Novel compounds and their use in treating bacterial infections - Patents.com

Abstract

The present invention relates to a compound represented by the general formula (I) TIFF2024534515000435.tif44108 (in the formula, R 1 , R 2 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , L and W are as described herein. The present invention provides novel compounds having the formula:

Description

[Technical Field]

[0001] The present invention provides compounds exhibiting broad spectrum antibacterial activity, their preparation, pharmaceutical compositions containing them and their use as medicaments for the treatment of microbial infections, in particular diseases and infections caused by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, more particularly gram-negative bacteria, even more particularly Escherichia coli.

[0002] The present invention relates to a compound of formula (I) [ka] (In the formula, A 1 is -N-; A 2 teeth, i)-N-, and ii) -CH- Selected from; A 3 is -CH-; A 4 teeth, i) -O-, and ii) -S- Selected from; A 5 is -CH-; A 6 is -O-; W is a ring system: [ka] Selected from; R 2 is H; R 3 and R 4 teeth, i) H, ii) C1~6 - alkyl, iii) halogens, iv) OH, and v) Cyano are independently selected from; L is -L1-NR 10 -L2- and; L1 is (CH2) x (wherein x represents an integer of 1 to 6); L2 is (CH2) y (wherein y represents an integer of 1 to 5); R 1 is H and R 10 teeth, i) H, and ii) C 1~6 -Alkyl Selected from; Or, R 1 , R 10 and L2 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single N heteroatom, or Or, R 1 and L2 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R 11 teeth, i) NH2, ii) C 1~6 -alkyl, iii) heterocycloalkyl, iv) heterocycloalkylalkyl, v) substituted cycloalkyl, vi) substituted heterocycloalkyl, vii) substituted heterocycloalkylalkyl, viii) aminoalkyl, ix) alkylaminoalkyl, x) (dialkylamino)alkyl, xi) alkylaminoacetamides, xii) aminohydroxyalkyl, xiii) hydroxyalkyl, xiv) hydroxy(alkylamino)alkyl, xv)-(CH2) n NR a R b , and xvi) -CH2-O-(CH2) n NR a R b , xvii) (dialkylamino)hydroxyalkyl, and xviii)H is selected from n is an integer of either 1 or 2, The substituted cycloalkyl, substituted heterocycloalkyl, and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, OH, oxo, and dioxo; R a teeth, [ka] Selected from; R b is H or C 1~6 - selected from alkyl; R 12 teeth, i) H, ii) C 1~6- Alkyl, iii) aminoalkyl, iv) (alkylamino)acetamidoalkyl, and v) -(CH2)2NR c R d , vi) cycloalkylalkyl substituted by amino; vii) cyclopropylaminoalkyl, viii) heterocycloalkyl, ix) alkylaminoalkyl, and x) (dialkylamino)alkyl is selected from R c teeth, [ka] Selected from; R d is H or C 1~6 - selected from alkyl; Or, R 11 and R 12 together form a 6-membered heterocycle containing one or two N heteroatoms; R 13 teeth, i) H, and ii) aminoalkyl Selected from; R 14 is aminoalkyl; R 15 teeth, i) NH2, and ii) (Alkylamino) alkylamino Selected from; R 20 is alkylaminoalkyl; R 21 is aminoalkyl, alkylaminoalkyl, or (dialkylamino)alkyl; R 22 is an aminoalkyl) or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Bacterial infections pose a continuing medical problem because antibiotics eventually develop resistance in the bacteria against which they are used. Bacterial resistance to almost all current antibiotics is increasing. Many forms of antibiotic resistance can spread with alarming speed, even across national borders. Therefore, new classes of antibacterial compounds are urgently needed. Summary of the Invention

[0004] The object of the present invention is the novel compounds of formula (I), their preparation, medicaments based on the compounds according to the invention and their preparation, as well as the use of the compounds of formula (I) for treating or preventing bacterial infections, in particular for treating diseases and infections caused by Escherichia coli.

[0005] "C 1~6 The term "-alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical of 1 to 6 carbon atoms. 1~6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. 1~6 -Alkyl groups are methyl, ethyl and n-butyl. A more particular example is methyl.

[0006] "C 1~6 The term "-alkoxy" refers to a compound in which R' is C 1~6 represents a group of the formula -O-R', which is an alkyl group. 1~6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particular example is methoxy.

[0007] "C 3~8 The term "cycloalkyl" or "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic refers to a ring system consisting of two saturated carbocyclic rings having one or two carbon atoms in common. Monocyclic C 3~8 Examples of -cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Particular monocyclic cycloalkyl groups are C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 - 3~6 A more particular monocyclic cycloalkyl group is cyclobutyl.

[0008] The term "cyano" refers to the group --CN.

[0009] The term "halogen" refers to fluoro, chloro, bromo, or iodo. Particular halogens are chloro and fluoro. A more particular example is fluoro.

[0010] The term "heterocycloalkyl" or "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon optionally substituted with oxo. Bicyclic means consisting of two rings having 1 or 2 ring atoms in common. Heterocycloalkyl is preferably a monovalent saturated or partially unsaturated monocyclic ring system of 4 to 6 ring atoms containing 1 or 2 ring heteroatoms selected from N, O, and S (4- to 6-membered heterocycloalkyl). Examples of monocyclic saturated heterocyclyls are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-4-yl, 3-oxo-morpholin-6-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, or dihydropyranyl. Heterocyclyl is preferably azetidinyl, piperidyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, azabicyclo[2.1.1]hexan-1-yl, or thiazinanyl.

[0011] The term "heterocycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a heterocycloalkyl group. Examples are tetrahydrofuranylalkyl, pyrrolidinylalkyl, piperidylalkyl, morpholinylalkyl, and thiazinylalkyl. Specific examples are azetidinylmethyl, morpholinylmethyl, and thiazinylmethyl.

[0012] The term "hydroxy" refers to the group --OH.

[0013] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxymethylethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl. Specific examples are hydroxymethylpropyl and hydroxymethylethyl.

[0014] The term "amino" refers to the group --NH.sub.2.

[0015] The term "alkylamino" refers to an amino group in which one hydrogen atom of the amino group has been replaced by an alkyl group. An example is methylamino.

[0016] The term "dialkylamino" refers to an amino group in which two hydrogen atoms of the amino group have been replaced by two alkyl groups. An example is dimethylamino.

[0017] The term "aminoalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an amino group. Examples of aminoalkyl include aminomethyl, aminoethyl, and aminopropyl.

[0018] The term "alkylaminoalkyl" refers to an aminoalkyl group in which one hydrogen atom of the amino group is replaced by an alkyl group. Examples of alkylaminoalkyl groups include methylaminomethyl and methylaminoethyl.

[0019] The term "(dialkylamino)alkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a dialkylamino group. Examples of (dialkylamino)alkyl include (dimethylamino)methyl and (dimethylamino)ethyl.

[0020] The term "(alkylamino)alkylamino" refers to an alkylamino group in which one hydrogen atom of the alkylamino group has been replaced by an alkylamino group. An example is (methylamino)ethylamino.

[0021] The term "hydroxy(alkylamino)alkyl" refers to an "alkylaminoalkyl" group in which one hydrogen atom of the alkylaminoalkyl group is replaced by a hydroxyl group. Examples of hydroxy(alkylamino)alkyl include hydroxy(methylamino)ethyl and hydroxy(methylamino)propyl. Specifically, there are 2-hydroxy-1-(methylamino)ethyl and 3-hydroxy-2-(methylamino)propyl.

[0022] The term "aminohydroxyalkyl" refers to a hydroxyalkyl group in which one hydrogen atom of the hydroxyalkyl group has been replaced by an amino group. Examples of aminohydroxyalkyl groups include aminohydroxypropyl (specifically, 1-amino-2-hydroxypropyl), and aminohydroxyethyl.

[0023] The term "(dialkylamino)hydroxyalkyl" refers to a hydroxyalkyl group in which one hydrogen atom of the hydroxyalkyl group has been replaced by a dialkylamino group. An example of a (dialkylamino)hydroxyalkyl is (dimethylamino)-3-hydroxypropyl.

[0024] The term "acetamido" refers to a group of formula -NH-C(=O)CH3.

[0025] The term "alkylaminoacetamide" refers to an acetamide group in which one hydrogen atom of the methyl moiety of the acetamide group has been replaced by an alkylamino group. Examples of aminoacetamides include methylaminoacetamide, specifically (-NH-C(=O)-CHNHCH).

[0026] The terms "alkylaminoacetamidoalkyl" or "(alkylamino)acetamidoalkyl" refer to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an alkylaminoacetamido group. An example of an "alkylaminoacetamidoalkyl" is 2-[[2-(methylamino)acetyl]amino]ethyl, specifically (-CHCHNHC(=O)CHNHCH).

[0027] The term "oxo" refers to a divalent oxygen atom =O.

[0028] The term "4- to 6-membered ring" refers to a monocyclic saturated or unsaturated ring system of 4 to 6 ring atoms. A "4- to 6-membered ring" can contain 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon optionally substituted with oxo. Examples of 4- to 6-membered rings are cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, and piperidine. A specific 4- to 6-membered ring is cyclohexane.

[0029] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, lactic acid, and the like. In addition, these salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, and the like. 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, etc. Specific pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride, methanesulfonate, lactate, and citrate salts.

[0030] The compound of the present invention may absorb moisture or water and form a hydrate when left in the air. Such hydrates are also included in the salt of the present invention.

[0031] Furthermore, the compounds of the present invention may absorb certain other solvents to form solvates, and such solvates are also encompassed in the present invention as salts of the compounds of formula (I).

[0032] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can be selectively carried out at an otherwise unprotected reactive site, in the sense conventionally associated with synthetic chemistry. The protecting group can be removed at an appropriate time. Exemplary protecting groups are an amino-protecting group, a carboxy-protecting group, or a hydroxy-protecting group. Specific protecting groups are the tert-butoxycarbonyl (Boc) group, the benzyloxycarbonyl (Cbz) group, the fluorenylmethoxycarbonyl (Fmoc) group, and the benzyl (Bn) group. Even more specific protecting groups are the tert-butoxycarbonyl (Boc) group and the fluorenylmethoxycarbonyl (Fmoc) group. An even more specific protecting group is the tert-butoxycarbonyl (Boc) group.

[0033] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0034] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0035] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0036] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0037] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0038] Also, certain embodiments of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, particularly compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

[0039] One embodiment of the present invention is 4 is —O—.

[0040] One embodiment of the present invention is 2 is -N-.

[0041] One embodiment of the present invention is 3 and R 4 but, i) H, and ii) Halogen The present invention provides a compound according to formula (I) described herein, wherein the compound is independently selected from:

[0042] An embodiment of the present invention provides a compound according to formula (I) described herein, wherein W is selected from ring systems A, B, C, D, G, H and I.

[0043] A specific embodiment of the present invention provides a compound according to formula (I) described herein, wherein W is selected from ring systems A, B, C, D and I.

[0044] One embodiment of the present invention is 11 but, i) NH2, ii) C 1~6 -alkyl, iii) 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iv) a 6-membered heterocycloalkylalkyl containing one N atom and one O atom; v) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; vi) a 6-membered substituted heterocycloalkylalkyl containing one N atom and one S atom; vii) aminoalkyl, viii) alkylaminoalkyl, ix) (dialkylamino)alkyl, x) alkylaminoacetamides, xi) aminohydroxyalkyl, xii) hydroxyalkyl, and xiii) hydroxy(alkylamino)alkyl, xiv) H, xv) (dialkylamino)hydroxyalkyl, and xvi)-(CH2) n NR a R b is selected from n is an integer of either 1 or 2, R a but, [ka] Selected from; R b is H; Provided herein are compounds according to formula (I) wherein the substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, OH, oxo, and dioxo.

[0045] A specific embodiment of the present invention is 11 but, i) a 4- to 6-membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, vi) alkylaminoacetamides, vii) aminohydroxyalkyl, and viii) Hydroxy(alkylamino)alkyl is selected from Provided herein are compounds according to formula (I) wherein the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH.

[0046] The most specific embodiment of the present invention is 11 but, i) a 5-membered substituted heterocycloalkyl containing one N atom; ii) a 4-membered heterocycloalkyl containing one N atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, and vi) aminohydroxyalkyl is selected from Compounds according to formula (I) described herein are provided wherein the substituted heterocycloalkyl is substituted with OH.

[0047] One embodiment of the present invention is 12 but, i) H, ii) C 1~6- Alkyl, iii) aminoalkyl, iv) 4-membered heterocycloalkyl containing one N atom; v) alkylaminoalkyl, and vi) (dialkylamino)alkyl The present invention provides a compound according to formula (I) described herein, selected from:

[0048] A specific embodiment of the present invention is 12 is selected from H, alkylaminoalkyl, aminoalkyl, or a 4-membered heterocycloalkyl ring containing one N atom.

[0049] A preferred embodiment of the present invention is 12 is H.

[0050] One embodiment of the present invention is 11and R 12 taken together form a 6-membered heterocycle containing two N heteroatoms.

[0051] One embodiment of the present invention is 1 and R 10 is H or or R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] or forming a piperidine ring such as or R 1 and L2 and the atoms to which they are attached are as follows: [ka] Compounds according to formula (I) described herein are provided which form a four-membered cycloalkyl ring such as:

[0052] One embodiment of the present invention is 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] The present invention provides compounds according to formula (I) described herein which form a piperidine ring such as:

[0053] An embodiment of the present invention comprises: A 1 is -N-; A 2 but, i)-N-, and ii) -CH- Selected from; A 3 is -CH-; A 4 is -O-; A 5 is -CH-; A6 is -O-; W is a ring system: [ka] Selected from; R 2 is H; R 3 and R 4 are independently selected from H and halogen; L is -L1-NR 10 -L2- and; L1 is (CH2) x (wherein x represents an integer of 1 to 6); L2 is (CH2) y (wherein y represents an integer of 1 to 5); R 1 is H and R 10 but, i) H, and ii) C 1~6 -Alkyl Selected from; Or, R 1 , R 10 and L2 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single N heteroatom, or Or, R 1 and L2 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R 11 but, i) NH2, ii) C 1~6 -alkyl, iii) 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iv) a 6-membered heterocycloalkylalkyl containing one N atom and one O atom; v) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; vi) a 6-membered substituted heterocycloalkylalkyl containing one N atom and one S atom; vii) aminoalkyl, viii) alkylaminoalkyl, ix) (dialkylamino)alkyl, x) alkylaminoacetamides, xi) aminohydroxyalkyl, xii) hydroxyalkyl, and xiii) Hydroxy(alkylamino)alkyl xiv) H, xv) (dialkylamino)hydroxyalkyl, and xvi)-(CH2) n NR a R b is selected from n is an integer of either 1 or 2, R a but, [ka] Selected from; R b is H; substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, OH, oxo, and dioxo; R 12 but, i) H, ii) C 1~6- Alkyl, iii) aminoalkyl, iv) (alkylamino)acetamidoalkyl, v) -(CH2)2NR c R d , vi) cycloalkylalkyl substituted by amino; vii) cyclopropylaminoalkyl, viii) heterocycloalkyl, ix) alkylaminoalkyl, and x) (dialkylamino)alkyl Selected from; Rc but, [ka] Selected from; R d But H or C 1~6 - selected from alkyl; Or, R 11 and R 12 together form a 6-membered heterocycle containing one or two N heteroatoms; R 13 is selected from H and aminoalkyl; R 14 is aminoalkyl; R 15 is selected from NH and (alkylamino)alkylamino; R 20 is alkylaminoalkyl; R 21 is aminoalkyl or alkylaminoalkyl; R 22 is aminoalkyl; or a pharmaceutically acceptable salt thereof.

[0054] A preferred embodiment of the present invention comprises: A 1 is -N-; A 2 but, i)-N-, and ii) -CH- Selected from; A 3 is -CH-; A 4 is -O-; A 5 is -CH-; A 6 is -O-; W is selected from the ring systems A, B, C, D, G, H and I; R 2 is H; R 3 and R 4 but, i) H, and ii) Halogen are independently selected from; L is -L1-NR 10 -L2- and; L1 is (CH2) x where x is 1; R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] and forming a piperidine ring such as R 11 but, i) a 4- to 6-membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, vi) alkylaminoacetamides, vii) aminohydroxyalkyl, and viii) Hydroxy(alkylamino)alkyl is selected from the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH; R 12 but, i) H, ii) C 1~6- Alkyl, iii) aminoalkyl, iv) 4-membered heterocycloalkyl containing one N atom; v) aminoalkyl, vi) alkylaminoalkyl, and vii) (dialkylamino)alkyl is selected from R 20 is alkylaminoalkyl; R 21 is alkylaminoalkyl or aminoalkyl; or a pharmaceutically acceptable salt thereof.

[0055] The most preferred embodiment of the present invention comprises: A 1 is -N-; A 2 is -N-; A 3 is -CH-; A 4 is -O-; A 5 is -CH-; A 6 is -O-; W is selected from ring systems A, B, C, D and I; R 2 is H; R 3 and R 4 but, i) H, and ii) Fluoro are independently selected from; L is -L1-NR 10 -L2- and; L1 is (CH2) x where x is 1; R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] and forming a piperidine ring such as R 11 but, i) 5-membered substituted heterocycloalkyl containing one N atom substituted with OH; ii) a 4-membered heterocycloalkyl containing one N atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, and vi) aminohydroxyalkyl is selected from R 12 is selected from H, alkylaminoalkyl, aminoalkyl, or a 4-membered heterocycloalkyl ring containing 1 N atom, or a pharmaceutically acceptable salt thereof.

[0056] An embodiment of the present invention comprises: A 1 is -N-; A 2 but, i)-N-, and ii) -CH- Selected from; A 3 is -CH-; A 4 but, i) -O-, and ii) -S- Selected from; A 5 is -CH-; A 6 is -O-; W is a ring system: [ka] Selected from; R 2 is H; R 3 and R 4 but, i) H, ii) C 1~6 -alkyl, iii) halogens, iv) OH, and v) Cyano are independently selected from; L is -L1-NR 10 -L2- and; L1 is (CH2) x (wherein x represents an integer of 1 to 6); L2 is (CH2) y (wherein y represents an integer of 1 to 5); R 1 is H and R 10 but, i) H, and ii) C 1~6 -Alkyl Selected from; Or, R 1 , R 10 and L2 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single N heteroatom, or Or, R 1 and L2 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R 11 but, i) NH2, ii) C 1~6 -alkyl, iii) heterocycloalkyl, iv) heterocycloalkylalkyl, v) substituted cycloalkyl, vi) substituted heterocycloalkyl, vii) substituted heterocycloalkylalkyl, viii) aminoalkyl, ix) alkylaminoalkyl, x) (dialkylamino)alkyl, xi) alkylaminoacetamides, xii) aminohydroxyalkyl, xiii) hydroxyalkyl, xiv) Hydroxy(alkylamino)alkyl xv)-(CH2) n NR a R b , xvi) -CH2-O-(CH2) n NR a R b is selected from n is an integer of either 1 or 2, The substituted cycloalkyl, substituted heterocycloalkyl, and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, OH, oxo, and dioxo; R a but, [ka] is selected from R b But H or C 1~6 - selected from alkyl; R 12 but, i) H, ii) C 1~6- alkyl, and iii) aminoalkyl, iv) (alkylamino)acetamidoalkyl, and v) -(CH2)2NR c R d is selected from R c but, [ka] is selected from R d But H or C 1~6 - selected from alkyl; Or, R 11 and R 12 together form a 6-membered heterocycle containing one or two N heteroatoms; R 13 but, i) H, and ii) aminoalkyl Selected from; R 14 is aminoalkyl; R 15 but, i) NH2, and ii) (Alkylamino) alkylamino or a pharmaceutically acceptable salt thereof.

[0057] Another embodiment of the present invention is A 1 is -N-; A 2 but, i)-N-, and ii) -CH- Selected from; A 3 is -CH-; A 4 is -O-; A 5 is -CH-; A 6 is -O-; W is a ring system [ka] is selected from R 2 is H; R 3 and R 4 but, i) H, and ii) Halogen are independently selected from; L is -L1-NR 10 -L2- and; L1 is (CH2) x where x is 1; R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] and forming a piperidine ring such as R 11 but, i) 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, vi) alkylaminoacetamides, vii) aminohydroxyalkyl, viii) Hydroxy(alkylamino)alkyl is selected from the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH; R 12 but, i) H, ii) C 1~6- alkyl, and iii) aminoalkyl or a pharmaceutically acceptable salt thereof.

[0058] Furthermore, a specific embodiment of the present invention is A 1 is -N-; A 2 is -N-; A 3 is -CH-; A 4 is -O-; A 5 is -CH-; A 6 is -O-; W is a ring system [ka] Selected from; R 2 is H; R 3 and R 4 but, i) H, and ii) Fluoro are independently selected from; L is -L1-NR10 -L2- and; L1 is (CH2) x where x is 1; R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] and forming a piperidine ring such as R 11 but, i) a 5-membered substituted heterocycloalkyl containing one N atom; ii) aminoalkyl, iii) alkylaminoalkyl, and iv) (dialkylamino) alkyl is selected from the substituted heterocycloalkyl is substituted with OH; R 12 but, i) H, and ii) Aminoethyl or a pharmaceutically acceptable salt thereof.

[0059] One embodiment of the present invention is 4 is —O—.

[0060] One embodiment of the present invention is 2 is -N-.

[0061] One embodiment of the present invention is 3 and R 4 but, i) H, and ii) Halogen The present invention provides a compound according to formula (I) described herein, wherein the compound is independently selected from:

[0062] One embodiment of the present invention is where W is a ring system [ka] The present invention provides a compound according to formula (I) described herein, selected from:

[0063] One embodiment of the present invention is 11 but, i) NH2, ii) C 1~6 -alkyl, iii) 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iv) a 6-membered heterocycloalkylalkyl containing one N atom and one O atom; v) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; vi) a 6-membered substituted heterocycloalkylalkyl containing one N atom and one S atom; vii) aminoalkyl, viii) alkylaminoalkyl, ix) (dialkylamino) alkyl x) alkylaminoacetamides, xi) aminohydroxyalkyl, xii) hydroxyalkyl, and xiii) Hydroxy(alkylamino)alkyl is selected from Provided herein are compounds according to formula (I) wherein the substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, OH, oxo, and dioxo.

[0064] A specific embodiment of the present invention is 11 but, i) 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5- to 6-membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl vi) alkylaminoacetamides, vii) aminohydroxyalkyl, and xiii) Hydroxy(alkylamino)alkyl is selected from Provided herein are compounds according to formula (I) wherein the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH.

[0065] The most specific embodiment of the present invention is 11 but, i) a 5-membered substituted heterocycloalkyl containing one N atom; ii) aminoalkyl, iii) alkylaminoalkyl, iv) (dialkylamino) alkyl is selected from Compounds according to formula (I) described herein are provided wherein the substituted heterocycloalkyl is substituted with OH.

[0066] One embodiment of the present invention is 12 but, i) H, ii) C 1~6- alkyl, and iii) aminoalkyl The present invention provides a compound according to formula (I) described herein, selected from:

[0067] A specific embodiment of the present invention is 12 but, i) H, and ii) Aminoethyl The present invention provides a compound according to formula (I) described herein, selected from:

[0068] One embodiment of the present invention is 11 and R 12 taken together form a 6-membered heterocycle containing two N heteroatoms.

[0069] One embodiment of the present invention is 1 and R 10 is H or or R 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] or forming a piperidine ring such as or R 1 and L2 and the atoms to which they are attached are as follows: [ka] Compounds according to formula (I) described herein are provided which form a four-membered cycloalkyl ring such as:

[0070] A specific embodiment of the present invention is 1 , R 10 and L2 and the atoms to which they are attached are as follows: [ka] The present invention provides compounds according to formula (I) described herein which form a piperidine ring such as:

[0071] Methods for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0072] The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings previously indicated herein, unless otherwise indicated.

