Fluorescent Probe for MAGL

Abstract

The present invention provides a compound having the general formula (I) (wherein A, L, R 1 and R 2 are as described herein), a composition containing the compound, a method for producing the compound, and a method for using the compound. TIFF2025521353000172.tif31165

Description

Technical Field

[0001] Field of the Invention The present invention relates to an organic compound useful as a fluorescent probe for monoacylglycerol lipase (MAGL).

Background Art

[0002] Background of the Invention Fluorescent imaging probes have emerged as high-resolution tools for examining protein localization in living cells, such as expression levels, protein distribution, structure, dynamics, and function during health and disease (L.A. Stoddart, L.E. Kilpatrick, S.J. Briddon, S.J. Hill, Neuropharmacology, 2015, 98, 48-57). Such probes can be applied, for example, to cell transport studies using flow cytometry fluorescence-activated cell sorting (FACS) experiments or confocal live cell imaging. Furthermore, fluorescent imaging probes enable real-time monitoring of ligand-receptor interactions and visualization of proteins with high spatiotemporal accuracy (A.J. Vernall, S.J. Hill, B. Kellam, Br. J. Pharmacol. 2014, 171, 1073-1084; C. Iliopoulos-Tsoutsouvas, R.N. Kulkarni, A. Makriyannis, S.P. Nikas, Expert Opin. Drug Discov. 2018, 13, 933-947). Furthermore, such probes offer the possibility of generating equilibrium and kinetic binding data in a high-throughput manner without handling radioactive substances, for example, using time-resolved fluorescence resonance energy transfer (TR-FRET). Fluorescent imaging probes can also be useful in supporting the translation of preclinical pharmacological animal data to the clinic and can be applied to dose selection in humans. They can be used, for example, as markers of target engagement through the generation of ex vivo quantitative receptor binding data in whole blood. Depending on each application, fluorescent imaging probes need to meet specific criteria including affinity, selectivity, and specificity for each target, favorable photophysical properties, and applicability across different technologies and cell types.

Summary of the Invention

[0003] In a first aspect, the present invention relates to a compound of formula (I)

Chemical Formula

[0004] In a further aspect, the present invention provides a method for producing a compound of formula (I) as described herein, the method comprising (a) a first amine 1

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0005] In a further aspect, the present invention provides a compound of formula (I) as described herein when produced according to the method described herein.

[0006] In a further aspect, the present invention provides a method for studying MAGL occupancy, which comprises contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) as described herein.

[0007] In a further aspect, the present invention provides a method for imaging diagnosis of MAGL in a mammal, which comprises contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) as described herein.

[0008] In a further aspect, the present invention provides a method for generating equilibrium and kinetic binding data of MAGL, which comprises contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) as described herein.

Mode for Carrying Out the Invention

[0009] Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in connection with specific aspects, embodiments or examples of the present invention are to be understood as applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All features disclosed in this specification (including any accompanying patent claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the foregoing embodiments. The present invention extends to any novel one or any novel combination of the features disclosed in this specification (including any accompanying patent claims, abstract and drawings), or any novel one or any novel combination of the steps of any method or process so disclosed.

[0010] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C1-C6-alkyl"). In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl.

[0011] The term "alkoxy", as defined previously, refers to an alkyl group bonded to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, the alkoxy group contains 1 to 12 carbon atoms. In some preferred embodiments, the alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

[0012] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0013] The term "aryl" refers to a total of 6 to 14 ring members ("C 6~14-aryl"), preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, and at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of aryl is phenyl.

[0014] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, at least one ring of the system is aromatic, and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O, S, and N. Some preferred but non-limiting examples of heteroaryl include thiazolyl (e.g., thiazol-2-yl); oxazolyl (e.g., oxazol-2-yl); oxadiazolyl; 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g., 2-pyridyl); pyrazolyl (e.g., pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g., imidazol-1-yl); benzoxazolyl (e.g., benzoxazol-2-yl), 2,3-dihydrobenzofuranyl; and oxazolo[5,4-c]pyridin-2-yl. Some particularly preferred but non-limiting examples of heteroaryl include oxadiazolyl; pyridyl; triazolyl; tetrazolyl; pyrazinyl and imidazolyl.

[0015] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. These salts may also be prepared by adding an inorganic base or an organic base to the free acid. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of salts derived from organic bases include 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, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc., but are not limited thereto. A specific pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride.

[0016] The term "protecting group" (PG) refers to a group that has been conventionally associated in synthetic chemistry with the meaning of selectively blocking a reactive site of a polyfunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino protecting groups, carboxy protecting groups or hydroxy protecting groups. Specific protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). Even more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T.W.Greene and P.G.M.Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

[0017] The term "urea-forming reagent" refers to a compound that can be made to react a first amine with a second amine, thereby forming a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, and 1,1'-carbonyldiimidazole. The urea-forming reagents described in G. Sartori et al., Green Chemistry 2000, 2, 140 are incorporated herein by reference.

[0018] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0019] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can be of the "R" or "S" configuration.

[0020] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0021] The compounds of the present invention In a first aspect (A1), the present invention provides a compound of formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0022] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0023] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0024] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0025] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0026] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0027] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0028] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0029] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0030] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 2 is

Chemical formula

Chemical formula

[0031] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 2 is

Chemical formula

Chem.

[0032] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 2 is

Chem.

[0033] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein A is (i)

Chem.

Chem.

Chem.

[0034] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein, A is, (i)

Chemical formula

Chemical formula

Chemical formula

[0035] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein, A is,

Chemical formula

[0036] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0037] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0038] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

Chemical formula

Chemical formula

[0039] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0040] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is

Chemical formula

[0041] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, phenyl, and

Chemical formula

[0042] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0043] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is (i)

Chemical formula

Chemical formula

Chemical formula

[0044] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0045] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 2 is

Chemical formula

[0046] In a preferred embodiment, the present invention provides that R 3 is hydrogen and [Chemical formula] To provide a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, selected from

[0047] In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is (i) [Chemical formula] selected from L is -O-; and (ii) [Chemical formula] selected from wherein (i) X is CH; L is selected from -CH2- and -O-; or (ii) X and L together form a group [Chemical formula] (wherein the wavy line indicates the bonding point of L and R 2 and the two asterisks indicate the bonding points of X with each adjacent atom within ring A) to form; wherein the wavy line indicates the bonding point to L; the asterisk indicates the bonding point to the carbonyl group of formula (I).

[0048] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is [Chemical formula] (wherein the wavy line indicates the bonding point to the carbonyl group of formula (I)) selected from.

[0049] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 is [Chemical formula] and the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0050] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 is [Chemical formula] and the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0051] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 2 is [Chemical formula] and the wavy line indicates the point of attachment to L.

[0052] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 2 is [Chemical formula] and the wavy line indicates the point of attachment to L.

[0053] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 3 is hydrogen.

