analogy to the preparation of compound 1d in Example 1 by using intermediate A11 instead of Intermediate B12 and intermediate B14 instead of intermediate A15-c. LCMS (M+H ⁺ ): 378. Step 5: preparation of (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]- 2,6 8,11 20,24 13-methyl-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 338) To a microwave tube was added (8S,11S)-13-methyl-4,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (338d, 50 mg, 132 μmol), 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3, 70.4 mg, 265 μmol), CsF (100.6 mg, 662 μmol), DIPEA (51.4 mg, 69.4 μL, 397 μmol) and DMSO (4mL). After being stirred at 90 °C for 12 hrs, the mixture was filtered and the filtrate was purified via prep-HPLC to give Example 338 (21 mg), LCMS (M+H ⁺ ): 607. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.26 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.77 (dd, J = 1.3, 7.9 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.44 - 7.33 (m, 2H), 7.29 - 7.16 (m, 4H), 7.09 (t, J = 4.6 Hz, 1H), 5.51 - 5.37 (m, 1H), 5.10 - 4.96 (m, 1H), 4.80 - 4.75 (m, 1H), 4.68 - 4.51 (m, 1H), 4.48 - 4.30 (m, 1H), 4.22 - 4.05 (m, 2H), 3.07 (s, 3H), 2.93 – 2.88 (m, 1H), 2.69 - 2.54 (m, 2H), 2.15 - 2.01 (m, 1H), 1.54 - 1.39 (m, 1H). Example 340 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3-methoxypropyl)- 2,6 8,11 20,24 4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]-N-(3- methoxypropyl)carbamate (compound 340a) To a flask was added tert-butyl N-[3-(7-bromobenzimidazol-1-yl)propyl]carbamate (compound A15-c, 2.5 g, 3.53 mmol), 1-bromo-3-methoxy-propane (1.08 g, 7.06 mmol), DMF (15mL). Then NaH (60% purity, 423.4 mg, 10.59 mmol) was added. The mixture was stirred at room temperature for 12 hrs, then it was quenched with water. The mixture was poured into 150 mL EA, and then washed with 50 mL water for three times. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 340a (1.5 g), LCMS (M+H ⁺ ): 427. Step 2: preparation of tert-butyl N-(3-methoxypropyl)-N-[3-[7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]carbamate (compound 340b) Compound 340b was prepared in analogy to the preparation of compound 294d by using compound 340a instead of compound 294c. LCMS (M+H ⁺ ): 474. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[3-[tert- butoxycarbonyl(3-methoxypropyl)amino]propyl]benzimidazol-4-y l]pyrazin-2- yl]amino]pyrrolidine-1,2-dicarboxylate (compound 340c) Compound 340c was prepared in analogy to the preparation of compound 338a by using compound 340b instead of intermediate A11. LCMS (M+H ⁺ ): 702. Step 4~7: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-(3-methoxypropyl)-4,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]-hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one (Example 340) Example 340 was prepared in analogy to the preparation of Example 1 by using compound 340c instead of compound 1a. LCMS (M+H ⁺ ): 666. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (s, 1H), 8.26 - 8.19 (m, 3H), 8.15 - 8.08 (m, 1H), 7.77 (dd, J = 1.1, 7.9 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.48 - 7.40 (m, 1H), 7.39 - 7.33 (m, 1H), 7.28 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.23 - 7.14 (m, 1H), 5.57 - 5.45 (m, 1H), 5.27 - 4.99 (m, 1H), 4.61 - 4.49 (m, 1H), 4.42 - 4.29 (m, 1H), 4.23 - 4.12 (m, 1H), 3.94 – 3.88 (m, 1H), 3.56 - 3.43 (m, 2H), 3.42 - 3.35 (m, 2H), 3.35 (s, 3H), 3.02 – 2.96 (m, 1H), 2.71 - 2.62 (m, 1H), 2.63 - 2.54 (m, 1H), 2.13 - 1.99 (m, 1H), 1.96 - 1.74 (m, 2H), 1.70 - 1.57 (m, 1H), 1.43 - 1.26 (m, 1H). Example 344 and Example 345 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-methoxy-13- 2,6 8,11 20,24 methyl-4,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13- methyl-4,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one Example 344 and 345 were prepared in analogy to the preparation of Example 250 and 251 by using intermediate A3 instead of intermediate A4 and intermediate B13 instead of compound 250a. SFC conditions: Instrument: SFC 80; Column: AS, 250×20 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for methanol (0.1% NH ₃ H ₂ O); Gradient: B 25%; Flow rate: 50 mL /min; Back pressure: 100 bar. Column temperature: 35℃ Example 344, faster eluted, LCMS (M+H ⁺ ): 638. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.61 (s, 1H), 8.39 - 8.25 (m, 2H), 8.22 - 8.10 (m, 2H), 7.79 - 7.70 (m, 2H), 7.60 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.40 - 7.24 (m, 3H), 5.94 - 5.80 (m, 1H), 5.53 - 5.44 (m, 1H), 5.00 - 4.81 (m, 2H), 4.53 - 4.45 (m, 1H), 4.34 - 4.31 (m, 1H), 4.27 - 4.17 (m, 2H), 4.02 - 3.92 (m, 1H), 3.80 - 3.60 (m, 1H), 3.23 - 3.13 (m, 1H), 3.12 (s, 1H), 3.02 (s, 2H), 2.84 (s, 2H), 2.80 (s, 1H), 2.62 - 2.53 (m, 1H). Example 345, slower eluted, LCMS (M+H ⁺ ): 638. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.59 (s, 1H), 8.43 - 8.26 (m, 3H), 8.20 - 8.14 (m, 1H), 7.85 - 7.80 (m, 1H), 7.78 - 7.70 (m, 1H), 7.64 - 7.57 (m, 1H), 7.43 - 7.29 (m, 2H), 7.37 - 7.30 (m, 1H), 6.41 - 6.24 (m, 1H), 5.50 - 5.29 (m, 2H), 4.81 - 4.72 (m, 2H), 4.48 - 4.10 (m, 4H), 3.86 - 3.75 (m, 1H), 3.06 (s, 1H), 2.97 (s, 2H), 2.90 - 2.81 (m, 1H), 2.79 (s, 2H), 2.76 (s, 1H), 2.66 - 2.56 (m, 1H). Example 350 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-16-oxa- 2,6 8,11 22,26 7,10,13,19,21,28-hexazapentacyclo[17.6.1.1 .1 .0 ]octacosa- 1(25),2(28),3,5,20,22(26),23-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 12 by using Intermediate A28 instead of Intermediate A12. Example 350 was obtained. LCMS (M+H ⁺ ): 637. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 9.60 - 9.13 (m, 1H), 8.54 - 8.15 (m, 2H), 8.02 - 7.86 (m, 2H), 7.74 - 7.52 (m, 3H), 7.32 - 7.14 (m, 2H), 7.11 - 6.71 (m, 2H), 5.57 - 5.25 (m, 1H), 4.60 - 4.26 (m, 4H), 4.25 - 3.59 (m, 5H), 3.27 - 2.95 (m, 3H), 2.83 - 2.62 (m, 3H), 2.34 - 2.15 (m, 1H). Example 363 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared analogy to the preparation of Example 179 by using intermediate C28 instead of intermediate C2. LCMS (M+H ⁺ ): 695, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.52 - 7.46 (m, 1H), 7.43 - 7.37 (m, 1H), 7.30 - 7.24 (m, 1H), 7.22 - 7.16 (m, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.92 (dd, J = 4.3, 15.5 Hz, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.70 - 4.65 (m, 1H), 4.54 - 4.51 (m, 1H), 4.51 - 4.38 (m, 2H), 4.34 - 4.26 (m, 1H), 4.24 - 4.16 (m, 1H), 3.98 - 3.86 (m, 1H), 3.43 (s, 3H), 3.06 (s, 3H), 2.95 - 2.87 (m, 2H), 2.87 (s, 3H), 2.66 (s, 3H), 2.58 - 2.47 (m, 2H). Example 370 (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)-3,5-difluoro-pheno l (370a) To a tube was added 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (120 mg, 0.405 mmol) and dichloromethane (1 mL), the solution was cooled with ice bath and 1 M boron trichloride (solution in DCM) (1.62 mL, 1.62 mmol) was added. The mixture was warmed to r.t. and stirred for 16 hrs. The mixture was quenched with water and extracted with 15 mL DCM for 3 times. The organic layer was concentrated to give an oil, and then it was purified via prep-HPLC to give compound 370a (38 mg). LCMS (M+H ⁺ ): 397. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 370) To a flask was added (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one (compound 370b, 60.78 mg, 0.110 mmol, prepared analogy to compound 12d by using intermediate A6 instead of intermediate A11 in step 1), 2-(4-chloropyrazolo[3,4- d]pyrimidin-1-yl)-3,5-difluoro-phenol (compound 370a, 31.09 mg, 0.110 mmol), DIEA (56.87 mg, 76.85 μL, 0.440 mmol) and acetonitrile (3 mL). The mixture was heated to 85 °C and stirred for about 1 hr. The mixture was concentrated and the residue was purified by prep-HPLC to give Example 370 (58 mg). LCMS (M+H ⁺ ): 685, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.54 (s, 1H), 8.20 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.44 (dd, J = 2.1, 7.7 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.17 - 7.09 (m, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.71 - 6.60 (m, 2H), 5.96 (br dd, J = 4.1, 15.4 Hz, 1H), 5.49 (br d, J = 8.9 Hz, 1H), 4.68 (br t, J = 4.7 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.39 - 4.31 (m, 1H), 4.27 - 4.17 (m, 1H), 4.01 - 3.88 (m, 1H), 3.05 (s, 3H), 2.96 - 2.91 (m, 1H), 2.90 (s, 3H), 2.90 - 2.85 (m, 1H), 2.70 (s, 3H), 2.58 - 2.48 (m, 2H). Example 391 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(1-pyrim idin-5-ylpyrazolo[3,4- 2,6 8,11 20,24 d]pyrimidin-4-yl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(1H- pyrazolo[3,4-d]pyrimidin-4-yl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 391b) The mixture of compound 370b (30 mg, 0.06 mmol), DIEA (0.03 mL, 0.19 mmol) and 4- chloro-1H-pyrazolo[3,4-d]pyrimidine (10.25 mg, 0.070 mmol) in ACN (2 mL) was stirred at 85 °C for 1 h. The mixture was purified by prep-HPLC to give compound 391b (20 mg). LCMS (M+H) ⁺ : 557. Step 2: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(1- pyrimidin-5-ylpyrazolo[3,4-d]pyrimidin-4-yl)-7,10,13,17,19,2 6- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (Example 391) To a solution of compound 391b (17.0 mg, 0.03 mmol), 5-iodopyrimidine (7.55 mg, 0.04 mmol) and CuI (0.58 mg, 0.004 mmol) in NMP (1 mL) was added (1R,2R)-N ₁ ,N ₂ - dimethylcyclohexane-1,2-diamine (1.12 mg, 0.006 mmol) and K ₃ PO ₄ (19.45 mg, 0.09 mmol) under N ₂ , and the reaction mixture was stirred for 2 h at 110 °C. The mixture was purified by prep-HPLC to give Example 391 (6.91 mg). LCMS (M+H) ⁺ : 635. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 9.78 - 9.68 (m, 2H), 9.12 (s, 1H), 8.64 - 8.53 (m, 1H), 8.39 (s, 1H), 7.91 - 7.83 (m, 1H), 7.59 - 7.47 (m, 2H), 7.19 - 7.11 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.16 - 5.93 (m, 1H), 5.52 - 5.40 (m, 1H), 4.67 (br d, J = 3.1 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.38 - 4.24 (m, 2H), 3.99 - 3.90 (m, 1H), 3.17 - 3.04 (m, 3H), 3.04 - 2.98 (m, 1H), 2.97 - 2.95 (m, 3H), 2.87 (br d, J = 13.0 Hz, 1H), 2.82 - 2.75 (m, 3H), 2.63 - 2.49 (m, 2H). Example 392 (11S,14S,18R)-13-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrim idin-4-yl]-25-fluoro-18- methoxy-16,21-dimethyl-5-oxa-10,13,16,20,22,29- 2,9 11,14 3,7 23,27 hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa-1(26),2(29),3(7),8,21,23(27),24-heptaen- 15-one The title compound was prepared according to the following scheme:

Step 1: preparation of 2,6-dichloropyridine-3,4-dicarboxylic acid (compound 392-b) To a solution of NaIO ₄ (129.54 g, 605.91 mmol) in DCM (40 mL), ACN (40 mL) and water (80 mL) was added RuCl ₃ (0.1 g, 0.5 mmol) at 0 °C, then 1,3-dichloroisoquinoline (compound A392-a, 10 g, 50.49 mmol) was added portion wise over 30 min at 0 °C. After being stirred at 50 °C for 16 hours, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give compound 392-b (9.7 g). LCMS (M+H) ⁺ : 236. Step 2: preparation of dimethyl 2,6-dichloropyridine-3,4-dicarboxylate (compound 392-c) To a solution of 2,6-dichloropyridine-3,4-dicarboxylic acid (compound 392-b, 9.7 g, 41.1 mmol) in DMF (100 mL) was added cesium carbonate (20.09 g, 61.65 mmol) and iodomethane (7.68 mL, 123.3 mmol) at 0 °C. After stirring at 50 °C for 16 hours, the reaction mixture was poured into water and extracted with EA, the organic layer was dried and concentrated to give the crude product, which was purified by flash chromatography to give compound 392-c (5 g). LCMS (M+H) ⁺ : 264. Step 3: preparation of [2,6-dichloro-3-(hydroxymethyl)-4-pyridyl]methanol (compound 392-d) To a solution of dimethyl dimethyl 2,6-dichloropyridine-3,4-dicarboxylate (compound 392-c, 5.0 g, 18.94 mmol) in THF (73 mL) was added calcium chloride (8.41 g, 75.74 mmol) and NaBH ₄ (6.45 g, 170.42 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 hours. The mixture was quenched with H ₂ O and adjusted pH to 2 with HCl (1 M), the resulting aqueous phase was extracted with EtOAc. The organic layer was dried and concentrated to give compound 392-d (4 g). LCMS (M+H) ⁺ : 208. Step 4: preparation of 4,6-dichloro-1,3-dihydrofuro[3,4-c]pyridine (compound 392e) To a stirred solution of [2,6-dichloro-3-(hydroxymethyl)-4-pyridyl]methanol (compound 392-d, 3.4 g, 16.34 mmol) in DCM (170 mL) was added manganese(IV) oxide (7.1 g, 81.72 mmol). The reaction mixture was cooled to 0 °C and triethylsilane (15.62 mL, 98.04 mmol) was added dropwise over a period of 10 mins, maintaining the reaction temperature at -5 °C. Then TFA (18.81 mL, 187.67 mmol) was added dropwise over a period of 15 mins. After stirring at 0 °C for 1 h, the mixture was stirred at 35 °C for 16 hours. The reaction was quenched with water and the mixture was filtered, the filtrate was extracted with EA. The organic layer was concentrated and the residue was purified by flash chromatography to give compound 392e (760 mg), LCMS (M+H) ⁺ : 190. Step 5: preparation of tert-butyl N-[(2R)-3-[7-(6-chloro-1,3-dihydrofuro[3,4- c]pyridin-4-yl)-5-fluoro-2-methyl-benzimidazol-1-yl]-2-metho xy-propyl]-N-methyl- carbamate;2,2,2-trifluoroacetic acid (compound 392f) A solution of intermediate A6 (2.52 g, 5.28 mmol), 4,6-dichloro-1,3-dihydrofuro[3,4- c]pyridine (compound 392e, 1.0 g, 5.28 mmol), Pd(dppf) ₂ Cl ₂ (0.77 g, 1.06 mmol) and K ₂ CO ₃ (2.19 g, 15.85 mmol) in water (2.28 mL) and 1,4-dioxane (20 mL) was stirred 85 °C for 2 h. The mixture was filtered and concentrated, the residue was purified by column chromatography to give compound 392f (1000 mg). LCMS (M+H) ⁺ : 505. Step 6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[4-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-me thyl-benzimidazol-4-yl]- 1,3-dihydrofuro[3,4-c]pyridin-6-yl]amino]pyrrolidine-1,2-dic arboxylate (compound 392g) To a solution of compound 392f (1000.0 mg, 1.98 mmol), O1-benzyl O2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate hydrochloride (934.97 mg, 2.97 mmol), cesium carbonate (1935.64 mg, 5.94 mmol) and S-Phos (162.59 mg, 0.400 mmol) in 1,4-dioxane (15 mL) was added Pd ₂ (dba) ₃ (181.34 mg, 0.200 mmol) in one portion under N ₂ . The mixture was stirred at 90 °C for 16 hours under N ₂ . The reaction mixture was filtered and the filtrate was concentrated to afford compound 392g (2000 mg). LCMS (M+H) ⁺ : 747. Step 7~11: preparation of (11S,14S,18R)-13-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-25-fluoro-18-methoxy-16,21-dimethyl-5-oxa- 10,13,16,20,22,29- 2,9 11,14 3,7 23,27 hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa-1(26),2(29),3(7),8,21,23(27),24-heptaen- 15-one (Example 392) The title compound was prepared in the analogy to the preparation of Example 12 by using compound 392g instead of compound 12a. LCMS (M+H) ⁺ : 711, ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.56 (s, 1H), 8.39 - 8.20 (m, 1H), 7.70 - 7.62 (m, 1H), 7.60 (dd, J = 2.5, 7.3 Hz, 1H), 7.45 (dd, J = 2.4, 10.1 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.24 - 7.18 (m, 1H), 6.89 - 6.72 (m, 1H), 6.04 - 5.85 (m, 1H), 5.53 - 5.36 (m, 2H), 5.26 - 5.07 (m, 2H), 4.69 - 4.66 (m, 1H), 4.57 - 4.46 (m, 2H), 4.38 (br d, J = 12.0 Hz, 1H), 4.33 - 4.23 (m, 2H), 3.98 - 3.91 (m, 1H), 3.70 - 3.57 (m, 1H), 3.19 (s, 1H), 3.10 (s, 2H), 3.00 (s, 3H), 2.84 - 2.78 (m, 3H), 2.62 - 2.45 (m, 2H). Example 393 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[1-methy l-6-(3-thienyl)pyrazolo[4,3- 2,6 8,11 20,24 c]pyridin-3-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: To a solution of intermediate C59 (20 mg, 0.07 mmol), compound 370b (48 mg, 0.1 mmol), cesium carbonate (77 mg, 0.240 mmol) and xantphos (7.87 mg, 0.01 mmol) in 1,4- dioxane (1 mL) was added bis(dibenzylideneacetone)palladium (3.91 mg, 0.010 mmol) under N ₂ . The mixture was degassed with N ₂ for 5 mins, then the mixture was stirred at 115 °C for 24 hours. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to give Example 393 (1.4 mg). LCMS(M+H) ⁺ : 652. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.94 (s, 1H), 8.27 (t, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.91 - 7.87 (m, 1H), 7.78 (d, J = 2.2 Hz, 2H), 7.55 (dd, J = 2.4, 7.6 Hz, 1H), 7.48 - 7.45 (m, 1H), 7.18 - 7.15 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.05 - 6.00 (m, 1H), 5.15 - 5.13 (m, 1H), 4.64 (br s, 1H), 4.34 - 4.30 (m, 2H), 4.16 (m, 1H), 4.03 (s, 3H), 3.98 (br d, J = 5.4 Hz, 1H), 3.10 (s, 3H), 3.02 (s, 1H), 2.96 (s, 3H), 2.93 - 2.90 (m, 1H), 2.78 (s, 3H), 2.72 (s, 2H). Example 394 (8S,11S,15R)-10-[6-(2,4-difluorophenyl)-1-methyl-pyrazolo[4, 3-c]pyridin-3-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in the analogy to the preparation of Example 393 by using intermediate C60 instead of intermediate C59. LCMS (M+H) ⁺ : 682, ¹ H NMR (400 MHz, METHANOL-d4) δ = 9.10 (s, 1H), 7.96 (s, 1H), 7.92 - 7.81 (m, 2H), 7.59 (dd, J = 2.7, 7.6 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.35 - 7.25 (m, 2H), 7.16 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.08 (dd, J = 4.4, 15.2 Hz, 1H), 5.14 (d, J = 8.8 Hz, 1H), 4.63 (t, J = 4.6 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.17 (d, J = 10.8 Hz, 1H), 4.02 (s, 3H), 3.99 - 3.92 (m, 1H), 3.08 (s, 3H), 3.00 (br d, J = 15.2 Hz, 1H), 2.97 (s, 3H), 2.93 (br d, J = 13.7 Hz, 1H), 2.81 (s, 3H), 2.65 - 2.55 (m, 2H). Example 395 (8S,11S)-21,23-difluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 2-bromo-1,3,5-trifluoro-4-nitro-benzene (compound 395a) To a solution of 2-bromo-1,3,5-trifluoro-benzene (13.0 g, 61.6 mmol) in H ₂ SO ₄ (80 mL) was added HNO ₃ (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then poured into ice water (0.2 L). The mixture was extracted with EtOAc (0.5 L), and the organic layer was washed with water (0.2 L twice) and brine (0.2 L), dried and concentrated to give compound 395a (15.1 g). LCMS (M+H ⁺ ): 256. Step 2: preparation of 1-amino-3-(2-bromo-3,5-difluoro-6-nitro-anilino)propan-2-ol (compound 395b) To a solution of compound 395a (1.9 g, 21.1 mmol) in MeCN (0.1 L) was added 1,3- diaminopropan-2-ol (2.6 g, 10.2 mmol) dropwise. The reaction mixture was stirred at 20 °C for 1 h, and then concentrated. The residue was diluted with a mixture solvent of petroleum ether: EtOAc (10/1, v/v, 50 mL), and stirred for 0.5 h. Then the mixture was filtered, and filter cake was collected to give compound 395b (3.1 g) as a yellow solid. LCMS (M+H ⁺ ): 326. Step 3: preparation of benzyl N-[3-(2-bromo-3,5-difluoro-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 395c) A mixture of compound 395b (2.7 g, 8.3 mmol), N-(benzyloxycarbonyloxy)succinimide (2.2 g, 8.8 mmol) and NaHCO ₃ in water (24 mL) and THF (24 mL) was stirred for 12 hours at 20 °C. The mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by Prep-HPLC to give compound 395c (3.5 g). LCMS (M+H ⁺ ): 460. Step 4: preparation of benzyl N-[3-(2-amino-6-bromo-3,5-difluoro-anilino)-2- hydroxy-propyl]carbamate (compound 395d) To a solution of compound 395c (3.5 g, 7.6 mmol) and Raney Ni (3.5 g) in methanol (50 mL) was added N ₂ H ₄ •H ₂ O (3 mL) dropwise at 20 °C and stirred for 2 hours. Then the mixture was filtered and concentrated, the residue was partitioned between EtOAc and water. The organic layer was separated, dried and concentrated to give compound 395d (3.2 g), which was used in next step directly. LCMS (M+H ⁺ ): 430. Step 5: preparation of benzyl N-[3-(7-bromo-4,6-difluoro-2-methyl-benzimidazol-1- yl)-2-hydroxy-propyl]carbamate (compound 395e) A mixture of pyridinium p-toluenesulfonate (130.0 mg, 0.5 mmol), trimethyl orthoacetate (3.0 g, 25.0 mmol) and compound 395d (3.1 g, 7.2 mmol) in anhydrous THF (60 mL) was stirred for 12 hours at 20 °C. The mixture was poured into water (0.1 L) and extracted with EtOAc (0.1 L twice). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by prep-HPLC to give compound 395e (1.3 g). LCMS (M+H ⁺ ): 454. Step 6: preparation of benzyl N-[3-(7-bromo-4,6-difluoro-2-methyl-benzimidazol-1- yl)-2-methoxy-propyl]-N-methyl-carbamate (compound 395f) To a mixture of compound 395e (1.3 g, 2.9 mmol) and iodomethane (1.3 g, 9.2 mmol) in anhydrous DMF (15 mL) was added sodium hydride (60% in oil, 0.5 g, 20.8 mmol) in portions at 0 °C, and the reaction mixture was stirred for 1 h. The mixture was poured into NH ₄ Cl aq. (0.1 L) and extracted with EtOAc (0.1 L twice). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give compound 395f (1.1 g). LCMS (M+H ⁺ ): 484. Step 7~13: preparation of (8S,11S)-21,23-difluoro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimet hyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 209 (Step 7~13) by using compound 395f instead of compound 209f. LCMS (M+H ⁺ ): 699. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.49 - 8.52 (m, 1H), 8.16 - 8.20 (m, 1H), 7.68 - 7.82 (m, 1H), 7.39 - 7.52 (m, 1H), 6.86 - 7.10 (m, 3H), 6.79 (m, 2H), 5.39 - 5.57 (m, 1H), 4.71 - 4.84 (m, 1H), 4.55 - 4.69 (m, 2H), 4.27 - 4.52 (m, 2H), 4.09 - 4.23 (m, 1H), 3.74 - 3.97 (m, 4H), 3.68 (m, 1H), 3.12 - 3.21 (m, 1H), 3.05 - 3.11 (m, 3H), 2.79 - 3.02 (m, 4H), 2.52 - 2.74 (m, 3H). Example 396 (8S,11S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-15-ethoxy- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one Step 1: preparation of benzyl (8S,11S)-15-ethoxy-13,18-dimethyl-12-oxo-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaene-10-carboxylate (compound 396-a) To a mixture of HATU (4.13 g, 10.9 mmol) and N,N-diisopropylethylamine (3.51 g, 27.2 mmol) in acetonitrile (400 mL) was added (2S,4S)-1-benzyloxycarbonyl-4-[4-[3-[2-ethoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]pyrimidin-2- yl]oxy-pyrrolidine-2-carboxylic acid (compound 63-b, 3.2 g, 5.4 mmol) in acetonitrile (1400 mL) dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, then the reaction mixture was concentrated, the residue was partitioned between water and EtOAc. The organic layer was s ^{eparated, dried and concentrated to afford compound 396-a (4.0 g). LCMS (M+H)+: 571.} Step 2: preparation of (8S,11S)-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 396-b) A solution of benzyl (8S,11S)-15-ethoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19 ,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaene-10- carboxylate (compound 396-a, 610 mg, 1.1 mmol) in TFA (5 mL, 64.9 mmol) was heated at 90 °C for 10 mins under microwave irritation. Then the reaction was concentrated to give compound 396-b (720 mg). LCMS (M+H) ⁺ : 437. Step 3: preparation of (8S,11S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17, 19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 396) A mixture of (8S,11S)-15-ethoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 396-b, 40 mg, 0.06 mmol), 4-chloro-1-(2,4-difluoro-6- methoxy-phenyl)pyrazolo[3,4-d]pyrimidine (21 mg, 0.07 mmol) and N,N-diisopropylethylamine (22 mg, 0.17 mmol) in acetonitrile (1 mL) was heated at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to afford Example 396 (9 mg). LCMS (M+H) ⁺ : 697. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.83 - 8.11 (m, 3H), 7.87 - 7.44 (m, 3H), 7.32 - 7.22 (m, 1H), 7.21 - 7.09 (m, 2H), 5.86 - 5.27 (m, 3H), 4.53 - 4.35 (m, 1H), 4.25 - 3.88 (m, 2H), 3.85 - 3.70 (m, 3H), 3.52 - 3.40 (m, 1H), 3.20 - 3.10 (m, 1H), 3.05 - 2.58 (m, 6H), 2.56 - 2.52 (m, 3H), 2.47 - 2.39 (m, 2H), 0.48 - 0.34 (m, 3H). Example 397 (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-y l]-15-ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 396 by using Intermediate C3 instead of Intermediate C61. Example 397 was obtained. LCMS (M+H ⁺ ): 666. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.89 - 8.11 (m, 2H), 7.85 - 7.65 (m, 3H), 7.62 - 7.42 (m, 3H), 7.38 - 7.22 (m, 3H), 5.82 - 5.39 (m, 3H), 4.68 - 4.13 (m, 3H), 4.09 - 3.80 (m, 4H), 3.17 - 3.10 (m, 1H), 3.05 - 2.68 (m, 4H), 2.62 - 2.57 (m, 1H), 2.56 - 2.52 (m, 3H), 0.46 - 0.37 (m, 3H). Example 398 (8S,11S)-10-[2-(2,4-difluorophenoxy)-4-pyridyl]-15-ethoxy-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 396 by using Intermediate C67 instead of Intermediate C61. Example 398 was obtained. LCMS (M+H ⁺ ): 642. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.85 - 8.71 (m, 1H), 7.81 (br t, J = 9.2 Hz, 1H), 7.75 - 7.52 (m, 3H), 7.48 - 7.25 (m, 3H), 7.10 (br t, J = 8.3 Hz, 1H), 6.49 - 5.94 (m, 2H), 5.85 - 4.89 (m, 3H), 4.21 - 3.73 (m, 5H), 3.21 - 3.13 (m, 1H), 3.05 - 2.82 (m, 4H), 2.78 - 2.57 (m, 6H), 0.49 - 0.36 (m, 3H). Example 399 (8S,11S)-15-ethoxy-10-[1-[4-fluoro-2-(2-oxopyrrolidin-1-yl)p henyl]pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 396 by using Intermediate C68 instead of Intermediate C61. Example 399 was obtained. LCMS (M+H ⁺ ): 732. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.84 - 8.70 (m, 1H), 8.59 - 7.77 (m, 2H), 7.76 - 7.44 (m, 5H), 7.40 - 7.34 (m, 1H), 7.29 (td, J = 7.7, 15.5 Hz, 1H), 5.82 - 5.43 (m, 3H), 4.50 - 4.16 (m, 2H), 4.12 - 3.77 (m, 2H), 3.58 - 3.41 (m, 2H), 3.19 - 3.12 (m, 1H), 3.06 - 2.85 (m, 4H), 2.82 - 2.58 (m, 3H), 2.57 - 2.53 (m, 3H), 2.48 - 2.40 (m, 1H), 2.19 - 2.06 (m, 2H), 1.98 - 1.84 (m, 2H), 0.48 - 0.37 (m, 3H). Example 400 and Example 401 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,15,18-trimethyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,15,18-trime thyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-(2-fluoro-3-nitro- phenyl)pyrimidin-2-yl]oxypyrrolidine-1,2-dicarboxylate (compound 400-a) A mixture of 2-(2-fluoro-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxab orolane (1.36 g, 5.1 mmol), O1-benzyl O2-methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2- dicarboxylate (2 g, 5.1 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (187 mg, 0.26 mmol) and potassium carbonate (2.12 g, 15.3 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was heated to 100 °C for 1 h with microwave irritation under nitrogen. The reaction mixture was diluted with water and extracted two times with EtOAc, the combined organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give compound 400-a (2.9 g). LCMS (M+H) ⁺ : 497. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-[2-[[3-(tert- butoxycarbonylamino)-2-methyl-propyl]amino]-3-nitro-phenyl]p yrimidin-2- yl]oxypyrrolidine-1,2-dicarboxylate (compound 400-b) To a mixture of O1-benzyl O2-methyl (2S,4S)-4-[4-(2-fluoro-3-nitro-phenyl)pyrimidin-2- yl]oxypyrrolidine-1,2-dicarboxylate (400-a 2.9 g, 4.97 mmol) and potassium carbonate (2.06 g, 14.9 mmol) in acetonitrile (30 mL) was added tert-butyl N-(3-amino-2-methyl-propyl)carbamate (1.03 g, 5.46 mmol), the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered; the filtrate was concentrated to give compound 400-b (3.25 g). LCMS (M+H) ⁺ : 665. Step 3: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[4-[2-[[3-(tert- butoxycarbonylamino)-2-methyl-propyl]amino]-3-nitro-phenyl]p yrimidin-2-yl]oxy- pyrrolidine-2-carboxylic acid (compound 400-c) A mixture of O1-benzyl O2-methyl (2S,4S)-4-[4-[2-[[3-(tert-butoxycarbonylamino)-2- methyl-propyl]amino]-3-nitro-phenyl]pyrimidin-2-yl]oxypyrrol idine-1,2-dicarboxylate (3.25 g, 4.4 mmol) and lithium hydroxide monohydrate (compound 400-b, 923 mg, 22mmol) in tetrahydrofuran (30 mL) and water (10 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water, acidified to pH = 5 with 1 M aq. HCl, and then extracted with DCM. The organic layer was dried and concentrated to afford compound 400-c (3.55 g). LCMS (M+H) ⁺ : 651. Step 4: preparation of (2S,4S)-4-[4-[2-[(3-amino-2-methyl-propyl)amino]-3-nitro- phenyl]pyrimidin-2-yl]oxy-1-benzyloxycarbonyl-pyrrolidine-2- carboxylic acid;2,2,2- trifluoroacetic acid (compound 400-d) A mixture of (2S,4S)-1-benzyloxycarbonyl-4-[4-[2-[[3-(tert-butoxycarbonyl amino)-2- methyl-propyl]amino]-3-nitro-phenyl]pyrimidin-2-yl]oxy-pyrro lidine-2-carboxylic acid (compound 400-c, 3.55 g, 4.4 mmol) and TFA (10 mL) in dichloromethane (30 mL) was stirred at room temperature for 2 h. Then the mixture was concentrated to give compound 400-d (3.43 g. LCMS (M+H) ⁺ : 551. Step 5: preparation of benzyl (14S,17S)-10-methyl-6-nitro-13-oxo-18-oxa- 8,12,15,20,23-pentazatetracyclo[17.3.1.1 ^14,17 .0 ^2,7 ]tetracosa-1(23),2,4,6,19,21-hexaene-15- carboxylate (compound 400-e) To a mixture of HATU (3.14 g, 8.3 mmol) and N,N-diisopropylethylamine (2.67 g, 20.6 mmol) in N,N-dimethylformamide (20 mL) was added (2S,4S)-4-[4-[2-[(3-amino-2-methyl- propyl)amino]-3-nitro-phenyl]pyrimidin-2-yl]oxy-1-benzyloxyc arbonyl-pyrrolidine-2-carboxylic acid 2,2,2-trifluoroacetic acid (compound 400-d, 3.43 g, 4.1 mmol) in acetonitrile (2000 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C to room temperature for 1 h. After removing ACN under reduced pressure, the mixture was diluted with water and EtOAc, then extracted with EtOAc. The combined organic layer was dried and concentrated to afford compound 400-e (2.97 g). LCMS (M+H) ⁺ : 533. Step 6: preparation of benzyl (14S,17S)-6-amino-10-methyl-13-oxo-18-oxa- 8,12,15,20,23-pentazatetracyclo[17.3.1.1 ^14,17 .0 ^2,7 ]tetracosa-1(23),2,4,6,19,21-hexaene-15- carboxylate (compound 400-f) A mixture of (14S,17S)-10-methyl-6-nitro-13-oxo-18-oxa-8,12,15,20,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,1 9,21-hexaene-15-carboxylate (compound 400-e, 2.97 g, 3.9 mmol) and zinc (2.55 g, 39 mmol) in acetic acid (30 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was then dissolved in N,N-dimethylformamide and diluted with water, the resulted precipitation was filtered, the filter cake was collected and dried to afford compound 400-f (1.60 g). LCMS (M+H) ⁺ : 503. Step 7: preparation of benzyl (8S,11S)-15,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 400-g) A mixture of benzyl (14S,17S)-6-amino-10-methyl-13-oxo-18-oxa-8,12,15,20,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,1 9,21-hexaene-15-carboxylate (compound 400-f, 1.6 g, 3.2 mmol) and 1,1,1-trimethoxyethane (9.4 g, 78.2 mmol) in p- toluenesulfonic acid monohydrate (30 mg, 0.16 mmol) was heated at 70 °C for 1 h. After cooling to room temperature, the mixture was concentrated and the residue was purified by flash chromatography to afford compound 400-g (585 mg). LCMS (M+H) ⁺ : 527. Step 8: preparation of (8S,11S)-15,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 400-h) A solution of benzyl (8S,11S)-15,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 400-g, 585 mg, 1.0 mmol) in TFA (5 mL) was heated at 90 °C for 10 mins under microwave irritation. Then the mixture was concentrated to give compound 400-h (1.02 g). LCMS (M+H) ⁺ : 393. Step 9: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- 2,6 8,11 20,24 yl]-15,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 400-i) A mixture of (8S,11S)-15,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 400-h, 510 mg, 0.45 mmol), intermediate C2 (121 mg, 0.45 mmol) and potassium phosphate (385 mg, 1.81 mmol) in anhydrous acetonitrile (2 mL) was heated at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted with DCM, and then the combined organic layer was washed with brine, dried and concentrated to afford compound 400- i (308 mg) as a brown foam. LCMS (M+H) ⁺ : 623. Step 10: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,15,18-trimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 400-j) To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 400-i, 308 mg, 0.42 mmol) and NaH (50 mg, 1.3 mmol) in anhydrous DMF (2 mL) was added iodomethane (179 mg, 1.3 mmol), the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between water and DCM, the separated aqueous layer was extracted with DCM, and then the combined organic layer was washed with brine, dried and concentrated, the residue was purified by prep-HPLC to afford compound 400-j (130 mg). LCMS (M+H) ⁺ : 637. Step 11: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,15,18-trimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-13,15,18- 2,6 8,11 20,24 trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 400 and Example 401) (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,15,18-trimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 400-j, 120 mg, 0.18 mmol) was separated by SFC (Instrument: SFC 80, Column: IA, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 50%, Flow rate: 50 mL /min, Back pressure: 100 bar, Column temperature: 35℃) to afford Example 400 and Example 401. Example 400 (33 mg, faster eluted) was obtained. LCMS (M+H) ⁺ : 637. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.84 - 8.61 (m, 2H), 8.42 - 8.23 (m, 1H), 7.80 - 7.69 (m, 3H), 7.65 - 7.55 (m, 2H), 7.37 - 7.27 (m, 2H), 5.72 - 5.35 (m, 3H), 4.53 - 4.15 (m, 2H), 3.95 - 3.75 (m, 2H), 3.14 - 2.75 (m, 5H), 2.70 - 2.60 (m, 1H), 2.60 - 2.52 (m, 3H), 2.48 - 2.38 (m, 1H), 0.22 - 0.08 (m, 3H). Example 401 (53 mg, slower eluted) was obtained. LCMS (M+H) ⁺ : 637. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.83 - 8.75 (m, 1H), 8.68 - 8.20 (m, 2H), 7.81 - 7.70 (m, 2H), 7.64 - 7.55 (m, 2H), 7.52 - 7.46 (m, 1H), 7.37 - 7.26 (m, 2H), 5.86 - 5.28 (m, 3H), 4.51 - 4.40 (m, 1H), 4.33 - 4.05 (m, 3H), 3.13 - 2.95 (m, 3H), 2.94 - 2.63 (m, 3H), 2.56 - 2.52 (m, 3H), 2.48 (s, 1H), 0.17 - 0.06 (m, 3H). Example 402 and Example 403 (8S,11S,15R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d ]pyrimidin-4-yl]-13,15,18- 2,6 8,11 20,24 trimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,15,18-trimethyl-7-o xa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 400 and Example 401 by using Intermediate C11 instead of Intermediate C2 and SFC separation (Instrument: SFC 80, Column: MB-S, 250×30 mm I.D., 5μm, Mobile phase: A for CO ₂ and B for IPA (0.1% NH ₃ H ₂ O), Gradient: B 30%, Flow rate: 50 mL /min, Back pressure: 100 bar, Column temperature: 35℃) to afford Example 402 and Example 403. Example 402 (26 mg, faster eluted) was obtained. LCMS (M+H) ⁺ : 649. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.81 (dd, J = 1.2, 5.3 Hz, 1H), 7.81 - 7.72 (m, 2H), 8.57 - 7.71 (m, 2H), 7.64 - 7.57 (m, 1H), 7.49 - 7.38 (m, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 2.7, 11.1 Hz, 1H), 6.99 - 6.91 (m, 1H), 5.73 - 5.36 (m, 3H), 4.49 - 4.12 (m, 2H), 3.93 - 3.77 (m, 2H), 3.75 (s, 3H), 3.11 - 2.74 (m, 5H), 2.71 - 2.55 (m, 4H), 2.52 - 2.38 (m, 1H), 0.20 - 0.13 (m, 3H). Example 403 (50 mg, slower eluted) was obtained. LCMS (M+H) ⁺ : 649. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.81 (d, J = 5.3 Hz, 1H), 8.57 - 7.66 (m, 3H), 7.64 - 7.49 (m, 2H), 7.48 - 7.39 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.20 (td, J = 3.0, 11.0 Hz, 1H), 6.99 - 6.91 (m, 1H), 5.87 - 5.33 (m, 3H), 4.52 - 4.07 (m, 4H), 3.78 - 3.69 (m, 3H), 3.16 - 2.87 (m, 4H), 2.85 - 2.62 (m, 2H), 2.60 - 2.45 (m, 4H), 0.16 - 0.08 (m, 3H). Example 404 and 405 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,1 8-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme:

Step 1: preparation of 1-amino-3-benzyloxy-propan-2-ol (compound 404b) To benzyl glycidyl ether (compound 404a, 20.0 g, 121.8 mmol) was added NH ₃ /H ₂ O (300.0 mL) dropwise at 20 °C, and the reaction was stirred at 20 °C for 16 hours. The reaction mixture was concentrated to afford compound 404b (24 g). LCMS (M+H) ⁺ : 182. Step 2: preparation of 1-benzyloxy-3-[(2-nitro-3-pyridyl)amino]propan-2-ol (compound 404c) To a solution of 3-fluoro-2-nitropyridine (compound 404b, 5.0 g, 35.19 mmol) and N,N- diisopropylethylamine (6.82 g, 52.78 mmol) in DMSO (70 mL) was added 1-amino-3- benzyloxy-propan-2-ol (10.0 g, 44.69 mmol) at 20 °C. The mixture was stirred at 60 °C for 6 hours and then the reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to afford compound 404c (10.5 g). LCMS (M+H) ⁺ : 304. Step 3: preparation of 1-[(2-amino-3-pyridyl)amino]-3-benzyloxy-propan-2-ol (compound 404d) To a solution of 1-benzyloxy-3-[(2-nitro-3-pyridyl)amino]propan-2-ol (compound 404c, 10.5 g, 34.62 mmol) and Raney Ni (8.13 g, 138.47 mmol) in methanol (100 mL) was added hydrazine hydrate (16.83 mL, 346.18 mmol) dropwise at 20 °C, and the mixture was stirred at 20 °C for 1 h. The reaction was filtered and the filtrate was concentrated to afford compound 404d (10 g). LCMS (M+H) ⁺ : 274. Step 4: preparation of 1-benzyloxy-3-(2-methylimidazo[4,5-b]pyridin-1-yl)propan-2- ol (compound 404e) To a stirred solution of 1-[(2-amino-3-pyridyl)amino]-3-benzyloxy-propan-2-ol (compound 404d, 9 g, 32.93 mmol) in trimethyl orthoacetate (90 mL) was added HCl/H ₂ O (0.9 mL, 10.8 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 16 hours. The reaction was concentrated and the residue was poured into sat.aq.NaHCO ₃ , extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 404e (11 g). LCMS (M+H) ⁺ : 298. Step 5: preparation of 1-(3-benzyloxy-2-ethoxy-propyl)-2-methyl-imidazo[4,5- b]pyridine (compound 404f) To a solution of 1-benzyloxy-3-(2-methylimidazo[4,5-b]pyridin-1-yl)propan-2-o l (compound 404e, 5.5 g, 14.98 mmol) in DMF (70 mL) was added sodium hydride (0.76 g, 18.96 mmol) at 0 °C, and the reaction was stirred at 0 °C for 0.5 hours. Then iodoethane (1.8 mL, 22.49 mmol) was added and the reaction was stirred at 0 °C for 1.5 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate, the organic phase was dried and concentrated to afford compound 404f (6 g). LCMS (M+H) ⁺ : 326. Step 6: preparation of 1-(3-benzyloxy-2-ethoxy-propyl)-2-methyl-4-oxido- imidazo[4,5-b]pyridin-4-ium (compound 404g) To a solution of 1-(3-benzyloxy-2-ethoxy-propyl)-2-methyl-imidazo[4,5-b]pyrid ine (compound 404f, 5.0 g, 15.37 mmol) in DCM (60 mL) was added mCPBA (4.0 g, 19.7 mmol) at 0 °C, and the reaction was stirred at 20 °C for 5 hours. The reaction was poured into sat.aq.NaHCO ₃ and extracted with DCM. The organic phase was dried and concentrated to afford compound 404g (5.7 g). LCMS (M+H) ⁺ : 342. Step 7: preparation of 1-(3-benzyloxy-2-ethoxy-propyl)-7-bromo-2-methyl- imidazo[4,5-b]pyridine (compound 404h) To a solution of 1-(3-benzyloxy-2-ethoxy-propyl)-2-methyl-4-oxido-imidazo[4,5 - b]pyridin-4-ium (compound 404g, 4.5 g, 13.18 mmol) in DCM (50 mL) was added Phosphorus Oxybromide (5670.0 mg, 19.78 mmol) at 0 °C, and the reaction was stirred at 20 °C for 16 hrs. The reaction mixture was concentrated, the residue was poured into sat.aq.NaHCO ₃ and extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by prep-HPLC to afford compound 404h (600 mg). LCMS (M+H) ⁺ : 406. Step 8: preparation of 1-(3-benzyloxy-2-ethoxy-propyl)-7-(6-chloro-2-pyridyl)-2- methyl-imidazo[4,5-b]pyridine (compound 404i) To a solution of 1-(3-benzyloxy-2-ethoxy-propyl)-7-bromo-2-methyl-imidazo[4,5 - b]pyridine (compound 404h, 600.0 mg, 1.48 mmol), 6-chloropyridine-2-boronic acid pinacol ester (450.0 mg, 1.88 mmol) and K ₃ PO ₄ (450.0 mg, 2.12 mmol) in 1,4-dioxane (10 mL) and Water (1 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (60.0 mg) in one portion under N ₂ at 25°C. The reaction mixture was stirred at 55 °C for 24 hours under N ₂ , then the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed, dried and concentrated, the residue was purified by silica gel to afford compound 404i (645 mg). LCMS (M+H) ⁺ : 437. Step 9: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[1-(3-benzyloxy-2- ethoxy-propyl)-2-methyl-imidazo[4,5-b]pyridin-7-yl]-2-pyridy l]amino]pyrrolidine-1,2- dicarboxylate (compound 404j) To a solution of 1-(3-benzyloxy-2-ethoxy-propyl)-7-(6-chloro-2-pyridyl)-2-met hyl- imidazo[4,5-b]pyridine (compound 404i, 645.0 mg, 1.48 mmol) , O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate;hydrochloride (580.0 mg, 2.07 mmol), Cesium carbonate (1300.0 mg, 3.99 mmol) and S-Phos (121.0 mg, 0.290 mmol) in 1,4-dioxane (10 mL) was added Pd ₂ (dba) ₃ (121.0 mg, 0.130 mmol) in one portion under N ₂ . The mixture was stirred at 90 °C for 16 hours under N ₂ , then the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by prep-TLC to afford compound 404j (550 mg). LCMS (M+H) ⁺ : 645. Step 10: preparation of methyl (4S)-4-[[6-[1-(2-ethoxy-3-hydroxy-propyl)-2-methyl- imidazo[4,5-b]pyridin-7-yl]-2-pyridyl]amino]pyrrolidine-2-ca rboxylate (compound 404k) To a solution of compound 404j (450 mg, 0.7 mmol) in DCM (10 mL) was added BCl ₃ (1.8 mL, 1.8 mmol) at 0 °C, and the mixture was stirred at 20 °C for 24 hours under N ₂ . To the reaction mixture was added 5 mL MeOH, and the mixture was stirred at 20 °C for 0.25 hours. Then the reaction mixture was concentrated to afford compound 404k (317 mg). LCMS (M+H) ⁺ : 455. Step 11: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[1-(2-ethoxy-3-hydroxy- propyl)-2-methyl-imidazo[4,5-b]pyridin-7-yl]-2-pyridyl]amino ]pyrrolidine-1,2- dicarboxylate (compound 404l) To a solution of compound 404k (317 mg, 0.7 mmol) and DIEA (0.36 mL, 2.09 mmol) in DCM (10 mL) was added Boc ₂ O (400.0 mg, 1.83 mmol) at 0 °C, and the mixture was stirred at 20 °C for 4 hours under N ₂ . The reaction mixture was concentrated and the residue was purified by prep-TLC to afford compound 404l (300 mg). LCMS (M+H) ⁺ : 555. Step 12: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[1-(2-ethoxy-3- methylsulfonyloxy-propyl)-2-methyl-imidazo[4,5-b]pyridin-7-y l]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 404m) To a solution of compound 404l (600 mg, 1.08 mmol) and DIEA (0.54 mL, 3.1 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.39 mL, 5.06 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into aq.NaHCO ₃ (20 mL, 5%) and extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 404m (684 mg). LCMS (M+H) ⁺ : 633. Step 13: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[1-[2-ethoxy-3- (methylamino)propyl]-2-methyl-imidazo[4,5-b]pyridin-7-yl]-2- pyridyl]amino]pyrrolidine- 1,2-dicarboxylate (compound 404n) To a solution of compound 404m (684.0 mg, 1.08 mmol) in acetonitrile (8 mL) was added methylamine/THF (2.5 mL, 5 mmol) at 20 °C, and the reaction mixture was stirred at 80 °C for 16 hrs. The reaction was concentrated and the residue was purified by prep-TLC to afford compound 404n (200 mg). LCMS (M+H) ⁺ : 568. Step 14: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[1-[2-ethoxy-3- (methylamino)propyl]-2-methyl-imidazo[4,5-b]pyridin-7-yl]-2- pyridyl]amino]pyrrolidine- 2-carboxylic acid (compound 404o) To a solution of compound 404n (200.0 mg, 0.350 mmol) in methanol (2 mL) and THF (2 mL) was added LiOH•H ₂ O (60.0 mg, 1.43 mmol) in water (1.5 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 16 hrs. The reaction was concentrated and the residue was purified by prep-HPLC to afford compound 404o (210 mg). LCMS (M+H) ⁺ : 554. Step 15: preparation of tert-butyl (8S,11S)-15-ethoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 404p) To a mixture of HATU (190.0 mg, 0.500 mmol) and DIEA (114.0 mg, 0.880 mmol) in DMF (75 mL) was added compound 404o (190.0 mg, 0.280 mmol) in DMF (225 mL) dropwise at 0 °C for 0.5 hours, then the mixture was stirred for 2 hrs at 0 °C. The reaction was concentrated and the residue was purified by prep-HPLC to afford compound 404p (55 mg) as. LCMS (M+H) ⁺ :536. Step 16: preparation of (8S,11S)-15-ethoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;hydrochloride (compound 404q) To a solution of compound 404p (56 mg, 0.07 mmol) in 1,4-dioxane (0.5 mL) was added HCl/1,4-dioxane (0.5 mL, 4 mol/L) dropwise at 0 °C, then the mixture was stirred for 1 hr at 0 °C. The reaction was concentrated and the residue was purified by prep-HPLC to afford compound 404q (40 mg). LCMS (M+H) ⁺ : 436. Step 17: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-13,18-dimethyl-7,10,13,17,19,21, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,21,26-heptazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 404 and 405) To a solution of compound 404q (40 mg, 0.07 mmol) and 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (20.0 mg, 0.080 mmol) in acetonitrile (1 mL) was added DIEA (40.0 mg, 0.310 mmol) at 25 °C, and the mixture was stirred at 80 °C for 1 h. The reaction mixture was purified by prep-HPLC and SFC to give Example 404 (4.4 mg) and 405 (10.9 mg). SFC condition: Instrument: waters 80Q; Column: DAICEL CHIRALCEL OD (250mm×30mm, 10μm); Mobile phase: Phase A for Supercritical CO ₂ , and Phase B for IPA+ACN(0.1%NH ₃ H ₂ O); Gradient: 60%Phase B (40% Phase A); Flow rate: 70g/min; Back pressure: 100 bar to keep the CO ₂ in Supercritical flow; Column temperature: 30℃. Example 404, faster eluted, LCMS (M+H) ⁺ : 666. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.64 (d, J = 5.4 Hz, 1H), 8.59 (s, 1H), 8.40 - 8.24 (m, 1H), 7.93 (t, J = 7.9 Hz, 1H), 7.86 - 7.79 (m, 1H), 7.72 - 7.60 (m, 1H), 7.36 - 7.19 (m, 3H), 6.90 - 6.84 (m, 1H), 6.15 - 5.99 (m, 1H), 5.57 - 5.41 (m, 1H), 4.74 - 4.72 (m, 1H), 4.59 - 4.54 (m, 1H), 4.40 - 4.30 (m, 2H), 4.00 (dd, J = 9.5, 14.4 Hz, 1H), 3.47 - 3.40 (m, 1H), 3.16 - 3.11 (m, 1H), 3.06 - 2.98 (m, 3H), 2.97 - 2.90 (m, 1H), 2.87 - 2.84 (m, 3H), 2.82 - 2.69 (m, 3H), 2.64 - 2.52 (m, 1H), 0.68 - 0.60 (m, 3H). Example 405, slower eluted, LCMS (M+H) ^+: 666. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.67 - 8.53 (m, 2H), 8.41 - 8.20 (m, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.82 - 7.60 (m, 2H), 7.35 - 7.27 (m, 1H), 7.26 - 7.17 (m, 2H), 6.91 - 6.80 (m, 1H), 6.29 - 5.90 (m, 1H), 5.59 - 5.46 (m, 1H), 4.79 - 4.74 (m, 1H), 4.64 - 4.54 (m, 1H), 4.41 - 4.23 (m, 3H), 4.08 (d, J = 14.7 Hz, 1H), 3.77 (dd, J = 2.6, 4.5 Hz, 1H), 3.41 - 3.33 (m, 2H), 3.20 - 3.09 (m, 3H), 2.91 - 2.87 (m, 1H), 2.86 - 2.83 (m, 3H), 2.79 - 2.57 (m, 2H), 0.64 - 0.58 (m, 3H). Example 406 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21-fluoro-18-hydroxy- 2,6 8,11 20,24 13-methyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one The title compounds were prepared according to the following scheme:

Step 1: preparation of 1-bromo-2,4-difluoro-3-nitro-benzene (compound 406a) To a mixture of 1,3-difluoro-2-nitro-benzene (5.0 g, 31.4 mmol) in sulfuric acid (10 mL) and trifluoroacetic acid (20 mL) was added N-bromosuccinimide (6.7 g, 37.7 mmol) and the mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with saturated aq.NaHCO ₃ and brine, then dried and concentrated. The residue was purified by flash chromatography to afford compound 406a (7.3 g). Step 2: preparation of tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N- methyl-carbamate (compound 406b) To a solution of 1-bromo-2,4-difluoro-3-nitro-benzene (compound 406a, 7.3 g, 30.6 mmol) and tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (5.8 g, 30.6 mmol) in N,N- dimethylformamide (100 mL) was added N,N-diisopropylethylamine (11 mL, 61.3 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was removed in vacuo, the residue was purified by column chromatography to give compound 406b (9.0 g). LCMS (M-100+H) ⁺ : 306. Step 3: preparation of tert-butyl N-[3-(2-amino-6-bromo-3-fluoro-anilino)propyl]-N- methyl-carbamate (compound 406c) To a solution of tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N-methyl- carbamate (compound 406b, 7.0 g, 17.2 mmol) in methanol (250 mL) was added Raney Ni (7.0 g), followed by hydrazine hydrate (4 mL) added dropwise, meanwhile keeping the temperature below 25 °C. The reaction mixture was stirred at room temperature for 1 h, then filtered and the filtrate was concentrated in vacuo to give compound 406c (4.0 g). LCMS (M+H) ⁺ : 376. Step 4: preparation of tert-butyl N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazol-1- yl)propyl]-N-methyl-carbamate (compound 406d) To a solution of tert-butyl N-[3-(2-amino-6-bromo-3-fluoro-anilino)propyl]-N-methyl- carbamate (compound 406c, 4.0 g, 10.6 mmol) and N, N'-carbonyldiimidazole (2.2 g, 13.8 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (4.4 g, 31.9 mmol), the reaction mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was removed in vacuo, the residue was purified by column chromatography to give compound 406d (2.0 g). LCMS (M-100+H) ⁺ : 302. Step 5: preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2- oxo-1H-benzimidazol-4-yl]boronic acid (compound 406e) To a solution of bis(neopentyl glycolato)diboron (1.4 g, 6.2 mmol), tert-butyl N-[3-(7- bromo-4-fluoro-2-oxo-3H-benzimidazol-1-yl)propyl]-N-methyl-c arbamate (compound 406d, 1.0 g, 2.5 mmol), XPhos (240 mg, 0.3 mmol) and Pd ₂ (dba) ₃ (240 mg, 0.4 mmol) in 1,4-dioxane (20 mL) was added sodium acetate (0.4 g, 5.0 mmol), and the reaction mixture was stirred at 100 °C for 12 h under argon. After cooling to room temperature, the reaction mixture was poured into water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a crude product, which was purified by prep-HPLC to give compound 406e (0.8 g). LCMS (M+H) ⁺ : 368. Step 6: preparation of [7-fluoro-3-[3-(methylamino)propyl]-2-oxo-1H-benzimidazol- 4-yl]boronic acid 2,2,2-trifluoroacetic acid (compound 406f) A solution of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-o xo-1H- benzimidazol-4-yl]boronic acid (compound 406e, 0.8 g, 2.2 mmol) in TFA (10 mL) was stirred at room temperature for 1 h. Then the reaction mixture was concentrated to give compound 406f (0.5 g). LCMS (M+H) ⁺ : 268. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[7-fluoro-3-[3- (methylamino)propyl]-2-oxo-1H-benzimidazol-4-yl]phenoxy]pyrr olidine-1,2-dicarboxylate (compound 406g) To a solution of [7-fluoro-3-[3-(methylamino)propyl]-2-oxo-1H-benzimidazol-4- yl]boronic acid;2,2,2-trifluoroacetic acid (compound 406f, 0.5 g, 3.0 mmol), Intermediate B33 (1.4 g, 3.6 mmol), Pd(dppf)Cl ₂ (0.2 g, 0.40 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added potassium phosphate (1.6 g, 7.5 mmol), and the reaction mixture was stirred at 100 °C for 12 h under argon. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to get a crude product, which was purified by prep-HPLC to give compound 406g (250 mg). LCMS (M+H) ⁺ : 543. Step 8: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[7-fluoro-3-[3- (methylamino)propyl]-2-oxo-1H-benzimidazol-4-yl]phenoxy]pyrr olidine-2-carboxylic acid (compound 406h) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[7-fluoro-3-[3- (methylamino)propyl]-2-oxo-1H-benzimidazol-4-yl]phenoxy]pyrr olidine-1,2-dicarboxylate (compound 406g, 250 mg, 0.5 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide hydrate (110 mg, 4.6 mmol), then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was acidified with 1 M HCl to pH = 6, then purified by reversed flash column to give compound 406h (0.2 g). LCMS (M+H) ⁺ : 529. Step 9: preparation of tert-butyl (8S,11S)-21-fluoro-13-methyl-12,18-dioxo-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,20,22-hexaene- 10-carboxylate (compound 406i) To a solution of PyBOP (236 mg, 0.45 mmol), DIEA (97 mg, 0.8 mmol) in DMF (150 mL) was added a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[7-fluoro-3-[3- (methylamino)propyl]-2-oxo-1H-benzimidazol-4-yl]phenoxy]pyrr olidine-2-carboxylic acid (compound 406h, 0.2 g, 0.4 mmol) in N,N-dimethylformamide (150 mL). The resulting mixture was stirred at 0 °C for 1 h, then the reaction mixture was concentrated in vacuo to get a crude product, which was purified by reversed flash to give compound 406i (150 mg, 0.3 mmol). LCMS (M+H) ⁺ : 511. Step 10: preparation of (8S,11S)-21-fluoro-13-methyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,20,22-hexaene-12,18- dione;2,2,2-trifluoroacetic acid (compound 406j) A solution of tert-butyl (8S,11S)-21-fluoro-13-methyl-12,18-dioxo-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,20,22-hexaene-10-carboxylate (compound 406i, 150 mg, 0.3 mmol) in TFA (5.0 mL) was stirred at room temperature for 1 h. Then the reaction mixture was concentrated in vacuo to give compound 406j (0.1 g). LCMS (M+H) ⁺ : 411. Step 11: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-21-fluoro-18-hydroxy-13-methyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 406) To a solution of (8S,11S)-21-fluoro-13-methyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,20,22-hexaene-12,18- dione;2,2,2-trifluoroacetic acid (compound 406j, 62 mg, 0.15 mmol) and Intermediate C2 (40 mg, 0.15 mmol) in NMP (3 mL) was added N,N-diisopropylethylamine (0.5 mL), and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was directly purified by prep- HPLC to give Example 406 (11 mg). LCMS (M+H) ⁺ : 641. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.54 (s, 1H), 8.21 (s, 1H), 7.70 - 7.59 (m, 1H), 7.48 (m, 1H), 7.30 - 7.25 (m, 1H), 7.23 - 7.18 (m, 2H), 7.00 - 6.96 (m, 1H), 6.89 - 6.85 (m, 2H), 6.82 - 6.77 (m, 1H), 5.59 (m, 1H), 5.51 - 5.43 (m, 1H), 4.60 (s, 1H), 4.52 - 4.31 (m, 2H), 4.11 - 4.04 (m, 1H), 3.72 - 3.64 (m, 1H), 3.08 (s, 1H), 2.98 (s, 3H), 2.79 - 2.66 (m, 2H), 2.39 - 2.29 (m, 1H), 1.58 - 1.49 (m, 1H). Example 407 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compounds were prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(4-methoxy-2-nitro-anilino)propyl]-N-methyl- carbamate (compound 407a) A mixture of 1-fluoro-4-methoxy-2-nitro-benzene (7.0 g, 40.9 mmol), tert-butyl N-(3- amino-2-methyl-propyl)carbamate (8.0 g, 42.5 mmol) and N,N-diisopropylethylamine (6.0 g, 46.4 mmol) in anhydrous THF (150 mL) was stirred at 80 °C for 12 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water and brine, the separated organic layer was dried over and concentrated to give the crude product, which was purified by flash chromatography to afford compound 407a (12 g). LCMS (M+H ⁺ ): 340. Step 2: preparation of tert-butyl N-[3-(2-bromo-4-methoxy-6-nitro-anilino)propyl]-N- methyl-carbamate (compound 407b) To a mixture of tert-butyl N-[3-(4-methoxy-2-nitro-anilino)propyl]-N-methyl-carbamate (compound 407-a, 5.0 g, 14.7 mmol) and N-bromosuccinimide (6.6 g, 36.8 mmol) in anhydrous THF (100 mL) was added p-toluenesulfonic acid monohydrate (0.4 g, 0.3 mmol), the reaction mixture was stirred at room temperature for 12 h. Then the reaction mixture was diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was removed in vacuo to get a crude product, which was purified by column chromatography to give compound 407b (1.0 g). LCMS (M+H ⁺ ): 418. Step 3: preparation of tert-butyl N-[3-(2-amino-6-bromo-4-methoxy-anilino)propyl]- N-methyl-carbamate (compound 407c) To a solution of tert-butyl N-[3-(2-bromo-4-methoxy-6-nitro-anilino)propyl]-N-methyl- carbamate (compound 407b, 1.0 g, 2.4 mmol) and Raney Ni (1.0 g) in methanol (50 mL) was added hydrazine hydrate (1.0 g) dropwise. The reaction mixture was stirred at room temperature for 1 h, then the reaction mixture was filtered and filtrate was concentrated. The residue was dissolved in EtOAc and then washed with brine, The organic layer was dried and concentrated to give compound 407c (0.8 g). LCMS (M+H ⁺ ): 388. Step 4: preparation of tert-butyl N-[3-(7-bromo-5-methoxy-2-methyl-benzimidazol-1- yl)propyl]-N-methyl-carbamate (compound 407d) To a solution of tert-butyl N-[3-(2-amino-6-bromo-4-methoxy-anilino)propyl]-N-methyl- carbamate (compound 407c, 0.8 g, 2.1 mmol), trimethyl orthoacetate (371 mg, 3.1 mmol) in THF (10 mL) was added pyridinium p-toluenesulfonate (0.2 g). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was removed in vacuo to get a crude product, which was purified by column chromatography to give compound 407-d (0.8 g). LCMS (M+H ⁺ ): 412. Step 5: preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-6-methoxy-2- methyl-benzimidazol-4-yl]boronic acid (compound 407e) To a solution of tert-butyl N-[3-(7-bromo-5-methoxy-2-methyl-benzimidazol-1-yl)propyl]- N-methyl-carbamate (compound 407d, 0.8 g, 1.33 mmol), bis(neopentyl glycolato)diboron (0.6 g, 2.7 mmol), XPhos (150 mg, 0.3 mmol) and sodium acetate (1.5 g, 4.0 mmol) in 1,4-dioxane (20 mL) was added Pd ₂ (dba) ₃ (150 mg, 0.4 mmol), the resulting mixture was stirred at 100 °C for 12 h under argon. Then the reaction mixture was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ . After filtration, the solvent was removed in vacuo to get a crude product, which was purified by column chromatography to give compound 407e (0.3 g). LCMS (M+H ⁺ ): 378. Step 6: preparation of [6-methoxy-2-methyl-3-[3-(methylamino)propyl]benzimidazol- 4-yl]boronic acid;2,2,2-trifluoroacetic acid (compound 407f) A solution of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-6-methoxy-2- methyl- benzimidazol-4-yl]boronic acid (compound 407e, 0.2 g, 0.5 mmol) in TFA (5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give compound 407f (140 mg). LCMS (M+H ⁺ ): 278. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[6-methoxy-2-methyl-3- [3-(methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]py rrolidine-1,2-dicarboxylate (compound 407-g) To a solution of [6-methoxy-2-methyl-3-[3-(methylamino)propyl]benzimidazol-4- yl]boronic acid;2,2,2-trifluoroacetic acid (compound 407f, 0.1 g, 0.4 mmol), Intermediate B8 (0.2 g, 0.5 mmol), potassium phosphate (153 mg, 0.72 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added Pd(dppf)Cl ₂ (40 mg, 0.4 mmol), the reaction mixture was stirred at 100 °C for 12 h under argon. The reaction mixture was filtered and the filtrate was purified by reversed flash to give compound 407g (80 mg). LCMS (M+H ⁺ ): 553. Step 8: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[6-methoxy-2-methyl-3-[3 - (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrro lidine-2-carboxylic acid (compound 407h) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[6-methoxy-2-methyl-3-[3- (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrro lidine-1,2-dicarboxylate (compound 407g, 80 mg, 0.14 mmol) in methanol (2 mL) and water (0.5 mL) was added lithium hydroxide hydrate (61 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered and the filtrate was purified by reversed flash to give compound 407-h (30 mg). LCMS (M+H ⁺ ): 539. Step 9: preparation of tert-butyl (8S,11S)-22-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 407i) To a solution of HATU (20 mg, 0.08 mmol) and N,N-diisopropylethylamine (14 mg, 0.11 mmol) in N,N-dimethylformamide (15 mL) was added a solution of (2S,4S)-1-tert- butoxycarbonyl-4-[[6-[6-methoxy-2-methyl-3-[3-(methylamino)p ropyl]benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 407h, 30 mg, 0.06 mmol) in N,N- dimethylformamide (15 mL) dropwise and then the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated and the residue was purified by reversed flash to give compound 407-i (15 mg). LCMS (M+H ⁺ ): 521. Step 10: preparation of (8S,11S)-22-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 407j) A solution of tert-butyl (8S,11S)-22-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 407i, 15 mg, 0.03 mmol) in TFA (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give compound 407j (5.0 mg). LCMS (M+H ⁺ ): 421. Step 11: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 407) To a solution of (8S,11S)-22-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one;2,2,2-trifluoroacetic acid (compound 407j, 5.0 mg, 0.01 mmol) and Intermediate C2 (3.0 mg, 0.01 mmol) in NMP (0.5 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.02 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, the filtrate was purified by reversed flash to give Example 407 (1.4 mg). LCMS (M+H ⁺ ): 651. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 (s, 1H), 8.51 (br s, 1H), 7.81 - 7.76 (m, 1H), 7.70 - 7.60 (m, 1H), 7.32 - 7.26 (m, 1H), 7.24 - 7.17 (m, 1H), 7.12 (m,1H), 6.92 - 6.87 (m, 1H), 6.85 - 6.81 (m, 1H), 6.77 - 6.72 (m, 1H), 5.54 - 5.42 (m, 1H), 4.75 (s, 1H), 4.31 - 4.21 (m, 1H), 4.06 (m, 1H), 3.84 (s, 3H), 3.66 - 3.61 (m, 1H), 3.59 - 3.49 (m, 1H), 3.14 (s, 1H), 3.05 (s, 2H), 3.01 - 2.84 (m, 2H), 2.73 - 2.58 (m, 2H), 2.58 - 2.55 (m, 3H), 2.24 - 2.06 (m, 1H), 1.43 (m, 1H). Example 408 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaene-14-carboxylic acid

The title compounds were prepared according to the following scheme: Step 1: preparation of 2-(benzyloxycarbonylamino)-4-(2-bromo-6-nitro- anilino)butanoic acid (compound 408-a) A mixture of 1-bromo-2-fluoro-3-nitro-benzene (8.0 g, 36.4 mmol), 4-amino-2- (benzyloxycarbonylamino)butanoic acid (9.6 g, 38.0 mmol) and N,N-diisopropylethylamine (8.0 g, 61.9 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 12 h. The mixture was concentrated to give the crude product, which was purified by prep-HPLC to give compound 408-a (12 g). LCMS (M+H ⁺ ): 454. Step 2: preparation of 4-(2-amino-6-bromo-anilino)-2- (benzyloxycarbonylamino)butanoic acid (compound 408-b) A mixture of 2-(benzyloxycarbonylamino)-4-(2-bromo-6-nitro-anilino)butano ic acid (compound 408-a, 1.0 g, 2.21 mmol) and Pt/C (200 mg) in anhydrous EtOAc (10 mL) was stirred at room temperature for 4 h under hydrogen. The mixture was filtered and the filtrate was concentrated to give compound 408-b (675 mg). LCMS (M+H ⁺ ): 422. Step 3: preparation of 2-(benzyloxycarbonylamino)-4-(7-bromo-2-methyl- benzimidazol-1-yl)butanoic acid (compound 408-c) A mixture of 4-(2-amino-6-bromo-anilino)-2-(benzyloxycarbonylamino)butano ic acid (compound 408-b, 9.0 g, 21.3 mmol), trimethyl orthoacetate (6.0 g, 49.9 mmol) and pyridinium p-toluenesulfonate (0.4 g, 1.59 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 12 h. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated to give compound 408-c (8.0 g). LCMS (M+H ⁺ ): 446. Step 4: preparation of 2-[benzyloxycarbonyl(methyl)amino]-4-(7-bromo-2-methyl- benzimidazol-1-yl)butanoic acid (compound 408-d) To a solution of 2-(benzyloxycarbonylamino)-4-(7-bromo-2-methyl-benzimidazol- 1- yl)butanoic acid (compound 408-c, 1.0 g, 2.2 mmol) and iodomethane (1.0 g, 7.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added NaH (300 mg, 7.5 mmol) at 0 °C, and the mixture was stirred at room temperature for 11 h. The mixture was poured into water, then adjusted to pH=3 with 1 M HCl, and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product, which was purified by prep-HPLC to give compound 408-d (0.9 g). LCMS (M+H ⁺ ): 462. Step 5: preparation of tert-butyl 2-[benzyloxycarbonyl(methyl)amino]-4-(7-bromo-2- methyl-benzimidazol-1-yl)butanoate (compound 408-e) A solution of 2-[benzyloxycarbonyl(methyl)amino]-4-(7-bromo-2-methyl-benzi midazol-1- yl)butanoic acid (compound 408-d, 4.0 g, 8.7 mmol), Boc ₂ O (2.3 g, 10.4 mmol), DMAP (318 mg, 2.6 mmol) in tert-butanol (50 mL) was stirred at 60 °C for 2 h. The reaction mixture was poured into water, then the resulting mixture was filtered, the filter cake was collected and dried to give compound 408-e (4.0 g). LCMS (M+H ⁺ ): 516. Step 6: preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]-4-tert-butoxy-4-oxo- butyl]-2-methyl-benzimidazol-4-yl]boronic acid (compound 408-f) A solution of tert-butyl 2-[benzyloxycarbonyl(methyl)amino]-4-(7-bromo-2-methyl- benzimidazol-1-yl)butanoate (compound 408-e, 4.0 g, 7.8 mmol), bis(neopentyl glycolato)diboron (2.2 g, 9.3 mmol), Pd ₂ (dba) ₃ (1.2 g, 0.04 mmol), X-phos (1.2 g, 2.5 mmol) and sodium acetate (1.3 g, 15.5 mmol) in N,N-dimethylformamide (90 mL) was stirred at 100 °C for 12 h. The reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to get a crude product, which was purified by prep-HPLC to give compound 408-f (2.2 g). LCMS (M+H ⁺ ): 482. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3- [benzyloxycarbonyl(methyl)amino]-4-tert-butoxy-4-oxo-butyl]- 2-methyl-benzimidazol-4- yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 408-g) To a solution of Intermediate B8 (2.2 g, 5.5 mmol), Pd(dppf)Cl ₂ (600 mg, 0.04 mmol) and sodium carbonate (969 mg, 9.1 mmol) in N,N-dimethylformamide (80 mL) and water (1.5 mL) were added [3-[3-[benzyloxycarbonyl(methyl)amino]-4-tert-butoxy-4-oxo-b utyl]-2-methyl- benzimidazol-4-yl]boronic acid (compound 408-f, 2.2 g, 4.6 mmol), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried and then concentrated to get a crude product, which was purified by column chromatography to give compound 408-g (2.8 g, 3.7 mmol). LCMS (M+H ⁺ ): 757. Step 8: preparation of (2S,4S)-4-[[6-[3-[3-[benzyloxycarbonyl(methyl)amino]-4-tert- butoxy-4-oxo-butyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]am ino]-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 408-h) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3- [benzyloxycarbonyl(methyl)amino]-4-tert-butoxy-4-oxo-butyl]- 2-methyl-benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 408-g, 2.8 g, 3.7 mmol) in methanol (20 mL) and water (1 mL) were added lithium hydroxide hydrate (310 mg, 7.4 mmol), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was adjusted with saturated aq.NH ₄ Cl to pH=6, then the mixture was poured into water (0.1 L), and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to get a crude product, which was purified by reversed flash to give compound 408- h (600 mg). LCMS (M+H ⁺ ): 743. Step 9: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[4-tert-butoxy-3- (methylamino)-4-oxo-butyl]-2-methyl-benzimidazol-4-yl]-2-pyr idyl]amino]pyrrolidine-2- carboxylic acid (compound 408-i) A suspension of (2S,4S)-4-[[6-[3-[3-[benzyloxycarbonyl(methyl)amino]-4-tert- butoxy-4- oxo-butyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]amino]-1-te rt-butoxycarbonyl-pyrrolidine-2- carboxylic acid (compound 408-h, 600 mg, 0.81 mmol) and Pd/C (100 mg) in THF (3 mL) and i- PrOH (3 mL) was stirred at 50 °C for 1 h under hydrogen. The reaction mixture was filtered and the filtrate was concentrated to get a crude product, which was purified by prep-HPLC to afford compound 408-i (260 mg). LCMS (M+H ⁺ ): 609. Step 10: preparation of (8S,11S)-10-tert-butoxycarbonyl-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaene-14-carboxylic acid (compound 408-j) To a solution of HATU (145 mg, 0.62 mmol) in DMF (100 mL) was added N,N- diisopropylethylamine (159 mg, 1.2 mmol) at 0 °C. And then (2S,4S)-1-tert-butoxycarbonyl-4- [[6-[3-[4-tert-butoxy-3-(methylamino)-4-oxo-butyl]-2-methyl- benzimidazol-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 408-i, 250 mg, 0.4 mmol) in N,N- dimethylformamide (100 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, and then concentrated to get a crude product, which was purified by reversed flash to give compound 408-j (150 mg). LCMS (M+H ⁺ ): 591. Step 11: preparation of (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaene-14- carboxylic acid;hydrochloride (compound 408-k) A solution of (8S,11S)-10-tert-butoxycarbonyl-13,18-dimethyl-12-oxo-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaene-14- carboxylic acid (compound 408-j, 150 mg, 0.25 mmol) in TFA (1.0 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to get a crude product, which was purified by reversed flash column to give compound 408-k (100 mg). LCMS (M+H ⁺ ): 435. Step 12: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaene-14- carboxylic acid (Example 408) A solution of (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaene-14- carboxylic acid;hydrochloride (compound 408-k, 36 mg, 0.08 mmol), Intermediate C2 (20 mg, 0.08 mmol) and N,N-diisopropylethylamine (97 mg, 0.8 mmol) in NMP (1 mL) was stirred at 80 °C for 2 h. The reaction mixture was directly purified by prep-HPLC to give Example 408 (3.5 mg). LCMS (M+H ⁺ ): 665. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.40 - 8.26 (m, 2H), 8.22 - 8.12 (m, 1H), 7.94 (m, 1H), 7.68 (m, 1H), 7.64 - 7.58 (m, 1H), 7.50 - 7.40 (m, 1H), 7.37 - 7.31 (m, 1H), 7.30 - 7.23 (m, 2H), 7.21 - 7.14 (m, 1H), 5.81 - 5.58 (m, 1H), 4.61 - 4.48 (m, 2H), 4.45 - 4.33 (m, 1H), 4.23 (m, 1H), 3.98 - 3.83 (m, 1H), 3.04 - 2.76 (m, 1H), 2.72 - 2.61 (m, 4H), 2.40 - 2.28 (m, 3H), 2.27 - 2.02 (m, 1H), 1.73 - 1.50 (m, 2H). Example 409 (8S,11S,15R)-10-[6-ethoxy-1-(4-fluoro-2-methoxy-phenyl)pyraz olo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 410 by using intermediate C26 instead of intermediate C25 in step 1 and using 3M NaOEt solution in EtOH instead of 5 M NaOMe solution in MeOH in step 2. LCMS (M+H ⁺ ): 725, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.32 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 6.1, 8.5 Hz, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.16 (dd, J = 2.5, 10.5 Hz, 1H), 7.12 - 7.06 (m, 1H), 7.02 (dd, J = 2.6, 10.7 Hz, 1H), 6.83 (dt, J = 2.6, 8.3 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.79 (dd, J = 4.3, 15.5 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.67 - 4.56 (m, 1H), 4.50 - 4.39 (m, 2H), 4.34 - 4.11 (m, 4H), 3.92 (dd, J = 9.2, 14.1 Hz, 1H), 3.77 (s, 3H), 3.03 (s, 3H), 2.90 - 2.85 (m, 1H), 2.84 (s, 3H), 2.57 (s, 3H), 2.49 (tt, J = 4.4, 9.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). Example 410 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methoxy-pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[6-bromo-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 410a) To a flask was added (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one;2,2,2-trifluoroacetic acid (compound 370b, 96.14 mg, 0.174 mmol), 6-bromo-4- chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C25, 81.4 mg, 0.209 mmol), DIEA (151.5 mg, 204 μL, 1.17 mmol) and ethanol (3 mL). The mixture was stirred at 40 °C for about 4 hrs. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 410a (130 mg). LCMS (M+H ⁺ ): 747. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methoxy- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 410) To a microwave tube was added (8S,11S,15R)-10-[6-bromo-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one (compound 410a, 65 mg, 0.075 mmol), 5 M NaOMe solution in MeOH (105.62 μL, 0.528 mmol) and MeOH (1 mL). The solution was stirred at 60 °C for 24 hrs. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 410 (30 mg). LCMS (M+H ⁺ ): 699, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.39 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.33 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 (ddd, J = 2.7, 8.8, 10.2 Hz, 1H), 7.20 (dd, J = 2.4, 10.4 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 4.3, 15.5 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.67 - 4.61 (m, 1H), 4.47 (dd, J = 6.0, 11.3 Hz, 1H), 4.33 - 4.24 (m, 1H), 4.17 (dd, J = 10.8, 15.4 Hz, 1H), 4.00 - 3.92 (m, 2H), 3.84 (s, 3H), 3.03 (s, 3H), 2.91 - 2.86 (m, 1H), 2.85 (s, 3H), 2.60 (s, 3H), 2.53 - 2.46 (m, 2H). Example 411 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-ethoxy-pyrazolo[3, 4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 410 by using 3M NaOEt in solution EtOH instead of 5 M NaOMe solution in MeOH. LCMS (M+H ⁺ ): 713, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.38 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.32 (dd, J = 2.6, 8.4 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.18 (m, 1H), 7.18 - 7.13 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.42 (d, J = 9.0 Hz, 1H), 4.66 - 4.62 (m, 1H), 4.50 - 4.40 (m, 2H), 4.35 - 4.11 (m, 4H), 3.92 (dd, J = 9.2, 14.2 Hz, 1H), 3.03 (s, 3H), 2.91 - 2.86 (m, 1H), 2.85 (s, 3H), 2.59 (s, 3H), 2.53 - 2.44 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). Example 412 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(morpholinomethyl) pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of 1-(2,4-difluorophenyl)-6-(hydroxymethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 412a) NaBH ₄ (56.7 mg, 1.5 mmol) was added to a solution of ethyl 1-(2,4-difluorophenyl)-4- oxo-5H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (compound 214b, 160 mg, 0.500 mmol) in methanol (5 mL) at room temperature. The reaction mixture was stirred at r.t. for 1 h and then heated to 70 °C for 6 hrs. The mixture was concentrated and the residue was purified by reversed-phase HPLC to give compound 412a (50 mg). LCMS (M+H ⁺ ): 279. Step 2: preparation of 6-(chloromethyl)-1-(2,4-difluorophenyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 412b) To a tube was added 1-(2,4-difluorophenyl)-6-(hydroxymethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 412a, 47 mg, 0.169 mmol), toluene (2 mL) and SOCl ₂ (80.4 mg, 49 μL, 0.676 mmol). The suspension was heated to 100 °C and stirred for 2 hrs. The mixture was diluted with EA and then the organic layer was washed with water, then concentrated to give compound 412b (52 mg). LCMS (M+H ⁺ ): 297. Step 3: preparation of 1-(2,4-difluorophenyl)-6-(morpholinomethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 412c) To a tube was added 6-(chloromethyl)-1-(2,4-difluorophenyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 412b, 52 mg, 0.175 mmol), morpholine (45.8 mg, 46 μL, 0.526 mmol) and acetonitrile (1 mL). The solution was heated to 70 °C and stirred for 2 hrs. The mixture was concentrated to give compound 412c (60 mg). LCMS (M+H ⁺ ): 348. Step 4: preparation of 4-[[4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 6- yl]methyl]morpholine (compound 412d) A solution of 1-(2,4-difluorophenyl)-6-(morpholinomethyl)-5H-pyrazolo[3,4- d]pyrimidin- 4-one (compound 412c, 60 mg, 0.173 mmol) in phosphorus oxychloride (830.5 mg, 505 μL, 5.42 mmol) was stirred at 90 °C for 16 hrs. The mixture was concentrated directly to give an oil, which was purified by prep-HPLC to give compound 412d (50 mg). LCMS (M+H ⁺ ): 366. Step 5: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- (morpholinomethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 412) To a flask was added (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one;2,2,2-trifluoroacetic acid (compound 370b, 70 mg, 0.105 mmol), 4-[[4-chloro-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]methyl]mor pholine;2,2,2-trifluoroacetic acid (compound 412d, 50.4 mg, 0.105 mmol), DIEA (121 mg, 163 μL, 0.935 mmol) and acetonitrile (2 mL). The mixture was heated to 85 °C and stirred for about 1 hr, then concentrated to give an oil, which was purified prep-HPLC to give Example 412 (59.7 mg). LCMS (M+H ⁺ ): 768, ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.32 - 7.26 (m, 2H), 7.22 - 7.14 (m, 2H), 7.12 - 7.08 (m, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.74 (dd, J = 4.3, 15.6 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.54 - 4.45 (m, 1H), 4.36 - 4.27 (m, 1H), 4.11 (dd, J = 10.9, 15.5 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.94 - 3.84 (m, 2H), 3.84 - 3.69 (m, 5H), 3.14 - 3.08 (m, 1H), 3.05 (s, 3H), 2.95 - 2.84 (m, 4H), 2.83 (s, 3H), 2.56 (s, 3H), 2.53 - 2.44 (m, 2H). Example 413 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-isopropyl-13-methyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-(2-fluoro-3-nitro- phenyl)pyrimidin-2-yl]oxypyrrolidine-1,2-dicarboxylate (compound 413a) A mixture of K ₂ CO ₃ (3.17 g, 22.97 mmol), 2-(2-fluoro-3-nitro-phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (2.04 g, 7.66 mmol), intermediate B15 (3 g, 7.66 mmol) and PdCl ₂ (dppf) (280 mg, 0.38 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated to 100 °C for 12 hours under N ₂ . The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel to give compound 413a (2.94 g). LCMS (M+H ⁺ ): 497. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[4-[2-[3-[tert- butoxycarbonyl(methyl)amino]propylamino]-3-nitro-phenyl]pyri midin-2- yl]oxypyrrolidine-1,2-dicarboxylate (compound 413b) Compound 413a (2.94 g, 5.03 mmol) and K ₂ CO ₃ (2.09 g, 15.1 mmol) were dissolved in acetonitrile (20 mL) and N-(3-aminopropyl)-N-methyl-carbamic acid tert-butyl ester (0.94 g, 5.03 mmol) was added at rt. The mixture was stirred at 25 °C for 12hours. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was washed with brine, dried and concentrated. The crude material was purified by silica gel to give compound 413b (2.8 g). LCMS (M+H ⁺ ): 665. Step 3-6: preparation of (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-12-methyl-6-nitro-18-oxa-8,12,15,20,23- pentazatetracyclo[17.3.1.1 ^14,17 .0 ^2,7 ]tetracosa-1(23),2,4,6,19,21-hexaen-13-one (compound 413f) Compound 413f was prepared in analogy to the preparation of Example 12 by using compound 413b instead of compound 12a. LCMS (M+H ⁺ ): 629. Step 7: preparation of (14S,17S)-6-amino-15-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-12-methyl-18-oxa-8,12,15,20,23- pentazatetracyclo[17.3.1.1 ^14,17 .0 ^2,7 ]tetracosa-1(23),2,4,6,19,21-hexaen-13-one (compound 413g) A mixture of compound 413f (1.0 g, 1.59 mmol), zinc (1.0 g, 15.91 mmol) and NH ₄ Cl (170.19 mg, 3.18 mmol) in ethanol (10 mL) and water (1 mL) was stirred at 25 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give compound 413g(500 mg). LCMS (M+H ⁺ ): 599. Step 8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- yl]-18-isopropyl-13-methyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 413) Compound 413g (50.0 mg, 0.084 mmol) and 1,1,1-trimethoxy-2-methyl-propane (123.0 mg, 0.835 mmol) were dissolved in methanol (1 mL), and then 1-mesyl-4-methyl-benzene (1 mg, 0.004 mmol) was added at rt. The mixture was stirred for 12 hours at 25 °C and then purified by prep-HPLC to give Example 413(7.6 mg). LCMS (M+H ⁺ ): 651. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.86 - 8.81 (m, 1H), 8.61 - 8.06 (m, 2H), 7.92 - 7.86 (m, 1H), 7.75 - 7.70 (m, 2H), 7.58 (d, J = 5.3 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.22 (m, 2H), 5.97 - 5.41 (m, 3H), 4.59 - 4.33 (m, 2H), 4.33 - 4.21 (m, 1H), 4.19 - 4.09 (m, 1H), 3.60 - 3.51 (m, 1H), 3.11 - 2.99 (m, 3H), 2.98 - 2.85 (m, 2H), 2.83 - 2.75 (m, 1H), 2.21 (s, 1H), 1.91 - 1.78 (m, 1H), 1.54 - 1.48 (m, 6H). Example 414 Methyl (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-methyl-12- 2,6 8,11 20,24 oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-18-carboxylate The title compound was prepared in analogy to the preparation of Example 413 by using the reaction condition with 2,2,2-trimethoxyacetic acid methyl ester instead of 1,1,1-trimethoxy- 2-methyl-propane. Example 414. LCMS (M+H ⁺ ): 667. ¹ H NMR (500 MHz, METHANOL-d ₄₎ δ = 8.86 - 8.82 (m, 1H), 8.75 - 8.04 (m, 2H), 8.00 - 7.95 (m, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.63 - 7.57 (m, 1H), 7.38 - 7.32 (m, 1H), 7.22 (d, J = 7.9 Hz, 2H), 6.07 - 5.34 (m, 3H), 4.69 - 4.59 (m, 2H), 4.28 - 4.16 (m, 1H), 4.08 - 4.02 (m, 2H), 3.13 - 2.99 (m, 3H), 2.99 - 2.93 (m, 1H), 2.91 - 2.86 (m, 1H), 2.38 - 2.35 (m, 3H), 2.08 - 1.99 (m, 1H), 1.65 - 1.48 (m, 1H). Example 415 (8S,11S)-18-(chloromethyl)-10-[1-(2,4-difluorophenyl)pyrazol o[3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 413 by using the reaction condition with 2-chloro-1,1,1-trimethoxy-ethane instead of 1,1,1-trimethoxy-2- methyl-propane. LCMS (M+H ⁺ ): 658. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.83 - 8.76 (m, 1H), 8.62 - 7.89 (m, 2H), 7.87 (dd, J = 0.9, 8.1 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.61 - 7.56 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.22 (br d, J = 8.1 Hz, 1H), 5.94 - 5.76 (m, 1H), 5.73 - 5.63 (m, 1H), 5.60 - 5.33 (m, 1H), 5.13 - 5.02 (m, 2H), 4.61 - 4.09 (m, 4H), 3.09 - 2.97 (m, 3H), 2.92 - 2.74 (m, 2H), 2.36 (s, 1H), 2.24 - 1.99 (m, 1H), 1.91 - 1.75 (m, 1H). Example 416 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-18-hydroxy-13-methyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Compound 413g (80 mg, 0.134 mmol) and CDI (32.51 mg, 0.200 mmol) were dissolved in tetrahydrofuran (2 mL) and DIEA (34.54 mg, 0.267 mmol) was added at rt. The mixture was stirred for 12 hours at 25 °C. The reaction mixture was added MeOH and purified by prep-HPLC to give Example 416(5.3 mg). LCMS (M+H ⁺ ): 625. ¹ H NMR (500 MHz, METHANOL-d4) δ = 8.71 - 8.65 (m, 1H), 8.57 - 8.24 (m, 2H), 8.23 - 8.17 (m, 1H), 7.70 - 7.62 (m, 1H), 7.43 - 7.34 (m, 1H), 7.32 - 7.25 (m, 2H), 7.25 - 7.15 (m, 3H), 6.19 - 5.94 (m, 1H), 5.63 - 5.52 (m, 1H), 5.40 - 5.32 (m, 1H), 4.59 - 4.55 (m, 1H), 4.53 - 4.40 (m, 1H), 3.12 - 2.98 (m, 3H), 2.42 - 2.36 (m, 1H), 2.21 - 2.18 (m, 1H), 2.17 - 2.08 (m, 1H), 2.07 - 2.01 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 - 1.57 (m, 1H). Example 417 (8S,11S)-18-amino-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]p yrimidin-4-yl]-13-methyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Compound 413g (50 mg, 0.084 mmol) and cyanogen bromide (11.5 mg, 0.109 mmol) were dissolved in acetonitrile (5 mL) and water(5 mL). The mixture was stirred for 12 hours at 25 °C. The reaction mixture was added MeOH and purified by prep-HPLC to give Example 417(4.4 mg). LCMS (M+H ⁺ ): 624. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.76 - 8.72 (m, 1H), 8.58 - 7.85 (m, 2H), 7.74 - 7.62 (m, 1H), 7.46 - 7.38 (m, 2H), 7.35 - 7.28 (m, 1H), 7.25 - 7.17 (m, 3H), 6.00 - 5.82 (m, 1H), 5.62 - 5.47 (m, 1H), 5.39 - 5.32 (m, 1H), 5.20 - 5.10 (m, 1H), 4.86 - 4.84 (m, 2H), 4.56 (s, 1H), 4.27 - 4.17 (m, 1H), 3.90 - 3.81 (m, 1H), 3.12 - 2.99 (m, 3H), 2.84 - 2.73 (m, 2H), 2.05 (br d, J = 5.3 Hz, 1H), 1.99 - 1.88 (m, 1H), 1.70 - 1.55 (m, 1H). Example 418 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-N,13-dimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-18-carboxamide

The title compound was prepared according to the following scheme: Example 414 (60 mg, 0.090 mmol) was dissolved in methanol (1 mL) and then methylamine/MeOH (28 mg, 0.90 mmol) was added at rt. The mixture was stirred at 80 °C for 12 hours, then the reaction mixture was purified by prep-HPLC to give Example 418 (4.9 mg). LCMS (M+H ⁺ ): 666. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.87 - 8.80 (m, 1H), 8.66 - 7.90 (m, 2H), 7.89 (d, J = 2.0 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.63 - 7.57 (m, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.41 (m, 1H), 7.36 - 7.30 (m, 1H), 7.22 - 7.15 (m, 1H), 5.94 - 5.46 (m, 2H), 5.38 - 5.26 (m, 2H), 4.55 - 4.44 (m, 1H), 4.33 - 4.12 (m, 1H), 3.99 - 3.90 (m, 1H), 3.01 - 2.87 (m, 3H), 2.84 - 2.79 (m, 3H), 2.77 - 2.64 (m, 2H), 2.58 - 2.51 (m, 1H), 2.17 - 2.07 (m, 1H), 1.46 (br d, J = 7.2 Hz, 1H). Example 419 (8S,11S,15R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazol o[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 81 by using intermediate C17 instead of intermediate C2. Example 419, LCMS (M+H ⁺ ): 723. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.84 - 8.71 (m, 1H), 8.50 - 7.74 (m, 2H), 7.69 - 7.59 (m, 1H), 7.50 - 7.37 (m, 3H), 7.35 - 7.26 (m, 1H), 6.97 - 6.82 (m, 1H), 5.90 - 5.65 (m, 2H), 5.60 - 5.27 (m, 1H), 4.54 - 4.25 (m, 2H), 4.21 - 4.12 (m, 1H), 4.05 - 3.95 (m, 1H), 3.89 - 3.78 (m, 1H), 3.29 - 3.24 (m, 1H), 3.17 - 2.97 (m, 3H), 2.96 - 2.77 (m, 2H), 2.77 - 2.68 (m, 1H), 2.63 (s, 3H), 2.61 (s, 1H), 2.57 (dd, J = 7.0, 9.2 Hz, 1H), 0.77 - 0.69 (m, 2H), 0.64 - 0.52 (m, 5H). Example 420 N-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimid in-4-yl]-13-methyl-12-oxo-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-18-yl]acetamide The title compound was prepared according to the following scheme:

Example 417 (30 mg, 0.048 mmol) and Et ₃ N (9.74 mg, 0.096 mmol) were dissolved in tetrahydrofuran (3 mL) and then AcCl (3.78 mg, 0.048 mmol) was added at 0 °C. After being stirred at 0 °C for 2 hours, the reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was dried and concentrated, the crude material was purified by prep-HPLC to give Example 420(4.3 mg). LCMS (M+H ⁺ ): 666. ¹ H NMR (500 MHz, DMSO-d6) δ = 10.43 - 10.29 (m, 1H), 8.86 - 8.77 (m, 1H), 8.68 - 7.85 (m, 2H), 7.79 - 7.68 (m, 2H), 7.65 - 7.57 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.38 - 7.29 (m, 2H), 5.83 - 5.45 (m, 2H), 5.14 - 4.96 (m, 1H), 4.52 - 4.12 (m, 2H), 3.97 - 3.79 (m, 2H), 2.97 - 2.83 (m, 3H), 2.83 - 2.70 (m, 1H), 2.69 - 2.59 (m, 2H), 2.14 - 2.03 (m, 3H), 1.68 - 1.44 (m, 1H), 1.12 - 0.94 (m, 1H). Example 421 (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 81 by using intermediate C61 instead of intermediate C2. Example 421, LCMS (M+H ⁺ ): 715. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ = 8.86 - 8.80 (m, 1H), 8.62 - 7.81 (m, 2H), 7.80 - 7.75 (m, 1H), 7.61 - 7.54 (m, 1H), 7.52 - 7.44 (m, 1H), 7.20 - 7.09 (m, 2H), 5.77 - 5.42 (m, 3H), 4.51 - 3.97 (m, 3H), 3.93 - 3.82 (m, 1H), 3.81 - 3.71 (m, 3H), 3.30 - 3.23 (m, 1H), 3.22 - 3.08 (m, 1H), 2.98 - 2.87 (m, 3H), 2.86 - 2.75 (m, 1H), 2.73 - 2.65 (m, 2H), 2.55 - 2.52 (m, 3H), 2.47 - 2.44 (m, 1H), 0.44 - 0.37 (m, 3H). Example 422 (8S,11S)-18-cyclopropyl-10-[1-(2,4-difluorophenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-13- 2,6 8,11 20,24 methyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 413 by using cyclopropanecarboxaldehyde instead of 1,1,1-trimethoxy-2-methyl-propane. LCMS (M+H ⁺ ): 649. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.86 - 8.81 (m, 1H), 8.67 - 7.88 (m, 2H), 7.79 - 7.67 (m, 2H), 7.64 - 7.52 (m, 2H), 7.48 - 7.39 (m, 1H), 7.37 - 7.26 (m, 2H), 5.89 - 5.66 (m, 1H), 5.59 - 5.46 (m, 1H), 5.37 - 5.14 (m, 1H), 4.54 - 3.97 (m, 4H), 3.00 - 2.88 (m, 3H), 2.82 - 2.67 (m, 2H), 2.59 (br d, J = 14.5 Hz, 1H), 2.26 (br d, J = 3.7 Hz, 1H), 2.05 - 1.95 (m, 1H), 1.94 - 1.72 (m, 1H), 1.18 - 0.98 (m, 4H). Example 424 (8S,11S)-10-[1-(2-fluoro-4-tetrahydrofuran-3-yl-phenyl)pyraz olo[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 283 by using compound 197d instead of compound 283a and intermediate C72 instead of intermediate C44. LCMS (M+H ⁺ ): 703. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.20 - 8.60 (m, 2H), 7.77 - 7.85 (m, 1H), 7.52 - 7.65 (m, 2H), 7.25 - 7.39 (m, 4H), 6.89 - 7.14 (m, 1H), 6.69 (dd, J = 14.55, 8.44 Hz, 1H), 5.40 - 5.57 (m, 1H), 4.50 - 4.58 (m, 1H), 4.28 - 4.37 (m, 1H), 4.06 - 4.22 (m, 4H), 3.91 - 4.01 (m, 2H), 3.78 - 3.84 (m, 1H), 3.56 - 3.64 (m, 1H), 3.03 - 3.21 (m, 4H), 2.76 - 2.89 (m, 4H), 2.45 - 2.65 (m, 6H), 2.05 - 2.14 (m, 1H), 1.37 (d, J = 6.60 Hz, 1H). Example 425 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22,23-difluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-(3-amino-2-hydroxy-propyl)carbamate (compound 425a) To a solution of 1,3-diamino-2-propanol (250.0 g, 2.8 mol) in chloroform (2 L) was added a solution of N-(benzyloxycarbonyloxy)succinimide (34.6 g, 0.12 mol) in chloroform (0.7 L) dropwise over 6 hours at 0 °C. The mixture was stirred at 20 °C for 18 hours, and then washed with brine (0.5 L for three times). The organic layer was dried and concentrated to give compound 425a (15.0 g). LCMS (M+H ⁺ ): 225. Step 2: preparation of benzyl N-[3-(4,5-difluoro-2-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 425b) To a solution of 1,2,4-trifluoro-5-nitro-benzene (10.0 g, 0.05 mol) and DIEA (14.6 g, 0.1 mol) in DMF (0.1 L) was added a solution of compound 425a (12.7 g, 0.05 mol) in DMF (0.1 L). The mixture was stirred at 20 °C for 12 hours, and then concentrated. The residue was purified by flash column to give compound 425b (4.0 g). LCMS (M+H ⁺ ): 382. Step 3: preparation of benzyl N-[3-(2-bromo-3,4-difluoro-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound 425c) A mixture of compound 425b (2.7 g, 7.1 mmol) and bromine (2.3 g, 14.2 mmol) in DMF (20 mL) was stirred at 60 °C for 1 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL twice). The combined organic layer was washed with brine (20 mL twice), dried and concentrated. The residue was purified by flash column to give compound 425c (2.3 g). LCMS (M+H ⁺ ): 460. Step 4: preparation of benzyl N-[3-(6-amino-2-bromo-3,4-difluoro-anilino)-2- hydroxy-propyl]carbamate (compound 425d) To a solution of compound 425c (2.0 g, 4.3 mmol) in ethyl acetate (10 mL) was added Pt/C (0.1 g) and the mixture stirred at 20 °C for 1 h under H ₂ . The mixture was filtered and the filtrate was concentrated to give compound 425d (1.5 g). LCMS (M+H ⁺ ): 430. Step 5~13: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22,23-difluoro-15-methoxy-13,18-dimethyl-7 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared in analogy to the preparation of Example 395 (Step 5~13) by using compound 425d instead of compound 395d, and intermediate C1 instead of intermediate C11. LCMS (M+H ⁺ ): 687. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.21 - 8.59 (m, 2H), 6.71 - 7.87 (m, 7H), 5.34 - 5.59 (m, 2H), 4.05 - 4.55 (m, 3H), 3.78 - 4.02 (m, 1H), 3.03 - 3.22 (m, 4H), 2.78 - 2.96 (m, 5H), 2.50 - 2.66 (m, 5H). Example 426 (8S,11S)-10-[1-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]pyra zolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)propyl]- N-methyl-carbamate (compound 426a) To a mixture of compound 134b (10.0 g, 29.0 mmol) in THF (0.2 L) was added 1,1,1- trimethoxyethane (7.0 g, 58.1 mmol) and TsOH•pyridine (1.5 g, 5.8 mmol). The mixture was stirred at 25 °C for 12 hours, and then concentrated. The residue was purified by pre-HPLC to give compound 426a (4.0 g). LCMS (M+H ⁺ ): 368. Step 2: preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-2-methyl- benzimidazol-4-yl]boronic acid (compound 426b) To a mixture of compound 426a (3.0 g, 7.8 mmol) and bis(pinacolato)diboron (3.0 g, 11.7 mmol) in 1,4-dioxane (30 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride toluene (0.6 g, 0.7 mmol) and potassium acetate (2.3 g, 23.4 mmol). Then the mixture was stirred at 100 °C for 12 hours under N ₂ , and then filtered. The filtrate was concentrated and the residue was purified by pre-HPLC to compound 426b (1.2 g). LCMS (M+H ⁺ ): 348. Step 3: preparation of [2-methyl-3-[3-(methylamino)propyl]benzimidazol-4- yl]boronic acid (compound 426c) A mixture of compound 426b (1.2 g, 3.5 mmol) in DCM (10 mL) and TFA (3 mL) was stirred at 20 °C for 2 hours. The mixture was concentrated to give compound 426c (0.8 g). LCMS (M+H ⁺ ): 248. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-methyl-3-[3- (methylamino)propyl]benzimidazol-4-yl]-2-pyridyl]amino]pyrro lidine-1,2-dicarboxylate (compound 426d) To the mixture of compound 426c (0.8 g, 3.2 mmol) and intermediate B8 (1.5 g, 3.9 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Na ₂ CO ₃ (1.0 g, 9.7 mmol) and 1,1'- bis(diphenylphosphino)ferrocenepalladium(II) dichloride toluene (0.2 g, 0.3 mmol) under N ₂ . After stirring at 80 °C for 12 hours, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL twice). The organic layer was dried and concentrated, the residue was purified by pre-HPLC to give compound 426d (0.2 g). LCMS (M+H ⁺ ): 523. Step 5~8: preparation of (8S,11S)-10-[1-[2-fluoro-4-(2-oxopyrrolidin-1- yl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10 ,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (Example 426) The title compound was prepared in analogy to the preparation of Example 295 (step 11~14) by using compound 426d instead of compound 295j, and intermediate C73 instead of intermediate C11. LCMS (M+H ⁺ ): 686. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.21 - 8.58 (m, 2H), 7.92 - 8.05 (m, 1H), 7.79 - 7.83 (m, 1H), 7.59 - 7.65 (m, 3H), 7.25 (dt, J=14.95, 7.38 Hz, 2H), 6.91 (d, J=7.58 Hz, 1H), 6.77 (br d, J=8.19 Hz, 1H), 5.53 (br d, J=8.56 Hz, 1H), 5.05 - 5.16 (m, 2H), 3.90 - 4.35 (m, 4H), 3.05 - 3.18 (m, 3H), 2.85 - 3.01 (m, 1H), 2.54 - 2.75 (m, 8H), 2.24 (br t, J=7.58 Hz, 3H), 1.22 - 1.43 (m, 2H). Example 427 and 428 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,1 8-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compounds were prepared according to the following scheme: Step 1: preparation of tert-butyl (8S,11S,15S)-15-ethoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate and tert-butyl (8S,11S,15R)-15-ethoxy- 13,18-dimethyl-12-oxo-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-10- carboxylate (compound 427b-1 & 427b-2) SFC preparation of compound 427a (the synthesis was refer to compound 404p by using 3- fluoro-4-nitropyridine instead of 3-fluoro-2-nitropyridine) to give compound 427a-1 (slower eluted) and compound 427a-2 (faster eluted). SFC condition: Instrument: SHIMADZU LC- 30ADsf); Column: (S,S)Whelk-O1100×4.6mm I.D., 3.5um; Mobile phase: Phase A for Supercritical CO ₂ , and Phase B for MeOH+ACN(0.05%DEA); Gradient: 40% Phase B (60% Phase A); Flow rate: 3mL/min; Back pressure: 100Bar; Column temperature: 35 °C. LCMS (M+H) ⁺ : 536. Step 2~3: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-13,18-dimethyl-7,10,13,17,19,23, 26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15-ethoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1. 1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 427 & 428) The title compounds were prepared in analogy to the preparation of Example 289 by using compound 427a-1 instead of compound 289c and compound 427a-2 instead of compound 289c respectively. Example 427, LCMS (M+H) ⁺ : 666. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.60 (s, 1H), 8.49 (d, J = 6.4 Hz, 1H), 8.41 - 8.25 (m, 1H), 8.11 (d, J = 6.4 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.73 - 7.61 (m, 1H), 7.35 - 7.18 (m, 3H), 7.03 - 6.95 (m, 1H), 5.54 (d, J = 8.8 Hz, 1H), 4.82 - 4.77 (m, 1H), 4.67 - 4.56 (m, 1H), 4.44 - 4.33 (m, 1H), 4.32 - 4.22 (m, 1H), 4.15 - 4.03 (m, 1H), 3.83 - 3.73 (m, 1H), 3.40 - 3.33 (m, 1H), 3.20 (s, 1H), 3.09 (s, 2H), 2.89 - 2.81 (m, 3H), 2.71 - 2.63 (s, 1H), 2.71 - 2.61 (m, 1H), 1.40 - 1.35 (m, 3H), 0.59 (t, J = 6.8 Hz, 3H). Example 428, LCMS (M+H) ⁺ : 666. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.52 (m, 1H), 8.50 (d, J = 6.4 Hz, 1H), 8.38 - 8.20 (m, 1H), 8.08 - 8.04 (m, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.43 - 7.36 (m, 1H), 7.33 - 7.26 (m, 1H), 7.25 - 7.18 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.97 (dd, J = 15.2, 4.0 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.41 - 4.32 (m, 2H), 4.05 - 3.95 (m, 1H), 3.41 - 3.35 (m, 1H), 3.16 - 3.02 (m, 4H), 3.00 - 2.89 (m, 1H), 2.86 - 2.76 (m, 4H), 2.74 - 2.69 (m, 1H), 2.67 - 2.54 (m, 2H), 0.69 - 0.55 (m, 3H). Example 430 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-22-fluoro-18- methyl-15-(trideuteriomethoxy)-13-(trideuteriomethyl)-7-oxa- 5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 12 by using Intermediate A30 instead of Intermediate A11 and Intermediate B15 instead of Intermediate B10. LCMS (M+H) ⁺ : 677. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ = 8.76 (dd, J = 3.4, 5.2 Hz, 1H), 8.69 - 8.34 (m, 1H), 8.30 - 7.82 (m, 1H), 7.75 (dtd, J = 6.1, 8.7, 11.6 Hz, 1H), 7.66 - 7.45 (m, 3H), 7.40 - 7.27 (m, 2H), 5.76 (s, 2H), 5.58 - 5.41 (m, 2H), 4.55 - 4.13 (m, 2H), 4.10 - 3.82 (m, 2H), 3.20 - 2.96 (m, 1H), 2.93 - 2.62 (m, 2H), 2.53 (d, J = 2.7 Hz, 3H). Example 431 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyraz olo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound 431a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C47, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol) and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at rt for 2 hours. Then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, the residue was purified by silica gel to give to give compound 431a (400 mg). LCMS (M+H ⁺ ): 373. Step 2: preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(oxetan-3- yl)pyrazolo[3,4-d]pyrimidine (compound 431b) To an 8 mL vial equipped with a stir bar was added photocatalyst Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (15 mg, 0.013 mmol), tris(trimethylsilyl)silane (67 mg, 0.27 mmol), compound 431a (100 mg, 0.27 mmol), 3-bromooxetane (73.5 mg, 0.54 mmol), NiCl ₂ (dtbbpy) (10.68 mg, 0.027 mmol) and Na ₂ CO ₃ (85 mg, 0.8 mmol). The vial was sealed and placed under nitrogen before 4 mL of DME was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-455 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hours. The reaction was quenched by exposure to air and concentrated in vacuo, the residue was purified by silica gel to give compound 431b (60 mg). LCMS (M+H ⁺ ): 395. Step 3: preparation of 1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4- d]pyrimidin-4-ol (compound 431c) A mixture of compound 431b (60 mg, 0.15 mmol) and Pd(OH) ₂ (21 mg, 0.15 mmol) in methanol (12 mL) was stirred at rt 2 hours under H ₂ atmosphere. Then the reaction mixture was filtered and the filtrate was concentrated to give compound 431c (40 mg). LCMS (M+H ⁺ ): 305. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 431) A mixture of compound 431c (17 mg, 0.055 mmol), (1-hydroxy-1H-benzotriazolato-o)tri- 1-pyrrolidinylphosphorus hexafluorophosphate (36 mg, 0.068 mmol) and DIPEA (30 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was stirred at rt for 1 hour, then compound 370b (20 mg, 0.046 mmol) was added. The reaction was stirred at 50 °C for 16 hours and then the reaction mixture was purified by prep-HPLC to give Example 431 (7 mg). LCMS (M+H ⁺ ): 725. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.43 - 8.29 (m, 1H), 7.83 - 7.71 (m, 1H), 7.61 - 7.35 (m, 3H), 7.25 - 7.00 (m, 3H), 6.74 - 6.65 (m, 1H), 6.16 - 5.91 (m, 1H), 5.55 - 5.28 (m, 1H), 5.03 - 4.79 (m, 4H), 4.66 - 4.57 (m, 1H), 4.50 - 4.40 (m, 1H), 4.29 - 4.13 (m, 3H), 3.90 - 3.72 (m, 1H), 3.07 - 2.99 (m, 3H), 2.98 - 2.89 (m, 1H), 2.89 - 2.84 (m, 3H), 2.76 - 2.67 (m, 4H), 2.63 - 2.41 (m, 2H). Example 432 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-tetrahydrofuran-3- yl-pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one To an 8 mL vial equipped with a stir bar was added photocatalyst Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (3 mg, 0.003 mmol), tris(trimethylsilyl)silane (14 mg, 0.057 mmol), compound 213a (40 mg, 0.057 mmol ), 3-iodotetrahydrofuran (23 mg, 0.114 mmol), NiCl ₂ (dtbbpy) (2.3 mg, 0.006 mmol) and Na ₂ CO ₃ (18 mg, 0.17 mmol). The vial was sealed and placed under nitrogen before 4 mL of DME was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-455 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hours. The reaction was quenched by exposure to air and concentrated in vacuo, the residue was purified by HPLC to give compound 432 (9 mg). LCMS (M+H ⁺ ): 739. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.50 - 7.59 (m, 3H), 7.57 - 7.46 (m, 1H), 7.36 - 7.18 (m, 2H), 7.11 - 6.95 (m, 2H), 6.64 - 6.50 (m, 1H), 5.78 - 5.56 (m, 1H), 5.52 - 5.40 (m, 1H), 5.38 - 5.22 (m, 1H), 4.57 - 4.05 (m, 3H), 4.01 - 3.89 (m, 2H), 3.87 - 3.77 (m, 1H), 3.75 - 3.61 (m, 3H), 3.01 - 2.74 (m, 5H), 2.69 - 2.61 (m, 3H), 2.54 - 2.47 (m, 1H), 2.41 - 2.37 (m, 3H), 2.33 - 2.20 (m, 2H), 2.15 - 1.93 (m, 2H). Example 433 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-tetrahydropyran-4- yl-pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 433 was prepared in analogy to the preparation of Example 432 by using 4- iodotetrahydropyran instead of 3-iodotetrahydrofuran. Example 433 (15 mg). LCMS (M+H ⁺ ): 753. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.58 - 7.69 (m, 3H), 7.65 - 7.55 (m, 1H), 7.41 - 7.27 (m, 2H), 7.18 - 7.04 (m, 2H), 6.74 - 6.58 (m, 1H), 5.84 - 5.65 (m, 1H), 5.61 - 5.50 (m, 1H), 5.46 - 5.33 (m, 1H), 4.68 - 4.15 (m, 3H), 4.12 - 3.97 (m, 1H), 3.95 - 3.70 (m, 4H), 3.05 - 2.95 (m, 3H), 2.94 - 2.85 (m, 2H), 2.82 - 2.68 (m, 4H), 2.65 - 2.58 (m, 1H), 2.49 - 2.45 (m, 3H), 2.42 - 2.33 (m, 1H), 1.95 - 1.65 (m, 5H). Example 434 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-ylmethyl )pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 434 was prepared in analogy to the preparation of Example 432 by using 3- (iodomethyl)oxetane instead of 3-iodotetrahydrofuran. Example 434 (7 mg). LCMS (M+H ⁺ ): 739. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.35 - 7.58 (m, 2H), 7.56 - 7.40 (m, 1H), 7.22 - 6.88 (m, 5H), 6.61 - 6.49 (m, 1H), 5.70 - 5.50 (m, 1H), 5.36 - 5.18 (m, 1H), 4.56 - 4.31 (m, 5H), 4.17 - 3.97 (m, 2H), 3.88 - 3.69 (m, 1H), 3.47 - 3.26 (m, 1H), 3.07 - 2.86 (m, 6H), 2.82 - 2.68 (m, 5H), 2.50 - 2.32 (m, 5H). Example 435 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-2-ylmethyl )pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 435 was prepared in analogy to the preparation of Example 432 by using 2- (iodomethyl)oxetane instead of 3-iodotetrahydrofuran. Example 435 (10 mg). LCMS (M+H ⁺ ): 739. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ= 8.36 - 7.60 (m, 2H), 7.59 - 7.44 (m, 1H), 7.23 - 6.95 (m, 5H), 6.63 - 6.50 (m, 1H), 5.74 - 5.55 (m, 1H), 5.43 - 5.07 (m, 2H), 4.61 - 4.33 (m, 4H), 4.22 - 4.12 (m, 1H), 4.10 - 3.96 (m, 1H), 3.88 - 3.77 (m, 1H), 3.08 - 2.92 (m, 5H), 2.87 - 2.69 (m, 5H), 2.64 - 2.33 (m, 7H). Example 436 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylsulfonyl azetidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1~3: preparation of tert-butyl 3-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22- fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]azetidine-1-carboxyl ate (compound 436c) Compound 436c was prepared in analogy to the preparation of Examples 431 by using tert- butyl 3-(iodomethyl)azetidine-1-carboxylate instead of 3-bromooxetane. LCMS (M+H ⁺ ): 507. Step 4: preparation of (8S,11S,15R)-10-[6-(azetidin-3-ylmethyl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 436d) A mixture of compound 436c (35 mg, 0.042 mmol ) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at rt for 1 h, then the reaction was concentrated to give compound 436d (30 mg). LCMS (M+H ⁺ ): 738. Step 5: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1- methylsulfonylazetidin-3-yl)methyl]pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 436) To a solution of compound 436d (30 mg, 0.04 mmol) and DIPEA (26 mg, 0.2 mmol, 5.0) in dichloromethane (2 mL) was added methanesulfonic anhydride (14 mg, 0.08 mmol) at rt. Then the mixture was stirred at rt for 1 hour, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 436 (7 mg). LCMS (M+H ⁺ ): 816. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.45 (m, 1H), 7.95 - 7.84 (m, 1H), 7.72 - 7.48 (m, 3H), 7.35 - 7.10 (m, 3H), 6.84 - 6.73 (m, 1H), 6.21 - 6.01 (m, 1H), 5.54 - 5.33 (m, 1H), 4.73 - 4.66 (m, 1H), 4.57 - 4.47 (m, 1H), 4.43 - 4.26 (m, 2H), 4.02 - 3.82 (m, 5H), 3.11 - 3.08 (m, 3H), 3.03 - 2.89 (m, 7H), 2.88 - 2.76 (m, 7H), 2.63 - 2.51 (m, 2H). Example 437 (8S,11S,15R)-10-[6-[(1-acetylazetidin-3-yl)methyl]-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 437 was prepared in analogy to the preparation of Example 436 by using acetyl acetate instead of methanesulfonic anhydride. Example 437 (17 mg). LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.46 (m, 1H), 7.96 - 7.85 (m, 1H), 7.73 - 7.53 (m, 3H), 7.38 - 7.14 (m, 3H), 6.84 - 6.76 (m, 1H), 6.23 - 6.03 (m, 1H), 5.56 - 5.40 (m, 1H), 4.75 - 4.68 (m, 1H), 4.58 - 4.49 (m, 1H), 4.42 - 4.27 (m, 3H), 4.19 - 3.86 (m, 4H), 3.19 - 3.11 (m, 4H), 3.09 - 3.03 (m, 3H), 3.01 - 2.98 (m, 3H), 2.94 - 2.79 (m, 4H), 2.74 - 2.52 (m, 2H), 1.93 - 1.78 (m, 3H). Example 438 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyraz olo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one