[0073] More specifically, the compound of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction order is not limited to those shown in Schemes 1 to 10, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0074] The present compounds of formula (I) and their pharmaceutically acceptable salts can be prepared by the method described below (Scheme 1). [ka]

[0075] Reductive amination of an aldehyde of formula (II) with an amine of formula (III) provides a compound of formula (I). Typical conditions include sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as methanol, THF or 1,2-dichloroethane, optionally in the presence of an additive such as N,N-diisopropylethylamine or triethylamine or acetic acid or powdered molecular sieves, at a temperature such as room temperature.

[0076] Alternatively, compounds of formula (I) can be prepared as shown in Scheme 2. [ka]

[0077] Reaction of intermediates of formula (IV), where LG is a leaving group such as iodo, bromo, mesyloxy or tosyloxy, with amines of formula (III) provides compounds of formula (I). Typical conditions include a base such as potassium carbonate or cesium carbonate in a solvent such as MeCN, DMF, DMA or NMP at elevated temperature such as 80°C.

[0078] Intermediates of formula (III) may be prepared as shown in Scheme 3. [ka]

[0079] Coupling of a compound of formula (V), where PG is a suitable amine-protecting group, with a heteroaryl bromide of formula (VI), optionally protected with a protecting group (PG), provides an optionally protected intermediate of formula (VII). Typical conditions include the use of catalytic amounts of copper(I) iodide and trans-N,N'-dimethylcyclohexane-1,2-diamine or tris(dibenzylideneacetone)dipalladium(0) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene in the presence of a base such as potassium carbonate in a solvent such as 1,4-dioxane at a temperature such as 100°C. Typical protecting groups in the protected amine (V) include BOC and benzyloxycarbonyl. Typical optional protecting groups in the heteroaryl bromide of formula (VI) include 2-trimethylsilylethoxymethyl. Deprotection of the compound of formula (VII) provides an intermediate of formula (III). Typical conditions for removing BOC and 2-trimethylsilylethoxymethyl protecting groups include an acid such as hydrochloric acid in a solvent such as methanol or ethyl acetate, or trifluoroacetic acid in a solvent such as DCM at an elevated temperature such as 25° C. Typical conditions for removing benzyloxycarbonyl protecting groups include hydrogenation under a hydrogen atmosphere in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol or THF at a temperature such as room temperature.

[0080] Alternatively, intermediates of formula (VII) can be prepared as shown in Scheme 4. [ka]

[0081] Coupling of a protected amine compound of formula (V) with a heteroaryl bromide of formula (VIII) provides an intermediate of formula (IX). Typical conditions include the use of catalytic amounts of copper(I) iodide and trans-N,N'-dimethylcyclohexane-1,2-diamine or tris(dibenzylideneacetone)dipalladium(0) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene in the presence of a base such as potassium carbonate in a solvent such as 1,4-dioxane at a temperature such as 100°C. Reduction of intermediate (IX) provides an intermediate of formula (VII). Typical conditions include iron in acetic acid at a temperature such as 60°C.

[0082] Intermediates of formula (II) may be prepared as shown in Scheme 5. [ka]

[0083] Reduction of the ester of formula (X) provides the alcohol of formula (XI). Typical conditions include a reducing agent such as lithium aluminum hydride in a solvent such as THF at temperatures such as -78°C to room temperature, or sodium borohydride in the presence of calcium chloride in a solvent such as THF and ethanol or methanol at temperatures such as 0°C. Oxidation of the alcohol of formula (XI) provides the aldehyde of formula (II). Typical conditions include Dess-Martin periodinane in a solvent such as DCM at temperatures such as 0°C to 25°C, or sulfur trioxide pyridine complex in the presence of triethylamine and anhydrous dimethyl sulfoxide in a solvent such as DCM at temperatures such as 0°C to 25°C.

[0084] Alternatively, reduction of the ester of formula (X) provides the aldehyde of formula (II). Typical conditions include a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a solvent such as THF at low temperature such as -78°C to -20°C.

[0085] Intermediates of formula (IV) where LG is a leaving group such as iodo, bromo, mesyloxy, or tosyloxy can be prepared as shown in Scheme 5. Activation of an alcohol of formula (XI) affords intermediates of formula (IV). Typical conditions include p-toluenesulfonyl chloride or methanesulfonyl chloride, N,N-diisopropylethylamine or triethylamine, and DMAP in a solvent such as DCM at a temperature such as 0° C. to room temperature, optionally followed by reaction of the resulting mesyloxy or tosyloxy derivative with a halide salt such as sodium iodide or potassium bromide in a solvent such as MeCN at a temperature such as 60° C.

[0086] Intermediates of formula (X) where W is ring system A can be prepared as shown in Scheme 6. In the following scheme, R3 / R4 are R 3 or R 4 and R4 / R3 is R 4 or R 3 Each ring system represents one of R 3 and R 4 It has a substituent. [ka]

[0087] Nitration of the intermediate of formula (XII) provides the intermediate of formula (XIII). Typical conditions include a mixture of nitric acid and sulfuric acid at low temperatures, such as -10 to 0°C. Reduction of the intermediate of formula (XIII) provides the intermediate of formula (XIV). Typical conditions include hydrogenation under a hydrogen atmosphere in the presence of a catalyst, such as palladium on carbon, in a solvent, such as ethanol, at a temperature, such as room temperature. Cyclization of the intermediate of formula (XIV) provides the intermediate of formula (XIV) where W is ring system A and R 12is H. Typical conditions include acetic acid at a temperature such as 60° C. When W is ring system A and R 12 is H and an intermediate of formula (X) 12 Reaction of -LG with an alkylating agent gives an intermediate of formula (X) where W is ring system A. Typical conditions include an alkylating agent such as dimethyl carbonate (optionally used as a solvent) in the presence of a base such as DBU at a temperature such as 90°C.

[0088] Alternatively, reduction of the intermediate of formula (XIV) provides an intermediate of formula (XV). Typical conditions include borane-THF complex in a solvent such as THF at a temperature such as 0-25°C. The intermediate of formula (XV) can be converted to an intermediate of formula (X) where W is ring system A using a two-step procedure. Typical conditions for the first step include reaction of an intermediate of formula R with a borane-THF complex in a solvent such as DCM, DMF or MeCN at a temperature such as room temperature in the presence of a base such as N,N-diisopropylethylamine, DMAP or 1-methylimidazole, in the presence of a coupling agent such as TCFH, T3P or HATU. 11 Alternatively, typical conditions for the first step include the reaction of a compound of formula R with a carboxylic acid such as COOH in the presence of a base such as triethylamine or N,N-diisopropylethylamine in a solvent such as DCM, DMA or THF at a temperature such as -10°C to 25°C. 11 Typical conditions for the second step include reaction of COCl with an acid chloride. Typical conditions for the second step include acetic acid at a temperature such as 60°C.

[0089] Intermediates of formula (X) where W is ring system C and D may be prepared as shown in Scheme 7. [ka]

[0090] Hydrolysis of the amide of formula (XIII) provides an amine of formula (XVI). Typical conditions include an acid such as sulfuric acid in a solvent such as ethanol at a temperature such as 78°C. Reduction of the amine of formula (XVI) provides a diamine of formula (XVII). Typical conditions include hydrogenation under a hydrogen atmosphere in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol at a temperature such as room temperature. The diamine of formula (XVII) can be converted to an intermediate of formula (XVIII). Typical conditions include reaction with sodium nitrite in aqueous hydrochloric acid at a temperature such as 0°C. Alkylation of the intermediate of formula (XVIII) provides an intermediate of formula (X) where W is the ring system C and D. Typical conditions include reaction with an alkyl halide in the presence of a base such as potassium carbonate in a solvent such as MeCN at a temperature such as 80°C.

[0091] Intermediates of formula (X) where W is ring system B may be prepared as shown in Scheme 8. [ka]

[0092] Esters of formula (XIX) can be converted to phenols of formula (XX) using a two-step procedure. Typical conditions for the first step include 4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3,4,7,8-tetramethyl-1,10-phenanthroline in the presence of a catalyst such as (1,5-cyclooctadiene)(methoxy)iridium(I) dimer at a temperature such as 65°C. Typical conditions for the second step include sodium perborate monohydrate in water at a temperature such as 0-25°C. Nitration of phenols of formula (XX) gives nitro compounds of formula (XXI). Typical conditions include nitric acid in a solvent such as DCM at a low temperature such as 0°C. Reduction of nitro compounds of formula (XXI) gives amines of formula (XXII). Typical conditions include hydrogenation under a hydrogen atmosphere in the presence of a catalyst such as palladium on carbon in a solvent such as ethanol at a temperature such as room temperature. The reaction of amines of formula (XXII) with amines of formula R11 Reaction of COOH with a carboxylic acid provides an amide of formula (XXIII). Typical conditions include a coupling agent such as TCFH, T3P, or HATU in the presence of a base such as N,N-diisopropylethylamine, DMAP, or 1-methylimidazole in a solvent such as DCM, DMF, or MeCN at a temperature such as room temperature. Cyclization of the intermediate of formula (XXIII) provides an intermediate of formula (X) where W is ring system B. Typical conditions include triphenylphosphine and diisopropyl azodicarboxylate in the presence of 4 Å molecular sieves in a solvent such as THF at a temperature such as 0-25°C.

[0093] Alternatively, a compound of formula (XXII) and a compound of formula R 11 C(=NH)OCH2CH3 or R 11 Reaction of the imidate with C(=NH)OCH3 provides an intermediate of formula (X) where W is ring system B. Typical conditions include reaction with the hydrochloride salt of the imidate in a solvent such as DCM at a temperature such as room temperature.

[0094] Intermediates of formula (X) where W is ring system E may be prepared as shown in Scheme 9. [ka]

[0095] The mono-N-alkylated diamine of formula (XV) can be converted to an intermediate of formula (X) where W is the ring system E. Typical conditions include N,N'-carbonyldiimidazole in a solvent such as DCM at a temperature such as room temperature.

[0096] The intermediate of formula (X) where W is the ring system F can be prepared as shown in Scheme 9. Diamines of formula (XVII) can be converted to intermediates of formula (XXIV). Typical conditions include ethyl glyoxalate in a solvent such as MeCN at a temperature such as room temperature. The intermediate of formula (XXIV) can be converted to intermediates of formula (XXV). Typical conditions include phosphorus oxychloride at a temperature such as room temperature to 100°C. The intermediate of formula (XXV) can be converted to intermediates of formula (X) where W is the ring system F. Typical conditions include the addition of a diamine of formula R to a diamine of formula R in the presence of a base such as N,N-diisopropylethylamine in a solvent such as THF at a temperature such as 60 to 120°C. 15 Examples include the reaction of H with amines.

[0097] Intermediates of formula (XII) where n=0 may be prepared as shown in Scheme 10. [ka]

[0098] Indan-1-one of formula (XXVI) can be converted to ester of formula (XVII) or ester of formula (XIX) using a two-step procedure. Typical conditions for the first step include reaction with dimethyl or diethyl carbonate in the presence of a base such as sodium hydride in a solvent such as toluene or THF at a temperature such as 60-120°C. Typical conditions for the second step include hydrogenation in the presence of an acid such as HCl or sulfuric acid using a catalyst such as palladium on carbon in a solvent such as ethanol at a temperature such as room temperature. Bromide of formula (XVII) can be converted to intermediate of formula (XII). Typical conditions include reaction of an indan-1-one of formula (XXVII) with an ester of formula (XVII) in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), a phosphine ligand such as xantphos or XPhos, and a base such as cesium carbonate in a solvent such as 1,4-dioxane at a temperature such as 90-100°C. 11 Alternatively, the reaction of the amide of formula R 11Reaction under similar conditions with tert-butyl carbamate in place of the amide of CONH2 provides an intermediate which can be readily converted to an amine of formula (XXIX) using an acid such as HCl or TFA in a solvent such as EtOH, EtOAc or DCM at a temperature such as room temperature.

[0099] Nitration of the intermediate of formula (XIX) gives the intermediate of formula (XXVIII). Typical conditions include nitric acid in a solvent such as DCM at low temperature, such as 0°C. Reduction of the nitro compound of formula (XXVIII) gives the amine of formula (XXIX). Typical conditions include hydrogenation under a hydrogen atmosphere in the presence of a catalyst, such as palladium on carbon, in a solvent such as ethanol at a temperature such as room temperature. Reaction of the amine of formula (XXIX) with a compound of formula R 11 Reaction of COOH with a carboxylic acid provides an amide of formula (XXII). Typical conditions include a coupling agent such as TCFH, T3P or HATU in the presence of a base such as N,N-diisopropylethylamine, DMAP or 1-methylimidazole in a solvent such as DCM, DMF or MeCN at a temperature such as room temperature.

[0100] Alternatively, an amine of formula (XXIX) and a compound of formula R 11 Reaction of COCl with an acid chloride gives the amide of formula (XII). Typical conditions include the presence of a base such as triethylamine or N,N-diisopropylethylamine in a solvent such as DCM, DMA or THF at a temperature such as -10°C to 25°C.

[0101] Specific examples of compounds of formula (I) described herein include: 6-[5-[2-[(4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[5-[2-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(1-hydroxy-1-methyl-ethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(4-methylmorpholin-2-yl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(morpholinomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3R)-morpholin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3R)-morpholin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-5-oxopyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-5-oxopyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[(10,16-difluoro-2,5,8-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),7,10,15-tetraen-13-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-(methylamino)pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-4-hydroxy-2-piperidyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-4-hydroxy-2-piperidyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[2-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(1-amino-1-methyl-ethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S,4R)-4-aminotetrahydrofuran-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(2-amino-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-azabicyclo[2.1.1]hexan-1-yl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-2-(methylamino)acetamide; 6-[8-[[2-[(1S,2S)-1-amino-2-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-methoxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[5-[2-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[5-[2-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-3-hydroxy-2-(methylamino)propyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(methylamino)acetamide; or a pharmaceutically acceptable salt thereof.

[0102] Other specific examples of compounds of formula (I) described herein include: 6-[8-[[2-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-(dimethylamino)-3-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(dimethylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[2-(methylamino)ethyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2-methoxyethylamino)methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methylamino]-N-methyl-acetamide; 6-[8-[[1-(2-aminoethyl)-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(1R)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-1,6,7,8-tetrahydrocyclopenta[e]benzimidazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-7,8-dihydro-6H-cyclopenta[e][1,3]benzoxazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(3-hydroxyazetidin-1-yl)methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(aminomethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; Formic acid;6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid;6-[2-oxo-8-[[3-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[3-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-Aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;Formic acid; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(2S)-2-Aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-[(2S)-2-Aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;hydrochloric acid; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[2-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)propanamide; (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(dimethylamino)propanamide; (2R)-2-(dimethylamino)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]propanamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(dimethylamino)-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-N-methyl-acetamide; (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]pyrrolidine-2-carboxamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(methylamino)acetamide; N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-2-(methylamino)acetamide; 2,2,2-trifluoroacetic acid; N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl-2-(methylamino)acetamide; (2R)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]pyrrolidine-2-carboxamide; 2,2,2-trifluoroacetic acid; (2R)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]pyrrolidine-2-carboxamide; (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]pyrrolidine-2-carboxamide; (2R,4S)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide; (2R,4S)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide; 2-Amino-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide;Formic acid; 2-Amino-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; 2-Amino-N-methyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)acetamide; (2R)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-2-(methylamino)propanamide; 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; or a pharmaceutically acceptable salt thereof.

[0103] Further specific examples of formula (I) described herein are: 6-[8-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(1-amino-1-methyl-ethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S,4R)-4-aminotetrahydrofuran-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-azabicyclo[2.1.1]hexan-1-yl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-2-(methylamino)acetamide; 6-[8-[[2-[(1S,2S)-1-amino-2-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-methoxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; or a pharmaceutically acceptable salt thereof.

[0104] Other further specific examples of formula (I) described herein are: 6-[8-[[3-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-1,6,7,8-tetrahydrocyclopenta[e]benzimidazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-7,8-dihydro-6H-cyclopenta[e][1,3]benzoxazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(aminomethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; Formic acid;6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-Aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; or a pharmaceutically acceptable salt thereof.

[0105] The most specific examples of formula (I) described herein are: 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-Fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-Trifluoroacetic acid; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; or a pharmaceutically acceptable salt thereof.

[0106] Another most specific example of formula (I) described herein is 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid;6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-Aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-Amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one or a pharmaceutically acceptable salt thereof.

[0107] Also an object of the present invention are compounds according to formula (I) as described herein for use as therapeutically active substances.

[0108] Likewise, an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

[0109] As mentioned above, the compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties for treating or preventing infections and resulting diseases caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0110] The compounds of formula (I) and their pharmaceutically acceptable salts are active as antibiotics, in particular as antibiotics against Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly against Gram-negative bacteria, and even more particularly against Escherichia coli.

[0111] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antibacterial pharmaceutical ingredients suitable for the treatment and prevention of bacterial infections, in particular bacterial infections caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli.

[0112] The compounds of the present invention can be used, alone or in combination with other drugs, to treat or prevent infections and resulting diseases caused by pathogens, in particular bacteria, more particularly Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly Gram-negative bacteria, even more particularly Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0113] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0114] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients, for the treatment or prevention of infections and resulting diseases caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0115] A particular embodiment of the present invention relates to a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance, in particular for use as a therapeutically active substance for treating or preventing infections and resulting diseases caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0116] A particular embodiment of the present invention relates to a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections and resulting diseases caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0117] A particular embodiment of the present invention relates to a method for treating or preventing infections and resulting diseases, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli, which method comprises administering to a subject a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0118] A particular embodiment of the present invention relates to the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the treatment or prevention of infections and resulting diseases caused by pathogens, in particular by bacteria, more particularly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly by Gram-negative bacteria, even more particularly by Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0119] A specific embodiment of the present invention relates to the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing infections and resulting diseases caused by pathogens, in particular bacteria, more particularly Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii or Staphylococcus aureus, more particularly Gram-negative bacteria, even more particularly Escherichia coli, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such a medicament comprises a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0120] Also an embodiment of the present invention is a compound of formula (I) as described herein when prepared according to any one of the methods described.

[0121] Assay procedure Minimum inhibitory concentration (MIC) and determination: MICs of antibacterial compounds against multiple species and strains were determined using the broth microdilution method according to the M07-A10 Clinical and Laboratory Standards Institute (CLSI) guidelines [1] using appropriate broth media. Briefly, compound plates were prepared by dispensing 100 μl of each stock solution into the first well of a 96-well microtiter plate (MTP) at a concentration 100-fold higher than the desired final concentration in broth. Eleven serial two-fold dilutions of the highest concentration were performed in DMSO for novel compounds and in water (or an appropriate solution) for reference compounds [2]. 1 μL of each well was transferred to a new MTP, which served as the test plate for subsequent inoculation. This bacterial suspension was prepared from strains that were first subcultured on agar plates and incubated for 18–24 hours as needed. After incubation, inocula were prepared from isolated colonies and adjusted to a 0.5 McFarland turbidity standard (1–2 × 10 colony-forming units (CFU) / mL) in 0.9% saline. The bacterial suspension was then diluted 1:200 in the appropriate sterile medium and 100 µL / well was dispensed within 15 minutes. Negative controls (absence of bacterial cells) and growth control wells (absence of compound) were included in every plate. MTPs were incubated at 35 ± 2 °C in ambient air for 18–24 h. The MIC value of each compound, expressed as µg / mL, was determined as the lowest concentration required for complete growth inhibition (no visible growth).

[0122] [1] CLSI (2015) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved Standard, 10th Edition. CLSI Document M7-A10 (ISBN 1-56238-987-4). Wayne, Pennsylvania: Clinical and Laboratory Standards Institute, 19087, USA.

[0123] [2] CLSI(2017) Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. CLSI Document M100-S27, CLSI, Wayne, PA 19087, USA.

[0124] Table 1 shows the minimum inhibitory concentrations (MICs) in micrograms per milliliter of compounds of the present invention obtained against Escherichia coli ATCC 25922 strain.

[0125] Particular compounds of the invention exhibit an MIC (Escherichia coli ATCC25922) < 4 μg / mL.

[0126] More particular compounds of the invention exhibit an MIC (Escherichia coli ATCC25922) < 1 μg / mL.

[0127] Most particular compounds of the present invention exhibit an MIC (Escherichia coli ATCC25922) < 0.25 μg / mL. [Table 1-1] [Table 1-2] [Table 1-3]

[0128] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically to the eye (e.g., in the form of solutions, ointments, gels, or water-soluble polymer inserts). However, administration can also be carried out parenterally (e.g., in the form of sterile injection solutions), such as intramuscularly, intravenously, or intraocularly.

[0129] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0130] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0131] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0132] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0133] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0134] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0135] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants, which may also contain other therapeutically valuable substances.

[0136] The dosage can vary within a wide range and, of course, will be adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which may, if appropriate, consist of equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered either in a single dose per day or per week, or in multiple doses (2 to 4 times) per day or per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0137] Preparation of Pharmaceutical Compositions Containing Compounds of the Invention Tablets of the following composition are prepared in the usual manner: [Table 2]

[0138] Manufacturing Procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0139] Capsules of the following composition are prepared: [Table 3] Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0140] The compound of formula I, lactose and cornstarch are mixed first in a mixer, then in a pulverizer.The mixture is returned to the mixer; talc is added and mixed thoroughly.The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0141] An injection solution of the following composition is prepared: [Table 4]

[0142] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0143] Where preparations are obtained as mixtures of enantiomers, pure enantiomers may be obtained by methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization. [Example]

[0144] Abbreviation MeOH: methanol, AcOH: acetic acid, prep-HPLC: preparative reversed-phase high-performance liquid chromatography, MS: mass spectrum, M: molecular mass, ESP: electrospray ionization (positive charge detection), ESN: electrospray ionization (negative charge detection), DCM: dichloromethane, EtOAc: ethyl acetate, DMF: N,N-dimethylformamide, RT, rt or rt: room temperature, DIPEA: N,N-diisopropylethylamine, i-PrOH: 2-propanol, h: hour, THF: tetrahydrofuran, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, TFA: trifluoroacetic acid, dioxane: 1,4-dioxane, sat.: saturated, quant.: quantitative, EI: electron ionization, dppf: 1,1'-ferrocenediyl-bis(diphenylphosphine), HATU: 1-[bis(dimethylamino)methylene]-1H-1 ,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, RM: reaction mixture, t-BuOH: 2-methylpropan-2-ol, prep-TLC: preparative thin layer chromatography, SFC: supercritical fluid chromatography, ether: diethyl ether, BOC: tert-butyloxycarbonyl, Pd / C: palladium on carbon, TMSCl: trimethylsilyl chloride, MeCN: acetonitrile , NMR: nuclear magnetic resonance spectroscopy, s: singlet, d(NMR): doublet, t: triplet, q: quartet, m: multiplet, dd: doublet of doublet, dt: doublet of triplet, br: broad, J: coupling constant, δ: chemical shift (parts per million), PE: petroleum ether, NMP: N-methyl-2-pyrrolidone, DMA: N,N-dimethylacetamide, Dess-Martin periodinane or DMP: 1,1,1-triacetoxy-1,1-dihydro-1,2-Benziodoxol-3(1H)-one, LDA: lithium diisopropylamide, MTBE: methyl tert-butyl ether, MOMCl: methyl chloromethyl ether, DMAP: 4-dimethylaminopyridine, tBu: tert-butyl, LiHMDS: lithium bis(trimethylsilyl)amide, TsCl: tosyl chloride, HPLC: preparative reversed-phase high-performance liquid chromatography, TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate, DMSO: dimethyl sulfoxide, d (hours): days, TEMPO: (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl, TBSCl: tert-butyldimethylsilyl chloride, dba: dibenzylideneacetone, t-BuXphos: 2- Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, TBAF: tetra-n-butylammonium fluoride, t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, PyBOP: benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate.

