Fluorescent probe for MAGL

Abstract

The present invention provides: compounds having the general formula (I) wherein A, L, R1 and R2 are as described herein; comprising the compound; methods of making the compounds; and methods of using the compounds. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to organic compounds useful as fluorescent probes for monoacylglycerol lipase (MAGL). Background Art

[0002] Fluorescence imaging probes have become high-resolution tools (LAStoddart, LEKilpatrick, SJBriddon, SJHill, Neuropharmacology 2015, 98, 48-57) for studying positioning (e.g., expression levels and protein distribution in health and disease states, structure, dynamics and function of proteins in living cells). Such probes can be applied to flow cytometry fluorescence activated cell sorting (FACS) experiments or cell transport studies, for example, using confocal live cell imaging. In addition, fluorescence imaging probes allow real-time monitoring of ligand-receptor interactions and protein visualization with high spatiotemporal precision (AJVernall, SJHill, B.Kellam, Br.J.Pharmacol. 2014, 171, 1073–1084; C.Iliopoulos-Tsoutsouvas, RNKulkarni, A.Makriyannis, SPNikas, ExpertOpin.Drug Discov. 2018, 13, 933–947). In addition, such probes provide the potential for generating equilibrium and kinetic binding data in a high-throughput manner without the need to use, for example, time-resolved fluorescence resonance energy transfer (TR-FRET) to process radioactive materials. Fluorescence imaging probes can also be used to support the conversion of preclinical pharmacology animal data into clinical pharmacology animal data, and can be applied to human dose selection. They can be used as markers for target engagement, for example, via the generation of in vitro quantitative receptor binding data in whole blood. Depending on their respective applications, fluorescence imaging probes need to match specific criteria, including affinity, selectivity and specificity to their respective targets, favorable photophysical properties, and applicability in different techniques and cell types. Summary of the invention

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

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein A, L, R 1 and R 2 As defined herein.

[0006] In another aspect, the present invention provides a method for making a compound of formula (I) as described herein, the method comprising:

[0007] (a) making a first amine 1,

[0008]

[0009] Where A and R 2 As defined herein;

[0010] and a second amine selected from:

[0011]

[0012] reacting in the presence of a base and a urea forming agent,

[0013] To form the compound of formula (I); or

[0014] (b) making amine 1,

[0015]

[0016] Where A and R 2 As defined herein;

[0017] and a carboxylic acid selected from the group consisting of:

[0018]

[0019] In the presence of a base and an amide coupling agent,

[0020] To form the compound of formula (I).

[0021] In another aspect, the present invention provides a compound of formula (I) as described herein, manufactured according to a method described herein.

[0022] In another aspect, the present invention provides a method of studying the occupancy of monoacylglycerol lipase (MAGL), the method comprising contacting MAGL with a compound of formula (I) as described herein.

[0023] In another aspect, the present invention provides a method for diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammal, the method comprising contacting MAGL with a compound of formula (I) as described herein.

[0024] In another aspect, the invention provides a method of generating equilibrium and kinetic binding data for monoacylglycerol lipase (MAGL), the method comprising contacting MAGL with a compound of formula (I) described herein. DETAILED DESCRIPTION

[0025] definition

[0026] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0027] The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms ("C 1 -C 6 -alkyl"). In other embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl is methyl.

[0028] The term "alkoxy" refers to an alkyl group as defined above attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 12 carbon atoms. In some preferred embodiments, an alkoxy group contains 1 to 6 carbon atoms ("C 1 -C 6 -alkoxy"). In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In 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.

[0029] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

[0030] The term "aryl" refers to a group having a total of 6 to 14 ring members ("C 6-14-aryl”), a monocyclic, bicyclic or tricyclic carbocyclic ring system of preferably 6 to 12 ring members and more preferably 6 to 10 ring members, and wherein at least one ring in the ring 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.

[0031] The term "heteroaryl" refers to a monovalent or multivalent monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5-10 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; pyridinyl (e.g., 2-pyridinyl); pyrazolyl (e.g., pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g., imidazolyl); benzoxazolyl (e.g., benzoxazolyl-2-yl), 2,3-dihydrobenzofuranyl; and oxazolo[5,4-c]pyridin-2-yl. Some particularly preferred but non-limiting examples of heteroaryl include oxadiazolyl; pyridinyl; triazolyl; tetrazolyl; pyrazinyl and imidazolyl.

[0032] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (particularly 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, methylsulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, 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, and the like). A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0033] As used herein, the term "protecting group" (PG) represents a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction selectively occurs on another unprotected reactive site that is usually associated therewith in synthetic chemistry. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxy protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butyloxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described in, for example, TW Greene and PGM Wutts, Protective Groups in Organic Chemistry, 5th edition, 2014, John Wiley & Sons, NY.

[0034] The term "urea forming agent" refers to a compound that can convert a first amine into a substance that can react with a second amine to form a urea derivative. Non-limiting examples of urea forming agents include bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, and 1,1'-carbonyldiimidazole. Urea forming agents are described by G. Sartori et al. (Green Chemistry 2000, 2, 140), which is incorporated herein by reference.

[0035] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (eg racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0036] According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be in either the "R" or "S" configuration.

[0037] The abbreviation "MAGL" refers to monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0038] Compounds of the present invention

[0039] In the first aspect (A1), the present invention provides a compound of formula (I)

[0040]

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] R 1 Selected from:

[0043]

[0044] wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I);

[0045] R 2 Selected from:

[0046]

[0047] The wavy line indicates the connection point with L;

[0048] Each R 3 are independently selected from hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl,

[0049]

[0050] n is 1, 2 or 3;

[0051] Ar is C 6 -C 10 - aryl or 5- to 14-membered heteroaryl;

[0052] A is selected from:

[0053] (i) and

[0054] L is selected from a covalent bond, –CH 2 –, –O–, –OCH 2 –, –CH 2 O– and–

[0055] CH 2 OCH 2 -;as well as

[0056] (ii) in

[0057] (i) X is N; and L is selected from a covalent bond, –CH 2 – and –OCH 2 -;or

[0058] (ii) X is CH; and L is selected from a covalent bond, –CH 2 –, –NH–, –NMe–,

[0059] –O–, –OCH 2 –, –CH 2 O– and –CH 2 OCH 2-;or

[0060] (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0061] wherein the wavy line indicates the point of connection with L; and

[0062] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0063] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 Selected from

[0064]

[0065] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0066] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 Selected from

[0067]

[0068] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0069] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 Selected from

[0070]

[0071] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0072] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 Selected from

[0073]

[0074] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0075] 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 Selected from

[0076]

[0077] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0078] 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 for Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0079] 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 for Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0080] 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 for Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0081] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0082] R 2 Selected from:

[0083]

[0084] The wavy line indicates the connection point with L;

[0085] R 3 Selected from hydrogen, phenyl and and

[0086] n is 1.

[0087] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0088] R 2 Selected from:

[0089]

[0090] The wavy line indicates the connection point with L;

[0091] R 3 Selected from hydrogen and and

[0092] n is 1.

[0093] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0094] R 2 for:

[0095]

[0096] The wavy line indicates the connection point with L;

[0097] R 3 is hydrogen; and

[0098] n is 1.