Example 438 as prepared in analogy to the preparation of Example 431 by using compound 326d-1 instead of compound 370b. Example 438 (22 mg). LCMS (M+H ⁺ ): 740. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.78 - 8.62 (m, 1H), 8.58 - 7.75 (m, 1H), 7.73 - 7.58 (m, 3H), 7.35 - 7.13 (m, 3H), 6.04 - 5.77 (m, 1H), 5.66 - 5.37 (m, 1H), 5.16 - 5.10 (m, 1H), 5.06 - 5.01 (m, 1H), 4.98 - 4.93 (m, 5H), 4.55 - 4.21 (m, 3H), 4.05 - 3.93 (m, 1H), 3.52 - 3.42 (m, 1H), 3.21 - 3.09 (m, 3H), 3.08 - 2.99 (m, 1H), 2.89 - 2.50 (m, 6H), 0.72 - 0.53 (m, 3H). Example 439 and 440 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-hydroxy-1- (hydroxymethyl)ethyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethox y-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [1-(hydroxymethyl)-2-methoxy-ethyl]pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: A mixture of Example 438 (10 mg, 13 umol) and TFA (0.5 mL, 6.5 mmol) in methanol (0.5 mL) and water (0.5 mL) was stirred at 50 °C for 16 hours, then the reaction was concentrated and the residue was purified by prep-HPLC to give Example 439 and Example 440. Example 439, 5 mg, LCMS (M+H ⁺ ): 758. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.60 - 8.48 (m, 1H), 8.43 - 7.66 (m, 1H), 7.65 - 7.46 (m, 3H), 7.22 - 6.97 (m, 3H), 5.83 - 5.61 (m, 1H), 5.39 - 5.23 (m, 1H), 4.55 - 4.32 (m, 1H), 4.29 - 4.07 (m, 2H), 3.98 - 3.67 (m, 5H), 3.40 - 3.30 (m, 2H), 3.08 - 3.02 (m, 1H), 3.00 - 2.90 (m, 4H), 2.90 - 2.81 (m, 1H), 2.73 - 2.58 (m, 5H), 2.57 - 2.40 (m, 1H), 0.59 - 0.45 (m, 3H). Example 440, 2 mg, LCMS (M+H ⁺ ): 772. ¹ H NMR (400 MHz, METHANOL-d ₄ )δ = 8.57 - 8.47 (m, 1H), 8.42 - 7.64 (m, 1H), 7.63 - 7.51 (m, 1H), 7.46 - 7.30 (m, 2H), 7.23 - 6.96 (m, 3H), 5.71 - 5.49 (m, 1H), 5.42 - 5.23 (m, 1H), 4.57 - 4.31 (m, 1H), 4.30 - 4.06 (m, 2H), 3.95 - 3.57 (m, 5H), 3.56 - 3.35 (m, 1H), 3.32 - 3.25 (m, 1H), 3.19 (br s, 3H), 3.09 - 2.80 (m, 6H), 2.65 - 2.54 (m, 5H), 2.50 - 2.39 (m, 1H), 0.57 - 0.43 (m, 3H). Example 441 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methylsulfonyla zetidin-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Example 441 was prepared in analogy to the preparation of Example 436 by using tert- butyl 3-iodoazetidine-1-carboxylate instead of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate. Example 441 (6 mg). LCMS (M+H ⁺ ): 802. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.45 - 7.67 (m, 2H), 7.59 - 7.38 (m, 3H), 7.22 - 7.04 (m, 3H), 6.73 - 6.67 (m, 1H), 6.11 - 5.91 (m, 1H), 5.54 - 5.39 (m, 1H), 4.49 - 4.42 (m, 1H), 4.28 - 3.96 (m, 6H), 3.88 - 3.79 (m, 1H), 3.72 - 3.64 (m, 1H), 3.07 - 2.96 (m, 4H), 2.91 - 2.81 (m, 7H), 2.79 - 2.63 (m, 4H), 2.54 - 2.42 (m, 2H). Example 442 (8S,11S,15R)-10-[6-(1-acetylazetidin-3-yl)-1-(2,4-difluoroph enyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 442 was prepared in analogy to the preparation of Example 436 by using tert- butyl 3-iodoazetidine-1-carboxylate instead of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate and acetyl acetate instead of methanesulfonic anhydride. Example 441 (22 mg). LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.45 - 7.65 (m, 2H), 7.61 - 7.36 (m, 3H), 7.23 - 7.00 (m, 3H), 6.75 - 6.65 (m, 1H), 6.12 - 5.91 (m, 1H), 5.48 - 5.29 (m, 1H), 4.48 - 4.40 (m, 2H), 4.31 - 4.09 (m, 5H), 3.86 - 3.76 (m, 1H), 3.68 - 3.60 (m, 1H), 3.07 - 2.84 (m, 8H), 2.74 - 2.66 (m, 4H), 2.59 - 2.42 (m, 2H), 1.84 - 1.71 (m, 3H). Example 443 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methylsulfonylp yrrolidin-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-1-carboxylate (compound 443a) To an 8 mL vial equipped with a stir bar was added Na ₂ CO ₃ (45 mg, 0.42 mmol), photocatalyst(Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (8 mg, 0.007 mmol), NiCl ₂ (dtbbpy) (6 mg, 0.014 mmol), tris(trimethylsilyl)silane (35 mg, 0.14 mmol), tert-butyl 3-iodopyrrolidine-1-carboxylate (85 mg, 0.28 mmol) and compound 213a (100 mg, 0.14 mmol) in 1,4-dioxane (6 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-450 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hours. Then the reaction was filtered and the filtrate was concentrated to give compound 443a (120 mg). LCMS (M+H ⁺ ): 838. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-pyrrolidin-3-yl- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 443b) A mixture of compound 443a (100 mg, 0.12 mmol) in 4 M 4 M HCl in dioxane (2 mL, 8 mmol) and dichloromethane (2 mL) was stirred at rt for 2 hours, then the solid was collected by filtration to give compound 443b (60 mg). LCMS (M+H ⁺ ): 738. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1- methylsulfonylpyrrolidin-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl] -22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 443) A mixture of compound 443b (30 mg, 0.04 mmol ), DIPEA (53 mg, 0.41 mmol) and methanesulfonic anhydride (35 mg, 0.20 mmol) in dichloromethane (2 mL) was stirred at rt for 30 mins, then the reaction was concentrated and the residue was purified by HPLC to give Examples 443 (14 mg). LCMS (M+H ⁺ ): 816. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.37 (m, 1H), 7.98 - 7.83 (m, 1H), 7.74 - 7.50 (m, 3H), 7.36 - 7.12 (m, 3H), 6.89 - 6.76 (m, 1H), 6.29 - 6.03 (m, 1H), 5.59 - 5.37 (m, 1H), 4.77 - 4.66 (m, 1H), 4.59 - 4.48 (m, 1H), 4.45 - 4.25 (m, 2H), 4.09 - 3.93 (m, 1H), 3.86 - 3.71 (m, 1H), 3.67 - 3.39 (m, 4H), 3.21 - 3.09 (m, 3H), 3.08 - 2.96 (m, 4H), 2.90 - 2.70 (m, 7H), 2.66 - 2.50 (m, 2H), 2.43 - 2.19 (m, 2H). Example 444 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2,2,2-trifluor oacetyl)pyrrolidin-3- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Examples 444 was prepared in analogy to the preparation of Example 443 by using (2,2,2- trifluoroacetyl) 2,2,2-trifluoroacetate instead of methanesulfonic anhydride. Example 444 (7 mg). LCMS (M+H ⁺ ): 834. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.44 (m, 1H), 7.93 - 7.85 (m, 1H), 7.73 - 7.49 (m, 3H), 7.37 - 7.11 (m, 3H), 6.88 - 6.74 (m, 1H), 6.27 - 6.02 (m, 1H), 5.57 - 5.31 (m, 1H), 4.74 - 4.65 (m, 1H), 4.60 - 4.45 (m, 1H), 4.40 - 4.23 (m, 2H), 4.18 - 3.86 (m, 3H), 3.85 - 3.54 (m, 3H), 3.20 - 3.03 (m, 3H), 3.02 - 2.95 (m, 4H), 2.90 - 2.76 (m, 4H), 2.74 - 2.51 (m, 2H), 2.48 - 2.07 (m, 2H). Example 445 (8S,11S,15R)-10-[6-(1-acetylpyrrolidin-3-yl)-1-(2,4-difluoro phenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 445 was prepared in analogy to the preparation of Example 443 by using acetyl acetate instead of methanesulfonic anhydride. Example 445 (11 mg). LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 - 7.75 (m, 2H), 7.73 - 7.52 (m, 3H), 7.37 - 7.10 (m, 3H), 6.81 (br d, J = 8.5 Hz, 1H), 6.27 - 5.98 (m, 1H), 5.58 - 5.34 (m, 1H), 4.74 - 4.66 (m, 1H), 4.61 - 4.48 (m, 1H), 4.38 - 4.25 (m, 2H), 4.08 - 3.72 (m, 3H), 3.71 - 3.46 (m, 3H), 3.22 - 2.98 (m, 7H), 2.92 - 2.76 (m, 4H), 2.74 - 2.49 (m, 2H), 2.46 - 2.17 (m, 2H), 2.16 - 2.00 (m, 3H). Example 446 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylsulfonyl pyrrolidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Examples 446 was prepared in analogy to the preparation of Example 443 by using tert- butyl 3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl 3-iodopyrrolidine-1- carboxylate. Example 446 (14 mg). LCMS (M+H ⁺ ): 830. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 (d, J = 3.1 Hz, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.75 - 7.46 (m, 3H), 7.38 - 7.12 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.15 (td, J = 4.7, 15.3 Hz, 1H), 5.59 - 5.31 (m, 1H), 4.71 (br t, J = 4.6 Hz, 1H), 4.61 - 4.49 (m, 1H), 4.48 - 4.25 (m, 2H), 4.20 - 3.90 (m, 1H), 3.61 - 3.39 (m, 3H), 3.22 - 3.07 (m, 4H), 3.06 - 2.96 (m, 5H), 2.93 - 2.78 (m, 8H), 2.76 - 2.64 (m, 1H), 2.63 - 2.50 (m, 2H), 2.28 - 2.07 (m, 1H), 1.88 - 1.66 (m, 1H). Example 447 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[1-(2,2,2-trifluo roacetyl)pyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 447 was prepared in analogy to the preparation of Example 443 by using tert- butyl 3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl 3-iodopyrrolidine-1- carboxylate and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate instead of methanesulfonic anhydride. Example 447 (9 mg). LCMS (M+H ⁺ ): 848. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 (s, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.75 - 7.47 (m, 3H), 7.36 - 7.10 (m, 3H), 6.87 - 6.75 (m, 1H), 6.25 - 6.02 (m, 1H), 5.61 - 5.36 (m, 1H), 4.75 - 4.66 (m, 1H), 4.60 - 4.48 (m, 1H), 4.42 - 4.24 (m, 2H), 4.09 - 3.79 (m, 2H), 3.77 - 3.46 (m, 2H), 3.20 - 3.03 (m, 4H), 3.02 - 2.91 (m, 5H), 2.90 - 2.78 (m, 5H), 2.76 - 2.67 (m, 1H), 2.66 - 2.49 (m, 2H), 2.30 - 2.07 (m, 1H), 1.94 - 1.66 (m, 1H). Example 448 (8S,11S,15R)-10-[6-[(1-acetylpyrrolidin-3-yl)methyl]-1-(2,4- difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 448 was prepared in analogy to the preparation of Example 443 by using tert- butyl 3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl 3-iodopyrrolidine-1- carboxylate and acetyl acetate instead of methanesulfonic anhydride. Example 448 (12 mg). LCMS (M+H ⁺ ): 794. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.45 (m, 1H), 7.96 - 7.79 (m, 1H), 7.73 - 7.48 (m, 3H), 7.35 - 7.14 (m, 3H), 6.88 - 6.76 (m, 1H), 6.22 - 6.01 (m, 1H), 5.60 - 5.36 (m, 1H), 4.73 - 4.68 (m, 1H), 4.59 - 4.49 (m, 1H), 4.40 - 4.23 (m, 2H), 4.04 - 3.82 (m, 1H), 3.74 - 3.55 (m, 2H), 3.54 - 3.43 (m, 1H), 3.21 - 3.06 (m, 4H), 3.03 - 2.94 (m, 5H), 2.91 - 2.80 (m, 5H), 2.74 - 2.49 (m, 3H), 2.21 - 1.99 (m, 4H), 1.90 - 1.63 (m, 1H). Example 449 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methyl-4-piperi dyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1-2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4- piperidyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one ( compound 449b) Compound 449b was prepared in analogy to the preparation of compound 443b by using tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl 3-iodopyrrolidine-1- carboxylate. LCMS (M+H ⁺ ): 752. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methyl-4- piperidyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 449) A mixture of compound 449b (30 mg, 0.04 mmol), formaldehyde (12 mg, 0.4 mmol) and NaBH ₃ CN (25 mg, 0.4 mmol) was stirred at 40 °C for 6 hours, then the solid was fitered off, the filtrate was concentrated and the residue was purified by prep-HPLC to give Example 449 (5 mg). LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.42 - 7.60 (m, 2H), 7.59 - 7.49 (m, 1H), 7.25 - 6.94 (m, 5H), 6.65 - 6.49 (m, 1H), 5.79 - 5.50 (m, 1H), 5.47 - 5.21 (m, 1H), 4.62 - 4.35 (m, 2H), 4.28 - 4.13 (m, 1H), 4.09 - 3.97 (m, 1H), 3.90 - 3.70 (m, 1H), 3.08 - 2.93 (m, 3H), 2.92 - 2.60 (m, 7H), 2.58 - 2.35 (m, 6H), 2.29 - 2.16 (m, 3H), 2.14 - 1.86 (m, 3H), 1.85 - 1.70 (m, 3H). Example 452 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl-13- 2,6 8,11 20,24 (3-morpholinopropyl)-7,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1-7: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-13-(3-hydroxypropyl)-18-methyl-7,10,13,17,19 ,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 452g) Examples 452g was prepared in analogy to the preparation of Examples 156 by using intermediate A14-c (the synthesis was refer to intermediate A15-c) instead of intermediate A15-c. LCMS (M+H ⁺ ): 683. Step 8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4- yl]-22-fluoro-18-methyl-13-(3-morpholinopropyl)-7,10,13,17,1 9,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 452) To a mixture of compound 452g (200 mg, 0.26 mmol) and DIPEA (340 mg, 2.64 mmol) in dichloromethane (10 mL) was added methanesulfonic anhydride (184 mg, 1.05 mmol) and then stirred at rt for 30 mins. The reaction mixture was diluted with EA, washed with water and brine, the organic layer was concentrated to a residue. Then the residue was dissolved in acetonitrile (2 mL), morpholine (34 mg, 0.4 mmol) and DIPEA (51 mg, 0.4 mmol) was added, the reaction mixture stirred at 80 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by HPLC to Example 452 (3 mg). LCMS (M+H ⁺ ): 752. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (s, 1H), 8.28 - 7.75 (m, 2H), 7.75 - 7.56 (m, 1H), 7.39 - 7.16 (m, 3H), 7.13 - 6.96 (m, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.85 - 6.68 (m, 1H), 5.65 (br d, J = 4.0 Hz, 1H), 5.04 (br s, 1H), 4.80 - 4.74 (m, 1H), 4.64 - 4.49 (m, 1H), 4.39 - 4.23 (m, 1H), 4.03 - 3.80 (m, 2H), 3.77 - 3.67 (m, 4H), 3.58 - 3.45 (m, 1H), 3.13 - 2.98 (m, 1H), 2.70 - 2.35 (m, 11H), 2.31 - 2.16 (m, 1H), 1.96 - 1.59 (m, 2H), 1.46 - 1.21 (m, 2H). Example 453 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl-13- [3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl]-7,10,13,17, 19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 453 was prepared in analogy to the preparation of Examples 452 by using 2-oxa- 5-azabicyclo[2.2.1]heptane instead of morpholine. Example 453 (5 mg). LCMS (M+H ⁺ ): 764. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.63 - 8.34 (m, 1H), 8.31 - 7.76 (m, 2H), 7.73 - 7.52 (m, 2H), 7.40 - 7.15 (m, 3H), 7.12 - 6.86 (m, 2H), 6.84 - 6.69 (m, 1H), 5.71 - 5.45 (m, 1H), 5.12 - 4.97 (m, 1H), 4.80 - 4.69 (m, 1H), 4.68 - 4.51 (m, 1H), 4.49 - 4.39 (m, 1H), 4.38 - 4.20 (m, 1H), 4.07 - 3.82 (m, 3H), 3.68 - 3.58 (m, 2H), 3.58 - 3.48 (m, 1H), 3.10 - 2.99 (m, 1H), 2.95 - 2.84 (m, 1H), 2.81 - 2.65 (m, 2H), 2.64 - 2.56 (m, 6H), 2.35 - 2.15 (m, 1H), 1.94 - 1.72 (m, 3H), 1.66 - 1.49 (m, 1H), 1.38 - 1.31 (m, 1H). Example 454 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-18-methyl-13- [3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl]-7,10,13,17,19,2 6- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 454 was prepared in analogy to the preparation of Examples 452 by using 2-oxa- 6-azaspiro[3.3]heptane instead of morpholine. Example 454 (6 mg). LCMS (M+H ⁺ ): 764. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.68 - 8.35 (m, 1H), 8.30 - 7.73 (m, 2H), 7.73 - 7.55 (m, 1H), 7.37 - 7.17 (m, 3H), 7.11 - 6.90 (m, 2H), 6.79 (d, J = 8.3 Hz, 1H), 5.58 (br d, J = 7.3 Hz, 1H), 5.12 - 4.96 (m, 1H), 4.75 (s, 5H), 4.68 - 4.51 (m, 1H), 4.42 - 4.12 (m, 1H), 4.01 - 3.79 (m, 2H), 3.48 - 3.38 (m, 5H), 3.04 - 2.89 (m, 1H), 2.67 - 2.32 (m, 7H), 2.28 - 2.04 (m, 1H), 1.83 - 1.38 (m, 2H), 1.31 (br s, 2H). Example 455 (8S,11S)-13-[3-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxi no[2,3-c]pyrrol-6-yl]propyl]- 10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-18-methyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 454 was prepared in analogy to the preparation of Examples 452 by using (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrr ole instead of morpholine. Example 455 (8 mg). LCMS (M+H ⁺ ): 794. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.66 - 8.35 (m, 1H), 8.25 (s, 1H), 7.89 - 7.57 (m, 2H), 7.42 - 7.14 (m, 3H), 7.12 - 6.87 (m, 2H), 6.78 (d, J = 8.3 Hz, 1H), 5.73 - 5.47 (m, 1H), 5.14 - 4.97 (m, 1H), 4.79 - 4.70 (m, 1H), 4.63 - 4.51 (m, 1H), 4.40 - 4.22 (m, 1H), 4.17 - 4.03 (m, 2H), 4.00 - 3.72 (m, 4H), 3.69 - 3.44 (m, 3H), 3.30 - 3.21 (m, 1H), 3.09 - 2.85 (m, 3H), 2.85 - 2.74 (m, 2H), 2.71 - 2.48 (m, 6H), 2.30 - 2.13 (m, 1H), 2.02 - 1.79 (m, 1H), 1.79 - 1.53 (m, 1H), 1.42 - 1.18 (m, 2H). Example 456 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-ethylsulfonyla zetidin-3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,18-dim ethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one Examples 456 was prepared in analogy to the preparation of Examples 436 by using compound 427b-2 instead of compound 370b and ethanesulfonyl chloride instead of methylsulfonyl methanesulfonate. Example 456 (9 mg). LCMS (M+H ⁺ ): 827. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.43 - 8.35 (m, 1H), 8.32 - 8.22 (m, 1H), 7.83 - 7.70 (m, 1H), 7.61 - 7.49 (m, 2H), 7.44 - 7.25 (m, 1H), 7.23 - 7.01 (m, 2H), 6.74 - 6.62 (m, 1H), 5.95 - 5.76 (m, 1H), 5.48 - 5.26 (m, 1H), 4.64 - 4.54 (m, 1H), 4.48 - 4.41 (m, 1H), 4.27 - 4.09 (m, 2H), 4.00 - 3.64 (m, 5H), 3.05 - 2.76 (m, 10H), 2.75 - 2.65 (m, 1H), 2.65 - 2.29 (m, 7H), 1.25 - 1.09 (m, 3H), 0.55 - 0.39 (m, 3H). Example 457 (8S,11S,15R)-10-[6-[(1-cyclopropylsulfonylazetidin-3-yl)meth yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,1 8-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Examples 457 was prepared in analogy to the preparation of Examples 436 by using compound 427b-2 instead of compound 370b and cyclopropanesulfonyl chloride instead of methylsulfonyl methanesulfonate. Example 457 (9 mg). LCMS (M+H ⁺ ): 839. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.41 - 8.33 (m, 1H), 8.32 - 8.24 (m, 1H), 7.82 - 7.73 (m, 1H), 7.61 - 7.46 (m, 2H), 7.38 - 7.32 (m, 1H), 7.23 - 7.03 (m, 2H), 6.72 - 6.62 (m, 1H), 5.93 - 5.73 (m, 1H), 5.48 - 5.25 (m, 1H), 4.62 - 4.58 (m, 1H), 4.45 - 4.41 (m, 1H), 4.24 - 4.11 (m, 2H), 3.96 - 3.71 (m, 5H), 3.04 - 2.95 (m, 4H), 2.95 - 2.86 (m, 2H), 2.84 - 2.79 (m, 1H), 2.75 - 2.69 (m, 1H), 2.60 - 2.54 (m, 4H), 2.54 - 2.35 (m, 3H), 1.06 - 0.84 (m, 4H), 0.81 - 0.70 (m, 1H), 0.52 - 0.43 (m, 3H). Example 458 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[1-(2,2,2-trifluo roethyl)azetidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-13,18-dim ethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one Examples 458 was prepared in analogy to the preparation of Examples 436 by using compound 427b-2 instead of compound 370b and 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of methylsulfonyl methanesulfonate. Example 458 (5 mg). LCMS (M+H ⁺ ): 817. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.00 - 7.92 (m, 1H), 7.90 - 7.77 (m, 1H), 7.41 - 7.30 (m, 1H), 7.20 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 6.80 - 6.64 (m, 2H), 6.30 - 6.23 (m, 1H), 5.56 - 5.33 (m, 1H), 5.04 - 4.83 (m, 1H), 4.26 - 4.16 (m, 1H), 4.07 - 3.94 (m, 1H), 3.84 - 3.63 (m, 2H), 3.55 - 3.39 (m, 1H), 3.22 - 3.07 (m, 2H), 2.74 - 2.53 (m, 8H), 2.49 - 1.96 (m, 11H), 0.13 - -0.01 (m, 3H). Example 459 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(pyrrolidine-1-carbony l)pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S)-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 459b) A mixture of compound 459a (1.2 g, 2.21 mmol, prepared in analogy to compound 12c by using intermediate A14 instead of intermediate A11) in TFA (20 mL) was stirred for 4 hours at 100 ^o C, then the reaction was concentrated, the residue was dissolved in EA, 4M HCl in dioxane (10 mL) was added, then off white solid was precipitated, the solid was collected by filtration to give compound 459b (1 g) as off-white solid. LCMS (M+H ⁺ ): 409. Step 2: preparation of methyl 1-(2,4-difluorophenyl)-4-[(8S,11S)-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxylate (compound 459c) A mixture of compound 459b (150 mg, 0.37 mmol), intermediate C78 (131 mg, 0.4 mmol) and DIPEA (237 mg, 1.8 mmol) in acetonitrile (10 mL) was stirred at 45 °C for 1 hour, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 459c (200 mg) as light yellow foam. LCMS (M+H ⁺ ): 697. Step 3: preparation of 1-(2,4-difluorophenyl)-4-[(8S,11S)-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidine-6-carboxylic acid (compound 459d) A mixture of compound 459d (200 mg, 0.29 mmol) and 2 M LiOH (718 μL, 1.44 mmol,) in methanol (10 mL) was stirred at rt for 2 hours, then the reaction was adjusted to pH = 6. The resulted mixture was concentrated and the residue was dissolved in MeOH, after the solid was removed by filtration, the filtrated was concentrated to give compound 459d (150 mg) as light yellow solid. LCMS (M+H ⁺ ): 683. Step 3: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(pyrrolidine-1- carbonyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dime thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 459) A mixture of compound 459d (50 mg, 0.07 mmol), pyrrolidine (52 mg, 0.73 mmol), HATU (55 mg, 0.14 mmol ) and DIPEA (95 mg, 0.73 mmol) in N,N-dimethylformamide (3 mL) was stirred at rt for 1 hour, then the reaction mixture was purified by prep-HPLC to give Example 459 (30 mg) as white powder. LCMS (M+H ⁺ ): 736, ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.85 - 7.69 (m, 1H), 7.65 - 7.40 (m, 2H), 7.38 - 7.29 (m, 1H), 7.25 - 7.02 (m, 2H), 7.01 - 6.86 (m, 1H), 6.80 - 6.66 (m, 1H), 5.68 - 5.30 (m, 2H), 4.66 (s, 1H), 4.53 - 4.42 (m, 1H), 4.26 - 4.15 (m, 1H), 4.10 - 3.87 (m, 2H), 3.56 - 3.28 (m, 4H), 3.11 - 2.89 (m, 3H), 2.87 - 2.73 (m, 4H), 2.71 - 2.54 (m, 1H), 2.54 - 2.39 (m, 1H), 2.08 - 1.72 (m, 5H), 1.39 - 1.16 (m, 1H). Example 460 1-(2,4-difluorophenyl)-4-[(8S,11S)-22-fluoro-13,18-dimethyl- 12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- N-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidine-6-carboxamide

