Bicyclic macrocycles for the treatment of autoimmune disease

Abstract

The present invention relates to compounds of formula (Ia), wherein R2, T1 to T4, and M1 to M3 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

Case 38670 Bicyclic 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 known as familial chilblain lupus (FCL). 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. In addition, mutations in proteins, such as COP and WAS protein, that regulates STING intracellular trafficking and signaling also presented monogenic disorders known as COPA syndrome and Wiskott-Aldrich syndrome, respectively. Apart from genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role of STING in a range of inflammation-associated disorders including but not limited to: SLE, IBD, RA, dermatomyositis, diabetic kidney disease (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR) and Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) associated vasculitis. For example: 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. In addition, cGAS- and cGAMP-independent mode of STING activation also affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C (NPC). 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 bychromosomal 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 compound of formula (I),wherein A1is N or CR4, wherein R4is H or halogen; A2is N or CR4, wherein R4is H or halogen; A3is N or CR4, wherein R4is H or halogen; A4is N or CR4, wherein R4is H or halogen; A5is N or CR4, wherein R4is H or halogen; A6is N or CR4, wherein R4is H or halogen; A7is N or CR4, wherein R4is H or halogen; A8is N and A9is C, or A8is C and A9is N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene; R3is; whereinY1is heterocyclyl, heteroaryl or carbonylheteroaryl, each of which has three bonds connecting to N, Q3and Q4, and is further substituted by R5, wherein R5is H, deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy; Y2is a bond, heteroarylene or arylene, each of which is once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently selected from heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene, C1-6alkylene, carbonyl, carbonyl(C1-6alkyl)amino, - COO-, O and sulfonyl, wherein heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene and C1-6alkylene are unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2,heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl; each L3is independently C1-6alkylene, C2-6alkenylene, C2-6alkynylene, heteroaryl or heterocyclylene, each of which is unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2, heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl; each L4is independently NH, S, SO, SO2, O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Another object of the present invention is related to novel compounds of formula (Ia), (I), (I-1) or (I-2). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (Ia), (I), (I-1) or (I-2) 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 (Ia), (I), (I-1) or (I-2) show superior STING antagonism activity. In addition, the compounds of formula (Ia), (I), (I-1) or (I-2) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG 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 “C1-6alkyl” 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 “C1-6alkyl” groups are methyl, ethyl and n-propyl. The term “C1-6alkylene” denotes a divalent C1-6alkyl. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C1-6alkoxy” denotes C1-6alkyl-O-. The term “C2-6alkenyl” 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 C2-6alkenyl include ethenyl (or vinyl), propenyl, allyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl. The term “C2-6alkenylene” denotes a divalent C2-6alkenyl. Examples of C2-6alkenylene groups include butenylene and (methyl)butenylene. The term “C2-6alkynyl” 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 C2-6alkynyl include ethynyl (–C ^CH), prop-1-ynyl (–C ^CCH3), prop-2-ynyl (propargyl, –CH2C ^CH), but-1-ynyl, but-2-ynyl, and but- 3-ynyl. The term “C2-6alkynylene” denotes a divalent C2-6alkynyl. Examples of C2-6alkynylene groups include butynylene. The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.The term “haloC1-6alkyl” denotes a C1-6alkyl group wherein at least one of the hydrogen atoms of the C1-6alkyl 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 “haloC1-6alkoxy” denotes haloC1-6alkyl-O-. The term “haloC2-6alkenylene” denotes a divalent C2-6alkenyl group wherein at least one of the hydrogen atoms of the C2-6alkenylene group has been replaced by same or different halogen atoms, particularly fluoro atoms. Example of haloC2-6alkenylene group includes fluorobutenylene. The term “C3-7cycloalkyl” 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 “C3-7cycloalkylene” denotes a divalent C3-7cycloalkyl. The term “haloC3-7cycloalkyl” denotes a C3-7cycloalkyl group wherein at least one of the hydrogen atoms of the C3-7cycloalkyl group has been replaced by same or different halogen atoms, particularly fluoro atom. The term “C3-7cycloalkoxy” denotes C3-7cycloalkyl-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, heterocyclylincludes 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, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+Cl-, [NR4]+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, 2,3,4a,5,7,7a- hexahydro-[1,4]dioxino[2,3-c]pyrrolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl,2,7-diazaspiro[4.4]nonanyl and 2-oxa-5-azabicyclo[4.1.0]heptanyl. Particularly, heterocyclyl herein canThe 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.) 13thed. 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 optionallysubstituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents. Suitable substituents of an “optionally substituted” group may be selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl, RSO2C1-6alkyl, RNHSO2C1-6alkyl, R2NSO2C1-6alkyl, RSO(NR)C1-6alkyl and R3SiC1-6alkyl; wherein R is H, Ra, Rbor Rc; Rais C1-6alkyl optionally substituted by Rbor Rc; Rbis C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rcis selected from deuterio, C1-6alkyl, (C1-6alkyl)3Si, haloC1-6alkyl, deuterioC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, deuterioC1-6alkoxy, C2-6alkenyl, haloC2-6alkenyl, deuterioC2-6alkenyl, C2-6alkynyl, haloC2-6alkynyl, deuterioC2-6alkynyl, C3-7cycloalkyl, haloC3-7cycloalkyl, deuterioC3-7cycloalkyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylcarbonylamino, haloC1-6alkylamino, haloC1-6alkylcarbonylamino, (haloC1-6alkyl)2amino, C3-7cycloalkylamino, C3-7cycloalkylcarbonylamino, (C3-7cycloalkyl)2amino, haloC3-7cycloalkylamino, (haloC3-7cycloalkyl)2amino, C3-7cycloalkyl(C1-6alkyl)amino, haloC3-7cycloalkyl(C1-6alkyl)amino, C1-6alkylsulfonylamino, haloC1-6alkylsulfonylamino, C1-6alkoxyC1-6alkyl, (haloC1-6alkoxy)C1-6alkyl, C1-6alkoxy(halo)C1-6alkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylhaloC1-6alkyl, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkoxycarbonyl, haloC1-6alkoxycarbonyl, C3-7cycloalkoxycarbonyl, haloC3-7cycloalkoxycarbonyl, C1-6alkylaminocarbonyl, (C1- 6alkyl)2aminocarbonyl, C3-7cycloalkylaminocarbonyl, (C3-7cycloalkyl)2aminocarbonyl, C1-6alkylC3-7cycloalkylaminocarbonyl, haloC1-6alkylaminocarbonyl, halo(C1-6alkyl)2aminocarbonyl, haloC3-7cycloalkylaminocarbonyl, halo(C3-7cycloalkyl)2aminocarbonyl, haloC1-6alkylC3- 7cycloalkylaminocarbonyl, C1-6alkylhaloC3-7cycloalkylaminocarbonyl, (C1-6alkyl)3ammonio, C1-6alkylsulfanyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfanyl, C3-7cycloalkylsulfinyl, C3-7cycloalkylsulfonyl, haloC1-6alkylsulfanyl, haloC1-6alkylsulfinyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfanyl, haloC3-7cycloalkylsulfinyl, haloC3-7cycloalkylsulfonyl, haloC1-6alkoxysulfonyl, C1-6alkylaminosulfonyl, (haloC1-6alkylamino)sulfonyl, (C1-6alkyl)2aminosulfonyl, (haloC1-6alkyl)2aminosulfonyl, (C1-6alkyl)2phosphoryl, (C1-6alkoxy)2phosphoryl, hydroxy(C1-6alkoxy)phosphoryl, C1-6alkoxyphosphoryl, hydroxy, hydroxyC1-6alkyl, hydroxyhaloC1-6alkyl, hydroxyC1-6alkoxy, hydroxylhaloC1-6alkoxy, hydroxyC3-7cycloalkyl, hydroxyhaloC3-7cycloalkyl and sulfonimidoyl, each of which is substituted by H, halogen, C1-6alkyl, C1-6alkoxy, aryl, heteroaryl or heterocyclyl.The term “sulfinimidoyl” denotes . The term “carbonyl(C1-6alkyl)amino” denotes . The term “-COO-” denotes. The term “pyrrolidinylene” denotes a divalent pyrrolidinyl. The term “triazolylene” denotes a divalent triazolyl. The term “halopyrrolidinylene” denotes a pyrrolidinylene group wherein at least one of the hydrogen atoms of the pyrrolidinylene group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of halopyrrolidinylene include fluoropyrrolidinylene and difluoropyrrolidinylene. The term “1,4-oxazepanylene” denotes a divalent 1,4-oxazepanylene. The term “morpholinylene” denotes a divalent morpholinylene. The suffix “ene” denotes a divalent group. For example, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5- azabicyclo[4.1.0]heptanylene and 3,6-diazabicyclo[3.1.1]heptanylene denote divalent 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 2,7-diazaspiro[4.4]nonanyl, 2-oxa-5- azabicyclo[4.1.0]heptanyl and 3,6-diazabicyclo[3.1.1]heptanyl respectively. a “ ” denotes bond “a”, and the same applies to bond “b”, “c”, “d” and “e”. This was used to show the connection relationship between functional groups. The term “PG” denotes protecting groups. The term “cis” and “trans” denote the relative stereochemistry of the molecule or moiety. For example: compound 67a,used in Example 67 synthesis, as the trans-isomer, refers to a mixture The way of showing relative stereochemistry also applies to the final compounds. 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 thepolarity 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 practitioner, 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. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products. ANTAGONIST OF STING The present invention relates to (i) a compound of formula (Ia),(Ia),wherein M1is heteroarylene optionally substituted by R1; wherein R1is deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl, RSO2C1-6alkyl, RNHSO2C1-6alkyl, R2NSO2C1-6alkyl, RSO(NR)C1-6alkyl or R3SiC1-6alkyl; wherein R is H, Ra, Rbor Rc; Rais C1-6alkyl optionally substituted by Rbor Rc; Rbis C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rcis selected from deuterio, C1-6alkyl, (C1-6alkyl)3Si, haloC1-6alkyl, deuterioC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, deuterioC1-6alkoxy, C2-6alkenyl, haloC2-6alkenyl, deuterioC2-6alkenyl, C2-6alkynyl, haloC2-6alkynyl, deuterioC2-6alkynyl, C3- 7cycloalkyl, haloC3-7cycloalkyl, deuterioC3-7cycloalkyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylcarbonylamino, haloC1-6alkylamino, haloC1-6alkylcarbonylamino, (haloC1-6alkyl)2amino, C3-7cycloalkylamino, C3-7cycloalkylcarbonylamino, (C3-7cycloalkyl)2amino, haloC3-7cycloalkylamino, (haloC3-7cycloalkyl)2amino, C3-7cycloalkyl(C1-6alkyl)amino, haloC3- 7cycloalkyl(C1-6alkyl)amino, C1-6alkylsulfonylamino, haloC1-6alkylsulfonylamino, C1-6alkoxyC1-6alkyl, (haloC1-6alkoxy)C1-6alkyl, C1- 6alkoxy(halo)C1-6alkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylhaloC1-6alkyl, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkoxycarbonyl, haloC1-6alkoxycarbonyl, C3- 7cycloalkoxycarbonyl, haloC3-7cycloalkoxycarbonyl, C1-6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, C3-7cycloalkylaminocarbonyl, (C3-7cycloalkyl)2aminocarbonyl, C1-6alkylC3-7cycloalkylaminocarbonyl, haloC1-6alkylaminocarbonyl, halo(C1-6alkyl)2aminocarbonyl, haloC3- 7cycloalkylaminocarbonyl, halo(C3-7cycloalkyl)2aminocarbonyl, haloC1-6alkylC3-7cycloalkylaminocarbonyl, C1-6alkylhaloC3-7cycloalkylaminocarbonyl, (C1-6alkyl)3ammonio, C1-6alkylsulfanyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C3- 7cycloalkylsulfanyl, C3-7cycloalkylsulfinyl, C3-7cycloalkylsulfonyl, haloC1- 6alkylsulfanyl, haloC1-6alkylsulfinyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfanyl, haloC3-7cycloalkylsulfinyl, haloC3-7cycloalkylsulfonyl,haloC1-6alkoxysulfonyl, C1-6alkylaminosulfonyl, (haloC1-6alkylamino)sulfonyl, (C1-6alkyl)2aminosulfonyl, (haloC1-6alkyl)2aminosulfonyl, (C1-6alkyl)2phosphoryl, (C1-6alkoxy)2phosphoryl, hydroxy(C1-6alkoxy)phosphoryl, C1-6alkoxyphosphoryl, hydroxy, hydroxyC1-6alkyl, hydroxyhaloC1-6alkyl, hydroxyC1-6alkoxy, hydroxylhaloC1-6alkoxy, hydroxyC3-7cycloalkyl, hydroxyhaloC3-7cycloalkyl and sulfonimidoyl, each of which is optionally substituted by H, halogen, C1-6alkyl, C1-6alkoxy, aryl, heteroaryl or heterocyclyl; M2is arylene, heterocyclylene or heteroarylene, said arylene, heterocyclylene or heteroarylene being optionally substituted by R1; M3is heterocyclylene which is substituted by R3and optionally substituted by R1; R2is deuterio, R, ROC1-6alkyl, RSC1-6alkyl, RSO2C1-6alkyl, RNHC1-6alkyl or (R)2NC1-6alkyl; T1is -W-, -W-O-W-, -W-S-W-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C1- 6alkylene-W-C1-6alkylene- or -W-N(R)-W-; wherein each W is independently selected from C1-6alkylene, -C1-6alkylene-O-, -C1-6alkylene-S-, C3-7cycloalkylene, arylene, heteroarylene and heterocyclylene, each of which is unsubstituted or optionally substituted by the substituents independently selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R2N, RSO2, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl and RSO2C1-6alkyl; or T1and R2, or T1and R1which is the substitution on M1, together with the atoms they attached to form a heterocyclylene or C3-7cycloalkylene; T2is C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, heterocyclylene, heteroarylene or arylene; R3is; wherein M4is optionally substituted aryl, carbonylaryl, heteroaryl, carbonylheteraryl or heterocyclyl with three bonds connecting to M3, T3and T4; M5is a bond, or optionally substituted arylene, heteroarylene or heterocyclylene;T3is ; wherein each L1, L2, L3and L4is independently selected from a bond, C1-6alkylene optionally substituted by R1, haloC1-6alkylene optionally substituted by R1, N(R), O, S, SO, SO2,SO(NR), P(O)R, PO(NR), Se, SiR2, C3-7cycloalkylene optionally substituted by R1, carbonyl, carbonyl(C1-6alkyl)amino, - COO-, C2-6alkenylene optionally substituted by R1, haloC1-6alkenylene optionally substituted by R1, C2-6alkynylene optionally substituted by R1, haloC1-6alknylene optionally substituted by R1, arylene optionally substituted by R1, heteroarylene optionally substituted by R1, and heterocyclylene optionally substituted by R1; g, h, j and k are each independently 0, 1, 2 or 3; T4is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (I),wherein A1is N or CR4, wherein R4is H or halogen; A2is N or CR4, wherein R4is H or halogen; A3is N or CR4, wherein R4is H or halogen; A4is N or CR4, wherein R4is H or halogen; A5is N or CR4, wherein R4is H or halogen; A6is N or CR4, wherein R4is H or halogen; A7is N or CR4, wherein R4is H or halogen;A8is N and A9is C, or A8is C and A9is N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;; wherein Y1is heterocyclyl, heteroaryl or carbonylheteroaryl, each of which has three bonds connecting to N, Q3and Q4, and is further substituted by R5, wherein R5is H, deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy; Y2is a bond, heteroarylene or arylene, each of which is once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy;; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently selected from heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene, C1-6alkylene, carbonyl, carbonyl(C1-6alkyl)amino, - COO-, O and sulfonyl, wherein heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene and C1-6alkylene are unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2, heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl; each L3is independently C1-6alkylene, C2-6alkenylene, C2-6alkynylene, heteroaryl or heterocyclylene, each of which is unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2, heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl;each L4is independently NH, S, SO, SO2, O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (iii) a compound of formula (I) according to (i) or (ii), A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH or N; A8is N and A9is C, or A8is C and A9is N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;H or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2-6alkynylene, hydroxyC1-6alkylene or piperazinylene; each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.Another embodiment of present invention is (iv) a compound of formula (I-1) according to any one of (i) to (iii),wherein A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH or N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;; whereinH or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2-6alkynylene, hydroxyC1-6alkylene or piperazinylene; each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.Another embodiment of present invention is (v) a compound of formula (I-2) according to any one of (i) to (iv),wherein A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH or N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene; R3is; whereinH or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2-6alkynylene, hydroxyC1-6alkylene or piperazinylene; each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.A further embodiment of present invention is (vi) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein A1is N. A further embodiment of present invention is (vii) a compound of formula (Ia), (I), (I-1) or (I-2) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein A4is CH. A further embodiment of present invention is (viii) a compound of formula (Ia), (I), (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein A6is CR4, wherein R4is H or fluoro. A further embodiment of present invention is (ix) a compound of formula (Ia), (I), (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein A7is CH. A further embodiment of present invention is (x) a compound of formula (Ia), (I), (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein Q1is methylene unsubstituted or substituted by methoxy or ethoxy. A further embodiment of present invention is (xi) a compound of formula (Ia), (I), (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1. A further embodiment of present invention is (xii) a compound of formula (Ia), (I), (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein Q2is NH. A further embodiment of present invention is (xiii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R1is methyl. A further embodiment of present invention is (xiv) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein R2is methyl; or R2and Q1together with the atoms they attached to form 1,4-oxazepanylene.A further embodiment of present invention is (xv) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xiv), or a pharmaceutically acceptable salt thereof, whereinwherein R5is H. A further embodiment of present invention is (xvi) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xv), or a pharmaceutically acceptable salt thereof, wherein Y2is phenylene substituted by halogen. A further embodiment of present invention is (xvii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xvi), or a pharmaceutically acceptable salt thereof, wherein Y2is phenylene substituted by fluoro. A further embodiment of present invention is (xviii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xvii), wherein each L1is independently a bond, C1-6alkylene or O. A further embodiment of present invention is (xix) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xviii), or a pharmaceutically acceptable salt thereof, wherein each L1is independently a bond, methylene or O. A further embodiment of present invention is (xx) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xix), or a pharmaceutically acceptable salt thereof, wherein each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinylene, 2-oxa-5- azabicyclo[4.1.0]heptanylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl(C1-6alkyl)amino, -COO-, halopyrrolidinylene, morpholinylene, O or pyrrolidinylene. A further embodiment of present invention is (xxi) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xx), or a pharmaceutically acceptable salt thereof, wherein each L2is 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinylene, 2-oxa-5- azabicyclo[4.1.0]heptanylene, carbonyl(methyl)amino, -COO-, cyclobutylene, difluoropyrrolidinylene, ethylene, methoxypyrrolidinylene, methylene, morpholinylene, O or pyrrolidinylene. A further embodiment of present invention is (xxii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxi), or a pharmaceutically acceptable salt thereof,wherein each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene or C2-6alkynylene. A further embodiment of present invention is (xxiii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxii), or a pharmaceutically acceptable salt thereof, wherein each L3is independently fluorobutenylene, butenylene, butylene, butynylene, ethylene or methylene. A further embodiment of present invention is (xxiv) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxiii), or a pharmaceutically acceptable salt thereof, wherein each L4is O. A further embodiment of present invention is (xxv) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxiv), or a pharmaceutically acceptable salt thereof, wherein g, j and k are 1. A further embodiment of present invention is (xxvi) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxv), or a pharmaceutically acceptable salt thereof, wherein h is 1 or 2. A further embodiment of present invention is (xxvii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (i) to (xxv), or a pharmaceutically acceptable salt thereof, wherein Q4is a bond. Another embodiment of present invention is (xxviii) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (ii) to (v), wherein A1is N; A2is CH or N; A3is CH; A4is CH; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;Y2is phenylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene or O; each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4- b][1,4]oxazinylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl(C1-6alkyl)amino, -COO-, halopyrrolidinylene, morpholinylene, O or pyrrolidinylene; each L3is independently C1-6alkylene, C2-6alkenylene or C2-6alkynylene; each L4is O; g, j and k are 1; h is 1 or 2; Q4is a bond; m is 1; n is 1; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxix) a compound of formula (Ia), (I), (I-1) or (I-2), according to any one of (ii) to (xxviii), wherein A1is N; A2is CH or N; A3is CH; A4is CH;A5is CH or N; A6is CR4, wherein R4is H or fluoro; A7is CH; Q1is C1-6alkylene unsubstituted or substituted by methoxy or ethoxy; Q2is NH; R1is methyl; R2is methyl; or R2and Q1together with the atoms they attached to form 1,4- oxazepanylene;Y2is phenylene substituted by fluoro;; wherein each L1is independently a bond, methylene or O; each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4- b][1,4]oxazinylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, carbonyl(methyl)amino, -COO-, cyclobutylene, difluoropyrrolidinylene, ethylene, methoxypyrrolidinylene, methylene, morpholinylene, O or pyrrolidinylene; each L3is independently (methyl)butenylene, butenylene, butylene, butynylene, ethylene or methylene; each L4is O; g, j and k are 1; h is 1 or 2;Q4is a bond; m is 1; n is 1; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xxx) is a compound of formula (Ia), (I), (I-1) or (I-2) selected from the following: (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-3,5-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10Z)-5,10-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-12-oxo-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2,4,6,13,15(18),16-hexaen-14-yl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazapentacyclo[13.5.2.110,12.02,7.018,21]tricosa-2,4,6,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18-dimethyl-7-oxa- 5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18- dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,3,16,20,22- pentazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,12,13,14,17,21,23-heptazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaen-18-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one;(8S,11S,15R)-22-fluoro-10-(5-fluoro-13-oxo-1,12,18- triazatetracyclo[10.6.1.02,7.016,19]nonadeca-2(7),3,5,14,16(19),17-hexaen-15-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (14S)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17, 19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen- 12-one; (15R)-5-fluoro-19-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,12,18,22,24-pentazapentacyclo [15.5.2.112,15.02,7.020,23]pentacosa- 2(7),3,5,17(24),18,20(23),21-heptaen-11-one; (6S)-17-fluoro-25-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-14-oxa-2,8,21,22,26,27-hexazahexacyclo [19.5.2.02,6.08,12.015,20.024,28]octacosa- 1(26),15(20),16,18,22,24,27-heptaen-7-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(15S)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo [15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen- 19-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (14R)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (6S)-14-fluoro-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8,11-dioxa-2,18,19,23,24-pentazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(24),12,14,16,19,21(25),22-heptaen-7-one; (8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-3,6-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),2,4,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(5R)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(5S)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(14R)-5-fluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (6S)-4,4,14-trifluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-11-oxa-2,8,18,19,23,24-hexazapentacyclo [16.5.2.02,6.012,17.021,25]pentacosa-1(24),12,14,16,19,21(25),22-heptaen-7-one; 12-fluoro-6-methyl-20-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-9-oxa-2,6,16,17,21,22-hexazapentacyclo[14.5.2.12,4.010,15.019,23]tetracosa- 1(21),10(15),11,13,17,19,22-heptaen-5-one; 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-12-oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.12,5.05,9.013,18.022,26]heptacosa- 1(25),13(18),14,16,20,22(26),23-heptaen-10-one; 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-12-oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,6.013,18.022,26]heptacosa- 1(24),13(18),14,16,20,22,25-heptaen-10-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(14S)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3-diazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,18R)-25-fluoro-21-methyl-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa- 2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24- heptaen-22-yl]-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa-2,8,18,19,23,24- hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24-heptaen-22-yl]- 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3-diazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one;(8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-2,3-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18- hexaen-14-one; 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one; 5-fluoro-14-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,11,17-triazatetracyclo[9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16- hexaen-12-one; (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3,7-triazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-15-methyl-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa- 2(7),3,5,15,17(20),18-hexaen-14-one; (8S,11S,15R)-22-fluoro-10-[(14R)-5-fluoro-10-oxo-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (6S)-14-fluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-11-oxa-2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(23),12(17),13,15,19,21,24-heptaen-7-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-10-yn-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-11,11-dioxo-11λ⁶-thia-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(6S)-4,4,14-trifluoro-8-methyl-7- oxo-11-oxa-2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(23),12(17),13,15,19,21,24-heptaen-22-yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-14-oxo-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-16-yl)-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 16-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- 5-fluoro-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14- one; (8S,11S,18S)-25-fluoro-10-(5-fluoro-14-oxo-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-16-yl)-21-methyl-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-15-oxa-1,9,12,17,21,23-hexazapentacyclo[14.5.2.29,12.02,7.019,22]pentacosa- 2,4,6,16(23),17,19(22),20-heptaen-8-one; 5,13,13-trifluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(14-fluoro-11-oxa-2,3,7- triazatricyclo[10.4.0.02,6]hexadeca-1(16),3,5,12,14-pentaene-5-carbonyl)-13,18-dimethyl- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S)-13,18-dimethyl-10-(5,13,13-trifluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18-yl)- 5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa- 2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (6S)-17-fluoro-25-[rac-(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]- 14-oxa-2,8,21,22,26,27-hexazahexacyclo[19.5.2.02,6.08,12.015,20.024,28]octacosa- 1(26),15(20),16,18,22,24,27-heptaen-7-one; (8S,11S)-10-(15-fluoro-12-oxa-2,3-diazatricyclo[11.4.0.02,6]heptadeca-1(17),3,5,13,15- pentaene-5-carbonyl)-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(13S,14R)-5-fluoro-13-methoxy- 8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(13R,14S)-5-fluoro-13-methoxy- 8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one;(8S,11S,15R)-22-fluoro-10-(16-fluoro-2-imino-13-oxa-2λ⁴-thia-4,6- diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-5-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(12-methylene-10-oxa-1,2,6- triazatricyclo[6.5.1.04,14]tetradeca-2,4(14),5,7-tetraen-5-yl)-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[12-(hydroxymethyl)-10-oxa-1,2,6- triazatricyclo[6.5.1.04,14]tetradeca-2,4(14),5,7-tetraen-5-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 16-fluoro-5-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]-13-oxa-4,6-diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-2-one; (8S,11S,18S)-25-fluoro-10-[(15R)-5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]-21-methyl-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[-(15R)-5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(16-fluoro-2-hydroxy-13-oxa-4,6- diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-5-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(6R,7S)-15-fluoro-5,12-dioxa-2,9,19,20,24,25- hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25-heptaen-23-yl]- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(6S,7R)-15-fluoro-5,12-dioxa- 2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25- heptaen-23-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(6S,7R)-15-fluoro-5,12-dioxa- 2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25- heptaen-23-yl]-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(16R)-5-fluoro-8,15-dioxa- 1,11,19,23,25-pentazahexacyclo[16.5.2.111,16.02,7.012,14.021,24]hexacosa-2,4,6,18,20,22,24- heptaen-20-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16R)-5-fluoro-20-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8,15-dioxa-1,11,19,23,25- pentazahexacyclo[16.5.2.111,16.02,7.012,14.021,24]hexacosa-2,4,6,18,20,22,24-heptaen-10-one; (3S,5R)-17-fluoro-25-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-14-oxa-2,7,21,22,26,27-hexazahexacyclo[19.5.2.13,7.02,5.015,20.024,28]nonacosa- 1(26),15(20),16,18,22,24,27-heptaen-8-one; and (8S,11S,15R)-22-fluoro-10-[(3S,5R)-17-fluoro-14-oxa-2,7,21,22,26,27- hexazahexacyclo[19.5.2.13,7.02,5.015,20.024,28]nonacosa-1(26),15(20),16,18,22,24,27-heptaen-25-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xxxi) is a process for the preparation of a compound according to any one of (i) to (xxx) comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between compound offormula (VIII), (VIII), and R3X in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VIII) and R3X in the presence of a catalyst; or via nucleophilic substitution between compound of formula (VIII) and R3SO2Me under a basic condition; or via condensation reaction between compound of formula (VIII) and R3OH in the presence of coupling reagent; wherein X is halogen; the base is DIEA; the catalyst is Pd2(dba)3; the basic condition is DIPEA; the coupling reagent is PyBOP or HATU; R1, R2, Q1, Q2, A1to A6are as defined as in any one of (i) to (xxix). Another embodiment of present invention (xxxii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxx) for use as therapeutically active substance. Another embodiment of present invention (xxxiii) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xxx) and a pharmaceutically acceptable excipient. Another embodiment of present invention (xxxiv) is related to the use of a compound according to any one of (i) to (xxx) for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovasculardiseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. Another embodiment of present invention (xxxv) is related to the use of a compound according to any one of (i) to (xxx) for the preparation of a medicament 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 (xxxvi) is related to the use of a compound or pharmaceutically acceptable salt according to any one of (i) to (xxx) 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 (xxxvii) is related to the use of a compound or pharmaceutically acceptable salt according to any one of (i) to (xxx) for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. Another embodiment of present invention (xxxviii) is related to the use of a compound or pharmaceutically acceptable salt according to any one of (i) to (xxx) for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. Another embodiment of present invention (xxxix) is related to the use of a compound according to any one of (i) to (xxx) for the inhibition of STING. Another embodiment of present invention (xl) is related to the use of a compound according to any one of (i) to (xxx) for the preparation of a medicament for the inhibition of STING.Another embodiment of present invention (xli) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxx), when manufactured according to a process of (xxxi). Another embodiment of present invention (xlii) 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 (xxx). 