[0099] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0100] A is selected from:

[0101] (i) and

[0102] L is selected from a covalent bond, –O– and –OCH 2 -;and

[0103] (ii) in

[0104] (i) X is N; and L is –CH 2 -;or

[0105] (ii) X is CH; and L is selected from -CH 2 –, –NH– and –O–; or

[0106] (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0107] wherein the wavy line indicates the point of connection with L; and

[0108] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0109] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0110] A is selected from:

[0111] (i) and

[0112] L is –O–; and

[0113] (ii) in

[0114] (i) X is CH; and L is selected from -CH 2 – and –O–; or

[0115] (ii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0116] wherein the wavy line indicates the point of connection with L; and

[0117] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0118] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0119] A is

[0120] X is CH; and

[0121] L is –CH 2 –

[0122] wherein the wavy line indicates the point of connection with L; and

[0123] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0124] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0125] R 1 Selected from

[0126]

[0127] wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I);

[0128] R 2 Selected from:

[0129]

[0130] The wavy line indicates the connection point with L;

[0131] R 3 Selected from hydrogen, phenyl and

[0132] n is 1;

[0133] A is selected from:

[0134] (i) and

[0135] L is selected from a covalent bond, –O– and –OCH 2 -;and

[0136] (ii) wherein (i) X is N; and L is –CH 2 -;or

[0137] (ii) X is CH; and L is selected from -CH 2 –, –NH– and –O–; or

[0138] (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0139] wherein the wavy line indicates the point of connection with L; and

[0140] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0141] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0142] R 1 Selected from

[0143]

[0144] wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I);

[0145] R 2 Selected from:

[0146]

[0147] The wavy line indicates the connection point with L;

[0148] R 3 Selected from hydrogen and

[0149] n is 1;

[0150] A is selected from:

[0151] (i) and

[0152] L is –O–; and

[0153] (ii) in

[0154] (i) X is CH; and L is selected from -CH 2 – and –O–; or

[0155] (ii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0156] wherein the wavy line indicates the point of connection with L; and

[0157] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0158] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0159] R 1 Selected from

[0160]

[0161] wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I);

[0162] R 2 for:

[0163]

[0164] The wavy line indicates the connection point with L;

[0165] R 3 is hydrogen;

[0166] n is 1;

[0167] A is

[0168] X is CH; and

[0169] L is –CH 2 –

[0170] wherein the wavy line indicates the point of connection with L; and

[0171] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0172] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0173] R 1 Selected from

[0174]

[0175] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0176] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 2 Selected from:

[0177]

[0178] The wavy line indicates the connection point with L.

[0179] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 3 Selected from hydrogen, phenyl and

[0180] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein n is 1.

[0181] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein A is selected from:

[0182] (i) and

[0183] L is selected from a covalent bond, –O– and –OCH 2 -;and

[0184] (ii) in

[0185] (i) X is N; and L is –CH 2 -;or

[0186] (ii) X is CH; and L is selected from -CH 2 –, –NH– and –O–; or

[0187] (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0188] wherein the wavy line indicates the point of connection with L; and

[0189] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0190] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 1 Selected from

[0191]

[0192] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0193] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 2 Selected from:

[0194]

[0195] The wavy line indicates the connection point with L.

[0196] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 3 Selected from hydrogen and

[0197] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein A is selected from:

[0198] (i) and

[0199] L is –O–; and

[0200] (ii) in

[0201] (i) X is CH; and L is selected from -CH 2 – and –O–; or

[0202] (ii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0203] wherein the wavy line indicates the point of connection with L; and

[0204] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0205] 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 Selected from

[0206]

[0207] Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0208] 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 for Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0209] 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 for Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

[0210] 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 for The wavy line indicates the connection point with L.

[0211] 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 for The wavy line indicates the connection point with L.

[0212] 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 3 For hydrogen.

[0213] 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 for

[0214] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0215] A is

[0216] X is CH; and

[0217] L is –CH 2 –

[0218] wherein the wavy line indicates the point of connection with L; and

[0219] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0220] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0221] A is and

[0222] L is –O–.

[0223] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0224] A is

[0225] X is CH; and

[0226] L is selected from –CH 2 – and –O–;

[0227] wherein the wavy line indicates the point of connection with L; and

[0228] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0229] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0230] A is

[0231] X is CH; and

[0232] L is selected from –CH 2 – and –O–;

[0233] wherein the wavy line indicates the point of connection with L; and

[0234] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0235] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0236] A is

[0237] X and L together form a group The wavy lines indicate L and R 2 The connection point,

[0238] and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0239] wherein the wavy line indicates the point of connection with L; and

[0240] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0241] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0242] A is and

[0243] X and L together form a group The wavy lines indicate L and R 2 The connection point,

[0244] and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A;

[0245] wherein the wavy line indicates the point of connection with L; and

[0246] The asterisk indicates the point of attachment to the carbonyl group of formula (I).

[0247] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (I) is selected from:

[0248] (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;

[0249] (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carbonyl)

[0250] Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0251] (4aR,8aS)-6-(3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carbonyl)

[0252] Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0253] (4aR,8aS)-6-(6-((2-oxo-2H-chromen-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)

[0254] Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0255] (4aR,8aS)-6-(4-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carbonyl)hexahydro

[0256] -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0257] (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;

[0258] (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;

[0259] (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;

[0260] (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;

[0261] (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0262] 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;

[0263] (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;

[0264] 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;

[0265] (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]diazaborinine-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0266] (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;

[0267] (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;

[0268] (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;

[0269] (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;

[0270] (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;

[0271] 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;

[0272] 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;

[0273] 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;

[0274] 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;

[0275] 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;

[0276] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone;

[0277] (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone;

[0278] (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide;

[0279] (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;

[0280] (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]

[0281] diazaborin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0282] (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-

[0283] c: 2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0284] (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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone;

[0285] (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]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone;

[0286] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone;

[0287] 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;

[0288] (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;

[0289] (S)-1-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonyl)pyrrolidine-3-carboxamide;

[0290] (7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone;

[0291] (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;

[0292] 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

[0293] [3.4] octan-6-one;

[0294] (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]diazaborinine-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone;

[0295] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone;

[0296] 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;

[0297] (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;

[0298] (S)-1-(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-7-azaspiro[3.5]nonane-7-carbonyl)pyrrolidine-3-carboxamide;

[0299] (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

[0300] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone.

[0301] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (I) is selected from:

[0302] (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;

[0303] (4aR,8aS)-6-(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)oxy)-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

[0304] 2-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -Bipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin

[0305] trien-10-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one;

[0306] 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;

[0307] (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;

[0308] (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;

[0309] (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;

[0310] 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;

[0311] 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;

[0312] 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;

[0313] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone;

[0314] (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide;

[0315] (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;

[0316] (4aR,8aS)-6-(6-((5,5-difluoro-3-phenyl-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]

[0317] diazaborin-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro

[0318] -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and

[0319] (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-

[0320] c: 2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0321] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (I) is selected from:

[0322] (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;

[0323] (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone; and

[0324] (4aR,8aS)-6-(6-((5,5-difluoro-3-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-

[0325] c: 2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0326] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, 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.

[0327] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (I) is (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((5,5-difluoro-5H-4λ4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone.

[0328] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, 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.

[0329] In a particular embodiment, the invention provides a pharmaceutically acceptable salt of a compound according to formula (I) as described herein. In another particular embodiment, the invention provides a compound according to formula (I) as described herein as a free base.

[0330] Manufacturing Process

[0331] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or concurrent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following method descriptions have the meanings provided herein.

[0332] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before applying key steps of methods well known in the art (such as "Protective Groups in Organic Chemistry" by TW Greene and PGM Wutts, 5th edition, 2014, John Wiley & Sons, NY). Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature.

[0333] If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC or chiral crystallization). Racemic compounds can be separated into corresponding enantiomers, for example, by diastereomeric salts, which are crystallized with optically pure acids, or by specific chromatography separations of enantiomers using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can also be separated to provide starting materials and intermediates enriched in diastereomers / enantiomers. Using such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce diastereomers / enantiomer-enriched compounds of the corresponding formula (I).

[0334] Those skilled in the art will recognize that in the synthesis of compounds of formula (I) (if not desired), an "orthogonal protecting group strategy" will be applied, which allows multiple protecting groups to be cleaved each time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0335] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and nature of the intermediates.