Examples 460 was prepared in analogy to the preparation of Examples 459 by using 2- aminoethanol instead of pyrrolidine. LCMS (M+H ⁺ ): 726. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.56 - 7.71 (m, 2H), 7.67 - 7.51 (m, 1H), 7.45 (dd, J = 2.5, 7.3 Hz, 1H), 7.40 - 7.29 (m, 1H), 7.25 - 7.03 (m, 2H), 7.02 - 6.86 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.85 - 5.30 (m, 2H), 4.66 - 4.58 (m, 1H), 4.55 - 4.41 (m, 1H), 4.36 - 4.19 (m, 1H), 4.12 - 3.89 (m, 2H), 3.73 - 3.52 (m, 2H), 3.50 - 3.29 (m, 2H), 3.08 - 2.94 (m, 3H), 2.93 - 2.80 (m, 1H), 2.76 - 2.70 (m, 3H), 2.63 (s, 1H), 2.55 - 2.36 (m, 1H), 2.10 - 1.67 (m, 1H), 1.41 - 1.08 (m, 1H). Example 461 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(morpholine-4-carbonyl )pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 461 was prepared in analogy to the preparation of Examples 459 by using morpholine instead of pyrrolidine. LCMS (M+H ⁺ ): 752. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.88 - 7.69 (m, 1H), 7.57 (dq, J = 5.8, 8.7 Hz, 1H), 7.46 (dd, J = 2.4, 7.4 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.25 - 7.04 (m, 2H), 6.99 - 6.89 (m, 1H), 6.80 - 6.65 (m, 1H), 5.65 - 5.31 (m, 2H), 4.64 (br t, J = 5.1 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.30 - 4.11 (m, 1H), 4.11 - 3.88 (m, 2H), 3.73 - 3.40 (m, 6H), 3.38 - 3.24 (m, 2H), 3.07 - 2.90 (m, 3H), 2.89 - 2.72 (m, 4H), 2.69 - 2.57 (m, 1H), 2.53 - 2.40 (m, 1H), 2.03 - 1.76 (m, 1H), 1.34 - 1.14 (m, 1H). Example 463 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-(methoxymethyl)pyr azolo[4,3-c]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of 3-bromo-4-chloro-5-((2-(2,4-difluorophenyl)hydrazineylidene) methyl)pyridine (compound 463c) The mixture of 2,4-difluorophenylhydrazine hydrochloride (983 mg, 5.44 mmol,) and compound 463b (1000 mg, 4.54 mmol) in DMF (10 mL) was stirred at 25 °C for 4 hrs. The mixture was poured into water (30 mL) to afford a solid, the resulting solid was filtered and the filter-cake was washed with water (30 mL), then dried under reduced pressure to give compound 463c (1300 mg). LCMS (M+2H ⁺ ): 348. Step 2: preparation of 7-bromo-1-(2, 4-difluorophenyl)-1H-pyrazolo [4, 3-c] pyridine (compound 463d) A suspension of compound 463c (3000 mg, 8.66 mmol), DBU (2649 mg, 17 mmol,) and molecular sieve (200 mg) in NMP (100 mL) was stirred at 100 °C for 16 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel to give compound 463d (710 mg). LCMS (M+2H ⁺ ): 312. Step 3: preparation of 1-(2,4-difluorophenyl)-7-(methoxymethyl)-1H-pyrazolo[4,3- c]pyridine(compound 463e) To a mixture of compound 463d (500 mg, 1.29 mmol), potassium methoxymethyl trifluoroborate (392 mg, 2.58 mmol) and Cs ₂ CO ₃ (2102 mg, 6.45 mmol) in 1,4-Dioxane (7 mL) and water (3 mL) was added Pd(dppf)Cl ₂ (168 mg, 0.26 mmol), then the mixture was stirred at 100 °C for 16 hrs. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL×3). The combined organic layer was concentrated under reduced pressure to obtained a residue, the residue was purified by prep-HPLC to give compound 463e (190 mg). LCMS (M+H ⁺ ): 276. Step 4: preparation of 1-(2,4-difluorophenyl)-7-(methoxymethyl)-1H-pyrazolo[4,3- c]pyridine 5-oxide (compound 463f) To a solution of compound 463e (150 mg, 0.54 mmol) in DCM (5 mL) was added mCPBA (140.6 mg, 0.82 mmol), then the mixture was stirred at 25 °C for 5 hrs. The reaction mixture was quenched with sat. aq. Na ₂ SO ₃ (10 mL×2), and extracted with EtOAc (5 mL×3). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give the compound 463f (60 mg). LCMS (M+H ⁺ ): 292. Step 5: preparation of 4-chloro-1-(2,4-difluorophenyl)-7-(methoxymethyl)-1H- pyrazolo[4,3-c]pyridine (compound 463g) A solution of compound 463f (60 mg, 0.21 mmol) in POCl ₃ (1 ml) was stirred at 90 °C for 5 hrs. The reaction mixture was quenched with sat.aq. NaHCO ₃ (5 mL) at 0 °C, then extracted with DCM(10 mL×3), the combined organic layer was concentrated under reduced pressure to give a residue, the residue was purified by prep-HPLC to give compound 463g (50 mg). LCMS (M+H ⁺ ): 310. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7- (methoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-22-fluoro-15-met hoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 463) A mixture of compound 370b (142 mg, 0.32 mmol), CsF (25 mg, 0.16 mmol), compound 463g (50 mg, 0.16 mmol) and DIEA (63 mg, 0.48 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 130 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (DCM/MeOH=10/1) to give Example 463 (7.0 mg). LCMS (M+H ⁺ ): 712. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.68 - 8.47 (m, 1H), 7.84 - 7.64 (m, 3H), 7.62 - 7.53 (m, 1H), 7.39 - 7.26 (m, 2H), 7.22 (s, 1H), 7.16 - 7.07 (m, 2H), 6.65 (br d, J = 8.8 Hz, 1H), 5.73 - 5.51 (m, 2H), 5.47 - 5.27 (m, 2H), 4.67 - 4.41 (m, 2H), 4.07 - 3.99 (m, 2H), 3.98 - 3.92 (m, 1H), 3.82 - 3.72 (m, 1H), 3.50 (s, 2H), 3.01 - 2.89 (m, 3H), 2.72 (d, J = 1.6 Hz, 6H), 2.34 - 2.32 (m, 1H), 2.03 - 1.94 (m, 3H). Example 464 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyra zolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-5,13,18-trimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[(2R)-3-[7-(6-chloro-5-methyl-2-pyridyl)-5-fluoro- 2-methyl-benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carba mate (compound 464b) To a suspension of compound 464a (2036 mg, 12.57 mmol), intermediate A6 (1000 mg, 2.09 mmol) and K ₂ CO ₃ (867 mg, 6.28 mmol) in 1,4-Dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl ₂ (342 mg, 0.42 mmol), then the mixture was stirred at 70 °C for 8 hrs under nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 464b (450 mg). LCMS (M+H ⁺ ): 477. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-me thyl-benzimidazol-4-yl]- 3-methyl-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 464d) To a suspension of 464c(439 mg, 1.58 mmol), 464b (400.0 mg, 0.79 mmol) and Cs ₂ CO ₃ (1028 mg, 3.15 mmol) in 1,4-Dioxane (5 mL) was added t-Bu ₃ P-Pd-G2 (80.72 mg, 0.16 mmol) under nitrogen atmosphere, then the mixture was stirred at 90 °C for 16 hrs. The reaction mixture was concentrated to give compound 464d (600 mg). LCMS (M+H ⁺ ): 719. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[6-fluoro-3-[(2S)-2- methoxy-3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]-3 -methyl-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 464e) To a solution of compound 464d (600 mg, 0.83 mmol) in 1,4-Dioxane (10 mL) was added HCl/Dioxane (4 M, 10 mL), then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give compound 464e (500 mg). LCMS (M+H ⁺ ): 619. Step 4: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[(2S)-2- methoxy-3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]-3 -methyl-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 464f) To a solution of compound 464e (500 mg, 0.81 mmol) in methanol (3 mL) was added a solution of LiOH (372 mg, 16.16 mmol) in water (1 mL), then the mixture was stirred at 25 °C for 0.5 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give compound 464f (480 mg). LCMS (M+H ⁺ ): 605. Step 5: benzyl (8S,11S,15R)-22-fluoro-15-methoxy-5,13,18-trimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaene-10-carboxylate (compound 464g) To a solution of HATU (560 mg, 1.47 mmol) and DIPEA (253 mg, 1.96 mmol) in DMF (120 mL) was added a solution of compound 464f (297 mg, 0.49 mmol) in DMF (360 mL) slowly, then the mixture was stirred at 25 °C for 0.5 hrs. The reaction was concentrated and the residue was purified by prep-HPLC (0.1%TFA) to give compound 464g (50 mg). LCMS (M+H ⁺ ): 587. Step 6: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-5,13,18-trimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one (compound 464h) A solution of compound 464g (50 mg, 0.09 mmol) in TFA (2 mL) was stirred at 90 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give compound 464h (50 mg). LCMS (M+H ⁺ ): 453. Step 7: preparation of (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-5,13,18-tri methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 464) A mixture of compound 464h (50 mg, 0.11 mmol), DIEA (57 mg, 0.44 mmol) and intermediate C11 (31 mg, 0.11 mmol) in ACN (2 mL) was stirred at 85 °C for 1 hr. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 464 (14 mg). LCMS (M+H ⁺ ): 695. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.12 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.39 - 7.37 (m, 1H), 7.24 - 7.16 (m, 2H), 6.98 - 6.90 (m, 1H), 6.48 (d, J = 7.2 Hz, 1H), 5.64 - 5.51 (m, 1H), 5.19 - 5.05 (m, 1H), 4.67 (d, J = 10.9 Hz, 1H), 4.45 (s, 2H), 4.32 (s, 1H), 4.20 (dd, J = 4.0, 10.8 Hz, 1H), 4.07 (s, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.87 - 2.81 (m, 3H), 2.75 - 2.70 (m, 3H), 2.47 (s, 1H), 2.41 (s, 2H), 2.11 (s, 3H). Example 465 (8S,11S,15R)-10-[1-(1,3-dihydroisobenzofuran-4-yl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1~3: preparation of 1-(1,3-dihydroisobenzofuran-4-yl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound 465d) Compound 465d was prepared in analogy to the preparation of intermediate C10 by using compound 465a instead of O-anisidine, LCMS (M+H ⁺ ): 255. Step 4: preparation of (8S,11S,15R)-10-[1-(1,3-dihydroisobenzofuran-4- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 465) A mixture of compound 465d (10.4 mg, 0.04 mmol), PyBOP (27.8 mg, 0.05 mmol) and DIEA (13.3 mg, 0.1 mmol) in DMF (0.5 mL) was stirred at 20 °C for 0.5 hrs, then the compound 370b (18.0 mg, 0.04 mmol) was added and the mixture was stirred at 20 °C for 12 hrs. The reaction mixture was purified by prep-HPLC to give Example 465 (1.9 mg). LCMS (M+H ⁺ ): 675. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 (s, 1H), 8.45 - 8.27 (m, 1H), 8.04 - 7.95 (m, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.61 - 7.45 (m, 3H), 7.40 - 7.33 (m, 1H), 7.20 - 7.13 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.19 - 6.01 (m, 1H), 5.51 - 5.41 (m, 1H), 5.28 - 5.22 (m, 2H), 5.18 (s, 2H), 4.71 - 4.67 (m, 1H), 4.57 - 4.50 (m, 1H), 4.41 - 4.23 (m, 2H), 4.00 - 3.87 (m, 1H), 3.35 (s, 1H), 3.16 (s, 1H), 3.06 (s, 2H), 2.97 (s, 3H), 2.90 - 2.80 (m, 1H), 2.82 (s, 3H), 2.67 - 2.49 (m, 2H). Example 466 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methyl-6-oxo-pyraz olo[3,4-b]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound 466b) To a solution of 2,4-difluorophenylhydrazine hydrochloride (5.0 g, 28 mmol) in ethanol (50 mL) was added compound 466a (5.62 g, 33 mmol) and DIPEA (9.81 mL, 55 mmol) at 25 °C, then the mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was purified by flash chromatography to afford compound 466b (6.4 g). LCMS (M+H ⁺ ): 268. Step 2: preparation of ethyl 5-acetamido-1-(2,4-difluorophenyl)pyrazole-4- carboxylate (compound 466c) To a solution of compound 466b (2.0 g, 7.5 mmol) in chloroform (10 mL) was added acetyl chloride (1 mL, 15 mmol) at 25 °C, and the mixture was stirred at 65 °C for 16 hrs. The reaction was concentrated in vacuo. The residue was purified by flash chromatography to afford compound 466c (2.13 g). LCMS (M+H ⁺ ): 310. Step 3: preparation of ethyl 5-[acetyl(methyl)amino]-1-(2,4-difluorophenyl)pyrazole- 4-carboxylate (compound 466d) To a solution of NaH (327 mg, 8.2 mmol) in DMF (20 mL) was added compound 466c (2.1 g, 6.79 mmol) in DMF (10 mL) dropwise at 0 °C under N ₂ atmosphere, after being stirred at 0 °C for 0.5 hrs, iodomethane (0.85 mL, 13.6 mmol) was added. The reaction mixture was stirred at 20 °C for 1.5 hrs, then the reaction was poured into sat.NH ₄ Cl (50 mL) and extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by flash chromatography to afford compound 466d (1.93 g). LCMS (M+H ⁺ ): 324. Step 4: preparation of 1-(2,4-difluorophenyl)-4-hydroxy-7-methyl-pyrazolo[3,4- b]pyridin-6-one (compound 466e) To a stirred solution of compound 466d (1.8 g, 5.57 mmol) in THF (20 mL) was added LDA (6.96 mL, 13.92 mmol) dropwise at -78°C under N ₂ atmosphere, and the mixture was stirred at 20 °C for 2 hrs. The reaction was poured into water (50 mL) and extracted with ethyl acetate. The aqueous phase was adjusted pH to 4-5, and extracted with ethyl acetate, the organic phase was dried and concentrated to afford compound 466e (0.9 g). LCMS (M+H ⁺ ): 278. Step 5: preparation of 4-chloro-1-(2,4-difluorophenyl)-7-methyl-pyrazolo[3,4- b]pyridin-6-one (compound 466f) To a solution of compound 466e (100 mg, 0.36 mmol) in MeCN (1 mL) was added phosphorus oxychloride (0.04 mL, 0.39 mmol) dropwise at 25 °C, and the reaction mixture was stirred at 80 °C for 3 hrs. The reaction was poured into sat.NaHCO ₃ (15 mL) at 0 °C, and extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by flash chromatography to afford compound 466f (60.0 mg). LCMS (M+H+): 296. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methyl-6-oxo- pyrazolo[3,4-b]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dime thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 466) To a solution of compound 466f (7 mg, 0.02 mmol) and compound 370b (11 mg, 0.02 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (0.01 mL, 0.03 mmol) and cesium fluoride (6.0 mg, 0.04 mmol), the reaction mixture was stirred at 130 °C for 6 hrs. Then the reaction mixture was purified by prep-HPLC to afford Example 466 (4.03 mg). LCMS (M+H ⁺ ): 698. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.33 (s, 1H), 7.92 - 7.81 (m, 2H), 7.65 - 7.58 (m, 2H), 7.59 - 7.43 (m, 2H), 7.37 - 7.34 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.84 - 5.67 (m, 2H), 5.41 - 5.18 (m, 1H), 4.94 - 4.85 (m, 1H), 4.50 - 4.43 (m, 1H), 4.28 - 4.17 (m, 2H), 3.91 - 3.82 (m, 2H), 3.01 (s, 3H), 2.98 (s, 2H), 2.81 (s, 3H), 2.69 (s, J = 1.5 Hz, 3H), 2.67 (s, 1H), 2.33 (s, 3H). Example 467 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1 -hydroxy-ethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of [4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6- yl]methanol (compound 467b) To a solution of intermediate C28 (500 mg, 1.6 mmol) in DCM (20 mL) was added BCl ₃ /DCM (8.05 mL, 8.05 mmol) slowly at -78 °C, then the mixture was stirred at -78 °C for 1 h and stirred at 25 °C for 16 hrs. The reaction mixture was quenched with ice-water, and then extracted with DCM. The organic layer was dried and concentrated to give the compound 467b (450 mg) as a light yellow solid. LCMS (M+H ⁺ ): 297. Step 2: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6- carbaldehyde (compound 467c) To a solution of compound 467b (190 mg, 0.64 mmol) in toluene (10 mL) was added Manganese (IV) oxide (1.1 g, 12.8 mmol). After addition, the mixture was stirred at 110 °C for 8 hrs. Then the mixture was filtered and concentrated to give compound 467c (110 mg) as a yellow solid. LCMS (M+H ⁺ ): 295. Step 3: preparation of 1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5, 18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-carba ldehyde (compound 467d) A suspension of compound 370b (36 mg, 0.07 mmol), DIPEA (0.03 mL, 0.2 mmol) and compound 467c (20 mg, 0.07 mmol) in ACN (1 mL) was stirred at 85 °C for 1 h. The reaction mixture was cooled to room temperature, EtOAc (40 mL) and water (40 mL) were added and layers were separated. The organic layer was dried and concentrated to give compound 467d (60 mg) as a yellow solid. LCMS (M+H ⁺ ): 697. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1 - hydroxy-ethyl)pyrazolo [3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 467) To an ice-water cooled solution of compound 467d (10.0 mg, 0.01 mmol) in DMF (1 mL) was added K ₂ CO ₃ (5.9 mg, 0.04 mmol), then trifluoromethyltrimethylsilane (20.0 mg, 0.14 mmol) was added dropwise to the solution at 0 °C. Then the reaction was stirred at 20 °C for 2 hrs, the solid was filtered off and the filtrate was purified by preparative HPLC to give Example 467 (2.2 mg). LCMS (M+H ⁺ ): 767. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.49 (m, 1H), 7.92 - 7.80 (m, 1H), 7.76 - 7.60 (m, 1H), 7.57 - 7.44 (m, 2H), 7.37 - 7.26 (m, 1H), 7.24 - 7.13 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.20 - 5.94 (m, 1H), 5.70 - 5.39 (m, 1H), 4.90 (s, 1H), 4.71 (br s, 1H), 4.59 - 4.49 (m, 1H), 4.39 - 4.20 (m, 2H), 4.01 - 3.80 (m, 1H), 3.16 - 3.05 (m, 3H), 3.05 - 2.98 (m, 1H), 2.98 - 2.93 (m, 3H), 2.85 (br d, J = 13.2 Hz, 1H), 2.81 - 2.74 (m, 3H), 2.71 - 2.48 (m, 2H). Example 468 (8S,11S,15R)-10-[7-cyclopropyl-1-(2,4-difluorophenyl)-6-oxo- pyrazolo[3,4-b]pyridin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-[acetyl(cyclopropyl)amino]-1-(2,4- difluorophenyl)pyrazole-4-carboxylate (compound 468a) A suspension of cyclopropylboronic acid (560 mg, 6.5 mmol), compound 466c (1.0 g, 3.3 mmol), 2,2'-bipyridine (510 mg, 3.3 mmol), sodium carbonate (690 mg, 6.5 mmol) and Cu(OAc) ₂ (590 mg, 3.3 mmol) in DCE (15 mL) was stirred at 80 °C for 16 hrs under O ₂ atmosphere. Then the reaction mixture was filtered and the filtrate was concentrated, the residue was purified by flash chromatography to afford compound 468a (900 mg). LCMS (M+H ⁺ ): 350. Step 2: preparation of 7-cyclopropyl-1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- b]pyridin-6-one (compound 468b) To a solution of compound 468a (500.0 mg, 1.43 mmol) in THF (5 mL) was added LDA (1.43 mL, 2.86 mmol) dropwise at -78 °C under N ₂ atmosphere, then the mixture was stirred at 20 °C for 1 h. The reaction was poured into water (15 mL) and extracted with ethyl acetate. The aqueous phase was adjusted pH to 4~5, and extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 468b (90 mg). LCMS (M+H ⁺ ): 304. Step 3: preparation of 4-chloro-7-cyclopropyl-1-(2,4-difluorophenyl)pyrazolo[3,4- b]pyridin-6-one (compound 468c) To a solution of compound 468b (50.0 mg, 0.16 mmol) in MeCN (1 mL) was added phosphorus oxychloride (0.02 mL, 0.18 mmol) dropwise at 25 °C, and the reaction mixture was stirred at 80 °C for 3 hrs. The reaction mixture was poured into sat.NaHCO ₃ (8 mL) at 0 °C slowly, and then extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by prep-TLC to afford compound 468c (15 mg). LCMS (M+H ⁺ ): 322. Step 4: preparation of (8S,11S,15R)-10-[7-cyclopropyl-1-(2,4-difluorophenyl)-6-oxo- pyrazolo[3,4-b]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dime thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 468) To a solution of compound 370b (15.0 mg, 0.03 mmol) and compound 468c (10.0 mg, 0.03 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (0.01 mL, 0.05 mmol) and cesium fluoride (8.0 mg, 0.05 mmol, 1.54 eq), then the reaction mixture was stirred at 130 °C for 6 hrs. The reaction mixture was purified by prep-HPLC to give Example 468 (1.8 mg). LCMS (M+H ⁺ ): 724. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 - 8.18 (m, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.60 - 7.53 (m, 2H), 7.32 - 7.17 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.14 - 6.09 (m, 1H), 4.81 (s, 1H), 4.56 (s, 1H), 4.35 - 4.29 (m, 1H), 3.98 - 3.92 (m, 1H), 3.35 (s, 2H), 3.28 (s, 1H), 3.08 - 2.97 (m, 7H), 2.83 (s, 3H), 2.61 - 2.54 (m, 3H), 0.77 - 0.48 (m, 4H). Example 469 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-(2-methoxyethyl)-6 -oxo-pyrazolo[3,4-b]pyridin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-[acetyl(2-methoxyethyl)amino]-1-(2,4- difluorophenyl)pyrazole-4-carboxylate (compound 469a) To a suspension of NaH (156.0 mg, 3.9 mmol) in DMF (7 mL) was added a solution of 2- bromoethyl methyl ether (0.61 mL, 6.48 mmol) in DMF (3 mL) slowly at 0 °C under N ₂ , then the mixture was stirred at 0 °C for 0.5 hrs and compound 466c (1000.0 mg, 3.2 mmol) was added to the mixture. After being stirred at 20 °C for 15 hrs, the reaction mixture was poured into sat.NH ₄ Cl (40 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was dried and concentrated, the residue was purified by flash chromatography to afford compound 469a (800 mg). LCMS (M+H ⁺ ): 368. Step 2: preparation of 1-(2,4-difluorophenyl)-4-hydroxy-7-(2- methoxyethyl)pyrazolo[3,4-b]pyridin-6-one (compound 469b) To a solution of compound 469a (500 mg, 1.36 mmol) in THF (5 mL) was added LDA (1.36 mL, 2.72 mmol) dropwise at -78 °C under N ₂ , and the mixture was stirred at 20 °C for 1 h under N ₂ . The reaction was poured into water (15 mL) and extracted with ethyl acetate. The aqueous phase was adjusted pH to 4~5, and extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 469b (150 mg). LCMS (M+H ⁺ ): 322. Step 3: preparation of 4-chloro-1-(2,4-difluorophenyl)-7-(2- methoxyethyl)pyrazolo[3,4-b]pyridin-6-one (compound 469c) To a solution of compound 469b (50 mg, 0.16 mmol) in MeCN (1 mL) was added phosphorus oxychloride (0.02 mL, 0.16 mmol) dropwise at 25°C, and then reaction mixture was stirred at 80 °C for 3 hrs. The reaction mixture was poured into sat.NaHCO ₃ (10 mL) at 0 °C, and then extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by prep-TLC to afford compound 469c (15 mg). LCMS (M+H ⁺ ): 340. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-(2-methoxyethyl)-6 - oxo-pyrazolo[3,4-b]pyridin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 469) To a solution of compound 469c (10 mg, 0.03 mmol) and compound 370b (15 mg, 0.03 mmol) in DMSO (1 mL) was added DIPEA (0.01 mL, 0.05 mmol) and cesium fluoride (8.0 mg, 0.05 mmol), then the reaction mixture was stirred at 130 °C for 6 hrs. The reaction mixture was purified by prep-HPLC directly to give Example 469 (3.75 mg). LCMS (M+H ⁺ ): 742. ¹ H NMR (400 MHz, METHANOL-d ₄ ) = 8.01 - 7.97 (m, 1H), 7.87 (t, J = 7.94 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.59 - 7.58 (m, 1H), 7.57 - 7.55 (m, 1H), 7.36 - 7.19 (m, 3H), 7.15 (d, J = 7.38 Hz, 1H), 6.76 (d, J = 8.50 Hz, 1H), 6.14 - 6.09 (m, 1H), 4.98 - 4.92 (m, 1H), 4.57 (s, 1H), 4.37 - 4.28 (m, 1H), 4.13 - 4.05 (m, 1H), 4.01 - 3.85 (m, 2H), 3.38 - 3.34 (m, 3H), 3.29 - 3.25 (m, 2H), 3.14 (s, 3H), 3.12 (s, 3H), 3.04 - 3.00 (m, 1H), 2.97 (s, 3H), 2.86 - 2.83 (m, 3H), 2.66 - 2.54 (m, 2H). Example 470 and Example 471 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3 ,4-c]pyridin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4- difluorophenyl)-7-methoxy-pyrazolo[3,4-c]pyridin-4-yl]-22-fl uoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 3,5-dibromo-2-methoxy-pyridine-4-carbaldehyde (compound 470b) To a solution of compound 470a (8.0 g, 30 mmol) in THF (80 mL) was added LDA (22.5 mL, 2 M) dropwise at -70 °C under N ₂ , the mixture was stirred at -70 °C for 1 h, DMF (11.6 mL, 150 mmol) was added to the mixture slowly which was then stirred at rt for 1 h. The reaction was quenched with ice water (300 mL), and the resulted mixture was extracted with EtOAc, the organic layer was dried and concentrated to give compound 470b (7.27 g). Step 2: preparation of N-[ (3,5-dibromo-2-methoxy-4-pyridyl)methyleneamino]-2,4- difluoro-aniline (compound 470c) A mixture of compound 470b (7.27 g, 24.6 mmol) and 2,4-difluorophenylhydrazine hydrochloride (5.34 g, 29.6 mmol) in DMF (145 mL) was stirred at 20 °C for 16 hrs. Then the reaction mixture was poured into ice water (600 mL), yellow precipitate formed, the mixture was filtered and the filter-cake was dried to give compound 470c (9.79 g) as a yellow solid. LCMS (M+H ⁺ ): 422. Step 3: preparation of 4-bromo-1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3,4- c]pyridine (compound 470d) and 4-bromo-1-(2,4-difluorophenyl)-5-methoxy-pyrazolo[3,4- c]pyridine(compound 471d) To a suspension of compound 470c (9.79 g, 23.2 mmol) in DMF (90 mL) was added K ₂ CO ₃ (9.64 g, 69.8 mmol) and CuI (0.44 g, 2.3 mmol). The mixture was stirred at 100 °C for 12 hrs, then the mixture was diluted with EA, washed with water and brine, the organic layer was dried and concentrated. The residue was purified by silica gel to give a crude product (1.1 g), which was purified by SFC (DAICEL CHIRALPAK IC(250mm×30mm,5um), 0.1%NH ₃ •H ₂ O MEOH, begin 15% B (MeOH) to 15% B, rate:50mL/min) to give compound 470d (0.8 g, faster eluted) as yellow solid and compound 471d (0.3 g, slower eluted) as yellow solid. LCMS (M+H ⁺ ): 340. Step 4: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3 ,4-c]pyridin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-methoxy-pyrazolo[3 ,4-c]pyridin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 470 & 471) A mixture of compound 370b (90.0 mg, 0.21 mmol), compound 470d (40.0 mg, 0.12 mmol), BINAP (14.6 mg, 0.02 mmol), bis(dibenzylideneacetone)palladium (6.8 mg, 0.01 mmol) and cesium carbonate (153.0 mg, 0.47 mmol) in THF (1.5 mL) was stirred at 90 °C for 12 hrs under N ₂ . The mixture was diluted with H ₂ O and extracted with EA, the organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 470 (35.0 mg). LCMS (M+H ⁺ ): 698. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.61 (s, 1H), 7.86 (s, 1H), 7.68 (dt, J = 5.6, 8.8 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.60 - 7.51 (m, 2H), 7.36 - 7.29 (m, 1H), 7.25 - 7.18 (m, 1H), 7.16 - 7.13 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.27 (dd, J = 4.4, 15.2 Hz, 1H), 5.67 (d, J = 8.8 Hz, 1H), 4.73 - 4.65 (m, 1H), 4.57 (t, J = 4.8 Hz, 1H), 4.38 - 4.26 (m, 2H), 3.93 (dd, J = 9.2, 14.3 Hz, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 3.03 (br d, J = 14.0 Hz, 1H), 3.00 - 2.97 (m, 3H), 2.82 (s, 3H), 2.74 - 2.67 (m, 1H), 2.64 - 2.55 (m, 1H), 2.49 (ddd, J = 4.4, 8.8, 13.2 Hz, 1H). A mixture of compound 370b (90 mg, 0.21 mmol), compound 471d (40.0 mg, 0.12 mmol), BINAP (14.6 mg, 0.02 mmol), bis(dibenzylideneacetone)palladium (6.8 mg, 0.01 mmol) and cesium carbonate (153.0 mg, 0.47 mmol) in THF (1.5 mL) was stirred at 90 °C for 12 hrs under N ₂ . The mixture was diluted with H ₂ O and extracted with EA, the organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 471 (7.0 mg) as a white solid. LCMS (M+H ⁺ ): 698. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.16 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.52 (dd, J = 2.4, 10.0 Hz, 1H), 7.22 (ddd, J = 2.4, 8.8, 10.0 Hz, 1H), 7.18 - 7.11 (m, 2H), 6.92 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.12 (dd, J = 4.8, 15.0 Hz, 1H), 5.10 (d, J = 8.8 Hz, 1H), 4.58 (t, J = 4.4 Hz, 1H), 4.31 (dd, J = 11.2, 15.2 Hz, 1H), 4.24 (dd, J = 5.6, 10.4 Hz, 1H), 4.02 - 3.93 (m, 2H), 3.80 (s, 3H), 3.13 (s, 3H), 3.07 - 3.01 (m, 1H), 2.97 (s, 3H), 2.88 (d, J = 13.2 Hz, 1H), 2.81 (s, 3H), 2.64 - 2.52 (m, 2H). Example 472 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-methoxycyclopro pyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 4-chloro-1-(2,4-difluorophenyl)-6-(1- methoxycyclopropyl)pyrazolo[3,4-d]pyrimidine (compound 472b) To a solution of intermediate C2 (400 mg, 1.5 mmol) in ACN (5 mL) was added 1- methoxycyclopropanecarboxylic acid (348 mg, 3.0 mmol) and silver nitrate (2032 mg, 12.0 mmol). The reaction mixture was heated at 60 °C and then a solution of ammonium persulfate (1.71 g, 7.5 mmol) in water (5 mL) was added slowly. After being stirred at 60 °C for 2 hours, the reaction mixture was diluted with H ₂ O (30mL) and extracted with EA. The organic layer was dried and concentrated, the residue was purified by column chromatography to give compound 473b (50 mg), LCMS (M+H ⁺ ): 319, and compound 472b (35 mg), LCMS (M+H ⁺ ): 337. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1- methoxycyclopropyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 472) A mixture of compound 472b (38 mg, 0.11 mmol), compound 370b (50 mg, 0.11 mmol) and DIPEA (0.06 mL, 0.34 mmol) in ACN (1 mL) was stirred at 85 °C for 1 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 472 (20 mg). LCMS (M+H ⁺ ): 739. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.45 (s, 1H), 7.90 - 7.84 (m, 1H), 7.70 - 7.62 (m, 1H), 7.62 - 7.52 (m, 2H), 7.30 - 7.22 (m, 1H), 7.21 - 7.13 (m, 2H), 6.82 - 6.74 (m, 1H), 6.27 - 6.01 (m, 1H), 5.51 - 5.37 (m, 1H), 4.69 (t, J = 4.8 Hz, 1H), 4.54 - 4.46 (m, 1H), 4.36 - 4.19 (m, 2H), 4.00 - 3.80 (m, 1H), 3.44 (s, 3H), 3.16 - 3.07 (m, 3H), 3.05 - 3.00 (m, 1H), 3.00 - 2.96 (m, 3H), 2.85 - 2.80 (m, 3H), 2.80 - 2.74 (m, 1H), 2.64 - 2.48 (m, 2H), 1.30 - 1.15 (m, 4H). Example 473 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1-hydroxycyclopro pyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 1-(2,4-difluorophenyl)-6-(1-hydroxycyclopropyl)pyrazolo[3,4- d]pyrimidin-4-ol (compound 473c) To a solution of compound 473b (10 mg, 0.03 mmol) in DCM (1 mL) was added BCl ₃ /DCM (0.5 mL, 0.5 mmol, 1 M) dropwise at -70 °C and then the mixture was stirred at 30 °C for 48 hours. The reaction was quenched with ice-water and the mixture was extracted with DCM, the organic layer was dried and concentrated to give compound 473c (9 mg). LCMS (M+H ⁺ ): 305. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1- hydroxycyclopropyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 473) A mixture of compound 370b (17.3 mg, 0.04 mmol), compound 473c (12.0 mg, 0.04 mmol), PyBOP (26.7 mg, 0.05 mmol) and DIEA (12.7 mg, 0.1 mmol) in DMF (1 mL) was s stirred at 20 °C for 12 hrs. The reaction mixture was directly purified by prep-HPLC to give Example 473 (5 mg). LCMS (M+H ⁺ ): 725. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.43 (s, 1H), 7.85 - 7.78 (m, 1H), 7.75 - 7.64 (m, 1H), 7.33 - 7.22 (m, 2H), 7.21 - 7.07 (m, 3H), 6.69 (d, J = 8.4 Hz, 1H), 5.86 - 5.60 (m, 1H), 5.47 - 5.32 (m, 1H), 4.58 (s, 1H), 4.54 - 4.45 (m, 1H), 4.30 - 4.10 (m, 2H), 3.95 - 3.85 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.13 (s, 1H), 3.04 (s, 2H), 2.95 - 2.88 (m, 1H), 2.85 (s, 3H), 2.58 - 2.54 (m, 3H), 2.51 - 2.46 (m, 1H), 1.18 (t, J = 7.0 Hz, 4H). Example 474 (8S,11S,15R)-10-[1-[2-(azetidin-1-yl)-4-fluoro-phenyl]pyrazo lo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 474 was prepared according to the following scheme: To a microwave tube was added: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 252, 48 mg, 0.068 mmol), ethanol (0.5 mL) and azetidine (500 mg, 8.76 mmol). The suspension was heated to 90 °C for 24 hrs. The mixture was concentrated and purified via prep- HPLC. Example 474 (22 mg) was obtained as white powder. LCMS (M+H ⁺ ): 706. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 8.20 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.30 (dd, J = 2.4, 8.5 Hz, 1H), 7.17 (dd, J = 2.4, 10.5 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.54 (dt, J = 2.7, 8.3 Hz, 1H), 6.37 (dd, J = 2.5, 11.1 Hz, 1H), 5.76 (dd, J = 4.2, 15.5 Hz, 1H), 5.47 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.54 - 4.48 (m, 1H), 4.34 (br d, J = 11.4 Hz, 1H), 4.14 (br dd, J = 11.0, 15.3 Hz, 1H), 3.97 - 3.89 (m, 1H), 3.43 - 3.35 (m, 4H), 3.13 - 3.02 (m, 3H), 2.89 (br t, J = 12.3 Hz, 2H), 2.84 (s, 3H), 2.56 (s, 3H), 2.53 - 2.45 (m, 2H), 2.09 (quin, J = 7.3 Hz, 2H). Example 475 and Example 476 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-morpholino-phenyl)p yrazolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacy clo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-10-[1-(2- fluoro-4-morpholino-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15 -methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 475 and Example 476 were prepared in analogy to the preparation of Examples 474 by using morpholine instead of azetidine. Example 475, LCMS (M+H ⁺ ): 736. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 (s, 1H), 8.24 (s, 1H), 7.87 (dd, J = 0.9, 8.6 Hz, 1H), 7.60 (dd, J = 2.5, 7.4 Hz, 1H), 7.53 (dd, J = 2.6, 10.3 Hz, 1H), 7.39 (dd, J = 6.0, 8.6 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.01 (dd, J = 2.6, 10.8 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.14 (dd, J = 4.4, 15.4 Hz, 1H), 5.50 (d, J = 8.9 Hz, 1H), 4.72 - 4.67 (m, 1H), 4.56 - 4.50 (m, 1H), 4.41 - 4.34 (m, 1H), 4.32 - 4.27 (m, 1H), 3.96 (dd, J = 9.4, 14.4 Hz, 1H), 3.37 - 3.33 (m, 4H), 3.17 - 3.13 (m, 1H), 3.06 (s, 3H), 2.98 - 2.95 (m, 3H), 2.92 - 2.86 (m, 1H), 2.83 (s, 3H), 2.75 - 2.65 (m, 4H), 2.63 - 2.52 (m, 2H). Example 476, LCMS (M+H ⁺ ): 736. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 (s, 1H), 8.21 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.57 (br d, J = 7.4 Hz, 1H), 7.51 (dd, J = 2.4, 10.1 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.18 - 7.12 (m, 1H), 6.96 - 6.87 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.10 (dd, J = 4.4, 15.4 Hz, 1H), 5.48 (br d, J = 8.9 Hz, 1H), 4.69 (br t, J = 4.6 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.40 - 4.31 (m, 1H), 4.30 - 4.22 (m, 1H), 3.94 (br dd, J = 9.4, 14.4 Hz, 1H), 3.90 - 3.81 (m, 4H), 3.30 - 3.25 (m, 4H), 3.16 - 3.11 (m, 1H), 3.06 (s, 3H), 2.95 (s, 3H), 2.91 - 2.85 (m, 1H), 2.80 (s, 3H), 2.62 - 2.50 (m, 2H). Example 477 (8S,11S,15R)-22-fluoro-10-[1-[4-fluor-2-(2-oxa-6-azaspiro[3. 3]heptan-6- yl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-di methyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 477 was prepared in analogy to the preparation of Examples 474 by using 2-oxa- 6-azaspiro[3.3]heptane instead of azetidine. Example 477, LCMS (M+H ⁺ ): 748. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 - 8.45 (m, 1H), 8.22 - 8.15 (m, 1H), 7.86 - 7.79 (m, 1H), 7.35 - 7.29 (m, 1H), 7.22 - 7.17 (m, 1H), 7.17 - 7.08 (m, 2H), 6.69 (dd, J = 5.8, 8.4 Hz, 1H), 6.64 - 6.55 (m, 1H), 6.45 - 6.37 (m, 1H), 5.84 - 5.68 (m, 1H), 5.51 - 5.38 (m, 1H), 4.87 (s, 2H), 4.72 - 4.65 (m, 1H), 4.63 - 4.60 (m, 2H), 4.53 (dt, J = 5.9, 11.9 Hz, 1H), 4.40 - 4.25 (m, 1H), 4.21 - 4.14 (m, 1H), 4.14 - 4.09 (m, 2H), 3.94 (ddd, J = 5.4, 9.1, 14.3 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.15 - 3.02 (m, 3H), 2.97 - 2.86 (m, 2H), 2.85 (d, J = 2.6 Hz, 3H), 2.58 (d, J = 1.6 Hz, 3H), 2.55 - 2.44 (m, 2H). Example 478 (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6-(methox ymethyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 478 was prepared according to the following scheme: Step 1: preparation of N-[4-cyano-2-(2,4-difluoro-6-methoxy-phenyl)pyrazol-3-yl]-2- methoxy-acetamide (compound 478a) To a tube was added compound C61-e (1300 mg, 5.2 mmol), methoxyacetyl chloride (1.16 g, 975 μL, 10.7 mmol) and sulfolane (16.51 g, 13 mL). After being heated to 55 °C and stirred for 16 hrs, the reaction mixture was poured into 100 mL sat. NaHCO ₃ aq. and extracted with 20 mL EA for 3 times. The organic layer was concentrated to give an oil and purified via flash column (EA/PE=0~60%), some oil was obtained containing with some sulfolane. Then it was purified again via prep-HLC (ACN/TFA 0.05% aq.=0~25%), the elution was concentrated to remove most ACN. The residue was extracted with 80 mL EA for 4 times. The organic layer was dried and concentrated to give compound 478a (1.1 g) as yellow solid. LCMS (M+H ⁺ ): 323. Step 2: preparation of 4-chloro-1-(2,4-difluoro-6-methoxy-phenyl)-6- (methoxymethyl)pyrazolo[3,4-d]pyrimidine (compound 478b) To a microwave tube was added compound 478a (1100 mg, 3.41 mmol) and phosphorus oxychloride (8.23 g, 5 mL, 53.64 mmol), the suspension was heated to 100 °C and further stirred for 8 hrs. The mixture was concentrated to give an oil which was purified via flash column (EA/PE=0~30%) to give compound 478b (800 mg). LCMS (M+H ⁺ ): 341. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6- (methoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 478) To a tube was added (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 2,2,2-trifluoroacetic acid (compound 370b, 60 mg, 0.109 mmol), 4-chloro-1- (2,4-difluoro-6-methoxy-phenyl)-6-(methoxymethyl)pyrazolo[3, 4-d]pyrimidine (compound 478b, 37.0 mg, 0.109 mmol), DIEA (112.3 mg, 151.7 μL, 0.869 mmol) and acetonitrile (2 mL). The mixture was heated to 85 °C and stirred for about 1 hr. The mixture was concentrated to give a light brown oil, which was purified via prep-HPLC to give Example 478 (51 mg), LCMS (M+H ⁺ ): 743. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 (d, J = 1.4 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.16 (dd, J = 2.5, 10.5 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.96 - 6.88 (m, 1H), 6.86 - 6.78 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.82 - 5.73 (m, 1H), 5.59 (d, J = 8.8 Hz, 1H), 4.68 - 4.63 (m, 1H), 4.51 - 4.48 (m, 1H), 4.47 - 4.36 (m, 2H), 4.33 - 4.24 (m, 1H), 4.19 - 4.08 (m, 1H), 3.89 (dd, J = 9.6, 14.0 Hz, 1H), 3.81 - 3.74 (m, 4H), 3.46 - 3.40 (m, 3H), 3.14 - 3.02 (m, 3H), 2.91 - 2.86 (m, 1H), 2.83 (d, J = 1.5 Hz, 3H), 2.58 - 2.54 (m, 3H), 2.49 (dt, J = 4.4, 9.1 Hz, 2H). Example 479 (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(3-methoxycyclobuto xy)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26 -hexazapentacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 479 was prepared according to the following scheme: Step 1: preparation of 3-benzyloxycyclobutanol (compound 479a) To a solution of 3-benzyloxycyclobutanone (5.0 g, 28.4 mmol) in ethanol (75 mL) was added NaBH ₄ (1.08 g, 28.4 mmol) portion wise. The mixture was stirred at 0 °C for 1 h. Then it was quenched with NH ₄ Cl aq. until pH=7. After concentration, the mixture was extracted with EA. The organic layer was concentrated and purified via silica gel column to give compound 479a (4.85 g) as yellow liquid. LCMS (M+H ⁺ ): 179. Step 2: preparation of 2-(3-benzyloxycyclobutoxy)-4-fluoro-1-nitro-benzene (compound 479b) To a mixture of compound 479a (4.45 g, 25.0 mmol), 5-fluoro-2-nitrophenol (5.88 g, 37.4 mmol) and PPh ₃ (9.82 g, 37.4 mmol) in toluene (55 mL) was added DIAD (6.58 mL, 37.4 mmol) at 0 °C under N ₂ . Then it was stirred at 100 °C for 1 h under N ₂ . The mixture was concentrated and purified via silica gel column to afford compound 479b (6.8 g) as yellow liquid. LCMS (M+H ⁺ ): 318. Step 3: preparation of 3-(5-fluoro-2-nitro-phenoxy)cyclobutanol (compound 479c) To a solution of compound 479b (5.25 g, 16.6 mmol) in MeCN (52.5 mL) was added iodotrimethylsilane (5.89 mL, 41.4 mmol) slowly at 0°C. After being stirred at 40 °C for 12 h, the mixture was poured into water and extracted with EtOAc, the organic layer was concentrated and the residue was purified via silica gel column to give compound 479c (3.2 g) as brown solid. LCMS (M+H ⁺ ): 228. Step 4: preparation of 4-fluoro-2-(3-methoxycyclobutoxy)-1-nitro-benzene (compound 479d) To a solution of compound 479c (3.2 g, 14.1 mmol) in DMF (32 mL) was added iodomethane (2.63 mL, 42.3 mmol) at -10 °C under N ₂ , and then sodium hydride (60% in oil, 1.13 g, 28.2 mmol) was added slowly. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with cold NH ₄ Cl aq. and extracted with EtOAc. The organic layer was washed with NaCl aq., dried and concentrated, compound 479d (3.0 g) was obtained as yellow liquid. LCMS (M+H ⁺ ): 242. Step 5: preparation of 4-fluoro-2-(3-methoxycyclobutoxy)aniline (compound 479e) To the mixture of compound 479d (1.5 g, 6.22 mmol) in methanol (15 mL) was added Pd/C (300.0 mg, 18.72 mmol), and then it was stirred at 20 °C for 12 h under H ₂ . The mixture was filtered, the filtrate was concentrated to give compound 479e (1.28 g) as brown liquid. LCMS (M+H ⁺ ): 212. Step 6: preparation of 4-chloro-6-[4-fluoro-2-(3-methoxycyclobutoxy)anilino] pyrimidine-5-carbaldehyde (compound 479f) To the mixture of compound 479e (500 mg, 2.37 mmol) and TEA (478 mg, 4.73 mmol) in DCM (5 mL) was added 4,6-dichloro-5-pyrimidinecarbaldehyde (423 mg, 2.39 mmol). Then it was stirred at 20 °C for 12 h. The mixture was poured into water, the organic layer was dried and concentrated to give compound 479f (760 mg) as yellow solid. LCMS (M+H ⁺ ): 352. Step 7: preparation of [(E)-[4-chloro-6-[4-fluoro-2-(3-methoxycyclobutoxy)anilino] pyrimidin-5-yl]methyleneamino] hydrogen sulfate (compound 479g) To a solution of compound 479f (0.76 g, 2.16 mmol) in ACN (10 mL) was added hydroxylamine-o-sulfonic acid (1.47 g, 12.96 mmol). The reaction mixture was stirred at 20 °C for 2 h under N ₂ . The mixture was used for next step directly. Compound 479g, LCMS (M+H ⁺ ): 447. Step 8: preparation of 1-[4-fluoro-2-(3-methoxycyclobutoxy)phenyl]pyrazolo[3,4- d]pyrimidin-4-ol (compound 479h) To the solution of compound 479g (0.97 g, 2.2 mmol) in ACN (10 mL) was added NaOH aq. (12.8 mL, 38.5 mmol, 3 M). The reaction mixture was stirred at 50 °C for 2 h under N ₂ . The mixture was concentrated to give a solid. The solid was suspended in some MeOH and filtered. The filtrate was concentrated to give a yellow oil, which was purified via pre-HPLC to give compound 479h (190.0 mg) as off-white solid. LCMS (M+H ⁺ ): 331. Step 9: preparation of 4-chloro-1-[4-fluoro-2-(3-methoxycyclobutoxy)phenyl]pyrazolo [3,4-d]pyrimidine (compound 479i) A mixture of compound 479h (0.56 g, 1.7 mmol) and POCl ₃ (6.0 mL) was stirred at 100 °C for 2 h. The mixture was concentrated to give a solid which was dissolved in 40 mL DCM, and then the reaction was quenched with 100 mL cold NaHCO ₃ aq. The organic layer was concentrated to give compound 479i (170.0 mg) as yellow oil. LCMS (M+H ⁺ ): 349. Step 10: preparation of (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(3- methoxycyclobutoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 479) To a tube was added compound 370b (50 mg, 0.090 mmol), compound 479i (31.6 mg, 0.090 mmol), DIEA (93.6 mg, 126.4 μL, 0.724 mmol) and acetonitrile (2 mL). The mixture was heated to 85 °C and stirred for 1 hr. The mixture was concentrated to give a light brown oil, which was purified via prep-HPLC to give Example 479 (34.5 mg) as white powder. LCMS (M+H ⁺ ): 751. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 8.16 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.37 (dd, J = 6.0, 8.6 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.83 - 6.72 (m, 2H), 6.69 (d, J = 8.4 Hz, 1H), 6.08 - 5.95 (m, 1H), 5.39 (d, J = 8.9 Hz, 1H), 4.63 - 4.58 (m, 1H), 4.49 - 4.42 (m, 1H), 4.32 (br d, J = 11.4 Hz, 1H), 4.28 - 4.12 (m, 2H), 3.91 - 3.78 (m, 2H), 3.12 - 3.08 (m, 3H), 2.96 (s, 3H), 2.91 - 2.78 (m, 5H), 2.74 (s, 3H), 2.53 - 2.43 (m, 2H), 2.26 (dq, J = 4.8, 6.8 Hz, 2H), 2.09 (tdd, J = 3.5, 7.0, 10.5 Hz, 2H). Example 480 (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-[1-(methoxymethyl)c yclopropoxy]phenyl] pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,1 0,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 480 was prepared in analogy to the preparation of Example 479 by using compound 480c instead of Intermediate 479d in step 5. Compound 480c was prepared according to the following scheme: Step 1: preparation of methyl 1-(5-fluoro-2-nitro-phenoxy)cyclopropanecarboxylate (compound 480a) To a solution of 2,4-difluoro-1-nitro-benzene (6.89 mL, 62.86 mmol) in THF (150 mL) was added sodium hydride (3.02 g, 75.46 mmol) at 0 °C. After 0.5 h, to the mixture was added methyl 1-hydroxy-1-cyclopropane (7.3 g, 62.88 mmol) and 15-crown- 5 (277.0 mg, 1.26 mmol) at 0 °C under N ₂ . The mixture was warmed to r.t. and stirred for 14 h. The reaction was quenched with NH ₄ Cl (150mL), and the mixture was extracted with EtOAc. The organic layer was washed with sat. NaCl aq. and concentrated. The residue was purified by silica gel column to afford compound 480a (13.0 g) as a light yellow solid. LCMS (M+H ⁺ ): 256. Step 2: preparation of [1-(5-fluoro-2-nitro-phenoxy)cyclopropyl]methanol (compound 480b) To a solution of lithium borohydride (4.27 g, 195.92 mmol) in THF (200 mL) was added another solution of compound 480a (10.0 g, 39.18 mmol) in THF (50 mL) slowly at 25 °C. And then it was stirred at 60 °C for 2 h. To the reaction was added 1N HCl aq. dropwise to pH=7, and then it was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was purified by silica gel column to afford compound 480b (6.3 g) as a brown solid. LCMS (M+H ⁺ ): 228. Step 3: preparation of 4-fluoro-2-[1-(methoxymethyl)cyclopropoxy]-1-nitro-benzene (compound 480c) To a solution of sodium hydride (60% in oil, 0.76 g, 18.93 mmol) in DMF (22 mL) was added compound 480b (2.15 g, 9.46 mmol) at -10 °C under N ₂ . And then iodomethane (1.77 mL, 28.39 mmol) was added slowly. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with cold NH ₄ Cl aq. and extracted with ethyl acetate. The organic layer was washed with brine and concentrated to give compound 480c (2.2 g) as a brown liquid. LCMS (M+H ⁺ ): 242. Example 480, LCMS (M+H ⁺ ): 751. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.49 (s, 1H), 8.18 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.32 (dd, J = 2.5, 8.4 Hz, 1H), 7.19 (dd, J = 2.5, 10.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.06 (br dd, J = 2.5, 10.6 Hz, 1H), 6.90 (dt, J = 2.6, 8.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.84 - 5.70 (m, 1H), 5.48 (d, J = 8.9 Hz, 1H), 4.67 (br t, J = 4.9 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.37 - 4.30 (m, 1H), 4.29 - 4.15 (m, 1H), 4.14 - 4.11 (m, 2H), 3.99 - 3.88 (m, 1H), 3.13 - 3.03 (m, 3H), 3.02 - 2.98 (m, 3H), 2.93 - 2.85 (m, 2H), 2.85 (s, 3H), 2.60 - 2.55 (m, 3H), 2.55 - 2.45 (m, 2H), 0.72 - 0.63 (m, 2H), 0.56 - 0.50 (m, 2H). Example 481 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(hydroxymethyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 481 was prepared according to the following scheme: Step 1: preparation of 1-(2,4-difluorophenyl)-6-(hydroxymethyl)pyrazolo[3,4- d]pyrimidin-4-ol (compound 481a) To a tube was added 4-chloro-1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3, 4- d]pyrimidine (Intermediate C28, 100.0 mg, 0.322 mmol) and dichloromethane (2 mL), the solution was cooled with dry ice/EtOH bath and boron trichloride (1 M in DCM) (966 μL, 0.966 mmol) was added into. The mixture warmed to r.t. and stirred for 16 hrs. The mixture was quenched with ice water and diluted with some DCM. The mixture was separated, the organic layer was concentrated and purified via flash column chromatography (MeOH/DCM=0~30%), the elution was concentrated to give compound 481a (63 mg) as white solid. LCMS (M+H ⁺ ): 279. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- (hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 481) To a flask was added 1-(2,4-difluorophenyl)-6-methylol-pyrazolo[3,4-d]pyrimidin-4 -ol (compound 481a, 30.0 mg, 0.108 mmol), (1-hydroxy-1H-benzotriazolato-o)tri-1- pyrrolidinylphosphorus hexafluorophosphate (84.2 mg, 0.162 mmol), DIEA (83.6 mg, 113.0 μL, 0.647 mmol) and N,N-dimethylformamide (2 mL), the mixture was stirred at r.t. for 1 hr, and compound 370b (100 mg, 0.150 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hrs. The mixture was concentrated and purified via prep-HPLC to give Example 481 (57 mg). LCMS (M+H ⁺ ): 699. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.34 (dd, J = 2.5, 8.3 Hz, 1H), 7.30 - 7.14 (m, 3H), 7.13 - 7.07 (m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.85 - 5.70 (m, 1H), 5.63 - 5.38 (m, 1H), 4.67 - 4.63 (m, 1H), 4.62 - 4.49 (m, 2H), 4.49 - 4.45 (m, 1H), 4.30 (d, J = 3.8 Hz, 1H), 4.20 - 4.10 (m, 1H), 3.94 (dd, J = 9.3, 14.3 Hz, 1H), 3.14 - 3.02 (m, 3H), 2.99 - 2.86 (m, 2H), 2.85 (s, 3H), 2.61 - 2.56 (m, 3H), 2.54 - 2.44 (m, 2H). Example 482 (8S,11S,15R)-4,22-difluoro-10-[1-(4-fluoro-2-methoxy-phenyl) pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacy clo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 482 was prepared in analogy to the preparation of Example 12 by using Intermediate A6 and compound 482a instead of Intermediate A11 and Interdiate B10 in step 1 and using Intermediate C11 instead of Intermediate C2 in step 5. The compound 482a was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-4-fluoro-2- pyridyl)amino]pyrrolidine-1,2-dicarboxylate (compound 482a) A mixture of 2-bromo-4,6-difluoro-pyridine (970.0 mg, 5.0 mmol), DIPEA (1.62 g, 2.18 mL, 12.5 mmol) and O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate; hydrochloride (1.57 g, 5.0 mmol) in DMSO (10 mL) was stirred at 110 °C for about 16 hrs. The reaction mixture was poured into 150 mL water and extracted with 30 mL EA for 3 times. The organic layer was dried and concentrated, the residue was purified via flash column (EA/PE= 0~30%) to give isomer A (1.6 g white solid) and isomer B (300 mg colorless oil). According to the 2 D NMR spectrum the isomer B was the desired compound 482a. LCMS (M+H ⁺ ): 452. Example 482, LCMS (M+H ⁺ ): 699. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 8.17 (s, 1H), 7.44 (dd, J = 6.1, 8.6 Hz, 1H), 7.33 (dd, J = 2.4, 8.4 Hz, 1H), 7.21 (dd, J = 2.4, 10.4 Hz, 1H), 7.06 (dd, J = 2.4, 10.6 Hz, 1H), 6.96 - 6.82 (m, 2H), 6.52 - 6.43 (m, 1H), 5.75 (br dd, J = 4.3, 15.5 Hz, 1H), 5.49 (d, J = 8.9 Hz, 1H), 4.63 (br t, J = 4.9 Hz, 1H), 4.54 - 4.42 (m, 1H), 4.35 (d, J = 11.4 Hz, 1H), 4.26 (br s, 1H), 4.19 - 4.08 (m, 1H), 4.00 - 3.89 (m, 1H), 3.76 (s, 3H), 3.20 - 3.05 (m, 3H), 2.94 - 2.87 (m, 1H), 2.86 (s, 3H), 2.57 (s, 3H), 2.56 - 2.47 (m, 2H). Example 483 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2-dioxo-2λ⁶- thia-6-azaspiro[3.3]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15 .6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 483 was prepared according to the following scheme: To a tube was added DIEA (32.2 mg, 0.249 mmol), 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide;hydrochloride (22.9 mg, 0.124 mmol), compound 213a (35.0 mg, 0.050 mmol), and acetonitrile (2 mL). The mixture was heated to 90 °C and stirred for 4 hrs. The mixture was filtered, the filtrate was concentrated and purified via prep-HPLC to give Example 483 (30 mg) as a white powder. LCMS (M+H ⁺ ): 814. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.65 - 7.51 (m, 3H), 7.27 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.27 - 6.05 (m, 1H), 5.44 - 5.29 (m, 1H), 4.67 (br t, J = 4.7 Hz, 1H), 4.46 (br dd, J = 5.8, 11.3 Hz, 1H), 4.40 - 4.29 (m, 6H), 4.27 - 4.14 (m, 4H), 3.94 (dd, J = 9.2, 14.2 Hz, 1H), 3.15 - 3.06 (m, 3H), 3.06 - 3.00 (m, 1H), 3.00 - 2.95 (m, 3H), 2.86 - 2.80 (m, 3H), 2.75 (br d, J = 13.6 Hz, 1H), 2.68 - 2.45 (m, 2H). Example 484 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl) azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 484 was prepared in analogy to the preparation of Example 483 by using azetidin- 3-ylmethanol instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 484, LCMS (M+H ⁺ ): 754. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.30 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.61 - 7.57 (m, 1H), 7.54 (dd, J = 2.3, 10.3 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.20 - 7.14 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.29 - 6.03 (m, 1H), 5.46 - 5.33 (m, 1H), 4.67 (br t, J = 4.8 Hz, 1H), 4.48 (br dd, J = 5.8, 11.2 Hz, 1H), 4.38 - 4.17 (m, 3H), 4.14 - 4.01 (m, 1H), 3.99 - 3.88 (m, 2H), 3.86 - 3.73 (m, 2H), 3.70 (br d, J = 6.5 Hz, 2H), 3.14 - 3.05 (m, 3H), 3.04 - 3.00 (m, 1H), 2.99 - 2.94 (m, 3H), 2.86 - 2.81 (m, 3H), 2.76 (br d, J = 13.8 Hz, 1H), 2.69 - 2.47 (m, 2H). Example 485 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-6-azaspiro[ 3.3]heptan-6-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 485 was prepared in analogy to the preparation of Example 483 by using 2-oxa-6- azaspiro[3.3]heptane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 485, LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.28 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.51 (m, 3H), 7.29 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.29 - 6.04 (m, 1H), 5.45 - 5.31 (m, 1H), 4.80 (s, 4H), 4.70 - 4.57 (m, 1H), 4.51 - 4.42 (m, 1H), 4.32 - 4.25 (m, 2H), 4.25 - 4.16 (m, 2H), 4.15 - 4.09 (m, 1H), 3.94 (br dd, J = 9.3, 14.3 Hz, 1H), 3.89 - 3.73 (m, 1H), 3.16 - 3.07 (m, 3H), 3.07 - 3.01 (m, 1H), 3.01 - 2.95 (m, 3H), 2.87 - 2.79 (m, 3H), 2.78 - 2.71 (m, 1H), 2.68 - 2.46 (m, 2H). Example 486 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxy-1-me thyl-ethyl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 486 was prepared in analogy to the preparation of Example 483 by using 2- (azetidin-3-yl)propan-2-ol;hydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 486, LCMS (M+H ⁺ ): 782. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.29 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.54 (dd, J = 2.4, 10.3 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.21 - 7.13 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.28 - 6.04 (m, 1H), 5.48 - 5.29 (m, 1H), 4.67 (br t, J = 4.8 Hz, 1H), 4.48 (br dd, J = 5.9, 11.4 Hz, 1H), 4.38 - 4.22 (m, 2H), 4.15 - 4.07 (m, 1H), 4.06 - 3.88 (m, 4H), 3.15 - 3.06 (m, 3H), 3.05 - 3.00 (m, 1H), 3.00 - 2.95 (m, 3H), 2.86 - 2.80 (m, 3H), 2.80 - 2.64 (m, 2H), 2.63 - 2.47 (m, 2H), 1.21 - 1.13 (m, 6H). Example 487 (8S,11S,15R)-10-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl ]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 487 was prepared according to the following scheme: The compound 487a was prepared in analogy to the preparation of Example 483 by using tert-butyl N-[(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate;hydrochloride instead of 2λ ⁶ -thia-6- azaspiro[3.3]heptane 2,2-dioxide. Compound 487a, LCMS (M+H ⁺ ): 871. Step 2: preparation of (8S,11S,15R)-10-[6-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl ]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluo ro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Examples 487) The compound 487a was dissolved in dichloromethane (2 mL) and TFA, the solution was stirred at r.t. for 1 hr. The mixture was concentrated and purified via prep-HPLC to give Example 487. LCMS (M+H ⁺ ): 771. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.29 (s, 1H), 7.92 - 7.84 (m, 1H), 7.68 - 7.51 (m, 3H), 7.27 - 7.19 (m, 1H), 7.19 - 7.12 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.29 - 6.06 (m, 1H), 5.47 - 5.36 (m, 1H), 5.36 - 5.22 (m, 1H), 4.68 (br t, J = 4.8 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.36 - 4.18 (m, 2H), 4.15 - 3.83 (m, 5H), 3.76 - 3.65 (m, 1H), 3.17 - 3.07 (m, 3H), 3.02 (br d, J = 15.4 Hz, 1H), 3.00 - 2.96 (m, 3H), 2.85 - 2.81 (m, 3H), 2.78 (br d, J = 13.6 Hz, 1H), 2.70 - 2.48 (m, 2H). Example 488 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(dimethylamino )methyl]azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 488 was prepared in analogy to the preparation of Example 483 by using azetidin- 3-ylmethyl(dimethyl)amine;dihydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide. Example 488, LCMS (M+H ⁺ ): 781. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.28 (s, 1H), 7.92 - 7.83 (m, 1H), 7.65 - 7.51 (m, 3H), 7.27 - 7.19 (m, 1H), 7.19 - 7.12 (m, 2H), 6.81 - 6.74 (m, 1H), 6.28 - 6.04 (m, 1H), 5.43 - 5.30 (m, 1H), 4.67 (br t, J = 4.5 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.38 - 4.26 (m, 2H), 4.25 - 4.13 (m, 2H), 3.99 - 3.87 (m, 2H), 3.86 - 3.72 (m, 1H), 3.53 - 3.42 (m, 2H), 3.22 - 3.14 (m, 1H), 3.06 (s, 3H), 3.04 - 2.99 (m, 1H), 2.98 (d, J = 2.6 Hz, 3H), 2.92 - 2.87 (m, 6H), 2.85 - 2.80 (m, 3H), 2.76 (br d, J = 13.6 Hz, 1H), 2.68 - 2.46 (m, 2H). Example 489 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyla zetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 489 was prepared in analogy to the preparation of Example 483 by using 3- mesylazetidine;hydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 489, LCMS (M+H ⁺ ): 802. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.28 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.50 (m, 3H), 7.26 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 6.78 (br d, J = 8.5 Hz, 1H), 6.28 - 6.03 (m, 1H), 5.45 - 5.30 (m, 1H), 4.66 (br t, J = 4.8 Hz, 1H), 4.46 (br dd, J = 5.8, 11.4 Hz, 1H), 4.41 - 4.36 (m, 1H), 4.35 - 4.19 (m, 6H), 3.94 (dd, J = 9.1, 14.3 Hz, 1H), 3.15 - 3.06 (m, 3H), 3.04 - 2.99 (m, 1H), 2.97 (d, J = 6.5 Hz, 6H), 2.86 - 2.79 (m, 3H), 2.78 - 2.71 (m, 1H), 2.68 - 2.45 (m, 2H). Example 490 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(tetrahydrofuran-3 -ylmethoxy)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 490 was prepared according to the following scheme: To a tube was added tetrahydrofuran-3-ylmethanol (15.3 mg, 0.149 mmol) and tetrahydrofuran (1.5 mL), the solution was cooled in dry ice/EtOH bath and then NaH (8.0 mg, 0.199 mmol) was added. The mixture was stirred for 30 mins and compound 213a (35.0 mg, 0.050 mmol) was added. After being warmed to r.t. slowly and stirred for 1 hr, the mixture was quenched and filtered, the filtrate was purified via prep-HPLC to give Example 490 (6.6 mg) as white solid. LCMS (M+H ⁺ ): 769. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.40 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.63 (dq, J = 6.2, 8.7 Hz, 1H), 7.54 (dd, J = 2.2, 7.4 Hz, 1H), 7.48 (dd, J = 1.6, 10.1 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.21 - 7.13 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 6.14 - 5.96 (m, 1H), 5.49 - 5.37 (m, 1H), 4.68 (br t, J = 4.7 Hz, 1H), 4.50 (dd, J = 5.7, 11.4 Hz, 1H), 4.34 - 4.28 (m, 2H), 4.28 - 4.23 (m, 1H), 4.21 (d, J = 7.3 Hz, 1H), 3.94 (br dd, J = 9.5, 13.9 Hz, 1H), 3.90 - 3.78 (m, 2H), 3.77 - 3.72 (m, 1H), 3.65 - 3.59 (m, 1H), 3.16 - 3.05 (m, 3H), 3.05 - 2.96 (m, 1H), 2.95 (s, 3H), 2.88 - 2.82 (m, 1H), 2.81 - 2.76 (m, 3H), 2.75 - 2.63 (m, 1H), 2.62 - 2.49 (m, 2H), 2.14 - 2.01 (m, 1H), 1.80 - 1.64 (m, 1H). Example 491 (8S,11S,15R)-10-[6-(1-cyclopropylazetidin-3-yl)oxy-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 491 was prepared in analogy to the preparation of Example 490 by using 1- cyclopropylazetidin-3-ol instead of tetrahydrofuran-3-ylmethanol. Example 491, LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.39 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.66 - 7.54 (m, 1H), 7.34 - 7.22 (m, 2H), 7.17 (br dd, J = 2.6, 10.4 Hz, 2H), 7.12 - 7.07 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.80 - 5.65 (m, 1H), 5.41 - 5.32 (m, 1H), 5.29 - 5.01 (m, 1H), 4.63 (br t, J = 4.6 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.33 - 4.25 (m, 1H), 4.23 - 4.04 (m, 2H), 3.93 (br dd, J = 9.4, 14.1 Hz, 2H), 3.81 (br t, J = 7.4 Hz, 1H), 3.58 - 3.42 (m, 2H), 3.11 - 3.03 (m, 3H), 2.90 - 2.85 (m, 1H), 2.85 - 2.81 (m, 3H), 2.58 - 2.54 (m, 3H), 2.53 - 2.44 (m, 2H), 2.25 (br s, 1H), 0.65 - 0.41 (m, 4H). Example 492 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(4-methylpipera zin-1-yl)ethoxy]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 492 was prepared in analogy to the preparation of Example 490 by using 2-(4- methylpiperazino)ethanol instead of tetrahydrofuran-3-ylmethanol. Example 492, LCMS (M+H ⁺ ): 811. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.37 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.69 - 7.55 (m, 1H), 7.29 (dd, J = 2.2, 8.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.19 - 7.11 (m, 2H), 7.11 - 7.05 (m, 1H), 6.69 - 6.62 (m, 1H), 5.79 - 5.65 (m, 1H), 5.44 - 5.32 (m, 1H), 4.61 (br t, J = 4.5 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.46 - 4.29 (m, 3H), 4.25 (br d, J = 15.4 Hz, 1H), 4.19 - 4.08 (m, 1H), 3.94 (br dd, J = 9.4, 13.9 Hz, 1H), 3.12 - 3.01 (m, 3H), 2.94 (br d, J = 14.0 Hz, 1H), 2.87 (br s, 1H), 2.82 (s, 3H), 2.79 (br t, J = 6.0 Hz, 1H), 2.76 - 2.69 (m, 2H), 2.68 - 2.57 (m, 2H), 2.57 - 2.54 (m, 3H), 2.54 - 2.35 (m, 6H), 2.26 (s, 3H). Example 493 (8S,11S,15R)-10-[6-[[1-(2,2-difluoroacetyl)azetidin-3-yl]met hoxy]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 493 was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[6-(azetidin-3-ylmethoxy)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 493a) To a tube was added tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (24.0 mg, 0.128 mmol) and tetrahydrofuran (2.5 mL), the solution was cooled in dry ice/EtOH bath and then NaH (13.6 mg, 0.341 mmol) was added. The mixture was stirred for 30 mins and compound 213a (60.0 mg, 0.085 mmol) was added, then it was warmed to r.t. slowly and stirred for 1 hr. The reaction was quenched with MeOH, and then the mixture was diluted with 20 mL water, extracted with 15 mL EA twice, the organic layer was dried and concentrated to give a residue which was purified via flash column (EA/PE=0~100%) to give a white solid. The solid was dissolved in dichloromethane (2 mL) and TFA (1 mL), the solution was stirred at r.t. for 1 hr. The mixture was concentrated to give light yellow oil which was purified via prep-HPLC (ACN/TFA 0.05% aq.=0~30%) to give compound 493a (80 mg). LCMS (M+H ⁺ ): 754. Step 2: preparation of (8S,11S,15R)-10-[6-[[1-(2,2-difluoroacetyl)azetidin-3- yl]methoxy]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4 -yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 493) To a tube was added compound 493a (10.0 mg, 0.011 mmol), DIEA (8.5 mg, 11.47 μL, 0.066 mmol), dichloromethane (1 mL) and difluoroacetic anhydride (5.7 mg, 3.6 μL, 0.033 mmol). The solution was stirred at r.t. for 4 hrs, then the reaction was quenched with MeOH. The mixture was concentrated and purified via prep-HPLC to give Example 493 (5.7 mg). LCMS (M+H ⁺ ): 832. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.41 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.33 - 7.27 (m, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.13 (m, 2H), 7.10 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.13 (dt, J = 1.9, 53.3 Hz, 1H), 5.82 - 5.65 (m, 1H), 5.46 - 5.35 (m, 1H), 4.63 (s, 1H), 4.60 - 4.52 (m, 2H), 4.52 - 4.39 (m, 3H), 4.34 - 4.09 (m, 4H), 4.03 - 3.89 (m, 2H), 3.13 - 3.02 (m, 3H), 2.99 - 2.85 (m, 2H), 2.84 (s, 3H), 2.59 - 2.55 (m, 3H), 2.50 (tt, J = 4.5, 9.0 Hz, 2H). Example 494 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methylpiperazin -1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 494 was prepared in analogy to the preparation of Example 483 by using 1- methylpiperazine instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 494, LCMS (M+H ⁺ ): 767. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.22 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.30 (dd, J = 2.4, 8.6 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.11 (m, 2H), 7.09 (br d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.89 - 5.64 (m, 1H), 5.41 - 5.25 (m, 1H), 4.64 (br t, J = 4.9 Hz, 1H), 4.56 (s, 1H), 4.44 (br dd, J = 5.8, 10.8 Hz, 1H), 4.28 - 4.09 (m, 3H), 3.94 - 3.68 (m, 5H), 3.13 - 3.02 (m, 3H), 2.97 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.59 - 2.55 (m, 3H), 2.54 (br s, 1H), 2.47 (br s, 4H), 2.38 - 2.32 (m, 3H). Example 495 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylazetidin -3-yl)methoxy]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 495 was prepared in analogy to the preparation of Example 490 by using (1- methylazetidin-3-yl)methanol instead of tetrahydrofuran-3-ylmethanol. Example 495, LCMS (M+H ⁺ ): 768. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 - 8.42 (m, 1H), 7.88 (dt, J = 4.0, 7.9 Hz, 1H), 7.71 - 7.58 (m, 1H), 7.57 - 7.53 (m, 1H), 7.49 (br d, J = 10.3 Hz, 1H), 7.37 - 7.27 (m, 1H), 7.22 (br d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 2.8, 8.4 Hz, 1H), 6.16 - 5.99 (m, 1H), 5.48 - 5.39 (m, 1H), 4.69 (br d, J = 2.3 Hz, 1H), 4.59 - 4.45 (m, 2H), 4.43 - 4.14 (m, 7H), 4.08 - 3.87 (m, 2H), 3.17 - 3.02 (m, 4H), 2.99 - 2.93 (m, 4H), 2.93 - 2.85 (m, 3H), 2.78 (d, J = 2.4 Hz, 3H), 2.72 - 2.49 (m, 2H). Example 496 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1-methylpyrrolid in-3-yl)methoxy]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 496 was prepared in analogy to the preparation of Example 490 by using (1- methylpyrrolidin-3-yl)methanol instead of tetrahydrofuran-3-ylmethanol. Example 496, LCMS (M+H ⁺ ): 782. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.44 (br s, 1H), 7.91 - 7.84 (m, 1H), 7.69 - 7.59 (m, 1H), 7.56 (dd, J = 2.1, 7.4 Hz, 1H), 7.50 (br dd, J = 2.7, 10.2 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.25 - 7.18 (m, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 3.0, 8.4 Hz, 1H), 6.16 - 5.99 (m, 1H), 5.49 - 5.39 (m, 1H), 4.72 - 4.66 (m, 1H), 4.51 (br dd, J = 5.2, 11.3 Hz, 1H), 4.43 - 4.18 (m, 4H), 4.00 - 3.87 (m, 1H), 3.84 - 3.61 (m, 2H), 3.29 - 3.21 (m, 1H), 3.18 - 3.10 (m, 2H), 3.10 - 3.02 (m, 3H), 2.95 (s, 7H), 2.92 - 2.83 (m, 1H), 2.79 (d, J = 5.4 Hz, 3H), 2.72 - 2.49 (m, 2H), 2.48 - 2.17 (m, 1H), 2.16 - 1.88 (m, 1H). Example 497 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-fluoroethyl) azetidin-3-yl]oxy-pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one To a tube was added compound 497a (10.0 mg, 0.012 mmol), K ₂ CO ₃ (9.7 mg, 0.070 mmol), 1-fluoro-2-iodo-ethane (12.2 mg, 0.070 mmol) and acetonitrile (0.5 mL). The suspension stirred at r.t. for 16 hrs. Then it was filtered, the filtrate was purified via prep-HPLC to give Example 497 (6.6 mg). LCMS (M+H ⁺ ): 786. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.40 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.66 - 7.55 (m, 1H), 7.32 - 7.21 (m, 2H), 7.21 - 7.13 (m, 2H), 7.12 - 7.06 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.81 - 5.65 (m, 1H), 5.45 - 5.34 (m, 1H), 5.09 (quin, J = 6.0 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.55 - 4.45 (m, 2H), 4.41 (t, J = 4.5 Hz, 1H), 4.29 (d, J = 11.6 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.97 - 3.87 (m, 1H), 3.86 - 3.69 (m, 2H), 3.67 - 3.46 (m, 1H), 3.22 - 3.16 (m, 1H), 3.12 - 3.03 (m, 3H), 2.94 - 2.86 (m, 3H), 2.86 - 2.82 (m, 3H), 2.82 - 2.78 (m, 1H), 2.59 - 2.55 (m, 3H), 2.54 - 2.44 (m, 2H). Example 498 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-ylmethox y)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 498 was prepared in analogy to the preparation of Example 490 by using oxetan- 3-ylmethanol instead of tetrahydrofuran-3-ylmethanol. Example 498, LCMS (M+H ⁺ ): 755. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.40 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.30 (dd, J = 2.4, 8.5 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.13 (m, 2H), 7.12 - 7.08 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.81 - 5.66 (m, 1H), 5.46 - 5.34 (m, 1H), 4.66 (br t, J = 4.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.54 - 4.43 (m, 3H), 4.33 - 4.22 (m, 1H), 4.20 - 4.09 (m, 1H), 3.94 (br dd, J = 9.4, 14.2 Hz, 1H), 3.66 - 3.57 (m, 1H), 3.51 - 3.43 (m, 1H), 3.43 - 3.34 (m, 1H), 3.13 - 3.02 (m, 3H), 2.99 - 2.85 (m, 2H), 2.84 (s, 3H), 2.60 - 2.55 (m, 3H), 2.44 (br s, 2H). Example 499 (8S,11S,15R)-10-[6-[(3S,4S)-3-amino-4-methoxy-pyrrolidin-1-y l]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 499 was prepared in analogy to the preparation of Example 487 by using tert- butyl N-[(3S,4S)-4-methoxypyrrolidin-3-yl]carbamate instead of tert-butyl N-[(3R,4R)-4- fluoropyrrolidin-3-yl]carbamate;hydrochloride. Example 499, LCMS (M+H ⁺ ): 783. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (br s, 1H), 7.96 (br d, J = 6.9 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.68 - 7.61 (m, 1H), 7.58 (dd, J = 2.1, 10.1 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.28 - 7.21 (m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 6.92 (br d, J = 5.5 Hz, 1H), 6.13 - 5.83 (m, 1H), 5.62 - 5.44 (m, 1H), 4.76 (br s, 1H), 4.61 - 4.52 (m, 1H), 4.42 - 4.25 (m, 2H), 4.23 - 3.83 (m, 6H), 3.75 - 3.64 (m, 1H), 3.62 - 3.56 (m, 1H), 3.50 - 3.43 (m, 3H), 3.18 - 3.12 (m, 3H), 3.09 (br dd, J = 6.9, 13.9 Hz, 1H), 3.04 - 2.98 (m, 3H), 2.86 (br d, J = 7.4 Hz, 3H), 2.78 -2.56 (m, 2H). Example 500 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(dimethylamino) azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 500 was prepared in analogy to the preparation of Example 483 by using N,N- dimethylazetidin-3-amine;dihydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 494, LCMS (M+H ⁺ ): 767. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.24 (s, 1H), 7.84 - 7.75 (m, 1H), 7.64 - 7.55 (m, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.87 - 5.65 (m, 1H), 5.43 - 5.25 (m, 1H), 4.64 - 4.57 (m, 1H), 4.48 - 4.36 (m, 1H), 4.27 - 4.11 (m, 3H), 4.11 - 4.02 (m, 1H), 4.02 - 3.91 (m, 2H), 3.91 - 3.75 (m, 2H), 3.12 - 3.02 (m, 3H), 2.97 - 2.87 (m, 1H), 2.85 - 2.81 (m, 3H), 2.80 - 2.72 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.39 (m, 2H), 2.28 - 2.20 (m, 6H). Example 501 (8S,11S,15R)-10-[6-(3-amino-3-methyl-azetidin-1-yl)-1-(2,4-d ifluorophenyl)pyrazolo [3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The Example 501 was prepared in analogy to the preparation of Example 487 by using tert- butyl N-(3-methylazetidin-3-yl)carbamate;hydrochloride instead of tert-butyl N-[(3R,4R)-4- fluoropyrrolidin-3-yl]carbamate;hydrochloride. Example 501, LCMS (M+H ⁺ ): 753. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.23 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.30 (dd, J = 2.4, 8.4 Hz, 1H), 7.22 (ddd, J = 2.8, 8.9, 10.1 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.10 - 7.05 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.88 - 5.66 (m, 1H), 5.40 - 5.25 (m, 1H), 4.64 - 4.53 (m, 1H), 4.42 (dd, J = 5.9, 11.2 Hz, 1H), 4.24 - 4.11 (m, 2H), 3.97 - 3.86 (m, 2H), 3.85 - 3.72 (m, 3H), 3.11 - 3.01 (m, 3H), 2.90 (br d, J = 14.4 Hz, 1H), 2.86 - 2.82 (m, 3H), 2.75 (br d, J = 13.6 Hz, 1H), 2.59 - 2.54 (m, 3H), 2.53 - 2.41 (m, 2H), 1.47 - 1.40 (m, 3H). Example 502 (8S,11S,15R)-10-[6-[1-(2,2-difluoroethyl)azetidin-3-yl]oxy-1 -(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The Example 502 was prepared in analogy to the preparation of Example 497 by using 2,2- difluoroethyl trifluoromethanesulfonate instead of 1-fluoro-2-iodo-ethane and using condition (DIPEA, THF, reflux) instead of condition ( K ₂ CO ₃ , ACN, r.t.) LCMS (M+H ⁺ ): 804. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.40 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.13 (m, 2H), 7.12 - 7.07 (m, 1H), 6.70 - 6.64 (m, 1H), 6.00 - 5.81 (m, 1H), 5.76 (dd, J = 4.3, 15.4 Hz, 1H), 5.43 - 5.33 (m, 1H), 5.08 (quin, J = 6.0 Hz, 1H), 4.68 - 4.55 (m, 1H), 4.50 - 4.42 (m, 1H), 4.33 - 4.26 (m, 1H), 4.19 - 4.11 (m, 1H), 3.96 - 3.88 (m, 1H), 3.83 (br t, J = 7.1 Hz, 1H), 3.72 (br t, J = 7.3 Hz, 1H), 3.37 - 3.33 (m, 1H), 3.24 (dd, J = 5.9, 8.5 Hz, 1H), 3.12 - 3.03 (m, 3H), 2.97 - 2.85 (m, 4H), 2.85 - 2.81 (m, 3H), 2.59 - 2.54 (m, 3H), 2.54 - 2.45 (m, 2H). Example 503 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-morpholinoazeti din-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 503 was prepared in analogy to the preparation of Example 483 by using 4- (azetidin-3-yl)morpholine;dihydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 503, LCMS (M+H ⁺ ): 809. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.24 (s, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.86 - 5.65 (m, 1H), 5.42 - 5.26 (m, 1H), 4.64 - 4.59 (m, 1H), 4.46 - 4.38 (m, 1H), 4.27 - 4.12 (m, 3H), 4.08 - 3.94 (m, 2H), 3.93 - 3.79 (m, 2H), 3.76 - 3.65 (m, 4H), 3.26 - 3.15 (m, 1H), 3.12 - 3.01 (m, 3H), 2.98 - 2.87 (m, 1H), 2.85 - 2.80 (m, 3H), 2.76 (br d, J = 13.5 Hz, 1H), 2.60 - 2.54 (m, 3H), 2.53 - 2.37 (m, 6H). Example 504 (8S,11S,15R)-10-[6-[[1-(2,2-difluoroethyl)azetidin-3-yl]meth oxy]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 504 was prepared in analogy to the preparation of Example 493 by using 2,2- difluoroethyl trifluoromethanesulfonate instead of difluoroacetic anhydride in step 2. LCMS (M+H ⁺ ): 818. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.49 - 8.42 (m, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 - 7.58 (m, 1H), 7.32 - 7.23 (m, 2H), 7.21 - 7.18 (m, 1H), 7.15 (dd, J = 2.6, 10.6 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.73 - 6.65 (m, 1H), 6.00 - 5.81 (m, 1H), 5.81 - 5.65 (m, 1H), 5.63 - 5.35 (m, 1H), 4.67 (br d, J = 5.1 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.34 - 4.28 (m, 1H), 4.15 (dd, J = 11.0, 15.3 Hz, 1H), 3.94 (dd, J = 9.1, 14.1 Hz, 1H), 3.89 - 3.71 (m, 4H), 3.67 - 3.62 (m, 1H), 3.54 - 3.49 (m, 1H), 3.13 - 3.07 (m, 3H), 2.94 - 2.86 (m, 3H), 2.85 - 2.82 (m, 3H), 2.56 (s, 3H), 2.54 - 2.45 (m, 2H). Example 505 (8S,11S,15R)-10-[6-[1-(2,2-difluoroethyl)azetidin-3-yl]-1-(2 ,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 505 was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-1-carboxylate (compound 505a) To an 8 mL vial equipped with a stir bar was added photocatalyst Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (16.0 mg, 0.014 mmol), Na ₂ CO ₃ (45.2 mg, 0.43 mmol), NiCl ₂ (dtbbpy) (5.7 mg, 0.014 mmol), tris(trimethylsilyl)silane (35.4 mg, 43.9 μL, 0.142 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (120.8 mg, 74.1 μL, 0.427 mmol), compound 213a (100.0 mg, 0.142 mmol) and ethylene glycol dimethyl ether (4 mL). The vial was sealed and placed. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-450 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hrs. The mixture was filtered, the filtrate was concentrated to give compound 505a (117 mg). LCMS (M+H ⁺ ): 824. Step 2: preparation of (8S,11S,15R)-10-[6-(azetidin-3-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 505b) To the flask containing compound 505a (115 mg, 0.14 mmol) was added dichloromethane (2 mL) and TFA (1 mL). The solution was stirred at r.t. for 1 hr and concentrated. The crude oil was purified via prep-HPLC (ACN/0.05%TFA aq.=0~30%) to give compound 505b (80 mg). LCMS (M+H ⁺ ): 724. Step 3: preparation of (8S,11S,15R)-10-[6-(azetidin-3-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 505) To a tube was added compound 505b (40.0 mg, 0.048 mmol), trifluoromethanesulfonic acid 2,2-difluoroethyl ester (30.7 mg, 19 μL, 0.143 mmol), DIEA (61.7 mg, 84 μL, 0.48 mmol) and tetrahydrofuran (4 mL), the solution was heated to reflux for 2 hrs. The mixture was concentrated and purified via prep-HPLC (basic condition) to give Example 505 (9.8 mg). LCMS (M+H ⁺ ): 788. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.49 - 8.42 (m, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 - 7.58 (m, 1H), 7.32 - 7.23 (m, 2H), 7.21 - 7.18 (m, 1H), 7.15 (dd, J = 2.6, 10.6 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.73 - 6.65 (m, 1H), 6.00 - 5.81 (m, 1H), 5.81 - 5.65 (m, 1H), 5.63 - 5.35 (m, 1H), 4.67 (br d, J = 5.1 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.34 - 4.28 (m, 1H), 4.15 (dd, J = 11.0, 15.3 Hz, 1H), 3.94 (dd, J = 9.1, 14.1 Hz, 1H), 3.89 - 3.71 (m, 4H), 3.67 - 3.62 (m, 1H), 3.54 - 3.49 (m, 1H), 3.13 - 3.07 (m, 3H), 2.94 - 2.86 (m, 3H), 2.85 - 2.82 (m, 3H), 2.56 (s, 3H), 2.54 - 2.45 (m, 2H). Example 506 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]ethyl acetate Example 506 was prepared according to the following scheme: Step 1: preparation of 1-[4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6 - yl]ethyl acetate (compound 506a) To a 8 mL vial equipped with a stir bar was added photocatalyst Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (67.3 mg, 0.060 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo [3,4-d]pyrimidine (Intermediate C2, 400.0 mg, 1.5 mmol), ethyl acetate (10.8 g, 12 mL, 122 mmol), tert-butyl peroxybenzoate (2.33 g, 2.26 mL, 12 mmol), and (1S)-(+)-10-camphorsulfonic acid (174 mg, 0.75 mmol). The vial was sealed and placed. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-450 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hours. The mixture was concentrated and purified via flash column (EA/PE=0~15%), the elution was concentrated to give compound 506a (245 mg). LCMS (M+H ⁺ ): 353. Step 2: preparation of 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]ethyl acetate (Example 506) To a flask was added compound 370b (100.0 mg, 0.18 mmol), DIEA (118.0 mg, 159 μL, 0.91 mmol), compound 506a (64.4 mg, 0.18 mmol) and acetonitrile (2 mL). The brown solution was heated to 60 °C for 1 hr. The mixture was concentrated and purified via prep-HPLC (ACN/TFA 0.05% aq.=0~50%), the elution was freeze dried to give Example 506 (105 mg). LCMS (M+H ⁺ ): 755. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 (d, J = 2.5 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.60 - 7.51 (m, 2H), 7.31 - 7.24 (m, 1H), 7.23 - 7.18 (m, 1H), 7.18 - 7.13 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.22 - 6.01 (m, 1H), 5.69 - 5.57 (m, 1H), 5.57 - 5.45 (m, 1H), 4.72 - 4.67 (m, 1H), 4.55 - 4.48 (m, 1H), 4.37 - 4.23 (m, 2H), 3.99 - 3.88 (m, 1H), 3.16 - 3.08 (m, 3H), 3.07 - 3.00 (m, 1H), 2.99 - 2.95 (m, 3H), 2.88 - 2.78 (m, 4H), 2.63 - 2.49 (m, 2H), 2.10 - 2.02 (m, 3H), 1.62 - 1.48 (m, 3H). Example 507 (8S,11S,15R)-22-fluoro-10-[1-(5-fluoro-3-methylsulfanyl-2-py ridyl)-6-methylsulfanyl- pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,1 0,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 507 was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(3,5-difluoro-2- pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy- 13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 507a) To a flask was added compound 370b;hydrogen chloride (150 mg, 0.27 mmol), DIEA (176.9 mg, 239 μL, 1.37 mmol), 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4- d]pyrimidine (Intermediate C77, 91.0 mg, 0.30 mmol) and acetonitrile (3 mL). The brown solution was heated to 60 °C for 1 hr. The mixture was concentrated to give an oil, and then it was purified via flash column (EA/PE=0~100% & MeOH/EA=10%) to give compound 507a (150 mg). LCMS (M+H ⁺ ): 704. Step 2: preparation of (8S,11S,15R)-22-fluoro-10-[1-(5-fluoro-3-methylsulfanyl-2- pyridyl)-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 507) To a tube was added compound 507a (30 mg, 0.043 mmol), NaSMe (12 mg, 0.17 mmol) and methanol (2 mL). After being heated to 60 °C and stirred at for 16 hrs, the mixture was concentrated and purified via prep-HPLC to give Example 507 (2 mg) and isomer (2.3 mg). LCMS (M+H ⁺ ): 744. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.41 (s, 1H), 8.27 - 8.24 (m, 1H), 7.88 - 7.85 (m, 1H), 7.84 (td, J = 2.8, 5.8 Hz, 1H), 7.49 (dd, J = 2.5, 7.6 Hz, 1H), 7.42 (dd, J = 2.5, 10.4 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.78 - 6.72 (m, 1H), 6.11 - 5.91 (m, 1H), 5.53 - 5.36 (m, 1H), 4.69 (t, J = 4.9 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.35 - 4.24 (m, 2H), 3.97 - 3.88 (m, 1H), 3.14 - 3.06 (m, 3H), 2.98 (dd, J = 1.2, 14.3 Hz, 1H), 2.94 - 2.91 (m, 3H), 2.86 - 2.78 (m, 1H), 2.77 - 2.73 (m, 3H), 2.59 - 2.50 (m, 3H), 2.49 - 2.44 (m, 3H), 2.40 (s, 2H). Example 508 and Example 509 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R)-1-hydroxyeth yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S)-1-hydroxyeth yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 508 and Example 509 were prepared according to the following scheme: Step 1: preparation of the two isomers (isomer A and isomer B) Example 506 (105 mg) was separated via SFC (condition: Instrument: SFC 150 Mgm; Column: C-4, 250×30 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for methanol (0.1% NH ₃ H ₂ O); Gradient: B 50%; Flow rate: 80 mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) to give isomer A (30 mg, faster eluted) and isomer B (36 mg, slower eluted). Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R)-1- hydroxyethyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-met hoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S)-1-hydroxyethyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluor o-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 508 and Example 509) To a flask was added isomer A (30 mg) or isomer B (36 mg), 2 M LiOH (~ 2 N aq.) (2 mL, 4 mmol) and tetrahydrofuran (2 mL). The suspension was stirred at r.t. for 1 hr. The mixture was neutralized with 1N HCl aq., and the residue was concentrated to remove the THF and then it was purified via prep-HPLC to give Example 508 (11.7 mg) or Example 509 (17.2 mg). Example 508, LCMS (M+H ⁺ ): 713. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.45 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.70 - 7.60 (m, 1H), 7.32 - 7.23 (m, 2H), 7.21 - 7.13 (m, 2H), 7.11 - 7.06 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.82 - 5.64 (m, 1H), 5.63 - 5.36 (m, 1H), 4.77 - 4.59 (m, 2H), 4.51 - 4.43 (m, 1H), 4.32 - 4.25 (m, 1H), 4.18 - 4.07 (m, 1H), 3.97 - 3.86 (m, 1H), 3.13 - 3.03 (m, 3H), 2.98 - 2.84 (m, 2H), 2.84 - 2.79 (m, 3H), 2.58 - 2.53 (m, 3H), 2.53 - 2.43 (m, 2H), 1.53 - 1.39 (m, 3H). Example 509, LCMS (M+H ⁺ ): 713. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.72 - 7.61 (m, 1H), 7.32 - 7.23 (m, 2H), 7.21 - 7.13 (m, 2H), 7.11 - 7.07 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.83 - 5.82 (m, 1H), 5.83 - 5.64 (m, 1H), 5.59 - 5.35 (m, 1H), 4.78 - 4.62 (m, 2H), 4.53 - 4.46 (m, 1H), 4.34 - 4.27 (m, 1H), 4.18 - 4.08 (m, 1H), 3.98 - 3.85 (m, 1H), 3.13 - 3.03 (m, 3H), 2.98 - 2.85 (m, 2H), 2.85 - 2.80 (m, 3H), 2.58 - 2.53 (m, 3H), 2.50 (ddd, J = 4.2, 9.3, 13.4 Hz, 2H), 1.54 - 1.40 (m, 3H). Example 510 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-6-azaspiro[ 3.3]heptan-6- ylmethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 510 was prepared according to the following scheme: Step 1: preparation of [1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy - 2,6 8,11 20,24 13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]methyl methanesulfonate (compound 510a) To a flask was added Example 481 (147 mg, 0.21 mmol), DIEA (54 mg, 73 μL, 0.42 mmol ), dichloromethane (3 mL) and methanesulfonic anhydride (58 mg, 0.34 mmol). The solution was stirred at r.t. for 2 hrs. The mixture was diluted with 20 mL DCM and washed with 20 mL sat. NaCl aq. twice. The organic layer was dried over Na ₂ SO ₄ and concentrated, compound 510a (190 mg) was obtained as yellow solid. LCMS (M+H ⁺ ): 777. Step 2: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-6-azaspiro[ 3.3]heptan-6- ylmethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 510) To tube was added compound 510a (46.6 mg, 0.060 mmol), 2-oxa-6-azaspiro[3.3] heptane (8.9 mg, 0.090 mmol), DIEA (15.5 mg, 21 μL, 0.120 mmol) and acetonitrile (2.5 mL). The solution was heated to 85 °C and stirred for 2 hrs. The mixture was concentrated and purified via prep-HPLC to give Example 510. LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.86 - 7.79 (m, 1H), 7.69 - 7.59 (m, 1H), 7.32 - 7.24 (m, 2H), 7.22 - 7.13 (m, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.71 - 6.66 (m, 1H), 5.82 - 5.66 (m, 1H), 5.63 - 5.35 (m, 1H), 4.75 - 4.69 (m, 4H), 4.69 - 4.63 (m, 1H), 4.52 - 4.46 (m, 1H), 4.34 - 4.26 (m, 1H), 4.20 - 4.08 (m, 1H), 3.96 (dd, J = 9.4, 14.0 Hz, 1H), 3.74 - 3.65 (m, 2H), 3.62 - 3.49 (m, 4H), 3.13 - 3.06 (m, 3H), 2.95 - 2.88 (m, 2H), 2.86 - 2.81 (m, 3H), 2.59 - 2.54 (m, 3H), 2.54 - 2.45 (m, 2H). Example 511 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(morpholinometh yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 511 was prepared in analogy to the preparation of Example 483 by using 4- (azetidin-3-ylmethyl)morpholine;dihydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide. Example 503, LCMS (M+H ⁺ ): 823. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.20 (s, 1H), 7.82 - 7.75 (m, 1H), 7.62 - 7.54 (m, 1H), 7.33 - 7.26 (m, 1H), 7.25 - 7.17 (m, 1H), 7.14 (dd, J = 2.5, 10.5 Hz, 1H), 7.06 (d, J = 7.4 Hz, 2H), 6.66 - 6.59 (m, 1H), 5.84 - 5.65 (m, 1H), 5.36 - 5.22 (m, 1H), 4.55 - 4.37 (m, 1H), 4.34 - 4.27 (m, 1H), 4.23 - 4.13 (m, 2H), 4.13 - 4.05 (m, 1H), 4.05 - 3.98 (m, 1H), 3.92 (dd, J = 9.1, 14.1 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.67 (br t, J = 4.5 Hz, 4H), 3.62 (dt, J = 5.8, 8.3 Hz, 1H), 3.09 - 2.98 (m, 3H), 2.98 - 2.83 (m, 2H), 2.83 - 2.81 (m, 3H), 2.72 (br d, J = 13.5 Hz, 1H), 2.64 - 2.57 (m, 2H), 2.57 - 2.51 (m, 3H), 2.51 - 2.35 (m, 6H). Example 512 2-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]acetonitrile Example 512 was prepared in analogy to the preparation of Example 510 by using trimethylsilylformonitrile instead of 2-oxa-6-azaspiro[3.3] heptane and K ₂ CO ₃ instead of DIPEA in step 2. Example 512, LCMS (M+H+): 708. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 - 8.47 (m, 1H), 7.84 - 7.78 (m, 1H), 7.69 - 7.59 (m, 1H), 7.32 - 7.23 (m, 2H), 7.22 - 7.17 (m, 1H), 7.15 (dd, J = 2.6, 10.5 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.71 - 6.63 (m, 1H), 5.86 - 5.63 (m, 1H), 5.54 - 5.36 (m, 1H), 4.71 - 4.64 (m, 1H), 4.60 - 4.53 (m, 1H), 4.50 (br dd, J = 6.1, 11.6 Hz, 1H), 4.30 (br d, J = 11.0 Hz, 1H), 4.14 (dd, J = 11.0, 15.5 Hz, 1H), 3.99 - 3.86 (m, 1H), 3.13 - 3.02 (m, 3H), 2.98 - 2.87 (m, 1H), 2.84 (s, 3H), 2.83 - 2.79 (m, 1H), 2.68 - 2.59 (m, 1H), 2.58 - 2.54 (m, 3H), 2.54 - 2.45 (m, 2H). Example 513 (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-1-( 2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 513 was prepared according to the following scheme: Compound 513a was prepared in analogy to the preparation of Example 510 by using tert- butyl 4,7-diazaspiro[2.5]octane-4-carboxylate instead of 2-oxa-6-azaspiro[3.3] heptane. LCMS (M+H ⁺ ): 893. Step 2: preparation of (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro -15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 513) To a tube was added compound 513a (71.4 mg, 0.080 mmol), TFA (1 mL) and dichloromethane (2 mL). The solution was stirred at r.t. for 1 hr, then concentrated and purified via prep-HPLC to give Example 513 (13.5 mg). LCMS (M+H ⁺ ): 793. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.46 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.69 - 7.57 (m, 1H), 7.32 - 7.22 (m, 2H), 7.21 - 7.13 (m, 2H), 7.12 - 7.06 (m, 1H), 6.70 - 6.63 (m, 1H), 5.79 - 5.65 (m, 1H), 5.63 - 5.33 (m, 1H), 4.67 - 4.54 (m, 1H), 4.50 - 4.42 (m, 1H), 4.32 - 4.25 (m, 1H), 4.18 - 4.07 (m, 1H), 3.92 (br dd, J = 9.4, 14.0 Hz, 1H), 3.74 - 3.58 (m, 2H), 3.13 - 3.01 (m, 3H), 2.98 - 2.84 (m, 4H), 2.82 (s, 3H), 2.76 - 2.68 (m, 1H), 2.66 - 2.57 (m, 2H), 2.57 - 2.53 (m, 3H), 2.53 - 2.43 (m, 3H), 0.63 - 0.55 (m, 2H), 0.53 - 0.44 (m, 2H). Example 514 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[4-(oxetan-3-yl)pi perazin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 514 was prepared in analogy to the preparation of Example 483 by using 1- (oxetan-3-yl)piperazine instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 514, LCMS (M+H ⁺ ): 809. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.21 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 - 7.56 (m, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.88 - 5.65 (m, 1H), 5.41 - 5.25 (m, 1H), 4.72 - 4.66 (m, 2H), 4.62 (q, J = 5.8 Hz, 3H), 4.43 (br dd, J = 5.9, 11.0 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.91 - 3.82 (m, 2H), 3.81 - 3.68 (m, 3H), 3.53 - 3.44 (m, 1H), 3.12 - 3.02 (m, 3H), 2.98 - 2.87 (m, 1H), 2.86 - 2.82 (m, 3H), 2.76 (br d, J = 13.5 Hz, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.41 (m, 2H), 2.40 - 2.28 (m, 4H). Example 515 (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-yl)-1-(2,4-di fluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The Example 515 was prepared in analogy to the preparation of Example 487 by using tert- butyl 4,7-diazaspiro[2.5]octane-4-carboxylate instead of tert-butyl N-[(3R,4R)-4- fluoropyrrolidin-3-yl]carbamate;hydrochloride. Example 515, LCMS (M+H ⁺ ): 779. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.20 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.89 - 5.66 (m, 1H), 5.36 - 5.25 (m, 1H), 4.66 - 4.54 (m, 1H), 4.43 (dd, J = 6.1, 11.1 Hz, 1H), 4.24 - 4.08 (m, 2H), 3.98 - 3.83 (m, 2H), 3.76 - 3.57 (m, 2H), 3.57 - 3.51 (m, 1H), 3.11 - 2.99 (m, 3H), 2.94 - 2.86 (m, 2H), 2.86 - 2.80 (m, 4H), 2.77 - 2.69 (m, 1H), 2.59 - 2.53 (m, 3H), 2.53 - 2.42 (m, 2H), 0.66 - 0.48 (m, 4H). Example 516 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[4-(2H-tetrazol-5- yl)-1-piperidyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 516 was prepared in analogy to the preparation of Example 483 by using 4-(2H- tetrazol-5-yl)piperidine;hydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 516, LCMS (M+H ⁺ ): 820. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.24 (s, 1H), 7.90 - 7.82 (m, 1H), 7.67 - 7.61 (m, 1H), 7.60 - 7.57 (m, 1H), 7.55 - 7.51 (m, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.28 - 6.05 (m, 1H), 5.44 - 5.30 (m, 1H), 4.70 - 4.62 (m, 2H), 4.48 (br dd, J = 5.9, 11.2 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.99 - 3.80 (m, 1H), 3.39 - 3.33 (m, 1H), 3.17 - 3.10 (m, 2H), 3.08 (s, 3H), 3.06 - 2.98 (m, 2H), 2.97 (s, 3H), 2.84 - 2.80 (m, 3H), 2.73 (br d, J = 13.5 Hz, 1H), 2.62 - 2.48 (m, 2H), 2.13 - 1.95 (m, 2H), 1.85 - 1.66 (m, 2H). Example 517 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methyl-4,7-diaz aspiro[2.5]octan-7- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 517 was prepared according to the following scheme: Step 1~2: preparation of (8S,11S,15R)-10-[6-(4,7-diazaspiro[2.5]octan-7-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 515) To a tube was added: DIEA (14.7 mg, 20 μL, 0.114 mmol), tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (18.1 mg, 0.085 mmol), compound 213a (40.0 mg, 0.057 mmol) and acetonitrile (2.5 mL). The mixture was heated to 85 °C and stirred for 2 hrs. The mixture was concentrated to give an oil (compound 517a), and then it was dissolved in TFA (0.5 mL) and dichloromethane (1 mL). The solution was stirred at r.t. for 1 hr and concentrated to give an oil. The oil was purified via prep-HPLC to give Example 515 (17.5 mg). LCMS (M+H ⁺ ): 779. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 517) To a tube was added Example 515 (6 mg, 0.007 mmol), formaldehyde (22 mg, 20 μL, 0.73 mmol) and methanol (2 mL). The solution was stirred at r.t. for 30 mins and then sodium triacetoxyborohydride (15.5 mg, 0.074 mmol) was added. The mixture was stirred for another 1 hr and then concentrated to give a residue which was purified via prep-HPLC to give Example 517 (5 mg) as white powder. LCMS (M+H ⁺ ): 793. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.29 (s, 1H), 7.88 - 7.82 (m, 1H), 7.65 - 7.55 (m, 1H), 7.48 - 7.43 (m, 1H), 7.38 - 7.32 (m, 1H), 7.26 - 7.23 (m, 1H), 7.27 - 7.21 (m, 1H), 7.18 - 7.11 (m, 2H), 6.73 (d, J = 8.5 Hz, 1H), 6.05 - 5.87 (m, 1H), 5.42 - 5.29 (m, 1H), 4.68 - 4.63 (m, 1H), 4.50 - 4.43 (m, 1H), 4.28 - 4.14 (m, 3H), 4.11 - 3.98 (m, 2H), 3.97 - 3.93 (m, 1H), 3.92 - 3.83 (m, 1H), 3.54 - 3.37 (m, 2H), 3.14 - 3.01 (m, 6H), 3.00 - 2.93 (m, 1H), 2.93 - 2.89 (m, 3H), 2.72 - 2.67 (m, 3H), 2.58 - 2.46 (m, 2H), 1.24 - 0.97 (m, 4H). Example 518 (8S,11S,15R)-10-[1-(3,5-difluoro-2-pyridyl)-6-(3-morpholinoa zetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7,10,13 ,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 518 was prepared according to the following scheme: The compound 518a was prepared in analogy to the preparation of Example 12 by using intermediate A7 instead of intermediate A11 in step 1 and using intermediate C77 instead of intermediate C2 in step 5. Step 1: preparation of (8S,11S,15R)-10-[1-(3,5-difluoro-2-pyridyl)-6-(3- morpholinoazetidin-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-et hoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 518) To a tube was added DIEA (32.3 mg, 44 μL, 0.25 mmol), 4-(azetidin-3- yl)morpholine;dihydrochloride (10.8 mg, 0.050 mmol), compound 518a (30.0 mg, 0.042 mmol) and acetonitrile (1.5 mL). The mixture was heated to 90 °C and stirred for 4 hrs, then concentrated to give a residue which was purified via prep-HPLC to give example 518 (15.9 mg) as white powder. LCMS (M+H ⁺ ): 824. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.45 - 8.43 (m, 1H), 8.31 (s, 1H), 7.94 - 7.88 (m, 1H), 7.84 - 7.79 (m, 1H), 7.36 (dd, J = 2.3, 8.1 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.11 - 7.08 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.94 - 5.74 (m, 1H), 5.41 - 5.28 (m, 1H), 4.63 (t, J = 5.0 Hz, 1H), 4.47 - 4.41 (m, 1H), 4.26 - 4.15 (m, 3H), 4.12 - 4.01 (m, 2H), 3.97 - 3.87 (m, 2H), 3.78 - 3.73 (m, 4H), 3.48 - 3.36 (m, 1H), 3.11 - 3.01 (m, 3H), 2.94 - 2.85 (m, 1H), 2.78 (d, J = 13.6 Hz, 1H), 2.70 - 2.53 (m, 10H), 2.47 (ddd, J = 4.3, 9.1, 13.5 Hz, 1H), 1.39 - 1.37 (m, 3H). Example 519 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-3,6-diaz abicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 519 was prepared in analogy to the preparation of Example 483 by using 3- methyl-3,6-diazabicyclo[3.1.1]heptane;2,2,2-trifluoroacetic acid instead of 2λ ⁶ -thia-6- azaspiro[3.3]heptane 2,2-dioxide. Example 519, LCMS (M+H ⁺ ): 779. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.35 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.33 - 7.28 (m, 1H), 7.28 - 7.21 (m, 1H), 7.16 (td, J = 2.7, 10.4 Hz, 2H), 7.12 - 7.08 (m, 1H), 6.73 - 6.66 (m, 1H), 5.84 - 5.70 (m, 1H), 5.42 - 5.34 (m, 1H), 4.69 - 4.64 (m, 1H), 4.53 - 4.43 (m, 2H), 4.37 - 4.32 (m, 1H), 4.27 - 4.18 (m, 1H), 4.13 (br dd, J = 11.0, 15.6 Hz, 1H), 3.98 - 3.84 (m, 1H), 3.82 - 3.68 (m, 1H), 3.66 - 3.46 (m, 3H), 3.14 - 3.01 (m, 3H), 3.01 - 2.90 (m, 1H), 2.88 - 2.84 (m, 3H), 2.84 - 2.70 (m, 4H), 2.60 - 2.54 (m, 3H), 2.54 - 2.46 (m, 2H), 1.40 - 1.34 (m, 2H). Example 520 (8S,11S,15R)-10-[6-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a] pyrazin-2-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 520 was prepared in analogy to the preparation of Example 483 by using 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide. Example 520, LCMS (M+H ⁺ ): 793. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.30 (s, 1H), 7.88 (dt, J = 3.0, 8.0 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.57 - 7.52 (m, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.13 (m, 2H), 6.79 (d, J = 8.5 Hz, 1H), 6.27 - 6.05 (m, 1H), 5.49 - 5.34 (m, 1H), 4.68 (br t, J = 4.9 Hz, 1H), 4.53 - 4.45 (m, 1H), 4.35 - 4.17 (m, 3H), 4.14 - 3.78 (m, 3H), 3.77 - 3.52 (m, 2H), 3.51 - 3.37 (m, 1H), 3.18 - 3.08 (m, 4H), 3.07 - 3.00 (m, 2H), 3.00 - 2.94 (m, 4H), 2.83 (d, J = 7.5 Hz, 3H), 2.81 - 2.76 (m, 1H), 2.69 - 2.47 (m, 2H), 2.35 - 2.04 (m, 3H), 2.00 - 1.70 (m, 1H). Example 521 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[[(2R,8S)-2-fluoro -1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 521 was prepared in analogy to the preparation of Example 490 by using [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]metha nol instead of tetrahydrofuran-3- ylmethanol. Example 521, LCMS (M+H ⁺ ): 826. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.46 (s, 1H), 7.92 - 7.85 (m, 1H), 7.69 - 7.60 (m, 1H), 7.60 - 7.57 (m, 1H), 7.54 (ddd, J = 2.6, 5.1, 10.3 Hz, 1H), 7.30 (dddd, J = 2.8, 4.8, 8.6, 10.3 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.18 (dd, J = 3.4, 7.4 Hz, 1H), 6.79 (dd, J = 3.3, 8.4 Hz, 1H), 6.23 - 6.03 (m, 1H), 5.63 - 5.40 (m, 2H), 4.73 - 4.63 (m, 1H), 4.59 - 4.49 (m, 2H), 4.37 (d, J = 12.3 Hz, 1H), 4.33 - 4.22 (m, 2H), 4.04 - 3.77 (m, 4H), 3.47 - 3.38 (m, 1H), 3.17 - 3.07 (m, 3H), 3.06 - 3.00 (m, 1H), 2.97 (s, 3H), 2.91 - 2.84 (m, 1H), 2.81 (d, J = 6.8 Hz, 3H), 2.73 - 2.49 (m, 4H), 2.40 - 2.26 (m, 3H), 2.20 - 2.02 (m, 1H). Example 522 (8S,11S,15R)-10-[6-[(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahyd ropyrrolo[3,4-c]pyrrol-5-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluo ro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 522 was prepared in analogy to the preparation of Example 483 by using (3aR,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c] pyrrole instead of 2λ ⁶ -thia-6- azaspiro[3.3]heptane 2,2-dioxide. Example 522, LCMS (M+H ⁺ ): 793. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.46 (s, 1H), 7.92 - 7.85 (m, 1H), 7.69 - 7.60 (m, 1H), 7.60 - 7.57 (m, 1H), 7.54 (ddd, J = 2.6, 5.1, 10.3 Hz, 1H), 7.30 (dddd, J = 2.8, 4.8, 8.6, 10.3 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.18 (dd, J = 3.4, 7.4 Hz, 1H), 6.79 (dd, J = 3.3, 8.4 Hz, 1H), 6.23 - 6.03 (m, 1H), 5.63 - 5.40 (m, 2H), 4.73 - 4.63 (m, 1H), 4.59 - 4.49 (m, 2H), 4.37 (d, J = 12.3 Hz, 1H), 4.33 - 4.22 (m, 2H), 4.04 - 3.77 (m, 4H), 3.47 - 3.38 (m, 1H), 3.17 - 3.07 (m, 3H), 3.06 - 3.00 (m, 1H), 2.97 (s, 3H), 2.91 - 2.84 (m, 1H), 2.81 (d, J = 6.8 Hz, 3H), 2.73 - 2.49 (m, 4H), 2.40 - 2.26 (m, 3H), 2.20 - 2.02 (m, 1H). Example 523 (8S,11S,15R)-10-[6-cyclopentyl-1-(3,5-difluoro-2-pyridyl)pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 523 was prepared in analogy to the preparation of compound 505a by using compound 507a and iodocyclopentane instead of compound 213a and tert-butyl 3-iodoazetidine- 1-carboxylate. Example 523, LCMS (M+H ⁺ ): 738. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 - 8.45 (m, 2H), 7.99 - 7.91 (m, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.15 (dd, J = 2.6, 10.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.87 - 5.65 (m, 1H), 5.52 - 5.36 (m, 1H), 4.72 - 4.66 (m, 1H), 4.54 - 4.47 (m, 1H), 4.33 - 4.25 (m, 1H), 4.19 - 4.10 (m, 1H), 3.86 (dd, J = 9.2, 14.1 Hz, 1H), 3.65 - 3.63 (m, 1H), 3.13 (s, 1H), 3.12 - 3.04 (m, 3H), 2.96 - 2.87 (m, 1H), 2.86 - 2.82 (m, 3H), 2.59 - 2.55 (m, 3H), 2.51 (br dd, J = 4.3, 8.9 Hz, 2H), 2.05 - 1.62 (m, 8H). Example 524 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- ylmethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy -13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 524 was prepared in analogy to the preparation of Example 510 by using 3-oxa-6- azabicyclo[3.1.1]heptane;hydrochloride instead of 2-oxa-6-azaspiro[3.3] heptane in step 2. LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 - 8.45 (m, 2H), 7.99 - 7.91 (m, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.15 (dd, J = 2.6, 10.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.87 - 5.65 (m, 1H), 5.52 - 5.36 (m, 1H), 4.72 - 4.66 (m, 1H), 4.54 - 4.47 (m, 1H), 4.33 - 4.25 (m, 1H), 4.19 - 4.10 (m, 1H), 3.86 (dd, J = 9.2, 14.1 Hz, 1H), 3.65 - 3.63 (m, 1H), 3.13 (s, 1H), 3.12 - 3.04 (m, 3H), 2.96 - 2.87 (m, 1H), 2.86 - 2.82 (m, 3H), 2.59 - 2.55 (m, 3H), 2.51 (br dd, J = 4.3, 8.9 Hz, 2H), 2.05 - 1.62 (m, 8H). Example 525 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(4aR,7aR)-4-methy l-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]pyrazolo[3,4-d]pyrim idin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 525 was prepared in analogy to the preparation of Example 517 by using tert- butyl (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxaz ine-4-carboxylate instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. Example 525, LCMS (M+H ⁺ ): 809. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.25 - 8.21 (m, 1H), 7.84 - 7.77 (m, 1H), 7.66 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.87 - 5.66 (m, 1H), 5.42 - 5.26 (m, 1H), 4.65 - 4.53 (m, 2H), 4.46 - 4.36 (m, 1H), 4.28 - 4.10 (m, 3H), 4.02 - 3.74 (m, 5H), 3.71 - 3.57 (m, 1H), 3.15 - 3.11 (m, 1H), 3.10 - 3.00 (m, 3H), 2.96 - 2.86 (m, 1H), 2.86 - 2.83 (m, 3H), 2.82 - 2.71 (m, 1H), 2.59 - 2.54 (m, 3H), 2.52 - 2.42 (m, 2H), 2.32 (br d, J = 5.6 Hz, 2H), 2.30 - 2.22 (m, 3H). Example 526 1-benzyl-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro -15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]piperazine-2- carboxylic acid Example 526 was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O3-methyl 4-benzylpiperazine-1,3-dicarboxylate (compound 526a) To a flask was added O1-tert-butyl O3-methyl piperazine-1,3-dicarboxylate (500.0 mg, 2.05 mmol), benzaldehyde (260.6 mg, 2.46 mmol) and methanol (10 mL). The suspension was stirred at 60 °C for 30 mins and then sodium triacetoxyborohydride (1.08 g, 5.12 mmol) was added. The mixture was concentrated and the residue was purified via flash column (EA/PE=0~50%) to give compound 526a (137 mg). LCMS (M+H ⁺ ): 335. Step 2: preparation of methyl 1-benzylpiperazine-2-carboxylate (compound 526b) To the flask containing the compound 526a (137 mg, 0.41 mmol) was added dichloromethane (2 mL) and TFA (1 mL). After being stirred at r.t for 1 hr, the mixture was concentrated to give compound 526b as an oil. LCMS (M+H ⁺ ): 235. Step 3: preparation of 1-benzyl-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro - 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]piperazine-2-carboxylic acid (Example 526) To a tube was added methyl 1-benzylpiperazine-2-carboxylate (compound 526b, 43.73 mg, 0.075 mmol), compound 213a (35 mg, 0.050 mmol), DIEA (64 mg, 87 μL, 0.498 mmol), and acetonitrile (3.5 mL). After being stirred at 90 °C for 6 hrs, the mixture was concentrated to give an oil, which was dissolved in methanol (500 μL) and tetrahydrofuran (500 μL). Then LiOH (2 M, aq.) (1.0 mL, 2 mmol) was added. The mixture was stirred for 2 hrs and neutralized with 2 N HCL aq. The mixture was concentrated and the residue was purified via prep-HPLC to give Example 526, LCMS (M+H ⁺ ): 887. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (d, J = 2.5 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.62 (dt, J = 6.0, 8.5 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.46 (br dd, J = 2.8, 3.6 Hz, 3H), 7.32 (dd, J = 2.5, 8.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.15 - 7.06 (m, 2H), 6.69 (dd, J = 3.8, 8.3 Hz, 1H), 5.88 (td, J = 4.7, 15.5 Hz, 1H), 5.49 - 5.41 (m, 1H), 4.70 - 4.53 (m, 3H), 4.46 (dd, J = 5.9, 11.2 Hz, 1H), 4.26 - 4.12 (m, 2H), 4.04 (br d, J = 12.5 Hz, 1H), 3.87 (ddd, J = 9.2, 14.4, 17.9 Hz, 1H), 3.64 - 3.50 (m, 1H), 3.28 - 3.15 (m, 2H), 3.12 - 3.07 (m, 3H), 3.06 - 3.03 (m, 1H), 3.03 - 2.91 (m, 2H), 2.91 - 2.83 (m, 3H), 2.78 (br dd, J = 3.7, 13.4 Hz, 1H), 2.66 - 2.59 (m, 3H), 2.59 - 2.55 (m, 1H), 2.55 - 2.44 (m, 2H). Example 527 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(9-methyl-3-oxa-7, 9-diazabicyclo[3.3.1]nonan-7- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 527 was prepared in analogy to the preparation of Example 517 by using tert- butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate instead of tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate. Example 527, LCMS (M+H ⁺ ): 809. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (d, J = 2.5 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.62 (dt, J = 6.0, 8.5 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.46 (br dd, J = 2.8, 3.6 Hz, 3H), 7.32 (dd, J = 2.5, 8.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.15 - 7.06 (m, 2H), 6.69 (dd, J = 3.8, 8.3 Hz, 1H), 5.88 (td, J = 4.7, 15.5 Hz, 1H), 5.49 - 5.41 (m, 1H), 4.70 - 4.53 (m, 3H), 4.46 (dd, J = 5.9, 11.2 Hz, 1H), 4.26 - 4.12 (m, 2H), 4.04 (br d, J = 12.5 Hz, 1H), 3.87 (ddd, J = 9.2, 14.4, 17.9 Hz, 1H), 3.64 - 3.50 (m, 1H), 3.28 - 3.15 (m, 2H), 3.12 - 3.07 (m, 3H), 3.06 - 3.03 (m, 1H), 3.03 - 2.91 (m, 2H), 2.91 - 2.83 (m, 3H), 2.78 (br dd, J = 3.7, 13.4 Hz, 1H), 2.66 - 2.59 (m, 3H), 2.59 - 2.55 (m, 1H), 2.55 - 2.44 (m, 2H). Example 528 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-oxazol-5-yl-1-p iperidyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 528 was prepared in analogy to the preparation of Example 483 by using 5-(4- piperidyl)oxazole instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 528, LCMS (M+H ⁺ ): 819. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.21 (s, 1H), 8.07 (s, 1H), 7.80 (br t, J = 7.9 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.32 (dd, J = 2.3, 8.3 Hz, 1H), 7.25 - 7.04 (m, 4H), 6.85 (s, 1H), 6.67 (br d, J = 8.5 Hz, 1H), 5.91 - 5.69 (m, 1H), 5.42 - 5.25 (m, 1H), 4.68 - 4.57 (m, 2H), 4.43 (br dd, J = 5.9, 11.1 Hz, 1H), 4.32 - 4.06 (m, 3H), 3.97 - 3.81 (m, 1H), 3.15 - 2.89 (m, 7H), 2.88 - 2.81 (m, 3H), 2.75 (br d, J = 13.3 Hz, 1H), 2.66 - 2.56 (m, 3H), 2.55 - 2.43 (m, 2H), 2.07 - 1.89 (m, 2H), 1.70 - 1.50 (m, 2H). Example 529 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl- 2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 529 was prepared in analogy to the preparation of Example 483 by using (3R)-3- ethyl-1-methyl-piperazine;dihydrochloride instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide. Example 529, LCMS (M+H ⁺ ): 779. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.85 - 7.78 (m, 1H), 7.67 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.87 - 5.67 (m, 1H), 5.45 - 5.28 (m, 1H), 4.78 - 4.74 (m, 1H), 4.69 - 4.62 (m, 1H), 4.50 - 4.42 (m, 1H), 4.27 - 4.09 (m, 3H), 4.00 - 3.71 (m, 3H), 3.46 - 3.38 (m, 1H), 3.13 - 3.04 (m, 4H), 3.02 - 2.88 (m, 2H), 2.86 - 2.82 (m, 3H), 2.71 - 2.62 (m, 3H), 2.59 - 2.55 (m, 3H), 2.54 - 2.44 (m, 2H), 2.18 - 1.98 (m, 2H). Example 530 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-methylsulfonyl-pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound 530a) A mixture of ethyl (E)-2-cyano-3-ethoxy-prop-2-enoate (4.68 g, 27.7 mmol), (2,4- difluorophenyl)hydrazine;hydrochloride (5 g, 27.7 mmol) and TEA (5.6 g, 55.4 mmol) in ethanol (50 mL) was heated to 90 °C for 4 hrs. The solvent was removed under reduce pressure and then the residue was purified by silica gel chromatography to afford compound 530a (6.0 g) as a yellow powder. LCMS (M+H) ⁺ : 268. Step 2: preparation of ethyl 5-(benzoylcarbamothioylamino)-1-(2,4- difluorophenyl)pyrazole-4-carboxylate (compound 530b) To a solution of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound 530a, 2.3 g, 8.61 mmol) in acetonitrile (115 mL) was added isothiocyanato(phenyl)methanone (1.4 g, 8.61 mmol), the resulting mixture was stirred at room temperature for 16 hrs. The mixture was poured into water and neutralized with solid NaHCO ₃ , then extracted with DCM for three times. The combined organic layer was dried over anhydrous magnesium sulfate, evaporated in vacuo to give some residue. The residue was purified by silica gel chromatography to give compound 530b (3.1 g). LCMS (M+H) ⁺ : 431. Step 3: preparation of 1-(2,4-difluorophenyl)-6-thioxo-7H-pyrazolo[3,4-d]pyrimidin- 4-one (compound 530c) To a solution of ethyl 5-(benzoylcarbamothioylamino)-1-(2,4-difluorophenyl)pyrazole -4- carboxylate (compound 530b, 3.1 g, 6.97 mmol) in ethanol (40 mL) was added sodium tert- butoxide (1.4 g, 13.94 mmol) at room temperature, the resulting mixture was stirred at 60 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was poured into water and neutralized with 1 M aq. HCl, then extracted with DCM for three times. The combined organic layer was dried over anhydrous magnesium sulfate, evaporated in vacuo to give some residue. The residue was purified by silica gel chromatography to give compound 530c (2.1 g) as a yellow solid. LCMS (M+H) ⁺ : 281. Step 4: preparation of 1-(2,4-difluorophenyl)-6-methylsulfanyl-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound 530d) To a mixture of 1-(2,4-difluorophenyl)-6-thioxo-7H-pyrazolo[3,4-d]pyrimidin- 4-one (compound 530c, 2.0 g, 7.14 mmol) and NaOH (0.57 g, 14.27 mmol) in water (5 mL) and acetonitrile (50 mL) was added iodomethane (1.01 g, 7.14 mmol) at room temperature, the resulting mixture was stirred at room temperature for 2 hrs, then diluted with water and extracted with EtOAc twice. The combined organic layer was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give crude compound 530d (2.0 g) as a yellow solid. LCMS (M+H) ⁺ : 295. Step 5: preparation of 4-chloro-1-(2,4-difluorophenyl)-6-methylsulfanyl-pyrazolo[3, 4- d]pyrimidine (compound 530e) A mixture of 1-(2,4-difluorophenyl)-6-methylsulfanyl-5H-pyrazolo[3,4-d]py rimidin-4-one (compound 530d, 0.40 g, 1.36 mmol) in phosphoryl chloride (2.08 g, 13.59 mmol) was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and then diluted with aq. NaOH, extracted with EtOAc twice. The combined organic layer was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give some crude. The crude was purified by flash chromatography on silica gel to give compound 530e (0.35 g) as a white solid. LCMS (M+H) ⁺ : 313. Step 6: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-methylsulfanyl- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7-oxa 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 530f) A mixture of (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10, 13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 78d-2, 110.0 mg, 0.17 mmol), DIEA (67.1 mg, 0.52 mmol) and 4-chloro-1-(2,4- difluorophenyl)-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidine (compound 530e, 54.1 mg, 0.17 mmol) in anhydrous DMF (3 mL) was stirred at 80 °C for 30 minutes. After being cooled to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted with DCM/MeOH, the combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some crude. The crude was purified by prep-HPLC to give compound 530f (53 mg) as a white solid. LCMS (M+H) ⁺ : 717. Step 7: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-methylsulfonyl- pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-di methyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 530) To a solution of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-methylsulfanyl-pyr azolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa 5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 530f, 53 mg, 0.07 mmol) in DCM (3 mL) was added mCPBA (25.52 mg, 0.15 mmol) at room temperature, the resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc twice. The combined organic layer was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give some crude. The crude was purified by prep-HPLC to give Example 530 (4 mg) as a white solid. LCMS (M+H) ⁺ : 749. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.84 - 7.99 (m, 2H), 7.87 - 7.73 (m, 1H), 7.72 - 7.61 (m, 1H), 7.57 (m, 1H), 7.50 (m, 1H), 7.42 - 7.29 (m, 2H), 5.83 - 5.26 (m, 3H), 4.60 - 4.43 (m, 1H), 4.39 - 4.21 (m, 1H), 4.08 - 3.85 (m, 2H), 3.40 - 3.19 (m, 5H), 3.17 - 3.06 (m, 1H), 3.05 - 2.93 (m, 3H), 2.72 - 2.66 (m, 3H), 2.55 - 2.51 (m, 3H), 2.05 - 1.94 (m, 1H). Example 531 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(3-prop- 1-ynylimidazo[1,5- a]pyrazin-8-yl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ^2,6 .1 ^8,11 .0 ^20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-(3-bromoimidazo[1,5-a]pyrazin-8-yl)-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 531a) A mixture of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17, 19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 370b, 152.6 mg, 0.32 mmol), 3-bromo-8-chloro-imidazo[1,5-a]pyrazine (75.0 mg, 0.32 mmol) and DIEA (207.2 mg, 1.61 mmol) in NMP (2 mL) was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep- HPLC to give compound 531a (150 mg) as a brown oil. LCMS (M+H) ⁺ : 636. Step 2: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(3- prop-1-ynylimidazo[1,5-a]pyrazin-8-yl)-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (example 531) To a mixture of (8S,11S,15R)-10-(3-bromoimidazo[1,5-a]pyrazin-8-yl)-22-fluor o-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 531a, 50 mg, 0.10 mmol), 1- (trimethylsilyl)-1-propyne (11.5 mg, 0.10 mmol), TEA (23.9 mg, 0.24 mmol) and CuI (50.0 mg, 0.10mmol) in DMF (1 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (27.7 mg, 0.04 mmol) and 1 M TBAF in THF (0.1 mL, 0.10 mmol), the resulting mixture was stirred at 60 °C for 12 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was directly purified by prep-HPLC to give Example 531 (18.4 mg) as a white solid. LCMS (M+H) ⁺ : 594. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.10 - 7.67 (m, 2H), 7.58 - 7.43 (m, 1H), 7.39 - 6.96 (m, 4H), 6.63 (d, J = 8.4 Hz, 1H), 5.88 - 5.65 (m, 1H), 5.44 - 5.24 (m, 1H), 4.60 - 4.23 (m, 3H), 4.21 - 4.04 (m, 1H), 3.98 - 3.75 (m, 1H), 3.02 (s, 3H), 2.90 - 2.70 (m, 5H), 2.67 - 2.35 (m, 5H), 2.27 - 2.12 (m, 3H). Example 532 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methylsulfanyl-pyr azolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