[0145] Example 1 6-[5-[2-[(4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0146] A solution of 4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde (Intermediate 8, 30.7 mg, 0.130 mmol, 1 equiv.), 6-[5-(2-aminoethyl)-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 1, 51.1 mg, 0.130 mmol, 1 equiv.) and DIPEA (34.33 uL, 0.200 mmol, 1.5 equiv.) in DMA (0.657 mL) and THF (0.657 mL) was stirred at 25 °C for 15 minutes. Acetic acid (18.79 uL, 0.330 mmol, 2.5 equiv) was added, followed by sodium triacetoxyborohydride (41.77 mg, 0.200 mmol, 1.5 equiv). The mixture was stirred at 25 °C overnight. The mixture was diluted with saturated aqueous NaHCO and extracted with EtOAc (3 times). The organic phase was dried over NaSO and concentrated in vacuo. The mixture was purified by silica cartridge chromatography (DCM / MeOH 9:1, then gradient to 100% DCM / MeOH / NHOH 10:1:0.1) to afford the title compound (15.5 mg, 0.030 mmol, 22.4% yield) as a white solid. MS (ESP): m / z = 500.2 [M+H] + .

[0147] The following examples were prepared similarly to Example 1. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0148] Example 9 6-[8-[[4,8-Difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0149] Step 1: tert-butyl N-[[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-N-methyl-carbamate [ka]

[0150] A solution of 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2) (3.28 g, 7.81 mmol, 1.05 equiv.), tert-butyl N-[(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)methyl]-N-methylcarbamate (Intermediate 11) (2.72 g, 7.44 mmol, 1 equiv.) and DIPEA (1.94 mL, 11.16 mmol, 1.5 equiv.) in DMA (26.15 mL) and THF (48.24 mL) was stirred at 25° C. for 15 minutes. Acetic acid (1.06 mL, 18.6 mmol, 2.5 equiv.) was added, followed by sodium triacetoxyborohydride (2.36 g, 11.16 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x1). The organic phase was washed with brine (x1), dried over Na2SO4, and concentrated in vacuo. The mixture was purified by silica cartridge chromatography [DCM / (DCM / MeOH / NH4OH 10:1:0.1) 8:2 to 2:8] to give the title compound (2070 mg, 3.16 mmol, 42.5% yield). MS (ESP): m / z = 655.3 [M+H] + .

[0151] Step 2: 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0152] To a stirred suspension of tert-butyl N-[[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-N-methyl-carbamate (2070.0 mg, 3.16 mmol, 1 equiv.) in DCM (32.08 mL) was added trifluoroacetic acid (7.31 mL, 94.86 mmol, 30 equiv.), and the mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and co-evaporated in the presence of MeCN. The resulting mixture was purified by silica cartridge chromatography [DCM / (DCM / MeOH / NH4OH 5:1:0.1) 70:30 to 20:80] to give the title compound (1700 mg, 3.07 mmol, 96.95% yield). MS (ESP): m / z = 555.2 [M+H] + .

[0153] The following examples were prepared similarly to Example 9. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16]

[0154] Example 46 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one;2,2,2-trifluoroacetic acid [ka]

[0155] Step 1: tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]pyrrolidine-1-carboxylate [ka]

[0156] Crude tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate (Intermediate 32) (250.0 mg, 0.480 mmol, 1 equiv.), 6-(2-oxo-1-oxa-3,8-diaza A solution of spiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2) (221.04 mg, 0.530 mmol, 1.1 equiv.) and DIPEA (125.21 uL, 0.720 mmol, 1.5 equiv.) in DMA (2.4 mL) and THF (2.4 mL) was stirred at 25 °C for 15 min. Acetic acid (68.52 uL, 1.2 mmol, 2.5 equiv.) was added, followed by sodium triacetoxyborohydride (152.35 mg, 0.720 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with saturated aqueous NaHCO and extracted with EtOAc (x1). The organic phase was dried over NaSO and concentrated in vacuo. The mixture was purified by silica cartridge chromatography (50 g, DCM / MeOH 99.5:0.5 to 95:5) to give the title compound (237 mg, 0.290 mmol, 60.98% yield) as a pale yellow solid. MS (ESP): m / z = 811.3 [M+H] + .

[0157] Step 2: tert-butyl (2S,4R)-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylate [ka]

[0158] To a stirred solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]pyrrolidine-1-carboxylate (237.0 mg, 0.290 mmol, 1 equiv.) in anhydrous THF (2.92 mL) was added 1 M tetrabutylammonium fluoride in THF (584.49 μL, 0.580 mmol, 2 equiv.), and the mixture was stirred at room temperature for 16 h. The reaction was diluted with saturated aqueous NaHCO and extracted with EtOAc (2×). The organic phase was filtered through a phase separator and concentrated in vacuo. The mixture was purified by silica cartridge chromatography (25 g, [DCM / (DCM / MeOH / NH4OH 10:1:0.1) 95:5 to 0:100] to give the title compound (144 mg, 0.210 mmol, 70.72% yield) as a white solid. MS (ESP): m / z = 697.2 [M+H] + .

[0159] Step 3: 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0160] To a stirred suspension of tert-butyl (2S,4R)-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylate (100.0 mg, 0.140 mmol, 1 equiv.) in DCM (2 mL) was added trifluoroacetic acid (221.16 μL, 2.87 mmol, 20 equiv.), and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo. The resulting mixture was triturated with diethyl ether and filtered. The solid was suspended in HO / MeCN and lyophilized to give the title compound (110 mg, 0.130 mmol, 88.29% yield) as a white solid. MS (ESP): m / z = 597.2 [M+H] + .

[0161] The following examples were prepared similarly to Example 46. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0162] Example 58 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0163] Step 1: 6-[8-[[2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0164] To a suspension of 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2, 67.28 mg, 0.160 mmol, 1 equiv.) and 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde (Intermediate 56, 69.89 mg, 0.13 mmol, 1 equiv.) in DMA (0.401 mL) and THF (1.2 mL) at room temperature was added DIPEA (0.07 mL, 0.400 mmol, 2.5 equiv.). The reaction mixture was stirred at room temperature. After 30 min, acetic acid (0.04 mL, 0.720 mmol, 4.5 equiv) and sodium triacetoxyborohydride (85.01 mg, 0.400 mmol, 2.5 equiv) were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and NaHCO3 (saturated aqueous solution). The phases were separated, and the organic layer was washed with NaHCO3 (saturated aqueous solution) (x2) and brine (x1). The organic phase was filtered through a phase separator, and the volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (0% to 10% MeOH / DCM) to afford the title compound (85 mg, 0.120 mmol, 73.09% yield) as a white solid. MS (ESP): m / z = 725.5 [M+H] + .

[0165] Step 2: 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0166] To a solution of 6-[8-[[2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (80.0 mg, 0.110 mmol, 1 equiv.) in THF (1.1 mL) was added tetrabutylammonium fluoride (0.5 mL, 0.500 mmol, 4.5 equiv.), and the mixture was stirred at room temperature for 0.75 h. The volatiles were removed under reduced pressure, and the residue was evaporated several times with MeCN. The residue was suspended in DCM and pentane, stirred, and the supernatant was removed. The procedure was repeated three times. The remaining solid was dried under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound (14.5 mg, 0.020 mmol, 21.09% yield) as an off-white solid. MS (ESP): m / z = 611.4 [M+H] + .

[0167] Example 59 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one Enantiomer A and Example 60 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer B [ka]

[0168] 6-[8-[[8-Fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Enantiomers of 2,2,2-trifluoroacetic acid (Example 12, 29.7 mg, 0.030 mmol, 1 equiv.) separated by chiral SFC Peak 1: 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer A (6.4 mg, 0.010 mmol, 37.87% yield) as a white solid; MS(ESP) m / z = 537.3 [M+H] + and peak 2: 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer B (6.8 mg, 0.010 mmol, 40.24% yield) as a white solid; MS (ESP): m / z = 537.3 [M+H] + was obtained as.

[0169] Example 61 N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(methylamino)acetamide [ka]

[0170] Step 1: tert-butyl N-[2-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethylamino]-2-oxo-ethyl]-N-methyl-carbamate [ka]

[0171] To a stirred solution of N-BOC sarcosine [CAS no. 13734-36-6] (20.44 mg, 0.110 mmol, 1 equiv.) in DMF (1.03 mL) was added N,N-diisopropylethylamine (0.03 mL, 0.160 mmol, 1.5 equiv.), HATU (49.28 mg, 0.130 mmol, 1.2 equiv.) and 6-[8-[[1-(2-aminoethyl)-4,8- Difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 42, 60.0 mg, 0.110 mmol, 1 equiv.) was added, and the resulting mixture was stirred at 25 °C for 1.5 h. The mixture was then diluted with water (3 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL). The organic layer was collected, dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica cartridge chromatography (NH-silica, 28 g, DCM / MeOH 100:0 to 90: / 10) to give the title compound (57 mg, 0.080 mmol, 72.62% yield) as a pale yellow solid. MS(ESP)m / z=727.4[M+H] + .

[0172] Step 2: N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(methylamino)acetamide [ka]

[0173] To a stirred solution of tert-butyl N-[2-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethylamino]-2-oxo-ethyl]-N-methyl-carbamate (54.0 mg, 0.070 mmol, 1 equiv) in DCM (0.784 mL) was added trifluoroacetic acid (0.11 mL, 1.49 mmol, 20 equiv) and the resulting mixture was stirred at 25° C. for 1.5 h. The mixture was then concentrated in vacuo to give the crude product, which was purified by silica cartridge chromatography (NH-silica, 28 g, DCM / MeOH 100:0 to 90: / 10) to give the title compound (33 mg, 0.050 mmol, 70.17% yield) as a white solid. MS (ESP): m / z = 627.3 [M+H] + .

[0174] Example 62 6-[8-[[2-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0175] The title compound was prepared from Intermediate 2 and Intermediate 58 in a similar manner to Example 1 and obtained as a white solid. MS (ESP): m / z=566.2 [M+H] + .

[0176] Example 63 6-[8-[[2-[(2S)-2-(dimethylamino)-3-hydroxypropyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0177] Step 1: tert-butyl N-[(1S)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]carbamate [ka]

[0178] The title compound was prepared from Intermediate 2 and Intermediate 59 in a similar manner to Example 1 and obtained as a yellow solid. MS (ESP): m / z=799.5 [M+H] + .

[0179] Step 2: tert-butyl N-[(1S)-1-[[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-2-hydroxy-ethyl]carbamate [ka]

[0180] A mixture of tert-butyl N-[(1S)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]carbamate (88.0 mg, 0.11 mmol, 1.0 equiv) and tetrabutylammonium fluoride (1 M in THF, 0.22 mL, 0.22 mmol, 2.0 equiv) in THF (2 mL) was stirred at 20 °C for 16 h. The mixture was concentrated and purified by flash column chromatography (silica, 0-10% MeOH in DCM) to give the title compound (46.0 mg, 0.07 mmol, 61.0% yield) as a pale yellow oil. MS (ESP): m / z = 685.5 [M+H] + .

[0181] Step 3: 6-[8-[[2-[(2S)-2-amino-3-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0182] A mixture of tert-butyl N-[(1S)-1-[[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-2-hydroxy-ethyl]carbamate (46.0 mg, 0.07 mmol, 1.0 equiv) and trifluoroacetic acid (0.05 mL, 0.67 mmol, 10.0 equiv) in DCM (1.5 mL) was stirred at room temperature for 4 h. The mixture was concentrated and purified by flash column chromatography (silica-NH, 0-20% MeOH in DCM) to give the title compound (27.7 mg, 0.05 mmol, 70.5% yield) as a white solid. MS (ESP): m / z = 585.3 [M+H] + .

[0183] Step 4: 6-[8-[[2-[(2S)-2-(dimethylamino)-3-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0184] A mixture of 6-[8-[[2-[(2S)-2-amino-3-hydroxypropyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (27.7 mg, 0.05 mmol, 1.0 equiv.) and formaldehyde (9.61 mg, 0.12 mmol, 2.5 equiv.) in tetrahydrofuran (1 mL) and DMA (0.5 mL) was stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (25.1 mg, 0.12 mmol, 2.5 equiv.) was added. The mixture was stirred at room temperature overnight. Additional formaldehyde (9.61 mg, 0.12 mmol, 2.5 equiv.), acetic acid (2.85 mg, 0.05 mmol, 1.0 equiv.), and sodium cyanoborohydride (4.47 mg, 0.07 mmol, 1.5 equiv.) were added, and the mixture was stirred for an additional 18 h. The mixture was concentrated and purified by flash column chromatography (silica-NH, 0-20% MeOH in DCM) to afford the title compound (8.8 mg, 0.01 mmol, 28.8% yield) as a white solid. MS (ESP): m / z = 613.3 [M+H] + .

[0185] Example 64 6-[8-[[1-[2-(dimethylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0186] The title compound was prepared from 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 42) in analogy to Example 63, Step 4, and obtained as a white solid. MS (ESP): m / z = 584.3 [M+H] + .

[0187] Example 65 6-[8-[[3-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0188] The title compound was prepared from 6-[8-[[3-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 75) in analogy to Example 63, Step 4, and obtained as a white solid. MS (ESP): m / z = 566.3 [M+H] + .

[0189] Example 66 6-[8-[[4,8-Difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one Enantiomer A [ka] and Example 67 6-[8-[[4,8-Difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one Enantiomer B [ka]

[0190] Step 1: tert-butyl N-[2-tert-butoxy-1-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]-N-methyl-carbamate [ka]

[0191] tert-Butyl N-[2-tert-butoxy-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methylcarbamate (Intermediate 60, 142.0 mg, 0.31 mmol, 1.0 equiv.) and 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4 To a suspension of H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2, 131.9 mg, 0.31 mmol, 1.0 equiv.) in tetrahydrofuran (2.6 mL) / DMA (0.5 mL) at room temperature, N-ethyldiisopropylamine (82.17 μL, 0.47 mmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 15 minutes. Acetic acid (45.0 μL, 0.79 mmol, 2.5 equiv.) and sodium triacetoxyborohydride (100.0 mg, 0.47 mmol, 1.5 equiv.) were added, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with EtOAc and quenched with NaHCO3 (saturated aqueous solution). The phases were separated, and the organic layer was washed with water (twice). The combined organic phases were filtered through a phase separator and the volatiles removed under reduced pressure to give the crude compound (63 mg, pale yellow foam), which was purified by silica cartridge chromatography (10 g silica, 100% DCM to 97:3 DCM / MeOH) and further purified by silica cartridge chromatography (11 g silica-NH, 100% DCM to 85:15 DCM / [EtOAc / MeOH 9:1]) to give the title compound (85.0 mg, 0.11 mmol, 36.5% yield) as a white amorphous solid. MS (ESN): m / z = 739.6 [M−H] - .

[0192] Step 2: 6-[8-[[4,8-difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0193] A solution of tert-butyl N-[2-tert-butoxy-1-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]-N-methylcarbamate (85.0 mg, 0.11 mmol, 1.0 equiv) in trifluoroacetic acid (1.5 mL, 19.5 mmol, 170 equiv) was stirred at room temperature for 21 hours. The volatiles were removed under reduced pressure, and the residue was redissolved in MeCN and added to EtO. The resulting white precipitate was collected by centrifugation to give the crude title compound (84.0 mg, 0.1 mmol, 90.1% yield) as a white solid.

[0194] Step 3: 6-[8-[[4,8-difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer A and 6-[8-[[4,8-difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer B [ka]

[0195] The enantiomers of 2,2,2-trifluoroacetic acid (90.0 mg, 0.11 mmol, 1.0 equiv.) were separated by chiral HPLC to give peak 1: 6-[8-[[4,8-difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer A (30.0 mg, 0.05 mmol, 44.0% yield) was obtained as a white solid, and peak 2: 6-[8-[[4,8-difluoro-2-[2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one enantiomer B (11.0 mg, 0.02 mmol, 17.0% yield) was obtained as a white solid. MS (ESP): m / z = 585.3 [M+H] + .

[0196] The following examples were prepared analogously to Example 67. Single stereoisomers were prepared by separation of the corresponding stereoisomeric mixtures obtained in Step 1 or Step 2 by chiral HPLC or chiral SFC. The non-salt stereoisomeric mixtures were obtained from the corresponding 2,2,2-trifluoroacetate salts by flash column chromatography (NH-silica). [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13] [Table 8-14] [Table 8-15] [Table 8-16]

[0197] Examples 72 and 73: The two regioisomers were separated by preparative LCMS and obtained as an off-white solid and a white solid, respectively. The structures of the compounds were determined by 2D NMR.

[0198] Example 79: The compound was further purified by preparative HPLC (formic acid / MeCN).

[0199] Example 113 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid enantiomer A [ka]

[0200] Step 1: tert-Butyl 3-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]azetidine-1-carboxylate Enantiomer A [ka]

[0201] To a solution of 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Intermediate 2, 200.0 mg, 0.66 mmol, 1.0 equiv.) and tert-butyl 3-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)azetidine-1-carboxylate (Intermediate 90, 283.3 mg, 0.79 mmol, 1.2 equiv.) in methanol (5 mL) and THF (2 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.98 mmol, 1.5 equiv.), and the mixture was stirred at 20° C. for 20 minutes. Acetic acid (0.09 mL, 1.64 mmol, 2.5 equiv.) was added, followed by the addition of sodium cyanoborohydride (0.1 mL, 1.64 mmol, 2.5 equiv.). The mixture was stirred at 20° C. for 2 hours. NaHCO was added to the mixture to adjust the pH to >7, and then the mixture was filtered. The filter cake was collected, and the filtrate was extracted with EtOAc (20 mL×3). The combined organic phase was concentrated in vacuo to give the crude racemic product (0.09 g). The enantiomers were separated by chiral SFC to give the title compound (41.0 mg, 0.06 mmol, 9.5% yield) and tert-butyl 3-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]azetidine-1-carboxylate enantiomer B (33.0 mg, 0.05 mmol, 7.8% yield). MS(ESP) m / z = 650.2 [M+H], respectively. + and 650.3 [M+H] + .

[0202] Step 2: 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic Acid Enantiomer A [ka]

[0203] tert-Butyl 3-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]azetidine-1-carboxylate enantiomer A (41.0 mg, 0.06 mmol, 1.0 equiv.) was dissolved in formic acid (2.0 mL, 50.4 mmol, 800 equiv.), and the mixture was stirred at 20 ° C. for 3 hours. The mixture was washed with water (20 mL) and then dried by lyophilization to give the title compound (25.5 mg, 0.04 mmol, 57.5% yield) as a white solid. MS (ESP): m / z = 550.0 [M + H] + .

[0204] The following examples were prepared similarly to Example 113. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0205] Example 124 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid enantiomer A [ka] and Example 125 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid enantiomer B [ka]

[0206] Step 1: tert-butyl N-cyclopropyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]carbamate [ka]

[0207] To a solution of 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2, 309.5 mg, 0.74 mmol, 1.0 equiv.) in methanol (3 mL) and THF (1.5 mL) was added DIPEA (143.09 mg, 1.11 mmol, 1.5 equiv.) at 25° C. The solution was stirred at 25° C. for 5 minutes. To the solution, tert-butyl N-cyclopropyl-N-[2-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)ethyl]carbamate (Intermediate 95, 300.0 mg, 0.74 mmol, 1.0 equiv) and acetic acid (110.8 mg, 1.85 mmol, 2.5 equiv) were added at 25° C. The resulting solution was stirred at 25° C. for 20 minutes. To the mixture, sodium cyanoborohydride (116.3 mg, 1.85 mmol, 2.5 equiv) was added. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into NH4Cl (saturated aqueous solution, 50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to a residue that was triturated with MTBE (5 mL) and stirred for 5 min. The mixture was filtered, and the residue was concentrated under reduced pressure to give the title compound (150.0 mg, 0.22 mmol, 28.6% yield) as an off-white solid. MS (ESP): m / z = 696.1 [M+H] + .

[0208] Step 2: 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one hydrochloride [ka]

[0209] To a solution of tert-butyl N-cyclopropyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]carbamate (150.0 mg, 0.22 mmol, 1.0 equiv.) in DCM (2 mL) was added HCl in dioxane (2.0 mL, 8.0 mmol, 37.1 equiv.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was triturated with MTBE (20 mL × 2). The upper solution was poured off and the residue was concentrated under reduced pressure to give the title compound (145.0 mg, 0.23 mmol, quantitative yield) as an off-white solid. MS (ESP): m / z = 596.1 [M+H] + .

[0210] Step 3: 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; formic acid enantiomer A and enantiomer B [ka]

[0211] The enantiomers of 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one hydrochloride (90.0 mg, 0.14 mmol, 1.0 equiv.) were separated by preparative SFC. Peak 1 was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (formic acid conditions) and lyophilized to give the title compound enantiomer A (18.65 mg, 0.03 mmol, 18.2% yield) as a white solid. Peak 2 was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (formic acid condition) and lyophilized to give the title compound Enantiomer B (8.25 mg, 0.01 mmol, 8.1% yield) as a white solid. MS (ESP): m / z = 596.1 [M+H] + .

[0212] The following examples were prepared similarly to Examples 124 and 125. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0213] Examples 130 and 131: After step 1, the epimers were separated by chiral SFC.

[0214] Examples 132-135: After step 1, the enantiomers were separated by chiral SFC.

[0215] Example 136 6-[8-[[8-Fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one Enantiomer A [ka]

[0216] Step 1: tert-Butyl N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate Enantiomer A [ka]

[0217] The racemic title compound was prepared from Intermediate 3 and Intermediate 29 similarly to Example 125, Step 1, and obtained as a white solid. MS (ESP) m / z=637.2 [M+H] + The enantiomers were separated by chiral SFC to give Peak 1: tert-butyl N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate Enantiomer A and peak 2: tert-butyl N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate enantiomer B were obtained.

[0218] Step 2: 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one Enantiomer A [ka]

[0219] To a solution of tert-butyl N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate enantiomer A (100.0 mg, 0.16 mmol, 1.0 equiv.) in DCM (2.5 mL) was added iodo(trimethyl)silane (0.65 mL, 0.16 mmol, 1.0 equiv.). The resulting mixture was stirred at -20 °C for 0.75 h. The reaction mixture was diluted with EtOAc (6 mL). The solid was collected by filtration under the protection of nitrogen. The filter cake was then quickly dissolved in methanol (12 mL), and Amberlyst® A21 basic resin was added to the solution until the pH was greater than 7. The suspension was filtered, and the filter cake was washed with methanol (10 mL x 2). The combined filtrate was concentrated and triturated with MTBE (4 mL). The resulting solid was collected by filtration, and the filter cake was dried under vacuum to give the title compound (45.2 mg, 0.08 mmol, 51.8% yield) as a pale gray solid. MS (ESP): m / z = 537.3 [M+H] + .

[0220] Example 137 6-[8-[[8-Fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one Enantiomer B [ka]

[0221] The title compound was prepared from tert-butyl N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate Enantiomer B (Example 136, Step 1) in analogy to Example 136, Step 2, and obtained as a pale gray solid. MS (ESP): m / z = 537.3 [M+H] + .

[0222] Example 138 6-[8-[[2-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0223] The title compound was prepared from Intermediate 2 and Intermediate 100 in analogy to Example 136 and obtained as a pale grey solid. MS (ESP): m / z=580.4 [M+H] + .