[0336] In more detail, the compound of formula (I) can be manufactured by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. Similarly, the reaction conditions affecting the reaction reported in the relevant literature are described, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is convenient to react in the presence or absence of a solvent. There are no particular restrictions on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents at least to a certain extent. The described reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the present invention. The above reaction can be conveniently performed in a temperature range of -78°C to reflux. The time required for the reaction can also vary over a wide range, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, it usually takes 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the one shown in the schemes, but, depending on the starting materials and their respective reactivity, the order of the reaction steps can be freely varied.

[0337] If starting materials or intermediates were not commercially available or their synthesis was not reported in the literature, they could be prepared by analogy to existing preparations of close analogs or as outlined in the experimental section.

[0338] The following abbreviations are used in this text:

[0339] AcOH = acetic acid, ACN = acetonitrile, Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, Cbz = benzyloxycarbonyl, Cs 2 CO 3 = 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, H 2O=water, H 2 SO 4 = 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, I 2 = iodine, IPA = 2-propanol, (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 = [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridyl-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate, ISP = ion spray positive (mode), ISN = ion spray negative (mode), K 2 CO 3 = Potassium carbonate, KHCO 3 = Potassium bicarbonate, KI = Potassium iodide, KOH = Potassium hydroxide, K 3 PO 4 = Tripotassium phosphate, LiAlH 4 or LAH = lithium aluminum hydride, LiHMDS = lithium bis(trimethylsilyl)amide, LiOH = lithium hydroxide, MgSO 4 = magnesium sulfate, min = minute, mL = milliliter, MPLC = medium pressure liquid chromatography, MS = mass spectrometry, NaH = sodium hydride, NaHCO 3 =Sodium bicarbonate, NaNO 2 =Sodium nitrite, NaOH =Sodium hydroxide, Na 2 CO 3 =Sodium carbonate, Na 2 SO 4 =Sodium sulfate, Na 2 S 2 O 3 = sodium thiosulfate, NBS = N-bromosuccinimide, nBuLi = n-butyllithium, NEt 3 = triethylamine (TEA), NH 4 Cl = ammonium chloride, NiCl 2 glyme = nickel(II) chloride ethylene glycol dimethyl ether complex, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T 3 P = propylphosphonic anhydride, P2O5 = phosphorus pentoxide, PE = petroleum ether, PG = protecting group, Pd-C = palladium on carbon, PdCl2 (dppf)-CH 2 Cl 2 =1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex, Pd 2 (dba) 3 =Tris(dibenzylideneacetone)dipalladium(0), Pd(OAc) 2 = Palladium(II) acetate, Pd(OH) 2 = Palladium hydroxide, Pd(PPh 3 ) 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, ZnCl 2 = zinc chloride, Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0340] Compounds of formula I can be prepared by procedures analogous to those of the literature and / or as for example Solution 1 Synthesized as described in.

[0341]

[0342] Solution 1

[0343] Thus, an R containing an N at the point of attachment to the rest of Formula I is reacted with an appropriate base and solvent such as, for example, sodium bicarbonate in DCM in the presence of a urea forming agent such as bis(trichloromethyl) carbonate. 1 Reaction with intermediate 1 to produce a compound of formula I ( Step a1 ). Other urea forming agents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, 1,1'-carbonyldiimidazole or 1,1'-carbonyl-di-(1,2,4-triazole). Such reactions and the use of such reagents are widely described in the literature (e.g., G. Sartori et al., Green Chemistry 2000, 2, 140). Those skilled in the art will recognize that the order of adding the reagents may be important in such reactions due to the reactivity and stability of the intermediate formed carbamoyl reagent and to avoid the formation of undesired symmetrical urea by-products. R containing C at the point of attachment to the rest of Formula I 1The moiety is introduced as a carboxylic acid, which is coupled with the intermediate amine 1 to form the corresponding amide (step a2). This type of amide coupling is accomplished by using one of the well-known coupling agents (such as DCC, HATU, EDCI, HOBt, TBTU, T3P, etc.) and a base (such as Hünig's base, triethylamine or DMAP) in a suitable solvent (such as N,N-dimethylformamide, DMA, DCM or 1-4-dioxane), preferably between 0°C and room temperature.

[0344] Fluorescent probes of general formula I can be obtained by a variety of synthetic routes, depending on their specific structure. Molecules of structure Ia, wherein L=O, or containing L=CH 2 Probes of the BODIPY scaffold of Ic, or their precursors linked via conjugated double bonds Ib, as specified in the claims, can be used, for example Solution 2 Synthesized as shown in .

[0345]

[0346] Solution 2

[0347] Intermediates 3 and 5 are commercially available or can be prepared according to literature methods. Intermediate 3 can be connected to R as described in Scheme 1 (step a) 1 According to the literature method, the functional hydroxyl group can be used to connect R 2 groups, such as reaction with PPh3 and diethyl azodicarboxylate under mitsunobu conditions or in nucleophilic substitution (S N ) reaction (step c) to produce compound Ia, wherein L = O.

[0348] N-Boc protected alcohols 3 can be converted to the corresponding ketones 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 readily converted to the corresponding vinylboronates 6 (e.g. vinylboronic acid pinacol ester) as described in the literature (step e, Kovalenko et al. 2019). Boronic acids and their derivatives are considered to be universal building blocks for transition metal-mediated cross-coupling reactions. N-boc protected vinylboronates 6 can be selectively boc-deprotected under widely used conditions, such as DCM with TFA at ambient temperature, followed by coupling to the same R as described in step a of Scheme 1. 1part. After the borate ester 7 is hydrolyzed to the corresponding boronic acid 8 by ammonium acetate buffered water / acetone mixture and sodium periodate (step f), they can be connected to 8-methylthio-BODIPY 9 and its three substituted analogs 10 and 11 by Liebeskind-Srogl reaction conditions with copper (I) salts such as Cu(I)TC, palladium catalysts such as but not limited to tris(dibenzylideneacetone)dipalladium and palladium ligands such as tri-(2-furyl)-phosphine in a suitable solvent such as THF to give compounds of formula Ib. This type of reaction has been described in the literature (Arroyo et al. 2011). Reduction of the conjugated double bonds of compound Ib to methylene-bridged BODIPY analogs Ic greatly improves the fluorescence quantum yield. As known to those skilled in the art, this property is essential for high-quality fluorescent probes. This reduction can be achieved by the widely used hydrogenation technique using elemental hydrogen or hydrogen generating reagents such as triethylsilane over a suitable catalyst such as Pd or Pd(OH) on carbon. 2 This is accomplished in the presence of a suitable solvent such as MeOH, EtOH, EtOAc or a mixture thereof at 0°C to reflux. Molecules of structure Id, wherein L = NH or NMe, can be prepared as in, for example, Scheme 3 Synthesized as described in .

[0349]

[0350] The commercially available N-Boc diamine 12 can be linked to the fluorescent moiety R via nucleophilic aromatic substitution. 2 , i.e. using 4-chloro-7-nitrobenzofuran or 8-methylthio-BODIPY in the absence or presence of an additional base such as triethylamine or potassium carbonate in a suitable solvent such as MeOH, DCM or THF at 0° C. to reflux temperature. Modification of free NH groups by methylation is a practice known to those skilled in the art and can be carried out on intermediates 12, 13 or Id by methylating agents such as iodomethane or dimethyl sulfate with additional bases such as triethylamine, Hünig's base, potassium carbonate or cesium carbonate in a suitable solvent such as DMF or DMSO.

[0351] Correspondingly, a molecule of structure Ia, wherein L=O, may be, for example Solution 4 as an alternative to that shown in Scheme 2.

[0352]

[0353] Solution 4

[0354] Commercially available intermediate 3 can be connected to R by etherification reaction according to literature methods. 2, for example, under the mitsunobu condition with PPh 3 and diethyl azodicarboxylate or in nucleophilic substitution (S N ) reaction (step c) to generate the Boc protected intermediate 14. The final molecule can be synthesized according to Scheme 1 (step a).