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, alternativelyabout 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 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 usingconventional 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 mgLactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compound of the invention inhibit the binding of cGAMP to STING and its downstream signaling. Accordingly, the compound of the invention are useful for blocking STING activation, signaling, downstream cytokine, chemokine production and cellular processes such as apoptosis and autophagy. Compounds of the invention are useful for inhibition of STING. Alternatively, compounds of invention are useful for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. More broadly, the compound can be useful 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. 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, R1to R5, Q1, Q2, A1to A6are 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 1I VIII VII Wherein Rxis 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 (IIa) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (V), which can also be obtained via the Suzuki coupling between boronic ester compound of formula (IIIb) and halide (III). On the other hand, Suzuki coupling between compound of formula (III) and boronic ester (IIIa) provides anintermediate 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 H2). 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 H2) 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 R3X 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 Pd2(dba)3. It can also be obtained by nucleophilic substitution between compound of formula (VIII) and R3SO2Me under a basic condition, such as DIPEA. Besides, compound of formula (I) can be obtained via condensation reaction between compound of formula (VIII) and R3OH in the presence of coupling reagent, such as PyBOP and HATU. The preparation of the R3X was refered to Example 8, 45, 47, 49, Example 22, 29, 34, 67, Example 33, 79, Example 44, Example 69 and Example 70, 71. The preparation of the R3SO2Me was refered to Example 72. The preparation of R3OH was refered to Example 6, 9, 41, 42, 53, Example 14, Example 15, Example 17, 20, 50, Example 18, 26-28, 36, 48, Example 21, 25 and Example 54. 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) comprising the following step:a) the formation of compound of formula (I) via nucleophilic substitution between compound offormula (VIII), (VIII), and R3X in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VIII) and R3X in the presence of a catalyst; or via nucleophilic substitution between compound of formula (VIII) and R3SO2Me under a basic condition; or via condensation reaction between compound of formula (VIII) and R3OH in the presence of coupling reagent; wherein X is halogen; the base can be, for example, DIEA; the catalyst can be, for example, Pd2(dba)3; the basic condition can be, for example, DIPEA; the coupling reagent can be, for example, PyBOP or HATU. A compound of formula (I) 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 Boc2O: di-tert butyl dicarbonate CuI: copper(I) iodide DCM: dichloromethane DCE: dichloroethane DIPEA or DIEA: N,N-diisopropylethylamineDIBAL-H: diisobutylaluminium hydride DIAD: diisopropyl azodicarboxylate DMA: N,N-Dimethylacetylamine DMF: N,N-Dimethylformamide DMSO: dimethyl sulfoxide EA or EtOAc: ethyl acetate FA: formic acid H2: hydrogen 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 i-PrMgCl: isopropylmagnesium chloride IC50: half inhibition concentration Ir[dF(CF3)ppy]2(dtbpy)(PF6): [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 K3PO4: tripotassium phosphate LCMS: liquid chromatography-mass spectrometry LDA: lithium diisopropylamide LiHMDS: hexamethyldisilazane lithium salt L-selectride: lithium tri-sec-butylborohydride mCPBA: meta-chloroperoxybenzoic acid min(s): minute(s) MeOH: methanol MS: mass spectrometry N2: nitrogen NaH: sodium hydride NMP: N-Methylpyrrolidone NiCl2(dtbbpy): [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride PE: petroleum ether prep-HPLC: preparative high performance liquid chromatographyprep-TLC: preparative thin layer chromatography PPh3: triphenylphosphine Pd(OH)2 / C: palladium hydroxide on carbon Pd / C: palladium on carbon Pd(dppf)Cl2·DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane Pd(dtbpf)Cl2: [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd-PEPPSI-IPentCl: Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) PyBOP: Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate p-TsOH: p-Toluenesulfonic acid (R)-binap : (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Rf: retention factor rt, r.t.: room temperature RT: retention time SFC: supercritical fluid chromatography TBAF: Tetra-n-butylammonium fluoride TBSCl: tert-butyldimethylsilyl chloride TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl TEA: trimethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography TPP: triphenylphosphine TTMSS: Tris(trimethylsilyl)silane 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, particlesize: 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 XBridgeTMPrep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFireTMPrep-C18 (5 µm, OBDTM30 × 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: CO2and IPA (0.5% TEA in IPA) or CO2and MeOH (0.1% NH3∙H2O in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm. LC / MS spectra of compounds were obtained using a LC / MS (WatersTMAlliance 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 H2O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic condition II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral condition: A: H2O; 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-[(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-carbamateThe 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 A1-b) To a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxy-propyl]carbamate (59.6 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitro-benzene (A1-a, 71.0 g, 298.33 mmol) in ACN (710 mL) was added potassium carbonate (82.4 g, 596.66 mmol). After being stirred at 50 °C for 2 hrs, the mixture was filtered and the filtrate was concentrated to give compound A1-b (131 g). LCMS (M+H)+: 408.Step 2: preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoro-anilino)-2- hydroxy-propyl]carbamate (compound A1-c) To a solution of compound A1-b (63.0 g, 154.33 mmol) in methanol (1000 mL) was added Raney Ni (36.2 g, 617.31 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol). After being stirred at 25 °C for 1 hr, 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 A1-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 A1-d) To a solution of compound A1-c (123.0 g, 325.19 mmol) in anhydrous THF (1500 mL) was added trimethyl orthoacetate (136.7 mL, 1.10 mol) and pyridinium p-toluenesulfonate (11.7 g, 46.62 mmol). The reaction was stirred for 1 hr at 20 °C. The mixture was concentrated under reduced pressure to give compound A1-d (160 g). LCMS (M+H)+: 402. 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 A1-e) To a solution of compound A1-d (80.0 g, 198.88 mmol) and imidazole (40.6 g, 596.63 mmol) in DMF (765 mL) was added tert-butyldimethylchlorosilane (59.9 g, 397.75 mmol), then the mixture was stirred for 18 hrs at 30 °C. The mixture was poured into cold NH4Cl aq. (2000 mL), extracted with EtOAc (800 mL) twice. The organic layer was dried and concentrated to give compound A1-e (94 g). LCMS (M+H)+: 516. 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-carbamate (compound A1-f) To a solution of compound A1-e (82.0 g, 158.75 mmol) in DMF (800 mL) was added sodium hydride (60% in oil, 15.8 g, 396.89 mmol) at 0 °C and then the mixture was stirred at 0 °C for 1 hr. Then iodomethane (90.1 g, 635.02 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 1 hr. The reaction was quenched with water and extracted with EA. The organic layer was dried, concentrated and purified via column chromatography to give compound A1-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 A1-g) A mixture of compound A1-f (39.8 g, 75.02 mmol) and TBAF / THF (1M, 150.0 mL, 150 mmol) was stirred at 20 °C for 2 hrs. Then the mixture was concentrated and the residue wasdiluted with EtOAc (600mL), washed with water and brine. The organic layer was dried and concentrated to give compound A1-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 A1-h) To a solution of compound A1-g (17.4 g, 41.8 mmol) and iodoethane (5.0 mL, 62.7 mmol) in DMF (174 mL) was added sodium hydride (2.2 g, 55.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hrs. The reaction was then quenched with water and extracted with EA. The organic layer was dried and concentrated to give compound A1-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 A1) To a mixture of compound A1-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 (8.6 g, 87.3 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 N2for three times, and then stirred at 130 °C for 2 hrs. 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 via column chromatography to give intermediate A1 (15 g). LCMS (M+H)+: 492. Intermediate A2 tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-methoxy-propyl]-N-methyl-carbamate (compound A2-a) To a solution of compound A1-d (10.0 g, 26.02 mmol) in DMF (200 mL) was added CH3I (11.08 g, 78.07 mmol) at -10 °C under N2, then NaH (2.6 g, 65.06 mmol) was added slowly in portions. The mixture was stirred at -10 °C for 5 hrs, then 20 °C for another 12 hrs. The reaction was quenched with ice and cold NH4Cl aq., and extracted with EA twice. The organic layer was dried and concentrated to afford compound A2-a (11.7 g). LCMS (M+H)+: 430. Step 2: preparation of tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (Intermediate A2) The title compound was prepared in analogy to the preparation of intermediate A1 by using compound A2-a instead of compound A1-h in step 8. LCMS (M+H)+: 478. Intermediate A3 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-methoxy-propyl]-N-methyl-carbamateThe title compound was prepared according to the following scheme:The title compound was prepared in analogy to the preparation of intermediate A2 by using compound A3-a instead of compound A1-d in step 1. LCMS (M+H)+: 478. The compound A3-a was prepared in analogy to the preparation of compound A1-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 in step 1. LCMS (M+H)+: 402. Intermediate A4tert-butyl N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamateThe title compound was prepared according to the following scheme:The title compound was prepared in analogy to the preparation of intermediate A2 by using compound A4-a instead of compound A1-d in step 1. LCMS (M+H)+: 448. The compound A4-a was prepared in analogy to the preparation of compound A1-d by using tert-butyl N-(3-aminopropyl)carbamate instead of tert-butyl N-[(2R)-3-amino-2-hydroxy- propyl]carbamate in step 1. LCMS (M+H)+: 386. Intermediate A5 tert-butyl 2-[[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]methyl]-1,4-oxazepane-4-carboxylateThe title compound was prepared according to the following scheme:A5-f A5-g Intermediate A5Step 1: preparation of N-[(4-benzyl-1,4-oxazepan-2-yl)methyl]-2,2,2-trifluoro- acetamide (compound A5-b) To a solution of compound A5-a (5.0 g, 22.7 mmol) in DCM (70 mL) was added DIEA (11.1 mL, 68.09 mmol) and trifluoroacetic anhydride (4.8 mL, 34.04 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs, then poured into ice-water (100 ml), extracted with ethyl acetate. The combined organic layer was dried and concentrated. The residue was purified via silica gel column chromatography to give compound A5-b (15 g) as a yellow oil. LCMS (M+H)+: 317. Step 2: preparation of tert-butyl 2-[[(2,2,2-trifluoroacetyl)amino]methyl]-1,4- oxazepane-4-carboxylate (compound A5-c) To a solution of compound A5-b (12.5 g, 39.5 mmol) and di-t-butyldicarbonate (12.9 g, 59.28 mmol) in methanol (1000 mL) was added wet Pd(OH)2 / C (6.4 g, 9.13 mmol) under N2at 20 °C. The mixture was stirred under H2 (50 psi) at 40 °C for 18 hrs, then filtered with diatomaceous earth and the filtrate was concentrated. The residue was purified via silica gel column chromatography to give compound A5-c (24.0 g) as a colorless oil. LCMS (M+H)+: 327. Step 3: preparation of tert-butyl 2-(aminomethyl)-1,4-oxazepane-4-carboxylate (compound A5-d) To a mixture of compound A5-c (24.0 g, 73.54 mmol) in methanol (240 mL) was added K2CO3(101.6 g, 735.5 mmol), the mixture was stirred at 60 °C for 2 hrs. The reaction mixturewas filtered and the filtrate was concentrated to give compound A5-d (34.0 g) as a yellow oil. LCMS (M+H)+: 231. Step 4: preparation of tert-butyl 2-[(2-bromo-4-fluoro-6-nitro-anilino)methyl]-1,4- oxazepane-4-carboxylate (compound A5-e) A mixture of 1-bromo-2,5-difluoro-3-nitro-benzene (2.8 g, 11.8 mmol), compound A5-d (13.9 g, 60.5 mmol) and potassium carbonate (6969 mg, 50.4 mmol) in ACN (40 mL) was stirred at 50 °C for 2 hrs under N2. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified via silica gel column chromatography to give compound A5-e (21.0 g) as a yellow oil. LCMS (M+H)+: 448. Step 5: preparation of tert-butyl 2-[(2-amino-6-bromo-4-fluoro-anilino)methyl]-1,4- oxazepane-4-carboxylate (compound A5-f) To a solution of compound A5-e (10.0 g, 22.31 mmol) in methanol (100 mL) was added Raney Ni (5.2 g, 89.4 mmol) and hydrazine hydrate (5.8 g, 115.8 mmol) slowly at 25 °C. The mixture was stirred at 25 °C for 1 hr, and then the mixture was filtered, the filtrate was concentrated at 30 °C. The crude product was dissolved in 200 mL DCM, washed with water, dried over Na2SO4and then concentrated to give compound A5-f (8.3 g) as a yellow oil. LCMS (M+H)+: 418. Step 6: preparation of tert-butyl 2-[(7-bromo-5-fluoro-2-methyl-benzimidazol-1- yl)methyl]-1,4-oxazepane-4-carboxylate (compound A5-g) To a solution of compound A5-f (4.2 g, 10.0 mmol) in THF (42 mL) was added trimethyl orthoacetate (4.2 mL, 33.79 mmol) and pyridinium p-toluenesulfonate (420 mg, 1.67 mmol). The reaction was stirred for 1 hr at 20 °C and then it was concentrated to give crude compound A5-g (10.5 g) as a brown oil. LCMS (M+H)+: 442 Step 7: preparation of tert-butyl 2-[[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]methyl]-1,4-oxazepane-4-carboxylate (Intermediate A5) To a mixture of compound A5-g (10.5 g, 23.74 mmol) and bis(pinacolato)diboron (15.1 g, 59.35 mmol) in DMSO (105 mL) was added potassium acetate (4.7 g, 47.48 mmol), bis(triphenylphosphine)palladium(II) chloride (2.5 g, 3.56 mmol) and butyldi-1- adamantylphosphine (2.5 g, 7.12 mmol). The mixture was degassed with N2 for three times and stirred at 130 °C for 2 hrs under N2. The mixture was poured into water (300 mL) and extracted with ethyl acetate, the organic phase was washed with brine, dried over Na2SO4, filtered andconcentrated to give the crude product. The crude product was purified via column chromatography to give intermediate A5 (5.5 g) as yellow gum. LCMS (M+H)+: 490. Intermediate A6 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:A6-a Intermediate A6Step 1: preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A6- a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142 mmol) in THF (400 mL) was added in one portion at -78 °C under nitrogen. And the LDA (107 mL, 214 mmol) was added dropwise into the mixture which was stirred for 1 hr. Then the 1-chloro-3-iodopropane (43.6 g, 213 mmol) was added dropwise at -78 °C. After being stirred at -78 °C for 2 hrs, the reaction mixture was warmed to 25 °C for 12 hrs, then diluted with EtOAc, and poured into saturated ammonium chloride solution, extracted with EtOAc twice. The organic layer was washed with brine, dried over anhydrous Na2SO4. After filtration, the solvent was concentrated to afford crude product, which was purified via prep-HPLC to obtained compound A6-a (30 g) as a colorless solid, LCMS (M+H)+: 287. Step 2: preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3- dione (Intermediate A6) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A6-a, 2 g, 3.8 mmol), potassium phthalimide (1.4 g, 7.5 mmol) and sodium iodide (1.7 g, 11.3 mmol) in DMF (30 mL) was heated at 100 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extractedwith EtOAc for three times, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude product. The crude solid precipitated from EtOAc / hexane to give intermediate A6 (1.9 g) as a yellow solid, which was used directly in next step without further purification, LCMS (M+H)+: 398. Intermediate A7 tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol- 3-yl]propyl]carbamateStep 1: preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (compound A7-a) To a mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A6-a, 6 g, 20.9 mmol) and DIPEA (5.4 g, 41.7 mmol) was added 33% methylamine in ethanol solution (40 mL). The resulting mixture was stirred at 90 °C for 16 hrs. And then it was concentrated to give crude compound A7-a (6 g) as an off-white solid, LCMS (M+H)+: 282. Step 2: preparation of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N- methyl-carbamate (compound A7-b) A mixture of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (compound A7-a, 6 g, 21.3 mmol), DIPEA (8.2 g, 63.8 mmol) and Boc anhydride (5.1 g, 23.4 mmol) in DCM (100 mL) was stirred at room temperature for 1 hr. Then it was concentrated and purified via flash column to give compound A7-b (8 g) as a colorless oil, LCMS (M+H)+: 382. Step 3: preparation of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate (Intermediate A7) A mixture of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (compound A7-b, 6 g, 15.7 mmol), bis(pinacolato)diboron (8.0 g, 31.4 mmol) and potassiumacetate (3.1 g, 31.4 mmol) in DMSO (73 mL) was bubbled with nitrogen for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (1.1 g, 1.6 mmol,) and butyldi-1- adamantylphosphine (1.1 g, 3.1 mmol) were added. The resulting mixture was stirred at 130 °C for 4 hrs, then diluted with water, extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, concentrated to give a light brown oil. Then it was purified via flash column to give intermediate A7 (4.0 g) as a light brown oil, LCMS (M+H)+: 430. Intermediate B1 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylateThe 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 hrs. The mixture was cooled and poured into 150 mL water, then it was extracted with 25 mL EA for three times. The organic layer was concentrated to give an oil, then it was purified via prep- HPLC to give intermediate B1 (5.1 g), LCMS (M+H)+: 434. Intermediate B2 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylateThe title compound was prepared according to the following scheme:Intermediate B2A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28.0 g, 99.73 mmol), DIPEA (69.5 mL, 398.93 mmol) and 2-bromo-6-fluoropyridine (21.1 g, 119.68 mmol) in DMSO (140 mL) was heated to 110 °C for 16 hrs. The mixture was diluted with water and extracted with EA, the organic layer was concentrated to give intermediate B2 (34 g), LCMS (M+H)+: 400. Intermediate B3 and B4 O1-benzyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B3) and O1-benzyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin- 4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B4)The title compound was prepared according to the following schemeA mixture of 2,4-dichloropyrimidine (5.3 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5.0 g, 18 mmol), K2CO3(5.0 g, 35.9 mmol) and DIPEA (4.6 g, 35.9 mmol) in ACN was stirred at rt for 48 hrs. The reaction was filtered and concentrated, the residue was purified via silica gel column chromatography to give intermediate B3 (faster eluted, 1 g) and intermediate B4 (slower eluted, 6 g), LCMS (M+H)+: 391. Intermediate B5 O1-benzyl O2-methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylateThe 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 r.t. for 16 hrs. The mixture was poured into NH4Cl aq. (200 mL) and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product, then it was purified via silica gel column chromatography to give intermediate B5 (27.0 g). LCMS (M+H)+: 392. Intermediate B6 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-bromo-2-pyridyl)oxy]pyrrolidine-1,2-dicarboxylateThe title compound was prepared according to the following scheme:Intermediate B6 To a mixture of 4-bromo-2-hydroxypyridine (10.6 g, 61.16 mmol), O1-tert-butyl O2- methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.77 mmol) and PPh3 (16.0 g, 61.16 mmol) in Toluene (100 mL) was added DIAD (12.3 g, 61.16 mmol) at 0 °C under N2, then the mixture was stirred at 100 °C for 1 hr. The mixture was concentrated and the residue was purified via prep-HPLC to afford intermediate B6 (12.5 g). LCMS (M-56+H)+: 345. Intermediate B7O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-1,2-dicarboxylateThe title compound was prepared according to the following scheme:Intermediate B7To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (2.0 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.8 g, 8.15 mmol) and Ph3P (2.5 g, 9.38 mmol) in THF (50 mL) was added a solution of 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. The residue was purified via silica gel column chromatography to give intermediate B7 (1.2 g), LCMS: (M+H)+: 448. Intermediate B8 and B9 O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate and O1-tert-butyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin-4- yl)amino]pyrrolidine-1,2-dicarboxylateIntermediate B8 Intermediate B9The title compounds were prepared in analogy to the preparation of intermediate B3 and B4 by using 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate instead of 1- benzyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate. LCMS (M+H)+: 357. Intermediate C1(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C10 by using intermediate A1 instead of intermediate A5 in step 1, using intermediate B3 instead of intermediate B2 in step2 and using reaction temperature 100oC instead of room temperature in step 5. LCMS (M+H)+: 454. Intermediate C2 (8S,11S,15R)-15-ethoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[(2S)-3-[benzyl(methyl)amino]-2-hydroxy-propyl]isoindoline- 1,3-dione (compound C2-b) To a solution of N-methylbenzylamine (38.1 mL, 295.29 mmol) in ethanol (500 mL) was added 2-[[(2R)-oxiran-2-yl]methyl]isoindoline-1,3-dione (C2-a, 50.0 g, 246.08 mmol). The reaction was stirred at 80 °C for 3 hrs. The mixture was concentrated and purified via flash column to give compound C2-b (65.0 g) as a colorless oil. LCMS: (M+H)+: 325. Step 2: preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy- propyl]-N-methyl-carbamate (compound C2-c) To a solution of compound C2-b (60.0 g, 184.97 mmol) and di-t-butyldicarbonate (60.5 g, 277.46 mmol) in methanol (1 L) was added wet Pd(OH)2(30.0 g, 42.73 mmol) under N2atmosphere at 20 °C. The reaction was stirred at 40 °C under 50 psi of H2 for 2 hrs. The mixture was filtered through celite. The filtrate was concentrated and purified via flash column to give compound C2-c (44 g) as a white solid. LCMS (M+H-100)+: 235. Step 3: preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-ethoxy- propyl]-N-methyl-carbamate (compound C2-d) To a suspension of NaH (6.46 g, 161.5 mmol) in dry DMF (250 mL) was added iodoethane (34.5 mL, 430.7 mmol) at 0 °C under N2 atmosphere. The reaction was stirred at 0 °C for 0.5 hrand a solution of compound C2-c (36.0 g, 107.67 mmol) in dry DMF (150 mL) was added. The mixture was stirred at 0 °C for 1 hr and warmed to r.t. for 12 hrs. The reaction mixture was combined with another batch of reaction which started from compound C2-c (10 g), and quenched with cold NH4Cl aq. (1000 mL), then extracted with EA (800 mL × 3). The combined organic layer was washed with brine (800 mL × 5), dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography to give compound C2-d (44.0 g) as a colorless oil. LCMS (M+H-100)+: 263. Step 4: preparation of tert-butyl N-[(2R)-3-amino-2-ethoxy-propyl]-N-methyl- carbamate (compound C2-e) To a solution of compound C2-d (17.0 g, 46.91 mmol) in ethanol (300 mL) was added methylamine in ethanol (170.0 g, 1.86 mol) dropwise at 20 °C. The reaction was stirred at 60 °C for 1 hr. The mixture was combined with another batch of reaction which started from compound C2-d (15 g), and concentrated to afford compound C2-e (40.0 g) as a white solid. LCMS (M+H- 100)+: 233. Step 5: preparation of tert-butyl N-[(2R)-3-[(2-bromo-4-nitro-3-pyridyl)amino]-2- ethoxy-propyl]-N-methyl-carbamate (compound C2-f) To the mixture of compound C2-e (40.0 g, 172.18 mmol) and K2CO3 (47.6 g, 344.35 mmol) in ACN (800 mL) was added 2-bromo-3-fluoro-4-nitro-pyridine (38.0 g, 172.18 mmol). The reaction was stirred at 50 °C for 3 hrs. The mixture was concentrated and purified via prep- HPLC. The solution was concentrated to remove most of the ACN. The residue was extracted with EA (1500 mL × 3). The organic layer was washed with brine (1500 mL), dried over Na2SO4, filtered and concentrated to give compound C2-f (17.0 g) as a yellow oil. LCMS (M+H-100)+: 334. Step 6: preparation of tert-butyl N-[(2R)-3-[(4-amino-2-bromo-3-pyridyl)amino]-2- ethoxy-propyl]-N-methyl-carbamate (compound C2-g) To a solution of compound C2-f (16.0 g, 36.93 mmol) in methanol (340 mL) was added Raney Ni (8.0 g, 136.31 mmol) under N2 atmosphere. Then hydrazine hydrate (9.2 g, 184.63 mmol) was added dropwise at 20 °C. The reaction was stirred at 20 °C for 3 hrs. The mixture was filtered through celite and the filtrate was concentrated at 30 °C to give compound C2-g (15.0 g) as a crude solid. LCMS (M+H)+: 405. Step 7: preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methyl-imidazo[4,5-c]pyridin- 3-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound C2-h)To a solution of pyridinium p-toluenesulfonate (2.5 g, 10.04 mmol) in anhydrous THF (150 mL) was added trimethyl orthoacetate (32.1 mL, 240.26 mmol) and compound C2-g (15.0 g, 37.19 mmol). The reaction was stirred at 80 °C for 12 hrs. The mixture was concentrated and purified via reversed phase HPLC to give compound C2-h (8.1 g) as a yellow oil. LCMS (M+H)+:429. Step 8: preparation of tert-butyl N-[(2R)-3-[4-(6-chloro-2-pyridyl)-2-methyl- imidazo[4,5-c]pyridin-3-yl]-2-ethoxy-propyl]-N-methyl-carbamate (compound C2-i) To a mixture of compound C2-h (2.0 g, 4.68 mmol), 6-chloropyridine-2-boronic acidified pinacol ester (1.12 g, 4.68 mmol) and K3PO4(1.99 g, 9.36 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was added chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (626.8 mg, 0.94 mmol) in one portion under N2 atmosphere. The reaction was stirred at 60 °C for 12 hrs under N2atmosphere. The mixture was combined with another three batches of reactions which started with compound C2-h (5 g)) and concentrated. The residue was purified via column chromatography to give compound C2-i (6.5 g) as yellow oil. LCMS: (M+H)+: 460. Step 9: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-ethoxy-propyl]-2-methyl-imidazo[4,5-c]pyridin-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound C2-j) To a suspension of cesium carbonate (11.3 g, 34.82 mmol), compound C2-i (6.0 g, 13.04 mmol) and O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate; hydrochloride (4.9 g, 15.65 mmol) in 1,4-Dioxane (120 mL) was added (2’-amino-[1,1’-biphenyl]-2- yl)(dicyclohexyl(2’,6’-diisopropoxy-[1,1‘-biphenyl]-2-yl)phosphoranyl)palladium(II) chloride (CAS 1375325-68-0, Ruphos Pd G2) (1.5 g, 1.96 mmol) in one portion under N2 atmosphere. The reaction was stirred at 90 °C for 16 hrs. The mixture was filtered and concentrated to give compound C2-j (13.0 g) as a yellow oil, which was used in the next step directly. LCMS: (M+H)+: 702. Step 10: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2S)-2-ethoxy-3- (methylamino)propyl]-2-methyl-imidazo[4,5-c]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine- 1,2-dicarboxylate;hydrochloride (compound C2-k) To a solution of compound C2-j (13.0 g, 18.52 mmol) in DCM (100 mL) was added HCl / dioxane (100.0 mL, 400.0 mmol) dropwise. The reaction was stirred at 20 °C for 1 hr. The mixture was concentrated to give compound C2-k (13.0 g) as a brown solid. LCMS: (M+H)+: 602.Step 11: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[(2S)-2-ethoxy-3- (methylamino)propyl]-2-methyl-imidazo[4,5-c]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine- 2-carboxylic acidified (compound C2-l) To a solution of compound C2-k (14.0 g, 21.94 mmol) in THF (140 mL) and methanol (140 mL) was added LiOH•H2O / water (109.7 mL, 109.69 mmol). The reaction was stirred at 20 °C for 12 hrs. The mixture was purified via reverse phase HPLC to give compound C2-l (3.5 g) as a yellow solid. LCMS: (M+H)+: 588. Step 12: preparation of benzyl (8S,11S,15R)-15-ethoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaene-10-carboxylate (compound C2-m) To a solution of HATU (650.2 mg, 1.71 mmol) and DIPEA (452.1 µL, 2.74 mmol) in acetonitrile (430 mL) was added a solution of compound C2-l (480.0 mg, 0.68 mmol) in acetonitrile (1300 mL) dropwise at 20 °C. The reaction was stirred at 20 °C for 16 hrs. The mixture was combined with other six batches of reactions which started with compound C2-m (500 mg) and concentrated. The residue was purified via reverse phase HPLC to give compound C2-m (1.27 g) as a yellow solid. LCMS: (M+H)+: 570. Step 13: preparation of (8S,11S,15R)-15-ethoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Intermediate C2) A solution of compound C2-m (130 mg, 0.228 mmol) in TFA (2.0 mL, 26.1 mmol) was stirred at 100 °C for 4 hrs. The mixture was concentrated, the residue was dissolved in EA (10 mL) and 4 M HCl in dioxane (10 mL) was added. The suspension was filtered, the collected solid was dried to give intermediate C2 as a gray solid. LCMS: (M+H)+: 436. Intermediate C3 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C10 by using intermediate A2 instead of intermediate A5 in step 1, using intermediate B3 instead ofintermediate B2 in step2 and using reaction temperature 100oC instead of room temperature in step 5. LCMS (M+H)+: 440. Intermediate C4 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C10 by using intermediate A1 instead of intermediate A5 in step 1 and intermediate B6 instead of intermediate B2 in step 2. LCMS (M+H)+: 454. Intermediate C5 (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C6 by using intermediate A3 instead of intermediate A2 and using intermediate B5 instead of intermediate B1. LCMS (M+H)+: 441. Intermediate C6 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-methyl-benzimidazol-4-yl]- 2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound C6-a) To a flask was added K2CO3(3.3 g, 24.3 mmol), compound B1 (5.3 g, 12.2 mmol), compound A2 (5.8 g, 12.15 mmol), 1,4-dioxane (60 mL) and water (1 mL). The suspension was bubbled with N2 for 5 mins and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (992.2 mg, 1.21 mmol) was added. The reaction was heated to 90oC and stirred for 16 hrs. The mixture was poured into 200 mL water and extracted with 50 mL EA for 3 times. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified via flash column to give compound C6-a (6.8 g) as a yellow oil. LCMS (M+H)+: 705. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[(2S)-2-methoxy -3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound C6-b) To the flask which contained compound C6-a (6.8 g, 9.65 mmol) was added tetrahydrofuran (20 mL). The brown solution was stirred at r.t. and 2 M LiOH (aq.) (20 mL, 40 mmol) was added drop-wise. The final mixture was stirred at r.t. for 2 hrs. The mixture was diluted with 20 mL water, and the pH was adjusted to 4 with 2 N aq. solution of HCl, and then the mixture was extracted with 30 mL DCM for 3 times. The combined organic layer was dried and concentrated to give a foamy solid.The solid was dissolved in dichloromethane (5 mL) and TFA (5 mL, 64.9 mmol). The brown solution was stirred at r.t. for 1 hr. Then it was concentrated to give compound C6-b (4.9 g) as an oil. LCMS (M+H)+: 591. Step 3: preparation of benzyl (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound C6-c) To a solution of HATU (4.6 g, 12.02 mmol), DIEA (10.5 mL, 60.1 mmol) in acetonitrile (1200 mL) was added the solution of compound C6-b (4.9 g, 6.01 mmol) in acetonitrile (1200 mL) dropwise over 4 hrs. The mixture was concentrated to give a residue, which was dissolved in 200 mL EA, washed with 100 mL sat. NaCl aq. twice. The organic layer was concentrated to give an oil (~8 g) and purified via prep-HPLC. The fraction was combined and concentrated to remove the ACN. The residue was extracted with 200 mL EA twice. The organic layer was dried and concentrated to give compound 6C-c (3.5 g) as a yellow foam. LCMS (M+H)+: 573. Step 4: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Intermediate C6) To the flask containing compound C6-c (3.5 g, 6.11 mmol) was added TFA (30 mL, 389.41 mmol). The brown solution was heated to reflux and stirred for 3 hrs. The mixture was concentrated to give Intermediate C6 (7 g) as a crude oil (containing some TFA). LCMS (M+H)+: 439. Intermediate C7 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C6 by using intermediate A1 instead of intermediate A2 and using intermediate B5 instead of intermediate B1 in step 1. LCMS (M+H)+: 455. Intermediate C8(8S,11S)-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C6 by using intermediate A4 instead of intermediate A2 and using intermediate B3 instead of intermediate B1 in step 1. LCMS (M+H)+: 410. Intermediate C9 (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C6 by using intermediate A3 instead of intermediate A2 in step 1. LCMS (M+H)+: 439. Intermediate C10 (8S,11S,18S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-1-yl]methyl]-1,4-oxazepane (compound C10-a) To a solution of intermediate A5 (5.5 g, 11.24 mmol) in DCM (23 mL) was added HCl / dioxane (23.0 mL, 92.0 mmol) at 0 °C, and then it was stirred at 20 °C for 4 hrs. The mixture was concentrated and the residue was purified via trituration with dioxane to give compound C10-a (4.4 g) as a white solid. LCMS (M+H)+: 390. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[6-fluoro-2-methyl-3- (1,4-oxazepan-2-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound C10-b) To the mixture of compound C10-a (20 g, 46.95 mmol) and intermediate B2 (18.8 g, 46.95 mmol) in 1,4-dioxane (45 mL) and water (4.5 mL) was added K3PO4(30 g, 141 mmol) and (dtbpf)PdCl2 (0.9 g, 5.55 mmol). The mixture was degassed with N2 for three times and stirred at 85 °C for 1 hr under N2. The mixture was poured into water (500 mL) and extracted with EtOAc (500 mL). The organic layer was dried and concentrated to give compound C10-b (44.0 g) as a brown oil. LCMS (M+H)+: 583. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-(1,4- oxazepan-2-ylmethyl)benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound C10-c) To a solution of compound C10-b (22.0 g, 37.76 mmol) in THF (60 mL) and methanol (60 mL) was added a solution of LiOH•H2O (11.1 g, 265.79 mmol) in Water (60 mL) at 0 °C, andthen it was stirred at 20 °C for 4 hrs. The mixture was concentrated and the residue was acidified with TFA to pH 7 to give a crude product which was purified via prep-HPLC to give compound C10-c (31.5 g) as a brown solid. LCMS (M+H)+: 569. Step 4: preparation of tert-butyl (8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound C10-d1) To a solution of HATU (836 mg, 2.2 mmol) and DIPEA (0.7 mL, 4.42 mmol) in ACN (360 mL) was added the solution of compound C10-c (1.0 g, 1.46 mmol) in ACN (1100 mL) dropwise over 8 hrs. The reaction mixture was stirred at r.t. for 1 h. Then it was concentrated and the residue was purified via prep-HPLC to give compound C10-d1 (0.5 g) as a brown solid and its isomer compound C10-d2. LCMS (M+H)+: 551. The absolute configuration of compound C10-d1 was confirmed by X-Ray Single Crystal Diffraction. (Figure 1) Step 5: preparation of (8S,11S,18S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen- 12-one (Intermediate C10) To a solution of compound C10-d1 (0.2 g, 0.36 mmol) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C, then it was stirred at r.t. for 2 hrs. The mixture was concentrated to give a brown oil, the crude product was purified via prep-HPLC to give intermediate C10 (30 mg). LCMS (M+H)+: 451. Intermediate C11 (8S,11S,18R)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C10 by using compound C10-d2 instead of compound C10-d1 in step 5. LCMS (M+H)+: 451. Intermediate C12 (8S,11S)-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin- 2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound C12- a) A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (intermediate A6, 2.5 g, 6.3 mmol), 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 (intermediate B7, 3.6 g, 8.2 mmol), Pd(dppf)Cl2·DCM (230 mg, 0.3 mol) and potassium carbonate (2.6 g, 18.8 mmol) in 1,4- dioxane (50 mL) and water (5 mL) was heated at 100 °C for 16 hrs under argon. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude product. Then it was purified via flash column to afford compound C12-a (3.3 g) as a light yellow solid, LCMS (M+H)+: 639. Step 2: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4- yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound C12-b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2- yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound C12-a, 3.3 g, 4.1 mmol) and hydrazine hydrate (1.0 g, 20.7 mmol) in MeOH (60 mL) was heated at 70 °Cfor 16 hrs in a sealed tube. After being cooled to room temperature, the reaction mixture was diluted with water, then extracted with EtOAc for three times. The combine organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to give a yellow oil. The yellow oil was dissolved in MeOH (28 mL) and water (7 mL), then lithium hydroxide monohydrate (759 mg, 18.1 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs, and then diluted with water, acidified by HOAc, extracted with DCM for three times. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude compound C12-b (2.3 g) as a light yellow solid, LCMS (M+H)+: 495. Step 3: preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound C12-c) To a mixture of DIPEA (4.0 g, 31.0 mmol) and HATU (8.0 g, 42.0 mmol) in DMF (1.5 L) was added a solution of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]phenoxy]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound C12-b, 8.0 g, 16.2 mmol) in DMF (1.5 L) at 0 °C dropwise and then stirred at 0 °C for 2 hrs. The mixture was concentrated to give a crude residue, which was diluted with EtOAc, then washed with water, 0.5 N aq. HCl solution, saturated sodium bicarbonate aqueous solution and brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give crude compound C12-c (5.2 g) as a yellow solid, which was used in next step directly, LCMS (M+H)+: 477. Step 4: preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (Intermediate C12) To a solution of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound C12-c, 118 mg, 0.17 mol) in DMF (3 mL) was added sodium hydride (35 mg, 0.87 mmol) at 0 °C.30 mins later, iodomethane (123 mg, 0.87 mmol) was added, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. The reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford intermediate C12 (160 mg) as a yellow oil, LCMS (M+H)+: 491.Intermediate C13 (8S,11S)-13,18-dimethyl-5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C10 by using intermediate A7 instead of intermediate A5 in step 1 and intermediate B8 instead of intermediate B2 in step 2. LCMS (M+H)+: 392. Intermediate C14 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of intermediate C6 by using intermediate B5 instead of intermediate B1. LCMS (M+H)+: 441. Intermediate C15 (8S,11S,15R)-15-methoxy-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- oneThe title compound was prepared according to the following scheme:intermediate C15Step 1: preparation of tert-butyl N-[(2R)-2-methoxy-3-[(2-nitro-3-pyridyl)amino] propyl]-N-methyl-carbamate (compound C15-b) A mixture of 3-fluoro-2-nitropyridine (30.0 g, 105.57 mmol), compound C15-a (80.0 g, 183.24 mmol) and K2CO3(58.36 g, 211.13 mmol) in ACN (300 mL) was stirred at 50 °C for 2 hrs. The mixture was cooled and filtered, the filtrate was concentrated to give compound C15-b (100.0 g) as a brown oil. LCMS (M+H-56)+: 285. Step 2: preparation of tert-butyl N-[(2R)-3-[(2-amino-3-pyridyl)amino]-2-methoxy- propyl]-N-methyl-carbamate (compound C15-c) To a solution of compound C15-b (100.0 g, 308.49 mmol) in methanol (1000 mL) was added Raney Ni (73.5 g, 1.25 mol) under N2atmosphere. Then hydrazine hydrate (76.2 g, 1.52 mol) was added dropwise at 20 °C. The resulted mixture was stirred for 1 hr and filtered. The filtrate was concentrated and diluted with 150 mL water. The mixture was extracted with DCM (100 mL × 3), the organic layer was concentrated to give compound C15-c (73.0 g) as a brown oil. LCMS (M+H)+: 311. Step 3: preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methylimidazo[4,5- b]pyridin-1-yl)propyl]-N-methyl-carbamate (compound C15-d) To a solution of compound C15-c (73.0 g, 112.76 mmol) in anhydrous THF (350 mL) was added trimethyl orthoacetate (50.6 mL, 379.09 mmol) and pyridinium p-toluenesulfonate (4.6 g, 18.12 mmol). The reaction mixture was stirred at 80 °C for 3 hrs and concentrated. The residue was purified via flash column and prep-HPLC to give compound C15-d (24.0 g) as a yellow oil. LCMS (M+H)+: 335. Step 4: preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methyl-4-oxido-imidazo[4,5- b]pyridin-4-ium-1-yl)propyl]-N-methyl-carbamate (compound C15-e)To a solution of compound C15-d (10.0 g, 29.9 mmol) in DCM (100 mL) was added 3- chlorobenzenecarboperoxoic acid (9.1 g, 44.82 mmol). The reaction mixture was stirred at 40 °C for 5 hrs, and then washed with sat. NaHCO3 (100 mL) and sat. Na2SO3 (100 mL). The organic layer was dried and concentrated to give compound C15-e (10.0 g) as a yellow oil. LCMS (M+H)+: 351. Step 5: preparation of tert-butyl N-[(2R)-3-(7-bromo-2-methyl-imidazo[4,5-b]pyridin- 1-yl)-2-methoxy-propyl]-N-methyl-carbamate (compound C15f) To a solution of compound C15-e (9.0 g, 0.23 mmol) in DMF (90 mL) and THF (90 mL) was added POBr3(18 g, 1.57 mmol) in one portion at 0 °C. The reaction was stirred at 20 °C for 3 hrs, and then it was quenched with cold sat. NaHCO3 (500 mL). The resulted mixture was extracted with DCM, the organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound C15-f (2.7 g) as yellow oil. LCMS (M+H+): 413. Intermediate C15 (LCMS (M+H+): 422) was prepared in analogy to the preparation of intermediate C2 by using compound C15-f instead of compound C2-h.in step 8. Example 1 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:A mixture of compound 41j (15 mg, 0.045 mmol), PyBOP (35 mg, 0.066 mmol) and DIPEA (29 mg, 0.22 mmol) in DMF (2 mL) was stirred at 50 °C for 3 hours, then intermediate C1 (20 mg, 0.044 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours, and then the reaction mixture was purified by prep-HPLC to give Example 1 (24 mg) as a white powder. LCMS (M+H)+: 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.56 (d, J = 5.1 Hz, 1H), 8.42 - 7.63 (m, 1H), 7.62 - 7.53 (m, 2H), 7.52 - 7.36 (m, 1H), 7.24 - 7.11 (m, 1H), 7.11 - 7.01 (m, 1H), 6.91 - 6.75 (m, 1H), 6.00 - 5.85 (m, 1H), 5.83 - 5.65 (m, 1H), 5.62 - 5.49 (m, 1H), 5.48 - 5.25 (m, 1H), 4.61 - 4.19 (m, 8H), 4.15 - 4.02 (m, 2H), 3.97 - 3.81 (m, 1H), 3.42 - 3.29 (m, 1H), 3.09 - 2.80 (m, 5H), 2.79 - 2.58 (m, 5H), 2.57 - 2.37 (m, 1H), 0.60 - 0.45 (m, 3H). Example 2 (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 1 by using intermediate C2 instead of intermediate C1. LCMS (M+H)+: 746.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 - 7.60 (m, 3H), 7.59 - 7.52 (m, 1H), 7.51 - 7.28 (m, 2H), 7.22 - 7.08 (m, 1H), 6.93 - 6.77 (m, 1H), 6.72 - 6.59 (m, 1H), 5.98 - 5.74 (m, 2H), 5.62 - 5.14 (m, 2H), 4.63 - 4.31 (m, 6H), 4.25 - 3.97 (m, 5H), 3.95 - 3.81 (m, 1H), 3.08 - 2.92 (m, 3H), 2.90 - 2.68 (m, 2H), 2.63 - 2.34 (m, 6H), 0.52 - 0.39 (m, 3H). Example 3 (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-3,5-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 41 by using 2,4- difluoro-6-methoxy-aniline instead of 4-fluoro-2-methoxy-aniline in step 1 and intermediate C2 instead of intermediate C6 in step 10. LCMS (M+H)+: 764.1H NMR (400 MHz, METHANOL- d4) δ = 8.48 - 8.35 (m, 2H), 8.06 - 7.88 (m, 2H), 7.38 - 7.24 (m, 1H), 7.15 - 6.99 (m, 1H), 6.96 - 6.76 (m, 2H), 5.97 - 5.78 (m, 2H), 5.68 - 5.32 (m, 2H), 4.69 - 4.59 (m, 1H), 4.56 - 4.41 (m, 2H), 4.40 - 4.17 (m, 3H), 4.13 - 3.86 (m, 4H), 3.37 - 3.28 (m, 1H), 3.17 - 2.79 (m, 5H), 2.78 - 2.68 (m, 4H), 2.67 - 2.44 (m, 3H), 0.61 - 0.42 (m, 3H). Example 4 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 1 by using intermediate C3 instead of intermediate C1. LCMS (M+H)+: 750.1H NMR (400 MHz, METHANOL-d4) δ = 8.52 - 8.37 (m, 1H), 8.35 - 7.52 (m, 1H), 7.52 - 7.37 (m, 1H), 7.34 - 7.23 (m, 1H), 7.22 - 7.08 (m, 2H), 7.05 - 6.87 (m, 1H), 6.87 - 6.76 (m, 1H), 5.96 - 5.78 (m, 1H), 5.62 - 5.21 (m, 3H), 4.61 - 4.42 (m, 3H), 4.41 - 4.27 (m, 2H), 4.26 - 3.80 (m, 6H), 3.14 - 2.92 (m, 4H), 2.90 - 2.70 (m, 4H), 2.62 - 2.35 (m, 5H). Example 5(8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:A mixture of intermediate C4 (26mg, 0.057 mmol), compound 44b (20 mg, 0.057 mmol) and DIPEA (22 mg, 0.17 mmol) in acetonitrile (2 mL) was stirred at rt for 1 hour. Then the reaction was diluted with EA, washed with water and brine, the organic layer was concentrated and the residue was purified by prep-HPLC to give Example 5 (6 mg) as white powder. LCMS (M+H)+: 768.1H NMR (400 MHz, METHANOL-d4) δ = 8.35 - 8.25 (m, 1H), 8.24 - 8.15 (m, 1H), 7.86 - 7.73 (m, 1H), 7.71 - 7.57 (m, 1H), 7.39 - 7.30 (m, 1H), 7.12 - 6.96 (m, 2H), 6.92 - 6.69 (m, 2H), 5.59 - 5.46 (m, 1H), 5.28 - 5.18 (m, 1H), 4.78 - 4.50 (m, 3H), 4.39 - 4.07 (m, 3H), 4.06 - 3.95 (m, 1H), 3.92 - 3.82 (m, 1H), 3.73 - 3.49 (m, 3H), 3.48 - 3.37 (m, 2H), 3.19 - 3.09 (m, 2H), 3.04 - 2.93 (m, 2H), 2.84 - 2.36 (m, 8H), 0.72 - 0.47 (m, 3H). Example 6 (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10Z)-5,10-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[tert-butyl(diphenyl)silyl]oxyethanol (compound 6b) To a solution of compound 6a (4.5 mL, 80.55 mmol) in DCM (30 mL) was added imidazole (6.8 g, 100.69 mmol) and tert-butylchlorodiphenylsilane (11.1 g, 40.28 mmol) at 0 °C under N2 atmosphere. After being stirred at 0 °C for 2 hrs, the reaction was quenched with water (60 mL) and then extracted with EA. The organic layer was dried and concentrated, the residue was purified via silica gel column chromatography to give compound 6b (3.6 g) as a whitesemisolid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.72 - 7.64 (m, 4H), 7.48 - 7.38 (m, 6H), 3.81 - 3.74 (m, 2H), 3.74 - 3.66 (m, 2H), 2.15 (br t, J = 5.6 Hz, 1H), 1.08 (s, 9H). Step 2: preparation of 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (compound 6c) To a solution of oxalyl chloride (730 µL, 8.65 mmol) in DCM (20 mL) was added dimethylsulfoxide (1.5 mL, 17.31 mmol) dropwise at -78 °C. The reaction was stirred at -78 °C for 0.5 h, then compound 6b (1.3 g, 4.33 mmol) in DCM (5 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hrs, triethylamine (4.8 mL, 34.61 mmol) was then added dropwise at -78 °C. The reaction mixture was stirred at 0 °C for another 0.5 hr and then poured into ice-water (20 mL) and DCM (20 mL). The organic phase was separated, dried and concentrated to afford compound 6c (1.29 g) as a colorless oil. Step 3: preparation of ethyl (Z)-4-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-but-2-enoate (compound 6e) To a solution of triethyl 2-fluoro-2-phosphonoacetate (1.15 g, 4.75 mmol) in THF (12 mL) was added sodium hydride (190 mg, 4.75 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 0.5 hr, compound 6c (1.3 g, 4.32 mmol) in THF (4 mL) was added and then the mixture was stirred at 0 °C for 1.5 hrs. The reaction was quenched with ice-water (30 mL) and extracted with EA, the organic layer was dried and concentrated. The residue was purified via silica gel column chromatography to give compound 6e (950 mg) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.73 - 7.61 (m, 4H), 7.48 - 7.35 (m, 6H), 6.36 - 6.06 (m, 1H), 4.69 (dd, J = 3.5, 5.6 Hz, 1H), 4.45 (dd, J = 2.9, 6.2 Hz, 1H), 4.29 (d, J = 7.1 Hz, 1H), 4.20 - 4.14 (m, 1H), 1.31 - 1.17 (m, 3H), 1.07 (s, 9H). Step 4: preparation of (Z)-4-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-but-2-en-1-ol (compound 6f) To a solution of compound 6e (850 mg, 2.2 mmol) in THF (10 mL) was added DIBAL-H (7 mL, 7 mmol) at -78 °C under N2atmosphere and then stirred at 0 °C for 1 hr. To the stirred reaction solution was added 50 mL of THF, 0.7 mL of water, 0.7 mL of 10% NaOH in water and 1.4 mL of water in sequence. After being stirred at 20 °C for 0.5 hr, the reaction mixture was dried over Na2SO4, filtered and concentrated to give compound 6f (520 mg) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.71 - 7.65 (m, 4H), 7.49 - 7.36 (m, 6H), 5.47 - 5.01 (m, 1H), 4.38 - 4.19 (m, 2H), 4.11 - 4.01 (m, 2H), 1.81 - 1.57 (m, 1H), 1.06 (d, J = 2.2 Hz, 9H). Step 5: preparation of [(Z)-4-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-but-2-enyl] ethanesulfonate (compound 6g)To a solution of compound 6f (300 mg, 0.87 mmol) and triethylamine (240 µL, 1.74 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (170 µL, 1.74 mmol) dropwise at 0 °C. After being stirred at 0 °C for 1 hr, the reaction was poured into water (8 mL) and extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 6g (350 mg) as a brown oil. Step 6: preparation of [4-benzyloxy-1-[2-[(Z)-4-[tert-butyl(diphenyl)silyl]oxy-2-fluoro- but-2-enoxy]-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methanol (compound 6i) To a solution of compound 41g (300 mg, 0.82 mmol) and cesium carbonate (400 mg, 1.23 mmol) in DMF (3 mL) was added compound 6g (380 mg, 0.87 mmol) in DMF (2 mL) dropwise at 0 °C. After being stirred at 20 °C for 15 hrs, the reaction was quenched with water (20 mL) and extracted with EA. The organic layer was dried and concentrated, the residue was purified via silica gel column chromatography to give compound 6i (250 mg) as a light brown oil. LCMS (M+H)+: 693. Step 7: preparation of (Z)-4-[2-[4-benzyloxy-6-(hydroxymethyl)pyrazolo[3,4- d]pyrimidin-1-yl]-5-fluoro-phenoxy]-3-fluoro-but-2-en-1-ol (compound 6j) A mixture of compound 6i (240 mg, 0.35 mmol) and TBAF (1 mL, 1 M) in THF (3 mL) was stirred at 20 °C for 1 hr. Then the reaction was quenched with water (20 mL) and then extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel to give compound 6j (180 mg) as a light brown gum. LCMS (M+H)+: 455. Step 8: preparation of [(Z)-4-[2-[4-benzyloxy-6-(hydroxymethyl)pyrazolo[3,4- d]pyrimidin-1-yl]-5-fluoro-phenoxy]-3-fluoro-but-2-enyl] ethanesulfonate (compound 6k) To a solution of compound 6j (130 mg, 0.29 mmol) and triethylamine (60 µL, 0.43 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (20 µL, 0.23 mmol) dropwise at 0 °C. After being stirred at 20 °C for 15 hrs, the reaction was quenched with water (20 mL) and extracted with DCM. The organic layer was dried and concentrated to give compound 6k (100 mg) as a light yellow oil. LCMS (M+H)+: 547. Step 9: preparation of (10Z)-17-benzyloxy-5,10-difluoro-8,13-dioxa-1,16,20,22- 2,7 18,21 tetrazatetracyclo[13.5.2.0 .0 ]docosa-2(7),3,5,10,15(22),16,18(21),19-octaene (compound 6l) To a solution of compound 6k (150 mg, 0.27 mmol) in THF (40 mL) was added NaH (44 mg, 1.1 mmol) at 0 °C under N2 atmosphere. After being stirred at 20 °C for 16 hrs, the reaction was quenched with cold NH4Cl aq. (50 mL) and extracted with EA. The organic layer was driedand concentrated, the residue was purified via prep-TLC to give compound 6l (23.mg) as a white solid. LCMS (M+H)+: 437. Step 10: preparation of (10Z)-5,10-difluoro-8,13-dioxa-1,16,20,22- 2,7 18,21 tetrazatetracyclo[13.5.2.0 .0 ]docosa-2(7),3,5,10,15(22),16,18(21),19-octaen-17-ol (compound 6m) A mixture of compound 6l (35 mg, 0.08 mmol) in DCE (2 mL) and TFA (200 µL) was stirred at 20 °C for 16 hrs. Then the reaction mixture was poured into ice-water (5 mL) and pH was adjusted to around 7. The resulting solution was extracted with EA, the organic layer was dried and concentrated, the residue was purified via prep-TLC to give compound 6m (25 mg) as a light yellow semisolid. LCMS (M+H)+: 347.1H NMR (400 MHz, CHLOROFORM-d) δ = 10.50 - 10.43 (m, 1H), 8.31 (s, 1H), 7.65 - 7.60 (m, 1H), 6.96 - 6.91 (m, 2H), 5.58 - 5.48 (m, 1H), 4.73 - 4.66 (m, 2H), 4.55 (s, 2H), 4.37 (dd, J = 1.2, 8.3 Hz, 2H). Step 11: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,11,14-trioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17- yl)-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 6) The title compound was prepared in analogy to the preparation of example 1 by using intermediate C2 instead of intermediate C1 and compound 6m instead of compound 41j. LCMS (M+H)+: 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.41 - 8.25 (m, 2H), 7.88 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.55 - 7.39 (m, 1H), 7.38 - 7.28 (m, 1H), 7.09 - 6.99 (m, 1H), 6.94 - 6.81 (m, 1H), 6.77 - 6.63 (m, 1H), 5.94 - 5.75 (m, 1H), 5.49 - 5.39 (m, 1H), 5.39 - 5.23 (m, 1H), 4.64 - 4.31 (m, 5H), 4.29 - 4.04 (m, 5H), 3.97 - 3.77 (m, 1H), 3.07 - 2.91 (m, 4H), 2.90 - 2.68 (m, 2H), 2.63 - 2.39 (m, 6H), 0.57 - 0.39 (m, 3H). Example 7 (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-15-methoxy- 13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 1 by using intermediate C5 instead of intermediate C1 and compound 10C instead of compound 41j. LCMS (M+H)+: 750.1H NMR (400 MHz, METHANOL-d4) δ = 8.67 - 8.54 (m, 1H), 8.44 - 7.59 (m, 1H), 7.55 - 7.15 (m, 4H), 7.02 - 6.89 (m, 1H), 6.85 - 6.69 (m, 1H), 5.88 - 5.62 (m, 1H), 5.62 - 5.27 (m, 1H), 4.54 - 4.26 (m, 5H), 4.14 - 3.92 (m, 4H), 3.77 - 3.55 (m, 2H), 3.46 - 3.30 (m, 1H), 3.14 - 2.91 (m, 4H), 2.85 - 2.62 (m, 4H), 2.60 - 2.35 (m, 3H), 1.74 - 1.54 (m, 2H), 1.31 - 1.15 (m, 2H), 1.13 - 0.92 (m, 1H). Example 8 (8S,11S,15R)-22-fluoro-10-(5-fluoro-12-oxo-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2,4,6,13,15(18),16-hexaen-14-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:The compound 8a was prepared in analogy to the preparation of compound 18a by using (4-fluoro-2-iodo-phenyl)hydrazine;hydrochloride instead of intermediate 41b in step 1. Step 1: preparation of ethyl 5-amino-1-(4-fluoro-2-iodo-phenyl)pyrazole-4- carboxylate (compound 8b) To a solution of compound 8a (10 g, 26.65 mmol) in chloroform (200 mL) was added acetyl chloride (2.8 mL, 39.95 mmol) at 0 °C under N2. The mixture was then stirred at 70 °C for 16 hrs. The reaction was quenched with water (200 ml) and extracted with DCM (100 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified via flash silica gel chromatography to give compound 8b (8 g) as a brown oil. LCMS (M+H)+: 418. Step 2: preparation of ethyl 5-acetamido-1-[2-[3-[tert-butyl(dimethyl)silyl]oxyprop- 1-ynyl]-4-fluoro-phenyl]pyrazole-4-carboxylate (compound 8c) To a solution of compound 8b (8.0 g, 11.98 mmol) in THF (200 mL) was added tert- butyldimethyl(2-propynyloxy)silane (5.1 g, 29.96 mmol), DIEA (5.9 mL, 35.95 mmol), CuI (137 mg, 0.72 mmol) and bis(triphenylphosphine)palladium(II)dichloride (841 mg, 1.2 mmol) under N2 atmosphere. The reaction mixture was stirred at 40 °C for 16 hrs and concentrated. Theresidue was purified via flash chromatography to give compound 8c (6 g) as a brown oil. LCMS (M+H)+: 460. Step 3: preparation of ethyl 5-acetamido-1-[2-[3-[tert- butyl(dimethyl)silyl]oxypropyl]-4-fluoro-phenyl]pyrazole-4-carboxylate (compound 8d) To a solution of compound 8c (6.0 g, 13.06 mmol) in methanol (200 mL) was added Pd(OH)2 / C (2.0 g) at 25 °C. The reaction was stirred at 25 °C for 16 hrs under H2(45 psi). The mixture was filtered, the filtrate was concentrated to give a crude compound 8d (5.5 g) as a yellow oil, which was used in the next step without further purification. LCMS (M+H)+: 464. Step 4: preparation of ethyl 5-acetamido-1-[4-fluoro-2-(3-hydroxypropyl)phenyl] pyrazole-4-carboxylate (compound 8e) To a solution of compound 8d (5.5 g, 11.85 mmol) in THF (120 mL) was added tetrabutylammonium fluoride (1M THF solution) (11.8 mL, 11.85 mmol) at 0 °C. The reaction was warmed to 30 °C and stirred for 16 hrs. The mixture was poured into water (100 mL) and extracted with EA (120 mL × 2). The combined organic layer was washed with brine (200 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to give compound 8e (3.3 g) as yellow oil. LCMS (M+H)+: 350. Step 5: preparation of ethyl 7-acetyl-13-fluoro-2,3,7- 2,6 triazatricyclo[9.4.0.0 ]pentadeca-1(11),3,5,12,14-pentaene-5-carboxylate (compound 8f) To a solution of compound 8e (3.3 g, 9.45 mmol) and triphenylphosphane (4.0 g, 15.12 mmol) in DCM (120 mL) was added diisopropyl azodicarboxylate (1 mL, 4.72 mmol) at 0 °C under N2. The reaction was stirred at 40 °C for 16 hrs. The mixture was poured into water (200 mL) and extracted with EA (100 mL × 2). The combined organic layer was washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to give compound 8f (4.2 g) as a white solid. LCMS (M+H)+: 332. 