EP4747260A1 - Macrocycles for the treatment of autoimmune disease - Google Patents

Macrocycles for the treatment of autoimmune disease

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Publication number
EP4747260A1
EP4747260A1 EP24748291.2A EP24748291A EP4747260A1 EP 4747260 A1 EP4747260 A1 EP 4747260A1 EP 24748291 A EP24748291 A EP 24748291A EP 4747260 A1 EP4747260 A1 EP 4747260A1
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EP
European Patent Office
Prior art keywords
difluorophenyl
pyrazolo
methyl
oxa
pyrimidin
Prior art date
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EP24748291.2A
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German (de)
French (fr)
Inventor
Xingchun Han
Min Jiang
Buyu KOU
Haixia Liu
Yafei Liu
Hong Shen
Yao Wu
Zhenhong Zhang
Zhiwei Zhang
Wei Zhu
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication of EP4747260A1 publication Critical patent/EP4747260A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 by chromosomal instability during cancer metastasis, and that STING-deficiency confers protection against colorectal and skin cancer in the mouse. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I), wherein M1 is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1 is 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, Rb or Rc; Ra is C1-6alkyl optionally substituted by Rb or Rc; Rb is C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rc is 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; M2 is 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; M3 is heterocyclylene which is substituted by R2 and optionally substituted by R1; wherein R2 is 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; Q2 is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3 is 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; Q4 is 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 4 carbon atoms with at least one double bond. Examples of C2-6alkenyl include ethenyl (or vinyl), propenyl, allyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl. The term “C2-6alkenylene” denotes a divalent C2-6alkenyl. Examples of C2-6alkenylene groups include butenylene and (methyl)butenylene. The term “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 heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, 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.) 13th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. In one embodiment, heteroaryl includes 7-12 membered bicyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2- a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyridazine, imidazo[1,5- a]pyrazine, imidazo[5,1-f][1,2,4]triazine, [1,2,4]triazolo[4,3-a]pyrazine, 1H-pyrazolo[3,4- c]pyridazine, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4- c]pyridine, 1H-pyrazolo[4,3-c]pyridine and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl. 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, Rb or Rc; Ra is C1-6alkyl optionally substituted by Rb or Rc; Rb is C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rc is 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 inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary 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 M1 is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1 is 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, Rb or Rc; Ra is C1-6alkyl optionally substituted by Rb or Rc; Rb is C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rc is 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; M2 is 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; M3 is heterocyclylene which is substituted by R2 and optionally substituted by R1; wherein R2 is 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; Q2 is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3 is 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; Q4 is 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 M1 is arylene, heterocyclylene or heteroarylene, each of which is once, twice or three times substituted by R1; wherein R1 is 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 M1 is [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 M1 is 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 M1 is 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 M2 is 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 M2 is 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 M2 is 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 M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; wherein R2 is heterocyclyl, heteroaryl, aryl, heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl, each of which is optionally substituted by R3, R4 and 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 M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; ; wherein R3 is C1-6alkyl; R4 is phenyl or phenylC1-6alkyl, each of which is once or twice substituted by substituents independently selected from halogen and C1-6alkoxy; R5 is 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 (ix) a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; 2 wherein R is , or ; wherein R4 is phenyl twice substituted by halogen; R5 is 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 M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and methyl; wherein R2 is , or ; wherein R4 is 2,4-difluorophenyl; R5 is 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 Q1 is L1 is a bond, C1-6alkylene, hydroxyC1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is 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 R6 is 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; L3 is a bond, NH, carbonyl, pyrrolidinylene, CONH or (C1-6alkyl)amino; L4 is 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; L5 is a bond, O, NR7 or piperazinylene unsubstituted or substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7 is H, (carboxymorpholinyl)C1-6alkyl, C1-6alkoxyC1- 6alkyl, C1-6alkyl, morpholinylC1-6alkyl, phenylC1-6alkyl or thiazolylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are 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 Q1 is , wherein L1 is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4 is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene or C1-6alkylene; L5 is a bond, O, NR7 or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7 is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are 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 Q1 is , wherein L1 is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2 is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (methyl)amino; L4 is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5 is a bond, O, NR7 or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7 is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4 and L5 are 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 Q2 is 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 Q2 is a bond. A further embodiment of present invention is (xvi) a compound of formula (I), according to any one of (i) to (xv), wherein Q3 is 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 Q4 is 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 Q4 is 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 M1 is 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; M2 is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; wherein R2 is ; wherein R4 is phenyl twice substituted by halogen; R5 is 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; Q1 is , wherein L1 is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4 is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1- 6alkylene or C1-6alkylene; L5 is a bond, O, NR7 or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7 is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously; Q2 is a bond; Q3 is O or NH; Q4 is 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 M1 is 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; M2 is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and methyl; wherein R2 is ; wherein R4 is 2,4-difluorophenyl; R5 is 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; Q1 is , wherein L1 is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2 is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (methyl)amino; L4 is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5 is a bond, O, NR7 or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7 is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously; Q2 is a bond; Q3 is O or NH; Q4 is 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 M1 is , , , , , , , , ; wherein R1a is H or C1-6alkyl; R1b is H or halogen; R1c is 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 M1 is , , , wherein R1a is H or C1-6alkyl; R1b is 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 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; Re is H or C1-6alkyl. Rf is R or R7; Q1 to Q3, M1 and M2 are 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), 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 (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 be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit STING interaction with IRF3, NF-kB, NLRP3 etc., for blocking downstream type I IFN and pro-inflammatory cytokine (e.g. IL-6, TNFa, ISGs) production, cellular responses/conditions (e.g. autophagy, apoptosis, cell senescence). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg/kg, alternatively about 0.1 to 1000 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.1 to 1000 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the invention compounded with about 0.1 to 1000 mg anhydrous lactose, about 0.1 to 1000 mg sodium croscarmellose, about 0.1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 0.1 to 1000 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferonopathies, autoimmune and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infection or selective type of cancer. The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compound of the invention inhibit the binding of cGAMP to STING and its downstream signaling. Accordingly, the compound of the invention are useful for blocking STING activation, signaling, downstream cytokine, chemokine production and cellular processes such as apoptosis and autophagy. Compounds of the invention are useful for inhibition of STING. Alternatively, compounds of invention are useful for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. More broadly, the compound can be useful for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of autoimmune diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of inflammatory diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of neurological disorders diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of cardiovascular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of ocular diseases. In some embodiments, compounds of the invention are useful for the treatment or prophylaxis of selective types of cancers where overexpression or activation of STING is implicated. Alternatively, compounds of the invention are useful for the treatment of subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. More broadly, the compounds can be used for the treatment of all pathological cellular processes which are STING dependent. Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1 to R7, Q1, Q2, A1 to A7 are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic route for preparing the compound of the invention are shown in following scheme. Scheme 1 Wherein Rd is H or PG, wherein PG can be, for example, Boc or Cbz; X is halogen; Re is H or C1-6alkyl. Rf is 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 of formula (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; Re is H or C1-6alkyl. Rf is 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 hydride DIAD: 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 chromatography PyBOP/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 XBridgeTM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFireTM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm) or AD (10 µm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and 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 (WatersTM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in 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-carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)-2-hydroxy- propyl]carbamate (compound A1-b) To a solution of 1,3-diamino-2-propanol (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 at 20 °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 N2 three times and stirred at 130 °C for 2 hours. The reaction mixture was poured into water (1000 mL) and extracted with EA (300 mL) twice. The organic phase was washed with brine (300 mL), dried and concentrated, the residue was purified by silica gel 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-carbamate Intermediate 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-carbamate The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-anilino)-2- hydroxy-propyl]carbamate (compound 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-carbamate The 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-amine The 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)acetate The title compound was prepared according to the following scheme: Intermediate A6 A 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]carbamate The title compound was prepared according to the following scheme: Intermediate A7 A 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]carbamate The 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-dione The 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 flash column 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]carbamate The 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-dione The 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]carbamate Step 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 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 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-carboxylate The 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 A14 2-[2-[4-[2-(4-bromoindazol-2-yl)ethyl]piperazin-1-yl]-2-oxo-ethyl]isoindoline-1,3- dione The 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)propanamide The title compound was prepared according to the following scheme: Intermediate A15 Step 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)acetamide The 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-dione The 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 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 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-ol A 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-dione A 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. The filtrated 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-dione The 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 concentrated to 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]carbamate The 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-dione The 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-dione The 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 (compound A23-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 Na2SO4 and 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 acid Step 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 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 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 acid The 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 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 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 acid The 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 the crude 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 acid The 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 acid The 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 for 1 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-carbamate The title compound was prepared according to the following scheme: Intermediate A29 To 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 room temperature 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]carbamate The title compound was prepared according to the following scheme: A30-a Intermediate A30 Step 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]carbamate The 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)-CH2Cl2 adduct (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 combined organic 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-carbamate The 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-carbamate The title compound was prepared according to the following scheme: A33-c Intermediate 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-dione The title compound was prepared according to the following scheme: Intermediate A34 A 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-dione The 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-dione The 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-dione The 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-dione The 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]carbamate The title compound was prepared according to the following scheme: intermediate A39 Step 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 NaHCO3 was 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 the residue 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]carbamate The 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]carbamate The 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-dicarboxylate The title compound was prepared according to the following scheme: Intermediate B1 Intermediate B2 A 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 80 oC for 16 hours. Then the reaction was diluted with EtOAc, washed with water and brine, the organic layer was concentrated, the residue was purified by silica gel 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-dicarboxylate Intermediate B3 Intermediate B4 The title compound was prepared according to the following scheme Intermediate B3 Intermediate B4 A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), 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- dicarboxylate The title compound was prepared according to the following scheme: Intermediate B5 A 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-dicarboxylate The 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- dicarboxylate The title compound was prepared according to the following scheme: A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2- dicarboxylate;hydrochloride (4.7 g, 14.9 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-dicarboxylate The title compound was prepared according to the following scheme: Intermediate B8 To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (2 g, 8.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.8 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 mixture was 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-dicarboxylate The 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- dicarboxylate The 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-dicarboxylate The 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- dicarboxylate To 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 B13 O1-tert-butyl O2-methyl (2S,4S)-4-[(5-bromo-3-pyridyl)oxy]pyrrolidine-1,2- dicarboxylate The title compound was prepared in the analogy to the preparation of Intermediate 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]pyrimidine The title compound was prepared in analogy to the preparation of intermediate C2 by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloro-5-pyrimidinecarbaldehyde. LCMS (M+H+): 301. Intermediate C2 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine The title compound was prepared according to the following scheme:. Step 1: preparation of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro- aniline (compound C2-b) A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 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 with water and brine, the organic layer was dried and concentrated to give the crude compound C2-b (34.5 g). LCMS (M+H)+: 303. Step 2: preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (Intermediate C2) To a solution of N-[(4,6-dichloropyrimidin-5-yl)methyleneamino]-2,4-difluoro-aniline (compound C2-b,18.5 g, 61 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]pyrazine Step 1: preparation of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (compound C3-b) To a mixture of 2,4-difluorobenzoic acid (compound C3-a, 8 g, 50.6 mmol) in DCM (100 mL) was added thionyl chloride (260 mL) at 25 °C. After being stirred at 80 °C for 2 h, the mixture was concentrated and diluted with DCM. Then to the 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. Then mixture was concentrated, the residue was added to a vigorously stirring mixture of EA (300 mL, contained 10 mL of triethylamine) and 50 g NaHCO3 in 300 mL water at 0 °C. The organic layer was separated, dried and concentrated to give intermediate C3 (15.4 g). LCMS (M+H)+: 266. Intermediate C4 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carboxylate (compound 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 acid The 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- carbonitrile The title compound was prepared according to the following scheme:
Step 1: preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound 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 90 oC 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 40 oC 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]amine The title compound was prepared according to the following scheme: Step 1: preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound 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-ol The 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]pyrimidine The 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 petroleum ether 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 Na2SO4 and 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 Na2SO4 and 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-one The 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 lithium hydroxide 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-one The title compound was prepared according to the following scheme: Example 1 Step 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-one The 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-one The 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- dione The 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)-CH2Cl2 adduct (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-dione The 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 anhydrous Na2SO4, 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)-CH2Cl2 adduct (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-dione The 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)-CH2Cl2 adduct (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, concentrated under 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) and acetonitrile (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-one The 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)-CH2Cl2 adduct (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 (compound 7c, 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-one The 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 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 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- dione The 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- dione The 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-one The 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)- CH2Cl2 adduct (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 room temperature 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-carboxylate The 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-dione The 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-one The 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)-CH2Cl2 adduct (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 (3 mL) 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-one The 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-one The 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-one The 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-one The 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-one The 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-one The 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-one The 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-one The 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-acetamide The 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-one The 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]acetamide The 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-one The 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 acid The 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 resutling mixture was stirred at 100 oC 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-one The 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 temperature for 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-one The 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-one The 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-acetamide The 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-dione The 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-dione The 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- dione The 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- dione The 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-one The 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-one The 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-dione The 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 80 oC 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 80 oC 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 90 oC 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 90 oC 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-dione Example 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-dione The 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 80 oC 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-dione Example 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-dione Example 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-carboxylate The 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 80 oC 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 80 oC 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-dione Example 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-dione Example 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-dione The 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 100 oC 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 80 oC 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-carboxamide The title compound was prepared according to the following scheme: Example 50 Example 51 Step 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: preparation of (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-carboxamide (Example 50 & Example 51) A mixture of compound 50a (30 mg, 38.5 µmol), phenylmethanamine (8.26 mg, 77 µmol), DIPEA (25 mg, 3193 µmol) and HATU (29.3 mg, 77 µmol) in DMF (5 mL) was stirred at rt for 2 hours, then the reaction was purified by HPLC to give Example 50 (2 mg, faster eluted) and Example 51 (0.5 mg, slower eluted) as white powders. LCMS (M+H+): 868. Example 52 and Example 53 (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 and (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 Examples 52 and 53 was prepared in analogy to the preparation of Examples 50 and 51 by using Example 46 instead of Example 45. Example 52, faster eluted, 0.5 mg, white powder, LCMS (M+H+): 868. Example 53, slower eluted, 2 mg, white powder, LCMS (M+H+): 868.1H NMR (400 MHz, METHANOL-d4) δ = 8.58 - 8.39 (m, 2H), 8.08 - 7.95 (m, 1H), 7.67 - 7.52 (m, 2H), 7.52 - 7.44 (m, 1H), 7.41 - 7.33 (m, 1H), 7.33 - 7.10 (m, 11H), 5.44 - 5.31 (m, 1H), 5.17 - 5.03 (m, 1H), 4.77 - 4.56 (m, 2H), 4.54 - 4.22 (m, 5H), 3.98 - 3.78 (m, 3H), 3.74 - 3.49 (m, 2H), 3.28 - 3.10 (m, 2H), 3.07 - 2.87 (m, 3H), 2.83 - 2.71 (m, 1H), 2.63 - 2.40 (m, 2H). Example 54 (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 The 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 54b-1) A mixture of intermediate B11 (1 g, 2.5 mmol) and LiOH (2 M, 3.75 mL) in THF/MeOH (2:1) (10 mL) was stirred at rt for 16 hours, then the pH of the reaction was adjusted to 6 with 1 M hydrochloric acid. The resulted mixture was extracted with DCM, then the organic layer was dried and concentrated to give compound 54b-1 (1 g) as light yellow foam. LCMS (M+H+): 386. Step 2: preparation of methyl (3S)-4-[2-(4-bromoindazol-2-yl)ethyl]morpholine-3- carboxylate (compound 54d-1a) A mixture of compound 39c (2 g, 6.27 mmol), methyl (3S)-morpholine-3-carboxylate (1.37 g, 9.41 mmol) and DIPEA (2.43 g, 18.8 mmol) in DMF (20 mL) was stirred at 100 oC for 16 hours. Then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 54d-1a (2.5 g) as light brown oil. LCMS (M+H+): 368. Step 3: preparation of methyl (3S)-4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-2-yl]ethyl]morpholine-3-carboxylate (compound 54d-1) A mixture of compound 54d-1a (2.5 g, 6.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (3.1 g, 12.2 mmol), potassium acetate (1.8 g, 18.3 mmol) and PdCl2(DPPF)DCM (0.49 g, 0.6 mmol) in dioxane/DMSO (10:1) (50 mL) was stirred at 90 oC for 2 hours. Then the reaction was concentrated, the residue was dissolved in 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 54d-1 (2 g) as light brown oil. LCMS (M+H+): 416. Step 4: preparation of 9H-fluoren-9-ylmethyl N-[(2S)-2-(tert-butoxycarbonylamino)- 3-(4-methylpiperazin-1-yl)-3-oxo-propyl]carbamate (compound 54a) A mixture of 1-methylpiperazine (564 mg, 5.63 mmol, Eq: 1.2), HATU (2.67 g, 7.03 mmol), (2S)-2-(tert-butoxycarbonylamino)-3-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (2 g, 4.69 mmol) and DIPEA (1.82 g, 14.1 mmol) in DMF (30 mL) was stirred at rt for 30 mins. Then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 54a (2.5 g) as light yellow oil. LCMS (M+H+): 509. Step 5: preparation of 9H-fluoren-9-ylmethyl N-[(2S)-2-amino-3-(4-methylpiperazin- 1-yl)-3-oxo-propyl]carbamate (compound 54b) To a mixture of compound 54a (2.5 g, 4.42 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (10 mL), the reaction was stirred at rt for 16 hours and then concentrated to give compound 54b (1.8 g) as light yellow solid. LCMS (M+H+): 409. Step 6: preparation of tert-butyl (2S,4S)-4-(3-bromophenoxy)-2-[[(1S)-1-[(9H-fluoren- 9-ylmethoxycarbonylamino)methyl]-2-(4-methylpiperazin-1-yl)-2-oxo- ethyl]carbamoyl]pyrrolidine-1-carboxylate (compound 54c) A mixture of compound 54b-1 (500 mg, 1.29 mmol), compound 54b (635 mg, 1.55 mmol), HATU (738 mg, 1.94 mmol) and DIPEA (837 mg, 6.47 mmol) in DMF (15 mL) was stirred at rt for 1 hour, then the reaction was diluted with EA, washed with water and brine, the organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound 54c (600 mg) as a light yellow solid. LCMS (M+H+): 776. Step 7: preparation of tert-butyl (2S,4S)-2-[[(1S)-1-(aminomethyl)-2-(4- methylpiperazin-1-yl)-2-oxo-ethyl]carbamoyl]-4-(3-bromophenoxy)pyrrolidine-1- carboxylate (compound 54d) A mixture of compound 54c (600 mg, 772 µmol) and LiOH (1.16 mL, 2 M) in MeOH (15 mL) was stirred at rt for 16 hours. The reaction was concentrated, the residue was diluted with water (20 mL), washed with PE/EA (10:1), the aqueous layer was lyophilized to give compound 54d (400 mg) as an off-white solid. LCMS (M+H+): 554. Step 8: preparation of methyl (3S)-4-[2-[4-[3-[(3S,5S)-5-[[(1S)-1-(aminomethyl)-2-(4- methylpiperazin-1-yl)-2-oxo-ethyl]carbamoyl]-1-tert-butoxycarbonyl-pyrrolidin-3- yl]oxyphenyl]indazol-2-yl]ethyl]morpholine-3-carboxylate (compound 54e) A mixture of compound 54d (400 mg, 721 µmol), compound 54d-1 (449 mg, 1.08 mmol), PdCl2(DPPF)DCM (118 mg, 144 µmol) and K2CO3 (199 mg, 1.44 mmol) in Dioxane/ H2O (10:1) (10 mL) was stirred at 90 oC for 2 hours. Then the reaction was concentrated to give crude compound 54e (600 mg) as black oil, which was used in next step directly. LCMS (M+H+): 763. Step 9: preparation of (3S)-4-[2-[4-[3-[(3S,5S)-5-[[(1S)-1-(aminomethyl)-2-(4- methylpiperazin-1-yl)-2-oxo-ethyl]carbamoyl]-1-tert-butoxycarbonyl-pyrrolidin-3- yl]oxyphenyl]indazol-2-yl]ethyl]morpholine-3-carboxylic acid (compound 54f) A mixture of compound 54e (600 mg, 551 µmol) and LiOH (1.38 mL, 2.75 mmol) in THF/MeOH (2:1) (10 mL) was stirred at rt for 2 hours, then the pH of the reaction was adjusted to 5 with 1 M hydrochloric acid. The resulted mixture was concentrated, the residue was purified by flash column (MeCN/ 0.5% TFA in water) to give compound 54f (220 mg) as an off-white solid. LCMS (M+H+): 749. Step 10: preparation of tert-butyl (17S,21S,24S,27S)-21-(4-methylpiperazine-1- carbonyl)-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-25-carboxylate (compound 54g) To a mixture of HATU (223 mg, 588 µmol) and DIPEA (380 mg, 2.94 mmol) in DMF/MeCN (1:20) (50 mL) was added compound 54f (220 mg, 294 µmol) in MeCN (100 mL) dropwise in 2 hours, then the mixture was stirred at rt for 30 mins, the reaction was concentrated, the residue was purified by flash column (MeCN/ 0.5% TFA in water) to give compound 54g (150 mg) as an off-white solid. LCMS (M+H+): 731. Step 11: preparation of (17S,21S,24S,27S)-21-(4-methylpiperazine-1-carbonyl)-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-18,23-dione (compound 54h) A mixture of compound 54g (150 mg, 205 µmol) in DCM/TFA (1:1) (5 mL) was stirred at rt for 30 mins, then the reaction was concentrated to give compound 54h (150 mg) as light yellow oil. LCMS (M+H+): 631. Step 12: preparation of (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 (Example 54) A mixture of compound 54h (100 mg, 159 µmol), intermediate C2 (42 mg, 159 µmol) and DIPEA (102 mg, 800 µmol) in MeCN (5 mL) was stirred at rt for 16 hours, then the reaction was concentrated, the residue was purified by HPLC to give Example 54 (10) mg as white powder. LCMS (M+H+): 861.1H NMR (400 MHz, METHANOL-d4) δ = 8.69 - 8.55 (m, 1H), 8.54 - 8.43 (m, 1H), 8.36 - 8.23 (m, 1H), 7.72 - 7.56 (m, 2H), 7.52 - 7.36 (m, 3H), 7.34 - 7.15 (m, 4H), 7.15 - 7.02 (m, 1H), 5.41 - 5.28 (m, 1H), 5.26 - 5.13 (m, 1H), 4.72 - 4.62 (m, 1H), 4.61 - 4.48 (m, 1H), 4.46 - 4.33 (m, 2H), 4.22 - 4.06 (m, 1H), 3.94 - 3.80 (m, 3H), 3.77 - 3.57 (m, 2H), 3.55 - 3.49 (m, 1H), 3.30 - 3.17 (m, 8H), 3.11 - 2.96 (m, 2H), 2.94 - 2.45 (m, 8H). Example 55 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 2-bromo-N-methyl-6-nitro-aniline (compound 55a) A mixture of 1-bromo-2-fluoro-3-nitrobenzene (9 g, 40.9 mmol), methanamine in EtOH (14 mL, 82 mmol) and DIPEA (21 mL, 123 mmol) in MeCN (100 mL) was stirred at rt for 1 hour. Then the reaction was concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 55a (9 g) as an orange liquid. LCMS (M+H+): 231. Step 2: preparation of 3-bromo-N2-methyl-benzene-1,2-diamine (compound 55b) To a mixture of compound 55a (8 g, 34.6 mmol) and aluminum-nickel alloy (2.97 g, 34.6 mmol) in MeOH (100 mL) was added hydrazine (11.1 g, 173 mmol) slowly at ice-water bath, then the mixture was stirred for 15 mins. The reaction was filtered and concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 55b (6 g) as brown oil. LCMS (M+H+): 201. Step 3: preparation of 2-(7-bromo-1-methyl-benzimidazol-2-yl)ethanol (compound 55c) A mixture of compound 55b (1 g, 4.97 mmol) and 3-hydroxypropanoic acid in water (7 mL, 25 mmol) in hydrochloric acid (12 N, 7 mL) was stirred at 110 oC for 16 hours, then the reaction was cooled to rt and the pH was adjusted to 11 with 2 M NaOH. The resulted mixture was extracted with EA, the organic layer was dried and concentrated to give compound 55c (1 g) as brown solid. LCMS (M+H+): 255. Step 4~5: preparation of methyl (3S)-4-[2-(7-bromo-1-methyl-benzimidazol-2- yl)ethyl]morpholine-3-carboxylate (compound 55e) Compound 55e was prepared in analogy to the preparation of compound 39d by using compound 55c instead of compound 39b and (3S)-morpholine-3-carboxylate instead of methyl morpholine-3-carboxylate. LCMS (M+H+): 382. Step 6: preparation of methyl (3S)-4-[2-[1-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzimidazol-2-yl]ethyl]morpholine-3-carboxylate (compound 55f) A mixture of compound 55e (2 g, 5.23 mmol), potassium acetate (1.54 g, 15.7 mmol), butyldi-1-adamantylphosphine (375 mg, 1.05 mmol), bis(pinacolato)diboron (2.66 g, 10.5 mmol) and bis(triphenylphosphine)PdCl2 (367 mg, 523 µmol) in DMSO (15 mL) was stirred at 100 oC for 4 hours. Then the reaction was diluted with EA, washed with water and brine, the organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound 55f Step 7~10: preparation of (17S,25S,28S)-26-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-8-methyl-15-oxa-8,12,19,23,26,29,33,34,36- 6,9 25,28 2,7 12,17 nonazahexacyclo[28.3.1.1 .1 .0 .0 ]hexatriaconta-1(33),2,4,6,9(36),30(34),31- heptaene-18,24-dione (Example 55) Example 55 was prepared in analogy to the preparation of Example 49 by using compound 55f instead of intermediate B8 and intermediate B2 instead of compound 49c. LCMS (M+H+): 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.51 - 8.26 (m, 3H), 7.95 - 7.86 (m, 1H), 7.76 - 7.51 (m, 3H), 7.35 - 6.87 (m, 3H), 5.06 - 5.00 (m, 1H), 4.47 - 4.26 (m, 1H), 4.05 - 3.90 (m, 2H), 3.81 - 3.62 (m, 4H), 3.60 - 3.33 (m, 8H), 3.25 - 3.02 (m, 5H), 2.95 - 2.78 (m, 2H), 2.52 - 2.39 (m, 1H), 1.83 - 1.63 (m, 2H). Example 56 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of (4aS,7aR)-4-[2-(4-bromoindazol-2-yl)ethyl]-6-methyl- 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine (compound 56a) A mixture of compound 39c (1 g, 3.13 mmol), tert-butyl (4aS,7aR)-hexahydropyrrolo[3,4- b][1,4]oxazine-6(2H)-carboxylate (1.07 g, 4.7 mmol) and DIPEA (1.21 g, 9.4 mmol) in DMF (20 mL) was stirred at 90 oC 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 silica gel column chromatography to give compound 56a (1 g) as light brown oil, LCMS (M+H+): 451. Step 2: preparation of (4aS,7aR)-4-[2-(4-bromoindazol-2-yl)ethyl]-3,4a,5,6,7,7a- hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine (compound 56b) A mixture of compound 56a (1 g, 2.22 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 16 hours, then the reaction was concentrated to give compound 56b (0.9 g) as light yellow solid. LCMS (M+H+): 351. Step 3: preparation of tert-butyl N-[(1S)-2-[(4aS,7aR)-4-[2-(4-bromoindazol-2- yl)ethyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]-1-[(3-methylimidazol-4- yl)methyl]-2-oxo-ethyl]carbamate (compound 56c) A mixture of compound 56b (800 mg, 2.28 mmol), (2S)-2-(tert-butoxycarbonylamino)-3- (3-methylimidazol-4-yl)propanoic acid (736 mg, 2.73 mmol), HATU (866 mg, 2.28 mmol) and DIPEA (294 mg, 2.28 mmol) in DMF (10 mL) was stirred at rt for 1 hour, then the reaction was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to compound 56c (1 g) as light yellow oil. LCMS (M+H+): 602. Step 4: preparation of (2S)-1-[(4aS,7aR)-4-[2-(4-bromoindazol-2-yl)ethyl]- 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]-2-amino-3-(3-methylimidazol-4- yl)propan-1-one (compound 56d) A mixture of compound 56c (1 g, 1.33 mmol) in DCM/TFA(1:1) (10 mL) was stirred at rt for 30 mins. Then the reaction was concentrated, the residue was purified by reversed flash column (MeCN/TFA in water) to give compound 56d (600 mg) as an off-white solid. LCMS (M+H+): 502. Step 5~9: preparation of (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- 6,9 16,19 24,27 2,7 12,17 dioxa-9,12,19,22,25,36-hexazaheptacyclo[27.3.1.1 .1 .1 .0 .0 ]hexatriaconta- 1(32),2,4,6(36),7,29(33),30-heptaene-20,23-dione (Example 56) Example 56 was prepared in analogy to the preparation of Example 54 by using compound 56d instead of compound 54d and intermediate B8 instead of compound 54d-1. LCMS (M+H+): 841.1H NMR (400 MHz, METHANOL-d4) δ = 8.64 - 8.42 (m, 2H), 8.35 - 8.22 (m, 1H), 7.90 - 7.75 (m, 1H), 7.70 - 7.46 (m, 3H), 7.41 - 7.33 (m, 1H), 7.31 - 7.23 (m, 2H), 7.23 - 7.15 (m, 3H), 7.14 - 6.84 (m, 2H), 5.39 - 5.10 (m, 2H), 4.75 - 4.48 (m, 4H), 4.41 - 4.25 (m, 1H), 3.82 - 3.63 (m, 4H), 3.62 - 3.45 (m, 4H), 3.41 - 3.35 (m, 1H), 3.23 - 3.01 (m, 4H), 2.99 - 2.85 (m, 2H), 2.84 - 2.63 (m, 2H), 2.60 - 2.40 (m, 2H). Example 57 and Example 58 (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 and (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- 6,9 24,27 2,7 12,17 9,12,19,22,25,28,32,33,35-nonazahexacyclo[27.3.1.1 .1 .0 .0 ]pentatriaconta- 1(32),2,4,6(35),7,29(33),30-heptaene-18,23-dione Examples 57 and 58 were prepared in analogy to the preparation of Example 49 by using compound 54d-1 instead of intermediate B8, intermediate B2 instead of compound 49c and compound 57b instead of propane-1,3-diamine. Example 57, 25 mg, faster eluted, white powder. LCMS (M+H+): NMR (400 MHz, METHANOL-d4) δ = 9.50 - 9.41 (m, 1H), 8.82 - 8.72 (m, 1H), 8.58 - 8.49 (m, 1H), 8.48 - 8.40 (m, 1H), 8.40 - 8.32 (m, 1H), 8.31 - 8.22 (m, 1H), 8.03 - 8.00 (m, 2H), 7.60 - 7.53 (m, 2H), 7.41 - 7.35 (m, 1H), 7.28 - 7.21 (m, 1H), 7.18 - 7.11 (m, 1H), 7.11 - 7.07 (m, 1H), 7.07 - 7.01 (m, 1H), 5.11 - 5.02 (m, 2H), 5.01 - 4.92 (m, 2H), 4.67 - 4.58 (m, 1H), 4.45 - 4.39 (m, 1H), 4.38 - 4.33 (m, 1H), 4.32 - 4.25 (m, 1H), 4.24 - 4.17 (m, 1H), 4.13 - 4.05 (m, 1H), 4.00 - 3.86 (m, 4H), 3.75 - 3.64 (m, 3H), 3.02 - 2.93 (m, 3H), 2.87 - 2.76 (m, 3H), 2.75 - 2.65 (m, 2H), 2.50 - 2.41 (m, 1H), 2.23 - 2.13 (m, 1H), 1.89 - 1.77 (m, 1H). Example 58, 6 mg, slower eluted, white powder. LCMS (M+H+): 925. 