Macrocycles for the treatment of autoimmune disease

Abstract

The present invention relates to compounds of formula (I), wherein Q1 to Q4, 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 38697 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 compounds of formula (I),wherein M1is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1is deuterio, halogen, cyano, carboxy, NO2, 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 C2-6alkenylene, arylene, heterocyclylene heteroarylene, C3-7cycloakylene, haloC3-7cycloakylene, cubanylene, bicycle[1.1.1]pentanylene, or admentanylene, each of which is optionally substituted by R1; M3is heterocyclylene which is substituted by R2and optionally substituted by R1; wherein R2is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, each of which is optionally substituted by Rb;SO(NR)-W-, -W-SiR2-W-, -C1-6alkylene-W-C1-6alkylene-, -W-CONH-W-, -W- CON(R)-W-, -W-N(R)CO-W- or -W-N(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, 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; Q2is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3is C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; Q4is a bond, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; or a pharmaceutically acceptable salt thereof. Another object of the present invention is related to novel compounds of formula (I). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as STING antagonist, and for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, or selective types of cancers where overexpression or activation of STING is implicated. The compounds of formula (I) show superior STING antagonism activity. In addition, the compounds of formula (I) 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 “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 4carbon 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 “C1-6alkoxy” denotes C1-6alkyl-O-. 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 “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 “halopyrrolidinyl” denotes a pyrrolidinyl group wherein at least one of the hydrogen atoms of the pyrrolidinyl group has been replaced by same or different halogen atoms, particularly fluoro atom. The term “cubanylene” denotes a divalent cubanyl. The term “bicycle[1.1.1]pentanylene” denotes a divalent bicycle[1.1.1]pentanyl. The term “admentanylene” denotes a divalent admentanyl. 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 heteroatomselected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, 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 and oxopiperazinyl. The term “heterocyclylene” denotes a divalent heterocyclyl 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. 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, forexample benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl. The term “heteroarylene” denotes a divalent heteroaryl group. In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. The term “optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents. 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 optionally substituted by H, halogen, C1-6alkyl, C1-6alkoxy, aryl, heteroaryl or heterocyclyl. The suffix “ene” denotes a divalent group. For example, [1,2,4]triazolo[4,3-a]pyridinylene and 1H-pyrazolo[3,4-b]pyridinylene denotes bivalent [1,2,4]triazolo[4,3-a]pyridinyl and 1H- pyrazolo[3,4-b]pyridinyl. The term “PG” denotes protecting groups. 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 inorganicbases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary 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 (I),wherein M1is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1is deuterio, halogen, cyano, carboxy, NO2,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 C2-6alkenylene, arylene, heterocyclylene heteroarylene, C3-7cycloakylene, haloC3- 7cycloakylene, cubanylene, bicycle[1.1.1]pentanylene, or admentanylene, each of which is optionally substituted by R1; M3is heterocyclylene which is substituted by R2and optionally substituted by R1; wherein R2is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, each of which is optionally substituted by Rb;SO(NR)-W-, -W-SiR2-W-, -C1-6alkylene-W-C1-6alkylene-, -W-CONH-W-, -W- CON(R)-W-, -W-N(R)CO-W- or -W-N(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, 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; Q2is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3is C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; Q4is a bond, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (I), wherein M1is arylene, heterocyclylene or heteroarylene, each of which is once, twice or three times substituted by R1; wherein R1is independently selected from H, deuterio, halogen, cyano, NO2, C1-6alkyl, haloC1-6alkyl and C1-6alkylaminocarbonyl. Another embodiment of present invention is (iii) a compound of formula (I) according to (i) or (ii), wherein M1is [1,2,4]triazolo[4,3-a]pyridinylene, 1H-pyrazolo[3,4-b]pyridinylene, 2,3-dihydropyrrolo[3,2-b]pyridinylene, 2-oxo-1,3-benzothiazolylene, 2-oxo-1,4-dihydro-3,1-benzoxazinylene, 2-oxo-3H-benzimidazolylene unsubstituted or substituted by halogen, 2-oxoindolinyl, 2-oxopyridylene unsubstituted or twice substituted by substituents independently selected from halogen and C1-6alkyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinylene, 5,6-dihydropyrrolo[3,2-c]pyrazolylene substituted by C1-6alkyl, 5-oxo-1,2,4-triazolylene substituted by C1-6alkyl, 5-oxo-2,3-dihydro-1H-indolizinylene,benzimidazolylene unsubstituted or once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene, imidazo[1,2-a]pyridinylene, imidazolylene substituted by C1-6alkyl, indazolylene unsubstituted or substituted by halogen or C1-6alkyl, indolylene, oxoisoindolinylene, phenylene unsubstituted or substituted by cyano, NO2, C1-6alkyl, haloC1-6alkyl and C1-6alkylaminocarbonyl, pyrazolo[1,5-a]pyridinylene, pyrazolylene substituted by C1-6alkyl, pyridylene, pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl, pyrrolo[3,2-c]pyridinylene unsubstituted or substituted by halogen, or thiazolylene. Another embodiment of present invention is (iv) a compound of formula (I) according to any one of (i) to (iii), wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene, indazolylene unsubstituted or substituted by C1-6alkyl, or pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl. A further embodiment of present invention is (v) a compound of formula (I), wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from fluoro and methyl, benzotriazolylene, indazolylene unsubstituted or substituted by methyl, or pyrrolo[2,3-b]pyridinylene substituted by methyl. A further embodiment of present invention is a compound of formula (I), according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein M2is C2-6alkenylene, arylene, heterocyclylene heteroarylene, C3-7cycloakylene, cubanylene, bicycle[1.1.1]pentanylene,or admentanylene, each of which is optionally substituted by H, deuterio, halogen, cyano, NO2, C1-6alkyl, C1-6alkoxy, haloC1-6alkoxy or haloC1-6alkyl. A further embodiment of present invention is (vi) a compound of formula (I), according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein M2is C2-6alkenylene, phenylene, pyridylene, pyrimidinylene or thiazolylene. A further embodiment of present invention is (vii) a compound of formula (I), according to any one of (i) to (vi), wherein M2is phenylene, pyridylene, pyrimidinylene or thiazolylene. A further embodiment of present invention is a compound of formula (I), according to any one of (i) to (vi), wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl; wherein R2is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, each of which is optionally substituted by R3, R4and R5. A further embodiment of present invention is (viii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl;; wherein R3is C1-6alkyl; R4is phenyl or phenylC1-6alkyl, each of which is once or twice substituted by substituents independently selected from halogen and C1-6alkoxy; R5is H, oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1-6alkoxyC1- 6alkyl. A further embodiment of present invention is (ix) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl; 2wherein R is , or ; wherein R4is phenyl twice substituted by halogen; R5is H, oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1-6alkoxyC1- 6alkyl. A further embodiment of present invention is (x) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and methyl;wherein R2is , or ; wherein R4is 2,4-difluorophenyl; R5is H, 2-(cyanomethyl)azetidin-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3- methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, methoxymethyl or oxetan-3-yl.A further embodiment of present invention is (xi) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein Q1isL1is a bond, C1-6alkylene, hydroxyC1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, (C1-6alkyl)piperazinylene, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4- b][1,4]oxazinylene, carbonyl, halopyrrolidinylene, morpholinylene, NR6, O, oxopyrrolidinylene or piperazinylene; wherein R6is H, (C1-6alkyl)2aminocarbonylC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyl, C1-6alkylaminocarbonyl, C1-6alkylaminocarbonylC1- 6alkyl, C1-6alkylcarbonyl, carboxyC1-6alkyl, imidazolylcarbonyl, morpholinylcarbonylC1-6alkyl, phenylC1-6alkylcarbonyl, piperazinylcarbonylC1-6alkyl, pyrazolylC1-6alkylcarbonyl, pyridylC1-6alkylcarbonyl or pyrimidinyl; L3is a bond, NH, carbonyl, pyrrolidinylene, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (C1-6alkylimidazolyl)C1-6alkylene, (C1-6alkylpiperazinylcarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene, (pyridylpiperazinylcarbonyl)C1-6alkylene, C1-6alkylene, C1-6alkylenepiperazinyleneC1- 6alkylene or C2-6alkenylene; L5is a bond, O, NR7or piperazinylene unsubstituted or substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7is H, (carboxymorpholinyl)C1-6alkyl, C1-6alkoxyC1- 6alkyl, C1-6alkyl, morpholinylC1-6alkyl, phenylC1-6alkyl or thiazolylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously. A further embodiment of present invention is (xii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein Q1is, wherein L1is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene or C1-6alkylene; L5is a bond, O, NR7or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously.A further embodiment of present invention is (xiii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein Q1is, wherein L1is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (methyl)amino; L4is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5is a bond, O, NR7or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously. A further embodiment of present invention is (xiv) a compound of formula (I), according to any one of (i) to (xiii), wherein Q2is a bond, O, NH or (C1-6alkyl)amino. A further embodiment of present invention is (xv) a compound of formula (I), according to any one of (i) to (xiv), wherein Q2is a bond. A further embodiment of present invention is (xvi) a compound of formula (I), according to any one of (i) to (xv), wherein Q3is O or NH. A further embodiment of present invention is (xvii) a compound of formula (I), according to any one of (i) to (xvi), wherein Q4is a bond, carbonyl or tetrazolylene. A further embodiment of present invention is (xviii) a compound of formula (I), according to any one of (i) to (xvii), wherein Q4is carbonyl or tetrazolylene. A further embodiment of present invention is (xix) a compound of formula (I), according to any one of (i) to (xviii), wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene, indazolylene unsubstituted or substituted by C1-6alkyl, or pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl; M2is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl;wherein R2is ; wherein R4is phenyl twice substituted by halogen; R5is H, oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1-6alkoxyC1-6alkyl; Q1is, wherein L1is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1- 6alkylene or C1-6alkylene; L5is a bond, O, NR7or piperazinylene substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously; Q2is a bond; Q3is O or NH; Q4is carbonyl or tetrazolylene; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xx) a compound of formula (I), according to any one of (i) to (xix), wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from fluoro and methyl, benzotriazolylene,indazolylene unsubstituted or substituted by methyl, or pyrrolo[2,3-b]pyridinylene substituted by methyl; M2is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3is pyrrolidinylene substituted by R2, or twice substituted by R2and methyl; wherein R2is; wherein R4is 2,4-difluorophenyl; R5is H, 2-(cyanomethyl)azetidin-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3- methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, methoxymethyl or oxetan-3-yl; Q1is, wherein L1is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (methyl)amino; L4is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5is a bond, O, NR7or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously; Q2is a bond; Q3is O or NH; Q4is carbonyl or tetrazolylene; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is a compound of formula (I), according to any one of (i) to (xx), wherein M1is, , , , , , , ,; wherein R1ais H or C1-6alkyl; R1bis H or halogen; R1cis H, nitro, cyano, haloC1-6alkyl or C1-6alkylaminocarbonyl. A further embodiment of present invention is a compound of formula (I), according to any one of (i) to (xx), wherein M1is, , ,wherein R1ais H or C1-6alkyl; R1bis H or halogen.Another embodiment of present invention (xxi) is a compound of formula (I), selected from the following: (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2- 6,9 16,19 2,7 methoxyethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa- 6,9 16,19 2,7 9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-11,17-dione; (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26- oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione; (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27- oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta- 1(32),2,4,6(34),7,28,30-heptaene-15,22-dione; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29- tetrazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaen-17-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaene-11,16-dione; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30- pentazahexacyclo[21.3.1.16,9.112,15.118,21.02,7]triaconta-1(27),2,4,6(30),7,23,25-heptaene-11,17- dione; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22- one; Benzyl (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21- dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate;(15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa- 9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione; (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one; (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26- tetrazapentacyclo[18.3.1.16,9.115,18.02,7]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one; (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30- tetrazapentacyclo[22.3.1.16,9.119,22.02,7]triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-one; (11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one; (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo- ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]-N-methyl-acetamide;(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1- yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]acetamide; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazol-1- ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]acetic acid; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21- oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)- 21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]-N,N-dimethyl-acetamide; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34- hexazahexacyclo[25.2.2.14,7.112,16.118,21.06,11]tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene- 22,26-dione; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaene- 22,25-dione; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-oxa- 9,12,16,19,29-pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25- heptaene-13,17-dione;(17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaene-13,16-dione; (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-17-oxa- 1,4,20,23,26,33-hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta- 5,7(33),8,10,12(32),13,15-heptaen-22-one; (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-oxa- 9,14,17,22,27-pentazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23- heptaen-15-one; (17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10,29-dioxa-11(42),12,14,16,18,20(41),21-heptaene-5,32-dione; (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,27-dioxa- 6,9 12,16 23,26 2,7 9,12,18,21,24,35-hexazahexacyclo[26.3.1.1 .1 .1 .0 ]pentatriaconta- 1(31),2,4,6(35),7,28(32),29-heptaene-17,22-dione; (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,28-dioxa- 6,9 12,16 24,27 2,7 9,12,18,22,25,36-hexazahexacyclo[27.3.1.1 .1 .1 .0 ]hexatriaconta- 1(32),2,4,6(36),7,29(33),30-heptaene-17,23-dione; (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,28-dioxa- 6,9 24,27 2,7 12,17 9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione; Methyl (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23- 6,9 24,27 2,7 12,17 dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxylate;methyl (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23- 6,9 24,27 2,7 12,17 dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylate; (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro- 6,9 23,26 2,7 12,16 27-oxa-9,12,18,21,24,34-hexazahexacyclo[26.3.1.1 .1 .0 .0 ]tetratriaconta- 1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dione; (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro- 6,9 24,27 2,7 12,16 28-oxa-9,12,18,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-17,23-dione; (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-29-oxa- 6,9 25,28 2,7 12,17 9,12,15,19,23,26,36-heptazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 20-carboxamide; (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-(4- methylpiperazine-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione;(17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15-oxa- 6,9 25,28 2,7 12,17 8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[(3- methylimidazol-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36- 6,9 16,19 24,27 2,7 12,17 hexazaheptacyclo[27.3.1.1 .1 .1 .0 .0 ]hexatriaconta-1(32),2,4,6(36),7,29(33),30- heptaene-20,23-dione; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2- pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35- 6,9 24,27 2,7 12,17 nonazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2- pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35- 6,9 24,27 2,7 12,17 nonazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15,29- 6,9 25,28 2,7 12,17 dioxa-8,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-oxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-11-methyl-22-oxa- 6,9 18,21 2,7 11,16,19,29-tetrazapentacyclo[21.3.1.1 .1 .0 ]nonacosa-1(26),2(7),3,5,8,23(27),24- heptaene-10,17-dione; (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28- 6,9 17,20 2,7 pentazapentacyclo[20.3.1.1 .1 .0 ]octacosa-1(25),2,4,7,9(28),22(26),23-heptaen-16-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 6,9 15,18 2,7 9,13,16,19,24,26-hexazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22- heptaen-14-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-19-oxa- 6,9 15,18 2,7 9,13,16,26-tetrazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14- one;(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 7,10,13,19,21,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,17,20,22- heptaen-12-one; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2- 6,9 16,19 2,7 morpholinoethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-7-oxa-10,13,18,24- tetrazatetracyclo[18.3.1.12,6.18,11]hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,19-dione; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17- triazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6,21,23-hexaene-15,27-dione; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15-ethyl-8-methyl- 2,5,8,14,15,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),13,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13,17-trimethyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-17-oxa- 2,5,8,13,14,22-hexazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen-7- one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-17-oxa- 3,4,6,11,14-pentazatetracyclo[16.3.1.113,16.02,6]tricosa-1(22),2,18,20-tetraene-5,12-dione; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,13,17,22- hexazatetracyclo[16.3.1.13,6.112,16]tetracosa-1(21),12(23),13,15,18(22),19-hexaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,14,18,23- hexazatetracyclo[17.3.1.13,6.012,17]tetracosa-1(22),12,14,16,19(23),20-hexaen-7-one; (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-18-oxa- 3,4,6,12,15-pentazatetracyclo[17.3.1.114,17.02,6]tetracosa-1(23),2,19,21-tetraene-5,13-dione;(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl- 1,7,10,13,18,19,25-heptazapentacyclo[15.5.1.12,6.18,11.020,23]pentacosa-2,4,6(25),17(23),19- pentaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-1,10,13,20- tetrazapentacyclo[15.6.1.12,6.18,11.021,24]hexacosa-2(26),3,5,17,19,21(24)-hexaen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27- triazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3- phenylpropyl)-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa- 4,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),19,21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2- morpholinoethyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,20,22-hexaene-12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2- morpholinoethyl)-7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17,19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)- 7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,19,21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(thiazol-4- ylmethyl)-7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17,19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-19- thia-10,13,17-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),20,22-hexaene- 12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19,20-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),18,21- heptaen-12-one;(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 7,10,13,16,18,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl- 7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,20,22- hexaene-12,18-dione; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8- oxa-12,15,18,23-tetrazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8,12-dimethyl-6- nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaen-13- one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-13-oxo- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaene-6- carbonitrile; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6- (trifluoromethyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa- 1(23),2(7),3,5,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13- oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaene-6- carboxamide; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,17,18,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one;(13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3,11-dimethyl-8-oxa- 3,5,11,14,17,22-hexazatetracyclo[16.3.1.113,16.02,6]tricosa-1(22),2(6),4,18,20-pentaen-12-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-5-thia- 3,8,12,15,18,23-hexazatetracyclo[17.3.1.114,17.02,6]tetracosa-1(23),2(6),3,19,21-pentaene-7,13- dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.5.2.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-15-oxo-20- 16,19 2,7 oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaene-10- carboxamide; (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-16-oxo-21- 17,20 2,7 oxa-10,15,18-triazatetracyclo[20.3.1.1 .0 ]heptacosa-1(25),2,4,6,22(26),23-hexaene-10- carboxamide; (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-20-oxa- 16,19 2,7 10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-pyrimidin-2-yl-20- 16,19 2,7 oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-(1H-imidazole-2- 16,19 2,7 carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22- hexaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl- 2,6 8,11 12,15 22,26 7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),12(27),13,20,22,24-nonaene; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-methyl- 2,6 8,11 12,15 21,25 7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 1(25),2,4,6(28),12(26),13,19,21,23-nonaene; 1-[1-(2,4-difluorophenyl)-4-[(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-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3-carbonitrile; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one;(8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6,8,21,23-heptaene-10,15-dione; (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa- 6,9 17,20 2,7 6,10,15,18,28-pentazapentacyclo[20.3.1.1 .1 .0 ]octacosa-1(25),2,4,7,9(28),12,22(26),23- octaen-16-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-17-oxa-7,11,14- 13,16 2,7 triazatetracyclo[16.3.1.1 .0 ]tricosa-1(22),2,4,18,20-pentaene-6,12-dione; (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,18,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one;(43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-methyl-11H- 3,6-diaza-1(7,1)-benzo[d][1,2,3]triazola-2(2,6)-pyridina-4(3,5)-pyrrolidinacyclononaphan-5-one; (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-12-methyl-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-7,12,15,18,23- 14,17 2,7 pentazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2,4,19,21-pentaene-6,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa- 2,6 8,11 20,23 1,10,13,18,19-pentazapentacyclo[15.5.1.1 .1 .0 ]pentacosa-2(25),3,5,17(23),19-pentaen- 12-one; (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21- heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18- 2,6 8,11 21,25 oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),21(25),22- hexaene-12,19-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa- 2,6 8,11 21,25 7,10,13,20,27-pentazapentacyclo[15.7.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),21(25),22- hexaene-12,19-dione; (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41- 3,36 5,9 10,14 28,35 30,34 17,40 decazaoctacyclo[19.15.1.1 .1 .1 .1 .0 .0 ]hentetraconta- 5,7,9(41),10,12,14(40),15,28,31,33,35(39)-undecaene-27,37-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 2,6 8,11 21,24 1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22- heptaen-12-one; (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 2,6 8,11 21,24 1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-hydroxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one;(8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 2,6 8,11 19,23 10,13,19-triazapentacyclo[14.6.1.1 .1 .0 ]pentacosa-1(23),2(25),3,5,21-pentaene-12,20- dione; (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6,12- 14,17 2,7 dimethyl-6,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2(7),3,19,21- pentaene-5,13-dione; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-5,12-dimethyl- 14,17 2,7 5,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2(7),3,19,21-pentaene-6,13- dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13,17- 2,6 8,11 19,23 dimethyl-7,10,13,16,18,25-hexazapentacyclo[14.6.1.1 .1 .0 ]pentacosa- 1(23),2(25),3,5,17,19,21-heptaen-14-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-14-one; (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl- 17,20 2,7 8,12 8,15,18,21,26-pentazapentacyclo[20.3.1.1 .0 .0 ]heptacosa-1(26),2,4,6,22,24-hexaene- 9,16-dione; (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-16-methyl-5-oxa-8,11,16,17- tetrazatetracyclo[13.6.1.16,9.018,22]tricosa-1(21),2,15(22),17,19-pentaen-10-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,20(24),21-hexaene- 12,18-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,20(24),21-hexaene- 12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,24,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,19,21- heptaen-12-one;(16S,19S)-17-[5-(2-chloro-4-fluoro-phenyl)pyrazin-2-yl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-18-methyl-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)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-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; 4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-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-heptaen-13-yl]propyl]morpholine-3-carboxylic acid; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13- oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-8- carboxamide; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-(2- pyrazol-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21- hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-[2-(4- pyridyl)acetyl]-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21- hexaen-13-one; (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)- 7-oxa-10,13,18,19,24-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-2(26),3,5,17,19- pentaen-12-one;(7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy- 12,17-dimethyl-25-thia-4,6,9,12,16,18-hexazapentacyclo[14.6.1.12,5.17,10.019,23]pentacosa- 1(22),2,4,17,19(23),20-hexaen-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14- methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25- pentazapentacyclo[14.6.1.12,5.17,10.019,23]pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14- methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexazapentacyclo[14.6.1.12,5.17,10.019,23] pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one; and 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-2- yl]acetonitrile; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xxii) is a process for the preparation of a compound according to any one of (i) to (xxi) comprising the following step: a) the formation of compound of formula (Ia),via nucleophilic substitution between compound of formula (VII),(VII), and R2X, in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VII) and R2X in thepresence of a catalyst; or via condensation reaction between compound of formula (VII) and R2OH in the presence of coupling reagent; wherein the base in step a) is DIEA; the coupling reagent in step a) is HATU; the catalyst in step a) is Pd2(dba)3; X is halogen; Reis H or C1-6alkyl. Rfis R or R7; Q1to Q3, M1and M2are as defined as in any one of (i) to (xxi). Another embodiment of present invention (xxiii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) for use as therapeutically active substance. Another embodiment of present invention (xxiv) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xxi) and a pharmaceutically acceptable excipient. Another embodiment of present invention (xxv) is related to the use of a compound according to any one of (i) to (xxi) 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 (xxvi) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi) 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 (xxvii) is related to the use of a compound according to any one of (i) to (xxi) 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 (xxviii) is related to the use of a compound according to any one of (i) to (xxi) 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), familialchilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. Another embodiment of present invention (xxix) is related to the use of a compound according to any one of (i) to (xxi) 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 (xxx) is related to the use of a compound according to any one of (i) to (xxi) for the inhibition of STING. Another embodiment of present invention (xxxi) is related to the use of a compound according to any one of (i) to (xxi) for the preparation of a medicament for the inhibition of STING. Another embodiment of present invention (xxxii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xxi), when manufactured according to a process of (xxii). Another embodiment of present invention (xxxiii) 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 (xxi). 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 bestored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit STING interaction with IRF3, NF-kB, NLRP3 etc., for blocking downstream type I IFN and pro-inflammatory cytokine (e.g. IL-6, TNFa, ISGs) production, cellular responses / conditions (e.g. autophagy, apoptosis, cell senescence). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg / kg, alternatively about 0.1 to 1000 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.1 to 1000 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the invention compounded with about 0.1 to 1000 mg anhydrous lactose, about 0.1 to 1000 mg sodium croscarmellose, about 0.1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 0.1 to 1000 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathies, autoimmune and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infection or selective type of cancer. The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition AA compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The 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, oculardiseases, 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 R7, Q1, Q2, A1to A7are 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 route for preparing the compound of the invention are shown in following scheme.Scheme 1Wherein Rdis H or PG, wherein PG can be, for example, Boc or Cbz; X is halogen; Reis H or C1-6alkyl. Rfis R or R7. As depicted in Scheme 1, the synthesis of compounds of the present invention started from boronic ester compound of formula (III) or halide (II). Suzuki coupling between compound offormula (II) and compound of formula (IIb) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (IV), which can also be obtained via the Suzuki coupling between boronic ester compound of formula (III) and halide (IIIb). Compound of formula (IV) is hydrolyzed in the presence of LiOH directly and followed by appropriate deprotection to give compound of formula (V) (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd / C or Pd(OH)2 / C under H2). Compound of formula (V) can be cyclized to give compound of formula (VI) 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 (VII). Compound of formula (Ia) can be obtained by the reaction between compound of formula (VII) and R2X 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. On the other hand, compound of formula (Ia) can also be obtained via condensation reaction between compound of formula (VII) and R2OH in the presence of coupling reagent, such as HATU. Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. This invention also relates to a process for the preparation of a compound of formula (I) or (Ia) comprising the following step: a) the formation of compound of formula (Ia),via nucleophilic substitution between compound of formula (VII),(VII), and R2X, in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VII) and R2X in the presence of a catalyst; or via condensation reaction between compound of formula (VII) and R2OH in the presence of coupling reagent; wherein the base in step a) can be, for example, DIEA; the coupling reagent in step a) can be, for example, HATU; the catalyst in step a) can be, for example, Pd2(dba)3; X is halogen; Reis H or C1-6alkyl. Rfis R or R7. 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 BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-dinaphthalene CataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) DCM: dichloromethane DCE: dichloroethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: diisobutylaluminium hydrideDIAD: diisopropyl azodicarboxylate DMA: N,N-Dimethylacetylamine DMAP: 4-dimethylaminopyridine DMF: N,N-Dimethylformamide DMEDA: N,N'-Dimethylethylenediamine DMSO: dimethyl sulfoxide DPPP: 1,3-Bis(diphenylphosphino)propane EA or EtOAc: ethyl acetate FA: formic acid HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate h(s) or hr(s): hour (s) hPBMC: human peripheral blood mononuclear cells 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 LCMS: liquid chromatography-mass spectrometry mCPBA: meta-chloroperoxybenzoic acid min(s): minute(s) MS: mass spectrometry MsCl: methanesulfonyl chloride Ms2O: methanesulfonic anhydride NBS: N-bromosuccinimide NIS: N-iodosuccinimide NCS: N-Chlorosuccinimide 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 chromatography prep-TLC: preparative thin layer chromatographyPyBOP / BOP： (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylphosphorus hexafluorophosphate PPh3: triphenylphosphine Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) Pd PEPPSI-IPent: [1,3-Bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)dichloropalladium(II) (R)-binap : (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Rf: retention factor rt, r.t: room temperature RT: retention time RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’- biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) 2nd generation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: supercritical fluid chromatography S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBSCl: tert-butyldimethylsilyl chloride t-BuXPhos: 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl tBuXPhos Pd G3: Methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) tBu3P-Pd-G2 Chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2- yl)palladium(II) T3P: Propylphosphonic anhydride TEA: trimethylamine TFA: trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: tetrahydrofuran TLC: thin layer chromatography TMAD: N,N,N,N-Tetramethylazodicarboxamide XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)v / v volume ratio GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash column chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12 / 25 Cartridge module. ii) ISCO combi-flash column instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registry NO: Silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using 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-[2-methoxy-3-[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-[3-(2-bromo-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound A1-b) To a solution of 1,3-diamino-2-propanol (36 g, 396 mmol) in ACN was added 3-bromo-2- fluoronitrobenzene (compound A1-a, 43.5 g, 198 mmol) slowly at 25 °C. After being stirred at20 °C for 0.5 hours, the mixture was filtered, and the collected solid was dissolved in methanol. Then tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (106.8 g, 489.5 mmol) and DIPEA (63 g, 489 mmol) was added. After being stirred at 20 °C for 1 h, the mixture was concentrated, the residue was purified prep-HPLC to afford compound A1-b (51.5 g). LCMS (M-56+H)+: 336. Step 2: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)-2-hydroxy- propyl]carbamate (compound A1-c) To a solution of tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxy-propyl]carbamate (compound A1-b, 50.5 g, 129 mmol) in methanol (850 mL) was added Raney Ni (31 g, 518 mmol) and hydrazine hydrate (35 g, 695 mmol). After being stirred at 25 °C for 1 h, the mixture was filtered and concentrated. The crude product was dissolved in DCM (500 mL), washed with water (300 mL). The organic layer was dried and concentrated to give compound A1-c (43 g). LCMS (M+H)+: 360. Step 3: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- hydroxy-propyl] carbamate (compound A1-d) To a solution of tert-butyl N-[3-(2-amino-6-bromo-anilino)-2-hydroxy-propyl]carbamate (compound A1-c, 37.5 g, 104 mmol) in anhydrous THF (496 mL) was added trimethyl orthoacetate (45 mL) and pyridinium p-toluenesulfonate (3.75 g, 15 mmol). After being stirred for 1 h at 20 °C, the mixture was concentrated and the residue was triturated in PE / EA(1 / 1, 150 mL) to give compound A1-d (39 g). LCMS (M+H)+: 384. Step 4: preparation of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2- methoxy-propyl]-N-methyl-carbamate (compound A1-e) To a solution of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-hydroxy- propyl]carbamate (compound A1-d, 10.0 g, 26 mmol) in DMF (200 mL) was added CH3I (11 g, 78 mmol) at -10 °C under N2, then NaH (2.6 g, 65 mmol) was added slowly in portions. The mixture was stirred at -10 °C for 5 hours. The mixture was then stirred at 20 °C for another 12 h. The reaction was quenched with ice cold NH4Cl solution and extracted with EA twice, the organic layer was dried and concentrated to afford compound A1-e (11.7 g). LCMS (M+H)+: 412. Step 5: preparation of tert-butyl N-[2-methoxy-3-[2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate (Intermediate A1) To a mixture of tert-butyl N-[3-(7-bromo-2-methyl-benzimidazol-1-yl)-2-methoxy- propyl]-N-methyl-carbamate (compound A1-e, 10.5 g, 25.5 mmol) in DMSO (150 mL) was added potassium acetate (5.0 g, 51 mmol), bis(triphenylphosphine)palladium(II) chloride (2.68 g,3.8 mmol) and butyldi-1-adamantylphosphine (2.7 g, 7.6 mmol). The mixture was degassed with N2three times and stirred at 130 °C for 2 hours. The reaction mixture was poured into water (1000 mL) and extracted with EA (300 mL) twice. The organic phase was washed with brine (300 mL), dried and concentrated, the residue was purified by silica gel column chromatography to afford Intermediate A1 (8.8 g). LCMS (M+H)+: 460. Intermediate A2 tert-butyl N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamateIntermediate A2 was prepared in analogy to the preparation of Intermediate A1 by using 1- bromo-2,5-difluoro-3-nitro-benzene instead of 3-bromo-2-fluoronitrobenzene. LCMS (M+H)+: 478. Intermediate A3 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 A3-b) To a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxy-propyl]carbamate (59.6 g, 313.3 mmol) and 1-bromo-2,5-difluoro-3-nitro-benzene (71.0 g, 298.3 mmol) in ACN (710 mL) was added potassium carbonate (82.5 g, 596.7 mmol). After being stirred at 50 °C for 2 hours, the mixture was filtered and the filtrate was concentrated to give compound A3-b (131 g). LCMS (M+H)+: 352. Step 2: preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoro-anilino)-2- hydroxy-propyl]carbamate (compound A3-c) To a solution of compound A3-b (63.0 g, 154.33 mmol) in methanol (1000 mL) was added Raney Ni (36.2 g, 617.3 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol). After being stirred at 25 °C for 1 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM, washed with water and brine. The organic layer was dried and concentrated to give compound A3-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 A3-d) To a solution of compound A3-c (123.0 g, 325.2 mmol) in anhydrous THF (1500 mL) was added trimethyl orthoacetate (137 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g,46.6 mmol). The reaction was stirred for 1 h at 20 °C. The mixture was concentrated under reduced pressure to give compound A3-d (160 g). LCMS (M+H)+: 400. Step 4: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]carbamate (compound A3-e) To a solution of compound A3-d (80.0 g, 198.9 mmol) and imidazole (40.6 g, 596.6 mmol) in DMF (765 mL) was added tert-butyldimethylchlorosilane (59.9 g, 397.7 mmol), then the mixture was stirred for 18 hours at 30 °C. The mixture was poured into ice-aq.NH4Cl (2000 mL), extracted with EtOAc (800 mL) twice. The organic layer was dried and concentrated to give compound A3-e (94 g). LCMS (M+H)+: 518. Step 5: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate (compound A3-f) To a solution of compound A3-e (82 g, 158.7 mmol) in DMF (800 mL) was added sodium hydride (60% in oil, 15.9 g, 396.9 mmol) at 0°C and then stirred at 0 °C for 1 h. Iodomethane (90.1 g, 635 mmol) was then added at 0°C and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA. The organic layer was dried and concentrated, the crude product was purified by column chromatography to give compound A3-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 A3-g) A mixture of compound A3-f (39.8 g, 75 mmol) and TBAF / THF (1M, 150 mL, 150 mmol) was stirred at 20 °C for 2 hours. Then the mixture was concentrated and the crude product was diluted with EtOAc (600mL), washed with water and brine. The organic layer was dried and concentrated to give compound A3-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 A3-h) To a solution of compound A3-g (17.4 g, 41.8 mmol) and iodoethane (5 mL, 62.7 mmol) in DMF (174 mL) was added sodium hydride (2.2 g, 54.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction was then quenched with water, and the mixture was extracted with EA. The organic layer was dried and concentrated to give compound A3-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 A3)To a mixture of compound A3-h (19.4 g, 43.7 mmol) and bis(pinacolato)diboron (27.7 g, 109.2 mmol) in DMSO (194 mL) was added potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.6 mmol) and butyldi-1- adamantylphospine (4.7 g, 13.1 mmol). The mixture was degassed with N2 for three times, and then stirred at 130 °C for 2 hours. The reaction mixture was then poured into water (1000 mL) and extracted with EA (500 mL). The organic layer was dried and concentrated, the crude product was purified by column chromatography to give Intermediate A3 (15 g). LCMS (M+H)+: 478. Intermediate A4 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:Intermediate A4 was prepared in analogy to the preparation of Intermediate A1 by using compound A3-d instead of compound A1-d. LCMS (M+H)+: 478. Intermediate A5 N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]propan-1-amineThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A5- a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) in THF (400 mL) was added in one portion at -78 °C under nitrogen. And the LDA (107.1 mL, 214.3 mmol) was added dropwise into the mixture which was stirred for 1 hr. Then the 1-chloro-3-iodopropane (43.6 g, 213.2 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 by prep-HPLC to obtained compound A5-a (30 g) as a colorless solid, LCMS (M+H)+: 287. Step 2: preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4- methoxyphenyl)methyl]-N-methyl-propan-1-amine (compound A5-b) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A5-a, 3.0 g, 10.4 mmol), 4-methoxy-N-methylbenzylamine (2.0 g, 13.2 mmol), sodium iodide (2.0 g, 13.3 mmol) and potassium carbonate (2.0 g, 14.47 mmol) in anhydrous DMF (30 mL) was stirred at 120 °C for 2 hrs. The mixture was cooled to room temperature, and then poured into water. The resulted precipitate was filtered, the collected solid was dissolved in EtOAc. Then the resulting solution was dried over anhydrous Na2SO4, concentrated to give crude compound A5-b (3.7 g) as a yellow oil, which was used in next step directly, LCMS (M+H)+: 402. Step 3: preparation of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (intermediate A5)To a solution of 3-(4-bromo-2-methyl-indazol-3-yl)-N-[(4-methoxyphenyl)methyl]-N- methyl-propan-1-amine (compound A5-a, 3.7 g, 9.2 mmol), bis(pinacolato)diboron (4.5 g, 17.7 mmol) and potassium phosphate (4.0 g, 18.8 mmol) in 1,4-dioxane (30 mL) was added cataCXium A-Pd-G2 (0.5 g, 0.75 mmol), the resulting mixture was stirred at 100 °C for 12 hrs under argon. The mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc. The separated organic layer was washed with brine and dried over anhydrous Na2SO4, filtered, concentrated to give a crude product, which was purified by prep-HPLC to give intermediate A5 (2.3 g) as a yellow oil, which was used in next step directly, LCMS (M+H)+: 450. Intermediate A6 tert-butyl 2-(4-bromoindazol-2-yl)acetateThe title compound was prepared according to the following scheme:Intermediate A6A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), tert-butyl 2-bromoacetate (5.85 g, 30 mmol) and cesium carbonate (13 g, 40 mmol) in acetonitrile (50 mL) was stirred at room temperature for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford intermediate A6 (530 mg) as a white solid, LCMS (M+H)+: 311. Intermediate A7 tert-butyl N-[3-(4-bromoindazol-2-yl)propyl]carbamateThe title compound was prepared according to the following scheme:Intermediate A7A mixture of 4-bromo-1H-indazole (5 g, 25.4 mmol), tert-butyl (3-bromopropyl)carbamate (6.65 g, 27.9 mmol) and cesium carbonate (16.5 g, 50.8 mmol) in acetonitrile (62.5 mL) was stirred at 70 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford intermediate A7 (3.12 g) as a white oil, LCMS (M+H)+: 354. Intermediate A8 tert-butyl N-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1-yl]ethyl]carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a) A mixture of 4-bromo-1H-indazole (3.94 g, 20 mmol), 1,2-dichloroethane (9.9 g, 100 mmol) and potassium carbonate (5.53 g, 40 mmol) in MeCN (50 mL) was stirred at 70 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give some residue, the residue was purified by flash column chromatography to afford compound A8-a (728 mg) as a yellow solid, LCMS (M+H)+: 259. Step 2: preparation of tert-butyl N-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1- yl]ethyl]carbamate (intermediate A8) A mixture of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a, 130 mg, 0.5 mmol),tert-butyl N-(2-piperazin-1-ylethyl)carbamate (229 mg, 1 mmol) and DIPEA (194 mg, 1.5 mmol) in DMF (3 mL) was stirred at 100 °C for 16 hrs. 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 extracts was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford intermediate A8 (234 mg) as a brown oil, LCMS (M+H)+: 452. Intermediate A9 2-[(E)-4-(4-bromoindazol-2-yl)but-2-enyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromo-2-[(E)-4-bromobut-2-enyl]indazole (compound A9-a) A mixture of 4-bromo-1H-indazole (1.5 g, 7.61 mmol), (E)-1,4-dibromobut-2-ene (4.9 g, 22.8 mmol) and potassium carbonate (2.1 g, 15.2 mmol) in MeCN (20 mL) was stirred at 40 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford compound A9-a (0.9 g) as a white solid, LCMS (M+H)+: 329. Step 2: preparation of 2-[(E)-4-(4-bromoindazol-2-yl)but-2-enyl]isoindoline-1,3-dione (intermediate A9) A mixture of 4-bromo-2-[(E)-4-bromobut-2-enyl]indazole (compound A9-a, 0.9 g, 2.73 mmol), potassium phthalimide (0.6 g, 3.27 mmol) and sodium iodide (0.8 g, 5.45 mmol) in DMF (10 mL) was heated to 85 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under vacuum to give some crude compound which was purified by flashcolumn chromatography to afford intermediate A9 (0.91 g) as a white solid, LCMS (M+H)+: 396. Intermediate A10 tert-butyl N-[2-[2-(4-bromoindazol-2-yl)ethoxy]ethyl]carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate (compound A10-a) To a mixture of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (1.0 g, 4.87 mmol) and DIPEA (2.52 g, 19.5 mmol) in anhydrous DCM (15 mL) was added methanesulfonic anhydride (1.27 g, 7.31 mmol) portion wise. The resulting solution was stirred at room temperature for 2 hrs and then poured into water, the aqueous phase was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to give crude compound A10-a (1.3 g) as a colourless oil, LCMS (M+H)+: 284. Step 2: preparation of tert-butyl N-[2-[2-(4-bromoindazol-2- yl)ethoxy]ethyl]carbamate (intermediate A10) A mixture of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate (compound A10-a, 1.31 g, 4.62 mmol), 4-bromo-1H-indazole (0.7 g, 3.55 mmol) and cesium carbonate (3.47 g, 10.7 mmol) in DMF (6 mL) was stirred at 80 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford intermediate A10 (0.55 g) as a white solid, LCMS (M+H)+: 384. Intermediate A11 2-[4-(4-bromoindazol-2-yl)-3-hydroxy-butyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-but-3-enylisoindoline-1,3-dione (compound A11-a) A mixture of 4-bromobut-1-ene (2.0 g, 14.8 mmol), potassium phthalimide (3.29 g, 17.8 mmol) and sodium iodide (2.22 g, 14.8 mmol) in DMF (15 mL) was heated to 85 °C for 12 hrs. 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 and brine, dried over anhydrous Na2SO4, concentrated under vacuum to give some crude. The crude was purified by flash column chromatography to afford compound A11-a (2.7 g) as a white solid, LCMS (M+H)+: 202. Step 2: preparation of 2-(4-bromo-3-hydroxy-butyl)isoindoline-1,3-dione (intermediate A11-b) A mixture of 2-but-3-enylisoindoline-1,3-dione (compound A11-a, 2.7 g, 13.4 mmol), water (483 mg, 26.8 mmol) and 1-bromopyrrolidine-2,5-dione (4.78 g, 26.8 mmol) in DMSO (15 mL) was stirred at 85 °C for 12 hrs. 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 and brine, dried over anhydrous Na2SO4, concentrated under vacuum to give some crude. The crude was purified by flash column chromatography and prep-HPLC to afford compound A11-b (680 mg) as a white solid, LCMS (M+H)+: 298.Step 3: preparation of 2-[4-(4-bromoindazol-2-yl)-3-hydroxy-butyl]isoindoline-1,3- dione (intermediate A11) A mixture of 4-bromo-1H-indazole (450 mg, 2.28 mmol), 2-(4-bromo-3-hydroxy- butyl)isoindoline-1,3-dione (compound A11-b, 681 mg, 2.28 mmol) and cesium carbonate (1.49 g, 4.57 mmol) in DMF (10 mL) was stirred at 50 °C for 16 hrs. After being cooled to room temperature, the mixture was added water and acidified to PH~5 by HOAc, then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over with anhydrous Na2SO4, concentrated to give some crude product, which was purified by flash column chromatography and prep-HPLC to give intermediate A11 (120 mg) as white solid, LCMS (M+H)+: 414. Intermediate A12 tert-butyl N-[2-(4-bromoindazol-2-yl)ethyl]-N-[2-(1,3-dioxoisoindolin-2- yl)ethyl]carbamateStep 1: preparation of tert-butyl N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindolin-2- yl)ethyl]carbamate (compound A12-a) A mixture of tert-butyl N,N-bis(2-chloroethyl)carbamate (47.1 g, 194 mmol), potassium phthalimide (12.0 g, 64.8 mmol) and sodium iodide (29.1 g, 194 mmol) in DMF (100 mL) was heated to 85 °C for 0.5 hr. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAcfor three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give compound A12-a (4.2 g) as a colorless oil, LCMS (M+H-100)+: 253. Step 2: preparation of tert-butyl N-[2-(4-bromoindazol-2-yl)ethyl]-N-[2-(1,3- dioxoisoindolin-2-yl)ethyl]carbamate (intermediate A12) A mixture of 4-bromo-1H-indazole (3.0 g, 15.2 mmol), cesium carbonate (14.9 g, 45.7 mmol) and tert-butyl N-(2-chloroethyl)-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]carbamate (compound A12-a, 4.3 g, 12.2 mmol) in DMF (20 mL) was stirred at room temperature for 10 mins, then the mixture was heated at 50 °C and stirred for 12 hrs. 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 and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give intermediate A12 (1.95 g) as a colorless oil, LCMS (M+H)+: 513. Intermediate A13 tert-butyl 4-[2-(4-bromoindazol-2-yl)ethyl]piperazine-1-carboxylateThe title compound was prepared according to the following scheme:A mixture of 4-bromo-2-(2-chloroethyl)indazole (compound A8-a, 519 mg, 2 mmol), tert- butyl piperazine-1-carboxylate (745 mg, 4 mmol) and DIPEA (775 mg, 6 mmol) in DMF (6 mL) was stirred at 100 °C for 16 hrs. 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 brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford intermediate A13 (845 mg) as an orange solid, LCMS (M+H)+: 409. Intermediate A142-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1-yl]-2-oxo-ethyl]isoindoline-1,3- dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromo-2-(2-piperazin-1-ylethyl)indazole (compound A14-a) A mixture of tert-butyl 4-[2-(4-bromoindazol-2-yl)ethyl]piperazine-1-carboxylate (intermediate A12, 0.2 g, 0.49 mmol) and 4M HCl in 1,4-dioxane (2.44 mL, 2.44 mmol) in DCM (5 mL) was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure to give compound A14-a (200 mg) as a brown solid, LCMS (M+H)+: 309. Step 2: preparation of 2-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1-yl]-2-oxo- ethyl]isoindoline-1,3-dione (intermediate A14) To a mixture of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (73 mg, 0.36 mmol), DIPEA (230 mg, 1.78 mmol) and HATU (149 mg, 0.40 mmol) in DMF (3 mL) was added 4-bromo-2-(2- piperazin-1-ylethyl)indazole (compound A14-a, 110 mg, 0.36 mmol) in DMF (0.2 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C to room temperature for 12 hrs. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give intermediate A14 (200 mg) as a yellow oil, LCMS (M+H)+:496. Intermediate A15 N-[2-(4-bromoindazol-2-yl)ethyl]-3-(1,3-dioxoisoindolin-2-yl)propanamideThe title compound was prepared according to the following scheme:Intermediate A15Step 1: preparation of tert-butyl N-[2-(4-bromoindazol-2-yl)ethyl]carbamate (compound A15-a) A mixture of 4-bromo-2H-indazole (5 g, 25.4 mmol), tert-butyl N-(2- bromoethyl)carbamate (5.69 g, 25.4 mmol) and cesium carbonate (16.5 g, 50.8 mmol) in MeCN (50 mL) was stirred at 80 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to give compound A15-a (2.59 g) as a yellow solid, LCMS (M+H)+: 340. Step 2-3: preparation of N-[2-(4-bromoindazol-2-yl)ethyl]-3-(1,3-dioxoisoindolin-2- yl)propanamide (intermediate A15) The title compound was prepared in analogy to the preparation of intermediate A14 by using compound A15-a instead of intermediate A13 and 3-(1,3-dioxoisoindolin-2-yl)propanoic acid instead of 2-(1,3-dioxoisoindolin-2-yl)acetic acid, LCMS (M+H)+:441. Intermediate A16 N-[2-(4-bromoindazol-2-yl)ethyl]-2-(1,3-dioxoisoindolin-2-yl)acetamideThe title compound was prepared according to the following scheme:Intermediate A16 A15-b The title compound was prepared in analogy to the preparation of intermediate A15 by using 2-(1,3-dioxoisoindolin-2-yl)acetic acid instead of 3-(1,3-dioxoisoindolin-2-yl)propanoic acid, LCMS (M+H)+:427. Intermediate A17 2-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1-yl]ethyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:A mixture of 4-bromo-2-(2-piperazin-1-ylethyl)indazole (compound A14-a, 333 mg, 1.08 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (821 mg, 3.23 mmol), sodium iodide (484 mg, 3.23 mmol) and potassium carbonate (447 mg, 3.23 mmol) in DMF (6 mL) was stirred at 80 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was diluted with waterand then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give intermediate A17 (110 mg) as a yellow solid, LCMS (M+H)+: 482. Intermediate A18 4-(4-bromoindazol-2-yl)butan-1-olA mixture of 4-bromo-1H-indazole (788 mg, 4 mmol), 4-bromobutan-1-ol (1.22 g, 8 mmol), sodium iodide (1.2 g, 8 mmol) and cesium carbonate (2.61 g, 8 mmol) in MeCN (15 mL) was stirred at 50 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford intermediate A18 (248 mg) desired as a light pink solid, LCMS (M+H)+: 269. Intermediate A19 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]pentyl]isoindoline- 1,3-dioneA mixture of 2-[5-(4-bromoindazol-2-yl)pentyl]isoindoline-1,3-dione (intermediate A3, 289 mg, 0.7 mmol), bis(pinacolato)diboron (213 mg, 0.84 mmol), Pd(OAc)2 (7.9 mg, 0.035 mmol), butyldi-1-adamantylphosphine (25.1 mg, 0.07 mmol) and potassium acetate (206 mg, 2.1 mmol) in DME (4 mL) was heated to 70 °C for 1 hr under microwave irritation. After being cooled to room temperature, the reaction mixture was diluted with DME and then filtered. Thefiltrated was concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford desired intermediate A19 (281 mg) desired as a yellow oil, LCMS (M+H)+: 460. Intermediate A20 2-[3-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3- yl]propyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A20-a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142.1 mmol) in THF (400 mL) was added in one portion at -78 °C under nitrogen. And the LDA (107.1 mL, 214.3 mmol) was added dropwise into the mixture which was stirred for 1 hr. Then the 1-chloro-3-iodopropane (43.6 g, 213.2 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 combined organic layer was washed with brine, dried over anhydrous Na2SO4. After filtration, the solvent was concentratedto afford crude product, which was purified by prep-HPLC to obtained compound A20-a (30 g) as a colorless solid, LCMS (M+H)+: 289. Step 2: preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3- dione (compound A20-b) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A20-a, 2 g, 3.8 mmol), potassium phthalimide (1.39 g, 7.5 mmol) and sodium iodide (1.69 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 extracted with 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 precipitated from EtOAc / hexane to give crude compound A20-b (1.92 g) as a yellow solid, which was directly used in next step without further purification, LCMS (M+H)+: 398. Step 3: preparation of 2-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-3-yl]propyl]isoindoline-1,3-dione (intermediate A20) A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (compound A20-b, 1.81 g, 3.4 mmol), bis(pinacolato)diboron (1.3 g, 5.1 mmol), bis(triphenylphosphine)palladium(ii) dichloride (125 mg, 0.17 mmol) and potassium acetate (1 g, 10.2 mmol) in 1,4-dioxane (30 mL) was heated at 100 °C for 16 hrs under argon. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with 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 was purified by flash column to afford intermediate A20 (1.94 g) as a brown solid, LCMS (M+H)+: 446. Intermediate A21 tert-butyl N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazol-1- yl]propyl]carbamateThe title compound was prepared according to the following scheme:A21-c Intermediate A21 Step 1: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]carbamate (compound A21-a) A mixture of 1-bromo-2-fluoro-3-nitro-benzene (2.7 g, 12.3 mmol), tert-butyl N-(3- aminopropyl)carbamate (2.14 g, 12.3 mmol), potassium carbonate (1.7 g, 12.3 mmol) and MeCN (15 mL) was heated to 90 °C for 3 hrs. The mixture was cooled and filtered, the filtrate was concentrated and the residue was purified by silica gel column chromatography to give compound A21-a (4.8 g), LCMS (M+H)+: 374. Step 2: preparation of tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]carbamate (compound A21-b) To a flask was added nickel (2.9 g, 49.4 mmol), MeOH (100 mL) and tert-butyl N-[3-(2- bromo-6-nitro-anilino)propyl]carbamate (compound A21-a, 5 g, 13.4 mmol), the suspension was stirred vigorously and hydrazine (8.56 g, 8.32 mL, 134 mmol) was then added. After being stirred at room temperature for 1 hr, the reaction mixture was filtered and the filtrate was concentrated to give some residue. The residue was dissolved in DCM, which was washed with water and brine. The organic layer was dried and concentrated to give compound A21-b (4.6 g), LCMS (M+H)+: 344. Step 3: preparation of tert-butyl N-[3-(7-bromo-2-oxo-3H-benzimidazol-1- yl)propyl]carbamate (compound A21-c) To a solution of tert-butyl N-[3-(2-amino-6-bromo-anilino)propyl]carbamate (compound A21-b, 620 mg, 1.62 mmol) in MeCN (10 mL) was added N, N'-carbonyldiimidazole (657 mg, 4.05 mmol), the resulting mixture was stirred at 90 °C for 10 hrs. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give some crude.The crude was purified by flash column chromatography to afford compound A21-c (582 mg) as a pink solid), LCMS (M+H)+: 370. Step 4: preparation of tert-butyl N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo- benzimidazol-1-yl]propyl]carbamate (intermediate A21) A mixture of tert-butyl N-[3-(7-bromo-2-oxo-3H-benzimidazol-1-yl)propyl]carbamate (compound A21-c, 528 mg, 0.97 mmol), 1-(chloromethyl)-4-methoxybenzene (182 mg, 1.16 mmol) and potassium carbonate (268 mg, 1.94 mmol) in DMF (6 mL) was stirred at 40 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with EtOAc for three time. The combined organic layer was washed with water and brine, dried, concentrated to give intermediate A21 (873 mg) as a yellow oil, which was directly used for next step without purification, LCMS (M+H-100)+: 390. Intermediate A22 2-[3-(4-bromo-2-oxo-1,3-benzothiazol-3-yl)propyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:A mixture of 4-bromo-3H-1,3-benzothiazol-2-one (371 mg, 2 mmol), 2-(3- bromopropyl)isoindoline-1,3-dione (643 mg, 2.4 mmol), sodium iodide (300 mg, 2 mmol) and potassium carbonate (553 mg, 4 mmol) in DMF (5 mL) was heated to 80 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was diluted with water, the resulted precipitation was filtered. The collected solid was dried, intermediate A22 (602 mg) was obtained as a yellow solid, which was directly used for next step without further purification, LCMS (M+H)+: 373. Intermediate A23 2-[3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 4-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (compound A23-a) To a solution of 4-bromopyrazolo[1,5-a]pyridine (4.8 g, 24.36 mmol) in MeCN (87 mL) was added (chloromethylene)dimethyliminium chloride (7.37 g, 57.6 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated in vacuo to give some residue. The residue was dissolved in MeOH, basified by sodium bicarbonate aqueous solution, then stirred at room temperature for 1 hr. The mixture was filtered and the collected solid was dried under reduced pressure to give compound A23-a (4.6 g, 20.44 mmol) as a yellow solid, LCMS (M+H)+: 225. Step 2: preparation of ethyl (E)-3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-enoate (compound A23-b) A solution of 4-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (compound A23-a, 3.6 g, 16.0 mmol) and (carbethoxymethylene)triphenylphosphorane (7.42 g, 21.3 mmol) in toluene (76 mL) was stirred at 110 °C for 3 hrs. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give compound A23-b (4.1 g) as a yellow solid, LCMS (M+H)+: 295. Step 3: preparation of ethyl 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propanoate (compound A23-c) A mixture of ethyl (E)-3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-enoate (compoundA23-b, 4.36 g, 14.8 mmol) and PtO2 (220 mg, 14.8 mmol) in EtOH (40 mL) and THF (20 mL) was stirred at room temperature for 72 hrs under hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound A23-c (4.0 g) as a brown solid, LCMS (M+H)+: 297. Step 4: preparation of 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propan-1-ol (compound A23-d) To a mixture of ethyl 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propanoate (compound A23- d, 3.6 g, 12.1 mmol) and calcium chloride (2.0 g, 18.2 mmol) in anhydrous THF (25 mL) and EtOH (25 mL) was added sodium borohydride (1.0 g, 26.6 mmol) slowly at 0 °C, the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with DCM, and poured into cold ammonium chloride solution, then extracted with DCM. The separated organic layer was washed with brine, and dried over anhydrous Na2SO4, filtered, concentrated to give crude product, which was purified by column chromatography to give compound A23-d (1.15 g) as a white solid, LCMS (M+H)+: 255. Step 5: preparation of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e) A mixture of 3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propan-1-ol (compound A23-d,1.0 g, 3.92 mmol) in SOCl2(4.0 mL, 3.92 mmol) was stirred at 80 °C for 1 hr. After being cooled to room temperature, the reaction mixture was added dropwise into saturated sodium bicarbonate aqueous solution and pH was adjusted to 8, then the mixture was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to give compound A23-e (1.06 g) as a brown oil, LCMS (M+H)+: 273. Step 6: preparation of 2-[3-(4-bromopyrazolo[1,5-a]pyridin-3-yl)propyl]isoindoline- 1,3-dione (intermediate A23) A mixture of 4-bromo-3-(3-chloropropyl)pyrazolo[1,5-a]pyridine (compound A23-e, 950 mg, 3.47 mmol), potassium phthalimide (1.29 g, 6.95 mmol) and sodium iodide (1.56 g, 10.42 mmol)in DMF (10 mL) was heated to 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 extracted with EtOAc for three times, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude product. The crude was purified by flash column chromatography to give intermediate A23 (620 mg) as a yellow solid, which was directly used for next step without further purification, LCMS (M+H)+:383. Intermediate A24 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2- trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]boronic acidStep 1: preparation of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a) To a solution of 4-chloro-1H-pyrazolo[3,4-b]pyridine (4.0 g, 26.0 mmol) in DMF (80 mL), N-iodosuccinimide (7.0 g, 31.3 mmol) was added in one portion at room temperature, the resulting mixture was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by column chromatography to give compound A24-a (8.0 g) as a yellow solid, LCMS (M+H)+: 280. Step 2: preparation of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)prop-2- ynyl]-N-methyl-carbamate (compound A24-b) To a mixture of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound A24-a, 4.0 g, 14.3 mmol) and benzyl N-methyl-N-prop-2-ynyl-carbamate (3.5 g, 17.2 mmol) in DMF (50 mL) was added TEA (3.2 mL, 22.96 mmol) in one portion under N2, 5 mins later, dichlorobis(tri-o- tolylphosphine)palladium(II) (800 mg, 1.02 mmol) and copper(I) iodide (0.1 mL, 4.2 mmol) were added successively. The resulting mixture was stirred at 90 °C for 12 hrs. After beingcooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by prep-HPLC to give compound A24-b (2.0 g) as a brown solid, LCMS (M+H)+: 355. Step 3: preparation of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)propyl]- N-methyl-carbamate (compound A24-c) To a solution of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)prop-2-ynyl]-N- methyl-carbamate (compound A24-b, 2.0 g, 5.64 mmol) in THF (12 mL) and methanol (6.0 mL), PtO2 (640 mg, 2.82 mmol) was added in one portion, the resulting mixture was stirred at room temperature for 4 hrs under hydrogen. The reaction mixture was filtered, then the filtrate was concentrated in vacuo to get a crude compound A24-c (2.0 g), LCMS (M+H)+: 359. Step 4: preparation of benzyl N-[3-[4-chloro-2-(2- trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]propyl]-N-methyl-carbamate (compound A24-d) To a mixture of benzyl N-[3-(4-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)propyl]-N-methyl- carbamate (compound A24-c, 2.0 g, 5.57 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.36 mmol) in DMF (30 mL), sodium hydride (446 mg, 11.2 mmol) was added in one portion. The resulting mixture was stirred at 0 °C to room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and poured into saturated ammonium chloride solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by column chromatography to afford compound A24-d (660 mg) as a light yellow oil, LCMS (M+H)+: 489. Step 5: preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2- trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]boronic acid (intermediate A24) A mixture of bis(neopentyl glycolato)diboron (914 mg, 4.05 mmol), benzyl N-[3-[4- chloro-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]propyl]-N-methyl- carbamate (compound A24-d, 660 mg, 1.35 mmol), Pd2(dba)3 (330 mg, 0.4 mmol), X-PHOS (330 mg, 0.69 mmol) and sodium acetate trihydrate (367 mg, 2.70 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C for 4 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into saturated ammonium chloride solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude intermediate A24 (1.0 g) as a brown oil, which was used in next step directly, LCMS (M+H)+: 499.Intermediate A25 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2- trimethylsilylethoxymethyl)indazol-4-yl]boronic acidThe title compound was prepared according to the following scheme:Step 1: preparation of 2-[(4-bromoindazol-2-yl)methoxy]ethyl-trimethyl-silane (compound A25-a) To a solution of 4-bromo-2H-indazole (3.0 g, 15.2 mmol) in THF (50 mL), N-cyclohexyl- N-methylcyclohexanamine (3.0 g, 15.2 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (3.2 mL, 18.3 mmol) were added in one portion at 0 °C, the resulting mixture was stirred at 0 °C for 2 hrs. The reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some crude product, which was purified by column chromatography to afford compound A25-a (1.7 g) as a colorless oil, LCMS (M+H)+: 329. Step 2: preparation of 2-[[4-bromo-3-(3-chloropropyl)indazol-2-yl]methoxy]ethyl- trimethyl-silane (compound A25-b) To a solution of 2-[(4-bromoindazol-2-yl)methoxy]ethyl-trimethyl-silane (compound A25- a, 6.0 g, 18.3 mmol) in THF (70 mL) was added LDA (13.8 mL, 27.5 mmol) dropwise for 10 mins at -78 °C. Then 1-chloro-3-iodopropane (5.6 g, 27.5 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 2 hrs, the resulting mixture was warmed to room temperature over 12 hrs. The reaction mixture was diluted with EtOAc, and poured into saturated ammonium chloridesolution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by prep- HPLC to afford compound A25-b (3.4 g) as a colorless oil, LCMS (M+H)+: 405. Step 3: preparation of 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]-N- methyl-propan-1-amine (compound A25-c) To a mixture of TEA (1.2 mL, 8.91 mmol) and monomethylamine in water (15.0 mL, 2.97 mmol) was added 2-[[4-bromo-3-(3-chloropropyl)indazol-2-yl]methoxy]ethyl-trimethyl-silane (compound A25-b, 1.2 g, 2.97 mmol) in MeCN (2 mL) dropwise, the resulting mixture was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by column chromatography to give compound A25-c (1.2 g) as a colorless oil, LCMS (M+H)+: 398. Step 4: preparation of benzyl N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol- 3-yl]propyl]-N-methyl-carbamate (compound A25-d) To a mixture of 3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]-N-methyl- propan-1-amine (compound A25-c, 2.5 g, 6.27 mmol) and saturated sodium bicarbonate aqueous solution (25 mL) in THF (25 mL) was added N-(benzyloxycarbonyloxy)succinimide (1.7 g, 6.90 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,concentrated to get crude product, then the crude product was purified by column chromatography to give compound A25- d (2.3 g) as a colorless oil, LCMS (M+H)+: 534. Step 5: preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2- trimethylsilylethoxymethyl)indazol-4-yl]boronic acid (intermediate A25) A mixture of bis(neopentyl glycolato)diboron (1.1 g, 5.06 mmol), benzyl N-[3-[4-bromo-2- (2-trimethylsilylethoxymethyl)indazol-3-yl]propyl]-N-methyl-carbamate (compound A25-d, 900 mg, 1.70 mmol), Pd(dppf)Cl2(200 mg, 0.27 mmol) and potassium phosphate (716 mg, 3.40 mmol) and in 1,4-dioxane (15 mL) was stirred at 100 °C for 4 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,concentrated to get crude intermediate A25 (1.2 g) as a brown oil, LCMS (M+H)+: 498. Intermediate A26[3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazol-4-yl]boronic acidThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl N-(3-bromo-2-cyano-anilino)-N-methyl-carbamate (compound A26-a) To a solution of tert-butyl N-amino-N-methyl-carbamate (16.0 g, 110 mmol) in THF (200 mL) was added sodium hydride (2.64 g, 110 mmol) in one portion at 0 °C, 1 hr later, 2-bromo-6- fluorobenzonitrile (10.0 g, 50 mmol) was added into the mixture, the resulting mixture was stirred at 50 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into saturated ammonium chloride solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by prep-HPLC to give compound A26-a (4.6 g) as a brown oil, LCMS (M+H-100)+: 228. Step 2: preparation of 4-bromo-2-methyl-indazol-3-amine (compound A26-b) A mixture of tert-butyl N-(3-bromo-2-cyano-anilino)-N-methyl-carbamate (compound A26-a, 4.5 g, 13.8 mmol) and con. HCl (30 mL) in 1,4-dioxane (10 mL) was stirred at 100 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was concentrated in vacuo to give some residue. The residue was diluted with EtOAc, and poured into water, neutralized by saturated sodium bicarbonate aqueous solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get thecrude compound A26-b (3.1 g) as a yellow solid, which was used in next step directly, LCMS (M+H)+: 226. Step 3: preparation of tert-butyl N-[2-[(4-bromo-2-methyl-indazol-3-yl)amino]ethyl]- N-methyl-carbamate (compound A26-c) A mixture of 4-bromo-2-methyl-indazol-3-amine (compound A26-b, 1.3 g, 5.75 mmol), tert-butyl N-methyl-N-(2-oxoethyl)carbamate (1.3 g, 7.51 mmol) and titanium(IV)isopropoxide (260 mg, 0.91 mmol) in anhydrous 1,2-dichloroethane (20 mL) was stirred at room temperature for 12 hrs. Then sodium borohydride (260 mg, 6.87 mmol) was added, the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into saturated ammonium chloride solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude compound A26-c (2.65 g) as a yellow oil, which was used in next step directly, LCMS (M+H)+: 385. Step 4: preparation of tert-butyl N-(4-bromo-2-methyl-indazol-3-yl)-N-[2-[tert- butoxycarbonyl(methyl)amino]ethyl]carbamate (compound A26-d) A mixture of tert-butyl N-[2-[(4-bromo-2-methyl-indazol-3-yl)amino]ethyl]-N-methyl- carbamate (compound A26-c, 2.6 g, 2.04 mmol), Boc2O (1.5 g, 6.87 mmol), TEA (0.83 mL, 5.93 mmol) and DMAP (200 mg) in anhydrous DCM (20 mL) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with DCM, then washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude product, which was purified by prep-HPLC to afford compound A26-d (650 mg) as a yellow oil, LCMS (M+H)+: 483. Step 5: preparation of [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2- methyl-indazol-4-yl]boronic acid (intermediate A26) A mixture of bis(neopentyl glycolato)diboron (500 mg, 2.21 mmol), tert-butyl N-(4- bromo-2-methyl-indazol-3-yl)-N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]carbamate (compound A26-d, 500 mg, 1.03 mmol), Pd(dppf)Cl2(110 mg, 0.15 mmol) and sodium acetate (375 mg, 1.77 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 4 hrs. After being cooled to room temperature, the reaction mixture was diluted with DCM, and poured into water, then extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get the crude product, which was purified by prep-HPLC to afford intermediate A26 (350 mg) as a yellow oil, LCMS (M+H)+: 349. Intermediate A27 [3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-7-fluoro-2-(2- trimethylsilylethoxymethyl)indazol-4-yl]boronic acidThe title compound was prepared according to the following scheme:The title compound was prepared in the analogy to the preparation of intermediate A24 by using 4-bromo-7-fluoro-1H-indazole instead of 4-chloro-1H-pyrazolo[3,4-b]pyridine, LCMS (M+H)+: 516. Intermediate A28 [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2-oxo-1H-benzimidazol-4- yl]boronic acidThe title compound was prepared according to the following scheme:Step 1: preparation of 1-bromo-2,4-difluoro-3-nitro-benzene (compound A28-a) To a mixture of 2,6-difluoronitrobenzene (5.0 g, 31.4 mmol) in con. sulfuric acid (10 mL) and TFA (20 mL) was added N-bromosuccinimide (6.7 g, 37.7 mmol) in portions and the resulting mixture was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the mixture was poured into ice water and extracted with EtOAc twice. The combined organic layer was washed with saturated sodium bicarbonate aqueous solution, brine, dried and concentrated to give some residue. The residue was purified by flash column chromatography to afford compound A28-a (7.3 g) as yellow oil), LCMS (M+H)+: 238. Step 2: preparation of tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N- methyl-carbamate (compound A28-b) A mixture of 1-bromo-2,4-difluoro-3-nitro-benzene (compound A28-a, 7.3 g, 30.67 mmol), tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (5.8 g, 30.67 mmol) and DIPEA (10.7 mL, 61.35 mmol) in DMF (200 mL) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and poured into saturated ammonium chloride solution, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by column chromatography to give compound A28-b (9.0 g) as a yellow oil, LCMS (M+H-100)+: 306. Step 3: preparation of tert-butyl N-[3-(2-amino-6-bromo-3-fluoro-anilino)propyl]-N- methyl-carbamate (compound A28-c) To a mixture of tert-butyl N-[3-(6-bromo-3-fluoro-2-nitro-anilino)propyl]-N-methyl- carbamate (compound A28-b, 8.0 g, 19.69 mmol) and Raney-nickel (8.0 g) in methanol (50 mL), hydrazine (10.0 g) was added dropwise, the resulting mixture was stirred at room temperature for1 hr. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give compound A28-c (7.3 g) as an orange oil, which was used in next step directly, LCMS (M+H)+: 378. Step 4: preparation of tert-butyl N-[3-(7-bromo-4-fluoro-2-oxo-3H-benzimidazol-1- yl)propyl]-N-methyl-carbamate (compound A28-d) To a mixture of tert-butyl N-[3-(2-amino-6-bromo-3-fluoro-anilino)propyl]-N-methyl- carbamate (compound A28-c, 7.3 g, 19.4 mmol) and potassium carbonate (8.0 g, 58.2 mmol) in DMF (100 mL) was added N, N'-carbonyldiimidazole (4.1 g, 25.2 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get crude product, the crude was purified by prep-HPLC to afford compound A28-d (1.2 g) as a light brown solid, LCMS (M+H)+: 402. Step 5: preparation of [3-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-7-fluoro-2- oxo-1H-benzimidazol-4-yl]boronic acid (intermediate A28) A mixture of bis(neopentyl glycolato)diboron (1.7 g, 7.46 mmol), tert-butyl N-[3-(7- bromo-4-fluoro-2-oxo-3H-benzimidazol-1-yl)propyl]-N-methyl-carbamate (compound A28-d, 1.2 g, 2.98 mmol), Pd2(dba)3 (240 mg, 0.26 mmol) and sodium acetate (375 mg, 1.77 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get the crude product, which was purified by prep-HPLC to afford intermediate A28 (1.0 g) as a yellow oil, LCMS (M+H)+: 368. Intermediate A29 2-trimethylsilylethyl N-(3-hydroxypropyl)-N-methyl-carbamateThe title compound was prepared according to the following scheme:Intermediate A29To a solution of 3-(methylamino)propan-1-ol (0.3 g, 3.37 mmol) in saturated sodium bicarbonate aqueous solution (15 mL) and THF (15 mL) was added 2,5-dioxopyrrolidin-1-yl(2- (trimethylsilyl)ethyl)carbonate (1.05 g, 4.04 mmol), the resulting mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into water, and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give intermediate A29 (0.7 g) as a colorless oil), which was used in next step directly. Intermediate A30 tert-butyl N-[2-(4-bromoindazol-2-yl)ethyl]-N-[2-(1,3-dioxoisoindolin-2- yl)ethyl]carbamateThe title compound was prepared according to the following scheme:A30-a Intermediate A30Step 1: preparation of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-methyl- carbamate (compound A30-a) To a solution of tert-butyl N-[3-(methylamino)propyl]carbamate (5.0 g, 26.5 mmol) and N- (benzyloxycarbonyloxy)succinimide (7.9 g, 31.8 mmol) in THF (100 mL) was added saturated sodium bicarbonate aqueous solution (100 mL), the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc, then poured into water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some crude product, which was purified by column chromatography to afford compound A30-a (8.5 g) as a colorless oil, LCMS (M+H-56)+: 267. Step 2: preparation of tert-butyl N-[2-(4-bromoindazol-2-yl)ethyl]-N-[2-(1,3- dioxoisoindolin-2-yl)ethyl]carbamate (intermediate A30) A solution of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-methyl-carbamate (compound A30-a, 6.0 g, 18.61 mmol) in TFA (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give intermediate A30 (4.0 g) as a colorless oil, which was used in next step directly, LCMS (M+H)+: 223. Intermediate A31 tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-1- yl]propyl]carbamateThe title compound was prepared according to the following scheme:Intermediate A31 Step 1: preparation of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a) A mixture of 7-bromo-1H-indazole (1.0 g, 5.1 mmol),1-bromo-3-chloro-propane (2.4 g, 15.2 mmol) and potassium carbonate (1.4 g, 10.1 mmol in DMF (10 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured in water and extracted with EtOAc twice, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some residue. The residue was purified by flash column chromatography to afford compound A31-a (0.6 g) as a colorless oil, LCMS (M+H)+: 273. Step 2: preparation of tert-butyl N-[3-(7-bromoindazol-1-yl)propyl]-N-methyl- carbamate (compound A31-b) To a mixture of 7-bromo-1-(3-chloropropyl)indazole (compound A31-a, 8.0 g, 29.2 mmol) and tert-butyl N-methylcarbamate (3.8 g, 29.2 mmol) in DMF (100 mL) was added sodium hydride (2.4 g, 58.5 mmol) in portions at 0 °C, the resulting mixture was stirred at 0 °C for 2 hrs. The reaction mixture was poured into water and extracted with EtOAc twice, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some residue. The residue was purified by flash column chromatography to afford compound A31-b (5 g) as a colorless oil, LCMS (M+H)+: 368. Step 3: preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-1-yl]propyl]carbamate (intermediate A31) A mixture of tert-butyl N-[3-(7-bromoindazol-1-yl)propyl]-N-methyl-carbamate (compound A31-b, 4.0 g, 10.8 mmol), bis(pinacolato)diboron (3.3 g, 13.0 mmol), 1,1'- PdCl2(DPPF)-CH2Cl2adduct (0.9 g, 1.09 mmol) and potassium acetate (3.2 g, 32.6 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was poured into water and extracted with EtOAc twice, the combinedorganic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some residue. The residue was purified by prep-HPLC to afford intermediate A31 (1.5 g) as a colorless oil, LCMS (M+H)+: 416. Intermediate A32 benzyl N-[2-[(5-bromo-1-methyl-imidazol-4-yl)methoxy]ethyl]-N-methyl-carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of 4-(chloromethyl)-1-methyl-imidazole (compound A32-a) A mixture of (1-methylimidazol-4-yl)methanol (0.5 g, 4.5 mmol) and thionyl chloride (1.1 g, 8.9 mmol) in DCM (20 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to give crude compound A32-a (0.6 g) as a white solid, which was used in next step directly, LCMS (M+H)+: 131. Step 2: preparation of tert-butyl N-methyl-N-[2-[(1-methylimidazol-4- yl)methoxy]ethyl]carbamate (compound A32-b) To a solution of 4-(chloromethyl)-1-methyl-imidazole (compound A32-a, 0.5 g, 3.8 mmol, 1.0 eq) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (0.8 g, 4.6 mmol) in DMF (8 mL) was added sodium hydride (0.3 g, 7.7 mmol) in portions, the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into saturated ammonium chloride solution, then extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to get some crude product, which was purified by reversed phase flash column to afford compound A32-b (0.6 g) as a yellow oil, LCMS (M+H)+: 270.Step 3: preparation of N-methyl-2-[(1-methylimidazol-4-yl)methoxy]ethanamine (compound A32-c) To a mixture of tert-butyl N-methyl-N-[2-[(1-methylimidazol-4- yl)methoxy]ethyl]carbamate (1.0 g, 3.7 mmol) in DCM (10 mL) was added TFA (3 mL), the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to give compound A32-c (0.6 g) as a light yellow oil, which was used in next step directly, LCMS (M+H)+: 170. Step 4: preparation of benzyl N-methyl-N-[2-[(1-methylimidazol-4- yl)methoxy]ethyl]carbamate (compound A32-d) To a solution of N-methyl-2-[(1-methylimidazol-4-yl)methoxy]ethanamine (compound A32-c, 0.4 g, 2.4 mmol), N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.6 mmol) in THF (10 mL) was added saturated sodium bicarbonate aqueous solution (10 mL), the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into saturated ammonium chloride solution, and then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give some crude product, which was purified by column chromatography to afford compound A32-d (0.6 g) as a light brown oil, LCMS (M+H)+: 304. Step 5: preparation of benzyl N-[2-[(5-bromo-1-methyl-imidazol-4-yl)methoxy]ethyl]- N-methyl-carbamate (intermediate A32) To a solution of benzyl N-methyl-N-[2-[(1-methylimidazol-4-yl)methoxy]ethyl]carbamate (compound A32-d, 0.6 g, 1.6 mmol) in DMF (10 mL) was added NBS (0.4 g, 2.0 mmol) at 0 °C, the resulting mixture was stirred at room temperature for 2 hrs. The mixture was poured in water and extracted with EtOAc twice, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude intermediate A32 (0.6 g) as a light brown oil, which was used in next step directly, LCMS (M+H)+: 384. Intermediate A33 benzyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl-carbamateThe title compound was prepared according to the following scheme:A33-cIntermediate A33 Step 1: preparation of 4-bromothiazole-5-carboxylic acid (compound A33-a) To a mixture of ethyl 4-bromothiazole-5-carboxylate (2.5 g, 10.6 mmol) in methanol (50 mL) and water (5 mL) was added lithium hydroxide monohydrate (2.2 g, 52.9 mmol), the resulting mixture was stirred room temperature for 2 hrs. The reaction mixture was acidified by 1N aq. HCl solution to PH~5, and then poured into water, extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude compound A33-a (2.0 g) as a light yellow solid, which was used in next step directly, LCMS (M+H)+: 208. Step 2: preparation of tert-butyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N- methyl-carbamate (compound A33-b) To a mixture of 4-bromothiazole-5-carboxylic acid (compound A33-a, 1.6 g, 7.7 mmol) and DIPEA (2.9 g, 23.0 mmol) in DMF (50 mL) was added HATU (2.2 g, 9.3 mmol) at 0 °C, followed by tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (1.6 g, 8.5 mmol). The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, and then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude product, which was purified by column chromatography to afford compound A33-b (1.2 g) as a light yellow oil, LCMS (M+H-100)+: 280. Step 3: preparation of 4-bromo-N-[3-(methylamino)propyl]thiazole-5-carboxamide (compound A33-c) To a solution of tert-butyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl- carbamate (compound A33-b, 1.2 g, 3.17 mmol) in DCM (3 mL) was added TFA (3 mL), the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to give crude compound A32-c (0.8 g) as a yellow oil, which was used in next step directly, LCMS (M+H)+: 280.Step 4: preparation of benzyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N- methyl-carbamate (intermediate A33) To a mixture of 4-bromo-N-[3-(methylamino)propyl]thiazole-5-carboxamide (compound A32-c, 0.8 g, 2.9 mmol), N-(benzyloxycarbonyloxy)succinimide (0.9 g, 3.5 mmol) in THF (10 mL) was added saturated sodium bicarbonate aqueous solution (10 mL), the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into saturated ammonium chloride solution, and then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude product, which was purified by silica column chromatography to afford intermediate A33 (0.7 g) as a light yellow oil, LCMS (M+H)+: 412. Intermediate A34 2-[3-(4-bromoindazol-2-yl)propyl]isoindoline-1,3-dioneThe title compound was prepared according to the following scheme:Intermediate A34A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (95.25 g, 355.28 mmol), 4-bromo- 1H-indazole (70.0 g, 355.28 mmol) and cesium carbonate (231.64 g, 710.55 mmol) in acetonitrile (1400 mL) was stirred at 50 °C for 16 hrs. After being cooled to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to give Intermediate A34 (30.0 g) as a pink solid, LCMS (M+H)+: 384. Intermediate A35 2-[4-(4-bromoindazol-2-yl)butyl]isoindoline-1,3-dioneThe title compound was prepared in analogy to the preparation of Intermediate A34 by using 2-(4-bromobutyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione, LCMS (M+H)+: 398. Intermediate A36 2-[5-(4-bromoindazol-2-yl)pentyl]isoindoline-1,3-dioneThe title compound was prepared in analogy to the preparation of Intermediate A34 by using 2-(5-bromopentyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3- dione, LCMS (M+H)+: 412. Intermediate A37 2-[6-(4-bromoindazol-2-yl)hexyl]isoindoline-1,3-dioneThe title compound was prepared in analogy to the preparation of Intermediate A34 by using 2-(6-bromohexyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione, LCMS (M+H)+: 426. Intermediate A38 2-[7-(4-bromoindazol-2-yl)heptyl]isoindoline-1,3-dioneThe title compound was prepared in analogy to the preparation of Intermediate A34 by using 2-(7-bromoheptyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3- dione, LCMS (M+H)+: 440. Intermediate A39 tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazol- 1-yl]propyl]carbamateThe title compound was prepared according to the following scheme:intermediate A39Step 1: preparation of 3-(2-bromo-6-nitro-anilino)propan-1-ol (compound A39-b) To a solution of compound A39-a (14.2 g, 64.55 mmol) and potassium carbonate (17.84 g, 129.09 mmol) in ACN (200 mL) was added 3-amino-1-propanol (5.33 g, 71.0 mmol) slowly at 25 °C. The reaction was stirred at 85 °C for 2 h, then the mixture was filtered and concentrated to afford compound A39-b (17.5 g) as a yellow oil. LCMS (M+H+): 275. Step 2: preparation of 3-(2-amino-6-bromo-anilino)propan-1-ol (compound A39-c) To a solution of compound A39-b (17.5 g, 63.61 mmol) in methanol (422 mL) was added Raney Ni (15.0 g, 255.58 mmol) and hydrazine hydrate (15.92 g, 318.07 mmol). The reaction was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated, the residue was dissolved in 200 mL DCM, which was washed with water and brine. The organic layer was dried and concentrated to give compound A39-c (13.4 g) as yellow gum. LCMS (M+H+): 245. Step 3: preparation of 3-(7-bromobenzotriazol-1-yl)propan-1-ol (compound A39-d) To a solution of compound A39-c (3.6 g, 14.69 mmol) in AcOH (9.6 mL) was added HCl (4.8 mL, 0.610 mmol) in water (4.8 mL) and NaNO2(1.69 g, 24.53 mmol) in water (17 mL). The reaction was stirred at 25°C for 1 h, and then NaHCO3was added to mixture to adjust pH=8, the resulted mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to give compound A39-d (3.0 g) as a yellow oil. LCMS (M+H+): 256, Step 4: preparation of 7-bromo-1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole (compound A39-e) A solution of compound A39-d (1.0 g, 3.90 mmol) in SOCl2 (5 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated to give compound A39-e (1.1 g) as a white solid. LCMS (M+H+): 274. Step 5: preparation of 3-(7-bromo-1H-benzo[d][1,2,3]triazol-1-yl)-N-methylpropan-1- amine (compound A39-f) A solution of compound A39-e (1.1 g, 4.0 mmol) in MeNH2 / in ethanol (10 mL) was stirred at 70 °C for 3 h under N2 atmosphere in microwave. The reaction mixture was concentrated to give compound A39-f (1.0 g) as a white solid. LCMS (M+H+): 269. Step 6: preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzotriazol-1-yl]propyl]carbamate (compound A39-g) To a solution of compound A39-f (1.0 g, 3.72 mmol), DIEA (960.4 mg, 7.43 mmol) and DMAP (45.4 mg, 0.37 mmol) in DCM (10 mL) was added Boc2O (1.22 g, 5.57 mmol). The resulting mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated and theresidue was purified by silica gel column chromatography to give compound A39-g (800 mg) as colorless oil. LCMS (M+H+): 369. Step 7: preparation of tert-butyl N-methyl-N-[3-[7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzotriazol-1-yl]propyl]carbamate (Intermediate A39) The title compound was prepared in analogy to the preparation of Intermediate A1 by using compound A39-g instead of compound A1-e. LCMS (M+H+): 417. Intermediate A40 tert-butyl N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1- yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl]carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of 3-(7-bromobenzimidazol-1-yl)propan-1-ol (compound A40-a) To a solution of compound A39-c (21 g, 85.7 mmol) in anhydrous THF (400 mL) was added trimethyl orthoformate (32 mL, 291 mmol) and pyridinium p-toluenesulfonate (3.1 g, 12.3 mmol). The reaction mixture was stirred for 2 h at 20 °C and then concentrated. The residue was purified by silica gel column chromatography to give compound A40-a (8 g) as a yellow solid. LCMS (M+H)+: 255. Step 2: preparation of 7-bromo-1-(3-chloropropyl)benzimidazole (compound A40-b)A solution of compound A40-a (8.0 g, 31.36 mmol) in SOCl2 (40.0 mL) was stirred at 80 °C for 1 h. Then the reaction mixture was concentrated, the residue was diluted with EA, washed with aqueous NaHCO3 and brine. The organic layer was dried and concentrated to give compound A40-b (8 g) as a yellow oil. Step 3: preparation of tert-butyl N-[4-[3-(7-bromobenzimidazol-1- yl)propylamino]butyl]carbamate (compound A40-c) A mixture of compound A40-b (8 g, 29.24 mmol), N,N-diisopropylethylamine (12 mL, 70 mmol) and N-BOC-1,4-diaminobutane (7.5 g, 40 mmol) in DMF (100 mL) was stirred for 3 h at 110 °C. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound A40-c (3.3 g) as colorless gum. LCMS (M+H)+: 427. Step 4: preparation of tert-butyl (4-((3-(7-bromo-1H-benzo[d]imidazol-1- yl)propyl)amino)butyl)carbamate (compound A40-d) To a solution of compound A40-c (2.7 g, 6.35 mmol) and TEA (1.3 mL, 9.5 mmol), in DCM (30 mL) was added trifluoroacetic anhydride (1 mL, 6.98 mmol) at 0 °C. The reaction was stirred at 0 °C for 4 h and then concentrated. The residue was purified by prep-HPLC to give compound A40-d (1.84 g,) as colorless gum. LCMS (M+H)+: 523. Step 5: preparation of tert-butyl N-[4-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl-(2,2,2-trifluoroacetyl)amino]butyl]carbamate (intermediate A40) The title compound was prepared in analogy to the preparation of Intermediate A1 by using compound A40-d instead of compound A1-e. LCMS (M+H+): 569. Intermediate A41 tert-butyl N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]carbamateThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl N-[4-[2-(6-bromo-2-pyridyl)hydrazino]-4-oxo- butyl]carbamate (compound A41-b) To a solution of 2-bromo-6 hydrazinopyridine (3.5 g, 18.61 mmol), compound A41-a (4.16 g, 20.48 mmol) and DIPEA (4.81 g, 37.23 mmol) in DMF (40 mL) was added HATU (6.58 g, 27.97 mmol). After being stirred at 30 °C for 2 hours, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated to afford compound A41-b (7.0 g). LCMS (M+H)+: 375. Step 2: preparation of tert-butyl N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)propyl]carbamate (Intermediate A41) To a stirred solution of compound A41-b (7.0 g, 18.75 mmol), hexachloroethane (8.88 g, 37.51 mmol) and triphenylphosphine (9.84 g, 37.51 mmol) in THF (100 mL) was added triethylamine (10.46 mL, 75.02 mmol) dropwise at 20 °C. After being stirred at 20 °C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to afford Intermediate A41 (5.73 g). LCMS (M+H)+: 357. Intermediate B1 and B2 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-dicarboxylateThe title compound was prepared according to the following scheme:Intermediate B1 Intermediate B2A mixture of 2,4-dichloropyrimidine (19 g, 128 mmol), 1-(tert-butyl) 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (21 g, 86 mmol) and K2CO3 (36 g, 258 mmol) in DMF (100 mL) was stirred at 80oC for 16 hours. Then the reaction was diluted with EtOAc, washed withwater and brine, the organic layer was concentrated, the residue was purified by silica gel column chromatography to give intermediate B1 (faster eluted, 5 g), LCMS (M+H+): 357; and intermediate B2 (slower eluted, 25 g), LCMS (M+H+): 357. Intermediate B3 and B4 O1-benzyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate and O1-benzyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin-4- yl)amino]pyrrolidine-1,2-dicarboxylateIntermediate B3 Intermediate B4The title compound was prepared according to the following schemeIntermediate B3 Intermediate B4A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol) and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at rt for 48 hours. Then the reaction was filtered and concentrated, the residue was purified by silica gel column chromatography to give intermediate B3 (faster eluted, 1 g), LCMS (M+H+): 391; and intermediate B4 (slower eluted, 6 g), LCMS (M+H+): 391. Intermediate B5 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 B5A mixture of 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28 g, 99.7 mmol), DIPEA (69 mL, 398 mmol) and 2-bromo-6-fluoropyridine (21 g, 119 mmol) in DMSO (140 mL) was heated to 110 °C for 16 hours. The mixture was diluted with water and extracted with EA, the organic layer was concentrated to give intermediate B5 (34 g), LCMS (M+H+): 400. Intermediate B6 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl- amino]pyrrolidine-1,2-dicarboxylateThe title compound was prepared according to the following scheme:A mixture of intermediate B5 (12 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-t-butyldicarbonate (20 g, 90 mmol) and triethylamine (10 mL, 74 mmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give intermediate B6 (11.8 g), LCMS (M+H+): 500. Intermediate B7 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, 14.9 mmol), 2-bromo-6-fluoropyridine (3.2 g, 17.9 mmol) and DIPEA (13.0 mL, 74.7 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 h. The mixture was concentrated, the residue was purified by prep-HPLC to give intermediate B7 (5.1 g), LCMS (M+H+): 434. Intermediate B8 O1-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 B8To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (2 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.8 g, 8.15 mmol) and Ph3P (2.5 g, 9.38 mmol) in THF (50 mL) was added DIAD (1.9 g, 9.38 mmol) in THF (10 mL) dropwise at 0 °C. After being stirred at 20 °C overnight, the reaction mixturewas concentrated, and the residue was s purified by silica gel column chromatography to give intermediate B8 (1.2 g), LCMS: (M+H)+: 448. Intermediate B9 O1-benzyl 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 in analogy to the preparation of intermediate B8 by using 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate instead of 1-(tert-butyl) 2- methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate. LCMS: (M+H)+: 482. Intermediate B10 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 B10 To a mixture of 4-bromo-2-hydroxypyridine (10.7 g, 61.2 mmol), O1-tert-butyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) and PPh3 (16 g, 61.2 mmol) in Toluene (100 mL) was added DIAD (12.4 g, 61.2 mmol) at 0 °C under N2, then the mixture was stirred at 100 °C for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to afford intermediate B10 (12.5 g). LCMS (M-56+H)+: 345. Intermediate B11 O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2-dicarboxylateThe title compound was prepared according to the following scheme:Intermediate B11 To a mixture of 3-bromophenol (4.23 g, 24.5 mmol), O1-tert-butyl O2-methyl (2S,4R)-4- hydroxypyrrolidine-1,2-dicarboxylate (4 g, 16.3 mmol), triphenylphosphine (6.42 g, 24.5 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (4.95 g, 24.