[go: up one dir, main page]

WO2025017045A1 - Macrocycles for the treatment of autoimmune disease - Google Patents

Macrocycles for the treatment of autoimmune disease Download PDF

Info

Publication number
WO2025017045A1
WO2025017045A1 PCT/EP2024/070202 EP2024070202W WO2025017045A1 WO 2025017045 A1 WO2025017045 A1 WO 2025017045A1 EP 2024070202 W EP2024070202 W EP 2024070202W WO 2025017045 A1 WO2025017045 A1 WO 2025017045A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
pyrazolo
dimethyl
hexacosa
heptaen
Prior art date
Application number
PCT/EP2024/070202
Other languages
French (fr)
Inventor
Buyu KOU
Haixia Liu
Hong Shen
Yao Wu
Zhiwei Zhang
Wei Zhu
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2025017045A1 publication Critical patent/WO2025017045A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Case 38695 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.
  • Belimumab anti-BAFF antibody, the only FDA-approved new drug for SLE shows a slow onset of remission with modest efficacy in the clinic.
  • the heterogeneity of many autoimmune diseases with no-existing treatment illustrates the difficulty in finding efficacy through the blockade of one immune pathway.
  • Stimulator of interferon genes 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).
  • PAMPs or DAMPs pathogen-/ damage-associated molecular patterns
  • cGAS cyclic-GMP-AMP synthase
  • cGAS double-stranded DNA
  • dsDNA double-stranded DNA
  • cGAMP 2'3'- cyclic GMP-AMP
  • 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- ⁇ B) to initiate the expression of type-I IFN and a myriad of pro-inflammatory cytokines (e.g., IL-6 and TNF ⁇ ), respectively.
  • TNK1 TANK-binding kinase 1
  • IRF3 interferon regulatory factor 3
  • NF- ⁇ B nuclear factor-kappa B
  • 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.
  • CDNs cyclic-di-nucleotides
  • 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.
  • STING is implicated in DNA-driven inflammations, such as Aicardi-Gout Italian Syndrome (AGS) and genetic forms of lupus known as familial chilblain lupus (FCL).
  • AGS Aicardi-Gout Italian Syndrome
  • FCL familial chilblain lupus
  • 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.
  • genetic and pharmacological inhibition of STING ameliorates systemic inflammation and morbidity in the Trex1-/- mouse model.
  • 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.
  • membrane vesicles from apoptotic cells in SLE sera have high ISGs- stimulating activities dependent on cGAS-STING.
  • disrupting STING signaling ameliorated the development of lupus-like phenotypes in Fc ⁇ rIIb-/- mice.
  • multiple recent studies associate STING with distinct types of neurodegeneration.
  • 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).
  • NPC Niemann-Pick disease type C
  • 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.
  • the present invention relates to novel compounds of formula (I), wherein A 1 is CH or N; A 2 is CH or N; A 3 is CR 7 or N; wherein R 7 is H or halogen; A 4 is CH or N; A 5 is CH or N; R 1 is H or halogen; R 2 is C1-6alkyl; R 3 is H or C 1-6 alkoxy; R 4 is C 1-6 alkyl; R 5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC 1-6 alkylcarbonyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C 1-6 alkyl, oxetanyl or oxetanylC1-6alkyl, 3,3-dioxo-3
  • Another object of the present invention is related to novel compounds of formula (I) or (Ia). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or (Ia) as STING antagonist, and for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, or selective types of cancers where overexpression or activation of STING is implicated.
  • the compounds of formula (I) or (Ia) show superior STING antagonism activity.
  • the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, as well as low CYP inhibition.
  • C1-6alkyl groups are methyl, ethyl and n-propyl.
  • C 1-6 alkylene denotes a divalent C 1-6 alkyl. Examples of C 1-6 alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.
  • C 1-6 alkoxy denotes C 1-6 alkyl-O-.
  • halogen and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.
  • haloC 1-6 alkyl denotes a C 1-6 alkyl group wherein at least one of the hydrogen atoms of the C 1-6 alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • 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.
  • haloC1-6alkoxy denotes haloC1-6alkyl-O-.
  • C 3-7 cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms.
  • Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common.
  • Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.
  • haloC3-7cycloalkoxy denotes haloC3-7cycloalkyl-O-.
  • 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.
  • 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.
  • heterocyclyl includes 4-10 or 5-10 ring atoms.
  • heterocyclyl includes 1 to 4 heteroatoms.
  • heterocyclyl includes 1 to 3 heteroatoms.
  • heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon.
  • heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5-6 membered monocycles.
  • a heterocycloalkyl includes at least one nitrogen.
  • 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., [NR 4 ] + Cl-, [NR 4 ] + OH-).
  • 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, thi
  • Heterocyclyl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, haloC 1-6 alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, hydroxyC1-6alkoxy, aminoC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkoxy, haloC3-7cycloalkyl, haloC 3-7 cycloalkoxy, cyanoC 3-7 cycloalkyl, cyanoC 3-7 cycloalkoxy, hydroxyC 3-7 cycloalkyl, hydroxyC 3-7 cycloalkoxy, aminoC 3-7 cycloalkyl, aminoC 3-7 cycloalkyl, aminoC 3-7 cycloalkyl, aminoC 3-7 cycloalkyl, aminoC 3-7 cyclo
  • a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group.
  • 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
  • the heterocyclyl group or heteroaryl group is N-attached.
  • 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 ⁇ -carboline.
  • aryl denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.
  • Aryl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyanoC 1-6 alkoxy, hydroxyC 1-6 alkoxy, aminoC 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, haloC 3- 7cycloalkyl, haloC3-7cycloalkoxy, cyanoC3-7cycloalkyl, cyanoC3-7cycloalkoxy, hydroxyC3- 7cycloalkyl, hydroxyC
  • heteroaryl refers to any mono-, bi-, or tricyclic aromatic ring system containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13 th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • 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]pyrimidine, 1H-pyrazolo[3,
  • Heteroaryl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyanoC 1-6 alkoxy, hydroxyC 1-6 alkoxy, aminoC 1- 6alkoxy, C3-7cycloalkyl, C3-7cycloalkoxy, haloC3-7cycloalkyl, haloC3-7cycloalkoxy, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkoxy, hydroxyC3-7cycloalkyl, hydroxyC3-7cycloalkoxy, aminoC3- 7 cycloalkyl, aminoC 3-7 cycloalkyl, aminoC 3-7 cycloalkoxy, C 1-6 alkoxyC 1-6 alkyl, haloC
  • PG denotes protecting groups.
  • -COO- denotes .
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.
  • 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,
  • pharmaceutically acceptable base addition salt denotes those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • 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.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, trieth
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable 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.
  • the present invention relates to (i) a compound of formula (I), wherein A 1 is CH or N; A 2 is CH or N; A 3 is CR 7 or N; wherein R 7 is H or halogen; A 4 is CH or N; A 5 is CH or N; R 1 is H or halogen; R 2 is C 1-6 alkyl; R 3 is H or C 1-6 alkoxy; R 4 is C1-6alkyl; R 5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC 1-6 alkylcarbonyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC 1-6 alkyl, 3,3-dio
  • Another embodiment of present invention is (ii) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein R 5 is (cyanoC 3-7 cycloalkyl)C 1-6 alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]dodeca-2(6),3-dienyl substituted by C 1-6 alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]dodeca-2,5-dienyl substituted by C1-6alkyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC 1-6 al
  • Another embodiment of present invention is (iii) a compound of formula (Ia) according to (i) or (ii), wherein A 1 is CH or N; A 2 is CH or N; A 3 is CR 7 or N; wherein R 7 is H or halogen; A 4 is CH or N; A 5 is CH or N; R 1 is H or halogen; R 2 is C 1-6 alkyl; R 3 is H or C1-6alkoxy; R 4 is C1-6alkyl; R 5 is (cyanoC 3-7 cycloalkyl)C 1-6 alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]dodeca-2(6),3-dienyl substituted by C1-6alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.0 2,6 ]
  • a further embodiment of present invention is (iv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (iii), wherein A 3 is CH.
  • a further embodiment of present invention is (v) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (iii), wherein R 1 is H or fluoro.
  • a further embodiment of present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (v), wherein R 2 is methyl.
  • a further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), wherein R 3 is H, methoxy or ethoxy.
  • a further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R 4 is methyl.
  • a further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein R 5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C 3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3 ⁇ 6-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.0 2,6 ]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkylpyrazolyl, thiazolylcarbonyl, 1,3,4-
  • a further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R 5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by 2,2-difluoroethyl, 2-cyanoethyl, 2- fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxetan-3-yl or tetrahydropyran-4-yl, 3,3-dioxo-3 ⁇ 6-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.0 2,6 ]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by 1-methylpyra
  • a further embodiment of present invention is (xi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R 5 is 2-oxo- 3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-2-oxo-3,
  • a further embodiment of present invention is (xii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein R 6 is phenyl twice substituted by halogen.
  • a further embodiment of present invention is (xiii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein R 6 is phenyl twice substituted by fluoro.
  • a further embodiment of present invention is (xiv) a compound of formula (I) or (Ia),, according to any one of (i) to (xiii), wherein R 6 is 2,4-difluorophenyl.
  • a further embodiment of present invention is (xv) a compound of formula (I) or (Ia), according to any one of (i) to (xiv), wherein A 1 is CH or N; A 2 is CH or N; A 3 is CH; A 4 is CH or N; A 5 is CH or N; R 1 is H or halogen; R 2 is C1-6alkyl; R 3 is H or C 1-6 alkoxy; R 4 is C 1-6 alkyl; R 5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3 ⁇ 6-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triaza
  • a further embodiment of present invention is (xvi) a compound of formula (I) or (Ia), according to any one of (i) to (xv), wherein A 1 is CH or N; A 2 is CH or N; A 3 is CH; A 4 is CH or N; A 5 is CH or N; R 1 is H or fluoro; R 2 is methyl; R 3 is H, methoxy or ethoxy; R 4 is methyl; R 5 is 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]hept
  • Another embodiment of present invention (xvii) is a compound of formula (I) or (Ia), selected from the following: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidin-1-yl)ethyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydr
  • Another embodiment of present invention (xix) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for use as therapeutically active substance.
  • Another embodiment of present invention (xx) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xvii) and a pharmaceutically acceptable excipient.
  • Another embodiment of present invention (xxi) is related to the use of a compound according to any one of (i) to (xvii) 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 is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) 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 is related to the use of a compound according to any one of (i) to (xvii) 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 is related to the use of a compound according to any one of (i) to (xvii) 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-Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney disease
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • ANCA Anti-Neutrophilic Cytoplasmic Autoantibodies
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xvii) 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- Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney disease
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • ANCA Anti-Neutrophilic Cyto
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xvii) for the inhibition of STING.
  • Another embodiment of present invention is related to the use of a compound according to any one of (i) to (xvii) for the preparation of a medicament for the inhibition of STING.
  • Another embodiment of present invention is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii), when manufactured according to a process of (xviii).
  • Another embodiment of present invention (xxix) 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 (xvii).
  • 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.
  • 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.
  • 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.
  • a compound of formula (I) is formulated in an acetate buffer, at pH 5.
  • 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).
  • cytokine e.g. IL-6, TNFa, ISGs
  • cellular responses/conditions e.g. autophagy, apoptosis, cell senescence.
  • such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • 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.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • 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
  • 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.
  • An embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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- Goutines Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome.
  • SLE systemic lupus erythematosus
  • DKD diabetic kidney
  • 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.
  • compounds of the invention are useful for the treatment or prophylaxis of autoimmune diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of inflammatory diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of neurological disorders diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of cardiovascular diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of ocular diseases.
  • compounds of the invention are useful for the treatment or prophylaxis of selective types of cancers where overexpression or activation of STING is implicated.
  • 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.
  • 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.
  • a coupling reagent such as HATU
  • DIPEA a base
  • Boc deprotection in acidic condition HCl in dioxane or TFA in DCM
  • Cbz deprotection by catalytic hydrogenation Pd/C or Pd(OH)2/C under H2
  • TFA acidic condition
  • TFA acidic condition
  • This invention also relates to a process for the preparation of a compound of formula (I) comprising any one of the following steps: a) the formation of compound of formula (I) via nucleophilic substitution or Buchwald cross coupling between compound of formula (VIII), (VIII), and HR 5 ; b) the formation of compound of formula (I) via nucleophilic substitution reaction between compound of (IX), (IX), and halide or acid anhydride; or condensation reaction between compound of formula (IX) and acid; or reductive amination between compound of formula (IX) and ketone or aldehyde; the formation of compound of formula (I) via condensation reaction between compound of formula (VII), compound of formula (VIIb), reagent; wherein the coupling reagent in step c) can be, for example, PyBOP; X is halogen; HR a is heterocyclyl with reactive primary or secondary amino group.
  • a compound of formula (I) or (Ia) when manufactured according to the above process is also an object of the invention.
  • EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
  • 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).
  • LC/MS spectra of compounds were obtained using a LC/MS (Waters TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H 2 O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH 3 ⁇ H 2 O in H 2 O; B: acetonitrile; Basic condition II: A: 0.025% NH3 ⁇ H2O in H2O; B: acetonitrile; Neutral condition: A: H 2 O; B: acetonitrile.
  • Mass spectra 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.
  • Step 1 preparation of tert-butyl N-[(2R)-3-(2-bromo-4-fluoro-6-nitro-anilino)-2- hydroxy-propyl]carbamate (compound A1-b) To a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxy-propyl]carbamate (59.6 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitro-benzene (compound A1-a, 71.0 g, 298.33 mmol) in ACN (710 mL) was added potassium carbonate (82.4 g, 596.66 mmol).
  • Step 2 preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoro-anilino)-2- hydroxy-propyl]carbamate (compound A1-c) To a solution of compound A1-b (63.0 g, 154.33 mmol) in methanol (1000 mL) was added Raney Ni (36.2 g, 617.31 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol).
  • Step 3 preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]carbamate (compound A1-d)
  • compound A1-c 123.0 g, 325.19 mmol
  • trimethyl orthoacetate 136.7 mL, 1104 mmol
  • pyridinium p-toluenesulfonate (11.7 g, 46.62 mmol.
  • the reaction was stirred for 1 hr at 20 °C.
  • the mixture was concentrated under reduced pressure to give compound A1-d (160 g).
  • Step 5 preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate (compound A1-f)
  • DMF 800 mL
  • sodium hydride 60% in oil, 15.8 g, 396.89 mmol
  • Step 6 preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]-N-methyl-carbamate (compound A1-g)
  • a mixture of compound A1-f (39.8 g, 75.02 mmol) and TBAF/THF (1M, 150.0 mL, 150 mmol) was stirred at 20 °C for 2 hrs. The mixture was concentrated and the residue was diluted with EtOAc (600mL), washed with water and brine. The organic layer was dried and concentrated to give compound A1-g (39.4 g).
  • LCMS(M+H) + 416.
  • Step 7 preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound A1-h)
  • compound A1-g 17.4 g, 41.8 mmol
  • iodoethane 5.0 mL, 62.7 mmol
  • DMF 174 mL
  • sodium hydride 2.2 g, 55.0 mmol
  • Step 8 preparation of tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate (Intermediate A1) To a mixture of compound A1-h (19.4 g, 43.66 mmol) and bis(pinacolato)diboron (27.72 g, 109.15 mmol) in DMSO (194 mL) was added potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.55 mmol) and butyldi-1- adamantylphospine (4.7
  • Step 2 preparation of tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (Intermediate A2)
  • the title compound was prepared in analogy to the preparation of intermediate A1 via using compound A2-a instead of compound A1-h in step 8.
  • the compound A3-a was prepared in analogy to the preparation of compound A1-d via using tert-butyl N-(3-aminopropyl)carbamate instead of tert-butyl N-[(2R)-3-amino-2-hydroxy- propyl]carbamate in step 1.
  • LCMS (M+H) + 386.
  • the compound A4-a was prepared in analogy to the preparation of compound A1-d by using tert-butyl N-[(2S)-3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3- amino-2-hydroxy-propyl]carbamate in step 1.
  • LCMS (M+H) + 402.
  • 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 C1-b)
  • compound C1-a 6.8 g, 9.65 mmol
  • 2 M LiOH (aq.) (20 mL, 40 mmol) was added dropwise.
  • the final mixture was stirred at r.t.
  • Step 3 preparation of benzyl (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound C1-c) To a solution of HATU (4.57 g, 12.02 mmol,) and DIEA (10.5 mL, 60.1 mmol) in acetonitrile (1200 mL) was added another solution of compound C1-b (4.92 g, 6.01 mmol) in acetonitrile (1200 mL) dropwise in 4 hrs.
  • Step 4 preparation of (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Intermediate C1) To the flask containing compound C1-c (3.5 g, 6.11 mmol) was added TFA (30 mL).
  • Step 1 preparation of 2-[(2S)-3-[benzyl(methyl)amino]-2-hydroxy-propyl]isoindoline- 1,3-dione (compound C8-b)
  • compound C8-a 3-(benzyl(methyl)amino]-2-hydroxy-propyl]isoindoline- 1,3-dione
  • N- methylbenzylamine 23 mL, 177 mmol
  • Step 2 preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy- propyl]-N-methyl-carbamate (compound C8-c)
  • compound C8-c To a solution of compound C8-b (30.0 g, 92.49 mmol) and di-t-butyldicarbonate (30.28 g, 138.74 mmol) in methanol (667 mL) was added wet Pd(OH)2/C(15.0 g, 10%) under N2 at 20 °C. The reaction was stirred under 50 psi of H 2 at 40 °C for 12 h.
  • Step 3 preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-methoxy- propyl]-N-methyl-carbamate (compound C8-d) To a solution of NaH (5.8 g, 145 mmol) in dry DMF (220 mL) was added iodomethane (55 g, 387 mmol) at 0 °C under N 2 .
  • Step 4 preparation of tert-butyl N-[(2R)-3-amino-2-methoxy-propyl]-N-methyl- carbamate (compound C8-e)
  • methylamine/ethanol 557.97 g, 6.1 mol
  • the reaction was stirred at 60°C for 2 h. Then the reaction mixture was filtered and the filtrate was concentrated to give compound C8-e (80.0 g).
  • Step 5 preparation of tert-butyl N-[(2R)-3-[(2-bromo-4-nitro-3-pyridyl)amino]-2- methoxy-propyl]-N-methyl-carbamate (compound C8-f)
  • the mixture of 2-bromo-3-fluoro-4-nitro-pyridine (20.0 g, 90.51 mmol), compound C8-e (29.2 g, 133.77 mmol) and K 2 CO 3 (25.0 g, 180.9 mmol) in ACN (200 mL) was stirred at 50 °C for 2 h.
  • the reaction mixture was filtered and the filtrate was concentrated to give compound C8-f (120.0 g, four batches workup together).
  • Step 7 preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methyl-imidazo[4,5-c]pyridin- 3-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound C8-h)
  • compound C8-g 50.0 g, 123.97 mmol
  • trimethyl orthoacetate 56 mL, 417 mmol
  • pyridinium p-toluenesulfonate 5.0 g, 19.9 mmol
  • Step 6 ⁇ 11 preparation of (8S,11S,15R)-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Intermediate C11)
  • Intermediate C11 was prepared in analogy to the preparation of intermediate C8 by using compound C11-e instead of compound C8-h.
  • Step 1 preparation of (3,5-difluoro-2-pyridyl)hydrazine (compound D2-b) A mixture of compound D2-a (5.0 g, 37.57 mmol) and hydrazine hydrate (18.63 mL, 375.72 mmol) in ethanol (50 mL) was stirred at 65 °C for 16 h.
  • Step 2 preparation of 3,5-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5- yl)methyleneamino]pyridin-2-amine (compound D2-c) To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.0 g, 14.19 mmol) in DMF (30 mL) was added compound D2-b (2.0 g, 13.78 mmol) and then it was stirred at 25 °C for 2 h.
  • Step 3 preparation of 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4- d]pyrimidine (Intermediate D2)
  • a solution of compound D2-c (3.5 g, 10.34 mmol) in 1,4-dioxane (35 mL) was stirred at 120 °C for 4 h.
  • the reaction mixture poured into ice water and EA.
  • Step 2 ⁇ 3 preparation of 4, 6-dichloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3, 4-d] pyrimidine(Intermediate D3)
  • the title compound was prepared in analogy to the preparation of intermediate D2 by using compound D3-b instead of compound D2-b.
  • Step 1 preparation of (3-fluoro-4-pyridyl)hydrazine (compound D4-b) To a solution of compound D4-a (1.0 g, 7.6 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (9.71 mL, 195.77 mmol) at 0 °C. The reaction was stirred at 100 °C for 16 h. Then the reaction was diluted with water and extracted with EtOAc.
  • Step 2 preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carbonitrile (compound D4-d)
  • a mixture of compound D4-b (700.0 mg, 5.51 mmol), compound D4-c (672 mg, 5.51 mmol) and DIEA (2.9 mL, 16.52 mmol) in ethanol (12 mL) was heated to 80 °C for 2 h. Then the reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give compound D4-d (1 g) as a light brown solid.
  • Step 3 preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carboxamide (compound D4-e)
  • a solution of compound D4-d (1 g, 4.92 mmol) in sulfuric acid (6.0 mL) was stirred at 25 °C for 2 h. Then the mixture was poured into 50 mL ice-cold water and adjusted pH to 8, the aqueous phase was freeze-dried to give the crude product, which was dissolved in 50 mL of DCM/CH 3 OH (10:1).
  • Step 4 preparation of 1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4,6-diol (compound D4-f)
  • a mixture of compound D4-e (1 g, 4.52 mmol) and urea (13.6 g, 226.05 mmol) was stirred at 200 °C for 16 h.
  • the reaction mixture was cooled to 25 °C and then water (100 mL) was added.
  • Step 5 preparation of 4,6-dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine (Intermediate D4) To a solution of compound D4-f (140.0 mg, 0.57 mmol) in phosphorus oxychloride (3.0 mL) was added phosphorus pentachloride (590 mg, 2.83 mmol). The reaction was stirred at 80 °C for 16 h.
  • Step 1 ⁇ 3 preparation of 4, 6-dichloro-1-(2-fluoro-4-iodo-phenyl)pyrazolo [3,4- d]pyrimidine (compound D5-d)
  • Compound D5-d was prepared in analogy to the preparation of intermediate D3 by using compound D5-a instead of compound D3-a.
  • Step 4 preparation of 4-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoro- benzonitrile (Intermediate D5)
  • D5-d 400.0 mg, 0.98 mmol
  • DMF 3 mL
  • Step 2 preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-b)
  • a mixture of compound D9-a (1.30 g, 5.75 mmol) in 4 M HCl in dioxane (15.0 mL,) was stirred at 25 °C for 2 h.
  • the reaction was concentrated.
  • the residue was lyophilized to give compound D9-b (800 mg) as a yellow oil.
  • Step 3 preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-c)
  • a stirred mixture of compound D9-b (800 mg, 6.34 mmol), compound D15-a (1.18 g, 3.17 mmol) and DIPEA (2.50 g, 19.3 mmol) in ACN (10.0 mL) was stirred at 80 °C for 48 h. The reaction was concentrated and the residue was purified by silica gel column chromatography to give compound D9-c (1.20 g) as a yellow oil.
  • Step 1 preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound D15-a)
  • Step 2 preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound D15-b)
  • compound D15-a 1.25 g, 3.35 mmol
  • tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate 731 mg, 3.69 mmol
  • DMSO 20 mL
  • N,N-diisopropylethylamine (1.75 mL, 10 mmol
  • Step 2 preparation of tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylate (Intermediate D16) and tert-butyl 3-[4- benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1- carboxylate (Intermediate D17) To a solution of compound D16-b (800.0 mg, 1.58 mmol) in DCM (15 mL) was added ruthenium(IV) oxide (209 mg, 1.58 mmol) and a solution of sodium periodate (1.35 g, 6.31 mmol) in water (15 mL).
  • Step 2 preparation of 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]propanenitrile (Intermediate D18)
  • TFA 0.5 mL
  • the reaction was stirred at 40 °C for 1 hr under nitrogen, and then the mixture was concentrated, the residue was purified by prep-HPLC to afford Intermediate D18 (18.0 mg) as a white solid.
  • the vial was sealed and placed under nitrogen.
  • the reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away) with a cooling fan to keep the reaction temperature at 25 °C for 14 hr.
  • the reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by silica gel column chromatography to give compound D19-b (0.4 g) as a yellow solid.
  • Step 2 preparation of trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]cyclobutanecarbonitrile (intermediated D20) and cis-3-[1-(2,4- difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarbonitrile (intermediated D21)
  • D20-b1 100.0 mg, 0.24 mmol
  • Step 2 preparation of 1-[[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile (compound D22-c)
  • compound D15-a (300.0 mg, 0.8 mmol)
  • compound D22-b (267 mg, 1.29 mmol)
  • Ir[dF(CF 3 )ppy] 2 (dtbpy)(PF 6 ) (9 mg, 0.01 mmol)
  • NiCl2.dtbbpy 1.6 mg
  • tris(trimethylsilyl)silane (0.25 mL, 0.8 mmol
  • sodium carbonate (170 mg, 1.61 mmol) in DMA (6 mL).
  • Step 3 preparation of 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile (Intermediate D22)
  • TFA 1.0 mL
  • the reaction was stirred at 40 °C for 1 hr and then concentrated, the residue was purified by prep-HPLC to afford Intermediate D22 (55.0 mg) as a yellow oil.
  • Step 1 preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6- diazabicyclo [3.1.1]heptane-3-carboxylate (compound F1-b) A solution of Intermediate E1 (1 g, 1.42 mmol), compound F1-a (1.4 g, 7.11 mmol), CsF (1.08 g, 7.11 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.
  • Example 1 (3 mg) as a white powder.
  • Example 2 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H- [1,2,4]triazolo[4,3-a]pyrazin-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme: To a tube was added intermediate E1 (30 mg, 42.67 ⁇ mol), DIEA (27 mg, 37 ⁇ L, 213.3 ⁇ mol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,
  • Example 2 8 mg as a white powder.
  • Example 3 and Example 4 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2- difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1
  • Step 2 preparation of 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 3b)
  • TFA 1.48 g, 1 mL, 12.98 mmol, 179.308 eq
  • dichloromethane 1 mL
  • the solution was stirred at r.t. for 1 hr and concentrated to give compound 3b (37 mg) as a crude oil, which was used directly in the next step.
  • LCMS (M+H) + 177.
  • Step 3 preparation of (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1
  • Example 3 (2 mg, faster eluted) and Example 4 (2 mg, slower eluted) as white powders.
  • Example 5 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 5 was prepared in analogy to the preparation of Example 1 by using 2- (chloromethyl)thiazole instead of 1-(2-chloroethyl)-2-pyrrolidone in step 1.
  • Example 5 (5 mg) was obtained as a white solid.
  • Example 6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-
  • Example 6 was prepared in analogy to the preparation of Example 34 by using 2- oxaspiro[3.3]heptane-6-carboxylic acid instead of oxetane-2-carboxylic acid.
  • Example 6 (12 mg) was obtained as a white solid.
  • Example 7 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme: To a tube was added intermediate F1 (30 mg, 34.1 ⁇ mol), 1H-pyrazole-5-carbaldehyde (10 mg, 102.41 ⁇ mol), DIEA (13 mg, 18 ⁇ L, 102.4 ⁇ mol) and ethanol (2 mL
  • Example 7 (11 mg) as a white powder.
  • Example 8 and Example 9 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]
  • Example 8a Example 8 (42 mg, faster eluted) and Example 9 (50 mg, slower eluted) as a white powder.
  • Example 10 and Example 11 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4
  • Example 10 (16 mg, faster eluted) and Example 11 (15 mg, slower eluted) as a white powder.
  • SFC condition Instrument: SFC 80; Column: OD 250 ⁇ 30 mm I.D., 5 ⁇ m.; Mobile phase: A for CO 2 and B for Methanol «Mobile_phasePrep»; Gradient: B 30%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C).
  • Example 12 and Example 13 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,
  • Example 12 41 mg, faster eluted
  • Example 13 37 mg, slower eluted
  • Example 14 and Example 15 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophen
  • Example 14 17.1 mg, faster eluted
  • Example 15 (20 mg, slower eluted) as a white solid.
  • SFC condition Instrument: SFC 80; Column: OD 250 ⁇ 30 mm I.D., 5 ⁇ m.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C).
  • Example 16 and Example 17 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimi
  • Example 16 22 mg, faster eluted
  • Example 17 24 mg, slower eluted
  • Example 18 and Example 19 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2- difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(
  • Example 18 17.25 mg, faster eluted and Example 19 (18 mg, slower eluted) as a white powder.
  • Example 20 and Example 21 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo
  • Example 20 26 mg, faster eluted
  • Example 21 (19 mg, slower eluted) as a white powder.
  • Example 22 and Example 23 3-[(1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile and 3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,
  • Example 22 (19 mg, faster eluted) and Example 23 (19 mg, slower eluted) as a white powder.
  • Example 24 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (compound 24b)
  • the flask contained compound 24a (20 mg, 94.67 ⁇ mol) was cooled with dry ice/ethanol bath and methylmagnesium bromide (1 M
  • Step 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3- methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 24) To a tube was added intermediate E1 (40 mg, 56.89 ⁇ mol), DIEA (44 mg, 60 ⁇ L, 343.55 ⁇ mol
  • Example 24 (25 mg) as a white powder.
  • Example 26 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 26 was prepared in analogy to the preparation of Example 3 by using compound 3-fluoro-3-(iodomethyl)oxetane instead of 2,2-difluoroethyl trifluoromethanesulfonate.
  • Example 27 and Example 28 (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5
  • Example 27 14 mg, faster eluted
  • Example 28 11 mg, slower eluted
  • SFC condition Instrument: SFC 80; Column: Ethyl pyridine II 250 ⁇ 30 mm I.D., 5 ⁇ m; Mobile phase: A for CO2 and B for IPA «Mobile_phasePrep»; Gradient: B 25%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C).
  • Example 29 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidin-3- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme:
  • Step 1 preparation of 4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]pyrrolidin-2-one (compound 29a)
  • TFA 2 mL
  • the reaction mixture was stirred at 25 °C for 2 h and then concentrated to give compound 29a (100.0 mg) as light yellow oil, which was used directly without further purification.
  • LCMS M+H +
  • Step 2 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(5-oxopyrrolidin-3- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29b) To a solution of compound 29a (100.0 mg, 0.3 mmol), PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) was added DIEA (0.03 mL, 0.15 mmol) at 25 °C.
  • Step 3 preparation of (8S,11S,15R)-10-[6-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- oxo-pyrrolidin-3-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7,10,13,17,19,26 hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ] hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 29d) To a solution of compound 29b (50.0 mg, 0.07 mmol) in DMF (1 mL) was added NaH (5 mg, 0.2 mmol) at 0 °C under N 2 .
  • Step 4 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)- 5-oxo-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 29) To a solution of compound 29d (25.0 mg, 0.03 mmol) in THF (1 mL) was added TBAF in THF (0.05 mL, 0.07 mmol) at 0 °C.
  • Example 29 (8.0 mg) as a light yellow solid.
  • Example 30 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidin-3- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 30 was prepared in analogy to the preparation of Example 29 by using Intermediate D17 instead of Intermediate D16.
  • Example 30 (2.8 mg) as a white solid.
  • Example 31 6-[1-(2,4-difluorophenyl)-4-[ (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5, 18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-carboxamide
  • the title compound was prepared according to the following scheme: To a solution of Intermediate F1 (40.0 mg, 0.05 mmol), TEA (60.0 mg, 0.59 mmol) in DCM (1 mL) was added dimethylcarbamyl chloride (0.01 mL, 0.05 mmol) at 0 °C
  • Example 32 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5, 18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-sulfonamide
  • Example 32 was prepared in analogy to the preparation of Example 31 by using dimethylsulfamoylchloride instead of dimethylcarbamyl chloride.
  • Example 32 (25 mg) was obtained as a white solid.
  • Example 33 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one
  • Example 33 was prepared in analogy to the preparation of Example 31 by using methoxyacetyl chloride instead of dimethylcarbamyl chloride.
  • Example 33 (25 mg) was obtained as a white solid.
  • Example 34 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one
  • the title compound was prepared according to the following scheme: To a solution of Intermediate F1 (40.0 mg, 0.05 mmol), HATU (21 mg, 0.05 mmol), DIEA (0.03 mL, 0.18 mmol) in MeCN (0.5 mL) was added a mixture of oxetane
  • Example 35 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one
  • Example 35 was prepared in analogy to the preparation of Example 34 by using oxetane-3- carboxylic acid instead of oxetane-2-carboxylic acid.
  • Example 35 (18 mg) was obtained as a white solid.
  • 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.34 - 8.27 (m, 1H), 7.87 - 7.79 (m, 1H), 7.66 - 7.59 (m, 1H), 7.35 - 7.24 (m, 2H), 7.22 - 7.08 (m, 3H), 6.75 - 6.65 (m, 1H), 5.95 - 5.65 (m, 1H), 5.44 - 5.30 (m, 1H), 4.71 - 4.57 (m, 2H), 4.54 - 4.39 (m, 2H), 4.34 - 4.19 (m, 5H), 4.16 - 4.07 (m, 1H), 4.02 (s, 1H), 3.52 - 3.36 (m, 2H), 3.22 - 3.10 (m, 2H), 3.09 - 3.03 (m, 3H), 3.00 (s, 1H), 2.91 - 2.81 (m
  • Example 36 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo [3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-12-one
  • Example 36 was prepared in analogy to the preparation of Example 34 by using methanesulfonylacetic acid instead of oxetane-2-carboxylic acid.
  • Example 36 (15 mg) was obtained as a white solid.
  • Example 37 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3- carboxamide
  • Example 37 was prepared in analogy to the preparation of Example 31 by using methylaminoformyl chloride instead of dimethylcarbamyl chloride.
  • Example 37 (28 mg) was obtained as a white solid.
  • Example 38 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one
  • Example 38 was prepared in analogy to the preparation of Example 34 by using 2-(oxetan- 3-yl)acetic acid instead of oxetane-2-carboxylic acid.
  • Example 38 (13 mg) was obtained as a white solid.
  • Example 39 (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl - 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-12-one
  • Example 39 was prepared in analogy to the preparation of Example 34 by using 2- (difluoromethoxy)acetic acid instead of oxetane-2-carboxylic acid.
  • Example 39 (14 mg) was obtained as a white solid.
  • Example 40 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1] heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10, 2,6 8,11 20,24 13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-12-one
  • Example 40 was prepared in analogy to the preparation of Example 31 by using methanesulfonic anhydride instead of dimethylcarbamyl chloride.
  • Example 40 (24 mg) was obtained as a white solid.
  • Example 42 (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl (2S)-2-(iodomethyl) morpholine-4-carboxylate (compound 42b)
  • triphenylphosphine (16.42 g, 62.61 mmol)
  • 1H-imidazole 4
  • Step 2 preparation of O1-tert-butyl O2-methyl 2-(3-benzyloxypropyl) azetidine-1, 2- dicarboxylate (compound 42d)
  • a solution of LDA 14 mL, 28 mmol
  • THF 50 mL
  • a solution of compound 42c 5.0 g, 23 mmol
  • N- [bis(dimethylamino)phosphoryl]-N-methylmethanamine (8.33 g, 46.46 mmol) was added.
  • Step 3 preparation of O1-tert-butyl O2-methyl 2-(3-hydroxypropyl) azetidine-1, 2- dicarboxylate (compound 42e)
  • a mixture of compound 42d (1.0 g, 2.75 mmol) and Pd(OH) 2 /C(300 mg) in methanol (15 mL) was stirred at 40 °C for 16 h under the H2 (45 psi). Then the mixture was filtered and the filtrate was concentrated to give compound 42e (700.0 mg) as light brown oil.
  • Step 4 preparation of O1-tert-butyl O2-methyl 2-(3-oxopropyl) azetidine-1, 2- dicarboxylate (compound 42f)
  • DCM DCM
  • Dess- Martin periodinane 1303 mg, 3.07 mmol
  • the reaction was stirred at 20 °C for 2 h, then the reaction was quenched with saturated sodium bicarbonate solution, and extracted with DCM. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography to give compound 42f (500.0 mg) as colorless oil.
  • Step 5 preparation of O1-tert-butyl O2-methyl 2-[3-[benzyl (methyl) amino] propyl] azetidine-1, 2-dicarboxylate (compound 42g)
  • compound 42f 500.0 mg, 1.84 mmol
  • N-methylbenzylamine 670 mg, 5.53 mmol
  • sodium cyanoborohydride 231 mg, 3.69 mmol
  • the reaction was stirred at 20 °C for 2 h, then the reaction was quenched with water, and extracted with EtOAc.
  • Step 7 preparation of tert-butyl 8-methyl-9-oxo-1, 8-diazaspiro [3.5] nonane-1- carboxylate (compound 42i) To a solution of compound 42h (75.0 mg, 0.26 mmol) in THF (10 mL) was added TBD (18 mg, 0.13 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction solvent was concentrated and the residue was purified by silica gel column chromatography to give compound 42i (30.0 mg) as colorless oil.
  • Step 8 preparation of 8-methyl-1, 8-diazaspiro [3.5] nonan-9-one (compound 42j) To a solution of compound 42i (15.0 mg, 0.06 mmol) in DCM (0.5 mL) was added TFA (0.2 mL) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 42j (15 mg) as light brown oil, which was used in next step directly.
  • Step 9 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8- diazaspiro[3.5]nonan -1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26 -hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 42)
  • a solution of Intermediate E1 (20.0 mg, 0.03 mmol), compound 42g (15 mg, 0.06 mmol), CsF (21 mg, 0.14 mmol) and DIEA (0.05 mL, 0.28 mmol) in DMA (0.3 mL) was stirred at 120 °C for 12
  • Example 42 10 mg as a white solid.
  • Example 43 (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-(2-methoxyacetyl) azetidine-1-carboxylate (compound 43b)
  • LDA 13 mL, 26 m
  • Step 3 preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-carbamoyl-azetidine- 1-carboxylate (compound 43d)
  • DIPEA 1.8 g, 13.8 mmol
  • ammonium chloride 5.5 g, 10.3 mmol
  • HATU 1.5 g, 3.8 mmol
  • Step 5 preparation of tert-butyl 6-oxo-1, 7-diazaspiro [3.4] octane-1-carboxylate (compound 43f) To a solution of compound 43e (400.0 mg, 1.21 mmol) in methanol (17 mL) was added CoCl2 ⁇ 6H2O (216 mg, 0.91 mmol) and NaBH4 (460 mg, 12.11 mmol) at - 40 °C. After being stirred at -30 °C for 2 hrs, the reaction mixture was quenched with water and then filtered.
  • Step 6 preparation of tert-butyl 7-methyl-6-oxo-1, 7-diazaspiro [3.4] octane-1- carboxylate (compound 43g) To a mixture of compound 43f (50.0 mg, 0.22 mmol) and sodium hydroxide (22 mg, 0.33 mmol) in DMF (1 mL) was added iodomethane (38 mg, 0.27 mmol) at -10 °C and then stirred for 0.5 h.
  • Step 7 preparation of 7-methyl-1, 7-diazaspiro [3.4] octan-6-one (compound 43h) To a solution of compound 43g (13.0 mg, 0.05 mmol) in DCM (0.6 mL) was added TFA (0.5 mL, 0.02 mmol) at 0 ° C. The reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give compound 43h (13.0 mg) as light brown oil, which was used for next step directly.
  • Step 8 preparation of (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo- 1,7-diazaspiro[3.4] octan-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17, 19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 43) A mixture of Intermediate E1 (10 mg, 0.01 mmol), compound 43h (11 mg, 0.04 mmol), DIEA (18 mg, 0.14 mmol) and CsF (11 mg, 0.07 mmol) in DMA (0.2 mL) was stirred at 120 °C for 16 h.
  • Example 44 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]acetonitrile
  • Step 1 preparation of [3-(hydroxymethyl)oxetan-3-yl]methyl acetate (compound 44b) To a solution of compound 44a (3 g, 25.4 mmol), TEA (11 mL, 76.3 mmol) and DMAP (310 mg, 2.54 mmol) in THF
  • Step 2 preparation of 3-(acetoxymethyl)oxetane-3-carboxylic acid (compound 44c) To a solution of compound 44b (1 g, 6.24 mmol) in DCM (12 mL) and water (4 mL) was added (diacetoxyiodo)benzene (4 g, 12.5 mmol) and TEMPO (147 mg, 0.94 mmol) at 0 °C.
  • Step 3 preparation of [3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44d)
  • Intermediate D15-a 100.0 mg, 0.27 mmol
  • compound 44c 117 mg, 0.67 mmol
  • NiCl2(dtbbpy) 11 mg, 0.03 mmol
  • Cs 2 CO 3 (262 mg, 0.8 mmol
  • Step 4 preparation of [3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44e)
  • Pd/C 30 mg
  • the reaction mixture was stirred at 25 °C for 2 h under the H2 (balloon), then it was filtered and the filtrate was concentrated to give compound 44e (20.0 mg) as colorless oil.
  • Step 5 preparation of [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44f) To a solution of compound 44e (20.0 mg, 0.05 mmol), PyBOP (41 mg, 0.08 mmol) in DMF (0.2 mL) was added DIEA (0.02 mL, 0.13 mmol) at 25 °C.
  • Step 6 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3- (hydroxymethyl)oxetan-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 44g) To a solution of compound 44f (10.0 mg, 0.01 mmol) in methanol (0.5 mL) was added NaOH (0.5 mL, 0.05 mmol) at 0 °C.
  • Step 7 preparation of [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]methyl ethanesulfonate (compound 44h) To a solution of TEA (16 mg, 0.16 mmol) and compound 44g (40.0 mg, 0.05 mmol) in DCM (0.5 mL) was added ethanesulfonyl chloride (13.36 mg, 0.1 mmol) at 0 °C.
  • Example 45 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Step 1 preparation of ethyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 45b)
  • DMF 2 mL
  • Step 2 preparation of 1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 45c) To a solution of compound 45b (150.0 mg, 0.88 mmol) in THF (0.5 mL) and ethanol (0.5 mL) was added a solution of LiOH ⁇ H2O (184 mg, 4.38 mmol) in water (0.5 mL) at 0 °C and then stirred at 10 °C for 1 h. The reaction mixture was acidified with HCl (12 M) to pH 2 ⁇ 3, extracted with EA, the organic layer was dried and concentrated to give compound 45c (20.0 mg) as yellow oil.
  • Step 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo- pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 45) To a solution of Intermediate F1 (50.0 mg, 0.06 mmol), compound 45c (8 mg, 0.06 mmol), HATU (43 mg, 0.11 mmol) and DIPEA (0.1 mL, 0.57 mmol) in DMF (1 m
  • Example 46 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
  • the title compound was prepared according to the following scheme:
  • Step 1 preparation of tert-butyl 3-pyrimidin-4-yl-3, 6-diazabicyclo [3.1.1]heptane-6- carboxylate (compound 46b)
  • a solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300.0 mg, 1.51 mmol), compound 46a (457 mg, 3.03 mmol), CsF (1914.0 mg, 7.56 mmol), DIEA (1170.0 mg, 9.05 mmol) in DMA (3 mL) was stirred at 120°C for 12 h.
  • the reaction mixture was poured into H2O, extracted with ethyl acetate.
  • Step 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl- 3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 46) To a solution of Intermediate E4 (40.0 mg, 0.06 mmol), compound 46c (85 mg, 0.29 mmol), CsF (44.0 mg, 0.29 mmol) in DMA (0.5 mL) was added DIEA (0.06 mL, 0.34 mmol).
  • Example 47 3-fluoro-4-[4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10-yl]-6- (3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-1- yl]benzonitrile
  • the title compound was prepared according to the following scheme:
  • Example 47 was prepared in analogy to the preparation of Example 46 by using compound 47b instead of compound 46a and intermediate E6 instead of intermediate E4.
  • Example 48 (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 48 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E7 instead of intermediate E4.
  • Example 49 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 49 was prepared in analogy to the preparation of Example 46 by using 2- iodooxazole instead of compound 46a and intermediate E1 instead of intermediate E4.
  • Example 50 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme: A mixture of Intermediate E1 (50.0 mg, 0.07 mmol), compound 50a (33 mg, 0.28 mmol), K3PO4 (38 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis
  • Example 51 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme: A solution of Intermediate E1 (30.0 mg, 0.04 mmol), compound 51a (22 mg, 0.21 mmol), CsF (32 mg, 0.21 mmol) and DIEA (0.07 mL, 0.43 mmol) in DMA (1 mL) was stirred at 120 °C for 12 h.
  • Example 52 methyl 6-[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]-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate
  • the title compound was prepared according to the following scheme: To a solution of Intermediate F1 (50.0 mg, 0.07 mmol), DIEA (0.06 mL, 0.33 mmol) in DCM (0.5 mL) was added compound 52a (90.0 mg, 0.95 mmol) in DCM (0.5 mL) at 0
  • Example 52 (12 mg) as a white solid.
  • Example 54 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 54 was prepared in analogy to the preparation of Example 53 by using 4-iodo-1- methyl-pyrazole instead of 3-iodo-1-methyl-pyrazole (53a).
  • Example 55 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile
  • the title compound was prepared according to the following scheme: To a solution of Intermediate D18 (40.0 mg, 0.13 mmol), PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) was added DIEA (0.03 mL, 0.15 mmol) at 25 °C.
  • Example 56 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Example 56 was prepared in analogy to the preparation of Example 55 by using intermediate D19 instead of intermediate D18 and intermediate C1 instead of intermediate C2.
  • Example 57 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl (1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 57b)
  • compound 60d (200.0 mg, 0.94 mmol)
  • Step 2 preparation of (1S,5R)-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 57c)
  • compound 57b 220.0 mg, 0.97 mmol
  • DCM 2 mL
  • TFA 2.0 mL
  • the reaction was concentrated to give compound 57c (200.0 mg) as light yellow oil.
  • Step 3 preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 57) To a solution of intermediated E5 (50.0 mg, 0.07 mmol), compound 57c (19 mg, 0.15 mmol), cesium fluoride (56 mg, 0.37 mmol) in DMA (1 mL) was added DIEA (0.1 mL, 0.74 mmol) and then stirred at
  • Example 59 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
  • the title compound was prepared according to the following scheme: To a solution of Intermediate F2 (50.0 mg, 0.06 mmol), TBD (24 mg, 0.17 mmol) in THF (0.500 mL) was added methyl thiazole-2-carboxylate (12 mg, 0.09 mmol) at 0° C.
  • Example 60 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 60d)
  • the compound 60c (2.5 g, 11.
  • Step 2 preparation of (1R,5S)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 60e)
  • compound 60d 400.0 mg, 1.88 mmol
  • DCM 4 mL
  • TFA 4.0 mL
  • the reaction was stirred at 25 °C for 1 hr under N2 atmosphere.
  • the mixture was concentrated to give compound 60e (560.0 mg) as colorless oil, which was used directly without further purification.
  • Step 3 preparation of benzyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 60f)
  • compound 60e 560.0 mg, 2.48 mmol
  • sodium carbonate 315 mg, 2.97 mmol
  • THF 5 mL
  • water 5 mL
  • N-(benzyloxycarbonyloxy)succinimide 740 mg, 2.97 mmol
  • the reaction mixture was stirred at 20 °C for 16 h, and then the mixture was purified by prep-HPLC to give compound 60f (410.0 mg) as colorless oil.
  • Step 4 preparation of benzyl (1R,5S)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 60g)
  • sodium hydride 32 mg, 0.81 mmol
  • the reaction was stirred for 0.5 h at 0 °C, and then compound 60b (120 mg, 0.61 mmol) was added. After being stirred for 2 h at 25 °C, the reaction mixture was poured into ice water and extracted with EA.
  • Step 5 preparation of (1S,5R)-3-(oxetan-3-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-2- one (compound 60h) To a solution of compound 60g (150.0 mg, 0.47 mmol) in methanol (3 mL) was added wet Pd/C (30.0 mg) under N 2 at 25 °C.
  • Step 6 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan- 3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 60) A mixture of intermediate E4 (40.0
  • Example 61 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme:
  • Example 61 was prepared in analogy to the preparation of Example 60 by using 3- bromooxetane instead of compound 60b.
  • Example 62 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl 9-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,
  • Step 2 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 62b) To a solution of compound 62a (100 mg, 0.11 mmol) in DCM (1 mL) was added TFA (0.5 mL) at 0
  • Example 63 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 63 was prepared in analogy to the preparation of Example 53 by using 2-bromo- 1,3,4-thiadiazole instead of 3-iodo-1-methyl-pyrazole (53a).
  • Example 64 (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one
  • Example 64 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E8 instead of intermediate E4.
  • Example 65 Trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile
  • Example 65 was prepared in analogy to the preparation of Example 55 by using intermediate D20 instead of intermediate D18 and intermediate C8 instead of intermediate C2.
  • Example 66 Cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-
  • Example 66 was prepared in analogy to the preparation of Example 55 by using intermediate D21 instead of intermediate D18 and intermediate C8 instead of intermediate C2.
  • Example 67 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • the title compound was prepared according to the following scheme: To a solution of intermediated E1 (50.0 mg, 0.07 mmol), compound 67a (60 mg, 0.36 mmol), cesium fluoride (54 mg, 0.36 mmol) in DMA (1 mL) was added N,N- diisopropylethylamine (0.1 mL, 0.43 mmol)
  • Example 68 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 68 was prepared in analogy to the preparation of Example 67 by using (2- methylazetidin-2-yl)methanol;hydrochloride instead of compound 67a.
  • Example 69 (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl 7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octane-1- carboxylate (compound 69b)
  • compound 69a 200.0 mg
  • Step 2 preparation of 1-(1,7-diazaspiro[3.4]octan-7-yl)-2,2-difluoro-ethanone (compound 69c) To a solution of compound 69b (140.0 mg, 0.48 mmol) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C and then stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 69c (140.0 mg) as brown oil. LCMS (M+H + ): 191.
  • Step 3 (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 69) A solution of Intermediate E1 (50.0 mg, 0.07 mmol), compound 69c (68 mg, 0.36 mmol), CsF (54 mg, 0.36 mmol) and DIEA (0.1 mL, 0.71 mmol) in DMA (2 mL) was stirred at 120
  • Example 70 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
  • Example 70 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c.
  • Example 71 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one
  • Example 71 was prepared in analogy to the preparation of compound D9-c by using compound 60d-1 instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E5 instead of intermediate D15-a.
  • Example 72 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Example 72 was prepared in analogy to the preparation of Example 46 by using 2-chloro- pyrimidine instead of compound 46c.
  • Example 73 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile
  • Example 73 was prepared in analogy to the preparation of Example 55 by using intermediate D22 instead of intermediate D18.
  • Example 76 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • a mixture of Intermediate E1 (100.0 mg, 0.14 mmol), 3-thia-6-azabicyclo[3.1.1]heptane (123 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol) and DIEA (0.14 mL, 0.85 mmol) in DMA (1 mL) was stirred at 120 °C for
  • Example 76 (30 mg) as a white solid.
  • Example 77 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3 ⁇ 4 -thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one To a solution of Example 76 (26.0 mg, 0.03 mmol) in DCM (0.5 mL) was added mCPBA (7 mg, 0.03 mmol) at 0 °C.
  • Example 78 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3- (methoxymethyl)azetidine-3-carbonitrile
  • the title compound was prepared according to the following scheme:
  • Example 71 was prepared in analogy to the preparation of compound D9-c by using compound 78a instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E1 instead of intermediate D15-a.
  • Example 79 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3 ⁇ 6 -thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • M-CPBA 18 mg, 0.08 mmol
  • Example 80 2-[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[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24), 21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidin-3-yl]acetonitrile
  • Step 1 preparation of (3-methoxyazetidin-3-yl) methanol (compound 80b) To a solution of compound 80a (300.0 mg, 1.38 mmol) in DCM (7 mL) was added TFA (1.0 mL, 1.38 mmol) at 0 °
  • Step 2 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl)- 3-methoxy-azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 80c) A solution of Intermediate E1 (100.0 mg, 0.14 mmol), compound 80b (100.0 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol) and DIEA (0.
  • Step 4 preparation of 2-[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[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18, 20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidin-3-yl] acetonitrile(Example 80) To a solution of compound 80d (50.0 mg, 0.06 mmol) in DMF (1 mL) was added 18- crown-6 (2 mg, 0.01 mmol) and sodium cyanide (40.0 mg, 0.82 mmol).
  • Example 81 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7- azaspiro[3.4]octan-6-one
  • a mixture of intermediate E2 (30 mg, 0.04 mmol), 2-oxa-7-azaspiro[3.4]octan-6-one (26 mg, 0.2 mmol), potassium phosphate (18 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (8mg, 0.00
  • Example 81 (8 mg) as white powder.
  • Example 82 (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy- 22-fluoro-13,18-dimethyl-12-o
  • Step 2 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-oxo-2,6- diazaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 82b)
  • Compound 82b was prepared in analogy to the preparation of compound 62b by using compound 82a instead of compound 62a.
  • Example 83 and 84 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo
  • Example 84 slower eluted.
  • LCMS (M+H + ): 809. 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.90 - 8.73 (m, 1H), 8.40 - 8.23 (m, 1H), 7.73 - 7.56 (m, 2H), 7.51 - 7.35 (m, 2H), 7.31 - 7.10 (m, 2H), 5.92 - 5.60 (m, 2H), 5.54 - 5.22 (m, 1H), 4.69 - 4.50 (m, 1H), 4.47 - 4.26 (m, 2H), 4.24 - 4.08 (m, 2H), 4.04 - 3.78 (m, 2H), 3.32 - 3.17 (m, 2H), 3.11 - 2.97 (m, 3H), 2.92 - 2.72 (m, 6H), 2.71 - 2.50 (m, 6H), 1.88 - 1.71 (m, 1H), 0.69 - 0.52 (m, 3H).
  • Example 85 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methyl- azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of methyl 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,
  • Example 87 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin- 4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • the title compound was prepared according to the following scheme:
  • Example 87 was prepared in analogy to the preparation of Example 62 by using tert-butyl (4aR,7aS)-3,4,4a,5,7,7a-hexahydro-2
  • Example 88 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 88 was prepared in analogy to the preparation of Example 113 by using compound 87b instead of compound 62b.
  • Example 89 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 89 was prepared in analogy to the preparation of Example 112 by using compound 87b instead of compound 62b.
  • Example 90 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azetidine-3-carbonitrile
  • a mixture of intermediate C1 (30.0 mg, 0.04 mmol), 3-methylazetidine-3-carbonitrile (17 mg, 0.130 mmol) and DIPEA (0.04 mL, 0.21 mmol) in IPA (0.5 mL) was stirred for 4 h at 120 °C.
  • Example 91 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidine-3-carbonitrile
  • a mixture of intermediate C1 (30.0 mg, 0.04 mmol), 3-methoxyazetidine-3-carbonitrile (25 mg, 0.170 mmol) and DIPEA (0.04 mL, 0.21 mmol) in IPA (0.5 mL) was stirred for 4 h at 120 °C.
  • Example 92 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carbonitrile
  • K3PO4 63 mg, 0.3 mmol
  • tris(dibenzylideneacetone)dipalladium 36 mg, 0.04
  • Example 92 (17.0 mg) as a white solid.
  • Example 93 (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one
  • Example 93 was prepared in analogy to the preparation of Example 55 by using intermediate D10 instead of intermediate D18 and intermediate C1 instead of intermediate C2.
  • Example 94 faster eluted, LCMS (M+H + ): 825.
  • Example 95 slower eluted, LCMS (M+H + ): 825.
  • 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 8.89 (s, 1H), 8.41 (s, 1H), 7.90 - 7.74 (m, 2H), 7.73 - 7.61 (m, 2H), 7.60 - 7.51 (m, 1H), 7.37 - 7.21 (m, 1H), 5.79 - 5.52 (m, 2H), 5.48 - 5.32 (m, 1H), 4.60 - 3.80 (m, 9H), 3.63 - 3.13 (m, 4H), 3.01 - 2.75 (m, 5H), 2.74 - 2.40 (m, 7H), 1.79 - 1.59 (m, 1H), 0.52 - 0.39 (m, 3H).
  • Example 100 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 100 was prepared in analogy to the preparation of Example 51 by using 3-methyl- 3,8-diazabicyclo[3.2.1]octan-2-one instead of compound 51a.
  • Example 101 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
  • Example 101 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E10 instead of intermediate E4.
  • Example 102 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa- 3,10-diazabicyclo[4.3.1]decan-4-one
  • Example 102 was prepared in analogy to the preparation of Example 57 by using tert-butyl 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decane-10-carboxylate instead of compound 60d and intermediate E2 instead of intermediate E5.
  • Example 103, 104, 105 and 106 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- 2,6 [(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo
  • Example 103 & 104 & 105 & 106 Step 1: preparation of tert-butyl (1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-diene-12-carboxylate; tert-butyl (1R,8S)-4-methyl-10- 2,6 oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2,5-diene-12-carboxylate; tert-butyl (1S,8R)-5- 2,6 methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2(6),3-diene-12-carboxylate; tert-butyl 2,6 (1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2(6),3-diene-12-carboxylate (compound 103b-1
  • SFC condition Instrument: SFC 150 Mgm; Column: AD-H, 250 ⁇ 30 mm I.D., 5 ⁇ m; Mobile phase: A for CO 2 and B for ethanol (0.1% NH 3 H 2 O); Gradient: B 10%; Flow rate: 80 mL /min; Back pressure: 100 bar; Column temperature: 35 °C.
  • Step 2-3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl- 2,6 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]d
  • Example 103 LCMS (M+H + ): 846.
  • Example 104 LCMS (M+H + ): 846.
  • Example 105 LCMS (M+H + ): 846.
  • Example 106 LCMS (M+H + ): 846.
  • Example 107 and 108 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy- 13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.02,6]decan-9-yl]pyrazolo[3,
  • Step 2 preparation of 6-benzyl 3-tert-butyl 2-(3-methoxy-3-oxo-propyl)-3,6- diazabicyclo[3.1.1]heptane-3,6-dicarboxylate (compound 107d)
  • compound 107b 1.5 g, 4.51 mmol
  • CD 3 CN 3.0 mL, 4.51 mmol
  • diphenylmethanone 411 mg, 2.26 mmol
  • Cu(OAc)2 (16 mg, 0.09 mmol
  • compound 107c 600 mg, 6.97 mmol
  • Step 3 preparation of benzyl 2-(3-methoxy-3-oxo-propyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 107e) To a solution of compound 107d (300 mg, 0.72 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 °C.
  • Step 4 preparation of benzyl 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decane-9-carboxylate (compound 107f) To a solution of compound 107e (110.0 mg, 0.35 mmol) in THF (70 mL) was added TBD (24 mg, 0.17 mmol) at 25 °C.
  • Step 5 preparation of 6,9-diazatricyclo[6.1.1.02,6]decan-5-one (compound 107g) To a solution of compound 107f (55.0 mg, 0.19 mmol) in methanol (3 mL) was added wet Pd/C (55 mg) under N2 at 25 °C. The mixture was stirred under H2 (balloon) at 25 °C for 2 h. Then the mixture was filtered, the filtrate was concentrated to give compound 107g (40.0 mg) as light yellow semisolid.
  • Step 6 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo- 6,9-diazatricyclo[6.1.1.02,6]decan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,2R,8S)-5-oxo-6,9-diazatricyclo [6.1.1.02,6]decan-9-yl]pyrazolo[3,4
  • Example 107 and Example 108 SFC Method: Column DAICEL CHIRALPAK AD (250 mm ⁇ 30 mm,10 um); Condition CO 2 -EtOH (0.1%NH 3 ⁇ H 2 O); Begin B 60%; End B 60%; Gradient Time (min) 4.5; 100% B Hold Time (min) 0; Flow Rate (ml/min) 120.
  • Example 107 (6 mg), faster eluted.
  • Example 109 2-[(3R)-4-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3- yl]acetonitrile
  • the title compound was prepared according to the following scheme:
  • Step 1 preparation of methyl 2-[(3R)-4-[4-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-yl]acetate (compound 109b)
  • compound 109a (262 mg, 1.34 mmol) in 1,4-dioxane (5 mL) was added Pd-PEPPSI-IPentCl o-picoline (231 mg, 0.27 mmol) and Cs2CO3 (2.2 g, 6.71 mmol) at 25 °C.
  • Step 2 preparation of 2-[(3R)-4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetic acid (compound 109c)
  • a solution of compound 109b 400.0 mg, 0.81 mmol
  • methanol 4 mL
  • LiOH ⁇ H2O 169 mg, 4.04 mmol
  • the reaction was stirred at 25 °C for 3 h and then concentrated.
  • Step 4 preparation of 2-[(3R)-4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetonitrile (compound 109e)
  • TFAA 0.02 mL, 0.12 mmol
  • Example 109 (16 mg) as a white solid.
  • 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.30 (s, 1H), 7.95 - 7.85 (m, 1H), 7.70 - 7.51 (m, 3H), 7.31 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.88 - 6.74 (m, 1H), 6.28 - 6.06 (m, 1H), 5.47 - 5.33 (m, 1H), 4.72 - 4.62 (m, 2H), 4.55 - 4.45 (m, 1H), 4.38 - 4.21 (m, 3H), 4.03 - 3.88 (m, 3H), 3.74 - 3.63 (m, 1H), 3.58 - 3.48 (m, 1H), 3.28 - 3.19 (m, 4H), 3.09 - 3.08 (
  • Example 112 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one To a solution of compound 62b (30.0 mg, 0.03 mmol) in methanol (0.5 mL) was added 3- oxetanone (7 mg, 0.1 mmol) and sodium cyanoborohydride (4 mg, 0.07 mmol).
  • Example 113 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-ylmethyl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
  • a solution of compound 62b (20.0 mg, 0.02 mmol), 3-(iodomethyl)oxetane (7 mg, 0.03 mmol), CsF (10 mg, 0.07 mmol) and DIEA (0.01 mL, 0.07 mmol) in DMA (0.5 m
  • Example 114 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 114 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E2 instead of Intermediate E4.
  • Example 115 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 115 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E11 instead of Intermediate E4.
  • Example 116 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 116 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E3 instead of Intermediate E4.
  • Example 117 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo [3.1.1]heptane-6-carboxylate (compound 117b) To a solution of compound 60
  • Step 2 preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 117c) To a solution of compound 117b (180.0 mg, 0.71 mmol) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C.
  • Example 118 (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
  • Example 118 was prepared in analogy to the preparation of Example 117 by using Intermediate E12 instead of Intermediate E4.
  • Example 119 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
  • Example 119 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E12 instead of intermediate E4.
  • Example 120 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • the title compound was prepared according to the following scheme: i ntermediate D15-a 120b 120c Step 1: preparation of tert-butyl 3-oxazol-2-yl-3,6-diazabicyclo[3.1.1] heptane-6- carboxylate (compound 120b) To a 40 mL vial equipped
  • Step 2 preparation of 6-(3-azabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidin-4-ol (compound 120c)
  • TFA 1 mL
  • the reaction was stirred at 20°C for 12 h and then concentrated to give compound 120c (40.0 mg) as a white solid.
  • LCMS M+H + ): 344.
  • Step 3 preparation of 1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 120d)
  • compound 120c 40 mg, 0.12 mmol
  • oxetan-3-one 63 mg, 0.87 mmol
  • DCE mL
  • sodium triacetoxyborohydride 93 mg, 0.44 mmol
  • Example 121 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1] heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Example 121 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E13 instead of intermediate E4.
  • Example 122 (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Example 122 was prepared in analogy to the preparation of Example 60 by using 1,1- difluoro-2-iodo-ethane instead of compound 60b and intermediate E13 instead of intermediate E4.
  • Example 123 and Example 124 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.
  • Example 125 and Example 126 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-yl]pyrazolo[3,4-
  • Example 125 9 mg, faster eluted
  • Example 126 11 mg slower eluted
  • SFC condition Instrument: SFC-150 Mgm; Column: (S,S) whelk-O1 250 ⁇ 30 mm I.D., 5 ⁇ m; Mobile phase: A for CO2 and B for methanol «Mobile_phasePrep»; Gradient: B 40%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C
  • Step 1 preparation of tert-butyl 3-hydroxyimino-6-azabicyclo[3.1.1]heptane-6- carboxylate (compound 125a)
  • tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate 300 mg, 1.42 mmol
  • hydroxylamine hydrochloride 250 mg, 3.6 mmol
  • methanol 4 mL
  • water 4 mL
  • Step 2 preparation of tert-butyl 4-oxo-3,7-diazabicyclo[4.1.1]octane-7-carboxylate (compound 125b)
  • sodium carbonate 650 mg, 6.13 mmol
  • acetone 6 mL
  • water 4 mL
  • the suspension was stirred at r.t. and p- toluenesulfonyl chloride (550 mg, 2.88 mmol) was added portion-wise.
  • the resulted mixture was heated to 65 °C and stirred for 16 hrs.
  • the mixture was diluted with some water and extracted with 30 mL DCM for three times.
  • Step 3 preparation of tert-butyl 3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7- carboxylate (compound 125c) To a flask was added compound 125b (150 mg, 662.92 ⁇ mol), DMF (1.5 mL) and iodomethane (227 mg, 100 ⁇ L, 1.6 mmol). The suspension was stirred at r.t. for a while and NaH (80 mg, 2 mmol) was added. The reaction was stirred for 4 hrs.
  • Step 4 preparation of 3-methyl-3,7-diazabicyclo[4.1.1]octan-4-one (compound 125d) To a flask was added compound 125c (150 mg, 624.22 ⁇ mol), DCM (1.5 mL) and TFA (1.5 mL, 19.47 mmol,). The brown solution was stirred at r.t. for 1 hr and concentrated to give compound 125d (158 mg) as an oil, which was used directly in the next step.
  • Example 127 3-[-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]oxetane-3- carbonitrile
  • Example 127 was prepared in analogy to the preparation of Example 2 by using compound 127b instead of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyra
  • the compound 127b was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(3-cyanooxetan-3-yl)-3,6-diazabicyclo[3.1.1] heptane-6-carboxylate (compound 127a) To a tube was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 1.01 mmol) and acetic acid (2 mL). The solution was cooled with ice bath, oxetan-3-one (100 mg, 1.39 mmol) and TMS-CN (251 mg, 340 ⁇ L, 2.54 mmol) were added.
  • Step 2 preparation of 3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)oxetane-3-carbonitrile (compound 127b)
  • compound 127a 100 mg, 358. ⁇ mol
  • DCM 1 mL
  • TFA 1 mL, 12.98 mmol
  • the solution was stirred at r.t. for 1 hr and concentrated to give compound 127b (175 mg) as a crude oil, which was used in the next step directly.
  • LCMS (M+H) + 180.
  • Example 128 and Example 129 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-yl]pyrazolo[3,4-
  • Example 128 (18 mg, faster eluted) and Example 129 (12 mg, slower eluted) as a white powder.
  • SFC condition Instrument: SFC-150 Mgm; Column: OJ 250 ⁇ 30 mm I.D., 5 ⁇ m; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 20%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C).
  • Example 131, 132, 133 and 134 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- 2,6 [(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 ]undeca-2,
  • SFC condition of step 1 Instrument: SFC 150 Mgm; Column: REGIS (S,S) Whelk-01, 250 ⁇ 30 mm I.D., 5 ⁇ m; Mobile phase: A for CO 2 and B for Methanol (0.1% NH 3 H 2 O); Gradient: B 8%; Flow rate: 80 mL /min; Back pressure: 100bar; Column temperature: 35 °C. Compound 131b-1 (first eluted), 131b-2 (second eluted), 131b-3 (third eluted) and 131b-4 (forth eluted).
  • Example 132 LCMS (M+H + ): 830.
  • 1 H NMR (400 MHz, METHANOL-d4) ⁇ 8.26 - 8.16 (m, 1H), 7.92 - 7.78 (m, 1H), 7.70 - 7.57 (m, 1H), 7.39 - 7.02 (m, 6H), 6.76 - 6.65 (m, 1H), 5.88 - 5.68 (m, 1H), 5.57 - 5.48 (m, 1H), 5.41 - 5.17 (m, 1H), 5.10 - 4.90 (m, 1H), 4.69 - 4.54 (m, 1H), 4.53 - 4.33 (m, 1H), 4.30 - 4.06 (m, 2H), 4.01 - 3.79 (m, 1H), 3.72 - 3.57 (m, 3H), 3.20 - 2.93 (m, 5H), 2.93 - 2.75 (m, 4H), 2.70 - 2.45 (m, 6H), 2.41 - 2.08 (m, 2H), 1
  • Example 135 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Example 135 was prepared in analogy to the preparation of Example 53 by using 5- iodopyrimidine instead of 3-iodo-1-methyl-pyrazole 53a.
  • Example 136 (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl (8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0
  • Step 2 preparation of tert-butyl (8S,11S,15R)-3-chloro-15-methoxy-13,18-dimethyl- 12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaene-10-carboxylate (compound 136c) To a solution of compound 136b (20.0 mg, 0.04 mmol) in ACN (0.5 mL) was added a soluiton of N-chlorosuccinimide (8 mg, 0.06 mmol) at 70 °C.
  • Step 3 preparation of (8S,11S,15R)-3-chloro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 136d)
  • a solution of compound 136c (8.0 mg, 0.01 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at 20 °C for 1 h.
  • Example 137 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 137 was prepared in analogy to the preparation of Example 117 by using Intermediate E13 instead of Intermediate E4.
  • Example 138 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 138 was prepared in analogy to the preparation of Example 117 by using Intermediate E11 instead of Intermediate E4.
  • Example 139 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 139 was prepared in analogy to the preparation of Example 117 by using Intermediate E14 instead of Intermediate E4.
  • Example 140 and Example 141 (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile and (1R,5S)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- hexaza
  • the compound 140b was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 140a) To a flask was added tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24a, 100 mg, 473.35 ⁇ mol), diethylene glycol dimethyl ether (2 mL) and ethanol (500 ⁇ L).
  • Step 2 preparation of 6-azabicyclo[3.1.1]heptane-3-carbonitrile (compound 140b)
  • TFA 1 mL, 12.98 mmol
  • DCM 1 mL
  • the solution was stirred at r.t. for 2 hrs and concentrated to give compound 140b (20 mg) as a crude oil, which was used in the next directly.
  • LCMS (M+H) + 123.
  • Example 142 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 142 was prepared in analogy to the preparation of Example 60 by using iodomethylcyclopropane instead of compound 60b and intermediate E13 instead of intermediate E4.
  • Example 143 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 143 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b and intermediate E13 instead of intermediate E4.
  • Example 144 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 144 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b and intermediate E14 instead of intermediate E4.
  • Example 145 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 145 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b.
  • Example 146 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 146 was prepared in analogy to the preparation of Example 117 by using Intermediate E3 instead of Intermediate E4.
  • Step 4 preparation of tert-butyl (1R, 8S)-3, 6, 9-triazatricyclo [6.1.1.02, 6] deca-2, 4- diene-9-carboxylate (compound 147f) To a solution of compound 147e (1 g, 3.34 mmol) in toluene (20 mL) was added p- toluenesulfonic acid (86 mg, 0.5 mmol). The mixture was stirred at 110 °C for 16 h and then concentrated.
  • Step 6 preparation of (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9- 2,6 triazatricyclo[6.1.1.0 ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 147)
  • a mixture of Intermediate E4 (30.0 mg, 0.04 mmol), CsF (28 mg, 0.19 mmol), compound 147g (11 mg, 0.04 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DMA (2 mL) was stirred at 120
  • Example 148 (8S,11S,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 148 was prepared in analogy to the preparation of Example 117 by using Intermediate E16 instead of Intermediate E4.
  • Example 149 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- tdien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
  • the title compound was prepared according to the following scheme:
  • Example 149 was prepared in analogy to the preparation of Example 147 by using compound 60d instead of compound 60d-1.
  • Example 150 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 150 was prepared in analogy to the preparation of Example 147 by using compound 60d instead of compound 60d-1 and intermediate E2 instead of intermediate E4.
  • Example 151 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Example 151 was prepared in analogy to the preparation of Example 147 by using intermediate E2 instead of intermediate E4.
  • Example 152 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Example 152 was prepared in analogy to the preparation of Example 60 by using bromoethane instead of compound 60b and compound 60d instead of compound 60f.
  • Example 153 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Example 153 was prepared in analogy to the preparation of Example 60 by using 2- bromopropane instead of compound 60b and compound 60d instead of compound 60f.
  • Example 154 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl (1S,5R)-3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2- oxo-3,6-diazabicyclo[3.1.1]h
  • Step 2 ⁇ 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2- hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20,22-heptaen-12-one (Example 154)
  • Example 154 was prepared in analogy to the preparation of Example 147 by using compound 154b instead of compound 147f and Intermediate E1 instead of Intermediate E4.
  • Example 155 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl (1S, 5R)-2-oxo-3-tetrahydropyran-4-yl-3, 6- diazabicyclo [3.1.1] heptane-6-carboxylate (compound 155
  • Step 2 ⁇ 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3- tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20,22-heptaen-12-one (Example 155)
  • Example 155 was prepared in analogy to the preparation of Example 147 by using compound 155b instead of compound 147f.
  • Example 156 Cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile
  • Step 1 preparation of (3-cyanocyclobutyl) ethanesulfonate (compound 156b) To a solution of compound 156a (200 mg, 2.06 mmol) and triethy
  • Step 2 preparation of cis-tert-butyl (1S, 5R)-3-(3-cyanocyclobutyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate and trans-tert-butyl (1S, 5R)-3-(3- cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 156d and 156d-1) To a solution of compound 60d (200 mg, 0.94 mmol) in DMF (3 mL) was added sodium hydride (113 mg, 2.83 mmol) at 0 °C, after 0.5 h, compound 156c (357 mg, 1.88 mmol) was
  • Step 3 ⁇ 4 preparation of cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3- yl]cyclobutanecarbonitrile (Example 156)
  • Example 156 was prepared in analogy to the preparation of Example 147 by using compound 156d instead of compound 147f.
  • Example 157 Trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile
  • Example 157 was prepared in analogy to the preparation of Example 147 by using compound 156d-1 instead of compound 147f.
  • Example 158 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl 3-pyrazol-1-ylazetidine-1-carboxylate (compound 158b)
  • compound 158a 200 mg, 2.94 mmol
  • 1-BOC-3-iodoazetidine (1.66 g, 5.88 mmol
  • Step 2 ⁇ 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1- ylazetidin-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 158)
  • Example 158 was prepared in analogy to the preparation of Example 147 by using compound 158b instead of compound 147f and Intermediate E2 instead of Intermediate E4.
  • Example 159 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl 3-(2-bromoimidazol-1-yl)azetidine-1-carboxylate (compound 159b)
  • Step 2 preparation of tert-butyl 3-imidazol-1-ylazetidine-1-carboxylate (compound 159c) To a solution of compound 159b (120 mg, 0.4 mmol) in methanol (3 mL) was added wet Pd/C (60.0 mg) under N2 at 25 °C. The mixture was stirred under H2 (balloon) at 50 °C for 2 h, then the reaction mixture was filtered, the filtrate was concentrated to give compound 159c (85 mg) as colorless oil.
  • Example 159 was prepared in analogy to the preparation of Example 147 by using compound 159c instead of compound 147f and Intermediate E2 instead of Intermediate E4.
  • Example 160 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of benzyl 3-(1,2,4-triazol-1-yl)azetidine-1-carboxylate (compound 160b) To a solution of 1-N-Cbz-3-hydroxyazetidine (1.2 g, 5.79 mmol) and compound 160a (200.0 mg, 2.9 m
  • Step 2 ⁇ 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1- yl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 160)
  • Example 160 was prepared in analogy to the preparation of Example 60 by using compound 160b instead of compound 60g and Intermediate E2 instead of Intermediate E4..
  • Example 161 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
  • Step 1 preparation of tert-butyl 3-[[(E)-N-hydroxy-C-methyl-carbonimidoyl] carbamoyl]azetidine-1-carboxylate (compound 161c)
  • compound 161b 500.0 mg, 6.75
  • Step 2 preparation of tert-butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-1- carboxylate (compound 161d)
  • a solution of compound 161c (100.0 mg, 0.39 mmol) in toluene (2 mL) was heated to 100 °C and for 16 h. Then the reaction mixture was concentrated to give compound 161d (60.0 mg) as light yellow oil.
  • Step 3 ⁇ 4 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl- 1,2,4-oxadiazol-5-yl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 161)
  • Example 161 was prepared in analogy to the preparation of Example 147 by using compound 161d instead of compound 147f and Intermediate E2 instead of Intermediate E4.
  • Example 162A and Example 162B (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile and (1R,5S)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26- 2,6 8,11 20,24
  • Example 164A and Example 164B (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4- d]pyr
  • Example 164B faster eluted
  • Example 164A (16 mg, slower eluted) as a white powder.
  • Example 165A and Example 165B (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile and (1R,5S)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5
  • Example 166 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
  • Step 1 preparation of tert-butyl 3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 166a)
  • compound 127a 100 mg
  • Step 2 preparation of 3-(3-methyloxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane;2,2,2- trifluoroacetic acid (compound 166b)
  • compound 166a 30 mg, 111.79 ⁇ mol
  • DCM 1 mL
  • TFA 592 mg, 400 ⁇ L, 5.19 mmol
  • the solution was stirred at r.t. for 1 hr and then concentrated to give compound 166b (31 mg) as a crude oil, which was used directly in the next step.
  • LCMS (M+H) + 169.
  • Step 3 preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan- 3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 166) To a tube was added intermediate E4 (30 mg, 43.72 ⁇ mol), DIEA (37 mg, 50 ⁇ L, 286 ⁇ mol), compound 166b (30 mg, 106 ⁇ mol), cesium fluoride (20 mg, 131 ⁇ mol) and acetonitrile (2 m
  • Example 166 (24.2 mg) as a white powder.
  • Example 167 1-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptan-3-yl]azetidine-3- carbonitrile
  • Example 167 was prepared in analogy to the preparation of Example 2 by using compound 167b instead of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine.
  • the compound 167b was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(3-cyanoazetidin-1-yl)-6-azabicyclo[3.1.1]heptane- 6-carboxylate (compound 167a) To a tube was added tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24a, 20 mg, 94.67 ⁇ mol), DIEA (22 mg, 171.77 ⁇ mol), azetidine-3- carbonitrile;hydrochloride (20 mg, 168.69 ⁇ mol) and ethanol (2 mL). The solution was at r.t.
  • Step 2 preparation of1-(6-azabicyclo[3.1.1]heptan-3-yl)azetidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (compound 167b)
  • compound 167a (30 mg, 108.16 ⁇ mol) was added TFA (1.48 g, 1 mL, 12.98 mmol) and DCM (2 mL). The mixture was stirred at r.t. for 1 hr and concentrated. The compound 167b (30 mg) was obtained as a yellow oil and used directly in the next step.
  • Example 168 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).
  • CCD C-terminal Domain
  • STING ligand-binding domain of human stimulator of interferon genes
  • 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.
  • THP1- DualTM 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.
  • ISG54 interferon-stimulated gene
  • THP1 ⁇ DualTM 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 ⁇ LucTM (InvivoGen, cat.
  • test medium RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum
  • test medium RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum
  • stimulator final concentration is 20 ⁇ M of 2’3’cGAMP, or final concentration is 10 MOI baculovirus virus,
  • compound solution per well final 1% DMSO
  • Example THP1_IC50 Example THP1_IC50 NO. (nM) NO. (nM) NO. (nM) 1 6 59 5 119 13 2 8 61 51 121 3 3 8 63 29 122 8 4 2 64 29 123 53 5 4 67 48 124 8 6 13 68 29 125 14 7 49 69 12 126 7 8 3 70 2 127 54 9 28 71 86 129 69 10 14 72 13 131 23 11 68 73 30 132 18 1 2 14 76 23 133 11 14 13 78 17 134 15 16 70 79 27 135 18 19 19 80 18 136 46 2 0 3 82 73 137 5 21 30 83 40 138 1 23 8 84 94 139 9 2 4 7 85 19 140 2 28 16 87 21 141 6 31 5 88 32 142 8 3 2 2 89 32 143 2 33 10 90 18 144 5 34 10 91 18 145 3 35 7 92 67 146 2 36
  • IV intravenously
  • PO by gavage
  • Blood samples were collected via Jugular vein at 5 min (only for IV), 15 min, 30 min, 1 h, 2 h, 4 h, 7 h and 24 h post-dose.
  • Blood samples were placed into pre-chilled commercial EDTA-K2 tubes (vendor: Jiangsu Kangjian medical supplies co., LTD) and centrifuged at 3,200 g for 10 min at 4°C to separate plasma from the samples. After centrifugation, the resulting plasma was transferred to clean tubes for bioanalysis with LC/MS/MS.
  • the pharmacokinetic parameters were calculated using noncompartmental analysis.
  • the volume of distribution (Vss), half-life (T1/2) and clearance (CL) were obtained based on the plasma concentration-time curve after IV dose.
  • the peak concentration (C max ) was recorded directly from experimental observations after PO dose.
  • the area under the plasma concentration-time curve (AUC o-last ) was calculated using the linear trapezoidal linear interpolation rule up to the last detectable concentration.
  • the bioavailability (F) was calculated based on the dose normalized AUCo-last after IV and PO dose. Results of PK parameters following IV and PO administration are given in Table 3. Table 3. PK results for the compounds of this invention Example PO Cmax PO IV AUCo- CL Vss T1/2 NO.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The present application relates to compounds of formula (I), wherein R1 to R6, Q1 and A1 to AS are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds. The compounds of formula (I) are antagonists of STING and thus useful for the treatment of various diseases and disorders.