[0054] In a particularly preferred embodiment, the present invention relates to R 3 is

Chemical formula

[0055] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

[0056] ; X is CH; L is -CH2-; wherein the wavy line indicates the point of attachment to L; The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0057] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

[0058] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

[0059] ; X is CH; L is selected from -CH2- and -O-; wherein the wavy line indicates the point of attachment to L; the asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0060] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

[0061] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

Chemical formula

[0062] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein A is

Chemical formula

[0063] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and the compound of formula (I) is (4aR,8aS)-6-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((2-Oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((2-Oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-Oxo-2H-chromen-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((7-Methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((7-Nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4-(dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(2-((5,5-difluoro-5H-4λ4,5λ4-dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-((1R,5S,6R)-6-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4-(4-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; (6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; (S)-1-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4-dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide; (R)-4-(3-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone; 6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (R)-4-(3-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-3-oxopropyl)oxazolidin-2-one; (S)-1-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)pyrrolidine-3-carboxamide; (7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4-(2-((5,5-difluoro-5H-4λ ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 4 -(2-((5,5-difluoro-5H-4λ ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 4 (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(2-((5,5-difluoro-5H-4λ ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone; 4 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-((5,5-difluoro-5H-4λ ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone; 4 6-(2-((5,5-difluoro-5H-4λ ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 4 (R)-4-(3-(2-((5,5-difluoro-5H-4λ (S)-1-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)pyrrolidine-3-carboxamide; (2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; and (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-5λ 4 ,6λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone selected from.

[0064] In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and the compound of formula (I) is (4aR,8aS)-6-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(2-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(7-((5,5-Difluoro-5H-4λ 4 ,5λ 4-(6-((5,5-difluoro-5H-4λ 2-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone; (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide; (R)-4-(3-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)-3-oxopropyl)oxazolidin-2-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one selected from.

[0065] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; and (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4-(6-((5,5-difluoro-5H-4λ selected from

[0066] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0067] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone.

[0068] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0069] In certain embodiments, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) described herein. In further particular embodiments, the present invention provides the compounds of formula (I) described herein as the free base.

[0070] Manufacturing method The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques necessary for the execution of the reactions and the purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings indicated herein unless otherwise indicated.

[0071] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (e.g., those described in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Chemistry", 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced prior to the critical steps by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0072] When the starting material or intermediate contains a stereocenter, the compounds of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can be separated into their enantiomers via diastereomeric salts, for example, by crystallization with an optically pure acid or by specific chromatographic methods using either a chiral adsorbent or a chiral eluent to separate the enantiomers. It is likewise possible to separate starting materials and intermediates containing stereocenters to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. In the synthesis of the compounds of formula (I), the use of such diastereomerically / enantiomerically enriched starting materials and intermediates generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0073] One skilled in the art will recognize that in the synthesis of the compounds of formula (I) (if not otherwise desired), by applying an "orthogonal protecting group strategy", several protecting groups can be cleaved one at a time without affecting the other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and is also described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0074] One skilled in the art will recognize that the order of the reactions can vary depending on the reactivity and nature of the intermediates.

[0075] More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for the reaction conditions described in the literature that affect the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999). It has been found convenient to carry out the reactions in the presence or absence of a solvent. Regarding the nature of the solvent used, there is no particular limitation as long as it does not adversely affect the reaction or the reagents involved and it can dissolve the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The described reactions are conveniently carried out in the temperature range from -78 °C to reflux. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, usually, a period of 0.5 hours to several days is sufficient to obtain the described intermediates and compounds. The order of the reaction steps is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed according to the starting materials and their respective reactivities.

[0076] When the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared in the same manner as the existing procedures for closely related analogs or as outlined in the experimental section.

[0077] The following abbreviations are used in this specification. AcOH = acetic acid, ACN = acetonitrile, Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, Cbz = benzyloxycarbonyl, Cs2CO3 = cesium carbonate, CO = carbon monoxide, CuCl = copper(I) chloride, CuCN = copper(I) cyanide, CuI = copper(I) iodide, CuTC = Cu(I) 2-thiophenecarboxylate, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, DMEDA = N,N’-dimethylethylenediamine, DMF = N,N-dimethylformamide, DMP = Dess-Martin periodinane, DIPEA = N,N-diisopropylethylamine, dppf = 1,1-bis(diphenylphosphino)ferrocene, EDC.HCl = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, EI = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, Hal = halogen, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropylmagnesium chloride, I2 = iodine, IPA = 2-propanol, (Ir[dF(CF3)ppy]2(dtbpy))PF6 = [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1’]bis[3,5-Difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate, ISP = Ion Spray Positive (mode), ISN = Ion Spray Negative (mode), K2CO3 = Potassium carbonate, KHCO3 = Potassium hydrogen carbonate, KI = Potassium iodide, KOH = Potassium hydroxide, K3PO4 = Tripotassium phosphate, LiAlH4 or LAH = Lithium aluminum hydride, LiHMDS = Lithium bis(trimethylsilyl)amide, LiOH = Lithium hydroxide, MgSO4 = Magnesium sulfate, min = minute, mL = milliliter, MPLC = Medium pressure liquid chromatography, MS = Mass spectrum, NaH = Sodium hydride, NaHCO3 = Sodium hydrogen carbonate, NaNO2 = Sodium nitrite, NaOH = Sodium hydroxide, Na2CO3 = Sodium carbonate, Na2SO4 = Sodium sulfate, Na2S2O3 = Sodium thiosulfate, NBS = N-Bromosuccinimide, nBuLi = n-Butyllithium, NEt3 = Triethylamine (TEA), NH4Cl = Ammonium chloride, NiCl2 glyme = Nickel(II) ethylene glycol dimethyl ether complex, NMP = N-Methyl-2-pyrrolidone, OAc = Acetoxy, T3P = Propylphosphonic anhydride, P2O5 = Phosphorus pentoxide, PE = Petroleum ether, PG = Protecting group, Pd-C = Palladium-on-carbon, PdCl2(dppf)-CH2Cl2 = 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0), Pd(OAc)2 = Palladium(II) acetate, Pd(OH)2 = Palladium hydroxide, Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0), PTSA = p-Toluenesulfonic acid, R = Any group, RT = Room temperature, SFC = Supercritical fluid chromatography, S-PHOS = 2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, T3P = Propylphosphonic anhydride, TBAI = Tetrabutylammonium iodide, TEA = Triethylamine, TFA = Trifluoroacetic acid, THF = Tetrahydrofuran, TMEDA = N,N,N’,N’-Tetramethylethylenediamine, ZnCl2 = zinc chloride, Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.,

[0078] The compound of formula I can be synthesized in the same manner as the literature procedures and / or as shown, for example, in Scheme 1.,

Chemical Formula

[0079] Therefore, the R part containing N at the bonding point with the remaining part of formula I is reacted with intermediate 1 in the presence of a urea-forming reagent such as bis(trichloromethyl) carbonate using an appropriate base and solvent, for example, sodium bicarbonate in DCM, to obtain the compound of formula I (step a1). Further urea-forming reagents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, 1,1'-carbonyldiimidazole, or 1,1'-carbonyl-di-(1,2,4-triazole). This type of reaction and the use of these reagents are widely described in the literature (for example, G. Sartori et al., Green Chemistry 2000, 2, 140). Those skilled in the art will recognize that the order of addition of the reagents can be important in this type of reaction due to the reactivity and stability of the carbamoyl reagent formed as an intermediate and to avoid the formation of unwanted symmetric urea by-products. The R part containing C at the bonding point to the remaining part of formula I is introduced as a carboxylic acid and coupled with intermediate amine 1 to form the respective amides (step a2). This type of amide coupling can be achieved by using one of the well-known coupling reagents such as DCC, HATU, EDCI, HOBt, TBTU, T3P, etc. and a base such as Hunig's base, triethylamine or DMAP in an appropriate solvent such as N,N-dimethylformamide, DMA, DCM or 1,4-dioxane, preferably at 0 °C to room temperature., 1 1

[0080] ​​ The fluorescent probes of general formula I can be obtained by various synthetic routes depending on their specific structures. Molecules with structure Ia where L = O, or probes containing a BODIPY skeleton with L = CH2Ic, or their precursors linked by the conjugated double bond Ib specified in the claims can be synthesized, for example, as shown in Scheme 2.