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 4 hours, then concentrated and the residue was purified by flash column chromatography to afford Intermediate B11 (5.5 g). LCMS (M+H)+: 400. Intermediate B12 O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylateTo a solution of O1-tert-butyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (5.0 g, 17.8 mmol) and 2,6-dichloropyridine (3.0 g, 20.3 mmol) in 1,4-dioxane (50 mL) was added XPhos (3.4 g, 7.1 mmol), Pd2(dba)3 (3.26 g, 3.6 mmol) and cesium carbonate (11.6 g, 35.6 mmol). The resulting mixture was stirred at 90 °C for 16 hrs, and then the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give some residue, the residue was purified by flash column to give intermediate B12 (2.5 g) as a yellow solid, LCMS (M+H)+: 300. Intermediate B13O1-tert-butyl O2-methyl (2S,4S)-4-[(5-bromo-3-pyridyl)oxy]pyrrolidine-1,2- dicarboxylateThe title compound was prepared in the analogy to the preparation of Intermediate B10 by using 3-bromo-5-hydroxypyridine instead of 4-bromo-2-hydroxypyridine, LCMS (M+H)+: 401. Intermediate C1 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidineThe title compound was prepared in analogy to the preparation of intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloro-5-pyrimidinecarbaldehyde. LCMS (M+H+): 301. Intermediate C2 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidineThe title compound was prepared according to the following scheme:.Step 1: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b) A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 138 mmol) and potassium carbonate (21.2 g, 153.2 mmol) in DCM (400 mL) was stirred for 12 h at 20 °C. Then the mixture was washed withwater and brine, the organic layer was dried and concentrated to give the crude compound C2-b (34.5 g). LCMS (M+H)+: 303. Step 2: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2) To a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (compound C2-b,18.5 g, 61 mmol) in NMP (185 mL) was added 4A molecular sieve (2 g). The mixture was stirred at 110 °C for 40 h. The reaction was cooled and 300 mL of water was added into the reaction mixture within 20 mins. The precipitate was collected and dried to give intermediate C2 (8.5 g). LCMS (M+H)+: 267. Intermediate C3 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazineStep 1: preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (compound C3-b) To a mixture of 2,4-difluorobenzoic acid (compound C3-a, 8 g, 50.6 mmol) in DCM (100 mL) was added thionyl chloride (260 mL) at 25 °C. After being stirred at 80 °C for 2 h, the mixture was concentrated and diluted with DCM. Then to the solution was added (3- chloropyrazin-2-yl)methanamine hydrochloride (9.1 g, 50.7 mmol) and triethylamine (14 mL, 102 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was concentrated, the residue was diluted with DCM (400 mL), washed with water (500 mL) and brine. The organic layer was dried and concentrated to afford compound C3-b (7.6 g). LCMS (M+H)+: 284. Step 2: preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Intermediate C3) To a solution of compound C3-b (16.2 g, 57.1 mmol) in toluene (320 mL) was added phosphorus oxychloride (27 mL, 286 mmol). The mixture was stirred at 110 °C for 16 h. Thenmixture was concentrated, the residue was added to a vigorously stirring mixture of EA (300 mL, contained 10 mL of triethylamine) and 50 g NaHCO3in 300 mL water at 0 °C. The organic layer was separated, dried and concentrated to give intermediate C3 (15.4 g). LCMS (M+H)+: 266. Intermediate C4 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acidThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylate (compound C4-a) A mixture of 2-chloro-4-fluorophenylhydrazine hydrochloride (6 g, 30.5 mmol) and ethyl 2-formyl-3-oxopropanoate (4.4 g, 30.5 mmol) in ethanol (120 mL) was stirred for 16 hrs at 25 °C. Then the mixture was diluted with DCM and adjusted to pH=3 with aq. HCl (1 M). The organic layer was separated, dried and concentrated to give the crude compound C16-a (8.18 g). LCMS (M+H)+: 269. Step 2: preparation of 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (Intermediate C4) A mixture of compound C16-a (8.18 g, 30.5 mmol) and lithium hydroxide monohydrate (3.8 g, 91 mmol) in ethanol (100 mL) was stirred at 45 °C for 4 hrs. The mixture was concentrated to about 20 mL and then diluted with 80 mL of water, acidified to pH 3~4 with 1 M HCl solution. The solid was collected and dried to give intermediate C4 (6.2 g). LCMS (M+H)+: 241. Intermediate C5 2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carboxylic acidThe title compound was prepared according to the following scheme:intermediate C5 Step 1: preparation of methyl 2-bromo-3-methyl-imidazole-4-carboxylate (compound C5-a) To a solution of methyl 3-methylimidazole-4-carboxylate (5.0 g, 35.6 mmol) in carbon tetrachloride (300.0 mL) was added NBS (12.7 g, 71.4 mmol) and 2,2'-azobis(2- methylpropionitrile) (0.3 g, 1.8 mmol). The mixture was stirred at 60 °C for 12 h and then concentrated. The residue was purified by silica gel column chromatography to give compound C5-a (1.5 g). LCMS (M+H)+: 219. Step 2: preparation of methyl 2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carboxylate (compound C5-b) A solution of 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.1 mmol), compound C5-a (1.0 g, 4.6 mmol), Pd-Ad2nBuP Biphenyl (0.3 g, 0.46 mmol) and K3PO4 (2.9 g, 13.7 mmol) in THF (10.0 mL) and water (1.0 mL) was stirred at 80 °C for 2 h under N2. The reaction was quenched with water (20.0 mL) and the mixture was extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to afford compound C5-b (0.7 g) as a white solid. LCMS (M+H)+: 253. Step 3: preparation of 2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carboxylic acid(Intermediate C5) A solution of compound C5-b (0.7 g, 2.78 mmol) and LiOH•H2O (0.35 g, 8.33 mmol) in methanol (15.0 mL) and water (2.0 mL) was stirred at 20 °C for 12 h. The mixture was concentrated, the residue was dissolved in water (20 mL) and acidified with HCl (1M) to pH=4. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give Intermediate C5 (0.6 g). LCMS (M+H)+: 238. Intermediate C6 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrileThe title compound was prepared according to the following scheme:Step 1: preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound C6-a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C1, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol) and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at rt for 2 hours. Then the reaction mixture was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound C6-a (400 mg). LCMS (M+H+): 373. Step 2: preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxylate (compound C6-b) A mixture of compound C6-a (400 mg, 1.07 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (488.0 mg, 3.22 mmol) and DIPEA (1.39 g, 10.73 mmol) in acetonitrile (50 mL) was stirred at 90oC for 16 hours. Then the reaction solution was concentrated and the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound C6-b (500 mg), LCMS (M+H+): 452. Step 3: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3-carboxylic acid (compound C6-c) A mixture of compound C6-b (400 mg, 0.88 mmol) and lithium hydroxide (2.2 mL, 2 M) in methanol (8 mL) was stirred at rt for 4 hours, then the pH was adjusted to 6, and the mixture was diluted with water. The resulting mixture was extracted with EA for 2 times, and then the organic layer was concentrated to give compound C6-c (380 mg), LCMS (M+H+): 438. Step 4: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carboxamide (compound C6-d) A mixture of compound C6-c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol ) and HATU (462 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was stirred at 40oC for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel chromatography to give compound C6-d (300 mg). LCMS (M+H+): 437. Step 5: preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]azetidine-3-carbonitrile (compound C6-e) To a mixture of compound C6-d (280 mg, 0.65 mmol) and pyridine (254 mg, 3.2 mmol) in DCM (28 mL) was added TFAA (404 mg, 1.92 mmol) dropwise at rt. After being stirred at rt for 10 mins, the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was dried and concentrated to give compound C6-e (260 mg). LCMS (M+H+): 419. Step 6: preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]azetidine-3-carbonitrile (intermediate C6) A mixture of compound C6-e (240 mg, 0.49 mmol) in DCM (10 mL) and TFA (2 mL), was stirred at rt for 20 hours, then the reaction was concentrated to give intermediate C6 (120 mg). LCMS (M+H+): 329. Intermediate C7 [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-6-yl]amineThe title compound was prepared according to the following scheme:Step 1: preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C7-b) A solution of 2-cyano-3-ethoxy-acrylic acid ethyl ester (1.87 g, 11.1 mmol), (2,4- difluorophenyl)hydrazine;hydrochloride (2 g, 11.1 mmol) and Et3N (3.1 mL, 22.2 mmol) in ethanol (40 mL) was stirred at 90 °C for 12 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound C7-b (2.53 g) as a light yellow solid. LCMS (M+H)+: 268. Step 2: preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4- d]pyrimidin-4-one (compound C7-c) A mixture of compound C7-b (700 mg, 2.62 mmol), 2-methoxyacetonitrile (372 mg, 5.24 mmol) in 4 M HCl in dioxane (8 mL) was stirred at 100 °C for 14 hours, then the solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was separated and concentrated, the residue was purified by silica gel column chromatography to give compound C7-c (200 mg) as a light brown solid, LCMS (M+H)+: 293. Step 3: preparation of [4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidin-6-yl]amine (Intermediate C7) A suspension of compound C7-c (200 mg, 0.68 mmol)) in phosphorus oxychloride (2 mL) was stirred at 90 °C for 0.5 hours. Then the reaction mixture was concentrated to give an oil, which was purified by silica gel column chromatography to give intermediate C7 (104 mg) as a white solid. LCMS (M+H+): 311. Intermediate C8 1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidin-4-olThe title compound was prepared according to the following scheme:Step 1: preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(oxetan-3- yl)pyrazolo[3,4-d]pyrimidine (compound C8-a) To an 8 mL vial equipped with a stir bar was added photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(15 mg, 0.013 mmol), tris(trimethylsilyl)silane (67 mg, 0.27 mmol), compound C6-a (100 mg, 0.27 mmol), 3-bromooxetane (73.5 mg, 0.54 mmol), NiCl2(dtbbpy) (10.68 mg, 0.027 mmol) and Na2CO3 (85 mg, 0.8 mmol). The vial was sealed and placed under nitrogen before 4 mL of DME was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (450-455 nm, with cooling fan to keep the reaction temperature at 25 °C) for 16 hours. The reaction was quenched by exposure to air and concentrated in vacuo, the residue was purified by silica gel column chromatography to give compound C8-a (60 mg). LCMS (M+H+): 395. Step 2: preparation of 1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4- d]pyrimidin-4-ol (intermediate C8) A mixture of compound C8-a (60 mg, 0.15 mmol) and Pd(OH)2(21 mg, 0.15 mmol) in methanol (12 mL) was stirred at rt 2 hours under H2 atmosphere. Then the reaction mixture was filtered and the filtrate was concentrated to give intermediate C8 (40 mg). LCMS (M+H+): 305. Intermediate C9 4-Chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidineThe title compound was prepared according to the following scheme:Step 1: preparation of N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (compound C9-c) A solution of 2-bromo-5-fluoroanisole (compound C9-a, 10.0 g, 48.8 mmol), benzophenone hydrazone (compound C9-b, 10.0 g, 51.0 mmol), palladium (II) acetate (200 mg, 0.90 mmol), XantPhos (400 mg, 0.70 mmol) and sodium tert-butoxide (6.7 g, 69.7 mmol) in anhydrous toluene (150 mL) was stirred at 100 °C for 12 hrs under nitrogen. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated to give crude product, which was recrystallized from petroleum ether to give compound C9-c (12.0 g), which was used in next step directly, LCMS (M+H)+: 321. Step 2: preparation of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C9-d) A mixture of compound N-(benzhydrylideneamino)-4-fluoro-2-methoxy-aniline (compound C9-c, 11.0 g, 34.3 mmol) in EtOH (100 mL) and con. HCl (10 mL, 120 mmol) was stirred at 60 °C for 12 hrs. The mixture was concentrated, and then EtOAc was added. After being stirred for 5 mins, the mixture was filtered, the collected solid was washed with petroleumether and dried to give compound C9-d (4.5 g), which was used in next step directly, LCMS (M+H)+: 141. Step 3: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2- methoxy-aniline (compound C9-f) A mixture of (4-fluoro-2-methoxy-phenyl)hydrazine hydrochloride (compound C9-d, 4.3 g, 22.3 mmol), 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C9-e, 4.3 g, 24.3 mmol) and TEA (3.5 g, 34.6 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4and concentrated to give crude compound C9-f (5.2 g), which was used in next step directly, LCMS (M+H)+: 315. Step 4: preparation of 4-chloro-1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4- d]pyrimidine (Intermediate C9) A mixture of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-4-fluoro-2-methoxy-aniline (compound C9-f, 4.0 g, 12.7 mmol) and 4Å molecular sieve (1.0 g) in anhydrous DMF (10 mL) was stirred at 100 °C for 12 hrs. The mixture was diluted with EtOAc, washed with water and brine. The separated organic layer was dried over anhydrous Na2SO4and concentrated to give a crude product, which was purified by prep-TLC to give Intermediate C9 (747 mg), LCMS (M+H)+: 279. Intermediate 120e (8S,11S)-13,18-dimethyl-7,10,13,18,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]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-[[6-[3-[3-[(4- methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 120a) To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (intermediate A5, 1.39 g, 3.09 mmol) and O1-tert-butyl O2-methyl (2S,4S)-4-[(6-chloro-2-pyridyl)amino]pyrrolidine-1,2- dicarboxylate (intermediate B12, 1 g, 2.8 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added cataCXium A-Pd-G2 (282 mg, 0.42 mmol) and potassium phosphate (1.19 g, 5.62 mmol) under argon. The mixture was stirred at 80 °C for 2 hrs, then the reaction mixture was concentrated to give some residue, which was purified by flash column to give compound 120a (1.2 g) as a yellow solid, LCMS (M+H)+: 643. Step 2: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4- methoxyphenyl)methyl-methyl-amino]propyl]-2-methyl-indazol-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3-[(4-methoxyphenyl)methyl- methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 120a, 1.1 g, 1.71 mmol) in MeOH (22 mL) and water (11 mL) was added lithiumhydroxide monohydrate (300 mg, 7.15 mmol). After being stirred at room temperature for 12 hrs, the reaction mixture was adjust to pH = 4 ~ 6 by 1 N aq. HCl solution. Then the mixture was extracted with EtOAc, the separated organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 120b (0.8 g) as a yellow solid, LCMS (M+H)+: 629. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3- (methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c) To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3-[(4-methoxyphenyl)methyl- methyl-amino]propyl]-2-methyl-indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120b, 200 mg, 0.32 mmol) in THF (5 mL) and isopropanol (5 mL) was added Pd / C (338 mg, 0.32 mmol) under nitrogen. The reaction mixture was stirred at 40 °C for 6 hrs under hydrogen, then filtered and concentrated under reduced pressure to give compound 120c (160 mg) as a yellow solid, LCMS (M+H)+: 509. Step 4: preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 120d) To a solution of HATU (448 mg, 1.18 mmol) and DIPEA (254 mg, 1.97 mmol) in DMF (100 mL) was added (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3- (methylamino)propyl]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 120c, 500 mg, 0.98 mmol) in THF (100 mL) dropwise at -10 °C. Then the reaction mixture was stirred at -10 °C for 1 hr, the mixture was concentrated under reduced pressure to give some residue, which was purified by flash column to give compound 120d (300 mg) as a yellow solid, LCMS (M+H)+: 491. Step 5: preparation of (8S,11S)-13,18-dimethyl-7,10,13,18,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one (intermediate 120e) To a solution of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7,10,13,18,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 120d, 30 mg, 0.06 mmol) in DCM (0.5 mL) was added TFA (70 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 hrs, then concentrated under reduced pressure to give intermediate 120e (20 mg) as a yellow solid, LCMS (M+H)+: 391. Example 1(16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-oneThe title compound was prepared according to the following scheme:Example 1Step 1: preparation of 2-[4-(4-bromoindazol-2-yl)butyl]isoindoline-1,3-dione(compound 1a) A mixture of 4-bromo-1H-indazole (70 g, 0.35 mol), 2-(4-bromobutyl)isoindoline-1,3- dione (100.2 g, 0.36 mol) and Cs2CO3 (230 g, 0.7 mol) in acetonitrile (1.5 L) was stirred at 50 °C for 16 h. The mixture was poured into ice water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography to give compound 1a (35.0 g) as a pink solid. LCMS (M+H)+: 398. Step 2: preparation of 2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2- yl]butyl]isoindoline-1,3-dione (compound 1b) A mixture of bis(pinacolato)diboron (11.5 g, 45.2 mmol), compound 1a (15.0 g, 37.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.8 g, 3.8 mmol) and potassium acetate (7.35 g, 75.3 mmol) in 1,4-dioxane (200 mL) was stirred at 100 °C for 2 h under N2. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give compound 1b (12 g) as yellow oil. LCMS (M+H)+: 446. Step 3: preparation of O1-tert-butyl-O2-methyl-(2S,4S)-4-[3-[2-[4-(1,3- dioxoisoindolin-2-yl)butyl]indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (1c) A mixture of intermediate B11 (10 g, 25.0 mmol), compound 1b (12.0 g, 27.0 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.8 g, 2.5 mmol) and Cs2CO3 (24.4 g, 75.0 mmol) in 1,4-dioxane (200 mL) and water (10 mL) was stirred at 100 °C for 2 h under N2. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give compound 1c (10 g) as a yellow oil. LCMS (M+H)+: 639. Step 4: preparation of (2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4-yl]phenoxy]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 1d) A solution of compound 1c (6 g, 9.4 mmol) and lithium hydroxide monohydrate (2.4 g, 56.4 mmol) in methanol (60 mL) and water (5 mL) was stirred at 20 °C for 2 h, and then concentrated. The residue was dissolved in water (250 mL) and acidified with HCl (1 M) until pH was 4. The mixture was extracted with EtOAc, and the combined organic layer was dried and concentrated. The residue was dissolved in ethanol (60 mL), followed by addition of hydrazine hydrate (7.8 g, 0.16 mol). The resulting mixture was stirred at 80 °C for 12 h, and then purified by prep-HPLC to give compound 1d (3.5 g) as a yellow solid. LCMS (M+H)+: 495. Step 5: preparation of tert-butyl (16S,19S)-15-oxo-20-oxa-9,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),7,21(25),22-heptaene-17-carboxylate (compound 1e) To a solution of HATU (1.15 g, 3.0 mmol) and DIPEA (0.78 g, 6.0 mmol) in DMF (200 mL) was added a solution of compound 1d (1.0 g, 2.0 mmol) in THF (200 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h, and then concentrated under vacuum. The residue was purified by prep-HPLC to give compound 1e (0.5 g) as a white solid. LCMS (M+H)+: 477. Step 6: preparation of (16S,19S)-20-oxa-9,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-one (compound 1f) A solution of compound 1e (0.5 g, 1.1 mmol) and TFA (3.0 mL) in DCM (5.0 mL) was stirred at 20 °C for 2 h, and then concentrated. The residue was dissolved in MeOH (5 mL) and basified with NH3•H2O. The mixture was filtered and the filtrate was concentrated to give compound 1f (0.45 g) as a yellow oil. LCMS (M+H)+: 377. Step 7: preparation of (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4- 6,9 16,19 2,7 carbonyl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 1) A mixture of compound 1f (0.3 g, 0.8 mmol), HATU (0.45 g, 1.2 mmol) and intermediate C5 (0.2 g, 0.88 mmol) in DMF (15 mL) was stirred at 0 °C for 0.5 h. The mixture was purified by prep-HPLC to give Example 1 (0.35 g) as a white solid. LCMS (M+H)+: 597.1H NMR (400 MHz, METHANOL-d4) δ 8.62 = (br s, 1H), 7.80 - 7.56 (m, 3H), 7.53 - 7.46 (m, 1H), 7.44 - 7.13 (m, 8H), 5.29 (br s, 1H), 4.96 (br d, J = 9.8 Hz, 2H), 4.69 - 4.58 (m, 2H), 4.33 - 4.12 (m, 2H), 3.79 - 3.60 (m, 4H), 2.81 - 2.65 (m, 1H), 2.50 - 2.28 (m, 1H), 2.06 - 1.84 (m, 2H), 1.76 - 1.61 (m, 2H). Example 2 (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2-methoxyethyl)- 6,9 16,19 2,7 20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23- heptaen-15-oneThe title compound was prepared according to the following scheme:To a solution of Example 1 (60 mg, 0.1 mmol) in DMF (2 mL) was added NaH (8 mg, 0.2 mmol), and the mixture was stirred at 0 °C for 2 h. Then 2-brmoethyl methyl ether (0.02 mL, 0.2 mmol) was added and the resulting mixture was stirred at 20 °C for 3 h. The mixture was quenched by addition of water (0.5 mL) and purified by prep-HPLC to give Example 2 (10 mg) as a white solid. LCMS (M+H)+: 655.1H NMR (400 MHz, METHANOL-d4) δ ppm = 8.86 - 8.30 (m, 1 H), 7.78 - 7.49 (m, 3 H), 7.49 - 7.15 (m, 7 H), 7.12 - 6.97 (m, 1 H), 5.48 - 4.95 (m, 2 H), 4.81 - 4.21 (m, 4 H), 4.13 - 3.74 (m, 2 H), 3.72 - 3.58 (m, 5 H), 3.53 - 3.35 (m, 3 H), 3.30 - 2.91 (m, 3 H), 2.87 - 2.34 (m, 1 H), 2.22 - 2.00 (m, 2 H), 1.98 - 1.63 (m, 2 H). Example 3 (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa- 6,9 16,19 2,7 9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen- 15-oneThe title compound was prepared according to the following scheme:Step 1: preparation of (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- 6,9 16,19 2,7 carbonyl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 3a) A mixture of compound 1f (300 mg, 0.8 mmol), N,N-diisopropylethylamine (0.42 mL, 2.4 mmol), HATU (0.45 g, 1.2 mmol) and Intermediate C4 (0.2 g, 0.88 mmol) in DMF (5 mL) was stirred at 0 °C for 2 h. The mixture was purified by prep-HPLC to give compound 3a (100 mg) as a white solid. LCMS (M+H)+: 599. Step 2: preparation of (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- 6,9 16,19 2,7 carbonyl]-14-methyl-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 3) To a mixture of compound 3a (30 mg, 0.05 mmol) in DMF (1.0 mL) was added NaH (4.0 mg, 0.1 mmol) at -10 °C and the mixture was stirred at -10 °C for 0.5 h. Then iodomethane (0.01 mL, 0.1 mmol) was added and the mixture was stirred at -10 °C for additional 2 h. The mixture was diluted with MeOH (2.0 mL) and acidified to pH = 6 with formic acid. Then the mixture was purified by prep-HPLC to give Example 3 (6.0 mg) as a light yellow solid. LCMS (M+H)+: 613.1H NMR (400 MHz, METHANOL-d4) δ = 8.71 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.69 (dd, J = 5.4, 8.9 Hz, 1H), 7.60 (t, J = 9.4 Hz, 1H), 7.53 (dd, J = 2.8, 8.3 Hz, 1H), 7.50 - 7.28 (m, 6H), 7.27 - 7.15 (m, 1H), 7.12 - 6.97 (m, 1H), 5.37 - 5.11 (m, 2H), 4.77 - 4.56 (m, 2H), 4.54 - 4.36 (m, 2H), 4.15 - 4.05 (m, 1H), 3.27 - 3.07 (m, 4H), 2.91 - 2.55 (m, 2H), 2.14 - 1.88 (m, 4H). Example 4 (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-11,17- dioneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a) A mixture of 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 B8, 2.5 g, 5.59 mmol) and TFA (2.7 g, 27.9 mmol) in DCM (5 mL) was stirred at room temperature for 2 hrs. The reaction was quenched by saturated aq. NaHCO3, then the mixture was extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude compound 4a (2.3 g) as a colorless oil, LCMS (M+H)+: 348. Step 2: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carboxylate (compound 4b) A mixture of methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-2-carboxylate (compound 4a, 2.3 g, 3.32 mmol), 1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carboxylic acid (intermediate C4, 0.80 g, 3.32 mmol) and DIPEA (2.15 g, 16.6 mmol) in DCM (10 mL) was stirred for a while and then HATU (1.64 g, 4.32 mmol) was added. The resuling mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure to give an oil, the oil was purified by flash column chromatography to give compound 4b (0.73 g) as a colorless oil, LCMS (M+H)+: 570. Step 3: preparation of methyl (2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazol-4- yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c) A mixture of tert-butyl 2-(4-bromoindazol-2-yl)acetate (intermediate A6, 219 mg, 0.70 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 401 mg, 0.70 mmol), PdCl2(DPPF)-CH2Cl2adduct (25.7 mg, 0.035 mmol) and potassium carbonate (195 mg, 1.41 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was heated to 90 °C for 90 mins with microwave irritation. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude was purified by flash column chromatography to afford compound 4c (363 mg) as a yellow oil, LCMS (M+H)+: 674.Step 4: preparation of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-5-methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2-yl]acetic acid (compound 4d) A solution of methyl (2S,4S)-4-[3-[2-(2-tert-butoxy-2-oxo-ethyl)indazol-4-yl]phenoxy]-1- [1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4c, 363 mg, 0.54 mmol) in TFA (3 mL) was stirred at room temperature for 1 hr. After excess TFA was removed under reduced pressure, crude compound 4d (552 mg) was obtained as a brown oil, LCMS (M+H)+: 618. Step 5: preparation of methyl (2S,4S)-4-[3-[2-[2-[3-(tert- butoxycarbonylamino)propylamino]-2-oxo-ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 4e) A mixture of 2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5- methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2-yl]acetic acid (compound 4d,115 mg, 0.11 mmol), tert-butyl N-(3-aminopropyl)carbamate (39 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol) and DIEA (72 mg, 0.56 mmol) in DMF (1 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude compound 4e (116 mg) as a brown oil, LCMS (M+H)+: 774. Step 6: preparation of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]- 2-oxo-ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]pyrrolidine-2-carboxylic acid (compound 4f) A mixture of methyl (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2- oxo-ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]pyrrolidine-2-carboxylate (compound 4e, 116 mg, 0.10 mmol) and lithium hydroxide monohydrate (22 mg, 0.10 mmol) in MeOH (4 mL) and water (1 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water, acidified by HOAc. Then extracted with EtOAc for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford compound 4f (84 mg) as a yellow solid, LCMS (M+H)+: 760. Step 7: preparation of (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxo-ethyl]indazol- 4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid;hydrochloride (compound 4g)A solution of (2S,4S)-4-[3-[2-[2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo- ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2- carboxylic acid (compound 4f, 84 mg, 0.09 mmol) in 4 M HCl in dioxane (1 mL) was stirred at room temperature for 2 hrs. After excess solvent was removed under reduced pressure, crude compound 4g (87 mg) was obtained as a yellow solid, LCMS (M+H)+: 660. Step 8: preparation of (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa- 1(27),2,4,6(29),7,23,25-heptaene-11,17-dione (Example 4) To a solution of HATU (43.2 mg, 0.11 mmol) and DIEA (56.5 mg, 0.44 mmol) in DMF (3 mL) was added (2S,4S)-4-[3-[2-[2-(3-aminopropylamino)-2-oxo-ethyl]indazol-4-yl]phenoxy]-1- [1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid;hydrochloride (compound 4g, 87 mg, 0.09 mmol) in DMF (2 mL) and acetonitrile (45 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove the solvent, the rest was directly purified by prep-HPLC to afford Example 4 (8 mg) as a light yellow solid, LCMS (M+H)+: 642.1H NMR (400 MHz, METHANOL-d4) δ = 8.72 - 8.43 (m, 2H), 8.29 - 7.87 (m, 1H), 7.87 - 7.73 (m, 2H), 7.68 - 7.61 (m, 1H), 7.54 - 7.45 (m, 2H), 7.36 - 7.21 (m, 4H), 7.17 - 7.02 (m, 2H), 5.39 - 4.93 (m, 4H), 4.32 - 3.92 (m, 2H), 3.43 - 3.33 (m, 2H), 3.28 - 3.22 (m, 1H), 3.12 - 3.01 (m, 1H), 2.71 - 2.35 (m, 2H), 1.88 - 1.67 (m, 2H). Example 5 (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa- 9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 5a) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-1,2- dicarboxylate (Intermediate B11, 400 mg, 1 mmol) and lithium hydroxide monohydrate (168 mg, 4 mmol) in MeOH (8 mL) and water (2 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water, acidified by 1N aq. HCl solution. Then extracted with EtOAc for three time, the combined organic layer was washed with brine, dried over anhydrousNa2SO4, concentrated under reduced pressure to give compound 5a (358 mg) as a white foam, LCMS (M+H)+: 384. Step 2: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1- tert-butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5b) To a mixture of (2S,4S)-4-(3-bromophenoxy)-1-tert-butoxycarbonyl-pyrrolidine-2- carboxylic acid (compound 5a, 339 mg, 0.88 mmol), O1-benzyl O3-methyl (3S)-piperazine-1,3- dicarboxylate (293 mg, 1.05 mmol) and HATU (501 mg, 1.32 mmol) in DMF (6 mL) was added DIPEA (340 mg, 2.63 mmol), the resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was partitioned between EtOAc and water, then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give compound 5b (851 mg) as a brown oil, LCMS (M+H)+: 646. Step 3: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3- bromophenoxy)pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate;hydrochloride (compound 5c) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-tert- butoxycarbonyl-pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5b, 851 mg, 0.86 mmol) and 4 M HCl in dioxane (5 mL, 20 mmol) in MeOH (3 mL) was stirred at room temperature for 2 hrs. After excess solvent was removed under reduced pressure, crude compound 5c (906 mg) was obtained as a brown oil, which was directly used in next step without purification, LCMS (M+H)+: 546. Step 4: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1- [1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine- 1,3-dicarboxylate (compound 5d) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3-bromophenoxy)pyrrolidine-2- carbonyl]piperazine-1,3-dicarboxylate;hydrochloride (compound 5c, 906 mg, 0.78 mmol), 4- chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 311 mg, 1.17 mmol) and DIPEA (301 mg, 2.33 mmol) in DMSO (10 mL) was heated to 90 °C for 2 hrs. After being cooled to room temperature, the resulting mixture was partitioned between EtOAc and water. Then extracted with EtOAc for three times, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford compound 5d (400 mg) as a yellow solid, LCMS (M+H)+: 776.Step 5: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-1-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5e) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-(3-bromophenoxy)-1-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3- dicarboxylate (compound 5d, 360 mg, 0.