2,7 15,18 Step 6: preparation of 5-fluoro-14-hydroxy-1,11,17-triazatetracyclo[9.6.1.0 .0 ] octadeca-2(7),3,5,13,15(18),16-hexaen-12-one (compound 8g) To a solution of compound 8f (1 g, 3.02 mmol) in dry THF (10 mL) was added LiHMDS (16.0 mL, 30.18 mmol) at -78 °C under N2. The reaction was stirred at 30 °C for 4 hrs and quenched with ice-water (10 mL). After being acidified to pH 3-4 with 1M HCl aq., the solution was extracted with EA (10 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via flash silica gel chromatography to give compound 8g (300 mg) as a red solid. LCMS (M+H)+: 286.2,7 15,18 Step 7: preparation of 14-chloro-5-fluoro-1,11,17-triazatetracyclo[9.6.1.0 .0 ] octadeca-2(7),3,5,13,15(18),16-hexaen-12-one (compound 8h) To a solution of compound 8g (240 mg, 0.6 mmol) in ACN (5 mL) was added POCl3 (439 mg, 1.2 mmol) at 0 °C. The reaction was stirred at 80 °C for 16 hrs and concentrated. The residue was purified via prep-TLC to give compound 8h (200 mg) as a yellow oil. LCMS (M+H)+: 304. Step 8: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-12-oxo-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2,4,6,13,15(18),16-hexaen-14-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 8) To a solution of intermediate C6 (47 mg, 0.11 mmol), compound 8h (50 mg, 0.11 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (70 µL, 0.43 mmol) and cesium fluoride (65 mg, 0.43 mmol). The reaction was stirred at 130 °C for 2 hrs and purified via reversed phase HPLC to give Example 8 (16.5 mg) as a white solid. LCMS (M+H)+: 706,1H NMR (400 MHz, METHANOL-d4) δ = 7.87 (t, J = 7.9 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.62 - 7.58 (m, 1H), 7.57 - 7.52 (m, 1H), 7.25 - 7.18 (m, 1H), 7.18 - 7.13 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 6.23 - 6.03 (m, 1H), 4.83 (br d, J = 2.5 Hz, 2H), 4.76 - 4.64 (m, 1H), 4.61 - 4.53 (m, 1H), 4.40 - 4.26 (m, 1H), 4.44 - 4.20 (m, 1H), 4.04 - 3.84 (m, 1H), 3.67 - 3.56 (m, 1H), 3.53 - 3.39 (m, 1H), 3.18 - 3.07 (m, 3H), 3.02 (br d, J = 14.3 Hz, 1H), 2.97 (d, J = 5.0 Hz, 3H), 2.94 - 2.87 (m, 2H), 2.83 (d, J = 7.9 Hz, 3H), 2.62 - 2.48 (m, 3H), 2.21 - 2.05 (m, 1H), 1.69 - 1.54 (m, 1H), 1.18 (t, J = 7.1 hrz, 1H). Example 9 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazapentacyclo[13.5.2.110,12.02,7.018,21]tricosa-2,4,6,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 3-[[2-[4-benzyloxy-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin- 1-yl]-5-fluoro-phenoxy]methyl]cyclobutanone(compound 9a) To a solution of compound 41g (500 mg, 1.36 mmol) in DMF (20 mL) was added cesium carbonate (1.11 g, 3.41 mmol) at 0 °C. The reaction was stirred for 30 min, then 3- (bromomethyl)cyclobutanone (667 mg, 4.09 mmol) was added at 0 °C. The reaction mixture was heated to 80 °C and stirred for 16 hrs. The reaction was quenched with water (40 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtrated and concentrated. The residue was purified via flash chromatography to give compound 9a (250 mg) as a light yellow oil. LCMS (M+H)+: 449. Step 2: preparation of 3-[[2-[4-benzyloxy-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin- 1-yl]-5-fluoro-phenoxy]methyl]cyclobutanol (compound 9b) To a solution of compound 9a (250 mg, 0.56 mmol) in THF (15 mL) was added L- selectride (0.14 mL, 0.67 mmol) at -78 °C. The reaction was stirred at -78 °C for 2 hrs. The reaction was quenched with water (0.3 mL) and 10% aq. NaOH (0.9 mL). The mixture was stirred for 30 min and filtered through a pad of celite. The filtrate was concentrated and purified via TLC to give compound 9b (130 mg) as a light yellow solid. LCMS (M+H)+:451. Step 3: preparation of 3-[[2-[4-benzyloxy-6-(chloromethyl)pyrazolo[3,4-d]pyrimidin-1- yl]-5-fluoro-phenoxy]methyl]cyclobutanol (compound 9c ) To a solution of compound 9b (100 mg, 0.22 mmol) in DMSO (5 mL) was added 2,4,6- trichloro-1,3,5-triazine (20.5 mg, 0.11 mmol) at 15 °C. The mixture was stirred at 25 °C for 16 hrs. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified via prep-TLC to give compound 9c (50 mg) as a light yellow solid. LCMS (M+H)+: 361.Step 4: preparation of [1-[4-fluoro-2-[(3-hydroxycyclobutyl)methoxy]phenyl]-4- hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]methyl ethanesulfonate (compound 9d ) To a solution of compound 9c (50 mg, 0.14 mmol) and triethylamine (40 µL, 0.28 mmol) in DCM (4 mL) was added ethanesulfonyl chloride (10 µL, 0.1 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The reaction was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give the crude product compound 9d (60 mg) as a light yellow oil. LCMS (M+H)+: 453. Step 5: preparation of 5-fluoro-8,13-dioxa-1,16,20,22-tetrazapentacyclo [13.5.2.110,12.02,7.018,21]tricosa-2,4,6,15(22),16,18(21),19-heptaen-17-ol (compound 9e ) To a solution of compound 9d (60 mg, 0.13 mmol) in THF (12 mL) was added a suspension of NaH (16 mg, 0.4 mmol) in THF (6 mL) at 0 °C under N2atmosphere. The mixture was stirred at 25 °C for 16 hrs. The reaction was quenched with ice NH4Cl aq. (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified via Prep-TLC to give compound 9e (10 mg) as a white solid. LCMS (M+H)+: 343. Step 6: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazapentacyclo[13.5.2.110,12.02,7.018,21]tricosa-2,4,6,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 9) To a solution of compound 9e (10 mg, 0.03 mmol) in DMF (1 mL) was added intermediate C6 (13 mg, 0.03 mmol), PyBop (20 mg, 0.04 mmol) and DIEA (12 µL, 0.07 mmol). The reaction mixture was stirred at 20 °C for 16 hrs. Then it was purified via prep-HPLC (neutral system) to give Example 9 (4.8 mg) as a white solid. LCMS (M+H)+: 763,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.22 (s, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.44 - 7.39 (m, 1H), 7.13 - 7.08 (m, 2H), 6.84 - 6.78 (m, 3H), 6.45 (d, J = 8.1 hrz, 1H), 5.90 - 5.77 (m, 1H), 5.58 (d, J = 8.2 Hz, 1H), 5.10 (d, J = 8.1 hrz, 1H), 5.01 (br t, J = 7.5 Hz, 1H), 4.70 (br d, J = 10.4 Hz, 1H), 4.66- 4.48 (m, 2H), 4.43 - 4.34 (m, 1H), 4.32 - 4.24 (m, 1H), 4.22 - 4.12 (m, 3H), 4.08 - 4.01 (m, 2H), 3.08 (s, 1H), 2.99 (s, 3H), 2.77 (s, 3H), 2.57 (s, 3H), 2.51 - 2.34 (m, 2H), 2.19 - 2.06 (m, 2H), 1.92 (br s, 2H). Example 10 (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of [4-benzyloxy-1-[2-(4-bromobutoxy)-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methanol (compound 10a) To a solution of compound 41g (1.5 g, 4.09 mmol) in DMF (120 mL) was added cesium carbonate (2.0 g, 6.14 mmol) at 0 °C. The mixture was stirred for 1 hr and 1,4-dibromobutane (1.06 g, 4.91 mmol) was added at 0 °C. Then it was heated to 40 °C and stirred for 2 hrs. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified via flash chromatography to give compound 10a (1000 mg) as a light yellow oil. LCMS (M+H)+: 501. Step 2: preparation of 17-benzyloxy-5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaene (compound 10b)To a solution of compound 10a (800 mg, 1.6 mmol) in THF (100 mL) was added a suspension of NaH (191 mg, 4.79 mmol) in THF (50 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 16 hrs. The reaction was quenched with aq. NH4Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified via flash column chromatography to give compound 10b (300 mg) as a colorless oil. LCMS (M+H)+: 421. Step 3: preparation of 5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7. 018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-ol (compound 10c) To a solution of compound 10b (250 mg, 0.59 mmol) in DCE (25 mL) was added TFA (2.5 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 hrs and concentrated. The residue was purified via prep-TLC to give compound 10c (110 mg) as a white solid. LCMS (M+H)+: 331. Step 4: preparation of (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen- 17-yl)-13,18-dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 10 ) To a solution of compound 10c (20 mg, 0.06 mmol) in DMF (3 mL) was added intermediate C7 (27 mg, 0.06 mmol), PyBop (40 mg, 0.08 mmol) and DIEA (25 µL, 0.15 mmol). The reaction mixture was stirred at 20 °C for 2 hrs. The mixture was purified twice via prep- HPLC (basic system) and prep-HPLC (TFA system) to give Example 10 (7.3 mg) as a white solid. LCMS (M+H)+: 767,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.77 (d, J = 5.1 hrz, 1H), 8.28 (s, 1H), 8.08 - 7.96 (m, 1H), 7.57 - 7.49 (m, 1H), 7.49 - 7.41 (m, 1H), 7.49 - 7.40 (m, 1H), 6.82 (s, 2H), 6.06 - 5.95 (m, 1H), 5.90 - 5.80 (m, 1H), 4.71 - 4.60 (m, 2H), 4.54 - 4.41 (m, 2H), 4.30 - 4.21 (m, 1H), 4.16 - 4.02 (m, 4H), 3.88 - 3.80 (m, 1H), 3.77 - 3.70 (m, 1H), 3.34 - 3.26 (m, 1H), 3.06 (s, 1H), 2.94 (s, 3H), 2.84 (s, 3H), 2.69 (br s, 4H), 1.87 - 1.73 (m, 2H), 1.48 (br d, J = 6.8 Hz, 1H), 1.30 - 1.20 (m, 1H), 0.66 (t, J = 6.9 Hz, 3H). Example 11 (8S,11S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 10 by using intermediate C8 instead of intermediate C7 in step 4. Example 11 (9.7 mg), LCMS (M+H)+: 722,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.46 (br d, J = 4.8 Hz, 1H), 8.15 (s, 1H), 7.42 (br s, 2H), 7.07 (br s, 1H), 6.92 - 6.84 (m, 1H), 6.73 (br d, J = 8.5 Hz, 2H), 5.67 (br d, J = 7.1 hrz, 1H), 5.48 (br d, J = 8.1 hrz, 2H), 4.87 (br d, J = 4.1 hrz, 1H), 4.72 - 4.55 (m, 2H), 4.44 - 4.35 (m, 1H), 4.20 - 3.94 (m, 4H), 3.84 - 3.63 (m, 2H), 3.44 - 3.18 (m, 2H), 3.10 - 2.88 (m, 3H), 2.73 -2.48 (m, 5H), 2.46 - 2.35 (m, 1H), 1.86 (br s, 2H), 1.45-1.18 (br s, 3H). Example 12 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18- dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 44 by using intermediate C3 instead of intermediate C8 in step 3. Example 12 (6.4 mg), LCMS (M+H)+: 754,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.49 (t, J = 4.8 Hz, 1H), 8.19 (d, J = 12.9 Hz, 1H), 7.84 - 7.66 (m, 1H), 7.56 - 7.43 (m, 1H), 7.26 - 7.10 (m, 1H), 6.99 - 6.91 (m, 1H), 6.86 - 6.71 (m, 1H), 6.51 - 6.44 (m, 1H), 5.83 - 5.53 (m, 2H), 5.27 - 5.07 (m, 1H), 4.70 - 4.51 (m, 1H), 4.24 -3.94 (m, 6H), 3.83 - 3.68 (m, 2H), 3.57 - 3.37 (m, 2H), 3.23 - 3.12 (m, 1H), 2.82-2.66 (m, 6H), 2.60 (m, 2H), 2.46 (m, 3H) 2.42 - 2.37 (m, 3H).Example 13 (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 44 by using intermediate C9 instead of intermediate C8 in step 3. Example 13 (13.1 mg), LCMS (M+H)+: 753,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.11 - 8.06 (m, 1H), 7.75 - 7.49 (m, 2H), 7.45 - 7.26 (m, 2H), 7.01 - 6.89 (m, 1H), 6.83 (br d, J = 6.9 Hz, 1H), 6.76 - 6.67 (m, 2H), 6.38 - 6.28 (m, 2H), 5.49 - 5.41 (m, 1H), 5.33 - 5.25 (m, 1H), 5.16 - 5.07 (m, 1H), 5.03 - 4.88 (m, 1H), 4.39 - 4.24 (m, 1H), 4.12 - 3.99 (m, 3H), 3.89 - 3.77 (m, 1H), 3.70 - 3.30 (m, 5H), 3.11 - 3.02 (m, 1H), 2.98 - 2.78 (m, 1H), 2.74 - 2.67 (m, 6H), 2.49 (br d, J = 9.6 Hz, 3H), 2.39 - 2.26 (m, 2H). Example 14 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,3,16,20,22- pentazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:The compound 14a was prepared in analogy to the preparation of example 41c by using intermediate 3,5-difluoropyridin-2-amine instead of intermediate 4-fluoro-2-methoxy-aniline in step 1. Step 1: preparation of hex-5-enoyl chloride (compound 14b) To a solution of hex-5-enoic acid (2.0 g, 17.52 mmol) in DCM (10 mL) was added DMF (0.14 mL, 1.75 mmol) and (COCl)2(5.93 mL, 70.09 mmol) slowly at 0 °C under N2. The reaction mixture was stirred at 20 °C for 4 hr and concentrated directly to give compound 14b (2.0 g) as a yellow semisolid. Step 2: preparation of N-[4-cyano-2-(3,5-difluoro-2-pyridyl)pyrazol-3-yl]hex-5- enamide (compound 14c) To a solution of compound 14a (5.0 g, 22.61 mmol) in sulfolane (25.0 mL) was added compound 14b (6.0 g, 45.21 mmol) at 25 °C. The mixture was heated to 80 °C and stirred for 2 hrs, then it was cooled to 25 °C and filtered. The filtrate was purified via prep-HPLC to give compound 14c (2.0 g) as a light yellow semisolid. LCMS (M+H)+: 318.Step 3: preparation of 4-chloro-1-(3,5-difluoro-2-pyridyl)-6-pent-4-enyl-pyrazolo[3,4- d]pyrimidine (compound 14d ) To the compound 14c (200 mg, 0.63 mmol) was added POCl3 (2.0 mL) at 0 °C. The mixture was stirred at 100 °C for 16 hrs and then concentrated. The residue was poured into cold water and pH was adjusted to around 7 with aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 10 mL), the organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified via flash column chromatography to give compound 14d (100 mg) as a light yellow oil. LCMS (M+H)+: 336. Step 4: preparation of 4-benzyloxy-1-(3,5-difluoro-2-pyridyl)-6-pent-4-enyl- pyrazolo[3,4-d]pyrimidine (compound 14e) To a solution of benzyl alcohol (48 mg, 0.45 mmol) and compound 14d (100 mg, 0.3 mmol) in THF (2.5 mL) was added a solution of potassium tert-butoxide / THF (149 µL, 0.15 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hrs. Then it was purified via prep-TLC to give compound 14e (50 mg) as a colorless oil. LCMS (M+H+: 408. Step 5: preparation of 1-(3-allyloxy-5-fluoro-2-pyridyl)-4-benzyloxy-6-pent-4-enyl- pyrazolo[3,4-d]pyrimidine (compound 14f ) To a solution of allyl alcohol (0.35 mL, 5.17 mmol) in dry THF (20 mL) was added sodium hydride (118 mg, 2.95 mmol) at 0 °C under N2 atmosphere. The mixture was stirred for 1 hr and a solution of compound 14e (400 mg, 0.98 mmol) in THF (5 mL) was added at 0 °C. The reaction was heated to 40 °C and stirred for 15 hrs. The mixture was poured into NH4Cl aq. (30 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (2 × 30 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified with prep-TLC to give compound 14f (220 mg) as a light yellow oil. LCMS (M+H)+: 446. Step 6: preparation of (10E)-17-benzyloxy-5-fluoro-8-oxa-1,3,16,20,22- pentazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15(22),16,18(21),19-octaene (compound 14g) To a solution of compound 14f (220 mg, 0.49 mmol) in DCM (200 mL) was added second-generation Hoveyda-Grubbs (123 mg, 0.2 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 hrs, then heated to 40 °C and stirred for another 20 hrs. The mixture was filtered, the filtrate was concentrated and purified via prep-TLC to give compound 14g (40 mg) as a light yellow oil. LCMS (M+H)+: 418. Step 7: preparation of 5-fluoro-8-oxa-1,3,16,20,22-pentazatetracyclo[13.5.2.02,7.018,21] docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-ol (compound 14h )To a solution of compound 14g (30 mg, 0.07 mmol) in THF (2 mL) was added Pd / C (10 mg) at 0 °C. The reaction was stirred at 0 °C for 2 hrs. The mixture was filtered and the filtrate was concentrated to give a crude product compound 14h (20 mg) as a light yellow semisolid. LCMS (M+H)+: 330. Step 8: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,3,16,20,22- pentazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 14). To a solution of compound 14h (15 mg, 0.02 mmol) in DMF (0.5 mL) was added intermediate C6 (10 mg, 0.02 mmol), PyBop (15 mg, 0.03 mmol) and DIEA (10 µL, 0.06 mmol). The reaction was stirred at 25 °C for 4 hrs and purified via prep-HPLC to give crude product. Then it was purified again with prep-TLC to give Example 14 (1.1 mg) as a light yellow semisolid. LCMS (M+H)+: 750. Example 15 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,12,13,14,17,21,23-heptazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaen-18-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of [4-benzyloxy-1-(2-but-3-ynoxy-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]methanol (compound 15a) To a solution of compound 41g (1000 mg, 2.73 mmol) in ACN (20 mL) was added cesium carbonate (2668 mg, 8.19 mmol) at 0 °C and stirred for 0.5 hrs. A solution of 4-bromobut-1-yne (3.63 g, 27.3 mmol) in ACN (5 mL) was added. The reaction was heated to 80 °C and stirred for 16 hrs. The mixture was filtered and the filtrate was concentrated. The residue was purified via prep-HPLC to give compound 15a (300 mg) as a light yellow solid. LCMS (M+H)+: 419. Step 2: preparation of [4-benzyloxy-1-(2-but-3-ynoxy-4-fluoro-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]methyl methanesulfonate (compound 15b) To a solution of compound 15a (400 mg, 0.96 mmol) in DCM (20 mL) was added TEA (0.4 mL, 2.87 mmol) and methanesulfonyl chloride (0.7 mL, 9.43 mmol) at 0 °C. The reaction was warmed to 25 °C and stirred for 1 hrs. The reaction was quenched with H2O (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the crude product compound 15b (350 mg) as light yellow oil, which was used in the next step without further purification. LCMS (M+H)+: 497. Step 3: preparation of 6-(azidomethyl)-4-benzyloxy-1-(2-but-3-ynoxy-4-fluoro- phenyl)pyrazolo[3,4-d]pyrimidine (compound 15c) To a solution of compound 15b (350 mg, 0.7 mmol) in DMF (25 mL) was added NaN3(20 mg, 0.31 mmol) at 0 °C. The reaction was warmed to 25 °C and stirred for 16 hrs. The reaction was quenched with H2O (60 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give crude compound 15c (300 mg) as a light yellow oil, which was used in the next step without further purification. LCMS (M+H)+: 444.Step 4: preparation of 18-benzyloxy-5-fluoro-8-oxa-1,12,13,14,17,21,23- heptazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaene (compound 15d) To a solution of compound 15c (200 mg, 0.45 mmol) in acetonitrile (60 mL) were added CuSO4(7 mg, 0.05 mmol) and sodium L-ascorbate (9 mg, 0.05 mmol) at 0 °C. The reaction was heated to 100 °C and stirred for 16 hrs. The mixture was concentrated and purified via prep-TLC to give compound 15d (35 mg) as a light yellow solid. LCMS (M+H)+: 444. Step 5: preparation of 5-fluoro-8-oxa-1,12,13,14,17,21,23- heptazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaen-18- ol (compound 15e) To a solution of compound 15d (35 mg, 0.08 mmol) in DCE (5 mL) was added TFA (0.5 mL) at 0 °C. The reaction was warmed to 20 °C and stirred for 16 hrs. The mixture was washed with brine (20 mL), dried over Na2SO4 and concentrated to give the crude compound 15e (25 mg) as a light yellow oil, which was used in the next step without further purification. LCMS (M+H)+: 354. Step 6: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,12,13,14,17,21,23- heptazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaen- 18-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 15 ) To a solution of intermediate C6 (31 mg, 0.07 mmol) in DMF (1 mL) was added compound 15e (25 mg, 0.07 mmol), PyBop (48 mg, 0.09 mmol) and DIEA (29 µL, 0.18 mmol). The reaction was stirred at 25 °C for 8 hrs. The solution was purified via prep-HPLC to give Example 15 (8 mg) as a light yellow solid. LCMS (M+H)+: 774,1H NMR (400 MHz, METHANOL-d4) δ = 8.01 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.36 - 7.30 (m, 1H), 7.20 - 7.09 (m, 2H), 6.85 - 6.79 (m, 1H), 6.69 (d, J = 8.5 Hz, 1H), 5.71 - 5.37 (m, 2H), 4.66 - 4.56 (m, 4H), 4.33 - 4.11 (m, 2H), 3.51 - 3.44 (m, 3H), 3.12 - 3.06 (m, 3H), 2.89 - 2.81 (m, 3H), 2.58 -2.57 (br d, J = 15.4 Hz, 4H), 2.03 - 1.96 (m, 5H). Example 16 (8S,11S,15R)-22-fluoro-10-(5-fluoro-13-oxo-1,12,18- triazatetracyclo[10.6.1.02,7.016,19]nonadeca-2(7),3,5,14,16(19),17-hexaen-15-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 8 by using intermediate tert-butyl-but-3-ynoxy-dimethyl-silane instead of tert-butyldimethyl(2- propynyloxy)silane in step 2. Example 16 (5.2 mg), LCMS (M+H)+: 720,1H NMR (400 MHz, METHANOL-d4) δ = 7.89 (t, J = 7.9 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.36 - 7.28 (m, 2H), 7.25 - 7.16 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.19 - 6.09 (m, 1H), 4.85 (m, 3H), 4.60 (br s, 1H), 4.43 - 4.30 (m, 3H), 4.04 - 3.93 (m, 1H),3.42 - 3.37 (m, 2H), 3.11 (br s, 3H), 3.08 - 3.01 (m, 6H), 2.99 (d, J = 1.9 Hz, 3H), 2.64 - 2.63 (m, 1H), 2.64 - 2.55 (m, 2H), 1.98 - 1.89 (m, 1H), 1.85 - 1.71 (m, 2H), 1.69 - 1.58 (m, 1H). Example 17 (14S)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-10-oneThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl (3R)-3-(iodomethyl)pyrrolidine-1-carboxylate (compound 17a) To a solution of TPP (5.1 g, 19.38 mmol) and 1H-imidazole (1.3 g, 19.38 mmol) in DCM (50 mL) was slowly added iodine (4.9 g, 19.38 mmol) at 0 °C. After 30 mins, a solution of tert- butyl-(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.0 g, 14.91 mmol) in DCM (10 mL) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated and purified via silica gel column to give the desired compound 17a (3 g) as a colorless oil. Step 2: preparation of ethyl 2-[2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoro-phenoxy]acetate (compound 17b) To a solution of compound 42c (19 g, 63.4 mmol), ethyl glycolate (7.9 g, 76.25 mmol) and TPP (26.7g, 16.05 mmol) in toluene (890 mL) was added diisopropyl azodicarboxylate (2.9 mL, 15.05 mmol) dropwise at 0 °C. The solution was stirred at 90 °C for 1 hr under N2 atmosphere. The mixture was concentrated and purified via column chromatography to give compound 17b (14 g) as a white solid. LCMS (M+H)+: 385. Step 3: preparation of ethyl 2-[2-(4-benzyloxy-6-chloro-pyrazolo[3,4-d]pyrimidin-1- yl)-5-fluoro-phenoxy]acetate (compound 17c) To a solution of benzyl alcohol (7 g, 20 mmol) in THF (85 mL) was added potassium tert- butoxide (20 mL, 20 mmol) at -78 °C. The mixture was warmed to 15 °C and stirred for 0.5 hrs. Then it was heated to 70 °C and stirred for another 0.5 hr under N2 atmosphere. The mixture was cooled and added into a solution of compound 17b (7 g, 1.3mmol) in THF (85 mL) at 0 °C under an inert atmosphere. The final reaction was warmed slowly to ambient temperature and stirred for 1 hr. The mixture was poured into water (1500 mL) and extracted with ethyl acetate (1500mL × 3). The organic layer was washed with brine (1500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 17c (6.8 g) as a colorless oil. LCMS (M+H)+: 457. Step 4: preparation of tert-butyl (3S)-3-[[4-benzyloxy-1-[2-(2-ethoxy-2-oxo-ethoxy)-4- fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]pyrrolidine-1-carboxylate (compound 17d) To a solution of compound 17c (1.5 g, 3.3mmol), compound 17a (1328 mg, 0.85 mmol) in DME 30 mL) was added Ir[dF(CF3)ppy]2(dtbpy)(PF6) (11 mg, 0.05 mmol), NiCl2(dtbbpy) (2 mg, 0.01mmol), TTMSS (250 mg, 3.3 mmol), Na2CO3(212 mg, 6.55 mmol). The reaction was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 14 hrs. The mixture was filtered, the filtrate was concentrated to give compound 17d (2.4 g) as a yellow oil. LCMS (M+H)+: 606. Step 5: preparation of 2-[2-[6-[[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]methyl]-4- ethoxy-pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-phenoxy]acetic acidified (compound 17e) To a solution of compound 17d (2 g, 2.7 mmol) in ethanol (10 mL) and THF (10 mL) was added a solution of LiOH•H2O (740 mg, 17 mmol) in water (10 mL) at 0 °C. The reaction was stirred at 20 °C for 2 hrs. The mixture was concentrated to give compound 17e (3 g) as a yellow solid. LCMS (M+H)+: 578. Step 6: preparation of 2-[5-fluoro-2-[4-hydroxy-6-[[(3S)-pyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-1-yl]phenoxy]acetic acid (compound 17f) To a solution of compound 17e (1.3 g, 2.52 mmol) in DCM (10 mL) was added TFA (10.0 mL) at 0 °C. The reaction was warmed to 25 °C and stirred for 2 hrs. The mixture was concentrated and purified via prep-HPLC to afford compound 17f (0.7 g) as a yellow solid. LCMS (M+H)+: 388. Step 7: preparation of (14S)-5-fluoro-18-hydroxy-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2,4,6,16,18,20,22-heptaen-10-one (compound 17g) To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (933 mg, 1.14 mmol), DIEA (507 mg, 2.28 mmol) in DMF (190 mL) was added drop-wise a solution of compound 17f (380 mg, 1mmol) in DMF (1500 mL) at 20 °C. The reaction was stirred at 25 °C for 1 hr and concentrated. The residue was purified via prep-HPLC to give compound 17g (380 mg) as a yellow solid. LCMS (M+H)+: 370. Step 8: preparation of (14S)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2,4,6,16,18,20,22-heptaen-10-one (Example 17) To a solution of compound 17g (10 mg, 0.03 mmol), intermediate C6 (12 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (20 µL, 0.14 mmol) and PyBop (31 mg, 0.06 mmol). The reaction was stirred at 60 °C for 12 hrs. The mixture was concentrated and purified via prep- HPLC to give Example 17 (3 mg) as a white solid. LCMS (M+H)+: 790,1H NMR (400 MHz, METHANOL-d4) δ = 8.41 (s, 1H), 7.83 - 7.62 (m, 2H), 7.31 - 7.09 (m, 4H), 6.96 (br t, J = 8.1 hrz, 1H), 6.72 - 6.65 (m, 1H), 5.82 - 5.65 (m, 1H), 5.51 - 5.32 (m, 1H), 4.71 - 4.63 (m, 2H), 4.59 (s, 2H), 4.51 - 4.46 (m, 1H), 4.28 (br d, J = 11.5 Hz, 1H), 4.14 (br d, J = 4.3 Hz, 1H), 3.95 - 3.89 (m, 1H), 3.12 - 3.05 (m, 3H), 2.89 - 2.83 (m, 5H), 2.61 - 2.55 (m, 4H), 2.50 (br d, J = 4.0 Hz, 1H), 2.24 - 2.16 (m, 1H), 2.10 (br dd, J = 7.7, 13.4 Hz, 1H), 1.90 - 1.84 (m, 1H), 1.66 - 1.54 (m, 1H), 1.35 - 1.29 (m, 4H). Example 18 (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 5-amino-1-(4-fluoro-2-methoxy-phenyl) pyrazole-4- carboxylate (compound 18a) To a solution of compound 41b (11 g, 25.96 mmol) in ethanol (50 mL) was added ethyl 2- cyano-3-ethoxy-prop-2-enoate (11.6 g, 68.53 mmol) and DIEA (20.2 mL, 51.92 mmol) at 25 °C. The reaction solution was heated to 90 °C and stirred for 16 hrs. The reaction mixture was concentrated and purified via flash chromatography to afford compound 18a (11 g) as a red solid. LCMS (M+H)+: 280. Step 2: preparation of ethyl 5-amino-1-(4-fluoro-2-hydroxy-phenyl)pyrazole-4- carboxylate (compound 18b) To a solution of compound 18a (4.0 g, 14.32 mmol) in DCM (60 mL) was added BCl3 / DCM (71.6 mL, 71.62 mmol) at -78 °C. The mixture was stirred at 0 °C for 0.5 hr and at 25 °C for 16 hrs. The reaction was quenched with ice-water (120 mL) and extracted with DCM (50 mL × 3). The organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound 18b (2.8 g) as a yellow solid. LCMS (M+H)+: 266. Step 3: preparation of ethyl 5-[(2-chloroacetyl) amino]-1-(4-fluoro-2-hydroxy-phenyl) pyrazole-4-carboxylate (compound 18c) To a solution of compound 18b (1.8 g, 6.84 mmol) in chloroform (40 mL) was added chloroacetyl chloride (805 mg, 3.96 mmol) at 25 °C under N2 atmosphere. The reaction solution was stirred at 65 °C for 3 hrs. The mixture was poured into water (40 ml) and extracted with DCM (40 mL × 2). The combined organic layer was washed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated to give a crude compound 18c (2.9 g) as a yellow solid. LCMS (M+H)+: 342.Step 4: preparation of ethyl 13-fluoro-8-oxo-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6] pentadeca-1(11),3,5,12,14-pentaene-5-carboxylate (compound 18d) To a solution of compound 18c (2.2 g, 6.44 mmol) in ACN (3000 mL) was added cesium carbonate (3146 mg, 9.66 mmol) at 0 °C. The reaction was stirred at 40 °C for 24 hrs and filtered. The filtrate was concentrated to give crude compound 18d (2.4 g) as a yellow solid. LCMS (M+H)+: 306. Step 5: preparation of ethyl 13-fluoro-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carboxylate (compound 18e) To a solution of compound 18d (1200 mg, 3.96 mmol) in THF (12 mL) was added BH3•THF (40 mL, 40 mmol) at -15 °C. The mixture was stirred at the temperature for 1 hr. The reaction was quenched by methanol (2 mL) and stirred for another 1 hr. The solution was concentrated and purified via flash silica gel chromatography to give compound 18e (55 mg) as a white solid. LCMS (M+H)+: 292. Step 6: preparation of 13-fluoro-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carboxylic acid (compound 18f) To a solution of compound 18e (10 mg, 0.03 mmol) in methanol (0.1 mL) was added a solution of NaOH (13 mg, 0.34 mmol) in water (0.1 mL) at 0 °C. The reaction was warmed to 40 ºC and stirred for 2 hrs. The reaction solution was acidified with AcOH to pH 5 ~ 6 and filtered, the collected solid was dried to give compound 18f (3 mg) as a white solid. LCMS (M+H)+: 264. Step 7: preparation of (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3,7- triazatricyclo[9.4.0.02,6]pentadeca-1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 18) To a solution of compound 18f (3 mg, 0.01 mmol) in ACN (0.5 mL) was added DIPEA (10 µL, 0.07 mmol) and HATU (8 mg, 0.03 mmol). The reaction was stirred at 20 °C for 0.5 hr and intermediate C6 (6 mg, 0.01 mmol) was added. The mixture was stirred at 20 °C for 1 hr and purified via prep-HPLC to give Example 18 (0.7 mg) as a white solid. LCMS (M+H)+: 684. Example 19 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17, 19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen- 12-oneThe title compound was prepared in analogy to the preparation of example 14 by using compound 41c instead of compound 14a in step 2. Example 19 (9.6 mg), LCMS (M+H)+: 749,1H NMR (400 MHz, METHANOL-d4) δ = 8.58 (s, 1H), 7.97 - 7.86 (m, 1H), 7.72 - 7.56 (m, 3H), 7.25 - 7.15 (m, 1H), 7.12 - 7.04 (m, 1H), 7.00 - 6.93 (m, 1H), 6.81 (br d, J = 7.9 Hz, 1H), 6.19 - 6.08 (m, 1H), 5.61 (br d, J = 7.6 Hz, 1H), 4.73 (br s, 1H), 4.62 - 4.54 (m, 1H), 4.46 - 4.24 (m, 2H), 4.09 (br s, 2H), 4.03 - 3.93 (m, 1H), 3.17 (s, 2H), 3.08 (s, 3H), 2.98 (s, 6H), 2.83 (br d, J = 6.1 hrz, 4H), 2.79 - 2.67 (m, 2H), 2.66 - 2.54 (m, 2H), 1.68 - 1.57 (m, 2H), 1.53 - 1.40 (m, 2H). Example 20 (15R)-5-fluoro-19-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,12,18,22,24-pentazapentacyclo [15.5.2.112,15.02,7.020,23]pentacosa-2(7),3,5,17(24),18,20(23),21-heptaen-11-oneThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl-[3-[2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoro-phenoxy]propoxy]-dimethyl-silane (compound 20a) To a solution of compound 42c (400 mg, 1.34 mmol), 3-[tert-butyl(dimethyl)silyl] oxypropan-1-ol (1018 mg, 5.35 mmol) and triphenylphosphane (526 mg, 2.01 mmol) in toluene (12 mL) was added diisopropyl azodicarboxylate (320 µL, 1.6 mmol) at 0 °C. The reaction mixture was stirred at 90 °C for 1 hr and concentrated. The residue was purified via column chromatography to give compound 20a (1000 mg) as a yellow solid. LCMS (M+H)+: 471. Step 2: preparation of 3-[2-(4-benzyloxy-6-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoro-phenoxy]propoxy-tert-butyl-dimethyl-silane (compound 20b) To a solution of benzyl alcohol (72 mg, 0.67 mmol) in THF (3 mL) was added potassium tert-butoxide (670 µL, 0.67 mmol) at 0 °C. The reaction was warmed to 15 °C and stirred for 0.1 hr. Then it was stirred at 70 °C for 0.5 hr under N2 atmosphere. To a solution of compound 20b (300 mg, 0.64 mmol) in THF (3 mL) was added the above solution at -78 °C under an inert atmosphere. The reaction mixture was warmed slowly to 15 °C and stirred for 1 hr. The reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layer was washed brine (5 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified via flash column to give compound 20b (360 mg) as a colorless oil. LCMS (M+H)+: 543.Step 3: preparation of tert-butyl (3R)-3-[[4-benzyloxy-1-[2-[3-[tert- butyl(dimethyl)silyl]oxypropoxy]-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-6- yl]methyl]pyrrolidine-1-carboxylate (compound 20c ) The mixture of compound 20b (200 mg, 0.37 mmol), tert-butyl (3S)-3- (iodomethyl)pyrrolidine-1-carboxylate (149 mg, 0.48 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (4 mg, 0.0 mmol), NiCl2(dtbbpy) (2 mg, 0.0 mmol), TTMSS (91 mg, 0.37 mmol), Na2CO3(78 mg, 0.74 mmol) in DME (4 mL) was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 14 hrs. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with brine (10 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified via flash silica gel chromatography to give compound 20c (300 mg) as a colorless oil. LCMS (M+H)+: 692. Step 4: preparation of tert-butyl (3R)-3-[[4-benzyloxy-1-[4-fluoro-2-(3- hydroxypropoxy)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]pyrrolidine-1-carboxylate (compound 20d ) To a solution of compound 20c (150 mg, 0.22 mmol) in DMF (3 mL) was added CsF (329 mg, 2.17 mmol). The reaction was stirred at 60 °C for 2 hrs. The mixture was poured into water (5 mL), extracted with EtOAc (5 mL × 2). The combined organic layer was washed with brine (5 mL × 2), dried over Na2SO4, filtered and concentrated to give the crude compound 20d (300 mg) as a yellow oil, which was used directly in the next step. LCMS (M+H)+: 578. Step 5: 3-[2-[4-benzyloxy-6-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-phenoxy]propanoic acid (compound 20e) To a solution of compound 20d (50 mg, 0.09 mmol) in DCM (0.6 mL) and water (0.2 mL) was added TEMPO (2 mg, 0.01 mmol) and (diacetoxyiodo)benzene (55 mg, 0.17 mmol). The reaction was stirred at 25 °C for 4 hrs. The mixture was poured into water (2 ml) and extracted with DCM (2 mL × 2). The combined organic layer was washed with brine (2 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified via prep-TLC to give compound 20e (14 mg) as a yellow oil. LCMS (M+H)+: 592. Step 6: preparation of 3-[5-fluoro-2-[4-hydroxy-6-[[(3R)-pyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-1-yl]phenoxy]propanoic acid (compound 20f) To a solution of compound 20e (60 mg, 0.1 mmol) in DCM (1 mL) was added TFA (1 mL, 0.2 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 hrs. The mixture was concentrated and lyophilized to afford compound 20f (60 mg) as red oil. LCMS (M+H)+: 402.Step 7: preparation of (15R)-5-fluoro-19-hydroxy-8-oxa-1,12,18,22,24- pentazapentacyclo[15.5.2.112,15.02,7.020,23]pentacosa-2(7),3,5,17(24),18,20(23),21-heptaen-11- one (compound 20g) To a solution of HATU (83 mg, 0.22 mmol) and DIPEA (60 µL, 0.35 mmol) in DMF (20 mL) was added dropwise a solution of compound 20f (45 mg, 0.09 mmol) in DMF (60 mL) at 20 °C. The reaction was stirred at 20 °C for 1 hr and concentrated. The residue was purified via reversed phase HPLC to give compound 20g (30 mg) as a white solid. LCMS (M+H)+: 384. Step 8: preparation of (15R)-5-fluoro-19-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,12,18,22,24-pentazapentacyclo [15.5.2.112,15.02,7.020,23]pentacosa-2(7),3,5,17(24),18,20(23),21-heptaen-11-one (Example 20) To a solution of intermediate C6 (24 mg, 0.06 mmol) in DMF (0.5 mL) was added compound 20g (28 mg, 0.06 mmol), PyBop (38 mg, 0.07 mmol) and DIEA (20 µL, 0.14 mmol). The reaction was stirred at 20 °C for 2 hrs and purified via prep-HPLC to give Example 20 (7 mg) as a white solid. LCMS (M+H)+: 804,1H NMR (400 MHz, METHANOL-d4) δ = 8.49 (m, 1H), 7.88 - 7.86 (m, 1H), 7.60 - 7.57 (m, 3H), 7.56 - 7.53 (m, 2H), 7.17 - 7.15 (m, 1H), 6.92 - 6.77 (m, 1H), 6.23 - 6.08 (m, 1H), 5.61 (br d, J = 7.6 Hz, 1H), 4.88 (br s, 2H), 4.83 - 4.70 (m, 2H), 4.55 – 4.5 (m, 1H), 4.31 - 4.27 (m, 3H), 3.80 (br s, 2H), 3.32 - 3.30 (m, 1H), 3.29-3.07 (m, 5H), 3.08 (s, 5H), 2.98 (s, 6H), 2.57 - 2.54 (m, 2H), 2.15 - 2.10 (m, 2H). Example 21 (6S)-17-fluoro-25-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-14-oxa-2,8,21,22,26,27-hexazahexacyclo [19.5.2.02,6.08,12.015,20.024,28]octacosa-1(26),15(20),16,18,22,24,27-heptaen-7-oneThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl 2-[[2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoro-phenoxy]methyl]pyrrolidine-1-carboxylate (compound 21a) To a solution of compound 42c (3.6 g, 12 mmol), tert-butyl 2-(hydroxymethyl)pyrrolidine- 1-carboxylate (2.9 g, 14.44 mmol) and PPh3 (5.0 g, 19.26 mmol) in toluene (20 mL) was added dropwise diisopropyl azodicarboxylate (3.6 g, 18.06 mmol) at 0 °C under N2 atmosphere. The reaction solution was heated to 90 °C and stirred for 1 hr. The mixture was concentrated and purified via flash chromatography to give compound 21a (1.2 g) as a light yellow gum. LCMS (M+H)+: 483. Step 2: preparation of tert-butyl 2-[[2-(4-benzyloxy-6-chloro-pyrazolo[3,4- d]pyrimidin-1-yl)-5-fluoro-phenoxy]methyl]pyrrolidine-1-carboxylate (compound 21b) To a solution of benzyl alcohol (280 mg, 2.6 mmol) in THF (10 mL) was added potassium tert-butoxide (2.6 mL, 2.6 mmol) at 0 °C, then warmed to 20 °C and stirred for 0.1 hr. The reaction was stirred at 70 °C for 1 hr under N2atmosphere. To a solution of compound 21a (1.2 g, 2.6mmol) in THF (10 mL) was added to above solution at -78 °C under an inert atmosphere. The mixture was warmed slowly to 25 °C and stirred for 1 hr. The reaction was quenched with cold water (200 mL) and extracted with EA (2 × 50 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to give a crude compound 21b (1.2 g) as a white solid. LCMS (M+H)+: 554. Step 3: preparation of tert-butyl 2-[[2-[4-benzyloxy-6-[(2S)-2-tert- butoxycarbonylpyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro- phenoxy]methyl]pyrrolidine-1-carboxylate (compound 21c)To a solution of compound 21b (1.2 g, 2.08 mmol) and DIEA (1.1 mL, 6.23 mmol) in DMF (10 mL) was added tert-butyl-(2S)-pyrrolidine-2-carboxylate hydrochloric acid (517 mg, 2.49 mmol) at 25 °C under an inert atmosphere. The reaction solution was warmed to 60 °C and stirred for 8 hrs. The reaction was quenched with water (100 mL) and extracted with EA (2 × 50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4and concentrated to give compound 21c (1.6 g) as a light yellow gum. LCMS (M+H)+: 689. Step 4: preparation of (2S)-1-[1-[4-fluoro-2-(pyrrolidin-2-ylmethoxy)phenyl]-4- hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylic acid (compound 21d) To a solution of compound 21c (1420 mg, 2.06 mmol) in DCM (15 mL) was added TFA (15 mL, 4.12 mmol) at 0 °C. The reaction was warmed to 20 °C and stirred for 2 hrs. The mixture was concentrated and purified via prep-HPLC to afford compound 21d (740 mg) as a yellow oil. LCMS (M+H)+: 443. Step 5: preparation of (6S)-17-fluoro-25-hydroxy-14-oxa-2,8,21,22,26,27- hexazahexacyclo[19.5.2.02,6.08,12.015,20.024,28]octacosa-1(26),15(20),16,18,22,24,27-heptaen-7- one (compound 21e) To a solution of compound 21d (100 mg, 0.18 mmol) and HATU (63 mg, 0.27 mmol) in ACN (15 mL) was added a solution of DIEA (90 µL, 0.54 mmol) in ACN (3 mL) dropwise at 25 °C. The reaction mixture was stirred at 25 °C for 1 hr and concentrated. The residue was purified via prep-HPLC to afford compound 21e (25 mg) as a white solid. LCMS (M+H)+: 425. Step 6: preparation of (6S)-17-fluoro-25-[rac-(8S,11S,15R)-22-fluoro-15-methoxy- 13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-14-oxa-2,8,21,22,26,27-hexazahexacyclo [19.5.2.02,6.08,12.015,20.024,28]octacosa-1(26),15(20),16,18,22,24,27-heptaen-7-one (Example 21) To a solution of intermediate C6 (20 mg, 0.05 mmol) and compound 21e (20 mg, 0.03 mmol) in DMF (1 mL) was added DIEA (61.4 µL, 0.37 mmol), PyBop (48 mg, 0.09 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hrs and purified via prep-HPLC to give Example 21 (5 mg) as a white solid. LCMS (M+H)+: 845,1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.65 - 7.43 (m, 3H), 7.24 (dd, J = 2.4, 10.4 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.98 (tdd, J = 2.7, 5.6, 8.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.23 - 6.02 (m, 1H), 5.62 - 5.39 (m, 1H), 4.81 (br s, 1H), 4.75 - 4.67 (m, 1H), 4.63 (br s, 2H), 4.51 (br dd, J = 5.9, 11.5 Hz, 2H), 4.42 - 4.28 (m, 2H), 4.27 - 4.12 (m, 1H), 4.04 - 3.81 (m, 3H), 3.73 - 3.40 (m, 5H), 3.30 - 3.23 (m, 2H), 3.22 - 3.14 (m, 2H), 3.13 - 3.04 (m, 3H), 3.04 - 2.93 (m, 4H), 2.88 (br d, J = 13.8 Hz, 1H), 2.84 - 2.76 (m, 3H), 2.72 - 2.50 (m, 2H)Example 22 and Example 23 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen- 19-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-10-[(15S)-5-fluoro-8,14-dioxa-1,11,18,22,24-pentazapentacyclo [15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:The compound 22a was prepared in analogy to the preparation of example 17g by using tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate instead of tert-butyl-(3R)-3- (hydroxymethyl)pyrrolidine-1-carboxylate in step 1.Step 1: preparation of 5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-ol (compound 22b) To a solution of compound 22a (150 mg, 0.39 mmol) in THF (4 mL) was added BH3 / THF (3.9 mL, 3.9 mmol) at 0 °C. The reaction solution was stirred at 25 °C for 6 hrs. The reaction was quenched with 5 mL methanol dropwise at 0 °C and then stirred at 60 °C for 1 hr. The mixture was concentrated to give compound 22b (144 mg) as a white solid. LCMS (M+H)+: 372. Step 2: preparation of 19-chloro-5-fluoro-8,14-dioxa-1,11,18,22,24-pentazapentacyclo [15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaene (compound 22c) A solution of compound 22b (144 mg, 0.39 mmol) in phosphorus oxychloride (6.0 mL, 64.37 mmol) was stirred at 90 °C for 16 hrs. The mixture was poured into sat. NaHCO3 aq. (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified via prep- TLC to afford compound 22c (54 mg) as a light green solid. LCMS (M+H)+: 390. Step 3: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 22d) To a solution of intermediate C6 (50 mg, 0.11 mmol) and compound 22c (45 mg, 0.11 mmol) in ACN (1 mL) was added DIPEA (44 mg, 0.34 mmol) at 25 °C. The reaction solution was stirred at 80 °C for 1 hr and concentrated to afford compound 22d (90 mg) as a dark brown gum. LCMS (M+H)+: 792. Step 4: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(15R)-5- fluoro-8,14-dioxa-1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa- 2,4,6,17,19,21,23-heptaen-19-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(15S)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo [15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen- exa19-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 22 and Example 23) The compound 22d (90 mg, 0.11 mmol) was separated via SFC (Instrument: Waters 150Q; DAICEL CHIRALPAK IC (250mm×30mm, 10um), Mobile Phase: 60% MeOH:ACN (0.1%NH3in H2O) in Supercritical CO2; Flow Rate: 120 g / min; Cycle Time: 4.1 min, totaltime:80 min; Single injection volume: 1.0 ml; Back Pressure: 100 bar to keep the CO2 in Supercritical flow) to give two crude isomers Example 22 (faster eluted) and Example 23 (slower eluted). Then they were purified via prep-HPLC to give Example 22 (42 mg) and Example 23 (36 mg) as a white solid. Example 22: LCMS (M+H)+: 792,1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.65 - 7.43 (m, 3H), 7.24 (dd, J = 2.4, 10.4 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.98 (tdd, J = 2.7, 5.6, 8.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.23 - 6.02 (m, 1H), 5.62 - 5.39 (m, 1H), 4.81 (br s, 1H), 4.75 - 4.67 (m, 1H), 4.63 (br s, 2H), 4.51 (br dd, J = 5.9, 11.5 Hz, 2H), 4.35 - 4.23 (m, 2H), 3.96 - 3.88 (m, 2H), 3.73 - 3.40 (m, 5H), 3.30 - 3.22 (m, 2H), 3.22 - 3.13 (m, 2H), 3.12 - 3.02 (m, 3H), 3.00 - 2.96 (m, 3H), 2.88 (br d, J = 13.8 Hz, 1H), 2.84 - 2.76 (m, 3H), 2.72 - 2.50 (m, 2H) Example 23: LCMS (M+H)+: 792,1H NMR (400 MHz, METHANOL-d4) δ = 8.52 (s, 1H), 7.93 - 7.86 (m, 1H), 7.60 (dd, J = 2.5, 7.3 Hz, 1H), 7.58 - 7.45 (m, 2H), 7.24 (dd, J = 2.4, 10.4 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.03 - 6.94 (m, 1H), 6.85 - 6.76 (m, 1H), 6.22 - 6.04 (m, 1H), 5.63 - 5.37 (m, 1H), 4.83 (br s, 1H), 4.75 - 4.70 (m, 1H), 4.62 (br s, 2H), 4.60 - 4.50 (m, 2H), 4.31 - 4.21 (m, 2H), 3.92 (br dd, J = 9.0, 14.4 Hz, 2H), 3.71 - 3.40 (m, 5H), 3.30 - 3.22 (m, 2H), 3.21 - 3.13 (m, 2H), 3.11 - 3.05 (m, 3H), 2.98 - 2.96 (m, 1H), 3.01 - 2.96 (m, 2H), 2.88 (br d, J = 13.6 Hz, 1H), 2.85 - 2.77 (m, 3H), 2.68 - 2.50 (m, 2H). Example 24 (14R)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20 (24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-10-oneThe title compound was prepared in analogy to the preparation of example 17 by using tert-butyl -(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl -(3S)-3- (iodomethyl)pyrrolidine-1-carboxylate (compound 17a) in step 3. Example 24 (0.8 mg), LCMS (M+H)+: 790,1H NMR (400 MHz, METHANOL-d4) δ = 8.40 (s, 1H), 8.00 (s, 1H), 7.86 - 7.78 (m, 1H), 7.64 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.74 - 6.64 (m, 1H), 5.51 (d, J = 8.5 Hz, 1H), 4.71 - 4.66 (m, 2H), 4.59 (br s, 2H), 4.52 - 4.48 (m, 1H), 4.28 - 4.25 (m, 1H), 4.17 - 4.10 (m, 1H), 3.93 - 3.87 (m, 1H), 3.45 (br d, J = 2.4 Hz, 3H), 3.35 (br d, J = 2.5 Hz, 3H), 3.13 (s, 1H), 3.05 (s, 3H), 2.93 - 2.86 (m, 3H), 2.84 (s, 3H), 2.69 - 2.63 (m, 1H), 2.62 (br d, J = 7.0 Hz, 1H), 2.58 (s, 2H), 2.54 - 2.46 (m, 2H). Example 25 (6S)-14-fluoro-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8,11-dioxa-2,18,19,23,24- pentazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(24),12,14,16,19,21(25),22-heptaen-7- oneThe title compound was prepared according to the following scheme:The compound 25a was prepared in analogy to the preparation of example 21c by using 2- [tert-butyl(dimethyl)silyl]oxyethanol instead of tert-butyl 2-(hydroxymethyl)pyrrolidine-1- carboxylate in step 1. Step 1: preparation of (2S)-1-[1-[4-fluoro-2-[2-(2,2,2-trifluoroacetyl)oxyethoxy] phenyl]-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylic acid (compound 25b) To a solution of compound 25a (1.0 g, 1.51 mmol) in DCM (10 mL) was added TFA (20 mL) at 0 °C. The reaction was stirred at 20 °C for 12 hrs. The mixture was concentrated to give compound 25b (2 g) as a brown oil. LCMS (M+H)+: 500. Step 2: preparation of (2S)-1-[1-[4-fluoro-2-(2-hydroxyethoxy)phenyl]-4-hydroxy- pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylic acid (compound 25c) To a solution of compound 25b (2.0 g, 4.01 mmol) in THF (20 mL) was added LiOH•H2O (10 mL, 20.0 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 hr. The mixture was acidified with HCl aq. (1 M) to pH around 6 ~ 7. The solution was concentrated to remove the THF and the residue was purified via flash-HPLC to give compound 25c (300 mg) as a white solid. LCMS (M+H)+: 404.Step 3: preparation of methyl (2S)-1-[1-[4-fluoro-2-(2-hydroxyethoxy) phenyl]-4- hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylate (compound 25d) To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (424 mg, 1.12 mmol), N,N-diisopropylethylamine (0.3 mL, 1.79 mmol) in DMF (39 mL) was added a solution of compound 25c (180 mg, 0.45 mmol) in DMF (78 mL) at 20 °C. The reaction was stirred at 20 °C for 1 hr. The mixture was purified twice via prep-TLC and prep-HPLC to give by-product compound 25d (100 mg) as a yellow solid. LCMS (M+H)+: 418. Step 4: preparation of methyl (2S)-1-[1-[4-fluoro-2-(2-hydroxyethoxy)phenyl]-4- [(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylate (compound 25e) To a solution of compound 25d (100 mg, 0.24 mmol), PyBop (312 mg, 0.6 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (130 µL, 0.72 mmol) and intermediate C6 (114 mg, 0.24 mmol). The reaction was stirred at 20 °C for 15 hrs. The mixture was purified via prep- HPLC to give compound 25e (25 mg) as a yellow oil. LCMS (M+H)+: 838. Step 5: preparation of (2S)-1-[1-[4-fluoro-2-(2-hydroxyethoxy)phenyl]-4-[rac- (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]pyrrolidine-2-carboxylic acid (compound 25f) To a solution of compound 25e (25 mg, 0.03 mmol) in DCE (0.5 mL) was added Me3SnOH (100 mg, 0.55 mmol). The reaction was stirred at 60 °C for 15 hrs. The mixture was diluted with DCM (40 mL) and filtered. The filtrate was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to give compound 25f (30 mg) as a yellow oil. LCMS (M+H)+: 824. Step 6: preparation of (6S)-14-fluoro-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8,11-dioxa-2,18,19,23,24- pentazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(24),12,14,16,19,21(25),22-heptaen-7- one (Example 25) To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35 mg, 0.09 mmol), N,N-diisopropylethylamine (30 µL, 0.15 mmol) in DMF (10 mL) was added a solution of compound 25i (30 mg, 0.04 mmol) in DMF (20 mL) at 0°C. The reaction was stirred at 20 °C for 1 hr. The mixture was concentrated and purified via prep-HPLC to give Example 25 (10 mg) as a white solid. LCMS (M+H)+: 806.1H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.82 - 7.76 (m, 1H), 7.44 - 7.35 (m, 2H), 7.22 (br d, J = 11.1 hrz, 1H), 7.15 - 7.06 (m, 2H), 6.94 - 6.87 (m, 1H), 6.72 - 6.60 (m, 1H), 5.61 - 5.53 (m, 1H), 5.40 - 5.25 (m, 1H), 4.30 - 3.97 (m, 4H), 3.88 - 3.72 (m, 2H), 3.47 - 3.41 (m, 2H), 3.32 (s, 3H), 3.02 (s, 2H), 2.96 (s, 2H), 2.86 (br t, J = 14.8 Hz, 2H), 2.76 (d, J = 6.8 Hz, 2H), 2.72 (d, J = 3.5 Hz, 2H), 2.69 - 2.65 (m, 1H), 2.49 - 2.46 (m, 3H), 2.41 - 2.36 (m, 1H), 2.31 - 2.24 (m, 1H), 1.99 - 1.91 (m, 2H). Example 26 (8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-3,6-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),2,4,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl 3-(5-benzyloxypentyl)imidazole-4-carboxylate (compound 26a) To a solution of methyl 1H-imidazole-5-carboxylate (100 mg, 0.79 mmol), 5- benzyloxypentan-1-ol (154 mg, 0.79 mmol), triphenylphosphine (270 mg, 1.03 mmol) in toluene (2 mL) was added diisopropyl azodicarboxylate (230 µL, 1.19 mmol) at 0 °C under N2atmosphere. The reaction was stirred at 100 °C for 2 hrs. The mixture was concentrated and purified via prep-HPLC to give compound 26a (100 mg) as a colorless oil. LCMS (M+H)+: 303. Step 2: preparation of methyl 3-(5-benzyloxypentyl)-2-iodo-imidazole-4-carboxylate (compound 26b) To a solution of compound 26a (400 mg, 1.32 mmol) in carbon tetrachloride (1 mL) was added 2,2'-azobis(2-methylpropionitrile) (43 mg, 0.26 mmol) and N-iodosuccinimide (595 mg, 2.65 mmol). The reaction was stirred at 50 °C for 12 hrs. The mixture was concentrated and purified via flash column to give compound 26b (180 mg) as a yellow oil. LCMS (M+H)+: 429. Step 3: preparation of methyl 3-(5-benzyloxypentyl)-2-(4-fluoro-2-methoxy- phenyl)imidazole-4-carboxylate (compound 26c) To a solution of compound 26b (700 mg, 1.63 mmol) in 1,4-dioxane (10 mL) was added 4- fluoro-2-methoxyphenyl boronic acidified (417 mg, 2.45 mmol), Pd(PPh3)4(189 mg, 0.16 mmol) and Na2CO3(515 mg, 4.9 mmol). The reaction mixture was purged with N2for 3 times and stirred at 80 °C for 12 hrs under N2 atmosphere. The mixture was filtrated and the filtrate wasconcentrated. The residue was purified via prep-TLC to give compound 26c (300 mg) as colorless oil. LCMS (M+H)+: 427. Step 4: preparation of methyl 2-(4-fluoro-2-hydroxy-phenyl)-3-(5-hydroxypentyl) imidazole-4-carboxylate (compound 26d) To a solution of compound 26c (300 mg, 0.7 mmol) in DCM (5 mL) was added BCl3 / DCM (3.5 mL, 3.52 mmol) at -78 °C. The reaction was stirred at 20 °C for 14 hrs. The mixture was poured into cold water (20 mL) and DCM (100 mL). The two layers were separated and the water layer was extracted with DCM (100 mL × 5). The combined organic layer was concentrated and purified via prep-TLC to give compound 26d (80 mg) as a colorless oil. LCMS (M+H)+: 323. Step 5: preparation of methyl 15-fluoro-12-oxa-3,6-diazatricyclo[11.4.0.02,6] heptadeca-1(17),2,4,13,15-pentaene-5-carboxylate (compound 26e) To a solution of compound 26d (40 mg, 0.12 mmol), triphenylphosphine (81 mg, 0.31 mmol) in DCM (1.5 mL) was added diisopropyl azodicarboxylate (60 µL, 0.31 mmol) at 0 °C. The reaction was stirred at 20 °C for 12 hrs. The mixture was concentrated and purified via prep- TLC to give compound 26e (30 mg) as a yellow oil. LCMS (M+H)+: 305. Step 6: preparation of 15-fluoro-12-oxa-3,6-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),2,4,13,15-pentaene-5-carboxylic acid (compound 26f) To a solution of compound 26e (30 mg, 0.1 mmol) in THF (0.2 mL) and ethanol (0.2 mL) was added a solution of LiOH•H2O (12 mg, 0.49 mmol) in water (0.2 mL) at 0 °C. The reaction was stirred at 20 °C for 12 hrs. The mixture was concentrated and purified via prep-HPLC (TFA as additive) to give compound 26f (10 mg) as a white solid. LCMS (M+H)+: 291. Step 7: preparation of (8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-3,6- diazatricyclo[11.4.0.02,6]heptadeca-1(17),2,4,13,15-pentaene-5-carbonyl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 26) To a solution of compound 26f (10 mg, 0.03 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (29 mg, 0.08 mmol) and N,N-diisopropylethylamine (20 µL, 0.1 mmol) in DMF (0.15 mL) was added a solution of intermediate C6 (15 mg, 0.03 mmol) in DMF (150 µL). The reaction was stirred at 20 °C for 1 hr. The mixture was purified via prep-HPLC to give Example 26 (7 mg) as a white solid. LCMS (M+H)+: 711,1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 1H), 7.90 - 7.81 (m, 1H), 7.58 - 7.48 (m, 3H), 7.25 (br dd, J = 2.4, 10.3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.07 - 6.99 (m, 1H), 6.77 - 6.67 (m, 1H), 6.20 -6.05 (m, 1H), 5.20 (br d, J = 8.8 Hz, 1H), 4.99 - 4.93 (m, 1H), 4.52 (br d, J = 3.9 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.38 - 4.31 (m, 1H), 4.30 - 4.08 (m, 3H), 4.08 - 3.90 (m, 2H), 2.99 (d, J = 17.6 Hz, 3H), 2.92 (br d, J = 1.5 Hz, 2H), 2.85 (s, 3H), 2.78 (br d, J = 13.7 Hz, 1H), 2.68 - 2.30 (m, 3H), 2.17 (br d, J = 2.0 Hz, 2H), 1.92 - 1.78 (m, 2H), 1.76 - 1.56 (m, 2H). Example 27 and Example 28 (8S,11S,15R)-22-fluoro-10-[(5R)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-10-[(5S)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compounds were prepared according to the following scheme:Step 1: preparation of ethyl 5-hydroxy-3-oxo-hexanoate (compound 27a) To a solution of ethyl 3-oxobutanoate (8.0 g, 61.47 mmol) in THF (80 mL) was added sodium hydride (2.7 g, 67.62 mmol) at 20 °C. The reaction was stirred for 1 hr and cooled to -25 °C, then n-butyllithium (30 mL, 73.77 mmol) was added slowly.0.5 hr later, a solution of acetaldehyde in THF (14 mL, 67.62 mmol) was added. The reaction was stirred at -25 °C for 1 hr and warmed to 20 °C for 12 hrs. The reaction was quenched with ice water (200 mL) and extracted with EA (100 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 27a (4 g) as a yellow oil. LCMS (M+H)+: 175. Step 2: preparation of ethyl 3-oxo-5-tetrahydropyran-2-yloxy-hexanoate (compound 27b) To a solution of compound 27a (1 g, 5.74 mmol) in DCM (2 mL) was added p-TsOH (144 mg, 0.57 mmol) and dihydropyran (1.2 g, 14 mmol) at 20 °C. The reaction was stirred at 20 °C for 12 hrs and quenched with ice water (100 mL), and then it was extracted with EA (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 27b (1300 mg) as a colorless oil. LCMS (M+H)+: 259.Step 3: preparation of ethyl (2Z)-2-(dimethylaminomethylene)-3-oxo-5- tetrahydropyran-2-yloxy-hexanoate (compound 27c) A solution of compound 27b (1.3 g, 5.03 mmol) in N,N-dimethylformamide dimethyl acetal (600 mg, 5.03 mmol) was stirred at 20 °C for 14 hrs. The mixture was concentrated to give crude compound 27c (1500 mg) as a yellow oil. LCMS (M+H)+: 314. Step 4: preparation of ethyl 1-(4-fluoro-2-methoxy-phenyl)-5-(2-tetrahydropyran-3- yloxypropyl)pyrazole-3-carboxylate (compound 27d) To a solution of compound 27c (1880 mg, 5.74 mmol) in ethanol (20 mL) was added DIEA (2240 mg, 17.23 mmol) and (4-fluoro-2-methoxy-phenyl)hydrazine; hydrochloride (compound 41b, 1316 mg, 5.74 mmol). The mixture was stirred at 80 °C for 16 hrs. The reaction was quenched with ice water (100 mL) and extracted with EA (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 27d (1000 mg) as a yellow oil. LCMS (M+H)+: 407. Step 5: preparation of ethyl 1-(4-fluoro-2-hydroxy-phenyl)-5-(2-hydroxypropyl) pyrazole-3-carboxylate (compound 27e) To a solution of compound 27d (517 mg, 1.27 mmol) in DCM (6 mL) was added dropwise BCl3 / DCM (6 mL, 6.37 mmol) at -78 °C. The reaction was warmed to 20 °C and stirred for 16 hrs. The reaction was quenched with ice water (100 mL) and extracted with EA (50 mL × 3). The combined organic layer was concentrated and purified via prep-HPLC to give compound 27e (180 mg) as a yellow oil. LCMS (M+H)+: 309. Step 6: preparation of ethyl 8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-2-carboxylate (compound 27f) To a solution of compound 27e (66 mg, 0.22 mmol), triphenylphosphine (113 mg, 0.43 mmol) in THF (2 mL) was added diisopropyl azodicarboxylate (87 mg, 0.43 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction was quenched with ice water (100 mL) and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 27f (35 mg) as a yellow oil. LCMS (M+H)+: 291. Step 7: preparation of 8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1-d][1,5] benzoxazepine-3-carboxylic acid (compound 27g) To a solution of compound 27f (35 mg, 0.12 mmol) in THF (0.3 mL) and ethanol (0.3 mL) was added a solution of LiOH•H2O (30 mg, 0.72 mmol) in water (0.3 mL) at 0 °C. The reactionmixture was stirred at 20 °C for 12 hrs and concentrated. The residue was diluted with water (20 mL) and acidified with HCl (aq., 1 M) to pH = 5 ~ 6 at 0 °C. The mixture was filtered, the collected solid was dried to give compound 27g (30 mg) as a white solid. LCMS (M+H)+: 263. Step 8: preparation of (8S,11S,15R)-22-fluoro-10-(8-fluoro-5-methyl-4,5- dihydropyrazolo[5,1-d][1,5]benzoxazepine-3-carbonyl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 27h) To a solution of compound 27g (37 mg, 0.14 mmol), O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) and N,N- diisopropylethylamine (70 µL, 0.42 mmol) in DMF (0.5 mL) was added a solution of intermediate C6 (62 mg, 0.14 mmol) in DMF (0.5 mL). The mixture was stirred at 20 °C for 1 hr. The reaction was quenched with ice water (50 mL) and extracted with EA (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC to give compound 27h (62 mg) as a white solid. LCMS (M+H)+: 683. Step 9: preparation of (8S,11S,15R)-22-fluoro-10-[(5R)-8-fluoro-5-methyl-4,5- dihydropyrazolo[5,1-d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-10-[(5S)-8-fluoro-5- methyl-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 27 and Example 28) The compound 27h (60 mg, 0.08 mmol) was separated via SFC to afford Example 27 (14 mg) as a white solid (faster eluted) and Example 28 (15mg) as a grey solid (slower eluted). SFC Method: Column: DAICEL CHIRALCEL OX (250mm×30mm,10um), Condition ACN / MeOH (0.1% NH3•H2O) Begin B 60%, End B: 60% Gradient Time(min): 5.5, 100% B Hold Time (min), Flow Rate (mL / min): 80. Example 27: LCMS (M+H)+: 683,1H NMR (400 MHz, METHANOL-d4) δ = 8.22 (s, 1H), 7.84 - 7.72 (m, 2H), 7.30 (dd, J = 2.6, 8.6 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.11 - 7.06 (m, 2H), 7.03 (dd, J = 2.6, 9.2 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.86 - 5.71 (m, 1H), 5.15 (d, J = 8.9 Hz, 1H), 5.00 - 4.90 (m, 2H), 4.58 (s, 1H), 4.43 - 4.31 (m, 1H), 4.26 - 4.11 (m, 2H), 4.02 - 3.93 (m, 1H), 3.49 - 3.36 (m, 1H), 3.13 - 3.03 (m, 1H), 2.98 (s, 3H), 2.84 (s, 4H), 2.61 (s, 3H), 2.52 - 2.39 (m, 2H), 1.45 (d, J = 6.2 Hz, 3H).Example 28: LCMS (M+H)+: 683,1H NMR (400 MHz, METHANOL-d4) δ = 8.21 (s, 1H), 7.84 - 7.68 (m, 2H), 7.31 (br d, J = 8.8 Hz, 1H), 7.24 - 7.14 (m, 1H), 7.12 - 6.92 (m, 3H), 6.65 - 6.50 (m, 1H), 5.90 - 5.71 (m, 1H), 5.13 (br dd, J = 8.8, 12.7 Hz, 1H), 5.06 - 4.93 (m, 2H), 4.50 - 4.39 (m, 1H), 4.33 (td, J = 6.1, 11.9 Hz, 1H), 4.26 - 4.08 (m, 2H), 4.02 - 3.85 (m, 1H), 3.52 - 3.37 (m, 1H), 2.99 - 2.87 (m, 4H), 2.85 - 2.73 (m, 4H), 2.61 (s, 3H), 2.54 - 2.37 (m, 2H), 1.46 (dd, J = 3.4, 6.4 Hz, 3H). Example 29 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)-5-fluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18- yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compounds were prepared according to the following scheme:The compound 29a was prepared in analogy to the preparation of compound 17g by using tert-butyl -(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl -(3R)-3- (iodomethyl)pyrrolidine-1-carboxylate (compound 17a) in step 4. Step 1: preparation of (14R)-5-fluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18- ol (compound 29b)To a solution of compound 29a (100 mg, 0.27 mmol) in THF (2 mL) was added dropwise BH3•THF (0.5 mL, 0.54 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 hr and MeOH (1 mL) was added at 0 °C. The reaction was heated to 60 °C for 1 hr. The mixture was concentrated to give compound 29b (50 mg) as a white solid. LCMS (M+H)+: 356. Step 2: preparation of (14R)-18-chloro-5-fluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaene (compound 29c) A solution of compound 29b (50 mg, 0.14 mmol) in POCl3 (2 mL) was stirred at 100 °C for 1 hr. The reaction mixture was concentrated and the residue was quenched with a saturated solution of NaHCO3 (20 mL) at 0 °C. The mixture was extracted with DCM (20 mL × 3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give compound 29c (60 mg) as a brown oil. LCMS (M+H)+: 374. Step 3: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)- 5-fluoro-8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 29) To a solution of intermediate C6 (35 mg, 0.08 mmol), compound 29c (30 mg, 0.08 mmol) in ACN (2 mL) was added DIEA (0.03 mL, 0.2 