A mixture of (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 31.2 mg, 0.06 mmol), 4-chloro-1-(2,4-difluorophenyl)-6- (methylthio)pyrazolo[3,4-d]pyrimidine (18.9 mg, 0.06 mmol) and potassium phosphate (35.0 mg, 0.16 mmol) in anhydrous acetonitrile (1 mL) was stirred at 80 °C for 1 hr. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to afford Example 532 (7 mg) as a white solid. LCMS (M+H) ⁺ : 731. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.85 (d, J = 5.3 Hz, 1H), 8.57 - 7.81 (m, 1H), 7.80 - 7.68 (m, 2H), 7.65 - 7.48 (m, 3H), 7.36 - 7.28 (m, 1H), 5.77 - 5.45 (m, 3H), 4.51 - 4.32 (m, 1H), 4.23 - 4.01 (m, 2H), 3.92 - 3.79 (m, 1H), 3.22 - 3.13 (m, 2H), 3.01 - 2.86 (m, 4H), 2.83 - 2.63 (m, 3H), 2.60 - 2.52 (m, 4H), 2.38 - 2.29 (m, 2H), 0.49 - 0.36 (m, 3H). Example 533 (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6-[[1-(2- methoxyacetyl)azetidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro -13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluoro-6-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 533a) A mixture of (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 250 mg, 0.44 mmol), 4,6-dichloro-1-(2,4-difluoro-6-methoxy- phenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C79, 160.2 mg, 0.48 mmol ) and DIEA (284.2 mg, 2.2 mmol) in anhydrous acetonitrile (6 mL) was stirred at 50 °C for 1 hr. After being cooled to room temperature, the reaction mixture was concentrated in vacuo to give some residue. The residue was purified by flash chromatography to afford crude compound 533a (302 mg) as a light brown solid. LCMS (M+H) ⁺ : 750. Step 2: preparation of tert-butyl 3-[[1-(2,4-difluoro-6-methoxy-phenyl)-4- [(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-7-ox a-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]azetidine-1-carboxyl ate (compound 533b) To an 8 mL vial was added NiCl ₂ (dtbbpy) (8.0 mg, 0.02 mmol,), [4,4'-bis(1,1- dimethylethyl)-2,2'-bipyridine-n1,n1']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl- n]phenyl-c]iridium(iii) hexafluorophosphate (22.5 mg, 0.02 mmol), tris(trimethylsilyl)silane (49.8 mg, 0.20 mmol), sodium carbonate (63.7 mg, 0.60 mmol), (8S,11S,15R)-10-[6-chloro-1- (2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 533a, 250 mg, 0.20 mmol ) and tert- butyl 3-(iodomethyl)azetidine-1-carboxylate (178.5 mg, 0.60 mmol) successively, followed by addition of anhydrous ethylene glycol dimethyl ether (5 mL). The vial was sealed and placed. The resulting mixture was stirred and irradiated with a 34 W blue LED lamp (450-450 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hrs. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give an oil, which was purified by flash chromatography to afford crude compound 533b (123 mg) as a light yellow solid. LCMS (M+H) ⁺ : 885. Step 3: preparation of (8S,11S,15R)-10-[6-(azetidin-3-ylmethyl)-1-(2,4-difluoro-6- methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one;2,2,2-trifluoroa cetic acid (compound 533c) A mixture of tert-butyl 3-[[1-(2,4-difluoro-6-methoxy-phenyl)-4-[(8S,11S,15R)-15-eth oxy- 22-fluoro-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]azetidine-1-carboxyl ate (compound 533b, 123 mg, 0.10 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 hr. After removing excess TFA and DCM under reduced pressure, the crude compound 533c (178 mg) was obtained as a light yellow oil. LCMS (M+H) ⁺ : 785. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)-6-[[1-(2- methoxyacetyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 533) To a mixture of (8S,11S,15R)-10-[6-(azetidin-3-ylmethyl)-1-(2,4-difluoro-6-m ethoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one;2,2,2-trifluoroacetic acid (compound 533c, 66 mg, 0.03 mmol) and DIEA (51.3 mg, 0.40 mmol,) in anhydrous DCM (0.5 mL) was added methoxyacetyl chloride (7.2 mg, 0.07 mmol,) at 0 °C, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. After removing excess DCM under reduced pressure, the resulted residue was directly purified by prep-HPLC to afford Example 533 (14 mg) as a white solid. LCMS (M+H) ⁺ : 856. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.85 (d, J = 5.4 Hz, 1H), 8.55 - 7.73 (m, 2H), 7.66 - 7.47 (m, 2H), 7.20 - 7.04 (m, 2H), 5.78 - 5.38 (m, 3H), 4.50 - 4.23 (m, 2H), 4.21 - 3.94 (m, 3H), 3.93 - 3.67 (m, 8H), 3.63 - 3.48 (m, 1H), 3.26 - 3.14 (m, 5H), 3.02 - 2.85 (m, 6H), 2.83 - 2.65 (m, 3H), 2.60 - 2.52 (m, 3H), 0.47 - 0.39 (m, 3H). Example 534 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(3-methox y-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7- oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 4-benzyloxy-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4- d]pyrimidine (compound 534a) To a mixture of 4-chloro-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimidine (C20-e, 14.0 g, 37.4 mmol) and benzyl alcohol (4.0 g, 37.4 mmol) in THF (150 mL) was added t-BuOK (74.8 mL, 74.8 mmol) at 0 °C, the resulting mixture was stirred at 0 °C and allowed to warm to room temperature in 1 hr. The reaction was quenched by water and the mixture was then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some residue. The residue was purified by flash chromatography to afford compound 534a (10.0 g) as a colorless oil. LCMS (M+H) ⁺ : 447. Step 2: preparation of 4-[2-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro- phenyl]-2-methyl-but-3-yn-2-ol (compound 534b) To a mixture of 4-benzyloxy-1-(4-fluoro-2-iodo-phenyl)pyrazolo[3,4-d]pyrimid ine (compound 534a, 200.0 mg, 0.45 mmol), 2-methyl-3-butyn-2-ol (37.7 mg, 0.45 mmol) and CuI (17.0 mg, 0.09 mmol) in DMF (2 mL) was added TEA (135.8 mg, 1.34 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (62.9 mg, 0.09 mmol), the resulting mixture was stirred at 80 °C for 12 hrs under nitrogen. After being cooled to room temperature, the mixture was quenched by water and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some residue. The residue was purified by flash chromatography to give compound 534b (150 mg) as a white solid. LCMS (M+H) ⁺ : 403. Step 3: preparation of 4-benzyloxy-1-[4-fluoro-2-(3-methoxy-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidine (compound 534c) To a mixture of 4-[2-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phe nyl]-2- methyl-but-3-yn-2-ol (compound 534b, 300.0 mg, 0.75 mmol) and NaH (59.6 mg, 1.49 mmol) in anhydrous DMF (2 mL) was added iodomethane (211.6 mg, 1.49 mmol), the resulting mixture was stirred at 80 °C for 12 hrs under nitrogen. After being cooled to room temperature, the mixture was quenched by water and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some residue. The residue was purified by flash chromatography to give compound 534c (300.0 mg) as a yellow oil. LCMS (M+H) ⁺ : 417. Step 4: preparation of 1-[4-fluoro-2-(3-methoxy-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 534d) A mixture of 4-benzyloxy-1-[4-fluoro-2-(3-methoxy-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidine (compound 534c, 200.0 mg, 0.48 mmol), N,O- bis(trimethylsilyl)trifluoroacetamide (494.5 mg, 1.92 mmol) and TMSI (480.5 mg, 2.4 mmol) in DCM (4 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get some crude, which was purified by reversed flash chromatography to afford compound 534d (50.0 mg) as a brown solid. LCMS (M+Na) ⁺ : 349. Step 5: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(3- methoxy-3-methyl-but-1-ynyl)phenyl]pyrazolo[3,4-d]pyrimidin- 4-yl]-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 534) A mixture of (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 40.0 mg, 0.09 mmol), 1-[4-fluoro-2-(3-methoxy-3-methyl-but-1- ynyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 534d, 34.5 mg, 0.11 mmol), BOP (58.4 mg, 0.13 mmol) and DIEA (45.4 mg, 0.35 mmol) in DMF (1 mL) was stirred at room temperature for 12 hrs. The reaction mixture was filtered, the filtrate was purified by prep-HPLC to afford Example 534 (8.4 mg) as a white solid. LCMS (M+H) ⁺ : 763. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.79 (d, J=5.14 Hz, 1H), 8.57 - 8.33 (m, 1H), 8.24 - 7.79 (m, 1H), 7.67 - 7.53 (m, 2H), 7.48 - 7.32 (m, 4H), 5.90 - 5.71 (m, 2H), 5.60 - 5.44 (m, 1H), 4.62 - 3.94 (m, 4H), 3.20 - 2.97 (m, 7H), 2.96 - 2.89 (m, 1H), 2.88 - 2.70 (m, 2H), 2.68 - 2.54 (m, 5H), 1.25 - 1.11 (m, 6H), 0.58 (t, J=6.97 Hz, 3H). Example 535 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(3-methox ypyrrolidin-1- yl)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7-ox a-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: A mixture of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimi din-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 81, 50.0 mg, 0.07 mmol), 3-methoxypyrrolidine (7.4 mg, 0.07 mmol) and DIEA (50.0 mg, 0.14 mmol) in NMP (2 mL) was stirred at 100 °C for 1 hr. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to afford Example 535 (17.0 mg) as a white solid. LCMS (M+H) ⁺ : 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.79 (d, J = 5.4 Hz, 1H), 8.57 - 8.31 (m, 1H), 8.25 - 7.77 (m, 1H), 7.64 (d, J = 5.3 Hz, 1H), 7.53 - 7.40 (m, 2H), 7.38 - 7.04 (m, 1H), 6.70 - 6.44 (m, 2H), 5.90 - 5.68 (m, 2H), 5.59 - 5.44 (m, 1H), 4.60 - 4.28 (m, 1H), 4.23 - 3.79 (m, 3H), 3.58 - 3.34 (m, 3H), 3.29 - 3.24 (m, 1H), 3.22 - 3.03 (m, 3H), 3.02 - 2.86 (m, 5H), 2.85 - 2.69 (m, 3H), 2.68 - 2.55 (m, 5H), 2.29 - 2.10 (m, 1H), 1.98 - 1.77 (m, 1H), 0.58 (t, J = 7.0 Hz, 3H). Example 536 (8S,11S,15R)-10-[1-(2,4-difluoro-6-tetrahydrofuran-3-yloxy-p henyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 1-benzyloxy-3,5-difluoro-2-nitro-benzene (compound 536a) A mixture of 3,5-difluoro-2-nitro-phenol (10.0 g, 57.1 mmol), benzyl bromide (8.2 mL, 68.5 mmol) and potassium carbonate (15.8 g, 114.2 mmol) in DMF (200 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with aq. CaCl ₂ , brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to afford compound 536a (14.0 g) as a yellow solid, which was used for the next step directly. Step 2: preparation of 2-benzyloxy-4,6-difluoro-aniline (compound 536b) A mixture of 1-benzyloxy-3,5-difluoro-2-nitro-benzene (compound 536a, 7.0 g, 26.4 mmol) and iron powder (5.9 g, 105.6 mmol) in acetic acid (15 mL) was stirred at 100 °C for 2 hrs. The reaction mixture was poured into the water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some crude. The crude was purified by flash chromatography to afford compound 536b (4.0 g) as a light yellow oil. LCMS (M+H) ⁺ : 236. Step 3: preparation of (2-benzyloxy-4,6-difluoro-phenyl)hydrazine;hydrochloride (compound 536c) To a mixture of 2-benzyloxy-4,6-difluoro-aniline (compound 536b, 10.0 g, 42.5 mmol) in 6 M aq. HCl (200 mL) was added sodium nitrite (4.4 g, 63.8 mmol) slowly at -5 °C. After being stirred for 1 hr, the tin(II) chloride (4.1 mL, 85.0 mmol) in conc. HCl (50 mL) was added into the mixture, the resulting mixture was stirred at -5 °C for 1 hr. Then the reaction mixture was filtered, the filter cake was poured into the water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give compound 536c (10.0 g) as a light brown solid. LCMS (M-NH ₃ +H) ⁺ : 234. Step 4: preparation of 5-amino-1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazole-4- carbonitrile (compound 536d) A mixture of (2-benzyloxy-4,6-difluoro-phenyl)hydrazine;hydrochloride (compound 536c, 10.0 g, 40.0 mmol), ethoxymethylenemalononitrile (4.9 g, 40.0 mmol) and DIEA (10.3 g, 79.9 mmol) in ethanol (50 mL) was stirred at 60 °C for 1 hr. After being cooled to room temperature, the reaction mixture was poured into brine and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give crude compound 536d (10.0 g) as a yellow oil. LCMS (M+H) ⁺ : 327. Step 5: preparation of 1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound 536e) A solution of 5-amino-1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazole-4-carbon itrile (compound 536d, 10.0 g, 30.7 mmol) in formic acid (1.4 g, 30.7 mmol) was stirred at 100 °C for 1 hr. After being cooled to room temperature, the reaction mixture was poured into brine and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some residue. The residue was purified by prep-HPLC to afford compound 536e (2.0 g) as a yellow solid. LCMS (M+H) ⁺ : 355. Step 6: preparation of 1-(2-benzyloxy-4,6-difluoro-phenyl)-4-chloro-pyrazolo[3,4- d]pyrimidine (compound 536f) A mixture of 1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazolo[3,4-d]pyrimidin- 4-ol (compound 536e, 90.0 mg, 0.25 mmol) in phosphoryl chloride (2.0 mL) was stirred at 100 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was poured into aq. NH ₄ Cl, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some crude. The crude was purified by column chromatography to afford compound 536f (90.0 mg) as a light yellow solid. LCMS (M+H) ⁺ : 373. Step 7: preparation of (8S,11S,15R)-10-[1-(2-benzyloxy-4,6-difluoro- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 536g) A mixture of 1-(2-benzyloxy-4,6-difluoro-phenyl)-4-chloro-pyrazolo[3,4-d] pyrimidine (compound 536f, 90.0 mg, 0.24 mmol), (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 98.8 mg, 0.22 mmol) and DIEA (155.7 mg, 1.21 mmol) in NMP (1 mL) was stirred at 80 °C for 1 hr. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was directly purified by prep-HPLC to give compound 536g (70.0 mg) as a light yellow solid. LCMS (M+H) ⁺ : 791. Step 8: preparation of (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 536h) A mixture of (8S,11S,15R)-10-[1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazolo [3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 536g, 65.0 mg, 0.08 mmol) and Pd/C (60.0 mg) in methanol (2 mL) was stirred at room temperature for 1 hr under hydrogen. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give crude compound 536h (35.0 mg) as a grey solid, which was used for the next step directly. LCMS (M+H) ⁺ : 701. Step 9: preparation of (8S,11S,15R)-10-[1-(2,4-difluoro-6-tetrahydrofuran-3-yloxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 536) A mixture of (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy-phenyl)pyrazolo[3 ,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 536h, 15.0 mg, 0.02 mmol), 3-iodotetrahydrofuran (6.36 mg, 0.03 mmol) and potassium carbonate (5.9 mg, 0.04 mmol) in DMF (0.5 mL) was stirred at room temperature for 12 hrs. The reaction mixture was filtered, the filtrate was directly purified by prep-HPLC to afford Example 536 (4.0 mg) as white solid. LCMS (M+H) ⁺ : 771. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.82 - 8.73 (m, 1H), 8.60 - 8.16 (m, 2H), 7.89 - 7.30 (m, 4H), 7.01 - 6.82 (m, 2H), 5.92 - 5.70 (m, 2H), 5.63 - 5.42 (m, 1H), 5.13 - 5.02 (m, 1H), 4.64 - 4.26 (m, 3H), 4.23 - 3.82 (m, 3H), 3.80 - 3.46 (m, 3H), 3.16 - 2.71 (m, 6H), 2.67 - 2.49 (m, 5H), 2.24 - 2.07 (m, 1H), 2.04 - 1.88 (m, 1H), 0.58 (br d, J = 3.2 Hz, 3H). Example 537 2-[2-[4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12- oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]-3,5-difluoro-phenoxy]aceto nitrile The title compound was prepared according to the following scheme: A mixture of (8S,11S,15R)-10-[1-(2,4-difluoro-6-hydroxy-phenyl)pyrazolo[3 ,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 536h, 15.0 mg, 0.02 mmol), bromoacetonitrile (7.7 mg, 0.06 mmol) and potassium carbonate (5.9 mg, 0.04 mmol) in DMF (1 mL) was stirred at room temperature for 12 hrs. The reaction mixture was filtered, the filtrate was directly purified by prep-HPLC to afford Example 537 (6.4 mg) as a white solid. LCMS (M+H) ⁺ : 740. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.78 (d, J = 5.3 Hz, 1H), 8.62 - 7.86 (m, 2H), 7.64 (d, J = 5.3 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.18 - 6.97 (m, 2H), 5.89 - 5.69 (m, 2H), 5.63 - 5.42 (m, 1H), 5.11 - 4.97 (m, 2H), 4.56 - 3.66 (m, 5H), 3.29 - 3.04 (m, 1H), 3.02 - 2.70 (m, 5H), 2.68 - 2.52 (m, 5H), 0.62 - 0.51 (m, 3H). Example 538 (8S,11S,15S)-10-[1-[2,4-difluoro-6-[(1-methylsulfonylazetidi n-3- yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538a) Compound 538a was prepared in analogy to the preparation of compound 12d by using Intermediate A30 instead of Intermediate A11. LCMS (M+H ⁺ ): 439. Step 2: preparation of (8S,11S,15S)-10-[1-(2-benzyloxy-4,6-difluoro- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538b) A mixture of 1-(2-benzyloxy-4,6-difluoro-phenyl)-4-chloro-pyrazolo[3,4-d] pyrimidine (compound 536f, 150.0 mg, 0.4 mmol), (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one (compound 538a, 176.4 mg, 0.4 mmol) and DIEA (103.8 mg, 0.8 mmol) in anhydrous NMP (2 mL) was stirred at 80 °C for 1 hr. After being cooled to room temperature, the reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated to give some crude. The crude was purified by reversed flash chromatography to afford compound 538b (200 mg) as a brown oil. LCMS (M+H) ⁺ : 775. Step 3: preparation of (8S,11S,15S)-10-[1-(2,4-difluoro-6-hydroxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538c) A mixture of (8S,11S,15S)-10-[1-(2-benzyloxy-4,6-difluoro-phenyl)pyrazolo [3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538b, 200.0 mg, 0.26 mmol) and Pd/C (200.0 mg) in methanol (5 mL) was stirred at room temperature for 2 hrs under hydrogen. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give crude compound 538c (150.0 mg) as a light yellow solid. LCMS (M+H) ⁺ : 685. Step 4: preparation of tert-butyl 3-[[3,5-difluoro-2-[4-[(8S,11S,15S)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]phenoxy]methyl]azetidine-1- carboxylate (compound 538d) A mixture of tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (54.8 mg, 0.22 mmol), (8S,11S,15S)-10-[1-(2,4-difluoro-6-hydroxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[ 15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538c, 100.0 mg, 0.15 mmol) and potassium carbonate (40.4 mg, 0.29 mmol) in anhydrous DMF (2 mL) was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was purified by reversed flash chromatography to give compound 538d (120.0 mg) as a light yellow oil. LCMS (M+H) ⁺ : 854. Step 5: preparation of (8S,11S,15S)-10-[1-[2-(azetidin-3-ylmethoxy)-4,6-difluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538e) A mixture of tert-butyl 3-[[3,5-difluoro-2-[4-[(8S,11S,15S)-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-1- yl]phenoxy]methyl]azetidine-1-carboxylate (compound 538d, 120.0 mg, 0.14 mmol) in TFA (2.0 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to give crude compound 538e (65.0 mg) as a light yellow oil, which was used for the next step directly. LCMS (M+H) ⁺ : 754. Step 6: preparation of (8S,11S,15S)-10-[1-[2,4-difluoro-6-[(1-methylsulfonylazetidi n- 3-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro -15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 538) A mixture of (8S,11S,15S)-10-[1-[2-(azetidin-3-ylmethoxy)-4,6-difluoro- phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 538e, 60.0 mg, 0.08 mmol), methanesulfonic anhydride (27.7 mg, 0.16 mmol) and TEA (24.2 mg, 0.24 mmol) in anhydrous THF (2 mL) was stirred at room temperature for 12 hrs. The reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give crude product. The crude was purified by prep-HPLC to afford Example 538 (33.3 mg) as a white solid. LCMS (M+H) ⁺ : 832. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.58 - 8.28 (m, 1H), 8.24 - 7.72 (m, 2H), 7.28 (dd, J = 2.3, 8.6 Hz, 1H), 7.12 - 6.84 (m, 4H), 6.75 - 6.63 (m, 1H), 5.57 - 5.11 (m, 2H), 4.74 - 4.48 (m, 2H), 4.37 - 3.47 (m, 10H), 3.29 - 3.12 (m, 2H), 3.09 - 2.95 (m, 3H), 2.94 - 2.82 (m, 4H), 2.81 - 2.73 (m, 2H), 2.73 - 2.64 (m, 2H), 2.60 - 2.56 (m, 3H). Example 539 (8S,11S,15R)-4-(cyclopropylamino)-10-[1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,2 6- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared in analogy to the preparation of Example 289 by using Intermediate A7 instead of Intermediate A12, Intermediate B34 instead of Intermediate B11, Intermediate C2 instead of Intermediate C11. LCMS (M+H) ⁺ : 740. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.31 (m, 1H), 8.27 - 7.82 (m, 1H), 7.72 - 7.58 (m, 1H), 7.48 - 7.26 (m, 3H), 7.25 - 7.16 (m, 1H), 6.93 - 6.28 (m, 1H), 5.98 - 5.79 (m, 1H), 5.76 - 5.34 (m, 2H), 4.54 - 4.19 (m, 2H), 4.18 - 3.95 (m, 2H), 3.40 - 3.33 (m, 1H), 3.20 - 3.04 (m, 3H), 2.99 - 2.75 (m, 2H), 2.73 - 2.61 (m, 7H), 1.00 - 0.82 (m, 2H), 0.74 - 0.53 (m, 5H). Example 540 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(6-fluoro-1H-indazol- 5-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme: Step 1: preparation of 4-benzyloxy-1H-pyrazolo[3,4-d]pyrimidine (compound 540a) To a mixture of 4-chloro-1H-pyrazole[3,4-d]pyrimidine (8.0 g, 51.8 mmol) and benzyl alcohol (5.6 g, 51.8 mmol) in anhydrous DMF (100 mL) was added NaH (6.2 g, 155.3 mmol) at 0 °C, the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aq. NH ₄ Cl and then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated to dryness to give compound 540a (11.0 g) as a yellow solid. LCMS (M+H) ⁺ : 227. Step 2: preparation of 4-benzyloxy-1-(2-fluoro-5-methyl-4-nitro-phenyl)pyrazolo[3,4 - d]pyrimidine (compound 540b) To a mixture of 4,5-difluoro-2-nitrotoluene (5.0 g, 28.9 mmol) and 4-benzyloxy-1H- pyrazolo[3,4-d]pyrimidine (compound 540a, 7.2 g, 31.8 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (8.0 g, 57.78 mmol, 2.0 eq), the resulting mixture was stirred at 30 °C for 1 hr. The reaction mixture was quenched by water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give some residue. The residue was purified by reversed-phase chromatography to afford compound 540b (1.0 g) as a light yellow solid. LCMS (M+H) ⁺ : 380. Step 3: preparation of 4-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-2- methyl-aniline (compound 540c) To a solution of 4-benzyloxy-1-(2-fluoro-5-methyl-4-nitro-phenyl)pyrazolo[3,4 - d]pyrimidine (compound 540b, 1.00 g, 2.64 mmol) in EtOAc (10 mL) was added Pt/C (500.0 mg), the resulting mixture degassed and purged with nitrogen for four times, then stirred at room temperature for 1 hr under hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 540c (800 mg) as a white solid. LCMS (M+H) ⁺ : 350. Step 4: preparation of 4-benzyloxy-1-(6-fluoro-1H-indazol-5-yl)pyrazolo[3,4- d]pyrimidine (compound 540d) A solution of sodium nitrite (90.0 mg, 1.3 mmol) in water (1.5 mL) was added dropwise to a solution of 4-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-2-meth yl-aniline (compound 540c, 300.0 mg, 0.86 mmol) in acetic acid (5 mL), the resulting mixture was stirred at room temperature for 12 hrs. The reaction was quenched by aq. NaHCO ₃ , then the mixture was extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated to give some crude product. The crude was purified by reversed-phase chromatography to afford compound 540d (203.0 mg) as a brown solid, which was used for the next step directly. LCMS (M+H) ⁺ : 361. Step 5: preparation of 2-[[5-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-6-fluoro- indazol-1-yl]methoxy]ethyl-trimethyl-silane (compound 540e) To a mixture of 4-benzyloxy-1-(6-fluoro-1H-indazol-5-yl)pyrazolo[3,4-d]pyrim idine (compound 540d, 64.0 mg, 0.18 mmol) in anhydrous DMF (1 mL) was added NaH (36.7 mg, 0.92 mmol), the resulting mixture was stirred at 0 °C for 1 hr. Then 2- (trimethylsilyl)ethoxymethyl chloride (0.03 mL, 0.18 mmol) was added into the mixture, and the resulting mixture was stirred at room temperature for 1 hr. The reaction was quenched by water, then the mixture was directly purified by reversed-phase chromatography to give compound 540e (60.0 mg, 0.12 mmol) as an off-white solid, which was used for the next step directly. LCMS (M+H) ⁺ : 491. Step 6: preparation of 1-[6-fluoro-1-(2-trimethylsilylethoxymethyl)indazol-5- yl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 540f) A mixture of 2-[[5-(4-benzyloxypyrazolo[3,4-d]pyrimidin-1-yl)-6-fluoro-in dazol-1- yl]methoxy]ethyl-trimethyl-silane (compound 540e, 60.0 mg, 0.12 mmol) and Pd/C (10.0 mg) in methanol (1 mL) was stirred at room temperature for 2 hrs under hydrogen. The reaction mixture was filtered, the filtrate was concentrated to give compound 540f (50.0 mg) as a white solid, which was used for the next step directly. LCMS (M+H) ⁺ : 401. Step 7: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[6-fluoro-1-(2- trimethylsilylethoxymethyl)indazol-5-yl]pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 540g) A mixture of 1-[6-fluoro-1-(2-trimethylsilylethoxymethyl)indazol-5-yl]pyr azolo[3,4- d]pyrimidin-4-ol (compound 540f, 40.0 mg, 0.1 mmol), (8S,11S,15R)-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 326d-1, 45.3 mg, 0.1 mmol), BOP (66.3 mg, 0.15 mmol) and DIEA (0.1 mL, 0.5 mmol) in anhydrous DMF (2 mL) was stirred at 10 °C for 4 hrs. The reaction mixture was directly purified by reversed-phase chromatography to give compound 540g (5.0 mg) as a white powder, which was used for the next step directly. LCMS (M+H) ⁺ : 836. Step 8: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(6-fluoro-1H-indazol- 5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13 ,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 540) A mixture of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[6-fluoro-1-(2- trimethylsilylethoxymethyl)indazol-5-yl]pyrazolo[3,4-d]pyrim idin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 540g, 2.0 mg, 0.01 mmol) and TFA (0.2 mL) in DCM (1 mL) was stirred at room temperature for 2 hrs. The reaction mixture was adjusted with 1 M NH3H2O to pH = 7, then purified by prep-HPLC to afford Example 540 (1.2 mg) as a white powder. LCMS (M+H) ⁺ : 706. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.62 - 8.49 (m, 2H), 8.37 - 8.16 (m, 2H), 8.11 - 7.81 (m, 1H), 7.55 - 7.48 (m, 1H), 7.40 (br dd, J = 1.3, 8.1 Hz, 1H), 7.34 - 7.26 (m, 1H), 7.16 - 7.09 (m, 1H), 5.64 - 5.33 (m, 3H), 4.64 - 4.35 (m, 3H), 4.27 - 4.12 (m, 1H), 4.07 - 3.92 (m, 1H), 3.18 - 2.80 (m, 5H), 2.72 - 2.46 (m, 6H), 0.58 (br t, J = 6.8 Hz, 3H). Example 541 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)indazol-4-yl]-15-etho xy-22-fluoro-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 4-bromo-1-(2,4-difluorophenyl)indazole (compound 541a) A mixture of (2,4-difluorophenyl)hydrazine;hydrochloride (compound C2-a, 1.0 g, 5.54 mmol) and 2-bromo-6-fluorobenzaldehyde (1.35 g, 6.65 mmol) in NMP (30 mL) was stirred at room temperature for 1 hr. Then cesium carbonate (2.0 g, 6.14 mmol) was added, the resulting mixture was stirred at 140 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was poured into brine, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give some residue. The residue was purified by flash chromatography to afford compound 541a (650.0 mg) as a yellow solid. LCMS (M+H) ⁺ : 309. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)indazol-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 541) A mixture of 4-bromo-1-(2,4-difluorophenyl)indazole (compound 541a, 31.3 mg, 0.10 mmol), (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 46.0 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (9.3 mg, 0.01 mmol), cesium carbonate (33.0 mg, 0.10 mmol) and 2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1,1'-biphenyl (4.7 mg, 0.01 mmol) in 1,4-dioxane (0.5 mL) was stirred at 100 °C for 12 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give some crude product. The crude was purified by reversed-phase chromatography to afford Example 541 (2.3 mg) as a white solid. LCMS (M+H) ⁺ : 683. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.85 - 8.70 (m, 1H), 8.61 - 8.44 (m, 1H), 7.67 - 7.60 (m, 2H), 7.50 - 7.42 (m, 2H), 7.34 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 6.57 - 6.50 (m, 1H), 6.30 - 6.20 (m, 1H), 5.87 - 5.77 (m, 2H), 5.23 (m, 1H), 4.36 - 4.13 (m, 3H), 4.05 (m, 1H), 3.30 - 3.20 (m, 2H), 3.08 (s, 3H), 3.00 - 2.83 (m, 2H), 2.76 - 2.55 (m, 6H), 0.60 (m, 3H). Example 542 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(trideute riomethoxy)phenyl]-6-(oxetan- 3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13 ,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-15 -ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 542a) Compound 542a was prepared in analogy to the preparation of compound 213a by using compound 326d-1 instead of compound 370b and intermediate C76 instead of intermediate C74. LCMS (M+H ⁺ ): 733. Step 2: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2- (trideuteriomethoxy)phenyl]-6-(oxetan-3-yl)pyrazolo[3,4-d]py rimidin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 542) Example 542 was prepared in analogy to the preparation of Example 432 by using 3- iodooxetane instead of 3-iodotetrahydrofuran and compound 542a instead of compound 213a. LCMS (M+H ⁺ ): 755. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.66 - 8.53 (m, 1H), 8.46 - 7.65 (m, 1H), 7.48 - 7.34 (m, 2H), 7.33 - 7.23 (m, 1H), 7.15 - 7.07 (m, 1H), 7.06 - 7.00 (m, 1H), 6.93 - 6.81 (m, 1H), 5.71 - 5.27 (m, 2H), 5.11 - 4.91 (m, 4H), 4.79 - 4.49 (m, 1H), 4.48 - 4.07 (m, 4H), 4.03 - 3.88 (m, 1H), 3.30 - 3.26 (m, 1H), 3.19 - 2.78 (m, 5H), 2.70 - 2.46 (m, 6H), 0.65 - 0.48 (m, 3H). Example 543 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-[4-fluoro-2-(trideute riomethoxy)phenyl]-6-[3-oxa- 6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 543 was prepared in analogy to the preparation of Example 213 by using compound 542a instead of compound 213a and 3-oxa-6-azabicyclo[3.1.1]heptane instead of morpholine. LCMS (M+H ⁺ ): 796. ¹ H NMR (500 MHz, METHANOL-d ₄ ) δ = 8.50 - 8.38 (m, 1H), 8.20 - 7.39 (m, 1H), 7.34 - 7.15 (m, 3H), 7.07 - 6.97 (m, 1H), 6.94 - 6.86 (m, 1H), 6.77 - 6.67 (m, 1H), 5.61 - 5.34 (m, 1H), 5.30 - 5.13 (m, 1H), 4.68 - 4.50 (m, 1H), 4.35 - 4.01 (m, 7H), 3.94 - 3.75 (m, 1H), 3.68 - 3.51 (m, 2H), 3.19 - 3.12 (m, 1H), 3.04 - 2.86 (m, 3H), 2.84 - 2.70 (m, 2H), 2.61 - 2.31 (m, 7H), 1.76 - 1.69 (m, 1H), 0.55 - 0.41 (m, 3H). Example 545 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methyl-7-oxo-pyraz olo[3,4-c]pyridin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-7-hydroxy- pyrazolo[3,4-c]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dime thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (compound 545a) A mixture of Example 547 (100 mg, 0.11 mmol) in TFA (1 mL) was stirred at 50 °C for 2 hrs. The mixture was concentrated under reduced pressure to give a residue, which was diluted with ice sat. NaHCO ₃ solution (10 mL) and extracted with EA. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound 545a (70 mg). LCMS (M+H ⁺ ): 684. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-methyl-7-oxo- pyrazolo[3,4-c]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dime thyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 545) To a solution of compound 545a (20.0 mg, 0.03 mmol) and Cs ₂ CO ₃ (28.6 mg, 0.09 mmol) in DMF (1 mL) was added MeI (8.5 mg, 0.06 mmol) slowly at 20 °C under N ₂ , then the mixture the mixture was stirred at 20 °C for 2 hrs. The reaction was quenched with 10 mL of NH ₄ Cl solution and then extracted with ethyl acetate, the organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 545 (13 mg). LCMS (M+H ⁺ ): 698. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.01 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.66 - 7.52 (m, 4H), 7.22 - 7.05 (m, 3H), 6.80 - 6.69 (m, 1H), 6.12 (dd, J = 4.4, 15.2 Hz, 1H), 5.03 (br d, J = 8.8 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.34 (dd, J = 11.2, 15.2 Hz, 1H), 4.02 - 3.96 (m, 1H), 3.74 (br d, J = 10.4 Hz, 1H), 3.57 (s, 3H), 3.12 - 3.05 (m, 3H), 3.01 - 2.95 (m, 4H), 2.93 (d, J = 4.8 Hz, 1H), 2.89 - 2.86 (m, 1H), 2.84 (s, 3H), 2.62 - 2.50 (m, 2H). Example 546 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-methoxyethyl)-7 -oxo-pyrazolo[3,4-c]pyridin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one A mixture of compound 545a (5.0 mg, 0.01 mmol), Cs ₂ CO ₃ (7.2 mg, 0.02 mmol) and 2- bromoethyl methyl ether (2.0 mg, 0.015 mmol) in ACN (1 mL) was stirred at 90 °C for 2 hrs. The reaction was directly purified by prep-HPLC to give Example 546 (3.0 mg). LCMS (M+H ⁺ ): 742. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.00 (s, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.64 - 7.50 (m, 4H), 7.26 - 7.10 (m, 3H), 6.83 - 6.69 (m, 1H), 6.18 - 5.89 (m, 1H), 5.06 (br d, J = 8.4 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.41 - 4.30 (m, 1H), 4.20 (t, J = 5.2 Hz, 1H), 4.16 - 3.94 (m, 2H), 3.90 - 3.75 (m, 1H), 3.71 (m, 1H), 3.65 - 3.57 (m, 1H), 3.38 - 3.34 (m, 3H), 3.14 - 3.09 (m, 2H), 3.07 - 3.01 (m, 1H), 3.00 - 2.94 (m, 4H), 2.93 - 2.87 (m, 2H), 2.87 - 2.81 (m, 3H), 2.58 (br dd, J = 4.0, 8.8 Hz, 2H). Example 547 (8S,11S,15R)-10-[7-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[ 3,4-c]pyridin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 2-benzyloxy-3,5-dibromo-pyridine (compound 547b) To a solution of compound 547b (4.4 g, 17.3 mmol) in THF (44 mL) was added benzyl alcohol (1.68 g, 15.5 mmol) and t-BuOK (1.94 g, 17.3 mmol) at 0 °C, the mixture was stirred for 1 h at 0 °C. The reaction was quenched with ice water (300 mL), then the mixture was extracted with EA, the organic layer was dried and concentrated to give compound 547b (5.0 g). LCMS (M+H ⁺ ): 344. Step 2: preparation of 2-benzyloxy-3,5-dibromo-pyridine-4-carbaldehyde (compound 547c) To a solution of compound 547b (3.0 g, 8.7 mmol) in THF (24 mL) was added LDA (6.56 mL, 13.1 mmol) dropwise at -70 °C under N ₂ and then the mixture was stirred at -70 °C for 1 h. DMF (3.4 mL, 44 mmol) was added slowly and the mixture was stirred at rt for 1 h. The reaction was quenched with ice water (100 mL), then the mixture was extracted with EtOAc, the organic layer was dried and concentrated to give compound 547c (3.0 g) as a brown solid. Step 3: preparation of N-[(2-benzyloxy-3,5-dibromo-4-pyridyl)methyleneamino]-2,4- difluoro-aniline (compound 547d) A mixture of compound 547c (3.0 g, 8.09 mmol) and 2,4-difluorophenylhydrazine hydrochloride (1.75 g, 9.7 mmol) in DMF (60 mL) was stirred at 20 °C for 16 hrs. The reaction was quenched with ice water, and then the mixture was extracted with EA. The organic layer was dried and concentrated to give compound 547d (4.1 g). LCMS (M+H ⁺ ): 498. Step 4: preparation of 7-benzyloxy-4-bromo-1-(2,4-difluorophenyl)pyrazolo[3,4- c]pyridine (compound 547e) A mixture of compound 547d (6.7 g, 13.5 mmol), K ₂ CO ₃ (5.59 g, 40.4 mmol) and CuI (0.26 g, 1.35 mmol) in DMF (67 mL) was stirred at 100 °C for 1 h. The reaction mixture was diluted with water (300 mL), extracted with EA, the organic layer was dried and concentrated. The residue was purified by chromatography column and SFC [DAICEL CHIRALCEL OJ (250mm×30mm,10um), 0.1%NH ₃ H ₂ O ETOH, begin 60% B(ETOH) to 60% B, rate: 70mL/min)] to give compound 547e (1200 mg). LCMS (M+H ⁺ ): 416. Step 5: preparation of (8S,11S,15R)-10-[7-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-c]pyridin-4-yl]-22-fluoro-15-met hoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 547) To a solution of compound 370b (210.0 mg, 0.48 mmol) in THF (3 mL) was added compound 547e (200.0 mg, 0.48 mmol), BINAP (60.0 mg, 0.1 mmol), cesium carbonate (630.0 mg, 1.93 mmol) and bis(dibenzylideneacetone)palladium (30.0 mg, 0.05 mmol). The mixture was degassed with N ₂ for 3 times and then stirred at 110 °C for 12 hrs under N ₂ . The mixture was diluted with H ₂ O (30 mL) and extracted with EA (20 mL). The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 547 (100 mg). LCMS (M+H ⁺ ): 774. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.16 (s, 1H), 7.86 (br t, J = 8.0 Hz, 1H), 7.59 (br d, J = 4.4 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.27 - 7.24 (m, 3H), 7.13 (br d, J = 7.6 Hz, 1H), 7.08 - 6.92 (m, 5H), 6.78 (d, J = 8.8 Hz, 1H), 6.12 (dd, J = 4.4, 15.6 Hz, 1H), 5.22 (s, 2H), 5.10 (br d, J = 8.8 Hz, 1H), 4.59 - 4.53 (m, 1H), 4.36 - 4.18 (m, 2H), 4.00 - 3.93 (m, 2H), 3.12 (s, 3H), 3.03 (br d, J = 13.6 Hz, 1H), 2.97 (s, 3H), 2.87 (br d, J = 13.2 Hz, 1H), 2.81 (s, 3H), 2.57 (dt, J = 4.4, 9.2 Hz, 2H). Example 548 (8S,11S,15R)-10-[6-(cyclopropylmethyl)-1-(2,4-difluorophenyl )-7-oxo-pyrazolo[3,4- c]pyridin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 548 was prepared in analogy to the preparation of Example 546 by using (bromomethyl)cyclopropane instead of 2-bromoethyl methyl ether. Example 548. LCMS (M+H ⁺ ): 738. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.03 - 7.92 (m, 1H), 7.91 - 7.79 (m, 1H), 7.64 - 7.46 (m, 4H), 7.39 - 7.12 (m, 3H), 6.82 - 6.66 (m, 1H), 6.18 - 5.86 (m, 1H), 5.08 - 5.03 (m, 1H), 4.57 - 4.46 (m, 1H), 4.42 - 4.22 (m, 1H), 4.08 - 3.80 (m, 2H), 3.79 - 3.71 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.10 (s, 1H), 3.07 - 2.91 (m, 5H), 2.91 - 2.82 (m, 4H), 2.71 - 2.64 (m, 1H), 2.63 - 2.43 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H), 0.58 - 0.53 (m, 1H), 0.47 - 0.42 (m, 1H). Example 549 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3-yl)methyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of (1,1-dioxothietan-3-yl)methyl methanesulfonate (compound 549b) To a solution of compound 549a (700 mg, 5.14 mmol) and TEA (2.14 mL, 15.42 mmol) in DCM (7 mL) was added methanesulfonic anhydride (1.07 g, 6.17 mmol,) at 0 °C, the mixture was stirred at 0 °C for 1 h. The mixture was dilluted with H ₂ O (30 mL), and then extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound 549b (690 mg). Step 2: preparation of 3-(iodomethyl)thietane 1,1-dioxide (compound 549c) To a solution of compound 549b (690 mg, 3.22 mmol) in acetone (45 mL) were added NaI (1.80 g, 12 mmol) in one portion under N ₂ . The reaction was stirred at 60 °C for 16 hours. The mixture was concentrated in vacuo to give a residue, which was added water (20 mL) and EA (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , and concentrated to afford compound 549c (690 mg) as a yellow solid. Step 3: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3- yl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methox y-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 549) To a 15 mL vial equipped with a stir bar was added compound 550c (50.0 mg, 0.06 mmol), compound 549c (21.1 mg, 0.09 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (0.69 mg, 0.006 mmol), NiCl ₂ .dtbbpy (0.28 mg, 0.012 mmol), TTMSS (15.22 mg, 0.06 mmol), Na ₂ CO ₃ (13.0 mg, 0.12 mmol) in DME (5 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by flash-HPLC (TFA as additive) to give Example 549. LCMS (M+H ⁺ ):787. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.67 (dt, J = 6.4, 8.4 Hz, 1H), 7.57 (dd, J = 2.4, 7.2 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.36 - 7.27 (m, 1H), 7.27 - 7.18 (m, 1H), 7.10 - 6.98 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.57 (d, J = 9.2 Hz, 1H), 4.78 - 4.75 (m, 1H), 4.57 (br dd, J = 6.4, 11.2 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.22 - 4.12 (m, 2H), 3.96 - 3.87 (m, 1H), 3.80 (br d, J = 12.4 Hz, 1H), 3.63 (q, J = 7.2 Hz, 2H), 3.25 - 3.19 (m, 2H), 3.16 (s, 3H), 3.09 - 3.02 (m, 2H), 2.98 (s, 4H), 2.87 (s, 3H), 2.79 - 2.71 (m, 1H), 2.66 - 2.56 (m, 1H). Example 550 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15S)-22-fluoro-15-me thoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-1-yl]ac etonitrile The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 550b) A reaction mixture of compound 550a (500 mg, 0.87 mmol, synthesis refers to compound 12c by using intermediate A30 instead of intermediate A11) in TFA (5 mL) was stirred at 90 °C for 1 h. The reaction was concentrated to give compound 550b (482 mg). LCMS (M+H ⁺ ): 439. Step 2: preparation of (8S,11S,15S) (8S,11S,15S)-10-[6-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 550c) A mixture of compound 550b (450 mg, 0.81 mmol), intermediate C74 (257.5 mg, 0.86 mmol) and DIPEA (0.57 mL, 3.26 mmol) in ACN (5 mL) was stirred at 85 °C for 1 h. Then the reaction mixture was directly purified by flash-HPLC to give compound 550c (400 mg). LCMS (M+H ⁺ ): 703. Step 3~5: preparation of 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15S)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-1-yl]acetonitrile (Example 550) Examples 550 was prepared in analogy to the preparation of Example 443 by using bromoacetonitrile instead of methanesulfonic anhydride. LCMS (M+H ⁺ ): 763. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (s, 1H), 7.79 - 7.72 (m, 1H), 7.68 - 7.62 (m, 1H), 7.29 - 7.23 (m, 2H), 7.21 - 7.15 (m, 1H), 7.05 - 7.02 (m, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.67 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 4.4 Hz, 1H), 4.73 - 4.71 (m, 1H), 4.63 - 4.53 (m, 4H), 4.33 - 4.26 (m, 1H), 4.09 - 3.97 (m, 2H), 3.77 - 3.59 (m, 7H), 3.17 - 3.12 (m, 3H), 3.09 - 3.02 (m, 1H), 2.84 (s, 3H), 2.57 - 2.56 (m, 3H). Example 551 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothian-4- yl)pyrazolo[3,4-d]pyrimidin-4- yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 1-(2, 4-difluorophenyl)-6-(1, 1-dioxothian-4-yl) pyrazolo[3,4- d]pyrimidin-4-ol (compound 551c) To a solution of compound 551a (300 mg, 1.1 mmol) in ACN (4 mL) was added compound 551b (402 mg, 2.3 mmol) and silver nitrate (1.53 g, 9.0 mmol). The reaction was heated at 60 °C and then a solution of ammonium persulfate (1284.0 mg, 5.6 mmol) in water (4 mL) was added slowly. After being stirred at 60 °C for 2 hours, the mixture was diluted with H ₂ O (30mL) and extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 551c (60.0 mg) as a white solid. LCMS (M+H ⁺ ): 381. Step 2: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothian-4- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 551) A mixture of compound 551c (25 mg, 0.05 mmol), PyBOP (57.9 mg, 0.11 mmol) and N,N- diisopropylethylamine (0.02 mL, 0.13 mmol) in DMF (1 mL)was stirred at rt for 2 hours, then a solution of compound 550b (27.9 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.25 mmol) in DMF (1 mL) was added and stirred at 25 °C for 12 hrs. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 551 (5 mg ). LCMS (M+H ⁺ ):801. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.51 (s, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.17 (m, 1H), 7.06 (br dd, J = 2.4, 10.8 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.52 (d, J = 9.2 Hz, 1H), 4.80 - 4.75 (m, 2H), 4.62 - 4.56 (m, 2H), 4.29 (d, J = 12.0 Hz, 1H), 4.09 - 3.97 (m, 2H), 3.82 - 3.71 (m, 1H), 3.30 (br s, 1H), 3.20 (s, 1H), 3.15 (s, 3H), 3.13 - 3.07 (m, 2H), 3.05 - 2.98 (m, 1H), 2.87 (s, 3H), 2.74 - 2.66 (m, 1H), 2.65 - 2.61 (m, 1H), 2.60 (s, 3H), 2.52 - 2.28 (m, 4H). Example 552 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(methylsulfonyl methyl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(methylsulfonylmethyl)azetidine-1-carboxylate (compound 552b) To a solution of compound 552a (200.0 mg, 0.67 mmol) in DMF (20 mL) was added methylsulfinyloxysodium (137.4 mg, 1.35 mmol), then the mixture was stirred at 60 °C for 12 hrs. The reaction was quenched with water (80 mL) and the mixture was extracted with EA, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound 552b (150 mg) as a light yellow oil (crude). LCMS (M-C ₅ H ₉ O ₂ +H ⁺ ): 194. Step 2: preparation of 3-(methylsulfonylmethyl)azetidine;hydrochloride (compound 552c) To a solution of compound 552b (150 mg, 0.6 mmol) in DCM (1.5 mL) was added HCl/dioxane (1.5 mL, 6.0 mmol) dropwise. After being stirred at 20 °C for 1 h, the mixture was concentrated to give compound 552c (150 mg) as yellow oil that was used in next step directly. Step 3: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3- (methylsulfonylmethyl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin -4-yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 552) A solution of compound 550c (30.0 mg, 0.04 mmol), DIPEA (96 μL, 0.59 mmol) and compound 552b (54.5 mg, 0.29 mmol) in MeCN (2 mL) was stirred at 80 °C for 2 hrs. The mixture was directly purified by prep-HPLC to give Example 552 (16.3 mg). LCMS (M+H ⁺ ): 816. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.28 (dd, J = 2.4, 8.4 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.18 - 7.11 (m, 1H), 7.07 - 7.00 (m, 1H), 6.93 - 6.86 (m, 1H), 6.73 - 6.64 (m, 1H), 5.40 - 5.21 (m, 1H), 4.72 - 4.66 (m, 1H), 4.52 - 4.45 (m, 1H), 4.34 - 4.14 (m, 3H), 4.06 - 3.83 (m, 4H), 3.80 - 3.73 (m, 1H), 3.53 - 3.47 (m, 2H), 3.25 - 3.13 (m, 2H), 3.09 - 3.01 (m, 3H), 2.97 (s, 3H), 2.85 (s, 3H), 2.59 - 2.50 (m, 4H), 1.35 - 1.27 (m, 2H). Example 553 (8S,11S,15S)-10-[6-(1-cyclopropylazetidin-3-yl)-1-(2,4-diflu orophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of 6-(azetidin-3-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-ol (compound 553b) To a stirred solution of compound 441a (120 mg, 0.24 mmol) in DCM (1 mL) was added TFA (0.33 mL) at 0 °C. After being stirred at 0 °C for 0.5 hrs, the reaction mixture was concentrated to give compound 553b (100 mg). LCMS (M+H ⁺ ): 304. Step 2: preparation of 6-(1-cyclopropylazetidin-3-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (compound 553c) To a solution of compound 553b (50 mg, 0.12 mmol) and (1-ethoxycyclopropoxy) trimethylsilane (208.9 mg, 1.2 mmol) in THF (1 mL) was added acetic acid (71.9 mg, 1.2 mmol) and sodium cyanoborohydride (11.3 mg, 0.18 mmol) at 25°C under N ₂ , and the reaction mixture was stirred at 60 °C for 1 h under N ₂ . The reaction mixture was poured into water (20 mL) and extracted with EA, the organic phase was concentrated and the residue was purified by prep-TLC to afford compound 553c (15 mg). LCMS (M+H ⁺ ): 344. Step 4: preparation of (8S,11S,15S)-10-[6-(1-cyclopropylazetidin-3-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 553) To the solution of compound 550b (15 mg, 0.03 mmol) and compound 553c (10.0 mg, 0.03 mmol) in DMF (0.5 mL) were added DIEA (13 μL, 0.08 mmol), PyBOP (21.4 mg, 0.04 mmol) at 25 °C. Then the mixture was stirred at 25 °C for 16 h. The reaction mixture was directly purified by prep-HPLC to give Example 553 (3.2 mg). LCMS (M+H ⁺ ): 764. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.65 - 7.64 (m, 1H), 7.28 (dd, J = 2.0, 9.2 Hz, 2H), 7.21 - 7.17 (m, 1H), 7.04 (dd, J = 2.38, 10.0 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.74 - 6.72 (m, 1H), 5.63 (d, J = 8.8 Hz, 1H), 4.90 - 4.89 (m, 2H), 4.77 - 4.74 (m, 1H), 4.60 - 4.55 (m, 4H), 4.30 (d, J = 12.0 Hz, 1H), 4.08 - 3.98 (m, 2H), 3.75 - 3.67 (m, 4H), 3.55 - 3.47 (m, 1H), 3.12 (s, 3H), 2.84 (s, 3H), 2.58 (s, 3H), 2.00 - 1.97 (m, 1H), 0.47 - 0.36 (m, 4H). Example 554 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3- yl)methylsulfanyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