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (132 mg, 0.52 mmol), PdCl2(DPPF)-CH2Cl2 adduct (12.7 mg, 0.017 mmol) and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) was heated to 100 °C for 5 hrs under argon with microwave irritation. 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 extracts was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude compound 5e (408 mg) as a brown oil, which was directly used in next step without purification, LCMS (M+H)+: 824. Step 6: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-[3-(tert- butoxycarbonylamino)propyl]indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5f) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carbonyl]piperazine-1,3-dicarboxylate (160 mg, 0.14 mmol), tert-butyl N-[3-(4-bromoindazol-2- yl)propyl]carbamate (48.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2adduct (4.97 mg, 0.007 mmol) and potassium carbonate (56.4 mg, 0.41 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 100 °C for 1 hr under argon with microwave irritation. 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 and brine, dried over anhydrous Na2SO4, concentrated under vacuum to give some crude. The crude was purified by flash column chromatography to afford compound 5f (118 mg) as a yellow oil, LCMS (M+H)+: 971. Step 7: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-(3- aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5g)A solution of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-[3-(tert- butoxycarbonylamino)propyl]indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 5f, 118 mg, 0.12 mmol) in 4 M HCl in dioxane (3 mL, 12 mmol) was stirred at room temperature for 2 hrs. After removing excess solvent, compound 5g (150 mg) was obtained as a yellow solid, which was directly used in next step without purification, LCMS (M+H)+: 871. Step 8: preparation of (2S)-1-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]- 1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4- benzyloxycarbonyl-piperazine-2-carboxylic acid (compound 5h) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4- yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2- carbonyl]piperazine-1,3-dicarboxylate (compound 5g, 150 mg, 0.12 mmol) and lithium hydroxide monohydrate (48.6 mg, 1.16 mmol) in MeOH (4 mL) and water (1 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water, acidified by HOAc. Then extracted with DCM / MeOH for three times, the combined extracts was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude compound 5h (88 mg) as an off-white solid, LCMS (M+H)+: 857. Step 9: preparation of benzyl (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33- hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene- 17-carboxylate (Example 12) To a mixture of HATU (45.6 mg, 0.12 mmol) and DIPEA (35.7 mg, 0.28 mmol) in DMF (2 mL) was added (2S)-1-[(2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl- piperazine-2-carboxylic acid (compound 5h, 79 mg, 0.09 mmol) in DMF (48 mL) and acetonitrile (50 mL) dropwise at 0°C, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. After removing excess solvent under reduced pressure, the resulted residue was diluted with water and some precipitation was formed. The precipitation was filtered, the collected solid was collected and dried, Example 12 (89 mg) was obtained as a yellow solid, LCMS (M+H)+: 839. Step 10: preparation of (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene- 14,21-dione (Example 13) A mixture of benzyl (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-14,21-dioxo-26-oxa-9,13,17,20,23,33- hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene-17- carboxylate (Example 12, 69 mg, 0.07 mmol) and Pd(OH)2(14 mg, 0.10 mmol) in MeOH (12 mL) was heated to 60 °C for 5 hrs under hydrogen. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to afford desired Example 13 (37 mg) as a light yellow solid, LCMS (M+H)+: 705. Step 11: preparation of (15S,22S,25S)-17-benzyl-23-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa-9,13,17,20,23,33- hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta-1(30),2,4,6(33),7,27(31),28-heptaene- 14,21-dione (Example 5) A mixture of (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26- oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione (compound 5j, 20 mg, 0.03 mmol), (bromomethyl)benzene (6.3 mg, 0.04 mmol) and DIPEA (7.3 mg, 0.06 mmol) in DMF (0.5 mL) was stirred at 60 °C for 30mins. After being cooled to room temperature, the reaction mixture was purified by prep-HPLC to afford desired Example 5 (0.7 mg) as a white solid, LCMS (M+H)+: 795. Example 6 (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa- 9,14,18,21,24,34-hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta- 1(32),2,4,6(34),7,28,30-heptaene-15,22-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-1-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindolin-2- yl)butyl]indazol-4-yl]phenoxy]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6a) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carbonyl]piperazine-1,3-dicarboxylate (compound 5e, 160 mg, 0.14 mmol), 2-[4-(4- bromoindazol-2-yl)butyl]isoindoline-1,3-dione (54.2 mg, 0.14 mmol), PdCl2(DPPF)-CH2Cl2adduct (5.0 mg, 0.007 mmol) and potassium carbonate (56.4 mg, 0.41 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 100 °C for 1 hr under argon with microwave irritation. 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 and brine, dried over anhydrous Na2SO4, concentratedunder vacuum to give some crude product. The crude was purified by flash column chromatography to afford compound 6a (122 mg) as a yellow oil, LCMS (M+H)+: 1015. Step 2: preparation of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-(4- aminobutyl)indazol-4-yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]pyrrolidine-2-carbonyl]piperazine-1,3-dicarboxylate (compound 6b) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-1-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-4-[3-[2-[4-(1,3-dioxoisoindolin-2-yl)butyl]indazol-4-yl]phenoxy]pyrrolidine- 2-carbonyl]piperazine-1,3-dicarboxylate (compound 6a, 122 mg, 0.09 mmol) and hydrazine hydrate (13.5 mg, 0.27 mmol) in MeOH (2 mL) was heated to 70 °C for 16 hrs. 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 and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude compound 6b (101 mg) as a yellow oil, which was directly used in next step without purification, LCMS (M+H)+: 885. Step 3: preparation of (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4-yl]phenoxy]-1- [1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4- benzyloxycarbonyl-piperazine-2-carboxylic acid (compound 6c) A mixture of O1-benzyl O3-methyl (3S)-4-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4- yl]phenoxy]-1-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2- carbonyl]piperazine-1,3-dicarboxylate (compound 6b, 91 mg, 0.08 mmol) and lithium hydroxide monohydrate (32.4 mg, 0.77 mmol) in THF (2 mL) and water (0.5 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water, acidified by HOAc. Then extracted with DCM / MeOH for three times, the combined extracts was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give compound 6c (91 mg) as an off-white solid, LCMS (M+H)+: 871. Step 4: preparation of benzyl (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34- hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene- 18-carboxylate (compound 6d) To a mixture of HATU (29.5 mg, 0.08 mmol) and DIPEA (38.6 mg, 0.30 mmol) in DMF (2 mL) was added (2S)-1-[(2S,4S)-4-[3-[2-(4-aminobutyl)indazol-4-yl]phenoxy]-1-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidine-2-carbonyl]-4-benzyloxycarbonyl- piperazine-2-carboxylic acid (compound 6c, 52 mg, 0.06 mmol) in DMF (38 mL) andacetonitrile (40 mL) dropwise at 0°C, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. After removing excess solvent under reduced pressure, the residue was diluted with water and some precipitation was formed. The precipitation was filtered, the collected solid was collected and dried, crude compound 6d (43 mg) was obtained as a yellow solid, which was directly used in next step without purification, LCMS (M+H)+: 853. Step 5: preparation of (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34- hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene- 15,22-dione (compound 6e) A mixture of benzyl (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-15,22-dioxo-27-oxa-9,14,18,21,24,34- hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene-18- carboxylate (compound 6d, 43 mg, 0.05 mmol) and Pd(OH)2 (10 mg, 0.07 mmol) in MeOH (10 mL) was heated to 60 °C for 5 hrs under hydrogen. After being cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give compound 6e (25 mg) as a light yellow solid, LCMS (M+H)+: 719. Step 6: preparation of (16S,23S,26S)-18-benzyl-24-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27-oxa-9,14,18,21,24,34- hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta-1(32),2,4,6(34),7,28,30-heptaene- 15,22-dione (Example 6) A mixture of (16S,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27- oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta- 1(32),2,4,6(34),7,28,30-heptaene-15,22-dione (compound 6e, 25 mg, 0.03 mmol), (bromomethyl)benzene (6.0 mg, 0.03 mmol) and DIPEA (9.0 mg, 0.07 mmol) in DMF (0.5 mL) was stirred at 60 °C for 30 mins. After being cooled to room temperature, the reaction mixture was purified by prep-HPLC to afford Example 6 (5 mg) as an off-white solid, LCMS (M+H)+: 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 - 8.10 (m, 3H), 7.67 - 7.59 (m, 1H), 7.58 - 7.45 (m, 7H), 7.39 - 7.09 (m, 7H), 5.64 - 5.24 (m, 3H), 4.62 - 4.39 (m, 5H), 4.34 - 4.22 (m, 2H), 4.04 - 3.90 (m, 1H), 3.68 - 3.50 (m, 3H), 3.46 - 3.35 (m, 1H), 3.26 - 3.18 (m, 1H), 3.08 - 2.92 (m, 2H), 2.64 - 2.54 (m, 1H), 2.15 - 1.97 (m, 1H), 1.93 - 1.83 (m, 1H), 1.56 - 1.40 (m, 1H), 1.23 - 1.11 (m, 1H). Example 7(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a)To a flask was added O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine- 1,2-dicarboxylate (Intermediate B11, 4.5 g, 11.2 mmol) in DCM (5 mL), a pale yellow solution was formed. Then TFA (3.6 mL) was added dropwise, the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography to afford compound 7a (3.2 g) as a colorless oil, LCMS (M+H)+: 300. Step 2: preparation of methyl (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b) A mixture of 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid (intermediate C4, 1.5 g, 6.23 mmol), methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 7a, 1.87 g, 6.23 mmol) and DIPEA (4.03 g, 31.2 mmol) in DMF (15 mL) was stirred for a while and then HATU (3.56 g, 9.35 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated to give an oil, the oil was purified by flash column chromatography to afford compound 7b (1.8 g) as a brown oil, LCMS (M+H)+: 522. Step 3: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-[5-(1,3-dioxoisoindolin-2-yl)pentyl]indazol-4-yl]phenoxy]pyrrolidine-2- carboxylate (compound 7c) A mixture of 2-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2- yl]pentyl]isoindoline-1,3-dione (intermediate A19, 281 mg, 0.53 mmol), methyl (2S,4S)-4-(3- bromophenoxy)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 7b, 220 mg, 0.42 mmol), PdCl2(DPPF)-CH2Cl2adduct (15.4 mg, 0.02 mmol) and potassium carbonate (174 mg, 1.26 mmol) in DME (4 mL) and water (0.4 mL) was heated to 90 °C for 16 hrs under argon. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc, then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford compound 7c (143 mg) as a yellow oil, LCMS (M+H)+: 775. Step 4: preparation of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazol-4- yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d) A mixture of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2- [5-(1,3-dioxoisoindolin-2-yl)pentyl]indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound7c, 143 mg, 0.18 mmol) and lithium hydroxide monohydrate (31 mg, 0.74 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and acidified by HOAc, and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give compound 7d (113 mg) as a light yellow solid, LCMS (M+H)+: 779. Step 5: preparation of (2S,4S)-4-[3-[2-(5-aminopentyl)indazol-4-yl]phenoxy]-1-[1-(2- chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e) A mixture of (2S,4S)-4-[3-[2-[5-[(2-carboxybenzoyl)amino]pentyl]indazol-4-yl]phenoxy]- 1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7d, 113 mg, 0.14 mmol) and hydrazine hydrate (145 mg, 2.9 mmol) in EtOH (4 mL) was heated to 70 °C for 20 hrs. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with EtOAc for four times. The combined organic layer was washed with brine, concentrated under reduced pressure to give compound 7e (60 mg) as an off-white solid, LCMS (M+H)+: 631. Step 6: preparation of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-21-oxa-9,15,18,28-tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 7) To a solution of (2S,4S)-4-[3-[2-(5-aminopentyl)indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 7e, 55 mg, 0.09 mmol) in DMF (18 mL) was added HATU (43.1 mg, 0.11 mmol) at 0 °C, followed by DIPEA (56.3 mg, 0.44 mmol) in DMF (2 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C to room temperature for 1 hr. The reaction mixture was diluted with water, then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by prep-HPLC to afford Example 7 (4 mg) as a white solid, LCMS (M+H)+: 613.1H NMR (400 MHz, DMSO-d6) δ = 8.72 - 8.62 (m, 1H), 8.32 - 8.13 (m, 1H), 8.08 - 7.87 (m, 1H), 7.76 (m, 1H), 7.71 - 7.63 (m, 1H), 7.63 - 7.56 (m, 1H), 7.54 - 7.38 (m, 2H), 7.36 - 7.28 (m, 1H), 7.27 - 7.20 (m, 1H), 7.19 - 6.63 (m, 3H), 5.37 - 5.10 (m, 2H), 4.73 - 4.59 (m, 1H), 4.57 - 4.40 (m, 2H), 4.22 - 3.81 (m, 4H), 2.47 - 2.31 (m, 1H), 2.04 - 1.90 (m, 3H), 1.83 - 1.39 (m, 2H), 1.29 (m, 1H). Example 8(18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29- tetrazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaen-17-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-[6-(1,3-dioxoisoindolin-2-yl)hexyl]indazol-4-yl]phenoxy]pyrrolidine-2- carboxylate (compound 8a) A mixture of 2-[6-(4-bromoindazol-2-yl)hexyl]isoindoline-1,3-dione (Intermediate A37, 512 mg, 1.2 mmol), bis(pinacolato)diboron (366 mg, 1.44 mmol), Pd(OAc)2 (13.5 mg, 0.06 mmol), butyldi-1-adamantylphosphine (43 mg, 0.12 mmol) and potassium acetate (353 mg, 3.6 mmol) in DME (6 mL) was heated to 70 °C for 1 hr under microwave irritation. Then methyl (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2- carboxylate (compound 7b, 314 mg, 0.6 mmol), potassium carbonate (498 mg, 3.6 mmol), DME(6 mL) and H2O (1.2 mL) were added, the resulting mixture was heated to 90 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc, then extracted with EtOAc for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some residue. The residue was purified by flash column chromatography to afford compound 8a (235 mg) as a light grey solid, LCMS (M+H)+: 789. Step 2: preparation of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-5-methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2- yl]hexylcarbamoyl]benzoic acid (compound 8b) A mixture of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2- [6-(1,3-dioxoisoindolin-2-yl)hexyl]indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 8a, 200 mg, 0.25 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) in THF (8 mL) and water (2 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water and acidified by HOAc, and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give compound 8b (223 mg) as an off-white solid, LCMS (M+H)+: 793. Step 3: preparation of (2S,4S)-4-[3-[2-(6-aminohexyl)indazol-4-yl]phenoxy]-1-[1-(2- chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c) A mixture of 2-[6-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-5- methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2-yl]hexylcarbamoyl]benzoic acid (compound 8b, 223 mg, 0.24 mmol) and hydrazine hydrate (239 mg, 4.78 mmol) in EtOH (6 mL) was heated to 70 °C for 20 hrs. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with EtOAc for four times. The combined organic layer was washed with brine, concentrated under reduced pressure to give compound 8c (128 mg) as an off-white solid, LCMS (M+H)+: 645. Step 4: preparation of (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-22-oxa-9,16,19,29-tetrazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa- 1(27),2,4,6(29),7,23,25-heptaen-17-one (Example 8) To a mixture of (2S,4S)-4-[3-[2-(6-aminohexyl)indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 8c, 120 mg, 0.19 mmol) and HATU (92 mg, 0.24 mmol) in DMF (18 mL) was added DIPEA (120 mg, 0.93 mmol) in DMF (2 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C and warmed toroom temperature for 1 hr. The reaction mixture was diluted with water, then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude. The crude was purified by prep-HPLC to afford Example 8 (15 mg) as a white solid, LCMS (M+H)+: 627.1H NMR (400 MHz, DMSO-d6) δ = 8.64 - 8.10 (m, 3H), 7.89 (s, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.52 - 7.40 (m, 2H), 7.31 (m, 1H), 7.23 (m, 1H), 7.17 - 7.04 (m, 3H), 5.30 - 5.17 (m, 1H), 4.78 - 4.66 (m, 1H), 4.59 - 4.40 (m, 2H), 4.23 - 3.73 (m, 2H), 3.18 - 2.93 (m, 2H), 2.46 - 2.31 (m, 2H), 2.00 (m, 2H), 1.57 - 0.94 (m, 6H). Example 9 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaene-11,16- dioneThe title compound was prepared in analogy to the preparation of Example 4 by using tert- butyl N-(2-aminoethyl)carbamate instead of tert-butyl N-(3-aminopropyl)carbamate. Example 9 (14 mg) as a white solid, LCMS (M+H)+: 628.1H NMR (400 MHz, METHANOL-d4) δ = 8.64 - 8.37 (m, 2H), 8.09 - 8.04 (m, 1H), 7.86 - 7.78 (m, 1H), 7.65 - 7.32 (m, 5H), 7.31 - 7.18 (m, 4H), 7.15 - 7.01 (m, 1H), 5.23 - 5.10 (m, 2H), 4.95 (m, 1H), 4.65 - 4.54 (m, 1H), 4.33 - 4.10 (m, 2H), 3.66 - 3.40 (m, 3H), 3.25 - 3.16 (m, 1H), 2.82 - 2.70 (m, 1H), 2.40 - 2.29 (m, 1H). Example 10 (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30- pentazahexacyclo[21.3.1.16,9.112,15.118,21.02,7]triaconta-1(27),2,4,6(30),7,23,25-heptaene-11,17- dioneThe title compound was prepared in analogy to the preparation of Example 4 by using tert- butyl N-pyrrolidin-3-ylcarbamate instead of tert-butyl N-(3-aminopropyl)carbamate. Example 10 (7 mg) as a light brown solid, LCMS (M+H)+: 655. Example 11 (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaen- 22-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-4-[3-[2-[2-[4-[2-(tert- butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 11a) A mixture of tert-butyl N-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1- yl]ethyl]carbamate (intermediate A8, 170 mg, 0.26 mmol), methyl (2S,4S)-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 150 mg, 0.26 mmol), PdCl2(DPPF)- CH2Cl2adduct (9.6 mg, 0.013 mmol) and potassium carbonate (73 mg, 0.53 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was heated to 90 °C for 90 mins under microwave irritation. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude was purified by flash column chromatography to afford compound 11a (82 mg) as a yellow oil, LCMS (M+H)+: 815. Step 2: preparation of (2S,4S)-4-[3-[2-[2-[4-[2-(tert- butoxycarbonylamino)ethyl]piperazin-1-yl]ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 11b) A solution of methyl (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin- 1-yl]ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]pyrrolidine-2-carboxylate (compound 11a, 82 mg, 0.09 mmol) and lithium hydroxide monohydrate (19 mg, 0.45 mmol) in MeOH (2 mL) and water (0.5 mL) was stirred at roomtemperature for 16 hrs. The reaction mixture was diluted with water and acidified by HOAc. The resulted precipitation was filtered, the collected solid was collected and dried, compound 11b (90 mg) was obtained as a yellow solid, LCMS (M+H)+: 801. Step 3: preparation of (2S,4S)-4-[3-[2-[2-[4-(2-aminoethyl)piperazin-1- yl]ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]pyrrolidine-2-carboxylic acid;2,2,2-trifluoroacetic acid (compound 11c) A mixture of (2S,4S)-4-[3-[2-[2-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazin-1- yl]ethyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine- 2-carboxylic acid (90 mg, 0.09 mmol) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 1 hr. After excess TFA and solvent were removed, crude compound 11c (152 mg) was obtained as a brown oil, LCMS (M+H)+: 701. Step 4: preparation of (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-17-oxa-1,4,20,23,26,33-hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta- 5,7(33),8,10,12(32),13,15-heptaen-22-one (Example 11) To a solution of HATU (42 mg, 0.11 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (6 mL) was added (2S,4S)-4-[3-[2-[2-[4-(2-aminoethyl)piperazin-1-yl]ethyl]indazol-4-yl]phenoxy]- 1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid;2,2,2- trifluoroacetic acid (compound 11c,152 mg, 0.08 mmol) in DMF (4 mL) and MeCN (50 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C to room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give some crude, the crude was purified by prep-HPLC to afford Example 11 (12 mg) as a brown oil, LCMS (M+H)+: 683.1H NMR (400 MHz, METHANOL-d4) δ = 8.71 - 8.04 (m, 3H), 7.88 - 7.61 (m, 2H), 7.59 - 7.54 (m, 1H), 7.52 - 7.42 (m, 1H), 7.39 - 7.33 (m, 1H), 7.33 - 7.20 (m, 4H), 7.18 - 7.13 (m, 1H), 7.06 - 6.94 (m, 1H), 5.22 - 5.07 (m, 1H), 4.92 - 4.88 (m, 1H), 4.58 - 4.45 (m, 2H), 4.42 - 4.16 (m, 2H), 3.52 - 3.42 (m, 1H), 3.38 - 3.32 (m, 1H), 2.97 - 2.84 (m, 2H), 2.75 - 2.52 (m, 8H), 2.51 - 2.28 (m, 4H). Example 12 Benzyl (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21- dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylateThe synthesis of Example 12 was described in Example 5 as an intermediate, which was purified by prep-HPLC to afford Example 12 (4 mg) as a yellow solid, LCMS (M+H)+: 839. Example 13 (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa- 9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dioneThe synthesis of Example 13 was described in Example 5 as an intermediate, which was purified by prep-HPLC to afford Example 13 (2 mg) as a yellow solid, LCMS (M+H)+: 705. Example 14 (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-[(E)-4-(1,3-dioxoisoindolin-2-yl)but-2-enyl]indazol-4- yl]phenoxy]pyrrolidine-2-carboxylate (compound 14a) A mixture of 2-[(E)-4-(4-bromoindazol-2-yl)but-2-enyl]isoindoline-1,3-dione (intermediate A9, 250 mg, 0.60 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole- 4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carboxylate (compound 4b, 360 mg, 0.60 mmol), PdCl2(DPPF)-CH2Cl2adduct (42.6 mg, 0.06 mmol) and sodium carbonate (73 mg, 0.53 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 85 °C for 16 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude was purified by flash column chromatography to afford compound 14a (300 mg) as a brown oil, LCMS (M+H)+: 759. Step 2: preparation of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]but-2- enyl]indazol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]pyrrolidine-2-carboxylic acid (compound 14b) A mixture of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-[(E)-4- (1,3-dioxoisoindolin-2-yl)but-2-enyl]indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 14a, 300 mg, 0.4 mmol) and sodium hydroxide (15.8 mg, 0.4 mmol) in MeOH (3mL) and water (0.3 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with water and acidified to PH~5 with 2N aq. HCl solution, then extracted with EtOAc for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated to give compound 14b (300 mg) as a yellow oil, LCMS (M+H)+: 763. Step 3: preparation of (2S,4S)-4-[3-[2-[(E)-4-aminobut-2-enyl]indazol-4-yl]phenoxy]- 1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c) A mixture of (2S,4S)-4-[3-[2-[(E)-4-[(2-carboxybenzoyl)amino]but-2-enyl]indazol-4- yl]phenoxy]-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14b, 260 mg, 0.34 mmol) and hydrazine hydrate (341 mg, 6.81 mmol) in EtOH (5 mL) was heated to 70 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with EtOAc for three times. The combined organic layer was washed with brine, concentrated under reduced pressure to give compound 14c (200 mg) as a white solid, LCMS (M+H)+: 615. Step 4: preparation of (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa- 1(25),2,4,6(27),7,11,21,23-octaen-15-one (Example 14) To a mixture of DIPEA (105 mg, 0.81 mmol) and HATU (80.4 mg, 0.21 mmol) in DMF (40 mL) was added (2S,4S)-4-[3-[2-[(E)-4-aminobut-2-enyl]indazol-4-yl]phenoxy]-1-[1-(2- chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 14c, 100 mg, 0.16 mmol) in DMF (5 mL) dropwise at 0°C, the resulting mixture was stirred at 0°C and warmed to room temperature over 1 hr. The mixture was concentrated to give some crude product, which was purified by prep-HPLC to give Example 14 (13.5 mg) as a white soild, LCMS (M+H)+: 597.1H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.62 (m, 1H), 8.52 - 8.34 (m, 1H), 8.27 - 8.02 (m, 2H), 7.81 - 7.64 (m, 2H), 7.62 - 7.53 (m, 1H), 7.51 - 7.40 (m, 2H), 7.36 - 7.22 (m, 4H), 7.21 - 7.06 (m, 1H), 6.20 - 5.96 (m, 2H), 5.37 -5.16 (m, 1H), 5.02 - 4.87 (m, 2H), 4.83 - 4.68 (m, 1H), 4.29 - 4.01 (m, 2H), 3.99 - 3.67 (m, 2H), 2.47 - 2.29 (m, 2H). Example 15 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared in analogy to the preparation of Example 11 by using intermediate A10 instead of intermediate A8. Example 15 (13 mg) as a white solid, LCMS (M+H)+: 615. Example 16 (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26- tetrazapentacyclo[18.3.1.16,9.115,18.02,7]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-oneThe title compound was prepared according to the following scheme:Step 1: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-[3-(1,3-dioxoisoindolin-2-yl)propyl]indazol-4-yl]phenoxy]pyrrolidine-2- carboxylate (compound 16a) A mixture of 2-[3-(4-bromoindazol-2-yl)propyl]isoindoline-1,3-dione (Intermediate A34, 250 mg, 0.65 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2-carboxylate (compound 4b, 371 mg, 0.65 mmol), PdCl2(DPPF)-CH2Cl2 adduct (44 mg, 0.065 mmol) and sodium carbonate (207 mg, 1.95 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 85 °C for 16 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude was purified by flash column chromatography to afford compound 16a (270 mg) as a brown oil, LCMS (M+H)+: 747. Step 2: preparation of methyl (2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]- 1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b) A mixture of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2- [3-(1,3-dioxoisoindolin-2-yl)propyl]indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 16a, 270 mg, 0.36 mmol) and hydrazine hydrate (362 mg, 7.23 mmol) in EtOH (10 mL) was heated to 70 °C for 16 hrs. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc, then extracted with EtOAc for three times. The combined organic layer was washed with brine, concentrated under reduced pressure to give compound 16b (760 mg) as a white solid, LCMS (M+H)+:617. Step 3: preparation of (2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2- chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c) A mixture of methyl (2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2- chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 16b, 180 mg, 0.29 mmol) and sodium hydroxide (58 mg, 1.46 mmol) in MeOH (6 mL) and water (1 mL) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and acidified to PH~5 with 2N aq. HCl solution, then extracted with EtOAc for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated to give compound 16c (180 mg) as a yellow oil, LCMS (M+H)+: 603.Step 4: preparation of (15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-19-oxa-9,13,16,26-tetrazapentacyclo[18.3.1.16,9.115,18.02,7]hexacosa- 1(24),2,4,6(26),7,20,22-heptaen-14-one (Example 16) To a mixture of DIPEA (182 mg, 1.41 mmol) and HATU (139 mg, 0.37 mmol) in DMF (108 mL) was added (2S,4S)-4-[3-[2-(3-aminopropyl)indazol-4-yl]phenoxy]-1-[1-(2-chloro-4- fluoro-phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 16c, 170 mg, 0.28 mmol) in DMF (12 mL) dropwise at 0°C, the resulting mixture was stirred at 0°C to room temperature for 1hr. The mixture was concentrated to remove DMF and then added water, extracted with EtOAc for three times. The organic layers was combined and concentrated to give some crude product, which was purifed by prep-HPLC to give Example 16 (18 mg) as a white soild, LCMS (M+H)+: 585.1H NMR (400 MHz, METHANOL-d4) δ = 8.75 - 8.48 (m, 1H), 8.24 - 8.15 (m, 1H), 8.10 - 8.02 (m, 1H), 7.73 - 7.67 (m, 1H), 7.65 - 7.58 (m, 1H), 7.58 (m, 2H), 7.46 - 7.36 (m, 3H), 7.35 - 7.22 (m, 2H), 7.22 - 7.15 (m, 1H), 5.10 - 5.05 (m, 1H), 4.95 - 4.90 (m, 1H), 4.83 (s, 1H), 4.67 - 4.61 (m, 1H), 4.53 - 4.44 (m, 1H), 4.37 - 4.28 (m, 1H), 3.14 (m, 1H), 2.79 (m, 1H), 2.67 - 2.56 (m, 1H), 2.51 - 2.40 (m, 1H), 2.37 - 1.99 (m, 2H). Example 17 (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30- tetrazapentacyclo[22.3.1.16,9.119,22.02,7]triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-oneThe title compound was prepared in analogy to the preparation of Example 16 by using Intermediate A38 instead of Intermediate A34. Example 17 (11 mg) as a white solid, LCMS (M+H)+: 641.1H NMR (400 MHz, METHANOL-d4) δ = 8.71 - 8.39 (m, 2H), 8.22 - 8.11 (m, 1H), 7.92 - 7.74 (m, 1H), 7.60 (m, 1H), 7.52 - 7.45 (m, 1H), 7.42 - 7.34 (m, 1H), 7.33 - 7.22 (m, 4H), 7.20 - 7.13 (m, 1H), 7.13 - 7.05 (m, 1H), 5.38 - 5.20 (m, 1H), 4.93 - 4.89 (m, 1H), 4.59 - 4.47 (m, 2H), 4.37 - 3.97 (m, 2H), 3.24 - 3.03 (m, 2H), 2.74 - 2.50 (m, 2H), 2.13 - 1.97 (m, 2H), 1.62 - 1.50 (m, 1H), 1.48 - 1.39 (m, 1H), 1.37 - 1.18 (m, 5H), 1.06 - 0.87 (m, 1H). Example 18 & Example 19(11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen- 15-one and (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11- hydroxy-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-oneThe title compound was prepared in analogy to the preparation of Example 16 by using intermediate A11 instead of Intermediate A34. Example 18 (1.8 mg, faster eluted) as a white solid, LCMS (M+H)+: 615. Example 19 (1.5 mg, slower eluted) as a white solid, LCMS (M+H)+: 615. Example 20 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:Step 1-4: preparation of tert-butyl (17S,20S)-18-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaene-12- carboxylate (compound 20d) The compound 20d was prepared in analogy to the preparation of Example 16 by using intermediate A12 instead of Intermediate A34, LCMS (M+H)+: 714. Step 5: preparation of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 20) A mixture of tert-butyl (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]- 16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaene-12-carboxylate (compound 20d, 40 mg, 0.03 mmol) and TFA (15.1 mg, 0.15 mmol) in DCM (2 mL) was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure to give some crude, which was purified by prep-HPLC to give Example 20 (2 mg) as a white solid, LCMS (M+H)+: 614. Example 21 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-oneThe title compound was prepared according to the following scheme:A solution of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 35 mg, 0.05 mmol) was added to a solution of formaldehyde (1.6 mg, 0.05 mmol) and NaBH(OAc)3 (22.8 mg, 0.11 mmol) in anhydrous THF (2 mL). The mixture was stirred at room temperature for 0.5 hr and then directly purified by prep-HPLC to give Example 21 (4.5 mg) as a white solid, LCMS (M+H)+: 628. Example 22 (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-oneThe title compound was prepared according to the following scheme:A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 20 mg, 0.03 mmol) and triethylamine (9.3 mg, 0.09 mmol) in anhydrous DCM (5 mL) was added acetyl chloride (4.83 mg, 0.062 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 0.5 hr and then directly purified by prep-HPLC to give Example 22 (9.3 mg) as a white solid, LCMS (M+H)+: 656.1H NMR (400 MHz, DMSO-d6) δ = 8.98 - 8.89 (m, 1H), 8.69 - 8.51 (m, 1H), 8.34 - 7.93 (m, 2H), 7.92 - 7.65 (m, 1H), 7.60 (m, 1H), 7.55 - 7.46 (m, 1H), 7.46 - 7.39 (m, 1H), 7.38 - 7.32 (m, 1H), 7.32 - 7.18 (m, 2H), 7.16 - 6.98 (m, 2H), 5.39 - 5.03 (m, 1H), 4.88 - 4.58 (m, 3H), 4.27 - 4.04 (m, 2H), 4.00 - 3.63 (m, 2H), 3.57 - 3.35 (m, 3H), 3.28 - 2.94 (m, 1H), 2.42 - 2.25 (m, 1H), 2.06 - 1.78 (m, 3H), 0.97 - 0.89 (m, 1H). Example 23 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo- ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) in anhydrous MeCN (2 mL) was added 2-bromo-1-morpholino-ethanone (13 mg, 0.06 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hrs and then directly purified by prep-HPLC to give Example 23 (9.0 mg ) as a white solid, LCMS (M+H)+: 741.1H NMR (400 MHz, DMSO-d6) δ = 9.19 - 8.59 (m, 2H), 8.39 - 8.12 (m, 1H), 8.06 - 7.97 (m, 1H), 7.59 (m, 1H), 7.51 - 7.45 (m, 1H), 7.44 - 7.34 (m, 2H), 7.34 - 7.27 (m, 1H), 7.26 - 7.16 (m, 2H), 7.15 - 7.10 (m, 1H), 7.06 - 6.99 (m, 1H), 5.43 (m, 1H), 4.87 - 4.76 (m, 1H), 4.66 - 4.48 (m, 2H), 4.27 - 3.94 (m, 2H), 3.63 - 3.50 (m, 1H), 3.43 - 3.35 (m, 2H), 3.30 - 3.23 (m, 2H), 3.22 - 3.11 (m, 4H), 3.09 - 2.79 (m, 4H), 2.78 - 2.72 (m, 1H), 2.71 - 2.65 (m, 1H), 2.24 - 1.94 (m, 1H), 1.03 - 0.90 (m, 2H). Example 24 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-12-yl]-N-methyl-acetamideThe title compound was prepared according to the following scheme:A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 30 mg, 0.05 mmol) and DIPEA (18 mg, 0.14 mmol) in anhydrous MeCN (5 mL) was added 2-chloro-N-methyl-acetamide (10 mg, 0.09 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 12 hrs and then directly purified by prep-HPLC to give Example 24 (6.0 mg) as a white solid, LCMS (M+H)+: 685. Example 25 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1-yl- ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl 4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-12- yl]acetyl]piperazine-1-carboxylate (compound 25a) A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 20 mg, 0.03 mmol) and DIPEA (12 mg, 0.09 mmol) in anhydrous MeCN (5 mL) was added tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (19 mg, 0.06 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hrs and then concentrated under reduced pressure to give compound 25a (25 mg) as a yellow oil, LCMS (M+H)+: 840. Step 2: preparation of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-12-(2-oxo-2-piperazin-1-yl-ethyl)-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one (Example 25) A mixture of tert-butyl 4-[2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetyl]piperazine-1-carboxylate (compound 25a, 25 mg, 0.02 mmol) and 4M HCl in dioxane (4.34 mg, 0.12 mmol) in dry DCM (2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was directly purified by prep-HPLC to give Example 25 (14.5 mg) as a white solid, LCMS (M+H)+: 740.1H NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.61 (m, 2H), 8.43 - 8.11 (m, 1H), 8.04 - 7.94 (m, 2H), 7.92 - 7.74 (m, 1H), 7.59 (m, 1H), 7.50 - 7.44 (m, 1H), 7.44 - 7.36 (m, 2H), 7.36 - 7.27 (m, 1H), 7.25 - 7.16 (m, 2H), 7.12 (m, 1H), 7.07 - 6.97 (m, 1H), 5.46 - 5.25 (m, 1H), 4.80 (m, 1H), 4.62 - 4.46 (m, 2H), 4.25 - 3.92 (m, 2H), 3.83 - 3.50 (m, 1H), 3.47 - 3.36 (m, 2H), 3.31 - 3.26 (m, 2H), 3.25 - 3.15 (m, 3H), 3.13 - 3.00 (m, 2H), 2.85 (m, 3H), 2.78 - 2.70 (m, 1H), 2.65 - 2.57 (m, 1H), 2.44 (m, 1H), 2.31 - 2.16 (m, 2H). Example 26 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-12-yl]acetamideThe title compound was prepared according to the following scheme:A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 30 mg, 0.05 mmol), 2-bromoacetamide (14 mg, 0.10 mmol) and DIPEA (19 mg, 0.15 mmol) in MeCN (2 mL) was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to give Example 26 (11.5 mg) as a white solid, LCMS (M+H)+: 671.1H NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.52 (m, 2H), 8.42 - 8.13 (m, 1H), 8.10 - 7.87 (m, 2H), 7.81 - 7.55 (m, 1H), 7.52 - 7.44 (m, 1H), 7.44 - 7.29 (m, 2H), 7.29 - 7.14 (m, 3H), 7.12 - 7.03 (m, 1H), 5.48 - 5.25 (m, 1H), 4.87 - 4.61 (m, 3H), 4.26 - 3.93 (m, 2H), 3.89 - 3.33 (m, 4H), 3.32 - 2.86 (m, 2H), 2.49 (m, 3H), 2.48 - 2.37 (m, 2H), 2.35 - 2.25 (m, 1H). Example 27 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazol-1-ylacetyl)- 21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-pyrazol-1-ylacetic acid (5.1 mg, 0.04 mmol) and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperature for 1 hr. The reaction mixture was directly purified by prep-HPLC to give Example 27 (3.4 mg) as a white solid, LCMS (M+H)+: 722.1H NMR (400 MHz, DMSO-d6) δ = 9.15 - 8.14 (m, 3H), 8.03 - 7.87 (m, 3H), 7.86 - 7.56 (m, 2H), 7.51 - 7.44 (m, 1H), 7.39 (m, 2H), 7.35 - 7.28 (m, 1H), 7.27 - 7.10 (m, 3H), 7.08 - 6.98 (m, 1H), 5.44 - 5.30 (m, 1H), 4.87 - 4.74 (m, 2H), 4.74 - 4.49 (m, 3H), 4.24 - 3.77 (m, 4H), 3.69 - 3.54 (m, 1H), 3.36 - 3.21 (m, 1H), 3.18 - 2.92 (m, 1H), 2.32 - 2.13 (m, 3H). Example 28 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-12-yl]acetic acidThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-12- yl]acetate (compound 28a) A mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 40 mg, 0.06 mmol) and DIPEA (24 mg, 0.18 mmol) in anhydrous MeCN (5 mL) was added tert-butyl 2-bromoacetate (24 mg, 0.12 mmol) in anhydrous DCM (0.1 mL). The resulting mixture was stirred at room temperature for 2 hrs and then directly purified by prep-HPLC to give compound 28a (20 mg) as a white solid, LCMS (M+H)+: 728. Step 2: preparation of 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetic acid (Example 28) A mixture of tert-butyl 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-16-oxo-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-12-yl]acetate (compound 28a, 20 mg, 0.02 mmol) and lithium hydroxide monohydrate (3 mg, 0.12 mmol) in MeCN (2 mL) and water (0.4 mL). The resutlingmixture was stirred at 100oC for 2 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to give Example 28 (3.8 mg) as a white solid, LCMS (M+H)+: 672.1H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.85 (m, 1H), 8.67 - 8.23 (m, 1H), 8.19 - 8.02 (m, 1H), 8.02 - 7.94 (m, 1H), 7.90 - 7.57 (m, 2H), 7.54 - 7.46 (m, 1H), 7.43 - 7.25 (m, 4H), 7.24 - 6.94 (m, 2H), 6.24 - 6.12 (m, 1H), 5.37 - 5.11 (m, 2H), 5.03 - 4.61 (m, 3H), 4.38 - 4.00 (m, 2H), 3.95 - 3.47 (m, 3H), 3.44 - 3.36 (m, 1H), 3.31 - 3.07 (m, 2H), 2.47 - 2.35 (m, 2H). Example 29 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21- oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-oneThe title compound was prepared according to the following scheme:To a mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 2-phenylacetic acid (5.5 mg, 0.04 mmol) and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperaturefor 1 hr. The reaction mixture was directly purified by prep-HPLC to to give Example 29 (5.0 mg) as a white solid, LCMS (M+H)+: 732.1H NMR (400 MHz, DMSO-d6) δ = 9.01 - 8.87 (m, 1H), 8.21 - 8.06 (m, 1H), 8.00 - 7.88 (m, 2H), 7.66 - 7.57 (m, 1H), 7.53 - 7.45 (m, 1H), 7.42 - 7.30 (m, 3H), 7.29 - 7.08 (m, 4H), 7.03 - 6.85 (m, 5H), 5.22 (m, 1H), 4.95 - 4.64 (m, 3H), 4.38 - 3.93 (m, 3H), 3.84 - 3.72 (m, 2H), 3.68 - 3.58 (m, 1H), 3.56 - 3.35 (m, 4H), 3.22 - 2.98 (m, 1H), 2.45 (m, 1H). Example 30 (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)- 21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-oneThe title compound was prepared according to the following scheme:To a mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 25 mg, 0.04 mmol), DIPEA (21 mg, 0.12 mmol), 3-phenylpropanoic acid (6.1 mg, 0.04 mmol) and HATU (17 mg, 0.05 mmol) in DMF (2 mL) was stirred at room temperature for 1 hr. The reaction mixture was directly purified by prep-HPLC to to give Example 30 (2.0 mg) as a white solid, LCMS (M+H)+: 746.1H NMR (400 MHz, DMSO-d6) δ =8.79 (m, 1H), 8.44 - 8.30 (m, 1H), 8.28 - 8.10 (m, 1H), 8.01 - 7.78 (m, 2H), 7.62 - 7.55 (m, 1H), 7.53 - 7.44 (m, 1H), 7.42 - 7.23 (m, 4H), 7.21 - 7.03 (m, 5H), 7.02 - 6.90 (m, 1H), 6.88 - 6.72 (m, 1H), 5.36 - 5.03 (m, 1H), 4.90 - 4.58 (m, 3H), 4.28 - 4.02 (m, 2H), 4.00 - 3.56 (m, 2H), 3.52 - 3.34 (m, 3H), 3.31 - 2.89 (m, 1H), 2.84 - 2.64 (m, 2H), 2.62 - 2.51 (m, 2H), 2.46 - 2.34 (m, 2H). Example 31 (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen- 15-oneThe title compound was prepared according to the following scheme:Step 1-4: preparation of tert-butyl (16S,19S)-15-oxo-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17- carboxylate (compound 31d)The compound 31d was prepared in analogy to the preparation of Example 16 by using Intermediate B8 instead of compound 4b, Intermediate A35 instead of Intermediate A34, LCMS (M+H)+: 477. Step 5: preparation of tert-butyl (16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17- carboxylate (compound 31e) To a solution of tert-butyl (16S,19S)-15-oxo-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17- carboxylate (compound 31d, 80 mg, 0.17 mmol) in DMF (3 mL) was added sodium hydride (34 mg, 0.84 mmol) at 0 °C, 30 mins later, iodomethane (119 mg, 0.84 mmol) was added, the resulting mixture was stirred at 0 °C and warmed to room temperature over 16 hrs. The reaction mixture was diluted with water, extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give compound 31e (60 mg) as a brown oil, LCMS (M+H)+: 491. Step 6: preparation of (16S,19S)-14-methyl-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f) To a mixture of tert-butyl (16S,19S)-14-methyl-15-oxo-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaene-17- carboxylate (compound 31e, 60 mg, 0.06 mmol) and 4M HCl in dioxane (4.2 mL, 0.30 mmol) in DCM (3 mL) was stirred at room temperature for 12 hrs. The mixture was concentrated to give crude compound 31f as a light yellow solid, LCMS (M+H)+: 391. Step 7: preparation of (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8- yl]-14-methyl-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one (Example 31) A mixture of (16S,19S)-14-methyl-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one (compound 31f, 25 mg, 0.06 mmol), 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3, 15.6 mg, 0.06 mmol) and DIPEA (23 mg, 0.18 mmol) in DMSO (2 mL) was heated to 100 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was directly purified by pre-HPLC to afford Example 31 (4.8 mg) as a white solid, LCMS (M+H)+: 620.1H NMR (400 MHz, DMSO-d6) δ = 8.69 - 8.45 (m, 1H), 7.78 - 7.66 (m, 1H), 7.65 - 7.42 (m, 3H), 7.38 - 7.27 (m, 4H), 7.26 - 7.18 (m, 2H), 7.18 - 6.95 (m, 3H), 5.48 - 4.86 (m, 2H), 4.73 -4.49 (m, 2H), 4.48 - 4.00 (m, 3H), 3.25 - 2.85 (m, 3H), 2.80 - 2.66 (m, 1H), 2.23 - 2.05 (m, 1H), 2.04 - 1.91 (m, 2H), 1.89 - 1.72 (m, 2H), 1.63 - 1.40 (m, 1H). Example 32 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-12-yl]-N,N-dimethyl-acetamideThe title compound was prepared according to the following scheme:To a mixture of (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one (Example 20, 25 mg, 0.04 mmol) and DIPEA (16 mg, 0.12 mmol) in anhydrous MeCN (5 mL) was added 2-bromo-N,N-dimethylacetamide (14 mg, 0.08 mmol), the resulting mixture was stirred at 70 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to give Example 32 (6.6 mg) as a white solid, LCMS (M+H)+: 699.1H NMR (400 MHz, DMSO-d6) δ = 8.86 (m, 2H), 8.04 - 7.86 (m, 2H), 7.84 - 7.62 (m, 1H), 7.61 - 7.52 (m, 1H), 7.50 - 7.35 (m, 3H), 7.35 - 7.27 (m, 1H), 7.25 - 7.16 (m, 1H), 7.15 - 7.00 (m, 2H), 5.45 - 5.24 (m, 1H), 4.85 - 4.72 (m, 1H), 4.61 - 4.37 (m, 2H), 4.26 - 3.77 (m, 2H), 3.31 -3.05 (m, 4H), 3.03 - 2.79 (m, 2H), 2.72 - 2.67 (m, 1H), 2.63 - 2.55 (m, 2H), 2.49 - 2.40 (m, 6H), 2.31 - 2.16 (m, 1H). Example 33 (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34- hexazahexacyclo[25.2.2.14,7.112,16.118,21.06,11]tetratriaconta-5,7(34),8,10,12(33),13,15- heptaene-22,26-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of tert-butyl 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]-5-methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2- yl]ethyl]piperazine-1-carboxylate (compound 33a) A mixture of tert-butyl 4-[2-(4-bromoindazol-2-yl)ethyl]piperazine-1-carboxylate (intermediate A13, 292 mg, 0.5 mmol), methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole- 4-carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carboxylate (compound 4b, 285 mg, 0.5 mmol), PdCl2(DPPF)-CH2Cl2 adduct (18 mg, 0.025 mmol) and potassium carbonate (138 mg, 1 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was heated to 90 °C for 3 hrs under nitrogen. After being cooled to room temperature, the reaction mixture was diluted with water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude was purified by flash column chromatography to afford compound 33a (197 mg) as a light yellow solid, LCMS (M+H)+: 772. Step 2: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-(2-piperazin-1-ylethyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33b) A mixture of tert-butyl 4-[2-[4-[3-[(3S,5S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-5-methoxycarbonyl-pyrrolidin-3-yl]oxyphenyl]indazol-2-yl]ethyl]piperazine-1- carboxylate (compound 33a, 130 mg, 0.17 mmol) and 4M HCl in dioxane (0.2 mL) in DCM (2 mL) was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure to give compound 33b (130 mg) as a white solid, LCMS (M+H)+: 672. Step 3: preparation of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-4-[3-[2-[2-[4-[3-(1,3-dioxoisoindolin-2-yl)propanoyl]piperazin-1-yl]ethyl]indazol- 4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33c) To a mixture of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3- [2-(2-piperazin-1-ylethyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 33b, 50 mg, 0.07 mmol), DIPEA (23 mg, 0.21 mmol) and HATU (31 mg, 0.08 mmol) in DMF (2 mL) was added 3-(1,3-dioxoisoindolin-2-yl)propanoic acid (20 mg, 0.09 mmol) in DMF (0.5 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C to room temperature for 1 hr. The reaction mixture was diluted with water and extracted with EtOAc for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated,purified by flash column chromatography to give compound 33c (40 mg) as a white solid, LCMS (M+H)+: 873. Step 4-6: preparation of (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- carbonyl]-17-oxa-1,4,20,23,27,34-hexazahexacyclo[25.2.2.14,7.112,16.118,21.06,11]tetratriaconta- 5,7(34),8,10,12(33),13,15-heptaene-22,26-dione (Example 33) The title compound was prepared in analogy to the preparation of Example 16 by using compound 33c instead of compound 16a. Example 33 (1.4 mg) as a white solid, LCMS (M+H)+: 711. Example 34 (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaene- 22,25-dioneThe title compound was prepared in analogy to the preparation of Example 16 by using intermediate A14 instead of Intermediate A34. Example 34 (1 mg) as a white solid, LCMS (M+H)+: 697. Example 35 (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17- dioneThe title compound was prepared according to the following scheme:Step 1-4: preparation of tert-butyl (18S,21S)-13,17-dioxo-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-19- carboxylate (compound 35d) The compound 35d was prepared in analogy to the preparation of Example 31 by using intermediate A15 instead of Intermediate A35. Step 5: preparation of (18S,21S)-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17- dione (compound 35e) To a mixture of tert-butyl (18S,21S)-13,17-dioxo-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-19- carboxylate (compound 35d, 75 mg, 0.09 mmol) and 4 M HCl in dioxane (0.5 mL) in DCM (3 mL) was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure to give compound 35e (54 mg) as a yellow solid, LCMS (M+H)+: 420. Step 6: preparation of (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-oxa-9,12,16,19,29-pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa- 1(27),2,4,6(29),7,23,25-heptaene-13,17-dione (Example 35) A mixture of (18S,21S)-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-13,17-dione(compound 35e, 30 mg, 0.07 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 35 mg, 0.13 mmol) and DIPEA (42 mg, 0.33 mmol) in DMSO (1 mL) was heated to 100 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was directly purified by prep-HPLC to afford Example 35 (0.9 mg) as an off-white solid, LCMS (M+H)+: 650. Example 36 (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaene-13,16- dioneThe title compound was prepared in analogy to the preparation of Example 35 by using intermediate A16 instead of intermediate A15. Example 36 (0.9 mg) as a white solid, LCMS (M+H)+: 636.1H NMR (400 MHz, DMSO-d6) δ = 8.83 - 8.43 (m, 2H), 8.39 - 8.20 (m, 1H), 8.19 - 8.02 (m, 1H), 7.90 - 7.66 (m, 2H), 7.66 - 7.55 (m, 2H), 7.54 - 7.40 (m, 1H), 7.39 - 7.23 (m, 2H), 7.22 - 7.12 (m, 2H), 5.50 - 4.97 (m, 2H), 4.57 - 4.42 (m, 1H), 4.31 - 4.06 (m, 1H), 3.81 - 3.71 (m, 1H), 3.68 - 3.37 (m, 2H), 2.58 - 2.53 (m, 1H), 2.17 - 1.85 (m, 2H), 1.52 - 1.30 (m, 1H), 1.22 - 1.17 (m, 1H). Example 37 (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaen- 22-oneThe title compound was prepared in analogy to the preparation of Example 35 by using intermediate A17 instead of intermediate A15. Example 37 (15 mg) as a white solid, LCMS (M+H)+: 691.1H NMR (400 MHz, DMSO-d6) δ = 9.92 - 9.42 (m, 1H), 8.77 - 8.54 (m, 2H), 8.35 - 8.28 (m, 1H), 7.80 - 7.68 (m, 1H), 7.63 - 7.50 (m, 3H), 7.39 - 7.27 (m, 3H), 7.27 - 7.15 (m, 2H), 5.30 - 5.02 (m, 2H), 4.69 - 4.49 (m, 3H), 4.21 - 4.14 (m, 1H), 4.01 - 3.93 (m, 2H), 3.59 - 3.50 (m, 2H), 3.49 - 3.36 (m, 2H), 3.31 - 3.07 (m, 4H), 2.97 - 2.81 (m, 4H), 2.80 - 2.72 (m, 1H), 2.44 - 2.36 (m, 1H). Example 38 (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-oxa-9,14,17,22,27- pentazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-oneThe title compound was prepared according to the following scheme:To a microwave tube was added compound 38a (29 mg, 0.059 mmol, the synthesis refer to compound 1f by using intermediate B10 instead of intermediate B11), intermediate C2 (17 mg, 64 µmol), DIPEA (10 µL, 59 µmol) and acetonitrile (3 mL). The tube was sealed and stirred at 85 °C for 5 hrs. The mixture was concentrated to give a solid, which was purified via prep-HPLC to give Example 38 (22 mg) as a white powder. LCMS (M+H)+: 608,1H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.61 (s, 1H), 8.42 - 8.38 (m, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.16 (br t, J = 5.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.40 - 7.32 (m, 3H), 7.32 - 7.27 (m, 1H), 6.94 (s, 1H), 5.87 (t, J = 3.7 Hz, 1H), 5.10 (d, J = 9.4 Hz, 1H), 4.64 - 4.49 (m, 2H), 4.38 - 4.32 (m, 1H), 4.30 - 4.23 (m, 1H), 3.88 - 3.75 (m, 1H), 3.00 - 2.88 (m, 1H), 2.74 - 2.67 (m, 1H), 1.86 - 1.59 (m, 4H), 1.57 - 1.41 (m, 1H). Example 39 and Example 40(17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione and (17R,25S,28S)-26-[3-(2,4- difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36- 6,9 25,28 2,7 12,17 hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-18,24-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of 2-(4-bromoindazol-2-yl)ethoxy-tert-butyl-dimethyl-silane (compound 39a) A mixture of 4-bromo-2H-indazole (2.5 g, 12.7 mmol), (2-bromoethoxy)(tert- butyl)dimethylsilane (3.04 g, 12.7 mmol) and cesium carbonate (8.27 g, 25.4 mmol) in MeCN (30 mL) was stirred at 80oC for 2 hours, then the solid was filtered off, the filtrated was concentrated and the residue was purified by silica gel column chromatography (0%-20% PE in EA) to give compound 39a (2g) as light yellow oil, LCMS (M+H+): 355. Step 2: preparation of 2-(4-bromoindazol-2-yl)ethanol (compound 39b) A mixture of compound 39a (2 g, 5.63 mmol) in MeOH / 12 N hydrocloride acid (10:1) (25 mL) was stirred at rt for 2 hours, then the reaction was concentrated and the residue was slurried in PE to give compound 39b (1.2 g) as white solid. LCMS (M+H+): 241. Step 3: preparation of 2-(4-bromoindazol-2-yl)ethyl methanesulfonate (compound 39c)A mixture of compound 39b (1.2 g, 4.98 mmol), methanesulfonic anhydride (1.73 g, 9.95 mmol) and DIPEA (3.22 g, 4.35 ml, 24.9 mmol) in DCM (20 mL) was stirred at rt for 2 hours, then the reaction was quenched with NaHCO3, extracted with EA, the organic layer was dried and concentrated to give compound 39c (1.5 g) as light brown solid. LCMS (M+H+): 319. Step 4: preparation of methyl 4-[2-(4-bromoindazol-2-yl)ethyl]morpholine-3- carboxylate (compound 39d) A mixture of compound 39c (800 mg, 2.51 mmol), methyl morpholine-3-carboxylate (546 mg, 3.76 mmol) and DIPEA (324 mg, 2.51 mmol) in DMF (10 mL) was stirred at 80oC for 16 hours, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and conentrated to give compound 39d (900 mg) as light yellow oil. LCMS (M+H+): 368. Step 5: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[2-[2-(3- methoxycarbonylmorpholin-4-yl)ethyl]indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 39e) A mixture of compound 39d (1 g, 2.72 mmol), intermediate B11 (1.21 g, 2.72 mmol), PdCl2(DPPF) (222 mg, 272 µmol) and K2CO3(1.13 g, 8.15 mmol) in dioxane / H2O (5:1) (20 mL) was stirred at 90oC for 2 hours, then the reaction was concentrated, the residue was purified by silica gel column chromatography to give compound 39e (900 mg) as colorless oil. LCMS (M+H+): 609. Step 6: preparation of 4-[2-[4-[3-[(3S,5S)-1-tert-butoxycarbonyl-5-carboxy- pyrrolidin-3-yl]oxyphenyl]indazol-2-yl]ethyl]morpholine-3-carboxylic acid (compound 39f) A mixture of compound 39e (900 mg, 1.48 mmol) and LiOH (354 mg, 14.8 mmol) in MeOH / THF / H2O (3:2:1) (15 mL) was stirred at rt for 2 hours, then the pH of the reaction was adjusted to 7, the reaction was extracted with DCM. The organic layer was dried and concentrated to give compound 39f (700 mg) as a light yellow solid. LCMS (M+H+): 581. Step 7: preparation of tert-butyl (25S,28S)-18,24-dioxo-15,29-dioxa-9,12,19,23,26,36- 6,9 25,28 2,7 12,17 hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-26-carboxylate (compound 39g) To a mixture of compound 39f (300 mg, 517 µmol), HATU (393 mg, 1.03 mmol) and DIPEA (334 mg, 2.58 mmol) in DMF / MeCN (1:10) (100 mL) was added propane-1,3-diamine (38 mg, 0.52 mol) in MeCN (20 mL) dropwise in 30 mins, then the mixture was stirred at rt for 15 mins. The reaction was concentrated, the residue was purified by flash column(0.5% TFA in water / MeCN) to give compound 39g (200 mg) as light yellow solid. LCMS (M+H+): 619.Step 8: preparation of (25S,28S)-15,29-dioxa-9,12,19,23,26,36- 6,9 25,28 2,7 12,17 hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-18,24-dione (compound 39h) A mixture of compound 39g (200 mg, 323 µmol) in 1 M HCl in EA (10 mL) was stirred at rt for 2 hours, then the reaction was conentrated to give compound 39h (180 mg) as off-white solid. LCMS (M+H+): 519. Step 9: preparation of ((17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5- a]pyrazin-8-yl]-15,29-dioxa-9,12,19,23,26,36- 6,9 25,28 2,7 12,17 hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-18,24-dione and (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin- 6,9 25,28 2,7 12,17 8-yl]-15,29-dioxa-9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione (Example 39 & 40) A mixture of compound 39h (100 mg, 193 µmol), intermediate C3 (76.8 mg, 289 µmol), cesium fluoride (146 mg, 964 µmol) and DIPEA (249 mg, 1.93 mmol) in DMSO (5 mL) was stirred at 90oC for 16 hours, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Example 39 and Example 40. Example 39, faster eluted, 11 mg, white powder. LCMS (M+H+): 748.1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (s, 1H), 8.05 (s, 1H), 7.78 - 7.67 (m, 1H), 7.66 - 7.58 (m, 1H), 7.56 - 7.47 (m, 1H), 7.46 - 7.37 (m, 1H), 7.34 - 7.29 (m, 2H), 7.28 - 7.21 (m, 5H), 7.20 - 7.16 (m, 1H), 5.45 - 5.39 (m, 1H), 5.13 - 5.07 (m, 1H), 4.75 - 4.60 (m, 3H), 4.56 - 4.49 (m, 1H), 4.47 - 4.40 (m, 1H), 3.86 - 3.74 (m, 2H), 3.65 - 3.57 (m, 1H), 3.55 - 3.48 (m, 1H), 3.13 - 2.92 (m, 7H), 2.70 - 2.62 (m, 1H), 2.62 - 2.45 (m, 2H), 1.67 - 1.58 (m, 1H), 1.50 - 1.41 (m, 1H). Example 40, slower eluted, 11 mg, white powder. LCMS (M+H+): 748.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 - 8.50 (m, 1H), 8.15 - 8.05 (m, 1H), 7.78 - 7.67 (m, 1H), 7.64 - 7.59 (m, 1H), 7.56 - 7.49 (m, 1H), 7.46 - 7.39 (m, 1H), 7.36 - 7.17 (m, 8H), 5.44 - 5.37 (m, 1H), 5.09 - 5.03 (m, 1H), 4.69 - 4.58 (m, 2H), 4.51 - 4.43 (m, 1H), 3.98 - 3.83 (m, 2H), 3.73 - 3.64 (m, 1H), 3.56 - 3.45 (m, 2H), 3.28 - 2.90 (m, 7H), 2.87 - 2.78 (m, 1H), 2.69 - 2.61 (m, 1H), 2.60 - 2.45 (m, 2H), 1.65 - 1.54 (m, 1H), 1.36 - 1.30 (m, 1H). Example 41 (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10,29-dioxa- 6,9 11,15 20,23 16,21 26,31 1,4,7,23,26,33,36,41-octazaheptacyclo[34.2.2.1 .1 .1 .0 .0 ]tritetraconta- 11(42),12,14,16,18,20(41),21-heptaene-5,32-dioneExample 41 was prepared in analogy to the preparation of Example 39 by using 2-[4-(2- aminoethyl)piperazin-1-yl]ethanamine instead of propane-1,3-diamine. LCMS (M+H+): 846.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.38 (m, 1H), 8.02 - 7.90 (m, 1H), 7.75 - 7.62 (m, 2H), 7.59 - 7.51 (m, 1H), 7.49 - 7.40 (m, 2H), 7.33 - 7.11 (m, 7H), 5.42 - 5.33 (m, 1H), 5.13 - 5.04 (m, 2H), 4.76 - 4.37 (m, 3H), 3.94 - 3.79 (m, 2H), 3.61 - 3.39 (m, 5H), 3.29 - 3.17 (m, 1H), 3.08 - 2.84 (m, 3H), 2.81 - 2.65 (m, 3H), 2.48 - 2.29 (m, 2H), 2.27 - 1.62 (m, 11H). Example 42 (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,27-dioxa- 6,9 12,16 23,26 2,7 9,12,18,21,24,35-hexazahexacyclo[26.3.1.1 .1 .1 .0 ]pentatriaconta- 1(31),2,4,6(35),7,28(32),29-heptaene-17,22-dioneThe title compound was prepared according to the following scheme:Step 1-5: preparation of (23S,26S)-15,27-dioxa-9,12,18,21,24,35- 6,9 12,16 23,26 2,7 hexazahexacyclo[26.3.1.1 .1 .1 .0 ]pentatriaconta-1(31),2,4,6(35),7,28(32),29- heptaene-17,22-dione (compound 42e) Compound 42e was prepared in analogy to the preparation of compound 39h by using methyl morpholine-2-carboxylate instead of methyl morpholine-3-carboxylate, and ethane-1,2- diamine instead of propane-1,3-diamine. LCMS (M+H+): 505. Step 6: preparation of (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15,27-dioxa-9,12,18,21,24,35- 6,9 12,16 23,26 2,7 hexazahexacyclo[26.3.1.1 .1 .1 .0 ]pentatriaconta-1(31),2,4,6(35),7,28(32),29- heptaene-17,22-dione (Example 42) A mixture of intermediate C2 (53 mg, 198 µmol), compound 42e (100 mg, 198 µmol) and DIPEA (128 mg, 991 µmol) in MeCN / DMSO (2:1) (3 mL) was stirred at 80oC for 16 hours, then the reaction was purified by prep-HPLC to give Example 42 (10 mg) as light yellow solid. LCMS (M+H+): 735.1H NMR (400 MHz, METHANOL-d4) δ = 8.77 - 8.42 (m, 2H), 8.37 - 8.26(m, 1H), 7.76 - 7.59 (m, 2H), 7.58 - 7.46 (m, 1H), 7.43 - 7.09 (m, 7H), 5.32 - 5.19 (m, 1H), 5.10 - 4.95 (m, 1H), 4.76 - 4.64 (m, 2H), 4.42 - 4.27 (m, 1H), 3.82 - 3.61 (m, 2H), 3.56 - 3.40 (m, 1H), 3.22 - 3.07 (m, 4H), 3.03 - 2.64 (m, 9H). Example 43 (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,28-dioxa- 6,9 12,16 24,27 2,7 9,12,18,22,25,36-hexazahexacyclo[27.3.1.1 .1 .1 .0 ]hexatriaconta- 1(32),2,4,6(36),7,29(33),30-heptaene-17,23-dioneExample 43 was prepared in analogy to the preparation of example 42 by using propane- 1,3-diamine instead of ethane-1,2-diamine. LCMS (M+H+): 749.1H NMR (400 MHz, METHANOL-d4) δ = 8.60 - 8.35 (m, 2H), 8.33 - 7.98 (m, 1H), 7.74 - 7.58 (m, 2H), 7.55 - 6.98 (m, 8H), 5.46 - 5.25 (m, 1H), 5.17 - 4.91 (m, 3H), 4.81 - 4.56 (m, 1H), 4.54 - 4.29 (m, 1H), 4.27 - 3.89 (m, 2H), 3.87 - 3.43 (m, 3H), 3.27 - 2.40 (m, 10H), 1.55 - 1.28 (m, 2H). Example 44 (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,28-dioxa- 6,9 24,27 2,7 12,17 9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dioneExample 44 was prepared in analogy to the preparation of Example 39 by using ethane- 1,2-diamine instead of propane-1,3-diamine. LCMS (M+H+): 734. Example 45 and Example 46 Methyl (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23- dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxylate and methyl (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-20-carboxylateThe title compound was prepared according to the following scheme:Step 1: preparation of O25-tert-butyl O21-methyl (21S,24S,27S)-18,23-dioxo-15,28- 6,9 24,27 2,7 12,17 dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-21,25-dicarboxylate and O25-tert-butyl O20-methyl (20S,24S,27S)-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-20,25-dicarboxylate (compound 45a-1&45a-2) To a mixture of compound 39f (600 mg, 1.03 mmol), HATU (1.57 g, 4.13 mmol) and DIPEA (1.34 g, 10.3 mmol) in DMF / MeCN (1:20) (200 mL) was added methyl (S)-2,3- diaminopropanoate (122 mg, 1.03 mmol) in MeCN (100 mL) dropwise in 2 hours, then the mixture was stirred at rt for 30 mins. The reaction mixture was concentrated and the residue was purified by HPLC to give compound 45a-1 (80 mg) and compound 45a-2 (80 mg) as white solids. LCMS (M+H+): 663.Step 2: preparation of methyl (21S,24S,27S)-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxylate and methyl (20S,24S,27S)-18,23-dioxo-15,28-dioxa- 6,9 24,27 2,7 12,17 9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylate (compound 45b-1&45b-2) To a mixture of compound 45a-1 (80 mg, 121 µmol) in DCM (3 mL) was added 4 M HCl in dioxane (3 mL), then the reaction was stirred at rt for 16 hours, the reaction was concentrated to give compound 45b-1 (70 mg) as a light yellow solid. LCMS (M+H+): 562. To a mixture of compound 45a-2 (80 mg, 121 µmol) in DCM (3 mL) was added 4 M HCl in dioxane (3 mL), then the reaction was stirred at rt for 16 hours, the reaction was concentrated to give compound 45b-2 (70 mg) as a light yellow solid. LCMS (M+H+): 562. Step 3: preparation of Methyl (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxylate and methyl (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-20-carboxylate (Example 45&46) A mixture of methyl compound 45b-1 (70 mg, 124 µmol), intermediate C2 (50 mg, 187 µmol) and DIPEA (80 mg, 622 µmol) in MeCN (5 mL) was stirred at 80oC for 2 hours, then the reaction was concentrated and the residue was purified by HPLC to give Example 45 (30 mg) as white powder, LCMS (M+H+): 793. A mixture of methyl compound 45b-2 (70 mg, 124 µmol), intermediate C2 (50 mg, 187 µmol) and DIPEA (80 mg, 622 µmol) in MeCN (5 mL) was stirred at 80oC for 2 hours, then the reaction was concentrated and the residue was purified by HPLC to give Example 46 (30 mg) as white powder, LCMS (M+H+): 793. Example 47 (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-27- 6,9 23,26 2,7 12,16 oxa-9,12,18,21,24,34-hexazahexacyclo[26.3.1.1 .1 .0 .0 ]tetratriaconta- 1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dioneExample 47 was prepared in analogy to the preparation of Example 42 by using methyl (2R)-4,4-difluoropyrrolidine-2-carboxylate instead of methyl morpholine-2-carboxylate. LCMS (M+H+): 755. Example 48 (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro-28- 6,9 24,27 2,7 12,16 oxa-9,12,18,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-17,23-dioneExample 48 was prepared in analogy to the preparation of Example 42 by using methyl (2R)-4,4-difluoropyrrolidine-2-carboxylate instead of methyl morpholine-2-carboxylate and propane-1,3-diamine instead of ethane-1,2-diamine. LCMS (M+H+): 769. Example 49 (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-29-oxa- 6,9 25,28 2,7 12,17 9,12,15,19,23,26,36-heptazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dioneThe title compound was prepared according to the following scheme:Step 1: preparation of O1-tert-butyl O3-methyl 4-[2-(4-bromoindazol-2- yl)ethyl]piperazine-1,3-dicarboxylate (compound 49a) A mixture of compound 39c (1 g, 3.13 mmol), O1-tert-butyl O3-methyl piperazine-1,3- dicarboxylate (763 mg, 3.13 mmol) and DIPEA (1.21 g, 9.4 mmol) in DMF (10 mL) was stirred at 100oC for 16 hours. Then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentarted, the residue was purified by silica gel column chromatography to give compound 49a (500 mg) as a light yellow foam, LCMS (M+H+): 467. Step 2: preparation of methyl 1-[2-(4-bromoindazol-2-yl)ethyl]piperazine-2- carboxylate (compound 49b) A mixture of compound 49a (500 mg, 1.07 mmol) in 4 M HCl in dioxane (5 mL) was stirred at rt for 16 hours, then the reaction was concentrated to give compound 49b (400 mg) as a light yellow solid, LCMS (M+H+): 367. Step 3: preparation of methyl 1-[2-(4-bromoindazol-2-yl)ethyl]-4-methyl-piperazine- 2-carboxylate (compound 49c) A mixture of compound 49b (500 mg, 1.36 mmol), paraformaldehyde (204 mg, 6.81 mmol), AcOH (245 mg, 4.08 mmol) and NaBH3CN (257 mg, 4.08 mmol) in DCM / MeOH (10:1) (10 mL) was stirred at rt for 16 hours. Then the reaction was concentrated and the residue was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 49c (40 mg) as light yellow oil, LCMS (M+H+): 381. Step 4-7: preparation of (25S,28S)-15-methyl-29-oxa-9,12,15,19,23,26,36- 6,9 25,28 2,7 12,17 heptazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-18,24-dione (compound 49g) Compound 49g was prepared in analogy to the preparation of compound 39h by using compound 49c instead of compound 39d. LCMS (M+H+): 532. Step 8: preparation of (25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-15-methyl-29-oxa-9,12,15,19,23,26,36- 6,9 25,28 2,7 12,17 heptazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6(36),7,30(34),31- heptaene-18,24-dione (Example 49) A mixture of compound 49c (25 mg, 47 µmol), intermediate C2 (19 mg, 70.5 µmol) and DIPEA (30 mg, 235 µmol) in MeCN (2 mL) was stirred at 80oC for 2 hours, then the reaction was concentrated and then purified by prep-HPLC to give Example 49 (5 mg) as white powder. LCMS (M+H+): 762.1H NMR (400 MHz, METHANOL-d4) δ = 8.65 - 8.34 (m, 2H), 8.34 - 8.05 (m, 1H), 7.70 - 7.56 (m, 2H), 7.56 - 7.47 (m, 1H), 7.42 - 7.15 (m, 7H), 5.54 - 5.30 (m, 1H), 5.14- 4.89 (m, 2H), 4.79 - 4.15 (m, 4H), 3.47 - 3.37 (m, 1H), 3.26 - 2.78 (m, 9H), 2.74 - 2.50 (m, 4H), 2.50 - 2.32 (m, 3H), 1.69 - 1.47 (m, 1H), 1.43 - 1.30 (m, 1H). Example 50 and Example 51 (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxamide and (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxamideThe title compound was prepared according to the following scheme:Example 50Example 51Step 1: preparation of (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30- heptaene-21-carboxylic acid (compound 50a) A mixture of Example 45 (30 mg, 37.8 µmol) and LiOH (2 M, 189 µl, 378 µmol) in THF / MeOH (2:1) (3 mL) was stirred at rt for 16 hours. Then the pH of the reaction mixture was adjusted to 6-7, the mixture was concentrated to give crude compound 50a (30 mg), which was used in next step directly. LCMS (M+H+): 779. Step 2: pre...