[0224] Example 139 6-[8-[[2-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0225] The title compound was prepared from Intermediate 2 and Intermediate 100 in analogy to Example 136 and obtained as a pale grey solid. MS (ESP): m / z=580.3 [M+H] + .

[0226] Example 140 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0227] Step 1: tert-butyl (2R)-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]azetidine-1-carboxylate epimer B [ka]

[0228] The enantiomers of tert-butyl (2R)-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]azetidine-1-carboxylate (Example 108, Step 1) were separated by chiral SFC to give the title compound as a white solid. MS (ESP): m / z = 650.1 [M + H] + .

[0229] Step 2: 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0230] To a solution of tert-butyl (2R)-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]azetidine-1-carboxylate epimer B (100.0 mg, 0.15 mmol, 1.0 equiv.) in DCE (1 mL), ZnBr (341.4 mg, 1.54 mmol, 10.0 equiv.) was added, and the resulting mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the title compound (31.9 mg, 0.06 mmol, 37.7% yield) as a white solid. MS (ESP): m / z = 550.2 [M+H] + .

[0231] Example 141 6-[8-[[8-Fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0232] Step 1: tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]pyrrolidine-1-carboxylate epimer A [ka]

[0233] The racemic title compound was prepared from Intermediate 2 and Intermediate 101 similarly to Example 125, Step 1, and obtained as a white solid. MS (ESP): m / z=918.1 [M+H] +The enantiomers were separated by chiral SFC to give peak 1: tert-butyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]pyrrolidine-1-carboxylate. Peak 2: tert-butyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]pyrrolidine-1-carboxylate epimer B was obtained.

[0234] Step 2: tert-Butyl (2S,4R)-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylate epimer A [ka]

[0235] To a solution of tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]pyrrolidine-1-carboxylate epimer A (598.0 mg, 0.65 mmol, 1.0 equiv.) in methanol (3 mL) was added potassium fluoride (1200.0 mg, 20.66 mmol, 31.71 equiv.). The resulting mixture was stirred at 70 °C for 17 hours. The mixture was filtered, and the filter cake was washed with a mixture of 10% MeOH / DCM (100 mL). The filtrate was collected and concentrated in vacuo to give the crude product, which was washed with MTBE (20 mL x 2) to give the title compound (368.0 mg, 0.54 mmol, 83.1% yield). MS (ESP): m / z = 680.2 [M+H] + .

[0236] Step 3: 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0237] The title compound was prepared similarly to Example 136, Step 2, and obtained as a white solid. MS (ESP): m / z=580.2 [M+H] + .

[0238] Example 142 6-[8-[[8-Fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0239] The title compound was prepared from tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]pyrrolidine-1-carboxylate epimer B (Example 141, Step 1) in analogy with Example 141, Steps 2 and 3, and obtained as a white solid. MS (ESP): m / z = 580.2 [M+H] + .

[0240] Example 143 6-[8-[[2-[(1S)-1-Amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0241] Steps 1 and 2: tert-butyl ((1S)-1-(8-fluoro-6-((2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)methyl)-6,7-dihydro-5H-indeno[5,6-d]oxazol-2-yl)-2-hydroxyethyl)carbamate epimer A [ka]

[0242] The title compound was prepared from Intermediate 2 and Intermediate 102 similarly to Example 141, steps 1 and 2, and was obtained as a yellow solid. MS (ESP): m / z=654.2 [M+H] + .

[0243] Step 3: 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0244] The title compound was prepared similarly to Example 63, Step 3, and obtained as a white solid. MS (ESP): m / z=554.1 [M+H] + .

[0245] Example 144 6-[8-[[2-[(1S)-1-Amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0246] The title compound was prepared from Intermediate 3 and Intermediate 102 in analogy to Example 143 and obtained as a white solid. MS (ESP): m / z=554.1 [M+H] + .

[0247] Example 145 6-[8-[[8-Fluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0248] Step 1: tert-butyl N-[(1S)-2-[tert-butyl(diphenyl)silyl]oxy-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]ethyl]-N-methyl-carbamate [ka]

[0249] The title compound was prepared from Intermediate 2 and Intermediate 103 similarly to Example 141, Step 1, and was obtained as a brown solid. MS (ESP): m / z=906.4 [M+H] + .

[0250] Step 2: tert-Butyl N-[(1S)-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]-2-hydroxy-ethyl]-N-methyl-carbamate epimer A [ka]

[0251] To a solution of tert-butyl N-[(1S)-2-[tert-butyl(diphenyl)silyl]oxy-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]ethyl]-N-methyl-carbamate (1.0 g, 1.1 mmol, 1.0 equiv.) in THF (16 mL) was added tetrabutylammonium fluoride (1 M in THF, 1.32 mL, 1.32 mmol, 1.2 equiv.). The resulting mixture was stirred at 25 °C for 1 hour. The mixture was concentrated and the enantiomers were separated by chiral SFC, revealing peak 1: tert-butyl N-[(1S)-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]-2-hydroxy-ethyl]-N-methyl -carbamate epimer A and peak 2: tert-butyl N-[(1S)-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]-2-hydroxy-ethyl]-N-methyl-carbamate epimer B.

[0252] Step 3: 6-[8-[[8-fluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer A [ka]

[0253] The title compound was prepared similarly to Example 136, Step 2, and obtained as a white solid. MS (ESP): m / z=568.2 [M+H] + .

[0254] Example 146 6-[8-[[8-Fluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one epimer B [ka]

[0255] The title compound was prepared from tert-butyl N-[(1S)-1-[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]-2-hydroxy-ethyl]-N-methyl-carbamate epimer B (Example 145, Step 2) in analogy to Example 145, Step 3, and obtained as a gray solid. MS (ESP): m / z=568.2 [M+H] + .

[0256] Example 147 6-[8-[[8-Fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one epimer A [ka]

[0257] The title compound was prepared from Intermediate 3 and Intermediate 101 in analogy to Example 141 and obtained as an off-white solid. MS (ESP): m / z=579.3 [M+H] + .

[0258] Example 148 6-[8-[[8-Fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one epimer B [ka]

[0259] The title compound was prepared from Intermediate 3 and Intermediate 101 in analogy to Example 142 and obtained as an off-white solid. MS (ESP): m / z=579.3 [M+H] + .

[0260] Example 149 (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)propanamide [ka]

[0261] To a stirred solution of (2R)-2-(dimethylamino)propanoic acid [CAS no. 157431-09-9] (31.6 mg, 0.27 mmol, 1.0 equiv.) in DMF (2.7 mL) was added N,N-diisopropylethylamine (0.07 mL, 0.41 mmol, 1.5 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg, 0.32 To the resulting mixture was added 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 42, 150.0 mg, 0.27 mmol, 1.0 equiv.). The resulting mixture was stirred at 25° C. for 1.5 hours. Water was then added, and the mixture was extracted with EtOAc (3×10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude compound, which was purified by silica cartridge chromatography (NH-silica 28 g, DCM / MeOH 100:0 to 90:10) to give the title compound (141.2 mg, 0.22 mmol, 75.9% yield) as an off-white solid. MS (ESP): m / z = 655.3 [M+H] + .

[0262] The following examples were prepared similarly to Example 149. [Table 11-1] [Table 11-2] [Table 11-3]

[0263] Example 158 (2R)-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]pyrrolidine-2-carboxamide [ka]

[0264] Step 1: tert-butyl (2R)-2-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate [ka]

[0265] The title compound was prepared from 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 41) and BOC-D-PRO-OH [CAS number 37784-17-1] as a pale yellow solid. MS (ESP): m / z = 753.5 [M+H] + .

[0266] Step 2: (2R)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]pyrrolidine-2-carboxamide [ka]

[0267] A mixture of tert-butyl (2R)-2-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (143.0 mg, 0.19 mmol, 1.0 equiv) and trifluoroacetic acid (0.15 mL, 1.9 mmol, 10.0 equiv) in DCM (3 mL) was stirred at room temperature for 4 h. The mixture was concentrated and purified by flash column chromatography (silica-NH, 0-20% MeOH / DCM) to give the product, which was triturated in MeCN / EtO (1:1, 2 mL) to give the title compound (61.0 mg, 0.09 mmol, 49.2% yield) as a white solid. MS (ESP): m / z = 653.2 [M+H] + .

[0268] The following examples were prepared similarly to Example 158. [Table 12-1] [Table 12-2] [Table 12-3]

[0269] Example 165 2-Amino-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; Formic acid [ka]

[0270] The title compound was prepared from 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one (Example 41) and BOC-glycine in analogy with Example 158, except that formic acid was used instead of trifluoroacetic acid and DCM in step 2, and obtained as a yellow solid. MS (ESP) m / z = 627.0 [M+H] + .

[0271] Example 166 2-Amino-N-methyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]acetamide Enantiomer A [ka] and Example 167 2-Amino-N-methyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]acetamide Enantiomer B [ka]

[0272] The racemic title compound was prepared from racemic 6-[8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one hydrochloride (prepared similarly to Example 118) and BOC-glycine as a yellow solid, in analogy with Example 158, except that hydrochloric acid was used instead of trifluoroacetic acid and EtOH was used instead of DCM in step 2. MS (ESP) m / z = 627.0 [M+H] + The enantiomers were separated by chiral SFC and obtained as white solids.

[0273] Example 168 N-[2-[4,8-Difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)acetamide [ka]

[0274] The title compound was prepared from N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(methylamino)acetamide (Example 61) in analogy to Example 63, Step 4, and obtained as a white solid. MS (ESP): m / z = 641.3 [M+H] + .

[0275] Example 169 (2R)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-2-(methylamino)propanamide [ka]

[0276] The title compound was prepared from 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid (Intermediate 2) and tert-butyl N-[(1R)-2-[(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (Intermediate 105) in analogy to Example 9, and obtained as an off-white solid. MS (ESP): m / z = 609.3 [M+H] + .

[0277] Example 170 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride enantiomer A [ka] and Example 171 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride enantiomer B [ka]

[0278] The title compound was prepared from Intermediate 3 and Intermediate 73 in analogy to Examples 124 and 125, steps 1 and 2, except that the enantiomers were separated in the penultimate step, and was obtained as a white solid. MS (ESP): m / z=537.3 [M+H] + .

[0279] Intermediates Intermediate 1 6-[5-(2-aminoethyl)-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0280] Step 1: 6-Bromo-4H-pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0281] To a solution of methyl glycolate (60.0 mL, 777.31 mmol, 7.86 equiv) in 3,6-dibromopyrazin-2-amine [CAS number 2376926-19-9] (25.0 g, 98.86 mmol, 1 equiv) under N was added potassium tert-butoxide (34.0 g, 303 mmol, 3.07 equiv) at 60 °C under N. Methyl glycolate (10.0 mL, 98.86 mmol, 1 equiv) was added, and the mixture was stirred at 60 °C for 3 h. The reaction mixture was poured into aqueous HCl (1 N, 350 mL) and filtered. The filter cake was washed with HO (3 x 50 mL) and MTBE (3 x 50 mL) and dried under reduced pressure. The aqueous washes were extracted with EtOAc (3 x 150 mL), combined with the organic filtrate (MTBE), and the mixture was concentrated to give a residue. The filter cake and residue were combined to give the title compound (23 g, 100 mmol, quantitative yield).

[0282] Step 2: 5: 6-Bromo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0283] To a mixture of 6-bromo-4H-pyrazino[2,3-b][1,4]oxazin-3-one (15.0 g, 65.21 mmol, 1 equiv.) and potassium carbonate (27.0 g, 195.36 mmol, 3 equiv.) in DMF (100 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (18.0 mL, 101.7 mmol, 1.56 equiv.) at 0 °C. The reaction was then stirred at 15 °C for 0.5 h. The reaction mixture was diluted with HO (600 mL), and the resulting solid was collected by filtration. The solid was washed with water (50 mL × 3) and dried under reduced pressure to afford the title compound (23 g, 63.84 mmol, 97.9% yield) as a yellow solid.

[0284] Step 3: tert-butyl N-[2-[2-oxo-3-[3-oxo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-6-yl]oxazolidin-5-yl]ethyl]carbamate [ka]

[0285] To a solution of 6-bromo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-3-one (23.47 g, 65.14 mmol, 1 equiv.) and tert-butyl N-[2-(2-oxooxazolidin-5-yl)ethyl]carbamate [CAS number 2353503-50-9] (15.0 g, 65.14 mmol, 1 equiv.) in 1,4-dioxane (150 mL) was added copper(I) iodide (3722 mg, 19.54 mmol, 0.300 equiv.) and trans-N,N'-dimethylcyclohexane-1,2-diamine (5560.5 mg, 39.09 mmol, 0.600 equiv.) and potassium carbonate (27009.8 mg, 195.43 mmol, 3 equiv.). The mixture was stirred at 100° C. for 3 hours. The mixture was concentrated to give a residue. The residue was diluted with EtOAc (200 mL) and washed with brine (100 mL×2). The organic phase was dried over Na2SO4 and then concentrated to give the crude product. The crude product was purified by flash column chromatography (PE / EtOAc = 3:1 to 1:1) and concentrated to give the title compound (26.25 g, 51.51 mmol, 79.1% yield).

[0286] Step 4: 6-[5-(2-aminoethyl)-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0287] To a mixture of tert-butyl N-[2-[2-oxo-3-[3-oxo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-6-yl]oxazolidin-5-yl]ethyl]carbamate (47.2 g, 92.62 mmol, 1 equiv.) in DCM (100 mL) was added trifluoroacetic acid (472.0 mL, 6126 mmol, 66.15 equiv.), and the solution was stirred at 40° C. for 16 hours. Approximately 100 mL of solvent was removed by air distillation, and then another 100 mL of trifluoroacetic acid was added, and the temperature was increased to 70° C. and the mixture was stirred for 48 hours. The solvent was removed by concentration, and the residue was dissolved in 100 mL of water. The solution was extracted with EtOAc (100 mL×2), and the organic phase was discarded to form a solid. The solid was collected by filtration and dried under reduced pressure to give the title compound (14.0 g, 35.6 mmol, 35.36% yield) as a white solid. The filtrate was concentrated to give the crude product, which was azeotroped with 100 mL of toluene, and the resulting solid was triturated with 100 mL of MeCN. The solid was then collected by filtration and dried under reduced pressure to give additional title compound (15.3 g, 38.9 mmol, 38.6% yield) as an off-white solid. MS (ESP): m / z=280.1 [M+H] + .

[0288] Intermediate 2 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0289] The title compound was prepared analogously to Intermediate 1 using tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate [CAS number 169206-55-7] instead of tert-butyl N-[2-(2-oxooxazolidin-5-yl)ethyl]carbamate, and obtained as a pale yellow solid. MS (ESP): m / z = 306.1 [M+H] + .

[0290] Intermediate 3 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one hydrochloride [ka]

[0291] Step 1: tert-butyl 3-[5-(2-ethoxy-2-oxo-ethoxy)-6-nitro-2-pyridyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate [ka]

[0292] To a solution of potassium carbonate (2.43 g, 17.56 mmol, 1.5 equiv.) and N,N-dimethyl-ethylenediamine (412.49 mg, 4.68 mmol, 0.400 equiv.) in 1,4-dioxane (40 mL) was added copper(I) iodide (445.84 mg, 2.34 mmol, 0.200 equiv.), tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate [CAS number 169206-55-7] (3.0 g, 11.71 mmol, 1 equiv.), and ethyl 2-[(6-bromo-2-nitro-3-pyridyl)oxy]acetate [CAS number 443956-09-0] (3.57 g, 11.71 mmol, 1 equiv.). The mixture was degassed with nitrogen three times and stirred at 100° C. for 2 hours. The reaction was filtered, and the filtrate was concentrated to dryness. The residue was diluted with EtOAc (10 mL). The organic layer was washed with water (3 mL) and brine (3 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica column chromatography (PE / EtOAc=1:1) to give the title compound (5.0 g, 10.41 mmol, 88.91% yield) as a yellow solid.

[0293] Step 2: tert-butyl 2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate [ka]

[0294] To a solution of tert-butyl 3-[5-(2-ethoxy-2-oxo-ethoxy)-6-nitro-2-pyridyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (5.0 g, 10.41 mmol, 1 equiv.) in acetic acid (50 mL), iron (2.91 g, 52.03 mmol, 5 equiv.) was added, and the mixture was stirred at 60 °C for 2 h. The reaction was filtered and concentrated to dryness. The residue was diluted with EtOAc (50 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by silica column chromatography (PE / EtOAc = 1:1) to give the title compound (4 g, 9.89 mmol, 95.04% yield) as a yellow solid. MS (ESP): m / z = 405.2 [M+H] + .

[0295] Step 3: 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one hydrochloride [ka]

[0296] A solution of tert-butyl 2-oxo-3-(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (500.0 mg, 1.24 mmol, 1 equiv.) in 4 M hydrochloric acid in methanol (20.0 mL, 80 mmol, 64.7 equiv.) was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure. EtOAc (20 mL) was added to the residue, and the mixture was filtered. The filter cake was washed with EtOAc (10 mL) and then dried to give the title compound (238.8 mg, 0.700 mmol, 55.5% yield) as a gray solid. The combined filtrate and washings were concentrated to give additional title compound (150 mg, 0.440 mmol, 35.0% yield) as a yellow solid. MS (ESP): m / z = 305.0 [M+H] + .

[0297] Intermediate 4 6-(2-amino-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0298] Step 1: Benzyl N-(1-oxaspiro[2.3]hexan-5-yl)carbamate [ka]

[0299] 3-Chloroperbenzoic acid (787.95 mg, 4.57 mmol, 1.24 equiv) was added to a solution of benzyl N-(3-methylenecyclobutyl)carbamate [CAS No. 130368-98-8] (800.0 mg, 3.68 mmol, 1 equiv) in DCM (7.87 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then allowed to warm to room temperature and stirred at room temperature for 2 hours. Additional 3-chloroperbenzoic acid (127.09 mg, 0.740 mmol, 0.200 equiv) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous NaSO, saturated aqueous NaHCO (2x), and brine. The organic layer was dried, filtered, and concentrated to give the crude title compound (860 mg, 3.69 mmol, quantitative yield) as a white solid (as a mixture of cis:trans isomers). MS (ESP): m / z=234.4 [M+H] + .

[0300] Step 2: Benzyl N-[3-(azidomethyl)-3-hydroxy-cyclobutyl]carbamate [ka]

[0301] Sodium azide (479.37 mg, 7.37 mmol, 2 equiv.) and ammonium chloride (394.42 mg, 7.37 mmol, 2 equiv.) were added to a solution of benzyl N-(1-oxaspiro[2.3]hexan-5-yl)carbamate (860.0 mg, 3.69 mmol, 1 equiv.) in methanol (14.46 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and saturated aqueous NaHCO3. The organic phase was dried, filtered, and concentrated in vacuo to give the crude title compound (1020 mg, 3.69 mmol, quantitative yield) as a pale yellow oil. MS (ESP): m / z = 277 [M+H] + .

[0302] Step 3: Benzyl N-[3-(aminomethyl)-3-hydroxy-cyclobutyl]carbamate [ka]

[0303] Triphenylphosphine (1934.73 mg, 7.38 mmol, 2 equiv.) was added to a solution of benzyl N-[3-(azidomethyl)-3-hydroxycyclobutyl]carbamate (1019.0 mg, 3.69 mmol, 1 equiv.) in 12 mL of THF / 12 mL of water. The mixture was stirred at room temperature for 18 h, then diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2x) and 9:1 EtOAc / MeOH (2x). The combined organic phases were concentrated in vacuo, and the crude product was purified by flash column chromatography (0-10% MeOH in DCM) to afford the title compound (783 mg, 3.13 mmol, 85% yield) as a white gum. MS (ESP): m / z = 251.3 [M+H] + .

[0304] Step 4: Benzyl N-(6-oxo-5-oxa-7-azaspiro[3.4]octan-2-yl)carbamate [ka]

[0305] To a stirred solution of benzyl N-[3-(aminomethyl)-3-hydroxycyclobutyl]carbamate (273.0 mg, 1.09 mmol, 1 equiv.) in THF (6.54 mL) and DMF (1.31 mL) cooled to 0 °C, N,N'-carbonyldiimidazole (185.71 mg, 1.15 mmol, 1.05 equiv.) was added portionwise. The mixture was stirred at 0 °C for 20 min. The mixture was allowed to reach room temperature and stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, then diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic phase was dried over Na2SO4 and concentrated in vacuo. Water was added to the residue, and the resulting white precipitate was filtered, washed with water, and dried under vacuum to give the title compound (268 mg, 0.968 mmol, 89% yield). MS (ESP): m / z = 277.2 [M+H] + .

[0306] Step 5: Benzyl N-[6-oxo-7-[3-oxo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-6-yl]-5-oxa-7-azaspiro[3.4]octan-2-yl]carbamate [ka]

[0307] A mixture of benzyl N-(6-oxo-5-oxa-7-azaspiro[3.4]octan-2-yl)carbamate (660.0 mg, 2.39 mmol, 1 equiv.), 6-bromo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-3-one (860.63 mg, 2.39 mmol, 1 equiv.), potassium carbonate (990.47 mg, 7.17 mmol, 3 equiv.), copper(I) iodide (136.48 mg, 0.720 mmol, 0.300 equiv.), and (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine (203.87 mg, 1.43 mmol, 0.600 equiv.) was degassed by purging the system with vacuum / nitrogen atmosphere (three times). 2-Methyltetrahydrofuran (15.93 mL) was added, and the mixture was then degassed and heated at 80° C. for 6 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried, filtered, and the volatiles were removed under reduced pressure. The crude product was purified by silica cartridge chromatography (10-60% EtOAc / cyclohexane) to give the title compound (730 mg, 1.31 mmol, 55% yield) as a pale yellow solid. MS (ESP): m / z=556.2 [M+H] + .

[0308] Step 6: 6-(2-amino-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl)-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-3-one [ka]

[0309] A stirred solution of benzyl N-[6-oxo-7-[3-oxo-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-6-yl]-5-oxa-7-azaspiro[3.4]octan-2-yl]carbamate (370.0 mg, 0.670 mmol, 1 equiv.) in THF (60.47 mL) / ethanol (4.32 mL) was subjected to three nitrogen / vacuum cycles. Palladium on carbon 10% by weight (106.29 mg, 0.100 mmol, 0.150 equiv.) was added, and the mixture was subjected to three nitrogen / vacuum cycles followed by three hydrogen / vacuum cycles. The reaction mixture was then stirred under 1 atmosphere of hydrogen at room temperature for 16 hours. The reaction mixture was filtered and washed with ethanol, then the filtrate was concentrated under reduced pressure to give the crude title compound (303 mg, 0.720 mmol, quantitative yield) as a brown solid. MS (ESP): m / z=422.2 [M+H] + .

[0310] Step 7: 6-(2-amino-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl)-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid [ka]

[0311] A solution of 6-(2-amino-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl)-4-(2-trimethylsilylethoxymethyl)pyrazino[2,3-b][1,4]oxazin-3-one (280.0 mg, 0.660 mmol, 1 equiv.) in trifluoroacetic acid (6.23 mL, 80.83 mmol, 121.68 equiv.) was stirred at 60° C. for 15 hours. The volatiles were removed under reduced pressure to give the crude impure title compound (313 mg) as a dark brown solid, which was used in the next reaction without further purification. MS (ESP): m / z = 292.2 [M+H] + .