Description

Case 38695 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),
Figure imgf000004_0001
wherein A1 is CH or N; A2 is CH or N; A3 is CR7 or N; wherein R7 is H or halogen; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once or twice substituted by substituents independently selected from cyano, halogen, hydroxy, amino, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxy, heterocyclyl, heteroaryl, heteroarylcarbonyl and heterocyclylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, pyrrolidinyl substituted by hydroxyC1-6alkyl,
Figure imgf000005_0001
, , or ; wherein Y1 is CH, C or N; Y2 is CH, C or N; Y3 is O or S; Y4 is a bond, C1-6alkylene, -COO- or sulfonyl; W is CH or N; X1, X2, X3 and X4 are independently selected from C(R8)2, O, S, SO2, SO, NR9, N(CON(R9)2) and N(COOR9); wherein each R8 is independently H, deuterio, halogen, hydroxy, cyano, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC3- 7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, N(R9)2, OR9, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1- 6alkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3- 7cycloalkylsulfonyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl or heterocyclylsulfonyl; each R9 is independently H, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1- 6alkyl, haloC1-6alkyl, haloC3-7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC3-7cycloalkylC1-6alkyl, cyanoC1- 6alkoxyC1-6alkyl, cynanoC1-6alkoxyC3-7cycloalkyl, cyanoC1- 6alkoxyC3-7cycloalkylC1-6alkyl, hydoxyC1-6alkyl, hydroxyC3- 7cycloalkyl, hydroxyC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, aryl, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, haloC3- 7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfonyl, haloC1- 6alkylsulfonyl, haloC3-7cycloalkylsulfonyl or heterocyclylsulfonyl; R7 is C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC3-7cycloalkyl, haloC3- 7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxyC3-7cycloalkyl, hydroxyC3-7cycloalkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxyC3-7cycloalkyl, heterocyclyl, heterocyclylC1-6alkyl, aryl, arylC1-6alkyl, heteroaryl or heteroarylC1- 6alkyl; R10 is (C1-6alkyl)2aminocarbonyl, (C1-6alkyl)2aminosulfonyl, (C1- 6alkyl)oxopyrrolidinylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, arylC1-6alkyl, C1- 6alkylsulfonyl, C1-6alkylcarbonyl, haloC1-6alkoxycarbonyl, haloC1-6alkylsulfonyl, heterocyclylC1-6alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroarylC1-6alkylcarbonyl, arylcarbonyl, aryl, heterocyclyl or heteroaryl; Ring A is a aryl ring, heteroaryl ring or heterocyclyl ring, each of which is unsubstituted or substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, halogen, cyano or nitro; m, n, p, q, s, t are independently 0, 1 or 2, with the proviso that m, n, p, q, s, t are not 0 simultaneously; R6 is phenyl twice or three times substituted by substituents independently selected from halogen, cyano, hydroxy and C1-6alkoxy; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. Another object of the present invention is related to novel compounds of formula (I) or (Ia). Their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or (Ia) as STING antagonist, and for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, or selective types of cancers where overexpression or activation of STING is implicated. The compounds of formula (I) or (Ia) show superior STING antagonism activity. In addition, the compounds of formula (I) or (Ia) also show good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, as well as low CYP inhibition. BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray crystallographic analysis of compound 60d. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “deuterio” or “deuterium” denotes the isotope of hydrogen that has a single neutron as well as a proton in the nucleus. The term “C1-6alkyl” denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C1-6alkyl” groups are methyl, ethyl and n-propyl. The term “C1-6alkylene” denotes a divalent C1-6alkyl. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C1-6alkoxy” denotes C1-6alkyl-O-. The term “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 “haloC3-7cycloalkoxy” denotes haloC3-7cycloalkyl-O-. The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, 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. Heterocyclyl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, hydroxyC1-6alkoxy, aminoC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkoxy, haloC3-7cycloalkyl, haloC3-7cycloalkoxy, cyanoC3-7cycloalkyl, cyanoC3-7cycloalkoxy, hydroxyC3-7cycloalkyl, hydroxyC3-7cycloalkoxy, aminoC3-7cycloalkyl, aminoC3-7cycloalkoxy, C1-6alkoxyC1-6alkyl, haloC1-6alkoxyC1-6alkyl, cyanoC1-6alkoxyC1-6alkyl, hydroxyC1-6alkoxyC1-6alkyl, aminoC1- 6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1-6alkoxyC3- 7cycloalkyl, hydroxyC1-6alkoxyC3-7cycloalkyl, aminoC1-6alkoxyC3-7cycloalkyl, aryl or heteroaryl. In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring. In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Aryl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, hydroxyC1-6alkoxy, aminoC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkoxy, haloC3- 7cycloalkyl, haloC3-7cycloalkoxy, cyanoC3-7cycloalkyl, cyanoC3-7cycloalkoxy, hydroxyC3- 7cycloalkyl, hydroxyC3-7cycloalkoxy, aminoC3-7cycloalkyl, aminoC3-7cycloalkoxy, C1-6alkoxyC1- 6alkyl, haloC1-6alkoxyC1-6alkyl, cyanoC1-6alkoxyC1-6alkyl, hydroxyC1-6alkoxyC1-6alkyl, aminoC1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1- 6alkoxyC3-7cycloalkyl, hydroxyC1-6alkoxyC3-7cycloalkyl, aminoC1-6alkoxyC3-7cycloalkyl, heterocyclyl or heteroaryl. 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. Heteroaryl can be further optionally substituted by halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, hydroxyC1-6alkoxy, aminoC1- 6alkoxy, C3-7cycloalkyl, C3-7cycloalkoxy, haloC3-7cycloalkyl, haloC3-7cycloalkoxy, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkoxy, hydroxyC3-7cycloalkyl, hydroxyC3-7cycloalkoxy, aminoC3- 7cycloalkyl, aminoC3-7cycloalkoxy, C1-6alkoxyC1-6alkyl, haloC1-6alkoxyC1-6alkyl, cyanoC1- 6alkoxyC1-6alkyl, hydroxyC1-6alkoxyC1-6alkyl, aminoC1-6alkoxyC1-6alkyl, C1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1-6alkoxyC3-7cycloalkyl, hydroxyC1-6alkoxyC3- 7cycloalkyl, aminoC1-6alkoxyC3-7cycloalkyl, heterocyclyl or aryl. The term “PG” denotes protecting groups. The term “-COO-” denotes
Figure imgf000012_0001
. 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),
Figure imgf000014_0001
wherein A1 is CH or N; A2 is CH or N; A3 is CR7 or N; wherein R7 is H or halogen; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once or twice substituted by substituents independently selected from cyano, halogen, hydroxy, amino, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxy, heterocyclyl, heteroaryl, heteroarylcarbonyl and heterocyclylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, pyrrolidinyl substituted by hydroxyC1-6alkyl,
Figure imgf000015_0001
, , or ; wherein Y1 is CH, C or N; Y2 is CH, C or N; Y3 is O or S; Y4 is a bond, C1-6alkylene, -COO- or sulfonyl; W is CH or N; X1, X2, X3 and X4 are independently selected from C(R8)2, O, S, SO2, SO, NR9, N(CON(R9)2) and N(COOR9); wherein each R8 is independently H, deuterio, halogen, hydroxy, cyano, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC3- 7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, N(R9)2, OR9, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1- 6alkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3- 7cycloalkylsulfonyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl or heterocyclylsulfonyl; each R9 is independently H, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1- 6alkyl, haloC1-6alkyl, haloC3-7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC3-7cycloalkylC1-6alkyl, cyanoC1- 6alkoxyC1-6alkyl, cynanoC1-6alkoxyC3-7cycloalkyl, cyanoC1- 6alkoxyC3-7cycloalkylC1-6alkyl, hydoxyC1-6alkyl, hydroxyC3- 7cycloalkyl, hydroxyC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, aryl, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, haloC3- 7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfonyl, haloC1- 6alkylsulfonyl, haloC3-7cycloalkylsulfonyl or heterocyclylsulfonyl; R7 is C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC3-7cycloalkyl, haloC3- 7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxyC3-7cycloalkyl, hydroxyC3-7cycloalkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxyC3-7cycloalkyl, heterocyclyl, heterocyclylC1-6alkyl, aryl, arylC1-6alkyl, heteroaryl or heteroarylC1- 6alkyl; R10 is (C1-6alkyl)2aminocarbonyl, (C1-6alkyl)2aminosulfonyl, (C1- 6alkyl)oxopyrrolidinylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, arylC1-6alkyl, C1- 6alkylsulfonyl, C1-6alkylcarbonyl, haloC1-6alkoxycarbonyl, haloC1-6alkylsulfonyl, heterocyclylC1-6alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroarylC1-6alkylcarbonyl, arylcarbonyl, aryl, heterocyclyl or heteroaryl; Ring A is a aryl ring, heteroaryl ring or heterocyclyl ring, each of which is unsubstituted or substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, halogen, cyano or nitro; m, n, p, q, s, t are independently 0, 1 or 2, with the proviso that m, n, p, q, s, t are not 0 simultaneously; R6 is phenyl twice or three times substituted by substituents independently selected from halogen, cyano, hydroxy and C1-6alkoxy; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2(6),3-dienyl substituted by C1-6alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dienyl substituted by C1-6alkyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C1-6alkyl, C1- 6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, oxetanyl, oxetanylC1-6alkyl or tetrahydropyranyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (C1-6alkyl)2aminocarbonyl, (C1- 6alkyl)2aminosulfonyl, (C1-6alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C1- 6alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolylC1-6alkyl, 2-oxaspiro[3.3]heptanylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, C1- 6alkyloxetanyl, C1-6alkylpyrazolyl, C1-6alkylsulfonyl, C1-6alkylsulfonylC1- 6alkylcarbonyl, cyanooxetanyl, haloC1-6alkoxycarbonyl, oxazolyl, oxetanylC1- 6alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolylC1-6alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanyl substituted by oxetanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by oxetanyl or oxetanylC1-6alkyl, 3-oxo-2,6-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2(6),3-dienyl substituted by C1-6alkyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dienyl substituted by C1-6alkyl, 4-oxo-3,7-diazabicyclo[4.1.1]octanyl substituted by C1-6alkyl, 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl substituted by C1-6alkyl, 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano, C1-6alkyl and cyanoC3-7cycloalkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once substituted by pyrazolyl, 1,2,4-triazolyl or C1-6alkyl-1,2,4- oxadiazolyl, or twice substituted by substituents independently selected from cyano, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl and haloazetidinylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, or pyrrolidinyl substituted by hydroxyC1-6alkyl. Another embodiment of present invention is (iii) a compound of formula (Ia) according to (i) or (ii), wherein A1 is CH or N; A2 is CH or N; A3 is CR7 or N; wherein R7 is H or halogen; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2(6),3-dienyl substituted by C1-6alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dienyl substituted by C1-6alkyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C1-6alkyl, C1- 6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, oxetanyl, oxetanylC1-6alkyl or tetrahydropyranyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (C1-6alkyl)2aminocarbonyl, (C1- 6alkyl)2aminosulfonyl, (C1-6alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C1- 6alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolylC1-6alkyl, 2-oxaspiro[3.3]heptanylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, C1- 6alkyloxetanyl, C1-6alkylpyrazolyl, C1-6alkylsulfonyl, C1-6alkylsulfonylC1- 6alkylcarbonyl, cyanooxetanyl, haloC1-6alkoxycarbonyl, oxazolyl, oxetanylC1- 6alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolylC1-6alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanyl substituted by oxetanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by oxetanyl or oxetanylC1-6alkyl, 3-oxo-2,6-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2(6),3-dienyl substituted by C1-6alkyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dienyl substituted by C1-6alkyl, 4-oxo-3,7-diazabicyclo[4.1.1]octanyl substituted by C1-6alkyl, 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl substituted by C1-6alkyl, 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano, C1-6alkyl and cyanoC3-7cycloalkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once substituted by pyrazolyl, 1,2,4-triazolyl or C1-6alkyl-1,2,4- oxadiazolyl, or twice substituted by substituents independently selected from cyano, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl and haloazetidinylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, or pyrrolidinyl substituted by hydroxyC1-6alkyl; R6 is phenyl twice substituted by substituents independently selected from halogen, cyano, hydroxy and C1-6alkoxy; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (iv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (iii), wherein A3 is CH. A further embodiment of present invention is (v) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (iii), wherein R1 is H or fluoro. A further embodiment of present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (v), wherein R2 is methyl. A further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), wherein R3 is H, methoxy or ethoxy. A further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R4 is methyl. A further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (viii), wherein R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkylpyrazolyl, thiazolylcarbonyl, 1,3,4- thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and C1-6alkyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, C1-6alkyl and C1-6alkoxy. A further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by 2,2-difluoroethyl, 2-cyanoethyl, 2- fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxetan-3-yl or tetrahydropyran-4-yl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by 1-methylpyrazol-3-yl, thiazole-2-carbonyl, 1,3,4-thiadiazol-2-yl or thiazol-2-yl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and methyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, methyl and methoxy. A further embodiment of present invention is (xi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R5 is 2-oxo- 3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (3-cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ⁶-thia-6- azabicyclo[3.1.1]heptan-6-yl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano-3- methoxy-azetidin-1-yl, 3-cyano-3-methyl-azetidin-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-hydroxy-3- methyl-6-azabicyclo[3.1.1]heptan-6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl or 3- thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl. A further embodiment of present invention is (xii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein R6 is phenyl twice substituted by halogen. A further embodiment of present invention is (xiii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein R6 is phenyl twice substituted by fluoro. A further embodiment of present invention is (xiv) a compound of formula (I) or (Ia),, according to any one of (i) to (xiii), wherein R6 is 2,4-difluorophenyl. A further embodiment of present invention is (xv) a compound of formula (I) or (Ia), according to any one of (i) to (xiv), wherein A1 is CH or N; A2 is CH or N; A3 is CH; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkylpyrazolyl, thiazolylcarbonyl, 1,3,4- thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and C1-6alkyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, C1-6alkyl and C1-6alkoxy; R6 is phenyl twice substituted by halogen; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xvi) a compound of formula (I) or (Ia), according to any one of (i) to (xv), wherein A1 is CH or N; A2 is CH or N; A3 is CH; A4 is CH or N; A5 is CH or N; R1 is H or fluoro; R2 is methyl; R3 is H, methoxy or ethoxy; R4 is methyl; R5 is 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ⁶-thia-6- azabicyclo[3.1.1]heptan-6-yl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano- 3-methoxy-azetidin-1-yl, 3-cyano-3-methyl-azetidin-1-yl, 3-cyano-6- azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl, 3- isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl or 3-thiazol-2-yl- 3,6-diazabicyclo[3.1.1]heptan-6-yl; R6 is 2,4-difluorophenyl; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xvii) is a compound of formula (I) or (Ia), selected from the following: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidin-1-yl)ethyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H- [1,2,4]triazolo[4,3-a]pyrazin-7-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; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)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; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[(1R,5S)-6-[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]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; 3-[(1S,5R)-6-[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]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(3,5-difluoro-2-pyridyl)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; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(3,5-difluoro-2-pyridyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidin-3- 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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidin-3- 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; 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-carboxamide; 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-sulfonamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12- one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12- one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo [3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-12-one; 6-[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(24),2(26),3,5,18,20, 22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3- carboxamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6- diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)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(24),2(26),3,5,18,20, 22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1] heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10, 2,6 8,11 20,24 13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-12-one; (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-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; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; 3-fluoro-4-[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(24),2,4,6(26),18,20,22- heptaen-10-yl]-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-1- yl]benzonitrile; (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; methyl 6-[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]-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan- 9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; Trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile; Cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ4-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-(methoxymethyl)azetidine-3-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ6-thia-6-azabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[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]-3-methoxy-azetidin- 3-yl]acetonitrile; 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7- azaspiro[3.4]octan-6-one; (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methyl- azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-ylmethyl)-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carbonitrile; (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan- 8-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa- 3,10-diazabicyclo[4.3.1]decan-4-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[(3R)-4-[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(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3- yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-ylmethyl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1] heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]oxetane-3-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (1R,5S)-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; Cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile; Trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; and 1-[6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptan-3-yl]azetidine-3-carbonitrile; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention (xviii) is a process for the preparation of a compound according to any one of (i) to (xvii) comprising any one of the following steps: a) the formation of compound of formula (I) via nucleophilic substitution or Buchwald cross coupling between compound of formula (VIII),
Figure imgf000044_0001
(VIII), and HR5; b) the formation of compound of formula (I) via nucleophilic substitution reaction
Figure imgf000045_0001
between compound of (IX), (IX), and halide or acid anhydride; or condensation reaction between compound of formula (IX) and acid; or reductive amination between compound of formula (IX) and ketone or aldehyde;
Figure imgf000045_0002
reagent; wherein the coupling reagent in step c) is PyBOP; X is halogen; HRa is heterocyclyl with reactive primary or secondary amino group; R1 to R6, Q1 and A1 to A6 are as defined as in any one of (i) to (xvi). Another embodiment of present invention (xix) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for use as therapeutically active substance. Another embodiment of present invention (xx) is related to a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xvii) and a pharmaceutically acceptable excipient. Another embodiment of present invention (xxi) is related to the use of a compound according to any one of (i) to (xvii) 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 (xxii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) 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 (xxiii) is related to the use of a compound according to any one of (i) to (xvii) 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 (xxiv) is related to the use of a compound according to any one of (i) to (xvii) 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 (xxv) is related to the use of a compound according to any one of (i) to (xvii) 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 (xxvi) is related to the use of a compound according to any one of (i) to (xvii) for the inhibition of STING. Another embodiment of present invention (xxvii) is related to the use of a compound according to any one of (i) to (xvii) for the preparation of a medicament for the inhibition of STING. Another embodiment of present invention (xxvii) is related to a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii), when manufactured according to a process of (xviii). Another embodiment of present invention (xxix) 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 (xvii). 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 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 R6, Q1, A1 to A5 are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the compound of the invention are shown in following schemes. Scheme 1
Wherein HRa is heterocyclyl with reactive primary or secondary amino group; PG can be, for example, Boc or Cbz; X is halogen. As depicted in Scheme 1, the synthesis of compounds of the present invention started from boronic ester compound of formula (II). Suzuki coupling between compound of formula (II) and compound of formula (III) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (IV). Compound of formula (IV) is hydrolyzed in the presence of LiOH directly and followed by Boc deprotection (HCl in dioxane or TFA in DCM) to give compound of formula (V). 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 (VII) reacted with compound of formula (VIIa) via nucleophilic substitution in the presence of a base, such as DIEA to give compound of formula (VIII), which was directly reacted with H-R5 via nucleophilic substitution or Buchwald cross coupling to give the final compound of formula (I). On the other hand, compound of formula (VIII) reacted with H-Ra-Boc via nucleophilic substitution or Buchwald cross coupling, followed by Boc deprotection in acidic condition provide compound of formula (IX). The amino group of compound of formula (IX) reacts with halide or acid anhydride via nucleophilic substitution or with acid via condensation or with ketone or aldehyde via reductive amination to provide final compound of formula (I). Furthermore, compound of formula (I) can also be obtained via condensation reaction between compound of formula (VII) and compound of formula (VIIb) in the presence of coupling reagent, such as PyBOP. Scheme 2
Figure imgf000053_0001
Wherein X is halogen. As depicted in Scheme 2, the synthesis of compounds of the present invention started from halogen compound of formula (XI). Suzuki coupling between compound of formula (XI) and compound of formula (XII) with a catalyst, such as Pd(dppf)Cl2, and a base, such as K2CO3, provides compound of formula (XIII). The following Buchwald coupling between compound of formula (XIII) and compound of formula (XIV) with a catalyst, such as RuPhos Pd G2, and a base, such as Cs2CO3, provides compound of formula (IV). The synthesis of final compound of formula (I) from compound of formula (IV) is the same as described in Scheme 1. Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. This invention also relates to a process for the preparation of a compound of formula (I) comprising any one of the following steps: a) the formation of compound of formula (I) via nucleophilic substitution or Buchwald cross coupling between compound of formula (VIII),
Figure imgf000054_0001
(VIII), and HR5; b) the formation of compound of formula (I) via nucleophilic substitution reaction
Figure imgf000054_0002
between compound of (IX), (IX), and halide or acid anhydride; or condensation reaction between compound of formula (IX) and acid; or reductive amination between compound of formula (IX) and ketone or aldehyde; the formation of compound of formula (I) via condensation reaction between compound of formula (VII),
Figure imgf000055_0001
compound of formula (VIIb),
Figure imgf000055_0002
reagent; wherein the coupling reagent in step c) can be, for example, PyBOP; X is halogen; HRa is heterocyclyl with reactive primary or secondary amino group. A compound of formula (I) or (Ia) when manufactured according to the above process is also an object of the invention. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: ACN: acetonitrile 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 DMSO: dimethyl sulfoxide DPPP: 1,3-Bis(diphenylphosphino)propane EA or EtOAc: ethyl acetate FA: formic acid EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HOBT: 1-Hydroxybenzotrizole h(s) or hr(s): hour (s) HMPA: Hexamethylphosphoric triamide 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 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(dppf)Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd-PEPPSI-IPentCl: (SP-4-1)-[1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-Palladium (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) TBD: 1,5,7-Triazabicylo[4.4.0]dec-5-ene T3P: Propylphosphonic anhydride TEA: trimethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: tetrahydrofuran TLC: thin layer chromatography TEMPO: 2,2,6,6-tetramethylpiperidinyloxy TTMSS: tris(trimethylsilyl)silane 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-[(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
Figure imgf000059_0001
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 A1-b) To a mixture of tert-butyl N-[(2R)-3-amino-2-hydroxy-propyl]carbamate (59.6 g, 313.25 mmol) and 1-bromo-2,5-difluoro-3-nitro-benzene (compound A1-a, 71.0 g, 298.33 mmol) in ACN (710 mL) was added potassium carbonate (82.4 g, 596.66 mmol). After being stirred at 50 °C for 2 hours, the mixture was filtered and the filtrate was concentrated to give compound A1-b (131 g). LCMS (M+H)+: 408. Step 2: preparation of tert-butyl N-[(2R)-3-(2-amino-6-bromo-4-fluoro-anilino)-2- hydroxy-propyl]carbamate (compound A1-c) To a solution of compound A1-b (63.0 g, 154.33 mmol) in methanol (1000 mL) was added Raney Ni (36.2 g, 617.31 mmol) and hydrazine hydrate (29.2 g, 583.1 mmol). After being stirred at 25 °C for 1 hr, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM, washed with water and brine. The organic layer was dried and concentrated to give compound A1-c (128 g). LCMS (M+H)+: 378. Step 3: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]carbamate (compound A1-d) To a solution of compound A1-c (123.0 g, 325.19 mmol) in anhydrous THF (1500 mL) was added trimethyl orthoacetate (136.7 mL, 1104 mmol) and pyridinium p-toluenesulfonate (11.7 g, 46.62 mmol). The reaction was stirred for 1 hr at 20 °C. The mixture was concentrated under reduced pressure to give compound A1-d (160 g). LCMS (M+H)+: 402. Step 4: preparation of tert-butyl N-[(2S)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]carbamate (compound A1-e) To a solution of compound A1-d (80.0 g, 198.88 mmol) and imidazole (40.6 g, 596.63 mmol) in DMF (765 mL) was added tert-butyldimethylchlorosilane (59.9 g, 397.75 mmol), The reaction was stirred for 18 hrs at 30 °C. The mixture was poured into cold NH4Cl aq. (2000 mL), extracted with EtOAc (800 mL) twice. The organic layer was dried and concentrated to give compound A1-e (94 g). LCMS (M+H)+: 516. Step 5: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-[tert-butyl(dimethyl)silyl]oxy-propyl]-N-methyl-carbamate (compound A1-f) To a solution of compound A1-e (82.0 g, 158.75 mmol) in DMF (800 mL) was added sodium hydride (60% in oil, 15.8 g, 396.89 mmol) at 0 °C and then stirred at 0 °C for 1 hr. Then iodomethane (90.1 g, 635.02 mmol) was added at 0 °C and The reaction was stirred at 0 °C for 1 hr. The reaction was quenched with water and extracted with EA. The organic layer was dried, concentrated and purified via column chromatography to give compound A1-f (44.4 g). LCMS (M+H-56)+: 530. Step 6: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-hydroxy-propyl]-N-methyl-carbamate (compound A1-g) A mixture of compound A1-f (39.8 g, 75.02 mmol) and TBAF/THF (1M, 150.0 mL, 150 mmol) was stirred at 20 °C for 2 hrs. The mixture was concentrated and the residue was diluted with EtOAc (600mL), washed with water and brine. The organic layer was dried and concentrated to give compound A1-g (39.4 g). LCMS(M+H)+: 416. Step 7: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound A1-h) To a solution of compound A1-g (17.4 g, 41.8 mmol) and iodoethane (5.0 mL, 62.7 mmol) in DMF (174 mL) was added sodium hydride (2.2 g, 55.0 mmol) at 0 °C. The reaction was stirred at 0 °C for 3 hrs. The reaction was then quenched with water and extracted with EA. The organic layer was dried and concentrated to give compound A1-h (20.4 g). LCMS (M+H)+: 444. Step 8: preparation of tert-butyl N-[(2R)-2-ethoxy-3-[5-fluoro-2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate (Intermediate A1) To a mixture of compound A1-h (19.4 g, 43.66 mmol) and bis(pinacolato)diboron (27.72 g, 109.15 mmol) in DMSO (194 mL) was added potassium acetate (8.6 g, 87.3 mmol), bis(triphenylphosphine)palladium(II) chloride (4.6 g, 6.55 mmol) and butyldi-1- adamantylphospine (4.7 g, 13.1 mmol). The mixture was degassed with N2 for three times, and then stirred at 130 °C for 2 hrs. The reaction was then poured into water (1000 mL) and extracted with EA (500 mL). The organic layer was dried and concentrated, the crude product was purified via column chromatography to give intermediate A1 (15 g). LCMS (M+H)+: 492. Intermediate A2 tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate
Figure imgf000062_0001
The title compound was prepared according to the following scheme:
Figure imgf000062_0002
Step 1: preparation of tert-butyl N-[(2R)-3-(7-bromo-5-fluoro-2-methyl-benzimidazol- 1-yl)-2-methoxy-propyl]-N-methyl-carbamate (compound A2-a) To a solution of compound A1-d (10.0 g, 26.02 mmol) in DMF (200 mL) was added CH3I (11.08 g, 78.07 mmol) at -10 °C under N2, then NaH (2.6 g, 65.06 mmol) was added slowly in portions. The reaction was stirred at -10 °C for 5 hrs. The reaction was stirred at 20 °C for another 12 hrs. The reaction was quenched with ice and cold NH4Cl aq., and then it was extracted with EA twice. The organic layer was dried and concentrated to afford compound A2-a (11.7 g). LCMS (M+H)+: 430. Step 2: preparation of tert-butyl N-[(2R)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate (Intermediate A2) The title compound was prepared in analogy to the preparation of intermediate A1 via using compound A2-a instead of compound A1-h in step 8. LCMS (M+H)+: 478. Intermediate A3 tert-butyl N-[3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]propyl]-N-methyl-carbamate
Figure imgf000063_0001
The title compound was prepared according to the following scheme:
Figure imgf000063_0002
The title compound was prepared in analogy to the preparation of intermediate A2 via using compound A3-a instead of compound A1-d in step 1. LCMS (M+H)+: 448. The compound A3-a was prepared in analogy to the preparation of compound A1-d via using tert-butyl N-(3-aminopropyl)carbamate instead of tert-butyl N-[(2R)-3-amino-2-hydroxy- propyl]carbamate in step 1. LCMS (M+H)+: 386. Intermediate A4 tert-butyl N-[(2S)-3-[5-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzimidazol-1-yl]-2-methoxy-propyl]-N-methyl-carbamate
Figure imgf000063_0003
The title compound was prepared according to the following scheme:
Figure imgf000063_0004
The title compound was prepared in analogy to the preparation of intermediate A2 by using compound A3-a instead of compound A1-d in step 1. LCMS (M+H)+: 478. The compound A4-a was prepared in analogy to the preparation of compound A1-d by using tert-butyl N-[(2S)-3-amino-2-hydroxy-propyl]carbamate instead of tert-butyl N-[(2R)-3- amino-2-hydroxy-propyl]carbamate in step 1. LCMS (M+H)+: 402. Intermediate B1 O1-benzyl O2-methyl (2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate
Figure imgf000064_0001
The title compound was prepared according to the following scheme:
Figure imgf000064_0002
A mixture of O1-benzyl O2-methyl (2S,4S)-4-aminopyrrolidine-1,2- dicarboxylate;hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol) and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 hrs. The mixture was cooled and poured into 150 mL water, then it was extracted with 25 mL EA for three times. The organic layer was concentrated to give an oil, then it was purified via prep- HPLC to give intermediate B1 (5.1 g), LCMS (M+H)+: 434. Intermediate B2 and B3 O1-benzyl O2-methyl (2S,4S)-4-[(4-chloropyrimidin-2-yl)amino]pyrrolidine-1,2- dicarboxylate (Intermediate B2) and O1-benzyl O2-methyl (2S,4S)-4-[(2-chloropyrimidin- 4-yl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate B3)
Figure imgf000064_0003
Intermediate B2 Intermediate B3 The title compound was prepared according to the following scheme: A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol) and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at rt for 48 hrs. The reaction was filtered and concentrated, the residue was purified via silica gel column chromatography (eluting with 10%- 30% PE in EtOAc) to give intermediate B2 (faster eluted, 1 g) and intermediate B3 (slower eluted, 6 g), LCMS (M+H)+: 391. Intermediate B4 O1-benzyl O2-methyl (2S,4S)-4-(4-chloropyrimidin-2-yl)oxypyrrolidine-1,2-dicarboxylate
Figure imgf000065_0001
The title compound was prepared according to the following scheme:
Figure imgf000065_0002
Intermediate B4 To a mixture of O1-benzyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.0 g, 107.4 mmol) and 4-chloro-2-methylsulfonyl-pyrimidine (20.0 g, 103.8 mmol) in anhydrous THF (340 mL) was added sodium hydride (60% in oil, 4.4 g, 110 mmol) in portions at room temperature under nitrogen, the resulting mixture was stirred at r.t. for 16 hours. The mixture was poured into aq. NH4Cl (200 mL) and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product, then it was purified via silica gel column chromatography to give intermediate B4 (27.0 g). LCMS (M+H)+: 392. Intermediate B5 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:
Figure imgf000066_0001
Intermediate B5 To a mixture of 4-bromo-2-hydroxypyridine (10.64 g, 61.16 mmol), O1-tert-butyl O2- methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.77 mmol) and PPh3 (16.04 g, 61.16 mmol) in Toluene (100 mL) was added DIAD (12.37 g, 61.16 mmol) at 0 °C under N2, The reaction was stirred at 100 °C for 1 hr. The mixture was concentrated and the residue was purified via prep-HPLC to afford intermediate B5 (12.5 g). LCMS (M-56+H)+: 345. Intermediate C1 (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
Figure imgf000066_0002
The title compound was prepared according to the following scheme:
Figure imgf000066_0003
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 C1-a) To a flask was added K2CO3 (3.36 g, 24.3 mmol), compound B1 (5.28 g, 12.15 mmol), compound A2 (5.8 g, 12.15 mmol), 1,4-dioxane (60 mL) and water (1 mL). The suspension was bubbled with N2 for 5 mins and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (992 mg, 1.21 mmol) was added. The mixture was heated to 90 oC and stirred for 16 hrs. The mixture was poured into water and extracted with EA. The organic layer was dried over Na2SO4 and concentrated, a brown oil was obtained. Then it was purified via silica gel column chromatography to give compound C1-a (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 C1-b) To the flask which contained compound C1-a (6.8 g, 9.65 mmol) was added tetrahydrofuran (20 mL). The brown solution was stirred at r.t. and 2 M LiOH (aq.) (20 mL, 40 mmol) was added dropwise. The final mixture was stirred at r.t. for 2 hrs. The mixture was diluted with water and pH was adjusted to 4 with 2 N aq. solution of HCl, and then it was extracted with DCM. The organic layer was dried and concentrated to give a foamy solid, which was dissolved in dichloromethane (5 mL) and TFA (5 mL). The brown solution was stirred at r.t. for 1 hr. Then it was concentrated to give compound C1-b (4.9 g) as an oil. LCMS (M+H)+: 591. Step 3: preparation of benzyl (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-10-carboxylate (compound C1-c) To a solution of HATU (4.57 g, 12.02 mmol,) and DIEA (10.5 mL, 60.1 mmol) in acetonitrile (1200 mL) was added another solution of compound C1-b (4.92 g, 6.01 mmol) in acetonitrile (1200 mL) dropwise in 4 hrs. The reaction mixture was concentrated, and the residue was purified via prep-HPLC to give compound C1-c (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 (Intermediate C1) To the flask containing compound C1-c (3.5 g, 6.11 mmol) was added TFA (30 mL). The brown solution was heated to reflux and stirred for 3 hrs. Then the reaction mixture was concentrated to give compound C1 (7 g) as a crude oil. LCMS (M+H)+: 439. Intermediate C2 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000068_0001
The title compound was prepared in analogy to the preparation of intermediate C1 by using intermediate A1 instead of intermediate A2 and intermediate B2 instead of intermediate B1. LCMS (M+H)+: 440. Intermediate C3 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000068_0002
The title compound was prepared in analogy to the preparation of intermediate C1 by using intermediate B2 instead of intermediate B1. LCMS (M+H)+: 440. Intermediate C4 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000068_0003
The title compound was prepared according to the following scheme: The title compound was prepared in analogy to the preparation of intermediate C1 by using compound C4-a (obtained from deprotection of intermediate A1 in acidic condition) instead of intermediate A2 and intermediate B5 instead of intermediate B2. LCMS (M+H)+: 454. Intermediate C5 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000069_0001
The title compound was prepared in analogy to the preparation of intermediate C1 by using intermediate A3 instead of intermediate A2 and using intermediate B4 instead of intermediate B1. LCMS (M+H)+: 441. Intermediate C6 (8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000069_0002
The title compound was prepared in analogy to the preparation of intermediate C1 via using intermediate A1 instead of intermediate A2 and using intermediate B4 instead of intermediate B1 in step 1. LCMS (M+H)+: 455. Intermediate C7 (8S,11S)-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000070_0001
The title compound was prepared in analogy to the preparation of intermediate C1 via using intermediate A3 instead of intermediate A2 and using intermediate B2 instead of intermediate B1 in step 1. LCMS (M+H)+: 410. Intermediate C8 (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000070_0002
The title compound was prepared according to the following scheme:
Step 1: preparation of 2-[(2S)-3-[benzyl(methyl)amino]-2-hydroxy-propyl]isoindoline- 1,3-dione (compound C8-b) To a solution of compound C8-a (30.0 g, 147.65 mmol) in ethanol (300 mL) was added N- methylbenzylamine (23 mL, 177 mmol) at 20 °C in one portion. The reaction was stirred at 80 °C for 2 h and then concentrated. The residue was purified by silica gel column chromatography to give compound C8-b (40.0 g) as yellow oil. LCMS (M+H)+: 325. Step 2: preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy- propyl]-N-methyl-carbamate (compound C8-c) To a solution of compound C8-b (30.0 g, 92.49 mmol) and di-t-butyldicarbonate (30.28 g, 138.74 mmol) in methanol (667 mL) was added wet Pd(OH)2/C(15.0 g, 10%) under N2 at 20 °C. The reaction was stirred under 50 psi of H2 at 40 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated, the residue was purified by flash chromatography to give compound C8-c (125 g, three batches workup together). LCMS (M-100+H)+: 235. Step 3: preparation of tert-butyl N-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-methoxy- propyl]-N-methyl-carbamate (compound C8-d) To a solution of NaH (5.8 g, 145 mmol) in dry DMF (220 mL) was added iodomethane (55 g, 387 mmol) at 0 °C under N2. The reaction was stirred at 0°C for 0.5 h. A solution of compound C8-c (32.25 g, 96.45 mmol, 1.0 eq) in dry DMF (130 mL) was added, and then the reaction was stirred at 20 °C for 18 h. The reaction was quenched with ice aq. NH4Cl (5 L) and extracted with EA(2 L×3). The organic layer was washed with brine (2 L×3), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography to give compound C8-d (110.0 g, , three batches workup together). LCMS (M- 100+H)+: 249. Step 4: preparation of tert-butyl N-[(2R)-3-amino-2-methoxy-propyl]-N-methyl- carbamate (compound C8-e) To a solution of compound C8-d (100.0 g, 287.03 mmol) in ethanol (30 mL) was added methylamine/ethanol (557.97 g, 6.1 mol) dropwise at 20 °C. The reaction was stirred at 60°C for 2 h. Then the reaction mixture was filtered and the filtrate was concentrated to give compound C8-e (80.0 g). Step 5: preparation of tert-butyl N-[(2R)-3-[(2-bromo-4-nitro-3-pyridyl)amino]-2- methoxy-propyl]-N-methyl-carbamate (compound C8-f) The mixture of 2-bromo-3-fluoro-4-nitro-pyridine (20.0 g, 90.51 mmol), compound C8-e (29.2 g, 133.77 mmol) and K2CO3 (25.0 g, 180.9 mmol) in ACN (200 mL) was stirred at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give compound C8-f (120.0 g, four batches workup together). LCMS (M-100+H)+: 321. Step 6: preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methyl-imidazo[4,5-c]pyridin- 3-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound C8-g) To a solution of compound C8-f (30.0 g, 71.55 mmol) in methanol (300 mL) was added Raney Ni (42.0 g, 715.62 mmol) under N2. Then hydrazine hydrate (35.82 g, 715.54 mmol) was added dropwise at 20 °C. The reaction was stirred at 20 °C for 4 h and then the mixture was filtered, the filtrate was concentrated to give a residue, which was extracted with DCM to give compound C8-g (28.2 g). LCMS (M+H)+: 391. Step 7: preparation of tert-butyl N-[(2R)-3-(4-bromo-2-methyl-imidazo[4,5-c]pyridin- 3-yl)-2-ethoxy-propyl]-N-methyl-carbamate (compound C8-h) To a solution of compound C8-g (50.0 g, 123.97 mmol) in anhydrous THF (500 mL) was added trimethyl orthoacetate (56 mL, 417 mmol) and pyridinium p-toluenesulfonate (5.0 g, 19.9 mmol). The reaction was stirred for 12 h at 80 °C and then concentrated. The residue was diluted with H2O and extracted with EA, the organic layer was dried and concentrated to give compound C8-h (47.0 g). LCMS (M+H)+: 415. Step 8: preparation of tert-butyl N-[(2R)-3-[4-(6-chloro-2-pyridyl)-2-methyl- imidazo[4,5-c]pyridin-3-yl]-2-methoxy-propyl]-N-methyl-carbamate (compound C8-i) To a solution of compound C8-h (40.0 g, 96.78 mmol), 6-chloropyridine-2-boronic acid pinacol ester (20.69 g, 86.38 mmol) and K3PO4 (41.38 g, 194.94 mmol) in 1,4-dioxane (400 mL) and water (40 mL) was added CataCXium A Pd G2 (12.94 g, 19.35 mmol) in one portion under N2 at 25°C. The reaction was stirred at 60 °C for 5 h under N2. The mixture was concentrated and the residue was purified by silica gel column chromatography to give compound C8-i (26.0 g). LCMS (M+H)+: 446. Step 9: preparation of O1-benzyl O2-methyl (2S,4S)-4-[[6-[3-[(2R)-3-[tert- butoxycarbonyl(methyl)amino]-2-methoxy-propyl]-2-methyl-imidazo[4,5-c]pyridin-4-yl]-2- pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound C8-j) To a solution of compound C8-i (26.0 g, 58.3 mmol), 1-benzyl 2-methyl (2S,4S)-4- aminopyrrolidine-1,2-dicarboxylate (19.47 g, 69.96 mmol) and cesium carbonate (47.5 g, 145.79 mmol) in 1,4-Dioxane (520 mL) was added Ruphos Pd G2 (6.8 g, 8.75 mmol) in one portion under N2. The reaction was stirred at 90 °C for 16 h under N2. The mixture was concentrated and the residue was purified by silica gel column chromatography to give compound C8-j (12.0 g). LCMS (M+H)+: 688. Step 10~13: preparation of (8S,11S,15R)-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Intermediate C8) The title compound was prepared in analogy to the preparation of intermediate C1 via using compound C8-j instead of compound C1-a. LCMS (M+H)+: 422. Intermediate C9 (8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000073_0001