Claims

CLAIMS 1. A compound of formula (I),wherein M1is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1is deuterio, halogen, cyano, carboxy, NO2,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 C2-6alkenylene, arylene, heterocyclylene heteroarylene, C3-7cycloakylene, haloC3- 7cycloakylene, cubanylene, bicycle[1.1.1]pentanylene, or admentanylene, each of which is optionally substituted by R1; M3is heterocyclylene which is substituted by R2and optionally substituted by R1; wherein R2is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, each of which is optionally substituted by Rb;SO(NR)-W-, -W-SiR2-W-, -C1-6alkylene-W-C1-6alkylene-, -W-CONH-W-, -W- CON(R)-W-, -W-N(R)CO-W- or -W-N(R)-W-; wherein each W is independently selected from CONH, carbonyl, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, 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; Q2is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3is C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; Q4is a bond, N(R), carbonyl, -CONR-, SO2, SO(NR), P(O)R, PO(NR), Se, N(R), SiR2, optionally substituted heterocyclylene, optionally substituted heteroarylene or optionally substituted arylene; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein M1is arylene, heterocyclylene or heteroarylene, each of which is once, twice or three times substituted by R1; wherein R1is independently selected from H, deuterio, halogen, cyano, NO2, C1-6alkyl, haloC1-6alkyl and C1-6alkylaminocarbonyl.