[0312] Intermediate 5 Ethyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate [ka]

[0313] Step 1: Diethyl 4,7-difluoroindan-2,2-dicarboxylate [ka]

[0314] To a solution of diethyl malonate (3.39 mL, 22.34 mmol, 1 equiv.) in THF (709.14 mL) was added potassium tert-butoxide (5.26 g, 46.91 mmol, 2.1 equiv.) at 0 °C. The mixture was stirred at the same temperature for 1 h, and then 2,3-bis(bromomethyl)-1,4-difluorobenzene [CAS number 912999-77-0] (6.7 g, 22.34 mmol, 1 equiv.) dissolved in THF (354.57 mL) was added, and the mixture was stirred at 60 °C for 24 h. The reaction was concentrated in vacuo. The mixture was partitioned between water and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc (x1). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound (6.7 g, 22.46 mmol, quantitative yield) which was used in the next reaction without further purification.

[0315] Step 2: Ethyl 4,7-difluoroindan-2-carboxylate [ka]

[0316] A mixture of diethyl 4,7-difluoroindane-2,2-dicarboxylate (3.969 g, 13.3 mmol, 1 equiv.), water (3.94 mL), and lithium chloride (1.13 g, 26.6 mmol, 2 equiv.) in DMSO (26.3 mL) was stirred at 170 °C for 17 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with water (x1). The combined organic phases were dried over NaSO and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (70 g silica, 1% to 10% EtOAc / heptane) to give the title compound (2.047 g, 9.06 mmol, 66% yield) as a pale yellow oil. MS (ESP): m / z = 227.2 [M+H] + .

[0317] Step 3: Ethyl 4,7-difluoro-5-nitro-indan-2-carboxylate [ka]

[0318] To a solution of ethyl 4,7-difluoroindan-2-carboxylate (1.02 g, 4.52 mmol, 1 equiv.) in sulfuric acid (13.97 mL, 262.03 mmol, 58 equiv.) at 0 °C, nitric acid (0.29 mL, 4.52 mmol, 1 equiv.) was added, and the mixture was stirred at 0 °C for 30 min. The mixture was poured into water and ice at 0 °C and then extracted with EtOAc. The organic phase was washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (10 g, cyclohexane / EtOAc, 100% cyclohexane to 70:30) to afford the title compound (1240 mg, 4.57 mmol, quantitative yield) as a pale yellow liquid. MS (ESP): m / z = 272.1 [M+H] + .

[0319] Step 4: Ethyl 5-amino-4,7-difluoro-indan-2-carboxylate [ka]

[0320] Ethyl 4,7-difluoro-5-nitro-indan-2-carboxylate (1300.0 mg, 4.79 mmol, 1 equiv.) was stirred in ethanol (47.93 mL) in the presence of 10% palladium on carbon (510.09 mg, 0.480 mmol, 0.100 equiv.) under a hydrogen atmosphere (765 mmHg) at 25° C. for 16 hours. The reaction was filtered through a Celite® pad and concentrated in vacuo to give the title compound (1115 mg, 4.62 mmol, 96.43% yield) as a pink oil. MS (ESP): m / z=242.1 [M+H] + .

[0321] Step 5: Ethyl 5-acetamido-4,7-difluoro-indan-2-carboxylate [ka]

[0322] To a stirred solution of ethyl 5-amino-4,7-difluoro-indan-2-carboxylate (375.0 mg, 1.55 mmol, 1 equiv) in DCM (15.55 mL) was added acetic anhydride (154.01 uL, 1.63 mmol, 1.05 equiv) and the mixture was stirred at 25 °C for 2.5 hours. A saturated solution of NaHCO (aq) was added to the reaction. The phases were separated and the organic phase was dried over NaSO and concentrated in vacuo to give the title compound (430 mg, 1.52 mmol, 97.65% yield) as a red solid. MS (ESP): m / z = 284.2 [M+H] + .

[0323] Step 6: Ethyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate [ka]

[0324] To a solution of ethyl 5-acetamido-4,7-difluoro-indan-2-carboxylate (430.0 mg, 1.52 mmol, 1 equiv.) in sulfuric acid (4.69 mL, 88.04 mmol, 58 equiv.) at 0 °C, nitric acid (106.37 uL, 1.67 mmol, 1.1 equiv.) was added and the mixture was stirred at 0 °C for 80 minutes. The reaction was slowly added to a saturated aqueous solution of NaHCO at 0 °C. The aqueous phase was extracted with DCM (x1), and the organic phase was dried over NaSO and concentrated in vacuo to give the title compound (490.0 mg, 1.50 mmol, 98.3% yield) as a brown gum. MS (ESP): m / z = 329.4 [M+H] + .

[0325] Step 7: Ethyl 5-amino-4,7-difluoro-6-nitro-indan-2-carboxylate [ka]

[0326] To a stirred solution of ethyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate (1170.0 mg, 3.56 mmol, 1 equiv.) in ethanol (35.64 mL), sulfuric acid (2.09 mL, 39.2 mmol, 11 equiv.) was added, and the mixture was stirred at 78 °C for 16 h. The reaction was concentrated in vacuo and then slowly added to a stirred aqueous solution of NaHCO cooled to 0 °C. The aqueous phase was extracted with DCM (x2). The combined organic phases were dried over NaSO and concentrated in vacuo. The mixture was purified by silica cartridge chromatography (cyclohexane / EtOAc 97:3 to 70:30) to afford the title compound (850 mg, 2.97 mmol, 83.32% yield) as a yellow gum. MS (ESP): m / z = 287.2 [M+H] + .

[0327] Step 8: Ethyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate [ka]

[0328] Ethyl 5-amino-4,7-difluoro-6-nitro-indan-2-carboxylate (850.0 mg, 2.97 mmol, 1 equiv.) was stirred in ethanol (40 mL) in the presence of 10% palladium on carbon (316.03 mg, 0.300 mmol, 0.100 equiv.) under a hydrogen atmosphere (765 mmHg) at 25° C. for 2 hours. The reaction was filtered through a Celite® pad and concentrated in vacuo to give the title compound (690 mg, 2.69 mmol, 90.67% yield) as a pale yellow solid. MS (ESP): m / z=258.1 [M+H] + .

[0329] Intermediate 6 Methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate [ka]

[0330] Step 1: Methyl 4,7-difluoro-5-nitro-indan-2-carboxylate [ka]

[0331] To a solution of methyl 4,7-difluoroindan-2-carboxylate (Intermediate 6) (35.6 g, 167.77 mmol, 1 equiv.) in sulfuric acid (518.7 mL, 9731 mmol, 58 equiv.) at 0° C., nitric acid (10.69 mL, 167.77 mmol, 1 equiv.) was added, and the mixture was stirred at 0° C. for 30 minutes. The mixture was poured into ice water and then extracted with EtOAc (700 mL×3). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (44.7 g, 173.8 mmol, quantitative yield) as a light brown oil. MS (ESP): m / z=258.1 [M+H] + .

[0332] Step 2: Methyl 5-amino-4,7-difluoro-indan-2-carboxylate [ka]

[0333] Methyl 4,7-difluoro-5-nitro-indan-2-carboxylate (44.7 g, 173.8 mmol, 1 equiv.) was stirred in methanol (555.28 mL) in the presence of 10% palladium on carbon (50% wet) (18.5 g, 8.69 mmol, 0.050 equiv.) under a hydrogen atmosphere (100 psi) at 25° C. for 16 hours. The catalyst was filtered off and the organic phase was concentrated in vacuo to give the title compound (34.6 g, 152.28 mmol, 87.62% yield) as a purple oil. MS (ESP): m / z = 228.1 [M+H] + .

[0334] Step 3: Methyl 5-acetamido-4,7-difluoro-indan-2-carboxylate [ka]

[0335] To a stirred solution of methyl 5-amino-4,7-difluoro-indan-2-carboxylate (34.6 g, 152.28 mmol, 1 equiv.) in DCM (1437 mL) was added acetic anhydride (15.09 mL, 159.9 mmol, 1.05 equiv.) and the mixture was stirred at 25 °C for 16 h. A saturated solution of NaHCO was added to the reaction. The phases were separated and the organic phase was dried over NaSO and concentrated in vacuo to give the title compound (36.4 g, 135.2 mmol, 88.78% yield) as a pink solid. MS (ESP): m / z = 270.2 [M+H] + .

[0336] Step 4: Methyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate [ka]

[0337] To a solution of methyl 5-acetamido-4,7-difluoro-indan-2-carboxylate (36.4 g, 135.2 mmol, 1 equiv.) in sulfuric acid (418 mL, 7841 mmol, 58 equiv.) at 0 °C, nitric acid (9.47 mL, 148.71 mmol, 1.1 equiv.) was added and the mixture was stirred at 0 °C for 30 min. The reaction mixture was slowly added to ice water and extracted with DCM (x2). The combined organic phases were dried over Na SO and concentrated in vacuo to give the title compound (36.4 g, 115.8 mmol, 85.68% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 3.73-3.53 (m, 4H), 3.43-3.22 (m, 4H), 2.04 (s, 3H).

[0338] Step 5: Methyl 5-amino-4,7-difluoro-6-nitro-indan-2-carboxylate [ka]

[0339] To a stirred solution of methyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate (36.4 g, 115.84 mmol, 1 equiv.) in methanol (1000 mL) was added sulfuric acid (67.9 mL, 1274 mmol, 11 equiv.), and the mixture was stirred at 65° C. for 16 hours. The reaction was concentrated in vacuo and then slowly added to ice-cold saturated aqueous NaHCO solution. The aqueous phase was extracted with DCM (1000 mL×3). The combined organic phases were washed with water (500 mL), dried over NaSO, and concentrated in vacuo to give the title compound (32.2 g, 118.3 mmol, quantitative yield) as a brown solid. MS (ESP): m / z=273.1 [M+H] + .

[0340] Step 6: Methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate [ka]

[0341] Methyl 5-amino-4,7-difluoro-6-nitro-indan-2-carboxylate (27.2 g, 99.93 mmol, 1 equiv.) was suspended in methanol (358.16 mL), and the mixture was stirred under a hydrogen atmosphere (100 psi) in the presence of 10% palladium on carbon (50% wet) (6380 mg, 3 mmol, 0.030 equiv.) at 25 °C for 4 h. The catalyst was filtered off, and the organic phase was concentrated in vacuo to give the title compound (23.42 g, 96.69 mmol, 96.8% yield) as a brown solid. MS (ESP): m / z = 243.1 [M+H] + .

[0342] Intermediate 7 Ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate [ka]

[0343] Route A: Step 1: Ethyl 4-fluoro-1-oxo-indan-2-carboxylate [ka]

[0344] A mixture of sodium hydride, 60% in oil (7.99 g, 199.8 mmol, 3 equiv.) in toluene (120 mL) was cooled to 0 °C, and then diethyl carbonate (18.56 mL, 153.18 mmol, 2.3 equiv.) was added dropwise. The mixture was heated to 120 °C, and a solution of 4-fluoroindan-1-one (10.0 g, 66.6 mmol, 1 equiv.) in toluene (120 mL) was added dropwise over 1.5 h. The mixture was left stirring at 120 °C for 1 h. It was allowed to reach room temperature, and then the reaction mixture was slowly poured into cooled NH Cl (saturated aqueous solution), and the pH was adjusted to 5 by adding acetic acid. The product was extracted with EtOAc, the phases were separated, and the organic phase was dried over Na SO , filtered, and concentrated. The resulting crude product (18.1 g) was purified by silica cartridge chromatography (200 g, 0-12% EtOAc / cyclohexane). The fractions were concentrated under reduced pressure to give the title compound (13.86 g, 62.37 mmol, 91.78% yield) as a yellow oil. MS (ESP): m / z = 223.1 [M+H] + .

[0345] Step 2: Ethyl 4-fluoroindan-2-carboxylate [ka]

[0346] A solution of ethyl 4-fluoro-1-oxo-indan-2-carboxylate (13.2 g, 59.4 mmol, 1 equiv.) in ethanol (480 mL) and HCl (4.5 mL) was stirred under a hydrogen atmosphere in the presence of Pd / C (12.64 g, 11.88 mmol, 0.200 equiv.) for 4 hours. The mixture was filtered and washed with EtOAc, then concentrated in vacuo. This was diluted with EtOAc, washed with water (2×) and brine (1×), and concentrated in vacuo to give the title compound (12.7 g, 60.99 mmol, quantitative yield). MS (ESP): m / z = 209.1 [M+H] + .

[0347] Step 3: Ethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate; Ethyl 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate; Ethyl 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate [ka]

[0348] A stirred solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.09 mL, 186.72 mmol, 2 equiv.) and 3,4,7,8-tetramethyl-1,10-phenanthroline (882.46 mg, 3.73 mmol, 0.040 equiv.) was degassed three times, and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (1237.67 mg, 1.87 mmol, 0.020 equiv.) was added under a N atmosphere. N was bubbled through the reaction mixture for 15 minutes, and then ethyl 4-fluoroindan-2-carboxylate (19.44 g, 93.36 mmol, 1 equiv.) was added over 20 minutes. The mixture was stirred at 65 °C for 4 hours and then cooled to room temperature. EtOAc (200 mL) was added, the mixture was stirred for 30 min, the catalyst was filtered off, and the solvent was evaporated under reduced pressure to give a crude material containing the title compound mixture (35 g, 104.73 mmol, quantitative yield), which was used directly in the next step. MS (ESP): m / z=335.3 [M+H] + .

[0349] Step 4: Ethyl 4-fluoro-6-hydroxy-indan-2-carboxylate; Ethyl 4-fluoro-7-hydroxy-indan-2-carboxylate [ka]

[0350] To a stirred solution of ethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate; ethyl 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate; ethyl 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-2-carboxylate (3.24 g, 9.7 mmol, 1 equiv.) in THF (10 mL) was added sodium perborate monohydrate (2.9 g, 29.1 mmol, 3 equiv.) in water (10 mL). The mixture was stirred for 2 hours. Water was then added, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica cartridge chromatography (200 g, 0-20% EtOAc / cyclohexane) to give the title compound (253.2 mg, 1.13 mmol, 11.64% yield) as the first eluting isomer as a colorless oil. MS (ESP): m / z = 225.1 [M+H] + .

[0351] Step 5: Ethyl 4-fluoro-5-hydroxy-6-nitro-indan-2-carboxylate [ka]

[0352] To a solution of ethyl 4-fluoro-5-hydroxy-indan-2-carboxylate (1210.0 mg, 5.4 mmol, 1 equiv.) in DCM (25 mL) at 0 °C, nitric acid (385.02 uL, 6.04 mmol, 1.12 equiv.) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water, the phases were separated, and the aqueous layer was extracted with DCM (x1). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude compound, which was purified by silica cartridge chromatography (25 g, cyclohexane 100% to cyclohexane / EtOAc 9:1) to give the title compound (1267 mg, 4.71 mmol, 87.21% yield) as a light orange solid. MS (ESP): m / z = 270.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d) δ 1.20 (t, J = 7.1 Hz, 3H), 3.05-3.31 (m, 4H), 3.47 (tt, J = 8.8, 7.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 7.64 (d, J = 1.4 Hz, 1H), 10.83 (s, 1H); correlation between aromatic CH protons and adjacent benzylic CH protons.

[0353] Step 6: Ethyl 4-fluoro-6-nitro-5-(trifluoromethylsulfonyloxy)indan-2-carboxylate [ka]

[0354] To a solution of ethyl 4-fluoro-5-hydroxy-6-nitro-indan-2-carboxylate (1.0 g, 3.71 mmol, 1 equiv.) in DCM (7.43 mL) at 0 °C, DIPEA (0.65 mL, 3.71 mmol, 1 equiv.) was added, followed by the dropwise addition of a solution of trifluoromethanesulfonic anhydride (1.26 mL, 7.43 mmol, 2 equiv.) in DCM (7.43 mL). The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with DCM and brine, the phases were separated, and the aqueous layer was extracted with DCM (x2). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude product, which was purified by silica cartridge chromatography (50 g, cyclohexane 100% to cyclohexane / EtOAc 9:1) to give the title compound (1.26 g, 3.13 mmol, 84.2% yield) as a pale yellow oil. MS (ESP): m / z = 402.0 [M+H] + .

[0355] Step 7: Ethyl 5-acetamido-4-fluoro-6-nitro-indan-2-carboxylate [ka]

[0356] A suspension of ethyl 4-fluoro-6-nitro-5-(trifluoromethylsulfonyloxy)indan-2-carboxylate (1255.0 mg, 3.13 mmol, 1 equiv.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (361.92 mg, 0.630 mmol, 0.200 equiv.), tris(dibenzylideneacetone)dipalladium(0) (286.38 mg, 0.310 mmol, 0.100 equiv.), acetamide (738.95 mg, 12.51 mmol, 4 equiv.), and cesium carbonate (3056.92 mg, 9.38 mmol, 3 equiv.) in THF (15.64 mL) was prepared in a two-necked round-bottom flask equipped with a condenser. The system was degassed by purging with vacuum / argon atmosphere (three cycles). The reaction mixture was stirred at 75 °C for 0.75 h. The reaction mixture was diluted with EtOAc, filtered through a phase separator, and the volatiles removed under reduced pressure to give the crude product, which was purified by silica cartridge chromatography (100 g silica, 100% cyclohexane to 7:3 cyclohexane / EtOAc) to give the title compound (356 mg, 1.15 mmol, 36.69% yield) as a dark brown viscous oil and ethyl 4-fluoro-5-hydroxy-6-nitro-indan-2-carboxylate (261 mg, 0.970 mmol, 31% yield) as a pale yellow solid. MS (ESP): m / z = 311.1 [M+H] + .

[0357] Step 8: Ethyl 5-amino-4-fluoro-6-nitro-indan-2-carboxylate [ka]

[0358] To a solution of ethyl 5-acetamido-4-fluoro-6-nitro-indan-2-carboxylate (419.0 mg, 1.35 mmol, 1 equiv.) in ethanol (13.5 mL) at room temperature was added sulfuric acid (1079.73 μL, 20.26 mmol, 15 equiv.). The reaction mixture was stirred at 78 °C for 18 h. The reaction mixture was cooled to room temperature, the volatiles were removed under reduced pressure, and the residue was partitioned between NaHCO (saturated aqueous solution) and EtOAc. The phases were separated, and the aqueous layer was extracted with EtOAc (x1). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude product, which was purified by silica cartridge chromatography (25 g silica, cyclohexane 100% to cyclohexane / EtOAc 9:1) to give the title compound (95 mg, 0.350 mmol, 26.23% yield) as a bright yellow solid. MS (ESP): m / z = 269.1 [M+H] + .

[0359] Step 9: Ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate [ka]

[0360] A suspension of ethyl 5-amino-4-fluoro-6-nitro-indan-2-carboxylate (89.03 mg, 0.330 mmol, 1 equiv.) and 10% Pd / C, 55-65% wet (70.64 mg, 0.030 mmol, 0.100 equiv.) in ethanol (6.64 mL) was purged with vacuum / nitrogen atmosphere (3 cycles) and vacuum / hydrogen atmosphere (3 cycles). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was purged with vacuum / nitrogen atmosphere (3 cycles), filtered through a Celite® pad, the cake washed with EtOH, and the volatiles removed under reduced pressure to give the title compound (75 mg, 0.310 mmol, 94.84% yield) as a pale green waxy solid. MS (ESP): m / z = 239.1 [M+H] + .

[0361] Route B: Step 1: Methyl 5-acetamido-4-fluoro-7-methylsulfanyl-6-nitro-indan-2-carboxylate [ka]

[0362] To a solution of methyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate (Intermediate 6, Step 4) (15.0 g, 47.73 mmol, 1 equiv.) in DMF (225 mL) at 0° C. was added a solution of sodium methanethiolate (6.69 g, 95.47 mmol, 2 equiv.) in water (127 mL) dropwise. The reaction mixture was stirred at 0° C. for 45 min, then warmed to room temperature and stirred for an additional 1 h. The reaction mixture was quenched with 1 M HCl (aq.) and extracted with DCM (×2). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give a residue which was diluted with water, sonicated, and the precipitate was collected by filtration through a phase separator to give the crude title compound (29.1 g) as a black viscous oil. MS (ESP): m / z=343.1 [M+H] + .

[0363] Step 2: Ethyl 5-amino-4-fluoro-7-methylsulfanyl-6-nitro-indan-2-carboxylate [ka]

[0364] To a solution of methyl 5-acetamido-4-fluoro-7-methylsulfanyl-6-nitro-indan-2-carboxylate (17.98 g, 52.52 mmol, 1 equiv.) in ethanol (262.6 mL) at room temperature was added sulfuric acid (30.8 mL, 577.73 mmol, 11 equiv.). The reaction mixture was stirred at 78 °C for 17 h. The reaction mixture was cooled to room temperature, the volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (x3). The combined organic phase was filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude title compound (16.18 g, 51.47 mmol, 98.01% yield) as an orange solid. MS (ESP): m / z = 315.2 [M+H] + .

[0365] Step 3: Ethyl 5,6-diamino-4-fluoro-7-methylsulfanyl-indan-2-carboxylate [ka]

[0366] A suspension of ethyl 5-amino-4-fluoro-7-methylsulfanyl-6-nitro-indan-2-carboxylate (15.18 g, 48.29 mmol, 1 equiv.) and Raney nickel (50% slurry in water) (37.5 g, 48.29 mmol, 1 equiv.) in ethanol (150 mL) was purged with nitrogen (5 times), then with hydrogen (5 times), and stirred under hydrogen (7 bar) at room temperature for 23 hours. The reaction mixture was filtered through a Celite® pad, and the cake was washed with ethanol. Removal of the volatiles afforded the crude title compound (10.28 g, 36.15 mmol, 74.86% yield) as a light brown gum. MS (ESP): m / z = 285.2 [M+H] + .

[0367] Step 4: Ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate [ka]

[0368] To a solution of ethyl 5,6-diamino-4-fluoro-7-methylsulfanyl-indan-2-carboxylate (10.0 g, 35.17 mmol, 1 equiv.) in THF (325.63 mL) was added palladium(II) chloride (623.63 mg, 3.52 mmol, 0.100 equiv.), followed by triethylsilane (11.8 mL, 73.9 mmol, 2.1 equiv.) and trimethylchlorosilane (4.46 mL, 35.17 mmol, 1 equiv.), and the mixture was stirred at 35 °C for 15 h. The reaction mixture was diluted with water, and then 200 mL of EtOAc was added. The phases were separated, and the aqueous phase was basified to pH 8 with NaHCO (saturated aqueous solution) and extracted with 200 mL of EtOAc. The combined organic extracts were evaporated to give the title compound (2650 mg, 11.12 mmol, 31.63% yield) as an orange solid. MS (ESP): m / z=239.1 [M+H] + .

[0369] Intermediate 8 4,8-Difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0370] Step 1: Ethyl 5-acetamido-6-amino-4,7-difluoro-indan-2-carboxylate [ka]

[0371] Ethyl 5-acetamido-4,7-difluoro-6-nitro-indan-2-carboxylate (Intermediate 5, Step 6) (185.0 mg, 0.560 mmol, 1 equiv.) was stirred in ethanol (20 mL) in the presence of 10% palladium on carbon (59.97 mg, 0.060 mmol, 0.100 equiv.) under a hydrogen atmosphere (765 mmHg) at 25° C. for 16 hours. The reaction was filtered through a Celite® pad and concentrated in vacuo to give the title compound (159 mg, 0.530 mmol, 94.58% yield) as a pale gray solid. MS (ESP): m / z=299.2 [M+H] + .

[0372] Step 2: Ethyl 4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0373] Ethyl 5-acetamido-6-amino-4,7-difluoro-indan-2-carboxylate (148.0 mg, 0.500 mmol, 1 equiv.) was stirred in acetic acid (4 mL) at 60° C. for 16 hours. The reaction was concentrated in vacuo and then azeotroped with toluene to give the title compound (132 mg, 0.472 mmol, 94.3% yield) as a pale gray solid. MS (ESP): m / z=281.2 [M+H] + .