The title compound was prepared in analogy to the preparation of intermediate C1 by using intermediate B3 instead of intermediate B1. LCMS (M+H)+: 440. Intermediate C10 (8S,11S)-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one Intermediate C10 was prepared in analogy to the preparation of intermediate C8 by using N-(3-aminopropyl)-N-methylcarbamic acid tert-butylester instead of tert-butyl N-[(2R)-3-amino- 2-hydroxy-propyl]carbamate. LCMS (M+H)+: 392. Intermediate C11 (8S,11S,15R)-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000074_0001
The title compound was prepared according to the following scheme:
Figure imgf000074_0002
Step 1~3: preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methylimidazo[4,5- b]pyridin-1-yl)propyl]-N-methyl-carbamate (compound C11-c) Compound C11-c was prepared in analogy to the preparation of compound C8-h by using 3-fluoro-2-nitropyridine instead of 2-bromo-3-fluoro-4-nitro-pyridine. LCMS (M+H+): 335. Step 4: preparation of tert-butyl N-[(2R)-2-methoxy-3-(2-methyl-4-oxido-imidazo[4,5- b]pyridin-4-ium-1-yl)propyl]-N-methyl-carbamate (compound C11-d) To a solution of compound C11-c (10.0 g, 29.9 mmol) in DCM (100 mL) was added 3- chlorobenzenecarboperoxoic acid (9.1 g, 44.82 mmol). The reaction mixture was stirred at 40 °C for 5 h, and then washed with saturated NaHCO3 (100 mL) and Na2SO3 (100 mL). The organic layer was dried and concentrated to give compound C11-d (10.0 g) as yellow oil. LCMS (M+H+): 351. Step 5: preparation of tert-butyl N-[(2R)-3-(7-bromo-2-methyl-imidazo[4,5-b]pyridin- 1-yl)-2-methoxy-propyl]-N-methyl-carbamate (compound 121f) To a solution of compound C11-d (9.0 g, 0.23 mmol) in DMF (90 mL) and THF (90 mL) was added POBr3 (18 g, 1.57 mmol) in one portion at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, and then the mixture was quenched with ice saturated NaHCO3 (500 mL). The resulted mixture was extracted with DCM, the organic layer was dried and concentrated to give a crude product, which was purified by prep-HPLC to give compound C11-e (2.7 g) as yellow oil. LCMS (M+H+): 413. Step 6~11: preparation of (8S,11S,15R)-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Intermediate C11) Intermediate C11 was prepared in analogy to the preparation of intermediate C8 by using compound C11-e instead of compound C8-h. LCMS (M+H+): 422. Intermediate C12 (8S,11S,15S)-22-fluoro-15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000075_0001
The title compound was prepared in analogy to the preparation of intermediate C1 by using intermediate A4 instead of intermediate A2 and using intermediate B4 instead of intermediate B1. LCMS (M+H)+: 441. Intermediate D1 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000076_0001
The title compound was prepared according to the following scheme:
Figure imgf000076_0002
Step 1: preparation of 2,4-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5- yl)methyleneamino]aniline (compound D1-b) A mixture of compound D1-a (22.9 g, 126.9 mmol) and 2,4,6-trichloropyrimidine-5- carbaldehyde (22.4 g, 105.8 mmol) in DMF (400 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into water, a yellow solid formed, which was collected by filtration to give compound D1-b (41 g) as a yellow solid. LCMS (M+H+): 337 Step 2: preparation of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1) To a mixture of compound D1-b (42.0 g, 124.4 mmol) and 4Å MS (40.0 g) in NMP (400 mL) was stirred at 110 °C for 12 h. Then the reaction mixture was filtered and the filtrate was poured into water, and then extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give intermediate D1 (15.5 g) as a yellow solid. LCMS (M+H+): 301. Intermediate D2 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000076_0003
The title compound was prepared according to the following scheme: Step 1: preparation of (3,5-difluoro-2-pyridyl)hydrazine (compound D2-b) A mixture of compound D2-a (5.0 g, 37.57 mmol) and hydrazine hydrate (18.63 mL, 375.72 mmol) in ethanol (50 mL) was stirred at 65 °C for 16 h. After cooling to rt, white solid formed, which was collected by filtration to give compound D2-b (3.7 g). LCMS (M+H)+: 146. Step 2: preparation of 3,5-difluoro-N-[(Z)-(2,4,6-trichloropyrimidin-5- yl)methyleneamino]pyridin-2-amine (compound D2-c) To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.0 g, 14.19 mmol) in DMF (30 mL) was added compound D2-b (2.0 g, 13.78 mmol) and then it was stirred at 25 °C for 2 h. The reaction mixture was poured into water and a solid formed, which was collected by filtration to give compound D2-c (4.0 g). LCMS (M+H)+: 338. Step 3: preparation of 4,6-dichloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4- d]pyrimidine (Intermediate D2) A solution of compound D2-c (3.5 g, 10.34 mmol) in 1,4-dioxane (35 mL) was stirred at 120 °C for 4 h. The reaction mixture poured into ice water and EA. The organic layer was separated, dried and concentrated, the residue was purified by silica gel column chromatography to give Intermediate D2 (1.2 g) as a yellow solid. LCMS (M+H)+: 302. Intermediate D3 4,6-dichloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000077_0001
The title compound was prepared according to the following scheme: Step 1: preparation of (2-fluoro-4-methoxy-phenyl) hydrazine (compound D3-b) To a solution of 2-flouro-4-methoxyaniline (5.0 g, 35.43 mmol) in HCl/water (59 mL, 354 mmol) was added a solution of NaNO2 (3.67 g, 53.14 mmol) in water (17.5 mL) dropwise at 0 °C. After the reaction mixture was stirred for 1 h at 0 °C, a solution of tin(II) chloride dihydrate (19.98 g, 88.56 mmol) in conc. HCl (29.5 mL, 354.3 mmol) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h and then the reaction mixture was poured into ice water. The pH of aqueous layer was adjusted to around 10-12 with 20% aqueous sodium hydroxide and then it was extracted with EA. The organic layer was dried and concentrated to give the crude product compound D3-b (4.8 g) as a dark brown solid, which was used directly without further purification. Step 2~3: preparation of 4, 6-dichloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3, 4-d] pyrimidine(Intermediate D3) The title compound was prepared in analogy to the preparation of intermediate D2 by using compound D3-b instead of compound D2-b. LCMS (M+H)+: 313. Intermediate D4 4,6-dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine
Figure imgf000078_0001
The title compound was prepared according to the following scheme: Step 1: preparation of (3-fluoro-4-pyridyl)hydrazine (compound D4-b) To a solution of compound D4-a (1.0 g, 7.6 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (9.71 mL, 195.77 mmol) at 0 °C. The reaction was stirred at 100 °C for 16 h. Then the reaction was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give compound D4-b (700.0 mg) as a light yellow solid. LCMS (M+H+): 128. Step 2: preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carbonitrile (compound D4-d) A mixture of compound D4-b (700.0 mg, 5.51 mmol), compound D4-c (672 mg, 5.51 mmol) and DIEA (2.9 mL, 16.52 mmol) in ethanol (12 mL) was heated to 80 °C for 2 h. Then the reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give compound D4-d (1 g) as a light brown solid. LCMS (M+H+): 204. Step 3: preparation of 5-amino-1-(3-fluoro-4-pyridyl)pyrazole-4-carboxamide (compound D4-e) A solution of compound D4-d (1 g, 4.92 mmol) in sulfuric acid (6.0 mL) was stirred at 25 °C for 2 h. Then the mixture was poured into 50 mL ice-cold water and adjusted pH to 8, the aqueous phase was freeze-dried to give the crude product, which was dissolved in 50 mL of DCM/CH3OH (10:1). The solid was filtered off and the filtrate was concentrated to give compound D4-e (1 g) as a light yellow solid, which was used directly without further purification. LCMS (M+H+): 222. Step 4: preparation of 1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine-4,6-diol (compound D4-f) A mixture of compound D4-e (1 g, 4.52 mmol) and urea (13.6 g, 226.05 mmol) was stirred at 200 °C for 16 h. The reaction mixture was cooled to 25 °C and then water (100 mL) was added. The mixture was filtered and the filtrate was freeze-dried to give the crude product, which was purified by prep-HPLC to give compound D4-f (240.0 mg) as a light yellow solid. LCMS (M+H+): 248. Step 5: preparation of 4,6-dichloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidine (Intermediate D4) To a solution of compound D4-f (140.0 mg, 0.57 mmol) in phosphorus oxychloride (3.0 mL) was added phosphorus pentachloride (590 mg, 2.83 mmol). The reaction was stirred at 80 °C for 16 h. Then the mixture was concentrated and the residue was quenched with ice-cold sat.aq NaHCO3 and DCM. The organic layer was separated, dried and concentrated, the residue was purified by prep-TLC to give Intermediate D4 (30.0 mg) as a white solid. LCMS (M+H+): 284. Intermediate D5 4-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoro-benzonitrile
Figure imgf000080_0001
The title compound was prepared according to the following scheme:
Step 1~3: preparation of 4, 6-dichloro-1-(2-fluoro-4-iodo-phenyl)pyrazolo [3,4- d]pyrimidine (compound D5-d) Compound D5-d was prepared in analogy to the preparation of intermediate D3 by using compound D5-a instead of compound D3-a. Step 4: preparation of 4-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoro- benzonitrile (Intermediate D5) To a solution of compound D5-d (400.0 mg, 0.98 mmol) in DMF (3 mL) was added cuprous cyanide (438 mg, 4.89 mmol) at 25 °C. The reaction was stirred at 100 °C for 3 h. Then the reaction mixture was diluted with water and extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give Intermediate D5 (60.0 mg) as a light yellow solid. LCMS (M+H+): 308. Intermediate D6 2-(4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoro-phenol
Figure imgf000081_0001
The title compound was prepared according to the following scheme: To a solution of compound D6-1 (2.0 g, 6.39 mmol, the synthesis refer to the preparation of Intermediate D3 by using (4-fluoro-2-methoxy-phenyl)hydrazine instead of compound D3-a) in DCM (40 mL) was added BCl3/THF (32 mL, 32 mmol) at -78 °C and then stirred at 25 °C for 12 hours. The reaction was poured into ice-water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to give intermediate D6 (1.51 g), LCMS (M+H+): 299. Intermediate D9 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-3,6- diazabicyclo[3.1.1]heptan-2-one
Figure imgf000082_0001
The title compound was prepared according to the following scheme:
Figure imgf000082_0002
Step 1: preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound D9-a) To a stirred mixture of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.3 g, 6.1 mmol) in THF (20 mL) was added sodium hydride (441 mg, 18.3 mmol) in portions at 0 °C under nitrogen atmosphere. After 0.5 hours, iodomethane (1.82 g, 12.8 mmol) in THF (5 mL) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 h. The reaction solution was purified by reversed phase flash column to afford compound D9-a (1.3 g) as a white solid. LCMS (M+H+): 227. Step 2: preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-b) A mixture of compound D9-a (1.30 g, 5.75 mmol) in 4 M HCl in dioxane (15.0 mL,) was stirred at 25 °C for 2 h. The reaction was concentrated. The residue was lyophilized to give compound D9-b (800 mg) as a yellow oil. LCMS (M+H+): 127. Step 3: preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound D9-c) A stirred mixture of compound D9-b (800 mg, 6.34 mmol), compound D15-a (1.18 g, 3.17 mmol) and DIPEA (2.50 g, 19.3 mmol) in ACN (10.0 mL) was stirred at 80 °C for 48 h. The reaction was concentrated and the residue was purified by silica gel column chromatography to give compound D9-c (1.20 g) as a yellow oil. LCMS (M+H+): 463. Step 4: preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (intermediate D9) A mixture of compound D9-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25 °C for 2 h. The reaction was concentrated and the residue was lyophilized to give intermediate D9 (860 mg) as an off-white solid. LCMS (M+H+): 373. Intermediate D10 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]- 3,6-diazabicyclo[3.1.1]heptan-2-one
Figure imgf000083_0001
Intermediate D10 was prepared in analogy to the preparation of Intermediate D9 by using bromomethylcyclopropane instead of iodomethane. LCMS (M+H+): 413. Intermediate D11 3-(2,2-difluoroethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]- 3,6-diazabicyclo[3.1.1]heptan-2-one
Figure imgf000084_0001
Intermediate D11 was prepared in analogy to the preparation of Intermediate D9 by using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane. LCMS (M+H+): 423. Intermediate D12 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-2-one
Figure imgf000084_0002
Intermediate D12 was prepared in analogy to the preparation of Intermediate D9 by using 1-fluoro-2-iodo-ethane instead of iodomethane. LCMS (M+H+): 405. Intermediate D13 3-[6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile
Figure imgf000084_0003
Intermediate D13 was prepared in analogy to the preparation of Intermediate D9 by using 3-iodopropanenitrile instead of iodomethane. LCMS (M+H+): 412. Intermediate D14 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]-3-ethyl-3,6- diazabicyclo[3.1.1]heptan-2-one
Figure imgf000085_0001
Intermediate D14 was prepared in analogy to the preparation of Intermediate D9 by using iodoethane instead of iodomethane. LCMS (M+H+): 387. Intermediate D15 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol
Figure imgf000085_0002
The title compound was prepared according to the following scheme:
Figure imgf000086_0001
Step 1: preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidine (compound D15-a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate D1, 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. 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 D15-a (400 mg). LCMS (M+H+): 373. Multiple batches were repeated and combined. Step 2: preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound D15-b) To a solution of compound D15-a (1.25 g, 3.35 mmol), tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate (731 mg, 3.69 mmol) in DMSO (20 mL) was added N,N-diisopropylethylamine (1.75 mL, 10 mmol) and then stirred at 100 °C for 1 h. The reaction was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried and concentrated to give compound D15-b (2.0 g) as a brow oil. LCMS (M+H+):535. Multiple batches were repeated and combined. Step 3: preparation of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate D15) To a solution of compound D15-b (4.0 g, 7.48 mmol) in DCM (20 mL) was added TFA at 0 °C and then stirred at 25 °C for 2 hrs. The reaction was concentrated and the residue was diluted with water (50 mL), which was lyophilized to give Intermediate D15 (2.5 g) as a yellow solid. LCMS (M+H+): 345. Intermediate D16 and Intermediate D17 tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo- pyrrolidine-1-carboxylate and tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylate
Figure imgf000087_0001
The title compound was prepared according to the following scheme:
Figure imgf000087_0002
Step 1: preparation of tert-butyl 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]pyrrolidine-1-carboxylate (Intermediate D16-b) To a 40 mL vial equipped with a stir bar was added compound D15-a (1 g, 2.68 mmol), compound D16-a (1.3 g, 4.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (30. mg, 0.03 mmol), NiCl2.dtbbpy (5 mg, 0.01 mmol), tris(trimethylsilyl)silane (0.83 mL, 2.68 mmol), sodium carbonate (568 mg, 5.37 mmol) in DMA (10 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with a cooling fan to keep the reaction temperature at 25 °C for 14 hr. The reaction 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 give compound D16-b (1 g) as a yellow oil. LCMS (M+H+): 508. Step 2: preparation of tert-butyl 4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1-carboxylate (Intermediate D16) and tert-butyl 3-[4- benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-pyrrolidine-1- carboxylate (Intermediate D17) To a solution of compound D16-b (800.0 mg, 1.58 mmol) in DCM (15 mL) was added ruthenium(IV) oxide (209 mg, 1.58 mmol) and a solution of sodium periodate (1.35 g, 6.31 mmol) in water (15 mL). The reaction was stirred at 30 °C for 16 h and then the reaction mixture was filtered. The filtrate was extracted with DCM, dried and concentrated, the residue was purified by prep-TLC to give Intermediate D16 (170.0 mg, faster eluted, EtOAc:PE=1:2) and Intermediate D17 (130.0 mg, slower eluted, EtOAc:PE=1:2). LCMS (M+H+): 522. Intermediate D18 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile
Figure imgf000088_0001
Intermediate D18 The title compound was prepared according to the following scheme:
Figure imgf000088_0002
Step 1: preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]propanenitrile (compound D18-a) To a 40 mL vial equipped with a stir bar was added compound D15-a (100.0 mg, 0.27 mmol), compound D18-a (78 mg, 0.43 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (3.0 mg), NiCl2.dtbbpy (1 mg), tris(trimethylsilyl)silane (0.08 mL, 0.27 mmol), sodium carbonate (57 mg, 0.54 mmol) in DMA (10 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with a cooling fan to keep the reaction temperature at 25 °C for 14 hr. The reaction was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound D18-b (35.0 mg) as colorless oil. LCMS (M+H+): 392. Step 2: preparation of 3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]propanenitrile (Intermediate D18) To a solution of compound D18-b (35.0 mg, 0.09 mmol) in DCM (0.500 mL) was added TFA (0.5 mL) at 0 °C. The reaction was stirred at 40 °C for 1 hr under nitrogen, and then the mixture was concentrated, the residue was purified by prep-HPLC to afford Intermediate D18 (18.0 mg) as a white solid. LCMS (M+H+): 302. Intermediated D19 1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidin-4-ol
Figure imgf000089_0001
Step 1: preparation of 4-benzyloxy-1-(2,4-difluorophenyl)-6-(thietan-3- yl)pyrazolo[3,4-d]pyrimidine (compound D19-b) To an 20 mL vial equipped with a stir bar was added compound D15-a (500.0 mg, 1.34 mmol), thietane-3-carboxylic acid (317 mg, 2.68 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (15.0 mg, 0.01 mmol), NiCl2.dtbbpy (53.4 mg, 0.13 mmol), cesium carbonate (1311 mg, 4.02 mmol) in DMF (6 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away) with a cooling fan to keep the reaction temperature at 25 °C for 14 hr. The reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by silica gel column chromatography to give compound D19-b (0.4 g) as a yellow solid. LCMS (M+H+): 411 Step 2: preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]thietane 1,1-dioxide (compound D19-c) To a solution of compound D19-b (200.0 mg, 0.49 mmol) in DCM (3 mL) was added m- CPBA (210.2 mg, 0.97 mmol) at 0 °C and stirred at 20 °C for 1 h. The reaction was filtered, and the filtrate was washed with saturated Na2SO3, dried over Na2SO4 and then concentrated. The residue was purified by prep-TLC to give compound D19-c (50.0 mg) as colorless oil. LCMS (M+H+): 443 Step 3: preparation of 1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4- d]pyrimidin-4-ol (intermediate D19) To a solution of compound D19-c (50.0 mg, 0.11 mmol) in DCM ( 0.5 mL) was added TFA( 0.5 mL) at 0 °C and then stirred at 40 °C for 2 h. The reaction mixture was concentrated to give intermediate D19 (50.0 mg) as a brown oil. LCMS (M+H+): 353. Intermediated D20 and Intermediated D21 Trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile and cis-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]cyclobutanecarbonitrile
Figure imgf000090_0001
The title compound was prepared according to the following scheme: Step 1: preparation of 3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]cyclobutanecarbonitrile and 3-[4-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarbonitrile (compound D20-b1 & compound D20-b2) To a 40 mL vial equipped with a stir bar was added compound D15-a (1 g, 2.7 mmol), 3- cyanocyclobutanecarboxylic acid (503 mg, 4.0 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (300 mg, 0.03 mmol), NiCl2.dtbbpy (107 mg, 0.27 mmol), cesium carbonate (2.6 g, 8.05 mmol) in DMA (20 mL). The vial was sealed and placed under nitrogen was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling a fan to keep the reaction temperature at 25 °C for 14 hr. The reaction was poured into water, extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound D20-b1 (300.0 mg, faster eluted) and compound D20-b2 (170.0 mg, slower eluted). LCMS (M+H+): 418. The configuration of compound D20-b1 and compound D20-b2 were confirmed by 2D NMR. Step 2: preparation of trans-3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]cyclobutanecarbonitrile (intermediated D20) and cis-3-[1-(2,4- difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6-yl]cyclobutanecarbonitrile (intermediated D21) To a solution of compound D20-b1 (100.0 mg, 0.24 mmol) in DCM (1 mL) was added TFA(1 mL) at 0°C and then stirred at 20 °C for 1 h. The reaction was concentrated to give intermediated D20 (100.0 mg) as brown oil. LCMS (M+H): 328 To a solution of compound D21-b2 (100.0 mg, 0.24 mmol) in DCM (1 mL) was added TFA(1 mL) at 0°C and then stirred at 20 °C for 1 h. The reaction was concentrated to give intermediated D21 (100.0 mg) as brown oil. LCMS (M+H+): 328 Intermediate D22 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin-6- yl]methyl]cyclopropanecarbonitrile
Figure imgf000092_0001
The title compound was prepared according to the following scheme:
Figure imgf000092_0002
Step 1: preparation of 1-(iodomethyl)cyclopropanecarbonitrile (compound D22-b) To a solution of PPh3 (3.5 g, 13.39 mmol) and 1H-imidazole (0.91 g, 13.39 mmol) in DCM (15 mL) was added iodine (3.4 g, 13.39 mmol) slowly at 0 °C under N2. The reaction was stirred at 0° C for 0.5 h under N2 and then compound D22-a (1.0 g, 10.3 mmol) in DCM (5 mL) was added slowly. The reaction mixture was stirred at 25 °C for 15 hrs and then concentrated, the residue was purified by silica gel column chromatography to give compound D22-b (1.2 g) as a colorless oil. Step 2: preparation of 1-[[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile (compound D22-c) To a 40 mL vial equipped with a stir bar was added compound D15-a (300.0 mg, 0.8 mmol), compound D22-b (267 mg, 1.29 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (9 mg, 0.01 mmol), NiCl2.dtbbpy (1.6 mg), tris(trimethylsilyl)silane (0.25 mL, 0.8 mmol), sodium carbonate (170 mg, 1.61 mmol) in DMA (6 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with a cooling fan to keep the reaction temperature at 25 °C for 14 hr. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound D22-c (110.0 mg) as yellow oil. LCMS (M+H+): 418. Step 3: preparation of 1-[[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile (Intermediate D22) To a solution of compound D22-c (60.0 mg, 0.14 mmol) in DCM (0.5 mL) was added TFA (1.0 mL) at 0°C. The reaction was stirred at 40 °C for 1 hr and then concentrated, the residue was purified by prep-HPLC to afford Intermediate D22 (55.0 mg) as a yellow oil. LCMS (M+H+): 328. Intermediate E1 (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
Figure imgf000093_0001
The title compound was prepared according to the following scheme:
Figure imgf000093_0002
A mixture of intermediate C1 (0.90 g, 2.05 mmol), intermediate D1 (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, The reaction was concentrated and the residue was purified by silica gel column chromatography to give intermediate E1 (1 g), LCMS (M+H+): 703. Intermediate E2 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy- 22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000094_0001
Intermediate E2 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C2 instead of intermediate C1. LCMS (M+H+): 718. Intermediate E3 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000094_0002
Intermediate E3 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C3 instead of intermediate C1. LCMS (M+H+): 704. Intermediate E4 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000095_0001
Intermediate E4 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C8 instead of intermediate C1. LCMS (M+H+): 686. Intermediated E5 (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000095_0002
Intermediate E5 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C7 instead of intermediate C1. LCMS (M+H+): 674. Intermediate E6 4-[6-chloro-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-1-yl]-3-fluoro-benzonitrile Intermediate E6 was prepared in analogy to the preparation of Intermediate E1 by using intermediate D5 instead of intermediate D1. LCMS (M+H+): 710. Intermediate E7 (8S,11S,15R)-10-[6-chloro-1-(4-fluoro-2-hydroxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000096_0001
Intermediate E7 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C8 instead of intermediate C1 and intermediate D6 instead of intermediate D1. LCMS (M+H+): 684. Intermediate E8 (8S,11S,15R)-10-[6-chloro-1-(2-fluoro-4-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000096_0002
Intermediate E8 was prepared in analogy to the preparation of Intermediate E1 by using intermediate D3 instead of intermediate D1. LCMS (M+H+): 715. Intermediate E9 (8S,11S,15R)-10-[6-chloro-1-(3-fluoro-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000097_0001
Intermediate E9 was prepared in analogy to the preparation of Intermediate E1 by using intermediate D4 instead of intermediate D1. LCMS (M+H+): 715. Intermediate E10 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000097_0002
Intermediate E10 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C9 instead of intermediate C1. LCMS (M+H+): 704. Intermediate E11 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy- 22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Intermediate E11 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C6 instead of intermediate C1. LCMS (M+H+): 719. Intermediate E12 (8S,11S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo [15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2,4,6(26),18,20(24),21-heptaen-12-one
Figure imgf000098_0001
Intermediate E12 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C10 instead of intermediate C1. LCMS (M+H+): 656. Intermediate E13 (8S,11S,15R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000099_0001
Intermediate E13 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C11 instead of intermediate C1. LCMS (M+H+): 686. Intermediate E14 (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-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000099_0002
Intermediate E14 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C5 instead of intermediate C1. LCMS (M+H+): 705. Intermediate E15 (8S,11S,15S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000099_0003
Intermediate E15 was prepared in analogy to the preparation of Intermediate E1 by using intermediate C12 instead of intermediate C1. LCMS (M+H+): 705. Intermediate E16 (8S,11S,15R)-10-[6-chloro-1-(3,5-difluoro-2-pyridyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-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
Figure imgf000100_0001
Intermediate E16 was prepared in analogy to the preparation of Intermediate E1 by using intermediate D2 instead of intermediate D1. LCMS (M+H+): 705. Intermediate F1 (8S, 11S, 15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)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
Figure imgf000100_0002
The title compound was prepared according to the following scheme:
Step 1: preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24] hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6- diazabicyclo [3.1.1]heptane-3-carboxylate (compound F1-b) A solution of Intermediate E1 (1 g, 1.42 mmol), compound F1-a (1.4 g, 7.11 mmol), CsF (1.08 g, 7.11 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.11 mmol) in DMA (10 mL) was stirred at 120 °C for 15 hrs. The reaction solution was diluted with water and extracted with EA. The organic layer was dried and concentrated to give compound F1-b (1 g) as an off-white solid. LCMS (M+H)+: 865. Step 2: preparation of (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl) 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 (Intermediate F1) To a solution of compound F1-b (1 g, 1.16 mmol) in DCM (10 mL) was added TFA (5.0 mL) at 0° C. The reaction mixture was stirred at 20 °C for 1 h and then concentrated to give Intermediate F1 (1 g) as yellow oil. LCMS (M+H)+: 765. Intermediate F2 (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one Intermediate F2 was prepared in analogy to the preparation of Intermediate F1 by using intermediate E4 instead of intermediate E1. LCMS (M+H+): 748. Intermediate F3 (8S,11S,15R)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(3-fluoro-4-pyridyl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000102_0001
Intermediate F3 was prepared in analogy to the preparation of Intermediate F1 by using intermediate E9 instead of intermediate E1. LCMS (M+H+): 748. Example 1 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidin-1-yl)ethyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000102_0002
The title compound was prepared according to the following scheme:
Figure imgf000103_0001
To a tube was added intermediate F1 (20 mg, 22.76 µmol), 1-(2-chloroethyl)-2- pyrrolidone (17 mg, 113.79 µmol), potassium carbonate (15.7 mg, 113.79 µmol), sodium iodide (13.6 mg, 91.03 µmol) and DMF (1 mL). The suspension was heated to 100 °C and stirred for 16 hrs. The mixture was filtered and purified via prep-HPLC to give Example 1 (3 mg) as a white powder. LCMS (M+H)+: 876, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.52 - 7.46 (m, 1H), 7.39 (dd, J = 2.0, 10.0 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.22 - 7.16 (m, 1H), 7.15 - 7.11 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.03 (br dd, J = 4.1, 15.1 Hz, 1H), 5.42 - 5.36 (m, 1H), 4.71 - 4.66 (m, 1H), 4.55 - 4.48 (m, 1H), 4.40 - 4.30 (m, 2H), 4.29 - 4.20 (m, 2H), 4.13 - 4.02 (m, 1H), 3.96 - 3.78 (m, 3H), 3.64 - 3.50 (m, 2H), 3.47 - 3.33 (m, 3H), 3.16 - 3.14 (m, 1H), 3.06 (s, 3H), 3.05 - 2.94 (m, 2H), 2.94 - 2.92 (m, 3H), 2.86 - 2.77 (m, 2H), 2.74 - 2.67 (m, 3H), 2.59 - 2.48 (m, 2H), 2.46 - 2.31 (m, 2H), 2.12 - 2.00 (m, 2H), 1.98 - 1.84 (m, 1H). Example 2 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H- [1,2,4]triazolo[4,3-a]pyrazin-7-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
Figure imgf000103_0002
The title compound was prepared according to the following scheme: To a tube was added intermediate E1 (30 mg, 42.67 µmol), DIEA (27 mg, 37 µL, 213.3 µmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride (19 mg, 85.33 µmol), cesium fluoride (13 mg, 85.33 µmol) and dimethyl sulfoxide (1 mL). The solution was stirred at 100 °C for 16 hrs. The mixture was purified via prep-HPLC to give Example 2 (8 mg) as a white powder. LCMS (M+H)+: 859, 1H NMR (400 MHz, METHANOL- d4) δ = 8.30 (s, 1H), 7.91 - 7.84 (m, 1H), 7.65 (dt, J = 5.9, 8.7 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.57 - 7.52 (m, 1H), 7.26 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.21 (dd, J = 4.6, 15.5 Hz, 1H), 5.47 (d, J = 8.9 Hz, 1H), 5.30 - 5.03 (m, 2H), 4.68 (t, J = 4.8 Hz, 1H), 4.49 (dd, J = 5.9, 11.3 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.31 - 4.20 (m, 4H), 4.18 - 4.08 (m, 1H), 3.86 (dd, J = 9.1, 14.4 Hz, 1H), 3.17 - 3.13 (m, 3H), 3.13 - 3.07 (m, 1H), 3.02 - 2.95 (m, 3H), 2.81 (s, 3H), 2.80 - 2.76 (m, 1H), 2.65 - 2.50 (m, 2H). Example 3 and Example 4 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)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 and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2- difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)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
Figure imgf000104_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(2,2-difluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 3a) To a tube was added tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (80 mg, 376.91 µmol) and DMF (1 mL). The solution was stirred at r.t. and NaH (40 mg, 1.51 mmol) was added. A few minutes later, 2,2-difluoroethyl trifluoromethanesulfonate (161 mg, 99.94 µL, 753.83 µmol) was added. The final mixture was heated to 60 °C and stirred for 16 hrs. The reaction was quenched with water, and diluted with DCM. The organic layer was separated, dried and concentrated. The crude oil was purified via silica gel chromatography to give compound 3a (20 mg) as an oil. LCMS (M+H)+: 277. Step 2: preparation of 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 3b) To the flask containing compound 3a (20 mg, 72.39 µmol) was added TFA (1.48 g, 1 mL, 12.98 mmol, 179.308 eq) and dichloromethane (1 mL). The solution was stirred at r.t. for 1 hr and concentrated to give compound 3b (37 mg) as a crude oil, which was used directly in the next step. LCMS (M+H)+: 177. Step 3: preparation of (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)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 and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)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 (Example 3 & Example 4) To a tube was added intermediate E1 (30 mg, 42.67 µmol), DIEA (44.1 mg, 60 µL, 341.34 µmol), compound 3b (37 mg, 128. µmol), cesium fluoride (13 mg, 85 µmol) and dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 100 °C for 16 hrs and then purified via prep-HPLC to give Example 3 (2 mg, faster eluted) and Example 4 (2 mg, slower eluted) as white powders. Example 3, LCMS (M+H)+: 843, 1H NMR (400 MHz, METHANOL-d4) δ = 8.33 (s, 1H), 7.89 - 7.82 (m, 1H), 7.68 - 7.58 (m, 1H), 7.51 (dd, J = 2.3, 7.8 Hz, 1H), 7.44 (dd, J = 2.5, 10.3 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.76 (d, J = 8.8 Hz, 1H), 6.18 - 6.07 (m, 1H), 5.41 - 5.37 (m, 1H), 5.37 - 5.34 (m, 1H), 4.69 - 4.64 (m, 1H), 4.59 - 4.54 (m, 1H), 4.51 - 4.39 (m, 1H), 4.32 - 4.21 (m, 2H), 4.20 - 4.08 (m, 1H), 4.05 - 3.99 (m, 1H), 3.96 - 3.86 (m, 1H), 3.84 - 3.73 (m, 1H), 3.46 - 3.37 (m, 2H), 3.13 - 3.09 (m, 3H), 3.01 (br d, J = 13.5 Hz, 1H), 2.95 (s, 3H), 2.89 - 2.81 (m, 1H), 2.76 (s, 4H), 2.60 - 2.53 (m, 1H), 2.52 - 2.43 (m, 1H), 1.79 (d, J = 9.0 Hz, 1H). Example 4, LCMS (M+H)+: 843, 1H NMR (400 MHz, METHANOL-d4) δ = 8.34 (s, 1H), 7.90 - 7.81 (m, 1H), 7.63 - 7.57 (m, 1H), 7.56 - 7.46 (m, 2H), 7.28 - 7.21 (m, 1H), 7.20 - 7.11 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.11 (br dd, J = 4.5, 15.3 Hz, 1H), 6.04 - 5.80 (m, 1H), 5.46 (d, J = 8.6 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.61 - 4.56 (m, 1H), 4.54 - 4.48 (m, 1H), 4.43 (dd, J = 6.2, 11.4 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.25 - 4.16 (m, 2H), 4.15 - 4.01 (m, 2H), 3.40 (br d, J = 11.4 Hz, 1H), 3.15 - 3.10 (m, 1H), 3.07 (s, 3H), 2.98 - 2.95 (m, 1H), 2.95 - 2.92 (m, 3H), 2.87 - 2.80 (m, 1H), 2.78 (s, 1H), 2.75 (s, 3H), 2.61 - 2.43 (m, 2H), 2.09 - 1.98 (m, 1H). Example 5 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 5 was prepared in analogy to the preparation of Example 1 by using 2- (chloromethyl)thiazole instead of 1-(2-chloroethyl)-2-pyrrolidone in step 1. Example 5 (5 mg) was obtained as a white solid. LCMS (M+H)+: 862., 1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.86 - 7.79 (m, 1H), 7.66 - 7.56 (m, 2H), 7.48 - 7.41 (m, 1H), 7.38 (dd, J = 2.4, 8.1 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.18 - 7.13 (m, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.94 (br dd, J = 4.4, 15.6 Hz, 1H), 5.38 - 5.30 (m, 1H), 4.67 (t, J = 4.8 Hz, 1H), 4.52 - 4.44 (m, 1H), 4.43 - 4.33 (m, 1H), 4.30 - 4.23 (m, 2H), 4.23 - 4.18 (m, 1H), 4.17 - 3.93 (m, 3H), 3.92 - 3.83 (m, 1H), 3.67 - 3.43 (m, 2H), 3.16 - 3.05 (m, 2H), 3.04 - 2.96 (m, 3H), 2.91 - 2.86 (m, 3H), 2.83 - 2.72 (m, 1H), 2.70 - 2.59 (m, 4H), 2.59 - 2.44 (m, 2H), 1.89 - 1.79 (m, 1H). Example 6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-
Figure imgf000107_0001
Example 6 was prepared in analogy to the preparation of Example 34 by using 2- oxaspiro[3.3]heptane-6-carboxylic acid instead of oxetane-2-carboxylic acid. Example 6 (12 mg) was obtained as a white solid. LCMS (M+H)+: 889, 1H NMR (400 MHz, METHANOL-d4) δ = 8.28 (d, J = 4.5 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.67 - 7.55 (m, 1H), 7.42 - 7.32 (m, 1H), 7.31 - 7.21 (m, 2H), 7.17 (br t, J = 8.5 Hz, 1H), 7.14 - 7.08 (m, 1H), 6.75 - 6.67 (m, 1H), 5.95 (br dd, J = 4.3, 15.7 Hz, 1H), 5.42 - 5.28 (m, 1H), 4.72 - 4.57 (m, 3H), 4.54 - 4.39 (m, 3H), 4.38 - 4.33 (m, 1H), 4.32 - 4.26 (m, 2H), 4.26 - 4.10 (m, 3H), 4.00 - 3.86 (m, 1H), 3.44 - 3.34 (m, 2H), 3.15 - 3.02 (m, 4H), 3.02 - 2.93 (m, 1H), 2.92 - 2.86 (m, 3H), 2.86 - 2.79 (m, 1H), 2.79 - 2.57 (m, 5H), 2.55 - 2.26 (m, 5H), 2.22 - 1.91 (m, 1H). Example 7 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000108_0001
The title compound was prepared according to the following scheme:
Figure imgf000108_0002
To a tube was added intermediate F1 (30 mg, 34.1 µmol), 1H-pyrazole-5-carbaldehyde (10 mg, 102.41 µmol), DIEA (13 mg, 18 µL, 102.4 µmol) and ethanol (2 mL). The suspension was heated to 60 °C and stirred for 2 hrs, then sodium triacetoxyborohydride (25 mg, 119.4 µmol) was added. The mixture was kept stirring at the temperature for another 2 hrs. The mixture was concentrated and purified via prep-HPLC to give Example 7 (11 mg) as a white powder. LCMS (M+H)+: 845, 1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.84 - 7.77 (m, 1H), 7.57 - 7.49 (m, 1H), 7.29 (dd, J = 2.6, 8.4 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.17 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.19 - 5.94 (m, 1H), 5.88 (br d, J = 13.0 Hz, 1H), 5.40 - 5.25 (m, 1H), 4.69 - 4.63 (m, 1H), 4.50 - 4.41 (m, 1H), 4.39 - 4.10 (m, 5H), 3.90 (br dd, J = 9.2, 13.9 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.39 (br d, J = 9.9 Hz, 1H), 3.15 - 2.96 (m, 4H), 2.91 - 2.85 (m, 1H), 2.84 (s, 3H), 2.82 - 2.73 (m, 2H), 2.55 (s, 3H), 2.51 - 2.41 (m, 3H), 1.90 - 1.81 (m, 1H). Example 8 and Example 9 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000109_0001
The title compound was prepared according to the following scheme:
Figure imgf000109_0002
Example 8 and Example 9 To a tube was added (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinylphosphorus hexafluorophosphate (209 mg, 402.87 µmol), compound D9 (100 mg, 268.5 µmol), DIPEA (139 mg, 187 µL, 1.07 mmol) and DMF (6 mL). The solution was stirred at 50 °C for 2 hrs and compound C1 (179 mg, 322.3 µmol) was added. The mixture was stirred at 80 °C for another 2 hrs and purified via prep-HPLC to give compound 8a (110 mg) as a white powder. The compound 8a was separated via SFC to give Example 8 (42 mg, faster eluted) and Example 9 (50 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 45%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 8, LCMS (M+H)+: 793, 1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.84 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.16 (dt, J = 2.4, 9.8 Hz, 2H), 7.12 - 7.06 (m, 1H), 6.70 - 6.61 (m, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.45 (d, J = 8.8 Hz, 1H), 4.67 - 4.60 (m, 1H), 4.59 - 4.54 (m, 1H), 4.49 - 4.40 (m, 1H), 4.35 - 3.99 (m, 5H), 3.98 - 3.88 (m, 1H), 3.12 - 3.03 (m, 3H), 2.95 (br d, J = 13.3 Hz, 1H), 2.91 - 2.86 (m, 1H), 2.85 - 2.81 (m, 3H), 2.81 - 2.73 (m, 4H), 2.59 - 2.54 (m, 3H), 2.53 - 2.39 (m, 2H), 1.73 (d, J = 8.8 Hz, 1H). Example 9, LCMS (M+H)+: 793, 1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.69 - 7.57 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.15 (br dd, J = 2.6, 10.4 Hz, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 4.5, 15.5 Hz, 1H), 5.38 (d, J = 9.0 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.58 - 4.49 (m, 1H), 4.47 - 4.37 (m, 1H), 4.32 - 4.10 (m, 3H), 4.10 - 3.98 (m, 1H), 3.97 - 3.82 (m, 2H), 3.12 - 3.04 (m, 3H), 2.96 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.80 - 2.72 (m, 4H), 2.71 - 2.59 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.38 (m, 2H), 1.75 (d, J = 8.8 Hz, 1H). Example 10 and Example 11 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19- pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one Example 10 and Example 11 were prepared in analogy to the preparation of Example 8 and Example 9 by using Intermediate C4 instead of Intermediate C1. The mixture was separated via SFC to give Example 10 (16 mg, faster eluted) and Example 11 (15 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 30%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃). Example 10, LCMS (M+H)+: 808, 1H NMR (400 MHz, METHANOL-d4) δ = 8.36 - 8.30 (m, 2H), 7.69 - 7.57 (m, 1H), 7.36 - 7.31 (m, 1H), 7.27 - 7.20 (m, 1H), 7.19 - 7.08 (m, 2H), 7.07 - 7.02 (m, 1H), 6.99 (dd, J = 2.4, 10.0 Hz, 1H), 5.77 (t, J = 3.9 Hz, 1H), 5.43 (d, J = 9.3 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.58 - 4.52 (m, 1H), 4.50 - 4.28 (m, 3H), 4.20 - 4.02 (m, 3H), 3.52 - 3.42 (m, 1H), 3.41 - 3.33 (m, 1H), 3.30 - 3.26 (m, 1H), 3.08 - 2.98 (m, 3H), 2.91 - 2.78 (m, 2H), 2.78 - 2.73 (m, 4H), 2.73 - 2.63 (m, 2H), 2.63 - 2.58 (m, 3H), 1.73 (d, J = 8.8 Hz, 1H), 0.69 - 0.59 (m, 3H). Example 11, LCMS (M+H)+: 808, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 - 8.30 (m, 2H), 7.65 (dt, J = 5.9, 8.6 Hz, 1H), 7.33 (dd, J = 2.5, 8.6 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 7.12 - 7.03 (m, 2H), 6.99 (dd, J = 2.5, 10.0 Hz, 1H), 5.76 (t, J = 3.6 Hz, 1H), 5.34 (d, J = 9.6 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.59 - 4.51 (m, 1H), 4.50 - 4.43 (m, 1H), 4.36 (br dd, J = 4.0, 11.4 Hz, 1H), 4.15 - 4.01 (m, 3H), 3.94 - 3.84 (m, 1H), 3.50 - 3.39 (m, 1H), 3.38 - 3.33 (m, 1H), 3.29 - 3.25 (m, 1H), 3.10 (br d, J = 14.9 Hz, 1H), 3.07 - 3.00 (m, 3H), 2.90 - 2.79 (m, 2H), 2.79 - 2.72 (m, 3H), 2.72 - 2.63 (m, 2H), 2.62 - 2.58 (m, 3H), 1.75 (d, J = 8.8 Hz, 1H), 0.65 (t, J = 7.0 Hz, 3H). Example 12 and Example 13 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000112_0001
Example 12 and Example 13 were prepared in analogy to the preparation of Example 8 and Example 9 by using Intermediate C5 instead of Intermediate C1 and using Intermediate D10 instead of Intermediate D9. The mixture was separated via SFC to give Example 12 (41 mg, faster eluted) and Example 13 (37 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Ethanol «Mobile_phasePrep»; Gradient: B 40%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 12, LCMS (M+H)+: 835, 1H NMR (400 MHz, METHANOL-d4) δ = 8.79 - 8.74 (m, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.47 - 7.39 (m, 2H), 7.28 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 5.88 - 5.64 (m, 2H), 5.53 (d, J = 8.8 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.46 - 4.40 (m, 1H), 4.35 - 4.26 (m, 1H), 4.23 - 3.91 (m, 4H), 3.44 - 3.33 (m, 2H), 3.07 - 2.97 (m, 3H), 2.94 - 2.84 (m, 2H), 2.83 - 2.76 (m, 5H), 2.71 - 2.63 (m, 1H), 2.63 - 2.57 (m, 3H), 2.56 - 2.47 (m, 1H), 1.73 (d, J = 8.6 Hz, 1H), 0.96 - 0.82 (m, 1H), 0.39 - 0.13 (m, 4H). Example 13, LCMS (M+H)+: 835, 1H NMR (400 MHz, METHANOL-d4) δ = 8.77 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 7.68 - 7.58 (m, 2H), 7.48 - 7.38 (m, 2H), 7.29 - 7.20 (m, 1H), 7.20 - 7.11 (m, 1H), 5.90 - 5.61 (m, 2H), 5.52 (br d, J = 8.5 Hz, 1H), 4.70 - 4.50 (m, 1H), 4.49 - 4.42 (m, 1H), 4.41 - 4.35 (m, 1H), 4.19 (br dd, J = 11.4, 15.3 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.98 (br dd, J = 9.7, 13.8 Hz, 1H), 3.43 - 3.31 (m, 2H), 3.11 - 2.98 (m, 3H), 2.93 - 2.72 (m, 7H), 2.70 - 2.63 (m, 1H), 2.62 - 2.57 (m, 3H), 2.53 (br t, J = 8.5 Hz, 1H), 1.75 (d, J = 8.8 Hz, 1H), 0.82 - 0.49 (m, 1H), 0.40 - -0.19 (m, 4H). Example 14 and Example 15 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1R,5S)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000113_0001