[0355] In one aspect, the present invention provides a method of making a compound of formula (I) as described herein, the method comprising:

[0356] (a) making a first amine 1,

[0357]

[0358] Where A and R 2 As defined herein;

[0359] and a second amine selected from:

[0360]

[0361] reacting in the presence of a base and a urea forming agent,

[0362] To form the compound of formula (I); or

[0363] (b) making amine 1,

[0364]

[0365] Where A and R 2 As defined herein;

[0366] and a carboxylic acid selected from the group consisting of:

[0367]

[0368] In the presence of a base and an amide coupling agent,

[0369] To form the compound of formula (I).

[0370] In one embodiment, the urea forming agent 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 agent is bis(trichloromethyl)carbonate.

[0371] In one embodiment, the base in step (a) is sodium bicarbonate.

[0372] In one embodiment, step (a) is carried out in a suitable solvent, preferably an aprotic solvent, more preferably DCM.

[0373] In one embodiment, the amide coupling agent is selected from the group consisting of DCC, HATU, EDCI, HOBt, TBTU and T3P.

[0374] In one embodiment, the base in step (b) is selected from Hünig's base, trimethylamine and DMAP.

[0375] In one embodiment, step (b) is carried out in a suitable solvent, preferably in a solvent selected from N,N-dimethylformamide, DMA, DCM and 1-4-dioxane.

[0376] In one embodiment, step (b) is performed at between 0°C and room temperature.

[0377] In one aspect, the present invention provides a compound of formula (I) as described herein, manufactured according to any one of the methods described herein.

[0378] MAGL inhibitory activity

[0379] Compounds are analyzed for their inhibitory activity against MAGL by measuring enzymatic activity following hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG) to arachidonic acid, which can then be analyzed by mass spectrometry. This assay is hereinafter abbreviated as the "2-AG assay".

[0380] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner catalog number 784201) with a total volume of 20 μL. Compound dilutions were prepared in 100% DMSO (VWR Chemicals 23500.297) using a 3-fold dilution step in a polypropylene plate to allow the final concentration range of the assay to be 12.5 μM to 0.8 pM. 0.25 μL of compound dilution (100% DMSO) was added to 9 μL of MAGL in 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 RT for 15 min. 10 μL of 2-arachidonoylglycerol in assay buffer was added to start the reaction. The final concentrations in this assay were 50 pM MAGL and 8 μM 2-arachidonoylglycerol. After shaking and incubation at RT for 30 min, 40 μL of ACN containing 4 μM d8-arachidonic acid was added to quench the reaction. The content of arachidonic acid was tracked using an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent 6460). In the ACN / water liquid position, a C18 SPE cartridge (G9205A) was used. The mass spectrometer was operated in negative electrospray mode, with a mass ion pair of arachidonic acid of 303.1→259.1 and a mass ion pair of d8-arachidonic acid of 311.1→267.0. The activity of the compound was calculated based on the intensity ratio of [arachidonic acid / d8-arachidonic acid].

[0381] Table 1

[0382]

[0383] In one aspect, the present invention provides a compound of formula (I) as described herein and a pharmaceutically acceptable salt or ester thereof, wherein the compound of formula (I) and a pharmaceutically acceptable salt or ester thereof has a MAGL inhibition IC of less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM. 50 , as measured in the MAGL assay described herein.

[0384] In one embodiment, the compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have an IC between 0.000001 μM and 25 μM. 50 (MAGL inhibition) values, with specific compounds having IC between 0.000005 μM and 10 μM 50 values, and other specific compounds had IC values ​​between 0.00005 μM and 5 μM. 50 Value as measured in the MAGL assay described herein.

[0385] Use of the Compounds of the Invention

[0386] The compounds of formula (I) are fluorescent imaging probes with high affinity for MAGL. Therefore, they can be used as high-resolution tools to study localization (e.g., expression levels and protein distribution in healthy and diseased states, structure, dynamics and function of MAGL in living cells). They can also be applied, for example, to flow cytometry fluorescence activated cell sorting (FACS) experiments or cell trafficking studies using confocal live cell imaging.

[0387] In one aspect, the present invention provides a compound of formula (I) as described herein for use in monoacylglycerol lipase (MAGL) occupancy studies.

[0388] In another aspect, the present invention provides a compound such as a compound of formula (I) as described herein for use in the diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammal.

[0389] In another aspect, the present invention provides a compound of formula (I) as described herein for use in generating monoacylglycerol lipase (MAGL) equilibrium and kinetic binding data.

[0390] In another aspect, the present invention provides the use of a compound of formula (I) as described herein in monoacylglycerol lipase (MAGL) occupancy studies.

[0391] In another aspect, the present invention provides for the use of a compound of formula (I) as described herein in the diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammal.

[0392] In another aspect, the invention provides the use of a compound of formula (I) as described herein for generating monoacylglycerol lipase (MAGL) equilibrium and kinetic binding data.

[0393] In another aspect, the present invention provides a method of studying the occupancy of monoacylglycerol lipase (MAGL), the method comprising contacting MAGL with a compound of formula (I) as described herein.

[0394] In another aspect, the present invention provides a method for diagnostic imaging of monoacylglycerol lipase (MAGL) in a mammal, the method comprising contacting MAGL with a compound of formula (I) as described herein.

[0395] In another aspect, the invention provides a method of generating equilibrium and kinetic binding data for monoacylglycerol lipase (MAGL), the method comprising contacting MAGL with a compound of formula (I) described herein.

[0396] Examples

[0397] The present invention will be more fully understood by reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[0398] Where the preparation examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art such as chiral chromatography (eg chiral SFC) or crystallization.

[0399] If not stated otherwise, all reaction examples and intermediates were prepared under argon atmosphere.

[0400] 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

[0401]

[0402] Step 1) tert-Butyl 6-((2-oxo-2H-chromen-7-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0403] In N 2 Triphenylphosphine and DIAD were dissolved in 5 mL of anhydrous THF at 0 ° C for 15 minutes, and then 7-hydroxy-2H-chromen-2-one (162 mg, 1.0 mmol) (CAS: 93-35-6) and tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate (107 mg, 0.5 mmol) (CAS: 1147557-97-8) were added sequentially at 0 ° C. The mixture was allowed to warm to rt and stirred for 24 h. The mixture was concentrated and purified by silica gel chromatography eluting with a gradient of 0 to 50% ethyl acetate in cyclohexane to give the title compound (110 mg, 62%) as a colorless solid. LC-MS (ESI): m / z = 358.2 [M + H] + .

[0404] 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

[0405] Tert-butyl 6-((2-oxo-2H-chromen-7-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (28.6 mg, 0.08 mmol) was subjected to boc deprotection by stirring in 5 ml TFA:DCM (1:4) at rt for 3 h. To remove traces of TFA, it was co-evaporated twice with 5 mL toluene under reduced pressure. To a mixture of (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) was added 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 ACN and added dropwise to the mixture, which was then warmed to 50 °C for 3 h. The cooled reaction mixture was diluted with 20 mL EtOAc and washed with 10 mL saturated NaHCO 3 The organic layer was washed with 10 mL of saturated NaCl solution. 4 Dry, filter and concentrate under reduced pressure to give a colorless residue which was purified by RP-HPLC (15-85% ACN: 2 0 + 0.1% TFA) to give the title compound as a colorless solid (15 mg, 43%). LC-MS (ESI): m / z = 440.3 [M+H] + .

[0406] 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

[0407]

[0408] Step 1) tert-Butyl 3-(((2-oxo-2H-chromen-7-yl)oxy)methyl)azetidine-1-carboxylate

[0409] Analogously to the procedure described in Example 11), 7-hydroxy-2H-chromen-2-one (CAS: 93-35-6) and tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS: 142253-56-3) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 332.3 [M+H] + .