Chemical formula

[0081] Intermediates 3 and 5 are commercially available or can be prepared according to the methods in the literature. Intermediate 3 can be bonded to R as described in Scheme 1 (step a). Using the functional hydroxyl group, by etherification reaction according to the methods in the literature, for example, under Mitsunobu conditions using PPh3 and diethyl azodicarboxylate, or by nucleophilic substitution (S 1 ) reaction (step c), the R N group can be bonded to obtain compound Ia where L = O. 2

[0082] N-Boc protected alcohol 3 can be converted to the respective ketone 5 by oxidation, for example, by DMP, potassium dichromate or pyridinium chlorochromate in a suitable solvent such as DCM or toluene (step d). These can be easily converted to the respective vinyl boronic acid 6 (e.g., vinyl boronic acid pinacol ester) as described in the literature (step e, Kovalenko et al., 2019). Boronic acids and their derivatives are known as versatile building blocks for transition metal-mediated cross-coupling reactions. N-boc protected vinyl boronic acid 6 is selectively boc-deprotected under widely used conditions such as TFA in DCM at ambient temperature, followed by the same R as described in step a of Scheme 1 1 ​It can be coupled to the moiety. After hydrolyzing boronate 7 to the respective boronic acid 8 with ammonium acetate buffer / acetone mixture and sodium periodate (step f), in a suitable solvent such as THF, a copper(I) salt such as Cu(I)TC, a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (but not limited thereto), and a palladium ligand such as tri-(2-furyl)-phosphine are used under Liebeskind-Srogl reaction conditions to couple them to 8-methylthio-BODIPY 9 and its 3-substituted analogs 10 and 11 to obtain a compound of formula Ib. This type of reaction is described in the literature (Arroyo et al., 2011). The reduction of the conjugated double bond from compound Ib to methylene-bridged BODIPY analog Ic significantly improves the fluorescence quantum yield. This property is essential for high-quality fluorescent probes, as known to those skilled in the art. This reduction can be achieved by a widely used hydrogenation technique using elemental hydrogen or a hydrogen-generating reagent such as triethylsilane in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH)2 in a suitable solvent such as MeOH, EtOH, EtOAc, or a mixture thereof, between 0 °C and reflux.

[0083] Molecules with structure Id where L = NH or NMe can be synthesized, for example, as shown in Scheme 3.

Chemical formula

[0084] Commercially available N-Boc diamine 12 undergoes nucleophilic aromatic substitution, i.e., with 4-chloro-7-nitro-benzofurazan or 8-methylthio-BODIPY to the fluorescent moiety R, in a suitable solvent such as MeOH, DCM, or THF between 0 °C and reflux, in the absence or presence of an additional base such as triethylamine or potassium carbonate. 2It can be coupled. The modification of the free NH group by methylation is a process known to those skilled in the art and can be carried out on any of intermediates 12, 13 or Id using a methylating agent such as iodomethane or dimethyl sulfate in a suitable solvent such as DMF or DMSO in the presence of a further base such as triethylamine, Hunig's base, potassium carbonate or cesium carbonate.

[0085] Correspondingly, the molecule with structure Ia where L = O can be synthesized, for example, as shown in Scheme 4 as an alternative to those shown in Scheme 2.

Chemical formula

[0086] Commercially available intermediate 3 can be etherified by the method in the literature, for example, under Mitsunobu conditions using PPh3 and diethyl azodicarboxylate, or in a nucleophilic substitution (S N ) reaction (step c) to attach the R 2 group to obtain Boc-protected intermediate 14. The final molecule can be synthesized according to Scheme 1 (step a).

[0087] In one aspect, the present invention provides a method for producing a compound of formula (I) described herein, the method comprising (a) a first amine 1

Chemical formula

Chemical formula

[0088] In one embodiment, the urea forming reagent is selected from bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, 1,1'-carbonyldiimidazole, and 1,1'-carbonyl-di-(1,2,4-triazole). Preferably, the urea forming reagent is bis(trichloromethyl)carbonate.

[0089] In one embodiment, the base in step (a) is sodium bicarbonate.

[0090] In one embodiment, step (a) is carried out in a suitable solvent, preferably an aprotic solvent, more preferably DCM.

[0091] In one embodiment, the amide coupling reagent is selected from DCC, HATU, EDCI, HOBt, TBTU and T3P.

[0092] In one embodiment, the base in step (b) is selected from Hunig's base, trimethylamine and DMAP.

[0093] In one embodiment, step (b) is carried out in a suitable solvent, preferably selected from N,N-dimethylformamide, DMA, DCM and 1-4-dioxane.

[0094] In one embodiment, step (b) is carried out between 0 °C and room temperature.

[0095] In one aspect, the present invention provides a compound of formula (I) as described herein when manufactured according to any one of the methods described herein.

[0096] MAGL inhibitory activity The compounds were profiled for MAGL inhibitory activity by hydrolyzing the natural substrate 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid and tracking it by mass spectrometry to measure enzyme activity. Hereinafter, this assay is abbreviated as the "2-AG assay".

[0097] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog number 784201) with a total volume of 20 μL. The compounds were diluted in a polypropylene plate with 100% DMSO (VWR Chemicals 23500.297) in 3-fold dilution steps, and the final concentration range of the assay was set to 12.5 μM to 0.8 pM. 0.25 μL of the compound dilution (100% DMSO) was added to 9 μL of MAGL in the assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 mL), 0.01% (v / v) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. To initiate the reaction, 10 μL of 2-arachidonoylglycerol in the assay buffer was added. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglycerol. After shaking and incubation at room temperature for 30 minutes, the reaction was quenched by adding 40 μL of ACN containing 4 μM of d8-arachidonic acid. The amount of arachidonic acid was traced by combining an online SPE system (Agilent Rapidfire) and a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used in the ACN / water liquid setup. The mass spectrometer was operated in negative electrospray mode according to the mass transitions of arachidonic acid 303.1→259.1 and d8-arachidonic acid 311.1→267.0. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid]. [Table 1]

[0098] In one aspect, the present invention provides a compound of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein, wherein the compound of formula (I) and pharmaceutically acceptable salts or esters thereof have an IC of MAGL inhibition when measured in the MAGL assay described herein. 50is less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM.

[0099] In one embodiment, the compounds of formula (I) described herein and their pharmaceutically acceptable salts or esters, when measured in the MAGL assay described herein, have an IC 50 (MAGL inhibition) value between 0.000001 μM and 25 μM, and certain compounds have an IC 50 value between 0.000005 μM and 10 μM, and more certain compounds have an IC 50 value between 0.00005 μM and 5 μM.