Example 14 and Example 15 were prepared in analogy to the preparation of Example 8 and Example 9 by using Intermediate C8 instead of Intermediate C1 and using Intermediate D10 instead of Intermediate D9. The mixture was separated via SFC to give Example 14 (17 mg, faster eluted) and Example 15 (20 mg, slower eluted) as a white solid. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃). Example 14, LCMS (M+H)+: 816, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 7.89 - 7.82 (m, 1H), 7.67 - 7.57 (m, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 4.2, 15.3 Hz, 1H), 5.47 (d, J = 8.6 Hz, 1H), 4.69 - 4.54 (m, 2H), 4.51 - 4.38 (m, 1H), 4.37 - 4.04 (m, 5H), 3.58 - 3.45 (m, 1H), 3.44 - 3.34 (m, 1H), 3.12 - 3.02 (m, 3H), 3.02 - 2.94 (m, 1H), 2.92 - 2.85 (m, 1H), 2.85 - 2.82 (m, 3H), 2.81 - 2.69 (m, 2H), 2.68 - 2.62 (m, 3H), 2.59 - 2.51 (m, 1H), 2.51 - 2.40 (m, 1H), 1.73 (d, J = 8.8 Hz, 1H), 0.97 - 0.56 (m, 1H), 0.34 - -0.13 (m, 4H). Example 15, LCMS (M+H)+: 816, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.4 Hz, 1H), 8.31 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.11 (m, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.03 (br dd, J = 3.1, 14.9 Hz, 1H), 5.44 (br d, J = 8.9 Hz, 1H), 4.65 (br t, J = 4.9 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.50 - 4.35 (m, 1H), 4.32 - 4.10 (m, 3H), 4.09 - 3.92 (m, 2H), 3.45 - 3.32 (m, 2H), 3.19 - 3.02 (m, 3H), 3.01 - 2.85 (m, 2H), 2.85 - 2.75 (m, 4H), 2.75 - 2.68 (m, 1H), 2.65 (s, 3H), 2.60 - 2.50 (m, 1H), 2.49 - 2.38 (m, 1H), 1.74 (br d, J = 8.9 Hz, 1H), 0.92 - 0.49 (m, 1H), 0.40 - -0.18 (m, 4H). Example 16 and Example 17 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000114_0001
Example 16 and Example 17 were prepared in analogy to the preparation of Example 8 and Example 9 by using Intermediate C8 instead of Intermediate C1. The mixture was separated via SFC to give Example 16 (22 mg, faster eluted) and Example 17 (24 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL/min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 16, LCMS (M+H)+: 776, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 7.91 - 7.82 (m, 1H), 7.68 - 7.57 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.02 (dd, J = 4.3, 15.4 Hz, 1H), 5.48 (d, J = 8.8 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.60 - 4.53 (m, 1H), 4.47 (br dd, J = 6.6, 11.4 Hz, 1H), 4.33 - 4.03 (m, 4H), 3.98 - 3.88 (m, 1H), 3.30 - 3.27 (m, 1H), 3.14 - 3.03 (m, 3H), 3.02 - 2.90 (m, 1H), 2.87 - 2.80 (m, 4H), 2.80 - 2.75 (m, 3H), 2.74 - 2.68 (m, 1H), 2.67 - 2.62 (m, 3H), 2.62 - 2.51 (m, 1H), 2.46 (ddd, J = 4.4, 8.7, 13.4 Hz, 1H), 1.74 (d, J = 8.6 Hz, 1H). Example 17, LCMS (M+H)+: 776, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.4 Hz, 1H), 8.31 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.18 - 7.11 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.03 (dd, J = 4.3, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.68 - 4.62 (m, 1H), 4.57 - 4.51 (m, 1H), 4.50 - 4.39 (m, 1H), 4.31 - 4.16 (m, 2H), 4.13 - 4.03 (m, 1H), 3.95 (br dd, J = 9.1, 14.1 Hz, 1H), 3.87 (dd, J = 1.9, 11.8 Hz, 1H), 3.30 - 3.26 (m, 1H), 3.14 - 3.07 (m, 3H), 2.95 (br d, J = 13.9 Hz, 1H), 2.84 (s, 3H), 2.80 (br d, J = 12.4 Hz, 2H), 2.76 - 2.68 (m, 3H), 2.65 (s, 3H), 2.60 - 2.52 (m, 1H), 2.48 (ddd, J = 4.3, 9.1, 13.5 Hz, 1H), 1.75 (d, J = 8.8 Hz, 1H). Example 18 and Example 19 (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2- difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000115_0001
Example 18 and Example 19 were prepared in analogy to the preparation of Example 3 and Example 4 by using Intermediate E4 instead of Intermediate E1. The mixture was separated via prep-HPLC to give Example 18 (17 mg, faster eluted) and Example 19 (18 mg, slower eluted) as a white powder. Example 18, LCMS (M+H)+: 826, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.12 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.34 - 6.14 (m, 1H), 6.03 (dd, J = 4.4, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.60 - 4.52 (m, 1H), 4.51 - 4.41 (m, 1H), 4.36 (dt, J = 4.3, 14.0 Hz, 1H), 4.30 - 4.20 (m, 2H), 4.18 - 4.06 (m, 1H), 4.02 (br d, J = 11.3 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.86 - 3.69 (m, 1H), 3.47 - 3.39 (m, 1H), 3.17 - 3.05 (m, 3H), 2.96 (br d, J = 13.6 Hz, 1H), 2.84 (s, 3H), 2.81 - 2.79 (m, 1H), 2.73 (br d, J = 12.5 Hz, 1H), 2.68 - 2.60 (m, 3H), 2.60 - 2.52 (m, 1H), 2.51 - 2.41 (m, 1H), 1.79 (br d, J = 9.0 Hz, 1H). Example 19, LCMS (M+H)+: 826, 1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (d, J = 5.5 Hz, 1H), 8.34 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 5.4 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.24 (ddd, J = 2.8, 8.9, 10.1 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.97 (dd, J = 4.1, 15.4 Hz, 1H), 5.93 - 5.79 (m, 1H), 5.45 (d, J = 8.6 Hz, 1H), 4.68 - 4.62 (m, 1H), 4.62 - 4.55 (m, 1H), 4.43 (dd, J = 6.4, 11.4 Hz, 1H), 4.28 (d, J = 11.4 Hz, 1H), 4.24 - 4.14 (m, 2H), 4.14 - 4.06 (m, 2H), 4.05 - 3.98 (m, 1H), 3.40 (d, J = 11.5 Hz, 1H), 3.15 - 3.01 (m, 4H), 2.93 - 2.83 (m, 2H), 2.82 (s, 3H), 2.75 (d, J = 13.5 Hz, 1H), 2.62 (s, 3H), 2.54 (dt, J = 4.1, 9.6 Hz, 1H), 2.50 - 2.41 (m, 1H), 1.77 (d, J = 8.9 Hz, 1H). Example 20 and Example 21 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000116_0001
Example 20 and Example 21 were prepared in analogy to the preparation of Example 3 and Example 4 by using compound iodoethane instead of compound 2,2-difluoroethyl trifluoromethanesulfonate in step 1. The mixture was separated via SFC to give Example 20 (26 mg, faster eluted) and Example 21 (19 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm.; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 50%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 20, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.29 (s, 1H), 7.83 - 7.77 (m, 1H), 7.65 - 7.59 (m, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 (dt, J = 2.5, 9.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 8.4, 14.4 Hz, 1H), 5.81 (dd, J = 4.3, 15.5 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.46 - 4.35 (m, 1H), 4.20 (br d, J = 11.5 Hz, 1H), 4.17 - 4.02 (m, 3H), 4.02 - 3.89 (m, 1H), 3.46 - 3.35 (m, 1H), 3.30 - 3.23 (m, 1H), 3.14 - 3.00 (m, 4H), 2.96 - 2.87 (m, 1H), 2.87 - 2.80 (m, 4H), 2.79 - 2.72 (m, 1H), 2.59 - 2.53 (m, 3H), 2.52 - 2.37 (m, 2H), 1.79 - 1.66 (m, 1H), 0.99 - 0.72 (m, 3H). Example 21, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.63 (dt, J = 3.4, 8.9 Hz, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.19 - 7.11 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.69 - 6.63 (m, 1H), 5.81 (br dd, J = 4.2, 15.6 Hz, 1H), 5.40 (d, J = 9.0 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.58 - 4.48 (m, 1H), 4.47 - 4.34 (m, 1H), 4.30 - 4.21 (m, 1H), 4.20 - 4.00 (m, 2H), 3.98 - 3.82 (m, 2H), 3.50 - 3.35 (m, 1H), 3.27 (br d, J = 11.9 Hz, 1H), 3.08 (br s, 3H), 2.99 - 2.87 (m, 2H), 2.84 (s, 3H), 2.81 - 2.74 (m, 2H), 2.57 (s, 3H), 2.52 - 2.38 (m, 2H), 1.73 (d, J = 8.8 Hz, 1H), 0.88 - 0.63 (m, 3H). Example 22 and Example 23 3-[(1R,5S)-6-[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]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile and 3-[(1S,5R)-6-[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]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl]propanenitrile
Figure imgf000117_0001
Example 22 and Example 23 were prepared in analogy to the preparation of Example 3 and Example 4 by using compound 3-bromopropionitrile instead of compound 2,2-difluoroethyl trifluoromethanesulfonate in step 1. The mixture was purified and separated via prep-HPLC to give Example 22 (19 mg, faster eluted) and Example 23 (19 mg, slower eluted) as a white powder. Example 22, LCMS (M+H)+: 832, 1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 2H), 7.11 - 7.05 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.82 (dd, J = 4.4, 15.5 Hz, 1H), 5.40 (br d, J = 8.8 Hz, 1H), 4.68 - 4.43 (m, 3H), 4.39 - 4.06 (m, 4H), 4.05 - 3.99 (m, 1H), 3.98 - 3.85 (m, 2H), 3.13 - 2.99 (m, 4H), 2.93 (br d, J = 13.9 Hz, 1H), 2.89 - 2.82 (m, 4H), 2.81 - 2.65 (m, 1H), 2.62 - 2.54 (m, 3H), 2.53 - 2.28 (m, 4H), 1.78 (br d, J = 8.9 Hz, 1H). Example 23, LCMS (M+H)+: 832, 1H NMR (400 MHz, METHANOL-d4) δ = 8.32 (s, 1H), 7.85 - 7.77 (m, 1H), 7.71 - 7.63 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.24 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.10 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 4.3, 15.5 Hz, 1H), 5.48 (br d, J = 8.6 Hz, 1H), 4.67 - 4.61 (m, 1H), 4.61 - 4.54 (m, 1H), 4.41 (dd, J = 6.3, 11.4 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.23 - 4.05 (m, 4H), 4.02 - 3.89 (m, 1H), 3.43 - 3.33 (m, 1H), 3.10 - 3.04 (m, 3H), 3.03 - 2.95 (m, 1H), 2.94 - 2.87 (m, 1H), 2.87 - 2.83 (m, 3H), 2.83 - 2.77 (m, 2H), 2.60 (s, 3H), 2.57 - 2.47 (m, 2H), 2.46 - 2.33 (m, 2H), 1.77 (d, J = 8.9 Hz, 1H). Example 24 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000118_0001
The title compound was prepared according to the following scheme:
Figure imgf000118_0002
Step 1: preparation of tert-butyl 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (compound 24b) The flask contained compound 24a (20 mg, 94.67 µmol) was cooled with dry ice/ethanol bath and methylmagnesium bromide (1 M in THF) (600 µL, 600 µmol) was added portion-wise. The final mixture was warmed to r.t. slowly and stirred for 1 hr. The reaction was quenched with ice and then diluted with EA and water. The two-phase mixture was separated and the organic layer was dried and concentrated. The compound 24b (32 mg) was obtained as a crude oil and used in the next step directly. LCMS (M+H)+: 228. Step 2: preparation of 3-methyl-6-azabicyclo[3.1.1]heptan-3-ol (compound 24c) To the flask contained compound 24b (32 mg, 140.78 µmol) was added dichloromethane (1 mL) and TFA (1.48 g, 1 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr and concentrated to give compound 24c (45 mg) as a yellow oil, which was used in the next step directly. LCMS (M+H)+: 128. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3- methyl-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 24) To a tube was added intermediate E1 (40 mg, 56.89 µmol), DIEA (44 mg, 60 µL, 343.55 µmol), compound 24c (45 mg, 139.92 µmol) and DMSO (1.5 mL). The solution was stirred at 110 °C for 16 hrs. The mixture was purified via prep-HPLC to give Example 24 (25 mg) as a white powder. LCMS (M+H)+: 794, 1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.48 (dd, J = 2.6, 7.7 Hz, 1H), 7.40 (dd, J = 2.6, 10.4 Hz, 1H), 7.23 (ddd, J = 2.8, 8.8, 10.3 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 6.13 (dd, J = 4.6, 15.6 Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.66 (t, J = 4.9 Hz, 1H), 4.46 (dd, J = 6.1, 11.2 Hz, 1H), 4.39 - 4.11 (m, 4H), 4.01 - 3.85 (m, 1H), 3.14 - 3.03 (m, 3H), 2.99 (br d, J = 12.9 Hz, 1H), 2.95 - 2.91 (m, 3H), 2.77 - 2.69 (m, 4H), 2.68 - 2.61 (m, 1H), 2.61 - 2.46 (m, 3H), 2.44 - 2.33 (m, 1H), 2.21 (d, J = 8.1 Hz, 1H), 1.88 - 1.68 (m, 2H), 1.06 (s, 3H). Example 26 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000119_0001
Example 26 was prepared in analogy to the preparation of Example 3 by using compound 3-fluoro-3-(iodomethyl)oxetane instead of 2,2-difluoroethyl trifluoromethanesulfonate. LCMS (M+H)+: 850, 1H NMR (400 MHz, METHANOL-d4) δ = 8.39 - 8.18 (m, 2H), 7.90 - 7.82 (m, 1H), 7.66 - 7.53 (m, 2H), 7.45 (d, J = 7.3 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.12 (m, 1H), 6.74 (dd, J = 8.3, 19.3 Hz, 1H), 6.09 - 5.94 (m, 1H), 5.48 - 5.34 (m, 1H), 4.71 - 4.40 (m, 6H), 4.39 - 4.01 (m, 6H), 4.00 - 3.75 (m, 2H), 3.42 - 3.32 (m, 2H), 3.19 - 3.04 (m, 3H), 3.00 - 2.91 (m, 1H), 2.90 - 2.81 (m, 3H), 2.81 - 2.72 (m, 1H), 2.72 - 2.59 (m, 3H), 2.59 - 2.39 (m, 2H), 1.86 - 1.73 (m, 1H). Example 27 and Example 28 (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(3,5-difluoro-2-pyridyl)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 and (8S,11S,15R)-10-[6-[(1S,5R)-3- (cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(3,5-difluoro-2- pyridyl)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
Figure imgf000120_0001
Example 27 and Example 28 were prepared in analogy to the preparation of Example 3 and Example 4 by using intermediate E16 instead of intermediate E1 and iodomethylcyclopropane instead of 2,2-difluoroethyl trifluoromethanesulfonate. The mixture was separated via SFC to give Example 27 (14 mg, faster eluted) and Example 28 (11 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: Ethyl pyridine II 250 × 30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for IPA «Mobile_phasePrep»; Gradient: B 25%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 °C). Example 27, LCMS (M+H)+: 834, 1H NMR (400 MHz, METHANOL-d4) δ = 8.46 (br s, 1H), 8.37 (s, 1H), 7.93 (br t, J = 6.9 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.39 (dd, J = 2.1, 8.0 Hz, 1H), 7.28 (br dd, J = 2.3, 10.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.96 (dd, J = 4.6, 15.4 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.60 - 4.53 (m, 1H), 4.48 - 4.38 (m, 1H), 4.34 - 4.32 (m, 1H), 4.30 (dd, J = 1.9, 4.0 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.20 - 4.13 (m, 3H), 4.12 - 4.02 (m, 2H), 3.98 - 3.85 (m, 1H), 3.14 - 3.05 (m, 3H), 3.00 - 2.93 (m, 1H), 2.91 - 2.85 (m, 3H), 2.81 - 2.77 (m, 1H), 2.69 - 2.62 (m, 3H), 2.57 - 2.40 (m, 2H), 1.75 (d, J = 8.8 Hz, 1H), 0.68 - 0.50 (m, 1H), 0.24 - -0.18 (m, 4H). Example 28, LCMS (M+H)+: 834, 1H NMR (400 MHz, METHANOL-d4) δ = 8.46 (br s, 1H), 8.37 (s, 1H), 7.98 - 7.89 (m, 1H), 7.87 - 7.77 (m, 1H), 7.39 (dd, J = 2.4, 8.1 Hz, 1H), 7.30 (br dd, J = 2.4, 10.4 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.74 - 6.65 (m, 1H), 5.93 (dd, J = 4.3, 15.4 Hz, 1H), 5.47 (d, J = 8.8 Hz, 1H), 4.68 - 4.55 (m, 2H), 4.50 - 4.40 (m, 1H), 4.30 - 4.23 (m, 1H), 4.23 - 3.89 (m, 4H), 3.59 - 3.34 (m, 2H), 3.12 - 3.01 (m, 3H), 3.00 - 2.91 (m, 1H), 2.90 - 2.82 (m, 4H), 2.82 - 2.70 (m, 2H), 2.68 - 2.61 (m, 3H), 2.60 - 2.39 (m, 2H), 1.74 (d, J = 8.8 Hz, 1H), 0.90 - 0.54 (m, 1H), 0.34 - -0.12 (m, 4H). Example 29 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidin-3- 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
Figure imgf000121_0001
The title compound was prepared according to the following scheme:
Step 1: preparation of 4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidin- 6-yl]pyrrolidin-2-one (compound 29a) To a solution of compound Intermediate D16 (100.0 mg, 0.19 mmol) in DCM (2 mL) was added TFA (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h and then concentrated to give compound 29a (100.0 mg) as light yellow oil, which was used directly without further purification. LCMS (M+H+): 332. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(5-oxopyrrolidin-3- 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 29b) To a solution of compound 29a (100.0 mg, 0.3 mmol), PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) was added DIEA (0.03 mL, 0.15 mmol) at 25 °C. The reaction was stirred at 25 °C for 0.5 h and then a mixture of compound Intermediate C1 (150 mg, 0.27 mmol), DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added and stirred at 25 °C for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound 29b (70.0 mg) as a light yellow solid. LCMS (M+H+): 752. Step 3: preparation of (8S,11S,15R)-10-[6-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- oxo-pyrrolidin-3-yl]-1-(2,4-difluorophenyl)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 29d) To a solution of compound 29b (50.0 mg, 0.07 mmol) in DMF (1 mL) was added NaH (5 mg, 0.2 mmol) at 0 °C under N2. After being stirred at 0 °C for 2 h, a solution of compound 29c (24 mg, 0.1 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 25 °C for 6 h, then quenched with ice-cold NH4Cl solution and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound 29d (25.0 mg) as a light yellow solid. LCMS (M+H+): 910. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)- 5-oxo-pyrrolidin-3-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 (Example 29) To a solution of compound 29d (25.0 mg, 0.03 mmol) in THF (1 mL) was added TBAF in THF (0.05 mL, 0.07 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h and then diluted with water. The aqueous layer was extracted with EtOAc, the organic layer was washed with brine, dried and concentrated. The crude product was purified by prep-HPLC to give Example 29 (8.0 mg) as a light yellow solid. LCMS (M+H+): 796.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 1.9 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.51 - 7.42 (m, 2H), 7.25 - 7.16 (m, 1H), 7.15 - 7.03 (m, 2H), 6.69 (br d, J = 8.3 Hz, 1H), 6.10 - 6.01 (m, 1H), 5.42 - 5.29 (m, 1H), 4.64 - 4.58 (m, 1H), 4.44 - 4.38 (m, 1H), 4.25 - 4.17 (m, 2H), 3.87 - 3.78 (m, 2H), 3.58 - 3.48 (m, 4H), 3.08 - 3.04 (m, 1H), 3.00 - 2.94 (m, 3H), 2.90 - 2.83 (m, 4H), 2.77 - 2.67 (m, 5H), 2.50 - 2.42 (m, 2H), 1.64 - 1.53 (m, 1H), 1.34 - 1.30 (m, 1H). Example 30 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidin-3- 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
Figure imgf000123_0001
Example 30 was prepared in analogy to the preparation of Example 29 by using Intermediate D17 instead of Intermediate D16. Example 30 (2.8 mg) as a white solid. LCMS (M+H+): 796.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 - 8.45 (m, 1H), 7.95 - 7.86 (m, 1H), 7.72 - 7.64 (m, 1H), 7.62 - 7.58 (m, 1H), 7.57 - 7.52 (m, 1H), 7.34 - 7.27 (m, 1H), 7.26 - 7.16 (m, 2H), 6.80 (d, J = 8.5 Hz, 1H), 6.22 - 6.13 (m, 1H), 5.45 (d, J = 9.1 Hz, 1H), 4.74 - 4.69 (m, 1H), 4.56 - 4.51 (m, 1H), 4.36 - 4.29 (m, 2H), 3.99 - 3.91 (m, 2H), 3.71 - 3.60 (m, 4H), 3.51 - 3.41 (m, 1H), 3.19 - 3.14 (m, 1H), 3.11 - 3.06 (m, 3H), 3.03 - 2.97 (m, 4H), 2.87 - 2.79 (m, 5H), 2.72 - 2.64 (m, 1H), 2.61 - 2.52 (m, 2H). Example 31 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-carboxamide
Figure imgf000124_0001
The title compound was prepared according to the following scheme:
Figure imgf000124_0002
To a solution of Intermediate F1 (40.0 mg, 0.05 mmol), TEA (60.0 mg, 0.59 mmol) in DCM (1 mL) was added dimethylcarbamyl chloride (0.01 mL, 0.05 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 h and then concentrated. The residue was purified by prep-HPLC to give Example 31 (24 mg) as a white solid. LCMS (M+H)+: 836.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.91 - 7.83 (m, 1H), 7.65 - 7.53 (m, 3H), 7.30 - 7.12 (m, 3H), 6.78 (d, J = 8.5 Hz, 1H), 6.27 - 6.04 (m, 1H), 5.42 - 5.31 (m, 1H), 4.67 (t, J = 4.7 Hz, 1H), 4.46 (d, J = 5.9, 11.4 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.28 (d, J = 7.1 Hz, 2H), 4.26 - 4.15 (m, 2H), 4.07 - 3.87 (m, 2H), 3.55 - 3.41 (m, 2H), 3.17 - 3.10 (m, 1H), 3.09 - 3.02 (m, 3H), 3.00 - 2.97 (m, 3H), 2.88 - 2.81 (m, 3H), 2.76 (s, 1H), 2.74 - 2.68 (m, 6H), 2.67 - 2.61 (m, 1H), 2.61 - 2.47 (m, 2H), 1.61 - 1.50 (m, 1H). Example 32 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-sulfonamide
Figure imgf000125_0001
Example 32 was prepared in analogy to the preparation of Example 31 by using dimethylsulfamoylchloride instead of dimethylcarbamyl chloride. Example 32 (25 mg) was obtained as a white solid. LCMS (M+H)+: 872.1H NMR (400 MHz, METHANOL-d4) δ = 8.28 (s, 1H), 7.87 - 7.81 (m, 1H), 7.62 - 7.55 (m, 2H), 7.54 - 7.48 (m, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.10 (m, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.23 (dd, J = 4.8, 15.4 Hz, 1H), 5.31 (d, J = 9.0 Hz, 1H), 4.62 (t, J = 4.6 Hz, 1H), 4.47 - 4.36 (m, 2H), 4.30 (br s, 2H), 4.22 (br d, J = 11.3 Hz, 1H), 4.10 - 3.91 (m, 3H), 3.26 - 3.09 (m, 2H), 3.02 (s, 3H), 2.97 - 2.92 (m, 4H), 2.81 - 2.78 (m, 3H), 2.73 - 2.62 (m, 2H), 2.51 (s, 7H), 2.50 - 2.44 (m, 1H), 1.61 - 1.52 (m, 1H). Example 33 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one
Figure imgf000125_0002
Example 33 was prepared in analogy to the preparation of Example 31 by using methoxyacetyl chloride instead of dimethylcarbamyl chloride. Example 33 (25 mg) was obtained as a white solid. LCMS (M+H)+:837.1H NMR (400 MHz, METHANOL-d4) δ = 8.29 (d, J = 1.4 Hz, 1H), 7.87 (dt, J = 4.2, 8.0 Hz, 1H), 7.67 - 7.52 (m, 3H), 7.30 - 7.22 (m, 1H), 7.21 - 7.12 (m, 2H), 6.78 (d, J = 5.6, 8.4 Hz, 1H), 6.28 - 6.04 (m, 1H), 5.41 - 5.31 (m, 1H), 4.65 (m, 1H), 4.46 (d, J = 5.7, 11.3 Hz, 2H), 4.33 (d, J = 5.1 Hz, 2H), 4.31 - 4.17 (m, 4H), 4.17 - 4.11 (m, 1H), 4.00 - 3.91 (m, 1H), 3.57 - 3.43 (m, 2H), 3.38 - 3.34 (m, 3H), 3.14 (s, 1H), 3.07 (s, 3H), 3.02 - 2.97 (m, 3H), 2.92 (s, 1H), 2.88 - 2.81 (m, 2H), 2.80 - 2.67 (m, 2H), 2.63 - 2.48 (m, 2H), 1.64 - 1.51 (m, 1H). Example 34 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one
Figure imgf000126_0001
The title compound was prepared according to the following scheme:
Figure imgf000126_0002
To a solution of Intermediate F1 (40.0 mg, 0.05 mmol), HATU (21 mg, 0.05 mmol), DIEA (0.03 mL, 0.18 mmol) in MeCN (0.5 mL) was added a mixture of oxetane-2-carboxylic acid (6 mg, 0.05 mmol) in MeCN (0.5 mL). The reaction was stirred at 0° C for 0.2 h, then stirred at 20 °C for 5h. The reaction solution was purified by prep-HPLC to give Example 34 (13 mg) as a white solid. LCMS (M+H)+: 849.1H NMR (400 MHz, METHANOL-d4) δ = 8.33 - 8.22 (m, 1H), 7.87 - 7.78 (m, 1H), 7.65 - 7.58 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 - 7.08 (m, 3H), 6.69 (t, J = 8.0 Hz, 1H), 5.96 - 5.62 (m, 1H), 5.40 - 5.35 (m, 1H), 4.73 - 4.61 (m, 2H), 4.60 - 4.39 (m, 3H), 4.36 - 4.18 (m, 5H), 4.12 - 3.91 (m, 2H), 3.65 - 3.52 (m, 1H), 3.51 - 3.37 (m, 2H), 3.09 - 3.00 (m, 3H), 2.98 - 2.93 (m, 1H), 2.90 - 2.82 (m, 4H), 2.81 - 2.74 (m, 1H), 2.71 - 2.64 (m, 3H), 2.59 - 2.56 (m, 1H), 2.55 - 2.42 (m, 2H), 1.63 - 1.53 (m, 1H). Example 35 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one
Figure imgf000127_0001
Example 35 was prepared in analogy to the preparation of Example 34 by using oxetane-3- carboxylic acid instead of oxetane-2-carboxylic acid. Example 35 (18 mg) was obtained as a white solid. LCMS (M+H)+: 849.1H NMR (400 MHz, METHANOL-d4) δ = 8.34 - 8.27 (m, 1H), 7.87 - 7.79 (m, 1H), 7.66 - 7.59 (m, 1H), 7.35 - 7.24 (m, 2H), 7.22 - 7.08 (m, 3H), 6.75 - 6.65 (m, 1H), 5.95 - 5.65 (m, 1H), 5.44 - 5.30 (m, 1H), 4.71 - 4.57 (m, 2H), 4.54 - 4.39 (m, 2H), 4.34 - 4.19 (m, 5H), 4.16 - 4.07 (m, 1H), 4.02 (s, 1H), 3.52 - 3.36 (m, 2H), 3.22 - 3.10 (m, 2H), 3.09 - 3.03 (m, 3H), 3.00 (s, 1H), 2.91 - 2.81 (m, 4H), 2.81 - 2.71 (m, 1H), 2.71 - 2.65 (m, 3H), 2.61 - 2.43 (m, 3H), 1.60 - 1.50 (m, 1H). Example 36 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo [3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-12-one
Figure imgf000127_0002
Example 36 was prepared in analogy to the preparation of Example 34 by using methanesulfonylacetic acid instead of oxetane-2-carboxylic acid. Example 36 (15 mg) was obtained as a white solid. LCMS (M+H)+: 885.1H NMR (400 MHz, METHANOL-d4) δ = 8.35 - 8.25 (m, 1H), 7.87 - 7.77 (m, 1H), 7.72 - 7.59 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 - 7.12 (m, 2H), 7.11 - 7.04 (m, 1H), 6.75 - 6.64 (m, 1H), 5.90 - 5.67 (m, 1H), 5.47 - 5.26 (m, 1H), 4.71 - 4.60 (m, 1H), 4.45 (d, J = 6.2, 11.4 Hz, 1H), 4.42 - 4.21 (m, 5H), 4.21 - 4.10 (m, 1H), 4.10 - 3.98 (m, 1H), 3.77 - 3.61 (m, 1H), 3.57 - 3.44 (m, 1H), 3.17 - 3.10 (m, 1H), 3.10 - 3.03 (m, 5H), 3.02 - 2.90 (m, 2H), 2.90 - 2.81 (m, 4H), 2.78 (d, J = 14.8 Hz, 1H), 2.74 - 2.67 (m, 1H), 2.66 - 2.57 (m, 3H), 2.55 - 2.43 (m, 2H), 1.63 - 1.52 (m, 1H). Example 37 6-[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(24),2(26),3,5,18,20, 22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3- carboxamide
Figure imgf000128_0001
Example 37 was prepared in analogy to the preparation of Example 31 by using methylaminoformyl chloride instead of dimethylcarbamyl chloride. Example 37 (28 mg) was obtained as a white solid. LCMS (M+H)+: 822.1H NMR (400 MHz, METHANOL-d4) δ = 8.33 - 8.24 (m, 1H), 7.90 - 7.83 (m, 1H), 7.67 - 7.57 (m, 2H), 7.56 - 7.52 (m, 1H), 7.27 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 6.81 - 6.73 (m, 1H), 6.28 - 6.01 (m, 1H), 5.42 - 5.29 (m, 1H), 4.65 (t, J = 4.5 Hz, 1H), 4.46 (d, J = 6.1, 11.2 Hz, 2H), 4.38 - 4.28 (m, 2H), 4.27 - 4.15 (m, 2H), 3.97 - 3.90 (m, 1H), 3.51 - 3.34 (m, 1H), 3.28 - 3.18 (m, 1H), 3.14 (s, 1H), 3.10 - 3.01 (m, 3H), 3.01 - 2.94 (m, 4H), 2.91 - 2.81 (m, 3H), 2.78 - 2.71 (m, 1H), 2.70 - 2.60 (m, 4H), 2.60 - 2.46 (m, 2H), 1.61 - 1.47 (m, 1H). Example 38 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen- 12-one Example 38 was prepared in analogy to the preparation of Example 34 by using 2-(oxetan- 3-yl)acetic acid instead of oxetane-2-carboxylic acid. Example 38 (13 mg) was obtained as a white solid. LCMS (M+H)+: 863.1H NMR (400 MHz, METHANOL-d4) δ = 8.37 - 8.23 (m, 1H), 7.87 - 7.76 (m, 1H), 7.66 - 7.58 (m, 1H), 7.35 - 7.22 (m, 2H), 7.21 - 7.07 (m, 3H), 6.74 - 6.62 (m, 1H), 5.93 - 5.65 (m, 1H), 5.47 - 5.25 (m, 1H), 4.81 - 4.71 (m, 2H), 4.69 - 4.59 (m, 1H), 4.49 - 4.43 (m, 1H), 4.43 - 4.28 (m, 3H), 4.28 - 4.12 (m, 4H), 4.00 - 3.88 (m, 1H), 3.46 - 3.36 (m, 1H), 3.14 - 3.10 (m, 1H), 3.04 (d, J = 5.3 Hz, 3H), 3.00 - 2.91 (m, 2H), 2.88 - 2.82 (m, 4H), 2.80 - 2.73 (m, 2H), 2.72 - 2.67 (m, 1H), 2.63 (s, 1H), 2.62 - 2.54 (m, 3H), 2.54 - 2.40 (m, 2H), 1.61 - 1.49 (m, 1H). Example 39 (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)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(24),2(26),3,5,18,20, 22- heptaen-12-one
Figure imgf000129_0001
Example 39 was prepared in analogy to the preparation of Example 34 by using 2- (difluoromethoxy)acetic acid instead of oxetane-2-carboxylic acid. Example 39 (14 mg) was obtained as a white solid. LCMS (M+H)+: 873.1H NMR (400 MHz, METHANOL-d4) δ = 8.36 (d, J = 3.3 Hz, 1H), 7.93 - 7.83 (m, 1H), 7.74 - 7.62 (m, 1H), 7.62 - 7.51 (m, 2H), 7.33 - 7.24 (m, 1H), 7.24 - 7.12 (m, 2H), 6.92 - 6.62 (m, 1H), 6.38 - 6.04 (m, 1H), 5.49 - 5.33 (m, 1H), 4.71 - 4.58 (m, 2H), 4.53 - 4.48 (m, 1H), 4.48 - 4.36 (m, 3H), 4.34 - 4.25 (m, 2H), 4.24 - 4.14 (m, 1H), 4.11 - 3.99 (m, 1H), 3.95 - 3.83 (m, 1H), 3.62 - 3.54 (m, 1H), 3.53 - 3.43 (m, 1H), 3.17 - 3.10 (m, 1H), 3.10 - 3.04 (m, 3H), 3.04 - 2.95 (m, 4H), 2.94 - 2.85 (m, 2H), 2.85 - 2.79 (m, 2H), 2.79 - 2.72 (m, 1H), 2.66 - 2.47 (m, 2H), 1.68 - 1.57 (m, 1H). Example 40 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1] heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10, 2,6 8,11 20,24 13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-12-one
Figure imgf000130_0001
Example 40 was prepared in analogy to the preparation of Example 31 by using methanesulfonic anhydride instead of dimethylcarbamyl chloride. Example 40 (24 mg) was obtained as a white solid. LCMS (M+H)+: 843.1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.91 - 7.83 (m, 1H), 7.65 (t, J = 5.9, 8.6 Hz, 1H), 7.60 (dd, J = 2.5, 7.3 Hz, 1H), 7.53 (dd, J = 2.5, 10.3 Hz, 1H), 7.29 (ddd, J = 2.7, 8.5, 10.7 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.25 (dd, J = 4.8, 15.6 Hz, 1H), 5.35 (d, J = 9.0 Hz, 1H), 4.66 (t, J = 4.9 Hz, 1H), 4.53 - 4.43 (m, 2H), 4.37 - 4.28 (m, 2H), 4.25 (d, J = 11.0 Hz, 1H), 4.09 (dd, J = 8.9, 14.2 Hz, 1H), 4.04 - 3.94 (m, 2H), 3.38 (d, J = 11.3 Hz, 1H), 3.19 - 3.10 (m, 1H), 3.07 (s, 3H), 3.01 - 2.94 (m, 4H), 2.84 (s, 3H), 2.76 (d, J = 13.9 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.60 - 2.49 (m, 2H), 2.47 (s, 3H), 1.61 (d, J = 8.9 Hz, 1H). Example 42 (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:
Figure imgf000131_0001
Step 1: preparation of tert-butyl (2S)-2-(iodomethyl) morpholine-4-carboxylate (compound 42b) To a solution of triphenylphosphine (16.42 g, 62.61 mmol) and 1H-imidazole (4.26 g, 62.61 mmol) in DCM (120 mL) was added iodine (15.89 g, 62.61 mmol) slowly at 0 °C under N2. The reaction was stirred at 0° C for 0.5 h, then a solution of compound 42a (8.0 g, 48.16 mmol) in DCM (40 mL) was added. After being stirred at 25 °C for 15 h under N2, the reaction mixture was washed with water, the organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound 42b (10.2 g) as colorless oil. Step 2: preparation of O1-tert-butyl O2-methyl 2-(3-benzyloxypropyl) azetidine-1, 2- dicarboxylate (compound 42d) To a solution of LDA (14 mL, 28 mmol) in THF (50 mL) was added a solution of compound 42c (5.0 g, 23 mmol) in THF (50 mL) slowly at -78 °C, then N- [bis(dimethylamino)phosphoryl]-N-methylmethanamine (8.33 g, 46.46 mmol) was added. After being stirred at -78 °C for 0.3 h, compound 42b (16.03 g, 58.07 mmol) was added slowly, then the reaction mixture was stirred at 20 °C for 1 h. The reaction was quenched with NH4Cl, extracted with EA, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give compound 42d (2.67 g) as colorless oil. Step 3: preparation of O1-tert-butyl O2-methyl 2-(3-hydroxypropyl) azetidine-1, 2- dicarboxylate (compound 42e) A mixture of compound 42d (1.0 g, 2.75 mmol) and Pd(OH)2/C(300 mg) in methanol (15 mL) was stirred at 40 °C for 16 h under the H2 (45 psi). Then the mixture was filtered and the filtrate was concentrated to give compound 42e (700.0 mg) as light brown oil. LCMS (M- 100+H)+: 174. Step 4: preparation of O1-tert-butyl O2-methyl 2-(3-oxopropyl) azetidine-1, 2- dicarboxylate (compound 42f) To a solution of compound 42e (700.0 mg, 2.56 mmol) in DCM (40 mL) was added Dess- Martin periodinane (1303 mg, 3.07 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 h, then the reaction was quenched with saturated sodium bicarbonate solution, and extracted with DCM. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography to give compound 42f (500.0 mg) as colorless oil. Step 5: preparation of O1-tert-butyl O2-methyl 2-[3-[benzyl (methyl) amino] propyl] azetidine-1, 2-dicarboxylate (compound 42g) To a solution of compound 42f (500.0 mg, 1.84 mmol) and N-methylbenzylamine (670 mg, 5.53 mmol) in methanol (7.5 mL) was added sodium cyanoborohydride (231 mg, 3.69 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 h, then the reaction was quenched with water, and extracted with EtOAc. The organic layer was dried and concentrated, The residue was purified by silica gel column chromatography to give compound 42g (240.0 mg) as colorless oil. LCMS (M+H)+: 377. Step 6: preparation of O1-tert-butyl O2-methyl 2-[3-(methylamino) propyl] azetidine- 1, 2-dicarboxylate (compound 42h) A mixture of compound 42g (100.0 mg, 0.27 mmol) and Pd(OH)2/C (40 mg) in in IPA (2.5 mL) and THF (10 mL) was stirred at 40 °C for 3 h under the H2 (45 psi). Then the mixture was filtered and the filtrate was concentrated to give compound 42h (75.0 mg) as colorless oil. LCMS (M+H)+: 287. Step 7: preparation of tert-butyl 8-methyl-9-oxo-1, 8-diazaspiro [3.5] nonane-1- carboxylate (compound 42i) To a solution of compound 42h (75.0 mg, 0.26 mmol) in THF (10 mL) was added TBD (18 mg, 0.13 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction solvent was concentrated and the residue was purified by silica gel column chromatography to give compound 42i (30.0 mg) as colorless oil. LCMS (M-56+H)+: 199. Step 8: preparation of 8-methyl-1, 8-diazaspiro [3.5] nonan-9-one (compound 42j) To a solution of compound 42i (15.0 mg, 0.06 mmol) in DCM (0.5 mL) was added TFA (0.2 mL) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 42j (15 mg) as light brown oil, which was used in next step directly. Step 9: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8- diazaspiro[3.5]nonan -1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26 -hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 42) A solution of Intermediate E1 (20.0 mg, 0.03 mmol), compound 42g (15 mg, 0.06 mmol), CsF (21 mg, 0.14 mmol) and DIEA (0.05 mL, 0.28 mmol) in DMA (0.3 mL) was stirred at 120 °C for 12 h. The reaction was quenched with water, extracted with EA, the organic layer was dried and concentrated. The residue was purified by prep-HPLC to give Example 42 (10 mg) as a white solid. LCMS (M+H)+: 821.1H NMR (400 MHz, METHANOL-d4) δ = 8.21 (d, J = 9.2 Hz, 1H), 7.83 - 7.75 (m, 1H), 7.60 - 7.51 (m, 1H), 7.32 - 7.19 (m, 2H), 7.18 - 7.11 (m, 2H), 7.07 (s, 1H), 6.65 (br d, J = 8.1 Hz, 1H), 5.87 - 5.64 (m, 1H), 5.46 - 5.20 (m, 1H), 4.61 - 4.52 (m, 1H), 4.46 - 4.34 (m, 1H), 4.26 - 4.02 (m, 4H), 3.98 - 3.87 (m, 2H), 3.66 - 3.50 (m, 1H), 3.20 (s, 1H), 3.08 (s, 2H), 3.01 (d, J = 11.1 Hz, 3H), 2.97 (s, 1H), 2.83 (d, J = 7.5 Hz, 3H), 2.79 - 2.68 (m, 2H), 2.61 - 2.53 (m, 4H), 2.50 - 2.41 (m, 2H), 2.29 - 2.07 (m, 2H), 2.06 - 1.67 (m, 2H). Example 43 (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-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 The title compound was prepared according to the following scheme:
Figure imgf000134_0001
Step 1: preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-(2-methoxyacetyl) azetidine-1-carboxylate (compound 43b) To a solution of LDA (13 mL, 26 mmol) in THF (50 mL) was added a solution of compound 43a (5.0 g, 22 mmol) in THF (50 mL) slowly at -78 °C. The reaction was stirred at - 78 ºC for 1 h, and then a solution of HMPA (7.82 g, 43.62 mmol) in THF (5 mL) was added. After being stirred at -78 °C for 0.3 h, a solution of benzyl 2-bromoacetate (12.49 g, 54.52 mmol) in THF (25 mL) was added at -78 °C, then the reaction mixture was stirred at 20 °C for 1 h. The reaction was quenched with NH4Cl, extracted with EA, the organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound 43b (2 g) as light yellow oil. LCMS ([M-100+H+): 264. Step 2: preparation of 2- (2-benzyloxy-2-oxo-ethyl)-1-tert-butoxycarbonyl-azetidine- 2-carboxylic acid (compound 43c) A mixture of compound 43b (2 g, 5.5 mmol), lithium bromide (4.78 g, 55.04 mmol), TEA (2.78 g, 27.52 mmol) and water (0.5 mL, 27.52 mmol) in ACN (50 mL) was stirred at 20 °C for 3 h. The reaction mixture was concentrated and extracted with EA, the combined organic layer was dried and concentrated. The residue was purified by prep-HPLC to give compound 43c (1.2 g) as yellow oil. LCMS ([M-100+H+): 250. Step 3: preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-carbamoyl-azetidine- 1-carboxylate (compound 43d) A mixture of compound 43c (1.2 g, 3.43 mmol), DIPEA (1.8 g, 13.8 mmol), ammonium chloride (5.5 g, 10.3 mmol) and HATU (1.5 g, 3.8 mmol) in DMF (17.5 mL) was stirred at 0 °C for 1 h. The reaction mixture was purified by prep-HPLC to afford compound 43d (1 g) as yellow oil. LCMS (M-100+H+): 249. Step 4: preparation of tert-butyl 2-(2-benzyloxy-2-oxo-ethyl)-2-cyano-azetidine-1- carboxylate (compound 43e) To a solution of compound 43d (750.0 mg, 2.15 mmol) in DCM (15 mL) was added pyridine (0.7 mL, 8.61 mmol) and TFAA (904 mg, 4.31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then concentrated. The residue was purified by silica gel column chromatography to give compound 43e (750.0 mg) as yellow oil. LCMS (M-56+H+): 275. Step 5: preparation of tert-butyl 6-oxo-1, 7-diazaspiro [3.4] octane-1-carboxylate (compound 43f) To a solution of compound 43e (400.0 mg, 1.21 mmol) in methanol (17 mL) was added CoCl2·6H2O (216 mg, 0.91 mmol) and NaBH4 (460 mg, 12.11 mmol) at - 40 °C. After being stirred at -30 °C for 2 hrs, the reaction mixture was quenched with water and then filtered. The filtrate was concentrated and the residue was purified by prep-HPLC to give compound 43f (450.0 mg) as light red oil. LCMS (M-56+H+):171. Step 6: preparation of tert-butyl 7-methyl-6-oxo-1, 7-diazaspiro [3.4] octane-1- carboxylate (compound 43g) To a mixture of compound 43f (50.0 mg, 0.22 mmol) and sodium hydroxide (22 mg, 0.33 mmol) in DMF (1 mL) was added iodomethane (38 mg, 0.27 mmol) at -10 °C and then stirred for 0.5 h. The reaction mixture was purified by prep-HPLC to give compound 43g (13.0 mg) as colorless oil. LCMS (M-56+ H+): 185. Step 7: preparation of 7-methyl-1, 7-diazaspiro [3.4] octan-6-one (compound 43h) To a solution of compound 43g (13.0 mg, 0.05 mmol) in DCM (0.6 mL) was added TFA (0.5 mL, 0.02 mmol) at 0 ° C. The reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give compound 43h (13.0 mg) as light brown oil, which was used for next step directly. Step 8: preparation of (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo- 1,7-diazaspiro[3.4] octan-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 (Example 43) A mixture of Intermediate E1 (10 mg, 0.01 mmol), compound 43h (11 mg, 0.04 mmol), DIEA (18 mg, 0.14 mmol) and CsF (11 mg, 0.07 mmol) in DMA (0.2 mL) was stirred at 120 °C for 16 h. Then the reaction mixture was purified by prep-HPLC to give Example 43 (2 mg) as a white solid. LCMS (M+H+): 807.1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 1H), 7.81 (s, 1H), 7.62 - 7.52 (m, 1H), 7.32 - 7.28 (m, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.12 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.69 - 6.64 (m, 1H), 5.85 - 5.64 (m, 1H), 5.40 - 5.21 (m, 1H), 4.64 - 4.58 (m, 2H), 4.45 - 4.39 (m, 1H), 4.27 - 4.13 (m, 2H), 3.95 - 3.86 (m, 3H), 3.58 - 3.45 (m, 1H), 3.10 (s, 1H), 3.05 - 2.97 (m, 2H), 2.96 - 2.88 (m, 3H), 2.84 (d, J = 3.4 Hz, 4H), 2.59 - 2.55 (m, 4H), 2.54 - 2.37 (m, 6H). Example 44 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]acetonitrile
Figure imgf000136_0001
The title compound was prepared according to the following scheme: Step 1: preparation of [3-(hydroxymethyl)oxetan-3-yl]methyl acetate (compound 44b) To a solution of compound 44a (3 g, 25.4 mmol), TEA (11 mL, 76.3 mmol) and DMAP (310 mg, 2.54 mmol) in THF (50 mL) was added acetyl chloride (1.5 mL, 20.4 mmol) slowly at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, and then it was poured into ice water and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 44b (1 g) as light yellow oil. Step 2: preparation of 3-(acetoxymethyl)oxetane-3-carboxylic acid (compound 44c) To a solution of compound 44b (1 g, 6.24 mmol) in DCM (12 mL) and water (4 mL) was added (diacetoxyiodo)benzene (4 g, 12.5 mmol) and TEMPO (147 mg, 0.94 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, and then it was extracted with DCM. The organic layer was dried and concentrated, the residue was purified by prep-TLC to give compound 44c (450.0 mg) as a light yellow solid. Step 3: preparation of [3-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44d) To a 40 mL vial equipped with a stir bar was added Intermediate D15-a (100.0 mg, 0.27 mmol), compound 44c (117 mg, 0.67 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mg), NiCl2(dtbbpy) (11 mg, 0.03 mmol), Cs2CO3 (262 mg, 0.8 mmol) in DMA (2 mL). The vial was sealed and placed under nitrogen, then the reaction mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm away) with a cooling fan to keep the reaction temperature at 30 °C for 48 h. The reaction mixture was poured into water (10 ml), extracted with EA. The combined organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 44d (25.0 mg) as light yellow oil. LCMS (M+H+): 467. Step 4: preparation of [3-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44e) To a solution of compound 44d (25.0 mg, 0.05 mmol) in THF (3 mL) was added Pd/C (30 mg) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 2 h under the H2 (balloon), then it was filtered and the filtrate was concentrated to give compound 44e (20.0 mg) as colorless oil. LCMS (M+H+): 377. Step 5: preparation of [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]methyl acetate (compound 44f) To a solution of compound 44e (20.0 mg, 0.05 mmol), PyBOP (41 mg, 0.08 mmol) in DMF (0.2 mL) was added DIEA (0.02 mL, 0.13 mmol) at 25 °C. The reaction was stirred at 25 °C for 0.5 h, and then a mixture of Intermediate C2 (28 mg, 0.06 mmol), DIEA (0.02 mL, 0.13 mmol) in DMF (0.2 mL) was added. After being stirred at 25 °C for 2 h, the reaction mixture was purified by prep-HPLC to give compound 44f (10.0 mg) as a white solid. LCMS (M+H+): 812. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3- (hydroxymethyl)oxetan-3-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 44g) To a solution of compound 44f (10.0 mg, 0.01 mmol) in methanol (0.5 mL) was added NaOH (0.5 mL, 0.05 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h and then concentrated. The residue was diluted with water and extracted with EtOAc, the organic layer was dried and was concentrated to give compound 44g (5.0 mg) as a light yellow solid. LCMS (M+2+H+): 770. Multiple batches were repeated and combined. Step 7: preparation of [3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]methyl ethanesulfonate (compound 44h) To a solution of TEA (16 mg, 0.16 mmol) and compound 44g (40.0 mg, 0.05 mmol) in DCM (0.5 mL) was added ethanesulfonyl chloride (13.36 mg, 0.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then concentrated; the residue was purified by prep-TLC to give compound 44h (35.0 mg) as a light brown solid. LCMS (M+H+): 862. Step 8: preparation of 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22- fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]acetonitrile (Example 44) To a solution of compound 44h (35.0 mg, 0.04 mmol) in DMF (0.8 mL) was added 18- crown-6 (1 mg, 0.0 mmol) and sodium cyanide (50.0 mg, 1.02 mmol). The reaction was stirred at 50 °C for 2 h, and then it was purified by prep-HPLC to afford Example 44 (22 mg) as a white solid. LCMS (M+H+): 779. 1H NMR (400 MHz, METHANOL-d4) δ = 8.57 (d, J = 5.3 Hz, 1H), 8.51 (s, 1H), 7.75 - 7.65 (m, 1H), 7.40 (dd, J = 2.4, 8.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.23 - 7.15 (m, 1H), 7.14 - 7.09 (m, 1H), 5.66 - 5.37 (m, 2H), 5.23 - 5.04 (d, J = 6.0 Hz, 2H), 4.79 - 4.69 (d, J = 5.9 Hz, 1H), 4.62 - 4.60 (m, 3H), 4.36 (m, 1H), 4.33 (m, 1H), 4.20 - 4.10 (m, 1H), 3.96 (dd, J = 9.6, 14.1 Hz, 1H), 3.27 (d, J = 4.8 Hz, 2H), 3.16 - 3.02 (m, 4H), 2.95 - 2.86 (m, 1H), 2.65 - 2.61 (m, 2H), 2.61 - 2.59 (m, 3H), 2.58 (dt, J = 4.6, 9.1 Hz, 1H), 0.62 - 0.55 (m, 3H). Example 45 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:
Figure imgf000140_0001
Step 1: preparation of ethyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 45b) To a solution of compound 45a (200.0 mg, 1.27 mmol) in DMF (2 mL) was added NaH (102 mg, 2.55 mmol) at 0 °C and then stirred at 10 °C for 1 h. Iodomethane (361 mg, 2.55 mmol) was added at 0 °C and then stirred at 10 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 45b (150.0 mg) as brown oil. Step 2: preparation of 1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 45c) To a solution of compound 45b (150.0 mg, 0.88 mmol) in THF (0.5 mL) and ethanol (0.5 mL) was added a solution of LiOH·H2O (184 mg, 4.38 mmol) in water (0.5 mL) at 0 °C and then stirred at 10 °C for 1 h. The reaction mixture was acidified with HCl (12 M) to pH 2~3, extracted with EA, the organic layer was dried and concentrated to give compound 45c (20.0 mg) as yellow oil. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo- pyrrolidine-3-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 45) To a solution of Intermediate F1 (50.0 mg, 0.06 mmol), compound 45c (8 mg, 0.06 mmol), HATU (43 mg, 0.11 mmol) and DIPEA (0.1 mL, 0.57 mmol) in DMF (1 mL) was stirred at 10 °C for 1 h. The reaction mixture was purified by prep-HPLC to give Example 45 (16 mg) as a white solid. LCMS (M+H+): 890.1H NMR (400 MHz, METHANOL-d4) δ = 8.32 (d, J = 3.8 Hz, 1H), 7.94 - 7.81 (m, 1H), 7.66 - 7.51 (m, 3H), 7.37 - 7.14 (m, 3H), 6.85 - 6.73 (m, 1H), 5.41 - 5.32 (m, 1H), 4.71 - 4.64 (m, 2H), 4.49 (br dd, J = 4.6, 10.4 Hz, 2H), 4.41 - 4.31 (m, 3H), 4.29 - 4.20 (m, 3H), 3.55 - 3.47 (m, 2H), 3.45 - 3.37 (m, 2H), 3.13 - 3.04 (m, 4H), 3.01 - 2.95 (m, 4H), 2.90 (br d, J = 9.4 Hz, 2H), 2.84 - 2.79 (m, 3H), 2.75 - 2.68 (m, 3H), 2.62 - 2.48 (m, 3H), 1.61 - 1.52 (m, 1H), 1.32 - 1.28 (m, 1H). Example 46 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000141_0001
The title compound was prepared according to the following scheme:
Step 1: preparation of tert-butyl 3-pyrimidin-4-yl-3, 6-diazabicyclo [3.1.1]heptane-6- carboxylate (compound 46b) A solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300.0 mg, 1.51 mmol), compound 46a (457 mg, 3.03 mmol), CsF (1914.0 mg, 7.56 mmol), DIEA (1170.0 mg, 9.05 mmol) in DMA (3 mL) was stirred at 120°C for 12 h. The reaction mixture was poured into H2O, extracted with ethyl acetate. The organic layer was dried and concentrated to give compound 46b (400.0 mg) as yellow oil. LCMS (M+H+): 277. Step 2: preparation of 3-pyrimidin-4-yl-3, 6-diazabicyclo [3.1.1] heptane (compound 46c) To a solution of compound 46b (200.0 mg, 0.72 mmol) in DCM (1 mL) was added TFA (1.0 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h and then concentrated to give compound 46c (200.0 mg) as yellow oil. LCMS (M+H+): 177. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl- 3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 46) To a solution of Intermediate E4 (40.0 mg, 0.06 mmol), compound 46c (85 mg, 0.29 mmol), CsF (44.0 mg, 0.29 mmol) in DMA (0.5 mL) was added DIEA (0.06 mL, 0.34 mmol). The reaction was stirred at 120 °C for 15 hrs. Then the reaction mixture was purified by prep- HPLC to give Example 46 (9 mg) as a white solid. LCMS (M+H+): NMR (400 MHz, METHANOL-d4) δ = 8.52 - 8.40 (m, 1H), 8.39 - 8.34 (m, 1H), 8.24 (s, 1H), 8.11 (br d, J = 6.3 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.55 - 7.38 (m, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 6.78 - 6.71 (m, 1H), 6.64 - 6.57 (m, 1H), 6.07 - 5.81 (m, 1H), 5.49 - 5.26 (m, 1H), 4.80 - 4.77 (m, 1H), 4.69 - 4.64 (m, 1H), 4.57 (br s, 6H), 4.45 (br d, J = 5.9 Hz, 2H), 4.22 - 4.14 (m, 2H), 3.12 - 3.06 (m, 3H), 2.89 (s, 2H), 2.81 (s, 1H), 2.78 - 2.67 (m, 4H), 2.65 - 2.60 (m, 2H), 2.56 - 2.46 (m, 1H), 1.68 - 1.57 (m, 1H). Example 47 3-fluoro-4-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]-6- (3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-1- yl]benzonitrile