57a A mixture of (S)-2,3-bis((tert-butoxycarbonyl)amino)propanoic acid (600 mg, 1.97 mmol), 1-(pyridin-2-yl)piperazine (483 mg, 2.96 mmol), HATU (750 mg, 1.97 mmol) and DIPEA (255 mg, 1.97 mmol) in DMF (20 mL) was stirred at rt for 1 hour. Then the reaction was diluted with EA, washed with water and brine, the organic layer was concentrated and the residue was purified by silica gel column chromatography to give 600 mg colorless oil. The colorless oil was dissolved in 4 M HCl in dioxane (10 mL) and stirred at rt for 16 hours, then the reaction was filtered to give compound 57b (400 mg) as an off white solid. LCMS (M+H+): 250. Example 59 (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 Example 59 was prepared in analogy to the preparation of Example 49 by using compound 55e instead of compound 49c. LCMS (M+H+): 763.1H NMR (400 MHz, METHANOL-d4) δ = 8.57 - 8.33 (m, 1H), 8.31 - 7.93 (m, 1H), 7.67 - 7.55 (m, 2H), 7.55 - 7.46 (m, 1H), 7.34 - 7.04 (m, 6H), 6.87 - 6.72 (m, 1H), 5.57 - 5.22 (m, 1H), 5.14 - 4.94 (m, 1H), 4.64 - 4.16 (m, 2H), 3.95 - 3.73 (m, 2H), 3.72 - 3.57 (m, 1H), 3.56 - 3.40 (m, 1H), 3.34 - 3.32 (m, 2H), 3.29 - 3.04 (m, 6H), 3.04 - 2.36 (m, 8H), 1.68 - 1.26 (m, 2H). Example 60 (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 Example 60 was prepared in analogy to the preparation of Example 49 by using compound 54d-1 instead of intermediate B8 and intermediate B2 instead of compound 49c. LCMS (M+H+): 750.1H NMR (400 MHz, METHANOL-d4) δ = 9.39 - 9.21 (m, 1H), 8.58 - 8.46 (m, 1H), 8.41 - 8.24 (m, 2H), 8.08 - 7.92 (m, 2H), 7.70 - 7.47 (m, 2H), 7.34 - 7.23 (m, 1H), 7.22 - 7.12 (m, 1H), 7.09 - 6.96 (m, 1H), 5.09 - 4.97 (m, 2H), 4.74 - 4.57 (m, 2H), 4.55 - 4.37 (m, 2H), 3.69 - 3.36 (m, 6H), 3.03 - 2.81 (m, 5H), 2.77 - 2.56 (m, 1H), 2.54 - 2.41 (m, 1H), 2.32 - 2.16 (m, 1H), 1.94 - 1.62 (m, 3H). Example 61 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of tert-butyl N-[4-(1,3-dioxoisoindolin-2-yl)butyl]-N-methyl- carbamate (compound 61b) To a solution of compound 61a (2.0 g, 9.84 mmol), phthalimide (1.45 g, 9.84 mmol) and PPh3 (3.1 g, 11.81 mmol) in toluene (50 mL) was added DEAD (2.06 g, 11.81 mmol) under Ar at 0 °C. The reaction was stirred at 60 °C for 16 h under Ar. The reaction solution was concentrated and the residue was purified by prep-HPLC to give compound 61b (2.75 g) as colorless oil. LCMS (M-C5H8O2+H+): 233. Step 2: preparation of 2-[4-(methylamino)butyl]isoindoline-1,3-dione (compound 61c) To a solution of compound 61b (2.75 g, 8.27 mmol) in DCM (50 mL) was added TFA (10.0 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h and then concentrated. The residue was dissolved in 30 mL of NaHCO3 solution, and then extracted with DCM (30 mL×4). The organic layer was dried and concentrated to give compound 61c (1.9 g) as a yellow solid. LCMS (M+H+): 233. Step 3: preparation of 4-bromo-N-[4-(1,3-dioxoisoindolin-2-yl)butyl]-N-methyl-1H- indole-2-carboxamide (compound 61e) To a solution of compound 61d (1.5 g, 6.25 mmol) in DMF (20 mL) was added HATU (2.85 g, 7.5 mmol), DIEA (3.27 mL, 18.75 mmol) and compound 61c (1.45 g, 6.25 mmol) at 0 °C. The reaction was stirred at 10 °C for 2 h. The reaction was diluted with 60 mL of ethyl acetate. The organic layer was washed with 50 mL of brine, dried and concentrated, then the residue was purified by Prep-HPLC to give compound 61e (1.52 g) as a yellow solid. LCMS (M+H+): 456. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[2-[4-(1,3-dioxoisoindolin- 2-yl)butyl-methyl-carbamoyl]-1H-indol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 61f) To a solution of compound 61e (1.4 g, 3.08 mmol) in 1,4-dioxane (56 mL) was added intermediate B8 (1.65 g, 3.7 mmol), sodium carbonate (980 mg, 9.24 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (338 mg, 0.46 mmol) and water (6 mL). The reaction was stirred at 100 °C for 2 h and then concentrated to give crude product, which was purified by reversed flash column to give compound 61f (640.0 mg) as a yellow solid. LCMS (M+H+): 695. Step 5: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[2-[4-[(2- carboxybenzoyl)amino]butyl-methyl-carbamoyl]-1H-indol-4-yl]phenoxy]pyrrolidine-2- carboxylic acid (compound 61g) To a solution of compound 61f (640.0 mg, 0.92 mmol) in THF (10 mL) was added sodium hydroxide/H2O (2.0 mL, 20.0 mmol). The reaction was stirred at 15 °C for 3 h. The mixture was acidized with 0.5 M HCl solution to pH=3, and then extracted with DCM (20 mL×5). The organic layer was concentrated to give compound 61g (640.0 mg) as a yellow solid. LCMS (M+H+): 699. Step 6: preparation of (2S,4S)-4-[3-[2-[4-aminobutyl(methyl)carbamoyl]-1H-indol-4- yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 61h) To a solution of compound 61g (640.0 mg, 0.92 mmol) in ethanol (20 mL) was added hydrazine hydrate (10.0 g, 199.76 mmol). The reaction was stirred at 15 °C for 16 h under N2. The reaction solvent was concentrated in vacuo to give a residue, which was purified by prep- HPLC to afford compound 61h (350.0 mg) as an off-white solid. LCMS (M+H+): 551. Step 7: preparation of tert-butyl (18S,21S)-11-methyl-10,17-dioxo-22-oxa-11,16,19,29- 6,9 18,21 2,7 tetrazapentacyclo[21.3.1.1 .1 .0 ]nonacosa-1(26),2(7),3,5,8,23(27),24-heptaene-19- carboxylate (compound 61i) To a solution of HATU (450.0 mg, 1.18 mmol) and DIEA (0.43 mL, 2.45 mmol) in DMF (90 mL) was added a solution of compound 61h (450.0 mg, 0.82 mmol) in THF (90 mL) by drops at -10 °C over 0.5 h. The reaction was stirred at -10 °C for 0.5 h. The reaction solvent was concentrated and the residue was purified by prep-HPLC to give compound 61i (450.0 mg) as a yellow solid. LCMS (M+H+): 533. Step 8: preparation of (18S,21S)-11-methyl-22-oxa-11,16,19,29- 6,9 18,21 2,7 tetrazapentacyclo[21.3.1.1 .1 .0 ]nonacosa-1(26),2(7),3,5,8,23(27),24-heptaene-10,17- dione (compound 61j) To a solution of compound 61i (40.0 mg, 0.08 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (0.3 mL, 3.89 mmol). The reaction was stirred at 15 °C for 2 h. The reaction mixture was concentrated to give compound 61j (32.0 mg) as a yellow solid, which was used in the next step directly. LCMS (M+H+): 433. Step 9: preparation of(18S,21S)-19-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]- 6,9 18,21 2,7 11-methyl-22-oxa-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 (Example 61) To a solution of Intermediate C3 (20 mg, 0.07 mmol) in NMP (1 mL) was added compound 61j (32.0 mg, 0.07 mmol), potassium fluoride (17 mg, 0.3 mmol) and DIEA (0.04 mL, 0.22 mmol). The reaction mixture was stirred at 120 °C for 12 h, and then the reaction was diluted with 10 mL of DCM. The organic layer was concentrated and the residue was purified by prep- HPLC to give Example 61 (13.7 mg) as a yellow solid. LCMS (M+H+): 662.1H NMR (400 MHz, METHANOL-d4) δ (ppm) = 8.57 - 8.21 (m, 1H), 7.82 - 7.66 (m, 1H), 7.56 - 7.40 (m, 3H), 7.33 - 7.22 (m, 5H), 7.18 - 7.08 (m, 2H), 7.03 (d, J = 5.7 Hz, 1H), 6.94 (s, 1H), 5.34 (t, J = 4.3 Hz, 1H), 5.27 - 5.17 (m, 1H), 4.51 - 4.33 (m, 1H), 3.81 - 3.68 (m, 2H), 3.42 - 3.34 (m, 1H), 3.24 - 3.08 (m, 4H), 2.96 (br d, J = 14.3 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.02 (s, 1H), 1.95 - 1.83 (m, 1H), 1.81 - 1.71 (m, 3H). Example 62 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 2-[(E)-4-bromobut-2-enyl]isoindoline-1,3-dione (compound 62b) To a solution of compound 62a (10.0 g, 46.75 mmol) in anhydrous DMF (100 mL) was added potassium isoindolin-2-ide-1,3-dione (5.0 g, 26.99 mmol) at 0 °C. The reaction was stirred for 12 h at 20 °C. The reaction was quenched with water (100 mL), and extracted with EtOAc (100 mL×3). The organic layer was dried and concentrated to give the crude product, which was purified by flash column chromatography to give compound 62b (4.5 g) as a white solid. LCMS (M+H+): 280. Step 2: preparation of 2-[(E)-4-[(4-bromopyrazolo[1,5-a]pyridin-2-yl)amino]but-2- enyl]isoindoline-1,3-dione (compound 62c) To a solution of 4-bromopyrazolo[1,5-a]pyridin-2-amine (880.0 mg, 4.15 mmol) in anhydrous DMF (15 mL) was added sodium hydride(60% in oil, 240.0 mg, 6.0 mmol) at 0 °C, and stirred for 1 h. To a solution of compound 62b (1100.0 mg, 3.93 mmol) was added the above reaction mixture at 20 °C. The reaction mixture was stirred for another 11 h, and then diluted with EtOAc (100 mL), washed with water and brine. The organic layer was dried and concentrated to give compound 62c (1.6 g) as a yellow solid, which was used in next step directly. LCMS (M+H+): 411. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[2-[4-(1,3-dioxoisoindolin- 2-yl)butylamino]pyrazolo[1,5-a]pyridin-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 62d) To a solution of intermediate B8 (1.5 g, 3.35 mmol), compound 62c (1.5 g, 3.65 mmol) and K3PO4 (1.5 g, 7.07 mmol) in anhydrous 1,4-dioxane (15 mL) was added Pd(dppf)Cl2 (500.0 mg, 0.68 mmol, 0.2 eq) in glovebox under Ar. The reaction solution was stirred for 4 h at 100 °C. The reaction mixture was diluted with EtOAc (100 mL), and then washed with water and brine, the organic layer was dried and concentrated to give crude product, which was purified by prep- HPLC to give compound 62d (1.1 g) as a yellow solid. LCMS (M+H+): 652. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[2-[4-(1,3-dioxoisoindolin- 2-yl)butylamino]pyrazolo[1,5-a]pyridin-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 62e) A solution of compound 62d (500.0 mg, 0.77 mmol) and Pd/C (100.0 mg, 0.77 mmol) in EtOAc (10 mL) was stirred for 4 h at 20 °C under H2. The reaction mixture was filtered and concentrated to give crude compound 62e (500.0 mg) as a yellow solid, which was used in next step directly. LCMS (M+H+): 654. Step 5: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[2-[4-[(2- carboxybenzoyl)amino]butylamino]pyrazolo[1,5-a]pyridin-4-yl]phenoxy]pyrrolidine-2- carboxylic acid (compound 62f) A solution of compound 62e (500.0 mg, 0.76 mmol) and LiOH (100.0 mg, 2.38 mmol) in methanol (5 mL) and water (1 mL) was stirred for 12 h at 20 °C. The pH of the mixture was adjusted to 5 with aq.HCl (1 M), and then concentrated to give crude compound 62f (500.0 mg) as yellow oil, which was used in next step directly. LCMS (M+H+): 658. Step 6~9: preparation of (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8- 6,9 17,20 2,7 yl]-21-oxa-6,10,15,18,28-pentazapentacyclo[20.3.1.1 .1 .0 ]octacosa- 1(25),2,4,7,9(28),22(26),23-heptaen-16-one (Example 62) The title compound was prepared in analogy to Example 61 by using compound 62f instead of compound 61h. LCMS (M+H+): 621.1H NMR (400 MHz, DMSO-d4) δ (ppm) = 8.27 (d, J = 6.8 Hz, 1H), 8.24 - 8.13 (m, 1H), 7.81 - 7.71 (m, 1H), 7.61 - 7.55 (m, 2H), 7.51 - 7.46 (m, 2H), 7.48 - 7.41 (m, 1H), 7.40 - 7.31 (m, 2H), 7.24 - 7.13 (m, 3H), 6.64 (t, J = 6.9 Hz, 1H), 5.85 (s, 1H), 4.37 - 4.05 (m, 2H), 3.12 - 3.08 (m, 1H), 3.02 - 2.96 (m, 1H), 2.35 - 2.33 (m, 1H), 2.33 - 2.29 (m, 1H), 2.04 - 1.92 (m, 1H), 1.69 - 1.58 (m, 2H), 1.54 - 1.43 (m, 2H), 1.26 - 1.21 (m, 2H). Example 63 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 2-[3-(4-bromoindazol-2-yl)propyl]isoindoline-1,3-dione (compound 63c) A solution of compound 63b (16.2 g, 60.42 mmol), compound 63a (11.91 g, 60.42 mmol) and Cs2CO3 (39.4 g, 120.85 mmol) in acetonitrile (250 mL) was stirred at 50 °C for 16 h. The reaction mixture was filtered and concentrated to give the compound 63c (18.0 g) as a grey solid. LCMS (M+H+): 386. Step 2: preparation of 3-(4-bromoindazol-2-yl)propan-1-amine (compound 63d) To a solution of compound 63c (18.0 g, 46.85 mmol) in ethanol (250 mL) was added methylamine in ethanol (38.85 g, 374.78 mmol) dropwise at 20 °C. The mixture was stirred at 60 °C for 1 hour, and then the reaction mixture was concentrated to give compound 63d (25.5 g) as a white solid. LCMS (M+H+): 256. Step 3: preparation of tert-butyl N-[3-(4-bromoindazol-1-yl)propyl]carbamate (compound 63e) A solution of compound 63d (25.0 g, 98.4 mmol) and tert-butyl (2-methylpropan-2- yl)oxycarbonyl carbonate (43 g, 196.75 mmol) in methanol (50 mL) was stirred at 20 °C for 1 h. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 63e (2.0 g) as a white solid. LCMS (M+H+): 356. Step 4: preparation of tert-butyl N-[3-(4-bromoindazol-2-yl)propyl]-N-methyl- carbamate (compound 63f) To a solution of compound 63e (1.3 g, 3.67 mmol) in DMF (18 mL) was added NaH (264 mg, 6.61 mmol) at -10 °C under N2, then CH3I (0.5 mL, 8.07 mmol) was added. The reaction was stirred at -10 °C for 5 h, and then the reaction was quenched with water, extracted with EtOAc. The organic layer was dried and concentrated to give compound 63f (1.3 g) as colorless oil. LCMS (M+H+): 370. Step 5: preparation of tert-butyl N-methyl-N-[3-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-2-yl]propyl]carbamate (compound 63g) To a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (278 mg, 0.38 mmol) and potassium acetate (0.48 mL, 7.6 mmol) in 1,4-Dioxane (20 mL) was added compound 63f (1.4 g, 3.8 mmol) and bis(pinacolato)diboron (0.97 g, 3.8 mmol). The reaction was stirred at 90 °C for 2 h under the N2 and then concentrated. The residue was purified by silica gel column chromatography to give compound 63g (1.1 g) as yellow oil. LCMS (M+H+): 416. Step 6: preparation of N-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-2-yl]propan-1-amine (compound 63h) A solution of compound 63g (1000.0 mg, 2.41 mmol) in DCM (11 mL) was added HCl/dioxane (5.0 mL, 20.0 mmol). The reaction was stirred at 20 °C for 2 h and then concentrated to give compound 63h (900.0 mg) as a white solid. LCMS (M+ H+): 316. Step 7: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[[6-[2-[3-(methylamino) propyl] indazol-4-yl]-2-pyridyl] amino] pyrrolidine-1, 2-dicarboxylate (compound 63i) To a solution of intermediate B4 (615 mg, 1.54 mmol) in 1, 4-dioxane (1 mL) and water (0.1 mL) was added K2CO3 (470 mg, 3.41 mmol), Pd(dppf)Cl2 (249 mg, 0.34 mmol) and compound 63h (600.0 mg, 1.71 mmol). The reaction was stirred at 100 °C for 2 h under N2, then the mixture was filtered, the filtrate was concentrated to give compound 63i (1000 mg), which was used for next step directly. LCMS (M+H+): 510. Step 8: preparation of (2S, 4S)-1-tert-butoxycarbonyl-4-[[6-[2-[3-(methylamino) propyl] indazol-4-yl]-2-pyridyl] amino] pyrrolidine-2-carboxylic acid (compound 63j) To a solution of compound 63i (1000.0 mg, 1.97 mmol) in methanol (20 mL) was added a solution of Lithium hydroxide monohydrate (274 mg, 6.59 mmol) in water (10 mL) at 25 °C. The reaction was stirred at 25 °C for 2 h, and then pH was adjusted to 4 with 1 M HCl. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 63j (30 mg). LCMS (M+H+):495. Step 9: preparation of tert-butyl (15S,18S)-13-methyl-14-oxo-9,13,16,19,24,26 - 6,9 15,18 2,7 hexazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22-heptaene-16- carboxylate (compound 63k) To a solution of HATU (23 mg, 0.06 mmol) and DIPEA (15 mg, 0.12 mmol) in DMF (6 mL) was added a solution of compound 63j (23.0 mg, 0.05 mmol) in DMF (6 mL) dropwise at 0 °C in 0.5 h. The resulted mixture was stirred at 0 °C for 0.5 h, and then the reaction mixture was purified by prep-HPLC to give compound 63k (10.0 mg) as a white solid. LCMS (M+H+):477. Step 10: preparation of (15S,18S)-13-methyl-9,13,16,19,24,26-hexazapentacyclo 6,9 15,18 2,7 [18.3.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),7,20,22-heptaen-14-one (compound 63l) To a solution of compound 63k (10.0 mg, 0.02 mmol) in DCM (1 mL) was added HCl/dioxane (0.5 mL, 2.0 mmol). The reaction was stirred at 20°C for 2 h, and then the reaction mixture was concentrated to give compound 63l (10 mg). LCMS (M+H+):377. Step 11: preparation of (15S,18S)-16-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 6,9 15,18 2,7 4-yl]-13-methyl-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 (Example 63) A solution of Intermediate C2 (7 mg, 0.03 mmol), N, N-diisopropylethylamine (21 µL, 0.12 mmol) and compound 63l (10.0 mg, 0.03 mmol) in ACN (1 mL) was stirred at 85 °C for 2 h. Then the reaction mixture was purified by prep-HPLC to give Example 63 (4.0 mg) as a white solid. LCMS (M+H+):607.1HNMR(400MHz, METHANOL-d4) δ = 8.69 (s, 1H), 8.43 (s, 1H), 8.26 - 8.16 (m, 1H), 7.82 - 7.55 (m, 3H), 7.44-7.39 (m, 1H), 7.38 - 7.22 (m, 2H), 7.20 - 7.16 (m, 1H), 7.13 - 6.74 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.53 - 5.29 (m, 1H), 5.19 - 5.07 (m, 1H), 4.72 - 4.39 (m, 3H), 4.39 - 4.13 (m, 1H), 4.10 - 3.99 (m, 1H), 3.98 - 3.83 (m, 1H), 3.05 (s, 2H), 2.99 - 2.76 (m, 1H), 2.72 - 2.31 (m, 2H), 1.99 – 1.90 (m, 1H), 1.36 – 1,31 (m, 1H). Example 64 (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 The title compound was prepared in analogy to Example 63 by using intermediate B11 instead of intermediate B4. LCMS (M+H+): 607.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.39 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.75 - 7.70 (m, 2H), 7.60 - 7.54 (m, 1H), 7.52 - 7.41 (m, 2H), 7.35 (br d, J = 7.1 Hz, 1H), 7.24 (s, 1H), 7.18 (br d, J = 7.5 Hz, 1H), 7.06 (br t, J = 8.2 Hz, 2H), 5.41 (br d, J = 9.9 Hz, 1H), 5.34 (br t, J = 4.8 Hz, 1H), 4.82 - 4.73 (m, 2H), 4.43 - 4.34 (m, 2H), 4.30 - 4.21 (m, 1H), 3.46 (s, 3H), 3.02 - 2.91 (m, 1H), 2.62 (br d, J = 15.0 Hz, 1H), 2.53 - 2.43 (m, 3H). Example 65 (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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-methyl-N-prop-2-ynyl-carbamate (compound 65a) To a solution of N-methylprop-2-yn-1-amine (5.0 g) and N- (benzyloxycarbonyloxy)succinimide (19.8 g) in THF (50 mL) was added saturated NaHCO3 aqueous solution (50 mL). The mixture was stirred at 25 °C for 2 h, and then poured into water (200 mL) and extracted with EtOAc (200 mL twice). The combined organic layer were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep- HPLC to give compound 65a (12.1 g) as a colorless oil. LCMS (M+H+): 204. Step 2: preparation of benzyl N-methyl-N-[(E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)allyl]carbamate (compound 65b) To a mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g) and compound 65a (10.0 g) was added TEA (0.5 g) and zirconocene dichloride (1.4 g). The resulting mixture was stirred at 65 °C for 18 h, and then purified by prep-HPLC to give compound 65b (10.0 g) as yellow oil. LCMS (M+H+): 293. Step 3: preparation of 4-chloro-3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridine (compound 65c) To a mixture of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (3.0 g) in DMF (20 mL) was added NIS (4.1 g). The mixture was stirred at 20 °C for 2 h, and then poured into ice-water (30 mL). The resulting precipitate was filtered. The collected solid was washed with water, and dried to give compound 65c (5.0 g) as a pink solid. LCMS (M+H+): 293. Step 4: preparation of tert-butyl 4-chloro-3-iodo-2-methyl-pyrrolo[2,3-b]pyridine-1- carboxylate (compound 65d) To a mixture of compound 65c (4.0 g) and DMAP (1.6 g) in DCM (30 mL) was added di-t- butyldicarbonate (3.0 g). The mixture was stirred at 20 °C for 2 h under N2, and then poured into brine (20 mL) and extracted with EtOAc (20 mL twice). The combined organic layer were washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography to give compound 65d (4.0 g) as colorless oil. LCMS (M+H+): 393. Step 5: preparation of tert-butyl 3-[(E)-3-[benzyloxycarbonyl(methyl)amino]prop-1- enyl]-4-chloro-2-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate (compound 65e) To a mixture of compound 65d (3.0 g) and compound 65b (3.5 g) in 1,4-dioxane (20 mL) and water (5 mL) was added Pd(PPh3)4 (1.0 g) and Na2CO3 (2.9 g). The mixture was stirred at 60 °C for 2 h under N2, and then poured into water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried and concentrated. The residue was purified by pre-TLC to give compound 65e (2.0 g) as colorless oil. LCMS (M+H+): 470. Step 6: preparation of [3-[3-[benzyloxycarbonyl(methyl)amino]prop-1-enyl]-1-tert- butoxycarbonyl-2-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (compound 65f) To a mixture of compound 65e (2.0 g) and Pin2B2 (1.3 g) in 1,4-dioxane (20 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (0.35 g) and potassium acetate (1.3 g). The mixture was stirred at 110 °C for 2 h under N2, and then poured into water and extracted with EtOAc (100 mL twice). The combined organic layer were washed with brine (50 mL), dried and concentrated. The residue was purified by flash column chromatography to give compound 65f (0.5 g) as colorless oil. LCMS (M+H+): 480. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3- [benzyloxycarbonyl(methyl)amino]prop-1-enyl]-1-tert-butoxycarbonyl-2-methyl- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 65g) To a mixture of compound 65f (450 mg) and intermediate B5 (445 mg) in 1,4-dioxane (10 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride·toluene (80 mg) and Na2CO3 (450 mg). The mixture was stirred at 60 °C for 2 h under N2, and then poured into water (50 mL) and extracted with EtOAc (50 mL twice). The combined organic layer were washed with brine, dried and concentrated. The residue was purified by flash column chromatography to give compound 65g (300 mg) as colorless oil. LCMS (M+H+): 755. Step 8: preparation of (2S,4S)-4-[[6-[3-[3-[benzyloxycarbonyl(methyl)amino]prop-1- enyl]-2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]amino]-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 65h) To a mixture of compound 65g (300 mg) in THF (5 mL) and water (2 mL) was added LiOH•H2O (83 mg). The mixture was stirred at 20 °C for 2 h, and then pH was adjusted to 4 with HCl aq. solution (1M) and extracted with EtOAc (20 mL twice). The combined organic layer were washed with brine (20 mL), dried and concentrated to give compound 65h (200 mg) as yellow oil. LCMS (M+H+): 641. Step 9: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[3- (methylamino)propyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 65i) To a mixture of compound 65h (200 mg) in THF (5 mL) and IPA (5 mL) was added Pd/C (200 mg). The mixture was stirred at 50 °C for 2 h under H2, and then filtered. The filtrate was concentrated to give compound 65i (100 mg) as yellow oil. LCMS (M+H+): 509. Step 10: preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-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-heptaene-10- carboxylate (compound 65j) To a mixture of HATU (37 mg) and DIEA (63.4 mg) in DMF (10 mL) was added a solution of compound 65i (50 mg) in DMF (10 mL) at 0 °C dropwise. The mixture was stirred at 0 °C for 1 h, and then concentrated. The residue was purified by prep-HPLC to give compound 65j (30 mg) as a yellow solid. LCMS (M+H+): 491. Step 11: preparation of (8S,11S)-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 (compound 65k) To a mixture of compound 65j (15 mg) in DCM (3 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h, and then concentrated to give crude compound 65k (15 mg) as a yellow oil. LCMS (M+H+): 391. Step 12: preparation of (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 A mixture of intermediate C2 (10.0 mg), compound 65k (15 mg) and DIEA (24.2 mg) in ACN (1 mL) was stirred at 80 °C for 1 h. The mixture was filtered and the collected solid was collected and dried to give example 65 (8 mg) as a pink solid. LCMS (M+H+): 621.1H NMR (400 MHz, DMSO-d6) δ = 11.38 - 11.46 (m, 1 H) 7.83 - 8.66 (m, 3 H) 7.74 (br s, 2 H) 7.53 - 7.64 (m, 1 H) 7.26 - 7.40 (m, 1 H) 6.66 - 6.92 (m, 3 H) 5.22 - 5.61 (m, 2 H) 4.27 - 4.81 (m, 2 H) 4.07 (br d, J=11.49 Hz, 1 H) 3.88 - 3.98 (m, 1 H) 2.96 - 3.15 (m, 4 H) 2.66 - 2.74 (m, 2 H) 2.31 (br s, 4 H) 2.07 - 2.20 (m, 1 H) 1.02 - 1.12 (m, 1 H). Example 66 (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 The title compound was prepared according to the following scheme: To the solution of example 1 (60 mg, 0.1 mmol) in DMF (3 mL) was added NaH (8 mg, 0.2 mmol), and the mixture was stirred at 0 °C for 2 h. Then 4-(2-bromoethyl)morpholine (39 mg, 0.2 mmol) was added, and the mixture was stirred at 20 °C for 3 h. The mixture was purified by prep-HPLC to give example 66 (28.2 mg) as a white solid. LCMS (M+H)+: 710.1H NMR (400 MHz, METHANOL-d4) δ = 8.79 - 8.37 (m, 1 H), 7.80 - 7.55 (m, 3 H), 7.51- 6.96 (m, 8 H), 5.46 - 5.09 (m, 2 H), 4.76 - 4.26 (m, 2 H), 4.11 - 3.96 (m, 1 H), 3.79 - 3.59 (m, 8 H), 3.51 - 3.36 (m, 1 H), 3.16 - 2.27 (m, 7 H), 2.25 - 1.62 (m, 5 H). Example 67 (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 The title compound was prepared according to the following scheme: Step 1: preparation of methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate (compound 67a) A mixture of intermediate B11 (1.7 g) and trifluoroacetic acid (3 mL) in DCM (17.0 mL) was stirred at 20 °C for 2 h under N2. The mixture was concentrated to give compound 67a (1.1 g) as a white solid. LCMS (M+H+): 300. Step 2: preparation of methyl (2S,4S)-4-(3-bromophenoxy)-1-[2-(2,4-difluorophenyl)- 3-methyl-imidazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 67b) To a solution of compound 67a (600 mg, 2mmol) in DMF (36.0 mL) was added HATU (760 mg, 2 mmol), intermediate C5 (571 mg, 2 mmol) and N,N-diisopropylethylamine (0.6 mL, 3 mmol). The mixture was stirred at 0 °C for 2 h, and then poured into water (300 mL), and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 67b (850 mg) as colorless oil. LCMS (M+H+): 520. Step 3: preparation of methyl (2S,4S)-1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carbonyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-2- carboxylate (compound 67c) A solution of bis(pinacolato)diboron (781 mg), compound 67b (800 mg), Pd-Ad2nBuP Biphenyl Precat (G1) (205 mg) and potassium acetate (453 mg) in 1,4-dioxane (5 mL) was stirred at 100 °C for 2 h under N2. The reaction mixture was poured into water (300 mL) and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 67c (650 mg) as a white solid. LCMS (M+H+): 568. Step 4: preparation of 2-(4-azidobutyl)isoindoline-1,3-dione (compound 67e) To a solution of 2-(4-bromobutyl)isoindoline-1,3-dione (1.0 g) in DMF (20 mL) was added sodium azide (276 mg). The mixture was stirred at 60 °C for 12 h, and then poured into saturated Na2CO3 solution (50 mL) and extracted with EtOAc (50 mL twice). The combined organic layer were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give crude compound 67e (0.76 g) which was used directly in the next step. LCMS (M+H+): 217. Step 5: preparation of 2-(4-aminobutyl)isoindoline-1,3-dione (compound 67f) To a solution of compound 67e (13 g) in methanol (200 mL) was added palladium hydroxide (1.5 g) and a drop of hydrochloric acid. The mixture was stirred under H2 at 20 °C for 12 h, and then poured into saturated Na2CO3 solution (200 mL) and extracted with EtOAc (100 mL twice). The combined organic layer were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC to give compound 67f (3.5 g) as a white solid. LCMS (M+H+): 219. Step 6: preparation of 6-bromo-N-(4-(1,3-dioxoisoindolin-2-yl)butyl)picolinamide (67g) To a solution of compound 67f (300 mg) in DMF (5 mL) was added N,N- diisopropylethylamine (0.44 mL) and HATU (523 mg) and 6-bromopicolinic acid (333 mg). The mixture was stirred at 0 °C for 2 h, and then poured into water (100 mL), extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was recrystallized from MeOH (20 mL) to give compound 67f (260) as a white solid. LCMS (M+H+): 402. Step 7: preparation of methyl (2S,4S)-1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carbonyl]-4-[3-[6-[4-(1,3-dioxoisoindolin-2-yl)butylcarbamoyl]-2- pyridyl]phenoxy]pyrrolidine-2-carboxylate (compound 67h) A solution of compound 67g (213 mg), potassium carbonate (110 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg), and compound 67c (150 mg) in THF (3.0 mL) and water (0.3 mL) was stirred at 65 °C for 2 h under N2. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL twice). The combined organic layer were dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC to give compound 67h (95 mg) as a white solid. LCMS (M+H+): 763. Step 8: preparation of (2S,4S)-4-[3-[6-[4-[(2-carboxybenzoyl)amino]butylcarbamoyl]- 2-pyridyl]phenoxy]-1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]pyrrolidine-2- carboxylic acid (compound 67i) A solution of compound 67h (95 mg) and lithium hydroxide (9 mg) in methanol (2.0 mL) was stirred at 20 °C for 12 h under N2. The mixture was acidified to pH = 7, and then poured into water (100 mL) and extracted with EtOAc (100 mL twice). The combined organic layer were dried over Na2SO4 and concentrated to give crude compound 67i (80 mg) as yellow oil. LCMS (M+H+): 767. Step 9: preparation of (2S,4S)-4-[3-[6-(4-aminobutylcarbamoyl)-2-pyridyl]phenoxy]- 1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 67j) To a solution of compound 67i (80 mg) in ethanol (4 mL) was added hydrazine hydrate (15 mg). The mixture was stirred at 80 °C for 12 h, and then purified by prep-HPLC to give compound 67j (52 mg) as a white solid. LCMS (M+H+): 619. Step 10: preparation of (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 (example 67) To a solution of 1-methylimidazole (101 mg) and N,N,N′,N′- tetramethylchloroformamidinium hexafluorophosphate (36 mg) in MeCN (20 mL) was added compound 67j (40 mg). The mixture was stirred at 20 °C for 2 h, and then concentrated. The residue was purified by prep-HPLC to give example 67 (5 mg) as a white solid. LCMS (M+H+): 601.1H NMR (400 MHz, DMSO-d6) δ = 9.06 (br t, J=5.5 Hz, 1H), 7.78-8.03 (m, 4H), 7.53 (d, J=8.0 Hz, 2H), 7.37 (t, J=8.0 Hz, 1H), 6.99-7.15 (m, 3H), 5.09-5.31 (m, 1H), 4.76-4.90 (m, 1H), 4.09-4.48 (m, 2H), 3.60 (s, 7H), 2.48 (br s, 2H), 1.78-1.93 (m, 2H), 1.53-1.66 (m, 2H). Example 68 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 2-[4-(4-bromo-1-oxo-isoindolin-2-yl)butyl]isoindoline-1,3-dione (compound 68a) The solution of 4-bromoisoindolin-1-one (500 mg), potassium carbonate (326 mg) and 2- (4-bromobutyl)isoindoline-1,3-dione (865 mg) in DMF (10.0 mL) was stirred at 60 °C for 2 h under N2. The mixture was poured into water (300 mL) and extracted with EtOAc (200 mL twice). The combined organic layer were washed with brine and concentrated. The residue was purified by prep-HPLC (0.1 %TFA as additive) to give compound 68a (350 mg) as a white solid. LCMS (M+H+): 413. Step 2: preparation of methyl (2S,4S)-1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carbonyl]-4-[3-[2-[4-(1,3-dioxoisoindolin-2-yl)butyl]-1-oxo-isoindolin-4- yl]phenoxy]pyrrolidine-2-carboxylate (compound 68b) A solution of compound 68a (175 mg), potassium carbonate (88 mg), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (35 mg) and compound 67c (120 mg) in dioxane (2 mL) and water (0.2 mL) was stirred at 100 °C for 2 h under N2. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL twice). The combined organic layer were dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give compound 68b (110 mg) as a white solid. LCMS (M+H+): 774. Step 3: preparation of (2S,4S)-4-[3-[2-[4-[(2-carboxybenzoyl)amino]butyl]-1-oxo- isoindolin-4-yl]phenoxy]-1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4- carbonyl]pyrrolidine-2-carboxylic acid (compound 68c) A solution of compound 68b (110 mg), lithium hydroxide (10 mg) in methanol (1 mL) and water (0.1 mL) was stirred at 20 °C for 12 h under N2. The mixture was purified by prep-HPLC to give compound 68c (85 mg) as colorless oil. LCMS (M+H+): 778. Step 4: preparation of (2S,4S)-4-[3-[2-(4-aminobutyl)-1-oxo-isoindolin-4-yl]phenoxy]- 1-[2-(2,4-difluorophenyl)-3-methyl-imidazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 68d) To a solution of compound 68c (80 mg) in ethanol (3 mL) was added hydrazine hydrate (16 mg). The mixture was stirred at 80 °C for 12 h, and then purified by prep-HPLC to give compound 68d (42 mg) as a white solid. LCMS (M+H+): 630. Step 5: preparation of (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 (example 68) To a solution of compound 68d (42 mg) in DMF (50 mL) was added HATU (51 mg) and N,N-diisopropylethylamine (17 mg). The mixture was stirred at 0 °C for 2 h, and then concentrated and purified by prep-HPLC to example 68 (4 mg) as a white solid. LCMS (M+H+): 612.1H NMR (400 MHz, DMSO-d6) δ = 7.88-8.32 (m, 1H), 7.44-7.83 (m, 5H), 7.26 (br d, J=7.5 Hz, 5H), 5.10-5.22 (m, 1H), 4.61-4.83 (m, 2H), 4.20-4.40 (m, 2H), 3.35-4.13 (m, 9H), 2.34-3.23 (m, 2H), 1.40-2.02 (m, 4H). Example 69 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 2-(2-ethylpyrazol-3-yl)isoindoline-1,3-dione (compound 69a) To a solution of 2-methylpyrazol-3-amine (1.7 g) in acetic acid (20 mL) was added phthalic anhydride (2.5 g). The mixture was stirred at 100 °C for 12 h, and then poured into water (100 mL) and extracted with EtOAc (10 mL for three times). The combined organic layer were washed with brine and NaHCO3 aqueous solution, dried over Na2SO4, and concentrated to give compound 69a (3.2 g) as a white solid. LCMS (M+H+): 242. Step 2: preparation of 2-(2-ethyl-4-iodo-pyrazol-3-yl)isoindoline-1,3-dione (compound 69b) To a mixture of compound 69a (2.0 g) in DMF (20 mL) was added N-iodosuccinimide (3.7 g). The mixture was stirred at 100 °C for 1 h and then purified by prep-HPLC to give compound 69b (2.3 g) as a brown solid. LCMS (M+H+): 368. Step 3: preparation of benzyl N-[3-[5-(1,3-dioxoisoindolin-2-yl)-1-ethyl-pyrazol-4- yl]prop-2-ynyl]-N-methyl-carbamate (compound 69c) To a solution of compound 69b (1.4 g) in DMF (5 mL) was added triethylamine (1.7 mL), benzyl N-methyl-N-prop-2-ynyl-carbamate (0.93 g), copper(I) iodide (0.14 g) and bis(triphenylphosphine)palladium(II) chloride (0.27 g). The mixture was stirred at 70 °C for 2 h under Ar, and then purified by prep-HPLC to give compound 69c (640 mg) as a brown solid. LCMS (M+H+): 443. Step 4: preparation of benzyl N-[3-[5-(1,3-dioxoisoindolin-2-yl)-1-ethyl-pyrazol-4- yl]propyl]-N-methyl-carbamate (compound 69d) To a solution of compound 69c (0.6 g) in THF (10 mL) was added PtO2 (0.1 g). The mixture was stirred at 20 °C for 12 h under H2 (50 psi). The mixture was purified by prep-HPLC to give compound 69d (0.6 g) as a brown oil. LCMS (M+H+): 447. Step 5: preparation of benzyl N-[3-(5-amino-1-ethyl-pyrazol-4-yl)propyl]-N-methyl- carbamate (compound 69e) To a solution of compound 69d (0.6 g) in EtOH (10 mL) was added hydrazine hydrate (0.5 mL). The mixture was stirred at 80 °C for 12 h, and then concentrated. The residue was purified by prep-HPLC to give compound 69e (310 mg) as a brown solid. LCMS (M+H+): 317. Step 6: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[[4-[3- [benzyloxycarbonyl(methyl)amino]propyl]-2-ethyl-pyrazol-3-yl]amino]-2-pyridyl]-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 69f) To a mixture of intermediate B9 (0.47 g), compound 69e (0.3g), and cesium carbonate (0.7 g) in anhydrous 1,4-dioxane (4 mL) was added Xantphos (0.2 g) and Pd2(dba)3 (0.08 g) in glovebox under Ar. The mixture was stirred at 100 °C for 12 h, and then purified by prep-HPLC to give compound 69f (0.5 g) as a brown solid. LCMS (M+H+): 736. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[[2- ethyl-4-[3-(methylamino)propyl]pyrazol-3-yl]amino]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound 69g) A mixture of compound 69f (0.46 g) and Pd/C (0.1 g) in methanol (5 mL) was stirred at 20 °C under H2 for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 69g (0.35 g) as colorless oil. LCMS (M+H+): 602. Step 8: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[[2- ethyl-4-[3-(methylamino)propyl]pyrazol-3-yl]amino]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 69h) A solution of compound 69g (0.35 g) and LiOH•H2O (0.12 g) in methanol (10 mL) and water (1 mL) was stirred for 2 h at 20 °C. The pH of the mixture was adjusted to 6 and then it was purified by prep-HPLC to give compound 69h (0.3 g) as a white solid. LCMS (M+H+): 588. Step 9: preparation of ditert-butyl (3S,6S)-15-ethyl-8-methyl-7-oxo-2,5,8,14,15,17,22- heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),13,18(22),19-pentaene-2,5- dicarboxylate (compound 69i) To a solution of DIEA (0.2 g) and HATU (0.2 g) in DMF (50 mL) was added a solution of compound 69h (0.3 g) in DMF (50 mL) dropwise over 1 h. The resulting mixture was stirred at 0 °C for 1 h, and then concentrated. The residue was purified by prep-HPLC to give compound 69i (80 mg) as a white solid. LCMS (M+H+): 570. Step 10: preparation of (3S,6S)-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 (compound 69j) A solution of compound 69i (70 mg) in hydrogen chloride methanol solution (2 mL) was stirred at 30 °C for 1 h. The mixture was concentrated to compound 69j (40 mg) as a white solid. LCMS (M+H+): 370. Step 11: preparation of (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 (example 69) A mixture of compound 69j (43 mg), intermediate C3 (43 mg), DIEA (60 mg) and KF (6 mg) in DMSO (1 mL) was stirred at 110 °C for 2 h. The pH of the mixture was adjusted to 5 with formic acid, and then purified by prep-HPLC to give example 69 (20 mg) as a white solid. LCMS (M+H+): 599.1H NMR (400 MHz, METHANOL-d4) δ = 7.66 - 7.78 (m, 1 H), 7.19 - 7.52 (m, 6 H), 7.06 (m, 1 H), 6.02 - 6.19 (m, 2 H), 5.26 - 5.47 (m, 1 H), 4.96 (br s, 1 H), 4.36 - 4.52 (m, 2 H), 4.15 - 4.31 (m, 1 H), 4.02 (m, 2 H), 2.75 - 3.06 (m, 3 H), 2.40 - 2.66 (m, 3 H), 2.08 - 2.31 (m, 2 H), 1.82 - 1.94 (m, 1 H), 1.33 - 1.47 (m, 3 H), 1.15 - 1.27 (m, 1 H). Example 70 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 2-[3-(2-methylpyrazol-3-yl)prop-2-ynyl]isoindoline-1,3-dione (compound 70a) To a solution of 5-iodo-1-methyl-pyrazole (10 g) in DMF (20 mL) was added triethylamine (13 mL), 2-prop-2-ynylisoindoline-1,3-dione (9.3 g), copper(I) iodide (1.8 g) and bis(triphenylphosphine)palladium(II) chloride (3.4 g). The mixture was stirred at 70 °C for 1 h under Ar, and then purified by prep-HPLC to give compound 70a (11 g) as a light-yellow solid. LCMS (M+H+): 266. Step 2: preparation of 2-[3-(2-methylpyrazol-3-yl)propyl]isoindoline-1,3-dione (compound 70b) To a solution of compound 70a (10 g) in THF (0.3 L) was added PtO2 (2.0 g). The mixture was stirred at 50 °C for 4 h under H2. The mixture was filtered and the filtrate was concentrated to give compound 70b (9 g) as a yellow solid. LCMS (M+H+): 270. Step 3: preparation of 2-[3-(2-methyl-4-nitro-pyrazol-3-yl)propyl]isoindoline-1,3- dione (compound 70c) To a mixture of compound 70b (6 g) in sulfuric acid (15 mL) was added nitric acid (3.1 g) drop wise. The mixture was stirred at 20 °C for 2 h, and then poured into ice water (20 mL) and extracted with EtOAc (200 mL twice). The combined organic layer was washed with aq. NaHCO3, dried and concentrated. The residue was purified by prep-HPLC to give compound 70c (4 g) as a yellow solid. LCMS (M+H+): 315. Step 4: preparation of 2-[3-(4-amino-2-methyl-pyrazol-3-yl)propyl]isoindoline-1,3- dione (compound 70d) To a solution of compound 70c (4.0 g) in THF was added Pd/C (1.0 g) dropwise and the mixture was stirred at 20 °C for 12 h under H2. The mixture was filtered and the filtrate was concentrated to give compound 70d (3.5 g) as a dark green solid. LCMS (M+H+): 285. Step 5: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[[5- [3-(1,3-dioxoisoindolin-2-yl)propyl]-1-methyl-pyrazol-4-yl]amino]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 70e) To a solution of intermediate B9 (6.2 g), compound 70d (3.5 g) and cesium carbonate (8 g) in anhydrous 1,4-dioxane (30 mL) was added Xantphos (2.9 g) and Pd2(dba)3 (1.1 g) in glovebox under Ar. The mixture was stirred at 100 °C for 12 h, and then purified by prep-HPLC to give compound 70e (4 g) as a white solid. LCMS (M+H+): 704. Step 6: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[[5-[3- [(2-carboxybenzoyl)amino]propyl]-1-methyl-pyrazol-4-yl]amino]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 70f) A solution of compound 70e (4 g) and LiOH•H2O (1.19 g) in methanol (40 mL) and water (5 mL) was stirred at 20 °C for 2 h. The pH of the mixture was adjusted to 4, and the mixture was extracted with EtOAc (100 mL for three times). The combined organic layer was dried and concentrated to give compound 70f (3.5 g) as dark red oil. LCMS (M+H+): 708. Step 7: preparation of (2S,4S)-4-[[6-[[5-(3-aminopropyl)-1-methyl-pyrazol-4- yl]amino]-2-pyridyl]-tert-butoxycarbonyl-amino]-1-tert-butoxycarbonyl-pyrrolidine-2- carboxylic acid (compound 70g) A solution of hydrazine hydrate (1.3 g) and compound 70f (3.5 g) in ethanol (3 mL) was stirred at 60 °C for 12 h. The mixture was purified by prep-HPLC to give compound 70g (1.8 g) as a yellow solid. LCMS (M+H+): 560. Step 8: preparation of ditert-butyl (3S,6S)-13-methyl-7-oxo-2,5,8,13,14,17,22- heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaene-2,5- dicarboxylate (compound 70h) To a solution of HATU (0.2 g) and DIEA (0.14 g) in DMF (60 mL) was added a solution of compound 70g (0.2 g) in DMF (60 mL) at 0 °C in 1 h dropwise. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 70h (70 mg) as a white solid. LCMS (M+H+): 542. Step 9: preparation of (3S,6S)-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 (compound 70i) A solution of compound 70h (30 mg) and TFA (1 mL) in DCM (3 mL) was stirred at 20 °C for 2 h. The mixture was concentrated to give compound 70i (20 mg) as yellow oil. LCMS (M+H+): 342. Step 10: preparation of (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 (example 70) A mixture of compound 70i (20 mg), intermediate C3 (16 mg) and DIEA (38 mg) in DMSO (1 mL) was stirred at 110 °C for 4 h. The mixture was purified by prep-HPLC to give example 70 (7 mg) as a light-yellow solid. LCMS (M+H+): 571.1H NMR (400 MHz, DMSO-d6) δ = 7.83 - 8.04 (m, 1 H), 7.61 - 7.79 (m, 2 H), 7.50 - 7.60 (m, 1 H), 7.25 - 7.38 (m, 2 H), 7.23 (m, 1 H), 7.07 - 7.15 (m, 2 H), 5.90 (m, 1 H), 5.72 (m, 1 H), 5.23 - 5.40 (m, 1 H), 4.69 (m, 1 H), 4.13 - 4.39 (m, 4 H), 3.70 (s, 3 H), 3.00 - 3.07 (m, 2 H), 2.75 - 2.79 (m, 2 H), 1.60 - 1.71 (m, 2 H). Example 71 (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 The title compound was prepared according to the following scheme: Step 1: preparation of ditert-butyl (3S,6S)-8,13,17-trimethyl-7-oxo-2,5,8,13,14,17,22- heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19-pentaene-2,5- dicarboxylate (compound 71a) A solution of Me2SO4 (35 mg), compound 70h (30 mg) and NaOH (11 mg) in THF (1 mL) was stirred at 20 °C for 1 h. The mixture was purified by prep-HPLC to give compound 71a (20 mg) as a white solid. LCMS (M+H+): 570. Step 2: preparation of (3S,6S)-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 A solution of TFA (1 mL) and compound 71a (20 mg) in DCM (1 mL) was stirred at 20 °C for 3 h. The mixture was concentrated to compound 71b (10 mg) as a white solid. LCMS (M+H+): 370. Step 3: preparation of (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 A mixture of DIEA (16 mg), compound 71b (9 mg) and intermediate C3 (10 mg) in DMSO (1.0 mL) was stirred at 110 °C for 3 h. The mixture was purified by prep-HPLC to give example 71 (7 mg) as a light-yellow solid. LCMS (M+H+): 599.1H NMR (400 MHz, METHANOL-d4) δ = 7.67 - 7.75 (m, 1 H), 7.45 (m, 1 H), 7.33 (s, 1 H), 7.18 - 7.31 (m, 4 H), 7.07 (m, 1 H), 6.16 (m, 1 H), 6.02 (m, 1 H), 5.26 - 5.42 (m, 1 H), 4.44 - 4.52 (m, 1 H), 4.15 (m, 2 H), 3.80 (s, 3 H), 3.20 (s, 3 H), 3.02 - 3.06 (m, 3 H), 2.60 - 2.76 (m, 3 H), 2.35 - 2.56 (m, 2 H), 2.11 - 2.23 (m, 1 H), 1.82 - 1.95 (m, 1 H), 1.04 - 1.18 (m, 1 H). Example 72 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 5-[3-(1,3-dioxoisoindolin-2-yl)propyl]-1-methyl-pyrazole-4- carbaldehyde (compound 72a) To a solution of DMF (5.0 mL) was added POCl3 (3.0 mL) dropwise at 20 °C and the mixture was stirred at 20 °C for 1 h. Then compound 70b (1.0 g) was added and the mixture was stirred at 100 °C for 12 h. The mixture was poured into water and basified with NaHCO3, then extracted with DCM (40 mL). The combined organic layer was washed with brine (30 mL) and concentrated. The residue was purified by prep-HPLC to give compound 72a (0.8 g) as a yellow solid. LCMS (M+H+): 298. Step 2: preparation of 2-[3-(4-hydroxy-2-methyl-pyrazol-3-yl)propyl]isoindoline-1,3- dione (compound 72b) A mixture of compound 72a (0.8 g) and m-CPBA (0.9 g) in DCM (20 mL) was stirred at 20 °C for 4 h. The mixture was poured into NaHSO3 aq. and the pH of the mixture was adjusted to 9 with K2CO3. The mixture was stirred at 20 °C for 1 h, and then filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to compound 72b (0.2 g) as a white solid. LCMS (M+H+): 314. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[5- [3-(1,3-dioxoisoindolin-2-yl)propyl]-1-methyl-pyrazol-4-yl]oxy-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 72c) To a solution of compound 3 (0.2 g), intermediate B9 (0.5 g) in 1,4-dioxane (10 mL) was added Xphos Pd G3 (62 mg) and cesium carbonate (0.6 g) in glovebox under Ar. The mixture was stirred at 100 °C for 12 h, and then purified by prep-HPLC to give compound 72c (0.3 g) as a white solid. LCMS (M+H+): 705. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[5-[3- (1,3-dioxoisoindolin-2-yl)propyl]-1-methyl-pyrazol-4-yl]oxy-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 72d) A solution of LiOH•H2O (89 mg) and compound 4 (300 mg) in water (10 mL) was stirred at 20 °C for 2 h. The mixture was purified by prep-HPLC to give compound 72d (200 mg) as yellow oil. LCMS (M+H+): 709. Step 5: preparation of (2S,4S)-4-[[6-[5-(3-aminopropyl)-1-methyl-pyrazol-4-yl]oxy-2- pyridyl]-tert-butoxycarbonyl-amino]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 72e) A mixture of hydrazine hydrate (1.0 mL) and compound 72d (200 mg) in ethanol (5.0 mL) was stirred at 80 °C for 12 h. The mixture was purified by prep-HPLC to give compound 72e (80 mg) as a white solid. LCMS (M+H+): 561. Step 6: preparation of ditert-butyl (3S,6S)-13-methyl-7-oxo-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-pentaene-2,5- dicarboxylate (compound 72f) To a solution of HATU (100 mg) and DIEA (69 mg) in DMF (20 mL) was added a solution of compound 72e (100 mg) in DMF (20 mL) at 0 °C in 1 h dropwise. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 72f (60 mg) as a white solid. LCMS (M+H+): 543. Step 7: preparation of ditert-butyl (3S,6S)-8,13-dimethyl-7-oxo-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-pentaene-2,5- dicarboxylate (compound 72g) A solution of Me2SO4 (69 mg), compound 72f (30 mg) and NaOH (22 mg) in THF (1.0 mL) was stirred at 20 °C for 12 h. The pH of the mixture was adjusted to 6 and the mixture was filtered. The filtrate was purified by prep-HPLC to give compound 72g (20 mg) as a white solid. LCMS (M+H+): 557. Step 8: preparation of (3S,6S)-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 (compound 72h) A solution of TFA (1.0 mL) and compound 72g (20 mg) in DCM (2.0 mL) was stirred at 20 °C for 2 h. The mixture was concentrated to give compound 72h (10 mg) as yellow oil. LCMS (M+H+): 357. Step 9: preparation of (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 (example 72) A mixture of compound 72h (10 mg), intermediate C3 (9 mg) and DIEA (11 mg) in DMSO (1.0 mL) was stirred at 100 °C for 3 h. The mixture was purified by prep-HPLC to give example 72 (4 mg) as a white solid. LCMS (M+H+): 586.1H NMR (400 MHz, METHANOL-d4) δ = 7.68 - 7.75 (m, 1 H), 7.61 (m, 1 H), 7.20 - 7.31 (m, 5 H), 7.04 - 7.11 (m, 1 H), 6.34 (m, 2 H), 5.36 (m, 1 H), 4.97 - 5.03 (m, 1 H), 4.47 - 4.56 (m, 1 H), 4.08 - 4.29 (m, 2 H), 3.80 (s, 3 H), 3.04 (s, 3 H), 2.64 - 2.82 (m, 3 H), 2.41 - 2.57 (m, 2 H), 2.06 - 2.20 (m, 1 H), 1.96 (m, 1 H). Example 73 (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 The title compound was prepared according to the following scheme: Step 1: preparation of ditert-butyl (3S,6S)-17-[(4-methoxyphenyl)methyl]-13-methyl- 7-oxo-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa-1(21),12(16),14,18(22),19- pentaene-2,5-dicarboxylate (compound 73a) A mixture of Cs2CO3 (72 mg), compound 70h (40 mg) and 4-methoxybenzylchloride (0.02 mL) in DMSO (1.0 mL) was stirred at 20 °C for 12 h. The mixture was purified by prep-HPLC to give compound 73a (30 mg) as a white solid. LCMS (M+H+): 662. Step 2: preparation of ditert-butyl (3S,6S)-17-[(4-methoxyphenyl)methyl]-8,13- dimethyl-7-oxo-2,5,8,13,14,17,22-heptazatetracyclo[16.3.1.13,6.012,16]tricosa- 1(21),12(16),14,18(22),19-pentaene-2,5-dicarboxylate (compound 73b) A mixture of compound 73a (15.0 mg), Me2SO4 (13.3 mg) and NaOH (5 mg) in THF (1.0 mL) was stirred at 20 °C for 2 h. The mixture was purified by prep-HPLC to give compound 73b (15 mg) as a white solid. LCMS (M+H+): 676. Step 3: preparation of (3S,6S)-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 (compound 73c) To a mixture of compound 73b (15 mg) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give compound 73c (7 mg) as colorless oil. LCMS (M+H+): 356. Step 4: preparation of (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 (example 73) A mixture of compound 73c (7 mg), intermediate C3 (6 mg) and DIEA (13 mg) in DMSO (1.0 mL) was stirred at 110 °C for 3 h. The mixture was purified by prep-HPLC to give example 73 (2 mg) as a yellow solid. LCMS (M+H+): 585.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 - 8.54 (m, 2 H), 7.66 - 7.76 (m, 1 H), 7.48 - 7.53 (m, 1 H), 7.35 - 7.40 (m, 2 H), 7.21 - 7.34 (m, 5 H), 5.95 (m, 1 H), 5.45 (s, 1 H), 5.09 - 5.16 (m, 1 H), 4.40 - 4.49 (m, 1 H), 4.11 - 4.34 (m, 1 H), 3.80 (s, 3 H), 3.38 - 3.43 (m, 1 H), 3.07 (s, 3 H), 2.43 - 2.79 (m, 5 H), 2.20 - 2.31 (m, 1 H), 1.81 - 1.94 (m, 1 H). Example 74 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 3-benzyloxybenzonitrile (compound 74a) To a mixture of 3-hydroxybenzonitrile (6.0 g) and benzyl bromide (6.0 mL) in DMF (100 mL) was added potassium carbonate (14 mg). The mixture was stirred at 20 °C for 2 h, and then poured into water (200 mL) and extracted with EtOAc (200 mL twice). The combined organic layer was washed with brine (200 mL), dried and concentrated. The residue was purified by column chromatography to give compound 74a (8.5 g) as a white solid. Step 2: preparation of methyl 3-benzyloxybenzenecarboximidate (compound 74b) To a mixture of compound 74a (5.0 g) in methanol (50 mL) was added acetyl chloride (34.0 mL). The mixture was stirred at 20 °C for 12 h, and then filtered. The filtrate was concentrated to give compound 74b (4.5 g) as a white solid. LCMS (M+H+): 242. Step 3: preparation of 3-benzyloxy-N'-(methylamino)benzamidine (compound 74c) To a mixture of compound 74b (4.5 g) in methanol (90.0 mL) was added methylhydrazine (5.2 g). The mixture was stirred at 25 °C for 2 h and then concentrated. The residue was recrystallized from MeOH (30.0 mL) to give compound 74c (4.2 g) as a white solid. LCMS (M+H+): 256. Step 4: preparation of 5-(3-benzyloxyphenyl)-2-methyl-4H-1,2,4-triazol-3-one To a mixture of compound 74c (4.2 g) in DCM (80 mL) was added triethylamine (4.6 mL) and bis(trichloromethyl)carbonate (7.3 g). The mixture was stirred at 20 °C for 2 h, and then concentrated. The residue was recrystallized from MeOH (30 mL) to give compound 74d (2.5 g) as a white solid. LCMS (M+H+): 282. Step 5: preparation of 2-[4-[3-(3-benzyloxyphenyl)-1-methyl-5-oxo-1,2,4-triazol-4- yl]butyl]isoindoline-1,3-dione (compound 74e) To a mixture of compound 74d (500 mg) in THF (20.0 mL) was added cesium carbonate (1200 mg) and 2-(4-bromobutyl)isoindoline-1,3-dione (551 mg). The mixture was stirred at 60 °C for 10 h, and then concentrated. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with water (200 mL twice) and brine (200 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by prep-HPLC to give compound 74e (450 mg) as a white solid. LCMS (M+H+): 483. Step 6: preparation of 2-[4-[3-(3-hydroxyphenyl)-1-methyl-5-oxo-1,2,4-triazol-4- yl]butyl]isoindoline-1,3-dione (compound 74f) To a mixture of compound 74e (450 mg) in methanol (5.0 mL) was added Pd/C (200 mg). The mixture was stirred at 20 °C for 16 h, and then filtered. The filtrate was concentrated to give compound 74f (300 mg) as colorless oil. LCMS (M+H+): 393. Step 7: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[4-[4-(1,3-dioxoisoindolin- 2-yl)butyl]-1-methyl-5-oxo-1,2,4-triazol-3-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 74h) To a mixture of compound 74f (300 mg) and tributylphophine (232 mg) in THF (4.0 mL) was added O1-tert-butyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (206 mg) and TMAD (197 mg) at 0 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 12 h. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by prep-HPLC to give compound 74h (400 mg) as a white solid. LCMS (M+H+): 620. Step 8: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[4-[4-[(2- carboxybenzoyl)amino]butyl]-1-methyl-5-oxo-1,2,4-triazol-3-yl]phenoxy]pyrrolidine-2- carboxylic acid (compound 74i) The mixture of compound 74h (400 mg) in water (0.2 mL) and methanol (2.0 mL) was added LiOH (138 mg) at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 12 h, and then adjusted to pH = 4 and purified by prep-HPLC to give compound 74i (300 mg) as a white solid. LCMS (M+H+): 624. Step 9: preparation of (2S,4S)-4-[3-[4-(4-aminobutyl)-1-methyl-5-oxo-1,2,4-triazol-3- yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 74j) To the solution of compound 74i (307 mg) in ethanol (2.0 mL) was added hydrazine hydrate (123 mg) at 0 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for 12 h, and then purified by prep-HPLC to give compound 74j (120 mg) as a white solid. LCMS (M+H+): 476. Step 10: preparation of tert-butyl (13S,16S)-4-methyl-5,12-dioxo-17-oxa-3,4,6,11,14- pentazatetracyclo[16.3.1.113,16.02,6]tricosa-1(22),2,18,20-tetraene-14-carboxylate (compound 74k) To a solution of HATU (24 mg) and DIEA (8 mg) in DMF (15 mL) was added a solution of compound 74j (30 mg) in DMF (15 mL) dropwise and the mixture was stirred at 0 °C for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 74k (10 mg) as a white solid. LCMS (M+H+): 458. Step 11: preparation of (13S,16S)-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 (compound 74m) A solution of TFA (1.0 mL) and compound 74k (10 mg) in DCM (1.0 mL) was stirred at 20 °C for 1 h. The mixture was concentrated to give compound 74m (8 mg) as yellow oil. LCMS (M+H+): 358. Step 12: preparation of (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 (example 74) A mixture of compound 74m (7.0 mg), intermediate C3 (6 mg) and DIEA (13 mg) in DMSO (1.0 mL) was stirred at 100 °C for 4 h. The mixture was purified by prep-HPLC to give example 74 (1 mg) as a white solid. LCMS (M+H+): 587.1H NMR (400 MHz, DMSO-d6) δ = 7.97 (m 1 H), 7.68 - 7.74 (m, 1 H), 7.52 - 7.57 (m, 1 H), 7.40 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.19 - 7.31 (m, 4 H), 7.16 (m, 1 H), 5.46 (m, 1 H), 5.01 (m, 1 H), 4.54 (m, 1 H), 4.32 - 4.41 (m, 1 H), 3.93 (s, 1 H), 3.66 - 3.79 (m, 1 H), 3.50 - 3.54 (m, 3 H), 3.26 (br s, 2 H), 2.50 - 2.60 (m, 2 H), 1.51 - 1.66 (m, 4 H). Example 75 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of benzyl N-[3-[4-(tert-butoxycarbonylamino)-2-pyridyl]prop-2- ynyl]-N-methyl-carbamate (compound 75a) To a solution of tert-butyl N-(2-bromo-4-pyridyl)carbamate (1.0 g), benzyl N-methyl-N- prop-2-ynyl-carbamate (781 mg), copper(I) iodide (136 mg), triethylamine (1.0 mL) was add bis(triphenylphosphine)palladium(II) chloride (257 mg). The mixture was stirred at 70 °C for 2 h under N2. The mixture was filtered and the filtrate was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL for three times). The combined organic layer was washed with brine (100 mL), dried and concentrated to afford compound 75a (2.5 g) as yellow oil. LCMS (M+H+): 396. Step 2: preparation of benzyl N-[3-[4-(tert-butoxycarbonylamino)-2-pyridyl]propyl]- N-methyl-carbamate (compound 75b) To a solution of compound 75a (300 mg) in THF (6.0 mL) was added PtO2 (60 mg). The mixture was stirred at 20 °C for 12 h under H2 balloon. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 75b (250 mg) as brown oil. LCMS (M+H+): 400. Step 3: preparation of benzyl N-[3-(4-amino-2-pyridyl)propyl]-N-methyl-carbamate (compound 75c) To a solution of compound 75b (250 mg) in DCM (1.0 mL) was added trifluoroacetic acid (0.5 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h, and then concentrated to give the crude compound 75c (168 mg) as brown oil. LCMS (M+H+): 300. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[[2-[3- [benzyloxycarbonyl(methyl)amino]propyl]-4-pyridyl]amino]-2-pyridyl]-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 75d) To a mixture of compound 75c (501 mg), intermediate B9 (501 mg) and cesium carbonate (653 mg) in DMF (8.0 mL) was added 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthenes (58 mg) and tris(dibenzylideneacetone)dipalladium (0) (92 mg). The mixture was stirred at 70 °C for 2 h, and then quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL for three times). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 75d (300 mg) as a brown oil. LCMS (M+H+): 719. Step 5: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[[2- [3-(methylamino)propyl]-4-pyridyl]amino]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 75e) To a solution of compound 75d (300 mg) in methanol (6.0 mL) was added Pd/C (30 mg). The mixture was stirred at 20 °C for 16 h under H2 balloon. The reaction mixture was filtered and the filtrate was concentrated to give the crude compound 75e (250 mg) as a brown oil. LCMS (M+H+): 585. Step 6: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[[2-[3- (methylamino)propyl]-4-pyridyl]amino]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 75f) To a solution of compound 75e (250 mg) in methanol (5.0 mL) and water (0.5 mL) was added LiOH•H2O (90 mg). The mixture was stirred at 20 °C for 2 h, and then acidified by formic acid to pH = 2. The mixture was purified by prep-HPLC to give compound 75f (200 mg) as a colorless oil. LCMS (M+H+): 571. Step 7: preparation of ditert-butyl (3S,6S)-8-methyl-7-oxo-2,5,8,13,17,22- hexazatetracyclo[16.3.1.13,6.112,16]tetracosa-1(21),12(23),13,15,18(22),19-hexaene-2,5- dicarboxylate (compound 75g) To a solution of HATU (50 mg) and N,N-diisopropylethylamine (0.05 mL) in DMF (20 mL) was added a solution of compound 75F (50 mg) in DMF (20 mL) at 0 °C. The mixture was stirred at 20 °C for 16 h, and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 75g (50 mg) as a brown solid. LCMS (M+H+): 553. Step 8: preparation of (3S,6S)-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 (compound 75h) To a solution of compound 75g (50 mg) in DCM (2.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 1 h, and then concentrated under reduced pressure to give crude compound 75h (30 mg) as a brown oil. LCMS (M+H+): 353. Step 9: preparation of (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 (example 75) To a solution of compound 75h (50 mg), N,N-diisopropylethylamine (0.05 mL) in DMF (1.0 mL) was added intermediate B9 (38 mg). The mixture was stirred at 100 °C for 2 h, and then purified by prep-HPLC to give example 75 (7.0 mg) as a yellow solid. LCMS (M+H+): 582. 1H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.23 (br s, 1H), 8.17 - 8.12 (m, 1H), 7.74 (br d, J = 7.0 Hz, 1H), 7.50 - 7.57 (m, 1H), 7.33 (br t, J = 7.8 Hz, 3H), 7.25 (t, J = 4.4 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 2.7 Hz, 1H), 6.60 - 6.75 (m, 1H), 6.14 - 6.09 (m, 2H), 4.38 - 4.49 (m, 2H), 4.15 - 4.24 (m, 1H), 4.14 - 4.26 (m, 1H), 3.85-3.06 (m, 6H), 2.85 (s, 3H), 1.77 (s, 1H), 1.64 (br d, J = 11.1 Hz, 1H). Example 76 (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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-[3-(4-amino-3-pyridyl)prop-2-ynyl]-N-methyl- carbamate A mixture of 3-bromopyridin-4-amine (2.0 g), benzyl N-methyl-N-prop-2-ynyl-carbamate (1.9 g), copper(I) iodide (0.34 g), bis(triphenylphosphine)palladium(II) chloride (0.64 g) and triethylamine (2.5 mL) in DMF (20 mL) was stirred at 50 °C for 12 h under N2. The mixture was purified by prep-HPLC to give compound 76a (2.0 g) as green oil. LCMS (M+H+): 296. Step 2: preparation of benzyl N-[3-(4-amino-3-pyridyl)propyl]-N-methyl-carbamate (compound 76b) A mixture of PtO2 (0.4 g) and compound 2 (2.0 g) in methanol (20.0 mL) was stirred at 20 °C for 4 h. The mixture was purified by prep-HPLC to give compound 76b (1.5 g) as colorless oil. LCMS (M+H+): 300. Step 3~8: preparation of (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 (Example 76) The title compound was prepared in analogy to the preparation of Example 75 (Step 4~9) by using compound 76b instead of compound 75c. LCMS (M+H+): 582.1H NMR (400 MHz, METHANOL-d4) δ = 8.41 - 8.54 (m, 2 H), 8.32 (s, 1 H), 8.25 (m, 1 H), 7.70 (m, 1 H), 7.52 (m, 1 H), 7.18 - 7.32 (m, 4 H), 7.09 (m, 1 H), 6.41 (m, 1 H), 6.31 (m, 1 H), 5.37 - 5.51 (m, 1 H), 5.07 - 5.19 (m, 1 H), 4.27 - 4.56 (m, 3 H), 3.17 (s, 3 H), 2.95 (m, 1 H), 2.37 - 2.77 (m, 4 H), 2.00 - 2.14 (m, 1 H), 1.73 - 1.88 (m, 1 H). Example 77 (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 The title compound was prepared in analogy to the preparation of Example 74 (Step 5~12) by using 2-(5-bromopentyl)isoindoline-1,3-dione instead of 2-(4-bromobutyl)isoindoline-1,3- dione. LCMS (M+H+): 601.1H NMR (DMSO-d6) δ = 7.82-7.90 (m, 1H), 7.73 (td, J=8.4, 6.6 Hz, 1H), 7.49-7.58 (m, 2H), 7.26-7.36 (m, 3H), 7.20 (d, J=8.3 Hz, 1H), 7.13 (d, J=4.9 Hz, 1H), 6.96 (s, 1H), 5.30 (t, J=4.4 Hz, 1H), 4.95 (br d, J=9.0 Hz, 1H), 4.22-4.46 (m, 2H), 3.54 (br d, J=6.4 Hz, 2H), 3.39 (br s, 3H), 3.17 (s, 2H), 2.71-2.83 (m, 1H), 2.46-2.47 (m, 1H), 1.74-1.89 (m, 1H), 1.51-1.67 (m, 1H), 1.31-1.49 (m, 2H), 1.14-1.24 (m, 2H). Example 78 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 3-[(E)-2-ethoxyvinyl]-1-methyl-4-nitro-pyrazole (compound 78a) A mixture of 3-chloro-1-methyl-4-nitro-pyrazole (5.0 g), 2-(2-ethoxyvinyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (5.0 g), palladium (II) acetate (0.7 g), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.0 g) and potassium phosphate (9.0 g) in ACN (50 mL) and water (5 mL) was stirred at 70 °C for 16 h under N2. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL twice). The combined organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound 78a (5.2 g) as a yellow solid. LCMS (M+H+): 198. Step 2: preparation of 2-(1-methyl-4-nitro-pyrazol-3-yl)acetaldehyde (compound 78b) A mixture of compound 78a (5.2 g) and hydrochloric acid (25.0 mL) in THF (30.0 mL) was stirred at 60 °C for 2 h. The mixture was poured into ice NaHCO3 aq. (200 mL) and EtOAc (200 mL). The organic layer was separated and concentrated to about 40 mL containing compound 78b (4.0 g), which was used in next step directly. Step 3: preparation of tert-butyl N-[3-(2-hydroxyethyl)-1-methyl-pyrazol-4- yl]carbamate (compound 78c) To a mixture containing compound 78b (4.0 g) in methanol (30 mL) was added NaBH4 (2.7 g) at 0°C. The resulting mixture was stirred at 15 °C for 2 h, then di-tert-butyl dicarbonate (5.0 g) was added. The mixture was stirred at 15 °C for 12 h, and then poured into NH4Cl aq. (100 mL) and extracted with EtOAc (100 mL for three times). The combined organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound 78c (2.0 g) as light-brown oil. LCMS (M+H+): 242. Step 4: preparation of 2-[4-(tert-butoxycarbonylamino)-1-methyl-pyrazol-3-yl]ethyl methanesulfonate (compound 78d) To a solution of compound 78c (2.0 g) and TEA (1.7 g) in DCM (30 mL) was added methanesulfonic anhydride (1.7 g) at 0 °C. The mixture was stirred at 20 °C for 1 h, and then concentrated. The residue was purified by prep-HPLC to give compound 78d (2.0 g) as yellow oil. LCMS (M+H+): 320. Step 5: preparation of tert-butyl 2-methyl-5,6-dihydropyrrolo[3,2-c]pyrazole-4- carboxylate (compound 78e) To a solution of compound 78d (2.0 g) and KI (2.1 g) in THF (30 mL) was added potassium tert-butoxide (0.7 g). The mixture was stirred at 20 °C for 12 h, and then poured into water (50 mL) and extracted with EtOAc (50 mL twice). The combined organic layer was washed with brine, dried and concentrated to give compound 78e (1.2 g) as yellow oil. LCMS (M+H+): 224. Step 6: preparation of tert-butyl 3-iodo-2-methyl-5,6-dihydropyrrolo[3,2-c]pyrazole-4- carboxylate (compound 78f) To a mixture of compound 78e (1.1 g) and AcOH (0.06 g) in DMF (15.0 mL) was added NIS (1.6 g). The mixture was stirred at 60 °C for 3 h, and then poured into brine (20 mL) and extracted with EtOAc (20 mL for three times). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC to afford compound 78f (0.8 g) as a yellow solid. LCMS (M+H+): 350. Step 7: preparation of tert-butyl 3-[3-(1,3-dioxoisoindolin-2-yl)prop-1-ynyl]-2-methyl- 5,6-dihydropyrrolo[3,2-c]pyrazole-4-carboxylate (compound 78g) To a mixture of 2-prop-2-ynylisoindoline-1,3-dione (0.3 g), compound 78f (0.6 g), copper(I) iodide (65 mg) and triethylamine (0.5 g) in DMF (10.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (121 mg). The mixture was stirred at 50 °C for 3 h, and then purified by prep-HPLC to give compound 78g (0.2 g) as a yellow solid. LCMS (M+H+): 407. Step 8: preparation of tert-butyl 3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-5,6- dihydropyrrolo[3,2-c]pyrazole-4-carboxylate (compound 78h) To a solution of compound 78g (0.2 g) in THF (5.0 mL) and MeOH (5.0 mL) was added PtO2 (40 mg). The mixture was stirred at 20 °C for 3 h under H2 balloon. The mixture was filtered and the filtrate was concentrated to give compound 78h (180 mg) as a yellow oil. LCMS (M+H+): 411. Step 9: preparation of 2-[3-(2-methyl-5,6-dihydro-4H-pyrrolo[3,2-c]pyrazol-3- yl)propyl]isoindoline-1,3-dione (compound 78i) To a solution of compound 78h (180 mg) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 2 h, and then concentrated. The residue was purified by prep- HPLC to give crude compound 78i (120 mg) as yellow oil. LCMS (M+H+): 311. Step 10~14: preparation of (8S,11S)-18-methyl-1,7,10,13,18,19,25- heptazapentacyclo[15.5.1.12,6.18,11.020,23]pentacosa-2(25),3,5,17(23),19-pentaen-12-one (compound 78j) The title compound was prepared in analogy to the preparation of Example 70 (Step 5~9) by using compound 78i instead of compound 70d. LCMS (M+H+): 368. Step 15: preparation of (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 (example 78) To a solution of DIEA (16 mg) and intermediate C2 (7.8 mg) in ACN (1.0 mL) was added compound 78j (9.0 mg). The mixture was stirred at 80 °C for 2 h, and then purified by prep- HPLC to give example 78 (3 mg) as a yellow solid. LCMS (M+H+): 598.1H NMR (400 MHz, METHANOL-d4) δ = 8.45 - 8.60 (m, 2 H) 8.35 (br s, 1 H) 7.63 - 7.72 (m, 1 H) 7.45 (t, J=7.89 Hz, 1 H) 7.27 - 7.36 (m, 1 H) 7.19 - 7.26 (m, 1 H) 5.99 - 6.03 (m, 1 H) 5.96 (d, J=8.07 Hz, 1 H) 5.01 (br d, J=9.90 Hz, 1 H) 4.51 - 4.56 (m, 1 H) 4.10 - 4.36 (m, 4 H) 3.79 - 3.92 (m, 2 H) 3.74 (s, 3 H) 3.06 - 3.15 (m, 1 H) 2.97 - 3.05 (m, 1 H) 2.73 - 2.85 (m, 2 H) 2.60 (br s, 2 H) 1.63 - 1.78 (m, 1 H) 1.38 - 1.54 (m, 1 H). Example 79 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 7-chloropyrrolo[3,2-b]pyridine-1-carboxylate (compound 79a) To a mixture of 7-chloro-1H-pyrrolo[3,2-b]pyridine (4.0 g), triethylamine (5.5 mL) and 4- dimethylaminopyridine (1.6 g) in DCM (50 mL) was added di-tert-butyl dicarbonate (8.6 g). This reaction mixture was stirred at 20 °C for 16 h, and then quenched with saturated aqueous Na2CO3 (500 mL) solution and was extracted with EtOAc (500 mL twice). The combined organic layer was dried over Na2SO4 and concentrated. This residue was purified by column chromatography to give compound 79a (3.5 g) as colorless oil. LCMS (M+H+): 197. Step 2: preparation of tert-butyl 7-(3-ethoxy-3-oxo-prop-1-enyl)pyrrolo[3,2- b]pyridine-1-carboxylate To a mixture of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (3.2 g), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.9 g) and potassium carbonate (4.9 g) in 1,4-dioxane (50 mL) and water (3 mL) was added compound 79a (3.0 g). This mixture was stirred at 100 °C for 16 h, and then poured into water (100 mL) and extracted with EtOAc (100 mL twice). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give compound 79b (1.5 g) as light white solid. MS obsd. LCMS (M+H+): 317. Step 3: preparation of tert-butyl 7-(3-ethoxy-3-oxo-propyl)-2,3-dihydropyrrolo[3,2- b]pyridine-1-carboxylate (compound 79c) To a mixture of compound 79b (1.5 g) in ethanol (60 mL) was added PtO2 (1.0 g). The mixture was stirred at 20 °C for 72 h under H2 balloon, and then filtered and the filtrate was concentrated to give compound 79c (1.2 g) as colorless oil. LCMS (M+H+): 321. Step 4: preparation of tert-butyl 7-(3-hydroxypropyl)-2,3-dihydropyrrolo[3,2- b]pyridine-1-carboxylate (compound 79d) To a mixture of compound 79c (1.5 g) in THF (20 mL) was added lithium aluminum hydride (888 mg). The mixture was stirred at 0 °C for 2 h, and then quenched and filtered. The filtrate was concentrated to give compound 79d (1.1 g) as colorless oil. LCMS (M+H+): 278. Step 5: preparation of tert-butyl 7-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2,3- dihydropyrrolo[3,2-b]pyridine-1-carboxylate (compound 79e) To a mixture of compound 79d (1.0 g), isoindoline-1,3-dione (0.5 g) and tributylphosphine (1.0 g) in THF (20 mL) was added TMAD (843 mg) at 0 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 12 h, and then concentrated. The residue was taken up in EtOAc (100 mL) and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound 79e (0.7 g) as colorless oil. LCMS (M+H+): 408. Step 6: preparation of 2-[3-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-7- yl)propyl]isoindoline-1,3-dione (compound 79f) To a solution of TFA (0.5 mL) in DCM (5.0 mL) was added compound 79e (0.4 g). The mixture was stirred at 20 °C for 1 h, and then concentrated to give crude compound 79f (270 mg) as yellow oil which was used directly in next step. LCMS (M+H+): 308. Step 7~12: preparation of (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 The title compound was prepared in analogy to the preparation of Example 78 (Step 10~15) by using compound 79f instead of compound 78i and intermediate B33 instead of intermediate B9. LCMS (M+H+): 595.1H NMR (DMSO-d6) δ = 8.27 (s, 1H), 7.85-7.89 (m, 1H), 7.65-7.80 (m, 2H), 7.54-7.64 (m, 1H), 7.25-7.40 (m, 2H), 6.89-6.98 (m, 1H), 6.71-6.88 (m, 2H), 6.14-6.23 (m, 1H), 5.29-5.40 (m, 1H), 4.84-4.93 (m, 1H), 4.22-4.35 (m, 1H), 4.08 (br s, 2H), 3.83-3.98 (m, 1H), 3.19-3.24 (m, 2H), 3.01-3.11 (m, 2H), 2.42-2.48 (m, 2H), 2.06-2.32 (m, 2H), 1.70-2.00 (m, 2H). Example 80 (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 The 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-(4-hydroxybutyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 80a) A mixture of 4-(4-bromoindazol-2-yl)butan-1-ol (intermediate A18, 54 mg, 0.2 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, 114 mg, 0.2 mmol), PdCl2(DPPF)-CH2Cl2 adduct (7.3 mg, 0.01 mmol) and potassium carbonate (83 mg, 0.6 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was heated to 100 °C for 2 hrs 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 80a (121 mg) as a brown oil, LCMS (M+H)+: 632. Step 2: preparation of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4- [3-[2-(4-hydroxybutyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (compound 80b) A solution of methyl (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2- (4-hydroxybutyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylate (compound 80a, 121 mg, 0.19 mmol) and lithium hydroxide monohydrate (48 mg, 1.15 mmol) in MeOH (4 mL) and water (1 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water and acidified by HOAc. The resulted precipitation was filtered, the collected solid was dried, compound 80b (93 mg) was obtained as a light brown solid, LCMS (M+H)+: 618. Step 3: preparation of (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 (Example 80) A solution of (2S,4S)-1-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4-carbonyl]-4-[3-[2-(4- hydroxybutyl)indazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (compound 80b, 49 mg, 0.08 mmol), 2-chloro-1-methylpyridinium iodide (41 mg, 0.16 mmol) and DIPEA (51 mg, 0.4 mmol) in 1,2-dichloroethane (25 mL) was stirred at 80 °C for 3 hrs. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give some residue, the residue was directly purified by flash column chromatography to give some crude. The crude was precipitated from EtOAc and hexane to afford Example 80 (17 mg) as a light yellow solid, LCMS (M+H)+: 600.1H NMR (400 MHz, DMSO-d6) δ = 8.99 - 8.69 (m, 1H), 8.67 - 8.11 (m, 2H), 8.03 - 7.87 (m, 2H), 7.63 - 7.17 (m, 8H), 5.37 - 5.08 (m, 1H), 5.05 - 4.78 (m, 1H), 4.64 - 3.76 (m, 6H), 2.17 - 1.81 (m, 2H), 1.73 - 1.41 (m, 2H), 1.29 - 1.15 (m, 2H). Example 81 (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 The title compound was prepared according to the following scheme: Step 1-3: preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-5,10,13,18,19- pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 81c) The compound 81c was prepared in analogy to the preparation of Example 31 by using intermediate A20 instead of Intermediate A35 and Intermediate B10 instead of Intermediate B5. LCMS (M+H)+: 478. Step 4: preparation of (8S,11S)-18-methyl-7-oxa-5,10,13,18,19- pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12- one;hydrochloride (compound 81d) A mixture of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-5,10,13,18,19- pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 81c, 381 mg, 0.44 mmol) and 3 M HCl in MeOH (3 mL, 9 mmol) was stirred at room temperature for 3 hrs. After removing the excess solvent under reduced pressure, crude compound 81d (387 mg) was obtained as a brown oil, LCMS (M+H)+: 378. Step 5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-18-methyl-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one (compound 81e) A mixture of (8S,11S)-18-methyl-7-oxa-5,10,13,18,19- pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaen-12- one;hydrochloride (compound 81d, 203 mg, 0.22 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 76 mg, 0.29 mmol) and DIPEA (143 mg, 1.1 mmol) in DMSO (3 mL) was heated to 90 °C for 0.5 hr. 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 water and brine, dried, concentrated under reduced pressure to give some crude. The crude was purified by flash column chromatography to afford compound 81e (94 mg) as a brown oil, which was directly used for next step without further purification, LCMS (M+H)+: 608. Step 6: preparation of (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 (Example 81) To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-18- methyl-7-oxa-5,10,13,18,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one (compound 81e, 47 mg, 0.05 mmol) in DMF (1 mL) was added sodium hydride (11 mg, 0.27 mmol) at 0 °C, the resulting mixture was stirred at 0 °C for 30 mins. Then (3-iodopropyl)benzene (40 mg, 0.16 mmol) was added and stirred at 0 °C to room temperature for 16 hrs. The reaction mixture was directly purified by prep-HPLC to afford Example 81 (4 mg) as a white solid, LCMS (M+H)+: NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 8.35 - 8.28 (m, 1H), 8.21 (s, 1H), 7.77 - 7.54 (m, 2H), 7.36 - 7.16 (m, 8H), 7.03 - 6.97 (m, 1H), 6.94 - 6.88 (m, 1H), 6.83 - 6.77 (m, 1H), 6.03 - 5.75 (m, 1H), 5.41 - 5.23 (m, 1H), 4.53 - 4.38 (m, 2H), 4.32 - 4.19 (m, 1H), 4.14 - 4.07 (m, 3H), 4.01 (m, 1H), 3.28 - 3.19 (m, 1H), 3.01 - 2.89 (m, 1H), 2.79 - 2.58 (m, 4H), 2.42 - 2.29 (m, 2H), 2.11 - 2.00 (m, 2H), 1.86 - 1.71 (m, 2H). Example 82 (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 The title compound was prepared in analogy to the preparation of Example 81 by using Intermediate B13 instead of Intermediate B10. Example 82 (4 mg) as a white solid, LCMS (M+H)+: 608.1H NMR (400 MHz, METHANOL-d4) δ = 8.60 - 7.91 (m, 4H), 7.70 - 7.49 (m, 3H), 7.39 - 7.16 (m, 3H), 7.00 (m, 1H), 5.72 - 5.52 (m, 1H), 5.19 - 4.98 (m, 1H), 4.66 - 4.35 (m, 2H), 4.13 (s, 3H), 3.69 - 3.58 (m, 1H), 3.19 - 3.05 (m, 1H), 2.99 - 2.62 (m, 4H), 1.98 - 1.84 (m, 2H). Example 83 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 3-(3-aminopropyl)-4-bromo-1-[(4- methoxyphenyl)methyl]benzimidazol-2-one (compound 83a) A mixture of tert-butyl N-[3-[7-bromo-3-[(4-methoxyphenyl)methyl]-2-oxo-benzimidazol- 1-yl]propyl]carbamate (intermediate A21, 854 mg, 0.87 mmol) and TFA (2 mL, 26 mmol) in DCM (10 mL) was stirred at room temperature for 16 hrs. After removing excess DCM and TFA under reduced pressure, the residue was dissolved in EtOAc and then washed with saturated sodium bicarbonate aqueous solution, brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some crude product. The crude product was then purified by flash column chromatography to afford compound 83a (307 mg) as a yellow oil, LCMS (M+H)+: 390. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-aminopropyl)-1-[(4- methoxyphenyl)methyl]-2-oxo-benzimidazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 83b) A mixture of 3-(3-aminopropyl)-4-bromo-1-[(4-methoxyphenyl)methyl]benzimidazol-2- one (compound 83a, 286 mg, 0.70 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B8, 623 mg, 1.39 mmol), PdCl2(DPPF)-CH2Cl2 adduct (26 mg, 0.035 mmol) and potassium carbonate (289 mg, 2.09 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) was heated to 120°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 water and brine, dried, concentrated to give some crude product, which was then purified by flash column chromatography to afford compound 83b (302 mg) as a brown foam, LCMS (M+H)+: 631. Step 3: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-1-[(4-methoxyphenyl)methyl]- 2-oxo-benzimidazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 83c) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-aminopropyl)-1-[(4- methoxyphenyl)methyl]-2-oxo-benzimidazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 83b, 302 mg, 0.48 mmol) and lithium hydroxide monohydrate (100 mg, 2.39 mmol) in MeOH (4 mL) and water (1 mL) was stirred at 50 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was diluted with water, then acidified by 1N aq. HCl solution to PH~5. The resulted precipitation was filtered, the collected solid was collected and dried, compound 83c (226 mg) was obtained as a grey solid, LCMS (M+H)+: 617. Step 4: preparation of tert-butyl (8S,11S)-19-[(4-methoxyphenyl)methyl]-12,18-dioxo- 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-10-carboxylate (compound 83d) To a mixture of HATU (181 mg, 0.48 mmol) and DIPEA (237 mg, 1.83 mmol) in DMF (4 mL) was added (2S,4S)-4-[3-[3-(3-aminopropyl)-1-[(4-methoxyphenyl)methyl]-2-oxo- benzimidazol-4-yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 83c, 226 mg, 0.37 mmol) in DMF (6 mL) and MeCN (300 mL) dropwise at 0 °C, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. The reaction mixture was concentrated in vacuo to give some residue. The residue was diluted with water, the collected solid was filtered and dried, compound 83d (224 mg) was obtained as a brown foam which was directly used in next step without purification, LCMS (M+H)+: 599. Step 5: preparation of (8S,11S)-19-[(4-methoxyphenyl)methyl]-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;2,2,2-trifluoroacetic acid (compound 83e) A mixture of tert-butyl (8S,11S)-19-[(4-methoxyphenyl)methyl]-12,18-dioxo-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-10- carboxylate (compound 83d, 224 mg, 0.36 mmol) and TFA (0.8 mL) in DCM (6 mL) was stirred at room temperature for 2 hrs. After removing excess solvent and TFA under reduced pressure, compound 83e (319 mg) was obtained as a brown oil, which was directly used for next step without purification, LCMS (M+H)+: 499. Step 6: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-19-[(4-methoxyphenyl)methyl]-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 (compound 83f) A mixture of (8S,11S)-19-[(4-methoxyphenyl)methyl]-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;2,2,2-trifluoroacetic acid (compound 83e, 319 mg, 0.34 mmol), 4-chloro-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 120 mg, 0.41 mmol) and DIPEA (219 mg, 1.69 mmol) in DMSO (3 mL) was heated to 90 °C for 30 mins. After being cooled to room temperature, the reaction mixture was diluted with water. The resulted precipitation was filtered, the collected solid was collected and dried, compound 83f (278 mg) was obtained as a brown foam which was directly used in next step without purification, LCMS (M+H)+: 729. Step 7: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- yl]-19-[(4-methoxyphenyl)methyl]-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 (compound 83g) To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-[(4- methoxyphenyl)methyl]-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 (compound 83f, 80 mg, 0.09 mmol) and 4-(2- bromoethyl)morpholine (85 mg, 0.44 mmol) in DMF (1 mL) was added sodium hydride (18 mg, 0.44 mmol), the resulting mixture was stirred at room temperature for 5 hrs. The reaction mixture was quenched by MeOH and then diluted with water, extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to afford compound 83g (239 mg) as a brown oil, which was directly used for next step without purification, LCMS (M+H)+: 842. Step 8: preparation of (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 (Example 83) A solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-19-[(4- methoxyphenyl)methyl]-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 (compound 83g, 239 mg, 0.08 mmol) in TFA (0.5 mL) was heated to 80 °C for 16 hrs. After removing TFA under reduced pressure, the residue was dissolved in DCM and then basified by saturated sodium bicarbonate aqueous solution. The separated organic layer was washed with brine, dried, concentrated to give some crude. The crude was purified by prep-HPLC to afford Example 83 (9 mg) desired product as a light-yellow solid, LCMS (M+H)+: 722.1H NMR (400 MHz, METHANOL-d4) δ = 8.63 - 8.55 (m, 1H), 8.27 - 8.22 (m, 1H), 7.68 (m, 1H), 7.52 - 7.46 (m, 1H), 7.29 (m, 1H), 7.25 - 7.17 (m, 2H), 7.15 - 7.07 (m, 2H), 6.99 (s, 1H), 6.90 (m, 1H), 6.87 - 6.81 (m, 1H), 5.68 - 5.39 (m, 2H), 4.61 - 4.48 (m, 2H), 4.15 - 3.34 (m, 16H), 2.94 - 2.36 (m, 4H). Example 84 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 5-bromo-3-(3-chloropropyl)imidazo[1,2-a]pyridine (compound 84a) A mixture of 6-bromopyridin-2-amine (1.56 g, 9 mmol) and 2,5-dichloropentanal (2.09 g, 9.45 mmol) in EtOH (50 mL) was heated to 120 °C for 4 hrs. After removing excess solvent under reduced pressure, the residue was purified by flash column chromatography to afford compound 84a (1.65 g) as a yellow solid, LCMS (M+H)+: 273. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3- chloropropyl)imidazo[1,2-a]pyridin-5-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 84b) A mixture of 5-bromo-3-(3-chloropropyl)imidazo[1,2-a]pyridine (compound 84a, 410 mg, 1.5 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B8, 738 mg, 1.65 mmol), PdCl2(DPPF)- CH2Cl2 adduct (55 mg, 0.08 mmol) and potassium carbonate (622 mg, 4.5 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 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 water and brine, dried, concentrated to give some crude product, which was then purified by flash column chromatography to afford compound 84b (766 mg) as a brown oil, LCMS (M+H)+: 514. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin- 2-yl)propyl]imidazo[1,2-a]pyridin-5-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 84c) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-chloropropyl)imidazo[1,2- a]pyridin-5-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 84b, 766 mg, 1.27 mmol), potassium phthalimide (258 mg, 1.39 mmol) and sodium iodide (380 mg, 2.53 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. The crude was precipitated from EtOAc/hexane to give compound 84c (831 mg) as a brown oil, which was directly used for next step without further purification, LCMS (M+H)+: 625. Step 4-8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-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 (compound 84h) The title compound was prepared in analogy to the preparation of compound 81e by using compound 84c instead of compound 81a, LCMS (M+H)+: 593. Step 9: preparation of (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 (Example 84) To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-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 (compound 84h, 72 mg, 0.08 mmol) and 4-(2-bromoethyl)morpholine (83 mg, 0.42 mmol) in DMF (0.6 mL) was added sodium hydride (10 mg, 0.25 mmol), the resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was directly purified by prep- HPLC to afford Example 84 (18 mg) as a yellow solid, LCMS (M+H)+: 706.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.19 (m, 2H), 7.69 - 7.44 (m, 4H), 7.40 - 7.10 (m, 5H), 6.86 - 6.72 (m, 2H), 5.65 - 5.29 (m, 2H), 4.60 - 4.31 (m, 3H), 3.77 - 3.32 (m, 7H), 3.08 - 2.91 (m, 2H), 2.85 - 2.70 (m, 2H), 2.68 - 2.45 (m, 5H), 2.15 - 1.87 (m, 3H). Example 85 (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 The title compound was prepared according to the following scheme: To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa- 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 (compound 84h, 72 mg, 0.08 mmol) and 1-bromo-3-methoxypropane (65 mg, 0.42 mmol) in DMF (0.6 mL) was added sodium hydride (10 mg, 0.25 mmol), the resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was directly purified by prep- HPLC to afford Example 85 (12 mg) as a white solid, LCMS (M+H)+: 665.1H NMR (400 MHz, DMSO-d6) δ = 8.63 (s, 1H), 8.19 (s, 1H), 7.77 - 7.66 (m, 1H), 7.63 - 7.42 (m, 4H), 7.36 - 7.27 (m, 2H), 7.24 - 7.17 (m, 1H), 7.12 (m, 1H), 6.73 (m, 1H), 6.59 (s, 1H), 5.58 (m, 1H), 5.22 (m, 1H), 4.47 - 4.28 (m, 2H), 4.18 - 4.06 (m, 1H), 3.52 - 3.44 (m, 1H), 3.42 - 3.35 (m, 2H), 3.24 (s, 3H), 3.13 - 3.04 (m, 1H), 2.78 - 2.65 (m, 2H), 2.35 - 2.24 (m, 2H), 2.06 - 1.80 (m, 4H), 1.66 - 1.50 (m, 1H). Example 86 (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 The title compound was prepared according to the following scheme: To a mixture of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7-oxa- 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 (compound 84h, 72 mg, 0.08 mmol) and 4-(chloromethyl)thiazole;hydrochloride (43 mg, 0.25 mmol) in DMF (0.6 mL) was added sodium hydride (10 mg, 0.25 mmol), the resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was directly purified by prep-HPLC to afford Example 86 (16 mg) as a white solid, LCMS (M+H)+: 690.1H NMR (400 MHz, DMSO-d6) δ = 9.20 - 9.00 (m, 1H), 8.66 - 8.16 (m, 2H), 7.96 - 7.80 (m, 1H), 7.76 - 7.65 (m, 1H), 7.63 - 7.50 (m, 3H), 7.49 - 7.40 (m, 1H), 7.38 - 7.27 (m, 2H), 7.25 - 7.11 (m, 2H), 7.06 - 6.57 (m, 2H), 5.65 - 5.52 (m, 1H), 5.50 - 4.80 (m, 2H), 4.75 - 3.86 (m, 5H), 3.04 - 2.89 (m, 1H), 2.82 - 2.62 (m, 2H), 2.05 - 1.86 (m, 3H). Example 87 (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 The title compound was prepared in analogy to the preparation of Example 81 by using intermediate A22 instead of intermediate A20, Intermediate B8 instead of Intermediate B10, methyl iodide instead of (3-iodopropyl)benzene. Example 87 (12 mg) as a yellow solid, LCMS (M+H)+: 640.1H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.19 (m, 2H), 7.77 - 7.66 (m, 3H), 7.63 - 7.55 (m, 1H), 7.50 - 7.42 (m, 1H), 7.36 - 7.17 (m, 2H), 7.07 - 7.01 (m, 1H), 6.86 - 6.75 (m, 2H), 5.62 - 5.30 (m, 2H), 4.49 - 4.11 (m, 2H), 3.96 - 3.82 (m, 2H), 2.97 - 2.82 (m, 4H), 2.80 - 2.53 (m, 4H), 2.20 - 2.05 (m, 1H). Example 88 (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 The title compound was prepared in analogy to the preparation of Example 81 by using intermediate A23 instead of intermediate A20, Intermediate B8 instead of Intermediate B10, methyl iodide instead of (3-iodopropyl)benzene. Example 88 (12 mg) as a white solid, LCMS (M+H)+: 607.1H NMR (500 MHz, METHANOL-d4) δ = 8.54 - 8.19 (m, 3H), 7.92 - 7.77 (m, 1H), 7.69 - 7.59 (m, 1H), 7.50 (m, 1H), 7.31 - 7.15 (m, 3H), 7.04 - 6.93 (m, 3H), 6.85 (m, 1H), 5.65 - 5.44 (m, 2H), 4.57 - 4.12 (m, 3H), 3.16 - 3.02 (m, 3H), 3.00 - 2.23 (m, 7H). Example 89 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3- [benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4- b]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 89a) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine- 1,2-dicarboxylate (Intermediate B5, 602 mg, 1.50 mmol), [[3-[3- [benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4- b]pyridin-4-yl]boronic acid (intermediate A24, 1.0 g, 1.00 mmol), PdCl2(DPPF)-CH2Cl2 adduct (100 mg, 0.12 mmol) and potassium phosphate (426 mg, 2.01 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100°C for 2 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 89a (600 mg) as a light brown oil, LCMS (M+H)+: 774. Step 2: preparation of (2S,4S)-4-[[6-[3-[3-[benzyloxycarbonyl(methyl)amino]propyl]- 2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]-2-pyridyl]amino]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 89b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[3-[3- [benzyloxycarbonyl(methyl)amino]propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4- b]pyridin-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 89a, 600 mg, 0.78 mmol) and lithium hydroxide monohydrate (186 mg, 7.8 mmol) in methanol (10 mL) and water (2 mL) 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 compound 89b (500 mg) as a light yellow solid, LCMS (M+H)+: 760. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[3-[3- (methylamino)propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 89c) A mixture of (2S,4S)-4-[[6-[3-[3-[benzyloxycarbonyl(methyl)amino]propyl]-2-(2- trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]-2-pyridyl]amino]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 89b, 250 mg, 0.33 mmol) and Pd/C (100 mg) in THF (10 mL) and isopropanol (100 mL) was stirred at 60 °C for 4 hrs under hydrogen. And the reaction mixture was stirred at 60 °C for 4 hrs. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to get crude compound 89c (210 mg) as a brown oil, which was used in next step directly, LCMS (M+H)+: 626. Step 4: preparation of tert-butyl (8S,11S)-13-methyl-12-oxo-18-(2- trimethylsilylethoxymethyl)-7,10,13,18,19,21,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 89d) To a solution of HATU (83 mg, 0.35 mmol), DIPEA (0.1 mL, 0.35 mmol) in DMF (100 mL) were added in one portion at 0 °C.10 mins later, the (2S,4S)-1-tert-butoxycarbonyl-4-[[6- [3-[3-(methylamino)propyl]-2-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 89c, 200 mg, 0.32 mmol) in DMF (100 mL) was added dropwise into the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated in vacuo to get the crude product, which was purified by reversed-phase flash column to afford compound 89d (170 mg) as a brown solid, LCMS (M+H)+: 608. Step 5: preparation of (8S,11S)-13-methyl-7,10,13,18,19,21,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,20(24),21-heptaen-12- one (compound 89e) A mixture of tert-butyl (8S,11S)-13-methyl-12-oxo-18-(2-trimethylsilylethoxymethyl)- 7,10,13,18,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaene-10-carboxylate (compound 89d, 170 mg, 0.28 mmol) and TFA (5 mL) in DCM (9 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo, then ammonium hydroxide (3.0 mL, 0.28 mmol) in 1,4-dioxane (3 mL) were added. The resulting mixture was stirred at room temperature for 1 hr, then concentrated under reduced pressure to give some residue. The residue was diluted with MeOH, dried over anhydrous Na2SO4, concentrated to get crude compound 89e (120 mg) as a brown solid, which was used in next step directly, LCMS (M+H)+: 378. Step 6: preparation of (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 (Example 89) A mixture of (8S,11S)-13-methyl-7,10,13,18,19,21,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,20(24),21-heptaen-12-one (compound 89e, 68 mg, 0.18 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 40 mg, 0.15 mmol) and DIPEA (0.2 mL) in NMP (1.5 mL) was heated to 80 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was filtered, and filtrate was purified by prep-HPLC to afford Example 89 (10 mg) as a white solid, LCMS (M+H)+: 608.1H NMR (400 MHz, DMSO-d6) δ = 13.37 - 13.33 (m, 1H), 8.60 (s, 1H), 8.50 (m, 1H), 8.24 (s, 1H), 7.83 - 7.75 (m, 2H), 7.63 - 7.58 (m, 1H), 7.36 - 7.30 (m, 1H), 7.21 (m, 1H), 7.04 - 7.00 (m, 1H), 6.95 (m, 1H), 5.76 - 5.68 (m, 1H), 5.54 - 5.48 (m, 1H), 4.90 (s, 1H), 4.61 - 4.51 (m, 1H), 4.32 - 4.25 (m, 1H), 4.15 - 4.10 (m, 1H), 3.17 (s, 1H), 3.06 (s, 3H), 2.96 - 2.91 (m, 2H), 2.86 - 2.81 (m, 2H), 1.70 (s, 2H). Example 90 (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 The title compound was prepared in analogy to the preparation of Example 89 by using intermediate A25 instead of intermediate A24. Example 90 (10 mg) as a white solid, LCMS (M+H)+: 607.1H NMR (400 MHz, DMSO-d6) δ = 12.82 - 12.72 (m, 1H), 8.70 - 8.60 (m, 1H), 8.42 - 8.34 (m, 1H), 8.30 - 8.24 (m, 1H), 7.76 - 7.70 (m, 2H), 7.63 - 7.57 (m, 1H), 7.49 (m, 1H), 7.36 - 7.31 (m, 1H), 7.11 - 7.03 (m, 1H), 6.91 - 6.86 (m, 1H), 6.84 - 6.75 (m, 1H), 5.68 - 5.56 (m, 1H), 5.55 - 5.39 (m, 1H), 4.88 - 4.69 (m, 1H), 4.61 - 4.48 (m, 1H), 4.31 - 4.24 (m, 1H), 4.16 - 4.07 (m, 1H), 3.17 (s, 1H), 3.07 - 3.04 (m, 3H), 2.92 - 2.86 (m, 2H), 2.82 - 2.77 (m, 2H), 1.84 - 1.69 (m, 1H). Example 91 (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 The title compound was prepared according to the following scheme: Step 1: preparation of [2-methyl-3-[2-(methylamino)ethylamino]indazol-4-yl]boronic acid (compound 91a) A mixture of [3-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-methyl-indazol-4- yl]boronic acid (intermediate A26, 340 mg, 0.98 mmol) and 4 M HCl in 1,4-dioxane (5 mL, 20.0 mmol) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give compound 91a (220 mg) as a yellow solid, which was used in next step directly, LCMS (M+H)+: 249. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-methyl-3-[2- (methylamino)ethylamino]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 91b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine- 1,2-dicarboxylate (Intermediate B5, 300 mg, 0.75 mmol), [2-methyl-3-[2- (methylamino)ethylamino]indazol-4-yl]boronic acid (compound 91a, 200 mg, 0.81 mmol), Pd(dppf)Cl2 (60 mg, 0.09 mmol) and potassium phosphate (300 mg, 2.20 mmol) in 1,4-dioxane (7 mL) and water (0.5 mL) was stirred at 100 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was diluted with EtOAc. Then washed with water and brine, dried over anhydrous Na2SO4, concentrated to get crude product, which was purified by prep- HPLC to give compound 91b (301 mg) as a yellow oil, LCMS (M+H)+: 524. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[2-methyl-3-[2- (methylamino)ethylamino]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 91c) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-methyl-3-[2- (methylamino)ethylamino]indazol-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 91b, 300 mg, 0.57 mmol) and lithium hydroxide monohydrate (200 mg, 4.76 mmol) in methanol (5 mL) and water (1 mL) was stirred at room temperature for 12 hrs. The reaction mixture was acidified by 1N aq. HCl solution to PH~5, and then directly purified by prep-HPLC to give compound 91c (150 mg) as a yellow solid, LCMS (M+H)+: 510. Step 4-6: preparation of (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 (Example 91) The title compound was prepared in analogy to the preparation of Example 89 by using compound 91c instead of compound 89c. Example 91 (48 mg) as a yellow solid, LCMS (M+H)+: 622.1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1 H), 8.26 (s, 1 H), 7.76 - 7.80 (m, 1 H), 7.64 - 7.66 (m, 1 H), 7.40 - 7.46 (m, 1 H), 7.16 - 7.29 (m, 5 H), 6.72 - 6.74 (m, 1 H), 5.55 - 5.57 (m, 1 H), 4.75 (m, 1 H), 4.56 - 4.66 (m, 2 H), 4.21 - 4.24 (m, 1 H), 3.99 (s, 3 H), 3.21 (m, 1 H), 3.11 (s, 3 H), 2.96 - 3.00 (m, 2 H), 2.61 - 2.67(m, 1 H), 2.43 - 2.47 (m, 1 H). Example 92 (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 The title compound was prepared in analogy to the preparation of Example 89 by using intermediate A27 instead of intermediate A24. Example 92 (18 mg) as a white solid, LCMS (M+H)+: 625.1H NMR (400 MHz, METHANOL-d4) δ = 8.52 (s, 1H), 8.23 (s, 1H), 7.79 (m, 1H), 7.67 - 7.63 (m, 1H), 7.31 - 7.26 (m, 1H), 7.23 - 7.18 (m, 1H), 7.13 - 7.08 (m, 2H), 6.93 - 6.90 (m, 1H), 6.83 - 6.80 (m, 1H), 5.55 (m, 1H), 4.62 (m, 2H), 4.42 - 4.36 (m, 1H), 4.26 (m, 1H), 3.24 (s, 1H), 3.14 (s, 3H), 2.92 - 2.85 (m, 2H), 2.71 - 2.58 (m, 2H), 2.39 (m, 1H), 1.83 - 1.77 (m, 1H). Example 93 (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 The title compound was prepared in analogy to the preparation of Example 89 by using intermediate A28 instead of intermediate A24. Example 93 (62 mg) as a white solid, LCMS (M+H)+: 641.1H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.25 (s, 1H), 7.75 - 7.70 (m, 2H), 7.62 - 7.57 (m, 1H), 7.35 - 7.30 (m, 1H), 6.94 - 6.91 (m, 2H), 6.79 - 6.75 (m, 1H), 6.72 (m, 1H), 5.46 (m, 2H), 4.67 (m, 1H), 4.53 - 4.47 (m, 1H), 4.37 - 4.29 (m, 1H), 4.21 - 4.14 (m, 1H), 3.88 - 3.82 (m, 1H), 3.50 (m, 1H), 3.02 (s, 1H), 2.93 (s, 3H), 2.74 - 2.67 (m, 1H), 2.04 - 1.92 (m, 1H), 1.79 - 1.65 (m, 1H). Example 94 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-(2- fluoro-3-nitro-phenyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 94a) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (Intermediate B6, 1.3 g, 2.70 mmol), 2-(2- fluoro-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.6 g, 2.25 mmol) and sodium carbonate (476 mg, 4.5 mmol) in 1,4-dioxane (25 mL) and water (0.1 mL) was added Pd(dppf)Cl2 (150 mg, 0.4 mmol), the resulting mixture was stirred at 85 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was poured into water, then extracted with EtOAc for 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 94a (1.2 g) as colorless oil, LCMS (M+H)+: 561. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2- [3-(dimethylamino)propoxy]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound 94b) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-(2-fluoro-3- nitro-phenyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 94a, 550 mg, 1.0 mmol) and 2-trimethylsilylethyl N-(3-hydroxypropyl)-N-methyl-carbamate (intermediate A29, 275 mg, 1.2 mmol) in DMF (4 mL) were added sodium hydride (35 mg, 1.47 mmol) slowly at 0 °C, the resulting mixture was stirred at 0 °C for 2 hrs. The reaction mixture was poured into saturated ammonium chloride solution and then extracted with EtOAc for 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 94b (750 mg) as a yellow oil, LCMS (M+H)+: 774. Step 3: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[2-[3- (dimethylamino)propoxy]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 94c) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2-[3- (dimethylamino)propoxy]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 94b, 750 mg, 0.97 mmol) in methanol (5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (232 mg, 9.7 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into saturated ammonium chloride solution and then extracted with EtOAc for twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give compound 94c (0.6 g) as a yellow oil, LCMS (M+H)+: 760. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[2-[3- (methylamino)propoxy]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 94d) A mixture of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[2-[3- (dimethylamino)propoxy]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 94c, 0.7 g, 0.9 mmol) and 1 M TABF in THF (6 mL), the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, the filtrate was purified by reversed-phase flash column chromatography to give compound 94d (0.5 g) as a yellow solid, LCMS (M+H)+: 616. Step 5-7: preparation of (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 (Example 94) The title compound was prepared in analogy to the preparation of Example 89 by using compound 94d instead of compound 89c. Example 94 (46 mg) was obtained as a white solid, LCMS (M+H)+: 628.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 - 8.11 (m, 2H), 7.81 - 7.47 (m, 4H), 7.40 - 7.24 (m, 2H), 7.23 - 7.05 (m, 1H), 6.93 - 6.43 (m, 2H), 5.48 - 5.23 (m, 1H), 4.54 - 4.19 (m, 3H), 3.84 - 3.64 (m, 1H), 3.52 - 3.41 (m, 2H), 3.20 - 2.79 (m, 2H), 2.77 - 2.56 (m, 2H), 2.40 - 1.61 (m, 4H). Example 95 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2- [methyl-[3-(methylamino)propyl]amino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound 95a) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-(2-fluoro-3- nitro-phenyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 94a, 550 mg, 1.0 mmol,) and N,N'-dimethylpropane-1,3-diamine (120 mg, 1.2 mmol) in DMF (4 mL) was added DIEA (0.2 g, 1.5 mmol), the resulting mixture was stirred at 0 °C for 2 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 give compound 95a (600 mg) as an orange oil, LCMS (M+H)+: 643. Step 2: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[2- [methyl-[3-(methylamino)propyl]amino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 95b) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2-[methyl-[3- (methylamino)propyl]amino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 95a, 600 mg, 0.9 mmol) in methanol (5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (224 mg, 9.3 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was filtered, and then purified by reversed-phase flash column chromatography to give compound 95b (500 mg) as a yellow solid, LCMS (M+H)+: 629. Step 3-5: preparation of (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 (Example 95) The title compound was prepared in analogy to the preparation of Example 89 by using compound 95b instead of compound 89c. Example 95 (16 mg) as a yellow solid, LCMS (M+H)+: 641.1H NMR (400 MHz, DMSO-d6) δ = 8.39 - 8.35 (m, 1H), 8.66 - 8.35 (m, 1H), 8.26 (s, 1H), 8.32 - 8.22 (m, 1H), 7.75 - 7.70 (m, 1H), 7.82 - 7.66 (m, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.88 - 7.27 (m, 2H), 6.83 (m, 1H), 6.80 (s, 1H), 5.72 (m, 1H), 5.45 - 5.36 (m, 1H), 5.80 - 5.34 (m, 1H), 4.90 - 4.41 (m, 1H), 4.15 - 3.96 (m, 2H), 3.15 - 3.03 (m, 3H), 2.86 - 2.78 (m, 1H), 2.68 (m, 1H), 2.14 (s, 1H), 2.16 - 2.03 (m, 1H), 2.05 (s, 1H), 1.93 (m, 1H), 1.64 - 1.41 (m, 1H). Example 96 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-(3- cyano-2-fluoro-phenyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 96a) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (Intermediate B6, 1.2 g, 2.5 mmol), 2- fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.6 g, 2.4 mmol) and sodium carbonate (515 mg, 4.9 mmol) in 1,4-dioxane (25 mL) and water (0.1 mL) was added Pd(dppf)Cl2 (150 mg, 0.2 mmol), the resulting mixture was stirred at 100 °C for 12 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 96a (1.3 g) as colorless oil, LCMS (M+H)+: 541. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-[3- [benzyloxycarbonyl(methyl)amino]propylamino]-3-cyano-phenyl]-2-pyridyl]-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 96b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-(3-cyano-2- fluoro-phenyl)-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 96a, 1.0 g, 1.8 mmol), benzyl N-(3-aminopropyl)-N-methyl-carbamate (intermediate A30, 0.5 g, 2.2 mmol) and potassium carbonate (0.5 g, 3.70 mmol) in DMF (10 mL) was stirred at 80 °C for 12 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 96b (1.0 g) as a light yellow oil, LCMS (M+H)+: 743. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[3- cyano-2-[3-(methylamino)propylamino]phenyl]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound 96c) The solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-[3- [benzyloxycarbonyl(methyl)amino]propylamino]-3-cyano-phenyl]-2-pyridyl]-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 96b, 0.9 g, 1.2 mmol) and Pd/C (150 mg) in THF (6 mL) and isopropanol (6 mL) was stirred at 50 °C for 2 hrs under hydrogen. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 96c (0.6 g) as a light yellow oil, LCMS (M+H)+: 609. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3- cyano-2-[3-(methylamino)propylamino]phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 96d) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[3-cyano-2-[3- (methylamino)propylamino]phenyl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 96c, 0.7 g, 1.2 mmol) in methanol (5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (241 mg, 5.8 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was partitioned between EtOAc and water, acidified by 1N aq. HCl solution to PH~6, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give compound 96d (0.5 g) as a white solid, LCMS (M+H)+: 595. Step 5-7: preparation of (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 (Example 96) The title compound was prepared in analogy to the preparation of Example 89 by using compound 96d instead of compound 89c. Example 96 (18 mg) as a white solid, LCMS (M+H)+: 607.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.23 (m, 2H), 7.78 - 7.51 (m, 4H), 7.32 - 7.16 (m, 2H), 7.03 - 6.75 (m, 3H), 5.49 (m, 1H), 4.78 - 4.74 (m, 2H), 4.52 (m, 1H), 4.30 (m, 1H), 3.22 - 3.01 (m, 4H), 2.96 - 2.81 (m, 2H), 2.69 - 2.54 (m, 1H), 2.33 - 2.03 (m, 2H), 1.75 - 1.65 (m, 1H). Example 97 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2- fluoro-3-(trifluoromethyl)phenyl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 97a) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (Intermediate B6, 0.5 g, 1.0 mmol), 2-[2- fluoro-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 g, 1.0 mmol) and sodium carbonate (204 mg, 1.9 mmol) in 1,4-dioxane (15 mL) and water (0.1 mL) was added Pd(dppf)Cl2 (80 mg, 0.11 mmol), the resulting mixture was stirred at 80 °C for 12 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 97a (0.5 g) as a light yellow oil, LCMS (M+H)+: 584. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-[3- [benzyloxycarbonyl(methyl)amino]propylamino]-3-(trifluoromethyl)phenyl]-2-pyridyl]- tert-butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 97b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[6-[2-fluoro-3- (trifluoromethyl)phenyl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 97a, 450 mg, 0.77 mmol), benzyl N-(3-aminopropyl)-N-methyl-carbamate (intermediate A30, 343 mg, 1.54 mmol) and potassium carbonate (533 mg, 3.86 mmol) in DMSO (10 mL) was stirred at 120 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give crude product, which was purified by column chromatography to afford compound 97b (150 mg) as a colorless oil, LCMS (M+H)+: 786. Step 3: preparation of (2S,4S)-4-[[6-[2-[3- [benzyloxycarbonyl(methyl)amino]propylamino]-3-(trifluoromethyl)phenyl]-2-pyridyl]- tert-butoxycarbonyl-amino]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 97c) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[2-[3- [benzyloxycarbonyl(methyl)amino]propylamino]-3-(trifluoromethyl)phenyl]-2-pyridyl]-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 97b, 150.0 mg, 0.19 mmol) in methanol (3 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (80 mg, 1.91 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into water, then extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give compound 97c (140 mg) as a colorless oil, LCMS (M+H)+: 772. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[2-[3- (methylamino)propylamino]-3-(trifluoromethyl)phenyl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 97d) The solution of (2S,4S)-4-[[6-[2-[3-[benzyloxycarbonyl(methyl)amino]propylamino]-3- (trifluoromethyl)phenyl]-2-pyridyl]-tert-butoxycarbonyl-amino]-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 97c, 120.0 mg, 0.16 mmol) and Pd/C (50 mg) in THF (6 mL) and isopropanol (6 mL) was stirred at 50 °C for 1 hr under hydrogen. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 97d (95 mg) as a colorless oil, LCMS (M+H)+: 638. Step 5-7: preparation of (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 (Example 97) The title compound was prepared in analogy to the preparation of Example 89 by using compound 97d instead of compound 89c. Example 97 (17 mg) as a white solid, LCMS (M+H)+: 650.1H NMR (400 MHz, METHANOL-d4) δ = 8.52 (s, 1H), 8.37 - 8.15 (m, 1H), 7.77 - 7.70 (m, 1H), 7.69 - 7.62 (m, 1H), 7.57 (m, 2H), 7.31 - 7.25 (m, 1H), 7.22 - 7.09 (m, 2H), 6.87 - 6.66 (m, 2H), 5.46 - 5.39 (m, 1H), 4.73 (m, 1H), 4.69 - 4.40 (m, 3H), 4.33 - 4.27 (m, 1H), 3.16 - 3.01 (m, 3H), 2.74 (m, 1H), 2.65 - 2.56 (m, 1H), 2.40 (m, 1H), 2.35 - 2.25 (m, 1H), 1.85 - 1.74 (m, 1H), 1.66 - 1.56 (m, 1H). Example 98 (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 The title compound was prepared according to the following scheme: Step 1: preparation of methyl (14S,17S)-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-carboxylate (compound 98a) To a solution of ditert-butyl (14S,17S)-6-cyano-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-15,18-dicarboxylate (compound 96e, 200 mg, 0.35 mmol) in methanol (2 mL) was added con. sulfuric acid (2 mL) dropwise at room temperature. The mixture was stirred at 80 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was poured into water and then neutralized by saturated sodium bicarbonate aqueous solution. The mixture was freeze-dried to obtain compound 98a (120 mg) as a light yellow solid, which was used in next step directly, LCMS (M+H)+: 410. Step 2: preparation of methyl (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-carboxylate (compound 98b) A mixture of methyl (14S,17S)-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-carboxylate (compound 98a, 101 mg, 0.25 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 55.0 mg, 0.2 mmol) and DIPEA (266 mg, 2.1 mmol) in NMP (3 mL) was stirred at 80 °C for 2 hrs. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was purified by reversed flash column to give compound 98b (90 mg) as a white solid, LCMS (M+H)+: 640. Step 3: preparation of (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-carboxylic acid (compound 98c) To a solution of methyl (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-carboxylate (compound 98b, 80 mg, 0.13 mmol) in methanol (10 mL) and water (1 mL) was added lithium hydroxide monohydrate (52 mg, 1.3 mmol), the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was neutralized by 1N aq. HCl solution to PH~7, then directly purified by prep-HPLC to give compound 98c (40 mg) as a light yellow solid, LCMS (M+H)+: 626. Step 4: preparation of (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 (Example 98) A mixture of (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-carboxylic acid (compound 98c, 30 mg, 0.05 mmol), methylamine hydrochloride (7 mg, 0.10 mmol), HATU (17 mg, 0.07 mmol) and DIPEA (62 mg, 0.48 mmol) in DMF (2 mL) was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure to give some crude product, which was purified by prep-HPLC to afford Example 98 (11 mg) as a yellow solid, LCMS (M+H)+: 639.1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1 H), 8.23 (s, 1 H), 7.82 (m, 1 H), 7.62 - 7.71 (m, 2 H), 7.46 - 7.55 (m, 1 H), 7.16 - 7.32 (m, 2 H), 7.07 (m, 1 H), 6.94 (m, 1 H), 6.83 (m, 1 H), 5.44 (m, 1 H), 4.59 - 4.78 (m, 3 H), 4.49 (m, 1 H), 4.32 (m, 1 H), 3.05 - 3.18 (m, 3 H), 2.89 - 2.93 (m, 3 H), 2.76 - 2.84 (m, 1 H), 2.59 - 2.68 (m, 1 H), 2.41 - 2.52 (m, 2 H), 1.68 - 1.84 (m, 2 H). Example 99 (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 The title compound was prepared according to the following scheme: The title compound was prepared in analogy to the preparation of Example 91 by using intermediate A31 instead of intermediate A31 and Intermediate C9 instead of intermediate C2. Example 99 (18 mg) as a white solid, LCMS (M+H)+: 619.1H NMR (400 MHz, METHANOL- d4) δ = 8.48 (s, 1 H), 8.19 (s, 1 H), 8.13 (s, 1 H), 7.79 - 7.86 (m, 2 H), 7.46 (m, 1 H), 7.38 (m, 1 H), 7.17 - 7.27 (m, 1 H), 7.07 (m, 1 H), 6.79 - 6.97 (m, 3 H), 5.54 (m, 1 H), 4.79 (m, 1 H), 4.51 - 4.59 (m, 1 H), 4.11 - 4.43 (m, 3 H), 3.77 (s, 3 H), 2.75 - 3.22 (m, 4 H), 2.49 - 2.71 (m, 3 H), 1.65 - 1.80 (m, 2 H). Example 100 (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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-[2-[[5-(6-chloro-2-pyridyl)-1-methyl-imidazol-4- yl]methoxy]ethyl]-N-methyl-carbamate (compound 100a) A mixture of benzyl N-[2-[(5-bromo-1-methyl-imidazol-4-yl)methoxy]ethyl]-N-methyl- carbamate (intermediate A32, 0.5 g, 1.3 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (0.5 g, 2.0 mmol), Pd-Ad2nBuP Biphenyl (0.1 g, 0.02 mmol) and potassium phosphate (0.6 g, 2.6 mmol) in THF (10 mL) and water (1 mL) was stirred at 60 °C for 2 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 100a (0.4 g) as a light brown oil, LCMS (M+H)+: 437. Step 2: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[5-[2- [benzyloxycarbonyl(methyl)amino]ethoxymethyl]-3-methyl-imidazol-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 100b) A mixture of benzyl N-[2-[[5-(6-chloro-2-pyridyl)-1-methyl-imidazol-4- yl]methoxy]ethyl]-N-methyl-carbamate (compound 100a, 251 mg, 0.9 mmol), O1-tert-butyl O2- methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (0.3 g, 0.7 mmol), Pd2(dba)3 (150 mg, 0.16 mmol), S-phos (150 mg, 0.36 mmol) and cesium carbonate (471 mg, 1.45 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C for 2 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 100b (0.2 g) as a light brown oil, LCMS (M+H)+: 623. Step 3-7: preparation of (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 (Example 100) The title compound was prepared in analogy to the preparation of Example 89 by using compound 100b instead of compound 89a. Example 100 (4.4 mg) as a white solid, LCMS (M+H)+: 587.1H NMR (400 MHz, METHANOL-d4) δ = 8.34 - 8.42 (m, 1 H), 8.14 - 8.23 (m, 1 H), 7.60 - 7.67 (m, 2 H), 7.13 - 7.39 (m, 3 H), 6.72 - 6.87 (m, 1 H), 6.25 - 6.39 (m, 1 H), 5.22 - 5.32 (m, 1 H), 4.18 - 4.48 (m, 4 H), 4.01 (m, 1 H), 3.69 - 3.91 (m, 4 H), 3.33 - 3.57 (m, 3 H), 3.00 - 3.25 (m, 3 H), 2.41 - 2.79 (m, 1 H), 1.78 - 2.00 (m, 1 H). Example 101 (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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-[3-[[4-(6-chloro-2-pyridyl)thiazole-5- carbonyl]amino]propyl]-N-methyl-carbamate (compound 101a) A mixture of benzyl N-[3-[(4-bromothiazole-5-carbonyl)amino]propyl]-N-methyl- carbamate (intermediate A33, 0.6 g, 1.5 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (418 mg, 1.7 mmol), Pd-Ad2nBuP Biphenyl (150 mg, 0.02 mmol) and potassium phosphate (618 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 100 °C for 2 hrs. After being cooled to room temperature, 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 crude product, which was purified by column chromatography to afford compound 101a (0.6 g) as a light yellow oil, LCMS (M+H)+: 445. Step 2: preparation of (2S,4S)-4-[[6-[5-[3- [benzyloxycarbonyl(methyl)amino]propylcarbamoyl]thiazol-4-yl]-2-pyridyl]amino]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 101b) A mixture of benzyl N-[3-[[4-(6-chloro-2-pyridyl)thiazole-5-carbonyl]amino]propyl]-N- methyl-carbamate (compound 101a, 0.3 g, 0.67 mmol), O1-tert-butyl O2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (284 mg, 1.01 mmol), Pd2(dba)3 (80 mg, 0.09 mmol), S-phos (80 mg, 0.20 mmol) and cesium carbonate (659 mg, 2.02 mmol) in 1,4-dioxane (6 mL) was stirred at 100 °C for 2 hrs. After being cooled to room temperature, 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 crude product, which was purified by reversed-phase flash column to afford compound 101b (0.2 g) as a brown oil, LCMS (M+H)+: 639. Step 3-6: preparation of (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 (Example 101) The title compound was prepared in analogy to the preparation of Example 89 by using compound 100b instead of compound 89b. Example 101 (4.8 mg) as a pink solid, LCMS (M+H)+: 617.1H NMR (400 MHz, METHANOL-d4) δ = 9.01 - 9.07 (m, 1 H), 8.45 - 8.60 (m, 1 H), 8.11 - 8.37 (m, 1 H), 7.51 - 7.81 (m, 2 H), 7.14 - 7.42 (m, 3 H), 6.61 - 7.05 (m, 1 H), 5.25 - 5.65 (m, 1 H), 4.93 - 5.00 (m, 1 H), 3.94 - 4.59 (m, 3 H), 3.58 - 3.66 (m, 1 H), 2.71 - 3.27 (m, 6 H), 1.95 - 2.26 (m, 2 H), 1.54 - 1.84 (m, 1 H). Example 102 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(6-bromobenzimidazol-1-yl)propyl]carbamate (compound 102a) A mixture of 5-bromo-1H-benzo[d]imidazole (1 g, 5.08 mmol), tert-butyl (3- bromopropyl)carbamate (1.2 g, 5.08 mmol) and K2CO3 (1.4 g, 10.2 mmol) in MeCN (20 mL) was stirred at 80 oC for 12 hours, then the solid was filtered off and the filtrate was concentrated, the residue was purified by SFC to give compound 102a (550 mg, faster eluted) and 102a-2 (550 mg, slower eluted) as white solid. LCMS (M+H+): 354. SFC condition: Instrument: SFC 80Column: ID, 250×20 mm I.D., 5µm. Mobile phase: A for CO2 and B for Methanol (0.1% NH3H2O); Gradient: B 40%; Flow rate:50 mL /min; Back pressure: 100 bar; Column temperature: 35 oC. Step 2~6: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- 2,6 8,11 20,24 d]pyrimidin-4-yl]-7-oxa-10,13,17,19-tetrazapentacyclo[15.5.2.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 102) Example 102 was prepared in analogy to the preparation of compound 112g by using compound 102a instead of compound 112c, intermediate B8 instead of intermediate B1 and intermediate C2 instead of intermediate C1. LCMS (M+H+): 593.1H NMR (400 MHz, METHANOL-d4) δ = 8.59 - 8.54 (m, 1H), 8.47 - 8.36 (m, 2H), 8.28 - 8.25 (m, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.62 (m, 2H), 7.62 - 7.56 (m, 1H), 7.53 - 7.47 (m, 2H), 7.32 - 7.25 (m, 1H), 7.21 - 7.15 (m, 2H), 5.15 (br d, J = 10.8 Hz, 1H), 5.02 - 4.96 (m, 2H), 4.66 - 4.61 (m, 1H), 4.60 - 4.52 (m, 2H), 4.47 - 4.41 (m, 1H), 3.48 - 3.37 (m, 2H), 2.86 - 2.79 (m, 1H), 2.49 - 2.39 (m, 1H), 2.38 - 2.23 (m, 2H). Example 103 (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-15-oxo-20-oxa- 16,19 2,7 10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaene-10- carboxamide The title compound was prepared according to the following scheme:
Step 1: preparation of 2-[3-[2-(2-bromophenyl)ethylamino]propyl]isoindoline-1,3- dione (compound 103a) A mixture of 2-(2-bromophenyl)ethan-1-amine (2 g, 10 mmol) , 2-(3- bromopropyl)isoindoline-1,3-dione (2.7 g, 10 mmol) and K2CO3 (2.1 g, 15 mmol) in MeCN (30 mL) was stirred at 80 oC for 4 hours, then the reaction mixture was filtered and the filtrated was concentrated to give crude compound 103a (5 g) as light yellow solid, which was used in next step directly without further purification. LCMS (M+H)+: 387. Step 2: preparation of tert-butyl N-[2-(2-bromophenyl)ethyl]-N-[3-(1,3- dioxoisoindolin-2-yl)propyl]carbamate (compound 103b) A mixture of compound 103a (5 g, 6.46 mmol), Boc2O (2.82 g, 12.9 mmol) and DIPEA (2.5 g, 19.4 mmol) in DCM (30 mL) was stirred at rt for 1 hour, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 103b (2 g) as colorless oil. LCMS (M+H)+: 487. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[3-[2-[2-[tert-butoxycarbonyl- [3-(1,3-dioxoisoindolin-2-yl)propyl]amino]ethyl]phenyl]phenoxy]pyrrolidine-1,2- dicarboxylate (compound 103c) A mixture of intermediate B9 (2 g, 4.15 mmol), compound 103b (2.0 g, 4.15 mmol), PdCl2(DPPF)DCM (339 mg, 415 µmol) and K2CO3 (1.7 g, 12.5 mmol) in dioxane/H2O (10:1) (50 mL) was stirred at 90 oC for 16 hours under nitrogen atmosphere, then the reaction mixture was concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give crude compound 103c (4 g) as black foam, which was used in next step directly without further purification. LCMS (M+H)+: 762. Step 4: preparation of (2S,4S)-4-[3-[2-[2-[3-aminopropyl(tert- butoxycarbonyl)amino]ethyl]phenyl]phenoxy]-1-benzyloxycarbonyl-pyrrolidine-2- carboxylic acid (compound 103d) A mixture of compound 103c (4 g, 3.15 mmol) and LiOH (8 mL, 16 mmol, 2 M) in THF/MeOH (2:1) (50 mL) was stirred at rt for 4 hours, then the pH of reaction mixture was adjusted to about 2 and the mixture was extracted with EA. The organic layer was dried and concentrated to give a residue, which was dissolved in EtOH (50 mL). Then monohydrate hydrazine (5 mL, 104 mmol) was added and the resulting mixture was stirred at 85 oC for 16 hours. The reaction mixture was concentrated and the residue was purified by reverse flash column to give compound 103d (3 g) as light brown foam. LCMS (M+H)+: 618. Step 5: preparation of O17-benzyl O10-tert-butyl (16S,19S)-15-oxo-20-oxa-10,14,17- 16,19 2,7 triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaene-10,17- dicarboxylate (compound 103e) To a mixture of HATU (1.85 g, 4.86 mmol) and DIPEA (1.57 g, 12.1 mmol) in MeCN (300 mL) was added a solution of compound 103d (3 g, 2.43 mmol, Eq: 1) in MeCN (300 mL) dropwise at rt in 2 hours, After being stirred at rt for 30 mins, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give compound 103e (1.2 g) as light brown foam. LCMS (M+H)+: 600. Step 6: preparation of tert-butyl (16S,19S)-15-oxo-20-oxa-10,14,17- 16,19 2,7 triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaene-10-carboxylate (compound 103f) A mixture of compound 103e (1.2 g, 2 mmol) and Pd(OH)2/C(50 mg) in MeOH (50 mL) was stirred at 65 oC for 2 hours under Hydrogen atmosphere, then the reaction mixture was cooled to rt and filtered, the filtrate was concentrated to give compound 103f (800 mg) as light yellow solid. LCMS (M+H)+: 466. Step 7: preparation of tert-butyl (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5- 16,19 2,7 a]pyrazin-8-yl]-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa- 1(24),2,4,6,21(25),22-hexaene-10-carboxylate (compound 103g) A mixture of intermediate C3 (300 mg, 1.13 mmol), compound 103f (526 mg, 1.13 mmol, Eq: 1), CsF (515 mg, 3.39 mmol) and DIPEA (730 mg, 5.65 mmol) in DMSO (10 mL) was stirred at 100 oC for 3 hours, then the reaction mixture was diluted with EA, washed with water and brine, the organic layer was dried and concentrated to give compound 103g (500 mg) as light yellow foam. LCMS (M+H)+: 695. Step 8: preparation of (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8- 16,19 2,7 yl]-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen- 15-one (compound 103h) A mixture of compound 103g (500 mg, 720 µmol) in 4 M HCl in Dioxane (10 mL) was stirred at rt for 3 hours, then the reaction was concentrated to give compound 103h (400 mg) as light yellow solid. LCMS (M+H)+: 595. Step 9: preparation of (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8- 16,19 2,7 yl]-N-methyl-15-oxo-20-oxa-10,14,17-triazatetracyclo[19.3.1.1 .0 ]hexacosa- 1(24),2,4,6,21(25),22-hexaene-10-carboxamide (Example 103) To a mixture of compound 103h (30 mg, 50.4 µmol) and DIPEA (33 mg, 252 µmol) in DCM (2 mL) was added N-methyl-1H-imidazole-1-carboxamide (19 mg, 151 µmol) and then stirred at 40 oC for 16 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 103 (10 mg) as white solid. LCMS (M+H)+: 652.1H NMR (400 MHz, METHANOL-d4) δ = 8.58 - 8.16 (m, 1H), 7.87 - 7.72 (m, 1H), 7.57 - 7.38 (m, 3H), 7.37 - 7.22 (m, 4H), 7.21 - 7.13 (m, 1H), 7.12 - 7.01 (m, 2H), 6.97 - 6.87 (m, 2H), 5.41 - 5.29 (m, 1H), 5.26 - 5.07 (m, 1H), 4.62 - 4.32 (m, 2H), 3.29 - 3.10 (m, 5H), 3.08 - 2.79 (m, 4H), 2.75 - 2.65 (m, 4H), 1.70 - 1.53 (m, 1H), 1.53 - 1.35 (m, 1H). Example 104 (17S,20S)-18-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-N-methyl-16-oxo-21-oxa- 17,20 2,7 10,15,18-triazatetracyclo[20.3.1.1 .0 ]heptacosa-1(25),2,4,6,22(26),23-hexaene-10- carboxamide Example 104 was prepared in analogy to the preparation of Example 103 by using 2-(4- bromobutyl)isoindoline-1,3-dione instead of 2-(3-bromopropyl)isoindoline-1,3-dione in step one. LCMS (M+H)+: 666.1H NMR (400 MHz, METHANOL-d4) δ = 8.74 - 8.07 (m, 1H), 7.87 - 7.72 (m, 1H), 7.59 - 7.49 (m, 1H), 7.46 - 7.14 (m, 7H), 7.13 - 6.83 (m, 4H), 5.46 - 5.36 (m, 1H), 5.27 - 5.11 (m, 1H), 4.65 - 4.36 (m, 2H), 3.69 - 3.53 (m, 1H), 3.24 - 3.10 (m, 1H), 3.08 - 2.76 (m, 7H), 2.76 - 2.65 (m, 3H), 2.25 - 2.07 (m, 1H), 1.36 - 0.99 (m, 4H). Example 105 (16S,19S)-10-acetyl-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-20-oxa-10,14,17- 16,19 2,7 triazatetracyclo[19.3.1.1 .0 ]hexacosa-1(24),2,4,6,21(25),22-hexaen-15-one The title compound was prepared according to the following scheme: To a mixture of compound 103h (30 mg, 0.05 mmol) and DIPEA (98 mg, 0.76 mmol) in dichloromethane (2 mL) was added AcCl (40 mg, 0.51 mmol), after being stirred at rt for 10 mins, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 105 (10 mg) as white solid. LCMS (M+H)+: 637.1H NMR (400 MHz, METHANOL-d4) δ = 8.44 - 8.17 (m, 1H), 7.84 - 7.70 (m, 1H), 7.54 - 7.43 (m, 2H), 7.42 - 7.15 (m, 6H), 7.14 - 7.03 (m, 2H), 7.00 - 6.86 (m, 2H), 5.36 - 5.25 (m, 1H), 5.23 - 5.08 (m, 1H), 4.62 - 4.41 (m, 2H), 3.63 - 3.33 (m, 3H), 3.27 - 3.10 (m, 2H), 3.08 - 2.58 (m, 5H), 2.15 - 1.97 (m, 3H), 1.81 - 1.47 (m, 2H). Example 106 (16S,19S)-17-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]-10-pyrimidin-2-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 The title compound was prepared according to the following scheme: A mixture of compound 103h (30 mg, 0.05 mmol), 2-chloropyrimidine (12 mg, 0.10 mmol) and DIPEA (33 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was stirred at 100 oC for 16 hours, then the reaction solution was directly purified by prep-HPLC to give Example 106 (10 mg) as white solid. LCMS (M+H)+: 673.1H NMR (400 MHz, METHANOL-d4) δ = 8.42 - 8.22 (m, 3H), 7.83 - 7.69 (m, 1H), 7.54 - 7.42 (m, 3H), 7.36 - 7.16 (m, 5H), 7.14 - 7.03 (m, 2H), 7.03 - 6.87 (m, 2H), 6.63 - 6.48 (m, 1H), 5.39 - 5.28 (m, 1H), 5.20 - 5.09 (m, 1H), 4.59 - 4.38 (m, 2H), 3.77 - 3.58 (m, 3H), 3.28 - 3.10 (m, 3H), 3.04 - 2.91 (m, 2H), 2.87 - 2.69 (m, 2H), 1.80 - 1.53 (m, 2H). Example 107 (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 The title compound was prepared according to the following scheme: A mixture of compound 103h (30 mg, 0.05 mmol), DIPEA (33 mg, 0.25 mmol), 1H- imidazole-2-carboxylic acid (11 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in N,N- dimethylformamide (3 mL) was stirred at rt for 1 hour, then the reaction was purified by prep- HPLC to give Example 107 (10 mg) as white powder. LCMS (M+H)+: NMR (400 MHz, METHANOL-d4) δ = 8.59 - 8.17 (m, 1H), 7.82 - 7.69 (m, 1H), 7.59 - 7.40 (m, 2H), 7.39 - 7.14 (m, 8H), 7.12 - 6.89 (m, 4H), 5.41 - 5.30 (m, 1H), 5.29 - 5.04 (m, 1H), 4.65 - 4.32 (m, 2H), 4.13 - 3.81 (m, 2H), 3.72 - 3.33 (m, 3H), 3.21 - 2.69 (m, 5H), 1.92 - 1.51 (m, 2H). Example 109 (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 Example 109 was prepared in analogy to the preparation of Example 110 by using 3- aminopropan-1-ol instead of ethanolamine in step 6. LCMS (M+H+): 632.1H NMR (400 MHz, METHANOL-d4) δ = 8.62 - 8.38 (m, 1H), 8.32 - 7.88 (m, 1H), 7.80 - 7.66 (m, 2H), 7.64 - 7.57 (m, 1H), 7.37 - 7.12 (m, 4H), 6.97 - 6.80 (m, 1H), 6.74 - 6.55 (m, 1H), 6.11 - 5.92 (m, 1H), 4.78 - 4.68 (m, 1H), 4.62 - 4.24 (m, 4H), 3.56 - 3.43 (m, 1H), 3.29 - 3.21 (m, 1H), 2.78 - 2.57 (m, 4H), 2.23 - 2.10 (m, 1H), 1.83 - 1.53 (m, 2H). Example 110 (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 The title compound was prepared according to the following scheme: Step 1: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[(6-bromo-2- pyridyl)amino]pyrrolidine-2-carboxylic acid (compound 110a) A mixture of intermediate B7 (11 g, 0.025 mol) and LiOH (63 mL, 2M) in THF (300 mL) and MeOH (30 mL) was stirred at r.t. for 3 hours. Then the pH of reaction mixture was adjusted to 6 and the mixture was extract with EA. The organic layer was dried and concentrated to give compound 110a (12.9 g) as white solid. LCMS (M+H)+: 420. Step 2: preparation of benzyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]-2-carbamoyl- pyrrolidine-1-carboxylate (compound 110b) A mixture of compound 110a (1.3 g, 3.09 mmol), ammonium chloride (827 mg, 15.5 mmol), DIPEA (4 g, 31 mmol) and HATU (2.35 g, 6.19 mmol) in tetrahydrofuran (30 mL) was stirred at 60 oC for 2 hours, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 110b (1 g) as off-white solid. LCMS (M+H)+: 419. Step 3: preparation of benzyl (2S,4S)-4-[(6-bromo-2-pyridyl)-(2,2,2- trifluoroacetyl)amino]-2-cyano-pyrrolidine-1-carboxylate (compound 110c) To a mixture of compound 110b (5.5 g, 13 mmol) and pyridine (8.5 mL, 105 mmol ) in dichloromethane (100 mL) was added TFAA (9.3 mL, 65 mmol) dropwise at rt in 30 mins. After being stirred at rt for 15 mins, the reaction mixture was quenched with water, the organic layer was separated and concentrated to give compound 110c (6.5 g) as off-white solid. LCMS (M+H)+: 497. Step 4: preparation of benzyl (2S,4S)-4-[(6-bromo-2-pyridyl)-(2,2,2- trifluoroacetyl)amino]-2-(2H-tetrazol-5-yl)pyrrolidine-1-carboxylate (compound 110d) A mixture of compound 110c (5.5 g, 11 mmol), acetic acid [acetoxy(dibutyl)stannyl] ester (3.88 g, 11 mmol) and TMS-N3 (2.9 mL, 22 mmol) in toluene (100 mL) was stirred at 35 oC for 16 hours, then the reaction mixture was concentrated, the residue was slurried in PE. White solid was collected to give compound 110d (6 g) as off-white solid. LCMS (M+H)+: 540. Step 5: preparation of benzyl (2S,4S)-4-[[6-(2-fluoro-3-nitro-phenyl)-2- pyridyl]amino]-2-(2H-tetrazol-5-yl)pyrrolidine-1-carboxylate (compound 110e) A mixture of compound 110d (2 g, 4.5 mmol), 2-(2-fluoro-3-nitro-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.8 g, 6.75 mmol), K2CO3 (1.87 g, 13.5 mmol) and Pd(dppf)Cl2·DCM (368 mg, 0.45 mmol) in 1,4-dioxane (27 mL) and water (3 mL) was stirred at 90 oC for 2 hours under N2. Then the reaction mixture was concentrated to give the crude compound 110e (2 g), which was used in next step directly. LCMS (M+H)+: 505. Step 6: preparation of benzyl (2S,4S)-4-[[6-[2-(2-hydroxyethylamino)-3-nitro-phenyl]- 2-pyridyl]amino]-2-(2H-tetrazol-5-yl)pyrrolidine-1-carboxylate (compound 110f) A mixture of compound 110e (2 g, 4 mmol), K2CO3 (550 mg, 4 mmol) and ethanolamine (0.72 mL, 12 mmol) in acetonitrile (50 mL) was stirred at 60 oC for 1 hour, then the reaction mixture was concentrated and the residue was purified by reversed-phase flash column to give compound 110f (900 mg) as orange foam. LCMS (M+H)+: 546. Step 7: preparation of benzyl (15S,18S)-6-nitro-8,11,12,13,16,19,24,26- 11,14 15,18 2,7 octazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(23),2(7),3,5,12,14(26),20(24),21-octaene- 16-carboxylate (compound 110g) To a mixture of compound 110f (900 mg, 1.65 mmol) and Ph3P (865 mg, 3.3 mmol) in extra dry tetrahydrofuran (90 mL) was added DEAD (0.78 mL, 4.95 mmol) at rt under nitrogen atmosphere, then the mixture was stirred at rt for 30 mins. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 110g (1 g) as orange solid. LCMS (M+H)+: 528. Step 8: preparation of benzyl (15S,18S)-6-amino-8,11,12,13,16,19,24,26- 11,14 15,18 2,7 octazapentacyclo[18.3.1.1 .1 .0 ]hexacosa-1(23),2(7),3,5,12,14(26),20(24),21-octaene- 16-carboxylate (compound 110h) A mixture of compound 110g (1 g, 0.95 mmol), ammonium chloride (1.78 g, 33 mmol) and Fe (1.86 g, 33 mmol) in ethanol (50 mL) and water (10 mL) was stirred at 80 oC for 30 mins, then the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to give compound 110h (600 mg) as light brown foam. LCMS (M+H)+: 498. Step 9: preparation of benzyl (8S,11S)-19-methyl-7,10,13,14,15,18,20,26,28- 2,6 8,11 12,15 21,25 nonazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(25),2,4,6(28),12(26),13,19,21,23- nonaene-10-carboxylate (compound 110i) A mixture of compound 110h (300 mg, 0.6 mmol), 1,1,1-trimethoxyethane (362 mg, 3 mmol), p-toluenesulfonic acid monohydrate (12 mg, 0.06 mmol) in tetrahydrofuran (20 mL) was stirred at 60 oC for 30 mins, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 110i (200 mg), as light yellow foam. LCMS (M+H)+: 522. Step 10: preparation of (8S,11S)-19-methyl-7,10,13,14,15,18,20,26,28- 2,6 8,11 12,15 21,25 nonazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(25),2,4,6(28),12(26),13,19,21,23- nonaene (compound 110j) A mixture of compound 110i (200 mg, 0.35 mmol) in TFA (10 mL) was stirred at 100 oC for 2 hours, then the reaction mixture was concentrated to give compound 110j (200 mg) as light brown oil. LCMS (M+H)+: 388. Step 11: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-19-methyl-7,10,13,14,15,18,20,26,28- 2,6 8,11 12,15 21,25 nonazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(25),2,4,6(28),12(26),13,19,21,23- nonaene (Example 110) A mixture of compound 110j (30 mg, 0.08 mmol), intermediate C2 (21 mg, 0.08 mmol) and DIPEA (104 mg, 0.8 mmol ) in acetonitrile (2 mL) was stirred at 60 oC for 1 hour, then the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 110 (15 mg) as white powder. LCMS (M+H)+: 618.1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.25 (m, 1H), 8.15 - 7.97 (m, 1H), 7.63 - 7.43 (m, 3H), 7.23 - 7.13 (m, 2H), 7.12 - 7.06 (m, 1H), 6.98 - 6.92 (m, 1H), 6.66 - 6.53 (m, 2H), 5.94 - 5.73 (m, 1H), 5.13 - 4.96 (m, 1H), 4.71 - 4.59 (m, 2H), 4.58 - 4.34 (m, 3H), 3.97 - 3.82 (m, 1H), 2.74 - 2.46 (m, 5H). Example 111 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 The title compound was prepared according to the following scheme:
Step 1: preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound 111a) To a solution of 4-bromo-2-methyl-indazole (30.0 g, 142 mmol) in THF (400 mL) was added 1-chloro-3-iodo-propane (28.8 g, 142 mmol) in one portion at -78 °C under nitrogen. And the LDA (107 mL, 214 mmol) was added dropwise into the mixture which was stirred for 1 hr. Then the 1-chloro-3-iodopropane (43.6 g, 213 mmol) was added dropwise at -78 °C. After being stirred at -78 °C for 2 hrs, the reaction mixture was warmed to 25 °C for 12 hrs, then diluted with EtOAc, and poured into saturated ammonium chloride solution, extracted with EtOAc twice. The organic layer was washed with brine, dried over anhydrous Na2SO4. After filtration, the solvent was concentrated to afford crude product, which was purified by prep-HPLC to obtained compound A1-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 111b) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound A1-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 111b (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 O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3- dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 111c) A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (compound A1-b, 2.5 g, 6.3 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (intermediate B8, 3.65 g, 8.2 mmol), Pd(dppf)Cl2·DCM (230 mg, 0.3 mol) and potassium carbonate (2.6 g, 18.8 mmol) in 1,4- dioxane (50 mL) and water (5 mL) was heated at 100 °C for 16 hrs under argon. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give crude product. The crude was purified by flash column to afford compound 111c (3.35 g) as a light yellow solid, LCMS (M+H)+: 639. Step 4: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4- yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 1b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2- yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 111c, 3.3 g, 4.1 mmol) and hydrazine hydrate (1.03 g, 20.7 mmol) in MeOH (60 mL) was heated at 70 °C for 16 hrs in a sealed tube. After being cooled to room temperature, the reaction mixture was diluted with water, then extracted with EtOAc for three times. The combine organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to give some yellow oil. The yellow oil was dissolved in MeOH (28 mL) and water (7 mL), then lithium hydroxide monohydrate (759 mg, 18.1 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs, and then diluted with water, acidified by HOAc, extracted with DCM for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude compound 111d (2.35 g) as a light yellow solid, LCMS (M+H)+: 495. Step 5: preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 111e) To a mixture of DIPEA (4.0 g, 31.0 mmol) and HATU (8.0 g, 42.0 mmol) in DMF (1.5 L) was added a solution of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]phenoxy]-1-tert- butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 111d, 8.0 g, 16.2 mmol) in DMF (1.5 L) at 0 °C dropwise and then stirred at 0 °C for 2 hrs. The mixture was concentrated to give some residue, which was diluted with EtOAc, then washed with water, 0.5 N aq. HCl solution, saturated sodium bicarbonate aqueous solution and brine successively. The separated organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give crude compound 111e (5.2 g) as a yellow solid, which was used in next step directly, LCMS (M+H)+: 477. Step 6: preparation of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 111f) To a solution of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 111e, 118 mg, 0.17 mol) in DMF (3 mL) was added sodium hydride (35 mg, 0.87 mmol) at 0 °C, 30 mins later, iodomethane (123 mg, 0.87 mmol) was added, the resulting mixture was stirred at 0 °C to room temperature for 16 hrs. The reaction mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc for three times, the combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford compound 111f (160 mg) as a yellow oil, LCMS (M+H)+: 491. Step 7: preparation of (8S,11S)-13,18-dimethyl-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-12- one;hydrochloride (compound 111g) To a solution of tert-butyl (8S,11S)-13,18-dimethyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 111f, 160 mg, 0.16 mmol) in MeOH (2 mL) was added 4 M HCl in 1,4- dioxane solution (3 mL), the resulting mixture was stirred at room temperature for 1 hr. After being concentrated under reduced pressure, crude compound 111g (108 mg) was obtained as a yellow solid, LCMS (M+H)+: 391. Step 8: preparation of 1-[1-(2,4-difluorophenyl)-4-[(8S,11S)-13,18-dimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-10,13,18,19-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 (Example 111) A mixture of DIPEA (57 mg, 0.44 mmol), intermediate C6 (35 mg, 0.11 mmol) and (1- hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylphosphorus hexafluorophosphate (69 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 50 oC for 3 hours, then compound 111g (35 mg, 0.09 mmol) was added and the reaction mixture was stirred at 80 oC for 2 hours. The reaction solution was directly purified by HPLC preparation to give Example 111 (2 mg) as white powder. LCMS (M+H)+: 701.1H NMR (400 MHz, METHANOL-d4) δ = 8.19 - 8.08 (m, 1H), 7.56 - 7.46 (m, 1H), 7.43 - 7.32 (m, 2H), 7.24 - 6.97 (m, 4H), 6.92 - 6.79 (m, 2H), 6.78 - 6.66 (m, 1H), 5.53 - 5.21 (m, 2H), 4.45 - 4.34 (m, 1H), 4.33 - 4.09 (m, 4H), 4.08 - 3.92 (m, 5H), 3.61 - 3.49 (m, 1H), 3.09 - 2.92 (m, 3H), 2.87 - 2.41 (m, 5H), 2.37 - 2.14 (m, 1H), 1.53 - 1.35 (m, 1H). Example 112 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (compound 112a) To a mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound 111a, 6 g, 20.9 mmol) and DIPEA (5.39 g, 41.7 mmol) was added 33% methylamine in ethanol solution (40 mL), the resulting mixture was stirred at 90 °C for 16 hrs, then the reaction was concentrated to give crude compound 112a (6.0 g) as an off-white solid, LCMS (M+H)+: 282. Step 2: preparation of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N- methyl-carbamate (compound 112b) A mixture of 3-(4-bromo-2-methyl-indazol-3-yl)-N-methyl-propan-1-amine (compound 112a, 6 g, 21.3 mmol), DIPEA (8.24 g, 63.8 mmol) and Boc anhydride (5.1 g, 23.4 mmol) in DCM (100 mL) was stirred at room temperature for 1 hr, then the reaction was concentrated and the residue was purified by flash column to give compound 112b (8.0 g) as a colorless oil, LCMS (M+H)+: 382. Step 3: preparation of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate (compound 112c) A mixture of tert-butyl N-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]-N-methyl-carbamate (compound 112b, 6 g, 15.7 mmol), bis(pinacolato)diboron (7.97 g, 31.4 mmol) and potassium acetate (3.08 g, 31.4 mmol) in DMSO (73 mL) was bubbled with nitrogen for 5 mins and then bis(triphenylphosphine)palladium(ii) dichloride (1.1 g, 1.6 mmol,) and butyldi-1- adamantylphosphine (1.13 g, 3.1 mmol) were added. The resulting mixture was heated at 130 °C 4 hrs. The reaction mixture was diluted with water, and then extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, concentrated to give a light brown oil. The crude was purified by flash column to give compound 112c (4.0 g) as a light brown oil, LCMS (M+H)+: 430. Step 4: preparation of N-methyl-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (compound 112d) A mixture of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]propyl]carbamate (compound 112c, 100 mg, 0.23 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 4 hrs, then the reaction mixture was filtered to give compound 112d (80 mg), LCMS (M+H)+: 330. Step 5: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2-methyl-3-[3- (methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]amino]pyrrolidine-2-carboxylic acid (compound 112e) A mixture of potassium carbonate (2.32 g, 16.8 mmol), N-methyl-3-[2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]propan-1-amine (compound 112d, 2.77 g, 8.41 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (intermediate B1, 2 g, 5.61 mmol) and Pd(dppf)Cl2 (458 mg, 0.56 mmol) in 1,4- dioxane (50 mL) and water (10 mL) was stirred at 95 °C for 2 hrs. Then the reaction mixture was concentrated under reduced pressure to give some residue. The residue was purified by silica gel column chromatography to give an intermediate, which was dissolved in THF/MeOH (10 mL, 2:1), then 2 N aq. LiOH (2.39 mL, 4.77 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. The pH of the mixture was adjusted to 5, then concentrated to remove most organic solvent to give crude product, the crude was purified by flash column (ACN/TFA in water) to give compound 112e (220 mg), LCMS (M+H)+: 510. Step 6: preparation of (8S,11S)-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),2,4,6(26),17(24),19,21-heptaen-12- one;hydrochloride (compound 112f) To a mixture of HATU (298 mg, 0.78 mmol) and DIPEA (254 mg, 1.96 mmol) in DMF (10 mL) and ACN (100 mL) was added a solution of (2S,4S)-1-tert-butoxycarbonyl-4-[[4-[2- methyl-3-[3-(methylamino)propyl]indazol-4-yl]pyrimidin-2-yl]amino]pyrrolidine-2-carboxylic acid (compound 112e, 150 mg, 0.28 mmol) in DMF (10 mL) and ACN (100 mL) dropwise. The reaction mixture was stirred at room temperature for 1 hr, then concentrated in vacuo, the residue was purified by flash column (ACN/TFA in water) to give a light yellow solid, which was then dissolved in 4 M HCl in 1,4-dioxane (5 mL) and stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to give compound 112f (128 mg), LCMS (M+H)+: 392. Step 7: preparation of ((8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)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),2,4,6(26),17(24),19,21-heptaen-12- one (compound 112g) A mixture of compound 112f (100 mg, 0.26 mmol), intermediate C1 (77 mg, 0.26 mmol) and DIPEA (165 mg, 1.28 mmol) in acetonitrile (7 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 compound 112g (150 mg) as off-white solid. LCMS (M+H)+: 656. Step 8: preparation of (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- 2,6 8,11 20,24 5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 112) A mixture of compound 112g (30 mg, 0.046 mmol), 3-methyl-3,6- diazabicyclo[3.1.1]heptane (27 mg, 0.18 mmol), CsF (21 mg, 0.14 mmol) and DIPEA (30 mg, 0.23 mmol) in dimethyl sulfoxide (2 mL) was stirred at 110 oC for 16 hours, then the reaction solution was directly purified by prep-HPLC to give Example 112 (8 mg) as white powder. LCMS (M+H)+: 732.1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.36 (m, 1H), 8.21 - 8.11 (m, 1H), 7.63 - 7.47 (m, 2H), 7.31 - 7.17 (m, 1H), 7.16 - 7.00 (m, 3H), 6.88 - 6.78 (m, 1H), 5.40 - 5.22 (m, 1H), 5.08 - 4.94 (m, 1H), 4.51 - 4.37 (m, 2H), 4.20 - 4.12 (m, 2H), 4.10 - 3.92 (m, 5H), 3.59 - 3.48 (m, 1H), 3.11 - 2.94 (m, 5H), 2.92 - 2.71 (m, 4H), 2.65 - 2.33 (m, 3H), 2.26 - 2.08 (m, 4H), 1.97 - 1.79 (m, 1H). Example 114 (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 Example 114 was prepared in analogy to the preparation of Example 115 by using 1- fluoro-2-iodo-ethane instead of 1-bromo-2-methoxy-ethane. LCMS (M+H+): 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.48 - 8.35 (m, 1H), 8.20 - 8.11 (m, 1H), 7.62 - 7.45 (m, 2H), 7.30 - 7.18 (m, 1H), 7.16 - 6.98 (m, 3H), 6.92 - 6.77 (m, 1H), 5.38 - 5.23 (m, 1H), 4.96 - 4.88 (m, 1H), 4.51 - 4.25 (m, 4H), 4.22 - 3.93 (m, 7H), 3.70 - 3.49 (m, 1H), 3.31 - 3.24 (m, 1H), 3.11 - 2.95 (m, 3H), 2.92 - 2.59 (m, 6H), 2.52 - 2.38 (m, 2H), 2.37 - 2.30 (m, 1H), 2.16 - 1.97 (m, 1H), 1.87 - 1.74 (m, 1H), 1.34 - 1.14 (m, 1H). Example 115 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 115a) A mixture of 1-bromo-2-methoxy-ethane (701.05 mg, 5.04 mmol), tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.52 mmol) and K2CO3 (697 mg, 5.04 mmol) in acetonitrile (10 mL) was stirred at 60 oC for 6 hours, then the solid was filtered off, the filtrate was concentrated to give compound 115a (600 mg), LCMS (M+H+): 257. Step 2: preparation of 3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (compound 580b) A mixture of compound 115a (500 mg, 1.76 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 30 mins, then the reaction was concentrated to give compound 115b (300 mg), LCMS (M+H+): 157. Step 3: preparation of (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- 2,6 8,11 20,24 5,7,10,13,18,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,17(24),19,21-heptaen-12-one (Example 115) A mixture of compound 112f (30 mg, 0.046 mmol), compound 115b (29 mg, 0.18 mmol), CsF (21 mg, 0.14 mmol) and DIPEA (30 mg, 0.23 mmol) in dimethyl sulfoxide (2 mL) was stirred at 110 oC for 16 hours, then the reaction solution was directly purified by HPLC preparation to give Example 115 (4 mg) as white powder. LCMS (M+H+): NMR (400 MHz, METHANOL-d4) δ = 8.48 - 8.34 (m, 1H), 8.24 - 8.12 (m, 1H), 7.60 - 7.48 (m, 2H), 7.32 - 7.18 (m, 1H), 7.17 - 7.00 (m, 3H), 6.91 - 6.83 (m, 1H), 5.40 - 5.24 (m, 1H), 4.98 - 4.90 (m, 1H), 4.45 - 4.38 (m, 1H), 4.21 - 4.13 (m, 2H), 4.09 - 4.03 (m, 4H), 3.62 - 3.47 (m, 2H), 3.41 - 3.32 (m, 3H), 3.16 - 3.11 (m, 3H), 3.11 - 2.98 (m, 4H), 2.97 - 2.74 (m, 4H), 2.72 - 2.61 (m, 2H), 2.55 - 2.41 (m, 2H), 2.40 - 2.31 (m, 1H), 2.19 - 2.05 (m, 1H), 1.89 - 1.78 (m, 1H), 1.41 - 1.19 (m, 1H). Example 116 (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 The title compound was prepared according to the following scheme: Example 116 was prepared in analogy to the preparation of compound 112g by using intermediate A3 instead of compound 112c, intermediate B10 instead of intermediate B1 and intermediate C7 instead of intermediate C1. LCMS (M+H+): 728.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 - 8.47 (m, 1H), 8.44 - 8.28 (m, 1H), 7.72 - 7.61 (m, 1H), 7.40 - 7.17 (m, 3H), 7.15 - 6.94 (m, 3H), 5.85 - 5.62 (m, 1H), 5.62 - 5.31 (m, 1H), 4.69 - 4.59 (m, 1H), 4.56 - 4.35 (m, 4H), 4.30 - 4.03 (m, 2H), 3.50 - 3.46 (m, 1H), 3.37 - 3.29 (m, 3H), 3.26 - 3.17 (m, 1H), 3.15 - 2.98 (m, 3H), 2.92 - 2.56 (m, 7H), 0.73 - 0.59 (m, 3H). Example 117 and 118 (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 and (8S,11S,15S)-10-[1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa- 2,6 8,11 20,24 10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one The title compound was prepared according to the following scheme:
Step 1: preparation of O1-tert-butyl O2-methyl (2S,4R)-4-[tert- butyl(dimethyl)silyl]oxypyrrolidine-1,2-dicarboxylate (compound 117b) To a stirred mixture of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2- dicarboxylate (20.0 g, 81.5 mmol) and imidazole (16.6 g, 244.4 mmol) in DCM (400 mL) was added tert-butyldimethylchlorosilane (18.4 g, 122.3 mmol) in portions at 0 °C. The resulting mixture was stirred for 16 h at 25 °C under nitrogen atmosphere. Then the reaction mixture was poured into 500 mL of ice-water and extracted with DCM, the combined organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound 117b (25 g) as a yellow solid. LCMS (M+H)+: 360. Step 2: preparation of O1-tert-butyl O2-methyl (4R)-4-[tert-butyl(dimethyl)silyl]oxy- 2-methyl-pyrrolidine-1,2-dicarboxylate (compound 117c) To a stirred mixture of compound 117b (24 g, 63.9 mmol) in THF (500 mL) was added LiHMDS (96.0 mL, 96.0 mmol, 1M) dropwise at -20 °C. The resulting mixture was stirred for 1 h at -20 °C under nitrogen atmosphere, then iodomethane (18 g, 128 mmol) in THF (20 mL) was added dropwise at -20 °C. After being stirred for 3 h at 25 °C, the reaction mixture was poured into 800 mL of ice-water and extracted with ethyl acetate. The combined organic layer was concentrated and the residue was purified by silica gel column chromatography to afford compound 117c (10 g) as a yellow solid. LCMS (M+H)+: 374. Step 3: preparation of O1-tert-butyl O2-methyl (4R)-4-hydroxy-2-methyl-pyrrolidine- 1,2-dicarboxylate (compound 117d) To a stirred mixture of compound 117c (10.0 g, 27.8 mmol) in THF (300 mL) was added tetrabutylammonium fluoride (100 mL, 100 mmol, 1 M). The resulting mixture was stirred for 16 h at 25 °C under nitrogen atmosphere. The reaction mixture was poured into 600 mL of ice- water and extracted with ethyl acetate. The combined organic layer was concentrated and the residue was purified by silica gel column chromatography to afford compound 117d (6.0 g) as a yellow oil. LCMS (M+H)+: 260. Step 4: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-(3-bromophenoxy)-2- methyl-pyrrolidine-1,2-dicarboxylate (compound 117e) To a stirred mixture of compound 117d (6 g, 23.1 mmol), 3-bromophenol (4.02 g, 23.2 mmol) and triphenylphosphine (18.2 g, 69.3 mmol) in THF (100 mL) was added diisopropyl azodicarboxylate (9.4 g, 46.3 mmol) dropwise at 0 °C under nitrogen atmosphere. After being stirred for 16 h at 25 °C, the reaction mixture was poured into 400 mL of ice-water and extracted with ethyl acetate. The combined organic layer was concentrated and the residue was purified by silica gel column chromatography to afford compound 117e (3.0 g) (faster eluted) and compound 117e-2 (3.0 g, 25.04% yield) (slower eluted) as a yellow oil as a yellow oil. LCMS (M+H)+: 414. Step 5: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[2-methoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]phenoxy]-2-methyl-pyrrolidine-1,2- dicarboxylate (compound 117f) To a stirred mixture of compound 117e (2.5 g, 6. mmol) and compound 117f (2.75 g, 6.9 mmol, the synthesis refers to compound 112d by using intermediate A1 instead of compound 112c) in 1,4-dioxane (25 mL) and water (5 mL) was added potassium carbonate (2.5 g, 18.1 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1 g, 1.23 mmol). The resulting mixture was stirred for 3 h at 85 °C under nitrogen atmosphere, then the mixture was cooled to room temperature and poured into 400 mL of ice- water and extracted with ethyl acetate. The combined organic layer was concentrated and the residue was purified by silica gel column chromatography to afford compound 117f (1.3 g) as a yellow solid. LCMS (M+H)+: 567. Step 6: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[3-[2-methoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]phenoxy]-2-methyl-pyrrolidine-2- carboxylic acid (compound 117g) To a stirred mixture of compound 117f (1.3 g, 2.3 mmol) in THF (10 mL) and water (10 mL) was added LiOH (1.7 g, 70.6 mmol). The resulting mixture was stirred for 48 h at 50 °C under nitrogen atmosphere, then the mixture was cooled to room temperature. The reaction solution was directly purified by reverse flash column to afford compound 117g (600 mg) as a white solid. LCMS (M+H)+: 553.. Step 7: preparation of tert-butyl (8S,11S)-15-methoxy-11,13,18-trimethyl-12-oxo-7- 2,6 8,11 20,24 oxa-10,13,17,19-tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaene-10-carboxylate (compound 117h) To a stirred mixture of HATU (826 mg, 2.2 mmol) and DIPEA (702 mg, 5.4 mmol) in DMF (36 mL) and ACN (360 mL) was added a solution of compound 117g (600 mg, 1.09 mmol, 1.00 eq) in DMF (36 mL) and ACN (360 mL) dropwise at 25 °C. The resulting mixture was stirred for 16 h at 25 °C, then the mixture was concentrated and the residue was purified by reverse flash column to afford compound 117h (372 mg) as a white solid. LCMS (M+H)+: 535. Step 8: preparation of (8S,11S)-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 117i) To a mixture of compound 117h (350 mg, 0.65 mmol) in dichloromethane (10 mL) was added 4 M HCl in dioxane (3 mL) slowly, then the reaction was stirred at rt for 2 hours. The reaction mixture was concentrated to give compound 117i (300 mg) as an off-white solid. LCMS (M+H)+: 435. Step 9: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one and (8S,11S,15S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-11,13,18-trimethyl-7-oxa-10,13,17,19- 2,6 8,11 20,24 tetrazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 117 & 118) A mixture of compound 117i (40 mg, 0.09 mmol), compound C2 (30 mg, 0.11 mmol) and DIPEA (60 mg, 0.46 mmol) in acetonitrile (3 mL) was stirred at 100 oC for 16 hours, then the reaction was diluted with EA, washed with water and brine, the organic layer was concentrated and the residue was purified by prep-HPLC to give Example 117 (faster eluted) and Example 118 (slower eluted). Example 117, 2 mg, white powder, LCMS (M+H+): 665.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.26 (m, 1H), 8.18 - 7.98 (m, 1H), 7.61 - 7.49 (m, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.29 (m, 1H), 7.24 - 6.98 (m, 4H), 6.94 - 6.79 (m, 2H), 6.75 - 6.67 (m, 1H), 5.34 (br s, 1H), 4.54 - 4.44 (m, 2H), 4.39 - 4.30 (m, 1H), 4.12 - 3.97 (m, 1H), 3.92 - 3.76 (m, 1H), 3.62 - 3.50 (m, 1H), 3.49 - 3.32 (m, 2H), 2.93 - 2.65 (m, 6H), 2.56 - 2.29 (m, 5H), 2.09 - 1.98 (m, 2H). Example 118, 2 mg, white powder, LCMS (M+H+): 665.1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.36 (m, 1H), 8.31 - 8.10 (m, 1H), 7.67 - 7.27 (m, 4H), 7.24 - 6.88 (m, 6H), 5.51 - 5.25 (m, 1H), 4.53 - 4.32 (m, 3H), 4.14 - 3.99 (m, 1H), 3.95 - 3.84 (m, 1H), 3.69 - 3.46 (m, 1H), 3.14 - 2.88 (m, 2H), 2.87 - 2.71 (m, 4H), 2.70 - 2.28 (m, 6H), 2.10 - 1.82 (m, 3H). Example 119 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[2-[(4-bromo-1H-indole-2- carbonyl)amino]ethyl]carbamate (compound 119b) A mixture of compound 119a (450.0 mg, 1.87 mmol), HATU (855 mg, 2.25 mmol), N- BOC-ethylenediamine (330 mg, 2.06 mmol) and DIEA (0.98 mL, 5.62 mmol) in DMF (5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 119b (480.0 mg) as a yellow solid. LCMS(M-C5H8O2+H+): 282. Step 2: preparation of tert-butyl N-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indole-2-carbonyl]amino]ethyl]carbamate (compound 119c) To a solution of bis(pinacolato)diboron (571 mg, 2.25 mmol) in 1,4-dioxane (10 mL) was added compound 119b (430.0 mg, 1.12 mmol), Pd(dppf)Cl2 (164 mg, 0.22 mmol) and potassium acetate (0.21 mL, 3.37 mmol) in glove box. After being stirred at 70 °C for 3 h, the reaction mixture was concentrated to give crude compound 119c (1.27 g) as a grey solid. LCMS (M+H+): 430. Step 3: preparation of methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine-2-carboxylate hydrochloride (compound 119d) A mixture of Intermediate B11 (3.0 g, 7.5 mmol) and HCl/MeOH (30.0 mL, 120.0 mmol) was stirred at 25 °C for 2 h. Then the reaction mixture was concentrated to give compound 119d (2.52 g), which was used in the next step directly. LCMS (M+H+): 302. Step 4: preparation of methyl (2S,4S)-4-(3-bromophenoxy)-1-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 119e) A mixture of compound 119d (2.45 g, 7.27 mmol), N,N-diisopropylethylamine (3.8 mL, 21.82 mmol), HATU (3.32 g, 8.73 mmol) and Intermediate C4 (1.75 g, 7.27 mmol) in DMF (35 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 119e (1.7 g) as a yellow solid. LCMS (M+H+): 524. Step 5: preparation of methyl (2S,4S)-4-[3-[2-[2-(tert- butoxycarbonylamino)ethylcarbamoyl]-1H-indol-4-yl]phenoxy]-1-[1-(2-chloro-4-fluoro- phenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylate (compound 119f) To a solution of compound 119c (512 mg, 1.19 mmol) in 1,4-dioxane (25 mL) was added compound 119e (520.0 mg, 0.99 mmol), K3PO4 (0.25 mL, 2.98 mmol), cataCXium A-PD-G2 (133 mg, 0.2 mmol) and water (2.5 mL) in glove box. After being stirred at 80 °C for 16 h, the reaction mixture was concentrated and the residue was purified by column chromatography to give compound 119f (345.0 mg) as a yellow solid. LCMS (M+H+): 745. Step 6: preparation of (2S,4S)-4-[3-[2-[2-(tert-butoxycarbonylamino)ethylcarbamoyl]- 1H-indol-4-yl]phenoxy]-1-[1-(4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 119g) A mixture of compound 119f (335.0 mg, 0.47 mmol) and sodium hydroxide (188 mg, 4.71 mmol) in THF (20 mL) and water (2 mL) was stirred at 25 °C for 2 h. Then the reaction mixture was diluted with water and pH was adjusted to 3~4, then it was extracted with DCM. The organic layer was dried and concentrated to give compound 119g (330.0 mg) as a yellow solid. LCMS (M+H+): 731. Step 7: preparation of (2S,4S)-4-[3-[2-(2-aminoethylcarbamoyl)-1H-indol-4- yl]phenoxy]-1-[1-(4-fluorophenyl)pyrazole-4-carbonyl]pyrrolidine-2-carboxylic acid (compound 119h) A mixture of compound 119g (330.0 mg, 0.47 mmol) and HCl/1,4-dioxane (10.05 mL, 40.2 mmol) was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated, the residue was purified by prep-HPLC to give compound 119h (75.0 mg) as a yellow solid. LCMS (M+H+): 631. Step 8: preparation of (16S,19S)-17-[1-(2-chloro-4-fluoro-phenyl)pyrazole-4- 6,9 16,19 2,7 carbonyl]-20-oxa-11,14,17,27-tetrazapentacyclo[19.3.1.1 .1 .0 ]heptacosa- 1(25),2,4,6,8,21,23-heptaene-10,15-dione (Example 119) To a solution of HATU (43 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) in DMF (24 mL) was added a solution compound 119h (60.0 mg, 0.1 mmol) in THF (24 mL) dropwise at 0 °C for 30 min. Then the reaction mixture was concentrated, the residue was purified by prep-HPLC to give Example 119 (6 mg) as a yellow solid. LCMS (M+H+): 613. 1H NMR (400 MHz, METHANOL-d4) δ = 8.56 - 8.43 (m, 1H), 8.37 - 8.22 (m, 1H), 8.18 - 8.09 (m, 1H), 7.72 - 7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7.46 (br d, J = 7.9 Hz, 2H), 7.34 (br s, 3H), 7.22 (br d, J = 7.5 Hz, 1H), 7.12 (br s, 2H), 5.10 - 4.97 (m, 2H), 4.94 (br s, 1H), 4.63 - 4.37 (m, 1H), 4.25 - 4.11 (m, 1H), 4.03 - 3.89 (m, 1H), 3.82 - 3.70 (m, 1H), 3.44 - 3.37 (m, 1H), 3.23 - 3.10 (m, 1H), 3.04 - 2.92 (m, 1H), 2.63 - 2.47 (m, 1H). Example 122 (12E,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),12,22(26),23-octaen-16-one The title compound was prepared in analogy to Example 61 by using compound 62d instead of compound 61f. LCMS (M+H+): 619.1H NMR (400 MHz, DMSO-d4) δ (ppm) = 8.40 - 8.24 (m, 2H), 7.92 - 7.61 (m, 2H), 7.60 - 7.48 (m, 2H), 7.46 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1H), 7.30 - 7.16 (m, 3H), 7.07 (br d, J = 5.5 Hz, 1H), 6.70 - 6.63 (m, 1H), 5.95 - 5.75 (m, 2H), 5.59 - 5.24 (m, 1H), 5.12 - 4.86 (m, 1H), 4.31 - 4.08 (m, 2H), 3.61 - 3.58 (m, 2H), 2.71 - 2.62 (m, 1H), 2.35 - 2.30 (m, 1H), 1.67 - 1.42 (m, 1H), 1.27 - 1.01 (m, 1H). Example 125 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 2-[3-(2-bromo-6-oxo-1-pyridyl)propyl]isoindoline-1,3-dione (compound 125c) A mixture of compound 125b (4.61 g, 17.18 mmol), compound 125a (2.3 g, 13.22 mmol), KI (2.54 g, 15.86 mmol) and Cs2CO3 (8.61 g, 26.44 mmol) in ACN (23 mL) was stirred at 90 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography to give compound 125c (0.8 g) as a white solid. LCMS (M+H+): 361. Step 2~7: preparation of (13S,16S)-14-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin- 13,16 2,7 8-yl]-17-oxa-7,11,14-triazatetracyclo[16.3.1.1 .0 ]tricosa-1(22),2,4,18,20-pentaene-6,12- dione (Example125) The title compound was prepared in analogy to Example 61 by using compound 125c instead of compound 61e. LCMS (M+H+): 569. 1H NMR (400 MHz, METHANOL-d4) δ = 8.83 - 8.27 (m, 1H), 7.86 - 7.78 (m, 1H), 7.62 - 7.54 (m, 3H), 7.46 - 7.41 (m, 1H), 7.37 - 7.26 (m, 2H), 7.07 (br d, J = 7.5 Hz, 1H), 7.01 (s, 2H), 6.66 - 6.55 (m, 1H), 6.44 - 6.36 (m, 1H), 5.70 (br s, 1H), 4.73 - 4.59 (m, 2H), 4.11 - 4.02 (m, 1H), 3.72 - 3.60 (m, 1H), 3.52 - 3.41 (m, 1H), 2.90 - 2.81 (m, 1H), 2.79 - 2.72 (m, 1H), 2.70 - 2.60 (m, 1H), 2.60 - 2.59 (m, 1H), 2.44 (br t, J = 12.3 Hz, 1H), 2.10 - 1.96 (m, 1H). Example 126 (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 The title compound was prepared according to the following scheme: 126g 126j 126i Step 1: preparation of tert-butyl (2S,4S)-4-(3-bromophenoxy)-2-cyano-pyrrolidine-1- carboxylate (compound 126c) To a solution of compound 126b (5.0 g, 23.56 mmol), compound 126a (7.0 g, 40.46 mmol) and triphenylphosphine (7.0 g, 26.69 mmol) in anhydrous THF (100 mL) was added DIAD (6.0 g, 34.45 mmol) at 0 °C. The reaction was stirred for 12 h at 20 °C and then concentrated, the residue was purified by prep-HPLC to give compound 126c (5.8 g) as a white solid. LCMS (M+H+): 367. Step 2: preparation of tert-butyl (2S,4S)-4-(3-bromophenoxy)-2-(1H-tetrazol-5- yl)pyrrolidine-1-carboxylate (compound 126d) A solution of compound 126c (3.0 g, 8.17 mmol), sodium azide (1.0 g, 15.38 mmol) and NH4Cl (1.0 g, 18.7 mmol) in anhydrous DMF (30 mL) was stirred for 12 h at 100 °C. The reaction mixture was diluted with EtOAc and poured into ice-aq.NaOH (2 M, 100 mL). The organic layer was separated and concentrated to give crude compound 126d (3.2 g) as yellow oil, which was used in next step directly. LCMS (M+H+): 412. Step 3: preparation of tert-butyl (2S,4S)-4-(3-bromophenoxy)-2-[2-[3-(1,3- dioxoisoindolin-2-yl)propyl]tetrazol-5-yl]pyrrolidine-1-carboxylate (compound 126f) To a solution of compound 126d (1.4 g, 3.41 mmol), compound 126e (2.1 g, 7.83 mmol) and potassium carbonate (0.84 g, 6.08 mmol) in anhydrous DMF (14 mL) was stirred at 20 °C for 12 h. The reaction was diluted with DCM and water, and extracted with DCM (200 mL). The organic layer was concentrated , the residue was purified by prep-HPLC to give compound 126f (1.2 g) as yellow oil. LCMS (M+H+): 599. Step 4: preparation of tert-butyl 2-(4-bromoindazol-2-yl)acetate (compound 126i) To a solution of compound 126g (20.0 g, 101.51 mmol) in THF (200 mL) was added LiHMDS (122 mL, 122 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h and then compound 126h (19.8 g, 101.51 mmol) was added, the resulted reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water and then concentrated, the residue was purified by prep-HPLC to give compound 126i (8.0 g) as a light grey solid. LCMS (M- 56+H+): 254. Step 5: preparation of methyl 2-(4-bromoindazol-2-yl)acetate (compound 126j) A solution of compound 126i (3.0 g, 9.64 mmol) in HCl in MeOH (20.0 mL, 9.64 mmol) was stirred for 2 h at 80 °C. The reaction mixture was concentrated and then diluted with EtOAc. The organic layer was washed with NaHCO3, brine, and then concentrated to give crude compound 126j (2.2 g) as a yellow solid, which was used in next step directly. LCMS (M+H+): 269. Step 6: preparation of methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-2-yl]acetate (compound 126k) A mixture of compound 126j (1.0 g, 3.72 mmol), Pd(dppf)Cl2 (0.2 g, 0.36 mmol), K3PO4 (1.7 g, 8.01 mmol) and bis(pinacolato)diboron (1.5 g, 5.91 mmol) in anhydrous 1,4-dioxane (40 mL) was stirred for 12 h at 100 °C under N2. Then the reaction was concentrated, the residue was purified by prep-HPLC to give compound 126k (544.0 mg) as yellow oil, which was used in next step directly. LCMS (M+H+): 317. Step 7~12: preparation of(20S,23S)-21-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin- 6,9 16,19 20,23 2,7 8-yl]-24-oxa-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 (Example 126) The title compound was prepared in analogy to Example 61 by using compound 126f instead of compound 61e and compound 126k instead of intermediate B8. LCMS (M+H+): 674. 