[0100] Use of the compounds of the present invention The compounds of formula (I) are fluorescent imaging probes with high affinity for MAGL. Thus, they can be used as high-resolution tools to examine the localization of MAGL in living cells, such as the expression levels and protein distribution, structure, dynamics and functions during health and disease. They can also be applied to cell transport studies using, for example, fluorescence-activated cell sorting (FACS) experiments or confocal live cell imaging.

[0101] In one aspect, the present invention provides a compound of formula (I) described herein for use in the study of monoacylglycerol lipase (MAGL) occupancy.

[0102] In a further aspect, the present invention provides a compound of formula (I) described herein for use in the imaging diagnosis of monoacylglycerol lipase (MAGL) in mammals.

[0103] In a further aspect, the present invention provides a compound of formula (I) described herein for use in the generation of equilibrium and kinetic binding data for monoacylglycerol lipase (MAGL).

[0104] In a further aspect, the present invention provides the use of a compound of formula (I) described herein in the study of monoacylglycerol lipase (MAGL) occupancy.

[0105] In a further aspect, the present invention provides the use of a compound of formula (I) described herein in the imaging diagnosis of monoacylglycerol lipase (MAGL) in mammals.

[0106] In a further aspect, the present invention provides the use of a compound of formula (I) described herein for the generation of equilibrium and kinetic binding data of monoacylglycerol lipase (MAGL).

[0107] In a further aspect, the present invention provides a method for studying MAGL occupancy, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) described herein.

[0108] In a further aspect, the present invention provides a method for imaging diagnosis of MAGL in mammals, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) described herein.

[0109] In a further aspect, the present invention provides a method for generating equilibrium and kinetic binding data of MAGL, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) described herein.

Examples

[0110] The present invention will be more fully understood by reference to the following examples. However, the claims should not be construed as being limited to the scope of these examples.

[0111] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0112] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0113] Example 1 (4aR,8aS)-6-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0114] Step a1) (4aR,8aS)-6-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one tert-Butyl 6-((2-oxo-2H-chromen-7-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (28.6 mg, 0.08 mmol) was deprotected by stirring in 5 mL of TFA:DCM (1:4) at room temperature for 3 h. To remove traces of TFA, this was co-evaporated twice with 5 mL of toluene under reduced pressure. (4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium 2,3-bis((4-methylbenzoyl)oxy)succinate (59.5 mg, 0.08 mmol), ACN (1 mL) and TEA (101 μL, 0.56 mmol) were added to a mixture of CDT (13.1 mg, 0.08 mmol), and the mixture was stirred at room temperature for 2 h. The deprotected amine TFA salt was dissolved in 1 mL of ACN, added dropwise to the mixture, and then this was heated to 50 °C for 3 h. The cooled reaction mixture was diluted with 20 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution and 10 mL of saturated NaCl solution. The organic layer was dried over NaSO4, filtered, and concentrated under reduced pressure to give a colorless residue, which was purified by RP-HPLC (15~85% ACN:H2O + 0.1% TFA) to give the title compound as a colorless solid (15 mg, 43%). LC-MS (ESI): m / z = 440.3 [M+H] + 。

[0115] Example 2 (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0116] Step a1) (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in a) of Example 1, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) and tert-butyl 3-(((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carboxylate were condensed to obtain the title compound. LC-MS (ESI): m / z = 414.3 [M+H] + .

[0117] Example 3 (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [Chemical formula] Step l) tert-butyl 3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carboxylate In the same procedure as described in l) of Example 1, 4-hydroxy-2H-chromen-2-one (CAS: 1076-38-6) and tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS: 142253-56-3) were condensed to obtain the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 332.3 [M+H] + .

[0118] Step a1) (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in a of Example 1, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) and tert-butyl 3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carboxylate were condensed to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 414.3 [M+H] + 。

[0119] Example 4 (4aR,8aS)-6-(6-((2-oxo-2H-chromen-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0120] Step a1) (4aR,8aS)-6-(6-((2-oxo-2H-chromen-7-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in a of Example 1, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) and tert-butyl 3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carboxylate were condensed to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 440.2 [M+H] + 。

[0121] Example 5 (4aR,8aS)-6-(4-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0122] Step a1) (4aR,8aS)-6-(4-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one The boc-deprotected intermediate was condensed with (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) in the same procedure as described in a) of Example 1 to give the title compound as a colorless amorphous solid. LC-MS (ESI) 457.2 ([M + H] + )。

[0123] Example 6 (4aR,8aS)-6-(4-((7-Nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [Chemical formula] Step 1) tert-Butyl 4-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (200 mg, 1.0 mmol) (CAS: 87120-72-7) in anhydrous ACN (2 mL), sodium hydrogen carbonate (252 mg, 3.0 mmol) was added, and then 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (200 mg, 1.0 mmol) (CAS: 10199-89-0) in 1 mL of ACN was added. The mixture was stirred at ambient temperature in the dark for 18 hours, then filtered and concentrated to give a dark-colored crude product (300 mg, 83%), which was used without further purification. LC-MS (ESI): m / z = 364.2 [M+H] + .

[0124] Step a1) (4aR,8aS)-6-(4-((7-Nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in a of Example 1, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) and tert-butyl 4-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carboxylate were condensed to obtain the title compound as an orange amorphous solid. LC-MS (ESI): m / z = 468.1 [M+Na] + .

[0125] Example 7 (4aR,8aS)-6-(3-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chem.

[0126] Step l) (4aR,8aS)-6-(3-(((5,5-difluoro-5H-4λ 4 ,5λ 4-Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [2-[(Methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane)(CAS:892505-41-8)(7.1 mg, 30 μmol) was dissolved in 1.5 mL of anhydrous ACN in a dried Schlenk tube and purged with nitrogen for 5 minutes. CuTC (5.7 mg, 30 μmol) and (4aR,8aS)-6-(3-(hydroxymethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one were added, and the mixture was stirred for 5 minutes, then sodium carbonate (3.2 mg, 30 μmol) was added. The mixture was heated at 55 °C for 22 hours. After the mixture was concentrated under reduced pressure, it was purified via RP-HPLC (15~85% ACN:H2O + 0.1% TFA) to obtain the title compound as an orange powder having green fluorescence in solution (2.4 mg, 17%). LC-MS (ESI): m / z = 440.1 [M-F] +

[0127] Example 8 (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0128] Step l) (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same manner as the procedure described in l) of Example 7, (4aR,8aS)-6-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS (ESI): m / z = 466.1 [M-F] + .

[0129] Example 9 (4aR,8aS)-6-(4-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0130] Process l) (4aR,8aS)-6-(4-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in l) of Example 7, (4aR,8aS)-6-(4-Hydroxypiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS (ESI): m / z = 454.2 [M-F] + 。

[0131] Example 10 (4aR,8aS)-6-(7-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0132] Step l) (4aR,8aS)-6-(7-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in l) of Example 7, (4aR,8aS)-6-(4-hydroxypiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS (ESI): m / z = 494.1 [M-F] + 。

[0133] Example 11 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4-(6-((5,5-difluoro-5H-4λ

Chemical Structure

[0134] Step l) 2-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one Following the procedure described in l) of Example 7, 2-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder with green fluorescence in solution. LC-MS (ESI): m / z = 438.1 [M - F] + .

[0135] Example 12 (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ 4 ,5λ4 -(Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chem.