[0410] 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

[0411] Analogously to the procedure described in Example 1a), (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 give the title compound. LC-MS (ESI): m / z=414.3 [M+H] + .

[0412] 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

[0413]

[0414] Step 1) tert-Butyl 3-(((2-oxo-2H-chromen-4-yl)oxy)methyl)azetidine-1-carboxylate

[0415] Analogously to the procedure described in Example 11), 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 give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 332.3 [M+H] + .

[0416] 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

[0417] Analogously to the procedure described in Example 1a, (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 give the title compound as a colorless solid. LC-MS (ESI): m / z=414.3 [M+H] + .

[0418] 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

[0419]

[0420] Step 1) tert-Butyl 6-((2-oxo-2H-chromen-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0421] Analogously to the procedure described in Example 11), 4-hydroxy-2H-chromen-2-one (CAS: 1076-38-6) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97-8) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 358.3 [M+H] + .

[0422] 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

[0423] Analogously to the procedure described in Example 1a, (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 give the title compound as a colorless solid. LC-MS (ESI): m / z=440.2 [M+H] + .

[0424] 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

[0425]

[0426] Step 1) tert-Butyl 4-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)piperazine-1-carboxylate

[0427] A solution of 4-(bromomethyl)-7-methoxy-2H-chromen-2-one (134.5 mg, 0.5 mmol) (CAS: 35231-44-8) in DMF (1.25 mL) was treated with tert-butyl piperazine-1-carboxylate (186.3 mg, 1.0 mmol) (CAS: 57260-71-6), and the reaction mixture was stirred at room temperature for 3 h, then diluted with water (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with MgSO 4 The organic layer was concentrated under reduced pressure to provide a crude product, which was used in the next step without further purification. DCM / TFA (4:1, 5 mL) was added to the crude material obtained above, and the reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO was added to the reaction mixture. 3 solution (4 mL) and extracted with EtOAc (6 mL). The organic layer was purified by MgSO 4 Drying and then concentration gave the crude product, which was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH / DCM to give 7-methoxy-4-(piperazin-1-ylmethyl)-2H-chromen-2-one 2,2,2-trifluoroacetate (121 mg, 88% over 2 steps) as a colorless solid. LC-MS (ESI): m / z=275.1 [M+H] + .

[0428] 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

[0429] 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 a similar manner to the procedure described in Example 1a) to give the title compound as a colorless amorphous solid. LC-MS (ESI): 457.2 ([M+H] + ).

[0430] 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

[0431]

[0432] 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) was added sodium bicarbonate (252 mg, 3.0 mmol) followed by 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (200 mg, 1.0 mmol) (CAS: 10199-89-0) in 1 mL ACN. The mixture was stirred at ambient temperature in the dark for 18 h before being filtered and concentrated to give a dark crude product (300 mg, 83%) which was used without further purification. LC-MS (ESI): m / z=364.2 [M+H] + .

[0433] 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

[0434] Analogously to the procedure described in Example 1a, (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 give the title compound as an orange amorphous solid. LC-MS (ESI): m / z=468.1 [M+Na] + .

[0435] Example 7 (4aR, 8aS)-6-(3-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0436]

[0437] Step a1) (4aR,8aS)-6-(3-(Hydroxymethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0438] 3-(Hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (15 mg, 0.08 mmol) (CAS: 142253-56-3) was subjected to boc deprotection by stirring in 5 ml TFA:DCM (1:4) at rt for 3 h. To remove traces of TFA, it was co-evaporated twice with 5 mL of toluene under reduced pressure. To a mixture of (4aR, 8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium 2,3-bis((4-methylbenzoyl)oxy)succinate (CAS: 2377107-31-6) (59.5 mg, 0.08 mmol), ACN (1 mL) and TEA (101 μL, 0.56 mmol) was added 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 ACN and added dropwise to the mixture, which was then warmed to 50 °C for 18 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (5-75% ACN:H 2 O + 0.1% TFA) to obtain a colorless amorphous solid (12 mg, 56%). LC-MS (ESI): m / z = 270.1 [M + H] + and 292.1[M+Na] + .

[0439] Step 1) (4aR,8aS)-6-(3-(((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-10-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0440] [2-[(Methylthio)(2H-pyrrole-2-ylidene)methyl]-1-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) (7.1 mg, 30 μmol) was dissolved in 1.5 mL of anhydrous ACN in a dry 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]oxazine-3(4H)-one were added and the mixture was stirred for 5 min before sodium carbonate (3.2 mg, 30 μmol) was added. The mixture was heated to 55 °C for 22 h. The mixture was concentrated under reduced pressure and then analyzed by RP-HPLC (15% to 85% ACN:H 2O + 0.1% TFA) to give the title compound (2.4 mg, 17%) as an orange powder that emits green fluorescence in solution. LC-MS (ESI): m / z = 440.1 [MF] +

[0441] 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

[0442]

[0443] Step a1) (4aR, 8aS)-6-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0444] Analogously to the procedure described in Example 7a1), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97-8) and (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=296.1 [M+H] + .

[0445] Step 1) (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

[0446] Analogously to the procedure described in Example 71), (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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=466.1 [MF] + .

[0447] 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

[0448]

[0449] Step a1 (4aR, 8aS)-6-(4-hydroxypiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0450] Analogously to the procedure described in Example 7a1), tert-butyl 4-hydroxypiperidine-1-carboxylate (CAS: 109384-19-2) and (4aR, 8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z = 284.1 [M+H] + .

[0451] Step 1) (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

[0452] Analogously to the procedure described in Example 71), (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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=454.2 [MF] + .

[0453] 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

[0454]

[0455] Step a1) (4aR, 8aS)-6-(7-hydroxy-2-azaspiro[3.5]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0456] Analogously to the procedure described in Example 7a1), tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1363383-18-9) and (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=324.1 [M+H] + .

[0457] Step 1) (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

[0458] Analogously to the procedure described in Example 71), (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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=494.1 [MF] + .

[0459] Example 11 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

[0460]

[0461] Step a1) 2-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

[0462] Analogously to the procedure described in Example 7a1), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97-8) and 7-oxa-2,5-diazaspiro[3.4]octan-6-one (CAS: 1780174-72-2) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=268.1 [M+H] + .

[0463] Step 1) 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

[0464] Analogously to the procedure described in Example 71), 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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=438.1 [MF] + .

[0465] Example 12 (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

[0466]

[0467] Step a1) (4aR,8aS)-6-(2-hydroxy-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0468] 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (72.8 mg, 0.2 mmol) (CAS: 240401-28-9) was deprotected at rt for 3 h using 5 ml (1: 4 TFA: DCM). In order to remove traces of TFA, it was co-evaporated twice with 5 mL of toluene under reduced pressure. Immediately, triphosgene (42 mg, 0.14 mmol) (CAS: 32315-10-9) and sodium bicarbonate (67 mg, 0.8 mmol) were added to the deprotected intermediate in 1 mL of anhydrous DCM in an ice-cold suspension in 2 mL of DCM. The mixture was allowed to warm to rt overnight. The mixture was filtered and the filtrate was added dropwise to a solution of (4aR, 8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium 2,3-bis((4-methylbenzoyl)oxy)succinate (149 mg, 0.2 mmol) (CAS: 2377107-31-6) and DIPEA (136 μL, 0.8 mmol) in 1 mL DCM at 0°C. The mixture was allowed to warm to rt and stirred for an additional 3 h. The mixture was concentrated in vacuo and purified by RP-HPLC (5% to 75% ACN:H 20 + 0.1% TFA) to give the title compound (32 mg, 49%) as a colorless amorphous solid. LC-MS (ESI): m / z = 324.1 [M+H] + .