Figure imgf000143_0001
The title compound was prepared according to the following scheme:
Figure imgf000143_0002
Example 47 was prepared in analogy to the preparation of Example 46 by using compound 47b instead of compound 46a and intermediate E6 instead of intermediate E4. LCMS (M+H+): 855.1H NMR (400 MHz, METHANOL-d4) δ = 8.22 (s, 1H), 7.86 - 7.76 (m, 3H), 7.75 - 7.67 (m, 1H), 7.34 - 7.27 (m, 1H), 7.17 - 7.11 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.64 - 6.60 (m, 2H), 5.79 (dd, J = 4.4, 15.5 Hz, 1H), 5.33 - 5.19 (m, 1H), 4.58 - 4.54 (m, 4H), 4.42 (br s, 1H), 4.37 - 4.31 (m, 2H), 4.27 - 4.08 (m, 4H), 4.00 (br d, J = 9.5 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.08 - 3.01 (m, 3H), 3.00 - 2.93 (m, 1H), 2.85 (s, 2H), 2.81 - 2.67 (m, 2H), 2.61 (s, 2H), 2.52 - 2.43 (m, 2H), 1.71 - 1.58 (m, 1H). Example 48 (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000144_0001
Example 48 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E7 instead of intermediate E4. LCMS (M+H+): 829.1H NMR (400 MHz, METHANOL-d4) δ = 8.39 - 8.34 (m, 1H), 8.16 (s, 1H), 7.87 - 7.80 (m, 1H), 7.66 - 7.60 (m, 2H), 7.45 - 7.35 (m, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.79 - 6.73 (m, 1H), 6.72 - 6.66 (m, 2H), 6.63 (br d, J = 3.4 Hz, 1H), 5.99 (dd, J = 4.3, 15.3 Hz, 1H), 5.34 - 5.15 (m, 1H), 4.57 (br s, 5H), 4.49 - 4.36 (m, 2H), 4.28 - 4.19 (m, 2H), 4.11 (br d, J = 11.6 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.51 - 3.45 (m, 1H), 3.08 - 2.94 (m, 4H), 2.85 (s, 3H), 2.78 (s, 1H), 2.69 - 2.65 (m, 3H), 2.58 - 2.45 (m, 2H), 1.71 - 1.60 (m, 1H). Example 49 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000144_0002
Example 49 was prepared in analogy to the preparation of Example 46 by using 2- iodooxazole instead of compound 46a and intermediate E1 instead of intermediate E4. LCMS (M+H+): 832.1H NMR (400 MHz, METHANOL-d4) δ = 8.23 (s, 1H), 7.84 - 7.75 (m, 1H), 7.65 - 7.57 (m, 1H), 7.33 (s, 1H), 7.31 - 7.27 (m, 1H), 7.23 (br s, 1H), 7.15 (br dd, J = 2.6, 10.4 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.79 (s, 1H), 6.64 (d, J = 8.5 Hz, 1H), 5.82 (dd, J = 4.4, 15.6 Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.38 (br d, J = 6.1 Hz, 2H), 4.24 - 4.00 (m, 5H), 3.48 (br d, J = 11.5 Hz, 1H), 3.16 - 2.99 (m, 4H), 2.98 - 2.89 (m, 1H), 2.86 (s, 3H), 2.80 - 2.68 (m, 2H), 2.61 (s, 3H), 2.51 - 2.41 (m, 2H), 1.63 (d, J = 8.8 Hz, 1H), 1.31 (br d, J = 18.5 Hz, 1H). Example 50 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000145_0001
The title compound was prepared according to the following scheme:
Figure imgf000145_0002
A mixture of Intermediate E1 (50.0 mg, 0.07 mmol), compound 50a (33 mg, 0.28 mmol), K3PO4 (38 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated, the residue was purified by prep-HPLC to afford Example 50 (15 mg) as a white solid. LCMS (M+H+): 782.1H NMR (400 MHz, METHANOL-d4) δ = 8.41 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.74 - 7.63 (m, 1H), 7.28 (s, 1H), 7.26 - 7.21 (m, 1H), 7.14 (br s, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.69 - 6.60 (m, 1H), 5.85 - 5.64 (m, 1H), 5.49 - 5.31 (m, 1H), 4.66 - 4.52 (m, 2H), 4.44 (br s, 1H), 4.28 (br d, J = 5.8 Hz, 1H), 4.15 - 4.09 (m, 1H), 3.98 - 3.92 (m, 1H), 3.88 (s, 1H), 3.68 - 3.59 (m, 1H), 3.03 (br d, J = 1.3 Hz, 3H), 2.84 (s, 5H), 2.79 - 2.69 (m, 1H), 2.55 (s, 3H), 2.51 - 2.38 (m, 3H), 2.35 - 2.18 (m, 1H), 2.17 - 2.05 (m, 1H). Example 51 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000146_0001
The title compound was prepared according to the following scheme:
Figure imgf000146_0002
A solution of Intermediate E1 (30.0 mg, 0.04 mmol), compound 51a (22 mg, 0.21 mmol), CsF (32 mg, 0.21 mmol) and DIEA (0.07 mL, 0.43 mmol) in DMA (1 mL) was stirred at 120 °C for 12 h. The reaction mixture was purified by prep-HPLC to give Example 51 (10 mg) as a white solid. LCMS (M+H+): 768.1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 7.88 - 7.77 (m, 1H), 7.72 - 7.61 (m, 2H), 7.57 - 7.49 (m, 1H), 7.47 - 7.40 (m, 1H), 7.33 - 7.22 (m, 1H), 7.20 - 7.06 (m, 1H), 6.83 - 6.67 (m, 1H), 5.85 - 5.63 (m, 1H), 5.40 - 5.27 (m, 1H), 5.27 - 5.19 (m, 1H), 4.69 - 4.55 (m, 1H), 4.49 - 4.36 (m, 1H), 4.34 - 4.26 (m, 1H), 4.23 - 4.07 (m, 2H), 3.93 - 3.78 (m, 4H), 3.03 (s, 2H), 2.97 (s, 2H), 2.85 (s, 3H), 2.80 (s, 1H), 2.70 - 2.66 (m, 3H), 2.35 - 2.28 (m, 1H), 2.02 - 1.72 (m, 5H). Example 52 methyl 6-[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]-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate The title compound was prepared according to the following scheme:
Figure imgf000147_0001
To a solution of Intermediate F1 (50.0 mg, 0.07 mmol), DIEA (0.06 mL, 0.33 mmol) in DCM (0.5 mL) was added compound 52a (90.0 mg, 0.95 mmol) in DCM (0.5 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h and then concentrated. The residue was purified by prep- HPLC to afford Example 52 (12 mg) as a white solid. LCMS (M+H+): 823.1H NMR (400 MHz, METHANOL-d4) δ = 8.36 - 8.26 (m, 1H), 7.93 - 7.82 (m, 1H), 7.64 - 7.50 (m, 3H), 7.32 - 7.09 (m, 3H), 6.84 - 6.72 (m, 1H), 6.39 - 6.11 (m, 1H), 5.36 (d, J = 8.9 Hz, 1H), 4.74 - 4.61 (m, 1H), 4.57 - 4.42 (m, 2H), 4.31 (br d, J = 6.0 Hz, 2H), 4.28 - 4.21 (m, 1H), 4.02 (br t, J = 11.2 Hz, 2H), 3.71 (s, 1H), 3.67 (s, 2H), 3.64 - 3.60 (m, 1H), 3.10 - 3.05 (m, 3H), 3.02 - 2.97 (m, 3H), 2.92 - 2.81 (m, 3H), 2.79 - 2.73 (m, 1H), 2.72 - 2.61 (m, 2H), 2.60 - 2.45 (m, 2H), 2.04 (s, 1H), 1.65 - 1.44 (m, 1H), 1.19 (t, J = 7.1 Hz, 1H). Example 53 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000147_0002
The title compound was prepared according to the following scheme:
Figure imgf000148_0001
Step 1: preparation of tert-butyl 3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 53c) A mixture of compound 53a (100.0 mg, 0.48 mmol), compound 53b (143 mg, 0.72 mmol), tBuXPhos Pd G3 (38 mg, 0.05 mmol) and t-BuONa (138 mg, 1.44 mmol) in 1,4-dioxane (1 mL) was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated, the residue was purified by prep-TLC to give compound 53c (45.0 mg) as a colorless oil. LCMS (M- 56+H+): 223. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1- methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 53) Example 53 was prepared in analogy to the preparation of Example 46 by using compound 53c instead of compound 46b and intermediate E1 instead of intermediate E4. LCMS (M+H+): 845.1H NMR (400 MHz, METHANOL-d4) δ 8.28 (s, 1H), 7.92 - 7.83 (m, 1H), 7.68 - 7.52 (m, 5H), 7.32 - 7.22 (m, 1H), 7.21 - 7.14 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.32 - 6.02 (m, 1H), 5.46 - 5.27 (m, 1H), 4.72 - 4.63 (m, 1H), 4.61 - 4.53 (m, 1H), 4.52 - 4.40 (m, 2H), 4.36 - 4.27 (m, 1H), 4.24 (br d, J = 10.8 Hz, 1H), 4.19 - 4.06 (m, 2H), 4.04 - 3.97 (m, 1H), 3.97 - 3.88 (m, 1H), 3.79 - 3.74 (m, 3H), 3.14 (s, 1H), 3.11 - 3.06 (m, 3H), 3.03 - 2.96 (m, 3H), 2.88 (s, 2H), 2.81 (s, 2H), 2.66 - 2.47 (m, 2H), 2.12 - 1.98 (m, 1H), 1.80 - 1.61 (m, 1H), 1.44 - 1.26 (m, 1H). Example 54 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000149_0001
Example 54 was prepared in analogy to the preparation of Example 53 by using 4-iodo-1- methyl-pyrazole instead of 3-iodo-1-methyl-pyrazole (53a). LCMS (M+H+): 845.1H NMR (400 MHz, METHANOL-d4) δ = 8.27 - 8.18 (m, 1H), 7.84 - 7.78 (m, 1H), 7.67 - 7.56 (m, 1H), 7.35 - 7.27 (m, 1H), 7.27 - 7.18 (m, 2H), 7.18 - 7.13 (m, 2H), 7.11 - 7.05 (m, 2H), 6.77 - 6.63 (m, 1H), 5.92 - 5.64 (m, 1H), 5.47 - 5.23 (m, 1H), 4.67 - 4.61 (m, 2H), 4.50 - 4.37 (m, 1H), 4.26 - 4.08 (m, 5H), 3.95 - 3.85 (m, 2H), 3.81 - 3.68 (m, 5H), 3.25 - 3.20 (m, 1H), 3.11 - 3.05 (m, 3H), 2.91 - 2.82 (m, 3H), 2.62 - 2.54 (m, 3H), 2.13 - 1.99 (m, 1H), 1.75 - 1.64 (m, 1H), 1.32 - 1.27 (m, 1H), 1.18 (t, J = 7.0 Hz, 1H). Example 55 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile
Figure imgf000149_0002
The title compound was prepared according to the following scheme: To a solution of Intermediate D18 (40.0 mg, 0.13 mmol), PyBOP (48 mg, 0.09 mmol) in DMF (0.5 mL) was added DIEA (0.03 mL, 0.15 mmol) at 25 °C. The reaction was stirred at 25 °C for 0.5 h and then a mixture of Intermediate C2 (68 mg, 0.12 mmol) and DIEA (0.03 mL, 0.15 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 h and then the mixture was purified by prep-HPLC to give Example 55 (17 mg) as a white solid. LCMS (M+H+): 737.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 - 8.51 (m, 1H), 8.43 (s, 1H), 7.69 - 7.55 (m, 1H), 7.44 - 7.35 (m, 1H), 7.31 - 7.21 (m, 2H), 7.19 - 7.11 (m, 1H), 7.11 - 7.04 (m, 1H), 5.61 - 5.51 (m, 1H), 5.47 - 5.22 (m, 1H), 4.70 (br d, J = 4.0 Hz, 1H), 4.43 - 4.25 (m, 2H), 4.23 - 4.07 (m, 1H), 4.04 - 3.93 (m, 1H), 3.30 - 3.20 (m, 2H), 3.10 - 3.05 (m, 1H), 3.03 - 2.97 (m, 3H), 2.97 - 2.92 (m, 1H), 2.91 - 2.85 (m, 1H), 2.77 (br d, J = 13.0 Hz, 1H), 2.73 - 2.67 (m, 2H), 2.60 - 2.54 (m, 4H), 2.52 - 2.35 (m, 1H), 0.63 - 0.47 (m, 3H). Example 56 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4-d]pyrimidin- 4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000150_0001
Example 56 was prepared in analogy to the preparation of Example 55 by using intermediate D19 instead of intermediate D18 and intermediate C1 instead of intermediate C2. LCMS (M+H+): 773.1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.32 - 7.27 (m, 2H), 7.24 - 7.06 (m, 3H), 6.75 - 6.61 (m, 1H), 5.86 - 5.73 (m, 1H), 5.62 - 5.54 (m, 1H), 5.40 - 5.34 (m, 1H), 4.71 - 4.64 (m, 1H), 4.57 - 4.51 (m, 1H), 4.43 - 4.30 (m, 2H), 4.29 - 4.20 (m, 1H), 4.18 - 4.01 (m, 2H), 3.92 (br d, J = 14.0 Hz, 1H), 3.18 - 3.13 (m, 1H), 3.12 - 3.01 (m, 3H), 2.98 - 2.86 (m, 2H), 2.83 (s, 3H), 2.67 - 2.60 (m, 1H), 2.56 (s, 3H), 2.52 - 2.45 (m, 1H). Example 57 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000151_0001
The title compound was prepared according to the following scheme:
Figure imgf000151_0002
Step 1: preparation of tert-butyl (1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 57b) To a solution of compound 60d (200.0 mg, 0.94 mmol) in DMF (5 mL) was added NaH (45 mg, 1.13 mmol) at 0°C and then stirred at 15 °C for 1 h. Iodomethane (160 mg, 1.13 mmol) was added at 0°C. The reaction was stirred at 15 °C for 2 h. The reaction was poured into saturated ammonium chloride solution (20 mL), extracted with Ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL× 2), dried over Na2SO4, filtered and concentrated to give compound 57b (230 mg) as light yellow oil. Step 2: preparation of (1S,5R)-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 57c) To a solution of compound 57b (220.0 mg, 0.97 mmol) in DCM ( 2 mL) was added TFA ( 2.0 mL) at 0 °C and then stirred at 15 °C for 1 h. The reaction was concentrated to give compound 57c (200.0 mg) as light yellow oil. Step 3: preparation of (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 57) To a solution of intermediated E5 (50.0 mg, 0.07 mmol), compound 57c (19 mg, 0.15 mmol), cesium fluoride (56 mg, 0.37 mmol) in DMA (1 mL) was added DIEA (0.1 mL, 0.74 mmol) and then stirred at 120 °C for 12 h. The mixture was concentrated and the residue was purified by prep- HPLC to give Example 57 (13 mg) as a white solid. LCMS (M+H+): 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 7.68 - 7.56 (m, 1H), 7.42 - 7.31 (m, 1H), 7.22 (br s, 1H), 7.18 - 7.10 (m, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.37 (br d, J = 8.6 Hz, 1H), 5.31 - 5.15 (m, 1H), 4.70 - 4.49 (m, 2H), 4.46 - 4.34 (m, 1H), 4.32 - 4.12 (m, 2H), 4.12 - 3.95 (m, 3H), 3.86 (br d, J = 11.5 Hz, 1H), 3.09 (br s, 3H), 2.97 - 2.87 (m, 1H), 2.85 - 2.78 (m, 1H), 2.73 (s, 3H), 2.67 (br d, J = 13.6 Hz, 1H), 2.61 (s, 3H), 2.55 - 2.45 (m, 1H), 2.06 - 1.90 (m, 1H), 1.75 (br d, J = 8.8 Hz, 1H), 1.40 - 1.23 (m, 1H). Example 59 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000152_0001
The title compound was prepared according to the following scheme: To a solution of Intermediate F2 (50.0 mg, 0.06 mmol), TBD (24 mg, 0.17 mmol) in THF (0.500 mL) was added methyl thiazole-2-carboxylate (12 mg, 0.09 mmol) at 0° C. The reaction was stirred at 20 °C for 16 h. Then the reaction mixture was concentrated, the residue was purified by prep-HPLC to afford Example 59 (23 mg) as a white solid. LCMS (M+H+): 859.1H NMR (400 MHz, METHANOL-d4) δ = 8.40 - 8.32 (m, 1H), 8.23 - 8.10 (m, 1H), 8.02 - 7.90 (m, 1H), 7.87 - 7.73 (m, 2H), 7.68 - 7.61 (m, 1H), 7.59 - 7.50 (m, 1H), 7.49 - 7.35 (m, 1H), 7.29 - 7.16 (m, 1H), 7.15 - 7.05 (m, 1H), 6.77 - 6.58 (m, 1H), 5.97 - 5.80 (m, 1H), 5.42 - 5.19 (m, 1H), 4.61 (s, 2H), 4.44 - 4.29 (m, 4H), 4.24 - 4.03 (m, 3H), 4.01 - 3.85 (m, 1H), 3.78 - 3.57 (m, 1H), 3.09 - 3.00 (m, 3H), 2.98 - 2.90 (m, 1H), 2.88 (s, 1H), 2.83 (s, 1H), 2.79 (br d, J = 5.0 Hz, 1H), 2.74 (br s, 1H), 2.70 - 2.62 (m, 2H), 2.59 (br d, J = 7.5 Hz, 1H), 2.55 - 2.40 (m, 3H), 1.57 (br d, J = 9.0 Hz, 1H). Example 60 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000153_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 60d) The compound 60c (2.5 g, 11.80 mmol) was purified by SFC, concentrated to give compound 60d-1 (1.25 g) (peak 1, Rt=1.299 min, ee%=100%) as a white solid, and compound 60d (1.25 g) (peak 2, Rt=2.261 min, ee%= 99.13%) as a white solid. Condition of SFC: Instrument CASWH-Prep-SFC-H, Method Column DAICEL CHIRALPAK AD (250mm×30mm,10um), Condition CO2-EtOH (0.1%NH3H2O) Begin B 40, End B 40 Gradient Time (min) 3.9, 100% B Hold Time (min): 0, Flowrate (mL/min): 150. The structure of compound 60d was confirmed by X-Ray Single Crystal Diffraction in Figure 1. Step 2: preparation of (1R,5S)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 60e) To a solution of compound 60d (400.0 mg, 1.88 mmol) in DCM (4 mL) was added TFA (4.0 mL) at 0 °C. The reaction was stirred at 25 °C for 1 hr under N2 atmosphere. The mixture was concentrated to give compound 60e (560.0 mg) as colorless oil, which was used directly without further purification. Step 3: preparation of benzyl (1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (compound 60f) To a solution of compound 60e (560.0 mg, 2.48 mmol) and sodium carbonate (315 mg, 2.97 mmol) in THF (5 mL) and water (5 mL) was added N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h, and then the mixture was purified by prep-HPLC to give compound 60f (410.0 mg) as colorless oil. LCMS (M+H+): 247. Step 4: preparation of benzyl (1R,5S)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 60g) To a solution of compound 60f (100.0 mg, 0.41 mmol) in DMF (2 mL) was added sodium hydride (32 mg, 0.81 mmol). The reaction was stirred for 0.5 h at 0 °C, and then compound 60b (120 mg, 0.61 mmol) was added. After being stirred for 2 h at 25 °C, the reaction mixture was poured into ice water and extracted with EA. The organic layer was dried and concentrated to give compound 60g (150.0 mg) as colorless oil, which was used directly without further purification. LCMS (M+H+): 317. Step 5: preparation of (1S,5R)-3-(oxetan-3-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-2- one (compound 60h) To a solution of compound 60g (150.0 mg, 0.47 mmol) in methanol (3 mL) was added wet Pd/C (30.0 mg) under N2 at 25 °C. The reaction was stirred under H2 at 25 °C for 2 h, and then the mixture was filtered, the filtrate was concentrated to give compound 60h (60.0 mg) as a white solid, which was used directly without further purification. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan- 3-ylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 60) A mixture of intermediate E4 (40.0 mg, 0.06 mmol), compound 60h (32 mg, 0.17 mmol), CsF (22 mg, 0.15 mmol) and DIEA (0.02 mL, 0.15 mmol) in DMA (0.5 mL) was stirred at 120 °C for 16 h. Then the reaction mixture was purified by prep-HPLC to give Example 60 (13 mg) as a white solid. LCMS (M+H+): 832.1H NMR (400 MHz, METHANOL-d4) δ = 8.43 - 8.28 (m, 2H), 7.91 - 7.77 (m, 1H), 7.68 - 7.58 (m, 2H), 7.50 - 7.37 (m, 1H), 7.33 - 7.11 (m, 2H), 6.81 - 6.63 (m, 1H), 6.09 - 5.85 (m, 1H), 5.53 - 5.30 (m, 1H), 4.69 - 4.61 (m, 2H), 4.56 (br s, 4H), 4.52 - 4.42 (m, 2H), 4.32 - 4.23 (m, 4H), 4.19 - 4.13 (m, 2H), 4.11 - 4.02 (m, 2H), 4.01 - 3.91 (m, 1H), 3.18 - 3.14 (m, 1H), 3.12 (br s, 2H), 3.05 (br s, 3H), 2.86 - 2.81 (m, 3H), 2.68 - 2.61 (m, 3H), 2.57 - 2.46 (m, 1H), 1.82 - 1.68 (m, 1H). Example 61 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000156_0001
The title compound was prepared according to the following scheme:
Figure imgf000156_0002
Example 61 was prepared in analogy to the preparation of Example 60 by using 3- bromooxetane instead of compound 60b. LCMS (M+H+): 818.1H NMR (400 MHz, METHANOL-d4) δ = 8.42 - 8.28 (m, 2H), 7.92 - 7.80 (m, 1H), 7.66 - 7.62 (m, 2H), 7.50 - 7.40 (m, 1H), 7.31 - 7.23 (m, 1H), 7.13 (d, J = 3.4 Hz, 1H), 6.78 - 6.71 (m, 1H), 6.07 - 5.92 (m, 1H), 5.48 - 5.33 (m, 1H), 4.75 - 4.72 (m, 2H), 4.65 (br s, 1H), 4.58 (s, 4H), 4.49 - 4.44 (m, 1H), 4.26 - 4.16 (m, 5H), 3.11 (s, 1H), 3.05 (s, 3H), 2.93 - 2.86 (m, 2H), 2.85 (s, 3H), 2.83 - 2.81 (m, 1H), 2.72 (br d, J = 12.6 Hz, 1H), 2.68 (s, 3H), 2.63 (s, 1H), 1.75 (d, J = 9.1 Hz, 1H). Example 62 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000157_0001
The title compound was prepared according to the following scheme:
Figure imgf000157_0002
Step 1: preparation of tert-butyl 9-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro- 15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (compound 62a) A mixture of Intermediate E1 (150.0 mg, 0.21 mmol), 7-BOC-3-oxa-7,9- diazabicyclo[3.3.1]nonane (146 mg, 0.64 mmol), CsF (162 mg, 1.07 mmol) and DIEA (0.18 mL, 1.07 mmol) in DMA (2 mL) was stirred at 120 °C for 24 h. Then the reaction mixture was purified by prep-HPLC to give compound 62a (100 mg) as a brown solid. LCMS (M+H+): 895. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (compound 62b) To a solution of compound 62a (100 mg, 0.11 mmol) in DCM (1 mL) was added TFA (0.5 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h and then concentrated to give compound 62b (130 mg) as yellow oil, which was used directly without further purification. LCMS (M+H+): 795. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 62) To a solution of compound 62b (40.0 mg, 0.04 mmol) in DCM (0.5 mL) and methanol (0.5 mL) was added formaldehyde (20.0 mg, 0.25 mmol) and sodium cyanoborohydride (6 mg, 0.09 mmol). The reaction mixture was stirred at 25 °C for 12 h, then it was purified by prep-HPLC to give Example 62 (5 mg) as a white solid. LCMS (M+H+): 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.24 (s, 1H), 7.86 - 7.77 (m, 1H), 7.66 - 7.53 (m, 1H), 7.32 - 7.27 (m, 1H), 7.24 - 7.18 (m, 1H), 7.17 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.73 - 6.62 (m, 1H), 5.89 - 5.60 (m, 1H), 5.41 - 5.23 (m, 1H), 4.67 - 4.62 (m, 2H), 4.59 - 4.55 (m, 2H), 4.49 - 4.44 (m, 2H), 4.27 - 4.09 (m, 3H), 4.00 - 3.90 (m, 2H), 3.86 - 3.71 (m, 3H), 3.13 - 3.09 (m, 1H), 3.01 (s, 3H), 2.97 - 2.89 (m, 1H), 2.86 - 2.81 (m, 3H), 2.59 - 2.54 (m, 3H), 2.51 - 2.45 (m, 1H), 2.40 - 2.34 (m, 1H), 2.20 - 2.14 (m, 3H), 2.03 (s, 1H). Example 63 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000158_0001
Example 63 was prepared in analogy to the preparation of Example 53 by using 2-bromo- 1,3,4-thiadiazole instead of 3-iodo-1-methyl-pyrazole (53a). LCMS (M+H+): 832.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (s, 1H), 8.49 (d, J = 6.3 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.99 (br t, J = 8.0 Hz, 1H), 7.57 (br dd, J = 5.1, 7.3 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.19 - 7.10 (m, 1H), 6.96 (br d, J = 8.6 Hz, 1H), 5.98 (br dd, J = 4.4, 15.7 Hz, 1H), 5.37 (br d, J = 8.6 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.56 - 4.48 (m, 1H), 4.41 (br dd, J = 5.4, 11.6 Hz, 3H), 4.26 - 4.11 (m, 3H), 3.68 - 3.41 (m, 3H), 3.10 (s, 4H), 2.97 (s, 3H), 2.93 (br s, 3H), 2.77 (s, 1H), 2.70 - 2.62 (m, 1H), 2.58 (br dd, J = 4.1, 8.6 Hz, 1H), 2.51 (br dd, J = 4.9, 6.6 Hz, 1H), 1.67 (br d, J = 9.0 Hz, 1H). Example 64 (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one
Figure imgf000159_0001
Example 64 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E8 instead of intermediate E4. LCMS (M+H+): 860.1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.58 (br d, J = 7.1 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.48 - 7.38 (m, 1H), 7.29 (d, J = 3.9 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.97 - 6.85 (m, 3H), 6.78 (br d, J = 8.0 Hz, 1H), 6.19 (br dd, J = 4.8, 15.0 Hz, 1H), 5.41 (br d, J = 8.9 Hz, 1H), 4.69 - 4.56 (m, 2H), 4.46 (br d, J = 6.4 Hz, 2H), 4.39 - 4.27 (m, 2H), 4.26 - 4.16 (m, 2H), 4.15 - 3.97 (m, 2H), 3.65 - 3.48 (m, 2H), 3.15 - 3.05 (m, 4H), 3.03 - 2.94 (m, 4H), 2.86 (s, 3H), 2.83 - 2.74 (m, 2H), 2.67 - 2.36 (m, 2H), 1.81 - 1.67 (m, 1H), 1.43 (s, 1H). Example 65 Trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile
Figure imgf000160_0001
Example 65 was prepared in analogy to the preparation of Example 55 by using intermediate D20 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS (M+H+): 731.1H NMR (400 MHz, METHANOL-d4) δ = 8.47 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.66 (br d, J = 5.4 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.22 - 7.11 (m, 1H), 6.86 - 6.67 (m, 1H), 6.02 (dd, J = 4.4, 15.4 Hz, 1H), 5.58 (d, J = 8.8 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.54 (br dd, J = 6.2, 11.4 Hz, 1H), 4.37 - 4.18 (m, 2H), 3.98 - 3.85 (m, 1H), 3.79 - 3.69 (m, 1H), 3.68 - 3.59 (m, 1H), 3.48 - 3.39 (m, 1H), 3.18 - 3.15 (m, 1H), 3.10 (s, 3H), 2.99 (s, 1H), 2.88 - 2.82 (m, 4H), 2.73 - 2.68 (m, 2H), 2.66 - 2.63 (m, 3H), 2.60 - 2.51 (m, 2H). Example 66 Cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-
Figure imgf000160_0002
Example 66 was prepared in analogy to the preparation of Example 55 by using intermediate D21 instead of intermediate D18 and intermediate C8 instead of intermediate C2. LCMS (M+H+): 731.1H NMR (400 MHz, METHANOL-d4) δ = 8.47 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 5.4 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.05 (dd, J = 4.4, 15.4 Hz, 1H), 5.65 (d, J = 8.9 Hz, 1H), 4.77 - 4.68 (m, 1H), 4.62 - 4.50 (m, 2H), 4.35 - 4.17 (m, 2H), 3.96 (dd, J = 9.2, 14.3 Hz, 1H), 3.56 (t, J = 8.7 Hz, 1H), 3.26 (d, J = 9.1 Hz, 1H), 3.15 (s, 3H), 3.00 (br d, J = 13.3 Hz, 1H), 2.91 - 2.79 (m, 5H), 2.74 - 2.66 (m, 2H), 2.65 (s, 3H), 2.61 - 2.55 (m, 2H). Example 67 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000161_0001
The title compound was prepared according to the following scheme:
Figure imgf000161_0002
To a solution of intermediated E1 (50.0 mg, 0.07 mmol), compound 67a (60 mg, 0.36 mmol), cesium fluoride (54 mg, 0.36 mmol) in DMA (1 mL) was added N,N- diisopropylethylamine (0.1 mL, 0.43 mmol) and then stirred at 120 °C for 12 h. The reaction solution was purified by prep-HPLC to give Example 67 (7. mg) as a light yellow solid. LCMS (M+H+): 798.1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.66 - 7.51 (m, 3H), 7.27 - 7.10 (m, 3H), 6.79 (br d, J = 8.3 Hz, 1H), 6.25 (dd, J = 4.3, 15.2 Hz, 1H), 5.39 - 5.26 (m, 1H), 4.71 - 4.63 (m, 1H), 4.52 - 4.41 (m, 2H), 4.37 - 4.18 (m, 3H), 4.00 (br d, J = 11.8 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.74 (br t, J = 9.4 Hz, 1H), 3.54 - 3.45 (m, 2H), 3.43 - 3.40 (m, 1H), 3.34 (s, 3H), 3.18 - 3.05 (m, 4H), 2.99 (s, 4H), 2.88 - 2.79 (m, 3H), 2.64 - 2.49 (m, 2H), 2.45 - 2.26 (m, 1H), 2.13 - 1.96 (m, 1H). Example 68 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-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
Figure imgf000162_0001
Example 68 was prepared in analogy to the preparation of Example 67 by using (2- methylazetidin-2-yl)methanol;hydrochloride instead of compound 67a. LCMS (M+H+): 768.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (d, J = 3.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.54 (dd, J = 2.6, 10.3 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.21 - 7.14 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.28 - 6.02 (m, 1H), 5.43 - 5.28 (m, 1H), 4.68 (br s, 1H), 4.54 - 4.44 (m, 1H), 4.40 - 4.16 (m, 3H), 4.04 - 3.70 (m, 4H), 3.61 (q, J = 7.0 Hz, 1H), 3.15 - 3.04 (m, 4H), 3.00 - 2.96 (m, 3H), 2.87 - 2.80 (m, 3H), 2.66 - 2.48 (m, 2H), 2.45 - 2.17 (m, 1H), 2.02 - 1.91 (m, 1H), 1.61 - 1.27 (m, 3H). Example 69 (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)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
Figure imgf000162_0002
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octane-1- carboxylate (compound 69b) To a solution of compound 69a (200.0 mg, 0.94 mmol), triethylamine (0.41 mL, 2.96 mmol) in DCM (2 mL) was added 2,2-difluoroacetate (240.0 mg, 1.38 mmol) at 0 °C and then stirred at 25 °C for 1 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 69b (140.0 mg) as brown oil. LCMS (M-100+H+): 291. Step 2: preparation of 1-(1,7-diazaspiro[3.4]octan-7-yl)-2,2-difluoro-ethanone (compound 69c) To a solution of compound 69b (140.0 mg, 0.48 mmol) in DCM (2 mL) was added TFA (2.0 mL) at 0 °C and then stirred at 20 °C for 1 h. The reaction mixture was concentrated to give compound 69c (140.0 mg) as brown oil. LCMS (M+H+): 191. Step 3: (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)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 (Example 69) A solution of Intermediate E1 (50.0 mg, 0.07 mmol), compound 69c (68 mg, 0.36 mmol), CsF (54 mg, 0.36 mmol) and DIEA (0.1 mL, 0.71 mmol) in DMA (2 mL) was stirred at 120 °C for 15 h. The reaction solution was purified by prep-HPLC to give Example 69 (10 mg) as a red solid. LCMS (M+H+): 857.1H NMR (400 MHz, METHANOL-d4) δ = 8.21 (d, J = 3.5 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.65 - 7.50 (m, 1H), 7.29 (br d, J = 8.5 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.11 - 7.03 (m, 2H), 6.62 (br d, J = 8.4 Hz, 1H), 5.83 - 5.61 (m, 1H), 5.32 - 5.15 (m, 1H), 4.55 (br d, J = 1.9 Hz, 1H), 4.40 - 4.30 (m, 1H), 4.27 - 4.03 (m, 3H), 4.03 - 3.71 (m, 5H), 3.71 - 3.43 (m, 2H), 3.11 - 3.06 (m, 1H), 3.03 - 2.95 (m, 1H), 2.91 (br s, 2H), 2.85 - 2.78 (m, 4H), 2.78 - 2.71 (m, 1H), 2.59 - 2.51 (m, 3H), 2.50 - 2.22 (m, 4H), 2.12 - 1.94 (m, 1H). Example 70 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000164_0001
Example 70 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c. LCMS (M+H+): 831.1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 6.3 Hz, 1H), 8.28 (s, 1H), 8.11 - 8.06 (m, 1H), 8.01 (dd, J = 7.7, 8.3 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.41 - 7.33 (m, 2H), 7.29 - 7.22 (m, 1H), 7.21 - 7.14 (m, 1H), 7.01 - 6.92 (m, 2H), 6.08 - 5.85 (m, 1H), 5.44 - 5.32 (m, 1H), 4.73 - 4.66 (m, 1H), 4.65 - 4.51 (m, 1H), 4.50 - 4.43 (m, 2H), 4.42 - 4.31 (m, 2H), 4.25 (br d, J = 11.4 Hz, 1H), 4.13 - 4.01 (m, 1H), 3.70 - 3.53 (m, 2H), 3.15 - 3.08 (m, 3H), 3.07 - 3.01 (m, 1H), 3.00 - 2.89 (m, 4H), 2.84 (s, 3H), 2.76 (s, 1H), 2.73 - 2.64 (m, 1H), 2.57 (tdd, J = 4.4, 8.8, 13.2 Hz, 1H), 1.85 - 1.68 (m, 1H), 1.44 - 1.28 (m, 1H). Example 71 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one Example 71 was prepared in analogy to the preparation of compound D9-c by using compound 60d-1 instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E5 instead of intermediate D15-a. LCMS (M+H+): 764.1H NMR (400 MHz, METHANOL-d4) δ = 8.56 (d, J = 5.1 Hz, 1H), 8.31 (s, 1H), 7.70 - 7.58 (m, 1H), 7.37 (dd, J = 2.3, 8.5 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.21 - 7.11 (m, 2H), 7.01 - 6.94 (m, 1H), 5.46 (d, J = 8.4 Hz, 1H), 5.29 (br d, J = 8.6 Hz, 1H), 4.74 - 4.53 (m, 2H), 4.42 (br dd, J = 6.7, 11.4 Hz, 1H), 4.35 - 4.12 (m, 3H), 4.11 - 3.86 (m, 2H), 3.07 (s, 4H), 2.98 - 2.80 (m, 2H), 2.77 (s, 3H), 2.67 (br s, 1H), 2.63 (s, 3H), 2.56 - 2.44 (m, 1H), 2.23 - 2.00 (m, 1H), 1.74 (br d, J = 8.8 Hz, 1H), 1.44 - 1.21 (m, 1H). Example 72 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000165_0001
Example 72 was prepared in analogy to the preparation of Example 46 by using 2-chloro- pyrimidine instead of compound 46c. LCMS (M+H+): 826.1H NMR (400 MHz, METHANOL- d4) δ = 8.55 - 8.31 (m, 3H), 8.24 (s, 1H), 8.10 (d, J = 6.4 Hz, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.60 (dt, J = 6.1, 8.5 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.28 - 7.20 (m, 1H), 7.19 - 7.09 (m, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.84 - 6.73 (m, 1H), 6.06 - 5.75 (m, 1H), 5.48 - 5.28 (m, 1H), 4.69 - 4.58 (m, 1H), 4.54 - 4.36 (m, 3H), 4.33 - 4.15 (m, 4H), 4.10 (br d, J = 11.1 Hz, 1H), 3.72 (br dd, J = 7.1, 12.0 Hz, 1H), 3.62 (br d, J = 11.9 Hz, 1H), 3.13 - 3.07 (m, 3H), 3.07 - 2.95 (m, 3H), 2.93 - 2.80 (m, 4H), 2.78 - 2.74 (m, 1H), 2.71 - 2.62 (m, 1H), 2.61 - 2.43 (m, 2H), 1.75 - 1.60 (m, 1H). Example 73 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile
Figure imgf000166_0001
Example 73 was prepared in analogy to the preparation of Example 55 by using intermediate D22 instead of intermediate D18. LCMS (M+H+): 763.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (d, J = 5.3 Hz, 1H), 8.43 (s, 1H), 7.82 - 7.53 (m, 1H), 7.45 - 7.36 (m, 1H), 7.33 - 7.21 (m, 2H), 7.20 - 7.14 (m, 1H), 7.10 (br d, J = 5.3 Hz, 1H), 5.88 - 5.72 (m, 1H), 5.65 - 5.43 (m, 2H), 4.73 (br t, J = 4.6 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.32 - 4.27 (m, 1H), 4.24 - 4.08 (m, 1H), 4.06 - 3.92 (m, 1H), 3.71 - 3.53 (m, 1H), 3.29 - 3.22 (m, 1H), 3.13 - 3.02 (m, 3H), 3.02 - 2.98 (m, 1H), 2.95 - 2.88 (m, 1H), 2.88 - 2.77 (m, 2H), 2.68 (br t, J = 7.4 Hz, 1H), 2.62 (br d, J = 2.4 Hz, 1H), 2.60 - 2.56 (m, 3H), 2.53 - 2.42 (m, 1H), 2.03 - 1.76 (m, 1H), 1.39 - 1.23 (m, 1H), 0.66 - 0.49 (m, 3H). Example 76 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one A mixture of Intermediate E1 (100.0 mg, 0.14 mmol), 3-thia-6-azabicyclo[3.1.1]heptane (123 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol) and DIEA (0.14 mL, 0.85 mmol) in DMA (1 mL) was stirred at 120 °C for 15 h. The mixture was purified by prep-HPLC to give Example 76 (30 mg) as a white solid. LCMS (M+H+): 782.1H NMR (400 MHz, METHANOL-d4) δ = 8.28 (s, 1H), 7.87 - 7.74 (m, 1H), 7.68 - 7.53 (m, 1H), 7.34 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.92 - 5.63 (m, 1H), 5.46 - 5.25 (m, 1H), 4.66 - 4.55 (m, 2H), 4.50 - 4.38 (m, 3H), 4.29 - 4.08 (m, 3H), 3.91 - 3.79 (m, 1H), 3.78 - 3.69 (m, 1H), 3.66 - 3.55 (m, 1H), 3.10 (s, 1H), 3.06 - 2.92 (m, 3H), 2.87 - 2.81 (m, 3H), 2.74 - 2.68 (m, 2H), 2.59 - 2.54 (m, 3H), 2.52 - 2.43 (m, 2H), 1.96 - 1.86 (m, 1H). Example 77 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ4-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000167_0001
To a solution of Example 76 (26.0 mg, 0.03 mmol) in DCM (0.5 mL) was added mCPBA (7 mg, 0.03 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h and then filitered. The filtrated was concentrated, the residue was purified by prep-HPLC to afford Example 77 (13 mg) as a white solid. LCMS (M+H+): 798.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 - 8.23 (m, 1H), 7.85 - 7.76 (m, 1H), 7.68 - 7.56 (m, 1H), 7.33 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.18 - 7.12 (m, 2H), 7.10 - 7.05 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.84 - 5.64 (m, 1H), 5.41 - 5.26 (m, 1H), 4.58 (br s, 4H), 4.46 - 4.35 (m, 2H), 4.26 - 4.12 (m, 3H), 4.06 - 3.86 (m, 2H), 3.09 (s, 1H), 3.01 (s, 2H), 2.96 - 2.89 (m, 1H), 2.88 - 2.83 (m, 3H), 2.80 - 2.71 (m, 3H), 2.60 - 2.53 (m, 3H), 2.51 - 2.40 (m, 2H). Example 78 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3- (methoxymethyl)azetidine-3-carbonitrile
Figure imgf000168_0001
The title compound was prepared according to the following scheme:
Figure imgf000168_0002
Example 71 was prepared in analogy to the preparation of compound D9-c by using compound 78a instead of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and intermediate E1 instead of intermediate D15-a. LCMS (M+H+): 793.1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.68 - 7.52 (m, 1H), 7.36 - 7.27 (m, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.90 - 5.59 (m, 1H), 5.40 - 5.25 (m, 1H), 4.64 - 4.55 (m, 2H), 4.46 - 4.37 (m, 1H), 4.35 - 4.27 (m, 1H), 4.24 - 4.18 (m, 2H), 4.17 - 4.11 (m, 2H), 4.07 - 3.98 (m, 1H), 3.95 - 3.87 (m, 1H), 3.77 - 3.71 (m, 2H), 3.44 (s, 3H), 3.12 - 3.01 (m, 3H), 2.97 - 2.88 (m, 1H), 2.87 - 2.81 (m, 3H), 2.59 - 2.54 (m, 3H), 2.52 - 2.42 (m, 2H). Example 79 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ6-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000169_0001
To a solution of Example 76 (30.0 mg, 0.04 mmol) in DCM (0.5 mL) was added M-CPBA (18 mg, 0.08 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 h. Then the reaction mixture was purified by prep-HPLC to afford Example 79 (9 mg) as a white solid. LCMS (M+H+): 814. 1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.88 - 7.75 (m, 1H), 7.61 (s, 1H), 7.36 - 7.19 (m, 2H), 7.15 (br d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.1 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.79 (br d, J = 15.4 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.61 (br d, J = 11.7 Hz, 2H), 4.56 - 4.41 (m, 3H), 4.28 - 4.06 (m, 4H), 3.92 (br d, J = 14.1 Hz, 1H), 3.46 (br s, 2H), 3.11 (s, 1H), 3.00 (s, 2H), 2.90 (br d, J = 14.9 Hz, 1H), 2.86 - 2.82 (m, 3H), 2.78 (s, 1H), 2.60 - 2.54 (m, 3H), 2.48 (br s, 2H), 2.30 (br d, J = 9.8 Hz, 1H). Example 80 2-[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]-3-methoxy-azetidin-3-yl]acetonitrile
Figure imgf000169_0002
The title compound was prepared according to the following scheme: Step 1: preparation of (3-methoxyazetidin-3-yl) methanol (compound 80b) To a solution of compound 80a (300.0 mg, 1.38 mmol) in DCM (7 mL) was added TFA (1.0 mL, 1.38 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 h and then concentrated to give compound 80b (300.0 mg) as light brown oil, which was used for next step directly. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(hydroxymethyl)- 3-methoxy-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 80c) A solution of Intermediate E1 (100.0 mg, 0.14 mmol), compound 80b (100.0 mg, 0.43 mmol), CsF (108 mg, 0.71 mmol) and DIEA (0.25 mL, 1.42 mmol) in DMA (1.5 mL) was stirred at 80 °C for 2 h. The reaction mixture was purified by prep-HPLC to give compound 80c (80.0 mg) as a light brown solid. LCMS (M+H+): 784. Step 3: preparation of [1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 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]-3-methoxy-azetidin-3-yl]methyl ethanesulfonate (compound 80d) To a solution of compound 80c (80.0 mg, 0.1 mmol) and TEA (13 mg, 0.13 mmol) in DCM (2 mL) was added ethanesulfonyl chloride (20 mg, 0.15 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h. Then the reaction mixture was filtered, the filtrate was concentrated, the residue was purified by prep-TLC to give compound 80d (50.0 mg) as a light brown solid. LCMS (M+H+): 876. Step 4: preparation of 2-[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]-3-methoxy-azetidin-3-yl] acetonitrile(Example 80) To a solution of compound 80d (50.0 mg, 0.06 mmol) in DMF (1 mL) was added 18- crown-6 (2 mg, 0.01 mmol) and sodium cyanide (40.0 mg, 0.82 mmol). The reaction mixture was stirred at 50 °C for 2 h, and then the reaction mixture was purified by prep-HPLC to afford Example 80 (29 mg) as a white solid. LCMS (M+H+): 793.1H NMR (400 MHz, METHANOL- d4) δ = 8.26 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (t, J = 9.5 Hz, 1H), 7.18 - 7.12 (m, 2H), 7.08 (d, J = 7.1 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.86 - 5.66 (m, 1H), 5.40 - 5.28 (m, 1H), 4.66 - 4.54 (m, 1H), 4.46 - 4.41 (m, 1H), 4.24 - 4.13 (m, 3H), 4.08 - 4.00 (m, 2H), 3.94 - 3.87 (m, 2H), 3.37 - 3.34 (m, 3H), 3.10 (d, J = 7.9 Hz, 3H), 3.05 (s, 2H), 2.97 - 2.90 (m, 1H), 2.87 - 2.83 (m, 3H), 2.83 - 2.73 (m, 1H), 2.58 - 2.55 (m, 3H), 2.53 - 2.43 (m, 2H). Example 81 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7- azaspiro[3.4]octan-6-one
Figure imgf000171_0001
A mixture of intermediate E2 (30 mg, 0.04 mmol), 2-oxa-7-azaspiro[3.4]octan-6-one (26 mg, 0.2 mmol), potassium phosphate (18 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (8mg, 0.008 mmol), dimethylbisdiphenylphosphinoxanthene (10 mg, 0.016 mol) in 1,4-dioxane (2 mL) was heated to 110 oC for 16 h. Then the reaction was concentrated and the residue was purified by prep-HPLC to give Example 81 (8 mg) as white powder. LCMS (M+H+): 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H), 7.71 - 7.41 (m, 1H), 7.35 - 7.24 (m, 1H), 7.22 - 6.96 (m, 4H), 5.56 - 5.18 (m, 2H), 4.61 - 4.51 (m, 4H), 4.49 - 4.44 (m, 1H), 4.36 - 3.99 (m, 6H), 3.92 - 3.78 (m, 1H), 3.04 - 2.70 (m, 7H), 2.62 - 2.35 (m, 6H), 0.55 - 0.37 (m, 3H). Example 82 (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000172_0001
The title compound was prepared according to the following scheme:
Figure imgf000172_0002
Step 1: preparation of tert-butyl 6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy- 22-fluoro-13,18-dimethyl-12-oxo-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 82a) Compound 82a was prepared in analogy to the preparation of Example 81 by using tert- butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate instead of 2-oxa-7-azaspiro[3.4]octan-6-one. LCMS (M+H+): 908. Step 2: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-oxo-2,6- diazaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (compound 82b) Compound 82b was prepared in analogy to the preparation of compound 62b by using compound 82a instead of compound 62a. LCMS (M+H+): 808. Step 3: preparation of (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6- diazaspiro[3.4]octan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy- 22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 82) Example 82 was prepared in analogy to the preparation of Example 52 by using 2,2- difluoroethyl trifluoromethanesulfonate instead of compound 52a and compound 82b instead of intermediate F1. LCMS (M+H+): 872.1H NMR (400 MHz, METHANOL-d4) δ = 8.54 - 8.40 (m, 1H), 8.36 - 8.25 (m, 1H), 7.67 - 7.55 (m, 1H), 7.33 - 7.24 (m, 1H), 7.22 - 6.93 (m, 4H), 5.89 - 5.47 (m, 2H), 5.44 - 5.17 (m, 1H), 4.70 - 4.65 (m, 1H), 4.39 - 4.27 (m, 1H), 4.26 - 3.97 (m, 4H), 3.95 - 3.76 (m, 1H), 3.42 - 3.26 (m, 4H), 3.17 - 3.11 (m, 1H), 3.06 - 2.93 (m, 3H), 2.89 - 2.63 (m, 6H), 2.61 - 2.35 (m, 6H), 0.56 - 0.39 (m, 3H). Example 83 and 84 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one Examples 83 and 84 were prepared in analogy to the preparation of Example 55 by using intermediate D9 instead of intermediate D18 and intermediate C6 instead of intermediate C2. SFC condition: Instrument: SFC 150 Mgm; Column: OD, 200×30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for Methanol (0.1% NH3H2O); Gradient: B 30%; Flow rate: 80 mL /min; Back pressure: 100bar; Column temperature: 35 ℃. Example 83, faster eluted. LCMS (M+H+): 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.83 - 8.73 (m, 1H), 8.37 - 8.18 (m, 1H), 7.74 - 7.60 (m, 2H), 7.50 - 7.40 (m, 2H), 7.32 - 7.11(m, 2H), 5.89 - 5.63 (m, 2H), 5.55 - 5.29 (m, 1H), 4.68 - 4.55 (m, 1H), 4.46 - 4.24 (m, 2H), 4.22 - 4.08 (m, 3H), 4.07 - 3.84 (m, 1H), 3.31 - 3.25 (m, 1H), 3.17 - 2.93 (m, 4H), 2.91 - 2.74 (m, 6H), 2.71 - 2.50 (m, 6H), 1.85 - 1.68 (m, 1H), 0.65 - 0.52 (m, 3H). Example 84, slower eluted. LCMS (M+H+): 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.90 - 8.73 (m, 1H), 8.40 - 8.23 (m, 1H), 7.73 - 7.56 (m, 2H), 7.51 - 7.35 (m, 2H), 7.31 - 7.10 (m, 2H), 5.92 - 5.60 (m, 2H), 5.54 - 5.22 (m, 1H), 4.69 - 4.50 (m, 1H), 4.47 - 4.26 (m, 2H), 4.24 - 4.08 (m, 2H), 4.04 - 3.78 (m, 2H), 3.32 - 3.17 (m, 2H), 3.11 - 2.97 (m, 3H), 2.92 - 2.72 (m, 6H), 2.71 - 2.50 (m, 6H), 1.88 - 1.71 (m, 1H), 0.69 - 0.52 (m, 3H). Example 85 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methyl- azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one The title compound was prepared according to the following scheme:
Figure imgf000175_0001
Step 1: preparation of methyl 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-methyl-azetidine-2-carboxylate (compound 85a) Compound 85a was prepared in analogy to the preparation of compound 62a by using methyl 2-methylazetidine-2-carboxylate instead of 7-BOC-3-oxa-7,9-diazabicyclo[3.3.1]nonane. LCMS (M+H+): 796. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3- fluoroazetidine-1-carbonyl)-2-methyl-azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 85) Example 85 was prepared in analogy to the preparation of compound 109d by using compound 85a instead of compound 109b and 3-fluoroazetidine instead of NH4Cl. LCMS (M+H+): 839.1H NMR (400 MHz, METHANOL-d4) δ = 8.27 (br d, J = 3.8 Hz, 1H), 7.90 - 7.75 (m, 1H), 7.72 - 7.54 (m, 1H), 7.39 - 7.03 (m, 5H), 6.76 - 6.58 (m, 1H), 5.94 - 5.66 (m, 1H), 5.46 - 5.07 (m, 2H), 4.67 - 4.29 (m, 4H), 4.29 - 3.76 (m, 8H), 3.17 - 2.70 (m, 9H), 2.68 - 2.40 (m, 6H), 2.25 - 2.04 (m, 1H), 1.82 - 1.68 (m, 1H). Example 87 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin- 4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000176_0001
The title compound was prepared according to the following scheme:
Figure imgf000176_0002
Example 87 was prepared in analogy to the preparation of Example 62 by using tert-butyl (4aR,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate instead of 7- BOC-3-oxa-7,9-diazabicyclo[3.3.1]nonane. LCMS (M+H+): 809.1H NMR (400 MHz, METHANOL-d4) δ = 8.36 - 8.26 (m, 1H), 7.92 - 7.79 (m, 1H), 7.71 - 7.59 (m, 1H), 7.39 - 7.23 (m, 2H), 7.21 - 7.04 (m, 3H), 6.77 - 6.66 (m, 1H), 5.91 - 5.67 (m, 1H), 5.48 - 5.29 (m, 1H), 4.71 - 4.63 (m, 1H), 4.54 - 4.40 (m, 2H), 4.31 - 4.12 (m, 5H), 4.09- 3.84 (m, 4H), 3.68 - 3.60 (m, 2H), 3.21 - 3.03 (m, 5H), 3.00 - 2.79 (m, 7H), 2.70 - 2.47 (m, 5H). Example 88 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-ylmethyl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-
Figure imgf000177_0001
1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000177_0002
Example 88 was prepared in analogy to the preparation of Example 113 by using compound 87b instead of compound 62b. LCMS (M+H+): 865.1H NMR (400 MHz, METHANOL-d4) δ = 8.35 - 8.21 (m, 1H), 7.88 - 7.76 (m, 1H), 7.69 - 7.54 (m, 1H), 7.35 - 7.05 (m, 5H), 6.76 - 6.65 (m, 1H), 5.87 (br dd, J = 4.4, 15.6 Hz, 1H), 5.45 - 5.26 (m, 1H), 4.81 - 4.74 (m, 3H), 4.71 - 4.56 (m, 2H), 4.51 - 4.41 (m, 3H), 4.32 - 4.10 (m, 3H), 4.07 - 3.85 (m, 3H), 3.58 - 3.48 (m, 1H), 3.27 - 3.03 (m, 7H), 3.00 - 2.83 (m, 6H), 2.74 - 2.46 (m, 7H). Example 89 (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 89 was prepared in analogy to the preparation of Example 112 by using compound 87b instead of compound 62b. LCMS (M+H+): 851.1H NMR (400 MHz, METHANOL-d4) δ = 8.34 - 8.23 (m, 1H), 7.87 - 7.79 (m, 1H), 7.73 - 7.61 (m, 1H), 7.37 - 7.08 (m, 5H), 6.78 - 6.65 (m, 1H), 5.85 - 5.75 (m, 1H), 5.39 - 5.32 (m, 1H), 4.67 - 4.61 (m, 2H), 4.53 - 4.47 (m, 1H), 4.32 - 4.12 (m, 4H), 4.03 - 3.88 (m, 4H), 3.59 - 3.47 (m, 2H), 3.19 - 3.04 (m, 7H), 2.99 - 2.84 (m, 5H), 2.81 - 2.66 (m, 3H), 2.63 - 2.49 (m, 5H). Example 90 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azetidine-3-carbonitrile
Figure imgf000178_0001
A mixture of intermediate C1 (30.0 mg, 0.04 mmol), 3-methylazetidine-3-carbonitrile (17 mg, 0.130 mmol) and DIPEA (0.04 mL, 0.21 mmol) in IPA (0.5 mL) was stirred for 4 h at 120 °C. Then the reaction mixture was purified by prep-HPLC to give Example 90 (15 mg) as a white solid. LCMS (M+H+): 763.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.81 - 7.76 (m, 1H), 7.73 - 7.65 (m, 1H), 7.59 - 7.53 (m, 1H), 7.39 - 7.36 (m, 1H), 7.32 - 7.27 (m, 1H), 7.15 - 7.07 (m, 2H), 6.68 - 6.61 (m, 1H), 5.76 - 5.70 (m, 1H), 5.57 - 5.53 (m, 1H), 5.37 - 5.30 (m, 1H), 4.62 - 4.58 (m, 1H), 4.41 - 4.36 (m, 1H), 4.30 - 4.28 (m, 1H), 4.22 - 4.18 (m, 1H), 4.13 - 4.03 (m, 2H), 3.99 - 3.96 (m, 1H), 3.90 - 3.78 (m, 2H), 3.01 - 2.94 (m, 3H), 2.86 - 2.83 (m, 1H), 2.75 - 2.71 (m, 3H), 2.56 - 2.53 (m, 1H), 2.51 - 2.47 (m, 3H), 2.39 - 2.35 (m, 2H), 1.62 - 1.55(m, 3H). Example 91 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidine-3-carbonitrile
Figure imgf000179_0001
A mixture of intermediate C1 (30.0 mg, 0.04 mmol), 3-methoxyazetidine-3-carbonitrile (25 mg, 0.170 mmol) and DIPEA (0.04 mL, 0.21 mmol) in IPA (0.5 mL) was stirred for 4 h at 120 °C. Then the reaction mixture was purified by prep-HPLC to give Example 91 (15 mg) as a white solid. LCMS (M+H+): 779.1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.80 - 7.55 (m, 3H), 7.38 - 7.29 (m, 2H), 7.14 - 7.07 (m, 2H), 6.67 - 6.63 (m, 1H), 5.73 - 5.70 (m, 1H), 5.57 - 5.53 (m, 1H), 5.38 - 5.30 (m, 1H), 4.62 - 4.58 (m, 1H), 4.44 - 4.34 (m, 3H), 4.26 - 4.16 (m, 2H), 4.12 - 4.07 (m, 2H), 3.97 - 3.95 (m, 1H), 3.82 - 3.79 (m, 1H), 3.42 - 3.33 (m, 3H), 3.01 - 2.95 (m, 3H), 2.88 - 2.85 (m, 1H), 2.75 - 2.71 (m, 3H), 2.49 - 2.45 (m, 3H), 2.42 - 2.33 (m, 2H). Example 92 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carbonitrile
Figure imgf000179_0002