[0136] Step l) (4aR,8aS)-6-(2-((5,5-Difluoro-5H-4λ 4 ,5λ 4-Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in l) of Example 7, (4aR,8aS)-6-(2-hydroxy-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS (ESI): m / z = 494.2 [M - F] + 。

[0137] Example 13 2-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

Chemical formula

[0138] Step l) 2-(2-((5,5-difluoro-5H-4λ 4,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one In the same procedure as described in l) of Example 7, 2-(2-hydroxy-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS(ESI): m / z = 466.2 [M - F] + 。

[0139] Example 14 (4aR,8aS)-6-((1R,5S,6R)-6-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0140] Step l) (4aR,8aS)-6-((1R,5S,6R)-6-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in l) of Example 7, (4aR,8aS)-6-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were condensed to obtain the title compound as an orange powder having green fluorescence in solution. LC-MS (ESI): m / z = 466.1 [M-F] + .

[0141] Example 15 (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [Chemical formula] Step e) tert-Butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate Into an oven-dried vial equipped with a magnetic stir bar, 2,2,6,6-tetramethylpiperidine (311 mg, 2.2 mmol) was charged, dissolved in anhydrous THF (20 mL), and cooled to -78 °C under a nitrogen atmosphere. nBuLi (2.5 M in hexanes) (880 μL, 2.2 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 minutes. Next, a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (590 mg, 2.2 mmol) in THF (8 mL) was added dropwise. The reaction was stirred at room temperature for 5 hours. Then, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (232 mg, 1.1 mmol) in THF (12 mL) was added dropwise over 5 minutes. The reaction vial was slowly warmed to room temperature overnight. Once complete, the reaction was opened to air and filtered through a silica plug eluting with diethyl ether. The mixture was concentrated under reduced pressure and adsorbed onto isolute. The product was obtained as a white amorphous solid by silica gel chromatography with 0 - 20% ethyl acetate in cyclohexane. LC-MS (ESI): m / z = 336.1 [M+H] + 。

[0142] Step a) (4aR,8aS)-6-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one tert-Butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate (67 mg, 0.2 mmol) was deprotected by stirring in 5 ml of TFA:DCM (1:4) at room temperature for 3 h. To remove traces of TFA, this was co-evaporated twice with 5 mL of toluene under reduced pressure. (4aR,8aS)-3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-ium 2,3-bis((4-methylbenzoyl)oxy)succinate (149 mg, 0.2 mmol) (CAS: 2377107-31-6), a mixture of ACN (2 mL) and TEA (194 μL, 1.4 mmol), CDT was added, and the mixture was stirred at room temperature for 2 h. The deprotected amine TFA salt was dissolved in 1 mL of ACN, added dropwise to the mixture, and then this was heated to 50 °C for 3 h. The cooled reaction mixture was diluted with 20 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution and 10 mL of saturated NaCl solution. The organic layer was dried over NaSO4, filtered, and concentrated under reduced pressure to give a colorless oily substance, which was used without further purification. LC-MS (ESI): m / z = 418.2 [M+H] + 。

[0143] Step f) ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid (4aR,8aS)-6-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (83.5 mg, 0.2 mmol), sodium periodate (214 mg, 1.0 mmol), and ammonium acetate (77 mg, 1.0 mmol) were dissolved in acetone / water 2:1 (4 mL, 0.05 M) and stirred at ambient temperature for 24 h until LC-MS indicated consumption of the starting material. Acetone was removed in vacuo, 4 mL of ACN / H2O 1:1 was added, and the mixture was filtered. The filtrate was purified by RP-HPLC 5%–75% ACN:H2O (+0.1% TFA), and the product was obtained as a colorless amorphous solid after lyophilization. LC-MS (ESI): m / z = 336.1 [M+H] + 。

[0144] Step i) (4aR,8aS)-6-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one Into an oven-dried Schlenk tube equipped with a stir bar, under nitrogen, (2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid (33.5 mg, 0.1 mmol), [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) (24 mg, 0.1 mmol), and anhydrous THF (3 mL) were charged. Nitrogen was flowed through the stirred solution for 10 minutes, and then CuTC (57 mg, 0.3 mmol), Pd2(dba)3 (7 mg, 7.5 μmol), and TFP (5.2 mg, 22.5 μmol) were added under nitrogen. The reaction mixture was immersed in an oil bath preheated to 55 °C. The reaction was monitored by LC-MS, and when the boronic acid was consumed after 1 hour, the heating was stopped. The reaction mixture was carefully concentrated, 4 mL of ACN:H2O was added, filtered, and purified by RP-HPLC (15~85% ACN:H2O + 0.1% TFA) to obtain a dark red amorphous solid (22.1 mg, 46%). LC-MS (ESI): m / z = 482.2 [M+H] + and 462.2 [M−F] + .

[0145] Example 16 (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0146] Example 17 (4aR,8aS)-6-(4-((5,5-difluoro-5H-4λ 4 4 ,5λ 4 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0147] Step a1) (4aR,8aS)-6-(4-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in a1) of Example 12, tert-Butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate and (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to obtain the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 406.2 [M+H] +

[0148] Step f) ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid In the same procedure as described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 324.1 [M+H] +

[0149] Step i) (4aR,8aS)-6-(4-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same procedure as described in i) of Example 15, ((1 - ((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 450.1 [M - F] +

[0150] Example 18 (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0151] Step a1) (4aR,8aS)-6-(7-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same manner as the procedure described in a1) of Example 15, tert-butyl 7-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.5]nonane-2-carboxylate and (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to obtain the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 446.2 [M+H] +

[0152] Step f) ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.5]nonan-7-ylidene)methyl)boronic acid In the same manner as the procedure described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 364.1 [M+H] +

[0153] Step i) (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one In the same manner as the procedure described in i) of Example 15, ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 490.1 [M-F] +

[0154] Example 19 (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical formula

[0155] Example 20 2-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

Chemical formula

[0156] Step f) ((2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.5]nonan-7-ylidene)methyl)boronic acid Following the procedure described in f) of Example 15, the vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 336.1 [M+H] +

[0157] Step i) 2-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-ylidene)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one Following the procedure described in i) of Example 15, ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 461.2 [M-F] +

[0158] Example 21 2-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-ylidene)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

Chemical Structure

[0159] Example 22 2-(6-((5,5-Difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one [Chemical formula] Step a1) 2-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one In the same manner as the procedure described in a1) of Example 15, tert-butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate and 7-oxa-2,5-diazaspiro[3.4]octan-6-one (CAS: 1780174-72-2) were condensed to obtain the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 390.2 [M + H] + .

[0160] Step f) ((2-(6-Oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid In the same manner as the procedure described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 308.0 [M + H] +

[0161] Step i) 2-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one Following the procedure described in i) of Example 15, ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 461.2 [M - F] +

[0162] Example 23 2-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one [Chemical Structure] Step j) Following the procedure described in j) of Example 16, Example 22 was converted to Example 23 by reduction of the olefin double bond to obtain an orange solid having green fluorescence in solution. LC-MS (ESI): m / z = 436.1 [M - F] + .