[0469] Step 1) (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

[0470] Analogously to the procedure described in Example 71), (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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=494.2 [MF] + .

[0471] 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

[0472]

[0473] Step a1) 2-(2-hydroxy-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

[0474] Analogously to the procedure described in Example 12a1), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (CAS: 240401-28-9) and 7-oxa-2,5-diazaspiro[3.4]octan-6-one (CAS: 1780174-72-2) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=296.1 [M+H] + .

[0475] Step 1) 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

[0476] Analogously to the procedure described in Example 71), 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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=466.2 [MF] + .

[0477] 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

[0478]

[0479] Step a1) (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

[0480] Analogously to the procedure described in Example 12a1), (1R,5S,6r)-tert-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (CAS: 419572-18-2) and (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (CAS: 2377107-31-6) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=296.2 [M+H] + .

[0481] Step 1) (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

[0482] Analogously to the procedure described in Example 71), (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 give the title compound as an orange powder that fluoresces green in solution. LC-MS (ESI): m / z=466.1 [MF] + .

[0483] 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

[0484]

[0485] Step e) tert-Butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate

[0486] 2,2,6,6-tetramethylpiperidine (311 mg, 2.2 mmol) was placed in a dried vial with a magnetic stir bar, dissolved in anhydrous THF (20 mL), and cooled to -78 °C under a nitrogen atmosphere. nBuLi (2.5 M in hexane) (880 μL, 2.2 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. 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 for 5 minutes. 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 min. The reaction vial was slowly heated to rt overnight. After completion, the reaction was opened to air and filtered through a plug of silica gel, 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 (0 to 20% ethyl acetate in cyclohexane). LC-MS (ESI): m / z=336.1 [M+H] + .

[0487] 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

[0488] 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 subjected to boc deprotection by stirring in 5 ml TFA:DCM (1:4) at rt for 3 h. To remove traces of TFA, it was co-evaporated twice with 5 mL toluene under reduced pressure. To a mixture of (4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium 2,3-bis((4-methylbenzoyl)oxy)succinate (149 mg, 0.2 mmol) (CAS: 2377107-31-6), ACN (2 mL) and TEA (194 μL, 1.4 mmol) was added CDT and the mixture was stirred at room temperature for 2 h. The deprotected amine TFA salt was dissolved in 1 mL ACN and added dropwise to the mixture, which was then warmed to 50 °C for 3 h. The cooled reaction mixture was diluted with 20 mL EtOAc and washed with 10 mL saturated NaHCO 3 The organic layer was washed with 10 mL of saturated NaCl solution.4 Dry, filter and concentrate under reduced pressure to give a colorless oil which was used without further purification. LC-MS (ESI): m / z = 418.2 [M+H] + .

[0489] 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

[0490] (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 room temperature for 24 h until LC-MS indicated consumption of the starting material. Acetone was removed in vacuo and 4 mL of ACN / H 2 O 1:1 and filter the mixture. The filtrate was purified by RP-HPLC from 5% to 75% ACN:H 2 O (+0.1% TFA) and lyophilized to obtain the product as a colorless amorphous solid. LC-MS (ESI): m / z = 336.1 [M+H] + .

[0491] 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

[0492] In an oven-dried Schlenk tube equipped with a stir bar under nitrogen was charged ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptan-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). The stirred solution was sparged with nitrogen for 10 minutes, followed by the addition of CuTC (57 mg, 0.3 mmol), Pd2(dba)3 (7 mg, 7.5 μmol) and TFP (5.2 mg, 22.5 μmol) under nitrogen. The reaction mixture was immersed in a preheated oil bath at 55° C. The reaction was monitored by LC-MS and heating was stopped after 1 h when the boronic acid was consumed. The reaction mixture was carefully concentrated and 4 mL of ACN:H 2 O, filtered and analyzed by RP-HPLC (15% to 85% ACN: 2 O + 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[MF] + .

[0493] 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

[0494]

[0495] Step j)

[0496] Example 15 was converted to Example 16 by reduction of the olefin double bond. Thus, (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)-one (24 mg, 50 μmol) was dissolved in 5Ml anhydrous MeOH, purged with nitrogen, then Pd / C (10 wt%, 5.3 mg, 5 μmol) was added and cooled to 0 °C. Triethylsilane (120 μL, 750 μmol) was then added dropwise and the mixture was warmed to rt within 30 min. After the reaction was complete, 0.5 mL of water was added and the mixture was filtered and concentrated under reduced pressure. The crude material was purified by RP-HPLC (15% to 85% ACN:H 2 O + 0.1% TFA) to give the title compound (19 mg, 79%) as a red amorphous solid that emits green fluorescence in solution. MS (ESI): m / z = 484.2 [M+H] + and 464.1[MF] + .

[0497] Example 17 (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)piperidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0498]

[0499] Step e) tert-Butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate

[0500] Analogously to the procedure described in Example 15e), tert-butyl 4-oxopiperidine-1-carboxylate (CAS: 79099-07-3) was converted into the corresponding vinyl boronate, which was obtained as a colorless solid. LC-MS (ESI): m / z = 324.2 [M+H] +

[0501] 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

[0502] Analogously to the procedure described in Example 12a1), 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 give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=406.2 [M+H] +

[0503] Step f) ((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-ylidene)methyl)boronic acid

[0504] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=324.1 [M+H] +

[0505] 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)piperidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0506] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=450.1 [MF] +

[0507] 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

[0508]

[0509] Step e) tert-Butyl 7-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.5]nonane-2-carboxylate

[0510] Analogously to the procedure described in Example 15e), tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1363381-22-9) was converted to the corresponding vinyl boronate, which was obtained as a colorless solid. LC-MS (ESI): m / z=364.2 [M+H] +

[0511] 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

[0512] Analogously to the procedure described in Example 15a1), 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 give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=446.2 [M+H] +

[0513] 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

[0514] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=364.1 [M+H] +

[0515] 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

[0516] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=490.1 [MF] +

[0517] 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

[0518]

[0519] Step j)

[0520] Example 18 was converted to Example 19 by reducing the olefin double bond in analogy to the procedure described in Example 16j) to give an orange solid that fluoresces green in solution. LC-MS (ESI): m / z = 492.1 [MF] + .

[0521] 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

[0522]

[0523] Step a1) 2-(7-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

[0524] Analogously to the procedure described in Example 15a1), tert-butyl 7-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.5]nonane-2-carboxylate and 7-oxa-2,5-diazaspiro[3.4]octan-6-one (CAS: 1780174-72-2) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=418.1 [M+H] +

[0525] 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

[0526] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=336.1 [M+H] +

[0527] Step i) 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

[0528] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=461.2 [MF] +

[0529] Example 21 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

[0530]

[0531] Step j)

[0532] Example 20 was converted to Example 21 by reducing the olefin double bond in analogy to the procedure described in Example 16j) to give an orange solid that fluoresces green in solution. LC-MS (ESI): m / z = 463.2 [MF] + .

[0533] 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

[0534]

[0535] 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

[0536] Analogously to the procedure described in Example 15a1), 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 give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=390.2 [M+H] + .

[0537] 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

[0538] Analogously to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z = 308.0 [M+H] +

[0539] 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

[0540] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=461.2 [MF] +

[0541] 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)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-2,5-diazaspiro[3.4]octan-6-one

[0542]

[0543] Step j)

[0544] Example 22 was converted to Example 23 by reducing the olefin double bond in analogy to the procedure described in Example 16j) to give an orange solid that fluoresces green in solution. LC-MS (ESI): m / z = 436.1 [MF] + .

[0545] 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

[0546]

[0547] 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

[0548] 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 boc-deprotected by stirring in 5 ml TFA:DCM (1:4) at rt for 3 h. To remove traces of TFA, it was co-evaporated twice with 5 mL 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 rt for 30 minutes. The deprotected amine TFA salt dissolved in 0.5 mL DCM was added and the mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and purified by RP-HPLC (18% to 85% ACN: 2 0 + 0.1% TFA) to give the title compound as a colorless solid (19 mg, 46%). LC-MS (ESI): m / z = 411.2 [M+H] + .