To a stirred mixture of intermediate C1 (70 mg, 0.1 mmol) and 5-oxopyrrolidine-3- carbonitrile (55 mg, 0.5 mmol) in 1,4-dioxane (3 mL) were added K3PO4 (63 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (46 mg, 0.08 mmol). The mixture was stirred for 6 h at 110 °C under nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 92 (17.0 mg) as a white solid. LCMS (M+H+): 777.1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.80 - 7.44 (m, 4H), 7.38 - 7.30 (m, 3H), 7.15 - 7.10 (m, 2H), 6.68 - 6.62 (m, 1H), 5.80 - 5.38 (m, 3H), 4.62 - 4.42 (m, 1H), 4.30 - 4.05 (m, 4H), 3.94 - 3.59 (m, 3H), 3.02 - 2.75 (m, 6H), 2.72 - 2.53 (m, 3H), 2.49 - 2.44 (m, 3H), 2.37 - 2.34 (m, 1H). Example 93 (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one
Figure imgf000180_0001
Example 93 was prepared in analogy to the preparation of Example 55 by using intermediate D10 instead of intermediate D18 and intermediate C1 instead of intermediate C2. LCMS (M+H+): 833.1H NMR (400 MHz, DMSO-d6) δ = 8.35 - 8.33 (m, 1H), 7.84 - 7.81 (m, 1H), 7.67 - 7.56 (m, 3H), 7.41 - 7.39 (m, 1H), 7.30 - 7.28 (m, 1H), 7.16 - 7.12 (m, 1H), 6.74 - 6.68 (m, 1H), 6.00 - 5.90 (m, 1H), 5.74 - 5.52 (m, 2H), 5.37 - 5.24 (m, 1H), 4.63 - 4.60 (m, 1H), 4.44 - 4.35 (m, 2H), 4.22 - 4.01 (m, 4H), 3.85 - 3.75 (m, 2H), 3.05 - 2.89 (m, 4H), 2.83 - 2.78 (m, 4H), 2.71 - 2.60 (m, 5H), 2.42 - 2.37 (m, 2H), 1.72 - 1.65 (m, 1H), 0.85 - 0.45 (m, 1H), 0.15 - 0.00 (m, 1H), -0.05 - -0.20 (m, 2H). Example 94 and 95 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Examples 94 and 95 were prepared in analogy to the preparation of Example 55 by using intermediate D12 instead of intermediate D18 and intermediate C1 instead of intermediate C2. Example 94: faster eluted, LCMS (M+H+): 825.1H NMR (400 MHz, DMSO-d6) δ = 8.90 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.89 - 7.75 (m, 2H), 7.74 - 7.61 (m, 2H), 7.60 - 7.48 (m, 1H), 7.36 - 7.20 (m, 1H), 5.81 - 5.55 (m, 2H), 5.48 - 5.24 (m, 1H), 4.67 - 3.71 (m, 9H), 3.70 - 3.11 (m, 4H), 3.01 - 2.89 (m, 3H), 2.88 - 2.52 (m, 9H), 1.73 - 1.69 (m, 1H), 0.51 - 0.39 (m, 3H). Example 95: slower eluted, LCMS (M+H+): 825.1H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 1H), 8.41 (s, 1H), 7.90 - 7.74 (m, 2H), 7.73 - 7.61 (m, 2H), 7.60 - 7.51 (m, 1H), 7.37 - 7.21 (m, 1H), 5.79 - 5.52 (m, 2H), 5.48 - 5.32 (m, 1H), 4.60 - 3.80 (m, 9H), 3.63 - 3.13 (m, 4H), 3.01 - 2.75 (m, 5H), 2.74 - 2.40 (m, 7H), 1.79 - 1.59 (m, 1H), 0.52 - 0.39 (m, 3H). Example 100 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000181_0001
Example 100 was prepared in analogy to the preparation of Example 51 by using 3-methyl- 3,8-diazabicyclo[3.2.1]octan-2-one instead of compound 51a. LCMS (M+H+): 807.1H NMR (400 MHz, METHANOL-d4) δ = 8.34 - 8.22 (m, 1H), 7.90 - 7.72 (m, 1H), 7.67 - 7.56 (m, 1H), 7.38 - 7.28 (m, 1H), 7.25 - 7.07 (m, 4H), 6.74 - 6.61 (m, 1H), 5.91 - 5.69 (m, 1H), 5.47 - 5.23 (m, 1H), 4.74 - 4.69 (m, 1H), 4.66 - 4.60 (m, 1H), 4.49 - 4.38 (m, 1H), 4.26 - 4.12 (m, 2H), 3.97 - 3.86 (m, 1H), 3.81 - 3.67 (m, 1H), 3.12 - 3.05 (m, 3H), 3.04 - 2.93 (m, 2H), 2.89 - 2.83 (m, 3H), 2.82 - 2.73 (m, 4H), 2.66 - 2.54 (m, 4H), 2.53 - 2.42 (m, 2H), 2.35 - 2.10 (m, 2H), 2.09 - 1.98 (m, 1H), 1.96 - 1.79 (m, 1H). Example 101 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000182_0001
Example 101 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E10 instead of intermediate E4. LCMS (M+H+): 849.1H NMR (400 MHz, METHANOL-d4) δ = 8.60 - 8.48 (m, 1H), 8.32 - 8.21 (m, 1H), 7.84 - 7.69 (m, 1H), 7.67 - 7.52 (m, 2H), 7.34 - 7.14 (m, 3H), 6.91 - 6.69 (m, 2H), 6.04 - 5.74 (m, 1H), 5.52 - 5.30 (m, 1H), 4.78 - 4.57 (m, 2H), 4.54 - 4.40 (m, 2H), 4.37 - 4.23 (m, 3H), 4.21 - 3.93 (m, 2H), 3.68 - 3.42 (m, 3H), 3.23 - 3.04 (m, 4H), 3.01 - 2.89 (m, 3H), 2.86 - 2.54 (m, 7H). Example 102 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa- 3,10-diazabicyclo[4.3.1]decan-4-one
Figure imgf000182_0002
Example 102 was prepared in analogy to the preparation of Example 57 by using tert-butyl 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decane-10-carboxylate instead of compound 60d and intermediate E2 instead of intermediate E5. LCMS (M+H+): 852.1H NMR (400 MHz, METHANOL-d4) δ = 8.57 - 8.40 (m, 1H), 8.26 - 8.07 (m, 1H), 7.63 - 7.42 (m, 1H), 7.35 - 7.25 (m, 1H), 7.22 - 6.93 (m, 4H), 5.60 - 5.40 (m, 1H), 5.36 - 5.26 (m, 1H), 4.58 - 4.38 (m, 6H), 4.35 - 4.24 (m, 1H), 4.19 - 4.04 (m, 2H), 3.93 - 3.56 (m, 6H), 3.04 - 2.89 (m, 4H), 2.89 - 2.77 (m, 3H), 2.71 - 2.30 (m, 8H), 0.57 - 0.41 (m, 3H). Example 103, 104, 105 and 106 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- 2,6 [(1R,8S)-4-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
The title compound was prepared according to the following scheme:
Example 103 & 104 & 105 & 106 Step 1: preparation of tert-butyl (1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-diene-12-carboxylate; tert-butyl (1R,8S)-4-methyl-10- 2,6 oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2,5-diene-12-carboxylate; tert-butyl (1S,8R)-5- 2,6 methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2(6),3-diene-12-carboxylate; tert-butyl 2,6 (1R,8S)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2(6),3-diene-12-carboxylate (compound 103b-1, 103b-2, 103b-3 and 103b-4) A mixture of compound 103a (2 g, 8.29 mmol) and DMF-DMA (9.88 g, 82.9 mmol) in 1,4-dioxane (10 mL) was stirred at 110 oC for 16 hours, then the reaction mixture was concentrated to give a residue, to which was added DIPEA (4.8 g, 37 mmol), methylhydrazine;sulfuric acid (2.68 g, 18.57 mmol) and ethanol (88 mL). The resulted mixture was stirred at 80 oC for 4 hours and then concentrated. The residue was purified by reversed flash column chromatography and SFC to give compound 103b-1 (100 mg, the second eluted), 103b-2 (60 mg, the forth eluted), 103b-3 (the first eluted) and 103b-4 (the third eluted). LCMS (M+H+): 280. SFC condition: Instrument: SFC 150 Mgm; Column: AD-H, 250×30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for ethanol (0.1% NH3H2O); Gradient: B 10%; Flow rate: 80 mL /min; Back pressure: 100 bar; Column temperature: 35 ℃. Step 2-3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl- 2,6 10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- methoxy-13,18-dimethyl-
Figure imgf000186_0001
1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- 2,6 [(1S,8R)-5-methyl-10-oxa-4,5,12-triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 103 & 104 & 105 & 106) Examples 103, 104, 105 and 106 were prepared in analogy to the preparation of Example 57 by using compound 103b-1, 103b-2, 103b-3 and 103b-4 instead of compound 57b and intermediate E1 instead of intermediate E5. Example 103, LCMS (M+H+): 846.1H NMR (400 MHz, METHANOL-d4) δ = 8.31 - 8.20 (m, 1H), 7.96 - 7.82 (m, 1H), 7.64 - 7.50 (m, 3H), 7.46 - 7.34 (m, 1H), 7.32 - 7.10 (m, 3H), 6.85 - 6.74 (m, 1H), 6.32 - 5.98 (m, 1H), 5.66 - 5.24 (m, 2H), 4.68 - 4.49 (m, 1H), 4.45 - 4.15 (m, 3H), 4.08 - 3.51 (m, 9H), 3.25 - 2.92 (m, 9H), 2.89 - 2.74 (m, 4H), 2.70 - 2.47 (m, 2H). Example 104, LCMS (M+H+): 846.1H NMR (400 MHz, METHANOL-d4) δ = 8.31 - 8.19 (m, 1H), 7.92 - 7.78 (m, 1H), 7.69 - 7.56 (m, 1H), 7.35 - 7.22 (m, 3H), 7.21 - 7.06 (m, 3H), 6.77 - 6.62 (m, 1H), 5.93 - 5.80 (m, 1H), 5.60 - 5.51 (m, 1H), 4.52 - 4.44 (m, 2H), 4.24 - 4.15 (m, 3H), 4.04 - 3.93 (m, 3H), 3.85 - 3.70 (m, 5H), 3.15 - 3.03 (m, 5H), 2.94 - 2.79 (m, 5H), 2.68 - 2.48 (m, 6H). Example 105, LCMS (M+H+): 846.1H NMR (400 MHz, DMSO-d6 & METHANOL-d4) δ = 8.31 - 8.17 (m, 1H), 7.82 - 7.73 (m, 1H), 7.69 - 7.57 (m, 1H), 7.45 - 6.98 (m, 6H), 6.71 - 6.54 (m, 1H), 5.85 - 5.56 (m, 1H), 5.51 - 5.41 (m, 1H), 5.34 - 5.04 (m, 1H), 4.79 - 4.54 (m, 1H), 4.46 - 4.32 (m, 1H), 3.95 - 3.47 (m, 10H), 3.20 - 2.92 (m, 7H), 2.89 - 2.65 (m, 5H), 2.47 - 2.30 (m, 4H). Example 106, LCMS (M+H+): 846.1H NMR (400 MHz, METHANOL-d4) δ = 8.37 - 8.16 (m, 1H), 7.93 - 7.76 (m, 1H), 7.71 - 7.57 (m, 1H), 7.39 - 7.04 (m, 6H), 6.78 - 6.61 (m, 1H), 5.91 - 5.65 (m, 1H), 5.52 - 5.23 (m, 1H), 4.71 - 4.51 (m, 2H), 4.48 - 4.32 (m, 1H), 4.30 - 3.56 (m, 11H), 3.23 - 2.95 (m, 5H), 2.93 - 2.69 (m, 5H), 2.63 - 2.42 (m, 5H). Example 107 and 108 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,2R,8S)-5-oxo-6,9-diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000187_0001
The title compound was prepared according to the following scheme: Step 1: preparation of 6-benzyl 3-tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3,6- dicarboxylate (compound 107b) To a solution of compound 107a (5 g, 25.22 mmol) and sodium carbonate (8 g, 75.66 mmol) in THF (50 mL) and water (50 mL) was added N-(benzyloxycarbonyloxy) succinimide (7.5 g, 30.26 mmol). The reaction was stirred at 25 °C for 16 h and then quenched with water, and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by flash chromatography to give compound 107b (8 g) as colorless oil. LCMS (M+Na+): 355. Step 2: preparation of 6-benzyl 3-tert-butyl 2-(3-methoxy-3-oxo-propyl)-3,6- diazabicyclo[3.1.1]heptane-3,6-dicarboxylate (compound 107d) To a solution of compound 107b (1.5 g, 4.51 mmol) in CD3CN (3.0 mL, 4.51 mmol) was added diphenylmethanone (411 mg, 2.26 mmol), Cu(OAc)2 (16 mg, 0.09 mmol) and compound 107c (600 mg, 6.97 mmol) under N2. The mixture was stirred at 30 °C for 4 h under 365 nm LED irradiation. The reaction mixture was filtered and concentrated to give a crude product, which was purified by flash chromatography to give compound 107d (250 mg) as light yellow oil. LCMS (M+Na+): 441. Step 3: preparation of benzyl 2-(3-methoxy-3-oxo-propyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 107e) To a solution of compound 107d (300 mg, 0.72 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 °C. The reaction mixture was stirred for 2 h at 25 °C and then concentrated, the residue was purified by prep-HPLC to give compound 107e (110.0 mg) as light yellow oil. LCMS (M+H+): 319. Step 4: preparation of benzyl 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decane-9-carboxylate (compound 107f) To a solution of compound 107e (110.0 mg, 0.35 mmol) in THF (70 mL) was added TBD (24 mg, 0.17 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h and then concentrated, the residue was purified by prep-HPLC to give compound 107f (55.0 mg) as light yellow semisolid. LCMS (M+H+): 287. Step 5: preparation of 6,9-diazatricyclo[6.1.1.02,6]decan-5-one (compound 107g) To a solution of compound 107f (55.0 mg, 0.19 mmol) in methanol (3 mL) was added wet Pd/C (55 mg) under N2 at 25 °C. The mixture was stirred under H2 (balloon) at 25 °C for 2 h. Then the mixture was filtered, the filtrate was concentrated to give compound 107g (40.0 mg) as light yellow semisolid. Step 6: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo- 6,9-diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,2R,8S)-5-oxo-6,9-diazatricyclo [6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one (Example 107 and 108) A solution of Intermediate E1 (40.0 mg, 0.06 mmol), compound 107g (17 mg, 0.11 mmol), CsF (21 mg, 0.14 mmol) and DIPEA (0.02 mL, 0.14 mmol) in DMA (0.5 mL) was stirred at 120 °C for 16 h. Then the reaction mixture was purified by prep-HPLC and SFC to give Example 107 and Example 108. SFC Method: Column DAICEL CHIRALPAK AD (250 mm×30 mm,10 um); Condition CO2-EtOH (0.1%NH3·H2O); Begin B 60%; End B 60%; Gradient Time (min) 4.5; 100% B Hold Time (min) 0; Flow Rate (ml/min) 120. Example 107 (6 mg), faster eluted. LCMS (M+H+): 819.1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.23 - 7.17 (m, 1H), 7.17 - 7.11 (m, 1H), 7.08 - 7.02 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.76 - 5.55 (m, 1H), 5.30 - 5.19 (m, 1H), 4.57 - 4.52 (m, 1H), 4.47 (s, 3H), 4.38 - 4.33 (m, 1H), 4.26 - 4.21 (m, 1H), 4.16 - 4.01 (m, 3H), 3.90 - 3.73 (m, 1H), 3.60 - 3.49 (m, 1H), 3.04 - 2.93 (m, 3H), 2.84 (br d, J = 14.1 Hz, 1H), 2.77 - 2.71 (m, 3H), 2.67 (br d, J = 13.9 Hz, 1H), 2.55 - 2.44 (m, 4H), 2.44 - 2.34 (m, 2H), 2.24 - 2.15 (m, 1H), 2.06 - 1.97 (m, 1H), 1.65 - 1.46 (m, 2H). Example 108 (5 mg), slower eluted. LCMS (M+H+): 819.1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 1H), 7.75 - 7.68 (m, 1H), 7.57 - 7.48 (m, 1H), 7.23 - 7.18 (m, 1H), 7.17 - 7.11 (m, 1H), 7.09 - 7.03 (m, 2H), 7.01 - 6.97 (m, 1H), 6.57 (d, J = 8.3 Hz, 1H), 5.73 - 5.55 (m, 1H), 5.32 (br d, J = 8.5 Hz, 1H), 4.55 (br t, J = 5.3 Hz, 1H), 4.41 - 4.33 (m, 2H), 4.25 (br s, 1H), 4.16 - 4.10 (m, 3H), 4.00 - 3.49 (m, 3H), 3.01 (s, 1H), 2.94 (s, 3H), 2.91 - 2.88 (m, 1H), 2.78 - 2.69 (m, 4H), 2.52 - 2.44 (m, 4H), 2.43 - 2.35 (m, 2H), 2.26 - 2.18 (m, 1H), 1.96 - 1.85 (m, 1H), 1.70 - 1.58 (m, 1H), 1.54 - 1.50 (m, 1H), 1.49 - 1.47 (m,1H). Example 109 2-[(3R)-4-[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(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3- yl]acetonitrile
Figure imgf000190_0001
The title compound was prepared according to the following scheme:
Step 1: preparation of methyl 2-[(3R)-4-[4-benzyloxy-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3-yl]acetate (compound 109b) To a solution of Intermediate D15-a (500.0 mg, 1.34 mmol), compound 109a (262 mg, 1.34 mmol) in 1,4-dioxane (5 mL) was added Pd-PEPPSI-IPentCl o-picoline (231 mg, 0.27 mmol) and Cs2CO3 (2.2 g, 6.71 mmol) at 25 °C. The reaction was stirred at 100 °C for 3 h under N2 and then poured into water, extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by flash chromatography to give compound 109b (330.0 mg) as a light yellow solid. LCMS (M+H+): 496. Step 2: preparation of 2-[(3R)-4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetic acid (compound 109c) To a solution of compound 109b (400.0 mg, 0.81 mmol) in THF (4 mL) and methanol (4 mL) was added a solution of LiOH·H2O (169 mg, 4.04 mmol) in water (4 mL) at 0 °C. The reaction was stirred at 25 °C for 3 h and then concentrated. The residue was dissolved in EtOAc, washed with brine (10 mL), dried and concentrated to give compound 109c (300.0 mg) as a light yellow solid. LCMS (M+H+): 482. Step 3: preparation of 2-[(3R)-4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetamide (compound 109d) A mixture of compound 109c (300.0 mg, 0.62 mmol), NH4Cl (66 mg, 1.25 mmol), HATU (249 mg, 1.06 mmol) and DIEA (0.18 mL, 1.06 mmol) in DMF (5 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into water and then extracted with EtOAc, the organic layer was concentrated to give a crude product, which was purified by prep-TLC to give compound 109d (280.0 mg) as a light yellow solid. LCMS (M+H+): 481. Step 4: preparation of 2-[(3R)-4-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetonitrile (compound 109e) To a solution of compound 109d (50.0 mg, 0.1 mmol) and pyridine (0.03 mL, 0.31 mmol) in THF (5 mL) was added TFAA (0.02 mL, 0.12 mmol) slowly at 0 °C and then stirred at 0 °C for 1 h. The reaction mixture was poured into ice water, extracted with EtOAc, the organic layer was dried and concentrated to give compound 109e (50.0 mg) as light yellow oil. LCMS (M+H+): 463. Step 5: preparation of 2-[(3R)-4-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4- d]pyrimidin-6-yl]morpholin-3-yl]acetonitrile (compound 109f) To a solution of compound 109e (50.0 mg, 0.11 mmol) in DCM (2 mL) was added TFA (2 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h and then concentrated to give compound 109f (50.0 mg) as light yellow oil. LCMS (M+H+): 373. Step 6: preparation of 2-[(3R)-4-[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(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin- 3-yl]acetonitrile (Example 109) To a solution of compound 109f (50.0 mg, 0.1 mmol), PyBOP (80 mg, 0.15 mmol), DIEA (0.04 mL, 0.26 mmol) in DMF (1 mL) was added a solution of Intermediate C1 (51 mg, 0.09 mmol), DIEA (0.04 mL, 0.26 mmol) in DMF (1 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h and then purified by prep-HPLC to give Example 109 (16 mg) as a white solid. LCMS (M+H+): 793.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.95 - 7.85 (m, 1H), 7.70 - 7.51 (m, 3H), 7.31 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 6.88 - 6.74 (m, 1H), 6.28 - 6.06 (m, 1H), 5.47 - 5.33 (m, 1H), 4.72 - 4.62 (m, 2H), 4.55 - 4.45 (m, 1H), 4.38 - 4.21 (m, 3H), 4.03 - 3.88 (m, 3H), 3.74 - 3.63 (m, 1H), 3.58 - 3.48 (m, 1H), 3.28 - 3.19 (m, 4H), 3.09 - 3.08 (m, 1H), 3.10 - 2.96 (m, 5H), 2.88 - 2.82 (m, 3H), 2.80 - 2.77 (m, 1H), 2.67 - 2.52 (m, 2H). Example 112 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000193_0001
To a solution of compound 62b (30.0 mg, 0.03 mmol) in methanol (0.5 mL) was added 3- oxetanone (7 mg, 0.1 mmol) and sodium cyanoborohydride (4 mg, 0.07 mmol). The reaction mixture was stirred at 25 °C for 12 hr under N2, then the mixture was purified by prep-HPLC to give Example 112 (8 mg) as a white solid. LCMS (M+H+): 851.1H NMR (400 MHz, METHANOL-d4) δ (ppm) = 8.25 (s, 1H), 7.86 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.34 - 7.29 (m, 1H), 7.26 - 7.18 (m, 1H), 7.17 - 7.11 (m, 2H), 7.09 (d, J = 7.3 Hz, 1H), 6.71 - 6.65 (m, 1H), 5.89 - 5.63 (m, 1H), 5.41 - 5.27 (m, 1H), 4.73 (br t, J = 6.3 Hz, 2H), 4.66 - 4.57 (m, 6H), 4.51 - 4.42 (m, 2H), 4.28 - 4.09 (m, 3H), 3.98 - 3.77 (m, 5H), 3.12 - 3.01 (m, 3H), 2.95 - 2.88 (m, 2H), 2.87 - 2.82 (m, 3H), 2.76 (br d, J = 13.4 Hz, 1H), 2.59 - 2.55 (m, 3H), 2.52 - 2.43 (m, 2H), 2.35 - 2.24 (m, 1H). Example 113 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-ylmethyl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000193_0002
A solution of compound 62b (20.0 mg, 0.02 mmol), 3-(iodomethyl)oxetane (7 mg, 0.03 mmol), CsF (10 mg, 0.07 mmol) and DIEA (0.01 mL, 0.07 mmol) in DMA (0.5 mL) was stirred at 60 °C for 3 h. Then the reaction mixture was purified by prep-HPLC to give Example 113 (12 mg) as a white solid. LCMS (M+H+): 865.1H NMR (400 MHz, METHANOL-d4) δ = 8.27 (s, 1H), 7.87 - 7.78 (m, 1H), 7.67 - 7.55 (m, 1H), 7.34 - 7.28 (m, 1H), 7.27 - 7.19 (m, 1H), 7.19 - 7.13 (m, 2H), 7.12 - 7.08 (m, 1H), 6.73 - 6.65 (m, 1H), 5.89 - 5.64 (m, 1H), 5.40 - 5.30 (m, 1H), 4.84 - 4.76 (m, 2H), 4.68 - 4.59 (m, 1H), 4.55 - 4.41 (m, 4H), 4.29 - 4.09 (m, 3H), 4.00 - 3.90 (m, 2H), 3.88 - 3.75 (m, 3H), 3.12 (s, 1H), 3.05 - 3.00 (m, 3H), 2.98 - 2.90 (m, 1H), 2.88 - 2.83 (m, 3H), 2.81 - 2.73 (m, 2H), 2.57 (d, J = 3.6 Hz, 3H), 2.53 - 2.45 (m, 2H), 2.24 - 1.98 (m, 1H), 1.39 - 1.29 (m, 4H). Example 114 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000194_0001
Example 114 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E2 instead of Intermediate E4. LCMS (M+H+): 850.1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.31 (s, 1H), 7.68 - 7.61 (m, 1H), 7.46 - 7.38 (m, 1H), 7.33 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.21 - 7.14 (m, 1H), 7.11 (s, 1H), 5.67 - 5.45 (m, 1H), 5.43 - 5.25 (m, 1H), 5.22 - 5.05 (m, 1H), 4.73 (br d, J = 7.2 Hz, 4H), 4.59 (br s, 5H), 4.27 (s, 2H), 4.17 (br s, 3H), 3.12 - 2.99 (m, 3H), 2.97 - 2.90 (m, 1H), 2.87 - 2.79 (m, 1H), 2.63 (s, 3H), 2.58 (s, 2H), 2.51 - 2.37 (m, 1H), 2.04 (s, 1H), 1.88 - 1.66 (m, 1H), 0.59 (t, J = 6.8 Hz, 3H). Example 115 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000195_0001
Example 115 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E11 instead of Intermediate E4. LCMS (M+H+): 851.1H NMR (400 MHz, METHANOL-d4) δ = 8.82 - 8.73 (m, 1H), 8.38 - 8.28 (m, 1H), 7.71 - 7.59 (m, 2H), 7.52 - 7.41 (m, 2H), 7.32 - 7.10 (m, 2H), 5.93 - 5.63 (m, 2H), 5.54 - 5.31 (m, 1H), 5.22 - 5.06 (m, 2H), 4.78 - 4.69 (m, 3H), 4.60 (br s, 5H), 4.50 - 4.41 (m, 1H), 4.17 (br s, 3H), 2.98 (s, 3H), 2.89 - 2.77 (m, 3H), 2.66 (s, 5H), 2.04 (s, 1H), 1.87 - 1.64 (m, 1H), 0.59 (s, 3H). Example 116 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000195_0002
Example 116 was prepared in analogy to the preparation of Example 60 by using compound 61b instead of compound 60h and Intermediate E3 instead of Intermediate E4. LCMS (M+H+): 836.1H NMR (400 MHz, METHANOL-d4) δ = 8.61 - 8.49 (m, 1H), 8.32 (s, 1H), 7.70 - 7.58 (m, 1H), 7.44 - 7.36 (m, 1H), 7.34 - 7.25 (m, 2H), 7.22 - 7.16 (m, 1H), 7.15 - 7.05 (m, 1H), 5.70 - 5.45 (m, 1H), 5.41 (br d, J = 8.8 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.76 - 4.71 (m, 4H), 4.59 (s, 3H), 4.34 (br d, J = 6.5 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.21 - 4.18 (m, 1H), 4.18 - 4.14 (m, 2H), 4.12 (br s, 1H), 3.14 - 3.02 (m, 3H), 2.98 - 2.87 (m, 2H), 2.84 (s, 3H), 2.82 (s, 1H), 2.63 - 2.55 (m, 3H), 2.53 - 2.38 (m, 2H), 1.74 (d, J = 9.0 Hz, 1H). Example 117 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000196_0001
The title compound was prepared according to the following scheme:
Figure imgf000196_0002
Step 1: preparation of tert-butyl (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo [3.1.1]heptane-6-carboxylate (compound 117b) To a solution of compound 60d (500.0 mg, 2.36 mmol) in DCE (8 mL) was added cyclopropylboronic acid (1 g, 11.78 mmol), sodium carbonate (499 mg, 4.71 mmol), Cu(OAc)2 (642 mg, 3.53 mmol) and [2,2]bipyridinyl (552 mg, 3.53 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h under O2 atmosphere. Then the reaction mixture was poured into water and extracted with DCM. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 117b (200.0 mg) as colorless oil. LCMS (M-56+H+): 197. Step 2: preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 117c) To a solution of compound 117b (180.0 mg, 0.71 mmol) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h and then concentrated to give compound 117c (180.0 mg) as yellow oil. LCMS (M+H+): 153. Step 3: preparation of (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15- methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one (Example 117) A solution of Intermediate E4 (40.0 mg, 0.05 mmol), compound 117c (44 mg, 0.16 mol), CsF (38 mg, 0.25 mmol) and DIEA (0.05 mL, 0.3 mmol) in DMA (1 mL) was stirred at 120 °C for 16 h. Then the reaction mixture was purified by prep-HPLC to give Example 117 (10 mg) as a white solid. LCMS (M+H+): 802.1H NMR (400 MHz, METHANOL-d4) δ = 8.40 - 8.34 (m, 1H), 8.31 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.50 - 7.37 (m, 1H), 7.34 - 7.09 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.08 - 5.83 (m, 1H), 5.45 - 5.31 (m, 1H), 5.17 (br d, J = 0.8 Hz, 1H), 4.65 (br d, J = 1.0 Hz, 1H), 4.56 - 4.52 (m, 1H), 4.47 - 4.39 (m, 1H), 4.30 - 4.20 (m, 3H), 4.17 - 4.08 (m, 1H), 4.04 - 3.92 (m, 1H), 3.14 - 3.04 (m, 3H), 2.91 (br d, J = 13.4 Hz, 1H), 2.88 - 2.81 (m, 3H), 2.81 - 2.76 (m, 1H), 2.70 (br d, J = 13.9 Hz, 1H), 2.67 - 2.62 (m, 3H), 2.58 - 2.43 (m, 3H), 1.72 (d, J = 8.8 Hz, 1H), 1.07 - 0.86 (m, 1H), 0.81 - 0.52 (m, 2H), 0.20 - 0.02 (m, 1H). Example 118 (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000197_0001
Example 118 was prepared in analogy to the preparation of Example 117 by using Intermediate E12 instead of Intermediate E4. LCMS (M+H+): 772.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 - 8.29 (m, 2H), 7.84 (t, J = 7.9 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.35 - 7.11 (m, 3H), 6.79 (d, J = 8.1 Hz, 1H), 5.52 - 5.31 (m, 2H), 4.59 - 4.58 (m, 2H), 4.53 - 4.43 (m, 2H), 4.31 - 4.26 (m, 1H), 4.22 (d, J = 11.6 Hz, 1H), 4.17 - 4.05 (m, 2H), 4.02 - 3.95 (m, 1H), 3.27 (br s, 1H), 3.11 - 3.04 (m, 3H), 2.94 - 2.76 (m, 2H), 2.73 - 2.66 (m, 3H), 2.60 - 2.40 (m, 3H), 2.09 - 1.94 (m, 1H), 1.83 - 1.68 (m, 1H), 1.45 - 1.20 (m, 1H), 0.78 - 0.50 (m, 2H), 0.22 - 0.02 (m, 1H). Example 119 (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000198_0001
Example 119 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E12 instead of intermediate E4. LCMS (M+H+):801.1H NMR (400 MHz, METHANOL-d4) δ = 8.47 (d, J = 6.3 Hz, 1H), 8.28 (s, 1H), 8.14 - 8.04 (m, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.65 - 7.56 (m, 1H), 7.31 (d, J = 4.3 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.20 - 7.13 (m, 1H), 7.06 - 7.01 (m, 1H), 6.95 - 6.86 (m, 1H), 5.60 - 5.48 (m, 1H), 5.46 - 5.33 (m, 1H), 4.62 - 4.57 (m, 1H), 4.50 - 4.43 (m, 2H), 4.39 - 4.29 (m, 2H), 4.26 - 4.14 (m, 3H), 4.13 - 4.06 (m, 1H), 3.67 - 3.47 (m, 3H), 3.16 - 3.06 (m, 4H), 2.94 - 2.85 (m, 3H), 2.82 - 2.78 (m, 1H), 2.62 - 2.54 (m, 1H), 2.19 - 2.10 (m, 1H), 1.83 - 1.68 (m, 1H), 1.46 - 1.31 (m, 1H). Example 120 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one The title compound was prepared according to the following scheme:
Figure imgf000199_0001
intermediate D15-a 120b 120c
Figure imgf000199_0002
Step 1: preparation of tert-butyl 3-oxazol-2-yl-3,6-diazabicyclo[3.1.1] heptane-6- carboxylate (compound 120b) To a 40 mL vial equipped with a stir bar was added compound D15-a (500.0 mg, 1.3 mmol), 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (420 mg, 1.7 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (15 mg, 0.01 mmol), NiCl2.dtbbpy (3 mg, 0.01 mmol) in DME (20 mL) was added cesium carbonate (874 mg, 2.7 mmol). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away) with a cooling fan to keep the reaction temperature at 25 °C for 14 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 120b (420 mg) as colorless oil. LCMS (M+H+): 534. Step 2: preparation of 6-(3-azabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl) pyrazolo[3,4-d]pyrimidin-4-ol (compound 120c) To a solution of compound 120b (150.0 mg, 0.28 mmol) in DCM (1 mL) was added TFA (1 mL) at 0 °C. The reaction was stirred at 20°C for 12 h and then concentrated to give compound 120c (40.0 mg) as a white solid. LCMS (M+H+): 344. Step 3: preparation of 1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-ol (compound 120d) To a solution of compound 120c (40 mg, 0.12 mmol) and oxetan-3-one (63 mg, 0.87 mmol) in DCE (1 mL) was added sodium triacetoxyborohydride (93 mg, 0.44 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h and then concentrated. The residue was purified by prep-HPLC to give compound 120d (23 mg) as a white solid. LCMS (M+H+): 400. Step 4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo [15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 120) To a solution of compound 120d (60.0 mg, 0.12 mmol), PyBOP (60.0 mg, 0.12 mmol), N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) in DMF (0.5 mL) was added a solution of intermediated E4 (26 mg, 0.06 mmol), N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in DMF (0.5 mL). The reaction mixture was stirred at 20 °C for 2 h and then concentrated. The residue was purified by prep-HPLC to give Example 120 (9 mg) as a white solid. LCMS (M+H+): 803.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.49 - 7.39 (m, 1H), 7.32 - 7.23 (m, 1H), 7.21 - 7.14 (m, 1H), 6.81 - 6.71 (m, 1H), 6.04 (dd, J = 4.2, 15.4 Hz, 1H), 5.55 (br d, J = 8.8 Hz, 1H), 4.77 (t, J = 6.6 Hz, 2H), 4.74 - 4.69 (m, 3H), 4.56 - 4.48 (m, 1H), 4.41 - 4.16 (m, 3H), 4.06 - 3.80 (m, 3H), 3.14 (s, 1H), 3.06 (s, 4H), 2.99 (br d, J = 6.3 Hz, 2H), 2.93 (br d, J = 14.9 Hz, 1H), 2.86 - 2.81 (m, 3H), 2.66 - 2.61 (m, 4H), 2.59 - 2.45 (m, 3H), 1.63 - 1.52 (m, 1H), 1.38 - 1.27 (m, 1H). Example 121 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1] heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one Example 121 was prepared in analogy to the preparation of Example 46 by using compound 47d instead of compound 46c and intermediate E13 instead of intermediate E4. LCMS (M+H+): 831.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.87 - 7.80 (m, 1H), 7.60 - 7.51 (m, 1H), 7.38 (d, J = 5.3 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.15 - 7.05 (m, 2H), 6.73 - 6.66 (m, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.89 - 5.63 (m, 1H), 5.34 - 5.21 (m, 1H), 4.54 (br s, 1H), 4.38 (br d, J = 2.3 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.24 - 4.12 (m, 3H), 4.09 - 3.94 (m, 2H), 3.51 - 3.33 (m, 2H), 3.08 - 3.03 (m, 3H), 2.99 (br d, J = 13.6 Hz, 1H), 2.89 - 2.81 (m, 3H), 2.68 (s, 3H), 2.63 (br d, J = 19.4 Hz, 2H), 2.51 (tt, J = 4.5, 8.9 Hz, 2H), 1.70 - 1.52 (m, 1H). Example 122 (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]- 1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000201_0001
Example 122 was prepared in analogy to the preparation of Example 60 by using 1,1- difluoro-2-iodo-ethane instead of compound 60b and intermediate E13 instead of intermediate E4. LCMS (M+H+): 826.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.44 - 7.37 (m, 1H), 7.27 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 6.75 - 6.66 (m, 1H), 5.88 - 5.79 (m, 1H), 5.44 (d, J = 8.8 Hz, 1H), 4.64 - 4.59 (m, 2H), 4.40 (br dd, J = 6.2, 11.3 Hz, 1H), 4.27 (br d, J = 11.3 Hz, 1H), 4.21 - 4.14 (m, 2H), 4.14 - 4.02 (m, 3H), 3.40 (br d, J = 11.5 Hz, 1H), 3.10 (s, 1H), 3.04 (s, 3H), 2.88 (br d, J = 14.6 Hz, 2H), 2.85 (s, 3H), 2.83 - 2.80 (m, 1H), 2.74 (br d, J = 13.5 Hz, 1H), 2.64 - 2.59 (m, 3H), 2.55 - 2.41 (m, 2H), 1.86 - 1.74 (m, 1H). Example 123 and Example 124 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000202_0001
Example 123 and Example 124 were prepared in analogy to the preparation of Example 3 and Example 4 by using 1-iodo-2-methoxy-ethane instead of 2,2-difluoroethyl trifluoromethanesulfonate in step 1. The mixture was separated via SFC to give Example 123 (7 mg, faster eluted) and Example 124 (10 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 80; Column: OD 250 × 30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 45%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 123, LCMS (M+H)+: 837, 1H NMR (400 MHz, METHANOL-d4) δ = 8.32 (s, 1H), 7.85 - 7.77 (m, 1H), 7.69 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.12 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.84 (br dd, J = 4.2, 15.3 Hz, 1H), 5.41 (d, J = 9.0 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.59 - 4.50 (m, 1H), 4.49 - 4.38 (m, 1H), 4.25 (d, J = 11.3 Hz, 1H), 4.22 - 4.07 (m, 2H), 4.04 (br dd, J = 2.5, 11.9 Hz, 1H), 3.93 (br dd, J = 9.1, 14.1 Hz, 1H), 3.78 - 3.66 (m, 1H), 3.44 - 3.32 (m, 3H), 3.29 - 3.18 (m, 1H), 3.16 - 3.04 (m, 4H), 2.95 - 2.88 (m, 2H), 2.85 (s, 3H), 2.84 - 2.75 (m, 3H), 2.64 - 2.53 (m, 3H), 2.53 - 2.39 (m, 2H), 1.74 (br d, J = 8.8 Hz, 1H). Example 124, LCMS (M+H)+: 837, 1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.84 - 7.78 (m, 1H), 7.68 - 7.58 (m, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.20 - 7.13 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.84 (dd, J = 4.3, 15.4 Hz, 1H), 5.46 (br d, J = 8.6 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.59 - 4.51 (m, 1H), 4.49 - 4.39 (m, 1H), 4.36 - 4.18 (m, 2H), 4.18 - 4.08 (m, 3H), 4.07 - 3.89 (m, 1H), 3.70 - 3.61 (m, 1H), 3.45 - 3.32 (m, 3H), 3.11 - 3.03 (m, 4H), 3.02 - 2.95 (m, 2H), 2.93 - 2.88 (m, 1H), 2.87 - 2.81 (m, 4H), 2.81 - 2.74 (m, 1H), 2.58 (s, 3H), 2.54 - 2.39 (m, 2H), 1.73 (d, J = 8.8 Hz, 1H). Example 125 and Example 126 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1S,6R)-3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000203_0001
Example 125 and Example 126 were prepared in analogy to the preparation of Example 3 and Example 4 by using compound 125d instead of compound 3b in step 3. The mixture was separated via SFC to give Example 125 (9 mg, faster eluted) and Example 126 (11 mg slower eluted) as a white powder. (SFC condition: Instrument: SFC-150 Mgm; Column: (S,S) whelk-O1 250 × 30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for methanol «Mobile_phasePrep»; Gradient: B 40%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃) Example 125, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.23 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.60 (dt, J = 5.9, 8.6 Hz, 1H), 7.30 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (ddd, J = 2.7, 8.8, 10.2 Hz, 1H), 7.19 - 7.11 (m, 2H), 7.10 - 7.05 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.83 (dd, J = 4.5, 15.5 Hz, 1H), 5.34 (d, J = 8.9 Hz, 1H), 4.64 - 4.59 (m, 1H), 4.58 - 4.52 (m, 1H), 4.48 - 4.37 (m, 1H), 4.27 - 4.08 (m, 4H), 3.92 (br dd, J = 9.1, 14.1 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.38 (dd, J = 2.2, 13.8 Hz, 1H), 3.11 - 3.03 (m, 3H), 3.02 - 2.91 (m, 4H), 2.86 - 2.80 (m, 4H), 2.80 - 2.70 (m, 2H), 2.58 - 2.53 (m, 3H), 2.53 - 2.42 (m, 2H), 1.80 - 1.68 (m, 1H). Example 126, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.21 (s, 1H), 7.83 - 7.77 (m, 1H), 7.64 - 7.55 (m, 1H), 7.29 (dd, J = 2.5, 8.5 Hz, 1H), 7.24 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.07 (d, J = 7.4 Hz, 1H), 6.65 (br d, J = 8.4 Hz, 1H), 5.80 (dd, J = 4.5, 15.5 Hz, 1H), 5.35 (d, J = 8.9 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.57 - 4.51 (m, 1H), 4.46 - 4.32 (m, 2H), 4.27 - 4.11 (m, 3H), 4.11 - 4.02 (m, 1H), 3.96 - 3.71 (m, 1H), 3.52 - 3.41 (m, 1H), 3.38 - 3.32 (m, 1H), 3.11 - 3.02 (m, 3H), 2.95 (s, 3H), 2.93 (br s, 1H), 2.87 - 2.83 (m, 3H), 2.78 (br d, J = 10.3 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.60 (s, 3H), 2.52 - 2.41 (m, 2H), 1.77 - 1.68 (m, 1H). Compound 125d was prepared according to the following scheme:
Figure imgf000204_0001
Step 1: preparation of tert-butyl 3-hydroxyimino-6-azabicyclo[3.1.1]heptane-6- carboxylate (compound 125a) To a flask was added tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 1.42 mmol), hydroxylamine hydrochloride (250 mg, 3.6 mmol), methanol (4 mL) and water (4 mL). The solution was stirred at r.t. for 16 h and diluted with 20 mL DCM and 20 mL water. The water layer was extracted with 15 mL DCM twice. The combined organic layer was dried and concentrated to give compound 125a (340 mg) as a solid. LCMS (M+H)+: 227, 1H NMR (400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 4.08 (dt, J = 1.7, 3.0 Hz, 1H), 4.04 - 3.99 (m, 1H), 2.96 (br d, J = 15.9 Hz, 2H), 2.55 (br d, J = 18.3 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.38 (br t, J = 2.8 Hz, 1H), 1.35 (s, 9H), 1.16 (d, J = 9.1 Hz, 1H). Step 2: preparation of tert-butyl 4-oxo-3,7-diazabicyclo[4.1.1]octane-7-carboxylate (compound 125b) To the flask containing compound 125a (316 mg, 1.4 mmol) was added sodium carbonate (650 mg, 6.13 mmol), acetone (6 mL) and water (4 mL). The suspension was stirred at r.t. and p- toluenesulfonyl chloride (550 mg, 2.88 mmol) was added portion-wise. The resulted mixture was heated to 65 °C and stirred for 16 hrs. The mixture was diluted with some water and extracted with 30 mL DCM for three times. The organic layer was dried over Na2O4 and concentrated to give compound 125b (297 mg) as a light yellow solid. LCMS (M+H)+: 227. Step 3: preparation of tert-butyl 3-methyl-4-oxo-3,7-diazabicyclo[4.1.1]octane-7- carboxylate (compound 125c) To a flask was added compound 125b (150 mg, 662.92 µmol), DMF (1.5 mL) and iodomethane (227 mg, 100 µL, 1.6 mmol). The suspension was stirred at r.t. for a while and NaH (80 mg, 2 mmol) was added. The reaction was stirred for 4 hrs. and quenched with water. The mixture was extracted with some EA. The organic layer was dried and concentrated to give compound 125c (150 mg) as an oil, which was used directly in the next step. LCMS (M+H)+: 241. Step 4: preparation of 3-methyl-3,7-diazabicyclo[4.1.1]octan-4-one (compound 125d) To a flask was added compound 125c (150 mg, 624.22 µmol), DCM (1.5 mL) and TFA (1.5 mL, 19.47 mmol,). The brown solution was stirred at r.t. for 1 hr and concentrated to give compound 125d (158 mg) as an oil, which was used directly in the next step. LCMS (M+H)+: 141. Example 127 3-[-6-[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(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]oxetane-3- carbonitrile
Figure imgf000205_0001
Example 127 was prepared in analogy to the preparation of Example 2 by using compound 127b instead of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine;hydrochloride. Example 127 (3 mg), LCMS (M+H)+: 846, 1H NMR (400 MHz, METHANOL-d4) δ = 8.29 (s, 1H), 7.81 - 7.78 (m, 1H), 7.84 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.32 - 7.27 (m, 1H), 7.23 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.10 - 7.03 (m, 1H), 6.71 - 6.63 (m, 1H), 5.77 (br dd, J = 4.2, 15.4 Hz, 1H), 5.34 (d, J = 8.9 Hz, 1H), 4.69 - 4.62 (m, 2H), 4.59 - 4.53 (m, 2H), 4.49 - 4.39 (m, 2H), 4.34 - 4.19 (m, 3H), 3.99 - 3.89 (m, 1H), 3.66 - 3.57 (m, 1H), 3.45 - 3.36 (m, 1H), 3.12 - 2.97 (m, 4H), 2.97 - 2.87 (m, 2H), 2.86 - 2.81 (m, 4H), 2.78 (br d, J = 14.1 Hz, 1H), 2.65 - 2.57 (m, 3H), 2.56 - 2.41 (m, 3H). The compound 127b was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(3-cyanooxetan-3-yl)-3,6-diazabicyclo[3.1.1] heptane-6-carboxylate (compound 127a) To a tube was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 1.01 mmol) and acetic acid (2 mL). The solution was cooled with ice bath, oxetan-3-one (100 mg, 1.39 mmol) and TMS-CN (251 mg, 340 µL, 2.54 mmol) were added. The reaction was warmed to r.t. and stirred for 16 hrs. The mixture was poured into 20 mL sat. NaHCO3 aq. and extracted with 20 mL EA twice. The organic layer was concentrated and purified via silica gel chromatography to give compound 127a (280 mg) as a white solid. LCMS (M+H)+: 280, 1H NMR (400 MHz, DMSO-d6) δ = 4.72 (d, J = 7.1 Hz, 2H), 4.63 (br d, J = 7.5 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 3.01 - 2.85 (m, 2H), 2.85 - 2.71 (m, 2H), 2.40 - 2.32 (m, 1H), 1.64 (d, J = 8.1 Hz, 1H), 1.40 (s, 9H). Step 2: preparation of 3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)oxetane-3-carbonitrile (compound 127b) To a flask was added compound 127a (100 mg, 358. µmol), DCM (1 mL) and TFA (1 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr and concentrated to give compound 127b (175 mg) as a crude oil, which was used in the next step directly. LCMS (M+H)+: 180. Example 128 and Example 129 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5R)-2-methyl-3-oxo-2,6-diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one Example 128 and Example 129 were prepared in analogy to the preparation of Example 3 and Example 4 by using compound tert-butyl 3-oxo-2,6-diazabicyclo[3.2.1]octane-6-carboxylate instead of compound tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and using compound iodoethane instead of compound 2,2-difluoroethyl trifluoromethanesulfonate in step 1. The mixture was separated via SFC to give Example 128 (18 mg, faster eluted) and Example 129 (12 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC-150 Mgm; Column: OJ 250 × 30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for Methanol «Mobile_phasePrep»; Gradient: B 20%; Flow rate: «Flow_Rate» mL /min; Back pressure: 100 bar; Column temperature: 35 ℃). Example 128, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.22 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.09 (m, 2H), 7.07 (d, J = 7.4 Hz, 1H), 6.70 - 6.62 (m, 1H), 5.83 (dd, J = 4.4, 15.6 Hz, 1H), 5.34 (d, J = 9.0 Hz, 1H), 4.61 (br t, J = 4.9 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.28 - 4.02 (m, 3H), 4.02 - 3.96 (m, 1H), 3.95 - 3.86 (m, 1H), 3.71 - 3.59 (m, 1H), 3.57 - 3.43 (m, 1H), 3.05 (s, 3H), 2.98 (s, 3H), 2.96 - 2.89 (m, 1H), 2.85 (s, 3H), 2.83 - 2.71 (m, 2H), 2.57 (s, 3H), 2.55 - 2.39 (m, 3H), 2.22 - 2.01 (m, 2H). Example 129, LCMS (M+H)+: 807, 1H NMR (400 MHz, METHANOL-d4) δ = 8.22 (s, 1H), 7.84 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.29 (dd, J = 2.6, 8.5 Hz, 1H), 7.21 (ddd, J = 2.7, 8.8, 10.3 Hz, 1H), 7.14 (br dd, J = 2.5, 10.5 Hz, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.83 (dd, J = 4.5, 15.6 Hz, 1H), 5.43 (d, J = 8.9 Hz, 1H), 4.66 - 4.61 (m, 1H), 4.61 - 4.54 (m, 1H), 4.43 (dd, J = 6.1, 11.2 Hz, 1H), 4.29 - 4.17 (m, 2H), 4.08 - 3.94 (m, 2H), 3.82 - 3.66 (m, 1H), 3.48 - 3.41 (m, 1H), 3.06 (s, 3H), 2.99 (s, 3H), 2.96 - 2.89 (m, 1H), 2.85 (s, 3H), 2.76 (br d, J = 13.5 Hz, 1H), 2.70 - 2.61 (m, 1H), 2.60 - 2.53 (m, 3H), 2.48 (tt, J = 4.6, 9.1 Hz, 2H), 2.44 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H), 2.10 - 2.04 (m, 1H). Example 131, 132, 133 and 134 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- 2,6 [(1S,8R)-4-methyl-4,5,11-triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro- 15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000208_0001
The title compound was prepared according to the following scheme: Example 131 & 132& 133 & 134 Examples 131, 132, 133 and 134 were prepared in analogy to the preparation of Examples 103, 104, 105 and 106 by using compound 131a instead of compound 103a and intermediate E1 instead of intermediate E5. SFC condition of step 1: Instrument: SFC 150 Mgm; Column: REGIS (S,S) Whelk-01, 250×30 mm I.D., 5 µm; Mobile phase: A for CO2 and B for Methanol (0.1% NH3H2O); Gradient: B 8%; Flow rate: 80 mL /min; Back pressure: 100bar; Column temperature: 35 ℃. Compound 131b-1 (first eluted), 131b-2 (second eluted), 131b-3 (third eluted) and 131b-4 (forth eluted). Example 131, LCMS (M+H+): 830.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 - 8.17 (m, 1H), 7.90 - 7.76 (m, 1H), 7.68 - 7.56 (m, 1H), 7.41 - 7.04 (m, 6H), 6.76 - 6.64 (m, 1H), 5.90 - 5.69 (m, 1H), 5.58 - 5.43 (m, 1H), 5.42 - 5.23 (m, 1H), 4.71 - 4.56 (m, 2H), 4.49 - 4.35 (m, 1H), 4.27 - 4.11 (m, 2H), 4.02 - 3.73 (m, 4H), 3.18 - 2.94 (m, 5H), 2.92 - 2.76 (m, 4H), 2.66 - 2.42 (m, 6H), 2.39 - 2.28 (m, 1H), 2.26 - 2.07 (m, 1H), 1.94 - 1.64 (m, 2H). Example 132, LCMS (M+H+): 830.1H NMR (400 MHz, METHANOL-d4) δ = 8.26 - 8.16 (m, 1H), 7.92 - 7.78 (m, 1H), 7.70 - 7.57 (m, 1H), 7.39 - 7.02 (m, 6H), 6.76 - 6.65 (m, 1H), 5.88 - 5.68 (m, 1H), 5.57 - 5.48 (m, 1H), 5.41 - 5.17 (m, 1H), 5.10 - 4.90 (m, 1H), 4.69 - 4.54 (m, 1H), 4.53 - 4.33 (m, 1H), 4.30 - 4.06 (m, 2H), 4.01 - 3.79 (m, 1H), 3.72 - 3.57 (m, 3H), 3.20 - 2.93 (m, 5H), 2.93 - 2.75 (m, 4H), 2.70 - 2.45 (m, 6H), 2.41 - 2.08 (m, 2H), 1.99 - 1.82 (m, 1H), 1.83 - 1.62 (m, 1H). Example 133, LCMS (M+H+): 830.1H NMR (400 MHz, METHANOL-d4) δ = 8.28 - 8.13 (m, 1H), 7.94 - 7.77 (m, 1H), 7.67 - 7.56 (m, 1H), 7.39 - 7.03 (m, 6H), 6.77 - 6.66 (m, 1H), 5.99 - 5.80 (m, 1H), 5.70 - 5.38 (m, 1H), 5.35 - 5.24 (m, 1H), 4.72 - 4.54 (m, 1H), 4.53 - 4.35 (m, 1H), 4.33 - 4.10 (m, 2H), 4.08 - 3.88 (m, 1H), 3.79 - 3.68 (m, 3H), 3.27 - 3.18 (m, 1H), 3.16 - 2.95 (m, 4H), 2.94 - 2.74 (m, 4H), 2.73 - 2.29 (m, 8H), 2.26 - 2.09 (m, 1H), 1.97 - 1.60 (m, 2H). Example 134, LCMS (M+H+): 830.1H NMR (400 MHz, METHANOL-d4) δ = 8.29 - 8.17 (m, 1H), 7.88 - 7.78 (m, 1H), 7.64 - 7.55 (m, 1H), 7.35 - 7.06 (m, 6H), 6.74 - 6.63 (m, 1H), 5.93 - 5.63 (m, 1H), 5.51 - 5.35 (m, 1H), 5.31 - 5.17 (m, 1H), 4.97 - 4.91 (m, 1H), 4.69 - 4.54 (m, 1H), 4.53 - 4.35 (m, 1H), 4.27 - 4.09 (m, 2H), 4.01 - 3.84 (m, 1H), 3.74 - 3.59 (m, 3H), 3.39 - 3.35 (m, 1H), 3.27 - 2.91 (m, 5H), 2.90 - 2.77 (m, 3H), 2.74 - 2.43 (m, 6H), 2.40 - 2.30 (m, 1H), 2.28 - 2.09 (m, 1H), 1.99 - 1.82 (m, 1H), 1.80 - 1.64 (m, 1H). Example 135 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000210_0001
Example 135 was prepared in analogy to the preparation of Example 53 by using 5- iodopyrimidine instead of 3-iodo-1-methyl-pyrazole 53a. LCMS (M+H+): 826.1H NMR (400 MHz, METHANOL-d4) δ = 8.46 - 8.41 (m, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.25 (s, 2H), 8.21 (s, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 5.4 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.16 (br d, J = 0.8 Hz, 1H), 6.73 (br d, J = 8.5 Hz, 1H), 6.04 - 5.78 (m, 1H), 5.39 (br d, J = 9.5 Hz, 1H), 4.50 - 4.42 (m, 2H), 4.41 - 4.31 (m, 2H), 4.21 - 4.02 (m, 4H), 3.68 - 3.55 (m, 2H), 3.09 (s, 3H), 3.06 (br s, 1H), 2.87 (s, 3H), 2.85 - 2.80 (m, 2H), 2.79 - 2.72 (m, 2H), 2.65 - 2.46 (m, 3H), 1.66 (d, J = 9.1 Hz, 1H), 1.18 (t, J = 7.1 Hz, 1H). Example 136 (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000211_0001
The title compound was prepared according to the following scheme:
Figure imgf000211_0002
Step 1: preparation of tert-butyl (8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaene-10-carboxylate (compound 136b) To a solution of Intermediate C8 (100.0 mg, 0.22 mmol) in methanol (1.5 mL) was added DIEA (85.0 mg, 0.66 mmol) and Boc2O (70.0 mg, 0.32 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 h. Then the reaction mixture was concentated, the residue was purified by prep- TLC to give compound 136b (50.0 mg) as a white solid. LCMS (M+H+): 522. Step 2: preparation of tert-butyl (8S,11S,15R)-3-chloro-15-methoxy-13,18-dimethyl- 12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaene-10-carboxylate (compound 136c) To a solution of compound 136b (20.0 mg, 0.04 mmol) in ACN (0.5 mL) was added a soluiton of N-chlorosuccinimide (8 mg, 0.06 mmol) at 70 °C. After being stirred at 70 °C for 8 h, the reaction mixture was concentrated, the residue was purified by prep-TLC to give compound 136c (8.0 mg) as a yellow soild. LCMS (M+H+): 556. Step 3: preparation of (8S,11S,15R)-3-chloro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 136d) A solution of compound 136c (8.0 mg, 0.01 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at 20 °C for 1 h. Then the reaction mixture was concentrated to give compound 136d (8.0 mg) as yellow oil. LCMS (M+H+): 456. Step 4: preparation of (8S,11S,15R)-3-chloro-10-[6-chloro-1-(2,4- difluorophenyl)pyrazolo[5,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (compound 136e) A mixture of compound 136d (8.0 mg, 0.01 mmol), Intermediate D1 (4 mg, 0.01 mmol) and DIEA (0.01 mL, 0.07 mmol) in ACN (0.5 mL) was stirred at 80 °C for 1 h. Then the reaction mixture was concentrated to give compound 136e (10.0 mg) as a yellow solid. LCMS (M+H+): 720. Step 5: preparation of (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazol- 2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18- dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 136) A mixture of compound 136e (10.0 mg, 0.01 mmol), compound 47c (14 mg, 0.05 mmol), CsF (11 mg, 0.07 mmol) and DIEA (0.01 mL, 0.07 mmol) in DMA (0.5 mL) was stirred at 120 °C for 15 hrs. Then the reaction mixture was concentrated and the residue was purified by prep- HPLC to give Example 136 (0.5 mg) as a white solid. LCMS (M+H+): 865.1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 6.0 Hz, 1H), 8.29 - 8.24 (m, 1H), 8.02 - 7.96 (m, 2H), 7.63 - 7.55 (m, 2H), 7.25 - 7.22 (m, 2H), 6.92 (d, J = 9.5 Hz, 1H), 6.81 - 6.78 (m, 1H), 5.42 - 5.34 (m, 2H), 4.69 - 4.63 (m, 3H), 4.45 - 4.44 (m, 1H), 4.33 - 4.26 (m, 4H), 4.11 - 4.05 (m, 2H), 3.88 - 3.82 (m, 1H), 3.19 (s, 1H), 3.14 (s, 2H), 3.05 (s, 3H), 3.02 - 2.96 (m, 2H), 2.82 - 2.80 (m, 3H), 2.77 - 2.68 (m, 2H), 2.04 (s, 1H), 1.73 - 1.68 (m, 1H). Example 137 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000213_0001