[0163] Example 24 6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4-(dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one [Chemical Structure] Step a2) 6-(6-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one tert-Butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate (33.5 mg, 0.1 mmol) was deprotected by stirring in 5 mL of TFA:DCM (1:4) at room temperature for 3 hours. To remove traces of TFA, this was co-evaporated twice with 5 mL of toluene under reduced pressure. 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (29.0 mg, 0.15 mmol) (CAS: 134997-87-8), HATU (57.0 mg, 0.15 mmol) and triethylamine were dissolved in anhydrous DCM (1 mL) and stirred at room temperature for 30 minutes. The deprotected amine TFA salt dissolved in 0.5 mL of DCM was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by RP-HPLC (18 - 85% ACN:H2O + 0.1% TFA) to give the title compound as a colorless solid (19 mg, 46%). LC-MS (ESI): m / z = 411.2 [M+H] + .

[0164] Step f) ((2-(3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid Following the procedure described in f) of Example 15, the vinyl boronate was hydrolyzed to each boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z = 329.2 [M+H]+

[0165] Step i) 6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one Following the procedure described in i) of Example 15, ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 455.1 [M-F] +

[0166] Step j) 6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one Following the procedure described in j) of Example 16, an orange solid having green fluorescence in solution was obtained. LC-MS (ESI): m / z = 457.1 [M-F] + .

[0167] Example 25 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone

Chem.

[0168] Step 2) tert-Butyl 6-(3-Cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate (12.0 g, 41.2 mmol, purity 90.0%) in ACN (200 mL) were added 3-cyclopropyl-1H-1,2,4-triazole (CAS: 1211390-33-8) (4.50 g, 41.2 mmol) and Cs2CO3 (26.8 g, 82.4 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was further separated by SFC to obtain the title compound (6.77 g, 22.2 mmol, yield 54.0%) as a brown solid. MS(ESI): m / z = 305.2 [M+H] +

[0169] Step 3) 6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate To a solution of tert-butyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (6.00 g, 19.7 mmol) in DCM (120 mL) was added TFA (46.2 g, 405 mmol, 30 mL) at 25 °C. The mixture was stirred at 30 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The title compound (crude product 14.0 g) was used in the next step without further purification. MS (ESI): m / z = 205.2 [M+H] +

[0170] Step a1) (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptan-2-yl)methanone Following the procedure described in a1) of Example 15, tert-butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate and 6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 466.3 [M+H] + .

[0171] Step f) ((2-(6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-2-azaspiro[3.3]heptan-6-ylidene)methyl)boronic acid In the same manner as the procedure described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 329.1 [M+H] +

[0172] Step i) (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptan-2-yl)methanone In the same manner as the procedure described in i) of Example 15, ((2-(6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-2-azaspiro[3.3]heptan-6-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 455.1 [M-F] +

[0173] Step j) (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone In the same manner as the procedure described in j) of Example 16, an orange solid having green fluorescence in solution was obtained. LC-MS (ESI): m / z = 457.1 [M-F] + 。

[0174] Example 26 (6-((5,5-Difluoro-5H-4λ 4 ,5λ 4-dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone

Chemical Structure

[0175] Step f) ((2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptan-6-ylidene)methyl)boronic acid Following the procedure described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 398.2 [M+H] +

[0176] Step i) (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone In the same manner as the procedure described in i) of Example 15, ((1 - ((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 524.2 [M - F] +

[0177] Step j) (6 - ((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone In the same manner as the procedure described in j) of Example 16, an orange solid having green fluorescence in solution was obtained. LC-MS (ESI): m / z = 526.2 [M - F] + .

[0178] Example 27 (S)-1-(6 - ((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide

Chemical Structure

[0179] Step f) (S)-((2-(3-carbamoyl-1-pyrrolidinecarbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid In the same procedure as described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to obtain the title compound as a colorless solid. LC-MS (ESI): m / z = 294.1 [M+H] +

[0180] Step i) (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide In the same procedure as described in i) of Example 15, ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 420.2 [M-F] +

[0181] Step j) (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4-(dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide Following the procedure described in Example 16, j), an orange solid with green fluorescence is obtained in solution. LC-MS (ESI): m / z = 442.1 [M+H] + .

[0182] Example 28 (R)-4-(3-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one [Chemical formula] Synthesis of components: 3-[(4R)-2-oxooxazolidin-4-yl]propanoic acid (3 steps) Step 1) Methyl (S)-4-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate (R)-2-((tert-Butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (1 g, 3.83 mmol, CAS: 76379-01-6) in THF (15 mL) was added with N-methylmorpholine (421 μL, 3.83 mmol) at -10 °C, followed by ethyl chloroformate (368 μL, 3.83 mmol). The reaction mixture was stirred at this temperature for 10 minutes. No temperature rise occurred upon the addition of NaBH4 (434 mg, 11.5 mmol) all at once. MeOH (35 mL) was added dropwise over 30 minutes between -1 °C and 17 °C. Stirring was continued in an ice bath for 1 hour. After 1M KHSO4 aqueous solution (40 mL) was added dropwise to the reaction mixture, the organic solvent was evaporated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1M KHSO4 aqueous solution and saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, treated with silica gel, and evaporated. The crude compound was purified by silica gel chromatography using an MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 30:70) to obtain the title compound as a colorless oil (0.70 g, 66%). MS (ESI): m / z = 192.1 [M+H] + 。

[0183] Step 2) Methyl (R)-3-(2-oxooxazolidin-4-yl)propanoate To a solution of methyl (S)-4-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate (690 mg, 2.79 mmol, 1.0 equiv) in THF (8.8 mL) was added dropwise thionyl chloride (611 μL, 8.37 mmol, 3.0 equiv), and the solution was stirred at room temperature for 3 hours. Silica gel was added, and the reaction mixture was evaporated. The compound was purified by silica gel chromatography using an MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to obtain the title compound as a colorless oil (404 mg, 79%). MS (ESI): m / z = 174.1 [M+H] + 。

[0184] Step 3) (R)-3-(2-oxooxazolidin-4-yl)propanoic acid In 1,4-dioxane (2 mL) and water (2 mL), to a solution of methyl (S)-3-(2-oxooxazolidin-4-yl)propanoate (400 mg, 2.31 mmol, 1.0 equiv) was added lithium hydroxide monohydrate (107 mg, 2.54 mmol, 1.1 equiv), and the reaction mixture was stirred at room temperature for 2 h. 1,4-Dioxane was evaporated, and aqueous HCl solution (2.54 mL, 2.54 mmol, 1.1 equiv) was added dropwise to this solution. The aqueous layer was extracted 5 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated to give the title compound as a colorless solid (330 mg, 86%). MS (ESI): m / z = 160.1 [M+H] + 。

[0185] Step a2) (R)-4-(3-Oxo-3-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptan-2-yl)propyl)oxazolidin-2-one Following the procedure described in a2) of Example 25, tert-butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate and 3-[(4R)-2-oxooxazolidin-4-yl]propanoic acid were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 372.2 [M+H] + 。

[0186] Step f) (R)-((2-(3-(2-Oxooxazolidin-4-yl)propanoyl)-2-azaspiro[3.3]heptan-6-ylidene)methyl)boronic acid Following the procedure described in f) of Example 15, vinyl boronate was hydrolyzed to each boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z = 295.1 [M+H] +

[0187] Step i) (R)-4-(3-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4-(dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one Following the procedure described in Example 15 i), ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 421.2 [M - F] +

[0188] Step j) (R)-4-(3-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one Following the procedure described in Example 16 j), an orange solid with green fluorescence in solution was obtained. LC-MS (ESI): m / z = 423.2 [M - F] + 。

[0189] Example 29 (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Chemical Structure

[0190] Step i) (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one Following the procedure described in i) of Example 15, ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid and 5,5-difluoro-10-(methylthio)-3-phenyl-5H-5l4,6l4-dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinine were coupled to afford the title compound as a dark red solid. LC-MS (ESI): m / z = 538.2 [M-F] + 。

[0191] Step j) (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ 4 ,5λ4 -(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ Following the procedure described in Example 16, j), a red solid having orange fluorescence is obtained in solution. LC-MS (ESI): m / z = 540.2 [M - F] + .