The title compound was prepared according to the following scheme: Step 1: preparation of S-[(1,1-dioxothietan-3-yl)methyl] ethanethioate (compound 554b) To a solution of compound 554b (100 mg, 0.41 mmol) in DMF (5 mL) was added acetylsulfanylpotassium (100 mg, 0.88 mmol) and then the mixture was stirred at 25 °C for 12 hours. The reaction mixutre was diluted with ice-water (20 mL) and extracted with EA, the organic layer was concentrated and the residue was purified by prep-TLC to give compound 554b (60 mg) as a white solid. Step 2: preparation of (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[(1,1-dioxothietan -3- yl)methylsulfanyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-1 5-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 554) To a solution of compound 554b (20 mg, 0.1 mmol) in THF (0.1 mL) was added KOH (32 mg, 0.57 mmol) at 0 °C and then after the reaction mixture was stirred at 25 °C for 1 h, compound 550c (20 mg, 0.02 mmol) was added and such reaction mixture was stirred at 25 °C for another 11 hours. The reaction was quenched with water (20 mL), and then the mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried and concentrated, the residue was purified by prep-TLC and prep-HPLC to give Example 554 (0.8 mg). LCMS (M+H ⁺ ): 819. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.43 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.42 (br d, J = 5.3 Hz, 1H), 7.31 - 7.23 (m, 2H), 6.97 (br d, J = 7.1 Hz, 1H), 6.74 (br d, J = 7.9 Hz, 1H), 5.55 (br d, J = 9.0 Hz, 1H), 4.56 - 4.50 (m, 2H), 4.35 - 4.25 (m, 2H), 4.24 - 4.17 (m, 2H), 4.15 - 4.08 (m, 4H), 3.96 - 3.88 (m, 2H), 3.82 - 3.73 (m, 2H), 3.18 (s, 1H), 3.11 (s, 3H), 3.07 - 3.00 (m, 2H), 2.92 - 2.88 (m, 3H), 2.71 (d, J = 7.5 Hz, 3H). Example 555 (8S,11S,15R)-22-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy )phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Example 555 was prepared in analogy to the preparation of Example 213 by using intermediate C76 instead of intermediate C74 and 3-oxa-6-azabicyclo[3.1.1]heptane instead of morpholine. LCMS (M+H ⁺ ):781. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.10 (s, 1H), 7.83 (dd, J = 2.4, 7.2 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.14 (d, J = 7.4 Hz, 1H), 6.82 - 6.73 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 5.34 (d, J = 8.8 Hz, 1H), 5.18 (br d, J = 8.0 Hz, 1H), 4.60 - 4.48 (m, 2H), 4.47 - 4.31 (m, 4H), 4.30 - 4.16 (m, 4H), 3.93 (br dd, J = 8.8, 14.2 Hz, 2H), 3.80 (br d, J = 9.2 Hz, 1H), 3.74 (br d, J = 8.8 Hz, 1H), 3.00 (s, 3H), 2.98 - 2.93 (m, 3H), 2.91 - 2.80 (m, 4H), 2.62 - 2.44 (m, 2H). Example 556 (8S,11S,15R)-10-[6-(azetidin-1-yl)-1-[4-fluoro-2-(trideuteri omethoxy)phenyl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10 ,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 556b) A solution of compound 556a (200 mg, 0.29 mmol, synthesis refers to compound 12c by using intermediate A6 instead of intermediate A11 and intermediate B6 instead of intermediate B10) in TFA (3.0 mL) was stirred at 90 °C for 2 hs. The mixture was concentrated under vacuum to give compound 556 (180 mg). LCMS (M+H ⁺ ): 440. Step 2~3: preparation of (8S,11S,15R)-10-[6-(azetidin-1-yl)-1-[4-fluoro-2- (trideuteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-22 -fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 556) Example 556 was prepared in analogy to the preparation of Example 213 by using intermediate C76 instead of intermediate C74, compound 556b instead of compound 370b and azetidine instead of morpholine. LCMS (M+H ⁺ ): 740. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.55 (d, J = 5.2 Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J = 2.4, 8.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.18 (dd, J = 2.4, 10.4 Hz, 1H), 7.07 - 6.99 (m, 1H), 6.83 - 6.71 (m, 2H), 5.86 (dd, J = 4.0, 15.7 Hz, 1H), 5.68 (br d, J = 7.2 Hz, 1H), 5.32 (d, J = 8.6 Hz, 1H), 5.01 - 4.80 (m, 1H), 4.41 (dd, J = 6.1, 11.0 Hz, 1H), 4.32 - 4.02 (m, 4H), 3.98 (dt, J = 3.5, 7.4 Hz, 3H), 3.04 (s, 3H), 2.84 - 2.80 (m, 3H), 2.78 - 2.71 (m, 1H), 2.62 (s, 3H), 2.56 - 2.37 (m, 2H), 2.35 - 2.17 (m, 2H). Example 557 (8S,11S,15R)-10-[6-(azetidin-1-yl)-1-(2,4-difluorophenyl)pyr azolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme:

Example 557 was prepared in analogy to the preparation of Example 213 by using compound 556b instead of compound 370b and azetidine instead of morpholine. LCMS (M+H ⁺ ): 725. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.54 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 7.73 - 7.54 (m, 1H), 7.50 (dd, J = 2.0, 8.4 Hz, 1H), 7.22 - 7.11 (m, 1H), 7.02 (br dd, J = 5.2, 12.0 Hz, 3H), 5.68 (br d, J = 7.2 Hz, 1H), 5.32 (br d, J = 8.4 Hz, 1H), 5.03 - 4.80 (m, 1H), 4.39 (br dd, J = 6.3, 10.8 Hz, 1H), 4.33 - 4.05 (m, 5H), 4.05 - 3.94 (m, 3H), 3.16 - 3.00 (m, 3H), 2.86 - 2.79 (m, 3H), 2.77 (br s, 1H), 2.61 (s, 3H), 2.55 - 2.39 (m, 2H), 2.37 - 2.19 (m, 2H). Example 558 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one Example 558 was prepared in analogy to the preparation of Example 213 by using compound 557b instead of compound 213a and 3-oxa-6-azabicyclo[3.1.1]heptane instead of morpholine. LCMS (M+H ⁺ ): 767. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.63 (d, J = 5.1 Hz, 1H), 8.10 (s, 1H), 7.93 (br d, J = 6.9 Hz, 1H), 7.55 (br d, J = 6.1 Hz, 1H), 7.40 (br dd, J = 2.1, 9.4 Hz, 1H), 7.08 - 6.96 (m, 3H), 5.70 (br d, J = 6.9 Hz, 1H), 5.30 (br d, J = 8.8 Hz, 1H), 4.50 - 4.14 (m, 10H), 4.08 - 3.91 (m, 2H), 3.84 - 3.78 (m, 1H), 3.76 - 3.70 (m, 1H), 3.15 - 3.02 (m, 3H), 2.99 - 2.93 (m, 3H), 2.89 - 2.79 (m, 4H), 2.57 - 2.42 (m, 2H). Example 559 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicycl o[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 559 was prepared in analogy to the preparation of Example 483 by using 3-oxa-6- azabicyclo[3.1.1]heptane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 559, LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.29 (s, 1H), 7.84 - 7.78 (m, 1H), 7.66 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 2H), 7.11 - 7.06 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.88 - 5.67 (m, 1H), 5.39 - 5.29 (m, 1H), 4.65 (br t, J = 5.1 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.39 - 4.33 (m, 1H), 4.31 - 4.11 (m, 5H), 3.87 (br dd, J = 9.0, 14.1 Hz, 1H), 3.77 - 3.63 (m, 2H), 3.11 (s, 1H), 3.00 (s, 3H), 2.92 - 2.86 (m, 1H), 2.85 - 2.81 (m, 3H), 2.79 - 2.74 (m, 1H), 2.68 - 2.61 (m, 1H), 2.60 - 2.54 (m, 3H), 2.53 - 2.43 (m, 2H). Example 560 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(dimethylamino)pyr azolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazap entacyclo 2,6 8,11 20,24 [15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 560 was prepared in analogy to the preparation of Example 483 by using N- methylmethanamine instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 560, LCMS (M+H ⁺ ): 712. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.20 (s, 1H), 7.84 - 7.77 (m, 1H), 7.67 - 7.60 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.21 (ddd, J = 2.8, 8.8, 10.3 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.88 - 5.68 (m, 1H), 5.44 - 5.25 (m, 1H), 4.66 - 4.61 (m, 1H), 4.49 - 4.39 (m, 1H), 4.28 - 4.10 (m, 2H), 3.97 - 3.86 (m, 1H), 3.19 - 3.10 (m, 3H), 3.04 (s, 6H), 2.94 - 2.87 (m, 1H), 2.86 - 2.82 (m, 3H), 2.76 (d, J = 13.6 Hz, 1H), 2.59 - 2.55 (m, 3H), 2.53 - 2.42 (m, 2H). Example 561 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxa-5-azabicycl o[2.2.1]heptan-5- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 561 was prepared in analogy to the preparation of Example 483 by using 2-oxa-5- azabicyclo[2.2.1]heptane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 561, LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.26 - 8.21 (m, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.30 (dd, J = 2.4, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.11 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.88 - 5.67 (m, 1H), 5.44 - 5.26 (m, 1H), 4.67 - 4.62 (m, 1H), 4.62 - 4.51 (m, 2H), 4.44 (td, J = 5.5, 10.9 Hz, 1H), 4.25 - 4.11 (m, 2H), 3.93 (dd, J = 9.1, 14.2 Hz, 1H), 3.88 - 3.75 (m, 2H), 3.47 (br d, J = 11.1 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.11 - 3.03 (m, 3H), 2.98 - 2.90 (m, 1H), 2.86 - 2.82 (m, 3H), 2.76 (br d, J = 13.4 Hz, 1H), 2.59 - 2.54 (m, 3H), 2.53 - 2.42 (m, 2H), 1.97 - 1.84 (m, 2H). Example 562 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-oxa-3-azabicycl o[3.2.1]octan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 562 was prepared in analogy to the preparation of Example 483 by using 8-oxa-3- azabicyclo[3.2.1]octane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 562, LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.23 - 8.18 (m, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.21 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.08 (dd, J = 3.0, 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.89 - 5.66 (m, 1H), 5.41 - 5.25 (m, 1H), 4.66 - 4.61 (m, 1H), 4.48 - 4.41 (m, 1H), 4.40 - 4.32 (m, 2H), 4.26 - 4.08 (m, 4H), 3.97 - 3.82 (m, 1H), 3.12 - 3.04 (m, 4H), 3.04 - 2.98 (m, 1H), 2.97 - 2.89 (m, 1H), 2.87 - 2.81 (m, 3H), 2.77 (br d, J = 13.4 Hz, 1H), 2.59 - 2.54 (m, 3H), 2.54 - 2.41 (m, 2H), 1.92 - 1.83 (m, 2H), 1.83 - 1.71 (m, 2H). Example 563 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-8-azabicycl o[3.2.1]octan-8- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 563 was prepared in analogy to the preparation of Example 483 by using 3-oxa-8- azabicyclo[3.2.1]octane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. Example 563, LCMS (M+H ⁺ ): 780. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.23 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.31 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.18 - 7.11 (m, 2H), 7.10 - 7.06 (m, 1H), 6.67 (br d, J = 8.4 Hz, 1H), 5.88 - 5.67 (m, 1H), 5.41 - 5.26 (m, 1H), 4.69 - 4.61 (m, 1H), 4.60 - 4.39 (m, 3H), 4.25 - 4.10 (m, 2H), 3.88 - 3.69 (m, 3H), 3.64 - 3.47 (m, 2H), 3.12 - 2.99 (m, 3H), 2.98 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.75 (br d, J = 13.4 Hz, 1H), 2.61 - 2.54 (m, 3H), 2.54 - 2.42 (m, 2H), 2.06 - 1.88 (m, 4H). Example 564 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 564 was prepared according to the following scheme: Step 1: preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hep tane-3-carboxylate (compound 564a) To a tube was added compound 213a (200 mg, 284.45 μmol), tert-butyl (3R,5S)-3,5- dimethylpiperazine-1-carboxylate (160.0 mg, 807 μmol), DIEA (110.3 mg, 149 μL, 853 μmol) and dimethyl sulfoxide (3 mL). The mixture was heated to 100 °C and stirred for 16 hrs. The mixture was concentrated to give a solid, then it was purified via flash column (EA/PE=0~ 100%), the elution was concentrated to give compound 564a (213 mg) as white solid. LCMS (M+H ⁺ ): 865. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) - 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 564) To the flask containing compound 564a (213 mg, 246 μmol, 1.0 eq) was added dichloromethane (2 mL) and TFA (1.48 g, 12.98 mmol). The solution was stirred at r.t. for 1 hr. The mixture was concentrated to give an oil, which was obtained as a powder after freeze-drying. The powder (compound 564b, 30 mg, 34.14 μmol) was added into a tube, then K ₂ CO ₃ (18.9 mg, 136 μmol), 1-fluoro-2-iodo-ethane (35.6 mg, 205 μmol) and acetonitrile (500 μL) were added. The suspension was stirred at r.t. for 16 hrs. The mixture was filtered, the filtrate was purified via prep-HPLC, the elution was freezing dried to give Example 564 (6.7 mg), LCMS (M+H ⁺ ): 811. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.84 (dd, J = 4.4, 15.6 Hz, 1H), 5.32 (d, J = 8.9 Hz, 1H), 4.62 - 4.51 (m, 2H), 4.50 - 4.32 (m, 3H), 4.27 - 4.10 (m, 4H), 3.97 - 3.88 (m, 1H), 3.35 - 3.32 (m, 1H), 3.26 (br d, J = 10.4 Hz, 1H), 3.11 - 2.99 (m, 3H), 2.91 - 2.85 (m, 2H), 2.84 - 2.81 (m, 3H), 2.79 - 2.64 (m, 3H), 2.55 (s, 3H), 2.52 - 2.40 (m, 3H), 1.84 (d, J = 8.0 Hz, 1H). Example 565 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-imidazol-1-yl-pyra zolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4 - d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5 ,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 565a) A mixture of (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 81d-1, 110 mg, 0.19 mmol), 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C79, 58.2 mg, 0.19 mmol) and DIEA (125.0 mg, 0.97 mmol) in anhydrous acetonitrile (2.6 mL) was stirred at 50 °C for 1 hr. After being cooled to room temperature, the reaction mixture was concentrated in vacuo to give some residue. The residue was purified by flash chromatography to afford compound 565a (108 mg) as a light yellow solid. LCMS (M+H) ⁺ : 719. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-imidazol-1-yl- pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dim ethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-on (Example 565) A mixture of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4 -d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19 ,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 565a, 15.0 mg, 0.02 mmol), imidazole (1.4 mg, 0.02 mmol) and potassium carbonate (2.9 mg, 0.02 mmol) in DMF (0.5 mL) was stirred at 60 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to give Example 565 (2.1 mg) as a white powder. LCMS (M+H) ⁺ : 751. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.91 - 8.84 (m, 3H), 7.95 - 7.94 (m, 1H), 7.74 - 7.68 (m, 3H), 7.67 - 7.66 (m, 2H), 7.46 - 7.20 (m, 2H), 5.92 - 5.88 (m, 2H), 5.74 - 5.70 (m, 1H), 4.64 - 4.36 (m, 2H), 4.25 - 4.06 (m, 1H), 4.02 - 3.99 (m, 1H), 3.16 - 3.02 (m, 4H), 3.00 - 2.78 (m, 3H), 2.76 - 2.52 (m, 5H), 0.60 - 0.56 (m, 3H). Example 566 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2,2,2-trifluoroet hoxy)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19 ,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one A mixture of 2,2,2-trifluoroethanol (0.01 mL, 0.1 mmol) and NaH (10.0 mg, 0.25 mmol) in anhydrous DMF (1 mL) was stirred at 0 °C for 1 hr, then (8S,11S,15R)-10-[6-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one (compound 565a, 30.0 mg, 0.04 mmol) was added into the mixture. The resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was adjusted with 1 M aq. HCl to pH = 7, then directly purified by reversed flash chromatography to afford Example 566 (9.0 mg) as a white solid. LCMS (M+H) ⁺ : 783. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.78 (d, J = 5.0 Hz, 1H), 8.48 - 7.74 (m, 1H), 7.70 - 7.59 (m, 2H), 7.50 - 7.38 (m, 2H), 7.32 - 7.14 (m, 2H), 5.88 - 5.65 (m, 2H), 5.57 - 5.39 (m, 1H), 4.97 - 4.68 (m, 1H), 4.62 - 4.24 (m, 3H), 4.24 - 4.11 (m, 1H), 4.08 - 3.95 (m, 1H), 3.16 - 2.86 (m, 5H), 2.85 - 2.48 (m, 7H), 0.62 - 0.49 (m, 3H). Example 570 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-(oxetan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,1 7,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme: Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(4-fluoro-2-hydroxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13 ,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 570a) Compound 570a was prepared in analogy to the preparation of compound 639a by using compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 716. Step 2: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy- phenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18- dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 570) Example 570 was prepared in analogy to the preparation of Example 432 by using 3- iodooxetane instead of 3-iodotetrahydrofuran and compound 570a instead of compound 213a. LCMS (M+H ⁺ ): 738. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 - 8.42 (m, 1H), 8.39 - 7.59 (m, 1H), 7.51 - 7.41 (m, 1H), 7.33 - 7.22 (m, 1H), 7.22 - 7.14 (m, 1H), 7.07 - 6.87 (m, 1H), 6.75 - 6.59 (m, 2H), 5.59 - 5.20 (m, 2H), 5.01 - 4.79 (m, 4H), 4.70 - 4.59 (m, 1H), 4.50 - 3.99 (m, 5H), 3.92 - 3.76 (m, 1H), 3.06 - 2.72 (m, 5H), 2.60 - 2.37 (m, 6H), 0.54 - 0.39 (m, 3H). Example 571 (3S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]pyrrolidine-3- carbonitrile Example 571 was prepared in analogy to the preparation of Example 213 by using compound 326d-1 instead of compound 213a and (3S)-pyrrolidine-3-carbonitrile instead of morpholine. LCMS (M+H ⁺ ): 778. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.75 - 8.59 (m, 1H), 8.31 - 8.17 (m, 1H), 7.79 - 7.61 (m, 3H), 7.29 - 7.11 (m, 3H), 6.08 - 5.78 (m, 1H), 5.47 - 5.22 (m, 1H), 4.80 - 4.56 (m, 1H), 4.44 - 4.18 (m, 3H), 4.05 - 3.95 (m, 1H), 3.92 - 3.64 (m, 3H), 3.58 - 3.37 (m, 3H), 3.18 - 3.07 (m, 3H), 3.05 - 2.91 (m, 2H), 2.90 - 2.71 (m, 5H), 2.68 - 2.47 (m, 1H), 2.42 - 2.19 (m, 2H), 0.75 - 0.58 (m, 3H). Example 572 8-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]-6,7,9,9a- tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-4-one

Example 572 was prepared in analogy to the preparation of Example 213 by using compound 326d-1 instead of compound 213a and 1,6,7,8,9,9a-hexahydropyrazino[2,1- c][1,4]oxazin-4-one instead of morpholine. LCMS (M+H ⁺ ): 838. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.46 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.66 - 7.41 (m, 1H), 7.35 - 7.25 (m, 1H), 7.24 - 7.10 (m, 2H), 7.09 - 6.96 (m, 2H), 5.65 - 5.36 (m, 1H), 5.36 - 5.11 (m, 1H), 4.70 - 4.61 (m, 1H), 4.59 - 4.24 (m, 3H), 4.20 - 3.76 (m, 6H), 3.62 - 3.28 (m, 4H), 3.07 - 2.61 (m, 8H), 2.60 - 2.33 (m, 6H), 0.57 - 0.38 (m, 3H). Example 573 (8S,11S,15R)-10-[6-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c ][1,4]oxazin-8-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 573 was prepared in analogy to the preparation of Example 213 by using compound 326d-1 instead of compound 213a and 1,3,4,6,7,8,9,9a-octahydropyrazino[2,1- c][1,4]oxazine instead of morpholine. LCMS (M+H ⁺ ): 824. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.53 - 8.42 (m, 1H), 8.18 - 8.08 (m, 1H), 7.56 - 7.47 (m, 1H), 7.36 - 7.27 (m, 1H), 7.21 - 6.96 (m, 4H), 5.65 - 5.36 (m, 1H), 5.32 - 5.14 (m, 1H), 4.69 - 4.62 (m, 1H), 4.54 - 4.41 (m, 2H), 4.35 - 4.02 (m, 4H), 3.93 - 3.77 (m, 1H), 3.76 - 3.50 (m, 3H), 3.04 - 2.75 (m, 6H), 2.72 - 2.34 (m, 10H), 2.32 - 2.02 (m, 3H), 0.56 - 0.42 (m, 3H). Example 574 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile The title compound was prepared according to the following scheme: Step 1: preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylate (compound 574a) A mixture of compound 431a (400 mg, 1.1 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (488.0 mg, 3.2 mmol) and DIPEA (1.39 g, 10.7 mmol) in acetonitrile (50 mL) was stirred at 90 °C for 16 hours. Then the reaction solution was concentrated and the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 574a (500 mg), LCMS (M+H ⁺ ): 452. Step 2: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylic acid (compound 574b) A mixture of compound 574a (400 mg, 0.88 mmol) and lithium hydroxide (2.22 mL, 2 M) in methanol (8 mL) was stirred at rt for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted with EA for 2 times, and then the organic layer was dried and concentrated to give compound 574b (380 mg), LCMS (M+H ⁺ ): 438. Step 3: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxamide (compound 574c) A mixture of compound 574b (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol ) and HATU (462 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was stirred at 40 °C for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel chromatography to give compound 574c (300 mg). LCMS (M+H ⁺ ): 437. Step 4: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carbonitrile (compound 574d) To a mixture of compound 574c (280 mg, 0.65 mmol) and pyridine (253 mg, 3.21 mmol) in DCM (28 mL) was added TFAA (404 mg, 1.92 mmol) dropwise at rt. After being stirred at rt for 10 mins, the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was dried and concentrated to give compound 574d (260 mg). LCMS (M+H ⁺ ): 419. Step 5: preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin - 6-yl]azetidine-3-carbonitrile (compound 574e) A mixture of compound 574d (240.0 mg, 0.49 mmol) in DCM (10 mL) and TFA (2 mL), was stirred at rt for 20 hours, then the reaction was concentrated to give compound 574e (120 mg). LCMS (M+H ⁺ ): 329. Step 6: preparation of 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o- 2,6 8,11 20,24 13,18-dimethyl-12-oxo-5,7,10,13,17,19,26-heptazapentacyclo[1 5.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile (Example 574) A mixture of compound 574e (34.7 mg, 0.1 mmol), PyBOP (68.8 mg, 0.13 mmol) and DIPEA (57.0 mg, 0.44 mmol) in DMF (2 mL) was stirred at 50 °C for 3 hours. Then compound 326d-1 (40.0 mg, 0.09 mmol) was added and the reaction was stirred at 80 °C for 2 hours, the reaction mixture was directly purified by prep-HPLC to give Example 574 (20 mg). LCMS (M+H ⁺ ): 764. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.48 - 8.38 (m, 1H), 8.17 - 8.06 (m, 1H), 7.55 - 7.42 (m, 1H), 7.35 - 7.24 (m, 1H), 7.20 - 6.92 (m, 4H), 5.57 - 5.29 (m, 1H), 5.23 - 5.09 (m, 1H), 4.60 - 4.36 (m, 1H), 4.34 - 4.21 (m, 1H), 4.18 - 4.08 (m, 3H), 4.06 - 3.94 (m, 3H), 3.92 - 3.80 (m, 1H), 3.64 - 3.45 (m, 1H), 3.17 - 3.10 (m, 1H), 3.02 - 2.85 (m, 3H), 2.83 - 2.65 (m, 2H), 2.54 - 2.38 (m, 5H), 2.38 - 2.22 (m, 1H), 0.52 - 0.38 (m, 3H). Example 575 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-oxa-6-azabicycl o[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one The title compound was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4 - d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10, 13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (compound 575a) Compound 575a was prepared in analogy to the preparation of compound 213a by using compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 718. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-oxa-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 575) A mixture of compound 575a (45 mg, 0.06 mmol), 3-oxa-6-azabicyclo[3.1.1]heptane; hydrochloride (34 mg, 0.25 mmol), CsF (29 mg, 0.19 mmol) and DIPEA (41 mg, 0.32 mmol) in dimethyl sulfoxide (2 mL) was stirred at 110 °C for 16 hours, then the reaction solution was directly purified by prep-HPLC to give Example 575 (25 mg). LCMS (M+H ⁺ ): 781. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.63 - 8.49 (m, 1H), 8.32 - 7.54 (m, 2H), 7.45 - 7.35 (m, 1H), 7.33 - 7.18 (m, 2H), 7.17 - 7.01 (m, 2H), 5.71 - 5.45 (m, 1H), 5.36 - 5.22 (m, 1H), 4.77 - 4.70 (m, 1H), 4.57 - 4.42 (m, 1H), 4.40 - 4.32 (m, 2H), 4.30 - 4.11 (m, 4H), 4.05 - 3.86 (m, 1H), 3.80 - 3.53 (m, 2H), 3.29 - 3.21 (m, 1H), 3.13 - 2.95 (m, 3H), 2.94 - 2.81 (m, 2H), 2.76 - 2.57 (m, 6H), 2.52 - 2.36 (m, 1H), 1.90 - 1.74 (m, 1H), 0.68 - 0.46 (m, 3H). Example 576 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-oxa-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 576 was prepared in analogy to the preparation of Example 575 by using compound 570a instead of compound 575a. LCMS (M+H ⁺ ): 779. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.62 - 8.46 (m, 1H), 8.31 - 7.51 (m, 2H), 7.48 - 7.38 (m, 1H), 7.37 - 7.23 (m, 1H), 7.15 - 6.99 (m, 1H), 6.80 - 6.65 (m, 2H), 5.79 - 5.44 (m, 1H), 5.34 - 5.19 (m, 1H), 4.74 - 4.65 (m, 1H), 4.49 - 4.11 (m, 7H), 4.06 - 3.85 (m, 1H), 3.83 - 3.65 (m, 2H), 3.29 - 3.16 (m, 1H), 3.12 - 2.92 (m, 3H), 2.92 - 2.81 (m, 2H), 2.79 - 2.39 (m, 7H), 1.95 - 1.79 (m, 1H), 0.66 - 0.48 (m, 3H). Example 577 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 577 was prepared in analogy to the preparation of Example 575 by using compound 570a instead of compound 575a and 3-methyl-3,6-diazabicyclo[3.1.1]heptane instead of 3-oxa-6-azabicyclo[3.1.1]heptane. LCMS (M+H ⁺ ): 792. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.62 - 8.53 (m, 1H), 8.29 - 7.55 (m, 2H), 7.45 - 7.35 (m, 1H), 7.32 - 7.22 (m, 1H), 7.16 - 7.03 (m, 1H), 6.83 - 6.63 (m, 2H), 5.72 - 5.46 (m, 1H), 5.38 - 5.24 (m, 1H), 4.79 - 4.69 (m, 1H), 4.48 - 4.09 (m, 5H), 4.04 - 3.88 (m, 1H), 3.26 - 3.17 (m, 2H), 3.13 - 2.84 (m, 7H), 2.70 - 2.43 (m, 8H), 2.42 - 2.31 (m, 3H), 2.01 - 1.89 (m, 1H), 0.67 - 0.50 (m, 3H). Example 578 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile Example 578 was prepared in analogy to the preparation of Example 574 by using compound 81d-1 instead of compound 326d-1. LCMS (M+H ⁺ ): 765. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.76 - 8.61 (m, 1H), 8.28 - 8.08 (m, 1H), 7.60 - 7.47 (m, 2H), 7.41 - 7.29 (m, 2H), 7.18 - 6.99 (m, 2H), 5.81 - 5.71 (m, 1H), 5.69 - 5.55 (m, 1H), 5.45 - 5.18 (m, 1H), 4.40 - 4.26 (m, 2H), 4.23 - 3.96 (m, 5H), 3.94 - 3.86 (m, 1H), 3.66 - 3.51 (m, 1H), 3.03 - 2.84 (m, 4H), 2.83 - 2.68 (m, 2H), 2.65 - 2.41 (m, 6H), 0.54 - 0.40 (m, 3H). Example 579 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 579 was prepared in analogy to the preparation of Example 431 by using Intermediate C89 instead of compound 431c and compound 81d-1 instead of compound 370b. LCMS (M+H ⁺ ): 837. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.71 - 8.59 (m, 1H), 8.20 - 8.10 (m, 1H), 7.59 - 7.46 (m, 2H), 7.38 - 7.26 (m, 2H), 7.19 - 6.98 (m, 2H), 5.84 - 5.63 (m, 2H), 5.40 - 5.16 (m, 1H), 4.61 - 4.45 (m, 4H), 4.37 - 4.26 (m, 2H), 4.22 - 4.03 (m, 3H), 3.95 - 3.80 (m, 1H), 3.80 - 3.62 (m, 1H), 3.32 - 3.25 (m, 1H), 3.18 - 3.09 (m, 2H), 2.97 - 2.82 (m, 3H), 2.78 - 2.66 (m, 4H), 2.63 - 2.37 (m, 7H), 1.79 - 1.68 (m, 1H), 0.53 - 0.40 (m, 3H). Example 580 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 580a) A mixture of 1-bromo-2-methoxy-ethane (701.0 mg, 5.0 mmol), tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.5 mmol) and K ₂ CO ₃ (697 mg, 5.0 mmol) in acetonitrile (10 mL) was stirred at 60 °C for 6 hours, then the solid was filtered off, the filtrate was concentrated to give compound 580a (600.0 mg), LCMS (M+H ⁺ ): 257. Step 2: preparation of 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (compound 580b) A mixture of compound 580a (500 mg, 1.76 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 30 mins, then the reaction was concentrated to give compound 580b (300 mg), LCMS (M+H ⁺ ): 157. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl )- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 580) A mixture of compound 575a (30 mg, 0.04 mmol), compound 580b (26 mg, 0.16 mmol), CsF (19 mg, 0.12 mmol) and DIPEA (27 mg, 0.2 mmol) in DMSO (2 mL) was stirred at 110 °C for 16 hours, then the reaction solution was directly purified by prep-HPLC to give Example 580 (8 mg). LCMS (M+H ⁺ ): 838. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.64 - 8.52 (m, 1H), 8.36 - 8.26 (m, 1H), 7.70 - 7.56 (m, 1H), 7.47 - 7.39 (m, 1H), 7.35 - 7.06 (m, 4H), 5.73 - 5.65 (m, 1H), 5.41 - 5.32 (m, 1H), 4.62 - 4.55 (m, 4H), 4.46 - 4.41 (m, 1H), 4.33 - 4.27 (m, 2H), 4.21 - 4.15 (m, 1H), 4.02 - 3.96 (m, 1H), 3.64 - 3.52 (m, 4H), 3.30 - 3.28 (m, 2H), 3.17 - 2.85 (m, 8H), 2.74 - 2.43 (m, 8H), 2.03 - 1.89 (m, 1H), 0.70 - 0.52 (m, 3H). Example 581 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(2- methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3, 4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 581 was prepared in analogy to the preparation of Example 580 by using compound 570a instead of compound 575a. LCMS (M+H ⁺ ): 836. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.56 - 8.46 (m, 1H), 8.30 - 8.19 (m, 1H), 7.58 - 7.44 (m, 1H), 7.42 - 7.22 (m, 2H), 7.09 - 7.00 (m, 1H), 6.75 - 6.57 (m, 2H), 5.70 - 5.50 (m, 1H), 5.33 - 5.22 (m, 1H), 4.71 - 4.64 (m, 2H), 4.50 - 4.40 (m, 1H), 4.38 - 4.25 (m, 2H), 4.22 - 4.03 (m, 2H), 3.92 - 3.70 (m, 2H), 3.65 - 3.49 (m, 4H), 3.26 - 3.25 (m, 3H), 3.18 - 3.10 (m, 3H), 3.07 - 2.90 (m, 4H), 2.87 - 2.71 (m, 2H), 2.66 - 2.36 (m, 6H), 1.96 - 1.81 (m, 1H), 0.57 - 0.45 (m, 3H) Example 582 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[6-[3-(2-fluoroethyl)-3, 6-diazabicyclo[3.1.1]heptan-6- yl]-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 581 was prepared in analogy to the preparation of Example 580 by using 1- fluoro-2-iodo-ethane instead of 1-bromo-2-methoxy-ethane and compound 570a instead of compound 575a. LCMS (M+H ⁺ ): 824. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.58 - 8.48 (m, 1H), 8.26 - 8.19 (m, 1H), 7.59 - 7.36 (m, 3H), 7.10 - 7.00 (m, 1H), 6.74 - 6.60 (m, 2H), 5.79 - 5.56 (m, 1H), 5.28 - 5.17 (m, 1H), 4.70 - 4.59 (m, 2H), 4.50 - 4.23 (m, 3H), 4.23 - 4.08 (m, 2H), 3.96 - 3.80 (m, 2H), 3.79 - 3.60 (m, 3H), 3.43 - 3.26 (m, 3H), 3.08 - 2.72 (m, 6H), 2.67 - 2.52 (m, 6H), 2.47 - 2.35 (m, 1H), 1.98 - 1.89 (m, 1H), 0.55 - 0.47 (m, 3H). Example 583 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[8-(2-fluoroethyl) -5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 583 was prepared in analogy to the preparation of Example 564 by using tert- butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate instead of tert-butyl (3R,5S)-3,5- dimethylpiperazine-1-carboxylate and compound 575a instead of compound 213a. LCMS (M+H ⁺ ): 856. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 - 8.54 (m, 1H), 8.33 - 8.21 (m, 1H), 7.68 - 7.47 (m, 3H), 7.28 - 7.12 (m, 3H), 5.88 - 5.67 (m, 1H), 5.43 - 5.31 (m, 1H), 4.74 - 4.60 (m, 2H), 4.44 - 4.12 (m, 5H), 4.10 - 3.82 (m, 7H), 3.44 - 3.36 (m, 2H), 3.26 - 3.20 (m, 2H), 3.18 - 3.02 (m, 5H), 3.00 - 2.89 (m, 2H), 2.79 - 2.41 (m, 6H), 0.73 - 0.56 (m, 3H). Example 584 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[8-(2-methoxyethyl )-5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 584 was prepared in analogy to the preparation of Example 564 by using 8-oxa- 2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester instead of tert-butyl (3R,5S)-3,5- dimethylpiperazine-1-carboxylate, 1-bromo-2-methoxy-ethane instead of 1-fluoro-2-iodo-ethane and compound 575a instead of compound 213a. LCMS (M+H ⁺ ): 868. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.44 (m, 1H), 8.21 - 8.12 (m, 1H), 7.58 - 7.47 (m, 1H), 7.44 - 7.34 (m, 1H), 7.32 - 7.24 (m, 1H), 7.19 - 6.98 (m, 3H), 5.68 - 5.51 (m, 1H), 5.30 - 5.21 (m, 1H), 4.36 - 4.03 (m, 6H), 4.02 - 3.78 (m, 8H), 3.70 - 3.59 (m, 3H), 3.33 - 3.30 (m, 3H), 3.06 - 2.91 (m, 4H), 2.90 - 2.72 (m, 3H), 2.63 - 2.31 (m, 7H), 0.57 - 0.38 (m, 3H). Example 585 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[5-(2-fluoroethyl) -8-oxa-2,5- diazaspiro[3.5]nonan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 585 was prepared in analogy to the preparation of Example 580 by using 1- fluoro-2-iodo-ethane instead of 1-bromo-2-methoxy-ethane and tert-butyl 8-oxa-2,5- diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate. LCMS (M+H ⁺ ): 856. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.65 (d, J = 5.1 Hz, 1H), 8.35 - 8.23 (m, 1H), 7.71 - 7.54 (m, 3H), 7.34 - 7.08 (m, 3H), 5.97 - 5.69 (m, 1H), 5.46 - 5.27 (m, 1H), 4.82 - 4.76 (m, 1H), 4.68 - 4.62 (m, 1H), 4.61 - 4.49 (m, 1H), 4.46 - 4.35 (m, 1H), 4.35 - 4.13 (m, 3H), 4.11 - 3.84 (m, 3H), 3.83 - 3.73 (m, 5H), 3.49 - 3.39 (m, 1H), 3.20 - 3.04 (m, 5H), 3.02 - 2.93 (m, 2H), 2.91 - 2.71 (m, 7H), 2.68 - 2.49 (m, 1H), 0.70 - 0.57 (m, 3H). Example 586 4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-one