1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.84 (br t, J = 5.8 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.52 - 7.48 (m, 1H), 7.42 - 7.36 (m, 1H), 7.35 - 7.23 (m, 3H), 7.20 - 7.14 (m, 2H), 7.02 (br d, J = 5.7 Hz, 1H), 6.70 (br s, 1H), 6.32 - 5.90 (m, 1H), 5.64 - 5.54 (m, 1H), 5.25 - 5.09 (m, 2H), 4.66 - 4.42 (m, 4H), 3.41 (br s, 2H), 3.06 (br s, 2H), 2.26 - 2.14 (m, 2H). Example 127 (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 The title compound was prepared in analogy to Example 126 by using intermediate C2 instead of intermediate C3. LCMS (M+H+): 675.1H NMR (400 MHz, METHANOL-d4) δ = 8.48 (s, 1H), 8.40 - 8.32 (m, 1H), 8.19 (s, 1H), 7.69 - 7.60 (m, 2H), 7.53 - 7.46 (m, 1H), 7.41 - 7.36 (m, 1H), 7.31 - 7.11 (m, 5H), 6.83 (s, 1H), 6.19 - 6.06 (m, 1H), 5.62 - 5.41 (m, 1H), 5.22 - 5.09 (m, 2H), 4.64 - 4.25 (m, 4H), 3.48 - 3.34 (m, 2H), 2.97 - 2.86 (m, 1H), 2.77 - 2.66 (m, 1H), 2.24 - 2.07 (m, 2H). Example 128 (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 The title compound was prepared in analogy to the preparation of Example 162 by using intermediate B5 instead of compound 162c, intermediate C3 instead of intermediate C2 and intermediate A39 instead of intermediate B9. LCMS (M+H+): 607.1H NMR (400 MHz, DMSO- d6) δ = 8.09 (d, J = 8.3 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.67 (br d, J = 7.1 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.50 - 7.43 (m, 2H), 7.38 (dt, J = 2.1, 8.5 Hz, 1H), 7.08 (br d, J = 7.5 Hz, 2H), 6.76 (br d, J = 8.4 Hz, 1H), 6.11 - 5.91 (m, 1H), 5.85 - 5.26 (m, 2H), 4.70 - 4.52 (m, 3H), 4.27 - 3.96 (m, 2H), 3.08 - 2.77 (m, 5H), 2.63 - 2.57 (m, 1H), 2.02 - 1.89 (m, 1H), 1.48 - 1.37 (m, 1H). Example 129 (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 The title compound was prepared in analogy to the preparation of Example 162 by using intermediate B5 instead of compound 162c and intermediate A39 instead of intermediate B9. LCMS (M+H+): 608.1H NMR (400 MHz, DMSO–d6) δ = 8.62 (s, 1H), 8.40 - 8.25 (m, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.74 (dt, J = 6.1, 8.7 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.50 - 7.42 (m, 1H), 7.37 - 7.28 (m, 1H), 7.10 - 7.04 (m, 1H), 6.87 - 6.74 (m, 1H), 5.81 - 5.69 (m, 1H), 5.54 - 5.44 (m, 1H), 5.42 - 5.21 (m, 1H), 4.74 (br d, J = 2.3 Hz, 1H), 4.64 - 4.46 (m, 2H), 4.28 - 4.20 (m, 1H), 4.13 - 4.03 (m, 1H), 3.10 - 2.97 (m, 3H), 2.96 - 2.84 (m, 1H), 2.38 - 2.29 (m, 1H), 2.27 - 2.01 (m, 1H), 1.66 - 1.46 (m, 1H). Example 130 (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 To a solution of Example 126 (20.0 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added NaOH (2.38 mg, 0.06 mmol) at 0 °C. After 0.5 h at 0 °C, dimethyl sulfite (10 mg, 0.09 mmol) was added at 0 °C. The reaction mixture was stirred at 20 °C for 12 h and then purified by prep-HPLC to give Example 130 (10.0 mg) as a light yellow solid. LCMS (M+H+): 688.1H NMR (400 MHz, METHANOL-d4) δ = 8.29 - 8.15 (m, 2H), 7.77 - 7.67 (m, 1H), 7.64 - 7.56 (m, 1H), 7.52 - 7.41 (m, 2H), 7.40 - 7.33 (m, 1H), 7.32 - 7.17 (m, 4H), 7.15 - 7.09 (m, 1H), 7.01 (d, J = 5.5 Hz, 1H), 6.80 (br s, 1H), 6.27 - 6.06 (m, 1H), 5.67 - 5.29 (m, 3H), 4.73 - 4.40 (m, 4H), 4.00 - 3.82 (m, 1H), 3.50 - 3.37 (m, 1H), 3.09 - 2.89 (m, 5H), 2.45 - 2.19 (m, 2H). Example 131 (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 The title compound was prepared in analogy to Example 125 by using N-(4- bromobutyl)phthalimide instead of compound 125b and intermediate B5 instead of intermediate B11. LCMS (M+H+):583.1H NMR (400 MHz, METHANOL-d4) δ = 8.41 - 8.24 (m, 1H), 7.88 - 7.68 (m, 2H), 7.58 - 7.49 (m, 2H), 7.41 - 7.23 (m, 2H), 7.06 (d, J = 5.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 1.3, 9.2 Hz, 1H), 6.38 (dd, J = 1.3, 6.8 Hz, 1H), 5.17 - 5.02 (m, 1H), 4.65 (br d, J = 2.1 Hz, 1H), 4.49 - 4.31 (m, 2H), 4.07 - 3.92 (m, 1H), 3.27 - 3.10 (m, 3H), 2.78 - 2.64 (m, 2H), 2.29 - 2.13 (m, 1H), 1.84 - 1.55 (m, 2H), 1.23 - 1.02 (m, 1H). Example 132 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 2-[3-(9-borabicyclo[3.3.1]nonan-9-yl)propyl]isoindoline-1,3- dione (compound 132b) A solution of compound 132a (500.0 mg, 2.67 mmol) in THF (4 mL) was added 9-bora- bicyclo[3.3.1]nonane (8.0 mL, 4.0 mmol) at 0 °C. The reaction was stirred at 20 °C for 15 h. The reaction was used in next step directly. Step 2: preparation of 3-[(E)-2-ethoxyvinyl]-1-methyl-4-nitro-pyrazole (compound 132d) To a solution of 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane; vinyloxyethane (19.5 g, 91 mmol), palladium acetate (681 mg, 3.03 mmol), Sphos (2.99 g, 7.28 mmol) and potassium phosphate (2.25 g, 106.2 mmol) in ACN (40 mL) and water (20 mL) was added compound 132c (9.8 g, 60.7 mmol). The reaction was stirred at 70 °C for 16 h under N2, and then the mixture was filtered, the filtrate was diluted with brine and extracted with EtOAc. The organic layer was concentrated and the residue was purified by reversed-phase flash column to afford compound 132d (9.2 g) as an orange solid. LCMS (M+H+): 198. Step 3: preparation of 2-(1-methyl-4-nitro-pyrazol-3-yl)acetaldehyde (compound 132e) To a solution of compound 132d (9.2 g, 46.7 mmol) in THF (60 mL) was added HCl (20.0 mL, 120.0 mmol) at 15 °C. The reaction was stirred at 60 °C for 1 h and then the mixture was poured into saturated NaHCO3, extracted with EtOAc. The organic layer was dried and concentrated to afford compound 132e (7.89 g) as brown oil. Step 4: preparation of tert-butyl N-[3-(2-hydroxyethyl)-1-methyl-pyrazol-4- yl]carbamate (compound 132f) To a solution of compound 132e (7.89 g, 46.65 mmol) in methanol (500 mL) was added sodium tetrahydroborate (5.5 g, 145.5 mmol) at 0 °C. The reaction was stirred at 15 °C for 1 h and then Boc2O (10.96 g, 50.23 mmol) was added at 0 °C. The resulted mixture was stirred at 15 °C for 1 h and then quenched with saturated NH4Cl (100 mL). The mixture was concentrated, the residue was extracted EtOAc, the organic layer was dried and concentrated to give compound 132f (10.0 g) as light brown oil. LCMS (M-56+H+):186. Step 5: preparation of 2-[4-(tert-butoxycarbonylamino)-1-methyl-pyrazol-3-yl]ethyl methanesulfonate (compound 132g) To a solution of compound 132f (10.0 g, 30 mmol) and triethylamine (7.7 mL, 55.06 mmol) in DCM (300 mL) was added methanesulfonic anhydride (5.75 g, 33 mmol) at 0 °C. The reaction mixture was stirred at 15 °C for 2 h and then concentrated, the residue was purified by reversed- phase flash column to afford compound 132g (4.8 g) as light yellow oil. LCMS (M+H+): 320. Step 6: preparation of tert-butyl 2-methyl-5,6-dihydropyrrolo[3,2-c]pyrazole-4- carboxylate (compound 132h) To a solution of compound 132g (4.8 g, 15.03 mmol) and potassium iodide (0.95 mL, 17.95 mmol) in THF (250 mL) was added potassium tert-butoxide (2.17 g, 19.31 mmol) portion wise at 0 °C. The reaction mixture was stirred at 15 °C for 16 h and then concentrated, the residue, purified by reversed-phase flash column to afford compound 132h (3.2 g) as light yellow oil. LCMS (M+H+): 224. Step 7: preparation of tert-butyl 3-iodo-2-methyl-5,6-dihydropyrrolo[3,2-c]pyrazole- 4-carboxylate (compound 132i) To a solution of compound 132h (3.18 g, 14.24 mmol) and AcOH (180.0 mg, 3.0 mmol) in DMF (50 mL) was added NIS (4.67 g, 17.1 mmol) at 15 °C. The reaction mixture was stirred at 60 °C for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by reversed-phase flash column to afford compound 132i (3.5 g) as an off-white solid. LCMS (M+H+): 350. Step 8: preparation of tert-butyl 3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-5,6- dihydropyrrolo[3,2-c]pyrazole-4-carboxylate (compound 132j) A mixture of compound 132i (2.11 g, 6.04 mmol), compound 132b (64.0 mL, 11.33 mmol), Pd2(dba)3 (572.0 mg, 0.62 mmol), BINAP (391.0 mg, 0.63 mmol) and cesium carbonate (3.94 mg, 12.1 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 12 h under N2. Then the reaction mixture was filtered, the filtrate was concentrated and the residue was purified by reversed-phase flash column to afford compound 132j (223.0 mg) as light brown oil. LCMS (M+H+): 411. Step 9: preparation of 2-[3-(2-methyl-5,6-dihydro-4H-pyrrolo[3,2-c]pyrazol-3- yl)propyl]isoindoline-1,3-dione (compound 132k) To a solution of compound 132j (223.0 mg, 0.54 mmol) in DCM (5 mL) was added TFA (1.5 mL) at 15 °C. The reaction was stirred at 15 °C for 0.5 h and then concentrated, the residue was purified by prep-HPLC to afford compound 132k (330.0 mg) as light brown oil. LCMS (M+H+): 311. Step 10: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3- dioxoisoindolin-2-yl)propyl]-2-methyl-5,6-dihydropyrrolo[3,2-c]pyrazol-4- yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 132l) A mixture of Intermediate B11 (420.0 mg, 1.05 mmol), compound 132k (330.0 mg, 0.98 mmol), tris(dibenzylideneacetone)dipalladium (0) (92.0 mg, 0.1 mmol), 4,5- bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene (180.0 mg, 0.31 mmol) and cesium carbonate (683.0 mg, 2.1 mmol) in 1,4-dioxane (6 mL) was stirred at 100 °C for 4 h under Ar. The reaction mixture was filtered and then the filtrate was concentrated, the residue was purified by prep-HPLC to afford compound 132l (230.0 mg) as light brown oil. LCMS (M+H+): 630. Step 11~15: preparation of(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-18-methyl-7-oxa-1,10,13,18,19- 2,6 8,11 20,23 pentazapentacyclo[15.5.1.1 .1 .0 ]pentacosa-2(25),3,5,17(23),19-pentaen-12-one (Example 132) The title compound was prepared in analogy to the preparation of Example 70 by using compound 132l instead of compound 78e and intermediate C2 instead of intermediate C3. LCMS (M+H+): 598.1H NMR (400 MHz, METHANOL-d4) δ = 8.52 - 8.44 (m, 1H), 8.32 (s, 2H), 7.64 (dt, J = 6.1, 8.6 Hz, 2H), 7.33 - 7.25 (m, 2H), 7.24 - 7.17 (m, 2H), 5.48 - 5.27 (m, 2H), 5.13 - 5.09 (m, 1H), 5.02 - 4.96 (m, 2H), 4.93 - 4.91 (m, 2H), 4.79 - 4.72 (m, 2H), 4.48 - 4.06 (m, 4H), 2.89 - 2.47 (m, 6H). Example 133 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of ethyl 3-(1, 3-dioxoisoindolin-2-yl)-2-hydroxy-propanoate (compound 133b) To a solution of compound 133a (10.0 g, 86.12 mmol) in DMF (200 mL) was added phthalimide (11.0 g, 74.76 mmol) and potassium phthalimide (2.0 g, 10.8 mmol). The reaction was stirred at 90 °C for 5 h, and then the reaction mixture was diluted with water, extracted with EA. The organic layer was dried and concentrated to give compound 133b (19.0 g) as yellow oil. LCMS (M+H+): 264. Step 2: preparation of ethyl 3-(1, 3-dioxoisoindolin-2-yl)-2-oxo-propanoate (compound 133c) To a solution of compound 133b (18.0 g, 68.38 mmol) in DCM (200 mL) was added Dess- Martin periodinane (43.5 g, 102.56 mmol) at 0 °C. The reaction was stirred at 20 °C for 3 h and then the mixture was filtered, the filtrate was concertrated to give compound 133c (14.0 g) as a yellow solid. LCMS (M+H+): 262. Step 3: preparation of 2-[(5-hydroxy-3-sulfanyl-1, 2, 4-triazin-6-yl) methyl] isoindoline-1, 3-dione (compound 133d) To a solution of compound 133c (10.0 g, 38.28 mmol) in anhydrous ethanol (200 mL) was added thiosemicarbazide (3.49 g, 38.28 mmol) in one portion. The reaction mixture was stirred at 80 °C for 2 h and then N,N-diisopropylethylamine (6.67 mL, 38.28 mmol) was added. The reaction mixture was stirred at 40 °C for 6 h and then stirred at 20°C for 10 h. The reaction mixture was concentrated, the residue was dissolved in MeCN (80 mL) and then water (300 mL) was added, while a solid formed and was collected by filtration to give compound 133d (5.6 g) as a yellow solid. LCMS (M+H+): 289. Step 4: preparation of 2-[(5-hydroxy-1, 2, 4-triazin-6-yl) methyl] isoindoline-1, 3- dione (compound 133e) To a solution of compound 133d (1.0 g, 3.47 mmol) in ethanol (25 mL) was added Raney Ni (1.0 g, 3.47 mmol). The reaction was stirred at 80 °C for 12 h and then Et3SiH(3.6 g) was added. The reaction mixture was stirred at 80 °C for 12 h and then cooled to rt, the solid was filtered off and the filtrate was concentrated to give compound 133e (360.0 mg) as a yellow solid. LCMS (M+H+): 257. Step 5: preparation of 6-(aminomethyl)-1, 2, 4-triazin-5-ol (compound 133f) To a solution of compound 133e (100.0 mg, 0.39 mmol) in ethanol (1 mL) was added methylamine/ethanol (1.0 mL, 2.0 mmol) dropwise at 20°C. The reaction mixture was stirred at 60°C for 1 hour and then concentrated to give compound 133f (100 mg) as a yellow solid. Step 6: preparation of 2, 4-difluoro-N-[(5-hydroxy-1, 2, 4-triazin-6-yl) methyl] benzamide (compound 133g) To a solution of compound 133f (1.0 g, 7.93 mmol) in DMF (10 mL) was added HATU (2.24 g, 9.51 mmol), N,N-Diisopropylethylamine (4.14 mL, 23.79 mmol) and 2,4- difluorobenzoic acid (1.25 g, 7.93 mmol) at 0 °C. The reaction mixture was sitrred at 15 °C for 2 h and then purified by perp-HPLC to give compound 133g (450.0 mg) as a brown solid. LCMS (M+H+): 267. Step 7: preparation of 7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazin-4-ol (compound 133h) To a solution of compound 133g (100.0 mg, 0.38 mmol) in toluene (1 mL) was added pyridine (30.38 uL, 0.38 mmol) and phosphorus oxychloride (1.0 mL, 10.73 mmol). The reaction mixture was stirred at 110 °C for 12 h and then concentrated. The residue was diluted with EA (20 mL), washed with ice NaHCO3 (30 mL) and then concentrated to give compound 133h (80.0 mg) as a brown solid. LCMS (M+H+): 249. Step 8: preparation of 4-chloro-7-(2, 4-difluorophenyl) imidazo[5,1-f][1,2,4]triazine (compound 133i) To a solution of compound 133h (40.0 mg, 0.16 mmol) was added N,N- diisopropylethylamine (56.15 µL, 0.32 mmol) and phosphorus oxychloride (1.0 mL, 10.73 mmol). The reaction was stirred at 110 °C for 2 h and then concentrated. The residue was diluted with EA (20 mL), washed with ice NaHCO3 (30 mL) and then concentrated to give compound 133i (80 mg) as a brown solid. LCMS (M+H+): 267. Step 9: preparation of (8S,11S)-10-[7-(2,4-difluorophenyl)imidazo[5,1-f][1,2,4]triazin- 2,6 8,11 20,24 4-yl]-13,18-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 (Example 133) To a solution of compound 133i (30.0 mg, 0.11 mmol) in NMP (0.6 mL) was added compound 120e (57 mg, 0.11 mmol), KF (32.69 mg, 0.56 mmol) and N,N-diisopropylethylamine (118 uL, 0.68 mmol). The reaction mixture was stirred at 100 °C for 2 h and then purified by prep-HPLC to give Example 133 (10 mg) as a white solid. LCMS (M+H+): 621.1H NMR (400 MHz, METHANOL-d4) δ = 8.19 - 8.12 (m, 2H), 7.91 - 7.82 (m, 2H), 7.76 - 7.69 (m, 1H), 7.42 - 7.36 (m, 1H), 7.27 - 7.16 (m, 4H), 7.10 - 7.04 (m, 1H), 5.71 - 5.57 (m, 1H), 4.77 (dd, J = 6.8, 11.9 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.18 - 4.14 (m, 3H), 4.12 - 4.07 (m, 1H), 3.27 (s, 1H), 3.16 (s, 2H), 3.14 - 3.08 (m, 1H), 3.01 - 2.92 (m, 1H), 2.87 - 2.54 (m, 4H), 2.38 - 2.15 (m, 1H), 2.04 (s, 1H). Example 134 & 135 (8S,11S,17R)-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 and (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 2,6 8,11 21,25 4-yl]-13-methyl-18-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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-methyl-N-prop-2-ynyl-carbamate (compound 134b) To a solution of compound 134a (4.0 g, 57.88 mmol) and triethylamine (9.68 mL, 69.45 mmol) in DCM (50 mL) was added benzyl chloroformate (10.86 g, 63.67 mmol) solwly. The reaction mixture was stirred at 0 °C for 2 hours and then diluted with DCM, washed with water, saturated NaHCO3 and brine. The organic layer was dried and concentrated to afford compound 134b (13.0 g) as brown oil. LCMS (M+H+): 204. Step 2: preparation of benzyl N-[4-(2-bromo-6-nitro-phenyl)-4-hydroxy-but-2-ynyl]- N-methyl-carbamate (compound 134d) To a solution of compound 134b (5.3 g, 26.08 mmol) in THF (100 mL) at -78 °C was added n-BuLi (9.56 mL, 23.91 mmol) dropwise. After stirring for 30 min, compound 134c (5.0 g, 21.74 mmol) in THF (20 mL) was added -78 °C. The reaction mixture was stirred at -78 °C for 1 h and then quenched with sat. aq. NH4Cl, extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to afford compound 134d (6.6 g) as red oil. LCMS (M+H+): 433. Step 3: preparation of benzyl N-[4-(2-amino-6-bromo-phenyl)-4-hydroxy-butyl]-N- methyl-carbamate (compound 134e) A mixture of compound 134d (6.6 g, 15.23 mmol) and Pd/C (660 mg) in ethanol (150 mL) was stirred at 25 °C for 2 h under H2. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography to to give compound 134e (2.1 g) as a yellow solid. LCMS (M-OH+H+): 389. Step 4: preparation of benzyl N-[3-(5-bromo-2-oxo-1,4-dihydro-3,1-benzoxazin-4- yl)propyl]-N-methyl-carbamate (compound 134f) To a solution of compound 134e (2.1 g, 5.16 mmol) in THF (80 mL) was added a solution of bis(trichloromethyl)carbonate (1.9 g, 6.4 mmol) in THF (20 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes and then TEA (1.9 g, 18.78 mmol) was added dropwise at 0 °C. After being stirred for 1 h at 25 °C, the reaction was diluted with DCM, washed with H2O, the organic layer was dried and concentrated to give compound 134f (2.2 g) as brown oil. LCMS (M+H+): 433. Step 5: preparation of benzyl N-methyl-N-[3-[2-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,4-dihydro-3,1-benzoxazin-4-yl]propyl]carbamate (compound 134g) To a solution of compound 134f (2270.0 mg, 5.24 mmol) in 1,4-dioxane (46 mL) was added B2Pin2 (3995.2 mg, 15.73 mmol), KOAc (1543.6 mg, 15.73 mmol) and Pd(dppf)Cl2 (767.0 mg, 1.05 mmol). The reaction mixture was stirred at 110 °C for 12 h and then concentrated, the residue was purified by prep-HPLC to give compound 134g (1.9 g) as yellow oil. LCMS (M+H+): 481. Step 6: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[[6-[4-[3- [benzyloxycarbonyl(methyl)amino]propyl]-2-oxo-1,4-dihydro-3,1-benzoxazin-5-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 134h) A mixture of Intermediate B5 (756.0 mg, 1.89 mmol), compound 134g (900.0 mg, 1.87 mmol), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (125 mg, 0.19 mmol) and K3PO4 (791.67 mg, 3.75 mmol) in 1,4-dioxane (9 mL) and water (1 mL) was stirred 80 °C for 2 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 134h (1.1 g) as yellow oil. LCMS (M+H+): 674. Step 7: preparation of (2S,4S)-4-[[6-[4-[3-[benzyloxycarbonyl(methyl)amino]propyl]- 2-oxo-1,4-dihydro-3,1-benzoxazin-5-yl]-2-pyridyl]amino]-1-tert-butoxycarbonyl- pyrrolidine-2-carboxylic acid (compound 134i) A mixture of compound 134h (940.0 mg, 1.4 mmol) and LiOH (234.0 mg, 9.77 mmo).in methanol (10 mL) and water (1.25 mL) was stirred at 20 °C for 12 h. The reaction mixture was concentrated and the residue was diluted with H2O. The pH of aqueous phase was adjusted to 6 and then it was extrated with EtOAc, the organic layer was dried and concentrated to give compound 134i (40 mg) as yellow oil. LCMS (M+H+): 660. Step 8: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[4-[3- (methylamino)propyl]-2-oxo-1,4-dihydro-3,1-benzoxazin-5-yl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 134j) A mixture of compound 134i (200.0 mg, 0.3 mmol) and Pd/C (200.0 mg, 0.3 mmol) in THF (10 mL) and 2-propanol (10 mL) was stirred for 1 h at 50 °C under hydrogen balloon. Then the reaction mixture was filtered, the filtrate was concentrated to give compound 134j (180.0 mg) as a yellow solid. LCMS (M+H+): 526. Step 9: preparation of tert-butyl (8S,11S,17R)-13-methyl-12,19-dioxo-18-oxa- 7,10,13,20,27-pentazapentacyclo[15.7.1.12,6.18,11.021,25]heptacosa- 1(24),2,4,6(27),21(25),22-hexaene-10-carboxylate & tert-butyl (8S,11S,17S)-13-methyl- 12,19-dioxo-18-oxa-7,10,13,20,27-pentazapentacyclo[15.7.1.12,6.18,11.021,25]heptacosa- 1(24),2,4,6(27),21(25),22-hexaene-10-carboxylate(compound 134k & 134l) To a solution of HATU (134.0 mg, 0.35 mmol) and triethylamine (96.0 mg, 0.95 mmol) in DMF (35 mL) and THF (35 mL) was added a solution of compound 134j (180.0 mg, 0.34 mmol) in DMF (35 mL) and THF (35 mL) at 0 °C, and then the mixture was stirred for 1 h at 0 °C. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 134k (32.0 mg, faster eluted) as a yellow solid and compound 134l (30.0 mg, slower eluted) as a yellow solid. LCMS (M+H+): 508. Step 10~11: preparation of (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-18-oxa-7,10,13,20,27- 2,6 8,11 21,25 pentazapentacyclo[15.7.1.1 .1 .0 ]heptacosa-1(24),2,4,6(27),21(25),22-hexaene-12,19- dione and (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13- 2,6 8,11 21,25 methyl-18-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 (Example 134 & 135) The title compounds were prepared in analogy to the preparation of Example 70 by using compound 134k and 134l instead of compound 78h and intermediate C2 instead of intermediate C3. Example 134. Faster eluted. LCMS (M+H+): 638.1H NMR (400 MHz, DMSO-d6) δ = 10.26 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 7.64 - 7.60 (m, 2H), 7.54 - 7.40 (m, 1H), 7.21 - 7.18 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.81 - 6.77 (m, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 7.1 Hz, 1H), 5.73 - 5.68 (m, 1H), 5.28 - 5.21 (m, 2H), 4.59 - 4.53 (m, 2H), 4.35 - 4.30 (m, 1H), 4.02 (br d, J = 11.1 Hz, 2H), 3.24 (s, 3H), 1.97 - 1.87 (m, 2H), 1.74 - 1.61 (m, 2H), 1.64 - 1.54 (m, 1H). Example 135. Slower eluted. LCMS (M+H+): 638. Example 137 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 7-[(E)-3-ethoxy-3-oxo-prop-1-enyl] pyrrolo [3, 2-c] pyridine-1-carboxylate (compound 137c) A mixture of compound 137a (7.0 g, 23.56 mmol), compound 137b (7.0 g, 30.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.72 g, 2.36 mmol) and potassium carbonate (7.16 g, 51.83 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound 137c (6.06 g) as a light brown solid. LCMS (M+H+): 317. Step 2: preparation of 3-(1H- pyrrolo [3, 2-c] pyridin-7-yl) propan-1-ol (compound 137d) To a solution of compound 137c (5.0 g, 15.81 mmol) in THF (100 mL) was added lithium aluminum hydride (1.8 g, 47.42 mmol) at 0 °C. The reaction mixture was stirred at 25°C for 16 h and then quenched with water and 15% NaOH aq. The mixture was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to afford compound 137d (1.1 g) as light brown solid. LCMS (M+H+): 177. Step 3: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[tert-butoxycarbonyl- [6-[7- (3-hydroxypropyl) pyrrolo [3, 2-c] pyridin-1-yl]-2-pyridyl] amino] pyrrolidine-1, 2- dicarboxylate (compound 137e) To a solution of compound 137d (0.86 g, 4.88 mmol), Intermediate B6 (2.0 g, 4.0 mmol), DMEDA (0.35 g, 4.0 mmol) and potassium carbonate (1.66 g, 11.99 mmol) in toluene (20 mL) was added CuI (0.76 g, 4.0 mmol) under N2, and then the reaction was stirred at 120 °C for 16 h under N2. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound 137e (1.6 g) as a light yellow solid. LCMS (M+H+): 596. Step 4: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[tert-butoxycarbonyl- [6-[7- (3-methylsulfonyloxypropyl) pyrrolo [3, 2-c] pyridin-1-yl]-2-pyridyl] amino] pyrrolidine-1, 2-dicarboxylate (compound 137f) To a stirred solution of compound 137e (1.6 g, 2.38 mmol) and triethylamine (1.0 mL, 7.14 mmol) in DCM (40 mL) was added methanesulfonic anhydride (1.24 g, 7.14 mmol) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h and then poured into water and DCM. The organic layer was separated, dried and concentrated to afford compound 137f (2.2 g) as light brown oil. LCMS (M+H+): 674. Step 5: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[tert-butoxycarbonyl- [6-[7- [3-(methylamino) propyl] pyrrolo [3, 2-c] pyridin-1-yl]-2-pyridyl] amino] pyrrolidine-1, 2- dicarboxylate (compound 137g) To a solution of compound 137f (2.2 g, 1.53 mmol) in MeCN (22 mL) was added methylamine in THF (3.07 mL, 6.14 mmol), and then the reaction was stirred at 80 °C for 16 h. The reaction mixture was concentrated to afford compound 137g (2.0 g) as a light yellow solid. LCMS (M+H+): 609. Step 6: preparation of (2S, 4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl- [6-[7-[3- (methylamino) propyl] pyrrolo [3, 2-c] pyridin-1-yl]-2-pyridyl] amino] pyrrolidine-2- carboxylic acid (compound 137h) To a solution of compound 137g (50.0 mg, 0.02 mmol) in methanol (0.8 mL) and water (0.1 mL) was added lithium hydroxide monohydrate (20.0 mg, 0.48 mmol), and then the reaction was stirred at 25 °C for 16 h. The pH of reaction mixture was adjusted to 6 with 2N HCl, and then it was purified by prep-HPLC to afford compound 137h (8.0 mg) as a white solid. LCMS (M+H+): 595. Step 7: preparation of ditert-butyl (8S,11S)-13-methyl-12-oxo-1,7,10,13,19,26- 2,6 8,11 21,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22-heptaene-7,10- dicarboxylate (compound 137i) To a solution of HATU (8.0 mg, 0.02 mmol) and DIEA (4.0 mg, 0.03 mmol) in DMF (1 mL) was added compound 137h (8.0 mg, 0.01 mmol) in DMF (1 mL) dropwise at 0 °C. The reaction was stirred for 0.5 h at 0 °C and then poured into water, extracted with ethyl acetate. The organic phase was dried and concentrated to afford compound 137i (7.0 mg) as light yellow oil. LCMS (M+H+): 577. Step 8: preparation of (8S,11S)-13-methyl-1,7,10,13,19,26-hexazapentacyclo 2,6 8,11 21,24 [15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one;hydrochloride (compound j) To a stirred mixture of compound 137i (7.0 mg, 0.01 mmol) in DCM (0.5 mL) was added HCl in dioxane (0.5 mL, 2.0 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and then concentrated to afford compound 137j (5.0 mg) as a white solid. LCMS (M+H+):377. Step 9: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 21,24 yl]- 13-methyl-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 (Example 137) To a solution of compound 137j (5.0 mg, 0.01 mmol) and Intermediate C2 (4.0 mg, 0.02 mmol) in MeCN (1 mL) was added DIEA (5.0 mg, 0.04 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h and then purified by prep-HPLC to afford Example 137 (3 mg) as white solid. LCMS (M+H+): 607.1H NMR (400 MHz, METHANOL-d4) δ = 9.11 (s, 1H), 8.51 (s, 1H), 8.33 - 8.29 (m, 1H), 8.23 (s, 1H), 7.95 - 7.87 (m, 2H), 7.65 (dt, J = 6.1, 8.5 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.22 - 7.17 (m, 2H), 6.94 (dd, J = 4.5, 7.8 Hz, 2H), 5.49 (d, J = 9.3 Hz, 1H), 4.80 - 4.74 (m, 1H), 4.51 (dd, J = 6.4, 11.3 Hz, 1H), 4.38 - 4.26 (m, 2H), 3.24 - 3.14 (m, 3H), 3.00 - 2.63 (m, 4H), 2.48 (br d, J = 13.3 Hz, 1H), 2.31 - 2.20 (m, 1H), 1.81 - 1.60 (m, 1H). Example 138 (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 The title compound was prepared according to the following scheme: Step 1: preparation of ditert-butyl (8S, 11S)-13-methyl-12-oxo- 1,7,10,13,19,26 - 2,6 8,11 21,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22-heptaene-7,10- dicarboxylate (compound 138b) To a solution of HATU (80.0 mg, 0.21 mmol) and DIEA (40.0 mg, 0.31 mmol) in DMF (13.5 mL) was added compound 138a (80.0 mg, 0.13 mmol) in DMF (13.5 mL) dropwise at 0 °C for 0.25 h. The reaction mixture was stirred for 0.5 h at 0 °C and then poured into water and ethyl acetate. The organic layer was separated, dried and concentrated to afford compound 138b (75.0 mg) as light yellow solid. LCMS (M+H+): 577. Step 2: preparation of ditert-butyl (8S,11S)-22-chloro-13-methyl-12-oxo- 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- heptaene-7,10-dicarboxylate (compound 138c) To a solution of compound 138b (35.0 mg, 0.06 mmol) in DCM (1 mL) was added NCS (10.0 mg, 0.07 mmol) dropwise at 0 °C. The reaction mixture was stirred for 16 h at 20 °C and then concentrated. The residue was purified by prep-HPLC to afford compound 138c (20.0 mg) as white solid. LCMS (M+H+): 611. Step 3: preparation of (8S,11S)-22-chloro-13-methyl-1,7,10,13,19,26-hexazapentacyclo 2,6 8,11 21,24 [15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12-one;hydrochloride (compound 138d) To a solution of compound 138c (15.0 mg, 0.02 mmol) in DCM (0.5 mL) was added HCl in dioxane (1.0 mL, 4.0 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 25 °C and then concentrated to afford compound 138d (10.0 mg) as a yellow solid. LCMS (M+H+): 411. Step 4: preparation of (8S,11S)-22-chloro-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin -4-yl]-13-methyl-1,7,10,13,19,26- 2,6 8,11 21,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-2(26),3,5,17,19,21(24),22-heptaen-12- one;2,2,2-trifluoroacetic acid (Example 138) To a solution of compound 138d (10.0 mg, 0.02 mmol) and Intermediate C3 (8.0 mg, 0.03 mmol) in MeCN (1 mL) was added DIEA (10.0 mg, 0.08 mmol) at 25°C. The reaction mixture was stirred at 80 °C for 2 h and then purified by prep-HPLC to afford Example 138 (7 mg) as white solid. LCMS (M+H+): 641.1H NMR (400 MHz, METHANOL-d4) δ = 9.14 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.65 (t, J = 6.0, 8.6 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.22 - 7.16 (m, 1H), 6.98 - 6.89 (m, 2H), 5.49 (d, J = 9.0 Hz, 1H), 4.79 - 4.74 (m, 1H), 4.50 (dd, J = 6.1, 11.0 Hz, 1H), 4.38 - 4.26 (m, 2H), 3.24 - 3.12 (m, 3H), 2.95 - 2.84 (m, 1H), 2.76 - 2.63 (m, 3H), 2.46 (d, J = 13.1 Hz, 1H), 2.31 - 2.19 (m, 1H), 1.80 - 1.64 (m, 1H). Example 139 (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 The title compound was prepared according to the following scheme: Step 1: preparation of benzyl N-(3-hydroxypropyl)-N-methyl-carbamate (compound 139d) To a solution of N-(benzyloxycarbonyloxy)succinimide (33.55 g, 134.62 mmol) in THF (100 mL) and water (100 mL) were added sodium carbonate (23.78 g, 224.37 mmol), compound 139c (10.0 g, 112.18 mmol) in one portion. The reaction mixture was stirred at 20 °C for 1 h and then diluted with water, extracted with EtOAc. The organic layer was separated and concentrated, the residue was purified by silica gel column chromatography to give compound 139d (20.0 g) as colorless oil. LCMS (M+H+): 224. Step 2: preparation of benzyl N-methyl-N-(3-oxopropyl)carbamate (compound 139e) To a solution of compound 139d (8.5 g, 38.07 mmol) in DCM (85 mL) was added DMP (19.4 g, 45.68 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 h, then the mixture was diluted with EtOAc/PE (1:10). The mixture was filtered and the filtrate was concentrated to give compound 139e (10 g) as light yellow oil, which was used directly without further purification. LCMS (M+H+): 222. Step 3: preparation of benzyl N-[3-(4-bromo-2-methyl-indazol-3-yl)-3-hydroxy- propyl]-N-methyl-carbamate (compound 139f) To a solution of compound 139b (3 g, 14.21 mmol) in THF (50 mL) was added LDA in THF (11.5 mL, 28.75 mmol) at -78 ℃. After being stirred at -78 ℃ for 1 h, compound 139e (3.8 g, 17.06 mmol) in THF (20 mL) was added to the reaction mixture at -78 ℃. The reaction mixture was stirred at -78 ℃ for 1 h and at -30 ℃ for 3 h. The reaction was quenched with saturated ammonium chloride solution (100 mL) and then the mixture was extracted with ethyl acetate. The organic layer dried and concentrated to afford the crude product , which was purified by silica gel column chromatography to give compound 139f (1.7 g) as light brown oil. LCMS (M+H+): 432. Step 4: preparation of benzyl N-[3-hydroxy-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]propyl]-N-methyl-carbamate (compound 139g) To a solution of compound 139f (500 mg, 1.16 mmol) and potassium acetate (227 mg, 2.31 mmol) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl2 (47 mg, 0.06 mmol) and bis(pinacolato)diboron (440 mg, 1.73 mmol). The reaction mixture was degassed by N2 and then stirred at 80 °C for 16 h under N2. The mixture was filtered and the filtrate was concentrated to give compound 139g (700.0 mg) as light brown oil, which was used directly without further purification. LCMS (M+H+): 480. Step 5~10: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-16-hydroxy-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 (Example 139) The title compound was prepared in analogy to Example 80 by using compound 139g and of compound 80f. LCMS (M+H+): 637.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (s, 1H), 8.28 (s, 1H), 8.25 - 8.16 (m, 1H), 7.83 - 7.62 (m, 2H), 7.46 - 7.38 (m, 1H), 7.35 - 7.20 (m, 3H), 7.16 - 6.99 (m, 2H), 5.70 - 5.61 (m, 1H), 5.43 (br d, J = 12.0 Hz, 1H), 4.76 - 4.63 (m, 1H), 4.42 - 4.31 (m, 3H), 4.19 - 4.13 (m, 3H), 3.44 - 3.37 (m, 1H), 3.08 - 2.98 (m, 1H), 2.93 - 2.83 (m, 1H), 2.70 - 2.54 (m, 2H), 2.47 - 2.38 (m, 1H), 2.07 - 1.93 (m, 1H), 1.69 (br d, J = 6.9 Hz, 1H). Example 140 (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 Example 140 was prepared in analogy to the preparation of example 111 by using compound 116c compound instead of compound 111g and intermediate C8 instead of intermediate C6. LCMS (M+H+): 740.1H NMR (400 MHz, METHANOL-d4) δ = 8.44 - 8.33 (m, 1H), 8.27 - 8.18 (m, 1H), 7.57 - 7.44 (m, 1H), 7.29 - 7.23 (m, 1H), 7.18 - 7.01 (m, 2H), 6.98 - 6.88 (m, 3H), 5.71 - 5.52 (m, 1H), 5.44 - 5.24 (m, 1H), 4.98 - 4.94 (m, 1H), 4.89 - 4.86 (m, 1H), 4.82 - 4.77 (m, 4H), 4.44 - 4.30 (m, 3H), 4.16 - 4.06 (m, 1H), 4.05 - 3.90 (m, 2H), 3.37 - 3.28 (m, 2H), 3.11 - 3.02 (m, 1H), 2.99 - 2.87 (m, 3H), 2.79 - 2.68 (m, 1H), 2.63 - 2.53 (m, 3H), 0.60 - 0.47 (m, 3H). Example 141 (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 The title compound was prepared according to the following scheme: Step 1: preparation of ethyl (E)-3-(6-methoxy-2-pyridyl) prop-2-enoate (compound 141c) A mixture of compound 141a (20.0 g, 106.37 mmol), compound 141b (25.0 g, 110.58 mmol), Pd(dppf)Cl2 (2.0 g, 2.73 mmol) and sodium carbonate (30.0 g, 283.05 mmol) in 1,4- dioxane (200 mL) and water (20 mL) was stirred for 16 h at 80 °C under N2. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound 141c (22.0 g) as colorless oil. LCMS (M+H+): 208. Step 2: preparation of triethyl 2-(6-methoxy-2-pyridyl) propane-1, 1, 3-tricarboxylate (compound 141e) A solution of diethyl malonate (20.0 g, 124.87 mmol), compound 141c (22.0 g, 106.16 mmol) and potassium tert-butoxide (16.0 g, 142.59 mmol) in anhydrous ethanol (200 mL) was stirred for 16 h at 60 °C. Then reaction solvent was concentrated and the residue was purified by silica gel column chromatography to give compound 141e (34.0 g) as colorless oil. LCMS (M+H+): 368. Step 3: preparation of 3-(6-methoxy-2-pyridyl) pentanedioic acid (compound 141f) A solution of compound 141e (34.0 g, 92.54 mmol) in HCl/H2O (340.0 mL, 4080.0 mmol) was stirred for 16 h at 80 °C. Then the pH of reaction mixture was adjusted to 5 with NaHCO3, the solution was lyophilized to afford compound 141f (25.0 g) as a white solid. LCMS (M+H+): 240. Step 4: preparation of dimethyl 3-(6-methoxy-2-pyridyl) pentanedioate (compound 141g) A solution of compound 141f (17.0 g, 71.06 mmol) in HCl in MeOH (170.0 mL, 680.0 mmol) was stirred at 65 °C for 4 hrs. The reaction was concentrated and the residue was purified by silica gel column chromatography to afford compound 141g (7.15 g) as a white solid. LCMS (M+H+): 268. Step 5: preparation of 3-(6-methoxy-2-pyridyl) pentane-1, 5-diol (compound 141h) To a solution of compound 141g (7.15 g, 26.75 mmol) in THF (110 mL) was added Lithium Aluminum Hydride (2.44 g, 64.24 mmol) dropwise at -40 °C. The reaction was stirred at -40 °C for 3 h under N2 and then quenched in the following procedure: 1, added 1 mL of H2O and stirred for 10 min; 2, added 1 mL 15% NaOH aq. and stirred for 10 min; 3, added 1 mL H2O and stirred for 10 min. The mixture was filtered and the filtrate was concentrated to give compound 141h (5.42 g) as a white solid. LCMS (M+H+): 212. Step 6: preparation of 3-(3-bromo-6-methoxy-2-pyridyl) pentane-1, 5-diol (compound 141i) To a stirred solution of compound 141h (4.7 g, 22.25 mmol) in ethanol (80 mL) was added N-bromosuccinimide (4.36 g, 24.47 mmol) at 0 °C. The reaction was stirred at 50 °C for 1 hr and then concentrated, the residue was purified by prep-HPLC to afford compound 141i (900.0 mg) as colorless oil. LCMS (M+H+): 292.0 Step 7: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[3-[2-[3-hydroxy-1-(2- hydroxyethyl) propyl]-6-methoxy-3-pyridyl] phenoxy] pyrrolidine-1, 2-dicarboxylate (compound 141j) A mixture of compound 141i (0.9 g, 3.1 mmol), Intermediate B8 (1.65 g, 3.69 mmol), [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.24 g, 0.32 mmol) and sodium carbonate (0.99 g, 9.31 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred for 16 h at 105 °C under N2. Then reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound 141j (1.86 g) as dark brown oil. LCMS (M+H+): 531. Step 8: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[3-[1-(2-chloroethyl)-5-oxo- 2, 3-dihydro-1H-indolizin-8-yl] phenoxy] pyrrolidine-1, 2-dicarboxylate (compound k) To a solution of compound 141j (1.86 g, 2.87 mmol), DIPEA (1.5 mL, 8.68 mmol) in DCE (40 mL) was added methanesulfonyl chloride (1.1 mL, 14.32 mmol) dropwise at 0 °C. The reaction mixture was stirred at 65 °C for 15.5 h and then concentrated. The residue was purified by silica gel column chromatography to afford compound 141k (1.7 g) as a dark brown solid. LCMS (M+H+): 517. Step 9: preparation of O1-tert-butyl O2-methyl (2S, 4S)-4-[3-[1-[2-(methylamino) ethyl]-5-oxo-2, 3-dihydro-1H-indolizin-8-yl] phenoxy] pyrrolidine-1, 2-dicarboxylate (compound 141i) A solution of compound 141k (200.0 mg, 0.26 mmol) in methylamine/THF (5.0 mL, 10.0 mmol) was stirred at 80 °C for 16 hrs. The reaction mixture was concentrated to afford compound 141l (250.0 mg) as a dark brown solid. LCMS (M+H+): 512 Step 10~13: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-13-methyl-7-oxa-10,13,19- 2,6 8,11 19,23 triazapentacyclo[14.6.1.1 .1 .0 ]pentacosa-1(23),2(25),3,5,21-pentaene-12,20-dione (Example 141) The title compound was prepared in analogy to Example 80 by using compound 141l instead of compound 80i. LCMS (M+H+): 610.1H NMR (400 MHz, METHANOL-d4) δ = 8.58 (d, J = 4.6 Hz, 1H), 8.41 - 8.23 (m, 1H), 7.80 - 7.61 (m, 2H), 7.47 (dt, J = 3.3, 7.9 Hz, 1H), 7.33 - 6.98 (m, 5H), 6.53 (dd, J = 2.1, 9.2 Hz, 1H), 5.61 - 5.30 (m, 2H), 4.63 - 4.41 (m, 2H), 4.36 - 4.02 (m, 3H), 3.20 (s, 1H), 3.01 - 2.88 (m, 2H), 2.87 - 2.74 (m, 1H), 2.62 - 2.49 (m, 2H), 2.44 - 2.21 (m, 2H), 2.04 - 1.80 (m, 1H), 1.76 - 1.38 (m, 1H), 1.38 - 1.09 (m, 1H). Example 142 (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6,12-dimethyl- 14,17 2,7 6,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa-1(23),2(7),3,19,21-pentaene-5,13- dione The title compound was prepared according to the following scheme: Step 1: preparation of 6-chloro-1-methyl-pyridin-2-one (compound 142b) To a solution of compound 142a (10.0 g, 77.2 mmol) in DMF (40 mL) was added Li2CO3 (22.8 g, 308.9 mmol) and MeI (19.0 mL, 308.8 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for another 15 h. The reaction mixture was directly purified by prep-HPLC to give compound 142b (15.0 g) as a yellow solid. LCMS (M+H+): 144. Step 2: preparation of tert-butyl N-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-N- (1-methyl-6-oxo-2-pyridyl)carbamate (compound 142c) A solution of compound 142b (3 g, 18.74 mmol), tert-butyl (3- aminopropyl)(methyl)carbamate (5.3 g, 28.12 mmol) and DIPEA (7.3 g, 56.23 mmol,) in NMP (3 mL) was stirred at 160 °C for 2 hr under microwave. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give an intermediate, which was added into a solution of DIPEA (5 g, 38.92 mmol), DMAP (712 mg, 5.84 mmol) and di-tert-butyl dicarbonate (12.7g, 58.38 mmol) in ACN (100 mL). The reaction mixture was stirred at 25 °C for 12 h and then concentrated, the residue was purified by silica gel column chromatography to give compound 142c (3.19 g) as yellow oil. LCMS (M+H+): 396. Step 3: preparation of tert-butyl N-[3-[tert-butoxycarbonyl-(5-chloro-1-methyl-6-oxo- 2-pyridyl)amino]propyl]-N-methyl-carbamate (compound 142d) To a solution of compound 142c (3 g, 7.47 mmol) in ACN (10 mL) was added a solution of NCS (1.49 g, 11.2 mmol) in ACN (40 mL) dropwise at 25 °C. The reaction mixture was stirred at 85 °C for 12 h and then concentrated, the residue was purified by silica gel column chromatography to give compound 142d (700 mg) as yellow oil. LCMS (M+H+): 430. Step 4: preparation of tert-butyl N-(3-bromo-5-chloro-1-methyl-6-oxo-2-pyridyl)-N- [3-[tert-butoxycarbonyl(methyl)amino]propyl]carbamate (compound 142e) To a solution of compound 142d (650.0 mg, 1.5 mmol) in ACN (5 mL) was added a solution of NBS (267 mg, 1.5 mmol) in ACN (15 mL) dropwise at 25 °C. The reaction mixture was stirred at 25 °C for 12 h and then concentrated, the residue was purified by silica gel column chromatography to give compound 142e (650.0 mg) as yellow oil. LCMS (M+H+): 510. Step 5: preparation of tert-butyl N-[3-[tert-butoxycarbonyl-[5-chloro-3-(6-chloro-2- pyridyl)-1-methyl-6-oxo-2-pyridyl]amino]propyl]-N-methyl-carbamate (compound 142g) A mixture of compound 142e (600.0 mg, 1.18 mmol), K2CO3 (488 mg, 3.54 mmol), compound 142f (268 mg, 1.12 mmol) and Pd(dppf)Cl2 (153 mg, 0.24 mmol) was stirred at 90 °C for 2 h under nitrogen. Then the reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 142g (300 mg) as yellow oil. LCMS (M+H+): 541. Step 6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[2-[tert-butoxycarbonyl-[3- [tert-butoxycarbonyl(methyl)amino]propyl]amino]-5-chloro-1-methyl-6-oxo-3-pyridyl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 142i) A mixture of compound 142g (200 mg, 0.37 mmol), compound 142h (154 mg, 0.55 mmol), Cs2CO3 (361 mg, 1.11 mmol), S-Phos (30 mg, 0.07 mmol) and Pd(OAc)2 (15 mg, 0.05 mmol) in dioxane (10 mL) was stirred at 90 °C for 12 h. Then reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 142i (120.0 mg) as a yellow solid. LCMS (M+H+): 783. Step 7~11: preparation of (14S,17S)-4-chloro-15-[1-(2,4-difluorophenyl)pyrazolo[3,4- 14,17 2,7 d]pyrimidin-4-yl]-6,12-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 ( Example 142) The title compound was prepared in analogy to Example 157 by using compound 142i instead of compound 157f. LCMS (M+H+): 647. 