[0192] Example 30 (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ [Chemical formula] Step g) 5,5-difluoro-10-(methylthio)-3-(1H-pyrrol-2-yl)-5H-5λ 4 ,6λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinine A microwave vial equipped with a stir bar was charged with [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (71.4 mg, 0.3 mmol) (CAS: 892505-41-8) and 1H-pyrrole (1.04 mL, 15 mmol) (CAS: 109-97-7). The vial was sealed and heated to 150 °C for 3 hours by microwave irradiation. Excess 1H-pyrrole was evaporated under reduced pressure and the residue was purified by RP-HPLC (25 - 95% ACN: H2O + 0.1% TFA) to give the title compound as a dark purple solid (8.0 mg, 9%). LC-MS (ESI): m / z = 304.1 [M + H] + .

[0193] Step i) (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one Following the procedure described in Example 15 i), ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid and 5,5-difluoro-10-(methylthio)-3-(1H-pyrrol-2-yl)-5H-5λ 4 ,6λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinine were coupled to obtain the title compound as a dark red solid. LC-MS (ESI): m / z = 527.2 [M - F] + 。

[0194] Step j) (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one Following the procedure described in Example 16 j), a purple solid with red fluorescence in solution was obtained. LC-MS (ESI): m / z = 529.3 [M - F] + 。

[0195] Example 31 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-5λ 4 ,6λ 4(6 - ((5,5 - difluoro - 3 - (1H - pyrrol - 2 - yl)-5H - 5λ

Chemical Structure

[0196] Step j) (6-(3 - cyclopropyl - 1H - 1,2,4 - triazol - 1 - yl)-2 - azaspiro[3.3]heptan - 2 - yl)(6 - ((5,5 - difluoro - 3 - (1H - pyrrol - 2 - yl)-5H - 5λ 4 ,6λ 4 -dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl)-2 - azaspiro[3.3]heptan - 2 - yl)methanone

[0197] The title compound was synthesized from the above intermediate in the same manner as described in step j) of Example 16. The title compound was obtained as a purple solid having red fluorescence in solution. LC-MS (ESI): m / z = 597.2 [M+H] + .

[0198] The following examples can be prepared in the same manner as the above examples:

[0199] Example 32 (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone

Chemical Structure

[0200] Example 33 (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone

Chemical Structure

[0201] Example 34 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone

Chemical Structure

[0202] Example 356 - (7 - ((5,5 - difluoro - 5H - 4λ 4 ,5λ 4 - dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl) - 2 - azaspiro[3.5]nonane - 2 - carbonyl) - 2H - benzo[b][1,4]oxazin - 3(4H) - one

Chemical formula

[0203] Example 36 (R) - 4 - (3 - (7 - ((5,5 - difluoro - 5H - 4λ 4 ,5λ 4 - dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl) - 2 - azaspiro[3.5]nonan - 2 - yl) - 3 - oxopropyl)oxazolidin - 2 - one

Chemical formula

[0204] Example 37 (S) - 1 - (7 - ((5,5 - difluoro - 5H - 4λ 4 ,5λ 4 - dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl) - 2 - azaspiro[3.5]nonane - 2 - carbonyl)pyrrolidine - 3 - carboxamide

Chemical formula

[0205] Example 38 (7 - ((5,5 - difluoro - 5H - 4λ 4 ,5λ 4 - dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl) - 2 - azaspiro[3.5]nonan - 2 - yl)(4 - (5 - methyloxazolo[4,5 - b]pyridin - 2 - yl)piperazin - 1 - yl)methanone [Chemistry]

[0206] Example 39 (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [Chemistry]

[0207] Example 40 2-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one [Chemistry]

[0208] Example 41 (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone [Chemistry]

[0209] Example 42 (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone

Chemical Structure

[0210] Example 43 6-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

Chemical Structure

[0211] Example 44 (R)-4-(3-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-3-oxopropyl)oxazolidin-2-one

Chemical Structure

[0212] Example 45 (S)-1-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2’,1’-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)pyrrolidine-3-carboxamide

Chemical Structure

[0213] Example 46 (2 - ((5,5 - difluoro - 5H - 4λ 4 ,5λ 4 - dipyrrolo[1,2 - c:2’,1’ - f][1,3,2]diazaborinin - 10 - yl)methyl) - 7 - azaspiro[3.5]nonan - 7 - yl)(4 - (5 - methyloxazolo[4,5 - b]pyridin - 2 - yl)piperazin - 1 - yl)methanone [Chemical formula]

Claims

1. A compound of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof (wherein R １ is 【Chemical 2】 (wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I)) is selected from; R ２ is 【Chemical Formula 3】 (wherein the wavy line indicates the point of attachment to L) is selected from; Each R ３ is independently hydrogen, halogen, C １ to C ６ -alkyl, C １ to C ６ -alkoxy, phenyl, 【Chemical 4】 is selected from; n is 1, 2 or 3; Ar is C ６ ~C １０ -aryl or 5- to 14-membered heteroaryl; A is selected from the following (i) and (ii): (i) 【Chemical Formula 5】 L is a covalent bond, -CH ２ -, -O-, -OCH ２ -, -CH ２ O- and -CH ２ OCH ２ - selected from; and (ii) [[Chemical Formula 6]] (wherein (i) X is N; L is a covalent bond, -CH ２ -, and -OCH ２ - is selected from; or (ii) X is CH; L is a covalent bond, -CH ２ -, -NH-, -NMe-, -O-, -OCH ２ -, -CH ２ O- and -CH ２ OCH ２ - or is selected from; or (iii) X and L together form the group 【Chemical Formula 7】 (wherein the wavy line indicates the bonding point of L to R ２ and the two asterisks indicate the bonding points of X to each adjacent atom in ring A) is formed; (in the formula of A, the wavy line indicates the point of attachment to L; the asterisk indicates the point of attachment to the carbonyl group of formula (I)).

2. R １ is 【Chemical 8】 (wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I)) is selected from, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ is 【Chemical Formula 9】 (wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I)), is selected from, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R １ is 【Chemical 10】 (wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I)) is selected from, the compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof.

5. R １ is 【Chemical 11】 (wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I)) is selected from, the compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof.

6. R ２ is 【Chemical Formula 12】 (wherein the wavy line indicates the point of attachment to L) is selected from; R ３ is hydrogen, phenyl, and 【Chemical 13】 is selected from; n is 1, the compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R ２ is 【Chemical 14】 (wherein the wavy line indicates the point of attachment to L) is selected from; R ３ is hydrogen and 【Chemical Formula 15】 is selected from; n is 1, the compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof.

