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WO2025017045A1 - Macrocycles pour le traitement d'une maladie auto-immune - Google Patents

Macrocycles pour le traitement d'une maladie auto-immune Download PDF

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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
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WO
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Prior art keywords
pyrimidin
pyrazolo
dimethyl
hexacosa
heptaen
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PCT/EP2024/070202
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English (en)
Inventor
Buyu KOU
Haixia Liu
Hong Shen
Yao Wu
Zhiwei Zhang
Wei Zhu
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Publication of WO2025017045A1 publication Critical patent/WO2025017045A1/fr
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    • 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.

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  • 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)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I), (I), dans laquelle R1 à R6, Q1 et A1 à A5 sont tels que décrits dans la description, et leur sel pharmaceutiquement acceptable, ainsi que des compositions comprenant les composés et des procédés d'utilisation des composés. Les composés de formule (I) sont des antagonistes de STING et sont ainsi utiles pour le traitement de maladies et troubles divers.
PCT/EP2024/070202 2023-07-19 2024-07-17 Macrocycles pour le traitement d'une maladie auto-immune Pending WO2025017045A1 (fr)

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WO2025228889A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Composés hétérocycliques monoaryliques utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228899A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Autres composés hétérocycliques utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228892A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles et benzimidazoles à substitution monoaryle et hétaryle utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228895A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles et benzimidazoles à substitution hétaryle utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228900A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles substitués par arylamide et leur utilisation en tant que médicament
WO2025228902A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Acides hétérocycliques en tant qu'antagonistes de sting et leur utilisation en tant que médicament

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WO2017175156A1 (fr) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
WO2020132582A1 (fr) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Agonistes de sting et leurs utilisations
WO2020194160A1 (fr) * 2019-03-28 2020-10-01 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting
WO2021014365A1 (fr) * 2019-07-22 2021-01-28 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting et procédés et utilisations de ceux-ci
WO2023148129A1 (fr) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Macrocycles d'imidazole pour le traitement d'une maladie auto-immune

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WO2017175156A1 (fr) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
WO2020132582A1 (fr) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Agonistes de sting et leurs utilisations
WO2020194160A1 (fr) * 2019-03-28 2020-10-01 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting
WO2021014365A1 (fr) * 2019-07-22 2021-01-28 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting et procédés et utilisations de ceux-ci
WO2023148129A1 (fr) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Macrocycles d'imidazole pour le traitement d'une maladie auto-immune

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025228889A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Composés hétérocycliques monoaryliques utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228899A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Autres composés hétérocycliques utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228892A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles et benzimidazoles à substitution monoaryle et hétaryle utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228895A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles et benzimidazoles à substitution hétaryle utilisés en tant qu'antagonistes de sting et leur utilisation en tant que médicament
WO2025228900A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Indazoles substitués par arylamide et leur utilisation en tant que médicament
WO2025228902A1 (fr) 2024-04-30 2025-11-06 Boehringer Ingelheim International Gmbh Acides hétérocycliques en tant qu'antagonistes de sting et leur utilisation en tant que médicament

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