The title compound was prepared according to the following scheme: Step 1: preparation of 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-one (compound 586a) A mixture of compound 431a (680 mg, 1.82 mmol), morpholin-3-one (368.0 mg, 3.64 mmol), K ₃ PO ₄ (968 mg, 4.56 mmol,), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (211 mg, 0.36 mmol) and tris(dibenzylideneacetone) dipalladium (167.0 mg, 0.18 mmol) in 1,4- dioxane (8.00 mL) was stirred for 1 h at 110 °C under nitrogen atmosphere. The reaction mixture was poured into 100 mL of water/ice and extracted with ethyl acetate (100 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to afford compound 586a (350 mg) as an off-white solid. LCMS (M+H ⁺ ): 438. Step 2: preparation of 4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin - 6-yl]morpholin-3-one (compound 586b) A mixture of compound 586a (330 mg, 0.75 mmol) in dichloromethane (3.00 mL) and trifluoroacetic acid (3.00 mL) was stirred for 3 h at 25 °C. Then the reaction mixture was concentrated to give compound 586b (250 mg). LCMS (M+H ⁺ ): 348. Step 3: preparation of 4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-one (Example 586) A mixture of compound 586b (35.0 mg, 0.100 mmol), N,N-diisopropylethylamine (47.0 μL, 0.27 mmol) and PyBOP (53.0 mg, 0.100 mmol, 1.49 eq) in DMF (2 mL) was stirred for 1 h at 25 °C. Then compound 370b was added and the reaction mixture was stirred for 2 h at 50 °C. The reaction mixture was directly purified by prep-HPLC to give Example 586 (21 mg). LCMS (M+H ⁺ ): 768. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.55 - 7.84 (m, 1H), 7.78 - 7.72 (m, 2H), 7.64 - 7.60 (m, 1H), 7.38 - 7.33 (m, 2H), 7.14 - 7.07 (m, 2H), 6.67 - 6.61 (m, 1H), 5.84 - 5.61 (m, 2H), 5.55 - 5.35 (m, 1H), 4.65 - 4.30 (m, 2H), 4.28 - 3.60 (m, 9H), 3.05 - 2.80 (m, 4H), 2.77 - 2.61 (m, 4H), 2.47 - 2.30 (m, 5H). Example 587 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-py rrolidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one A mixture of compound 213a (40.0 mg, 0.06 mmol), 3-methyl-2-pyrrolidinone (28.0 mg, 0.28 mmol), K ₃ PO ₄ (36.0 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (0) (15.0 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (20.0 mg, 0.03 mmol) in 1,4- dioxane (2 mL) was stirred for 1 h at 110 °C under nitrogen atmosphere. Then the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 587 (19.2 mg). LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.47 (s, 1H), 7.80 - 7.75 (m, 2H), 7.62 - 7.55 (m, 1H), 7.38 - 7.31 (m, 2H), 7.14 - 7.07 (m, 2H), 6.67 - 6.61 (m, 1H), 5.80 - 5.61 (m, 2H), 5.45-5.37 (m, 1H), 4.66 - 3.58 (m, 7H), 3.05 - 2.56 (m, 9H), 2.47 - 2.43 (m, 4H), 2.41 - 2.13 (m, 2H), 1.68 - 1.52 (m, 1H), 1.14 - 1.09 (m, 3H). Example 588 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,8-diazabicyclo[3.2.1]octan-8- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 588 was prepared in analogy to the preparation of Example 564 by using tert- butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 825. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.15 (br dd, J = 2.8, 10.8 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.73 - 6.66 (m, 1H), 5.89 - 5.69 (m, 1H), 5.41 - 5.28 (m, 1H), 4.67 - 4.45 (m, 6H), 4.25 - 4.19 (m, 1H), 4.19 - 4.10 (m, 1H), 3.97 - 3.82 (m, 1H), 3.14 - 3.11 (m, 1H), 3.05 (s, 3H), 2.99 - 2.93 (m, 1H), 2.91 (br d, J = 14.3 Hz, 1H), 2.86 - 2.84 (m, 3H), 2.77 (br d, J = 13.0 Hz, 2H), 2.71 - 2.60 (m, 2H), 2.56 (s, 3H), 2.53 - 2.45 (m, 2H), 2.05 - 1.88 (m, 4H), 1.36 - 1.25 (m, 1H). Example 589 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 589 was prepared in analogy to the preparation of Example 431 by using Intermediate C88 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 836. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 (d, J = 5.1 Hz, 1H), 8.17 (s, 1H), 7.62 (br d, J = 6.1 Hz, 1H), 7.40 (d, J = 2.2, 8.3 Hz, 1H), 7.27 (dd, J = 2.0, 10.1 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.13 (br d, J = 4.6 Hz, 1H), 7.08 (br d, J = 5.1 Hz, 1H), 5.71 - 5.43 (m, 1H), 5.38 - 5.17 (m, 1H), 4.75 - 4.61 (m, 4H), 4.53 - 4.48 (m, 1H), 4.47 - 4.41 (m, 1H), 4.27 (br dd, J = 5.8, 10.9 Hz, 1H), 4.21 - 4.08 (m, 2H), 4.04 - 3.95 (m, 1H), 3.93 - 3.83 (m, 1H), 3.65 - 3.54 (m, 1H), 3.52 - 3.40 (m, 2H), 3.29 - 3.23 (m, 1H), 3.11 - 2.98 (m, 3H), 2.93 - 2.80 (m, 3H), 2.80 - 2.74 (m, 1H), 2.64 - 2.54 (m, 5H), 2.45 (ddd, J = 4.3, 8.9, 13.3 Hz, 1H), 1.97 - 1.79 (m, 2H), 0.63 - 0.51 (m, 3H). Example 590 (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 590 was prepared in analogy to the preparation of Example 431 by using Intermediate C81 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 844. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.56 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H), 7.70 - 7.56 (m, 1H), 7.41 (dd, J = 2.3, 8.4 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.18 - 7.06 (m, 2H), 5.66 (br dd, J = 3.8, 15.5 Hz, 1H), 5.31 (br d, J = 8.8 Hz, 1H), 4.99 (br d, J = 12.0 Hz, 2H), 4.69 (br s, 1H), 4.61 (s, 1H), 4.46 - 3.73 (m, 6H), 3.66 - 3.35 (m, 2H), 3.32 - 3.20 (m, 1H), 3.00 (s, 3H), 2.97 - 2.74 (m, 5H), 2.62 (br s, 1H), 2.59 (s, 3H), 2.57 - 2.38 (m, 2H), 1.71 (br d, J = 8.0 Hz, 1H), 0.59 (t, J = 6.9 Hz, 3H). Example 591 (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 591 was prepared in analogy to the preparation of Example 431 by using Intermediate C81 instead of compound 431c and compound 556b instead of compound 370b.. LCMS (M+H ⁺ ): 830. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.3 Hz, 1H), 8.24 (s, 1H), 7.71 - 7.53 (m, 1H), 7.39 (dd, J = 2.5, 8.5 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.17 - 7.04 (m, 2H), 5.66 (br dd, J = 4.1, 15.6 Hz, 1H), 5.31 (d, J = 8.9 Hz, 1H), 5.05 - 4.88 (m, 2H), 4.69 (br s, 1H), 4.59 (br s, 1H), 4.32 (br dd, J = 5.7, 11.2 Hz, 1H), 4.27 - 4.04 (m, 3H), 3.91 (br dd, J = 9.2, 14.1 Hz, 1H), 3.69 - 3.31 (m, 3H), 3.01 (s, 3H), 2.89 (br dd, J = 7.8, 12.9 Hz, 4H), 2.82 (s, 3H), 2.80 (br d, J = 3.9 Hz, 1H), 2.55 (s, 3H), 2.53 - 2.40 (m, 2H), 1.70 (d, J = 8.1 Hz, 1H). Example 592 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-5-(3-phenylpropylami no)pyrazole-4-carbonyl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of ethyl 5-acetamido-1-(2,4-difluorophenyl)pyrazole-4- carboxylate (compound 592b) To a mixture of compound 592a (1.8 g, 6.7 mmol) in Chloroform (10 mL) were added acetyl chloride (0.62 mL, 8.8 mmol) under N ₂ . After being heated to 65 °C for 16 hrs, the reaction mixture was poured into water, extracted with DCM. The organic layer was dried and concentrated, the residue was purified by flash chromatography to give compound 592b (1 g) as a yellow solid. LCMS (M+H ⁺ ): 310. Step 2: preparation of ethyl 5-[acetyl(3-phenylpropyl)amino]-1-(2,4- difluorophenyl)pyrazole-4-carboxylate (compound 592c) To a solution of compound 592b (200 mg, 0.65 mmol) in DMF (2 mL) was added sodium hydride (38.8 mg, 0.97 mmol) at 0 °C under N ₂ . The mixture was stirred at 0 °C for 0.5 hrs and then 1-iodo-3-phenylpropane (239 mg, 0.97 mmol) was added dropwise. After being stirred at 25 °C for 2 hrs, the reaction mixture was poured into sat. NH ₄ Cl (10 mL), and then extracted with ethyl acetate. The organic phase was dried and concentrated, the residue was purified by flash chromatography to afford compound 592c (90 mg) as a colorless oil. LCMS (M+H ⁺ ): 428. Step 3: preparation of 1-(2,4-difluorophenyl)-5-(3-phenylpropylamino)pyrazole-4- carboxylic acid (compound 592d) To a solution of compound 592c (90 mg, 0.21 mmol) in ethanol (1 mL) was added KOH (120 mg, 1.07 mmol) at 25 °C and then stirred at 60 °C for 3 hrs. The pH was adjusted to about 6, then the reaction mixture was concentrated, the residue was purified by prep-TLC to give compound 592d (35.0 mg) as colorless oil. LCMS (M+H ⁺ ): 358. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-5-(3- phenylpropylamino)pyrazole-4-carbonyl]-22-fluoro-15-methoxy- 13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one (Example 592) To a solution of compound 592d (35.0 mg, 0.1 mmol) in DMF (1 mL) were added HATU (81.9 mg, 0.22 mmol), compound 370b (43.0 mg, 0.1 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) at rt, and then the mixture was stirred at rt for 1 h. The reaction mixture was directly purified by prep-HPLC to give Example 592(22.2 mg). LCMS (M+H ⁺ ): 778. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ= 8.05 (br s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.59 - 7.44 (m, 1H), 7.36 - 7.26 (m, 1H), 7.25 - 7.12 (m, 5H), 7.10 - 7.02 (m, 4H), 6.62 (d, J = 8.3 Hz, 1H), 5.89 - 5.71 (m, 1H), 5.25 - 5.10 (m, 1H), 4.63 - 4.56 (m, 1H), 4.55 - 4.31 (m, 2H), 4.22 - 4.09 (m, 2H), 3.99 - 3.88 (m, 1H), 2.98 (s, 3H), 2.83 (s, 3H), 2.74 (br t, J = 6.8 Hz, 3H), 2.62 - 2.56 (m, 2H), 2.54 (s, 3H), 2.50 - 2.33 (m, 2H), 1.71 (br t, J = 7.0 Hz, 2H). Example 593 (8S,11S,15R)-10-[6-[(1S,5S)-3-cyclopropyl-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 593 was prepared in analogy to the preparation of Example 431 by using Intermediate C91 instead of compound 431c. LCMS (M+H ⁺ ): 805. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.66 - 7.52 (m, 1H), 7.30 (dd, J = 2.3, 8.4 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.16 (br dd, J = 2.4, 10.4 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.89 (br dd, J = 4.0, 15.1 Hz, 1H), 5.36 (d, J = 8.9 Hz, 1H), 4.59 (br d, J = 5.3 Hz, 1H), 4.41 (br dd, J = 6.1, 11.1 Hz, 1H), 4.25 - 4.06 (m, 4H), 3.94 (br dd, J = 9.2, 14.1 Hz, 1H), 3.49 - 3.33 (m, 2H), 3.01 (s, 3H), 2.91 (br d, J = 13.8 Hz, 1H), 2.85 (s, 4H), 2.78 - 2.70 (m, 2H), 2.68 - 2.58 (m, 1H), 2.55 (s, 3H), 2.53 - 2.39 (m, 3H), 1.66 (br d, J = 8.1 Hz, 1H), 0.52 - 0.04 (m, 4H). Example 594 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxopyrrolidin-1 -yl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 594 was prepared in analogy to the preparation of Example 586 by using 2- pyrrolidone instead of morpholin-3-one. LCMS (M+H ⁺ ): 752. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.48 - 7.80 (m, 3H), 7.62 - 7.55 (m, 1H), 7.40 - 7.28 (m, 2H), 7.16 - 7.07 (m, 2H), 6.71 - 6.60 (m, 1H), 5.79 - 5.68 (m, 1H), 5.63 - 5.51 (m, 1H), 5.45 - 5.36 (m, 1H), 4.67 - 3.90 (m, 5H), 3.89 - 3.65 (m, 2H), 3.04 - 2.68 (m, 7H), 2.60 - 2.52 (m, 1H), 2.49 - 2.39 (m, 6H), 2.38 - 2.28 (m, 1H), 2.07 - 1.86 (m, 2H). Example 595 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6-oxa-3-azabicycl o[3.1.1]heptan-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 595 was prepared in analogy to the preparation of Example 483 by using 6-oxa-3- azabicyclo[3.1.1]heptane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.83 - 7.78 (m, 1H), 7.69 - 7.63 (m, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.14 (dd, J = 2.5, 10.5 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.89 - 5.66 (m, 1H), 5.43 (d, J = 9.0 Hz, 1H), 4.66 (br d, J = 6.4 Hz, 2H), 4.59 (s, 2H), 4.46 - 4.42 (m, 1H), 4.32 - 4.09 (m, 4H), 3.89 (br dd, J = 8.8, 13.6 Hz, 2H), 3.22 - 3.17 (m, 1H), 3.11 (s, 1H), 3.04 (s, 3H), 2.98 - 2.86 (m, 2H), 2.84 (s, 3H), 2.56 - 2.55 (m, 3H), 2.52 - 2.45 (m, 2H). Example 596 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 596 was prepared in analogy to the preparation of Example 431 by using Intermediate C85 instead of compound 431c. LCMS (M+H ⁺ ): 811. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.22 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.32 (dd, J = 2.4, 8.4 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 7.11 - 7.06 (m, 1H), 6.71 - 6.64 (m, 1H), 5.92 - 5.65 (m, 1H), 5.45 - 5.22 (m, 1H), 4.50 - 4.37 (m, 2H), 4.23 - 4.11 (m, 2H), 3.99 - 3.82 (m, 2H), 3.77 - 3.69 (m, 2H), 3.65 - 3.60 (m, 2H), 3.12 - 3.03 (m, 3H), 2.99 - 2.90 (m, 1H), 2.87 - 2.83 (m, 3H), 2.75 (br d, J = 13.5 Hz, 1H), 2.68 - 2.59 (m, 2H), 2.59 - 2.55 (m, 3H), 2.48 (dt, J = 4.5, 8.7 Hz, 2H), 2.05 (s, 1H), 1.65 - 1.54 (m, 1H), 1.18 - 1.18 (m, 1H), 1.20 (t, J = 7.1 Hz, 2H). Example 597 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxeta n-3-yl)methyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one

Example 597 was prepared in analogy to the preparation of Example 431 by using Intermediate C90 instead of compound 431c. LCMS (M+H ⁺ ): 853. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.06 (s, 1H), 7.77 - 7.71 (m, 1H), 7.60 - 7.53 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 7.06 - 6.98 (m, 3H), 6.47 (d, J = 8.1 Hz, 1H), 6.16 - 5.98 (m, 1H), 5.29 (d, J = 9.0 Hz, 1H), 5.23 - 5.13 (m, 1H), 4.65 - 4.58 (m, 2H), 4.51 - 4.41 (m, 2H), 4.26 - 4.15 (m, 4H), 4.02 - 3.93 (m, 1H), 3.57 - 3.47 (m, 1H), 3.07 (s, 1H), 3.03 - 2.93 (m, 6H), 2.85 - 2.83 (m, 3H), 2.76 - 2.62 (m, 7H), 2.54 - 2.47 (m, 2H), 2.39 (br s, 2H). Example 598 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxeta n-3-yl)methyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 598 was prepared in analogy to the preparation of Example 431 by using Intermediate C90 instead of compound 431c and compound 78d-2 instead of compound 370b.. LCMS (M+H ⁺ ): 855. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.60 - 8.52 (m, 1H), 7.56 - 7.47 (m, 1H), 7.46 - 7.39 (m, 1H), 7.34 - 7.23 (m, 2H), 7.17 - 7.09 (m, 1H), 7.01 - 6.92 (m, 2H), 5.84 - 5.77 (m, 1H), 5.39 - 5.22 (m, 1H), 4.75 - 4.43 (m, 4H), 4.38 - 4.27 (m, 2H), 4.24 - 4.16 (m, 2H), 4.15 - 3.99 (m, 2H), 3.44 (s, 3H), 3.34 - 3.18 (m, 2H), 3.02 (s, 2H), 2.97 - 2.82 (m, 5H), 2.79 - 2.65 (m, 5H), 2.63 - 2.45 (m, 5H). Example 599 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-hydroxy-6-(trif luoromethyl)-2- azaspiro[3.3]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-f luoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 599 was prepared in analogy to the preparation of Example 483 by using 6- (trifluoromethyl)-2-azaspiro[3.3]heptan-6-ol instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2- dioxide. LCMS (M+H ⁺ ): 848. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.24 (s, 1H), 7.86 - 7.76 (m, 1H), 7.65 - 7.56 (m, 1H), 7.31 (dd, J = 2.4, 8.6 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.18 - 7.05 (m, 3H), 6.67 (d, J = 8.4 Hz, 1H), 5.88 - 5.65 (m, 1H), 5.42 - 5.25 (m, 1H), 4.62 - 4.57 (m, 2H), 4.49 - 4.36 (m, 1H), 4.24 - 4.10 (m, 3H), 4.04 - 3.92 (m, 3H), 3.14 - 3.02 (m, 3H), 2.98 - 2.88 (m, 1H), 2.88 - 2.81 (m, 3H), 2.80 - 2.70 (m, 1H), 2.70 - 2.61 (m, 2H), 2.60 - 2.54 (m, 3H), 2.53 - 2.42 (m, 2H), 2.41 - 2.31 (m, 2H). Example 600 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6-oxa-1-azaspiro[ 3.3]heptan-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 600 was prepared in analogy to the preparation of Example 483 by using 6-oxa-1- azaspiro[3.3]heptane instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.61 (dt, J = 6.1, 8.7 Hz, 1H), 7.31 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.09 (d, J = 7.6 Hz, 2H), 6.66 (d, J = 8.4 Hz, 1H), 5.80 (dd, J = 4.2, 15.5 Hz, 1H), 5.59 - 5.47 (m, 2H), 5.33 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 6.6 Hz, 1H), 4.63 - 4.53 (m, 3H), 4.48 - 4.37 (m, 1H), 4.27 (d, J = 11.0 Hz, 1H), 4.15 (dd, J = 10.9, 15.4 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.83 - 3.76 (m, 2H), 3.02 - 2.93 (m, 3H), 2.88 - 2.83 (m, 3H), 2.80 - 2.74 (m, 1H), 2.62 - 2.56 (m, 3H), 2.56 - 2.43 (m, 4H). Example 601 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(2-fluoroethyl) -1,6-diazaspiro[3.3]heptan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 601 was prepared in analogy to the preparation of Example 564 by using tert- butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 811. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (s, 1H), 7.88 - 7.79 (m, 1H), 7.71 - 7.61 (m, 1H), 7.33 (dd, J = 2.5, 8.5 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.22 - 7.14 (m, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.69 (br d, J = 8.3 Hz, 1H), 5.87 - 5.70 (m, 1H), 5.47 - 5.28 (m, 1H), 4.66 - 4.57 (m, 2H), 4.51 - 4.40 (m, 2H), 4.33 - 4.24 (m, 2H), 4.23 - 4.15 (m, 2H), 4.15 - 4.06 (m, 1H), 4.05 - 3.91 (m, 2H), 3.90 - 3.72 (m, 2H), 3.59 - 3.47 (m, 2H), 3.10 - 2.94 (m, 3H), 2.92 - 2.82 (m, 4H), 2.70 - 2.61 (m, 2H), 2.61 - 2.56 (m, 4H), 2.56 - 2.49 (m, 2H). Example 602 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,1 8-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one

Example 602 was prepared in analogy to the preparation of Example 431 by using Intermediate C80 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 826. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 (d, J = 5.3 Hz, 1H), 8.28 (s, 1H), 7.71 - 7.55 (m, 1H), 7.41 (dd, J = 2.5, 8.5 Hz, 1H), 7.30 (dd, J = 2.5, 10.3 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.14 (m, 1H), 7.12 (d, J = 5.1 Hz, 1H), 5.69 (dd, J = 4.1, 15.4 Hz, 1H), 5.34 (d, J = 8.8 Hz, 1H), 4.86 - 4.82 (m, 1H), 4.80 - 4.71 (m, 1H), 4.65 - 4.36 (m, 4H), 4.31 - 4.13 (m, 4H), 4.06 - 3.94 (m, 1H), 3.36 (br s, 1H), 3.30 - 3.23 (m, 1H), 3.12 (s, 1H), 3.09 - 2.96 (m, 3H), 2.94 - 2.84 (m, 3H), 2.83 - 2.70 (m, 2H), 2.68 - 2.64 (m, 1H), 2.61 (s, 4H), 2.56 - 2.45 (m, 2H), 0.61 (t, J = 6.9 Hz, 3H). Example 603 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-( 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

To a solution of compound 639a (40.0 mg, 0.06 mmol), 3-oxa-6-azabicyclo[3.1.1] heptane; hydrochloride (38.7 mg, 0.29 mmol) in ACN (1 mL) was added potassium carbonate (78.8 mg, 0.57 mmol) and then stirred at 95 °C for 16 hrs. The reaction mixture was poured into water (20 mL) and then extracted with EA (20 mL), the organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 603 (25 mg). LCMS (M+H ⁺ ): 764. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.34 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.62 - 7.58 (m, 2H), 7.16 (d, J = 7.4 Hz, 1H), 6.80 - 6.73 (m, 3H), 6.21 (dd, J = 4.6, 15.4 Hz, 1H), 5.41 (d, J = 9.0 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.56 - 4.18 (m, 8H), 4.01 - 3.52 (m, 4H), 3.17 - 2.99 (m, 4H), 2.98 (s, 3H), 2.85 (s, 3H), 2.75 (s, 1H), 2.69 - 2.46 (m, 2H). Example 604 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one Example 604 was prepared in analogy to the preparation of Example 431 by using Intermediate C83 instead of compound 431c. LCMS (M+H ⁺ ): 811. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.14 (s, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.62 (dt, J = 5.9, 8.6 Hz, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.13 (br dd, J = 2.6, 10.6 Hz, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.81 (dd, J = 4.5, 15.5 Hz, 1H), 5.29 (br d, J = 7.8 Hz, 1H), 4.69 - 4.48 (m, 3H), 4.44 (br t, J = 4.8 Hz, 1H), 4.30 (br dd, J = 5.9, 11.1 Hz, 1H), 4.19 - 4.04 (m, 2H), 3.83 (br dd, J = 9.1, 14.1 Hz, 1H), 3.74 - 3.65 (m, 1H), 3.59 (br s, 1H), 3.00 (s, 4H), 2.96 - 2.85 (m, 3H), 2.82 (s, 4H), 2.71 - 2.59 (m, 2H), 2.53 (s, 3H), 2.48 - 2.35 (m, 2H), 1.96 - 1.76 (m, 2H). Example 605 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one Example 605 was prepared in analogy to the preparation of Example 431 by using Intermediate C83 instead of compound 431c and compound 556b instead of compound 370b. LCMS (M+H ⁺ ): 812. 1H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 7.62 (dt, J = 6.1, 8.6 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.16 - 7.06 (m, 2H), 5.66 (dd, J = 4.1, 15.6 Hz, 1H), 5.34 (br d, J = 8.8 Hz, 1H), 4.70 (br t, J = 4.8 Hz, 1H), 4.58 (br dd, J = 5.3, 10.4 Hz, 2H), 4.44 (br d, J = 4.9 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.23 - 4.08 (m, 2H), 3.88 (br dd, J = 9.1, 14.1 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.65 - 3.62 (m, 1H), 3.28 (br s, 1H), 3.12 - 3.02 (m, 3H), 2.98 - 2.87 (m, 3H), 2.86 - 2.79 (m, 5H), 2.66 (br d, J = 9.8 Hz, 1H), 2.61 - 2.53 (m, 3H), 2.52 - 2.41 (m, 2H), 1.88 (br d, J = 14.1 Hz, 2H). Example 606 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluo roethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one

Example 606 was prepared in analogy to the preparation of Example 431 by using Intermediate C83 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 826. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.53 (d, J = 5.3 Hz, 1H), 8.14 (s, 1H), 7.62 (dt, J = 5.9, 8.6 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.26 (dd, J = 2.5, 10.3 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.15 - 7.03 (m, 2H), 5.63 (dd, J = 4.1, 15.6 Hz, 1H), 5.35 - 5.13 (m, 1H), 4.66 (br s, 1H), 4.57 (br d, J = 4.9 Hz, 2H), 4.44 (s, 1H), 4.28 - 4.19 (m, 1H), 4.17 - 4.06 (m, 2H), 3.89 (br dd, J = 9.3, 14.0 Hz, 1H), 3.71 (br d, J = 11.0 Hz, 1H), 3.61 (d, J = 7.1 Hz, 1H), 3.30 - 3.16 (m, 2H), 3.09 - 2.98 (m, 3H), 2.96 - 2.77 (m, 5H), 2.60 (br s, 2H), 2.60 - 2.51 (m, 4H), 2.43 (ddd, J = 4.3, 8.9, 13.5 Hz, 1H), 1.98 - 1.81 (m, 2H), 0.64 - 0.47 (m, 3H). Example 607 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 607 was prepared in analogy to the preparation of Example 431 by using Intermediate C89 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 836. ¹ H NMR (400 MHz, ACETONITRILE-d ₃ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.66 (dt, J = 6.1, 8.6 Hz, 1H), 7.44 (dd, J = 2.4, 8.9 Hz, 1H), 7.29 - 7.12 (m, 3H), 7.09 (d, J = 5.3 Hz, 1H), 5.85 - 5.62 (m, 2H), 5.26 (d, J = 8.8 Hz, 1H), 4.73 (br d, J = 4.6 Hz, 1H), 4.62 - 4.44 (m, 4H), 4.35 (br dd, J = 5.9, 11.2 Hz, 1H), 4.25 - 4.05 (m, 4H), 3.91 (br dd, J = 9.0, 13.8 Hz, 1H), 3.74 (br d, J = 10.4 Hz, 1H), 3.30 (s, 1H), 3.22 (br d, J = 9.5 Hz, 2H), 2.95 (s, 3H), 2.85 - 2.69 (m, 4H), 2.61 (dt, J = 3.1, 6.8 Hz, 2H), 2.55 (s, 3H), 2.51 - 2.40 (m, 2H), 0.64 - 0.51 (m, 3H). Example 608 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 608 was prepared in analogy to the preparation of Example 431 by using Intermediate C89 instead of compound 431c and compound 556b instead of compound 370b. LCMS (M+H ⁺ ): 822. ¹ H NMR (400 MHz, ACETONITRILE-d ₃ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.73 - 7.58 (m, 1H), 7.44 (dd, J = 2.5, 8.9 Hz, 1H), 7.26 - 7.12 (m, 3H), 7.09 (d, J = 5.1 Hz, 1H), 5.85 - 5.62 (m, 2H), 5.26 (d, J = 8.6 Hz, 1H), 4.73 (br d, J = 4.6 Hz, 1H), 4.63 - 4.43 (m, 4H), 4.35 (br dd, J = 6.0, 11.1 Hz, 1H), 4.27 - 4.05 (m, 4H), 3.91 (br dd, J = 8.8, 14.2 Hz, 1H), 3.81 - 3.68 (m, 1H), 3.30 (s, 1H), 3.27 - 3.13 (m, 2H), 2.97 (s, 3H), 2.80 (s, 6H), 2.53 (s, 3H), 2.51 - 2.40 (m, 3H). Example 609 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one

Example 609 was prepared in analogy to the preparation of Example 431 by using Intermediate C89 instead of compound 431c and compound 78d-2 instead of compound 370b. LCMS (M+H ⁺ ): 823. ¹ H NMR (400 MHz, ACETONITRILE-d ₃ ) δ = 8.67 (d, J = 5.3 Hz, 1H), 8.17 (s, 1H), 7.71 - 7.60 (m, 1H), 7.51 - 7.37 (m, 2H), 7.29 - 7.10 (m, 3H), 5.85 - 5.58 (m, 2H), 5.38 (br d, J = 8.1 Hz, 1H), 4.65 - 4.31 (m, 6H), 4.30 - 3.92 (m, 5H), 3.85 - 3.60 (m, 1H), 3.49 - 3.36 (m, 1H), 3.35 - 3.18 (m, 2H), 2.94 (s, 4H), 2.80 (br s, 1H), 2.79 - 2.73 (m, 3H), 2.73 - 2.65 (m, 2H), 2.55 (br d, J = 8.8 Hz, 5H). Example 610 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-d iazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5 ,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title was prepared according to the following scheme: Example 610 was prepared in analogy to the preparation of Example 431 by using Intermediate C89 instead of compound 431c and compound 610a (the synthesis refer to compound 289d by using intermediate A14 instead of intermediate A12) instead of compound 370b. LCMS (M+H ⁺ ): 792. ¹ H NMR (400 MHz, ACETONITRILE-d ₃ ) δ = 8.53 (d, J = 5.1 Hz, 1H), 8.14 (s, 1H), 7.64 (dd, J = 6.1, 8.6 Hz, 1H), 7.40 (dd, J = 2.5, 9.0 Hz, 1H), 7.24 - 7.05 (m, 3H), 6.94 (d, J = 5.0 Hz, 1H), 5.91 (br d, J = 8.1 Hz, 1H), 5.26 (br d, J = 5.5 Hz, 2H), 4.83 (br s, 1H), 4.50 (br d, J = 6.5 Hz, 5H), 4.24 - 4.11 (m, 3H), 4.06 - 3.88 (m, 2H), 3.70 (br t, J = 6.5 Hz, 1H), 3.30 (s, 1H), 3.17 (br d, J = 9.5 Hz, 2H), 2.94 (s, 3H), 2.86 - 2.68 (m, 3H), 2.54 (s, 3H), 2.50 - 2.44 (m, 2H), 1.78 (d, J = 7.9 Hz, 1H), 1.36 - 1.18 (m, 1H). Example 611 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 611 was prepared in analogy to the preparation of Example 431 by using Intermediate C92 instead of compound 431c. LCMS (M+H ⁺ ): 861. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.19 (d, J = 8.9 Hz, 1H), 7.77 (dt, J = 3.7, 7.9 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.32 - 7.25 (m, 1H), 7.25 - 7.20 (m, 1H), 7.17 - 7.10 (m, 2H), 7.09 - 7.01 (m, 1H), 6.64 - 6.57 (m, 1H), 5.80 - 5.60 (m, 1H), 5.28 - 5.18 (m, 1H), 4.59 (br s, 1H), 4.54 - 4.39 (m, 2H), 4.35 - 4.25 (m, 3H), 4.24 - 4.04 (m, 3H), 3.92 - 3.64 (m, 2H), 3.60 - 3.43 (m, 1H), 3.09 - 2.96 (m, 3H), 2.94 - 2.85 (m, 1H), 2.84 - 2.79 (m, 3H), 2.78 - 2.64 (m, 2H), 2.64 - 2.51 (m, 3H), 2.50 - 2.32 (m, 2H). Example 612 (8S,11S,15R)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one

Example 612 was prepared in analogy to the preparation of Example 431 by using Intermediate C93 instead of compound 431c. LCMS (M+H ⁺ ): 843. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 - 8.20 (m, 1H), 7.80 - 7.73 (m, 1H), 7.61 - 7.53 (m, 1H), 7.29 - 7.16 (m, 2H), 7.15 - 7.00 (m, 3H), 6.65 - 6.58 (m, 1H), 5.80 - 5.61 (m, 1H), 5.32 - 5.22 (m, 1H), 4.54 (br s, 4H), 4.40 - 4.33 (m, 1H), 4.30 - 4.18 (m, 3H), 4.16 - 4.09 (m, 1H), 3.91 - 3.79 (m, 1H), 3.70 - 3.57 (m, 1H), 3.49 - 3.36 (m, 2H), 2.99 (s, 3H), 2.94 - 2.85 (m, 1H), 2.83 - 2.77 (m, 3H), 2.77 - 2.61 (m, 2H), 2.60 - 2.50 (m, 3H), 2.48 - 2.34 (m, 2H). Example 613 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-hydroxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 613 was prepared in analogy to the preparation of Example 431 by using Intermediate C86 instead of compound 431c. LCMS (M+H ⁺ ): 809. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.80 (br t, J = 7.3 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.30 (br d, J = 7.8 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.15 (br d, J = 9.4 Hz, 2H), 7.08 (br d, J = 7.1 Hz, 1H), 6.65 (br d, J = 8.3 Hz, 1H), 5.91 - 5.70 (m, 1H), 5.34 (br d, J = 8.6 Hz, 1H), 4.69 - 4.51 (m, 2H), 4.42 (br s, 2H), 4.30 - 4.07 (m, 4H), 3.95 - 3.83 (m, 1H), 3.68 - 3.43 (m, 3H), 3.23 (br d, J = 10.5 Hz, 1H), 3.11 - 3.00 (m, 3H), 2.90 (br d, J = 15.8 Hz, 2H), 2.84 (br s, 3H), 2.74 (br d, J = 13.9 Hz, 1H), 2.58 (br s, 4H), 2.47 (br d, J = 6.6 Hz, 2H), 2.21 - 1.72 (m, 2H). Example 614 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl )-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 614 was prepared in analogy to the preparation of Example 431 by using Intermediate C87 instead of compound 431c. LCMS (M+H ⁺ ): 823. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.26 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.30 (dd, J = 2.4, 8.4 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.87 (dd, J = 4.1, 15.4 Hz, 1H), 5.37 (br d, J = 8.9 Hz, 1H), 4.64 (br d, J = 4.6 Hz, 1H), 4.46 (br dd, J = 6.4, 11.5 Hz, 2H), 4.24 - 4.09 (m, 4H), 3.91 (br dd, J = 8.9, 14.1 Hz, 1H), 3.47 - 3.37 (m, 3H), 3.26 - 3.21 (m, 4H), 3.01 (s, 3H), 2.94 - 2.88 (m, 2H), 2.85 (s, 4H), 2.75 (br d, J = 14.1 Hz, 1H), 2.65 - 2.60 (m, 2H), 2.58 (s, 3H), 2.53 - 2.41 (m, 3H). Example 615 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6 -diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-5 ,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 615 was prepared in analogy to the preparation of Example 431 by using Intermediate C80 instead of compound 431c and compound 610a instead of compound 370b. LCMS (M+H ⁺ ): 782. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.54 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H), 7.66 - 7.53 (m, 1H), 7.39 - 7.33 (m, 1H), 7.25 - 7.10 (m, 3H), 6.97 (d, J = 5.1 Hz, 1H), 5.36 - 5.22 (m, 2H), 4.82 (d, J = 4.1 Hz, 1H), 4.65 - 4.31 (m, 4H), 4.26 - 4.11 (m, 3H), 4.08 - 3.97 (m, 2H), 3.24 (d, J = 10.5 Hz, 1H), 3.10 - 2.98 (m, 3H), 2.96 - 2.81 (m, 3H), 2.79 - 2.62 (m, 3H), 2.59 (s, 3H), 2.55 - 2.42 (m, 2H), 1.96 - 1.75 (m, 2H), 1.35 - 1.21 (m, 1H). Example 616 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-1-yl]ac etonitrile Examples 616 was prepared in analogy to the preparation of Example 443 by using compound 557b instead of compound 213a, compound tert-butyl 3-iodoazetidine-1-carboxylate instead of tert-butyl 3-iodopyrrolidine-1-carboxylate and bromoacetonitrile instead of methanesulfonic anhydride. LCMS (M+H ⁺ ): 764. ¹ H NMR (400 MHz, ACETONITRILE-d ₃ ) δ = 8.64 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 7.82 (br dd, J = 1.8, 7.3 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.51 (dd, J = 2.1, 10.3 Hz, 1H), 7.30 - 7.17 (m, 2H), 7.15 - 7.08 (m, 1H), 5.95 - 5.84 (m, 1H), 5.81 - 5.71 (m, 1H), 5.60 - 5.20 (m, 1H), 4.82 - 4.56 (m, 1H), 4.46 - 4.29 (m, 3H), 4.27 - 4.10 (m, 4H), 4.08 - 3.85 (m, 4H), 3.17 - 3.11 (m, 1H), 3.11 - 3.04 (m, 3H), 2.95 - 2.91 (m, 3H), 2.80 - 2.79 (m, 3H), 2.58 - 2.47 (m, 2H). Example 617 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one

Example 617 was prepared in analogy to the preparation of Example 431 by using Intermediate C80 instead of compound 431c and compound 556b instead of compound 370b. LCMS (M+H ⁺ ): 812. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.3 Hz, 1H), 8.21 (s, 1H), 7.68 - 7.59 (m, 1H), 7.41 (dd, J = 2.4, 8.4 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.16 - 7.05 (m, 2H), 5.76 - 5.41 (m, 1H), 5.27 (br d, J = 8.8 Hz, 1H), 4.74 - 4.35 (m, 4H), 4.33 - 4.11 (m, 5H), 3.95 (br dd, J = 9.2, 14.2 Hz, 1H), 3.44 - 3.35 (m, 1H), 3.27 (br d, J = 10.3 Hz, 1H), 3.11 (s, 1H), 3.01 (s, 3H), 2.88 (br d, J = 4.5 Hz, 2H), 2.84 (s, 4H), 2.79 - 2.66 (m, 2H), 2.57 (s, 3H), 2.53 - 2.36 (m, 3H). Example 618 3-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicycl o[3.1.1]heptan-3- yl]propanenitrile Example 618 was prepared in analogy to the preparation of Example 564 by using 3- bromopropanenitrile instead of 1-fluoro-2-iodo-ethane. LCMS (M+H ⁺ ): 818. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.66 (dt, J = 6.1, 8.5 Hz, 1H), 7.32 (dd, J = 2.4, 8.5 Hz, 1H), 7.24 (br s, 1H), 7.17 (dd, J = 2.4, 10.4 Hz, 2H), 7.10 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.86 (dd, J = 4.4, 15.6 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.67 - 4.55 (m, 1H), 4.42 (br dd, J = 6.1, 11.1 Hz, 2H), 4.30 - 4.08 (m, 4H), 3.90 (br dd, J = 8.9, 14.1 Hz, 1H), 3.47 - 3.35 (m, 2H), 3.14 - 3.02 (m, 3H), 2.99 - 2.89 (m, 2H), 2.88 - 2.82 (m, 5H), 2.81 - 2.72 (m, 3H), 2.61 (s, 3H), 2.52 - 2.43 (m, 3H), 2.41 - 2.32 (m, 1H). Example 619 (8S,11S,15R)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy -22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 619 was prepared in analogy to the preparation of Example 431 by using Intermediate C84 instead of compound 431c and compound 326d-1 instead of compound 370b. LCMS (M+H ⁺ ): 844. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H), 7.53 (s, 1H), 7.40 (dd, J = 2.4, 8.4 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.17 - 7.05 (m, 2H), 6.04 - 5.70 (m, 1H), 5.69 - 5.44 (m, 1H), 5.39 - 5.20 (m, 1H), 4.78 - 4.67 (m, 2H), 4.59 (s, 3H), 4.32 (br dd, J = 5.9, 11.1 Hz, 1H), 4.22 - 4.10 (m, 2H), 3.90 (br dd, J = 9.4, 13.9 Hz, 1H), 3.69 - 3.53 (m, 2H), 3.35 (s, 3H), 3.09 (s, 1H), 3.02 (s, 3H), 2.92 - 2.80 (m, 3H), 2.60 - 2.57 (m, 3H), 2.47 (ddd, J = 4.6, 8.9, 13.6 Hz, 1H), 1.98 - 1.77 (m, 2H), 0.59 (t, J = 6.9 Hz, 3H). Example 620 (8S,11S,15R)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro -15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one

Example 619 was prepared in analogy to the preparation of Example 431 by using Intermediate C84 instead of compound 431c and compound 556b instead of compound 370b. LCMS (M+H ⁺ ): 830. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 7.63 (dt, J = 6.0, 8.6 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.26 (dd, J = 2.5, 10.3 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.15 - 7.04 (m, 2H), 6.04 - 5.81 (m, 1H), 5.74 - 5.60 (m, 1H), 5.33 (br d, J = 8.6 Hz, 1H), 4.75 - 4.50 (m, 3H), 4.29 (br dd, J = 5.8, 11.2 Hz, 1H), 4.20 - 4.10 (m, 2H), 4.00 - 3.84 (m, 1H), 3.70 - 3.52 (m, 2H), 3.35 (s, 3H), 3.10 (s, 1H), 3.03 (s, 3H), 2.98 - 2.87 (m, 3H), 2.83 (s, 3H), 2.67 (br d, J = 9.4 Hz, 1H), 2.58 - 2.53 (m, 3H), 1.95 - 1.75 (m, 2H). Example 621 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 621 was prepared in analogy to the preparation of Example 431 by using Intermediate C82 instead of compound 431c and compound 78d-2 instead of compound 370b. LCMS (M+H ⁺ ): 849. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 (d, J = 5.3 Hz, 1H), 8.28 (s, 1H), 7.68 - 7.56 (m, 1H), 7.48 - 7.38 (m, 2H), 7.32 - 7.13 (m, 3H), 5.90 - 5.63 (m, 2H), 5.51 - 5.41 (m, 1H), 4.59 (s, 2H), 4.54 - 4.39 (m, 2H), 4.36 - 4.08 (m, 4H), 4.07 - 3.93 (m, 1H), 3.68 - 3.52 (m, 1H), 3.52 - 3.33 (m, 3H), 3.13 - 3.04 (m, 3H), 3.02 (s, 3H), 2.81 (s, 3H), 2.76 - 2.70 (m, 1H), 2.62 - 2.57 (m, 3H), 2.56 (br s, 1H). Example 622 (8S,11S,15S)-10-[6-[(1R,4R)-5-(2,2-difluoroethyl)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 622 was prepared in analogy to the preparation of Example 431 by using Intermediate C84 instead of compound 431c and compound 78d-2 instead of compound 370b. LCMS (M+H ⁺ ): 831. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 (d, J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.70 - 7.55 (m, 1H), 7.47 - 7.43 (m, 1H), 7.42 - 7.38 (m, 1H), 7.31 (br s, 1H), 7.26 - 7.11 (m, 2H), 5.85 (br d, J = 3.9 Hz, 1H), 5.58 (s, 1H), 5.54 - 5.31 (m, 1H), 4.59 (br s, 4H), 4.51 - 4.36 (m, 2H), 4.28 - 4.04 (m, 2H), 3.99 (br d, J = 14.4 Hz, 1H), 3.72 - 3.58 (m, 2H), 3.12 (s, 2H), 3.04 (s, 3H), 2.98 (br d, J = 11.0 Hz, 1H), 2.81 (s, 3H), 2.78 - 2.65 (m, 3H), 2.62 - 2.58 (m, 3H), 1.98 - 1.81 (m, 2H). Example 623 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-5-(2-morpholinoethyl amino)pyrazole-4-carbonyl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 623 was prepared in analogy to the preparation of Example 592 by using 4-(2- chloroethyl)morpholine instead of 1-iodo-3-phenylpropane. LCMS (M+H ⁺ ): 773. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.13 - 7.99 (m, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 - 7.57 (m, 1H), 7.35 - 7.24 (m, 2H), 7.23 - 7.13 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 5.87 - 5.74 (m, 1H), 5.18 - 5.09 (m, 1H), 4.83 (s, 2H), 4.64 - 4.51 (m, 4H), 4.43 - 4.33 (m, 1H), 4.25 - 4.10 (m, 2H), 4.02 - 3.89 (m, 1H), 3.64 - 3.57 (m, 2H), 3.35 (s, 3H), 3.01 - 2.97 (m, 2H), 2.94 - 2.89 (m, 2H), 2.84 (s, 3H), 2.62 - 2.58 (m, 2H), 2.43 - 2.32 (m, 6H). Example 624 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 624 was prepared in analogy to the preparation of Example 431 by using Intermediate C88 instead of compound 431c and compound 556b instead of compound 370b. LCMS (M+H ⁺ ): 822. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H), 7.62 (dt, J = 6.1, 8.4 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.26 (dd, J = 2.4, 10.2 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.06 (m, 2H), 5.69 - 5.44 (m, 1H), 5.40 - 5.22 (m, 1H), 4.75 - 4.67 (m, 3H), 4.66 - 4.58 (m, 2H), 4.54 - 4.49 (m, 1H), 4.48 - 4.41 (m, 1H), 4.31 (br dd, J = 5.8, 11 Hz, 1H), 4.23 - 4.09 (m, 2H), 4.04 - 3.96 (m, 1H), 3.87 (br dd, J = 8.9, 14 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.46 (br d, J = 10.4 Hz, 1H), 3.35 (s, 1H), 3.28 - 3.17 (m, 1H), 3.12 - 3.02 (m, 3H), 2.88 (br d, J = 14.0 Hz, 2H), 2.84 - 2.80 (m, 3H), 2.56 (s, 3H), 2.54 - 2.42 (m, 2H), 1.96 - 1.78 (m, 2H). Example 625 (8S,11S,15R)-10-[11-benzyl-3-(2,4-difluorophenyl)-3,4,8,11- 2,6 tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 625 was prepared in analogy to the preparation of Example 646 by using compound 646j instead of compound 646l. LCMS (M+H ⁺ ): 799. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.87 (t, J = 7.9 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.56 (dd, J = 2.6, 7.4 Hz, 1H), 7.53 - 7.47 (m, 7H), 7.40 - 7.34 (m, 1H), 7.29 - 7.22 (m, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.17 - 6.04 (m, 1H), 5.44 (d, J = 9.1 Hz, 1H), 4.57 (s, 3H), 4.53 - 4.44 (m, 2H), 4.40 - 4.32 (m, 3H), 4.30 - 4.19 (m, 2H), 3.96 - 3.86 (m, 1H), 3.22 - 3.15 (m, 1H), 3.15 - 3.12 (m, 1H), 3.12 - 3.04 (m, 3H), 2.96 (s, 3H), 2.78 (s, 3H), 2.62 - 2.49 (m, 2H). Example 626 (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-11-methyl-3,4,8,11- 2,6 tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 626 was prepared in analogy to the preparation of Example 646 by using formaldehyde instead of 3-oxetanone. LCMS (M+H ⁺ ): 723. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.62 (s, 1H), 7.91 - 7.85 (m, 1H), 7.74 - 7.65 (m, 1H), 7.59 (dd, J = 2.5, 7.3 Hz, 1H), 7.54 (dd, J = 2.5, 10.1 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.32 - 7.24 (m, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.19 - 6.09 (m, 1H), 5.46 (d, J = 8.8 Hz, 1H), 4.69 - 4.59 (m, 2H), 4.58 - 4.46 (m, 2H), 4.46 - 4.33 (m, 2H), 4.27 (br dd, J = 10.8, 15.2 Hz, 2H), 3.93 (br dd, J = 9.4, 13.9 Hz, 1H), 3.15 (s, 1H), 3.10 (s, 5H), 3.05 - 3.00 (m, 1H), 2.97 (s, 3H), 2.94 - 2.85 (m, 1H), 2.81 (s, 3H), 2.65 - 2.51 (m, 2H). Example 627 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one Example 627 was prepared in analogy to the preparation of Example 431 by using Intermediate C88 instead of compound 431c. LCMS (M+H ⁺ ): 821. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.17 (br s, 1H), 7.78 (br t, J = 7.6 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.30 (br d, J = 8.3 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.17 - 7.03 (m, 3H), 6.63 (br d, J = 8.4 Hz, 1H), 5.90 - 5.61 (m, 1H), 5.41 - 5.19 (m, 1H), 4.76 - 4.60 (m, 3H), 4.59 - 4.41 (m, 3H), 4.40 - 4.31 (m, 1H), 4.20 - 4.07 (m, 2H), 4.04 - 3.94 (m, 1H), 3.92 - 3.77 (m, 1H), 3.61 - 3.43 (m, 2H), 3.35 (br s, 1H), 3.10 - 2.99 (m, 3H), 2.98 - 2.87 (m, 2H), 2.87 - 2.78 (m, 4H), 2.71 (br d, J = 13.6 Hz, 1H), 2.53 (br s, 3H), 2.46 (br s, 2H), 1.98 - 1.79 (m, 2H). Example 628 (8S,11S,15R)-10-[5-amino-1-(2,4-difluorophenyl)pyrazole-4-ca rbonyl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 628 was prepared in analogy to the preparation of Example 592 by using compound 592a instead of compound 592c. LCMS (M+H ⁺ ): 660. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.03 (br s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.35 - 7.24 (m, 2H), 7.30 - 7.15 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.81 (br d, J = 14.6 Hz, 1H), 5.18 - 5.10 (m, 1H), 4.81 - 4.72 (m, 1H), 4.64 - 4.51 (m, 2H), 4.36 (br s, 1H), 4.27 - 4.13 (m, 2H), 4.02 - 3.90 (m, 1H), 3.33 (s, 3H), 2.98 (br s, 2H), 2.84 (s, 3H), 2.61 (s, 3H), 2.54 - 2.43 (m, 1H), 2.37 (br s, 1H). Example 629 (8S,11S,15S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one Example 629 was prepared in analogy to the preparation of Example 431 by using Intermediate C81 instead of compound 431c and compound 78d-2 instead of compound 370b. LCMS (M+H ⁺ ): 831. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 (br d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 7.73 - 7.53 (m, 1H), 7.51 - 7.37 (m, 2H), 7.35 - 7.03 (m, 3H), 5.84 (br s, 1H), 5.46 (br d, J = 7.8 Hz, 1H), 5.13 - 4.90 (m, 2H), 4.59 (s, 2H), 4.53 - 4.30 (m, 2H), 4.27 - 3.95 (m, 4H), 3.66 - 3.33 (m, 3H), 3.01 (s, 4H), 2.86 (br s, 2H), 2.81 (s, 3H), 2.75 (br s, 2H), 2.59 (s, 3H), 2.54 - 2.42 (m, 1H), 1.75 (br d, J = 8.0 Hz, 1H). Example 630 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13, 18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one