mmol). The reaction was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated and purified via prep-HPLC to give Example 29 (20 mg) as a yellow solid. LCMS (M+H)+: 776,1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (s, 1H), 7.98 - 7.87 (m, 1H), 7.64 - 7.45 (m, 3H), 7.30 - 7.17 (m, 2H), 7.03 (dt, J = 2.5, 8.3 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.21 (dd, J = 4.4, 15.4 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.79 - 4.71 (m, 1H), 4.70 - 4.48 (m, 4H), 4.47 - 4.17 (m, 4H), 3.90 (br dd, J = 9.3, 14.3 Hz, 1H), 3.69 - 3.61 (m, 1H), 3.60 - 3.54 (m, 1H), 3.53 - 3.43 (m, 1H), 3.32 - 3.24 (m, 2H), 3.19 (s, 1H), 3.13 (br s, 1H), 3.11 (s, 3H), 3.04 (br s, 1H), 3.01 (s, 3H), 2.90 (br s, 1H), 2.87 (s, 3H), 2.62 (td, J = 4.2, 8.8 Hz, 2H), 2.52 - 2.39 (m, 1H) Example 30 (6S)-4,4,14-trifluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-11-oxa-2,8,18,19,23,24-hexazapentacyclo [16.5.2.02,6.012,17.021,25]pentacosa-1(24),12,14,16,19,21(25),22-heptaen-7-oneThe title compound was prepared in analogy to the preparation of example 21 by using tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylatem in step 1 and using (2S)-4,4-difluoropyrrolidine-2-carboxylic acid instead of tert-butyl-(2S)-pyrrolidine-2-carboxylate in step 3. Example 30 (33 mg), LCMS (M+H)+: 855,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.01 (s, 1H), 7.82 - 7.68 (m, 1H), 7.57 - 7.42 (m, 2H), 7.18 - 7.07 (m, 2H), 6.76 (br d, J = 9.3 Hz, 2H), 6.45 (br d, J = 8.6 Hz, 1H), 6.05 – 5.85 (m, 1H), 5.42 - 5.16 (m, 1H), 5.05 - 4.91 (m, 1H), 4.87 - 4.70 (m, 2H), 4.53 - 4.41 (m, 1H), 4.38 - 4.00 (m, 8H), 3.49 - 3.26 (m, 1H), 3.13 - 3.02 (m, 3H), 2.99 (s, 3H), 2.83 (br s, 1H), 2.80 (br s, 2H), 2.74 - 2.64 (m, 3H), 2.61 (br s, 3H), 2.54 - 2.43 (m, 2H). Example 31 12-fluoro-6-methyl-20-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-9-oxa-2,6,16,17,21,22-hexazapentacyclo[14.5.2.12,4.010,15.019,23]tetracosa- 1(21),10(15),11,13,17,19,22-heptaen-5-oneThe title compound was prepared in analogy to the preparation of example 21 by using tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylatem in step 1 and using tert-butyl azetidine-3-carboxylate instead of tert- butyl-(2S)-pyrrolidine-2-carboxylate in step 3.Example 31 (4 mg), LCMS (M+H)+: 805,1H NMR (400 MHz, CHLOROFORM-d) δ = 7.96 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 (dd, J = 6.4, 8.6 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.02 (br d, J = 7.6 Hz, 2H), 6.72 (br d, J = 9.9 Hz, 2H), 6.37 (d, J = 8.5 Hz, 1H), 5.45 (d, J = 8.6 Hz, 1H), 5.08 - 4.77 (m, 2H), 4.69 - 4.59 (m, 1H), 4.55 - 4.47 (m, 1H), 4.45 - 4.31 (m, 3H), 4.27 - 4.17 (m, 1H), 4.11 - 3.91 (m, 3H), 3.73 - 3.62 (m, 4H), 3.32 - 3.23 (m, 1H), 2.88 (s, 3H), 2.82 (s, 3H), 2.72 - 2.60 (m, 6H), 2.53 - 2.46 (m, 3H) Example 32 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-12- oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.12,5.05,9.013,18.022,26]heptacosa- 1(25),13(18),14,16,20,22(26),23-heptaen-10-oneThe title compound was prepared in analogy to the preparation of example 33 by using tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate instead of tert-butyl 1,7- diazaspiro[4.4]nonane-7-carboxylate in step 1. Example 32 (9 mg), LCMS (M+H)+: 831,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.00 (s, 1H), 7.73 - 7.58 (m, 2H), 7.49 - 7.38 (m, 2H), 7.17 - 7.05 (m, 2H), 6.98 - 6.80 (m, 2H), 6.47 (br d, J = 7.5 Hz, 1H), 5.52 - 5.18 (m, 1H), 5.06 - 4.90 (m, 3H), 4.79 - 4.53 (m, 2H), 4.51 - 4.38 (m, 2H), 4.27 - 4.10 (m, 3H), 4.06 - 3.92 (m, 1H), 3.73 - 3.54 (m, 3H), 3.51 - 3.40 (m, 1H), 3.35 - 3.18 (m, 1H), 3.04 (br d, J = 17.9 Hz, 3H), 2.79 (br s, 3H), 2.77 - 2.64 (m, 2H), 2.59 (br s, 3H), 2.11 - 1.81 (m, 6H). Example 33 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-12- oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,6.013,18.022,26]heptacosa- 1(24),13(18),14,16,20,22,25-heptaen-10-oneThe title compounds were prepared according to the following scheme:The compound 33a was prepared in analogy to the preparation of example 21b by using ethyl 2-hydroxyacetate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate in step 1. Step 1: preparation of tert-butyl 1-[4-benzyloxy-1-[2-(2-ethoxy-2-oxo-ethoxy)-4- fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]-1,7-diazaspiro[4.4]nonane-7-carboxylate (compound 33b) To a solution of compound 33a (500 mg, 1.09 mmol), tert-butyl 1,7- diazaspiro[4.4]nonane-7-carboxylate (371 mg, 1.64 mmol) in DMF (10 mL) was added DIPEA (570 µL, 3.28 mmol). The reaction was stirred at 60 °C for 14 hrs and diluted with water (40 mL). The mixture was extracted with EA (50 mL × 3). The organic layer was washed with brine (50 mL × 4), dried over Na2SO4, filtered and concentrated to give compound 33b (900 mg) as a brown oil. LCMS (M+H)+: 647. Step 2: preparation of 2-[2-[4-benzyloxy-6-(7-tert-butoxycarbonyl-1,7- diazaspiro[4.4]nonan-1-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-phenoxy]acetic acidified (compound 33c)To a solution of compound 33b (900 mg, 1.39 mmol) in THF (4.5 mL) and ethanol (4.5 mL) was added a solution of LiOH•H2O (291 mg, 6.96 mmol) in water (4.5 mL) at 25 °C. The reaction was stirred at 40 °C for 12 hrs. The mixture was concentrated to give compound 33c (900 mg) as a yellow solid. LCMS (M+H-100)+: 519. Step 3: preparation of 2-[2-[6-(1,7-diazaspiro[4.4]nonan-1-yl)-4-hydroxy- pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-phenoxy]acetic acid (compound 33d) To a solution of compound 33c (900 mg, 1.45 mmol) in DCM (5 mL) was added TFA (5 mL) at 0 °C. The reaction was stirred at 20 °C for 2 hrs and concentrated. The residue was purified via prep-HPLC to give compound 33d (95 mg) as a yellow solid. LCMS (M+H)+: 429. Step 4: preparation of 15-fluoro-23-hydroxy-12-oxa-2,9,19,20,24,25- hexazahexacyclo[17.5.2.16,9.02,6.013,18.022,26]heptacosa-1(24),13(18),14,16,20,22,25-heptaen- 10-one (compound 33e) To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol), DIPEA (136 µL, 0.78 mmol) in DMF (33 mL) was added a solution of compound 33d (85 mg, 0.16 mmol) in DMF (99 mL). The reaction mixture was stirred at 25 °C for 1 hr and concentrated. The residue was purified via prep-HPLC to give compound 33e (30 mg) as a white solid. LCMS (M+H)+: 411. Step 5: preparation of 23-chloro-15-fluoro-12-oxa-2,9,19,20,24,25-hexazahexacyclo [17.5.2.16,9.02,6.013,18.022,26]heptacosa-1(24),13(18),14,16,20,22,25-heptaen-10-one (compound 33f) A solution of compound 33e (12 mg, 0.02 mmol) in POCl3 was stirred at 100 °C for 1 hr. The mixture was concentrated and the residue was diluted with DCM (2 mL), which was poured into a aqueous solution of NaHCO3 (10 mL) and DCM (10 mL). Then it was extracted with DCM (20 mL × 3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give compound 33f (20 mg) as a brown oil. LCMS (M+H)+: 429. Step 6: preparation of 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-10-yl]-12-oxa-2,9,19,20,24,25- hexazahexacyclo[17.5.2.16,9.02,6.013,18.022,26]heptacosa-1(24),13(18),14,16,20,22,25-heptaen- 10-one (Example 33) To a solution of compound 33f (20 mg, 0.05 mmol), intermediated C6 (20 mg, 0.05 mmol) in ACN (1 mL) was added DIPEA (80 µL, 0.47 mmol). The reaction was stirred at 80 °C for 12 hrs. The mixture was purified via prep-HPLC to give Example 33 (17 mg) as a light yellowsolid. LCMS (M+H)+: 831,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.03 (s, 1H), 7.72 (br s, 1H), 7.47 (br d, J = 11.5 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.16 - 7.05 (m, 2H), 6.84 - 6.73 (m, 1H), 6.45 (dd, J = 3.3, 8.1 hrz, 1H), 5.65 (br dd, J = 10.7, 15.9 Hz, 1H), 5.40 - 5.26 (m, 1H), 5.24 - 5.13 (m, 1H), 5.07 - 4.93 (m, 1H), 4.79 - 4.71 (m, 1H), 4.70 - 4.57 (m, 2H), 4.45 (br dd, J = 7.1, 10.9 Hz, 1H), 4.38 - 4.12 (m, 3H), 4.10 - 3.96 (m, 2H), 3.69 - 3.29 (m, 2H), 3.08 - 3.01 (m, 3H), 3.00 - 2.92 (m, 2H), 2.80 (br d, J = 8.8 Hz, 3H), 2.61 - 2.55 (m, 3H), 2.49 (br dd, J = 5.1, 11.8 Hz, 2H), 2.42 - 2.19 (m, 2H), 1.99 - 1.78 (m, 4H). Example 34 and Example 35 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14S)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compounds were prepared according to the following scheme:The compound 34a was prepared in analogy to the preparation of example 17g by using tert-butyl 3,3-difluoro-4-(iodomethyl)pyrrolidine-1-carboxylate instead of tert-butyl-(3R)-3- (iodomethyl)pyrrolidine-1-carboxylate in step 4. Step 1: preparation of 5,13,13-trifluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2,4,6,16,18,20,22-heptaen-18-ol (compound 34b) To a solution of compound 34a (40 mg, 0.08 mmol) in THF (4 mL) was added BH3•THF (770 µL, 0.77 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 hr and MeOH (3 mL) was added at 0 °C. The reaction was stirred at 60 °C for 1 hr. The mixture was concentrated and purified via prep-HPLC to give compound 34b (60 mg) as a white solid. LCMS (M+H)+: 392. Step 2: preparation of 18-chloro-5,13,13-trifluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2,4,6,16,18,20,22-heptaene (compound 34c) A solution of compound 34b (50 mg, 0.13 mmol) in POCl3(0.5 mL) was stirred at 100 °C for 12 hrs. The reaction was concentrated and diluted with DCM (1 mL). The mixture was poured into aqueous solution of NaHCO3 (10 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with brine (10 mL) dried over Na2SO4 and concentrated. The residue was purified via prep-HPLC to give compound 34c (36 mg) as a yellow oil. LCMS (M+H)+: 410. Step 3: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10- (5,13,13-trifluoro-8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2,4,6,16,18,20,22-heptaen-18-yl)-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 34d) To a solution of compound 34c (36 mg, 0.09 mmol), intermediated C6 (38 mg, 0.09 mmol) in ACN (1 mL) was added N,N-diisopropylethylamine (80 µL, 0.44 mmol). The reaction wasstirred at 80 °C for 12 hrs. The mixture was concentrated and purified via prep-HPLC to give compound 34d (26 mg) as a yellow solid. LCMS (M+H)+: 812. Step 4: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)- 5,13,13-trifluoro-8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- oneand (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14S)-5,13,13-trifluoro-8- oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 34 and Example 35) The compound 34d was separated via SFC [condition: Instrument ACSWH-PREP-SFC-H , Column DAICEL CHIRALCEL OJ-H (250mm×30mm, 5 µm), Condition 0.1% NH3•H2O EtOH , Begin B 40 End B 40, Gradient Time (min) 4, Flowrate (mL / min) 150 )] to give Example 34 (8 mg) (faster eluted) and Example 35 (14 mg) (slower eluted). LCMS (M+H)+: 812. Example 34,1H NMR (400 MHz, CHLOROFORM-d) δ = 8.09 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.55 (dd, J = 6.1, 8.6 Hz, 1H), 7.41 (br d, J = 7.1 hrz, 1H), 7.14 - 6.99 (m, 2H), 6.75 (dt, J = 2.5, 8.4 Hz, 1H), 6.62 (dd, J = 2.6, 10.2 Hz, 1H), 6.39 (d, J = 8.3 Hz, 1H), 6.05-5.95 (m, 1H), 5.51 (br d, J = 9.0 Hz, 1H), 5.13 (br d, J = 8.3 Hz, 1H), 4.65 - 4.54 (m, 1H), 4.41 (br dd, J = 6.5, 11.3 Hz, 1H), 4.19 - 4.00 (m, 2H), 3.96 - 3.78 (m, 3H), 3.71 - 3.40 (m, 3H), 3.12 - 2.99 (m, 2H), 2.94 (s, 3H), 2.90 - 2.83 (m, 1H), 2.76 (s, 3H), 2.73 - 2.65 (m, 2H), 2.60 (s, 3H), 2.53 (br s, 1H), 2.49 - 2.39 (m, 2H), 2.37 - 2.25 (m, 2H) Example 35,1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 7.81 - 7.68 (m, 1H), 7.64 - 7.53 (m, 1H), 7.42 - 7.37 (m, 1H), 7.30 (br dd, J = 2.7, 10.3 Hz, 1H), 7.23 - 7.15 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.89 (br d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.98 - 5.77 (m, 1H), 5.48 - 5.32 (m, 1H), 4.60 (br d, J = 5.0 Hz, 1H), 4.44 - 4.40 (m, 1H), 4.19 - 4.10 (m, 2H), 3.93 - 3.78 (m, 3H), 3.55 (d, J = 11.0 Hz, 3H), 3.05 (s, 2H), 2.96 (s, 3H), 2.86 (br d, J = 12.8 Hz, 1H), 2.82 (s, 3H), 2.77 (s, 1H), 2.70 - 2.52 (m, 5H), 2.52 - 2.12 (m, 4H). Example 36 (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3-diazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compounds were prepared according to the following scheme:Step 1: preparation of ethyl 7-benzyloxy-3-oxo-heptanoate (compound 36a) To a solution of ethyl 3-oxobutanoate (1000 mg, 7.68 mmol) in THF (10 mL) was added sodium hydride (340 mg, 8.45 mmol) at 20 °C. After being stirred at 20 °C for 1 hr, the reaction mixture was cooled to -25 °C and n-butyllithium (3.7 mL, 9.22 mmol) was added slowly. The reaction was stirred at -25 °C for 0.5 hr and a solution of benzyl 3-bromopropyl ether (1940 mg, 8.45 mmol) in THF (2 mL) was added at -25°C. The reaction was stirred at the temperature for 1 hr and then warmed to 20 °C for 12 hrs. The reaction was quenched with cold water (100 mL) and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 36a (1.1 g) as a colorless liquid. LCMS (M+Na)+: 301. Step 2: preparation of ethyl (2E)-7-benzyloxy-2-(dimethylaminomethylene)-3-oxo- heptanoate (compound 36b) A solution of compound 36a (500 mg, 1.8 mmol) in N,N-dimethylformamide dimethyl acetal (5.0 mL, 37.64 mmol) was stirred at 25 °C for 12 hrs. The mixture was concentrated directly to give compound 36b (800 mg) as a yellow oil. LCMS (M+H)+: 334. Step 3: preparation of ethyl 5-(4-benzyloxybutyl)-1-(4-fluoro-2-methoxy-phenyl) pyrazole-4-carboxylate (compound 36c)To a solution of compound 36b (800 mg, 2.4 mmol) in ethanol (10 mL) was added (4- fluoro-2-methoxy-phenyl)hydrazine;hydrochloride (41b, 463 mg, 2.4 mmol), N,N- diisopropylethylamine (1.3 mL, 7.2 mmol). The reaction was stirred at 80 °C for 12 hrs. The mixture was concentrated and purified via column chromatography to give compound 36c (700 mg) as a yellow oil. LCMS (M+H)+: 427. Step 4: preparation of ethyl 1-(4-fluoro-2-hydroxy-phenyl)-5-(4-hydroxybutyl) pyrazole-4-carboxylate (compound 36d) To a solution of compound 36c (600 mg, 1.41 mmol) in DCM (6 mL) was added BCl3 / DCM (7 mL, 7.03 mmol) at -78 °C. The reaction was warmed to 20 °C and stirred for 4 hrs. The mixture was poured into a mixture of ice-water (50 mL) and DCM (50 mL). After separation, the organic layer was washed with brine (50 mL) and concentrated. The residue was purified via column chromatography to give compound 36d (300 mg) as a yellow oil. LCMS (M+H)+: 323. Step 5: preparation of ethyl 14-fluoro-11-oxa-2,3-diazatricyclo[10.4.0.02,6]hexadeca- 1(16),3,5,12,14-pentaene-5-carboxylate (compound 36e) To a solution of compound 36d (100 mg, 0.31 mmol), triphenylphosphine (163 mg, 0.62 mmol) in THF (8 mL) was added diisopropyl azodicarboxylate (120 µL, 0.62 mmol) at 0 °C. The reaction was stirred at 20 °C for 12 hrs. The mixture was concentrated and purified via column chromatography to give compound 36e (70 mg) as a colorless oil. LCMS (M+H)+: 305. Step 6: preparation of 14-fluoro-11-oxa-2,3-diazatricyclo[10.4.0.02,6]hexadeca- 1(16),3,5,12,14-pentaene-5-carboxylic acid (compound 36f) To a solution of compound 36e (70 mg, 0.23 mmol) in THF (0.4 mL) and ethanol (0.4 mL) was added a solution of LiOH•H2O (57 mg, 1.38 mmol) in water (0.4 mL) at 0 °C. The reaction was stirred at 20 °C for 12 hrs and concentrated. The residue was diluted with water (20 mL) and extracted with EA (50 mL × 3). The aqueous phase was acidified with HCl (aq., 1 M) to pH 2 ~ 3 at 0 °C. The precipitate was collected and dried to give compound 36f (30 mg) as a white solid. LCMS (M+H)+: 277. Step 7: preparation of (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3- diazatricyclo[10.4.0.02,6]hexadeca-1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 36) To a solution of compound 36f (30 mg, 0.11 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), N,N-diisopropylethylamine (60 µL, 0.33 mmol) in DMF (0.5 mL) was added a solution of intermediated C6 (48 mg, 0.11 mmol)in DMF (0.5 mL) at 20 °C. The reaction was stirred at 20 °C for 1 hr and purified via prep-HPLC to give Example 36 (43 mg) as a white solid. LCMS (M+H)+: 697,1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 1H), 7.87 (s, 1H), 7.65 - 7.61 (m, 1H), 7.55 - 7.49 (m, 2H), 7.29 - 7.14 (m, 2H), 7.06 - 6.97 (m, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.28 - 6.16 (m, 1H), 5.21 - 5.13 (m, 1H), 4.54 (br t, J = 4.8 Hz, 1H), 4.49 - 4.34 (m, 2H), 4.33 - 4.26 (m, 2H), 4.20 - 4.12 (m, 1H), 4.03 - 3.97 (m, 1H), 3.03 (s, 2H), 3.00 (s, 3H), 2.97 (s, 2H), 2.90 (s, 3H), 2.88 (br s, 1H), 2.72 (br s, 2H), 2.61 - 2.54 (m, 1H), 2.46 (ddd, J = 4.1, 9.0, 13.4 Hz, 1H), 2.11 - 1.92 (m, 2H), 1.85 - 1.77 (m, 2H) Example 37 (8S,11S,18R)-25-fluoro-21-methyl-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa- 2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(23),12(17),13,15,19,21,24-heptaen-22-yl]-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 21 by using tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylatem in step 1 and using intermediate C11 instead of intermediate C6 in step 6. Example 37 (50 mg), LCMS (M+H)+: 831,1H NMR (400 MHz, METHANOL-d4) δ = 8.20 - 7.99 (m, 1H), 7.84 - 7.73 (m, 1H), 7.52 - 7.22 (m, 2H), 7.18 - 7.09 (m, 1H), 7.07 - 6.93 (m, 1H), 6.92 - 6.64 (m, 2H), 6.63 - 6.45 (m, 1H), 5.34 (br t, J = 4.8 Hz, 1H), 5.19 (br d, J = 10.3 Hz, 1H), 5.06 - 4.91 (m, 1H), 4.78 (br s, 2H), 4.74 - 4.61 (m, 1H), 4.60 - 3.94 (m, 6H), 3.93 - 3.62 (m, 4H), 3.59 - 3.33 (m, 2H), 3.15 (dt, J = 3.7, 6.6 Hz, 3H), 3.10 - 2.84 (m, 4H), 2.83 - 2.62 (m, 1H), 2.61 - 2.45 (m, 3H), 2.41 - 2.14 (m, 1H), 1.89 - 1.80 (m, 4H) Example 38 (8S,11S,18S)-25-fluoro-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa-2,8,18,19,23,24- hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24-heptaen-22-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27] triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 21 by using tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylatem in step 1 and using intermediate C10 instead of intermediate C6 in step 6. Example 38 (50 mg), LCMS (M+H)+: 831.1H NMR (400 MHz, METHANOL-d4) δ = 8.14 - 8.10 (m, 1H), 7.78 - 7.70 (m, 1H), 7.52 - 7.42 (m, 1H), 7.41 - 7.32 (m, 1H), 7.31 - 7.24 (m, 1H), 7.10 (br dd, J = 2.4, 10.5 hrz, 1H), 6.94 - 6.89 (m, 1H), 6.84 - 6.76 (m, 1H), 6.66 - 6.56 (m, 1H), 6.10 - 5.84 (m, 1H), 5.44 - 5.31 (m, 1H), 5.27 - 5.15 (m, 1H), 4.68 - 4.60 (m, 1H), 4.59 - 4.51 (m, 1H), 4.46 (dt, J = 6.4, 12.7 Hz, 1H), 4.41 - 4.31 (m, 2H), 4.31 - 3.90 (m, 6H), 3.89 - 3.75 (m, 2H), 3.70 - 3.49 (m, 1H), 3.48 - 3.33 (m, 2H), 3.29 - 3.18 (m, 1H), 3.17 - 3.06 (m, 1H), 3.05 - 2.94 (m, 3H), 2.79 - 2.67 (m, 1H), 2.62 - 2.44 (m, 4H), 2.40 - 2.14 (m, 2H), 2.14 - 2.05 (m, 1H), 1.96 - 1.82 (m, 2H). Example 40 (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3-diazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 36 by usingbenzyl 2-bromoethyl ether instead of benzyl 3-bromopropyl ether in step 1. Example 40 (17 mg), LCMS (M+H)+: 683,1H NMR (400 MHz, METHANOL-d4) δ = 8.19 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.64 - 7.49 (m, 3H), 7.15 - 7.09 (m, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.20 (br dd, J = 4.3, 15.1 hrz, 1H), 5.22 - 5.11 (m, 1H), 4.81 - 4.68 (m, 2H), 4.55 - 4.47 (m, 1H), 4.41 - 4.31 (m, 2H), 4.3 - 4.15 (m, 2H), 4.12 (br d, J = 11.4 Hz, 1H), 3.98 (dt, J = 5.5, 9.1 hrz, 1H), 3.03 - 2.92 (m, 8H), 2.89 - 2.71 (m, 4H), 2.60 - 2.42 (m, 2H), 2.11 - 2.01 (m, 2H). Example 41 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe tile compound was prepared according to the following scheme:Step 1: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine; hydrochloride (compound 41b) To a solution of 4-fluoro-2-methoxy-aniline (compound 41a, 20.0 g, 141.7 mmol) in HCl / water (160 mL, 960.0 mmol) was added a solution of NaNO2 (1.47 g, 212.6 mmol) in water (50 mL) at 0 °C. The mixture was stirred for 1 hr, a solution of tin(II) chloride dihydrate (80 g, 354.53 mmol) in conc. HCl (80 mL, 960.0 mmol) was then added dropwise. The reaction was stirred at 25 °C for 16 hrs. The mixture was poured into ice water and adjusted to pH 10-12 with 20% aqueous sodium hydroxide. The solution was extracted with EA (400 mL × 3). The organic layer was dried over anhydrous Na2SO4and filtered. The filtrate was acidified with HCl / dioxane(4 M) to pH around 2 ~ 3. The suspension was filtered, the collected solid was dried to give compound 41b (22 g) as an off-white solid. LCMS (M+H)+: 157. Step 2: preparation of 5-amino-1-(4-fluoro-2-methoxy-phenyl)pyrazole-4-carbonitrile (compound 41c) To a solution of compound 41b (15 g, 77.87 mmol) in ethanol (160 mL) was added DIEA (41.6 mL, 233.62 mmol) and ethoxymethylenemalononitrile (19 g, 155.75 mmol). The reaction was stirred at 25 °C for 1 hr and at 90 °C for 16 hrs. The mixture was concentrated and purified via flash chromatography to give compound 41c (6 g) as a light yellow solid. LCMS (M+H)+: 233. Step 3: preparation of N-[4-cyano-2-(4-fluoro-2-methoxy-phenyl)pyrazol-3-yl]-2- methoxy-acetamide (compound 41d) To a solution of compound 41c (6 g, 25.84 mmol) in sulfolane (50 mL) was added 2- methoxyacetyl chloride (4.2 g, 38.76 mmol) slowly at 0 °C. The reaction was stirred at 100 °C for 16 hrs. After cooled to 25 °C, water (100 mL) and EtOAc (100 mL) was added. After separation, the organic layer was washed with brine (100 mL) and sat. CaCl2 aq. (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to give compound 41d (5 g) as a light yellow solid. LCMS (M+H)+: 305. Step 4: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)-6-(methoxymethyl) pyrazolo[3,4-d]pyrimidine (compound 41e) A solution of compound 41d (5 g, 16.43 mmol) in POCl3(50 mL) was stirred at 100 °C for 16 hrs. The reaction mixture was concentrated to give an oil. The residue was dissolved in EtOAc (100 mL) and poured into cold solution of NaHCO3 (50 mL). After separation, the organic layer was washed with brine (50 mL) and dried over Na2SO4. Then it was filtered andconcentrated under vacuum. The residue was purified via flash chromatography to give compound 41e (2.60 g) as a light yellow solid. LCMS (M+H)+: 323. Step 5: preparation of 2-[4-chloro-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-1-yl]- 5-fluoro-phenol (compound 41f) To a solution of compound 41e (2.6 g, 8.06 mmol) in DCM (100 mL) was added BCl3 / DCM (80 mL, 80.57 mmol) at -78 °C. The reaction was warmed to r.t. and stirred for 16 hrs. The reaction was quenched with ice-water (300 mL), then extracted with DCM (100 ml × 3). The organic layer was washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated to give compound 41f (2.5 g) as a light yellow solid. LCMS (M+H)+: 295. Step 6: preparation of 2-[4-benzyloxy-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-1- yl]-5-fluoro-phenol (compound 41g) To a solution of compound 41f (2.3 g, 7.81 mmol) and benzyl alcohol (1690 mg, 15.61 mmol) in THF (30 mL) was added potassium tert-butoxide (3.5 g, 31.22 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hrs. The reaction was quenched with sat. NH4Cl aq. (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 41g (1.8 g) as a light yellow solid. LCMS (M+H)+: 367. Step 7: preparation of [4-benzyloxy-1-[2-[(E)-4-bromobut-2-enoxy]-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methanol (compound 41h) To a solution of compound 41g (1 g, 2.73 mmol) in DMF (75 mL) was added cesium carbonate (1334 mg, 4.09 mmol) at 0 °C. The mixture was stirred for 30 min and trans-1,4- dibromo-2-butene (701 mg, 3.28 mmol) was added at 0 °C. The reaction was warmed to 40 °C and stirred for 2 hrs. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to give compound 41h (450 mg) as a light yellow oil. LCMS (M+H)+: 499. Step 8: preparation of (10E)-17-benzyloxy-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15(22),16,18(21),19-octaene (compound 41i) To a suspension of NaH (36 mg, 0.90 mmol) in dry THF (15 mL) was added a solution of compound 41h (150 mg, 0.30 mmol) in dry THF (60 mL) in one portion at 20 °C. The reaction mixture was stirred for 1 hr to give a colorless solution. The reaction was quenched with cold sat.NH4Cl aq. (20 mL) and extracted with DCM (80 mL × 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC to give compound 41i (30 mg) as a yellow solid. LCMS (M+H)+: 419. Step 9: preparation of (10E)-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15(22),16,18(21),19-octaen-17-ol (compound 41j) To a solution of compound 41i (30 mg, 0.05 mmol) in DCE (300 µL) was added TFA (300 µL). The mixture was stirred at 20 °C for 0.5 hr. The reaction was quenched with ice water and extracted with DCM (10 mL × 2). The combined organic layer was washed with NaHCO3aq. (10 mL), dried over Na2SO4, filtered and concentrated to give compound 41j (40 mg) as a light yellow oil. LCMS (M+H)+: 329. Step 10: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(10E)- 5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa- 2(7),3,5,10,15,17,19,21-octaen-17-yl]-7,10,13,17,19,26-hexazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 41) A solution of compound 41j (35 mg, 0.11 mmol) in DMF (1.2 mL) was added PyBop (72 mg, 0.14 mmol) and DIEA (44 µL, 0.27 mmol). The mixture was stirred for 30 mins and intermediate C6 (59 mg, 0.11 mmol) was added. The reaction was stirred at 20 °C for 2 hrs and concentrated. The residue was purified via Prep-TLC to give crude product. Then it was further purified via prep-HPLC to give Example 41 (1.6 mg) as a white solid. LCMS (M+H)+: 749,1H NMR (400 MHz, METHANOL-d4) δ = 8.45 (s, 1H), 7.92 - 7.84 (m, 1H), 7.62 - 7.51 (m, 3H), 7.32 - 7.23 (m, 1H), 7.20 - 7.13 (m, 1H), 7.00 - 6.90 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.21 - 5.92 (m, 2H), 5.72 - 5.38 (m, 2H), 4.55 - 4.47 (m, 4H), 4.35 - 4.28 (m, 2H), 4.21 - 4.13 (m, 2H), 4.00 - 3.89 (m, 1H), 3.10 - 3.03 (m, 3H), 2.97 (s, 5H), 2.90 - 2.85 (m, 1H), 2.84 - 2.79 (m, 3H), 2.74 - 2.46 (m, 3H) Example 42 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 4-fluoro-2-methoxy-N-[(Z)-(2,4,6-trichloropyrimidin-5- yl)methyleneamino]aniline (compound 42a) To a solution of compound 41b (9.8 g, 51.08 mmol) in DMF (180 mL) was added 2,4,6- trichloropyrimidine-5-carbaldehyde (9 g, 42.57 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 hrs and then poured into the cold water (200 mL). The precipitate was filtered, the collected solid was freeze-dried to give compound 42a (14 g) as a yellow solid. LCMS (Ml+H)+: 349 Step 2: preparation of 4,6-dichloro-1-(4-fluoro-2-methoxy-phenyl) pyrazolo[3,4- d]pyrimidine (compound 42b)To a solution of compound 42a (14 g, 40.62 mmol) in NMP (140 mL) was added 4 Å molecular sieve (14 g). The reaction was stirred at 110 °C for 16 hrs. The mixture was filtered; the filtrate was poured into water (500 mL) at 0 °C and extracted with ethyl acetate (500 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 42b (3.7 g) as a yellow solid. LCMS (M+H)+: 313. Step 3: preparation of 2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenol (compound 42c) To a solution of compound 42b (2 g, 6.39 mmol) in DCM (80 mL) was added BCl3 / DCM (32 mL, 31.94 mmol) at -78 °C. The reaction was stirred at -78 °C for 1 hr and then warmed to r.t. and stirred for 16 hrs. The reaction was quenched with cold water (100 mL) and extracted with DCM (100 mL × 3). The organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4 and concentrated to give compound 42c (1.3 g) as a yellow solid. LCMS (M+H)+: 299. Step 4: preparation of 2-(4-benzyloxy-6-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoro-phenol (compound 42d) To a solution of phenylmethanol (35 mg, 0.32 mmol) in THF (7 mL) was added NaH (25 mg, 0.65 mmol) at 0 °C. The mixture was stirred at 20 °C for 0.5 hr and compound 42c (194 mg, 0.64 mmol) was added.1 hr later, the reaction was quenched with saturated solution of NH4Cl (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified via column chromatography to give compound 42d (20 mg) as a yellow solid. LCMS (M+H)+: 371. Step 5: preparation of 2-[2-[2-(4-benzyloxy-6-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)- 5-fluoro-phenoxy]ethoxy]ethanol (compound 42e) To a solution of compound 42d (15 mg, 0.04 mmol) in DMF (3 mL) was added cesium carbonate (19 mg, 0.06 mmol) at 0 °C. The reaction was stirred at 20 °C for 0.5 hr and 2-(2- bromoethoxy)ethanol (8 mg, 0.05 mmol) was added. The mixture was warmed to 40 °C and stirred for 2 hrs. The reaction was quenched with H2O (50 mL) and was extracted with EA (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give compound 42e (25 mg) as a yellow solid. LCMS (M+H)+: 459. Step 6: preparation of 17-benzyloxy-5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaene(compound 42f)To a solution of compound 42e (20 mg, 0.04 mmol) in THF (12 mL) was added a suspension of NaH (5 mg, 0.14 mmol) in THF (4 mL) in one portion at 0 °C. The reaction was warmed to 20 °C and stirred for 1 hr. The reaction was quenched with NH4Cl aq. and extracted with EA (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give compound 42f (40 mg) as a yellow oil. LCMS (M+H)+: 423. Step 7: preparation of 5-fluoro-8,11,14-trioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-ol (compound 42g) To a solution of compound 42f (40 mg, 0.09 mmol) in DCE (1.0 mL) was added TFA (64 mg, 0.76 mmol) and DCE (2 mL). The reaction was stirred at 20 °C for 0.3 hrs. The reaction solution was diluted with ice water (10 mL) and extracted with EA (15 mL × 3). The organic layer was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated to give compound 42g (40 mg) as a brown oil. LCMS (M+H)+: 333. Step 8: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 42) To a solution of compound 42g (30 mg, 0.09 mmol) in DMF (2 mL) was added PyBop (46 mg, 0.09 mmol), DIEA (28 µL, 0.17 mmol) and intermediate C6 (30 mg, 0.07 mmol). The reaction was stirred at 20 °C for 2 hrs. The reaction solution was purified via prep-HPLC to give Example 42 (5 mg) as a light yellow solid. LCMS (M+H)+: 753,1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.87 - 7.77 (m, 1H), 7.55 - 7.45 (m, 1H), 7.33 - 7.26 (m, 1H), 7.20 - 7.13 (m, 1H), 7.12 - 7.06 (m, 2H), 6.93 - 6.84 (m, 1H), 6.72 - 6.63 (m, 1H), 5.82 - 5.66 (m, 1H), 5.42 - 5.29 (m, 1H), 4.67 - 4.54 (m, 4H), 4.50 - 4.41 (m, 2H), 4.27 (br d, J = 11.9 Hz, 1H), 4.20 - 4.07 (m, 2H), 4.02 - 3.87 (m, 2H), 3.85 - 3.70 (m, 3H), 3.16 - 3.08 (m, 1H), 3.01 (s, 3H), 2.85 (s, 3H), 2.60 - 2.53 (m, 3H), 2.51 - 2.40 (m, 2H) Example 43 (8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-2,3-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared in analogy to the preparation of example 36 by using 4- bromobutoxymethylbenzene instead of benzyl 3-bromopropyl ether in step 1. Example 43 (6 mg), LCMS (M+H)+: 711,1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.51 (m, 2H), 7.46 - 7.34 (m, 1H), 7.28 - 7.07 (m, 2H), 6.96 (dt, J = 2.8, 8.3 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.29 - 6.15 (m, 1H), 5.21 - 5.05 (m, 1H), 4.58 - 4.50 (m, 1H), 4.50 - 4.28 (m, 4H), 4.17 - 3.92 (m, 2H), 3.05 - 3.01 (m, 2H), 3.01 - 2.93 (m, 5H), 2.90 (s, 3H), 2.78 - 2.66 (m, 2H), 2.64 - 2.41 (m, 3H), 2.11 - 2.01 (m, 1H), 1.99 - 1.86 (m, 1H), 1.80 - 1.70 (m, 2H), 1.66 - 1.54 (m, 2H). Example 44 (8S,11S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[2-[2-(4, 6-dichloropyrazolo [3, 4-d] pyrimidin-1-yl)-5-fluoro- phenoxy] ethoxy] ethanol (compound 44a) To a solution of compound 42c (1.3 g, 4.29 mmol), 2-(2-hydroxyethoxy)ethanol (546 mg, 5.1 mmol), PPh3(1.7 g, 6.5 mmol) in toluene (80 mL) was added DIAD (1.2 mL, 5.59 mmol) at 0 °C. The reaction was heated to 100 °C and stirred for 2 hrs. The mixture was concentrated and purified via column chromatography to give compound 44a (700 mg) as a yellow solid. LCMS (M+H)+: 387. Step 2: preparation of 17-chloro-5-fluoro-8,11,14-trioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaene (compound 44b) To a solution of compound 44a (50 mg, 0.13 mmol) in DCM (5 mL) was added tetrabutylammonium iodide (4.8 mg, 0.01 mmol) and KOH (9 mg, 0.15 mmol) in water (5 mL) at 0 °C. The reaction mixture was stirred for 30 min and then warmed to 20 °C and stirred for 3 hrs. The reaction was quenched with ice water (20 mL) and extracted with DCM (3 × 20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4and concentrated. The residue was purified via prep-TLC to give compound 44b (21 mg) as a white solid. LCMS (M+H)+: 351. Step 3: preparation of (8S,11S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 44) To a solution of intermediate C8 (30 mg, 0.06 mmol) and compound 44b (20 mg, 0.06 mmol) in ACN (1 mL) was added DIEA (39 µL, 0.23 mmol). The reaction was stirred at 80 °C for 2 hrs. The mixture was purified twice via prep-HPLC to give Example 44 (7.1 mg) as awhite solid. LCMS (M+H)+: 724,1H NMR (400 MHz, METHANOL-d4) δ = 8.59 - 8.50 (m, 1H), 8.27 - 8.14 (m, 1H), 7.80 - 7.64 (m, 1H), 7.62 - 7.55 (m, 1H), 7.52 - 7.42 (m, 1H), 7.07 - 6.97 (m, 1H), 6.89 - 6.64 (m, 2H), 5.56 - 5.37 (m, 2H), 5.27 - 5.19 (m, 1H), 5.12 - 4.94 (m, 2H), 4.66 - 4.52 (m, 1H), 4.26 - 4.09 (m, 3H), 4.06 - 3.94 (m, 1H), 3.92 - 3.75 (m, 2H), 3.73 - 3.60 (m, 1H), 3.58 - 3.38 (m, 3H), 3.17 - 3.07 (m, 1H), 3.03 - 2.99 (m, 1H), 2.88 - 2.74 (m, 5H), 2.53 - 2.38 (m, 1H), 1.98 - 1.79 (m, 1H), 1.39 - 1.25 (m, 1H). Example 45 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- 8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-oneThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 5-acetamido-1-(4-fluoro-2-methoxy-phenyl) pyrazole-4- carboxylate (compound 45a) To a solution of compound 18a (5.7 g, 20.41 mmol) in chloroform (60 mL) was added acetyl chloride (1.9 mL, 26.53 mmol) at 25 °C. The reaction was stirred at 65 °C for 16 hrs andconcentrated. The residue was purified via flash chromatography to afford compound 45a (5.8 g) as a yellow solid. LCMS (M+H)+: 322. Step 2: preparation of ethyl 5-[acetyl (4-benzyloxybutyl) amino]-1-(4-fluoro-2- methoxy-phenyl) pyrazole-4-carboxylate (compound 45b) To a solution of compound 45a (5.8 g, 18.05 mmol) in DMF (70 mL) was added sodium hydride (871 mg, 21.77 mmol) at 0 °C under N2atmosphere. The reaction was stirred at 0 °C for 0.5 hr and 4-bromobutoxymethylbenzene (8.8 g, 36.18 mmol) was added dropwise. The reaction was warmed to 20 °C and stirred for 2 hrs. The mixture was then poured into NH4Cl aq. (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layer was washed with brine (4 × 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to afford compound 45b (6.8 g) as a colorless oil. LCMS (M+H)+: 484. Step 3: preparation of 7-(4-benzyloxybutyl)-1-(4-fluoro-2-methoxy-phenyl)-4- hydroxy-pyrazolo [3, 4-b] pyridin-6-one (compound 45c) To a solution of compound 45b (6.8 g, 14.06 mmol) in dry THF (70 mL) was added LDA (14 mL, 28.13 mmol) at -78 °C under N2atmosphere. The mixture was stirred at 20 °C for 4 hrs. The reaction was quenched with ice water (100 mL) and pH was adjusted to 5 with HCl aq. (1 M). Then it was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via column chromatography to give compound 45c (3.5 g) as a colorless oil. LCMS (M+H)+: 438. Step 4: preparation of 7-(4-bromobutyl)-1-(4-fluoro-2-hydroxy-phenyl)-4-hydroxy- pyrazolo [3, 4-b] pyridin-6-one (compound 45d) To a solution of compound 45c (1.37 g, 3.15 mmol) in DCM (30 mL) was added BBr3(4.72 g, 18.77 mmol) at -78 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction was quenched with methanol (10 mL) under dry ice bath and concentrated. The residue was purified via reversed phase chromatography to give compound 45d (710 mg) as a light yellow solid. LCMS (M+H)+: 396. Step 5: preparation of 5-fluoro-16-hydroxy-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one (compound 45e) To a solution of compound 45d (710 mg, 1.79 mmol) in ACN (450 mL) was added cesium carbonate (1.17 g, 3.57 mmol). The reaction was stirred at 40 °C for 2 hrs. After filtration, the filtrate was concentrated and purified via reversed phase HPLC to give compound 45e (950 mg) as a light yellow solid. LCMS (M+H)+: 316.Step 6: preparation of 16-chloro-5-fluoro-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one (compound 45f) To a solution of compound 45e (600 mg, 1.41 mmol) in ACN (4 mL) was added phosphorus oxychloride (212 µL, 2.28 mmol) dropwise at 25 °C. The reaction was stirred at 80 °C for 12 hrs. The mixture was concentrated and purified via prep-TLC to give compound 45f (50 mg) as a light yellow solid. LCMS (M+H)+: 334. Step 7: preparation of 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one (Example 45) To a solution of compound 45f (40 mg, 0.1 mmol) and intermediate C6 (42 mg, 0.1 mmol,) in DMSO (2 mL) was added DIEA (66 µL, 0.38 mmol) and cesium fluoride (58 mg, 0.38 mmol). The reaction was stirred at 130 °C for 6 hrs under N2 atmosphere. The mixture was purified via prep-HPLC to give Example 45 (14 mg) as an off-white solid. LCMS (M+H)+: 736,1H NMR (400 MHz, METHANOL-d4) δ = 7.96 - 7.83 (m, 1H), 7.63 - 7.50 (m, 3H), 7.20 - 7.11 (m, 2H), 7.02 - 6.93 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.18 - 6.05 (m, 1H), 4.92 - 4.89 (m, 3H), 4.83 - 4.79 (m, 2H), 4.61 - 4.52 (m, 1H), 4.49 - 4.39 (m, 1H), 4.38 - 4.28 (m, 2H), 4.02 - 3.90 (m, 2H), 3.76 - 3.65 (m, 1H), 3.08 (d, J = 1.8 Hz, 3H), 3.05 - 2.87 (m, 5H), 2.83 (d, J = 7.0 Hz, 3H), 2.61 - 2.51 (m, 2H), 2.46 - 2.32 (m, 1H), 1.81 - 1.48 (m, 3H). Example 46 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-oneThe title compound was prepared in analogy to the preparation of example 45 by using intermediate C3 instead of intermediate C6 in step 7. Example 46 (19.9 mg), LCMS (M+H)+: 737,1H NMR (400 MHz, METHANOL-d4) δ = 8.65 (d, J = 5.2 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.58 - 7.52 (m, 1H), 7.20 - 7.13 (m, 2H), 7.01 -6.94 (m, 1H), 5.93 - 5.81 (m, 1H), 4.84 - 4.79 (m, 4H), 4.69 - 4.65 (m, 1H), 4.47 - 4.41 (m, 1H), 4.39 - 4.32 (m, 2H), 4.03 - 3.93 (m, 2H), 3.76 - 3.67 (m, 1H), 3.19 - 3.09 (m, 4H), 3.05 - 2.95 (m, 4H), 2.85 - 2.80 (m, 3H), 2.64 - 2.52 (m, 2H), 2.47 - 2.34 (m, 1H), 1.81 - 1.71 (m, 1H), 1.69 - 1.61 (m, 1H), 1.59 - 1.50 (m, 1H). Example 47 5-fluoro-14-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- 8-oxa-1,11,17-triazatetracyclo[9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16-hexaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 5-[acetyl (2-benzyloxyethyl) amino]-1-(4-fluoro-2- methoxy-phenyl) pyrazole-4-carboxylate (compound 47a) To a solution of compound 45a (1.10 g, 3.42 mmol) in DMF (12 mL) was added sodium hydride (164 mg, 4.11 mmol) at 0 °C under N2 atmosphere. The reaction was stirred at 0 °C for 0.5 hr and benzyl 2-bromoethyl ether (1470 mg, 6.85 mmol) was added dropwise. The reactionwas warmed 20 °C to and stirred for 2 hrs. The mixture was poured into NH4Cl aq. (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified via flash chromatography to afford compound 47a (1.10 g) as a colorless oil. LCMS (M+H)+: 456. Step 2: preparation of ethyl 5- [acetyl (2-hydroxyethyl) amino]-1-(4-fluoro-2-hydroxy- phenyl) pyrazole-4-carboxylate (compound 47b) To a solution of compound 47a (1 g, 2.2 mmol) in DCM (8 mL) was added BCl3 / DCM (13.2 mL, 13.17 mmol) at -78 °C. The reaction was warmed to 20 °C and stirred for 12 hrs. The reaction was quenched with ice water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography to give compound 47b (450 mg) as a colorless oil. LCMS (M+H)+: 352. Step 3: preparation of ethyl 7-acetyl-13-fluoro-10-oxa-2,3,7- triazatricyclo[9.4.0.02,6]pentadeca-1(11),3,5,12,14-pentaene-5-carboxylate (compound 47c) To a solution of compound 47b (200 mg, 0.57 mmol) and PPh3(239 mg, 0.91 mmol) in DCM (12 mL) was added DIAD (168 µL, 0.85 mmol) at 0 °C under N2atmosphere. The reaction was warmed to 20 °C and stirred for 2 hrs. The mixture was concentrated and purified via column chromatography to give a crude solid. Then it was purified via prep-HPLC again to give compound 47c (90 mg) as a white solid. LCMS (M+H)+: 334. Step 4: preparation of 5-fluoro-14-hydroxy-8-oxa-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16-hexaen-12-one (compound 47d) To a solution of compound 47c (90 mg, 0.27 mmol) in dry THF (1 mL) was added LDA (270 µL, 0.54 mmol) at -78 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred for 4 hrs. The reaction was quenched with ice water and pH was adjusted to 5 with HCl aq. (1 M). The mixture was extracted with solvent of EA and MeOH (EA / MeOH, v / v = 10:1, 5 mL × 5). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via prep-TLC to give compound 47d (15 mg) as a yellow solid. LCMS (M+H)+: 288. Step 5: preparation of 14-chloro-5-fluoro-8-oxa-1,11,17-triazatetracyclo [9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16-hexaen-12-one (compound 47e) To a solution of compound 47d (15 mg, 0.05 mmol) in ACN (3 mL) was added POCl3 (27 mg, 0.08 mmol). The reaction was stirred at 80 °C for 12 hrs. The mixture was purified via prep- TLC to give compound 47e (3 mg) as a white solid. LCMS (M+H)+: 306.Step 6: preparation of 5-fluoro-14-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16-hexaen-12-one (Example 47) To a solution of compound 47e (3 mg, 0.01 mmol), intermediate C6 (3.6 mg, 0.01 mmol) in DMSO (300 µL) was added DIEA (7 µL, 0.04 mmol) and cesium fluoride (6 mg, 0.04 mmol). The reaction was stirred at 130 °C for 12 hrs. The mixture was purified via prep-HPLC to give Example 47 (3.2 mg) as a white solid. LCMS (M+H)+: 708,1H NMR (400 MHz, METHANOL- d4) δ = 7.91 - 7.84 (m, 1H), 7.83 - 7.75 (m, 1H), 7.63 - 7.50 (m, 2H), 7.26 - 7.11 (m, 3H), 6.81 - 6.68 (m, 1H), 6.23 - 6.05 (m, 1H), 4.95 - 4.91 (m, 2H), 4.83 - 4.79 (m, 2H), 4.62 - 4.54 (m, 1H), 4.51 - 4.39 (m, 1H), 4.37 - 4.19 (m, 3H), 4.06 - 3.95 (m, 3H), 3.15 - 3.04 (m, 3H), 3.00 - 2.95 (m, 4H), 2.86 - 2.78 (m, 4H), 2.63 - 2.50 (m, 2H). Example 48 (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3,7-triazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:The compound 48a was prepared in analogy to the preparation of compound 47c by using 3-bromopropoxymethylbenzene instead of benzyl 2-bromoethyl ether in step 1.Step 1: preparation of 14-fluoro-11-oxa-2,3,7-triazatricyclo[10.4.0.02,6]hexadeca- 1(16),3,5,12,14-pentaene-5-carboxylic acid (compound 48b) A mixture of compound 48a (100 mg, 0.29 mmol) in aqueous solution of KOH aq. (2 N, 2 mL) was stirred at 100 °C for 2 hrs. The reaction mixture was concentrated. The residue was diluted with THF (10 mL) and concentrated again. Then it was diluted with water (0.5 mL) and acidified with HCl (aq., 1 N), the collected solid was dried to give compound 48b (20 mg) as a yellow solid. LCMS (M+H)+: 278. Step 2: preparation of (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3,7- triazatricyclo[10.4.0.02,6]hexadeca-1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 48) To a solution of compound 48b (20 mg, 0.08 mmol), intermediate C6 (32 mg, 0.08 mmol), O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (33 mg, 0.08 mmol) in DMF (2 mL) was added DIEA (60 µL, 0.28 mmol). The mixture was stirred at 25 °C for 1 h and purified via prep-HPLC to give Example 48 (13.8 mg) as a white solid. LCMS (M+H)+: 698,1H NMR (400 MHz, METHANOL-d4) δ = 8.06 - 7.98 (m, 1H), 7.89 - 7.81 (m, 1H), 7.61 - 7.57 (m, 1H), 7.57 - 7.52 (m, 1H), 7.43 - 7.36 (m, 1H), 7.16 - 7.07 (m, 2H), 7.03 - 6.95 (m, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.25 - 6.11 (m, 1H), 5.22 - 5.09 (m, 1H), 4.60 - 4.50 (m, 1H), 4.47 - 4.30 (m, 4H), 4.22 - 4.05 (m, 2H), 4.00 - 3.90 (m, 1H), 3.28 - 3.25 (m, 1H), 3.03 - 2.94 (m, 7H), 2.88 - 2.85 (m, 3H), 2.74 - 2.66 (m, 1H), 2.60 - 2.35 (m, 2H), 2.07 - 1.98 (m, 2H) Example 49 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- 15-methyl-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18- hexaen-14-oneThe title compound was prepared according to the following scheme:The compound 49a was prepared in analogy to the preparation of compound 45c by using propionyl chloride instead of acetyl chloride in step 1. Step 1: preparation of 7-(4-bromobutyl)-1-(4-fluoro-2-hydroxy-phenyl)-4-hydroxy-5- methyl-pyrazolo [3, 4-b] pyridin-6-one (compound 49b) To a solution of compound 49a (1 g, 2.21 mmol) in DCM (40 mL) was added BBr3(1.3 mL, 13.29 mmol) at -78 °C. The reaction was warmed to 20 °C and stirred for 15 hrs. The reaction was quenched with methanol (20 mL) under dry ice bath (-40 °C). The residue was purified via reversed phase HPLC to give compound 49b (650 mg) as a yellow oil. LCMS (M+H)+: 410. Step 2: preparation of 3-(4-fluoro-2-hydroxy-phenyl)-8-methyl-10-oxa-1,3,4- triazatricyclo[7.5.0.02,6]tetradeca-2(6),4,8-trien-7-one (compound 49c) To a solution of compound 49b (550 mg, 1.34 mmol) in ACN (360 mL) was added cesium carbonate (873 mg, 2.68 mmol). The reaction was stirred at 40 °C for 2 hrs. The mixture was purified via prep-HPLC to give compound 49c (140 mg) as a light yellow solid. LCMS (M+H)+: 330. Step 3: preparation of 16-chloro-5-fluoro-15-methyl-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one (compound 49d) To a solution of compound 49c (70 mg, 0.21 mmol) in ACN (1.4 mL) was added phosphorus oxychloride (35 µL, 0.38 mmol) dropwise at 25 °C. The reaction was stirred at 80 °C for 12 hrs. The mixture was purified via prep-TLC to give compound 49d (20 mg) as a light yellow solid. LCMS (M+H)+: 348. Step 4: preparation of 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18- dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-15-methyl-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one (Example 49) To a solution of compound 49d (18 mg, 0.05 mmol), intermediate C6 (23 mg, 0.05 mmol) in 1,4-dioxane (200 µL) was added Pd-PEPPSI-IPentCl o-picoline (1 mg, 0.05 mmol) and Cs2CO3(54 mg, 0.16 mmol). The reaction was stirred at 100 °C for 3 hrs under N2atmosphere. The mixture was purified via prep-HPLC to give Example 49 (4 mg) as a white solid. LCMS (M+H)+: 750,1H NMR (400 MHz, METHANOL-d4) δ = 8.24 (d, J = 9.3 Hz, 1H), 7.93 - 7.80 (m, 1H), 7.64 - 7.51 (m, 3H), 7.20 - 7.10 (m, 2H), 7.02 - 6.91 (m, 1H), 6.82 - 6.71 (m, 1H), 6.25 - 6.14 (m, 1H), 5.36 - 5.26 (m, 1H), 5.21 (br d, J = 8.1 Hz, 1H), 4.59 - 4.52 (m, 1H), 4.49 - 4.27 (m, 4H), 4.07 - 3.96 (m, 1H), 3.93 - 3.84 (m, 1H), 3.80 - 3.69 (m, 1H), 2.99 (d, J = 4.4 Hz, 3H), 2.95 (s, 3H), 2.93 - 2.90 (m, 1H), 2.89 (br d, J = 7.7 Hz, 1H), 2.85 - 2.82 (m, 3H), 2.64 - 2.52 (m, 2H), 2.22 (d, J = 2.0 Hz, 3H), 1.81 - 1.64 (m, 2H), 1.58 - 1.27 (m, 2H). Example 50 (8S,11S,15R)-22-fluoro-10-[(14R)-5-fluoro-10-oxo-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-bromo-4-fluoro-N-[(Z)-(2, 4, 6-trichloropyrimidin-5-yl) methyleneamino] aniline (compound 50b) To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (10 g, 47.3 mmol) in DMF (100 mL) was added (2-bromo-4-fluoro-phenyl) hydrazine; hydrochloride (50a, 12.5 g, 52.03 mmol). The reaction was stirred at 20 °C for 2 hrs. The mixture was poured into water (1 L) and filtered, the collected solid was dried to give compound 50b (18 g) as a yellow solid. LCMS (M+H)+: 398. Step 2: preparation of 1-(2-bromo-4-fluoro-phenyl)-4, 6-dichloro-pyrazolo [3, 4-d] pyrimidine (50c) The mixture of compound 50b (18 g, 45.18 mmol) in 1, 4-dioxane (360 mL) was stirred at 120 °C for 12 hrs. The mixture was cooled, diluted with water (1 L) and extracted with ethyl acetate (500 mL × 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified via silica gel column to give a yellow solid. The yellow solid was slurried in a mixture of PE and EA (v / v = 10:1, 100 mL), then it was stirred at 20 °C for 12 hrs and filtered. The collected solid was dried to give compound 50c (13 g) as a yellow solid. LCMS (M+H)+: 361.Step 3: preparation of 4-benzyloxy-1-(2-bromo-4-fluoro-phenyl)-6-chloro-pyrazolo [3, 4-d] pyrimidine (compound 50d) To a solution of benzyl alcohol (1.25 g, 11.6 mmol) in THF (40 mL) at 0 °C was added potassium tert-butoxide (11.6 mL, 11.6 mmol). The reaction was stirred at 25 °C for a while and at 70 °C for 1 h under N2atmosphere. To a solution of compound 50c (4 g, 11.05mmol) in THF (40 mL) was added to the above solution at -78 °C. The reaction was warmed slowly to 25 °C and stirred for 12 hrs. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated. The residue was purified via column chromatography to give compound 50d (2.4 g) as a yellow solid. LCMS (M+H)+: 433. Step 4: preparation of ethyl (E)-3-[2-(4-benzyloxy-6-chloro-pyrazolo [3, 4-d] pyrimidin-1-yl)-5-fluoro-phenyl] prop-2-enoate (compound 50e) To the mixture of compound 50d (4 g, 9.22 mmol) and 2-ethoxycarbonylvinylboronic acidified pinacol ester (2 g, 9.22 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added K2CO3(3.82 g, 27.68 mmol) and [[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (810 mg, 1.10 mmol). The reaction was degassed with N2for three times and stirred at 50 °C for 12 hrs. The mixture was concentrated and purified via flash chromatography to give compound 50e (700 mg) as a yellow solid. LCMS (M+H)+: 453. Step 5: preparation of ethyl 3-[5-fluoro-2-(4-hydroxy-6-oxo-7H-pyrazolo [3, 4-b] pyridin-1-yl) phenyl] propanoate (compound 50f) To a solution of compound 50e (700 mg, 2.04 mmol) in methanol (35 mL) was added tris(triphenylphosphine)rhodium(I) chloride (140 mg, 0.15 mmol) at 25 °C under N2atmosphere. The reaction was purged with H2 and stirred at 70 °C for 2 hrs with H2 balloon. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4and concentrated. The residue was purified via column chromatography to give compound 50f (540 mg) as a yellow solid. LCMS (M+H)+: 455. Step 6: preparation of tert-butyl (3R)-3-[[4-benzyloxy-1-[2-(3-ethoxy-3-oxo-propyl)-4- fluoro-phenyl] pyrazolo [3, 4-d] pyrimidin-6-yl] methyl] pyrrolidine-1-carboxylate (compound 50g) The mixture of compound 50f (540 mg, 1.19 mmol), tert-butyl (3S)-3- (iodomethyl)pyrrolidine-1-carboxylate (480 mg, 1.54 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (14 mg, 0.01 mmol), NiCl2(dtbbpy) (5 mg, 0.01 mmol), TTMSS (295 mg, 1.19 mmol), Na2CO3(252mg, 2.37 mmol) in DME (4 mL) was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 14 hrs. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified via column chromatography to give compound 50g (500 mg) as a yellow solid. LCMS (M+H)+: 604. Step 7: preparation of 3-[5-fluoro-2-[4-hydroxy-6-[[(3R)-pyrrolidin-3- yl]methyl]pyrazolo[3,4-d]pyrimidin-1-yl]phenyl]propanoic acid (compound 50h) The solution of compound 50g (500 mg, 0.83 mmol) in con. hydrochloric acid (5 mL) was stirred at 50 °C for 2 hrs. The pH of the mixture was adjusted to 8 with NH3•H2O at 0 °C. Then it was concentrated and purified via prep-HPLC to give compound 50h (200 mg) as a white solid. LCMS (M+H)+: 386. Step 8: preparation of (14R)-5-fluoro-18-hydroxy-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-10- one (compound 50i) To a solution of compound 50h (80 mg, 0.18 mmol) and HATU (21 mg, 0.24 mmol) in DMF (184 mL) was added a solution of DIEA (83 µL, 0.48 mmol) in DMF (35 mL) at 25 °C. The reaction was stirred for 1 h and concentrated. The residue was purified via prep-HPLC to afford compound 50i (20 mg) as a white solid. LCMS (M+H)+: 368. Step 9: preparation of (8S,11S,15R)-22-fluoro-10-[(14R)-5-fluoro-10-oxo- 1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 49) To a solution of compound 50i (20 mg, 0.05 mmol) in DMF (1 mL) was added DIEA (22 µL, 0.14 mmol), PyBop (37 mg, 0.07 mmol) and intermediate C6 (24 mg, 0.05 mmol). The reaction stirred at 60 °C for 18 hrs. The mixture was purified via prep-HPLC to give Example 49 (6 mg) as a white solid. LCMS (M+H)+: 788,1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 7.90 - 7.78 (m, 1H), 7.51 - 7.42 (m, 1H), 7.36 - 7.26 (m, 2H), 7.24 - 7.15 (m, 2H), 7.13 - 7.09 (m, 1H), 6.75 - 6.65 (m, 1H), 5.64 - 5.38 (m, 1H), 4.73 - 4.66 (m, 1H), 4.60 (s, 3H), 4.54 - 4.45 (m, 1H), 4.40 - 4.33 (m, 1H), 4.31 - 4.26 (m, 1H), 4.21 - 4.05 (m, 2H), 3.98 - 3.81 (m, 2H), 3.43 - 3.37 (m, 1H), 3.17 - 3.06 (m, 4H), 3.02 - 2.91 (m, 3H), 2.89 - 2.84 (m, 4H), 2.77 - 2.74 (m, 1H), 2.72 - 2.69 (m, 1H), 2.63 (br d, J = 6.8 Hz, 1H), 2.61 - 2.56 (m, 4H), 2.53 - 2.49 (m, 1H), 2.37 - 2.25 (m, 1H).Example 51 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of 5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-ol (compound 51a) To a solution of compound 41i (25 mg, 0.06 mmol) in ethanol (1 mL) was added Pd / C (4 mg, 0.18 mmol). The reaction was stirred at 20 °C for 1 h under H2 balloon. The mixture was filtered and concentrated to give compound 51a (25 mg) as a brown oil. LCMS (M+H)+: 331. Step 2: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 51) To the solution of compound 51a (25 mg, 0.08 mmol) in DMF (2 mL) were added PyBop (51 mg, 0.1 mmol) and DIEA (31 µL, 0.19 mmol) and intermediate C6 (23 mg, 0.05 mmol). The reaction was stirred at 20 °C for 12 hrs. The mixture was purified via prep-HPLC to give Example 51 (5.6 mg) as a white solid. LCMS (M+H)+: 751,1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.40 (m, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.65 - 7.49 (m, 1H), 7.35 - 7.27 (m, 1H), 7.22 - 7.02 (m, 3H), 6.95 - 6.84 (m, 1H), 6.70 (d, J = 8.3 Hz, 1H), 5.83 - 5.65 (m, 1H), 5.60 - 5.35 (m, 1H), 4.56 - 4.54 (m, 2H), 4.47 - 4.41 (m, 1H), 4.36 - 4.26 (m, 1H), 4.21 - 4.08 (m, 3H), 4.00 - 3.90 (m, 1H), 3.81 - 3.56 (m, 2H), 3.14 (s, 1H), 3.05 (s, 2H), 2.89 (br d, J = 14.2 Hz, 1H), 2.86 - 2.82 (m, 3H), 2.68 - 2.44 (m, 6H), 1.82 - 1.68 (m, 2H), 1.40 - 1.26 (m, 2H), 1.22 - 1.15 (m, 1H). Example 52 (6S)-14-fluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-11-oxa-2,8,18,19,23,24- hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24-heptaen-7- oneThe title compound was prepared in analogy to the preparation of example 21 by using tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate instead of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylatem in step 1. Example 52 (6 mg), LCMS (M+H)+: 819.1H NMR (400 MHz, METHANOL-d4) δ = 8.21 - 8.11 (m, 1H), 7.88 - 7.73 (m, 1H), 7.47 - 7.39 (m, 2H), 7.33 - 7.26 (m, 1H), 7.15 - 7.12 (m, 1H), 7.09 - 7.05 (m, 1H), 6.84 - 6.78 (m, 1H), 6.70 - 6.64 (m, 1H), 5.93 - 5.64 (m, 1H), 5.49 - 5.37 (m, 1H), 5.29 - 5.23 (m, 1H), 4.49 - 4.43 (m, 2H), 4.31 - 4.12 (m, 4H), 3.97 - 3.85 (m, 2H), 3.65 - 3.54 (m, 1H), 3.51 - 3.40 (m, 2H), 3.39 - 3.33 (m, 1H), 3.13 - 3.08 (m, 2H), 3.05 (d, J = 2.8 Hz, 2H), 3.02 - 2.97 (m, 3H), 2.87 - 2.82 (m, 3H), 2.60 - 2.54 (m, 3H), 2.52 - 2.41 (m, 2H), 2.19 - 2.07 (m, 2H), 2.00 - 1.89 (m, 2H). Example 53 (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-10-yn-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of (Z)-1, 2, 4-tribromobut-2-ene (compound 53a) To a solution of but-2-yne-1,4-diol (10 g, 116.16 mmol) was added HBr / AcOH (496 g, 1161.58 mmol) dropwise at 0 °C. The reaction was stirred at 20 °C for 16 hrs and quenched with cold NaHCO3aq. (200 mL). The mixture was extracted with ethyl acetate (200 mL × 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column to give compound 53a (7 g) as a colorless oil. Step 2: preparation of [4-benzyloxy-1-[2-[(Z)-3,4-dibromobut-2-enoxy]-4-fluoro- phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]methanol (compound 53b) To a solution of compound 41g (200 mg, 0.55 mmol) and Na2CO3 (115 mg, 1.09 mmol) in DMF (2 mL) was added compound 53a (1.6 g, 5.46 mmol) at 20 °C. The reaction was stirred for 2 hrs and quenched with water (20 mL). Then it was extracted with ethyl acetate (20 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over anhydrous Na2SO4 andconcentrated. The residue was purified via flash chromatography to give compound 53b (240 mg) as a colorless oil. LCMS (M+H)+: 577. Step 3: preparation of preparation of 17-benzyloxy-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-10-yne & (10Z)-17-benzyloxy-11-bromo-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15(22),16,18(21),19-octaene (compound 53c) To a solution of sodium hydride (30 mg, 0.73 mmol) in dry THF (14 mL) was added a solution of compound 53b (140 mg, 0.24 mmol) in dry THF (56 mL) dropwise at -15 °C for 2 hrs under N2 atmosphere. The reaction was stirred at -15 °C for another 1 h and then it was quenched with 0.5 mL NH4Cl aq. The mixture was concentrated and purified via prep-TLC to give compound 53c (52 mg) as a light brown solid. LCMS (M+H)+: 417 and LCMS (M+H)+: 497. Step 4: preparation of 5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-10-yn-17- ol & (10Z)-11-bromo-5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2(7),3,5,10,15(22),16,18(21),19-octaen-17-ol (compound 53d) To a solution of compound 53c (52 mg, 0.07 mmol) in DCE (1 mL) was added TFA (0.2 mL). The reaction was stirred at 20 °C for 12 hrs and then it was quenched with cold NaHCO3(aq., 1 mL). The mixture was extracted with DCM (2 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude compound 53d (50 mg), which was used in the next step directly. LCMS (M+H)+: 327 and LCMS (M+H)+: 407. Step 5: preparation of 5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-10-yn-17- ol (compound 53e) To a solution of compound 53d (50 mg, 0.12 mmol) in DMF (1 mL) was added cesium carbonate (117 mg, 0.36 mmol) at 20 °C. The reaction was heated to 40 °C and stirred for 16 hrs. The reaction was quenched with ice water (3 mL) and the pH was adjusted to 6 with TFA. Then it was extracted with EA (3 mL × 3). The organic layer was washed with brine (3 mL × 3), dried over Na2SO4, filtered and concentrated to give compound 53e (43 mg) as a yellow oil. LCMS (M+H)+: 327. Step 6: preparation of (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-10-yn-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 53) To a solution of compound 53e (39 mg, 0.12 mmol) in DMF (2 mL) was added PyBop (62 mg, 0.12 mmol), DIEA (37 µL, 0.23 mmol) and intermediate C6 (40 mg, 0.09 mmol). The reaction was stirred at 20 °C for 2 hrs. The mixture was purified via prep-HPLC to give Example 53 (1.7 mg) as a light yellow solid. LCMS (M+H)+: 747,1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.33 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.19 - 7.13 (m, 1H), 7.12 - 7.06 (m, 1H), 7.04 - 6.97 (m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.82 - 5.67 (m, 1H), 5.54 - 5.33 (m, 1H), 4.59 (br s, 2H), 4.52 - 4.47 (m, 1H), 4.34 - 4.25 (m, 2H), 4.24 - 4.09 (m, 2H), 3.99 - 3.91 (m, 1H), 3.16 - 3.11 (m, 2H), 3.04 (s, 2H), 2.92 - 2.82 (m, 5H), 2.66 - 2.60 (m, 1H), 2.60 - 2.45 (m, 5H), 1.93 - 1.88 (m, 1H). Example 54 (8S,11S,15R)-22-fluoro-10-(5-fluoro-11,11-dioxo-11λ⁶-thia-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-oneThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 2-(3-iodopropylsulfanyl)acetate (compound 54a) To a solution of ethyl 2-sulfanylacetate (3.7 mL, 33.87 mmol) in ACN (120 mL) was added K2CO3 (14 g, 101.39 mmol) at 0 °C under N2 atmosphere. The reaction was stirred at 25 °C for 30 mins and a solution of 1,3-diiodopropane (15 g, 50.69 mmol) in ACN (30 mL) was added.4 hrs later, the reaction was quenched with cold NH4Cl aq. (200 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified via flash chromatography to give compound 54a (7 g) as a colorless oil. Step 2: preparation of 4-benzyloxy-6-chloro-1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidine (compound 54b) To a solution of benzyl alcohol (1381 mg, 12.78 mmol) in THF (30 mL) was added potassium tert-butoxide in THF (13 mL, 12.78 mmol) at 0 °C. The reaction was stirred at 70 °C for 0.5 h under N2 atmosphere. To a solution of compound 42b (4 g, 12.78 mmol) in THF (100 mL) was added the above solution at -78 °C. The mixture was warmed slowly to 20 °C and stirred for 1 hr. The reaction was quenched with cold water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layer was washed with brine (300 mL), dried overanhydrous Na2SO4 and concentrated. The residue was purified via flash chromatography to give compound 54b (5.8 g) as a yellow solid. LCMS (M+H)+: 385. Step 3: preparation of ethyl 2-[3-[4-benzyloxy-1-(4-fluoro-2-methoxy- phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]propylsulfanyl]acetate (compound 54c) The mixture of compound 54b (2 g, 5.2 mmol), compound 54a (3 g, 10.4 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (58 mg, 0.05 mmol), NiCl2(dtbbpy) (24 mg, 0.03 mmol), TTMSS (1.29 g, 5.2 mmol), Na2CO3 (1.1 g, 10.4 mmol) in DME (20 mL) was stirred and irradiated with a 34 W blue LED lamp at 25 °C for 14 hrs. The mixture was filtered and concentrated. The residue was purified via flash chromatography to give compound 54c (600 mg). LCMS (M+H)+: 511. Step 4: preparation of 2-[3-[4-benzyloxy-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]propylsulfanyl]ethanol (compound 54d) To a solution of compound 54c (300 mg, 0.59 mmol) in THF (10 mL) was added a solution of DIBAL-H in toluene (6 mL, 5.88 mmol) at -78 °C. The mixture was stirred at 25 °C for 6 hrs. The reaction was quenched with water (2 mL) and 10% NaOH aq. (6 mL) and Na2SO4(1 g). The mixture was stirred at 25 °C for 30 mins and filtered through a pad of celite. The filtrate was concentrated and purified via flash chromatography to give compound 54d (150 mg) as a light yellow oil. LCMS (M+H)+: 469. Step 5: preparation of 1-(4-fluoro-2-hydroxy-phenyl)-6-[3-(2- hydroxyethylsulfanyl)propyl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 54e) To a solution of compound 54d (150 mg, 0.32 mmol) in DCM (10 mL) was ...