8. R ２ is 【Chemical 16】 (wherein the wavy line indicates the point of attachment to L); R ３ is hydrogen, and n is 1, the compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof.

9. A is selected from the following (i) and (ii): (i) 【Chemical 17】 L is selected from a covalent bond, -O-, and -OCH ２ -; and (ii) 【Chemical 18】 (wherein (i) X is N; L is -CH ２ - or; or (ii) X is CH; L is selected from -CH ２ -, -NH-, and -O-; or or (iii) X and L together form the group 【Chemical Formula 19】 (wherein the wavy line indicates the bonding point of L to R ２ and the two asterisks indicate the bonding points of X to each adjacent atom in ring A) is formed; (in the formula of A, the wavy line indicates the point of attachment to L; the asterisk indicates the point of attachment to the carbonyl group of formula (I), the compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. A is selected from the following (i) and (ii): (i) 【Chemical 20】 L is -O-; and (ii) 【Chemical 21】 (wherein (i) X is CH; L is selected from -CH ２ - and -O-; or (ii) X and L together form the group 【Chemical 22】 (wherein the wavy line indicates the bonding point of L to R ２ and the two asterisks indicate the bonding points of X to each adjacent atom in ring A) are formed; In the formula of A, the wavy line indicates the bonding point to L; the asterisk indicates the bonding point to the carbonyl group of formula (I). The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof.

11. A is 【Chemical 23】 where; X is CH; L is -CH ２ -; In the formula, the wavy line indicates the bonding point to L; The asterisk indicates the bonding point to the carbonyl group of formula (I). The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof.

12. R １ is 【Chemical 24】 (wherein the wavy line indicates the bonding point to the carbonyl group of formula (I)) selected from; R ２ is 【Chemical 25】 (wherein the wavy line indicates the bonding point to L) selected from; R ３ is hydrogen, phenyl, and 【Chemical 26】 selected from; n is 1; A is selected from the following (i) and (ii): (i) 【Chemical 27】 L is selected from a covalent bond, —O—, and —OCH ２ —; and (ii) 【Chemical Formula 28】 In the formula, (i) X is N; L is -CH ２ - or; or (ii) X is CH; L is selected from -CH ２ -, -NH-, and -O-; or or (iii) X and L together form a group 【Chemical 29】 (wherein the wavy line indicates the bonding point of L to R ２ and the two asterisks indicate the bonding points of X to each adjacent atom in ring A) are formed; In the formula of A, the wavy line indicates the bonding point to L; the asterisk indicates the bonding point to the carbonyl group of formula (I). The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

13. R １ is 【Chemical 30】 (wherein the wavy line indicates the bonding point to the carbonyl group of formula (I)) selected from; R ２ is 【Chemical 31】 (wherein the wavy line indicates the bonding point to L) selected from; R ３ is hydrogen and 【Chemical Formula 32】 selected from; n is 1; A is selected from the following (i) and (ii): (i) 【Chemical 33】 L is -O-; and (ii) 【Chemical 34】 In the formula, (i) X is CH; L is selected from -CH ２ - and -O-; or (ii) X and L together form a group 【Chemical 35】 (wherein the wavy line indicates the bonding point of L to R ２ and the two asterisks indicate the bonding points of X to each adjacent atom in ring A) is formed; In the formula of A, the wavy line indicates the bonding point to L; the asterisk indicates the bonding point to the carbonyl group of formula (I). The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof.

14. R １ is 【Chemical 36】 (wherein the wavy line indicates the bonding point to the carbonyl group of formula (I)) selected from; R ２ is 【Chemical 37】 (wherein the wavy line indicates the bonding point to L); R ３ is hydrogen; n is 1; A is 【Chemical Formula 38】 where; X is CH; L is -CH ２ -. In the formula, the wavy line indicates the bonding point to L; The asterisk indicates the bonding point to the carbonyl group of formula (I). The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof.

15. The compound of formula (I) is (4aR,8aS)-6-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((((2-oxo-2H-chromen-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)piperidine-1-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ ４ , 5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(2-((((5,5-difluoro-5H-4λ4,5λ4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl))-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-((1R,5S,6R)-6-(((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ ４ , 5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; (6-((5,5-Difluoro-5H-4λ ４ ,5λ ４ -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; (S)-1-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide; (R)-4-(3-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone; 6-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (R)-4-(3-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-3-oxopropyl)oxazolidin-2-one; (S)-1-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)pyrrolidine-3-carboxamide; (7-((5,5-Difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; (4aR,8aS)-6-(2-((5,5-difluoro-5H-4λ ４ , 5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (S)-(3-(1H-1,2,3-triazol-5-yl)pyrrolidin-1-yl)(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone; 6-(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; (R)-4-(3-(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-3-oxopropyl)oxazolidin-2-one; (S)-1-(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)pyrrolidine-3-carboxamide; (2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone; and (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-5λ ４ ,6λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

16. The compound of formula (I) is (4aR,8aS)-6-(6-((((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl))hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(2-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)oxy)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ , 5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-(7-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; ((6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; (S)-1-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide; (R)-4-(3-(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-3-oxopropyl)oxazolidin-2-one; (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one A compound of formula (I) according to claim 15, or a pharmaceutically acceptable salt thereof, selected from:

17. The compound of formula (I) is (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ ４ , 5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (6-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)(6-((5,5-difluoro-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)methanone; and (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one A compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, selected from:

18. A process for preparing a compound of formula (I) according to any one of claims 1 to 17, comprising (a) in the presence of a base and a urea-forming reagent, a first amine 1 【Chemical Formula 39】 (wherein A and R ２ are as defined in any one of claims 1 to 17) is 【Chemical 40】 reacting with a second amine selected from to form the compound of formula (I); or (b) reacting with a carboxylic acid selected from in the presence of a base and an amide coupling reagent 【Chemical Formula 41】 (wherein A and R ２ are as defined in any one of claims 1 to 17) is 【Chemical 42】 to form the compound of formula (I). A process comprising.

19. A compound of formula (I) according to any one of claims 1 to 17 when produced according to the process of claim 18.

20. A compound of formula (I) according to any one of claims 1 to 17 for use in the study of monoacylglycerol lipase (MAGL) occupancy.

21. A compound of formula (I) according to any one of claims 1 to 17 for use in the imaging diagnosis of monoacylglycerol lipase (MAGL) in mammals.

22. In the generation of monoacylglycerol lipase (MAGL) equilibrium and kinetic binding data

23. Use of a compound of formula (I) according to any one of claims 1 to 17 in the study of monoacylglycerol lipase (MAGL) occupancy.

24. Use of a compound of formula (I) according to any one of claims 1 to 17 in the imaging diagnosis of monoacylglycerol lipase (MAGL) in mammals.

25. Use of a compound of formula (I) according to any one of claims 1 to 17 for generating monoacylglycerol lipase (MAGL) equilibrium and kinetic binding data.

26. A method for studying MAGL occupancy, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) according to any one of claims 1 to 17.

27. A method for imaging diagnosis of MAGL in mammals, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) according to any one of claims 1 to 17.

28. A method for generating equilibrium and kinetic binding data of MAGL, comprising contacting monoacylglycerol lipase (MAGL) with a compound of formula (I) according to any one of claims 1 to 17.

29. The invention as described herein.

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