3. A compound according to claim 1 or 2, wherein M1is [1,2,4]triazolo[4,3-a]pyridinylene, 1H-pyrazolo[3,4-b]pyridinylene, 2,3-dihydropyrrolo[3,2-b]pyridinylene, 2-oxo-1,3-benzothiazolylene, 2-oxo-1,4-dihydro-3,1-benzoxazinylene, 2-oxo-3H-benzimidazolylene unsubstituted or substituted by halogen, 2-oxoindolinyl, 2-oxopyridylene unsubstituted or twice substituted by substituents independently selected from halogen and C1-6alkyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinylene, 5,6-dihydropyrrolo[3,2-c]pyrazolylene substituted by C1-6alkyl, 5-oxo-1,2,4-triazolylene substituted by C1-6alkyl, 5-oxo-2,3-dihydro-1H-indolizinylene, benzimidazolylene unsubstituted or once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene,imidazo[1,2-a]pyridinylene, imidazolylene substituted by C1-6alkyl, indazolylene unsubstituted or substituted by halogen or C1-6alkyl, indolylene, oxoisoindolinylene, phenylene unsubstituted or substituted by cyano, NO2, C1-6alkyl, haloC1-6alkyl and C1-6alkylaminocarbonyl, pyrazolo[1,5-a]pyridinylene, pyrazolylene substituted by C1-6alkyl, pyridylene, pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl, pyrrolo[3,2-c]pyridinylene unsubstituted or substituted by halogen, or thiazolylene.

4. A compound according to any one of claims 1 to 3, wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene, indazolylene unsubstituted or substituted by C1-6alkyl, or pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl.

5. A compound according to any one of claims 1 to 4, wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from fluoro and methyl, benzotriazolylene, indazolylene unsubstituted or substituted by methyl, or pyrrolo[2,3-b]pyridinylene substituted by methyl.

6. A compound according to any one of claims 1 to 5, wherein M2is C2-6alkenylene, phenylene, pyridylene, pyrimidinylene or thiazolylene.

7. A compound according to any one of claims 1 to 6, wherein M2is phenylene, pyridylene, pyrimidinylene or thiazolylene.

8. A compound according to any one of claims 1 to 7, wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl;; wherein R3is C1-6alkyl; R4is phenyl or phenylC1-6alkyl, each of which is once or twice substituted by substituents independently selected from halogen and C1-6alkoxy; R5is H, oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1-6alkoxyC1- 6alkyl.

9. A compound according to any one of claims 1 to 8, wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl; 2wherein R is , or ;wherein R4is phenyl twice substituted by halogen; R5is H, oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1-6alkoxyC1- 6alkyl.

10. A compound according to any one of claims 1 to 9, wherein M3is pyrrolidinylene substituted by R2, or twice substituted by R2and methyl; wherein R2is; wherein R4is 2,4-difluorophenyl; R5is H, 2-(cyanomethyl)azetidin-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl, methoxymethyl or oxetan-3-yl.

11. A compound according to any one of claims 1 to 9, wherein Q1is, wherein L1is a bond, C1-6alkylene, hydroxyC1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, (C1-6alkyl)piperazinylene, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4- b][1,4]oxazinylene, carbonyl, halopyrrolidinylene, morpholinylene, NR6, O, oxopyrrolidinylene or piperazinylene; wherein R6is H, (C1-6alkyl)2aminocarbonylC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyl, C1-6alkylaminocarbonyl, C1-6alkylaminocarbonylC1-6alkyl, C1-6alkylcarbonyl, carboxyC1-6alkyl, imidazolylcarbonyl, morpholinylcarbonylC1-6alkyl, phenylC1-6alkylcarbonyl, piperazinylcarbonylC1-6alkyl, pyrazolylC1-6alkylcarbonyl, pyridylC1-6alkylcarbonyl or pyrimidinyl; L3is a bond, NH, carbonyl, pyrrolidinylene, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (C1-6alkylimidazolyl)C1-6alkylene, (C1- 6alkylpiperazinylcarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene, (pyridylpiperazinylcarbonyl)C1-6alkylene, C1-6alkylene, C1-6alkylenepiperazinyleneC1-6alkylene or C2-6alkenylene; L5is a bond, O, NR7or piperazinylene unsubstituted or substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7is H, (carboxymorpholinyl)C1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, morpholinylC1-6alkyl, phenylC1-6alkyl or thiazolylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously.

12. A compound according to any one of claims 1 to 11, wherein Q1is, wherein L1is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene or C1-6alkylene; L5is a bond, O, NR7or piperazinylene substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously.

13. A compound according to any one of claims 1 to 12, wherein Q1is, wherein L1is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (methyl)amino; L4is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene;L5is a bond, O, NR7or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously.

14. A compound according to any one of claims 1 to 13, wherein Q2is a bond, O, NH or (C1-6alkyl)amino.

15. A compound according to any one of claims 1 to 14, wherein Q2is a bond.

16. A compound according to any one of claims 1 to 15, wherein Q3is O or NH.

17. A compound according to any one of claims 1 to 16, wherein Q4is a bond, carbonyl or tetrazolylene.

18. A compound according to any one of claims 1 to 17, wherein Q4is carbonyl or tetrazolylene.

19. A compound according to any one of claims 1 to 18, wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from halogen and C1-6alkyl, benzotriazolylene, indazolylene unsubstituted or substituted by C1-6alkyl, or pyrrolo[2,3-b]pyridinylene substituted by C1-6alkyl; M2is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3is pyrrolidinylene substituted by R2, or twice substituted by R2and C1-6alkyl; 2wherein R is , or ; wherein R4is phenyl twice substituted by halogen; R5is H,oxetanyl, C1-6alkoxyC1-6alkyl, azetidinyl substituted by cyano or cyanoC1-6alkyl, or 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or C1- 6alkoxyC1-6alkyl; Q1is, wherein L1is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene or C1-6alkylene; L5is a bond, O, NR7or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously; Q2is a bond; Q3is O or NH; Q4is carbonyl or tetrazolylene; or a pharmaceutically acceptable salt thereof.

20. A compound according to any one of claims 1 to 19, wherein M1is benzimidazolylene once or twice substituted by substituents independently selected from fluoro and methyl, benzotriazolylene, indazolylene unsubstituted or substituted by methyl, or pyrrolo[2,3-b]pyridinylene substituted by methyl; M2is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3is pyrrolidinylene substituted by R2, or twice substituted by R2and methyl;wherein R2is ; wherein R4is 2,4-difluorophenyl; R5is H, 2-(cyanomethyl)azetidin-1-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3- methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl, methoxymethyl or oxetan-3-yl; Q1is, wherein L1is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3is a bond, carbonyl, NH, CONH or (methyl)amino; L4is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5is a bond, O, NR7or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4and L5are not bond simultaneously; Q2is a bond; Q3is O or NH; Q4is carbonyl or tetrazolylene; or a pharmaceutically acceptable salt thereof.

21. A compound selected from: (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2- 6,9 16,19 2,7 methoxyethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one;(16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14-methyl-20-oxa- 6,9 16,19 2,7 9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,29- pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaene-11,17-dione; (15S,22S,25S)-17-benzyl-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26- oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione; (16S,23S,26S)-18-benzyl-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-27- oxa-9,14,18,21,24,34-hexazahexacyclo[26.3.1.16,9.123,26.02,7.016,21]tetratriaconta- 1(32),2,4,6(34),7,28,30-heptaene-15,22-dione; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,16,19,29- tetrazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25-heptaen-17-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaene-11,16-dione; (18S,21S)-19-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-22-oxa-9,12,16,19,30- pentazahexacyclo[21.3.1.16,9.112,15.118,21.02,7]triaconta-1(27),2,4,6(30),7,23,25-heptaene-11,17- dione; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaen-22- one; Benzyl (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,21- dioxo-26-oxa-9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-17-carboxylate; (15S,22S,25S)-23-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-oxa- 9,13,17,20,23,33-hexazahexacyclo[25.3.1.16,9.122,25.02,7.015,20]tritriaconta- 1(30),2,4,6(33),7,27(31),28-heptaene-14,21-dione; (11E,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,11,21,23-octaen-15-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12,21-dioxa-9,15,18,28- tetrazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one;(15S,18S)-16-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-19-oxa-9,13,16,26- tetrazapentacyclo[18.3.1.16,9.115,18.02,7]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one; (19S,22S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-23-oxa-9,17,20,30- tetrazapentacyclo[22.3.1.16,9.119,22.02,7]triaconta-1(28),2,4,6(30),7,24,26-heptaen-18-one; (11S,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (11R,16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-11-hydroxy-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa-9,12,15,18,28- pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen-16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-methyl-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one; (17S,20S)-12-acetyl-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-morpholino-2-oxo- ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]-N-methyl-acetamide; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-oxo-2-piperazin-1- yl-ethyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]acetamide; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-pyrazol-1- ylacetyl)-21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa- 1(26),2,4,6(28),7,22,24-heptaen-16-one;2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]acetic acid; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(2-phenylacetyl)-21- oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-one; (17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-12-(3-phenylpropanoyl)- 21-oxa-9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaen-16-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-14-methyl-20-oxa- 9,14,17,27-tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15- one; 2-[(17S,20S)-18-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-16-oxo-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24-heptaen- 12-yl]-N,N-dimethyl-acetamide; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,27,34- hexazahexacyclo[25.2.2.14,7.112,16.118,21.06,11]tetratriaconta-5,7(34),8,10,12(33),13,15-heptaene- 22,26-dione; (18S,21S)-20-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-17-oxa-1,4,20,23,26,33- hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta-5,7(33),8,10,12(32),13,15-heptaene- 22,25-dione; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-oxa- 9,12,16,19,29-pentazapentacyclo[21.3.1.16,9.118,21.02,7]nonacosa-1(27),2,4,6(29),7,23,25- heptaene-13,17-dione; (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-oxa- 9,12,15,18,28-pentazapentacyclo[20.3.1.16,9.117,20.02,7]octacosa-1(26),2,4,6(28),7,22,24- heptaene-13,16-dione; (18S,21S)-20-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-17-oxa- 1,4,20,23,26,33-hexazahexacyclo[24.2.2.14,7.112,16.118,21.06,11]tritriaconta- 5,7(33),8,10,12(32),13,15-heptaen-22-one; (16S,19S)-17-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-oxa- 9,14,17,22,27-pentazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23- heptaen-15-one;(17S,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17R,25S,28S)-26-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,29-dioxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (6S,9S)-7-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10,29-dioxa- 6,9 11,15 20,23 16,21 26,31 1,4,7,23,26,33,36,41-octazaheptacyclo[34.2.2.1 .1 .1 .0 .0 ]tritetraconta- 11(42),12,14,16,18,20(41),21-heptaene-5,32-dione; (23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,27-dioxa- 6,9 12,16 23,26 2,7 9,12,18,21,24,35-hexazahexacyclo[26.3.1.1 .1 .1 .0 ]pentatriaconta- 1(31),2,4,6(35),7,28(32),29-heptaene-17,22-dione; (24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15,28-dioxa- 6,9 12,16 24,27 2,7 9,12,18,22,25,36-hexazahexacyclo[27.3.1.1 .1 .1 .0 ]hexatriaconta- 1(32),2,4,6(36),7,29(33),30-heptaene-17,23-dione; (24S,27S)-25-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15,28-dioxa- 6,9 24,27 2,7 12,17 9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione; Methyl (21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23- 6,9 24,27 2,7 12,17 dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-21-carboxylate; methyl (20S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18,23- 6,9 24,27 2,7 12,17 dioxo-15,28-dioxa-9,12,19,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-20-carboxylate; (16R,23S,26S)-24-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro- 6,9 23,26 2,7 12,16 27-oxa-9,12,18,21,24,34-hexazahexacyclo[26.3.1.1 .1 .0 .0 ]tetratriaconta- 1(31),2,4,6(34),7,28(32),29-heptaene-17,22-dione; (16R,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-14,14-difluoro- 6,9 24,27 2,7 12,16 28-oxa-9,12,18,22,25,35-hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-17,23-dione;(25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl-29-oxa- 6,9 25,28 2,7 12,17 9,12,15,19,23,26,36-heptazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (17S,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17R,21S,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17S,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 20-carboxamide; (17R,20R,24S,27S)-N-benzyl-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 18,23-dioxo-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 21-carboxamide; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-(4- methylpiperazine-1-carbonyl)-15,28-dioxa-9,12,19,22,25,35- 6,9 24,27 2,7 12,17 hexazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15-oxa- 6,9 25,28 2,7 12,17 8,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (16R,17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[(3- methylimidazol-4-yl)methyl]-15,28-dioxa-9,12,19,22,25,36- 6,9 16,19 24,27 2,7 12,17 hexazaheptacyclo[27.3.1.1 .1 .1 .0 .0 ]hexatriaconta-1(32),2,4,6(36),7,29(33),30- heptaene-20,23-dione; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2- pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35-6,9 24,27 2,7 12,17 nonazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione; (17S,21S,24S,27S)-25-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-[4-(2- pyridyl)piperazine-1-carbonyl]-15-oxa-9,12,19,22,25,28,32,33,35- 6,9 24,27 2,7 12,17 nonazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta-1(32),2,4,6(35),7,29(33),30-heptaene- 18,23-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8-methyl-15,29- 6,9 25,28 2,7 12,17 dioxa-8,12,19,23,26,36-hexazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6,9(36),30(34),31-heptaene-18,24-dione; (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-oxa- 6,9 25,28 2,7 12,17 9,12,19,23,26,29,33,34,36-nonazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta- 1(33),2,4,6(36),7,30(34),31-heptaene-18,24-dione; (18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-11-methyl-22-oxa- 6,9 18,21 2,7 11,16,19,29-tetrazapentacyclo[21.3.1.1 .1 .0 ]nonacosa-1(26),2(7),3,5,8,23(27),24- heptaene-10,17-dione; (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa-6,10,15,18,28- 6,9 17,20 2,7 pentazapentacyclo[20.3.1.1 .1 .0 ]octacosa-1(25),2,4,7,9(28),22(26),23-heptaen-16-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 6,9 15,18 2,7 9,13,16,19,24,26-hexazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22- heptaen-14-one; (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-19-oxa- 6,9 15,18 2,7 9,13,16,26-tetrazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14- one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 7,10,13,19,21,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,17,20,22- heptaen-12-one; (16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-14-(2- 6,9 16,19 2,7 morpholinoethyl)-20-oxa-9,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-10-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-7-oxa-10,13,18,24- tetrazatetracyclo[18.3.1.12,6.18,11]hexacosa-1(23),2(26),3,5,20(24),21-hexaene-12,19-dione;(16S,19S)-17-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]-20-oxa-9,14,17- triazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6,21,23-hexaene-15,27-dione; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-15-ethyl-8-methyl- 2,5,8,14,15,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),13,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13,17-trimethyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl-17-oxa- 2,5,8,13,14,22-hexazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen-7- one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8,13-dimethyl- 2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaen- 7-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-17-oxa- 3,4,6,11,14-pentazatetracyclo[16.3.1.113,16.02,6]tricosa-1(22),2,18,20-tetraene-5,12-dione; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,13,17,22- hexazatetracyclo[16.3.1.13,6.112,16]tetracosa-1(21),12(23),13,15,18(22),19-hexaen-7-one; (3S,6S)-5-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-methyl-2,5,8,14,18,23- hexazatetracyclo[17.3.1.13,6.012,17]tetracosa-1(22),12,14,16,19(23),20-hexaen-7-one; (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methyl-18-oxa- 3,4,6,12,15-pentazatetracyclo[17.3.1.114,17.02,6]tetracosa-1(23),2,19,21-tetraene-5,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl- 1,7,10,13,18,19,25-heptazapentacyclo[15.5.1.12,6.18,11.020,23]pentacosa-2,4,6(25),17(23),19- pentaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-1,10,13,20- tetrazapentacyclo[15.6.1.12,6.18,11.021,24]hexacosa-2(26),3,5,17,19,21(24)-hexaen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-14,20-dioxa-9,17,27- triazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(24),2,4,6(27),7,21(25),22-heptaen-15-one;(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-13-(3- phenylpropyl)-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa- 4,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),19,21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2- morpholinoethyl)-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,20,22-hexaene-12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(2- morpholinoethyl)-7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17,19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)- 7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,19,21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(thiazol-4- ylmethyl)-7-oxa-10,13,19,24-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17,19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa-19- thia-10,13,17-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),20,22-hexaene- 12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19,20-tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17(24),18,21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 7,10,13,16,18,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),17(24),19,21-heptaen-12-one;(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl- 7,10,13,18,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),17,20(24),21- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13-methyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,20,22- hexaene-12,18-dione; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro-8- oxa-12,15,18,23-tetrazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-8,12-dimethyl-6- nitro-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaen-13- one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-13-oxo- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaene-6- carbonitrile; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6- (trifluoromethyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa- 1(23),2(7),3,5,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13- oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2(7),3,5,19,21-hexaene-6- carboxamide; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,17,18,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),18,20(24),21- heptaen-12-one; (13S,16S)-14-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3,11-dimethyl-8-oxa- 3,5,11,14,17,22-hexazatetracyclo[16.3.1.113,16.02,6]tricosa-1(22),2(6),4,18,20-pentaen-12-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-5-thia- 3,8,12,15,18,23-hexazatetracyclo[17.3.1.114,17.02,6]tetracosa-1(23),2(6),3,19,21-pentaene-7,13- dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.5.2.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-15-oxo-20- 16,19 2,7 oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaene-10- carboxamide;(17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-16-oxo-21- 17,20 2,7 oxa-10,15,18-triazatetracyclo[20.3.1.1 .0 ]heptacosa-1(25),2,4,6,22(26),23-hexaene-10- carboxamide; (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-20-oxa- 16,19 2,7 10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-pyrimidin-2-yl-20- 16,19 2,7 oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one; (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-(1H-imidazole-2- 16,19 2,7 carbonyl)-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22- hexaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl- 2,6 8,11 12,15 22,26 7,10,13,14,15,19,21,27,29-nonazahexacyclo[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),12(27),13,20,22,24-nonaene; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-methyl- 2,6 8,11 12,15 21,25 7,10,13,14,15,18,20,26,28-nonazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 1(25),2,4,6(28),12(26),13,19,21,23-nonaene; 1-[1-(2,4-difluorophenyl)-4-[(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-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3-carbonitrile; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-5,7,10,13,18,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one;(8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 11,13,18-trimethyl-7-oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-20-oxa-11,14,17,27- 6,9 16,19 2,7 tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa-1(25),2,4,6,8,21,23-heptaene-10,15-dione; (12E,17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-21-oxa- 6,9 17,20 2,7 6,10,15,18,28-pentazapentacyclo[20.3.1.1 .1 .0 ]octacosa-1(25),2,4,7,9(28),12,22(26),23- octaen-16-one; (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-17-oxa-7,11,14- 13,16 2,7 triazatetracyclo[16.3.1.1 .0 ]tricosa-1(22),2,4,18,20-pentaene-6,12-dione; (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (20S,23S)-21-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (8S,11S)-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-13-methyl- 2,6 8,11 20,24 7,10,13,17,18,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (43S,45S)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-methyl-11H- 3,6-diaza-1(7,1)-benzo[d][1,2,3]triazola-2(2,6)-pyridina-4(3,5)-pyrrolidinacyclononaphan-5-one; (20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-12-methyl-24-oxa- 6,9 16,19 20,23 2,7 9,12,16,17,18,21,31,32-octazahexacyclo[23.3.1.1 .1 .1 .0 ]dotriaconta- 1(28),2,4,6(32),7,17,19(31),25(29),26-nonaen-11-one; (14S,17S)-15-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-7,12,15,18,23- 14,17 2,7 pentazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2,4,19,21-pentaene-6,13-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-7-oxa- 2,6 8,11 20,23 1,10,13,18,19-pentazapentacyclo[15.5.1.1 .1 .0 ]pentacosa-2(25),3,5,17(23),19-pentaen- 12-one;(8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazin-4-yl]-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21- heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18- 2,6 8,11 21,25 oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),21(25),22- hexaene-12,19-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-18-oxa- 2,6 8,11 21,25 7,10,13,20,27-pentazapentacyclo[15.7.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),21(25),22- hexaene-12,19-dione; (1S,3S)-31-(2,4-difluorophenyl)-4,15,17,21,26,30,32,36,39,41- 3,36 5,9 10,14 28,35 30,34 17,40 decazaoctacyclo[19.15.1.1 .1 .1 .1 .0 .0 ]hentetraconta- 5,7,9(41),10,12,14(40),15,28,31,33,35(39)-undecaene-27,37-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 2,6 8,11 21,24 1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22- heptaen-12-one; (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 2,6 8,11 21,24 1,7,10,13,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22- heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-hydroxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,18,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(oxetan-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19- 2,6 8,11 20,24 pentazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 2,6 8,11 19,23 10,13,19-triazapentacyclo[14.6.1.1 .1 .0 ]pentacosa-1(23),2(25),3,5,21-pentaene-12,20- dione; (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6,12- 14,17 2,7 dimethyl-6,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2(7),3,19,21- pentaene-5,13-dione;(14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-5,12-dimethyl- 14,17 2,7 5,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2(7),3,19,21-pentaene-6,13- dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-13,17- 2,6 8,11 19,23 dimethyl-7,10,13,16,18,25-hexazapentacyclo[14.6.1.1 .1 .0 ]pentacosa- 1(23),2(25),3,5,17,19,21-heptaen-14-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-14-one; (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methyl- 17,20 2,7 8,12 8,15,18,21,26-pentazapentacyclo[20.3.1.1 .0 .0 ]heptacosa-1(26),2,4,6,22,24-hexaene- 9,16-dione; (6S,9S)-8-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-16-methyl-5-oxa-8,11,16,17- tetrazatetracyclo[13.6.1.16,9.018,22]tricosa-1(21),2,15(22),17,19-pentaen-10-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,20(24),21-hexaene- 12,18-dione; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl-7-oxa- 10,13,19-triazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,20(24),21-hexaene- 12,18-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-methyl- 7,10,13,18,19,24,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,19,21- heptaen-12-one; (16S,19S)-17-[5-(2-chloro-4-fluoro-phenyl)pyrazin-2-yl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-13-benzyl-10-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-18-methyl-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)-10-[1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-18-methyl-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;4-[3-[(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-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-heptaen-13-yl]propyl]morpholine-3-carboxylic acid; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-6-nitro- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-8-acetyl-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl- 8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N,12-dimethyl-13- oxo-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-8- carboxamide; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-(2- pyrazol-1-ylacetyl)-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21- hexaen-13-one; (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-12-methyl-8-[2-(4- pyridyl)acetyl]-8,12,15,18,23-pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21- hexaen-13-one; (16S,19S)-17-[1-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-4-yl]-20-oxa-9,14,17,27- tetrazapentacyclo[19.3.1.16,9.116,19.02,7]heptacosa-1(25),2,4,6(27),7,21,23-heptaen-15-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3-methoxypropyl)- 7-oxa-10,13,18,19,24-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-2(26),3,5,17,19- pentaen-12-one; (7S,10S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14-methoxy- 12,17-dimethyl-25-thia-4,6,9,12,16,18-hexazapentacyclo[14.6.1.12,5.17,10.019,23]pentacosa- 1(22),2,4,17,19(23),20-hexaen-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14- methoxy-12,17-dimethyl-6-oxa-4-thia-9,12,16,18,25- pentazapentacyclo[14.6.1.12,5.17,10.019,23]pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one; (7S,10S,14R)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-fluoro-14- methoxy-12,17-dimethyl-4-thia-6,9,12,16,18,25-hexazapentacyclo[14.6.1.12,5.17,10.019,23] pentacosa-1(22),2,5(25),17,19(23),20-hexaen-11-one; and2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-2- yl]acetonitrile; or a pharmaceutically acceptable salt thereof.

22. A process for the preparation of a compound according to any one of claims 1 to 21 comprising the following step: a) the formation of compound of formula (Ia),via nucleophilic substitution between compound of formula (VII),(VII), and R2X, in the presence of a base; or via Buchwald-Hartwig reaction between compound of formula (VII) and R2X in the presence of a catalyst; or via condensation reaction between compound of formula (VII) and R2OH in the presence of coupling reagent; wherein the base in step a) is DIEA; the coupling reagent in step a) is HATU; the catalyst in step a) is Pd2(dba)3; X is halogen; Reis H or C1-6alkyl. Rfis R or R7; Q1to Q3, M1and M2are as defined as in any one of claim 1 to 19.

23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as therapeutically active substance.

24. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

25. The use of a compound according to any one of claims 1 to 21 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.

26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 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.

27. The use of a compound according to any one of claims 1 to 21 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.

28. The use of a compound according to any one of claims 1 to 21 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.

29. The use of a compound according to any one of claims 1 to 21 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.

30. The use of a compound according to any one of claims 1 to 21 for the inhibition of STING.

31. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the inhibition of STING.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, when manufactured according to a process of claim 22.

33. 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 claims 1 to 21.

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