Example 137 was prepared in analogy to the preparation of Example 117 by using Intermediate E13 instead of Intermediate E4. LCMS (M+H+): 802.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 5.1 Hz, 1H), 8.29 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.43 - 7.36 (m, 1H), 7.30 - 7.13 (m, 3H), 6.71 (d, J = 8.5 Hz, 1H), 5.96 - 5.71 (m, 1H), 5.43 - 5.29 (m, 1H), 4.61 (br d, J = 4.9 Hz, 1H), 4.56 - 4.50 (m, 1H), 4.39 (br s, 1H), 4.32 - 4.17 (m, 3H), 4.16 - 4.10 (m, 1H), 4.05 - 3.94 (m, 1H), 3.12 - 3.02 (m, 3H), 3.01 - 2.91 (m, 1H), 2.88 (s, 3H), 2.85 (s, 1H), 2.83 - 2.76 (m, 1H), 2.66 (s, 3H), 2.63 (s, 1H), 2.56 - 2.39 (m, 3H), 1.83 - 1.66 (m, 1H), 1.02 - 0.86 (m, 1H), 0.82 - 0.50 (m, 2H), 0.29 - 0.05 (m, 1H). Example 138 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 138 was prepared in analogy to the preparation of Example 117 by using Intermediate E11 instead of Intermediate E4. LCMS (M+H+): 835.1H NMR (400 MHz, METHANOL-d4) δ = 8.81 - 8.72 (m, 1H), 8.31 (s, 1H), 7.71 - 7.58 (m, 2H), 7.50 - 7.36 (m, 2H), 7.31 - 7.13 (m, 2H), 5.92 - 5.83 (m, 1H), 5.81 - 5.66 (m, 1H), 5.52 - 5.32 (m, 1H), 4.58 (s, 4H), 4.51 - 4.37 (m, 2H), 4.32 - 4.23 (m, 1H), 4.22 - 4.16 (m, 1H), 4.15 - 4.11 (m, 1H), 4.06 - 3.92 (m, 1H), 3.07 - 2.96 (m, 3H), 2.91 - 2.85 (m, 1H), 2.84 - 2.78 (m, 2H), 2.67 (br d, J = 4.8 Hz, 1H), 2.64 - 2.61 (m, 3H), 2.61 - 2.56 (m, 1H), 2.53 - 2.45 (m, 1H), 1.71 (d, J = 8.8 Hz, 1H), 1.07 - 0.95 (m, 1H), 0.84 - 0.65 (m, 1H), 0.63 - 0.54 (m, 4H), 0.26 - 0.13 (m, 1H). Example 139 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000214_0001
Example 139 was prepared in analogy to the preparation of Example 117 by using Intermediate E14 instead of Intermediate E4. LCMS (M+H+): 821.1H NMR (400 MHz, METHANOL-d4) δ = 8.89 - 8.85 (m, 1H), 8.33 (s, 1H), 7.80 - 7.76 (m, 1H), 7.74 - 7.69 (m, 2H), 7.68 - 7.59 (m, 1H), 7.30 - 7.22 (m, 1H), 7.19 (dt, J = 2.4, 8.0 Hz, 1H), 6.19 - 5.99 (m, 1H), 5.87 - 5.70 (m, 1H), 5.52 - 5.39 (m, 1H), 4.59 - 4.40 (m, 3H), 4.33 - 4.24 (m, 2H), 4.15 (dd, J = 3.7, 5.8 Hz, 1H), 4.02 - 3.94 (m, 1H), 3.10 (s, 1H), 3.04 (s, 3H), 2.99 - 2.92 (m, 4H), 2.86 - 2.81 (m, 4H), 2.79 (br s, 1H), 2.75 - 2.59 (m, 2H), 2.54 - 2.47 (m, 1H), 1.80 - 1.69 (m, 1H), 1.33 - 1.23 (m, 2H), 0.79 - 0.53 (m, 2H). Example 140 and Example 141 (1S,5R)-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile and (1R,5S)-6-[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(24),2,4,6(26),18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-carbonitrile
Figure imgf000215_0001
Example 140 and Example 141 were prepared in analogy to the preparation of Example 3 and Example 4 by using compound 140b instead of compound 3b in step 3. The mixture was purified and separated via prep-HPLC to give Example 140 (9 mg, faster eluted) and Example 141 (3 mg, slower eluted) as a white powder. Example 140, LCMS (M+H)+: 789, 1H NMR (400 MHz, METHANOL-d4) δ = 8.27 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.64 (dt, J = 5.9, 8.6 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.25 - 7.17 (m, 1H), 7.17 - 7.11 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.83 (dd, J = 4.5, 15.5 Hz, 1H), 5.37 (d, J = 8.9 Hz, 1H), 4.66 - 4.61 (m, 1H), 4.59 - 4.55 (m, 1H), 4.47 (dd, J = 6.1, 11.2 Hz, 1H), 4.29 - 4.11 (m, 4H), 4.01 - 3.91 (m, 1H), 3.55 - 3.43 (m, 1H), 3.12 - 3.00 (m, 3H), 2.92 - 2.86 (m, 1H), 2.83 (s, 3H), 2.81 - 2.77 (m, 1H), 2.69 - 2.60 (m, 1H), 2.59 - 2.53 (m, 3H), 2.53 - 2.43 (m, 3H), 2.24 - 2.00 (m, 2H), 1.68 (d, J = 9.3 Hz, 1H). Example 141, LCMS (M+H)+: 789, 1H NMR (400 MHz, METHANOL-d4) δ = 8.29 (s, 1H), 7.81 (dd, J = 7.6, 8.3 Hz, 1H), 7.64 (dt, J = 5.9, 8.6 Hz, 1H), 7.30 (dd, J = 2.6, 8.5 Hz, 1H), 7.24 (ddd, J = 2.8, 8.8, 10.3 Hz, 1H), 7.15 (dd, J = 2.5, 10.5 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.81 (dd, J = 4.5, 15.5 Hz, 1H), 5.41 (d, J = 8.8 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.58 - 4.56 (m, 1H), 4.51 - 4.43 (m, 1H), 4.31 - 4.09 (m, 4H), 3.96 - 3.85 (m, 1H), 3.13 - 3.02 (m, 3H), 2.96 - 2.89 (m, 1H), 2.88 - 2.83 (m, 3H), 2.83 - 2.78 (m, 1H), 2.76 - 2.61 (m, 3H), 2.60 - 2.54 (m, 3H), 2.54 - 2.44 (m, 2H), 2.02 - 1.88 (m, 2H), 1.56 (d, J = 9.1 Hz, 1H). The compound 140b was prepared according to the following scheme:
Figure imgf000216_0001
Step 1: preparation of tert-butyl 3-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 140a) To a flask was added tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24a, 100 mg, 473.35 µmol), diethylene glycol dimethyl ether (2 mL) and ethanol (500 µL). The solution was cooled with ice bath and p-toluenesulfonylmethyl isocyanate (130 mg, 665.85 µmol) was added, followed by potassium tert-butanolate (150 mg, 1.34 mmol). The final mixture was warmed to r.t. slowly and stirred for 16 hrs. The reaction mixture diluted with 10 mL DCM and 10 mL water. The water layer was extracted with 10 DCM twice. The combined organic layer was dried and concentrated. The crude oil was purified via silica gel chromatography to give compound 140a (20 mg) as an oil. LCMS (M+H)+: 223. Step 2: preparation of 6-azabicyclo[3.1.1]heptane-3-carbonitrile (compound 140b) To the flask containing compound 140a (20 mg, 89.98 µmol) was added TFA (1 mL, 12.98 mmol) and DCM (1 mL). The solution was stirred at r.t. for 2 hrs and concentrated to give compound 140b (20 mg) as a crude oil, which was used in the next directly. LCMS (M+H)+: 123. Example 142 (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000216_0002
Example 142 was prepared in analogy to the preparation of Example 60 by using iodomethylcyclopropane instead of compound 60b and intermediate E13 instead of intermediate E4. LCMS (M+H+): 816.1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 7.91 - 7.79 (m, 1H), 7.64 - 7.57 (m, 1H), 7.50 - 7.36 (m, 1H), 7.34 - 7.09 (m, 3H), 6.82 - 6.69 (m, 1H), 5.93 - 5.73 (m, 1H), 5.55 - 5.24 (m, 1H), 4.70 - 4.40 (m, 6H), 4.33 - 4.07 (m, 5H), 3.12 - 3.02 (m, 3H), 2.91 - 2.83 (m, 4H), 2.75 - 2.70 (m, 1H), 2.69 - 2.61 (m, 3H), 2.60 - 2.39 (m, 2H), 1.86 - 1.68 (m, 1H), 1.46 - 1.19 (m, 1H), 1.05 - 0.75 (m, 1H), 0.38 - 0.12 (m, 4H). Example 143 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000217_0001
Example 143 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b and intermediate E13 instead of intermediate E4. LCMS (M+H+): 816.1H NMR (400 MHz, METHANOL-d4) δ = 8.42 - 8.35 (m, 1H), 8.26 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.46 - 7.33 (m, 1H), 7.31 - 7.13 (m, 3H), 6.69 (d, J = 8.6 Hz, 1H), 5.92 - 5.66 (m, 1H), 5.44 - 5.25 (m, 1H), 4.83 (br s, 2H), 4.64 - 4.59 (m, 2H), 4.46 - 4.32 (m, 1H), 4.24 - 4.08 (m, 4H), 4.05 - 3.89 (m, 1H), 3.12 - 3.01 (m, 3H), 2.99 - 2.89 (m, 1H), 2.88 - 2.84 (m, 3H), 2.81 - 2.74 (m, 1H), 2.68 (br d, J = 13.5 Hz, 1H), 2.66 - 2.61 (m, 3H), 2.55 - 2.42 (m, 2H), 2.16 - 2.02 (m, 3H), 1.73 (br d, J = 9.0 Hz, 1H), 1.70 - 1.55 (m, 3H). Example 144 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one Example 144 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b and intermediate E14 instead of intermediate E4. LCMS (M+H+): 835.1H NMR (400 MHz, METHANOL-d4) δ = 8.81 - 8.71 (m, 1H), 8.30 (s, 1H), 7.72 - 7.55 (m, 2H), 7.50 - 7.38 (m, 2H), 7.32 - 7.10 (m, 2H), 5.89 - 5.79 (m, 1H), 5.78 - 5.63 (m, 1H), 5.53 - 5.30 (m, 1H), 4.67 - 4.62 (m, 1H), 4.59 (br s, 1H), 4.55 (br s, 1H), 4.49 - 4.35 (m, 2H), 4.27 (br s, 1H), 4.19 - 4.09 (m, 3H), 4.04 - 3.92 (m, 1H), 3.06 - 2.97 (m, 3H), 2.94 - 2.85 (m, 1H), 2.82 (s, 3H), 2.81 - 2.76 (m, 2H), 2.63 - 2.57 (m, 3H), 2.55 - 2.44 (m, 1H), 2.17 - 2.09 (m, 1H), 2.09 - 1.99 (m, 2H), 1.80 - 1.69 (m, 1H), 1.68 - 1.54 (m, 3H). Example 145 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000218_0001
Example 145 was prepared in analogy to the preparation of Example 60 by using iodocyclobutane instead of compound 60b. LCMS (M+H+): 816.1H NMR (400 MHz, METHANOL-d4) δ = 8.40 - 8.35 (m, 1H), 8.30 (s, 1H), 7.89 - 7.83 (m, 1H), 7.66 - 7.60 (m, 2H), 7.48 - 7.40 (m, 1H), 7.28 - 7.13 (m, 2H), 6.78 - 6.69 (m, 1H), 6.05 - 5.83 (m, 1H), 5.46 - 5.30 (m, 1H), 4.62 (br d, J = 4.5 Hz, 2H), 4.51 - 4.37 (m, 2H), 4.29 - 4.16 (m, 3H), 4.12 (br dd, J = 3.8, 5.8 Hz, 1H), 4.04 - 3.92 (m, 1H), 3.11 (s, 1H), 3.04 (s, 2H), 2.97 (br dd, J = 4.8, 13.3 Hz, 1H), 2.90 (br d, J = 14.3 Hz, 1H), 2.85 - 2.82 (m, 3H), 2.81 - 2.74 (m, 1H), 2.71 (br d, J = 13.6 Hz, 1H), 2.67 - 2.62 (m, 3H), 2.58 - 2.51 (m, 1H), 2.49 - 2.42 (m, 1H), 2.15 - 2.02 (m, 3H), 1.73 (br d, J = 8.6 Hz, 1H), 1.70 - 1.57 (m, 3H). Example 146 (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000219_0001
Example 146 was prepared in analogy to the preparation of Example 117 by using Intermediate E3 instead of Intermediate E4. LCMS (M+H+): 820.1H NMR (400 MHz, METHANOL-d4) δ = 8.59 - 8.55 (m, 1H), 8.30 (s, 1H), 7.68 - 7.59 (m, 1H), 7.41 (dd, J = 2.5, 8.5 Hz, 1H), 7.33 - 7.22 (m, 2H), 7.18 (br t, J = 7.7 Hz, 1H), 7.14 - 7.10 (m, 1H), 5.70 - 5.48 (m, 1H), 5.40 - 5.28 (m, 1H), 4.59 (s, 3H), 4.56 (br d, J = 2.3 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.29 - 4.24 (m, 1H), 4.23 - 4.18 (m, 1H), 4.17 - 4.11 (m, 2H), 4.04 - 3.95 (m, 1H), 3.13 - 3.04 (m, 3H), 2.99 - 2.89 (m, 1H), 2.90 - 2.85 (m, 3H), 2.85 - 2.77 (m, 2H), 2.63 - 2.56 (m, 3H), 2.55 - 2.41 (m, 3H), 1.81 - 1.70 (m, 1H), 0.81 - 0.53 (m, 2H), 0.24 - 0.07 (m, 1H). Example 147 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000219_0002
The title compound was prepared according to the following scheme:
Figure imgf000220_0001
Step 1: preparation of tert-butyl (1R, 5S)-2-thioxo-3, 6-diazabicyclo [3.1.1] heptane-6- carboxylate (compound 147b) To a stirred solution of compound 60d-1 (6 g, 17 mmol) in toluene (80 mL) was added Lawesson’s Reagent (4.1 g, 10.2 mmol) portion wise at 20 °C. The mixture was stirred at 95 °C for 1 h, and then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 147b (3.8 g) as a light yellow solid. LCMS (M+H+): 229. Step 2: preparation of tert-butyl (1R, 5S)-2-methylsulfanyl-3, 6-diazabicyclo [3.1.1] hept-2-ene-6-carboxylate (compound 147c) A mixture of compound 147b (4.2 g, 18.4 mmol) and MeI (11.5 mL, 184 mmol) in DCM (60 mL) was stirred at 20 °C for 16 h. Then the reaction mixture was washed with brine and then concentrated to give compound 147c (4.1g) as a yellow solid. LCMS (M+H+): 243. Step 3: preparation of tert-butyl (1R, 5S)-2-(2, 2-dimethoxyethylamino)-3, 6- diazabicyclo [3.1.1] hept-2-ene-6-carboxylate (compound 147e) A mixture of compound 147c (3.6 g, 14.9 mmol) and compound 147d (1.87 g, 17.8 mmol) in ethanol (50 mL) was stirred at 70 °C for 16 h. Then the reaction mixture was purified by prep- HPLC to afford compound 147e (3.6 g) as light yellow oil. LCMS (M+H+): 300. Step 4: preparation of tert-butyl (1R, 8S)-3, 6, 9-triazatricyclo [6.1.1.02, 6] deca-2, 4- diene-9-carboxylate (compound 147f) To a solution of compound 147e (1 g, 3.34 mmol) in toluene (20 mL) was added p- toluenesulfonic acid (86 mg, 0.5 mmol). The mixture was stirred at 110 °C for 16 h and then concentrated. The residue was purified by prep-HPLC to afford compound 147f (120.0 mg) as light brown oil. LCMS (M+H+): 236. Step 5: preparation of (1R,8S)-3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-diene (compound 147g) To a solution of compound 147f (60.0 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1.0 mL) at 0 °C. The reaction mixture was stirred for 2 h at 25 °C and then concentrated to give compound 147g (60.0 mg) as light yellow oil. LCMS (M+H+): 136. Step 6: preparation of (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9- 2,6 triazatricyclo[6.1.1.0 ]deca-2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy- 2,6 8,11 20,24 13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one (Example 147) A mixture of Intermediate E4 (30.0 mg, 0.04 mmol), CsF (28 mg, 0.19 mmol), compound 147g (11 mg, 0.04 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DMA (2 mL) was stirred at 120 °C for 18 h. The reaction mixture was purified by prep-HPLC to give the product Example 147 (5 mg) as a white solid. LCMS (M+H+): 785.1H NMR (400 MHz, METHANOL-d4) δ = 8.43 - 8.37 (m, 1H), 8.31 (s, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.61 - 7.52 (m, 1H), 7.49 - 7.42 (m, 1H), 7.31 - 7.19 (m, 4H), 6.84 - 6.77 (m, 1H), 6.10 - 5.86 (m, 1H), 5.51 - 5.31 (m, 1H), 4.55 - 4.44 (m, 1H), 4.35 - 4.17 (m, 4H), 4.05 - 3.89 (m, 1H), 3.68 - 3.56 (m, 1H) , 3.22 - 2.99 (m, 6H), 2.93 - 2.82 (m, 4H), 2.78 - 2.51 (m, 5H), 2.06 - 1.96 (m, 1H), 1.38 - 1.18 (m, 1H). Example 148 (8S,11S,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000221_0001
Example 148 was prepared in analogy to the preparation of Example 117 by using Intermediate E16 instead of Intermediate E4. LCMS (M+H+): 821.1H NMR (400 MHz, METHANOL-d4) δ = 8.74 - 8.64 (m, 1H), 8.32 (s, 1H), 7.68 - 7.55 (m, 1H), 7.45 (br d, J = 5.3 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.34 - 7.14 (m, 3H), 5.89 - 5.80 (m, 1H), 5.75 - 5.66 (m, 1H), 5.55 - 5.37 (m, 1H), 4.55 - 4.49 (m, 2H), 4.45 - 4.39 (m, 1H), 4.36 - 4.26 (m, 1H), 4.21 - 4.12 (m, 2H), 4.01 - 3.92 (m, 1H), 3.56 - 3.44 (m, 1H), 3.16 - 3.08 (m, 2H), 3.05 (s, 3H), 2.91 - 2.85 (m, 1H), 2.84 - 2.81 (m, 3H), 2.81 - 2.79 (m, 1H), 2.78 - 2.76 (m, 1H), 2.73 - 2.65 (m, 1H), 2.64 - 2.59 (m, 3H), 2.55 - 2.43 (m, 1H), 1.71 (d, J = 8.5 Hz, 1H), 0.77 - 0.50 (m, 2H), 0.15 (br d, J = 4.5 Hz, 1H). Example 149 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- tdien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000222_0001
The title compound was prepared according to the following scheme:
Figure imgf000222_0002
Example 149 was prepared in analogy to the preparation of Example 147 by using compound 60d instead of compound 60d-1. LCMS (M+H+): 785.1H NMR (400 MHz, METHANOL-d4) δ = 8.28 - 8.25 (m, 1H), 8.17 - 8.14 (m, 1H), 7.79 - 7.74 (m, 1H), 7.55 - 7.52 (m, 1H), 7.48 - 7.43 (m, 1H), 7.37 - 7.29 (m, 1H), 7.16 - 7.04 (m, 2H), 6.79 (d, J = 6.4 Hz, 1H), 6.68 - 6.62 (m, 2H), 5.94 - 5.74 (m, 1H), 5.43 - 5.15 (m, 1H), 4.61 - 4.54 (m, 1H), 4.49 - 4.43 (m, 1H), 4.39 - 4.32 (m, 1H), 4.16 - 4.04 (m, 3H), 4.00 - 3.94 (m, 1H), 3.87 - 3.78 (m, 1H), 3.06 - 2.95 (m, 4H), 2.91 - 2.84 (m, 1H), 2.74 (d, J = 17.1 Hz, 4H), 2.60 - 2.50 (m, 5H), 1.77 - 1.63 (m, 1H), 1.26 - 1.12 (m, 1H). Example 150 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000223_0001
Example 150 was prepared in analogy to the preparation of Example 147 by using compound 60d instead of compound 60d-1 and intermediate E2 instead of intermediate E4. LCMS (M+H+): 817.1H NMR (400 MHz, METHANOL-d4) δ = 8.62 - 8.51 (m, 1H), 8.26 (s, 1H), 7.61 - 7.53 (m, 1H), 7.46 - 7.38 (m, 1H), 7.35 - 7.17 (m, 3H), 7.12 (dd, J = 5.2, 7.6 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.78 (d, J = 1.2 Hz, 1H), 5.65 - 5.45 (m, 2H), 5.20 (br s, 4H), 4.34 - 3.93 (m, 5H), 3.17 - 3.13 (m, 1H), 3.09 (d, J = 5.6 Hz, 3H), 3.04 - 2.88 (m, 2H), 2.73 - 2.54 (m, 6H), 1.88 - 1.72 (m, 1H), 1.36 - 1.27 (m, 1H), 0.66 - 0.55 (m, 3H). Example 151 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca-2,4- dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo
Figure imgf000223_0002
hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000223_0003
Example 151 was prepared in analogy to the preparation of Example 147 by using intermediate E2 instead of intermediate E4. LCMS (M+H+): 802.1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.34 - 7.30 (m, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.15 (m, 2H), 7.14 - 7.09 (m, 1H), 6.92 - 6.89 (m, 1H), 6.80 - 6.76 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.86 - 5.78 (m, 1H), 5.46 - 5.40 (m, 1H), 4.74 - 4.64 (m, 2H), 4.49 - 4.37 (m, 1H), 4.30 - 4.13 (m, 3H), 4.09 - 3.92 (m, 1H), 3.18 - 3.06 (m, 4H), 3.01 - 2.96 (m, 1H), 2.90 - 2.81 (m, 4H), 2.67 - 2.44 (m, 6H), 1.87 - 1.77 (m, 1H), 1.45 - 0.96 (m, 1H). Example 152 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000224_0001
Example 152 was prepared in analogy to the preparation of Example 60 by using bromoethane instead of compound 60b and compound 60d instead of compound 60f. LCMS (M+H+): 790.1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 6.3 Hz, 1H), 8.31 (s, 1H), 8.08 (d, J = 6.4 Hz, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.62 (dt, J = 2.4, 8.4 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.29 - 7.21 (m, 1H), 7.18 (br t, J = 7.8 Hz, 1H), 7.00 - 6.90 (m, 1H), 6.03 (dd, J = 4.3, 15.6 Hz, 1H), 5.49 (d, J = 8.6 Hz, 1H), 4.73 - 4.69 (m, 1H), 4.65 - 4.50 (m, 2H), 4.46 (br dd, J = 6.4, 11.3 Hz, 1H), 4.41 - 4.19 (m, 3H), 4.16 (br dd, J = 3.7, 5.8 Hz, 1H), 4.01 (br dd, J = 2.3, 11.7 Hz, 1H), 3.45 - 3.35 (m, 1H), 3.15 - 3.05 (m, 4H), 2.95 (s, 4H), 2.86 - 2.74 (m, 4H), 2.66 (br d, J = 13.5 Hz, 1H), 2.58 - 2.45 (m, 2H), 1.83 - 1.68 (m, 1H), 0.97 - 0.72 (m, 3H). Example 153 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one Example 153 was prepared in analogy to the preparation of Example 60 by using 2- bromopropane instead of compound 60b and compound 60d instead of compound 60f. LCMS (M+H+): 804.1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.45 - 7.34 (m, 1H), 7.31 - 7.23 (m, 1H), 7.21 - 7.12 (m, 1H), 7.01 - 6.90 (m, 1H), 6.04 (dd, J = 4.1, 15.4 Hz, 1H), 5.56 - 5.31 (m, 1H), 4.73 - 4.68 (m, 1H), 4.66 - 4.59 (m, 1H), 4.53 - 4.39 (m, 2H), 4.36 - 4.24 (m, 2H), 4.22 - 4.09 (m, 2H), 3.93 (br dd, J = 2.7, 11.7 Hz, 1H), 3.24 (br d, J = 11.4 Hz, 1H), 3.08 (s, 3H), 3.00 - 2.91 (m, 4H), 2.82 (s, 4H), 2.69 - 2.61 (m, 1H), 2.59 - 2.47 (m, 2H), 1.81 - 1.65 (m, 1H), 1.12 (dd, J = 6.9, 13.0 Hz, 3H), 0.83 (br d, J = 1.1 Hz, 3H). Example 154 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000225_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl (1S,5R)-3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2- oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 154b) To a solution of compound 60d (200 mg, 0.94 mmol) in DMF (2 mL) was added sodium hydride (113 mg, 2.83 mmol) at 0 °C and then stirred for 1 h . Tert-butyl-(2-iodoethoxy)- dimethyl-silane (1.08 g, 3.77 mmol) in DMF (1 mL) was added to the reaction mixture at 0 °C, then the reaction mixture was stirred at 0 °C for another 2 h. The reaction mixture was poured into sat.aq. NH4Cl (10 mL) and extracted with EA. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 154b (130 mg) as yellow oil. LCMS (M+H+-56): 315. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2- hydroxyethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22- fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20,22-heptaen-12-one (Example 154) Example 154 was prepared in analogy to the preparation of Example 147 by using compound 154b instead of compound 147f and Intermediate E1 instead of Intermediate E4. LCMS (M+H+): 823.1H NMR (400 MHz, METHANOL-d4) δ = 8.41 - 8.30 (m, 1H), 7.90 - 7.83 (m, 1H), 7.69 - 7.60 (m, 1H), 7.58 - 7.48 (m, 2H), 7.29 - 7.20 (m, 1H), 7.19 - 7.12 (m, 2H), 6.76 (t, J = 8.3 Hz, 1H), 6.17 - 5.98 (m, 1H), 5.47 - 5.31 (m, 1H), 4.70 - 4.60 (m, 2H), 4.60 - 4.53 (m, 1H), 4.51 - 4.42 (m, 1H), 4.21 (br s, 3H), 4.16 (dd, J = 3.7, 5.7 Hz, 1H), 3.99 - 3.89 (m, 1H), 3.88 - 3.76 (m, 1H), 3.56 - 3.34 (m, 3H), 3.15 - 3.11 (m, 1H), 3.08 - 3.00 (m, 3H), 3.00 - 2.91 (m, 4H), 2.85 (br s, 3H), 2.79 - 2.73 (m, 1H), 2.64 - 2.45 (m, 2H), 1.91 - 1.73 (m, 1H). Example 155 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one
Figure imgf000227_0001
The title compound was prepared according to the following scheme:
Figure imgf000227_0002
Step 1: preparation of tert-butyl (1S, 5R)-2-oxo-3-tetrahydropyran-4-yl-3, 6- diazabicyclo [3.1.1] heptane-6-carboxylate (compound 155b) To a solution of compound 60d (100.0 mg, 0.47 mmol), lithium tert-butoxide (75 mg, 0.94 mmol), copper iodide (9.0 mg, 0.05 mmol) in DMF (0.8 mL) and ACN (5.4 mL) was added 4- bromo-tetrahydropyran (155 mg, 0.94 mmol) under N2 and then stirred at 25°C for 1 h under hv (254 nm). Then the reaction mixture was filtered and the filtrate was concentrated, the residue was poured into water (50 mL) and extracted with EA. The organic layer was dried and concentrated, the residue was purified by prep-HPLC to give compound 155b (44 mg) as yellow oil. LCMS (M+H+-56): 241. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3- tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ] hexacosa-1(23),2(26),3,5,18,20,22-heptaen-12-one (Example 155) Example 155 was prepared in analogy to the preparation of Example 147 by using compound 155b instead of compound 147f. LCMS (M+H+): 846.1H NMR (400 MHz, METHANOL-d4) δ = 8.49 (d, J = 6.3 Hz, 1H), 8.33 (s, 1H), 8.06 (d, J = 6.3 Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.21 - 7.12 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.10 - 5.83 (m, 1H), 5.52 (d, J = 8.4 Hz, 1H), 4.65 - 4.59 (m, 2H), 4.34 - 4.20 (m, 4H), 4.17 (br dd, J = 3.7, 5.8 Hz, 2H), 4.07 - 3.99 (m, 1H), 3.99 - 3.87 (m, 3H), 3.50 - 3.41 (m, 2H), 3.16 - 3.05 (m, 4H), 2.99 (br d, J = 15.3 Hz, 1H), 2.96 - 2.91 (m, 3H), 2.82 (s, 4H), 2.73 - 2.63 (m, 1H), 2.61 - 2.43 (m, 2H), 1.88 - 1.75 (m, 1H), 1.73 (d, J = 8.9 Hz, 1H), 1.62 - 1.48 (m, 2H). Example 156 Cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile
Figure imgf000228_0001
The title compound was prepared according to the following scheme: Step 1: preparation of (3-cyanocyclobutyl) ethanesulfonate (compound 156b) To a solution of compound 156a (200 mg, 2.06 mmol) and triethylamine (0.57 mL, 4.12 mmol) in DCM (4 mL) was added ethanesulfonyl chloride (0.29 mL, 3.09 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h an then poured into water (10 ml), extracted with DCM. The organic layer was dried and concentrated to give compound 156b (350.0 mg) as brown oil. Step 2: preparation of cis-tert-butyl (1S, 5R)-3-(3-cyanocyclobutyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate and trans-tert-butyl (1S, 5R)-3-(3- cyanocyclobutyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 156d and 156d-1) To a solution of compound 60d (200 mg, 0.94 mmol) in DMF (3 mL) was added sodium hydride (113 mg, 2.83 mmol) at 0 °C, after 0.5 h, compound 156c (357 mg, 1.88 mmol) was added and the reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography and SFC to give compound 156d (faster eluted, 160.0 mg) as a yellow solid and compound 156d-1 (slower eluted, 90.0 mg) as a yellow solid. LCMS (M+H+-56): 236. The configurations of compounds 156d and 156d-1 was confirmed by 2D NMR. SFC condition: Instrument CASWH-Prep-SFC-I; Method Column DAICEL CHIRALPAK IG (250mm×30mm,10µm); Condition CO2-EtOH(0.1%NH3H2O); Begin B 15; End B 15; Gradient Time(min) 3; 100% B Hold Time(min) 0; Flowrate(mL/min) 150. Step 3~4: preparation of cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15- methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6-diazabicyclo[3.1.1]heptan-3- yl]cyclobutanecarbonitrile (Example 156) Example 156 was prepared in analogy to the preparation of Example 147 by using compound 156d instead of compound 147f. LCMS (M+H+): 841.1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.43 (m, 1H), 8.34 (s, 1H), 8.09 - 7.94 (m, 2H), 7.64 (s, 1H), 7.42 - 7.35 (m, 1H), 7.31 - 7.16 (m, 2H), 6.95 (br d, J = 9.0 Hz, 1H), 6.15 - 5.88 (m, 1H), 5.58 - 5.38 (m, 1H), 4.93 - 4.92 (m, 1H), 4.78 - 4.76 (m, 2H), 4.70 (br s, 1H), 4.65 - 4.51 (m, 3H), 4.45 - 4.33 (m, 2H), 4.27 - 4.13 (m, 2H), 4.08 - 3.97 (m, 1H), 3.18 - 3.06 (m, 3H), 2.99 (br d, J = 1.5 Hz, 1H), 2.97 - 2.92 (m, 4H), 2.91 - 2.86 (m, 1H), 2.84 - 2.81 (m, 2H), 2.77 (s, 1H), 2.70 - 2.63 (m, 1H), 2.58 - 2.47 (m, 4H), 1.82 - 1.69 (m, 1H). Example 157 Trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile
Figure imgf000230_0001
Example 157 was prepared in analogy to the preparation of Example 147 by using compound 156d-1 instead of compound 147f. LCMS (M+H+): 841.1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 6.3 Hz, 1H), 8.33 (s, 1H), 8.15 - 7.90 (m, 2H), 7.73 - 7.57 (m, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.32 - 7.15 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.13 - 5.94 (m, 1H), 5.53 (d, J = 8.4 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.74 - 4.58 (m, 3H), 4.55 - 4.36 (m, 2H), 4.28 (br d, J = 11.0 Hz, 2H), 4.19 - 4.08 (m, 1H), 4.00 - 3.91 (m, 1H), 3.34 (br s, 1H), 3.16 - 3.07 (m, 3H), 3.02 (s, 1H), 2.98 (s, 3H), 2.94 (s, 1H), 2.85 (s, 3H), 2.82 - 2.77 (m, 1H), 2.71 - 2.60 (m, 2H), 2.57 - 2.48 (m, 1H), 2.46 - 2.35 (m, 1H), 2.31 - 2.21 (m, 2H), 1.73 (d, J = 8.9 Hz, 1H). Example 158 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000231_0001
The title compound was prepared according to the following scheme:
Figure imgf000231_0002
Step 1: preparation of tert-butyl 3-pyrazol-1-ylazetidine-1-carboxylate (compound 158b) To a solution of compound 158a (200 mg, 2.94 mmol) and 1-BOC-3-iodoazetidine (1.66 g, 5.88 mmol) in DMF (4 mL) was added cesium carbonate (2.87 g, 8.81 mmol) and then stirred at 90 °C for 16 h. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography to give compound 158b (300.0 mg) as yellow oil. LCMS (M+H+-56): 168. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1- ylazetidin-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 158) Example 158 was prepared in analogy to the preparation of Example 147 by using compound 158b instead of compound 147f and Intermediate E2 instead of Intermediate E4. LCMS (M+H+): 805.1H NMR (400 MHz, METHANOL-d4) δ = 8.65 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H), 7.79 - 7.75 (m, 1H), 7.73 - 7.67 (m, 2H), 7.67 - 7.58 (m, 3H), 7.24 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.19 - 7.13 (m, 2H), 6.34 (t, J = 2.1 Hz, 1H), 6.04 - 5.80 (m, 1H), 5.43 - 5.26 (m, 2H), 4.64 - 4.56 (m, 1H), 4.54 - 4.47 (m, 1H), 4.45 - 4.40 (m, 1H), 4.39 - 4.29 (m, 3H), 4.05 - 3.91 (m, 1H), 3.49 - 3.39 (m, 1H), 3.14 (s, 1H), 3.08 - 2.97 (m, 3H), 2.97 - 2.90 (m, 2H), 2.90 - 2.85 (m, 3H), 2.82 - 2.77 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.47 (m, 1H), 0.69 - 0.60 (m, 3H). Example 159 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000232_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-(2-bromoimidazol-1-yl)azetidine-1-carboxylate (compound 159b) A mixture of compound 159a (100.0 mg, 0.68 mmol), potassium carbonate (282 mg, 2.04 mmol) and 1-BOC-3-iodoazetidine (963 mg, 3.4 mmol) in DMF (2 mL) was stirred at 120 °C for 16 h. Then the reaction mixture was concentrated, the residue was purified by prep-HPLC to give compound 159b (120 mg) as a white soild. LCMS (M+2+H+): 304. Step 2: preparation of tert-butyl 3-imidazol-1-ylazetidine-1-carboxylate (compound 159c) To a solution of compound 159b (120 mg, 0.4 mmol) in methanol (3 mL) was added wet Pd/C (60.0 mg) under N2 at 25 °C. The mixture was stirred under H2 (balloon) at 50 °C for 2 h, then the reaction mixture was filtered, the filtrate was concentrated to give compound 159c (85 mg) as colorless oil. LCMS (M+H+): 224. Step 3~4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1- ylazetidin-1-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 159) Example 159 was prepared in analogy to the preparation of Example 147 by using compound 159c instead of compound 147f and Intermediate E2 instead of Intermediate E4.. LCMS (M+H+): 805.1H NMR (400 MHz, METHANOL-d4) δ= 8.55 (d, J = 5.3 Hz, 1H), 8.27 (s, 1H), 7.87 - 7.80 (m, 1H), 7.67 - 7.56 (m, 1H), 7.44 - 7.38 (m, 2H), 7.32 - 7.17 (m, 2H), 7.16 - 7.08 (m, 2H), 7.05 (s, 1H), 5.72 - 5.46 (m, 1H), 5.40 - 5.26 (m, 1H), 5.16 (br s, 1H), 4.76 - 4.70 (m, 1H), 4.55 - 4.43 (m, 2H), 4.39 - 4.31 (m, 1H), 4.29 - 4.23 (m, 1H), 4.22 - 4.09 (m, 3H), 4.03 - 3.88 (m, 1H), 3.27 - 3.21 (m, 1H), 3.14 - 2.98 (m, 3H), 2.96 - 2.80 (m, 2H), 2.67 - 2.55 (m, 5H), 2.53 - 2.42 (m, 1H), 0.63 - 0.54 (m, 3H). Example 160 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azetidin-1-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000234_0001
The title compound was prepared according to the following scheme:
Figure imgf000234_0002
Step 1: preparation of benzyl 3-(1,2,4-triazol-1-yl)azetidine-1-carboxylate (compound 160b) To a solution of 1-N-Cbz-3-hydroxyazetidine (1.2 g, 5.79 mmol) and compound 160a (200.0 mg, 2.9 mmol), triphenylphosphane (1139 mg, 4.34 mmol) in toluene (4 mL) was added diisopropyl azodicarboxylate (0.68 mL, 3.47 mmol) at 0 °C under N2. The reaction mixture was stirred at 100 °C for 16 h and then poured into ice water, extracted with EA. The organic layer was concentrated, the residue was purified by prep-HPLC to give compound 160b (400.0 mg) as colorless oil. LCMS (M+H): 259. Step 2~3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1- yl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one (Example 160) Example 160 was prepared in analogy to the preparation of Example 60 by using compound 160b instead of compound 60g and Intermediate E2 instead of Intermediate E4.. LCMS (M+H+): 806.1H NMR (400 MHz, METHANOL-d4) δ = 8.60 - 8.56 (m, 2H), 8.30 (s, 1H), 8.07 (s, 1H), 7.69 - 7.60 (m, 1H), 7.42 (dd, J = 2.5, 8.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.27 - 7.20 (m, 1H), 7.19 - 7.15 (m, 1H), 7.15 - 7.10 (m, 1H), 5.74 - 5.50 (m, 1H), 5.47 - 5.29 (m, 2H), 4.53 (br d, J = 8.8 Hz, 1H), 4.49 (br d, J = 6.1 Hz, 1H), 4.47 - 4.42 (m, 1H), 4.41 - 4.37 (m, 1H), 4.34 (dd, J = 3.7, 8.9 Hz, 1H), 4.32 - 4.27 (m, 1H), 4.25 - 4.15 (m, 2H), 4.05 - 3.93 (m, 1H), 3.13 (s, 1H), 3.03 (s, 2H), 2.97 - 2.91 (m, 1H), 2.86 (br d, J = 13.3 Hz, 1H), 2.70 - 2.57 (m, 6H), 2.56 - 2.46 (m, 1H), 0.64 - 0.56 (m, 3H). Example 161 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one
Figure imgf000235_0001
The title compound was prepared according to the following scheme: Step 1: preparation of tert-butyl 3-[[(E)-N-hydroxy-C-methyl-carbonimidoyl] carbamoyl]azetidine-1-carboxylate (compound 161c) To a solution of compound 161b (500.0 mg, 6.75 mmol) and compound 161a (1.36 g, 6.75 mmol) in DCM (20 mL) was added TEA (2.81 mL, 20.25 mmol), EDCI (1.94 g, 10.12 mmol) and HOBT (1.37 g, 10.12 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 16 h and then poured into water, extracted with DCM. The organic layer was dried and concentrated to give compound 161c (1 g) as light yellow oil. LCMS (M+H+): 258. Step 2: preparation of tert-butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-1- carboxylate (compound 161d) A solution of compound 161c (100.0 mg, 0.39 mmol) in toluene (2 mL) was heated to 100 °C and for 16 h. Then the reaction mixture was concentrated to give compound 161d (60.0 mg) as light yellow oil. Step 3~4: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl- 1,2,4-oxadiazol-5-yl)azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro- 2,6 8,11 20,24 13,18-dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one (Example 161) Example 161 was prepared in analogy to the preparation of Example 147 by using compound 161d instead of compound 147f and Intermediate E2 instead of Intermediate E4. LCMS (M+H+): 821.1H NMR (400 MHz, METHANOL-d4) δ = 8.57 (d, J = 5.3 Hz, 1H), 8.29 (s, 1H), 7.68 - 7.59 (m, 1H), 7.44 - 7.40 (m, 1H), 7.33 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.15 (m, 1H), 7.14 - 7.10 (m, 1H), 5.73 - 5.51 (m, 1H), 5.44 - 5.27 (m, 1H), 4.79 - 4.73 (m, 2H), 4.47 - 4.34 (m, 3H), 4.31 - 4.15 (m, 5H), 4.04 - 3.94 (m, 1H), 3.12 (s, 1H), 3.04 (s, 2H), 2.96 - 2.84 (m, 2H), 2.70 - 2.57 (m, 5H), 2.55 - 2.49 (m, 1H), 2.44 - 2.36 (m, 3H), 0.66 - 0.56 (m, 3H). Example 162A and Example 162B (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile and (1R,5S)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-exo-carbonitrile
Figure imgf000237_0001
Example 162A and Example 162B were prepared in analogy to the preparation of Example 3 and Example 4 by using 140b instead of compound 3b and using intermediate E4 instead of intermediate E1 in step 3. The mixture was purified and separated via prep-HPLC to give Example 162A (8.4 mg, faster eluted) and Example 162B (3.6 mg, slower eluted) as a white powder. Example 162A, LCMS (M+H)+: 772, 1H NMR (400 MHz, METHANOL-d4) δ = 8.36 (d, J = 5.5 Hz, 1H), 8.28 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.24 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.19 - 7.13 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.03 (dd, J = 4.4, 15.4 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.49 (dd, J = 6.1, 11.1 Hz, 1H), 4.35 - 4.12 (m, 4H), 4.04 - 3.93 (m, 1H), 3.56 - 3.43 (m, 1H), 3.15 - 3.02 (m, 3H), 3.01 - 2.87 (m, 1H), 2.83 (s, 3H), 2.77 - 2.65 (m, 2H), 2.65 - 2.61 (m, 3H), 2.61 - 2.46 (m, 4H), 2.22 - 2.01 (m, 2H), 1.68 (d, J = 9.3 Hz, 1H). Example 162B, LCMS (M+H)+: 772, 1H NMR (400 MHz, METHANOL-d4) δ = 8.39 - 8.35 (m, 1H), 8.30 (s, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 5.5 Hz, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.20 - 7.14 (m, 1H), 6.79 - 6.74 (m, 1H), 6.02 (dd, J = 4.4, 15.5 Hz, 1H), 5.44 (br d, J = 8.6 Hz, 1H), 4.71 - 4.67 (m, 1H), 4.65 - 4.55 (m, 2H), 4.50 (br dd, J = 6.1, 11.5 Hz, 1H), 4.30 - 4.21 (m, 3H), 3.93 (dd, J = 9.1, 13.9 Hz, 1H), 3.16 - 3.04 (m, 3H), 2.99 - 2.91 (m, 1H), 2.87 - 2.80 (m, 4H), 2.77 - 2.67 (m, 3H), 2.66 - 2.62 (m, 3H), 2.60 - 2.47 (m, 2H), 2.03 - 1.89 (m, 2H), 1.57 (d, J = 9.3 Hz, 1H). Example 164A and Example 164B (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one and (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6- [(1R,5S)-3-endo-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4- d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12- one
Figure imgf000238_0001
Example 164A and Example 164B were prepared in analogy to the preparation of Example 24 by using intermediate E4 instead of intermediate E1 in step 3. The mixture was purified via prep-HPLC and separated via SFC to give Example 164B (faster eluted) and Example 164A (16 mg, slower eluted) as a white powder. (SFC condition: Instrument: SFC 150 Mgm Column: GS Ethyl Pyridine Ⅱ, 50 × 20 mm I.D., 5 µm Mobile phase: A for CO2 and B for IPA (0.1% NH3- H2O) Gradient: B 40% Flow rate: 80 mL /min Back pressure: 100 bar Column temperature: 35 °C). Example 164A, LCMS (M+H)+: 777, 1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (d, J = 5.9 Hz, 1H), 8.26 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.66 - 7.59 (m, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.23 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.10 (dd, J = 4.4, 15.4 Hz, 1H), 5.41 (d, J = 8.8 Hz, 1H), 4.73 - 4.68 (m, 1H), 4.49 (dd, J = 6.1, 11.2 Hz, 1H), 4.39 - 4.20 (m, 4H), 4.02 - 3.93 (m, 1H), 3.16 - 3.05 (m, 3H), 3.03 - 2.96 (m, 1H), 2.94 - 2.88 (m, 3H), 2.76 - 2.72 (m, 3H), 2.71 - 2.63 (m, 1H), 2.63 - 2.48 (m, 4H), 2.45 - 2.34 (m, 1H), 2.22 (d, J = 8.3 Hz, 1H), 1.88 - 1.70 (m, 2H), 1.07 (s, 3H). Example 165A and Example 165B (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile and (1R,5S)-6-[1-(2,4-difluorophenyl)-4- [(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo-7-oxa-5,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-10- yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptane-3-endo-carbonitrile
Figure imgf000239_0001
Example 165A and Example 165B were prepared in analogy to the preparation of Example 3 and Example 4 by using 140b instead of compound 3b and using intermediate E15 instead of intermediate E1 in step 3. The mixture was purified and separated via prep-HPLC to give Example 165A (4.3 mg, slower eluted) and Example 165B (10.9 mg, faster eluted) as a white powder. Example 165A, LCMS (M+H)+: 791, 1H NMR (400 MHz, METHANOL-d4) δ = 8.78 (d, J = 5.3 Hz, 1H), 8.31 - 8.27 (m, 1H), 7.70 - 7.60 (m, 2H), 7.49 - 7.41 (m, 2H), 7.27 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 5.89 (dd, J = 4.0, 15.8 Hz, 1H), 5.83 (br t, J = 3.5 Hz, 1H), 5.48 (d, J = 8.8 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.41 - 4.19 (m, 4H), 4.08 - 3.97 (m, 1H), 3.56 - 3.46 (m, 1H), 3.10 - 2.98 (m, 3H), 2.97 - 2.87 (m, 1H), 2.87 - 2.81 (m, 4H), 2.79 - 2.72 (m, 1H), 2.71 - 2.63 (m, 1H), 2.63 - 2.55 (m, 3H), 2.55 - 2.46 (m, 2H), 2.45 - 2.36 (m, 1H), 2.22 - 1.98 (m, 2H), 1.74 - 1.67 (m, 1H). Example 165B, LCMS (M+H)+: 791, 1H NMR (400 MHz, METHANOL-d4) δ = 8.81 - 8.77 (m, 1H), 8.30 (s, 1H), 7.67 - 7.61 (m, 2H), 7.51 - 7.44 (m, 2H), 7.28 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 5.90 - 5.66 (m, 2H), 5.49 (d, J = 8.8 Hz, 1H), 4.50 - 4.34 (m, 2H), 4.33 - 4.16 (m, 3H), 4.03 - 3.91 (m, 1H), 3.10 - 2.99 (m, 3H), 2.95 - 2.85 (m, 2H), 2.85 - 2.81 (m, 4H), 2.81 - 2.65 (m, 4H), 2.65 - 2.61 (m, 3H), 2.59 - 2.49 (m, 1H), 2.04 - 1.87 (m, 2H), 1.55 (d, J = 9.0 Hz, 1H). Example 166 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one
Figure imgf000240_0001
The title compound was prepared according to the following scheme:
Figure imgf000240_0002
Step 1: preparation of tert-butyl 3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (compound 166a) To a solution of compound 127a (100 mg, 0.357 mmol) in dry THF (2 ml) was added MeMgBr (1.8 mL, 1 mol/L in THF) dropwise under N2 atmosphere at 25 °C. The reaction mixture was stirred at 60 °C for 48 h. The reaction was quenched with H2O (20 mL). The mixture was extracted with DCM (30 mL × 2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel column chromatography to give compound 166a (30 mg) as a colorless oil. LCMS (M+H)+: 269. Step 2: preparation of 3-(3-methyloxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane;2,2,2- trifluoroacetic acid (compound 166b) To a flask contained compound 166a (30 mg, 111.79 µmol) was added DCM (1 mL) and TFA (592 mg, 400 µL, 5.19 mmol). The solution was stirred at r.t. for 1 hr and then concentrated to give compound 166b (31 mg) as a crude oil, which was used directly in the next step. LCMS (M+H)+: 169. Step 3: preparation of (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan- 3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one (Example 166) To a tube was added intermediate E4 (30 mg, 43.72 µmol), DIEA (37 mg, 50 µL, 286 µmol), compound 166b (30 mg, 106 µmol), cesium fluoride (20 mg, 131 µmol) and acetonitrile (2 mL). The solution was stirred at 90 °C for 16 h, then the reaction mixture was filtered and the filtrate was purified via pre-HPLC to give Example 166 (24.2 mg) as a white powder. LCMS (M+H)+: 818, 1H NMR (400 MHz, METHANOL-d4) δ = 8.36 (d, J = 5.4 Hz, 1H), 8.28 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.23 (ddd, J = 2.8, 8.8, 10.2 Hz, 1H), 7.19 - 7.12 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.04 (dd, J = 4.4, 15.5 Hz, 1H), 5.36 (d, J = 8.9 Hz, 1H), 4.74 - 4.55 (m, 3H), 4.45 (br dd, J = 5.9, 11.1 Hz, 1H), 4.32 - 4.20 (m, 4H), 4.20 - 4.11 (m, 2H), 3.91 (dd, J = 9.3, 14.0 Hz, 1H), 3.43 - 3.34 (m, 2H), 3.13 - 3.00 (m, 3H), 2.96 - 2.89 (m, 1H), 2.83 (s, 3H), 2.80 (br d, J = 10.5 Hz, 2H), 2.70 (d, J = 13.6 Hz, 1H), 2.63 (s, 3H), 2.59 - 2.44 (m, 3H), 1.86 - 1.72 (m, 1H), 1.41 - 1.28 (m, 3H). Example 167 1-[6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6-azabicyclo[3.1.1]heptan-3-yl]azetidine-3- carbonitrile
Figure imgf000241_0001
Example 167 was prepared in analogy to the preparation of Example 2 by using compound 167b instead of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. Example 167 was obtained as a white powder, LCMS (M+H)+: 844, 1H NMR (400 MHz, METHANOL-d4) δ = 8.33 (s, 1H), 7.91 - 7.84 (m, 1H), 7.70 - 7.59 (m, 1H), 7.54 (dd, J = 2.5, 7.5 Hz, 1H), 7.47 (dd, J = 2.4, 10.2 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.13 (m, 2H), 6.81 - 6.75 (m, 1H), 6.13 (br dd, J = 4.6, 15.2 Hz, 1H), 5.43 (d, J = 8.9 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.54 - 4.39 (m, 2H), 4.38 - 4.12 (m, 8H), 4.09 - 4.01 (m, 1H), 3.96 - 3.78 (m, 2H), 3.18 - 3.15 (m, 1H), 3.09 - 3.03 (m, 3H), 2.96 (s, 3H), 2.83 - 2.77 (m, 3H), 2.77 - 2.73 (m, 1H), 2.70 - 2.48 (m, 3H), 2.38 - 2.19 (m, 2H), 2.19 - 2.07 (m, 1H), 1.61 (d, J = 9.6 Hz, 1H). The compound 167b was prepared according to the following scheme:
Figure imgf000242_0001
Step 1: preparation of tert-butyl 3-(3-cyanoazetidin-1-yl)-6-azabicyclo[3.1.1]heptane- 6-carboxylate (compound 167a) To a tube was added tert-butyl 3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (compound 24a, 20 mg, 94.67 µmol), DIEA (22 mg, 171.77 µmol), azetidine-3- carbonitrile;hydrochloride (20 mg, 168.69 µmol) and ethanol (2 mL). The solution was at r.t. for 1 hr and then sodium triacetoxyborohydride (50 mg, 235.92 µmol) was added. The final mixture was stirred at r.t. for 2 days, then the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated to give compound 167a (30 mg) as a crude oil, which was used in the next step directly. LCMS (M+H)+: 278. Step 2: preparation of1-(6-azabicyclo[3.1.1]heptan-3-yl)azetidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (compound 167b) To the flask contained compound 167a (30 mg, 108.16 µmol) was added TFA (1.48 g, 1 mL, 12.98 mmol) and DCM (2 mL). The mixture was stirred at r.t. for 1 hr and concentrated. The compound 167b (30 mg) was obtained as a yellow oil and used directly in the next step. LCMS (M+H)+: 178. Example 168 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). Table 1.The test results in TR-FRET assay Example FRET_IC50 Example FRET_IC50 Example FRET_IC50 NO. (nM) NO. (nM) NO. (nM) 1 0.9 55 0.7 117 0.4 2 2.8 56 1 118 0.4 3 0.5 57 2 119 1.5 4 1.2 59 0.7 120 1.8 5 1.6 60 1.1 121 1.7 6 1.5 61 0.6 122 1.3 7 1.2 62 2.1 123 1.1 8 0.5 63 0.5 124 1 9 0.8 64 5.2 125 0.3 10 0.7 65 3.3 126 0.9 11 1 66 2.3 127 1.9 12 0.5 67 3.9 128 2.8 13 2.1 68 3.5 129 3.2 14 0.5 69 3.1 131 3.7 15 3.8 70 0.8 132 3.9 16 0.8 71 1.2 133 3.4 17 2.8 72 0.9 134 3.8 18 2.2 73 1 135 0.5 19 0.6 76 1.8 136 3.1 20 0.8 77 0.7 137 0.5 21 1.3 78 1 138 0.3 22 1 79 0.8 139 0.8 23 0.7 80 0.8 140 1.6 24 1.3 81 0.7 141 1.1 26 2.5 82 1.6 142 0.7 27 5.9 83 0.7 143 0.7 28 1 84 0.7 144 0.9 29 1.1 85 1.6 145 0.8 30 0.7 87 0.9 146 1.1 31 1.5 88 1.2 147 1.5 32 3.7 89 1.3 148 0.8 33 0.9 90 1.2 149 1.8 34 1.5 91 1.5 150 1.7 35 0.9 92 0.7 151 1.5 36 1.2 93 1.6 152 1.6 37 1.6 94 1 153 1.2 38 1.5 95 0.6 154 2 39 1.9 100 1.7 155 1.1 40 2.2 101 0.9 156 0.9 42 0.7 102 1 157 1 43 1 103 2.9 158 1.8 44 2.2 104 2.8 159 1.3 45 1.4 105 2.7 160 1.7 46 0.6 106 5 161 6.7 47 3.3 107 1.2 162A 1.2 48 1.9 108 1.2 162B 1.4 49 1 109 3.8 164A 1.4 50 1.1 112 1.6 165A 1.1 51 2.4 113 2.4 165B 0.9 52 1.4 114 1.1 166 1.4 53 0.8 115 0.8 167 1.5 54 1.5 116 0.6 Example 169 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. Table 2. The test results in THP1 cellular assay Example THP1_IC50 Example THP1_IC50 Example THP1_IC50 NO. (nM) NO. (nM) NO. (nM) 1 6 59 5 119 13 2 8 61 51 121 3 3 8 63 29 122 8 4 2 64 29 123 53 5 4 67 48 124 8 6 13 68 29 125 14 7 49 69 12 126 7 8 3 70 2 127 54 9 28 71 86 129 69 10 14 72 13 131 23 11 68 73 30 132 18 12 14 76 23 133 11 14 13 78 17 134 15 16 70 79 27 135 18 19 19 80 18 136 46 20 3 82 73 137 5 21 30 83 40 138 1 23 8 84 94 139 9 24 7 85 19 140 2 28 16 87 21 141 6 31 5 88 32 142 8 32 2 89 32 143 2 33 10 90 18 144 5 34 10 91 18 145 3 35 7 92 67 146 2 36 64 93 6 148 14 37 10 94 51 150 8 38 34 95 3 151 69 39 18 100 14 152 49 40 6 101 2 153 28 42 39 102 95 154 20 43 48 103 45 155 32 44 76 104 12 156 78 46 45 105 33 157 37 47 8 106 74 158 28 48 6 107 36 161 35 49 1 109 50 162A 51 50 83 112 15 165A 64 51 9 113 51 165B 40 52 3 114 4 166 78 53 4 115 20 167 20 54 17 116 13 55 28 117 4 56 32 118 35 Example 170 Single dose pharmacokinetics (SDPK) study in Male C57BL/6J Mice Pharmacokinetic properties of compounds were assessed by single dose PK studies in Male C57BL/6J Mice (vendor: WTLH-BJ). Briefly, two groups of animals were administered a single dose of respective compound intravenously (IV, bolus) at 1 mg/kg or orally (PO, by gavage) at 10 mg/kg. Blood samples were collected via Jugular vein at 5 min (only for IV), 15 min, 30 min, 1 h, 2 h, 4 h, 7 h and 24 h post-dose. Blood samples were placed into pre-chilled commercial EDTA-K2 tubes (vendor: Jiangsu Kangjian medical supplies co., LTD) and centrifuged at 3,200 g for 10 min at 4°C to separate plasma from the samples. After centrifugation, the resulting plasma was transferred to clean tubes for bioanalysis with LC/MS/MS. The pharmacokinetic parameters were calculated using noncompartmental analysis. The volume of distribution (Vss), half-life (T1/2) and clearance (CL) were obtained based on the plasma concentration-time curve after IV dose. The peak concentration (Cmax) was recorded directly from experimental observations after PO dose. The area under the plasma concentration-time curve (AUCo-last) was calculated using the linear trapezoidal linear interpolation rule up to the last detectable concentration. The bioavailability (F) was calculated based on the dose normalized AUCo-last after IV and PO dose. Results of PK parameters following IV and PO administration are given in Table 3. Table 3. PK results for the compounds of this invention Example PO Cmax PO IV AUCo- CL Vss T1/2 NO. (ng/mL) last AUCo-last (mL/ F (%) (h×ng/mL) (h×ng/mL) min/kg) (L/kg) (h) 91 2453 18986 484 33.7 2.64 1.57 383