1H NMR (400 MHz, DMSO-d6) δ = 8.64 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.75 - 7.72 (m, 2H), 7.61 - 7.57 (m, 1H), 7.35 - 7.31 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.87 (br d, J = 8.3 Hz, 1H), 5.42 (d, J = 9.4 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.69 - 4.59 (m, 1H), 4.48 - 4.39 (m, 1H), 4.19 (br d, J = 11.3 Hz, 1H), 3.54 (s, 3H), 3.04 (s, 3H), 2.79 - 2.61 (m, 5H), 1.94 (br d, J = 13.1 Hz, 2H). Example 143 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 4-hydroxy-1-methyl-3-nitro-pyridin-2-one (compound 143b) To a solution of compound 143a (18.0 g, 115.31 mmol) in DMF (300 mL) was added sodium hydride, 60% in oil (10.2 g, 253.68 mmol) at 0 °C under N2. After the mixture was stirred at 0 °C for 30 min, iodomethane (8.6 mL, 138.37 mmol) in DMF (119.8 mL) was added dropwise. The reaction was stirred at 20 °C for 12 h and then poured into water, acidified to pH 2~3 at 0 °C with HCl (1 M). The precipitation was collected by filtration to give compound 143b (15.0 g) as a white solid. Step 2: preparation of 4-bromo-1-methyl-3-nitro-pyridin-2-one (compound 143c) A mixture of compound 143b (14.5 g, 85.23 mmol) and carbon tetrabromide (28.3 g, 85.23 mmol) in toluene (150 mL) was stirred at 100 °C for 1 h. The reation mixture was concentrated, the residue was purifed by silica gel column chromatography to give compound 143c (10 g) as a yellow solid. LCMS (M+H+): 233. Step 3: preparation of 3-amino-4-bromo-1-methyl-pyridin-2-one (compound 143d) To a solution of compound 143c (8.0 g, 34.33 mmol) and NH4Cl (18.36 g, 343.32 mmol) in methanol (100 mL) was added zinc (13.47 g, 206 mmol). The reaction was stirred at 20 °C for 2 h, and then the mixture was filtered. The filtrate was concentrated, the residue was purified by silica gel column chromatography to give compound 143d (2.6 g) as a brown solid. LCMS (M+H+): 205. Step 4: preparation of tert-butyl N-(4-bromo-1-methyl-2-oxo-3-pyridyl)-N-tert- butoxycarbonyl-carbamate (compound 143e) To a solution of compound 143d (100 mg, 0.49 mmol) and di-t-butyldicarbonate (322 mg, 1.48 mmol) in THF (12 mL) was added NaH (49 mg, 1.23 mmol). The reaction was stirred at 60 °C for 12 h and then concentrated. The residue was purified by prep-TLC to give compound 143e (150.0 mg) as brown oil. LCMS (M+H+): 403. Step 5: preparation of tert-butyl N-(4-bromo-1-methyl-2-oxo-3-pyridyl)-N-[3-[tert- butoxycarbonyl(methyl)amino]propyl]carbamate (compound 143f) To a solution of compound 143e (1.8 g, 4.46 mmol) in DMF (30 mL) was added sodium hydride (357 mg, 8.93 mmol) at 0 °C, and then 3-[tert-butoxycarbonyl(methyl)amino]propyl ethanesulfonate (2.5 g, 8.93 mmol) was added. The reaction was stirred at 20 °C for 0.5 h and then quenched with water, extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 143f (1.3 g) as yellow oil. LCMS (M-C5H8O2+H+): 374. Step 6: preparation of tert-butyl N-[3-[tert-butoxycarbonyl-[4-(6-chloro-2-pyridyl)-1- methyl-2-oxo-3-pyridyl]amino]propyl]-N-methyl-carbamate (compound 143g) A mixture of compound 143f (.3 g, 2.74 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (722 mg, 3.01 mmol), pd(dppf)Cl2 (447 mg, 0.55 mmol) and potassium carbonate (757 mg, 5.48 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 60 °C for 1 h. The reaction was concentrated and the residue was purified by silica gel column chromatography to give compound 143g (1 g) as brown oil. LCMS (M+H+): 507. Step 7: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[tert-butoxycarbonyl-[3- [tert-butoxycarbonyl(methyl)amino]propyl]amino]-1-methyl-2-oxo-4-pyridyl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 143h) To a suspension of compound 143g (900.0 mg, 1.78 mmol), O1-benzyl O2-methyl (2S,4S)- 4-aminopyrrolidine-1,2-dicarboxylate (741 mg, 2.66 mmol), Cs2CO3 (1.74 g, 5.33 mmol) was added S-Phos (146 mg, 0.36 mmol). The reaction was stirred at 90 °C for 12 h and then concentrated, the residue was purified by prep-HPLC to give compound 143h (680 mg) as a yellow solid. LCMS (M+H+): 749. Step 8~12: preparation of (14S,17S)-15-[1-(2,4-difluorophenyl)pyrazolo[3,4- 14,17 2,7 d]pyrimidin-4-yl]-5,12-dimethyl-5,8,12,15,18,23-hexazatetracyclo[17.3.1.1 .0 ]tetracosa- 1(23),2(7),3,19,21-pentaene-6,13-dione (Example 143) The title compound was prepared in analogy to Example 157 by using compound 143h instead of compound 157f. LCMS (M+H+): 613.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 - 8.51 (m, 1H), 8.30 - 8.23 (m, 1H), 8.16 - 8.09 (m, 1H), 7.69 - 7.64 (m, 1H), 7.35 - 7.30 (m, 2H), 7.29 - 7.25 (m, 1H), 7.25 - 7.22 (m, 2H), 6.47 (d, J = 7.2 Hz, 1H), 5.49 (d, J = 9.5 Hz, 1H), 4.71 (br t, J = 12.4 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.46 - 4.37 (m, 1H), 3.69 - 3.59 (m, 4H), 3.17 (s, 3H), 2.83 (br d, J = 14.2 Hz, 1H), 2.77 - 2.69 (m, 1H), 2.60 - 2.52 (m, 2H), 2.23 (br d, J = 13.8 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.95 - 1.85 (m, 1H). Example 144 (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 The title compound was prepared according to the following scheme: Step 1: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[(6-bromo-2-pyridyl) amino] pyrrolidine-2-carboxylic acid (compound 144b) A mixture of Intermediate B7 (5.0 g, 11.51 mmol) and LiOH•H2O (3.4 g, 81.03 mmol) in THF (30 mL), methanol (30 mL) and water (30 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated, the residue was acidified with TFA to pH=3, and then extracted with EtOAc. The organic layer was concentrated to give compound 144b (5.8 g) as a yellow solid. LCMS (M+H+): 420. Step 2: preparation of benzyl (2S,4S)-4-[(6-bromo-2-pyridyl) amino]-2- (methylcarbamoyl) pyrrolidine-1-carboxylate (compound 144c) A mixture of HATU (5.76 g, 15.15 mmol), DIPEA (14.4 mL, 87.16 mmol), compound 144b (4.8 g, 11.42 mmol) and methylamine hydrochloride (0.78 g, 11.55 mmol) in ACN (90 mL) was stirred at 20 °C for 1 h. The mixture was diluted with EtOAc, washed with water, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give compound 144c (5.3 g) as brown oil. LCMS (M+H+): 433. Step 3: preparation of benzyl (2S,4S)-4-[(6-bromo-2-pyridyl) amino]-2- (methylaminomethyl) pyrrolidine-1-carboxylate (compound d) To a stirred solution of compound 144c (4.9 g, 11.31 mmol) in THF (80 mL) was added BH3 in THF (57.0 mL, 1 M) at 0 °C. The reaction was stirred at 25 °C for 15 h and then quenched with water. The resulted mixture was cooled to 0 °C and pH was adjusted to 10, then extracted with EA. The organic layer was dried and concentrated to give compound 144d (4.0 g) as brown oil. LCMS (M+H+): 419. Step 4: preparation of benzyl (2S,4S)-4-[[6-[3-(2-tert-butoxy-2-oxo-ethyl)-6-fluoro-2- methyl-benzimidazol-4-yl]-2-pyridyl] amino]-2-(methylaminomethyl) pyrrolidine-1- carboxylate (compound f) A mixture of compound 144e (500.0 mg, 1.28 mmol, the synthesis refer to compound 145g), Pd(dppf)Cl2 (112 mg, 0.15 mmol), K2CO3 (354 mg, 2.56 mmol) and compound 144d (645 mg, 1.55 mmol) in 1, 4-dioxane (5 mL) and water (0.5 mL) was stirred at 85 °C for 3 h under the N2. Then mixture was concentrated and the residue was purified by prep-HPLC to afford compound 144f (330 mg) as a grey solid. LCMS (M+H+): 603. Step 5: preparation of 2-[7-[6-[[(3S,5S)-1-benzyloxycarbonyl-5-(methylaminomethyl) pyrrolidin-3 -yl] amino]-2-pyridyl]-5-fluoro-2-methyl-benzimidazol-1-yl] acetic acid (compound 144g) A mixture of compound 144f (330.0 mg, 0.55 mmol) in DCM (3 mL) and TFA (3.0 mL) was stirred at 25 °C for 6 h. Then the reaction mixture was concentrated to give compound 144g (500 mg) as brown oil. LCMS (M+H+): 547. Step 6~8: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-21-fluoro-13,17-dimethyl-7,10,13,16,18,25- 2,6 8,11 19,23 hexazapentacyclo[14.6.1.1 .1 .0 ]pentacosa-1(23),2(25),3,5,17,19,21-heptaen-14-one (Example 144) The title compound was prepared in analogy to Example 157 by using compound 144g instead of compound 157h. LCMS (M+H+): 625.1H NMR (400 MHz, METHANOL-d4) δ = 8.52 (s, 1H), 8.33 (s, 1H), 7.72 (s, 2H), 7.37 - 7.25 (m, 2H), 7.19 (d, J = 2.4 Hz, 2H), 6.91 (d, J = 7.5 Hz, 1H), 6.80 - 6.71 (m, 1H), 5.11 (dd, J = 3.8, 9.9 Hz, 1H), 4.59 (s, 2H), 4.38 - 4.22 (m, 2H), 4.00 - 3.82 (m, 1H), 3.74 - 3.57 (m, 1H), 2.92 - 2.73 (m, 3H), 2.44 (s, 3H), 2.40 - 2.12 (m, 2H), 2.06 - 2.01 (m, 1H). Example 145 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(2-bromo-4-fluoro-6-nitro-anilino) propanoate (compound 145c) To a solution of compound 145a (23.0 g, 96.64 mmol) and compound 145b (18.4 g, 101.29 mmol) in ACN (230 mL) was added potassium carbonate (33.4 g, 241.67 mmol). The reaction was stirred at 50 °C for 16 h, and then the mixture was filtered. The filtrate was concentrated to give compound 145c (39.5 g, 108.76 mmol) as yellow oil. LCMS (M-C4H8+H+): 307. Step 2: preparation of tert-butyl 3-(2-amino-6-bromo-4-fluoro-anilino) propanoate (compound 145d) To a solution of compound 145c (20.0 g, 55.07 mmol) in methanol (300 mL) was added Raney Ni (12.93 g, 220.31 mmol) and hydrazine hydrate (15.04 g, 300.44 mmol) slowly at 25 °C. The reaction was stirred at 25 °C for 1 h. Then the mixture was filtered, the filtrate was concentrated. The residue was dissolve in DCM, washed with water and brine. The organic layer was dried and concentrated to give compound 145d (15.0 g) as brown oil. LCMS (M-C4H8+H+): 279. Step 3: preparation of tert-butyl 3-(7-bromo-5-fluoro-2-methyl-benzimidazol-1-yl) propanoate (compound 145f) To a solution of compound 145d (15.0 g, 45.02 mmol) in anhydrous THF (150 mL) was added trimethyl orthoacetate (19 mL, 153.14 mmol) and pyridinium p-toluenesulfonate (1.6 g, 6.37 mmol). The reaction was stirred for 1 h at 20 °C and then concentrated to give compound 145f (16.0 g) as brown oil. LCMS (M+H+): 359. Step 4: preparation of tert-butyl 3-[5-fluoro-2-methyl-7-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl) benzimidazol-1-yl] propanoate (compound 145g) Compound 145g was prepared in analogy to the preparation of Intermediate A1 by using compound 145f instead of compound A1-e. LCMS (M+H+):405. Step 5~9: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-14-one (Example 145) The title compound was prepared in analogy to Example 144 by using compound 145g instead of compound 144e. LCMS (M+H+): 639.1H NMR (400 MHz, METHANOL-d4) δ = 8.47 (s, 1H), 8.43 - 8.34 (m, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.70 - 7.58 (m, 2H), 7.38 (dd, J = 2.4, 9.5 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.24 - 7.16 (m, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 4.79 - 4.72 (m, 1H), 4.51 (t, J = 5.9 Hz, 1H), 4.46 - 4.28 (m, 3H), 4.17 - 3.99 (m, 2H), 3.93 - 3.81 (m, 1H), 3.51 - 3.39 (m, 1H), 3.12 (ddd, J = 6.9, 12.2, 17.0 Hz, 1H), 2.92 (s, 3H), 2.85 (s, 3H), 2.74 - 2.66 (m, 1H), 2.65 - 2.55 (m, 1H). Example 146 (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 The title compound was prepared according to the following scheme: Step 1: preparation of methyl 1-(4-chlorophenyl)-5-oxo-pyrrolidine-2-carboxylate (compound 146b) To a soltuion of 1-chloro-4-iodobenzene (16.7 g, 69.86 mmol), compound 146a (8.16 mL, 69.86 mmol), copper(I) iodide (1.2 mL, 34.93 mmol), cesium carbonate (45.52g, 139.72 mmol) in DMF (200 mL) was added N,N'-Dimethyl-1,2-ethanediamine (6.2 g, 69.86 mmol). The reaction was stirred at 100 °C for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was dried and concentrated to give compound 146b (20.0 g) as brown oil. LCMS (M+H+): 254. Step 2: preparation of methyl 1-(2-bromo-4-chloro-phenyl)-5-oxo-pyrrolidine-2- carboxylate (compound 146c) To a solution of compound 146b (10.0 g, 39.42 mmol) was added Br2 (31.5 g, 197.1 mmol). The reaction was stirred at 80 °C for 0.5 h. Then reaction mixture was concentrated , the residue was purified by silica gel column chromatography to give compound 146c (5.0 g) as a white solid. LCMS (M+H+): 334. Step 3: preparation of 1-(2-bromo-4-chloro-phenyl)-5-(hydroxymethyl) pyrrolidin-2- one (compound 146d) To a solution of compound 146c (4.0 g, 12.03 mmol) in THF (40.091 mL) was added sodium borohydride (1.0 g, 26.46 mmol) at 0 °C. The reaction was stirred at 20 °C for 12 h. The reaction was quenched with ice-water and then extracted with EA. The organic layer was dried and concentrated to give compound 146d (2.6 g) as colorless oil. LCMS (M+H+): 306. Step 4: preparation of [1-(2-bromo-4-chloro-phenyl)-5-oxo-pyrrolidin-2-yl] methyl ethanesulfonate (compound 146e) To a solution of compound 146d (2.5 g, 8.21 mmol) and triethylamine (2.86 mL, 20.52 mmol) in DCM (40 mL) was added ethanesulfonyl chloride (1.17 mL, 12.31 mmol) at 0 °C . The reaction was stirred at 20 °C for 12 h. Then reaction mixture was poured into water and extracted with EA, the organic layer was dried and concentrated to give compound 146e (3.3 g) as brown oil. LCMS (M +H+): 398. Step 5: preparation of 2-[1-(2-bromo-4-chloro-phenyl)-5-oxo-pyrrolidin-2- yl]acetonitrile (compound 146f) To a solution of compound 146e (3.3 g, 8.32 mmol) in DMSO (30 mL) was added NaCN (1.24 g, 25.22 mmol). The reaction was stirred at 60 °C for 4 h. The reaction mixture was poured into water and extracted with EA. The organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound 146f (1.7 g) as yellow oil. LCMS (M +H+): 315. Step 6: preparation of 2-[1-[4-chloro-2-(6-chloro-2-pyridyl)phenyl]-5- (cyanomethyl)pyrrolidin-2-yl]acetonitrile (compound 146g) To a solution of compound 146f (1.6 g, 5.1 mmol), 6-chloropyridine-2-boronic acid pinacol ester (1.3 g, 5.36 mmol) in 1,4-dioxane (16 mL) and water (3.2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (832 mg, 1.02 mmol) and potassium carbonate (1.4 g, 10.2 mmol). The reaction was stirred at 60 °C for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 146g (1.6 g) as brown oil. LCMS (M+H+): 346. Step 7: preparation of tert-butyl N-[2-[1-[4-chloro-2-(6-chloro-2-pyridyl)phenyl]-5- oxo-pyrrolidin-2-yl]ethyl]carbamate (compound 146h) To a solution of di-t-butyldicarbonate (378 mg, 1.73 mmol), compound 146g (300 mg, 0.87 mmol), NiCl2•6H2O (20 mg, 0.09 mmol) in methanol (3 mL) was added sodium borohydride (172.0 mg, 4.55 mmol) at 0 °C and then sitrred at 20 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and then extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 146h (100.0 mg) as yellow oil. LCMS (M+H+): 450. Step 8: preparation of tert-butyl N-[2-[1-[4-chloro-2-(6-chloro-2-pyridyl)phenyl]-5- oxo-pyrrolidin-2-yl]ethyl]-N-methyl-carbamate (compound 146i) To a solution of compound 146h (280.0 mg, 0.62 mmol) in DMF (10 mL) was added NaH (50 mg, 1.24 mmol) at 0 °C. The reaction was stirred at 20 °C for 0.5 h, then Iodomethane (176.5 mg, 1.24 mmol) was added at 0 °C. The reaction was stirred at 20 °C for 12 h and then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, dried and concentrated to give compound 146i (300 mg) as yellow oil. LCMS (M+H+): 464. Step 9: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[2-[2-[2-[tert- butoxycarbonyl(methyl)amino]ethyl]-5-oxo-pyrrolidin-1-yl]-5-chloro-phenyl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 146j) A mixture of compound 146i (250 mg, 0.54 mmol), O1-benzyl O2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (225 mg, 0.81 mmol), S-Phos (44 mg, 0.11 mmol), Pd2(dba)3 (49.31 mg, 0.05 mmol) and Cs2CO3 (526.5 mg, 1.62 mmol) in 1,4-dioxane (5 mL) was stirred at 90 °C for 12 h. Then the reaction mixture was filtered, the filtrate was concentrated and the residue was pufieid by prep-TLC to give compound 146j (250 mg) as yellow oil. LCMS (M+H+): 706. Step 10~14: preparation of (17S,20S)-18-[1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methyl-8,15,18,21,26- 17,20 2,7 8,12 pentazapentacyclo[20.3.1.1 .0 .0 ]heptacosa-1(26),2,4,6,22,24-hexaene-9,16-dione (Example 146) The title compound was prepared in analogy to Example 157 by using compound 146j instead of compound 157h. LCMS (M+H+): 636.1H NMR (400 MHz, DMSO-d6) δ = 8.51 (s, 1H), 8.42 - 8.23 (m, 1H), 8.14 (s, 1H), 7.64 - 7.60 (m, 2H), 7.54 - 7.40 (m, 2H), 7.21 - 7.18 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.81 - 6.77 (m, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 7.1 Hz, 1H), 5.73 - 5.68 (m, 1H), 3.80 – 3.75 (m, 1H), 3.68 – 3.67 (m, 1H), 3.11 (s, 3H), 2.60 - 2.39 (m, 6H), 1.97 - 1.87 (m, 4H), 1.45 - 1.41 (m, 2H). Example 147 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of 4-bromo-3-(3-chloropropyl)-2-methyl-indazole (compound 147a) To the solution of 4-bromo-2-methyl-indazole (1.48 g, 7 mmol) in THF (15 mL) was added LDA (2 N, 4.55 mL, 9.1 mmol) at -78 ℃ dropwise, the mixture was stirred at 0 ℃ for 30 mins. Then the mixture was cooled to -78 ℃, and the solution of 1-chloro-3-iodo-propane (1.47 mL, 14 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at rt for 12 hrs. Then the mixture was quenched with sat. NH4Cl, then extracted with EA (50 mL×3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 147a (1.9 g, 60% purity), LCMS (M+H+): 287. Step 2: preparation of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3- dione (compound 147b) The mixture of compound 147a (1.9 g, 3.96 mmol, 60% purity), (1,3-dioxoisoindolin-2- yl)potassium (1.47 g, 7.93 mmol) and NaI (1.78 g, 11.89 mmol) in DMF (10 mL) was stirred at 100 oC for 2 hrs. Then the mixture was diluted with EA (40 mL), and washed with water (20 mL×3), the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 147b (1.3 g), LCMS (M+H+): 398. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-allyloxypyrrolidine-1,2- dicarboxylate (compound 147c) To the mixture of NaH (60% purity, 391 mg, 9.78 mmol) in THF (10 mL) was added the solution of O1-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.15 mmol) in THF (10 mL) dropwise at 0 ℃ in 15 mins, the mixture was stirred at rt for 15 mins, then 3-bromoprop-1-ene (1.18 g, 845 μL, 9.78 mmol) was added into. The mixture was stirred at rt for 12 hrs. Then the mixture was quenched by water, extracted with DCM (30 mL×2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 147c (0.8 g), LCMS (M+Na+): 308. Step 4: preparation of methyl (2S,4S)-4-allyloxypyrrolidine-2-carboxylate (compound 147d) The mixture of compound 147c (0.8 g, 2.8 mmol) in HCl in dioxane (4 N, 6 mL) was stirred at rt for 3 hrs. Then the mixture was concentrated to give crude compound 147d (0.7 g), LCMS (M+H+): 186. Step 5: preparation of methyl (2S,4S)-4-allyloxy-1-[3-(2,4-difluorophenyl)imidazo[1,5- a]pyrazin-8-yl]pyrrolidine-2-carboxylate (compound 147e) The suspension of compound 147d (170 mg, 0.77 mmol), Intermediate C3 (306 mg, 1.15 mmol) and Cs2CO3 (1 g, 3.07 mmol) in dioxane (5 mL) was bubbled with N2 for 5 mins, then RuPhos Pd G2 (119 mg, 0.15 mmol) was added. The mixture was stirred at 95 oC for 12 hrs, and then filtered and concentrated, the residue was diluted with EA (40 mL), washed with water (20 mL×3), the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 147e (80 mg), LCMS (M+H+): 415. Step 6: preparation of methyl (2S,4S)-1-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin- 8-yl]-4-[3-[3-[3-(1,3-dioxoisoindolin-2-yl)propyl]-2-methyl-indazol-4-yl]allyloxy]- pyrrolidine-2-carboxylate (compound 147f) The suspension of compound 147e (80 mg, 0.19 mmol) and K2CO3 (80 mg, 0.58 mmol) in DMF (6 mL) was bubbled with N2 for 5 mins, then Pd(OAc)2 (8.7 mg, 0.038 mmol) and tris-o- tolylphosphane (11.8 mg, 0.038 mmol) were added. The mixture was stirred at 100 oC for 12 hrs. The mixture was filtered and diluted with EA (40 mL), washed with water (20 mL×3), the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 147f (90 mg), LCMS (M+H+): 732. Step 7: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4- yl]allyloxy]-1-[3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazin-8-yl]pyrrolidine-2-carboxylic acid (compound 147g) The mixture of compound 147f (90 mg, 123 μmol) and hydrazine hydrate (18.5 mg, 18 μL, 369 μmol) in EtOH (4 mL) was stirred at 70 oC for 12 hrs. Then the mixture was diluted with water (40 mL) and extracted with EA (40 mL×3), the combined organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in MeOH (4 mL), then 2 N aqueous solution of LiOH (2 mL, 4 mmol) was added into the solution. The mixture was stirred at rt for 12 hrs. The mixture was acidified with 1 N HCl in water to pH ~ 5. The mixture was concentrated, the residue was purified by flash column chromatography to give compound 147g (55 mg), LCMS (M+H+): 588. Step 8: preparation of (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 (Example 147) To the solution of HATU (107 mg, 281 μmol) and DIPEA (121 mg, 936 μmol) in DMF (40 mL) was added a solution of compound 147g (55 mg, 94 μmol) in DMF (5 mL) and MeCN (40 mL) dropwise. The mixture was concentrated, and then diluted with EA (100 mL), washed with water (50 mL×3), the organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 147 (3 mg), LCMS (M+H+): 570.1H NMR (400 MHz, METHANOL-d4) δ = 7.99 (br s, 1H), 7.73 - 7.62 (m, 1H), 7.38 - 7.33 (m, 1H), 7.31 - 7.25 (m, 3H), 7.23 - 7.19 (m, 2H), 7.19 - 7.16 (m, 1H), 7.05 (d, J = 6.7 Hz, 1H), 6.29 (td, J = 3.2, 15.6 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H), 4.45 - 4.35 (m, 3H), 4.28 - 4.18 (m, 2H), 4.09 (s, 3H), 3.93 - 3.85 (m, 1H), 3.17 - 3.06 (m, 1H), 2.99 - 2.84 (m, 2H), 2.72 - 2.65 (m, 1H), 2.54 - 2.44 (m, 1H), 1.87 - 1.66 (m, 2H). Example 148 and Example 149 (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 and (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-[3-(4-bromo-2-oxo-indolin-3-yl)propyl]-N-methyl- carbamate (compound 148a) The neat mixture of 4-bromoindolin-2-one (2.6 g, 12.3 mmol), tert-butyl N-(3- hydroxypropyl)-N-methyl-carbamate (4.6 g, 24.5 mmol), Ruthenium(III) chloride trihydrate (128 mg, 0.5 mmol), NaOH (98 mg, 2.45 mmol) and Ph3P (257 mg, 0.98 mmol) was stirred at 110 °C for 12 hrs under nitrogen, then the mixture was cooled to rt and filtered, the collected solid was washed with DCM (25 mL×2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 148a (1.23 g), LCMS (M-BOC+H+): 283. Step 2: preparation of 4-bromo-3-[3-(methylamino)propyl]indolin-2-one (compound 148b) To the suspension of compound 148a (1.23 g, 3.2 mmol) in DCM (10 mL) was added 4 N HCl in dioxane (4 mL) dropwise, the mixture was stirred at rt for 1 h. Then the mixture was concentrated to give crude compound 148b (1.3 g, 80% purity). LCMS (M+H+): 283. Step 3: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3- (methylamino)propyl]-2-oxo-indolin-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 148c) The mixture of compound 148b (300 mg, 674 µmol), intermediate B8 (474 mg, 741 µmol), PdCl2(DPPF) (49 mg, 67 µmol) and K2CO3 (466 mg, 3.37 mmol) in dioxane/ H2O (7:1) (8 mL) was stirred at 90 oC for 12 hrs, then the mixture was filtered and concentrated. The residue was diluted with EA (100 mL), washed with water (25 mL×2), the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to give compound 148c (180 mg), LCMS (M+H+): 524. Step 4: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[3-[3- (methylamino)propyl]-2-oxo-indolin-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (compound 148d) To the solution of compound 148c (180 mg, 344 µmol) in MeOH (2 mL) was added 2 N LiOH in water (1.7 mL), the mixture was stirred at rt for 2 hrs. Then the mixture was adjusted to pH ~ 5 with HCl (1 N) and concentrated, the residue was purified by reversed-phase flash column chromatography to give compound 148d (240 mg), LCMS (M+H+): 510. Step 5: preparation of tert-butyl (8S,11S)-13-methyl-12,18-dioxo-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-10- carboxylate (compound 148e) To the solution of HATU (448 mg, 1.18 mmol) and DIPEA (609 mg, 4.7 mmol) in DMF (40 mL) and MeCN (160 mL) was added a solution of compound 148d (240 mg, 471 µmol) in DMF (40 mL) and MeCN (160 mL) dropwise via dropping funnel. Then the mixture was concentrated, the residue was purified by reverse flash column chromatography to give compound 148e (50 mg), LCMS (M+H+): 492. Step 6: preparation of (8S,11S)-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(compound 148f) To the mixture of compound 148e (50 mg, 102 µmol) in DCM (2 mL) was added TFA (1 mL), the mixture was stirred at rt for 1 h. Then the mixture was concentrated to give crude compound 148f (80 mg), LCMS (M+H+): 392. Step 7: preparation of (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 and (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 (Example 148 & 149) The mixture of compound 148f (80 mg, 109 µmol), intermediate C2 (35 mg, 131 µmol), and DIPEA (141 mg, 1.09 mmol) in MeCN (2 mL) was stirred at 80 oC for 2 hrs, then the mixture was filtered and purified by prep-HPLC to give Example 148 and Example 149. Example 148, faster eluted, 2 mg, white powder. LCMS (M+H+): 622.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 (s, 1H), 8.17 (s, 1H), 7.70 - 7.55 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.32 - 7.16 (m, 3H), 7.13 (dd, J = 2.1, 8.1 Hz, 1H), 6.97 - 6.81 (m, 3H), 6.76 - 6.68 (m, 1H), 5.57 (t, J = 3.8 Hz, 1H), 5.31 – 5.26 (m, 1H), 4.41 – 4.37 (m, 1H), 3.99 - 3.87 (m, 1H), 3.12 - 3.00 (m, 3H), 2.68 - 2.45 (m, 3H), 1.80 - 1.66 (m, 1H), 1.52 - 1.38 (m, 1H), 1.35 - 1.25 (m, 3H), 1.10 (dt, J = 5.6, 13.3 Hz, 1H). Example 149, slower eluted, 2 mg, white powder. LCMS (M+H+): 622.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 (s, 1H), 8.25 (s, 1H), 7.71 - 7.63 (m, 1H), 7.48 - 7.42 (m, 1H), 7.32 - 7.16 (m, 3H), 7.11 (dd, J = 2.3, 8.1 Hz, 1H), 7.06 (t, J = 1.8 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.85 (d, J = 7.2 Hz, 1H), 5.57 (t, J = 3.9 Hz, 1H), 5.37 (d, J = 10.0 Hz, 1H), 4.82 - 4.74 (m, 1H), 4.37 (dd, J = 4.3, 11.4 Hz, 1H), 4.25 - 4.08 (m, 1H), 3.09 - 2.96 (m, 3H), 2.78 - 2.62 (m, 2H), 2.51 - 2.47 (m, 1H), 2.20 - 2.07 (m, 1H), 1.65 - 1.46 (m, 2H), 1.35 - 1.26 (m, 1H), 1.08 - 0.96 (m, 1H). Example 150 (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 The title compound was prepared according to the following scheme: Step 1: preparation of [6-[[(3S,5S)-1-benzyloxycarbonyl-5-methoxycarbonyl- pyrrolidin-3-yl]amino]-2-pyridyl]boronic acid (compound 150a) To a microwave tube was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (435 mg, 1.71 mmol), intermediate B7 (372 mg, 0.857 mmol), potassium acetate (168 mg, 1.71 mmol) and 1,4-Dioxane (4 mL). The suspension was bubbled with N2 for 5 mins and then dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-3-yl)phosphane (82 mg, 0.171 mmol) & Pd(OAc)2 (19 mg, 0.086 mmol) were added. The mixture was heated to 80 °C and stirred for 16 hrs. The mixture was diluted with some EA and filtered. The filtrate was concentrated and purified via prep-HPLC to give compound 150a (200 mg) as powder. LCMS (M+H)+: 400. Step 2~6: preparation of (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 (Example 150) Example 150 was prepared in analogy to the preparation of example 163 by using compound 150a instead of intermediate A2 and intermediate A41 instead of compound 163b. LCMS (M+H)+: 608, 1H NMR (400 MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.27 (s, 1H), 7.86 - 7.79 (m, 1H), 7.79 - 7.69 (m, 2H), 7.64 - 7.53 (m, 1H), 7.41 - 7.27 (m, 2H), 7.05 (br d, J = 7.0 Hz, 1H), 6.98 - 6.85 (m, 2H), 6.02 - 5.82 (m, 1H), 5.40 (br d, J = 9.7 Hz, 1H), 4.80 - 4.53 (m, 1H), 4.51 - 4.32 (m, 2H), 4.26 - 4.06 (m, 1H), 3.07 (s, 3H), 2.97 - 2.69 (m, 2H), 2.68 - 2.55 (m, 1H), 2.47 - 2.37 (m, 1H), 2.13 - 1.74 (m, 3H). Example 151 (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 The title compound was prepared according to the following scheme: Step 1: preparation of (16S,19S)-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;hydrochloride (Compound 151a) A mixture 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, 0.40 g, 0.84 mmol) and 4M HCl in dioxane (4.2 mL, 4.2 mmol) in DCM (5 mL) was stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure to give crude compound 151a (310 mg) as a light yellow solid, LCMS (M+H)+: 377. Step 2: preparation of (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 (Example 151) A mixture of (16S,19S)-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;hydrochloride (compound 151a, 0.04 g, 0.10 mmol), 2-(2-chloro-4-fluoro-phenyl)-5-fluoro-pyrazine (0.02g, 0.11 mmol) and DIPEA (0.06 g, 0.48 mmol) in DMSO (1 mL) was heated to 100°C for 2 hrs. The reaction mixture was directly purified by prep-HPLC to afford Example 151(1.5 mg) as a white solid, LCMS (M+H)+: 583.1H NMR (400 MHz, DMSO-d6) δ = 8.55 - 8.51 (m, 1H), 8.43 - 8.38 (m, 1H), 8.17 - 8.12 (m, 1H), 8.04 - 7.97 (m, 1H), 7.64 - 7.55 (m, 3H), 7.54 - 7.47 (m, 1H), 7.39 - 7.30 (m, 3H), 7.25 - 7.11 (m, 2H), 5.38 - 5.29 (m, 1H), 4.73 - 4.66 (m, 1H), 4.60 - 4.49 (m, 2H), 3.95 - 3.79 (m, 2H), 3.65 - 3.51 (m, 1H), 3.06 - 2.94 (m, 1H), 2.59 (m, 1H), 2.43 - 2.36 (m, 1H), 1.80 - 1.71 (m, 2H), 1.64 - 1.53 (m, 1H), 1.52 - 1.43 (m, 1H). Example 152 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin- 2-yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 152a) A mixture of 2-[3-(4-bromo-2-methyl-indazol-3-yl)propyl]isoindoline-1,3-dione (intermediate A20-b, 2.5 g, 6.3 mmol), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B8, 3.65 g, 8.2 mmol), Pd(dppf)Cl2 (230 mg, 0.3 mol) and potassium carbonate (2.6 g, 18.8 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100 °C for 16 hours under N2. 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, dried over anhydrous Na2SO4, concentrated under reduced pressure to give some crude product which was purified by flash column chromatography to afford compound 152a (3.35 g) as a light yellow solid, LCMS (M+H)+: 639. Step 2: preparation of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4- yl]phenoxy]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 152b) A mixture of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-[3-(1,3-dioxoisoindolin-2- yl)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 152a, 3.3 g, 4.1 mmol) and hydrazine hydrate (1.03 g, 20.7 mmol) in methanol (60 mL) was heated at 70 °C for 16 hrs in a sealed tube. After being cooled to room temperature, the reaction mixture was diluted with water, extracted with EtOAc three times. The combined organic layer was washed with brine, dried, and concentrated in vacuo to give some yellow oil. The yellow oil was dissolved in methanol (28 mL) and water (7 mL), then lithium hydroxide monohydrate (759 mg, 18.1 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water, acidified by acetic acid, extracted with DCM for three times. The combined organic layer was washed with water, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude compound 152b (2.35 g) as a light yellow solid, LCMS (M+H)+: 495. Step 3: preparation of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene- 10-carboxylate (compound 152c) To a mixture of DIPEA (4.0 g, 31.0 mmol) and HATU (8.0 g, 42.0 mmol) in DMF (1500 mL) was added a solution of (2S,4S)-4-[3-[3-(3-aminopropyl)-2-methyl-indazol-4-yl]phenoxy]- 1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (compound 152b, 8.0 g, 16.2 mmol) in DMF (1500 mL) at 0 °C dropwise and then stirred at 0 °C for 2 hrs. The mixture was concentrated to give some residue, which was diluted with EtOAc three times, and washed with water. Then the organic layer was dried over anhydrous Na2SO4, filtered, concentrated to give crude compound 152c (5.2 g) as a yellow solid, which was used in next step directly, LCMS (M+H)+: 477. Step 4: preparation of (8S,11S)-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;2,2,2-trifluoroacetic acid (compound 152d) A mixture of tert-butyl (8S,11S)-18-methyl-12-oxo-7-oxa-10,13,18,19- tetrazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17(24),19,21-heptaene-10- carboxylate (compound 152c, 2.38 g, 5 mmol) and TFA (5 mL) in DCM (20 mL) was stirred at room temperature for 3 hrs. After excessive DCM and TFA were removed under reduced pressure, crude compound 152d (3.27 g) was obtained as a brown oil, LCMS (M+H)+: 377. Step 5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)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 (compound 152e) A mixture of (8S,11S)-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;2,2,2-trifluoroacetic acid (compound 152d, 3.27 g, 5 mmol), 8-chloro-3-(2,4- difluorophenyl)imidazo[1,5-a]pyrazine (intermediate C3, 2 g, 6 mmol) and DIPEA (3.23 g, 25 mmol) in DMSO (30 mL) was heated at 90 °C for 1 hr. After being cooled to room temperature, the reaction mixture was diluted with water and some precipitation formed. The collected solid was dried, then slurried in methanol, filtered, compound 152e (2.65 g) was obtained as a yellow solid, which was directly used in next step without further purification, LCMS (M+H)+: 607. Step 6: preparation of (8S,11S)-13-benzyl-10-[1-(2,4-difluorophenyl)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 (Example 152) To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)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 (compound 152e, 40 mg, 0.04 mmol) in DMF (6 mL) was added sodium hydride (7.9 mg, 0.20 mmol), the mixture was stirred at room temperature for 20 min. Then (bromomethyl)benzene (20 mg, 0.12 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with MeOH (2 mL) and purified by prep-HPLC to afford Example 152 (1.4 mg) as a white solid, LCMS (M+H+): 696. 1H NMR (400 MHz, DMSO-d6) δ = 8.23 - 8.14 (m, 1H), 7.78 - 7.73 (m, 1H), 7.55 - 7.48 (m, 4H), 7.43 (m, 3H), 7.35 - 7.31 (m, 2H), 7.23 - 7.19 (m, 2H), 7.14 (m, 2H), 6.97 (m, 1H), 6.88 (m, 1H), 6.79 (m, 1H), 5.69 - 5.61 (m, 1H), 5.47 - 5.40 (m, 1H), 5.34 - 5.29 (m, 1H), 4.91 - 4.77 (m, 1H), 4.74 - 4.61 (m, 1H), 4.50 - 4.38 (m, 1H), 4.32 - 4.20 (m, 1H), 4.03 - 4.00 (m, 2H), 3.79 - 3.68 (m, 1H), 3.30 (s, 3H), 2.64 - 2.61 (m, 1H), 2.47 - 2.40 (m, 2H), 2.30 - 2.22 (m, 1H). Example 153 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 4-chloro-1-[(2,4-difluorophenyl)methyl]pyrazolo[3,4- d]pyrimidine (compound 153a) A solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1.29 mmol) and potassium carbonate (358 mg, 2.59 mmol) in DMF (5 mL) was stirred at room temperature for 20min. Then 1-(bromomethyl)-2,4-difluorobenzene (321 mg, 1.55 mmol) was added and stirred at room temperature for 16 hrs. 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 and purified by flash column chromatography to give compound 153a (230 mg) as a white solid, LCMS (M+H+): 281. Step 2: preparation of (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 (Example 153) A mixture of (8S,11S)-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: 2,2,2-trifluoroacetic acid (compound 152d, 30 mg, 0.04 mmol), 4-chloro-1-[(2,4- difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidine (compound 153a, 16 mg, 0.06 mmol) and DIPEA (28 mg, 0.22 mmol) in DMSO (1.5 mL) was heated to 100°C for 2 hrs. After being cooled to room temperature, the reaction mixture was purified by prep-HPLC to give Example 153 (7.8 mg) as a white solid, LCMS (M+H)+: 621.1H NMR (400 MHz, DMSO-d6) δ = 8.45 - 8.15 (m, 2H), 8.02 - 7.60 (m, 1H), 7.55 - 7.45 (m, 2H), 7.38 - 7.10 (m, 4H), 7.08 - 6.85 (m, 3H), 5.65 - 5.51 (m, 2H), 5.41 - 5.30 (m, 1H), 4.92 - 4.87 (m, 1H), 4.42 - 4.35 (m, 1H), 4.29 - 4.19 (m, 1H), 4.14 (m, 1H), 4.07 (s, 3H), 3.60 - 3.41 (m, 2H), 2.93 - 2.84 (m, 1H), 2.83 - 2.68 (m, 2H), 2.65 - 2.55 (m, 1H), 2.49 - 2.41 (m, 1H). Example 154 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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-chloropropyl)-2- methyl-indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate(compound 154a) A mixture of 4-bromo-3-(3-chloropropyl)-2-methyl-2H-indazole (intermediate A20-a, 1.4 g, 4.87 mmol ), O1-tert-butyl O2-methyl (2S,4S)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]pyrrolidine-1,2-dicarboxylate (Intermediate B8, 2.61 g, 5.84 mmol ), Pd(dppf)Cl2 (178 mg, 0.24 mmol ) and K2CO3 (2.02 g, 14.6 mmol) in 1,4-dioxane (10 ml) and water (1 mL) was heated to 90°C for 2 hrs under nitrogen 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 were washes with brine, dried over anhydrous Na2SO4, concentrated under vacuum to give some crude, which was purified by flash column chromatography to afford compound 154a (2.8 g) as a light yellow solid, LCMS (M+H)+: 529. Step 2: preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[3-[3-[3-(3- hydroxypropylamino)propyl]-2-methyl-indazol-4-yl]phenoxy]pyrrolidine-2-carboxylic acid (compound 154b) To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-[3-[3-(3-chloropropyl)-2-methyl- indazol-4-yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 154a, 1.5 g, 2.27 mmol), sodium iodide (1.02 g, 6.82 mmol) and 3-aminopropan-1-ol (1.71 g, 22.7 mmol) in THF (60 mL) and DMF (30 mL) was stirred at 90oC for 12 hrs. After being cooled to room temperature, the mixture was added water (40 mL) and extracted with DCM/MeOH (20:1), the combined organic layer was purified by flash column chromatography to give 1.8 g product as a colorless oil. The colorless oil (1.8 g, 3.18 mmol), NaOH (635 mg, 15.9 mmol) in MeOH (6 mL) and water (2 mL) was stirred at room temperature for 6 hrs. The reaction mixture was diluted with water and acidified by HOAc to pH~6, 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 compound 154b (1.58 g) as a brown solid, LCMS (M+H)+: 553. Step 3-5: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin- 4-yl]-13-(3-hydroxypropyl)-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 (compound 154e) The compound 154e was prepared in analogy to the preparation of Example 155 by using compound 154b instead of compound 155d to give compound 154e (0.8 g) as a yellow solid, LCMS (M+H)+: 665. Step 6: preparation of (8S,11S)-13-(3-chloropropyl)-10-[1-(2,4- difluorophenyl)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 (compound 154f) To a solution of (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13-(3- hydroxypropyl)-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 (compound 154e, 0.40 g, 0.60 mmol) and TEA (0.20 g, 1.8 mmol) in DCM (10 mL) was added sulfurous dichloride (0.20 g, 1.2 mmol) at 0 °C under nitrogen protection, then the mixture was stirred at room temperature for 16 hrs. The mixture was added into water and extracted with EtOAc for three times, the combined organic layer was dried over anhydrous Na2SO4, concentrated to give compound 154f (510 mg) as a brown solid, LCMS (M+H)+: 683. Step 7: preparation of methyl 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-carboxylate (compound 154g) To a solution of (43S,45S)-6-(3-chloropropyl)-41-(1-(2,4-difluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-12-methyl-12H-3-oxa-6-aza-1(4,3)-indazola-4(3,5)-pyrrolidina-2(1,3)- benzenacyclononaphan-5-one (compound 154g, 50 mg, 0.05 mmol) and sodium iodide (25 mg, 0.17 mmol) in DMF (0.5 mL) was added methyl morpholine-3-carboxylate (40 mg, 0.27 mmol), the resulting mixture was stirred at 70oC for 2 hrs. The mixture was diluted with water and extracted with EtOAc for three times, the combined organic layer was dried over Na2SO4, concentrated to give crude compound 154g (50 mg) as a brown solid, LCMS (M+H)+: 792. Step 8: preparation of 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 (Example 154) A solution of methyl 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-carboxylate (compound 154g, 30 mg, 0.04 mmol) and LiOH (4.4 mg, 0.19 mmol) in MeOH (0.5 mL) and water (0.1 mL) was stirred at 25oC for 12 hrs. The mixture was directly purified by prep-HPLC to give Example 154 (2.6 mg) as a white solid, LCMS (M+H)+: 778.1H NMR (400 MHz, DMSO-d6) δ = 8.68 - 8.33 (m, 1H), 8.25 - 8.16 (m, 1H), 7.78 - 7.69 (m, 1H), 7.66 - 7.56 (m, 1H), 7.53 - 7.45 (m, 2H), 7.36 - 7.30 (m, 1H), 7.29 - 7.19 (m, 2H), 6.96 - 6.90 (m, 1H), 6.84 - 6.73 (m, 2H), 5.69 - 5.51 (m, 2H), 5.50 - 5.29 (m, 1H), 4.60 - 4.49 (m, 1H), 4.32 - 4.25 (m, 1H), 4.07 (s, 3H), 3.87 - 3.76 (m, 2H), 3.72 - 3.66 (m, 2H), 3.10 (m, 2H), 3.06 - 2.96 (m, 2H), 2.95 - 2.83 (m, 2H), 2.75 - 2.61 (m, 4H), 2.46 - 2.40 (m, 2H), 2.23 - 2.13 (m, 1H), 1.73 - 1.63 (m, 1H), 1.59 - 1.46 (m, 2H). Example 155 (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 The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-(2-fluoro-3-nitro-phenyl)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 155a) A mixture of K2CO3 (286 mg, 2.07 mmol), 2-(2-fluoro-3-nitro-phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (202 mg, 0.76 mmol), O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2- pyridyl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B7, 300 mg, 0.69 mmol) and Pd(dppf)Cl2 (25 mg, 0.04 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was heated to 100°C for 12 hrs under nitrogen protection. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated and purified by flash chromatography to give compound 155a (340 mg) as a yellow oil, LCMS (M+H)+: 495. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-(2-fluoro-3-nitro-phenyl)-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 155b) A mixture of O1-benzyl O2-methyl (2S,4S)-4-[[6-(2-fluoro-3-nitro-phenyl)-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 155a, 340 mg, 0.69 mmol) and lithium hydroxide monohydrate (288 mg, 6.89 mmol) in tetrahydrofuran (6 mL) and water (1.5 mL) was stirred at 25oC for 12 hrs. The pH of reaction mixture was adjusted to 5 with 1N HCl and it was extracted with DCM/MeOH (20:1) for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give crude compound 155b (320 mg) as a yellow oil, LCMS (M+H)+: 481. Step 3: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3-[tert- butoxycarbonyl(methyl)amino]propylamino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine- 2-carboxylic acid (compound 155c) A mixture of (2S,4S)-1-benzyloxycarbonyl-4-[[6-(2-fluoro-3-nitro-phenyl)-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 155b, 320 mg, 0.66 mmol), K2CO3 (275 mg, 1.99 mmol) and tert-butyl N-(3-aminopropyl)-N-methyl-carbamate (125 mg, 0.66 mmol) in acetonitrile (10 mL) was stirred at 60oC for 12 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash column chromatography to give compound 155c (430 mg) as a brown oil, LCMS (M+H)+: 649. Step 4: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3- (methylamino)propylamino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid; 2,2,2-trifluoroacetic acid (compound 155d) A mixture of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3-[tert- butoxycarbonyl(methyl)amino]propylamino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 155c, 430 mg, 0.66 mmol) and TFA (1.51 g, 13.26 mmol) in DCM (5 mL) was stirred at 25oC for 2 hrs. The reaction mixture was concentrated under reduced pressure to give crude compound 155d (450 mg) as a brown oil, LCMS (M+H)+: 549. Step 5: preparation of benzyl (14S,17S)-12-methyl-6-nitro-13-oxo-8,12,15,18,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-15-carboxylate (compound 155e) A mixture of HATU (554 mg, 1.46 mmol) and DIEA (471 mg, 3.65 mmol) was dissolved in acetonitrile (280 mL) and (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3- (methylamino)propylamino]-3-nitro-phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 155d, 400 mg, 0.73 mmol) in acetonitrile (120 mL) was added dropwise at rt. The mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated and diluted with water, extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give crude compound 155e (300 mg) as a yellow oil, LCMS (M+H)+: 531. Step 6: preparation of (14S,17S)-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 (compound 155f) A mixture of benzyl (14S,17S)-12-methyl-6-nitro-13-oxo-8,12,15,18,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-15-carboxylate (compound 155e, 300 mg, 0.57 mmol ) in TFA (645 mg, 5.65 mmol ) was stirred at 100oC for 10 min under microwave irradiation. The reaction mixture was concentrated to give crude compound 155f (300 mg) as a brown oil, LCMS (M+H)+: 397. Step 7: preparation of (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 (Example 155) A mixture of (14S,17S)-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 (compound 155f, 250 mg, 0.63 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 168 mg, 0.63 mmol) and DIEA (244 mg, 1.89 mmol) in dimethyl sulfoxide (3 mL) was stirred at 80oC for 1 hr. The reaction mixture was directly purified by prep-HPLC to give Example 155 (42 mg) as an orange solid, LCMS (M+H)+: 627. Example 156 (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 To a mixture of (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(22),2,4,6,19(23),20-hexaen- 13-one (Example 157, 40 mg, 0.07 mmol) and Et3N (21 mg, 0.21 mmol) in dichloromethane (2 mL) was added AcCl (8 mg, 0.10 mmol) at room temperature. The mixture was stirred at 25oC for 12 hrs. The reaction mixture was purified prep-HPLC to give Example 156 (4 mg) as a white solid, LCMS (M+H)+: 624. Example 157 (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 The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl N-(2-bromophenyl)-N-[3-(1,3-dioxoisoindolin-2- yl)propyl]carbamate (compound 157a) A mixture of tert-butyl N-(2-bromophenyl)carbamate (15.23 g, 55.95 mmol) and sodium hydride (1.49 g, 37.31 mmol) and 2-(3-bromopropyl)isoindoline-1,3-quinone (10.0 g, 37.31 mmol) in DMF (60 mL) was stirred at 25oC for 2 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash column chromatography to give compound 157a (7.2 g) as a yellow oil, LCMS (M+H)+: 459. Step 2: preparation of tert-butyl N-(3-aminopropyl)-N-(2-bromophenyl)carbamate (compound 157b) A mixture of tert-butyl N-(2-bromophenyl)-N-[3-(1,3-dioxoisoindolin-2- yl)propyl]carbamate (compound 157a, 5.0 g, 10.9 mmol) and hydrazine monohydrate (1.9 g, 32.7 mmol) in ethanol (50 mL) was stirred at 70oC for 2 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give crude compound 157b (3.5 g) as a yellow oil, LCMS (M+H)+: 329. Step 3: preparation of tert-butyl N-(2-bromophenyl)-N-[3-(tert- butoxycarbonylamino)propyl]carbamate (compound 157c) A mixture of N-(3-aminopropyl)-N-(2-bromophenyl)carbamic acid tert-butyl ester (compound 157b, 3.5 g, 10.6 mmol), triethylamine (2.15 g, 21.3 mmol) and (Boc)2O (2.32 g, 10.6 mmol ) in dichloromethane (20 mL) was stirred at 25oC for 2 hrs. The reaction mixture was diluted with sat. NaHCO3 solution and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give the crude material which was purified by flash column chromatography to give compound 157c (4.2 g) as a yellow oil, LCMS (M+H)+:429. Step 4: preparation of tert-butyl N-[3-(2-bromo-N-tert-butoxycarbonyl- anilino)propyl]-N-methyl-carbamate (compound 157d) A mixture of tert-butyl N-(2-bromophenyl)-N-[3-(tert- butoxycarbonylamino)propyl]carbamate (compound 157c, 4.20 g, 9.78 mmol) and methyl iodide (1.39 g, 9.78 mmol) in DMF (10 mL) was added sodium hydride (0.78 g, 19.56 mmol) at 0oC. The mixture was stirred at 70oC for 3 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash column chromatography to give compound 157d (4.5g) as a yellow oil, LCMS (M+H)+:443. Step 5: preparation of tert-butyl N-[3-[N-tert-butoxycarbonyl-2-(6-chloro-2- pyridyl)anilino]propyl]-N-methyl-carbamate (compound 157e) A mixture of K2CO3 (4.11 g, 29.77 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (2.85 g, 11.91 mmol), tert-butyl N-[3-(2-bromo-N-tert- butoxycarbonyl-anilino)propyl]-N-methyl-carbamate (compound 157d, 4.40 g, 1.35 mmol) and Pd(dppf)Cl2 (0.21 g, 0.29 mmol) in 1,4-dioxane (25 mL) and water (2.5 mL) was heated to 100°C for 12 hrs under nitrogen protection. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated and purified by flash chromatography to give compound 157e (3.0 g) as a yellow oil, LCMS (M+H)+: 476. Step 6: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[2-[tert-butoxycarbonyl-[3- [tert-butoxycarbonyl(methyl)amino]propyl]amino]phenyl]-2-pyridyl]amino]pyrrolidine- 1,2-dicarboxylate (compound 157f) A mixture of tert-butyl N-[3-[N-tert-butoxycarbonyl-2-(6-chloro-2-pyridyl)anilino]propyl]- N-methyl-carbamate (compound 157e, 3.8 g, 7.98 mmol), O1-benzyl O2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (3.01 g, 9.57 mmol), Pd PEPPSI-IPent (0.13 g, 0.15 mmol) and cesium carbonate (7.80 g, 0.13 mmol) in 1,4-dioxane (30 mL) was stirred at 100 oC for 12 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash column chromatography and give compound 157f (2.9 g) as a yellow oil, LCMS (M+H)+: 718. Step 7: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[tert-butoxycarbonyl-[3- [tert-butoxycarbonyl(methyl)amino]propyl]amino]phenyl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid(compound157g) A mixture of O1-benzyl O2-methyl (2S,4S)-4-[[6-[2-[tert-butoxycarbonyl-[3-[tert- butoxycarbonyl(methyl)amino]propyl]amino]phenyl]-2-pyridyl]amino]pyrrolidine-1,2- dicarboxylate (compound 157f, 2.90 g, 4.04 mmol) and lithium hydroxide (0.48 g, 20.20 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at 25oC for 12 hrs. The reaction mixture was adjusted PH~5 with 2N HCl and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give compound 157g (2.90 g) as a yellow oil, LCMS (M+H)+:704. Step 8: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3- (methylamino)propylamino]phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid(compound 157h) A mixture of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[tert-butoxycarbonyl-[3-[tert- butoxycarbonyl(methyl)amino]propyl]amino]phenyl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 157g, 2.90g, 4.12 mmol) and TFA (22.2 g, 194.7 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 hrs. The mixture was concentrated to give crude compound 157h (4.2 g) as a yellow foam, LCMS (M+H)+:504. Step 9: preparation of benzyl (14S,17S)-12-methyl-13-oxo-8,12,15,18,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-15-carboxylate (compound 157i) To a mixture of HATU (3.1 g, 8.16 mmol) and DIEA (3.16 g, 24.48 mmol) in DMF (100 mL) was added (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-[3-(methylamino)propylamino]phenyl]-2- pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 157h, 4.2 g, 4.08 mmol) in acetonitrile (1000 mL) and DMF (40 mL) dropwise, the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated in vacuo to remove acetonitrile, the rest of 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 afford crude compound 157i (1.5 g) as a brown foam, LCMS (M+H)+:486. Step 10: preparation of (14S,17S)-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; 2,2,2- trifluoroacetic acid (compound 157j) A mixture benzyl (14S,17S)-12-methyl-13-oxo-8,12,15,18,23- pentazatetracyclo[17.3.1.114,17.02,7]tetracosa-1(23),2,4,6,19,21-hexaene-15-carboxylate (compound 157i, 1.5 g, 3.09 mmol) in TFA (10 mL) was heated at 90°C for 10 min under microwave. The reaction mixture was concentrated to dryness and give crude compound 157j (1.8 g) as a brown oil, LCMS (M+H)+:352. Step 11: preparation of (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 (Example 157) A mixture of (14S,17S)-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 (compound 157j, 1.44g, 3.09 mmol), DIEA (2.0 g,15.47 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (intermediate C2, 0.82 g, 3.09 mmol) in DMF (45 mL) was stirred at 80°C for 30 min. After being cooled to room temperature, the reaction mixture was partitioned between water and DCM. The separated aqueous layer was extracted with DCM 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 slurried in Et2O and then filtered, the collected solid was collected and give 1.5 g crude product, the crude product was purified by prep-HPLC to give Example 157 (1.5 mg) as a white solid, LCMS (M+H)+: 582. Example 158 (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 The title compound was prepared according to the following scheme: A mixture of (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(22),2,4,6,19(23),20-hexaen- 13-one (Example 157, 20 mg, 0.03 mmol) and Et3N (10 mg, 0.10 mmol) in dichloromethane (1 mL) was added N-methylcarbamoyl chloride (6 mg, 0.07 mmol) at rt. The mixture was stirred at 25oC for 12 hrs. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by prep-HPLC to give Example 158 (5 mg) as a white solid, LCMS (M+H)+: 639.1H NMR (400 MHz, DMSO-d6) δ = 8.71 - 8.31 (m, 1H), 8.26 - 8.09 (m, 1H), 7.77 (s, 1H), 7.66 - 7.55 (m, 2H), 7.46 - 7.38 (m, 2H), 7.35 - 7.29 (m, 2H), 7.24 - 7.19 (m, 1H), 6.76 - 6.61 (m, 2H), 5.56 - 5.44 (m, 1H), 5.40 - 5.29 (m, 1H), 5.28 - 5.15 (m, 1H), 4.72 - 4.63 (m, 1H), 4.52 - 4.40 (m, 1H), 4.18 - 4.07 (m, 1H), 3.90 - 3.77 (m, 1H), 3.16 - 3.09 (m, 2H), 3.05 - 2.98 (m, 3H), 2.55 (m, 3H), 2.45 (m, 1H), 2.39 (m, 1H), 1.55 - 1.38 (m, 1H). Example 159 (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 The title compound was prepared according to the following scheme: A mixture of (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(22),2,4,6,19(23),20-hexaen- 13-one (Example 157, 40 mg, 0.07 mmol) and Et3N (21 mg, 0.21 mmol) in dichloromethane (2 mL) was added 2-pyrazol-1-ylacetyl chloride (15 mg, 0.10 mmol) at rt. The mixture was stirred at 25oC for 12 hrs. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude material was purified by prep-HPLC to give Example 159 (8 mg) as a yellow solid, LCMS (M+H)+: 690. Example 160 (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 The title compound was prepared according to the following scheme: A mixture of (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(22),2,4,6,19(23),20-hexaen- 13-one (Example 157, 40 mg, 0.07 mmol) and Et3N (21 mg, 0.21 mmol) in dichloromethane (2 mL) was added 2-(4-pyridyl)acetyl chloride (16 mg, 0.10 mmol) at rt. The mixture was stirred at 25oC for 12 hrs. The reaction mixture was diluted with water and extracted with EtOAc for three times. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude material was purified by prep-HPLC to give Example 160 (4.2 mg) as a yellow solid, LCMS (M+H)+: 701. Example 161 (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 The title compound was prepared according to the following scheme: Step 1: preparation of 4-chloro-1-(4-fluorophenyl)pyrazolo[4,3-c]pyridine (compound 161a) To a microwave tube was added 1-fluoro-4-iodobenzene (1450 mg, 6.51 mmol), 4-chloro- 1H-pyrazolo[4,3-c]pyridine (500 mg, 3.26 mmol), copper (I) iodide (124 mg, 651 µmol), Cs2CO3 (2120 mg, 6.51 mmol), 2,3,8,9-tetramethyl-1,10-phenanthroline (154 mg, 651 µmol) and NMP (12 mL). The tube was bubbled with N2 for 5 mins and sealed, and then it was reacted at 110 °C for 12 hrs. The mixture was diluted with 30 mL water and extracted with EA (30 mL × 2). The organic layer was dried and concentrated to give a residue which was purified via silica gel column chromatography to give compound 161a (122 mg) as pale yellow solid. LCMS (M+H)+: 248. Step 2: preparation of 4(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 (Example 161) To a flask was added compound 1f (30 mg, 0.08 mmol), K2CO3 (22 mg, 0.16 mmol), compound 161a (25 mg, 0.1 mmol ) and dimethyl sulfoxide (2 mL). The brown solution was heated to 120 °C and stirred for 24 hrs. The mixture was concentrated and purified via prep- HPLC to give Example 161 (9 mg) as white powder. LCMS (M+H)+: 588, 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (s, 1H), 8.49 (br s, 1H), 8.36 - 8.21 (m, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.52 - 7.39 (m, 3H), 7.39 - 7.32 (m, 2H), 7.32 - 7.29 (m, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.01 (dd, J = 2.0, 8.2 Hz, 1H), 6.94 (d, J = 6.0 Hz, 1H), 5.42 (td, J = 7.8, 15.8 Hz, 1H), 4.88 (br d, J = 9.0 Hz, 1H), 4.61 (br t, J = 8.3 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.96 - 3.87 (m, 1H), 3.09 (br d, J = 5.7 Hz, 2H), 2.65 (br dd, J = 5.7, 12.2 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.09 - 1.83 (m, 2H), 1.39 - 1.21 (m, 2H). Example 162 (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 The 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 162a) To a solution of (6-bromo-2-pyridyl)hydrazine (3.5 g, 18.61 mmol), 4-(tert- butoxycarbonylamino)butanoic acid (4.2 g, 20.48 mmol) and DIPEA (4.8 g, 37.23 mmol) in DMF (40 mL) was added HATU (6.6 g, 27.97 mmol). The reaction solution was stirred at 30 °C for 2 hrs. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2 × 150 mL). The organic phase was washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford compound 162a (7.0 g) as a brown solid. LCMS (M+H)+: 373. Step 2: preparation of tert-butyl (3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)propyl)carbamate (compound 162b) To a solution of compound 162a (7.0 g, 18.75 mmol), hexachloroethane (8.9 g, 37.51 mmol) and triphenylphosphine (9.8 g, 37.51 mmol) in THF (100 mL) was added triethylamine (10.5 mL, 75.02 mmol) dropwise at 20 °C. The reaction was stirred at 20 °C for 2 hrs. The mixture was poured into water (400 mL) and extracted with ethyl acetate (2 × 200 mL). The organic phase was washed with brine (3 × 300 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel column chromatography to afford compound 162b (5.7 g) as brown solid. LCMS (M+H)+: 355. Step 3: preparation of tert-butyl N-[3-(5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3- yl)propyl]-N-(3-methoxypropyl)carbamate (compound 162c) To a microwave tube was added compound 162b (600 mg, 1.69 mmol), 1-bromo-3- methoxypropane (171 mg, 1.12 mmol) and DMF (6 mL). Then NaH (405 mg, 10.1 mmol) was added in one portion and the reaction mixture was stirred for 1 hr. The mixture was poured into 100 mL water and extracted with EA for three times. The organic layer was dried over Na2SO4 and concentrated to give compound 162c as crude oil. LCMS (M+H)+: 427. Step 4: preparation of O1-benzyl O2-methyl (2S,4S)-4-[3-[3-[3-[tert- butoxycarbonyl(3-methoxypropyl)amino]propyl]-[1,2,4]triazolo[4,3-a]pyridin-5- yl]phenoxy]pyrrolidine-1,2-dicarboxylate (compound 162d) To a tube was added intermediate B9 (1350 mg, 1.4 mmol), compound 162c (400 mg, 936 µmol), K2CO3 (259 mg, 1.87 mmol), water (0.2 mL) and 1,4-Dioxane (5 mL). The suspension was bubbled with N2 for 5 mins and then PdCl2(DPPF)-CH2Cl2 adduct (68 mg, 93.6 µmol) was added. The mixture was heated to 100 °C and stirred for 3 hrs. The mixture was diluted with some EA and filtered, the filtrate was concentrated and the residue was purified via silica gel column chromatography to give compound 162d (488 mg) as an oil. LCMS (M+H)+: 702. Step 5: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[3-[3-[3-(3- methoxypropylamino)propyl]-[1,2,4]triazolo[4,3-a]pyridin-5-yl]phenoxy]pyrrolidine-2- carboxylic acid (compound 162e) To a flask was added compound 162d (488 mg, 695 µmol), MeOH (2 mL) and THF (2 mL) and LiOH (2 N, 0.4 mL). The reaction mixture was stirred at r.t. for 2 hrs and then diluted with water. After pH was adjusted to 4, the mixture was extracted with DCM, the organic layer was dried and concentrated to give a foamy solid (455 mg), which was dissolved in 1,4-Dioxane (3 mL). Then HCl (4 N in dioxane) (3 mL) was added and the reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was concentrated to give compound 162e (559 mg) as a crude solid, which was used in the next step directly. LCMS (M+H)+: 588. Step 6: preparation of benzyl (8S,11S)-13-(3-methoxypropyl)-12-oxo-7-oxa- 10,13,18,19,24-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,17,19,21- heptaene-10-carboxylate (compound 162f) To a 500 mL flask was added HATU (627 mg, 1.65 mmol), DIPEA (692 µL, 3.96 mmol), DMF (25 mL) and acetonitrile (100 mL), the solution was cooled with ice bath and then a solution of compound 162e (436 mg, 660 µmol) in DMF (25 mL) and acetonitrile (100 mL) was added via dropping funnel in about 2.5 hrs. The final mixture was stirred at r.t. for 16 hrs and then concentrated to remove the ACN and most DMF. The residue was purified via silica gel column chromatography to give compound 162f (400 mg) as a brown oil. LCMS (M+H)+: 570. Step 7: preparation of (8S,11S)-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 (compound 162g) To a 100 mL flask was added compound 162e (342 mg, 600 µmol), Pd(OH)2 (20% on carbon with 50% H2O) (50 mg, 356 µmol) and MeOH (20 mL), the suspension was purged with H2 for 5 times. Then it was heated to 65 °C and stirred for about 2 hrs. The mixture was filtered, the filtrate was concentrated to give compound 162g (300 mg) as an oil. LCMS (M+H)+: 440. Step 8: preparation of (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 (Example 162) To a microwave tube was added compound 162g (100 mg, 193 µmol), intermediate C2 (69 mg, 232 µmol), DIPEA (67.5 µL, 387 µmol) and acetonitrile (2 mL). The reaction was heated to 90 °C for about 2 hrs. The reaction mixture was concentrated and the residue was purified via prep-HPLC to give Example 162 (40 mg) as white powder. LCMS (M+H)+: 670, 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (s, 1H), 8.17 (s, 1H), 7.73 (dt, J = 5.7, 8.9 Hz, 1H), 7.59 (ddd, J = 2.8, 9.1, 10.4 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.07 (dd, J = 2.0, 8.1 Hz, 1H), 7.01 (br d, J = 7.7 Hz, 1H), 5.85 (s, 1H), 5.53 - 5.39 (m, 2H), 5.15 (d, J = 10.0 Hz, 1H), 4.36 - 4.22 (m, 2H), 3.52 - 3.43 (m, 1H), 3.40 - 3.35 (m, 1H), 3.31 - 3.27 (m, 1H), 3.23 (s, 3H), 3.00 - 2.84 (m, 2H), 2.78 (ddd, J = 6.2, 10.2, 16.7 Hz, 1H), 2.60 - 2.51 (m, 2H), 2.48 (br s, 1H), 2.41 - 2.29 (m, 1H), 2.27 - 2.12 (m, 2H), 2.04 - 1.91 (m, 2H), 1.91 - 1.65 (m, 4H), 1.63 - 1.47 (m, 1H), 0.82 - 0.67 (m, 1H). Example 163 (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 The title compound was prepared according to the following scheme:
Step 1: preparation of tert-butyl N-(5-bromothiazol-2-yl)carbamate (compound 163a) To a flask was added (5-bromothiazol-2-yl)amine (2 g, 11.17 mmol), DMAP (273 mg, 2.23 mmol), (Boc)2O (3.2 g, 14.52 mmol) and DCM (20 mL). The solution was stirred at rt for 2 days. Then the mixture was concentrated and the residue was purified via silica gel column chromatography to give compound 163a (2.5 g) as a white solid. LCMS (M+H)+: 279. Step 2: preparation of O1-benzyl O2-methyl (2S,4S)-4-[(5-bromothiazol-2-yl)-tert- butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate (compound 163b) To a flask of compound 163a (2.5 g, 8.96 mmol), (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylic acid O1-benzyl ester O2-methyl ester (2.8 g, 9.85 mmol) and triphenylphosphine (4.7 g, 17.91 mmol) in THF (7 mL) was added diisopropyl (E)-diazene-1,2-dicarboxylate (3.5 mL, 17.91 mmol) in one portion. After being stirred at rt for 1 h, the mixture was poured into water and extracted with EA. The organic layer was dried and concentrated to give a yellow oil. Then it was purified via silica gel column chromatography to give compound 163b (4.5 g) as a semi-solid. LCMS (M+H)+: 540. Step 3: preparation of O1-benzyl O2-methyl (2S,4S)-4-[tert-butoxycarbonyl-[5-[3-[3- [tert-butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-methyl-benzimidazol-4- yl]thiazol-2-yl]amino]pyrrolidine-1,2-dicarboxylate (compound 163c) To a flask was added compound 163b (770 mg, 1.42 mmol), intermediate A2 (900 mg, 1.89 mmol), K2CO3 (394 mg, 2.85 mmol), 1,4-dioxane (8 mL) and water (0.5 mL). The suspension was bubbled with N2 for 5 mins and then palladium (II) acetate (32 mg, 0.14 mmol) and 1,1'-bis(di-t-butylphosphino)ferrocene (138 mg, 0.28 mmol) were added. After being stirred at 90 °C for 16 hrs, the reaction mixture was poured into water and extracted with EA, the organic layer was dried over Na2SO4 and concentrated. The residue was purified via silica gel column chromatography to give compound 163c (560 mg) as light brown oil. LCMS (M+H)+: 811. Step 4: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[5-[6-fluoro-3-[2-methoxy-3- (methylamino)propyl]-2-methyl-benzimidazol-4-yl]thiazol-2-yl]amino]pyrrolidine-2- carboxylic acid (compound 163d) To the flask which containing the compound 163c (560 mg, 0.691 mmol) was added tetrahydrofuran (3 mL) and 2 M LiOH aq. (3 mL, 6 mmol). The reaction was stirred at r.t. for 2 hrs. The mixture was diluted with 20 mL water and pH was adjusted to 4 with 2 N HCL aq., then it was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to give a foamy solid, which was dissolved in DCM (1 mL) and TFA (1 mL). The brown solution was stirred at r.t. for 1 hr and then concentrated, the residue was purified via prep-HPLC to give compound 163d (310 mg) as white powder. LCMS (M+H)+: 597. Step 5: preparation of benzyl (7S,10S)-21-fluoro-14-methoxy-12,17-dimethyl-11-oxo- 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-hexaene-9-carboxylate (compound 163e) To a solution of HATU (461 mg, 1.21 mmol), DIEA (529 µL , 3.03 mmol) in acetonitrile (100 mL) was added another solution of compound 163d (0.5 g, 0.606 mmol) in acetonitrile (100 mL) in 2 hrs. Then the reaction mixture was concentrated, the residue was purified via prep- HPLC to give compound 163e (200 mg) as yellow oil. LCMS (M+H)+: 579. Step 6: preparation (7S,10S)-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 (compound 163f) To a flask was added methanol (30 mL), compound 163e (100 mg, 0.124 mmol) and 20% palladium hydroxide on carbon (with 50% H2O) (60 mg, 0.427 mmol). The mixture was purged with H2 for 3 times. Then it was heated to 60 °C and stirred for 4 hrs. The mixture was filtered, the filtrate was concentrated to give compound 163e (80 mg) as a yellow oil. LCMS (M+H)+: 445. Step 7: preparation of (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 (Example 163) To a tube was added compound 163e (80 mg, 0.12 mmol), DIEA (166 µL , 0.95 mmol), acetonitrile (2 mL) and intermediate C2 (38 mg, 0.143 mmol). The reaction was heated to 85 °C for 1 hr. The mixture was concentrated and the residue was purified via prep-HPLC to give Example 163 (14 mg) as white powder. LCMS (M+H)+: 675, 1H NMR (500 MHz, METHANOL-d4) δ = 8.41 (br s, 1H), 8.21 (s, 1H), 7.66 (tt, J = 5.7, 8.6 Hz, 1H), 7.54 (s, 1H), 7.35 (dd, J = 2.1, 8.7 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 7.01 - 6.92 (m, 1H), 5.24 (br d, J = 18.5 Hz, 1H), 4.65 - 4.53 (m, 1H), 4.45 - 4.34 (m, 1H), 4.24 - 4.07 (m, 1H), 3.90 - 3.85 (m, 1H), 3.73 - 3.54 (m, 2H), 3.51 - 3.39 (m, 3H), 3.13 (br d, J = 10.1 Hz, 1H), 3.03 - 2.90 (m, 3H), 2.90 - 2.82 (m, 1H), 2.64 (br d, J = 11.1 Hz, 3H), 2.20 - 2.08 (m, 1H), 1.90 (br d, J = 10.5 Hz, 1H). Example 164 (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 The title compound was prepared in analogy to the preparation of Example 163 by using 4- bromothiazol-2-ol instead of tert-butyl N-(5-bromothiazol-2-yl)carbamate in step 2 and using intermediate A4 instead of intermediate A2. Example 164 (34.2 mg), LCMS: (M+H)+: 676, 1H NMR (400 MHz, METHANOL-d4) δ = 8.57 - 8.50 (m, 1H), 8.25 (s, 1H), 7.71 - 7.60 (m, 1H), 7.40 - 7.33 (m, 1H), 7.33 - 7.24 (m, 2H), 7.24 - 7.15 (m, 1H), 7.10 (dd, J = 2.5, 9.9 Hz, 1H), 5.70 - 5.57 (m, 1H), 5.56 - 5.39 (m, 1H), 4.62 - 4.53 (m, 1H), 4.50 - 4.33 (m, 2H), 4.22 - 3.97 (m, 1H), 3.31 - 3.30 (m, 3H), 3.30 - 3.23 (m, 1H), 3.21 - 3.12 (m, 2H), 3.04 - 2.93 (m, 3H), 2.91 - 2.75 (m, 2H), 2.72 - 2.64 (m, 3H). Example 165 (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 The title compound was prepared in analogy to the preparation of Example 163 by using 4- bromothiazol-2-amine instead of 5-bromothiazol-2-amine in step 1 and using intermediate A4 instead of intermediate A2. Example 165 (7 mg), LCMS: (M+H)+: 675, 1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.24 (s, 1H), 7.71 - 7.61 (m, 1H), 7.60 - 7.54 (m, 1H), 7.52 (dd, J = 2.3, 7.4 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.17 (m, 1H), 6.44 - 6.27 (m, 1H), 5.46 (d, J = 9.1 Hz, 1H), 4.55 - 4.49 (m, 1H), 4.47 - 4.35 (m, 2H), 4.26 (br dd, J = 11.4, 15.0 Hz, 1H), 4.16 (dd, J = 8.1, 14.6 Hz, 1H), 3.19 - 3.12 (m, 3H), 3.03 (s, 3H), 2.99 - 2.91 (m, 1H), 2.86 (d, J = 8.1 Hz, 1H), 2.83 (s, 3H), 2.74 - 2.53 (m, 2H). Example 168 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-2- yl]acetonitrile The title compound was prepared according to the following scheme: Step 1: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-6-fluoro-2-methyl-benzimidazol-4-yl]- 2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 168a) To a flask was added K2CO3 (3.36 g, 24.3 mmol), compound B7 (5.28 g, 12.15 mmol), compound A4 (5.8 g, 12.15 mmol), 1,4-dioxane (60 mL) and water (1 mL). The suspension was bubbled with N2 for 5 mins and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (992 mg, 1.21 mmol) was added. The mixture was heated to 90 oC and stirred for 16 hrs. The mixture was poured into 200 mL water and extracted with 50 mL EA for 3 time. The organic layer was dried over Na2SO4 and concentrated, a brown oil was obtained. Then it was purified by silica gel column chromatography to give compound 168a (6.8 g) as yellow oil. LCMS (M+H)+: 705. Step 2: preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-3-[(2S)-2-methoxy -3-(methylamino)propyl]-2-methyl-benzimidazol-4-yl]-2-pyridyl]amino]pyrrolidine-2- carboxylic acid (compound 168b) To the flask which contained compound 168a (6.8 g, 9.65 mmol) was added tetrahydrofuran (20 mL). The brown solution was stirred at r.t. and 2 M LiOH (aq.) (20 mL, 40 mmol) was added drop-wise. The final mixture was stirred at r.t. for 2 hrs. The mixture was diluted with 20 mL water and pH was adjusted to 4 with 2 N aq. solution of HCl, and then it was extracted with 30 mL DCM for 3 times. The organic layer was dried and concentrated to give a foamy solid. The solid was dissolved in dichloromethane (5 mL) and TFA (7.4 g, 5 mL, 64.9 mmol). The brown solution was stirred at r.t. for 1 hr. Then it was concentrated to give compound 168b (4.9 g) as an oil. LCMS (M+H)+: 591. Step 3: preparation of benzyl (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound 168c) To a solution of HATU (4.57 g, 12.02 mmol), DIEA (7.77 g, 10.5 mL, 60.1 mmol) in acetonitrile (1200 mL) was added another solution of compound 168b (4.92 g, 6.01 mmol) in acetonitrile (1200 mL). The mixture was stirred at rt for 4hrs, then concentrated to give a residue, which was dissolved in 200 mL EA and then it was washed with 100 mL sat. NaCl aq. twice. The organic layer was concentrated to give an oil (~8 g). Then it was purified via prep-HPLC to give compound 168c (3.5 g) as yellow foam. LCMS (M+H)+: 573. Step 4: preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 168d) To a flask containing compound 168c (3.5 g, 6.11 mmol) was added TFA (44.4 g, 30 mL, 389.41 mmol). The brown solution was heated to reflux and stirred for 3 hrs. The mixture was concentrated to give compound 168d (7 g) as a crude oil. LCMS (M+H)+: 439. Step 5: preparation of (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 168e) A mixture of intermediate 168d (0.90 g, 2.05 mmol), intermediate C1 (618 mg, 2.05 mmol) and DIPEA (1.33 g, 10.26 mmol) in acetonitrile (60 mL) was stirred at 45 oC for 3 hours, then the reaction was concentrated and the residue was purified by silica gel column chromatography to give compound 168e (1 g), LCMS (M+H+): 703. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxym ethyl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5, 18,20(24),21-heptaen-12-one(compound 168f) A mixture of compound 168e (100.0 mg, 0.14 mmol), [(2S)-azetidin-2-yl]methanol (25 mg, 0.28 mmol), CsF (108 mg, 0.71 mmol) and DIEA (0.25 mL, 1.42 mmol) in DMA (3 mL) was stirred at 80 °C for 2 h. The mixture was purified by prep-HPLC to give compound 168f (60.0 mg) as a light brown solid. LCMS (M+H+): 754. Step 7: preparation of [(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin- 2-yl]methyl ethanesulfonate(compound 168g) To a solution of compound 168f (50.0 mg, 0.07 mmol) in DCM (2 mL) was added TEA (9 mg, 0.1 mmol) and ethanesulfonyl chloride (13 mg, 0.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound 168g (40.0 mg) as a light yellow solid. LCMS (M+H+): 846. Step 8: preparation of 2-[(2S)-1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidin- 2-yl]acetonitrile (Example 168) To a solution of compound 168g (40.0 mg, 0.05 mmol) in DMF (1 mL) was added sodium cyanide (10.0 mg, 0.2 mmol) and 18-crown-6 (1 mg). The reaction mixture was stirred at 50 °C for 16 h and then diluted with ice water. The aqueous solution was extracted with EA, the organic layer was dried and concentrated to give crude product. The crude product was purified by prep-HPLC to afford Example 168 (20 mg) as a white solid, LCMS (M+H+): 763.1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.30 (dd, J = 2.1, 8.2 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.05 (m, 3H), 6.67 - 6.59 (m, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.41 - 5.23 (m, 1H), 4.61 - 4.51 (m, 1H), 4.45 - 4.29 (m, 2H), 4.22 (s, 1H), 4.17 - 4.11 (m, 1H), 4.09 - 3.94 (m, 1H), 3.91 (dd, J = 5.5, 8.6 Hz, 2H), 3.08 (s, 1H), 3.02 (s, 4H), 2.90 (d, J = 14.2 Hz, 1H), 2.84 - 2.79 (m, 3H), 2.77 - 2.61 (m, 1H), 2.59 - 2.52 (m, 3H), 2.52 - 2.38 (m, 3H), 2.35 - 2.19 (m, 1H). Example 169 Microliter plate-based TR-FRET assay for binders of STING This is the competition-binding assay to test the compounds’ potency to the C-terminal Domain (CTD) and ligand-binding domain of human stimulator of interferon genes (STING). STING (139-379, Q86WV6, http://www.uniprot.org/uniprot) recombinant protein (in 20mM Tris, 150mM NaCl, pH 8.0, and expression in Escherichia coli (E. coil) BL21 (DE3)) with a C- terminal flag-tag was employed for the assay. When Alexa-488 labeled active site probe (refer to patent WO2017/175156 A1) bounds to STING (139-379), it accepts the 485 nm emission from Tb-M2-Flag-STING and results in an increase in fluorescence at 520 nm. Compounds that compete for the probe-binding site will reduce 520 nm signal. The assay was run in proxiplate- 384 plus (PerkinElmer, cat: 60150300) containing of 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, Lot: 17A) and 250 nM Alexa488 probe. Plates were centrifuged for 1 min at 1000 rpm, incubated for 30 min at room temperature, and then measured the dual fluorescence emission at 520 nM / 485 nM following 320 nm laser excitation on an Envision plate reader (Perkin-Elmer). The compounds’ effect on the STING binding is detected by measuring ratiometric fluorescence from time-resolved FRET. The percentage of inhibition of at each compound concentration is calculated on the basis of their changes of TR-FRET efficiency relative to the change of TR-FRET caused by positive control 2’3’cGAMP (Sigma, cat: SML1229). Example FRET_IC50 Example FRET_IC50 Example FRET_IC50 NO. (nM) NO. (nM) NO. (nM) 5 50.5 59 44.6 117 4.6 12 50 60 16 118 1.3 13 5.7 65 12 126 12.5 35 7.1 81 19.5 127 9.4 36 84.6 82 21.6 128 6.7 38 49 83 23.5 129 13 39 1 85 91.4 130 76.5 40 2.4 86 23.3 132 6.6 44 13.5 87 41.7 133 0.7 45 0.9 88 82.5 136 19.4 46 17.2 89 26.4 137 24.1 47 19.7 90 28.4 138 80.7 48 6.2 91 6.4 140 2.4 49 3.8 92 21 141 35.8 50 0.6 93 14.2 152 65.9 51 10.3 99 43.1 154 0.3 52 10.5 111 13.8 164 21.5 53 5.5 112 3.2 165 8 54 2.4 114 3.4 168 0.9 56 14.7 115 5.3 58 3 116 2.3 Example 170 THP1-Dual Lucia Reporter Gene Assay This is the cellular reporter assay to evaluate compounds’ antagonism to interferon regulatory factor (IRF) pathway in THP1-Dual™ cells (InvivoGen, cat.: thpd-nfis) . THP1- Dual™ cells were derived from the human THP-1 monocyte cell line by stable integration lucia luciferase gene, a new secreted luciferase reporter gene, under the control of an ISG54 (interferon-stimulated gene) minimal promoter in conjunction with five interferon (IFN)- stimulated response elements. As a result, THP1‑Dual™ cells allow the study of the IRF pathway, by assessing the activity of Lucia luciferase. Lucia luciferase protein is readily measurable in the cell culture supernatant when using QUANTI‑Luc™ (InvivoGen, cat. : rep- qlcg-500).2’3’cGAMP or baculovirus (a double stranded DNA virus, purchased from Genescript, pCMV-Dest Vector virus generation P2 BV stock virus, Sf-900 II medium with 5% FBS, Lot C9835DK230-2/P4DL001) were used as stimulator to induce the activation of IRF pathway. After THP1‑Dual™ cells was co-incubated with compound for 20-24 h, the compounds’ antagonism to IRF pathway and cell toxicity were tested by measuring luminescence and OD 450 on an Envision plate reader. On the day of experiment, 25 µL of test medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed in a white, 384-well plate (Grenier, cat.: 781098).24 μL of stimulator (final concentration is 20 µM of 2’3’cGAMP, or final concentration is 10 MOI baculovirus virus,) was added before 6 μL of compound solution per well (final 1% DMSO) was transferred by Agilent Bravo. Then 30 μL of cell suspension (~33,000 cells, 1.1 ×106 cells/mL) per well was added immediately by thermo multidrop combi dispenser for incubation 20-24 h at 37 °C, 5% CO2. At the end of the incubation, 10 μL of cellular supernatant was transferred to proxiplate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc™ Gold solution was added to the plate that proceeded with the measurement immediately. To detect cell viability, 30 μL of the CCK-8 working solution (Dojindo Molecular Technologies, cat.: CK04-20) was added to the cell plate, which was Incubated for 2 h in the incubator to measure the absorbance at 450 nm using Envision. Example THP1_IC50 Example THP1_IC50 Example THP1_IC50 NO. (nM) NO. (nM) NO. (nM) 1 6.8 30 35.1 54 2.7 5 116 65 755 127 391 12 53 81 17 128 752 44 488 91 256 130 100 45 29 111 154 133 18 46 214 112 48 136 966 47 651 114 117 140 14 48 186 115 122 152 92 50 2 116 32 165 285 51 463 117 519 168 7 52 107 118 62 53 11 126 304

Claims

CLAIMS 1. A compound of formula (I), wherein M1 is arylene, heterocyclylene or heteroarylene, each of which is optionally substituted by R1; wherein R1 is 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, Rb or Rc; Ra is C1-6alkyl optionally substituted by Rb or Rc; Rb is C3-7cycloalkyl, heterocyclyl, heteroaryl or aryl, said C3-7cycloalkyl, heterocyclyl, heteroaryl and aryl being unsubstituted or optionally substituted by deuterio, halogen or Rc; Rc is 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; M2 is 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; M3 is heterocyclylene which is substituted by R2 and optionally substituted by R1; wherein R2 is 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; Q2 is a bond, C1-6alkylene, O, S, SO, SO2, SO(NR), P(O)R, PO(NR), Se, N(R) or SiR2; Q3 is 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; Q4 is 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 M1 is arylene, heterocyclylene or heteroarylene, each of which is once, twice or three times substituted by R1; wherein R1 is 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 M1 is [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 M1 is 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 M1 is 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 M2 is C2-6alkenylene, phenylene, pyridylene, pyrimidinylene or thiazolylene. 7. A compound according to any one of claims 1 to 6, wherein M2 is phenylene, pyridylene, pyrimidinylene or thiazolylene. 8. A compound according to any one of claims 1 to 7, wherein M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; ; wherein R3 is C1-6alkyl; R4 is phenyl or phenylC1-6alkyl, each of which is once or twice substituted by substituents independently selected from halogen and C1-6alkoxy; R5 is 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 M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; 2 wherein R is , or ; wherein R4 is phenyl twice substituted by halogen; R5 is 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 M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and methyl; wherein R2 is ; wherein R4 is 2,4-difluorophenyl; R5 is 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 Q1 is , wherein L1 is a bond, C1-6alkylene, hydroxyC1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is 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 R6 is 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; L3 is a bond, NH, carbonyl, pyrrolidinylene, CONH or (C1-6alkyl)amino; L4 is 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; L5 is a bond, O, NR7 or piperazinylene unsubstituted or substituted by phenylC1-6alkyl or phenylC1-6alkoxycarbonyl; wherein R7 is H, (carboxymorpholinyl)C1-6alkyl, C1-6alkoxyC1- 6alkyl, C1-6alkyl, morpholinylC1-6alkyl, phenylC1-6alkyl or thiazolylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously. 12. A compound according to any one of claims 1 to 11, wherein Q1 is , wherein L1 is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4 is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1-6alkylene or C1-6alkylene; L5 is a bond, O, NR7 or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7 is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously. 13. A compound according to any one of claims 1 to 12, wherein Q1 is , wherein L1 is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2 is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (methyl)amino; L4 is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5 is a bond, O, NR7 or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7 is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously. 14. A compound according to any one of claims 1 to 13, wherein Q2 is a bond, O, NH or (C1- 6alkyl)amino. 15. A compound according to any one of claims 1 to 14, wherein Q2 is a bond. 16. A compound according to any one of claims 1 to 15, wherein Q3 is O or NH. 17. A compound according to any one of claims 1 to 16, wherein Q4 is a bond, carbonyl or tetrazolylene. 18. A compound according to any one of claims 1 to 17, wherein Q4 is carbonyl or tetrazolylene. 19. A compound according to any one of claims 1 to 18, wherein M1 is 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; M2 is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and C1-6alkyl; 2 wherein R is , or ; wherein R4 is phenyl twice substituted by halogen; R5 is 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; Q1 is , wherein L1 is a bond, C1-6alkylene or (C1-6alkoxy)C1-6alkylene; L2 is a bond, carbonyl, NH, morpholinylene or halopyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (C1-6alkyl)amino; L4 is a bond, (C1-6alkoxycarbonyl)C1-6alkylene, (phenylC1-6alkylaminocarbonyl)C1- 6alkylene or C1-6alkylene; L5 is a bond, O, NR7 or piperazinylene substituted by phenylC1-6alkyl or phenylC1- 6alkoxycarbonyl; wherein R7 is H, C1-6alkyl or phenylC1-6alkyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously; Q2 is a bond; Q3 is O or NH; Q4 is carbonyl or tetrazolylene; or a pharmaceutically acceptable salt thereof. 20. A compound according to any one of claims 1 to 19, wherein M1 is 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; M2 is phenylene, pyridylene, pyrimidinylene or thiazolylene; M3 is pyrrolidinylene substituted by R2, or twice substituted by R2 and methyl; wherein R2 is ; wherein R4 is 2,4-difluorophenyl; R5 is 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; Q1 is , wherein L1 is a bond, (ethoxy)ethylene, (methoxy)ethylene, ethylene, methylene or propylene; L2 is a bond, carbonyl, NH, morpholinylene or difluoropyrrolidinylene; L3 is a bond, carbonyl, NH, CONH or (methyl)amino; L4 is a bond, (benzylaminocarbonyl)ethylene, (methoxycarbonyl)ethylene, ethylene, methylene or propylene; L5 is a bond, O, NR7 or piperazinylene substituted by benzyl or benzyloxycarbonyl; wherein R7 is H, methyl, benzyl or phenylpropyl; with the proviso that L1, L2, L3, L4 and L5 are not bond simultaneously; Q2 is a bond; Q3 is O or NH; Q4 is 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; 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. 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; Re is H or C1-6alkyl. Rf is R or R7; Q1 to Q3, M1 and M2 are 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.
EP24748291.2A 2023-07-21 2024-07-19 Macrocycles for the treatment of autoimmune disease Pending EP4747260A1 (en)

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