[0549] 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

[0550] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z = 329.2 [M+H] +

[0551] 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

[0552] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=455.1 [MF] +

[0553] 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

[0554] Analogously to the procedure described in Example 16j), an orange solid was obtained which fluoresced green in solution. LC-MS (ESI): m / z = 457.1 [MF] + .

[0555] Example 25 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone

[0556]

[0557] Synthesis of building block 6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (3 steps):

[0558] Step 1) tert-Butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate

[0559] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97-8) (10.0 g, 46.9 mmol) in DCM (200 mL) was added TEA (7.12 g, 70.3 mmol, 9.79 mL) and MsCl (6.90 g, 60.2 mmol, 4.66 mL) at 0 ° C. The mixture was stirred at 30 ° C for 2 h. The reaction mixture was quenched by adding NaHCO3 aqueous solution (200 mL) and then extracted with DCM (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue (13.5 g crude material, 46.3 mmol, yield 98.8%), which was used in the next step without further purification. MS (ESI): m / z=236.2[M+H] +

[0560] Step 2) tert-Butyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0561] 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) were added 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) at 25 ° C. The mixture was stirred at 100 ° C for 16 h. 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] +

[0562] Step 3) 6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate

[0563] 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 directly in the next step without further purification. The title compound (14.0 g, crude) was used in the next step without further purification. MS (ESI): m / z=205.2[M+H] +

[0564] Step a1) (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-yl)methanone

[0565] Analogously to the procedure described in Example 15a1), 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] + .

[0566] Step f) ((2-(6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid

[0567] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=329.1 [M+H] +

[0568] Step i) (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl) (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methylene)-2-azaspiro[3.3]heptane-2-yl)methanone

[0569] Analogously to the procedure described in Example 15i), ((2-(6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid and [2-[(methylthio)(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (CAS: 892505-41-8) were coupled to give the title compound as a dark red solid. LC-MS (ESI): m / z=455.1 [MF] +

[0570] Step j) (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl) (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone

[0571] Analogously to the procedure described in Example 16j), an orange solid was obtained which fluoresced green in solution. LC-MS (ESI): m / z = 457.1 [MF] + .

[0572] Example 26 (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -2-Azaspiro[3.3]heptane-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone

[0573]

[0574] Step a1) (4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-yl)methanone

[0575] Analogously to the procedure described in Example 15a1), tert-butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate and 5-methyl-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine (CAS: 1035840-99-3) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=480.2 [M+H] + .

[0576] 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

[0577] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z = 398.2 [M+H] +

[0578] Step i) (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -2-Azaspiro[3.3]heptane-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone

[0579] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=524.2 [MF] +

[0580] Step j) (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -2-Azaspiro[3.3]heptane-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone

[0581] Analogously to the procedure described in Example 16j), an orange solid was obtained which fluoresced green in solution. LC-MS (ESI): m / z = 526.2 [MF] + .

[0582] Example 27 (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide

[0583]

[0584] Step a1) (S)-1-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide

[0585] Analogously to the procedure described in Example 15a1), tert-butyl 6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate and (S)-pyrrolidine-3-carboxamide hydrochloride (CAS: 1279048-81-5) were condensed to give the title compound as a colorless amorphous solid. LC-MS (ESI): m / z=376.2 [M+H] + .

[0586] Step f) (S)-((2-(3-carbamoylpyrrolidine-1-carbonyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid

[0587] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=294.1 [M+H] +

[0588] 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

[0589] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=420.2 [MF] +

[0590] Step j) (S)-1-(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrrolidine-3-carboxamide

[0591] Analogously to the procedure described in Example 16j), an orange solid was obtained which fluoresced green in solution. LC-MS (ESI): m / z = 442.1 [M+H] + .

[0592] 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]heptane-2-yl)-3-oxopropyl)oxazolidin-2-one

[0593]

[0594] Synthesis of building block: 3-[(4R)-2-oxooxazolidin-4-yl]propanoic acid (3 steps)

[0595] Step 1) (S)-4-((tert-Butyloxycarbonyl)amino)-5-hydroxypentanoic acid methyl ester

[0596] To a solution of (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 N-methylmorpholine (421 μL, 3.83 mmol) followed by ethyl chloroformate (368 μL, 3.83 mmol) at -10°C and the reaction mixture was stirred at this temperature for 10 minutes. NaBH 4(434 mg, 11.5 mmol) did not cause a temperature rise. MeOH (35 mL) was added dropwise between -1°C and 17°C over 30 min. Stirring was continued in an ice bath for 1 h. 1 M KHSO 4 Aqueous solution (40 mL) was added to the reaction mixture, and the organic solvent was then evaporated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M KHSO 4 Aqueous solution and saturated NaHCO 3 Wash with aqueous solution and MgSO 4 Dry, filter, treat with silica gel and evaporate. 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 afford the title compound as a colorless oil (0.70 g, 66%). MS (ESI): m / z=192.1 [M+H] + .

[0597] Step 2) Methyl (R)-3-(2-oxooxazolidin-4-yl)propanoate

[0598] To a solution of (S)-methyl 4-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate (690 mg, 2.79 mmol, 1.0 equiv) in THF (8.8 mL) was added thionyl chloride (611 μL, 8.37 mmol, 3.0 equiv) dropwise and the solution was stirred at RT for 3 h. 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 give the title compound (404 mg, 79%) as a colorless oil. MS (ESI): m / z=174.1 [M+H] + .

[0599] Step 3) (R)-3-(2-oxooxazolidin-4-yl)propanoic acid

[0600] To a solution of (S)-methyl 3-(2-oxooxazolidin-4-yl)propanoate (400 mg, 2.31 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (107 mg, 2.54 mmol, 1.1 equiv) and the reaction mixture was stirred at RT for 2 h. 1,4-dioxane was evaporated and aqueous HCl (2.54 mL, 2.54 mmol, 1.1 equiv) was added dropwise to the solution. The aqueous layer was extracted five times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated to give the title compound (330 mg, 86%) as a colorless solid. MS (ESI): m / z=160.1 [M+H]+ .

[0601] Step a2) (R)-4-(3-oxo-3-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)-2-azaspiro[3.3]heptane-2-yl)propyl)oxazolidin-2-one

[0602] Analogously to the procedure described in Example 25a2), 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] + .

[0603] Step f) (R)-((2-(3-(2-oxooxazolidin-4-yl)propanoyl)-2-azaspiro[3.3]heptane-6-ylidene)methyl)boronic acid

[0604] In analogy to the procedure described in Example 15f), the vinyl boronate was hydrolyzed to the corresponding boronic acid to give the title compound as a colorless solid. LC-MS (ESI): m / z=295.1 [M+H] +

[0605] 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]heptane-2-yl)-3-oxopropyl)oxazolidin-2-one

[0606] Analogously to the procedure described in Example 15i), ((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 give the title compound as a dark red solid. LC-MS (ESI): m / z=421.2 [MF] +

[0607] 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]heptane-2-yl)-3-oxopropyl)oxazolidin-2-one

[0608] Analogously to the procedure described in Example 16j), an orange solid was obtained which fluoresced green in solution. LC-MS (ESI): m / z = 423.2 [MF] + .