Claims

CLAIMS 1. A compound of formula (I),
Figure imgf000248_0001
(I), wherein A1 is CH or N; A2 is CH or N; A3 is CR7 or N; wherein R7 is H or halogen; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once or twice substituted by substituents independently selected from cyano, halogen, hydroxy, amino, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3-7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxy, heterocyclyl, heteroaryl, heteroarylcarbonyl and heterocyclylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, pyrrolidinyl substituted by hydroxyC1-6alkyl,
Figure imgf000249_0001
, , or ; wherein Y1 is CH, C or N; Y2 is CH, C or N; Y3 is O or S; Y4 is a bond, C1-6alkylene, -COO- or sulfonyl; W is CH or N; X1, X2, X3 and X4 are independently selected from C(R8)2, O, S, SO2, SO, NR9, N(CON(R9)2) and N(COOR9); wherein each R8 is independently H, deuterio, halogen, hydroxy, cyano, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC3- 7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, N(R9)2, OR9, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1- 6alkylcarbonyl, haloC3-7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3- 7cycloalkylsulfonyl, haloC1-6alkylsulfonyl, haloC3-7cycloalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl or heterocyclylsulfonyl; each R9 is independently H, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1- 6alkyl, haloC1-6alkyl, haloC3-7cycloalkyl, haloC3-7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, haloC1-6alkoxyC3-7cycloalkylC1-6alkyl, cyanoC1- 6alkoxyC1-6alkyl, cynanoC1-6alkoxyC3-7cycloalkyl, cyanoC1- 6alkoxyC3-7cycloalkylC1-6alkyl, hydoxyC1-6alkyl, hydroxyC3- 7cycloalkyl, hydroxyC3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3- 7cycloalkyl, cyanoC3-7cycloalkylC1-6alkyl, heterocyclyl, heteroaryl, aryl, C1-6alkylcarbonyl, C3-7cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, haloC3- 7cycloalkylcarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfonyl, haloC1- 6alkylsulfonyl, haloC3-7cycloalkylsulfonyl or heterocyclylsulfonyl; R7 is C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, haloC3-7cycloalkyl, haloC3- 7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxyC3-7cycloalkyl, C1-6alkoxyC3- 7cycloalkylC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxyC1-6alkyl, haloC1-6alkoxyC3- 7cycloalkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, cyanoC1-6alkoxyC3-7cycloalkyl, hydroxyC3-7cycloalkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxyC3-7cycloalkyl, heterocyclyl, heterocyclylC1-6alkyl, aryl, arylC1-6alkyl, heteroaryl or heteroarylC1- 6alkyl; R10 is (C1-6alkyl)2aminocarbonyl, (C1-6alkyl)2aminosulfonyl, (C1- 6alkyl)oxopyrrolidinylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, arylC1-6alkyl, C1- 6alkylsulfonyl, C1-6alkylcarbonyl, haloC1-6alkoxycarbonyl, haloC1-6alkylsulfonyl, heterocyclylC1-6alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroarylC1-6alkylcarbonyl, arylcarbonyl, aryl, heterocyclyl or heteroaryl; Ring A is a aryl ring, heteroaryl ring or heterocyclyl ring, each of which is unsubstituted or substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, halogen, cyano or nitro; m, n, p, q, s, t are independently 0, 1 or 2, with the proviso that m, n, p, q, s, t are not 0 simultaneously; R6 is phenyl twice or three times substituted by substituents independently selected from halogen, cyano, hydroxy and C1-6alkoxy; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) according to claim 1, wherein R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2(6),3-dienyl substituted by C1-6alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dienyl substituted by C1-6alkyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C1-6alkyl, C1- 6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, oxetanyl, oxetanylC1-6alkyl or tetrahydropyranyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (C1-6alkyl)2aminocarbonyl, (C1- 6alkyl)2aminosulfonyl, (C1-6alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C1- 6alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolylC1-6alkyl, 2-oxaspiro[3.3]heptanylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, C1- 6alkyloxetanyl, C1-6alkylpyrazolyl, C1-6alkylsulfonyl, C1-6alkylsulfonylC1- 6alkylcarbonyl, cyanooxetanyl, haloC1-6alkoxycarbonyl, oxazolyl, oxetanylC1- 6alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolylC1-6alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanyl substituted by oxetanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by oxetanyl or oxetanylC1-6alkyl, 3-oxo-2,6-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2(6),3-dienyl substituted by C1-6alkyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dienyl substituted by C1-6alkyl, 4-oxo-3,7-diazabicyclo[4.1.1]octanyl substituted by C1-6alkyl, 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl substituted by C1-6alkyl, 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano, C1-6alkyl and cyanoC3-7cycloalkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once substituted by pyrazolyl, 1,2,4-triazolyl or C1-6alkyl-1,2,4- oxadiazolyl, or twice substituted by substituents independently selected from cyano, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl and haloazetidinylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, or pyrrolidinyl substituted by hydroxyC1-6alkyl. 3. A compound of formula (Ia),
Figure imgf000253_0001
(Ia), wherein A1 is CH or N; A2 is CH or N; A3 is CR7 or N; wherein R7 is H or halogen; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is (cyanoC3-7cycloalkyl)C1-6alkyl, 1,1-dioxothietanyl, 1,7-diazaspiro[3.4]octanyl substituted by haloC1-6alkylcarbonyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2(6),3-dienyl substituted by C1-6alkyl, 10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dienyl substituted by C1-6alkyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl substituted by C1-6alkyl, oxetanyl or oxetanylC1-6alkyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by (halooxetanyl)C1-6alkyl, C1- 6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, oxetanyl, oxetanylC1-6alkyl or tetrahydropyranyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by (C1-6alkyl)2aminocarbonyl, (C1- 6alkyl)2aminosulfonyl, (C1-6alkyl)oxopyrrolidinylcarbonyl, (oxopyrrolidinyl)C1- 6alkyl, 1,3,4-thiadiazolyl, 1H-pyrazolylC1-6alkyl, 2-oxaspiro[3.3]heptanylcarbonyl, C1-6alkoxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylaminocarbonyl, C1- 6alkyloxetanyl, C1-6alkylpyrazolyl, C1-6alkylsulfonyl, C1-6alkylsulfonylC1- 6alkylcarbonyl, cyanooxetanyl, haloC1-6alkoxycarbonyl, oxazolyl, oxetanylC1- 6alkylcarbonyl, oxetanylcarbonyl, pyrimidinyl, thiazolyl, thiazolylC1-6alkyl or thiazolylcarbonyl, 3-azabicyclo[3.1.1]heptanyl substituted by oxetanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl substituted by oxetanyl or oxetanylC1-6alkyl, 3-oxo-2,6-diazabicyclo[3.2.1]octanyl substituted by C1-6alkyl, 3-oxo-3λ⁴-thia-6-azabicyclo[3.1.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2(6),3-dienyl substituted by C1-6alkyl, 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dienyl substituted by C1-6alkyl, 4-oxo-3,7-diazabicyclo[4.1.1]octanyl substituted by C1-6alkyl, 4-oxo-8-oxa-3,10-diazabicyclo[4.3.1]decanyl substituted by C1-6alkyl, 5-oxo-6,9-diazatricyclo[6.1.1.02,6]decanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl substituted by haloC1-6alkyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano, C1-6alkyl and cyanoC3-7cycloalkyl, 6-oxo-1,7-diazaspiro[3.4]octanyl substituted by C1-6alkyl, 6-oxo-2-oxa-7-azaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl substituted by haloC1-6alkyl, 9-oxo-1,8-diazaspiro[3.5]nonanyl substituted by C1-6alkyl, azetidinyl which is once substituted by pyrazolyl, 1,2,4-triazolyl or C1-6alkyl-1,2,4- oxadiazolyl, or twice substituted by substituents independently selected from cyano, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl and haloazetidinylcarbonyl, cyanoC1-6alkyl, C3-7cycloalkyl substituted by cyano, morpholinyl substituted by C1-6alkoxyC1-6alkyl or cyanoC1-6alkyl, oxetanyl substituted by cyanoC1-6alkyl, oxopyrrolidinyl substituted by cyano or hydroxyC1-6alkyl, or pyrrolidinyl substituted by hydroxyC1-6alkyl; R6 is phenyl twice substituted by substituents independently selected from halogen, cyano, hydroxy and C1-6alkoxy; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. 4. A compound according to any one of claims 1-3, wherein A3 is CH. 5. A compound according to any one of claims 1-4, wherein R1 is H or fluoro. 6. A compound according to any one of claims 1-5, wherein R2 is methyl. 7. A compound according to any one of claims 1-6, wherein R3 is H, methoxy or ethoxy. 8. A compound according to any one of claims 1-7, wherein R4 is methyl. 9. A compound according to any one of claims 1-8, wherein R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkylpyrazolyl, thiazolylcarbonyl, 1,3,4- thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and C1-6alkyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, C1-6alkyl and C1-6alkoxy. 10. A compound according to any one of claims 1-9, wherein R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by 2,2-difluoroethyl, 2-cyanoethyl, 2- fluoroethyl, 3-cyanocyclobutyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, oxetan-3-yl or tetrahydropyran-4-yl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by 1-methylpyrazol-3-yl, thiazole-2-carbonyl, 1,3,4-thiadiazol-2-yl or thiazol-2-yl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and methyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, methyl and methoxy. 11. A compound according to any one of claims 1-10, wherein R5 is 2-oxo-3-tetrahydropyran-4- yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6- yl, 3-(1-methylpyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2- fluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptan-6-yl, 3,6,9- triazatricyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano-3-methoxy-azetidin-1-yl, 3-cyano-3- methyl-azetidin-1-yl, 3-cyano-6-azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- ethyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan- 6-yl, 3-isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl or 3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl. 12. A compound according to any one of claims 1-11, wherein R6 is phenyl twice substituted by halogen. 13. A compound according to any one of claims 1-12, wherein R6 is phenyl twice substituted by fluoro. 14. A compound according to any one of claims 1-13, wherein R6 is 2,4-difluorophenyl. 15. A compound according to any one of claims 1-14, wherein A1 is CH or N; A2 is CH or N; A3 is CH; A4 is CH or N; A5 is CH or N; R1 is H or halogen; R2 is C1-6alkyl; R3 is H or C1-6alkoxy; R4 is C1-6alkyl; R5 is 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3- 7cycloalkylC1-6alkyl, cyanoC1-6alkyl, cyanoC3-7cycloalkyl, haloC1-6alkyl, oxetanyl or tetrahydropyranyl, 3,3-dioxo-3λ⁶-thia-6-azabicyclo[3.1.1]heptanyl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dienyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkylpyrazolyl, thiazolylcarbonyl, 1,3,4- thiadiazolyl or thiazolyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl once or twice substituted by substituents independently selected from hydroxy, cyano and C1-6alkyl, or azetidinyl which is twice substituted by substituents independently selected from cyano, C1-6alkyl and C1-6alkoxy; R6 is phenyl twice substituted by halogen; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. 16. A compound according to any one of claims 1-15, wherein A1 is CH or N; A2 is CH or N; A3 is CH; A4 is CH or N; A5 is CH or N; R1 is H or fluoro; R2 is methyl; R3 is H, methoxy or ethoxy; R4 is methyl; R5 is 2-oxo-3-tetrahydropyran-4-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1,3,4-thiadiazol-2-yl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-(2-cyanoethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(3-cyanocyclobutyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(thiazole-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3,3-dioxo-3λ⁶-thia-6- azabicyclo[3.1.1]heptan-6-yl, 3,6,9-triazatricyclo[6.1.1.02,6]deca-2,4-dien-9-yl, 3-cyano- 3-methoxy-azetidin-1-yl, 3-cyano-3-methyl-azetidin-1-yl, 3-cyano-6- azabicyclo[3.1.1]heptan-6-yl, 3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-hydroxy-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl, 3- isopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-thia-6-azabicyclo[3.1.1]heptan-6-yl or 3-thiazol-2-yl- 3,6-diazabicyclo[3.1.1]heptan-6-yl; R6 is 2,4-difluorophenyl; Q1 is NH or O; or a pharmaceutically acceptable salt thereof. 17. A compound selected from: (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(2-oxopyrrolidin-1-yl)ethyl]-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(trifluoromethyl)-6,8-dihydro-5H- [1,2,4]triazolo[4,3-a]pyrazin-7-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; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)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; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazol-2-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-oxaspiro[3.3]heptane-6-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1H-pyrazol-5-ylmethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- dimethyl-7-oxa-5,10,13,17,19-pentazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[(1R,5S)-6-[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]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; 3-[(1S,5R)-6-[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]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[(3-fluorooxetan-3-yl)methyl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(3,5-difluoro-2-pyridyl)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; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(3,5-difluoro-2-pyridyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-5-oxo-pyrrolidin-3- 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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[1-(2-hydroxyethyl)-2-oxo-pyrrolidin-3- 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; 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-carboxamide; 6-[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]-N,N-dimethyl-3,6-diazabicyclo [3.1.1]heptane-3-sulfonamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methoxyacetyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-2-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12- one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetane-3-carbonyl)-3,6-diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12- one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(2-methylsulfonylacetyl)-3,6-diazabicyclo [3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20, 22- heptaen-12-one; 6-[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(24),2(26),3,5,18,20, 22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-N-methyl-3,6-diazabicyclo[3.1.1]heptane-3- carboxamide; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-[2-(oxetan-3-yl)acetyl]-3,6- diazabicyclo[3.1.1] heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13, 17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[3-[2-(difluoromethoxy)acetyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)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(24),2(26),3,5,18,20, 22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methylsulfonyl-3,6-diazabicyclo[3.1.1] heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10, 2,6 8,11 20,24 13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24), 21- heptaen-12-one; (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(8-methyl-9-oxo-1,8-diazaspiro[3.5]nonan-1- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S, 11S, 15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-6-oxo-1,7-diazaspiro[3.4]octan-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; 2-[3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]oxetan-3-yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methyl-5-oxo-pyrrolidine-3-carbonyl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; 3-fluoro-4-[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(24),2,4,6(26),18,20,22- heptaen-10-yl]-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-1- yl]benzonitrile; (8S,11S,15R)-10-[1-(4-fluoro-2-hydroxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-5-oxo-pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(2S)-2-(hydroxymethyl)pyrrolidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; methyl 6-[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]-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1-methylpyrazol-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]propanenitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(1,1-dioxothietan-3-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(thiazole-2-carbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-ylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan- 9-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-22-fluoro-10-[1-(2-fluoro-4-methoxy-phenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; Trans-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile; Cis-3-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6- yl]cyclobutanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(3R)-3-(methoxymethyl)morpholin-4- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(hydroxymethyl)-2-methyl-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; (8S,11S,15R)-10-[6-[7-(2,2-difluoroacetyl)-1,7-diazaspiro[3.4]octan-1-yl]-1-(2,4- difluorophenyl)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; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; 1-[[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]methyl]cyclopropanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-oxo-3λ4-thia-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-(methoxymethyl)azetidine-3-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3,3-dioxo-3λ6-thia-6-azabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2-[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]-3-methoxy-azetidin- 3-yl]acetonitrile; 7-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxa-7- azaspiro[3.4]octan-6-one; (8S,11S,15R)-10-[6-[2-(2,2-difluoroethyl)-7-oxo-2,6-diazaspiro[3.4]octan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[2-(3-fluoroazetidine-1-carbonyl)-2-methyl- azetidin-1-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-ylmethyl)-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(4aR,7aS)-6-(oxetan-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b][1,4]oxazin-4-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-azetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methoxy-azetidine-3-carbonitrile; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-5-oxo-pyrrolidine-3-carbonitrile; (8S,11S,15R)-10-[6-[3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-fluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-fluoroethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan- 8-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7,10,13,17,19,26- 2,6 8,11 20,24 hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-3,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 10-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-ethoxy-22-fluoro-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3-methyl-8-oxa- 3,10-diazabicyclo[4.3.1]decan-4-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2,5-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-10-oxa-4,5,12- 2,6 triazatricyclo[6.3.1.0 ]dodeca-2(6),3-dien-12-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,2S,8R)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,2R,8S)-5-oxo-6,9- diazatricyclo[6.1.1.02,6]decan-9-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(24),2,4,6(26),18,20,22-heptaen-12-one; 2-[(3R)-4-[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(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]morpholin-3- yl]acetonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[7-(oxetan-3-ylmethyl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6-diazabicyclo[3.1.1] heptan- 6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,21,26- heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-(2,2-difluoroethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6- yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-methoxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.12,6.18,11.020,24]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,6S)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,6R)-3-methyl-4-oxo-3,7- diazabicyclo[4.1.1]octan-7-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(24),2,4,6(26),18,20,22-heptaen-12-one; 3-[-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-3,6- diazabicyclo[3.1.1]heptan-3-yl]oxetane-3-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5S)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5R)-2-methyl-3-oxo-2,6- diazabicyclo[3.2.1]octan-6-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(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-4-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2,5-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-5-methyl-4,5,11- 2,6 triazatricyclo[6.2.1.0 ]undeca-2(6),3-dien-11-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15- 2,6 8,11 20,24 methoxy-13,18-dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrimidin-5-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-3-chloro-10-[1-(2,4-difluorophenyl)-6-(3-thiazol-2-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22- heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-7-oxa- 2,6 8,11 20,24 5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (1R,5S)-6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (8S,11S,15R)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,21,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclobutyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl-7- 2,6 8,11 20,24 oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl-7,10,13,17,19,23,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,8R)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl- 2,6 8,11 20,24 5,7,10,13,17,19,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; 2,6 (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,8S)-3,6,9-triazatricyclo[6.1.1.0 ]deca- 2,4-dien-9-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(23),2(26),3,5,18,20(24),21- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-ethyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-isopropyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(2-hydroxyethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-15-methoxy-13,18- 2,6 8,11 20,24 dimethyl-7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-2-oxo-3-tetrahydropyran-4-yl-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2(26),3,5,18,20,22- heptaen-12-one; Cis-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12- 2,6 8,11 20,24 oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile; Trans-3-[(1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(24),2(26),3,5,18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-2-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl]cyclobutanecarbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-pyrazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-(3-imidazol-1-ylazetidin-1-yl)pyrazolo[3,4- d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(1,2,4-triazol-1-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidin-1- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-ethoxy-22-fluoro-13,18-dimethyl-5,7,10,13,17,19,26- 2,6 8,11 20,24 heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa-1(24),2,4,6(26),18,20,22-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-15-methoxy-13,18-dimethyl-12-oxo- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-exo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-endo-hydroxy-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; (1S,5R)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-exo-carbonitrile; (1R,5S)-6-[1-(2,4-difluorophenyl)-4-[(8S,11S,15R)-22-fluoro-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 12-oxo-7-oxa-5,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptane-3-endo-carbonitrile; (8S,11S,15R)-10-[1-(2,4-difluorophenyl)-6-[3-(3-methyloxetan-3-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-15-methoxy-13,18-dimethyl- 2,6 8,11 20,24 7,10,13,17,19,23,26-heptazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaen-12-one; and 1-[6-[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(24),2,4,6(26),18,20,22-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]-6- azabicyclo[3.1.1]heptan-3-yl]azetidine-3-carbonitrile; or a pharmaceutically acceptable salt thereof. 18. A process for the preparation of a compound according to any one of claims 1 to 17 comprising any one of the following steps: a) the formation of compound of formula (I) via nucleophilic substitution or Buchwald cross coupling between compound of formula (VIII),
Figure imgf000278_0001
(VIII), and HR5; b) the formation of compound of formula (I) via nucleophilic substitution reaction
Figure imgf000278_0002
between compound of (IX), (IX), and halide or acid anhydride; or condensation reaction between compound of formula (IX) and acid; or reductive amination between compound of formula (IX) and ketone or aldehyde; the formation of compound of formula (I) via condensation reaction between compound of formula (VII),
Figure imgf000279_0001
compound of formula (VIIb),
Figure imgf000279_0002
reagent; wherein the coupling reagent in step c) is PyBOP; X is halogen; HRa is heterocyclyl with reactive primary or secondary amino group; R1 to R6, Q1 and A1 to A6 are as defined as in any one of claim 1 to 16. 19. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 for use as therapeutically active substance. 20. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 30 and a pharmaceutically acceptable excipient. 21. The use of a compound according to any one of claims 1 to 17 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. 22. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 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. 23. The use of a compound according to any one of claims 1 to 17 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. 24. The use of a compound according to any one of claims 1 to 17 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. 25. The use of a compound according to any one of claims 1 to 17 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. 26. The use of a compound according to any one of claims 1 to 17 for the inhibition of STING. 27. The use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for the inhibition of STING. 28. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, when manufactured according to a process of claim 18. 29. 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 17.
PCT/EP2024/070202 2023-07-19 2024-07-17 Macrocycles for the treatment of autoimmune disease WO2025017045A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2023/108207 2023-07-19
CN2023108207 2023-07-19

Publications (1)

Publication Number Publication Date
WO2025017045A1 true WO2025017045A1 (en) 2025-01-23

Family

ID=91966078

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/070202 WO2025017045A1 (en) 2023-07-19 2024-07-17 Macrocycles for the treatment of autoimmune disease

Country Status (1)

Country Link
WO (1) WO2025017045A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2020132582A1 (en) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Sting agonists and uses thereof
WO2020194160A1 (en) * 2019-03-28 2020-10-01 Lupin Limited Macrocyclic compounds as sting agonists
WO2021014365A1 (en) * 2019-07-22 2021-01-28 Lupin Limited Macrocyclic compounds as sting agonists and methods and uses thereof
WO2023148129A1 (en) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Imidazole macrocycles for the treatment of autoimmune disease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2020132582A1 (en) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Sting agonists and uses thereof
WO2020194160A1 (en) * 2019-03-28 2020-10-01 Lupin Limited Macrocyclic compounds as sting agonists
WO2021014365A1 (en) * 2019-07-22 2021-01-28 Lupin Limited Macrocyclic compounds as sting agonists and methods and uses thereof
WO2023148129A1 (en) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Imidazole macrocycles for the treatment of autoimmune disease

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia", 2004, LIPPINCOTT, WILLIAMS & WILKINS
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
LANG'S: "Handbook of Chemistry", 1985
no. 63231-67-4
ROWE, RAYMOND C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS

Similar Documents

Publication Publication Date Title
US12077536B2 (en) BCL-2 inhibitors
US10988478B1 (en) Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
TWI841200B (en) Heterocyclic compounds, drug compositions and applications thereof
US20230072276A1 (en) Azaquinazoline pan-KRas inhibitors
WO2022015375A1 (en) Kras g12d inhibitors
IL294048A (en) sos1 inhibitors
TW202328124A (en) 1,4-oxazepane derivatives and uses thereof
CN115835908A (en) Bicyclic heterocycles as FGFR inhibitors
WO2023061294A1 (en) Nitrogen-containing heterocyclic derivative regulator, preparation method therefor and application thereof
JP2025506408A (en) Quinazoline pan-KRas inhibitors
CN114302886B (en) Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof
KR20250024842A (en) Azaquinazoline pan-KRAS inhibitor
EP4472739A1 (en) Imidazole macrocycles for the treatment of autoimmune disease
US20240287101A1 (en) Cereblon-based kras degrading protacs and uses related thereto
WO2023244604A1 (en) Tetrahydropyridopyrimidine pan-kras inhibitors
US11981658B2 (en) Substituted aminopyridine compounds as EGFR inhibitors
WO2025017045A1 (en) Macrocycles for the treatment of autoimmune disease
CN116829151A (en) Azaquinazoline pan KRAS inhibitors
TW202510858A (en) Macrocycles for the treatment of autoimmune disease
JP2022553261A (en) Compounds and compositions for the treatment of parasitic diseases
WO2025012057A1 (en) Macrocycles for the treatment of autoimmune disease
WO2025012195A1 (en) Bicyclic macrocycles for the treatment of autoimmune disease
WO2025021666A1 (en) Macrocycles for the treatment of autoimmune disease
US20240238425A1 (en) HSD17B13 Inhibitors and/or Degraders
TW202122396A (en) Kras g12d inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24746244

Country of ref document: EP

Kind code of ref document: A1