[0374] Step 3: (4,8-Difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methanol [ka]

[0375] To a solution of ethyl 4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (118.0 mg, 0.420 mmol, 1 equiv.) in THF (4.21 mL) at 0 °C, 2.3 M lithium aluminum hydride in Me-THF (411.87 μL, 0.950 mmol, 2.25 equiv.) was carefully added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with sodium sulfate decahydrate at 0 °C. The reaction was concentrated in vacuo and purified by silica cartridge chromatography (DCM / MeOH 99.5:0.5 to 93:7) to give the title compound (82.7 mg, 0.347 mmol, 82.69% yield). MS (ESP): m / z = 239.3 [M+H] + .

[0376] Step 4: 4,8-Difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0377] A suspension of (4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methanol (85.0 mg, 0.360 mmol, 1 equiv.) and Dess-Martin periodinane (317.94 mg, 0.750 mmol, 2.1 equiv.) in DCM (4 mL) and DMF (4 mL) was stirred at room temperature for 1 h. DMSO (2 mL) was added and stirring was prolonged for 16 h. The reaction was diluted with EtOAc, saturated aqueous NaSO, and saturated aqueous NaHCO and stirred for 15 min. Brine was added, the phases were separated, and the organic phase was dried over NaSO and concentrated in vacuo to give the crude title compound (217 mg) as a brown oil, which was used in the next reaction without further purification. MS (ESP): m / z = 237.1 [M+H] + .

[0378] Intermediate 9 2-[(Dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0379] Step 1: Ethyl 5-amino-6-[[2-(dimethylamino)acetyl]amino]-4,7-difluoro-indan-2-carboxylate [ka]

[0380] To a stirred solution of ethyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 5) (73 mg, 0.280 mmol, 1 equiv.) and N,N-dimethylglycine (29.38 mg, 0.280 mmol, 1 equiv.) in anhydrous MeCN (2.85 mL) was added 1-methylimidazole (68.12 μL, 0.850 mmol, 3 equiv.), followed by TCFH (127.89 mg, 0.460 mmol, 1.6 equiv.). The mixture was stirred at room temperature for 15 minutes. It was concentrated in vacuo and purified by silica cartridge chromatography (cyclohexane / EtOAc 97:3 to 0:100) to afford the title compound (90 mg, 0.260 mmol, 92.55% yield) as a pale yellow oil. MS (ESP): m / z = 342.4 [M+H] + .

[0381] Steps 2-4: Ethyl 2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0382] The title compound was prepared analogously to Intermediate 8, steps 2-4, and obtained as a yellow oil, which was used in the following reaction without further purification. MS (ESP): m / z=280.2 [M+H] + .

[0383] The following intermediates were prepared similarly to intermediate 9: [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5]

[0384] Intermediate 23 4,8-Difluoro-2-(1-hydroxy-1-methyl-ethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0385] Step 1: Ethyl 5-amino-4,7-difluoro-6-[(2-hydroxy-2-methyl-propanoyl)amino]indan-2-carboxylate [ka]

[0386] To a stirred solution of 2-hydroxy-2-methyl-propanoic acid (72.9 mg, 0.700 mmol, 1 equiv.) in anhydrous DMF (5.27 mL), DIPEA (305.87 μL, 1.76 mmol, 2.5 equiv.) was added, followed by HATU (534.18 mg, 1.4 mmol, 2 equiv.), and the mixture was stirred at room temperature for 10 minutes. The mixture was slowly added to a stirred solution of ethyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 5, 180.0 mg, 0.700 mmol, 1 equiv.) in anhydrous DMF (1.76 mL) at room temperature, and the mixture was stirred at this temperature for 16 hours. This was diluted with EtOAc and washed with a saturated solution of NaHCO (x2) and then with brine (x1). The organic phase was dried over NaSO and concentrated in vacuo. The mixture was purified by silica cartridge chromatography (cyclohexane / EtOAc 80:20 to 30:70) to give the title compound (160 mg, 0.470 mmol, 66.54% yield) as a yellow gum. MS (ESP): m / z = 343.4 [M+H] + .

[0387] Steps 2 to 4: 4,8-Difluoro-2-(1-hydroxy-1-methyl-ethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0388] The title compound was prepared analogously to Intermediate 9, steps 2-4, and obtained as a pink gum, which was used in the following reaction without further purification. MS (ESP): m / z=281.0 [M+H] + .

[0389] Intermediate 24 4,8-Difluoro-2-(4-methylmorpholin-2-yl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0390] Step 1: [4,8-difluoro-2-(4-methylmorpholin-2-yl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methanol [ka]

[0391] To a solution of tert-butyl 2-[4,8-difluoro-6-(hydroxymethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]morpholine-4-carboxylate (Intermediate 17, Step 3) (58.0 mg, 0.140 mmol, 1 equiv.) in anhydrous THF (1.42 mL) was added lithium aluminum hydride solution (0.18 mL, 0.420 mmol, 3 equiv.) (2 M solution in THF) at 0° C. The reaction mixture was gradually heated to 50° C. and stirred at this temperature for 3 h. After cooling, NaSO.10HO was carefully added at 0° C., and the mixture was stirred at room temperature for 30 min. The white solid was filtered off under vacuum, washed with EtOAc and the filtrate was evaporated under reduced pressure to give the title compound (26 mg, 0.080 mmol, 56.76% yield) as a colorless oil which was used directly in the next step.

[0392] Step 2: 4,8-Difluoro-2-(4-methylmorpholin-2-yl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0393] The title compound was prepared analogously to Intermediate 8, step 4, and was obtained as a pale yellow foam, which was used in the following reaction without further purification. MS (ESP): m / z=322.1 [M+H] + .

[0394] Intermediate 25 2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0395] Step 1: Methyl 2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0396] To a solution of methyl 4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 15, Step 2) (55.0 mg, 0.180 mmol, 1 equiv.) and formaldehyde (26.48 uL, 0.360 mmol, 2 equiv.) in THF (1.78 mL) at room temperature was added sodium triacetoxyborohydride (113.06 mg, 0.530 mmol, 3 equiv.) in one portion. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3, the phases were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic phases were filtered through a phase separator and the volatiles were removed under reduced pressure to give the crude product, which was purified by silica cartridge chromatography (DCM 100% to DCM / MeOH 9:1) to give the title compound (30 mg, 0.090 mmol, 52.18% yield) as a white foam. MS (ESN): m / z = 322.3 [M−H] - .

[0397] Steps 2 and 3: 2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0398] The title compound was prepared analogously to Intermediate 9, steps 3 and 4, and was obtained as a purple oil which was used in the following reaction without further purification.

[0399] Intermediate 26 tert-Butyl N-[(1R)-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0400] Step 1: Methyl 5-amino-6-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4,7-difluoro-indan-2-carboxylate [ka]

[0401] A mixture of BOC-N-methyl-D-alanine [CAS No. 19914-38-6] (169.32 mg, 0.830 mmol, 1.01 equiv.) in DCM (11.47 mL) was cooled to −15° C., and 4-dimethylaminopyridine (302.62 mg, 2.48 mmol, 3 equiv.) was added, followed by the dropwise addition of T3P (630.53 mg, 50% solution, 0.990 mmol, 1.2 equiv.). The mixture was stirred at −15° C. for 1 hour, and then methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6) (200.0 mg, 0.830 mmol, 1 equiv.) was added. The mixture was stirred for 1 hour while maintaining the temperature, then allowed to gradually reach room temperature and stirred at room temperature for 16 hours. DCM and NaHCO3 were added, the phases were separated, and the aqueous phase was extracted with DCM (x3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10 g silica, 0-3% MeOH / DCM) to give the title compound (208 mg, 0.490 mmol, 58.93% yield) as a yellow oil. MS (ESN): m / z = 426.5 [M−H] - .

[0402] Steps 2 to 4: tert-butyl N-[(1R)-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0403] The title compound was prepared similarly to Intermediate 8, steps 2-4, and obtained as a pale yellow oil, which was used in the following reaction without purification. MS (ESP): m / z=380.1 [M+H] + .

[0404] Intermediate 27 tert-Butyl (3R)-3-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)morpholine-4-carboxylate [ka]

[0405] The title compound was prepared from methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6) and 4-BOC-3(R)-morpholinecarboxylic acid [CAS number 869681-70-9] in analogy to Intermediate 23. MS (ESP): m / z = 408.2 [M + H] + .

[0406] Intermediate 28 tert-Butyl N-[2-(4,8-difluoro-6-formyl-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0407] Step 1: Methyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazole-6-carboxylate [ka]

[0408] A vial was charged with methyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 15, Step 2) (171.0 mg, 0.420 mmol, 1 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.420 mmol, 1 equiv.), and dimethyl carbonate (4.61 mL, 54.69 mmol, 130.94 equiv.). The mixture was heated to 90 °C overnight. The mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO3, filtered through a hydrophobic phase separator, and dried in vacuo. The crude product was purified by silica cartridge chromatography (10 g, 0% to 50% EtOAc / cyclohexane) to give the title compound (168 mg, 0.400 mmol, 94.99% yield) as a pale yellow oil. MS (ESP): m / z = 424.3 [M+H] + .

[0409] Step 2: tert-butyl N-[2-[4,8-difluoro-6-(hydroxymethyl)-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl]ethyl]-N-methyl-carbamate [ka]

[0410] To a stirred solution of methyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazole-6-carboxylate (223.0 mg, 0.530 mmol, 1 equiv.) in anhydrous THF (2.64 mL), ethanol (1.32 mL), calcium chloride (116.89 mg, 1.05 mmol, 2 equiv.), and sodium borohydride (59.77 mg, 1.58 mmol, 3 equiv.) were added, and the mixture was stirred at 25 °C for 18 h. The mixture was cooled to 0 °C, carefully quenched with saturated aqueous NH4Cl, and extracted with EtOAc (x3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (0-50% EtOAc / cyclohexane) to give the title compound (167 mg, 0.420 mmol, 80.19% yield) as a pale yellow foam. MS (ESP): m / z = 408.2 [M+H] + .

[0411] Step 3: tert-butyl N-[2-(4,8-difluoro-6-formyl-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0412] The title compound was prepared analogously to Intermediate 8, step 4, and obtained as a pale yellow oil. MS (ESP): m / z=396.4 [M+H] + .

[0413] Intermediate 29 tert-Butyl N-[(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0414] Step 1: Ethyl 6-amino-4-fluoro-5-hydroxy-indan-2-carboxylate [ka]

[0415] A suspension of ethyl 4-fluoro-5-hydroxy-6-nitro-indan-2-carboxylate (Intermediate 7, Step 5) (500.0 mg, 1.86 mmol, 1 equiv.) and Pd / C 55-65% wet (79.06 mg, 0.040 mmol, 0.020 equiv.) in ethanol (37.9 mL) was purged with vacuum / nitrogen atmosphere (3 cycles) and vacuum / hydrogen atmosphere (4 cycles). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was purged with vacuum / nitrogen atmosphere (3 cycles) and filtered through a Celite® pad, washing the cake with ethanol. The filtrate was concentrated under reduced pressure to give the crude title compound (411 mg, 1.72 mmol, 87.88% yield) as a colorless viscous oil. MS (ESP): m / z = 240.1 [M+H] + .

[0416] Step 2: Ethyl 6-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]amino]-4-fluoro-5-hydroxy-indan-2-carboxylate [ka]

[0417] To a stirred solution of BOC-SAR-OH (235.68 mg, 1.25 mmol, 1 equiv.) and HATU (506.77 mg, 1.33 mmol, 1.07 equiv.) in DMF (6.84 mL) was added DIPEA (1.08 mL, 6.23 mmol, 5 equiv.). After stirring for 5 minutes, ethyl 6-amino-4-fluoro-5-hydroxy-indan-2-carboxylate (298.0 mg, 1.25 mmol, 1 equiv.) was added to the resulting suspension, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between EtOAc and NaHCO. The organic phase was washed with brine, dried over Na2SO4, and evaporated in vacuo to give a residue that was purified by silica cartridge chromatography (25 g, cyclohexane 100% to cyclohexane / EtOAc 50:50) to give the title compound (228 mg, 0.560 mmol, 40.14% yield) as a pale yellow oil. MS (ESP): m / z = 411.2 [M+H] + .

[0418] Step 3: Ethyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0419] Ethyl 6-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]amino]-4-fluoro-5-hydroxy-indan-2-carboxylate (220.0 mg, 0.540 mmol, 1 equiv.) was dissolved in anhydrous THF (2.74 mL), followed by the addition of triphenylphosphine (309.29 mg, 1.18 mmol, 2.2 equiv.) and freshly activated 4 Å molecular sieves. The mixture was stirred under nitrogen at 0° C. for 1 hour. A solution of diisopropyl azodicarboxylate (0.23 mL, 1.18 mmol, 2.2 equiv.) was added dropwise. The resulting mixture was then warmed to room temperature. After stirring for 1 hour, the solvent was removed in vacuo. Diethyl ether was added, and the resulting mixture was stirred for 1 hour. The filtrate was concentrated and the residue was purified by silica cartridge chromatography (100% cyclohexane to 100% EtOAc) to give the impure title compound (388 mg). This material was used in the next step without further purification. MS (ESP): m / z = 393.2 [M+H] + .

[0420] Step 4: tert-butyl N-[[8-fluoro-6-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate [ka]

[0421] To a stirred solution of ethyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate (210.0 mg, 0.550 mmol, 1 equiv.) in anhydrous methanol (3.7 mL) and THF (7.4 mL) cooled to 0 °C, calcium chloride (123.18 mg, 1.11 mmol, 2 equiv.) was added, followed by sodium borohydride (62.99 mg, 1.66 mmol, 3 equiv.), and the mixture was stirred at this temperature for 5 min. The reaction was poured into a saturated solution of NH4Cl, cooled to 0 °C, and extracted with EtOAc (x1). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica cartridge chromatography (100% DCM to 95:5 DCM / MeOH) to give the title compound (110 mg, 0.310 mmol, 44.52% yield) as a pale yellow gum. MS (ESP): m / z = 351.5 [M+H] + .

[0422] Step 5: tert-butyl N-[(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0423] To a stirred solution of tert-butyl N-[[8-fluoro-6-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-N-methyl-carbamate (85.0 mg, 0.240 mmol, 1 equiv.) in DCM (2.67 mL), Dess-Martin periodinane (133.76 mg, 0.320 mmol, 1.3 equiv.) was added, and the mixture was stirred at room temperature for 50 min. Additional DMP was added, and stirring was extended for 30 min. The reaction was diluted with DCM, NaSO (saturated aqueous solution), and NaHCO (saturated aqueous solution) and stirred for 20 min. The organic phase was dried over NaSO and concentrated in vacuo to give the title compound (75 mg, 0.220 mmol, 88.74% yield) as a pale yellow oil. MS (ESP): m / z = 349.2 [M+H] + .

[0424] Intermediate 30 tert-Butyl 10,16-difluoro-13-formyl-2,5,8-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(16),7,9,11(15)-tetraene-5-carboxylate [ka]

[0425] Step 1: O5-tert-butyl O13-methyl 10,16-difluoro-2,5,8-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(16),7,9,11(15)-tetraene-5,13-dicarboxylate [ka]

[0426] To a stirred solution of methyl 2-[(tert-butoxycarbonylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 12, Step 2) (127.0 mg, 0.330 mmol, 1 equiv.) in DMF (1.4 mL) was added 1,2-dibromoethane (86.09 uL, 1 mmol, 3 equiv.), followed by cesium carbonate (217.0 mg, 0.670 mmol, 2 equiv.). The resulting mixture was stirred at 50° C. for 2 hours. Additional cesium carbonate (217.0 mg, 0.670 mmol, 2 equiv.) was then added, and the reaction mixture was stirred at 50° C. for 3 hours. A saturated aqueous solution of NH4Cl was then added, and the mixture was extracted with EtOAc (3×5 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica cartridge chromatography (25 g, cyclohexane / EtOAc 100:0 to 80:20) to give the title compound (94 mg, 0.230 mmol, 69.28% yield) as a white foam. MS (ESP): m / z = 408.2 [M+H] + .

[0427] Steps 2 and 3: tert-butyl 10,16-difluoro-13-formyl-2,5,8-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(16),7,9,11(15)-tetraene-5-carboxylate [ka]

[0428] The title compound was prepared analogously to Intermediate 8, steps 3 and 4, and obtained as a white foam. MS (ESP): m / z=378.2 [M+H] + .

[0429] Intermediate 31 tert-Butyl (2S,4R)-4-[tert-butoxycarbonyl(methyl)amino]-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate [ka]

[0430] Step 1: (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidine-2-carboxylic acid [ka]

[0431] A solution of (2S,4R)-1-tert-butoxycarbonyl-4-(tert-butoxycarbonylamino)pyrrolidine-2-carboxylic acid [CAS No. 254881-66-8] (200.0 mg, 0.610 mmol, 1 equiv.) in anhydrous THF (5.82 mL) was treated with NaH, dispersion in mineral oil (72.64 mg, 1.82 mmol, 3 equiv.) and stirred at room temperature for 10 minutes. Iodomethane (0.08 mL, 1.21 mmol, 2 equiv.) was added, and the resulting mixture was stirred at room temperature for 3 hours. Additional NaH, dispersion in mineral oil (48.43 mg, 1.21 mmol, 2 equiv.) and iodomethane (0.04 mL, 0.610 mmol, 1 equiv.) were added, and stirring was continued for 2 hours. Additional iodomethane (0.08 mL, 1.21 mmol, 2 equiv.) was added and stirring was continued for 2 h, then the reaction was carefully quenched with water. The aqueous phase was washed with EtO (x2) and then acidified to pH = 3 by addition of HCl (1 M aqueous solution), then extracted with CHCl (3 x 15 mL) and EtOAc (x1). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the title compound (207 mg, 0.600 mmol, 99.29% yield) as a pale yellow foam.

[0432] Steps 2 and 3: Methyl 2-[(2S,4R)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0433] The title compound was prepared analogously to Intermediate 9, steps 1 and 2, and was obtained as a pale yellow foam.

[0434] Step 4: tert-butyl (2S,4R)-4-[tert-butoxycarbonyl(methyl)amino]-2-[4,8-difluoro-6-(hydroxymethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]pyrrolidine-1-carboxylate [ka]

[0435] To a stirred solution of methyl 2-[(2S,4R)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (195.28 mg, 0.350 mmol, 1 equiv.) in THF (3 mL) at 0° C., DIBAL-H (1 M in THF) (1.06 mL, 1.06 mmol, 3 equiv.) was added dropwise. The reaction mixture was stirred at 25° C. for 3 hours, then cooled to 0° C., carefully diluted with saturated aqueous NH4Cl, and extracted with EtOAc (100 mL×3). The organic phase was collected, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica cartridge chromatography (25 g, DCM / MeOH 100:0 to 90:10) to give the title compound (52 mg, 0.170 mmol, 43.3% yield) as a colorless oil. MS (ESP): m / z = 523.5 [M+H] + .

[0436] Step 5: tert-butyl (2S,4R)-4-[tert-butoxycarbonyl(methyl)amino]-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate [ka]

[0437] The title compound was prepared analogously to Intermediate 8, step 4, and obtained as a yellow oil. MS (ESP): m / z=521.3 [M+H] + .

[0438] Intermediate 32 tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate [ka]

[0439] Step 1: (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-carboxylic acid [ka]

[0440] To a solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid [CAS No. 13726-69-7] (1000.0 mg, 4.32 mmol, 1 equiv.) in DCM (10 mL) and DMF (5 mL) at 0° C., imidazole (1471.94 mg, 21.62 mmol, 5 equiv.) was added in one portion. The mixture was stirred at 0° C. for 5 minutes, and then a solution of tert-butyldimethylchlorosilane (1433.88 mg, 9.51 mmol, 2.2 equiv.) in DCM (10 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and then at room temperature for 17 hours. The reaction mixture was quenched with NH4Cl (saturated aqueous solution), the phases were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organic phases were filtered through a phase separator and the volatiles removed under reduced pressure to give the crude product (2.75 g, colorless viscous oil), which was purified by silica gel chromatography (25 g silica cartridge, DCM 100% to DCM / MeOH 95:5) to give the title compound (770 mg, 2.23 mmol, 51.54% yield) as a colorless viscous oil. MS (ESN): m / z = 344.6 [M−H] - .

[0441] Steps 2 to 5: tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate [ka]

[0442] The title compound was prepared analogously to Intermediate 9, using (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-carboxylic acid instead of N,N-dimethylglycine in the first step, and was obtained as a white solid. MS (ESP): m / z = 540.5 [M + H - HO] + .

[0443] The following intermediates were prepared similarly to intermediate 32: [Table 14-1] [Table 14-2] [Table 14-3]

[0444] Intermediate 38 tert-Butyl (2R,3S)-3-[tert-butyl(dimethyl)silyl]oxy-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate

[0445] Steps 1~3: [ka]

[0446] The title compound was prepared from (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-2-carboxylic acid [CAS#187039-57-2] in analogy to Intermediate 32, steps 1-3, and obtained as a yellow oil. MS (ESP): m / z=552.2 [M+H] + .

[0447] Steps 4~5: [ka]

[0448] The title compound was prepared similarly to Intermediate 28, steps 2-3, and obtained as a pale yellow oil. MS (ESP): m / z = 522.2 [M+H] + .

[0449] Intermediate 39 tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(4,8-difluoro-6-formyl-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl)pyrrolidine-1-carboxylate [ka]

[0450] The title compound was prepared from methyl 2-[(2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 32, Step 3) in analogy to Intermediate 28, and obtained as a colorless oil. MS (ESP): m / z = 536.4 [M+H] + .

[0451] Intermediate 40 tert-Butyl N-[2-[tert-butyl(dimethyl)silyl]oxy-1-[4,8-difluoro-6-(hydroxymethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]-N-methyl-carbamate [ka]

[0452] Step 1: (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-[tert-butyl(dimethyl)silyl]oxy-propanoic acid [ka]

[0453] The title compound was prepared analogously to Intermediate 32, Step 1, using (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-hydroxypropanoic acid [CAS number 101772-29-6] instead of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid, and obtained as a white solid. MS (ESP): m / z = 334.3 [M+H] + .

[0454] Steps 2 to 5: tert-butyl N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-1-[4,8-difluoro-6-(hydroxymethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]ethyl]-N-methyl-carbamate [ka]

[0455] The title compound was prepared analogously to Intermediate 23 using (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-[tert-butyl(dimethyl)silyl]oxy-propanoic acid instead of 2-hydroxy-2-methyl-propanoic acid and obtained as a colorless oil. MS (ESP): m / z=510.2 [M+H] + .

[0456] Intermediate 41 tert-Butyl N-[(3R,4S)-4-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)tetrahydrofuran-3-yl]carbamate [ka]

[0457] The title compound was prepared analogously to Intermediate 31, steps 2-5, using (3R,4R)-4-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid [CAS number 1821806-18-1] instead of (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidine-2-carboxylic acid, and obtained as a light brown oil. MS (ESP): m / z = 408.1 [M+H] + .

[0458] Intermediate 42 tert-Butyl N-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)carbamate [ka]

[0459] Step 1: Methyl 2-(tert-butoxycarbonylamino)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0460] To a stirred solution of methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6, 350.0 mg, 1.44 mmol, 1 equiv.) in acetic acid (8.54 mL), N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea [CAS No. 107819-90-9] (503.51 mg, 1.73 mmol, 1.2 equiv.) was added, and the resulting mixture was stirred at 50 °C for 1.5 h. The mixture was then concentrated in vacuo to give the crude compound, which was purified by flash column chromatography (silica 50 g, cyclohexane / ethyl acetate 100:0 to 50:50) to give the title compound (625 mg, 1.7 mmol, quantitative yield) as a pale yellow solid. MS (ESP): m / z = 368.2 [M+H] + .