Claims

CLAIMS 1. A compound of formula (Ia),wherein M1is heteroarylene optionally substituted by R1; wherein R1is deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl, RSO2C1-6alkyl, RNHSO2C1-6alkyl, R2NSO2C1-6alkyl, RSO(NR)C1-6alkyl or R3SiC1-6alkyl; wherein R is H, Ra, Rbor Rc; Rais C1-6alkyl optionally substituted by Rbor Rc; Rbis C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rcis selected from deuterio, C1-6alkyl, (C1-6alkyl)3Si, haloC1-6alkyl, deuterioC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, deuterioC1-6alkoxy, C2-6alkenyl, haloC2-6alkenyl, deuterioC2-6alkenyl, C2-6alkynyl, haloC2-6alkynyl, deuterioC2-6alkynyl, C3- 7cycloalkyl, haloC3-7cycloalkyl, deuterioC3-7cycloalkyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylcarbonylamino, haloC1-6alkylamino, haloC1-6alkylcarbonylamino, (haloC1-6alkyl)2amino, C3-7cycloalkylamino, C3-7cycloalkylcarbonylamino, (C3-7cycloalkyl)2amino, haloC3-7cycloalkylamino, (haloC3-7cycloalkyl)2amino, C3-7cycloalkyl(C1-6alkyl)amino, haloC3- 7cycloalkyl(C1-6alkyl)amino, C1-6alkylsulfonylamino, haloC1-6alkylsulfonylamino, C1-6alkoxyC1-6alkyl, (haloC1-6alkoxy)C1-6alkyl, C1- 6alkoxy(halo)C1-6alkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylhaloC1-6alkyl, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkoxycarbonyl, haloC1-6alkoxycarbonyl, C3-7cycloalkoxycarbonyl, haloC3-7cycloalkoxycarbonyl, C1-6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, C3-7cycloalkylaminocarbonyl, (C3-7cycloalkyl)2aminocarbonyl, C1-6alkylC3-7cycloalkylaminocarbonyl, haloC1- 6alkylaminocarbonyl, halo(C1-6alkyl)2aminocarbonyl, haloC3- 7cycloalkylaminocarbonyl, halo(C3-7cycloalkyl)2aminocarbonyl, haloC1-6alkylC3-7cycloalkylaminocarbonyl, C1-6alkylhaloC3-7cycloalkylaminocarbonyl, (C1-6alkyl)3ammonio, C1-6alkylsulfanyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C3- 7cycloalkylsulfanyl, C3-7cycloalkylsulfinyl, C3-7cycloalkylsulfonyl, haloC1- 6alkylsulfanyl, haloC1-6alkylsulfinyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfanyl, haloC3-7cycloalkylsulfinyl, haloC3-7cycloalkylsulfonyl, haloC1-6alkoxysulfonyl, C1-6alkylaminosulfonyl, (haloC1-6alkylamino)sulfonyl, (C1-6alkyl)2aminosulfonyl, (haloC1-6alkyl)2aminosulfonyl, (C1-6alkyl)2phosphoryl, (C1-6alkoxy)2phosphoryl, hydroxy(C1-6alkoxy)phosphoryl, C1-6alkoxyphosphoryl, hydroxy, hydroxyC1-6alkyl, hydroxyhaloC1-6alkyl, hydroxyC1-6alkoxy, hydroxylhaloC1-6alkoxy, hydroxyC3-7cycloalkyl, hydroxyhaloC3-7cycloalkyl and sulfonimidoyl, each of which is optionally substituted by H, halogen, C1-6alkyl, C1-6alkoxy, aryl, heteroaryl or heterocyclyl; M2is arylene, heterocyclylene or heteroarylene, said arylene, heterocyclylene or heteroarylene being optionally substituted by R1; M3is heterocyclylene which is substituted by R3and optionally substituted by R1; R2is deuterio, R, ROC1-6alkyl, RSC1-6alkyl, RSO2C1-6alkyl, RNHC1-6alkyl or (R)2NC1-6alkyl; T1is -W-, -W-O-W-, -W-S-W-, -W-SO2-W-, -W-SO(NR)-W-, -W-SiR2-W-, -C1- 6alkylene-W-C1-6alkylene- or -W-N(R)-W-; wherein each W is independently selected from C1-6alkylene, -C1-6alkylene-O-, -C1-6alkylene-S-, C3-7cycloalkylene, arylene, heteroarylene and heterocyclylene, each of which is unsubstituted or optionally substituted by the substituents independently selected from deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, R2N, RSO2, ROC1-6alkyl, RSC1-6alkyl, RNHC1-6alkyl, (R)2NC1-6alkyl and RSO2C1-6alkyl; or T1and R2, or T1and R1which is the substitution on M1, together with the atoms they attached to form a heterocyclylene or C3-7cycloalkylene;T2is C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, heterocyclylene, heteroarylene or arylene; ; whereinaryl, carbonylaryl, heteroaryl, carbonylheteraryl or heterocyclyl with three bonds connecting to M3, T3and T4; M5is a bond, or optionally substituted arylene, heteroarylene or heterocyclylene; T3is; wherein each L1, L2, L3and L4is independently selected from a bond, C1-6alkylene optionally substituted by R1, haloC1-6alkylene optionally substituted by R1, N(R), O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, SiR2, C3-7cycloalkylene optionally substituted by R1, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, C2-6alkenylene optionally substituted by R1, haloC1- 6alkenylene optionally substituted by R1, C2-6alkynylene optionally substituted by R1, haloC1-6alknylene optionally substituted by R1, arylene optionally substituted by R1, heteroarylene optionally substituted by R1, and heterocyclylene optionally substituted by R1; g, h, j and k are each independently 0, 1, 2 or 3; T4is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I),wherein A1is N or CR4, wherein R4is H or halogen; A2is N or CR4, wherein R4is H or halogen; A3is N or CR4, wherein R4is H or halogen; A4is N or CR4, wherein R4is H or halogen; A5is N or CR4, wherein R4is H or halogen; A6is N or CR4, wherein R4is H or halogen; A7is N or CR4, wherein R4is H or halogen; A8is N and A9is C, or A8is C and A9is N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;Y1is heterocyclyl, heteroaryl or carbonylheteroaryl, each of which has three bonds connecting to N, Q3and Q4, and is further substituted by R5, wherein R5is H, deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy;Y2is a bond, heteroarylene or arylene, each of which is once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy or C1-6alkoxy; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently selected from heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene, C1-6alkylene, carbonyl, carbonyl(C1-6alkyl)amino, - COO-, O and sulfonyl, wherein heterocyclylene, heteroarylene, arylene, C3-7cycloalkylene and C1-6alkylene are unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2, heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl; each L3is independently C1-6alkylene, C2-6alkenylene, C2-6alkynylene, heteroaryl or heterocyclylene, each of which is unsubstituted or once or twice substituted by deuterio, halogen, CN, OH, amino, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkoxy, C1-6alkylSO2, haloC1-6alkylSO2,heterocyclyl, heteroaryl, C3-7cycloalkyl or haloC3-7cycloalkyl; each L4is independently NH, S, SO, SO2, O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2, wherein A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen;A7is CH or N; A8is N and A9is C, or A8is C and A9is N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;H or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen;; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1-6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2- 6alkynylene, hydroxyC1-6alkylene or piperazinylene; each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I-1) according to any one of claims 1-3,wherein A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH or N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O;R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene; ,; wherein R5is H or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen;; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2-6alkynylene, hydroxyC1-6alkylene or piperazinylene;each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously; Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I-2) according to any one of claims 1-4,wherein A1is CH or N; A2is CH or N; A3is CH; A4is CH or N; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH or N; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH or O; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;H or C1-6alkyl; Y2is a bond, phenylene once or twice substituted by halogen, or pyridylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene, NH or O; each L2is independently 1,7-diazaspiro[4.4]nonanylene, 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2,7-diazaspiro[4.4]nonanylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, 3,6- diazabicyclo[3.1.1]heptanylene, azetidinylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl, carbonyl(C1- 6alkyl)amino, -COO-, halopyrrolidinylene, O, morpholinylene, pyrrolidinylene, sulfonyl or triazolylene; each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene, C2- 6alkynylene, hydroxyC1-6alkylene or piperazinylene; each L4is independently O, carbonyl or C1-6alkylene; g, j and k are each independently 0 or 1; h is 0, 1, 2 or 3; with the proviso that g, h, j and k are not 0 simultaneously;Q4is a bond, carbonyl, hydroxyC1-6alkylene or sulfinimidoyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 2-5, wherein A1is N.

7. A compound according to any one of claims 2-6, wherein A4is CH.

8. A compound according to any one of claims 2-7, wherein A6is CR4, wherein R4is H or fluoro.

9. A compound according to any one of claims 2-8, wherein A7is CH.

10. A compound according to any one of claims 2-9, wherein Q1is methylene unsubstituted or substituted by methoxy or ethoxy.

11. A compound according to any one of claims 2-10, wherein m is 1 and n is 1.

12. A compound according to any one of claims 2-11, wherein Q2is NH.

13. A compound according to any one of claims 2-12, wherein R1is methyl.

14. A compound according to any one of claims 2-13, wherein R2is methyl; or R2and Q1together with the atoms they attached to form 1,4-oxazepanylene.

15. A compound according to any one of claims 2-14, wherein Y1iswherein R5is H.

16. A compound according to any one of claims 2-15, wherein Y2is phenylene substituted by halogen.

17. A compound according to any one of claims 2-16, wherein Y2is phenylene substituted by fluoro.

18. A compound according to any one of claims 2-17, wherein each L1is independently a bond, C1-6alkylene or O.

19. A compound according to any one of claims 2-18, wherein each L1is independently a bond, methylene or O.

20. A compound according to any one of claims 2-19, wherein each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinylene, 2-oxa-5- azabicyclo[4.1.0]heptanylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl(C1-6alkyl)amino, -COO-, halopyrrolidinylene, morpholinylene, O or pyrrolidinylene.

21. A compound according to any one of claims 2-20, wherein each L2is 2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b][1,4]oxazinylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, carbonyl(methyl)amino, -COO-, cyclobutylene, difluoropyrrolidinylene, ethylene, methoxypyrrolidinylene, methylene, morpholinylene, O or pyrrolidinylene.

22. A compound according to any one of claims 2-21, wherein each L3is independently C1-6alkylene, C2-6alkenylene, haloC2-6alkenylene or C2-6alkynylene.

23. A compound according to any one of claims 2-22, wherein each L3is independently fluorobutenylene, butenylene, butylene, butynylene, ethylene or methylene.

24. A compound according to any one of claims 2-23, wherein each L4is O.

25. A compound according to any one of claims 2-24, wherein g, j and k are 1.

26. A compound according to any one of claims 2-25, wherein h is 1 or 2.

27. A compound according to any one of claims 2-26, wherein Q4is a bond.

28. A compound according to any one of claims 2-5, wherein A1is N; A2is CH or N; A3is CH; A4is CH; A5is CH or N; A6is CR4, wherein R4is H or halogen; A7is CH; Q1is C1-6alkylene unsubstituted or substituted by C1-6alkoxy; Q2is NH; R1is C1-6alkyl; R2is C1-6alkyl; or R2and Q1together with the atoms they attached to form a heterocyclylene;; whereinY2is phenylene substituted by halogen; Q3is; wherein each L1is independently a bond, C1-6alkylene or O; each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4- b][1,4]oxazinylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, C1-6alkylene, C1-6alkoxypyrrolidinylene, C3-7cycloalkylene, carbonyl(C1-6alkyl)amino, -COO-, halopyrrolidinylene, morpholinylene, O or pyrrolidinylene; each L3is independently C1-6alkylene, C2-6alkenylene or C2-6alkynylene; each L4is O; g, j and k are 1; h is 1 or 2; Q4is a bond; m is 1; n is 1; or a pharmaceutically acceptable salt thereof.

29. A compound according to claim 28, wherein A1is N; A2is CH or N; A3is CH; A4is CH; A5is CH or N; A6is CR4, wherein R4is H or fluoro; A7is CH; Q1is C1-6alkylene unsubstituted or substituted by methoxy or ethoxy; Q2is NH;R1is methyl; R2is methyl; or R2and Q1together with the atoms they attached to form 1,4- oxazepanylene;Y2is phenylene substituted by fluoro; Q3is; wherein each L1is independently a bond, methylene or O; each L2is independently 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4- b][1,4]oxazinylene, 2-oxa-5-azabicyclo[4.1.0]heptanylene, carbonyl(methyl)amino, -COO-, cyclobutylene, difluoropyrrolidinylene, ethylene, methoxypyrrolidinylene, methylene, morpholinylene, O or pyrrolidinylene; each L3is independently (methyl)butenylene, butenylene, butylene, butynylene, ethylene or methylene; each L4is O; g, j and k are 1; h is 1 or 2; Q4is a bond; m is 1; n is 1; or a pharmaceutically acceptable salt thereof.

30. A compound selected from: (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10E)-3,5-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[(10Z)-5,10-difluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-12-oxo-1,11,17- triazatetracyclo[9.6.1.02,7.015,18]octadeca-2,4,6,13,15(18),16-hexaen-14-yl)-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one;(8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazapentacyclo[13.5.2.110,12.02,7.018,21]tricosa-2,4,6,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-13,18-dimethyl-7-oxa- 5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18- dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,3,16,20,22- pentazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,12,13,14,17,21,23-heptazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,11(24),12,16,18,20,22-nonaen-18-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-13-oxo-1,12,18- triazatetracyclo[10.6.1.02,7.016,19]nonadeca-2(7),3,5,14,16(19),17-hexaen-15-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (14S)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3,7-triazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8-oxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21] docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17, 19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen- 12-one; (15R)-5-fluoro-19-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,12,18,22,24-pentazapentacyclo [15.5.2.112,15.02,7.020,23]pentacosa- 2(7),3,5,17(24),18,20(23),21-heptaen-11-one; (6S)-17-fluoro-25-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-14-oxa-2,8,21,22,26,27-hexazahexacyclo [19.5.2.02,6.08,12.015,20.024,28]octacosa- 1(26),15(20),16,18,22,24,27-heptaen-7-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(15S)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo [15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen- 19-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (14R)-5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20 (24),21-heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (6S)-14-fluoro-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8,11-dioxa-2,18,19,23,24-pentazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(24),12,14,16,19,21(25),22-heptaen-7-one;(8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-3,6-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),2,4,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(5R)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(5S)-8-fluoro-5-methyl-4,5-dihydropyrazolo[5,1- d][1,5]benzoxazepine-3-carbonyl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(14R)-5-fluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (6S)-4,4,14-trifluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-11-oxa-2,8,18,19,23,24-hexazapentacyclo [16.5.2.02,6.012,17.021,25]pentacosa-1(24),12,14,16,19,21(25),22-heptaen-7-one; 12-fluoro-6-methyl-20-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-9-oxa-2,6,16,17,21,22-hexazapentacyclo[14.5.2.12,4.010,15.019,23]tetracosa- 1(21),10(15),11,13,17,19,22-heptaen-5-one; 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-12-oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.12,5.05,9.013,18.022,26]heptacosa- 1(25),13(18),14,16,20,22(26),23-heptaen-10-one; 15-fluoro-23-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]-12-oxa-2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,6.013,18.022,26]heptacosa- 1(24),13(18),14,16,20,22,25-heptaen-10-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(14R)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(14S)-5,13,13-trifluoro-8-oxa- 1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20- heptaen-18-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3-diazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,18R)-25-fluoro-21-methyl-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa- 2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24- heptaen-22-yl]-17-oxa-7,10,13,20,22,30-hexazahexacyclo [18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[(6S)-14-fluoro-8-methyl-7-oxo-11-oxa-2,8,18,19,23,24- hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa-1(23),12(17),13,15,19,21,24-heptaen-22-yl]- 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(13-fluoro-10-oxa-2,3-diazatricyclo[9.4.0.02,6]pentadeca- 1(11),3,5,12,14-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(10E)-5-fluoro-8,13-dioxa- 1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,10,15,17,19,21-octaen-17-yl]- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15(22),16,18(21),19-heptaen-17-yl)-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(15-fluoro-12-oxa-2,3-diazatricyclo[11.4.0.02,6]heptadeca- 1(17),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-22-fluoro-10-(5-fluoro-8,11,14-trioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one;5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18- hexaen-14-one; 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14-one; 5-fluoro-14-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,11,17-triazatetracyclo[9.6.1.02,7.015,18]octadeca-2(7),3,5,13,15(18),16- hexaen-12-one; (8S,11S,15R)-22-fluoro-10-(14-fluoro-11-oxa-2,3,7-triazatricyclo[10.4.0.02,6]hexadeca- 1(12),3,5,13,15-pentaene-5-carbonyl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 5-fluoro-16-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-15-methyl-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa- 2(7),3,5,15,17(20),18-hexaen-14-one; (8S,11S,15R)-22-fluoro-10-[(14R)-5-fluoro-10-oxo-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (6S)-14-fluoro-8-methyl-22-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-11-oxa-2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(23),12(17),13,15,19,21,24-heptaen-7-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-8,13-dioxa-1,16,20,22- tetrazatetracyclo[13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-10-yn-17-yl)-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(5-fluoro-11,11-dioxo-11λ⁶-thia-1,16,20,22-tetrazatetracyclo [13.5.2.02,7.018,21]docosa-2(7),3,5,15,17,19,21-heptaen-17-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(6S)-4,4,14-trifluoro-8-methyl-7- oxo-11-oxa-2,8,18,19,23,24-hexazapentacyclo[16.5.2.02,6.012,17.021,25]pentacosa- 1(23),12(17),13,15,19,21,24-heptaen-22-yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-22-fluoro-10-(5-fluoro-14-oxo-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-16-yl)-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 16-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]- 5-fluoro-8-oxa-1,13,19-triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-14- one; (8S,11S,18S)-25-fluoro-10-(5-fluoro-14-oxo-8-oxa-1,13,19- triazatetracyclo[11.6.1.02,7.017,20]icosa-2(7),3,5,15,17(20),18-hexaen-16-yl)-21-methyl-17-oxa- 7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 5-fluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-15-oxa-1,9,12,17,21,23-hexazapentacyclo[14.5.2.29,12.02,7.019,22]pentacosa- 2,4,6,16(23),17,19(22),20-heptaen-8-one; 5,13,13-trifluoro-18-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-8-oxa-1,11,17,21,23-pentazapentacyclo [14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-10-one; (8S,11S,15R)-15-ethoxy-22-fluoro-10-(14-fluoro-11-oxa-2,3,7- triazatricyclo[10.4.0.02,6]hexadeca-1(16),3,5,12,14-pentaene-5-carbonyl)-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S)-13,18-dimethyl-10-(5,13,13-trifluoro-8-oxa-1,11,17,21,23- pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa-2(7),3,5,16(23),17,19(22),20-heptaen-18-yl)- 5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-(5-fluoro-8,13-dioxa-1,16,20,22-tetrazatetracyclo[13.5.2.02,7.018,21]docosa- 2,4,6,15,17,19,21-heptaen-17-yl)-13,18-dimethyl-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (6S)-17-fluoro-25-[rac-(8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-10-yl]- 14-oxa-2,8,21,22,26,27-hexazahexacyclo[19.5.2.02,6.08,12.015,20.024,28]octacosa- 1(26),15(20),16,18,22,24,27-heptaen-7-one; (8S,11S)-10-(15-fluoro-12-oxa-2,3-diazatricyclo[11.4.0.02,6]heptadeca-1(17),3,5,13,15- pentaene-5-carbonyl)-13,18-dimethyl-7-oxa-10,13,18,19-tetrazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(13S,14R)-5-fluoro-13-methoxy- 8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(13R,14S)-5-fluoro-13-methoxy- 8-oxa-1,11,17,21,23-pentazapentacyclo[14.5.2.111,14.02,7.019,22]tetracosa- 2(7),3,5,16(23),17,19(22),20-heptaen-18-yl]-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(16-fluoro-2-imino-13-oxa-2λ⁴-thia-4,6- diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-5-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-(12-methylene-10-oxa-1,2,6- triazatricyclo[6.5.1.04,14]tetradeca-2,4(14),5,7-tetraen-5-yl)-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[12-(hydroxymethyl)-10-oxa-1,2,6- triazatricyclo[6.5.1.04,14]tetradeca-2,4(14),5,7-tetraen-5-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; 16-fluoro-5-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]-13-oxa-4,6-diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-2-one; (8S,11S,18S)-25-fluoro-10-[(15R)-5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]-21-methyl- 17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.12,6.18,11.113,18.023,27]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]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-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-13,18-dimethyl-10-[-(15R)-5-fluoro-8,14-dioxa-1,11,18,22,24- pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19-yl]- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(15R)-5-fluoro-8,14-dioxa- 1,11,18,22,24-pentazapentacyclo[15.5.2.111,15.02,7.020,23]pentacosa-2,4,6,17,19,21,23-heptaen-19- yl]-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-(16-fluoro-2-hydroxy-13-oxa-4,6- diazatricyclo[12.4.0.03,8]octadeca-1(18),3,5,7,14,16-hexaen-5-yl)-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[(6R,7S)-15-fluoro-5,12-dioxa-2,9,19,20,24,25- hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25-heptaen-23-yl]- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one;(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(6S,7R)-15-fluoro-5,12-dioxa- 2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25- heptaen-23-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-10-[(6S,7R)-15-fluoro-5,12-dioxa- 2,9,19,20,24,25-hexazahexacyclo[17.5.2.16,9.02,7.013,18.022,26]heptacosa-1(24),13,15,17,20,22,25- heptaen-23-yl]-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-10-[(16R)-5-fluoro-8,15-dioxa- 1,11,19,23,25-pentazahexacyclo[16.5.2.111,16.02,7.012,14.021,24]hexacosa-2,4,6,18,20,22,24- heptaen-20-yl]-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16R)-5-fluoro-20-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]-8,15-dioxa-1,11,19,23,25- pentazahexacyclo[16.5.2.111,16.02,7.012,14.021,24]hexacosa-2,4,6,18,20,22,24-heptaen-10-one; (3S,5R)-17-fluoro-25-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]-14-oxa-2,7,21,22,26,27-hexazahexacyclo[19.5.2.13,7.02,5.015,20.024,28]nonacosa- 1(26),15(20),16,18,22,24,27-heptaen-8-one; and (8S,11S,15R)-22-fluoro-10-[(3S,5R)-17-fluoro-14-oxa-2,7,21,22,26,27- hexazahexacyclo[19.5.2.13,7.02,5.015,20.024,28]nonacosa-1(26),15(20),16,18,22,24,27-heptaen-25- yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; or a pharmaceutically acceptable salt thereof.

31. A process for the preparation of a compound according to any one of claims 1 to 30 comprising the following step:a) the formation of compound of formula (I) via nucleophilic substitution between compound offormula (VIII), (VIII), and R3X in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VIII) and R3X in the presence of a catalyst; or via nucleophilic substitution between compound of formula (VIII) and R3SO2Me under a basic condition; or via condensation reaction between compound of formula (VIII) and R3OH in the presence of coupling reagent; wherein X is halogen; the base is DIEA; the catalyst is Pd2(dba)3; the basic condition is DIPEA; the coupling reagent is PyBOP or HATU; R1, R2, Q1, Q2, A1to A6are as defined as in any one of claim 1 to 29.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 30 for use as therapeutically active substance.

33. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 30 and a pharmaceutically acceptable excipient.

34. The use of a compound according to any one of claims 1 to 30 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.

35. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 30 for the preparation of a medicament 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.

36. The use of a compound according to any one of claims 1 to 30 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.

37. The use of a compound according to any one of claims 1 to 30 for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.

38. The use of a compound according to any one of claims 1 to 30 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.

39. The use of a compound according to any one of claims 1 to 30 for the inhibition of STING.

40. The use of a compound according to any one of claims 1 to 30 for the preparation of a medicament for the inhibition of STING.

41. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 30, when manufactured according to a process of claim 31.

42. 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 claims1 to 30.

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