[0609] 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

[0610]

[0611] Step g) 5,5-difluoro-10-(methylthio)-3-phenyl-5H-514,614-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine

[0612] [2-[(methylthio)(2H-pyrrole-2-ylidene)methyl]-1H-pyrrole](difluoroborane) (71.4 mg, 0.3 mmol) (CAS: 892505-41-8), aniline (55.9 mg, 0.6 mmol) (CAS: 62-53-3) and anhydrous ACN were charged into a drying flask equipped with a stirring bar. The mixture was stirred until the solid dissolved. Tert-butyl nitrite (107 μL, 0.9 mmol) (CAS: 540-80-7) was then added with a syringe. Thereafter, fine bubbling was observed. The reaction was heated to 40 °C for 18 h. Excess solvent was removed under vacuum and the crude material was dissolved in ACN:H 2 O (4:1) and analyzed by RP-HPLC (25% to 95% ACN:H 2 0 + 0.1% TFA) to give the title compound as a dark red solid (18.6 mg, 30%). LC-MS (ESI): m / z = 295.0 [MF] + .

[0613] 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

[0614] Analogously to the procedure described in Example 15i), ((2-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)-2-azaspiro[3.3]heptan-6-ylidene)methyl)boronic acid and 5,5-difluoro-10-(methylthio)-3-phenyl-5H-514,614-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine were coupled to give the title compound as a dark red solid. LC-MS (ESI): m / z=538.2 [MF] + .

[0615] Step j) (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

[0616] Analogously to the procedure described in Example 16j), a red solid was obtained which fluoresced orange in solution. LC-MS (ESI): m / z = 540.2 [MF] + .

[0617] Example 30 (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

[0618]

[0619] 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

[0620] [2-[(methylthio)(2H-pyrrole-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) were charged into a microwave vial with a stir bar. The vial was sealed and heated to 150 °C for 3 h by microwave irradiation. Excess 1H-pyrrole was evaporated under reduced pressure and the residue was purified by RP-HPLC (25% to 95% ACN:H 2 0 + 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] + .

[0621] 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

[0622] Analogously to the procedure described in Example 15i), ((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 coupling to give the title compound as a dark red solid. LC-MS (ESI): m / z = 527.2 [MF] + .

[0623] 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

[0624] Analogously to the procedure described in Example 16j), a purple solid was obtained which fluoresces red in solution. LC-MS (ESI): m / z = 529.3 [MF] + .

[0625] Example 31 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone

[0626]

[0627] Step i) (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-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]diazaborinine-10-yl)methylene)-2-azaspiro[3.3]heptane-2-yl)methanone

[0628] Analogously to the procedure described in Example 15i), ((2-(6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-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 coupling to give the title compound as a dark purple solid. LC-MS (ESI): m / z = 595.2 [M+H] + .

[0629] Step j) (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone

[0630] The title compound was synthesized from the above intermediate in analogy to the procedure described in Example 16j). The title compound was obtained as a purple solid that fluoresces red in solution. LC-MS (ESI): m / z=597.2 [M+H] + .

[0631] Similar to the above examples, the following examples were prepared:

[0632] 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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone

[0633]

[0634] 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]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone

[0635]

[0636] Example 34 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)methanone

[0637]

[0638] Example 35 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

[0639]

[0640] 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

[0641]

[0642] 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

[0643]

[0644] Example 38 (7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -2-Azaspiro[3.5]nonan-2-yl)(4-(5-methyloxazolo[4,5-b]pyridin-2-yl)piperazin-1-yl)methanone

[0645]

[0646] 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

[0647]

[0648] 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

[0649]

[0650] 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]diazaborinine-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone

[0651]

[0652] Example 42 (6-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methanone

[0653]

[0654] 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

[0655]

[0656] 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

[0657]

[0658] 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

[0659]

[0660] Example 46 (2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -2-pyrrolo[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

[0661]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from: wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I); R 2 Selected from: The wavy line indicates the connection point with L; Each R 3 are independently selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, phenyl, n is 1, 2 or 3; Ar is C6-C 10 - aryl or 5- to 14-membered heteroaryl; A is selected from: (i) and L is selected from the group consisting of a covalent bond, –CH2–, –O–, –OCH2–, –CH2O–, and –CH2OCH2–; and (ii) in (i) X is N; and L is selected from a covalent bond, -CH2- and -OCH2-; or (ii) X is CH; and L is selected from a covalent bond, -CH2-, -NH-, -NMe-, -O-, -OCH2-, -CH2O-, and -CH2OCH2-; or (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, wherein R 1 Selected from Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein R 1 Selected from Therein the wavy line indicates the point of attachment to the carbonyl group of formula (I).

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: R 2 Selected from: The wavy line indicates the connection point with L; R 3 Selected from hydrogen, phenyl and and n is 1.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 6, wherein: R 2 Selected from: The wavy line indicates the connection point with L; R 3 Selected from hydrogen and and n is 1.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 7, wherein: R 2 for: The wavy line indicates the connection point with L; R 3 is hydrogen; and n is 1.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: A is selected from: (i) and L is selected from the group consisting of a covalent bond, -O- and -OCH2-; and (ii) in (i) X is N; and L is -CH2-; or (ii) X is CH; and L is selected from -CH2-, -NH- and -O-; or (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, wherein: A is selected from: (i) and L is –O–; as well as (ii) in (i) X is CH; and L is selected from -CH2- and -O-; or (ii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein: A is X is CH; and L is –CH2–; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Selected from wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I); R 2 Selected from: The wavy line indicates the connection point with L; R 3 Selected from hydrogen, phenyl and n is 1; A is selected from: (i) and L is selected from the group consisting of a covalent bond, -O- and -OCH2-; and (ii) in (i) X is N; and L is -CH2-; or (ii) X is CH; and L is selected from -CH2-, -NH- and -O-; or (iii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: R 1 Selected from wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I); R 2 Selected from: The wavy line indicates the connection point with L; R 3 Selected from hydrogen and n is 1; A is selected from: (i) and L is –O–; as well as (ii) in (i) X is CH; and L is selected from -CH2- and -O-; or (ii) X and L together form a group The wavy lines indicate L and R 2 and two asterisks indicate the points of attachment of X to the corresponding adjacent atoms within ring A; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein: R 1 Selected from wherein the wavy line indicates the point of attachment to the carbonyl group of formula (I); R 2 for: The wavy line indicates the connection point with L; R 3 is hydrogen; n is 1; A is X is CH; and L is –CH2–; wherein the wavy line indicates the point of connection with L; and The asterisk indicates the point of attachment to the carbonyl group of formula (I).

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is selected from: (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]diazaborinine-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 (4aR,8aS)-6-(6-((5,5-difluoro-5H-4λ-bipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 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]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]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone; (6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-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]diazaborinine-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-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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-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]diazaborinine-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]heptane-2-yl)(7-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-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]diazaborinine-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]diazaborinine-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]diazaborinin-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]diazaborinine-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]heptane-2-yl)(2-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-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]diazaborinine-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]heptane-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]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)methanone.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein the compound of formula (I) is selected from: (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]diazaborinine-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 -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]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-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]diazaborinine-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-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.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 16, wherein the compound of formula (I) is selected from: (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]heptane-2-yl)(6-((5,5-difluoro-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine-10-yl)methyl)-2-azaspiro[3.3]heptane-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.

18. A method for producing a compound of formula (I) according to any one of claims 1 to 17, the method comprising: (a) making a first amine 1, Where A and R 2 As defined in any one of claims 1 to 17; and a second amine selected from: reacting in the presence of a base and a urea forming agent, To form the compound of formula (I); or (b) making amine 1, Where A and R 2 As defined in any one of claims 1 to 17; and a carboxylic acid selected from the group consisting of: In the presence of a base and an amide coupling reagent, To form the compound of formula (I).

19. A compound of formula (I) according to any one of claims 1 to 17, when manufactured 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 monoacylglycerol lipase (MAGL) occupancy studies.

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

22. A compound of formula (I) according to any one of claims 1 to 17 for use 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 monoacylglycerol lipase (MAGL) occupancy studies.

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

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

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

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

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

29. The invention as hereinbefore described.

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