[0461] Steps 2 and 3: tert-butyl N-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)carbamate [ka]

[0462] The title compound was prepared analogously to Intermediate 8, steps 3 and 4, and obtained as a pale yellow foam. MS (ESP): m / z=338.2 [M+H] + .

[0463] Intermediate 43 tert-Butyl N-[(4,8-difluoro-6-formyl-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0464] The title compound was prepared analogously to Intermediate 28 using methyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 11, Step 2) instead of methyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate, and obtained as a colorless oil. MS (ESP): m / z = 380.1 [M + H] + .

[0465] Intermediate 44 tert-Butyl 1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka]

[0466] Step 1: tert-butyl 1-[(6-amino-4,7-difluoro-2-methoxycarbonyl-indan-5-yl)carbamoyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka]

[0467] The title compound was prepared analogously to Intermediate 9, Step 1, using 2-tert-butoxycarbonyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid [CAS number 127926-24-3] instead of N,N-dimethylglycine, and obtained as a yellow foam. MS (ESP): m / z = 452.3 [M+H] + .

[0468] Step 2: Methyl 2-(2-tert-butoxycarbonyl-2-azabicyclo[2.1.1]hexan-1-yl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0469] A mixture of tert-butyl 1-[(6-amino-4,7-difluoro-2-methoxycarbonyl-indan-5-yl)carbamoyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (140.0 mg, 0.310 mmol, 1 equiv.) and Burgess reagent [CAS No. 29684-56-8] (295.59 mg, 1.24 mmol, 4 equiv.) in 1,2-dichloroethane (1.4 mL) was stirred at 120 °C for 30 min under microwave irradiation. The mixture was diluted with DCM and washed with water. The phases were separated, the aqueous phase was extracted with DCM, and the combined organic phases were dried over Na SO , filtered, and concentrated. The crude product was purified by flash column chromatography (10-80% EtOAc / cyclohexane) to give the title compound (79 mg, 0.180 mmol, 58.77% yield) as a white solid. MS (ESP): m / z = 434.3 [M+H] + .

[0470] Steps 3 and 4: tert-butyl 1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate [ka]

[0471] The title compound was prepared analogously to Intermediate 8, steps 3 and 4, and obtained as a yellow oil. MS (ESP): m / z=404.4 [M+H] + .

[0472] Intermediate 45 tert-Butyl N-[2-[(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)amino]-2-oxo-ethyl]-N-methyl-carbamate [ka]

[0473] Step 1: Methyl 2-amino-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0474] To a stirred solution of methyl 2-(tert-butoxycarbonylamino)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 42, Step 1, 100.0 mg, 0.270 mmol, 1 equiv.) in DCM (2.72 mL) was added trifluoroacetic acid (0.4 mL, 5.25 mmol, 19.29 equiv.), and the resulting mixture was stirred at 25 °C for 1.5 h. The mixture was then concentrated in vacuo to give the crude product, which was purified by silica cartridge chromatography (28 g silica-NH, DCM / MeOH 100:0 to 90:10) to give the title compound (55 mg, 0.210 mmol, 75.61% yield) as a pale yellow solid. MS (ESP): m / z = 268.2 [M+H] + .

[0475] Step 2: Methyl 2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]amino]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0476] The title compound was prepared from methyl 2-amino-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate and N-BOC sarcosine [CAS number 13734-36-6] in analogy to Intermediate 9, Step 1, and obtained as a white solid. MS (ESP): m / z = 439.5 [M+H] + .

[0477] Steps 3 and 4: tert-butyl N-[2-[(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)amino]-2-oxo-ethyl]-N-methyl-carbamate [ka]

[0478] The title compound was prepared analogously to Intermediate 31, steps 4 and 5, and obtained as a pale yellow foam. MS (ESP): m / z=409.2 [M+H] + .

[0479] Intermediate 46 tert-Butyl N-[1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)-1-methyl-ethyl]carbamate [ka]

[0480] The title compound was prepared analogously to Intermediate 23, using 2-(tert-butoxycarbonylamino)isobutyric acid [CAS number 30992-29-1] instead of 2-hydroxy-2-methyl-propanoic acid. MS (ESP): m / z = 380.2 [M+H] + .

[0481] Intermediate 47 tert-Butyl N-[(1S)-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0482] The title compound was prepared analogously to Intermediate 26, using BOC-N-methyl-L-alanine [CAS No. 16948-16-6] instead of BOC-N-methyl-D-alanine, and was obtained as a pale yellow foam. MS (ESP): m / z = 380.2 [M+H] + .

[0483] Intermediate 48 tert-Butyl N-[(1S)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0484] Step 1: (3S)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-butanoic acid [ka]

[0485] The title compound was prepared analogously to Intermediate 32, Step 1, using (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoic acid [CAS number 83345-44-2] instead of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid, and obtained as a colorless viscous oil. MS (ESP): m / z = 334.3 [M+H] + .

[0486] Step 2: (3S)-3-[tert-butoxycarbonyl(methyl)amino]-4-[tert-butyl(dimethyl)silyl]oxy-butanoic acid [ka]

[0487] To a solution of (3S)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-butanoic acid [CAS No. (340.0 mg, 1.02 mmol, 1 equiv.] in THF (4.85 mL) at 0° C., sodium hydride, 60% in oil (89.71 mg, 2.24 mmol, 2.2 equiv.) was added portionwise. The reaction mixture was stirred at 0° C. for 10 minutes, and then iodomethane (130.11 μL, 2.09 mmol, 2.05 equiv.) was added. The reaction mixture was stirred at 0° C. for 2.5 hours. Sodium hydride, 60% in oil (53.82 mg, 2.24 mmol, 2.2 equiv.) was then added at 0 °C, and the reaction mixture was stirred for an additional 15 min. Iodomethane (130.11 µL, 2.09 mmol, 2.05 equiv.) was then added at 0 °C, and stirring was extended for 1 h at 0 °C and then for an additional 23 h at 5 °C. The reaction mixture was quenched with water / ice. The aqueous layer was cooled in an ice bath, the pH was set to approximately 2–3 by adding solid KHSO 4 , and the mixture was extracted with EtOAc (x4). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude compound, which was purified by silica cartridge chromatography (25 g, 100% DCM to 97:3 DCM / MeOH) to give the title compound (250 mg, 0.720 mmol, 70.56% yield) as a colorless viscous oil. MS (ESP): m / z = 348.3 [M+H] + .

[0488] Steps 3 to 6: tert-butyl N-[(1S)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0489] The title compound was prepared from (3S)-3-[tert-butoxycarbonyl(methyl)amino]-4-[tert-butyl(dimethyl)silyl]oxy-butanoic acid and methyl 5,6-diamino-4,7-difluoro-indane-2-carboxylate (Intermediate 6) in analogy to Intermediate 9 and obtained as a brown oil. MS (ESP): m / z = 524.3 [M+H] + .

[0490] Intermediate 49 3-[(2,4-Dimethoxyphenyl)methylamino]-5,9-difluoro-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carbaldehyde [ka]

[0491] Step 1: Methyl 5,9-difluoro-3-hydroxy-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carboxylate [ka]

[0492] To a stirred solution of methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6, 800.0 mg, 3.3 mmol, 1 equiv.) in anhydrous MeCN (22.02 mL) was added ethyl glyoxalate (1.31 mL, 6.61 mmol, 2 equiv.). The mixture was stirred for 24 hours. The reaction mixture was concentrated in vacuo to afford the title compound (1250 mg, 4.46 mmol, 99.94% yield) as a cream-colored solid. The material was used in the next step without further purification. MS (ESP): m / z = 281.2 [M+H] + .

[0493] Step 2: Methyl 3-chloro-5,9-difluoro-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carboxylate [ka]

[0494] To a flask containing methyl 5,9-difluoro-3-hydroxy-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carboxylate (1250.0 mg, 3.3 mmol, 1 equiv.) was added phosphorus oxychloride (7.69 mL, 82.52 mmol, 25 equiv.) at room temperature, and the mixture was then stirred and heated to 100 °C for 3.5 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc and washed with water (×1). The phases were separated, and the aqueous phase was extracted with EtOAc (×2). The combined organic layers were then filtered through a phase separator and concentrated in vacuo to give a residue that was purified by silica cartridge chromatography (50 g, cyclohexane / EtOAc 100:0 to 70:30) to give the title compound (267 mg, 0.940 mmol, 28.42% yield) as an off-white solid. MS (ESP): m / z = 299.1 [M+H] + .

[0495] Step 3: Methyl 3-[(2,4-dimethoxyphenyl)methylamino]-5,9-difluoro-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carboxylate [ka]

[0496] To a solution of methyl 3-chloro-5,9-difluoro-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carboxylate (600.0 mg, 2.01 mmol, 1 equiv.) in dry THF (13.39 mL) in a sealed vial, 2,4-dimethoxybenzylamine (452.71 uL, 3.01 mmol, 1.5 equiv.) and DIPEA (600.0 uL, 3.44 mmol, 1.71 equiv.) were added, and the reaction mixture was heated in a microwave to 110° C. for 2 hours and then to 120° C. for 30 minutes. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The organic phase was washed with NaHCO (saturated aqueous solution), and the aqueous phase was then extracted with EtOAc (×1). The combined organic layers were filtered through a phase separator, concentrated in vacuo, and the residue was purified by silica cartridge chromatography (50 g, 10% to 60% EtOAc / cyclohexane) to give the title compound (689 mg, 1.6 mmol, 79.87% yield) as an off-white foam. MS (ESP): m / z = 430.5 [M+H] + .

[0497] Steps 4 and 5: 3-[(2,4-dimethoxyphenyl)methylamino]-5,9-difluoro-7,8-dihydro-6H-cyclopenta[g]quinoxaline-7-carbaldehyde [ka]

[0498] The title compound was prepared analogously to Intermediate 31, steps 4 and 5, and obtained as a yellow oil. MS (ESP): m / z=400.2 [M+H] + .

[0499] Intermediate 50 tert-Butyl N-[2-[(5,9-difluoro-7-formyl-7,8-dihydro-6H-cyclopenta[g]quinoxalin-3-yl)amino]ethyl]-N-methyl-carbamate [ka]

[0500] The title compound was prepared analogously to Intermediate 49, steps 3-5, using N-(2-aminoethyl)-N-methylcarbamic acid tert-butyl ester [CAS number 121492-06-6] instead of 2,4-dimethoxybenzylamine in the first step. MS (ESP): m / z = 407.2 [M+H] + .

[0501] Intermediate 51 tert-Butyl N-[2-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)ethyl]carbamate [ka]

[0502] Step 1: Methyl 4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzotriazole-6-carboxylate [ka]

[0503] To a stirred solution of methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6, 500.0 mg, 2.06 mmol, 1 equiv.) in HCl (3.0 mL, 36 mmol, 17.44 equiv.) was added a solution of sodium nitrite (156.68 mg, 2.27 mmol, 1.1 equiv.) in water (1.03 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. The mixture was then extracted with EtOAc (3 × 10 mL). The organic layer was collected, dried over Na SO , filtered, and concentrated in vacuo to give a residue that was purified by silica cartridge chromatography (50 g, DCM / MeOH 100:0 to 90:10) to give the title compound (417 mg, 1.65 mmol, 79.78% yield) as a colorless oil. MS (ESP): m / z = 254.1 [M+H] + .

[0504] Step 2: Methyl 2-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate and methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate [ka]

[0505] To a stirred solution of methyl 4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzotriazole-6-carboxylate (417.0 mg, 1.65 mmol, 1 equiv.) in MeCN (13.18 mL) was added N-BOC-2-chloroethylamine (443.78 mg, 2.47 mmol, 1.5 equiv.) and potassium carbonate (1365.68 mg, 9.88 mmol, 6 equiv.). The resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was then diluted with EtOAc (25 mL) and water (25 mL) was added. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by silica cartridge chromatography (50 g, cyclohexane / ethyl acetate 100:0 to 80:20) to give methyl 2-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate (279 mg, 0.700 mmol, 42.74% yield) as a colorless oil and methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate (242 mg, 0.610 mmol, 37.07% yield) as a colorless oil. MS (ESP): m / z = 397.5 [M+H] + .

[0506] Steps 3 and 4: tert-butyl N-[2-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)ethyl]carbamate [ka]

[0507] The title compound was prepared from methyl 2-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate in analogy to Intermediate 8, steps 3 and 4, and obtained as a white foam. (ESP): m / z=367.1 [M+H] + .

[0508] Intermediate 52 tert-Butyl N-[2-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)ethyl]carbamate [ka]

[0509] The title compound was prepared from methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate (Intermediate 51, Step 2) in analogy to Intermediate 8, Steps 3 and 4. MS (ESP): m / z = 367.1 [M+H] + .

[0510] Intermediate 53 tert-Butyl N-[2-[1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6-formyl-2-oxo-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate [ka]

[0511] Step 1: Methyl 4,8-difluoro-2-oxo-3,5,6,7-tetrahydro-1H-cyclopenta[f]benzimidazole-6-carboxylate [ka]

[0512] To a solution of methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6, 100.0 mg, 0.410 mmol, 1 equiv.) in DCM (1.38 mL) at room temperature, N,N'-carbonyldiimidazole (67.61 mg, 0.420 mmol, 1.01 equiv.) was added in one portion. The reaction mixture was stirred at room temperature for 18 hours. N,N'-carbonyldiimidazole (20.08 mg, 0.120 mmol, 0.300 equiv.) was added, and stirring at room temperature was extended for an additional hour. The reaction mixture was filtered through a phase separator, and the precipitate was washed with DCM. The solid was collected to give the crude title compound (95 mg, 0.350 mmol, 85.79% yield) as an off-white solid. MS (ESP): m / z = 269.1 [M+H] + .

[0513] Step 2: Methyl 1,3-bis[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-2-oxo-6,7-dihydro-5H-cyclopenta[f]benzimidazole-6-carboxylate [ka]

[0514] To a solution of methyl 4,8-difluoro-2-oxo-3,5,6,7-tetrahydro-1H-cyclopenta[f]benzimidazole-6-carboxylate (30.0 mg, 0.110 mmol, 1 equiv.), N-BOC-ethanolamine (36.06 mg, 0.220 mmol, 2 equiv.), and triphenylphosphine (44.0 mg, 0.170 mmol, 1.5 equiv.) in THF (2.24 mL) at 0° C., diisopropyl azodicarboxylate (33.03 μL, 0.170 mmol, 1.5 equiv.) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. Triphenylphosphine (44.0 mg, 0.170 mmol, 1.5 equiv) and diisopropyl azodicarboxylate (33.03 µL, 0.170 mmol, 1.5 equiv) were added, and the reaction mixture was further stirred at 0 °C for 1 h and then at room temperature for an additional 2 h. The reaction mixture was partitioned between water and EtOAc. The phases were separated, and the organic phase was washed with water (x1). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give a crude orange viscous oil, which was purified by silica cartridge chromatography (25 g silica, 100% DCM to 97.5:2.5 DCM / MeOH) to give an orange gum, which was further purified by reverse-phase chromatography (30 g, 9:1 water + 0.1% formic acid / acetonitrile to 4:6 water + 0.1% formic acid / acetonitrile) to give the title compound (43.9 mg, 0.079 mmol, 72% yield) as a colorless oil. MS (ESP): m / z = 555.4 [M+H] + .

[0515] Steps 3 and 4: tert-butyl N-[2-[1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-6-formyl-2-oxo-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate [ka]

[0516] The title compound was prepared analogously to Intermediate 8, steps 3 and 4, and obtained as a colorless viscous oil. MS (ESP): m / z = 425.2 [M+H-BOC] + .

[0517] Intermediate 54 tert-Butyl N-[2-(4,8-difluoro-6-formyl-2-oxo-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-1-yl)ethyl]carbamate [ka]

[0518] Step 1: Methyl 5-amino-6-[[2-(tert-butoxycarbonylamino)acetyl]amino]-4,7-difluoro-indan-2-carboxylate [ka]

[0519] The title compound was prepared from methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6) and N-BOC-glycine [CAS number 4530-20-5] in analogy to Intermediate 9, step 1, and obtained as an orange viscous oil. MS (ESP): m / z = 400.3 [M+H] + .

[0520] Step 2: Methyl 5-amino-6-[2-(tert-butoxycarbonylamino)ethylamino]-4,7-difluoro-indan-2-carboxylate [ka]

[0521] To a solution of methyl 5-amino-6-[[2-(tert-butoxycarbonylamino)acetyl]amino]-4,7-difluoro-indan-2-carboxylate (250.0 mg, 0.630 mmol, 1 equiv.) in THF (3.13 mL) at 0°C, borane-THF complex (2.19 mL, 2.19 mmol, 3.5 equiv.) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 3.5 hours. Borane-THF complex (1.0 mL, 1 mmol, 1.6 equiv.) was then added at 0°C, and the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was added dropwise to NH4Cl (saturated aqueous solution) and extracted with EtOAc (x1). The organic phase was filtered through a phase separator and the volatiles removed under reduced pressure to give a residue which was purified by silica cartridge chromatography (5 g silica, cyclohexane 100% to cyclohexane / EtOAc 7:3) to give the title compound (105 mg, 0.270 mmol, 43.52% yield) as a colorless oil. MS (ESP): m / z = 386.2 [M+H] + .

[0522] Step 3: Methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-2-oxo-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0523] The title compound was prepared from methyl 5-amino-6-[2-(tert-butoxycarbonylamino)ethylamino]-4,7-difluoro-indane-2-carboxylate in analogy to Intermediate 53, Step 1, and obtained as a white solid. MS (ESP): m / z=412.2 [M+H] + .

[0524] Steps 4 and 5: tert-butyl N-[2-(4,8-difluoro-6-formyl-2-oxo-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-1-yl)ethyl]carbamate [ka]

[0525] The title compound was prepared analogously to Intermediate 8, steps 3 and 4, and obtained as a yellow viscous oil. MS (ESN): m / z=380.3 [M−H] - .

[0526] Intermediate 55 tert-Butyl N-[(1R)-1-(8-fluoro-6-formyl-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]carbamate [ka]

[0527] Step 1: Ethyl 5-amino-6-[[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-4-fluoro-indan-2-carboxylate and ethyl 6-amino-5-[[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-4-fluoro-indan-2-carboxylate [ka]

[0528] To a solution of ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate (Intermediate 7, 150.0 mg, 0.630 mmol, 1 equiv.) and N-BOC-D-alanine [CAS No. 7764-95-6] (119.12 mg, 0.630 mmol, 1 equiv.) in DMF (3.15 mL) at room temperature, PyBOP (327.62 mg, 0.630 mmol, 1 equiv.) was added in one portion, followed by DIPEA (0.22 mL, 1.26 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with brine and diluted with EtOAc. The phases were separated, and the organic phase was washed with brine (×1). The combined organic phases were filtered through a phase separator and the volatiles removed under reduced pressure to give a residue that was purified by silica cartridge chromatography (10 g silica, DCM 100% to DCM / [EtOAc / MeOH 9:1] 9:1) to give ethyl 5-amino-6-[[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-4-fluoro-indan-2-carboxylate (155 mg, 0.380 mmol, 60.13% yield) as a pale yellow solid and ethyl 6-amino-5-[[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-4-fluoro-indan-2-carboxylate (21 mg, 0.050 mmol, 8.15% yield) as a pale yellow solid. MS (ESP): m / z = 410.3 [M+H] + .

[0529] Step 2: Ethyl 2-[(1R)-1-(tert-butoxycarbonylamino)ethyl]-8-fluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0530] The title compound was prepared analogously to Intermediate 8, step 2, and obtained as a pale yellow viscous oil. MS (ESP): m / z=392.3 [M+H] + .

[0531] Steps 3 and 4: tert-butyl N-[(1R)-1-(8-fluoro-6-formyl-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]carbamate [ka]

[0532] The title compound was prepared analogously to Intermediate 28, steps 2 and 3, and obtained as a yellow viscous oil. MS (ESP): m / z=348.3 [M+H] + .

[0533] Intermediate 56 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0534] Step 1: Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0535] A solution of methyl 2-[(2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 32, Step 3, 218.0 mg, 0.400 mmol, 1 equiv.) in 1,1,1,3,3,3-hexafluoro-2-propanol (4.36 mL, 41.51 mmol, 105.06 equiv.) was stirred at 145° C. for 1 hour under microwave irradiation. The volatiles were removed under reduced pressure to give the title compound (141 mg, 0.310 mmol, 79.02% yield) as a colorless oil. MS (ESP): m / z=452.4 [M+H] + .

[0536] Step 2: Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0537] The title compound was prepared analogously to Intermediate 25, Step 1, and obtained as a pale yellow oil. MS (ESP): m / z=466.3 [M+H] + .

[0538] Steps 3 and 4: 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidin-2-yl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carbaldehyde [ka]

[0539] The title compound was prepared analogously to Intermediate 28, steps 2 and 3, and obtained as a pale yellow oil. MS (ESP): m / z=436.4 [M+H] + .

[0540] Intermediate 57 tert-Butyl (2R,4S)-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)-4-methoxy-pyrrolidine-1-carboxylate [ka]

[0541] The title compound was prepared from methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6) and (2R,4S)-1-tert-butoxycarbonyl-4-methoxy-pyrrolidine-2-carboxylic acid [CAS number 147266-70-4] in analogy to Intermediate 38, steps 2-5, and obtained as a colorless oil. MS (ESP): m / z = 422.2 [M+H] + .

[0542] Intermediate 58 2-[2-(Dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carbaldehyde [ka]

[0543] The title compound was prepared analogously to Intermediate 29, steps 2-5, using 3-(dimethylamino)propanoic acid instead of BOC-SAR-OH, and was obtained as a light brown gum. MS (ESP): m / z = 277.2 [M+H] + .

[0544] Intermediate 59 tert-Butyl N-[(1S)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]carbamate [ka]

[0545] The title compound was prepared from (3S)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-butanoic acid (Intermediate 48, Step 1) and methyl 5,6-diamino-4,7-difluoro-indane-2-carboxylate (Intermediate 6) as in Intermediate 48, Steps 3-6, and obtained as a yellow oil. MS (ESP): m / z = 510.38 [M+H] + .

[0546] Intermediate 60 tert-Butyl N-[2-tert-butoxy-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0547] Step 1: (2R)-3-tert-butoxy-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid [ka]

[0548] To a solution of (2R)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid [CAS No. 248921-66-6] (1000.0 mg, 3.83 mmol, 1.0 equiv) in THF (12.5 mL) at −15° C. (ice / NaCl bath), sodium hydride (60% in oil, 336.73 mg, 8.42 mmol, 2.2 equiv) was added portionwise. The reaction mixture was stirred at −15° C. for 10 minutes, and then iodomethane (0.49 mL, 7.85 mmol, 2.05 equiv) and DMF (0.65 mL) were added. The reaction mixture was stirred at −15° C. for 2.5 hours. Additional iodomethane (0.12 mL, 1.91 mmol, 0.5 equiv) was added at −15° C., and the reaction mixture was further stirred at −15° C. After 1.5 h, sodium hydride, 60% in oil (82.65 mg, 3.44 mmol, 0.9 equiv.) was added at −15° C., and stirring was prolonged for 1 h at −15° C. and then for an additional 23 h at 5° C. (ice bath). The reaction mixture was quenched with water / ice and washed with EtOAc (×1). The aqueous layer was collected and cooled in an ice bath, then the pH was set to approximately 3 with 1 M aqueous HCl, diluted with NaSO (saturated aqueous), and extracted with EtOAc (×4). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude title compound (1260.0 mg) as a pale yellow viscous oil. MS (ESN): m / z = 374.3 [MH] - .