Example 630 was prepared in analogy to the preparation of Example 431 by using Intermediate C80 instead of compound 431c and compound 78d-2 instead of compound 370b. LCMS (M+H ⁺ ): 813. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.70 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 7.65 - 7.56 (m, 1H), 7.47 - 7.39 (m, 2H), 7.33 - 7.28 (m, 1H), 7.25 - 7.19 (m, 1H), 7.18 - 7.12 (m, 1H), 5.93 - 5.67 (m, 2H), 5.49 - 5.34 (m, 1H), 4.58 (s, 3H), 4.50 - 4.43 (m, 2H), 4.39 - 4.31 (m, 1H), 4.26 - 4.14 (m, 3H), 4.10 - 4.04 (m, 1H), 3.50 - 3.43 (m, 1H), 3.16 - 2.96 (m, 5H), 2.91 - 2.80 (m, 5H), 2.77 - 2.69 (m, 3H), 2.60 (s, 3H), 2.52 - 2.43 (m, 1H), 1.86 (d, J = 8.0 Hz, 1H). Example 631 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(methoxyme thyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 631 was prepared in analogy to the preparation of Example 213 by using (2S)-2- (methoxymethyl)pyrrolidine of morpholine. LCMS (M+H ⁺ ): 782. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.23 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.65 (dt, J = 6.0, 8.5 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.48 (dd, J = 2.3, 10.3 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.11 (m, 2H), 6.77 (d, J = 8.6 Hz, 1H), 6.25 - 6.00 (m, 1H), 5.39 - 5.28 (m, 1H), 4.73 - 4.61 (m, 1H), 4.47 (dd, J = 5.8, 10.8 Hz, 1H), 4.36 - 4.20 (m, 2H), 4.07 (br d, J = 4.4 Hz, 1H), 3.90 (dd, J = 9.3, 14.5 Hz, 1H), 3.81 - 3.65 (m, 1H), 3.44 (br s, 2H), 3.36 - 3.32 (m, 3H), 3.28 - 3.22 (m, 1H), 3.15 - 3.06 (m, 3H), 3.01 (br s, 1H), 2.98 - 2.95 (m, 3H), 2.82 - 2.77 (m, 3H), 2.73 (br d, J = 13.8 Hz, 1H), 2.62 - 2.48 (m, 2H), 2.04 - 1.86 (m, 4H). Example 632 2-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-me thoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]acetonitrile Example 632 was prepared in analogy to the preparation of Example 564 by using bromoacetonitrile instead of 1-fluoro-2-iodo-ethane in step 2. Example 632, LCMS (M+H ⁺ ): 804. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.26 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.36 - 7.30 (m, 1H), 7.26 - 7.12 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.89 (dd, J = 4.5, 15.6 Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.69 - 4.62 (m, 1H), 4.50 - 4.42 (m, 1H), 4.40 - 4.07 (m, 4H), 4.00 - 3.91 (m, 1H), 3.65 - 3.51 (m, 2H), 3.47 - 3.32 (m, 3H), 3.12 - 2.99 (m, 3H), 2.92 (br d, J = 14.4 Hz, 1H), 2.88 - 2.85 (m, 3H), 2.85 - 2.73 (m, 2H), 2.66 - 2.59 (m, 3H), 2.58 - 2.54 (m, 1H), 2.54 - 2.44 (m, 2H), 1.84 - 1.72 (m, 1H). Example 633 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 633 was prepared in analogy to the preparation of Example 564 by using oxetan- 3-one instead of 1-fluoro-2-iodo-ethane in step 2 (reaction condition: reductive amination via NaBH(OAc) ₃ in hot EtOH instead of alkylation via K ₂ CO ₃ in ACN). Example 633, LCMS (M+H ⁺ ): 821. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.30 (s, 1H), 7.86 - 7.79 (m, 1H), 7.67 - 7.59 (m, 1H), 7.34 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.21 - 7.13 (m, 2H), 7.10 (d, J = 7.4 Hz, 1H), 6.74 - 6.65 (m, 1H), 5.84 (dd, J = 4.4, 15.6 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 4.73 - 4.65 (m, 3H), 4.64 - 4.55 (m, 4H), 4.49 (br dd, J = 5.8, 11.2 Hz, 1H), 4.33 - 4.20 (m, 3H), 4.01 - 3.88 (m, 1H), 3.68 - 3.63 (m, 1H), 3.32 - 3.26 (m, 2H), 3.14 - 3.02 (m, 3H), 2.96 - 2.87 (m, 2H), 2.86 (s, 3H), 2.85 - 2.77 (m, 2H), 2.68 - 2.60 (m, 1H), 2.60 - 2.55 (m, 3H), 2.55 - 2.46 (m, 2H). Example 634 (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 634 was prepared in analogy to the preparation of Example 564 by using trifluoromethanesulfonic acid 2,2-difluoroethyl ester instead of 1-fluoro-2-iodo-ethane in step 2 (reaction condition: DIPEA in THF instead of K ₂ CO ₃ in ACN). Example 634, LCMS (M+H ⁺ ): 829. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.25 (s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.15 (br dd, J = 2.6, 10.4 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.64 (br d, J = 8.4 Hz, 1H), 6.00 - 5.65 (m, 2H), 5.34 (d, J = 8.9 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.40 (br dd, J = 5.9, 10.9 Hz, 1H), 4.27 - 4.19 (m, 2H), 4.19 - 4.08 (m, 2H), 3.89 (dd, J = 9.1, 14.0 Hz, 1H), 3.42 (dd, J = 2.0, 10.3 Hz, 1H), 3.36 - 3.32 (m, 1H), 3.11 - 2.98 (m, 3H), 2.98 - 2.85 (m, 3H), 2.83 (s, 3H), 2.82 - 2.69 (m, 3H), 2.54 (s, 3H), 2.53 - 2.39 (m, 3H), 1.71 (d, J = 8.0 Hz, 1H). Example 635 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) -3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,1 8-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 635 was prepared according to the following scheme: Step 1: preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy- 22-fluoro-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hep tane-3-carboxylate (compound 635b) To a tube was added 565a (109.0 mg, 151 μmol), DIEA (25.5 mg, 34 μL, 197 μmol), tert- butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (45.0 mg, 227 μmol), cesium fluoride (40.0 mg, 263 μmol) and dimethyl sulfoxide (1 mL). The mixture was heated to 100 °C and stirred for 4 hrs. Then it was poured into water and extracted with EA, the organic layer was concentrated and purified to give 635b (82 mg) as solid. LCMS (M+H ⁺ ): 881. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl) - 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6. 1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one To the flask containing 635b (41 mg, 46 μmol) was added dichloromethane (2 mL) and TFA (1.48 g, 1 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr and then concentrated to give an oil. The oil was dissolved in acetonitrile (2 mL) and then 1-fluoro-2-iodo-ethane (40.0 mg, 230 μmol), potassium carbonate (31.8 mg, 230 μmol) were added. After being heated to 80 °C and stirred for 2 hrs, the mixture was filtered and the filtrate was purified by prep-HPLC give Example 635 (27.7 mg). LCMS (M+H ⁺ ): 827. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.79 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 7.68 - 7.58 (m, 2H), 7.49 - 7.41 (m, 2H), 7.28 - 7.21 (m, 1H), 7.20 - 7.13 (m, 1H), 5.89 - 5.84 (m, 1H), 5.83 - 5.68 (m, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.78 - 4.58 (m, 3H), 4.55 - 4.43 (m, 2H), 4.39 - 4.30 (m, 2H), 4.26 - 4.12 (m, 1H), 4.05 - 3.96 (m, 1H), 3.95 - 3.74 (m, 2H), 3.73 - 3.53 (m, 2H), 3.46 - 3.37 (m, 1H), 3.29 - 3.23 (m, 1H), 3.09 - 2.96 (m, 3H), 2.95 - 2.69 (m, 4H), 2.68 - 2.63 (m, 1H), 2.63 (s, 3H), 2.60 - 2.54 (m, 1H), 2.06 - 1.91 (m, 1H), 0.58 (t, J = 6.9 Hz, 3H). Example 636 (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 636 was prepared in analogy to the preparation of Example 635 by using trifluoromethanesulfonic acid 2,2-difluoroethyl ester instead of 1-fluoro-2-iodo-ethane in step 3 (reaction condition: DIPEA in THF instead of K ₂ CO ₃ in ACN). LCMS (M+H ⁺ ): 845. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.79 - 8.75 (m, 1H), 8.28 (s, 1H), 7.65 - 7.59 (m, 2H), 7.47 - 7.40 (m, 2H), 7.26 - 7.19 (m, 1H), 7.19 - 7.11 (m, 1H), 5.86 (dd, J = 3.9, 15.6 Hz, 1H), 5.81 (t, J = 3.8 Hz, 1H), 5.45 (d, J = 8.9 Hz, 1H), 4.51 - 4.40 (m, 2H), 4.37 - 4.27 (m, 1H), 4.25 - 4.14 (m, 3H), 3.98 (dd, J = 9.6, 14.0 Hz, 1H), 3.38 (ddd, J = 1.7, 10.2, 18.5 Hz, 2H), 3.29 - 3.23 (m, 1H), 3.06 - 2.95 (m, 3H), 2.95 - 2.86 (m, 2H), 2.81 (br d, J = 14.5 Hz, 3H), 2.77 - 2.63 (m, 2H), 2.63 - 2.60 (m, 3H), 2.60 - 2.53 (m, 2H), 2.53 - 2.46 (m, 1H), 1.73 (d, J = 8.1 Hz, 1H), 0.61 - 0.54 (m, 3H) Example 637 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]py rimidin-6-yl]azetidine-3- carbonitrile Example 637 was prepared in analogy to the preparation of Example 574 by using compound 370b instead of compound 326d-1. Example 637, LCMS (M+H ⁺ ): 749. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.26 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 - 7.56 (m, 1H), 7.31 (dd, J = 2.5, 8.4 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.87 - 5.66 (m, 1H), 5.39 - 5.27 (m, 1H), 4.60 (br s, 1H), 4.43 - 4.34 (m, 1H), 4.31 - 4.20 (m, 3H), 4.19 - 4.12 (m, 2H), 4.12 - 4.04 (m, 1H), 3.93 (dd, J = 9.1, 14.3 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.10 - 3.01 (m, 3H), 2.90 (br d, J = 14.3 Hz, 1H), 2.86 - 2.81 (m, 3H), 2.76 (br d, J = 13.5 Hz, 1H), 2.60 - 2.54 (m, 3H), 2.53 - 2.40 (m, 2H). Example 638 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 638 was prepared in analogy to the preparation of Example 639b by using 3- methyl-3,6-diazabicyclo[3.1.1]heptane instead of tert-butyl 3,6-diazabicyclo[3.1.1] heptane-3- carboxylate in step 2. LCMS (M+H ⁺ ): 777. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.34 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.44 (dd, J = 2.5, 7.9 Hz, 1H), 7.34 (dd, J = 2.1, 10.4 Hz, 1H), 7.14 (dd, J = 2.4, 7.4 Hz, 1H), 6.79 - 6.71 (m, 3H), 6.02 - 5.86 (m, 1H), 5.44 - 5.36 (m, 1H), 4.56 - 4.47 (m, 2H), 4.44 - 4.37 (m, 1H), 4.30 - 4.15 (m, 3H), 3.98 - 3.83 (m, 2H), 3.74 - 3.62 (m, 2H), 3.15 - 3.03 (m, 4H), 3.02 - 2.95 (m, 1H), 2.93 - 2.90 (m, 3H), 2.87 - 2.83 (m, 1H), 2.80 (br s, 3H), 2.71 - 2.66 (m, 3H), 2.66 - 2.61 (m, 1H), 2.59 - 2.48 (m, 2H), 1.96 - 1.86 (m, 1H). Example 639 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 639 was prepared according to the following scheme:

Step 1: preparation of (8S,11S,15R)-10-[6-chloro-1-(4-fluoro-2-hydroxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-1 3,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 639a) To a tube was added 370b (370.8 mg, 669 μmol), intermediate C76a (200 mg, 669 μmol), DIPEA (345.7 mg, 467 μL, 2.67 mmol) and acetonitrile (5 mL). The solution was stirred at 60 °C for 1 hr. Then it was concentrated and purified by silica gel to give compound 639a (402 mg) as a pale yellow solid. LCMS (M+H ⁺ ): 701. Step 2: preparation of tert-butyl 6-[1-(4-fluoro-2-hydroxy-phenyl)-4-[(8S,11S,15R)-22- fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hep tane-3-carboxylate (compound 639b) To a tube was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (106.04 mg, 534.86 μmol), compound 639a (150 mg, 214 μmol), DIEA (55 mg, 75 μL, 428 μmol) and dimethyl sulfoxide (3 mL). After being stirred at 100 °C for 16 hrs, the reaction mixture was poured into water and extracted with EA. The organic layer was concentrated and purified by silica gel to give compound 639b (120 mg) as a pale brown solid. LCMS (M+H ⁺ ): 863. Step 3: preparation of (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3, 4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15. 6.1.1 .1 .0 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 639) To a flask was added compound 639b (120 mg, 139 μmol), dichloromethane (2 mL) and TFA (1.48 g, 1 mL). The solution was stirred at r.t. for 1 hr. Then it was concentrated and purified via prep-HPLC to give a white powder (120 mg). To a tube was added the white powder (40 mg, 46 μmol), oxetan-3-one (30 mg, 416 μmol), DIEA (17.7 mg, 24 μL, 137 μmol) and ethanol (2 mL). The solution was heated to reflux for 1 hr, and then sodium triacetoxyborohydride (24.17 mg, 114.05 μmol) was added. After being refluxed for 2 hrs, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 639 (3 mg). LCMS (M+H ⁺ ): 819. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.27 (s, 1H), 7.84 - 7.77 (m, 1H), 7.74 - 7.68 (m, 1H), 7.32 - 7.26 (m, 1H), 7.16 - 7.10 (m, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.78 - 6.71 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 5.81 (dd, J = 4.4, 15.6 Hz, 1H), 5.37 (d, J = 9.0 Hz, 1H), 4.68 - 4.59 (m, 3H), 4.59 - 4.53 (m, 6H), 4.49 - 4.41 (m, 1H), 4.37 - 4.29 (m, 2H), 4.28 - 4.18 (m, 2H), 4.04 - 3.95 (m, 1H), 3.94 - 3.86 (m, 1H), 3.27 - 3.21 (m, 1H), 3.12 - 3.00 (m, 3H), 2.94 - 2.86 (m, 2H), 2.84 (s, 3H), 2.65 - 2.57 (m, 1H), 2.57 - 2.53 (m, 3H), 2.48 (dt, J = 4.4, 8.7 Hz, 2H). Example 640 (8S,11S,15R)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(2-methoxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 640 was prepared in analogy to the preparation of Example 580 by using compound 213a instead of compound 575a. LCMS (M+H ⁺ ): 819. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.34 (s, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.49 (br dd, J = 1.5, 10.3 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.81 - 6.71 (m, 3H), 6.14 (br dd, J = 4.1, 15.4 Hz, 1H), 5.42 (d, J = 9.0 Hz, 1H), 4.72 - 4.67 (m, 1H), 4.57 - 4.46 (m, 2H), 4.43 - 4.36 (m, 1H), 4.31 - 4.20 (m, 2H), 4.10 - 3.79 (m, 3H), 3.74 - 3.59 (m, 4H), 3.30 - 3.20 (m, 6H), 3.16 - 3.05 (m, 3H), 3.04 - 2.98 (m, 1H), 2.96 (s, 3H), 2.88 - 2.82 (m, 1H), 2.81 - 2.76 (m, 3H), 2.65 - 2.47 (m, 2H), 2.10 - 1.97 (m, 1H). Example 641 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(2-fluoroethyl) -1,7-diazaspiro[3.5]nonan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 641 was prepared in analogy to the preparation of Example 564 by using tert- butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 839. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.30 - 8.23 (m, 1H), 7.92 - 7.86 (m, 1H), 7.62 - 7.58 (m, 2H), 7.57 - 7.51 (m, 2H), 7.18 (d, J = 7.4 Hz, 2H), 6.84 - 6.77 (m, 1H), 6.12 - 6.05 (m, 1H), 5.35 (br d, J = 8.9 Hz, 1H), 4.70 (br d, J = 3.8 Hz, 1H), 4.57 - 4.45 (m, 2H), 4.36 - 4.22 (m, 3H), 4.01 - 3.89 (m, 3H), 3.73 - 3.61 (m, 2H), 3.55 - 3.45 (m, 1H), 3.21 - 3.14 (m, 3H), 3.09 - 3.03 (m, 2H), 3.02 - 2.99 (d, J = 3.5 Hz, 1H), 2.83 (d, J = 7.0 Hz, 4H), 2.81 - 2.74 (m, 5H), 2.68 - 2.55 (m, 3H), 2.37 - 2.25 (m, 2H), 2.19 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H). Example 642 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-1 ,7-diazaspiro[3.5]nonan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-1,7-diazaspiro[3.5]nonane- 7-carboxylate (compound 642b) To a mixture of compound 213a (60.0 mg, 0.09 mmol), tert-butyl 1,7- diazaspiro[3.5]nonane-7-carboxylate (96.5 mg, 0.43 mmol) and CsF (12.9 mg, 0.09 mmol) in DMA (2 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.26 mmol). After being heated to 120 °C for 18 hrs, the reaction mixture was cooled to 25 °C and diluted with water (15 mL), extracted with EtOAc. The organic layer was dried and concentrated, the crude product was purified by TLC to give compound 642b (70 mg) as a light yellow solid. LCMS (M+H ⁺ ): 893. Step 2: preparation of (8S,11S,15R)-10-[6-(1,7-diazaspiro[3.5]nonan-1-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one (compound 642c) To a solution of compound 642b (70 mg, 0.08 mmol) in DCM (2 mL) was added TFA (2 mL) at 0 °C. Then the mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched with sat. NaHCO ₃ solution (50 mL), and then extracted with DCM (3×30 mL). The organic layer was dried and concentrated to give the compound 642c (60 mg) as a light yellow solid. LCMS (M+H ⁺ ): 793. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-1 ,7- diazaspiro[3.5]nonan-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 642) To a solution of compound 642c (50.0 mg, 0.06 mmol) in DCE (2 mL) were added 3- oxetanone (45.44 mg, 0.63 mmol) and sodium triacetoxyborohydride (66.83 mg, 0.32 mmol) at 0 °C under N ₂ . Then the mixture was stirred at 25 °C for 6 hrs. The reaction solution was concentrated and the residue was purified by prep-HPLC to give Example 642 (27.5 mg). LCMS (M+H ⁺ ): 849. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.22 (m, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.35 - 7.29 (m, 1H), 7.28 - 7.20 (m, 1H), 7.18 - 7.08 (m, 3H), 6.70 (d, J = 8.4 Hz, 1H), 5.98 - 5.84 (m, 1H), 5.40 (d, J = 9.0 Hz, 1H), 4.75 - 4.69 (m, 2H), 4.66 - 4.60 (m, 2H), 4.55 - 4.49 (m, 2H), 4.48 - 4.40 (m, 1H), 4.27 - 4.16 (m, 2H), 4.01 - 3.79 (m, 3H), 3.24 (s, 2H), 3.16 - 3.04 (m, 1H), 2.92 - 2.85 (m, 3H), 2.80 - 2.67 (m, 4H), 2.64 - 2.49 (m, 6H), 2.44 - 2.30 (m, 1H), 2.16 - 2.06 (m, 2H), 1.85 - 1.69 (m, 4H). Example 643 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[6-(oxetan-3-yl)-1 ,6-diazaspiro[3.3]heptan-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 643 was prepared in analogy to the preparation of Example 642 by using tert- butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate;oxalic acid instead of tert-butyl 1,7- diazaspiro[3.5]nonane-7-carboxylate. LCMS (M+H ⁺ ): 821. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.26 (s, 1H), 7.87 - 7.77 (m, 1H), 7.68 - 7.56 (m, 1H), 7.38 - 7.27 (m, 2H), 7.26 - 7.13 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.74 - 6.62 (m, 1H), 5.86 - 5.65 (m, 1H), 5.44 - 5.25 (m, 1H), 4.61 (br d, J = 3.9 Hz, 2H), 4.55 - 4.42 (m, 2H), 4.41 - 4.34 (m, 1H), 4.33 - 4.24 (m, 2H), 4.21 - 4.09 (m, 2H), 4.06 - 3.91 (m, 2H), 3.90 - 3.72 (m, 2H), 3.62 - 3.51 (m, 1H), 3.48 - 3.38 (m, 2H), 3.16 - 3.01 (m, 3H), 2.98 - 2.74 (m, 5H), 2.65 - 2.43 (m, 7H). Example 644 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(6,6-dioxo-6λ⁶- thia-1-azaspiro[3.3]heptan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 644 was prepared in analogy to the preparation of Example 483 by using 6λ⁶-thia- 1-azaspiro[3.3]heptane 6,6-dioxide instead of 2λ ⁶ -thia-6-azaspiro[3.3]heptane 2,2-dioxide. LCMS (M+H ⁺ ): 814. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.29 (s, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.15 (m, 2H), 7.14 - 7.06 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 5.76 - 5.60 (m, 1H), 5.21 - 5.01 (m, 1H), 4.51 - 4.33 (m, 2H), 4.27 (br d, J = 11.1 Hz, 1H), 4.21 - 4.00 (m, 4H), 3.97 - 3.89 (m, 2H), 3.15 - 3.01 (m, 2H), 2.97 (s, 3H), 2.90 - 2.75 (m, 5H), 2.75 - 2.63 (m, 2H), 2.60 - 2.54 (m, 3H), 2.53 - 2.42 (m, 2H). Example 645 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3 ,7-diazabicyclo[4.2.0]octan-7- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18 -dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one Example 645 was prepared in analogy to the preparation of Example 642 by using tert- butyl 3,7-diazabicyclo[4.2.0]octane-3-carboxylate;hydrochloride instead of tert-butyl 1,7- diazaspiro[3.5]nonane-7-carboxylate. LCMS (M+H ⁺ ): 835. ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.29 - 8.20 (m, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.29 (br d, J = 8.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.14 (br d, J = 10.1 Hz, 2H), 7.08 (br d, J = 7.5 Hz, 1H), 6.65 (br d, J = 8.4 Hz, 1H), 5.82 (dt, J = 4.4, 15.8 Hz, 1H), 5.42 - 5.19 (m, 2H), 4.73 - 4.67 (m, 2H), 4.58 (br s, 2H), 4.44 - 4.30 (m, 2H), 4.21 - 4.12 (m, 2H), 3.94 - 3.76 (m, 2H), 3.60 - 3.39 (m, 3H), 3.13 - 2.96 (m, 5H), 2.95 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.74 (br t, J = 13.2 Hz, 1H), 2.63 - 2.45 (m, 7H), 2.27 - 2.15 (m, 2H). Example 646 (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-11-(oxetan-3-yl)-3,4 ,8,11- 2,6 tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy-13, 18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:

Step 1: preparation of 1-tert-butyl O3-ethyl 4-amino-2,5-dihydropyrrole-1,3- dicarboxylate (compound 646b) To a solution of compound 646a (50.0 g, 194.3 mmol) in ethanol (500 mL) was added ammonium acetate (150.0 g, 1946.0 mmol). The mixture was stirred at 80 °C for 12 hrs, then the mixture was diluted with H ₂ O (2 L) and extracted with EA (1 L×2). The combined organic layer was dried and concentrated, the residue was purified by column chromatography to give compound 646b (42.0 g) as a yellow solid. LCMS (M-C ₄ H ₉ +H ⁺ ): 201. Step 2: preparation of 6-tert-butyl O3-methyl 2,4-dihydroxy-5,7-dihydropyrrolo[3,4- b]pyridine-3,6-dicarboxylate (compound 646c) To a solution of compound 646b (10.0 g, 39.0 mmol) in ethanol (60 mL) was added diethyl malonate (24.0 mL, 158.1 mmol) and sodium methoxide in MeOH (29.0 mL, 156.6 mmol). After being stirred at 120 °C for 12 hrs, the mixture was adjust pH = 7, and then poured into ice-water (1000 mL), while solid precipitated. The solid was collected by filtration and then dried to give compound 646c (38.0 g) as a brown solid. LCMS (M+H ⁺ ): 311. Step 3: preparation of methyl 2,4-dihydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine- 3-carboxylate (compound 646d) To a solution of compound 646c (38.0 g, 122.5 mmol) in DCM (300 mL) was added TFA (300.0 mL) at 0 °C, the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give compound 646d (38.0 g) as a brown oil. LCMS (M+H ⁺ ):211. Step 4: preparation of methyl 6-benzyl-2,4-dihydroxy-5,7-dihydropyrrolo[3,4- b]pyridine-3-carboxylate (compound 646e) To a solution of compound 646d (20.0 g, 95.15 mmol) and benzaldehyde (5.8 mL, 57.06 mmol) in methanol (160 mL) was added NaBH(OAc) ₃ (36.0 g, 169.81 mmol) at 0 °C. After being stirred at 25 °C for 1 h, the reaction was quenched with water (1 L), and then extracted with EA (500 mL×3). The combined organic layer was dried and concentrated to give compound 646e (16.0 g) as a brown oil. LCMS (M+H ⁺ ): 301. Step 5: preparation of methyl 6-benzyl-2,4-dichloro-5,7-dihydropyrrolo[3,4- b]pyridine-3-carboxylate(compound 646f) A mixture of compound 646e (3.0 g, 10.0 mmol) in POCl ₃ (30.0 mL, 10.0 mmol) was stirred at 120 °C for 36 hrs. Then the mixture was concentrated and then adjust pH = 8 by adding aq.sat.NAHCO ₃ , the resulted mixture was extracted with EtOAc. The organic layer was concentrated and the residue was purified by column chromatography to give compound 646f (1.5 g) as a yellow oil. LCMS (M+H ⁺ ):337. Step 6: preparation of (6-benzyl-2,4-dichloro-5,7-dihydropyrrolo[3,4-b]pyridin-3- yl)methanol(compound 646g) To a solution of compound 646f (1.3 g, 3.9 mmol) in DCM (25 mL) was added DIBAL-H (20.0 mL, 20.0 mmol) dropwise at 0 °C, then the mixture was stirred at 25 °C for 2 hrs. The reaction was quenched by adding water (1 mL), 15% NaOH (1 mL) and water (3 mL) slowly at 0 °C sequentially. Then 40 g of Na ₂ SO ₄ was added, and the mixture was stirred at 25 °C for 0.5 hrs. The mixture was filtered and the filtrate was concentrated to give compound 646g (1.1 g) as a yellow oil. LCMS (M+H ⁺ ): 309. Step 7: preparation of 6-benzyl-2,4-dichloro-5,7-dihydropyrrolo[3,4-b]pyridine-3- carbaldehyde(compound 646h) To a solution of oxalyl chloride (0.33 mL, 3.88 mmol) in DCM (50 mL) was added DMSO (0.46 mL, 6.47 mmol) in DCM (10 mL) dropwise at -70 °C. Then a solution of compound 646g (1.0 g, 3.23 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at -70°C, which was stirred at -70 °C for 2 hrs, then TEA (2.25 mL, 16.17 mmol, 5.0 eq) in DCM (20 mL) was then added at -70 °C. The reaction mixture was stirred at rt for 12 hours and then diluted with DCM (100 mL), the mixture was washed with brine (50 mL), dried and concentrated. The residue was purified by prep-TLC to give compound 646h (350.0 mg) as a yellow oil. LCMS (M+H ⁺ ): 307. Step 8: preparation of N-[(Z)-(6-benzyl-2,4-dichloro-5,7-dihydropyrrolo[3,4- b]pyridin-3-yl)methyleneamino]-2,4-difluoro-aniline (compound 646i) To a solution of compound 646h (350.0 mg, 1.14 mmol) in DMF (3 mL) was added 2,4- difluorophenylhydrazine hydrochloride (247.0 mg, 1.37 mmol), and then the mixture stirred at 25 °C for 2 hrs. The reaction was poured into water (20 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 646i (550.0 mg) as a yellow oil. LCMS (M+H ⁺ ): 433. Step 9: preparation of 11-benzyl-7-chloro-3-(2,4-difluorophenyl)-3,4,8,11- tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),4,7-tetraene (compound 646j) To a suspension of compound 646i (350.0 mg, 0.81 mmol) in DMF (3.5 mL) was added K ₂ CO ₃ (350.0 mg, 2.53 mmol), CuI (17.5 mg, 0.09 mmol) and (1R,2R)-cyclohexane-1,2-diamine (21.0 mg, 0.18 mmol). The mixture was stirred at 80 °C for 12 hrs and then concentrated, the residue was purified by flash chromatography to give compound 646j (120.0 mg) as a red solid. LCMS (M+H ⁺ ): 397. Step 10: preparation of 7-chloro-3-(2,4-difluorophenyl)-3,4,8,11- tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),4,7-tetraene(com pound 646k) To a solution of compound 646j (210.0 mg, 0.53 mmol) in DCE (2 mL) was added DIEA (0.13 mL, 0.81 mmol) and ACE-Cl (115.0 mg, 0.81 mmol) at 0 °C. The reaction mixture was stirred 25 °C for 2 hrs and then concentrated, the residue was dissolved in methanol (2 mL) and then heated at 60 °C for 2 hrs. The reaction mixture was directly purified by prep-HPLC to give compound 646k (110.0 mg) as a red solid. LCMS (M+H ⁺ ): 307. Step 11: preparation of 7-chloro-3-(2,4-difluorophenyl)-11-(oxetan-3-yl)-3,4,8,11- tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),4,7-tetraene(com pound 646l) A mixture of compound 646k (50.0 mg, 0.16 mmol) and 3-oxetanone (120.0 mg, 1.67 mmol) in methanol (1 mL) was stirred at 0 °C for 0.5 hrs, and then NaBH ₃ CN (51.0 mg, 0.81 mmol) and AcOH (20.0 mg, 0.33 mmol) was added at 0 °C. After being stirred at 25 °C for 7 hrs, the mixture was diluted with water, and then extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 646l (50.0 mg) as a brown solid. LCMS (M+H ⁺ ): 363. Step 12: preparation of (8S,11S,15R)-10-[3-(2,4-difluorophenyl)-11-(oxetan-3-yl)- 2,6 3,4,8,11-tetrazatricyclo[7.3.0.0 ]dodeca-1(9),2(6),4,7-tetraen-7-yl]-22-fluoro-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 646) A mixture of compound 370b (190.0 mg, 0.34 mmol), compound 646l (65.0 mg, 0.18 mmol), CsF (52.0 mg, 0.34 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) in DMA (2 mL) was stirred at 130 °C for 12 hrs. The reaction mixture was purified by prep-HPLC to give Example 646 (22.0 mg). LCMS (M+H ⁺ ): 765. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.57 - 8.20 (m, 1H), 7.84 - 7.75 (m, 1H), 7.67 - 7.58 (m, 1H), 7.35 - 7.25 (m, 2H), 7.23 - 7.13 (m, 2H), 7.07 (d, J = 7.4 Hz, 1H), 6.61 (br d, J = 7.9 Hz, 1H), 5.70 (br dd, J = 4.1, 15.4 Hz, 1H), 5.39 (br d, J = 8.8 Hz, 1H), 4.77 - 4.66 (m, 2H), 4.64 - 4.50 (m, 3H), 4.49 - 4.07 (m, 4H), 4.03 - 3.84 (m, 3H), 3.84 - 3.72 (m, 1H), 3.64 - 3.41 (m, 2H), 3.09 - 2.95 (m, 2H), 2.93 - 2.83 (m, 2H), 2.81 (s, 3H), 2.64 - 2.58 (m, 1H), 2.53 (s, 2H), 2.50 - 2.39 (m, 2H). Example 647 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(oxetan -3-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 647 was prepared in analogy to the preparation of Example 642 by using tert- butyl (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate;hydroch loride instead of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate. LCMS (M+H ⁺ ): 821. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.24 (s, 1H), 7.86 - 7.79 (m, 1H), 7.64 (dt, J = 5.9, 8.6 Hz, 1H), 7.37 - 7.28 (m, 1H), 7.23 (ddd, J = 2.6, 8.8, 10.1 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.70 (d, J = 8.5 Hz, 1H), 5.90 - 5.78 (m, 1H), 5.45 - 5.32 (m, 1H), 4.78 - 4.74 (m, 2H), 4.67 - 4.63 (m, 1H), 4.59 (br s, 2H), 4.51 - 4.40 (m, 1H), 4.28 - 4.10 (m, 3H), 4.09 - 3.99 (m, 1H), 3.96 - 3.74 (m, 3H), 3.53 - 3.45 (m, 1H), 3.13 (s, 1H), 3.09 - 3.04 (m, 3H), 3.03 - 2.96 (m, 1H), 2.93 - 2.84 (m, 4H), 2.78 (br d, J = 13.5 Hz, 1H), 2.59 (s, 3H), 2.55 - 2.44 (m, 2H), 2.21 - 2.12 (m, 1H), 2.04 - 1.97 (m, 1H). Example 648 (8S,11S,15S)-22-fluoro-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-[ 3-(2-methoxyethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 648 was prepared in analogy to the preparation of Example 639b by using compound 78d-2 and 580b instead of compound 370b and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 823. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.77 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 7.63 (br s, 2H), 7.54 - 7.49 (m, 2H), 6.80 - 6.72 (m, 2H), 5.92 (br s, 1H), 5.87 - 5.70 (m, 1H), 5.52 - 5.43 (m, 1H), 4.57 - 4.46 (m, 2H), 4.44 - 4.34 (m, 2H), 4.26 - 4.17 (m, 1H), 4.15 - 3.95 (m, 3H), 3.87 (br d, J = 12.0 Hz, 1H), 3.76 - 3.53 (m, 6H), 3.27 - 3.17 (m, 3H), 3.16 - 3.01 (m, 4H), 2.97 - 2.89 (m, 1H), 2.89 - 2.86 (m, 3H), 2.86 - 2.77 (m, 2H), 2.76 - 2.71 (m, 3H), 2.09 - 1.98 (m, 1H). Example 649 (8S,11S,15S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(4-fluoro-2- hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 649 was prepared in analogy to the preparation of Example 639b by using compound 78d-2 and 651b instead of compound 370b and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 829. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.71 (d, J = 5.1 Hz, 1H), 8.28 (s, 1H), 7.71 (dd, J = 6.2, 8.7 Hz, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.42 (dd, J = 2.6, 8.4 Hz, 1H), 7.33 (dd, J = 2.3, 10.1 Hz, 1H), 6.79 - 6.70 (m, 2H), 5.89 - 5.84 (m, 1H), 5.82 - 5.66 (m, 1H), 5.46 (d, J = 8.3 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.47 - 4.42 (m, 1H), 4.42 - 4.33 (m, 1H), 4.32 - 4.27 (m, 1H), 4.26 - 4.21 (m, 1H), 4.18 (br d, J = 16.6 Hz, 1H), 4.04 (d, J = 14.5 Hz, 1H), 3.51 - 3.43 (m, 1H), 3.42 - 3.34 (m, 2H), 3.19 - 3.13 (m, 1H), 3.13 - 3.01 (m, 4H), 3.01 - 2.97 (m, 1H), 2.95 - 2.88 (m, 1H), 2.88 - 2.83 (m, 1H), 2.82 (s, 3H), 2.79 - 2.71 (m, 2H), 2.64 - 2.59 (m, 3H), 2.58 - 2.52 (m, 1H), 1.79 (d, J = 8.1 Hz, 1H). Example 650 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[6-[3-(2-fluoroethyl)-3, 6-diazabicyclo[3.1.1]heptan-6- yl]-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Example 650 was prepared in analogy to the preparation of Example 580 by using compound 582b instead of compound 580b and compound 650a (the synthesis refer to compound 213a by using compound 81d-1 instead of compound 370b) instead of compound 575a. LCMS (M+H ⁺ ): 825. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.74 - 8.61 (m, 1H), 8.21 - 8.10 (m, 1H), 7.72 - 7.58 (m, 1H), 7.56 - 7.43 (m, 1H), 7.40 - 7.22 (m, 2H), 6.70 - 6.54 (m, 2H), 5.82 - 5.62 (m, 2H), 5.36 - 5.21 (m, 1H), 4.58 - 4.00 (m, 7H), 3.95 - 3.80 (m, 1H), 3.19 - 3.11 (m, 2H), 3.05 - 2.82 (m, 5H), 2.81 - 2.57 (m, 6H), 2.56 - 2.39 (m, 6H), 1.85 - 1.71 (m, 1H), 0.56 - 0.36 (m, 3H). Example 651 (8S,11S,15R)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3 .1.1]heptan-6-yl]-1-(4-fluoro-2- hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Example 651 was prepared in analogy to the preparation of Example 580 by using trifluoromethyl 2,2-difluoroethanesulfonate instead of 1-bromo-2-methoxy-ethane and compound 650a instead of compound 575a. LCMS (M+H ⁺ ): 843. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.76 - 8.60 (m, 1H), 8.28 - 8.06 (m, 1H), 7.73 - 7.44 (m, 2H), 7.41 - 7.27 (m, 2H), 6.73 - 6.54 (m, 2H), 5.95 - 5.50 (m, 3H), 5.38 - 5.15 (m, 1H), 4.43 - 4.26 (m, 2H), 4.26 - 4.02 (m, 3H), 4.00 - 3.74 (m, 1H), 3.45 - 3.25 (m, 2H), 3.02 - 2.66 (m, 10H), 2.61 - 2.38 (m, 7H), 1.86 - 1.60 (m, 1H), 0.54 - 0.40 (m, 3H). Example 652 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(2- methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3, 4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 652 was prepared in analogy to the preparation of Example 580 by using compound 650a instead of compound 575a. LCMS (M+H ⁺ ): 837. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.69 (d, J = 5.3 Hz, 1H), 8.29 - 8.17 (m, 1H), 7.65 - 7.46 (m, 2H), 7.44 - 7.26 (m, 2H), 6.75 - 6.58 (m, 2H), 5.83 - 5.58 (m, 2H), 5.41 - 5.26 (m, 1H), 4.57 - 4.20 (m, 5H), 4.17 - 3.72 (m, 4H), 3.71 - 3.36 (m, 6H), 3.13 - 2.85 (m, 6H), 2.82 - 2.40 (m, 9H), 2.00 - 1.78 (m, 1H), 0.59 - 0.40 (m, 3H). Example 653 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan -3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 653 was prepared in analogy to the preparation of Example 574 by using compound 81d-1 instead of compound 326d-1 and intermediate C88 instead of compound 574e. LCMS (M+H ⁺ ): 837. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.77 - 8.58 (m, 1H), 8.24 - 8.08 (m, 1H), 7.63 - 7.41 (m, 2H), 7.41 - 7.26 (m, 2H), 7.21 - 6.93 (m, 2H), 5.83 - 5.52 (m, 2H), 5.44 - 5.21 (m, 1H), 4.69 - 4.60 (m, 3H), 4.52 - 4.22 (m, 4H), 4.19 - 3.71 (m, 4H), 3.69 - 3.39 (m, 2H), 3.11 - 2.84 (m, 5H), 2.81 - 2.66 (m, 2H), 2.67 - 2.38 (m, 6H), 1.99 - 1.81 (m, 2H), 1.33 - 1.17 (m, 1H), 0.55 - 0.41 (m, 3H). Example 654 (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy-p henyl)-6-[3-(oxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 654a) A mixture of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 1 mmol) and oxetan-3-one (218 mg, 3 mmol) in ethanol (4 mL) was stirred at 60 °C for 2 hours, then NaBH ₃ CN (317 mg, 5 mmol) was added and stirred at 60 °C for 6 hours. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 654a (50 mg). LCMS (M+H ⁺ ): 255. Step 2-3: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-[1-(4-fluoro-2-hydroxy- phenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-y l]pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 20,24 yl]-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6 .1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 654) Example 654 was prepared in analogy to the preparation of Example 580 by using compound 570a instead of compound 575a and compound 654a instead of compound 580a. LCMS (M+H ⁺ ): 834. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.45 (d, J = 5.1 Hz, 1H), 8.24 - 8.09 (m, 1H), 7.66 - 7.57 (m, 1H), 7.38 - 7.26 (m, 1H), 7.24 - 7.05 (m, 1H), 7.03 - 6.91 (m, 1H), 6.74 - 6.56 (m, 2H), 5.57 - 5.40 (m, 1H), 5.28 - 5.16 (m, 1H), 4.64 - 4.41 (m, 6H), 4.39 - 4.03 (m, 5H), 4.00 - 3.75 (m, 2H), 3.18 - 3.09 (m, 2H), 3.06 - 2.69 (m, 7H), 2.61 - 2.33 (m, 7H), 1.79 (d, J = 8.1 Hz, 1H), 0.58 - 0.40 (m, 3H). Example 655 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-2-oxo-p yrrolidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 655 was prepared in analogy to the preparation of Example 587 by using 3- hydroxypyrrolidin-2-one instead of 3-methyl-2-pyrrolidinone. LCMS (M+H ⁺ ): 766. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.48 (s, 1H), 7.80 - 7.73 (m, 2H), 7.65 - 7.56 (m, 1H), 7.40 - 7.28 (m, 2H), 7.18 - 7.07 (m, 2H), 6.67 - 6.63 (m, 1H), 5.80 - 5.50 (m, 3H), 5.45 - 5.38 (m, 1H), 4.64 - 3.45 (m, 8H), 3.04 - 2.78 (m, 4H), 2.76 - 2.70 (m, 3H), 2.62 - 2.55 (m, 2H), 2.47 - 2.40 (m, 3H), 2.39 - 2.25 (m, 2H), 1.82 - 1.67 (m, 1H). Example 656 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(2-oxopyrrolidin-1 -yl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 656 was prepared in analogy to the preparation of Example 587 by using 2- pyrrolidinone instead of 3-methyl-2-pyrrolidinone and compound 575a instead of compound 370b. LCMS (M+H ⁺ ): 767. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 - 8.37 (m, 1H), 8.35 - 8.26 (m, 1H), 7.70 - 7.52 (m, 1H), 7.36 - 7.11 (m, 3H), 7.09 - 6.92 (m, 2H), 5.49 - 5.41 (m, 1H), 5.39 - 5.33 (m, 1H), 4.52 - 4.35 (m, 2H), 4.16 - 4.00 (m, 2H), 3.97 - 3.82 (m, 2H), 3.82 - 3.65 (m, 2H), 3.17 - 3.06 (m, 1H), 3.01 - 2.88 (m, 3H), 2.88 - 2.80 (m, 1H), 2.74 - 2.67 (m, 1H), 2.53 - 2.47 (m, 4H), 2.43 - 2.28 (m, 3H), 1.94 - 1.72 (m, 2H), 0.54 - 0.37 (m, 3H). Example 657 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluor o-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxazolidin-2-one Example 657 was prepared in analogy to the preparation of Example 587 by using oxazolidin-2-one instead of 3-methyl-2-pyrrolidinone and compound 575a instead of compound 370b. LCMS (M+H ⁺ ): 769. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.55 - 8.41 (m, 1H), 8.36 - 7.52 (m, 2H), 7.39 - 7.24 (m, 1H), 7.24 - 7.10 (m, 2H), 7.09 - 6.93 (m, 2H), 5.57 - 5.14 (m, 2H), 4.68 - 4.64 (m, 1H), 4.34 - 4.17 (m, 3H), 4.16 - 4.04 (m, 2H), 4.02 - 3.75 (m, 3H), 3.18 - 3.12 (m, 1H), 3.00 - 2.87 (m, 3H), 2.87 - 2.64 (m, 2H), 2.59 - 2.29 (m, 6H), 0.55 - 0.40 (m, 3H). Example 658 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-metho xy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxazolidin-2-one Example 658 was prepared in analogy to the preparation of Example 587 by using oxazolidin-2-one instead of 3-methyl-2-pyrrolidinone. LCMS (M+H ⁺ ): 754. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.37 (s, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.30 - 7.24 (m, 1H), 7.24 - 7.19 (m, 1H), 7.19 - 7.08 (m, 2H), 7.07 - 7.01 (m, 1H), 6.62 (d, J = 8.5 Hz, 1H), 5.70 (br dd, J = 3.4, 15.6 Hz, 1H), 5.43 (d, J = 8.9 Hz, 1H), 4.61 - 4.52 (m, 1H), 4.42 - 4.24 (m, 3H), 4.24 - 4.11 (m, 2H), 4.10 - 3.97 (m, 2H), 3.91 (br dd, J = 9.1, 14.2 Hz, 1H), 3.08 - 2.95 (m, 3H), 2.93 - 2.81 (m, 1H), 2.81 - 2.78 (m, 3H), 2.77 - 2.70 (m, 1H), 2.55 - 2.50 (m, 3H), 2.49 - 2.37 (m, 2H). Example 659 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(4-methyl-2-oxo-pi perazin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,1 3,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 659 was prepared in analogy to the preparation of Example 587 by using 4- methylpiperazin-2-one instead of 3-methyl-2-pyrrolidinone. LCMS (M+H ⁺ ): 771. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 (s, 1H), 7.84 - 7.78 (m, 1H), 7.71 - 7.60 (m, 1H), 7.30 (dd, J = 2.6, 8.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 7.12 - 7.06 (m, 1H), 6.70 - 6.63 (m, 1H), 5.82 - 5.64 (m, 1H), 5.49 - 5.37 (m, 1H), 4.69 - 4.64 (m, 1H), 4.61 - 4.55 (m, 1H), 4.51 (dd, J = 6.0, 11.5 Hz, 1H), 4.35 - 4.23 (m, 1H), 4.18 - 4.10 (m, 1H), 3.95 - 3.87 (m, 2H), 3.80 (t, J = 5.8 Hz, 1H), 3.27 - 3.18 (m, 2H), 3.12 - 2.99 (m, 3H), 2.91 - 2.84 (m, 2H), 2.84 - 2.81 (m, 3H), 2.81 - 2.72 (m, 1H), 2.58 - 2.54 (m, 3H), 2.53 - 2.44 (m, 2H), 2.41 - 2.34 (m, 3H). Example 660 (8S,11S,15S)-22-fluoro-10-[6-[3-(2-fluoroethyl)-3,6-diazabic yclo[3.1.1]heptan-6-yl]-1-(4- fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-me thoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 660 was prepared in analogy to the preparation of Example 639b by using compound 78d-2 and 582b instead of compound 370b and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 811. Example 661 (8S,11S,15S)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one

Example 661 was prepared in analogy to the preparation of Example 575 by using compound 78d-2 instead of compound 326d-1 and compound 661b instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. Example 661, LCMS (M+H ⁺ ): 863. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.81 - 8.75 (m, 1H), 8.33 - 8.28 (m, 1H), 7.70 - 7.50 (m, 4H), 7.28 - 7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 6.19 - 5.92 (m, 1H), 5.89 - 5.78 (m, 1H), 5.45 (br d, J = 8.9 Hz, 1H), 4.54 - 4.39 (m, 3H), 4.36 (br d, J = 6.1 Hz, 2H), 4.32 - 4.22 (m, 1H), 4.21 - 4.10 (m, 1H), 3.84 - 3.72 (m, 1H), 3.68 - 3.53 (m, 2H), 3.52 - 3.45 (m, 1H), 3.28 - 3.19 (m, 2H), 3.15 - 3.02 (m, 3H), 2.94 - 2.81 (m, 6H), 2.81 - 2.69 (m, 2H), 1.68 - 1.57 (m, 1H). The compound 661b was prepared according to the following scheme: Step 1: preparation tert-butyl 3-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1] heptane- 6-carboxylate (compound 661a) To a tube was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.5 mmol), DIEA (587 mg, 4.54 mmol), dichloromethane (5 mL) and TFAA (900 mg, 4.29 mmol). After being stirred at r.t. for 40 hrs, the reaction mixture was concentrated to give an oil, which was purified by silica gel to give compound 661a as an oil. LCMS (M+H ⁺ ): 295. Step 2: preparation 1-[3,6-diazabicyclo[3.1.1]heptan-3-yl]-2,2,2-trifluoro-ethan one (compound 661b) A mixture of compound 661b (656 mg, 2.23 mmol) in dichloromethane (2 mL) and TFA (2 mL) was stirred at r.t. for 4 hrs. Then the mixture was concentrated to give compound 661b as an oil. LCMS (M+H ⁺ ): 195. Example 662 (8S,11S,15S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 662 was prepared in analogy to the preparation of Example 575 by using compound 78d-2 instead of compound 326d-1 and compound 662b instead of tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS (M+H ⁺ ): 845. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.79 (t, J = 5.3 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.65 - 7.58 (m, 1H), 7.55 (dd, J = 5.3, 6.6 Hz, 1H), 7.24 (tt, J = 1.8, 9.1 Hz, 1H), 7.20 - 7.12 (m, 1H), 6.32 (t, J = 53.0 Hz, 1H), 6.15 - 5.91 (m, 1H), 5.89 - 5.81 (m, 1H), 5.46 (d, J = 9.0 Hz, 1H), 4.53 - 4.45 (m, 2H), 4.44 - 4.29 (m, 4H), 4.29 - 4.18 (m, 1H), 4.14 - 3.97 (m, 1H), 3.76 - 3.65 (m, 1H), 3.64 - 3.55 (m, 1H), 3.54 - 3.43 (m, 1H), 3.30 - 3.18 (m, 2H), 3.15 - 3.05 (m, 3H), 2.95 - 2.90 (m, 3H), 2.90 - 2.82 (m, 3H), 2.81 - 2.69 (m, 2H), 1.60 (dd, J = 4.1, 9.0 Hz, 1H). The compound 662b was prepared in analogy to the preparation of compound 661b by using (2,2-difluoroacetyl) 2,2-difluoroacetate instead of (2,2,2-trifluoroacetyl) 2,2,2- trifluoroacetate (TFAA). Example 663 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2,2,2-trifluor oacetyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one

Example 663 was prepared in analogy to the preparation of Example 575 by using compound 565a instead of compound 575a and compound 661b instead of 3-oxa-6- azabicyclo[3.1.1]heptane. LCMS (M+H ⁺ ): 877. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.97 - 8.81 (m, 1H), 8.36 - 8.27 (m, 1H), 7.80 - 7.54 (m, 4H), 7.35 - 7.10 (m, 2H), 6.13 - 5.96 (m, 1H), 5.90 - 5.79 (m, 1H), 5.50 - 5.35 (m, 1H), 4.62 - 3.94 (m, 8H), 3.90 - 3.73 (m, 1H), 3.68 - 3.39 (m, 2H), 3.15 - 2.99 (m, 3H), 2.99 - 2.61 (m, 9H), 1.67 - 1.56 (m, 1H), 0.70 - 0.54 (m, 3H). Example 664 (8S,11S,15R)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[ 3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-f luoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 664 was prepared in analogy to the preparation of Example 575 by using compound 565a instead of compound 575a and compound 662b instead of 3-oxa-6- azabicyclo[3.1.1]heptane. LCMS (M+H ⁺ ): 859. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.94 - 8.82 (m, 1H), 8.40 - 8.23 (m, 1H), 7.80 - 7.57 (m, 4H), 7.34 - 7.12 (m, 2H), 6.14 - 5.96 (m, 1H), 5.91 - 5.71 (m, 1H), 5.50 - 5.38 (m, 1H), 4.56 - 4.21 (m, 7H), 4.15 - 3.92 (m, 1H), 3.85 - 3.61 (m, 1H), 3.57 - 3.39 (m, 2H), 3.12 - 2.65 (m, 13H), 1.67 - 1.58 (m, 1H), 0.71 - 0.55 (m, 3H). Example 665 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-hydroxy-2-me thyl-propanoyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme: Step 1: preparation of [2-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-1,1-di methyl-2-oxo-ethyl] acetate (compound 665b) To a solution of compound C80-b (100 mg, 0.22 mmol), N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) was added 2-acetoxyisobutyryl chloride (43 mg, 0.26 mmol). After being stirred at 20°C for 1.5 hrs, the reaction was diluted with water and extracted with EA. The organic layer was dried and concentrated in vacuo to give compound 665b (52 mg) as yellow gum. LCMS (M+H ⁺ ): 473. Step 2: preparation of [2-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hep tan-3-yl]-1,1-dimethyl-2-oxo- ethyl] acetate (compound 665c) To a solution of compound 665b (52 mg, 0.11 mmol) was added DIEA (116 mg, 0.9 mmol) and PyBOP (70 mg, 0.14 mmol). After being stirred at rt for 10 mins, the reaction mixture was added with compound 370b (50.0 mg, 0.09 mmol) and stirred at 25 °C for 1 h, then diluted with water and extracted with EA, the organic layer was dried and concentrated to give compound 665c (35.0 mg) as yellow solid. LCMS (M+H ⁺ ): 893. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-hydroxy-2- methyl-propanoyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazol o[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 665) A mixture of compound 665c (35.0 mg, 0.04 mmol) and K ₂ CO ₃ (27 mg, 0.2 mmol) in methanol (2 mL) was at 60 °C for 5 hrs. The reaction was filtered and the filtrate was purified by prep-HPLC to give Example 665 (8 mg). LCMS (M+H ⁺ ): 851. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.37 - 8.26 (m, 1H), 7.88 - 7.78 (m, 1H), 7.68 - 7.55 (m, 3H), 7.46 - 7.40 (m, 1H), 7.32 - 7.25 (m, 1H), 7.18 - 7.11 (m, 1H), 6.82 - 6.65 (m, 1H), 5.99 - 5.67 (m, 1H), 5.57 - 5.31 (m, 1H), 5.28 - 5.15 (m, 1H), 4.68 - 4.49 (m, 1H), 4.48 - 4.29 (m, 2H), 4.28 - 4.03 (m, 6H), 2.95 (s, 3H), 2.91 - 2.83 (m, 2H), 2.83 - 2.79 (m, 3H), 2.71 - 2.63 (m, 4H), 2.40 - 2.30 (m, 2H), 1.57 - 1.35 (m, 2H), 1.35 - 1.17 (m, 6H). Example 666 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclo propanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:

A mixture of compound 564b (30 mg, 0.04 mmol), 1-hydroxycyclopropane-1-carboxylic acid (26 mg, 0.2 mmol), DIEA (53 mg, 0.41 mmol) and T ₃ P (52.0 mg, 0.08 mmol) in DMF (1 mL) was stirred at 25 °C for 16 hrs. Then reaction mixture was purified by prep-HPLC to give Example 666 (12.5 mg). LCMS (M+H ⁺ ): 849. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.18 - 7.99 (m, 1H), 7.89 - 7.65 (m, 2H), 7.61 - 7.49 (m, 1H), 7.23 - 6.91 (m, 4H), 6.64 - 6.39 (m, 1H), 5.31 - 5.20 (m, 1H), 4.64 - 4.57 (m, 1H), 4.51 - 4.34 (m, 3H), 4.32 - 4.21 (m, 2H), 4.19 - 4.06 (m, 2H), 3.99 - 3.86 (m, 1H), 3.13 - 3.06 (m, 1H), 3.04 - 2.96 (m, 3H), 2.95 - 2.88 (m, 4H), 2.87 - 2.81 (m, 3H), 2.79 - 2.74 (m, 1H), 2.67 (br s, 2H), 2.58 (br s, 2H), 2.08 - 1.98 (m, 2H), 1.65 - 1.41 (m, 2H), 0.96 - 0.79 (m, 2H). Example 667 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclo butanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 667 was prepared in analogy to the preparation of Example 666 by using 1- hydroxycyclobutanecarboxylic acid instead of 1-hydroxycyclopropane-1-carboxylic acid. LCMS (M+H ⁺ ): 863. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.07 (d, J = 7.8 Hz, 1H), 7.86 - 7.74 (m, 2H), 7.57 - 7.49 (m, 1H), 7.07 - 6.99 (m, 4H), 6.50 (br d, J = 8.0 Hz, 1H), 5.30 - 5.22 (m, 1H), 4.56 (s, 1H), 4.45 - 4.36 (m, 4H), 4.32 - 4.27 (m, 1H), 4.22 - 4.14 (m, 2H), 3.08 (s, 1H), 3.04 (s, 1H), 2.99 (s, 2H), 2.97 - 2.92 (m, 5H), 2.91 (s, 1H), 2.85 - 2.78 (m, 3H), 2.68 - 2.60 (m, 2H), 2.52 - 2.43 (m, 4H), 1.56 - 1.43 (m, 4H), 1.30 - 1.22 (m, 2H). Example 668 (8S,11S,15R)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicycl o[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-m ethoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one Example 668 was prepared in analogy to the preparation of compound 665c by using cyclopropanecarbonyl chloride instead of 2-acetoxyisobutyryl chloride. LCMS (M+H ⁺ ): 833. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.06 (d, J = 2.9 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.60 - 7.39 (m, 2H), 7.20 - 7.06 (m, 2H), 7.05 - 6.92 (m, 2H), 6.46 (br t, J = 7.8 Hz, 1H), 6.07 - 5.70 (m, 1H), 5.34 - 5.15 (m, 1H), 4.65 - 4.38 (m, 4H), 4.36 - 4.26 (m, 2H), 4.21 - 4.05 (m, 3H), 3.76 - 3.45 (m, 2H), 3.09 - 2.96 (m, 3H), 2.84 - 2.75 (m, 5H), 2.74 - 2.59 (m, 4H), 2.53 - 2.31 (m, 2H), 1.38 - 1.28 (m, 2H), 0.98 - 0.85 (m, 2H), 0.80 - 0.66 (m, 2H). Example 669 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-fluorocyclob utyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl ]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 669 was prepared in analogy to the preparation of Example 431 by using Intermediate C95 instead of compound 431c. LCMS (M+H ⁺ ): 837. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.10 - 7.98 (m, 1H), 7.75 - 7.66 (m, 1H), 7.60 - 7.49 (m, 1H), 7.40 (dd, J = 2.3, 8.6 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.99 (br t, J = 9.0 Hz, 2H), 6.48 - 6.37 (m, 1H), 5.99 - 5.73 (m, 1H), 5.36 - 5.23 (m, 1H), 5.19 - 5.07 (m, 1H), 5.06 - 4.73 (m, 1H), 4.68 - 4.52 (m, 1H), 4.46 - 4.36 (m, 1H), 4.28 (br s, 1H), 4.22 - 4.12 (m, 2H), 4.12 - 3.70 (m, 2H), 3.12 (br s, 1H), 3.11 - 2.99 (m, 2H), 2.95 (s, 3H), 2.82 (br d, J = 10.0 Hz, 1H), 2.77 (s, 3H), 2.74 - 2.62 (m, 2H), 2.57 (s, 3H), 2.55 - 2.40 (m, 4H), 2.38 - 2.15 (m, 2H), 2.12 - 1.90 (m, 2H). Example 670 Microliter plate-based TR-FRET assay for binders of STING This is the competition-binding assay to test the compounds’ potency to the C-terminal Domain (CTD) and ligand-binding domain of human stimulator of interferon genes (STING). STING (139-379, Q86WV6, http://www.uniprot.org/uniprot) recombinant protein (in 20mM Tris, 150mM NaCl, pH 8.0, and expression in Escherichia coli (E. coil) BL21 (DE3)) with a C- terminal flag-tag was employed for the assay. When Alexa-488 labeled active site probe (refer to patent WO2017/175156 A1) bounds to STING (139-379), it accepts the 485 nm emission from Tb-M2-Flag-STING and results in an increase in fluorescence at 520 nm. Compounds that compete for the probe-binding site will reduce 520 nm signal. The assay was run in proxiplate- 384 plus (PerkinElmer, cat: 60150300) containing of 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, Lot: 17A) and 250 nM Alexa488 probe. Plates were centrifuged for 1 min at 1000 rpm, incubated for 30 min at room temperature, and then measured the dual fluorescence emission at 520 nM / 485 nM following 320 nm laser excitation on an Envision plate reader (Perkin-Elmer). The compounds’ effect on the STING binding is detected by measuring ratiometric fluorescence from time-resolved FRET. The percentage of inhibition of at each compound concentration is calculated on the basis of their changes of TR-FRET efficiency relative to the change of TR-FRET caused by positive control 2’3’cGAMP (Sigma, cat: SML1229). Example 671 THP1-Dual Lucia Reporter Gene Assay This is the cellular reporter assay to evaluate compounds’ antagonism to interferon regulatory factor (IRF) pathway in THP1-Dual™ cells (InvivoGen, cat number thpd-nfis) . THP1-Dual™ cells were derived from the human THP-1 monocyte cell line by stable integration lucia luciferase gene, a new secreted luciferase reporter gene, under the control of an ISG54 (interferon-stimulated gene) minimal promoter in conjunction with five interferon (IFN)- stimulated response elements. As a result, THP1‑Dual™ cells allow the study of the IRF pathway, by assessing the activity of Lucia luciferase. Lucia luciferase protein is readily measurable in the cell culture supernatant when using QUANTI‑Luc™ (InvivoGen, cat: rep- qlcg-500). 2’3’cGAMP or baculovirus (a double stranded DNA virus, purchased from Genescript, pCMV-Dest Vector virus generation P2 BV stock virus, Sf-900 II medium with 5% FBS, Lot C9835DK230-2/P4DL001) were used as stimulator to induce the activation of IRF pathway. After co-incubation with compound for 20-24 h, the compounds’ antagonism to IRF pathway and cell toxicity were tested by measuring luminescence and OD 450 on an Envision plate reader. On the day of experiment, 25 μL of test medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed in a white, 384-well plate (Grenier, cat: 781098). 24 μL of stimulator (final concentration is 20 μM of 2’3’cGAMP, or final concentration is 10 MOI baculovirus virus,) was added before 6 μL of compound solution per well (final 1% DMSO) was transferred by Agilent Bravo. Then 30 μL of cell suspension (~33,000 cells, 1.1 x10 ⁶ cells/ml) per well was added immediately by thermo multidrop combi dispenser for incubation 20-24 h at 37 °C, 5% CO ₂ . At the end of the incubation, 10 μL of cellular supernatant was transferred to proxiplate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc™ Gold solution was added to the plate that proceeded with the measurement immediately. To detect cell viability, 30 μL of the CCK-8 working solution (Dojindo Molecular Technologies, cat: CK04-20) was added to the cell plate, which was Incubated for 2 h in the incubator to measure the absorbance at 450 nm using Envision.