[0549] Steps 2 and 3: Methyl 2-[2-tert-butoxy-1-[tert-butoxycarbonyl(methyl)amino]ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0550] The title compound was prepared from methyl 5,6-diamino-4,7-difluoro-indan-2-carboxylate (Intermediate 6) and (2R)-3-tert-butoxy-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid in analogy to Intermediate 23, steps 1 and 2, and obtained as a white foam. MS (ESP): m / z = 482.3 [M+H] + .

[0551] Steps 4 and 5: tert-butyl N-[2-tert-butoxy-1-(4,8-difluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0552] The title compound was prepared analogously to Intermediate 28, steps 2 and 3, and obtained as a colorless amorphous solid. MS (ESP): m / z=452.3 [M+H] + .

[0553] Intermediate 61 tert-Butyl N-[(1R-1-(4,8-difluoro-6-formyl-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-2-yl)ethyl]carbamate [ka]

[0554] The title compound was prepared from methyl 2-[(1R)-1-(tert-butoxycarbonylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (Intermediate 20, Step 2) analogously to Intermediate 28 and obtained as a pale yellow oil.

[0555] Intermediate 62 tert-Butyl N-[2-(8-fluoro-6-formyl-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0556] The title compound was prepared from 3-[tert-butoxycarbonyl(methyl)amino]propanoic acid [CAS number 124072-61-3] and Intermediate 7 in the same manner as Intermediate 9 and was obtained as a pale brown foam. MS (ESP) m / z = 362.2 [M+H] + .

[0557] Intermediate 63 tert-Butyl N-[(8-fluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)methyl]-N-(2-methoxyethyl)carbamate [ka]

[0558] Step 1: Ethyl 2-(chloromethyl)-8-fluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0559] A flask was charged with ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate (Intermediate 7, 150.0 mg, 0.63 mmol, 1.0 equiv.) and ethanimidic acid, 2-chloro-, ethyl ester, hydrochloride salt [CAS No. 36743-66-5] (1:1) (229.6 mg, 1.89 mmol, 3.0 equiv.) in methanol (6.3 mL) under a nitrogen atmosphere. The reaction mixture was heated to 65° C. for 0.5 h. The reaction was quenched with water and extracted with EtOAc (×3). The organic phases were combined and dried in vacuo to give the title compound (152.0 mg, 0.51 mmol, 81.4% yield) as a pale yellow solid. MS (ESP) m / z = 297.2, 299.2 [M+H] + .

[0560] Step 2: Ethyl 8-fluoro-2-[(2-methoxyethylamino)methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0561] To a flask charged with ethyl 2-(chloromethyl)-8-fluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (152.0 mg, 0.51 mmol, 1.0 equiv.) and potassium iodide (85.0 mg, 0.51 mmol, 1.0 equiv.) in acetonitrile (5.12 mL) under a nitrogen atmosphere was added 2-methoxyethylamine (0.11 mL, 1.28 mmol, 2.5 equiv.). The reaction was stirred at 25 °C for 4 h. The reaction was quenched with water and extracted with EtOAc (2x). The crude product was purified by flash column chromatography (silica-NH, 11 g, DCM to 80:20 DCM / MeOH) to afford the title compound (124.0 mg, 0.37 mmol, 72.2% yield) as a yellow oil. MS(ESP)m / z=336.2 [M+H] + .

[0562] Step 3: Ethyl 2-[[tert-butoxycarbonyl(2-methoxyethyl)amino]methyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate [ka]

[0563] To a stirred solution of methyl ethyl 8-fluoro-2-[(2-methoxyethylamino)methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazole-6-carboxylate (124.0 mg, 0.37 mmol, 1.0 equiv.) in anhydrous THF (4.6 mL) was added di-tert-butyl dicarbonate (177.5 mg, 0.81 mmol, 2.2 equiv.), and the mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C, carefully quenched with NH4Cl (saturated aqueous solution), and extracted with EtOAc (x3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the crude title compound (176.0 mg, 0.4 mmol, quantitative yield) as a colorless viscous oil, which was used in the next step without purification. MS (ESP) m / z = 436.4 [M+H] + .

[0564] Steps 4 and 5: tert-butyl N-[(8-fluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)methyl]-N-(2-methoxyethyl)carbamate [ka]

[0565] The title compound was prepared analogously to Intermediate 28, steps 2 and 3, and obtained as a colorless oil. MS (ESP): m / z=392.2 [M+H] + .

[0566] Intermediate 64 tert-Butyl N-[(8-fluoro-6-formyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl)methyl]-N-[2-(methylamino)-2-oxo-ethyl]carbamate [ka]

[0567] The title compound was prepared analogously to Intermediate 63, steps 2-5, using acetamide, 2-amino-N-methyl-, hydrochloride (1:1) [CAS No. 49755-94-4] instead of 2-methoxyethylamine in step 2, and obtained as a colorless oil. MS (ESP): m / z = 405.4 [M+H] + .

[0568] Intermediate 65 tert-Butyl N-[2-(4-fluoro-6-formyl-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl)ethyl]carbamate;tert-Butyl N-[2-(8-fluoro-6-formyl-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl)ethyl]carbamate [ka]

[0569] Step 1: Ethyl 5,6-diacetamido-4-fluoro-indan-2-carboxylate [ka]

[0570] To a solution of ethyl 5,6-diamino-4-fluoro-indan-2-carboxylate (Intermediate 7, 370.0 mg, 1.09 mmol, 1.0 equiv) in DCM (14.1 mL) and N,N-diisopropylethylamine (0.38 mL, 2.17 mmol, 2.0 equiv) was added acetyl chloride (0.09 mL, 1.3 mmol, 1.2 equiv) dropwise in an ice bath at 0 °C. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was quenched with NaHCO (saturated aqueous solution), extracted with DCM, then filtered through a hydrophobic phase separator and concentrated in vacuo. The residue was purified by silica cartridge chromatography (25 g, 0% to 40% EtOAc / cyclohexane) to afford the title compound (350.0 mg, 1.09 mmol, 99.9% yield) as a pale yellow oil. MS (ESP): m / z = 323.2 [M+H] + .

[0571] Step 2: N-[6-acetamido-7-fluoro-2-(hydroxymethyl)indan-5-yl]acetamide [ka]

[0572] To a stirred solution of methyl ethyl 5,6-diacetamido-4-fluoro-indan-2-carboxylate (350.0 mg, 1.09 mmol, 1.0 equiv.) in anhydrous THF (7.2 mL) and ethanol (3.6 mL), calcium chloride (241.0 mg, 2.17 mmol, 2.0 equiv.) and sodium borohydride (123.2 mg, 3.26 mmol, 3.0 equiv.) were added, and the mixture was stirred at room temperature for 48 h. The mixture was cooled to 0 °C, quenched with NH4Cl (saturated aqueous solution), and extracted with EtOAc (x3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica cartridge chromatography (0% to 20% MeOH / DCM) to afford the title compound (170.0 mg, 0.61 mmol, 55.9% yield) as a pale yellow oil. MS (ESP): m / z = 281.2 [M+H] + .

[0573] Step 3: (8-fluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methanol [ka]

[0574] N-[6-acetamido-7-fluoro-2-(hydroxymethyl)indan-5-yl]acetamide (170.0 mg, 0.61 mmol, 1.0 equiv) was suspended in toluene (6.1 mL), p-toluenesulfonic acid monohydrate (230.74 mg, 1.21 mmol, 2.0 equiv) was added, and the mixture was refluxed for 16 h. The reaction was quenched with water, extracted with EtOAc (x3), the combined organic phase was concentrated, and the crude product was purified by silica column chromatography (0%-15% MeOH / DCM) to afford the title compound (77.0 mg, 0.35 mmol, 57.6% yield) as a pale yellow oil. MS (ESP): m / z = 221.0 [M+H] + .

[0575] Step 4: tert-butyl-[(8-fluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methoxy]-dimethyl-silane [ka]

[0576] A mixture of (8-fluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methanol (77.0 mg, 0.35 mmol, 1.0 equiv.) and imidazole (119.0 mg, 1.75 mmol, 5.0 equiv.) in DCM (2.8 mL) and DMF (0.7 mL) was cooled to 0 °C, and then tert-butyldimethylchlorosilane (115.93 mg, 0.77 mmol, 2.2 equiv.) was added portionwise. The mixture was allowed to reach room temperature and stirred for 6 h. EtOAc was added, and the mixture was washed with water (x3), then dried over Na2SO4 and concentrated under reduced pressure to give the title compound (125.0 mg, 0.37 mmol, quantitative yield) as a pale yellow viscous oil. MS (ESP): m / z = 335.3 [M+H] + .

[0577] Step 5: tert-butyl N-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate; tert-butyl N-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate [ka]

[0578] To a stirred solution of tert-butyl-[(8-fluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methoxy]-dimethyl-silane (125.0 mg, 0.37 mmol, 1.0 equiv.) in MeCN (4.5 mL) was added N-BOC-2-chloroethylamine (100.7 mg, 0.56 mmol, 1.5 equiv.) and potassium carbonate (309.88 mg, 2.24 mmol, 6.0 equiv.). The resulting mixture was stirred at 80 °C for 18 h. The reaction mixture was then quenched by the addition of water, extracted with EtOAc (x3), and concentrated in vacuo. The crude mixture was purified by flash chromatography (silica, 10 g, 0% to 40% EtOAc / cyclohexane) to afford the title compound mixture (214.1 mg, 0.45 mmol, quantitative yield) as a pale yellow oil. MS(ESP):m / z=478.6, 478.4[M+H] + .

[0579] Step 6: tert-butyl N-[2-[4-fluoro-6-(hydroxymethyl)-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate; tert-butyl N-[2-[8-fluoro-6-(hydroxymethyl)-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate [ka]

[0580] To a solution of tert-butyl N-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate; tert-butyl N-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl]ethyl]carbamate (214.0 mg, 0.45 mmol, 1.0 equiv.) in tetrahydrofuran (5.2 mL) in an ice bath, tetrabutylammonium fluoride (1 M in THF, 1.12 mL, 1.12 mmol, 2.5 equiv.) was added, and the reaction mixture was stirred at 0° C. for 5 minutes, then at room temperature for 6 hours. The reaction mixture was diluted with EtOAc and NH4Cl (saturated aqueous solution). The phases were separated and the organic phase was washed with NH4Cl (saturated aqueous solution) (twice). The crude product was purified by silica gel chromatography (5 g silica, 0% to 100% EtOAc / cyclohexane) to give the title compound mixture (41 mg, 0.060 mmol, 67.3% yield) as a pale yellow oil. MS (ESP): m / z = 364.2 [M+H] + .

[0581] Step 7: tert-butyl N-[2-(4-fluoro-6-formyl-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl)ethyl]carbamate; tert-butyl N-[2-(8-fluoro-6-formyl-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-3-yl)ethyl]carbamate [ka]

[0582] The title compound mixture was prepared analogously to Intermediate 63, Step 5, and obtained as a pale yellow oil. MS (ESP): m / z=362.2 [M+H] + .

[0583] Intermediate 66 tert-Butyl N-[2-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)ethyl]carbamate [ka] and Intermediate 67 tert-Butyl N-[2-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-3-yl)ethyl]carbamate [ka] and Intermediate 68 tert-Butyl N-[2-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)ethyl]carbamate [ka]

[0584] The title compounds were prepared from Intermediate 7 in the same manner as Intermediate 51 and were obtained as an orange oil, a light brown oil, and a light brown oil, respectively. MS (ESP) m / z = 293.1 [M + H-tBu] + .

[0585] Intermediate 69 tert-Butyl N-[1-[(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)methyl]cyclopropyl]carbamate [ka] and Intermediate 70 tert-Butyl N-[1-[(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)methyl]cyclopropyl]carbamate [ka]

[0586] The title compound was prepared from Intermediate 6 in the same manner as Intermediate 51, using tert-butyl N-[1-(bromomethyl)cyclopropyl]carbamate [CAS number 387845-49-0] instead of N-BOC-2-chloroethylamine in Step 2, and obtained as a white foam. MS (ESP) m / z = 337.09 [M+H-tBu], respectively. + and 393.04[M+H] + .

[0587] Intermediate 71 tert-Butyl 3-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)azetidine-1-carboxylate [ka]

[0588] Steps 1 and 2: Methyl 2-(1-tert-butoxycarbonylazetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate [ka] and methyl 1-(1-tert-butoxycarbonylazetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate [ka]

[0589] The title compound was prepared from Intermediate 6 similarly to Intermediate 51, steps 1 and 2, using 1-BOC-3-iodoazetidine [CAS no. 254454-54-1] instead of N-BOC-2-chloroethylamine in step 2, and obtained as a colorless oil. MS (ESP): m / z = 353.3 [M + H-tBu] +.

[0590] Step 3: tert-Butyl 3-[4,8-difluoro-6-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]azetidine-1-carboxylate [ka]

[0591] To a solution of methyl 2-(1-tert-butoxycarbonylazetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate (200.0 mg, 0.49 mmol, 1.0 equiv.) in THF (5 mL) and ethanol (2.5 mL), calcium chloride (108.6 mg, 0.98 mmol, 2.0 equiv.) and sodium borohydride (1000.0 mg, 26.5 mmol, 54.0 equiv.) were added at 20° C. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was poured into water (50 mL) and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound (180.0 mg, 0.47 mmol, 96.6% yield) as a yellow solid.

[0592] Step 4: tert-butyl 3-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl)azetidine-1-carboxylate [ka]

[0593] The title compound was prepared analogously to Intermediate 8, step 4, and obtained as a yellow oil. MS (ESP): m / z=379.1 [M+H] + .

[0594] Intermediate 72 tert-Butyl 3-(4,8-difluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl)azetidine-1-carboxylate [ka]

[0595] The title compound was prepared from methyl 1-(1-tert-butoxycarbonylazetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazole-6-carboxylate (Intermediate 71, Step 2) in analogy with Intermediate 71, Steps 3 and 4, and obtained as a pale yellow foam. MS (ESP): m / z = 379.13 [M+H] + .

[0596] Intermediate 73 tert-Butyl N-[2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl)ethyl]carbamate [ka]

[0597] Step 1: Ethyl 7-fluoro-4-[(4-methoxyphenyl)methylamino]-5-nitro-indan-2-carboxylate [ka]

[0598] To a solution of ethyl 4,7-difluoro-5-nitro-indan-2-carboxylate (Intermediate 5, Step 3, 6000.0 mg, 22.12 mmol, 1.0 equiv.) in DMF (60 mL), 4-aminomethyl-anisole (3.18 mL, 24.33 mmol, 1.1 equiv.) and potassium carbonate (9172 mg, 66.37 mmol, 3.0 equiv.) were added, and the resulting mixture was stirred at 20 °C for 12 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate 50:1 to 10:1) to give the title compound (6.5 g, 16.74 mmol, 75.6% yield) as an orange oil. 1 HNMR(400MHz,CDCl3)δ=7.77(d,1H), 7.20(d,2H), 6.88(d,2H), 4.65-4.52(m,2H), 4.24-4.1 6(m,2H), 3.81(s,3H), 3.54-3.45(m,2H), 3.41-3.30(m,1H), 3.24(d,2H), 1.32-1.28(m,3H).

[0599] Step 2: Ethyl 4,5-diamino-7-fluoro-indan-2-carboxylate [ka]

[0600] To a solution of ethyl 7-fluoro-4-[(4-methoxyphenyl)methylamino]-5-nitro-indan-2-carboxylate (6.5 g, 16.74 mmol, 1.0 equiv.) in ethanol (200 mL) was added wet Pd / C (3.0 g), the atmosphere was exchanged with hydrogen three times, and the mixture was then stirred under hydrogen (15 Psi) at 20° C. for 12 h. The mixture was filtered through Celite®, and the filtrate was washed with EtOH (100 mL). The filtrate was collected and concentrated to give a residue that was purified by silica column chromatography (ethyl acetate / petroleum ether 0% to 55%) to give the title compound (2.8 g, 11.75 mmol, 70.2% yield) as a purple oil. MS (ESP): m / z = 239.1 [M+H] + .

[0601] Step 3: Ethyl 5-fluoro-1,6,7,8-tetrahydrocyclopenta[e]benzotriazole-7-carboxylate [ka]

[0602] To a stirred solution of ethyl 4,5-diamino-7-fluoro-indan-2-carboxylate (725.0 mg, 1.83 mmol, 1.0 equiv) in HCl (3.04 mL, 36.51 mmol, 20.0 equiv) at 0 °C, a solution of sodium nitrite (163.8 mg, 2.37 mmol, 1.3 equiv) in water (1.5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was then extracted with EtOAc (twice). The combined organic phases were filtered through a phase separator, and the volatiles were removed under reduced pressure to give the crude compound (350 mg, brown foam), which was purified by silica cartridge chromatography (25 g, DCM 100% to DCM / MeOH 98.5:1.5) to give the title compound (397.0 mg, 1.59 mmol, 87.2% yield) as a light brown solid. MS (ESP): m / z = 250.1 [M+H] + .

[0603] Steps 4 to 6: tert-butyl N-[2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl)ethyl]carbamate [ka]

[0604] The title compound was prepared analogously to Intermediate 51, steps 2-4, and obtained as an off-white foam.

[0605] Intermediate 74 tert-Butyl N-[2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-3-yl)ethyl]carbamate;tert-Butyl N-[2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[g]benzotriazol-1-yl)ethyl]carbamate [ka]

[0606] The title compound mixture was prepared from ethyl 5-fluoro-1,6,7,8-tetrahydrocyclopenta[e]benzotriazole-7-carboxylate (Intermediate 73, Step 3) in analogy to Intermediate 52 and obtained as a white foam. MS (ESP): m / z = 349.2 [M+H] + .

[0607] Intermediate 75 tert-Butyl N-[2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0608] The title compound mixture was prepared from ethyl 5-fluoro-1,6,7,8-tetrahydrocyclopenta[e]benzotriazole-7-carboxylate (Intermediate 73, Step 3) in analogy to Intermediate 71, Steps 2-4, using tert-butyl N-(2-chloroethyl)-N-methyl-carbamate [CAS No. 220074-38-4] instead of 1-BOC-3-iodoazetidine, yielding a colorless oil. MS (ESP) m / z = 263.1 [M+H-BOC] + .

[0609] Intermediate 76 tert-Butyl N-[(1S)-2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl)-1-methyl-ethyl]carbamate [ka]

[0610] Step 1: Ethyl 2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazole-7-carboxylate [ka]

[0611] A mixture of ethyl 5-fluoro-1,6,7,8-tetrahydrocyclopenta[e]benzotriazole-7-carboxylate (Intermediate 73, Step 3, 700.0 mg, 2.81 mmol, 1.0 equiv.), BOC-L-alaninol (2460.7 mg, 14.04 mmol, 5.0 equiv.), triphenylphosphine (883.3 mg, 3.37 mmol, 1.2 equiv.), and diisopropyl azodicarboxylate (681.1 mg, 3.37 mmol, 1.2 equiv.) in THF (10 mL) was stirred at 20 °C under a N atmosphere for 12 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography (18% ethyl acetate / petroleum ether) to give the title compound (930.0 mg, 2.29 mmol, 81.5% yield) as a yellow oil. MS (ESP): m / z = 351.1 [M+H-tBu] + .

[0612] Step 2: tert-butyl N-[(1S)-2-[5-fluoro-7-(hydroxymethyl)-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl]-1-methyl-ethyl]carbamate [ka]

[0613] To a solution of ethyl 2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazole-7-carboxylate (700.0 mg, 1.72 mmol, 1.0 equiv.) in methanol (20 mL) was added lithium chloride (730.0 mg, 17.2 mmol, 10.0 equiv.) and sodium borohydride (1303.0 mg, 34.4 mmol, 20.0 equiv.) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding NH4Cl (saturated aqueous solution, 40 mL). The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica column chromatography (petroleum ether / ethyl acetate 0% to 40%) to give the title compound (300.0 mg, 0.82 mmol, 47.8% yield) as a colorless oil. MS (ESP): m / z = 309.1 [M+H-BOC] + .

[0614] Step 3: tert-butyl N-[(1S)-2-(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e]benzotriazol-2-yl)-1-methyl-ethyl]carbamate [ka]

[0615] The title compound mixture was prepared similarly to Intermediate 8, step 4, and obtained as a yellow oil. MS (ESP): m / z = 307.4 [M + H-tBu] + .

[0616] Intermediate 77 tert-Butyl N-[(1R)-1(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)ethyl]carbamate [ka]

[0617] The title compound was prepared similarly to Intermediate 29, steps 2-5, using BOC-D-ALA-OH instead of BOC-SAR-OH, and was obtained as a brown gum. MS (ESP): m / z = 349.2 [M+H] + .

[0618] Intermediate 78 tert-Butyl N-[(1R)-2-tert-butoxy-1-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)ethyl]-N-methyl-carbamate [ka]

[0619] The title compound was prepared analogously to Intermediate 29, steps 2-5, using (2R)-3-tert-butoxy-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid [CAS number 1126450-26-7] instead of BOC-SAR-OH, and obtained as a pale yellow oil. MS (ESP): m / z = 435.2 [M+H] + .

[0620] Intermediate 79 tert-Butyl N-[(5-fluoro-7-formyl-1,6,7,8-tetrahydrocyclopenta[e]benzimidazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0621] The title compound was prepared from ethyl 4,5-diamino-7-fluoro-indan-2-carboxylate (Intermediate 73, Step 2) and BOC-SAR-OH analogously to Intermediate 9 and obtained as a brown oil. MS (ESP): m / z=348.2 [M+H] + .

[0622] Intermediate 80 tert-Butyl N-[(4-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0623] Step 1: Ethyl 4-fluoro-6-hydroxy-5-nitro-indan-2-carboxylate [ka]

[0624] To a solution of ethyl 4-fluoro-6-hydroxy-indan-2-carboxylate (Intermediate 7, Route A, Step 4, 2545.0 mg, 11.35 mmol, 1.0 equiv) in DCM (56.75 mL) at room temperature, a mixture of nitric acid (795.3 uL, 12.48 mmol, 1.1 equiv) and sulfuric acid (1.38 mL, 25.81 mmol, 2.27 equiv) was added dropwise, and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was poured into water and extracted with DCM (3 times). The combined organic phases were filtered through a phase separator and the volatiles removed under reduced pressure to give the crude product, which was purified by silica cartridge chromatography (250 g silica, cyclohexane 100% cyclohexane to cyclohexane / EtOAc 6:4) to give ethyl 7-fluoro-4-hydroxy-5-nitro-indan-2-carboxylate; ethyl 7-fluoro-5-hydroxy-4-nitro-indan-2-carboxylate (1530.0 mg, 2.84 mmol, 50.1% yield) as a yellow solid and the title compound (530.0 mg, 1.97 mmol, 17.3% yield) as a yellow solid. MS (ESP): m / z = 270.2 [M+H] + .

[0625] Step 2: Ethyl 5-amino-4-fluoro-6-hydroxy-indan-2-carboxylate [ka]

[0626] A suspension of ethyl 4-fluoro-6-hydroxy-5-nitro-indan-2-carboxylate (541.0 mg, 2.01 mmol, 1.0 equiv.) and Pd / C 55-65% wet (85.54 mg, 0.04 mmol, 0.02 equiv.) in ethanol (20.09 mL) was purged with vacuum / nitrogen (3 cycles) and vacuum / hydrogen (4 cycles), and the reaction mixture was stirred under hydrogen at room temperature for 1 h. The reaction mixture was purged with vacuum / nitrogen (3 cycles) and filtered through a Celite® pad, washing the cake with ethanol. The collected filtrate was concentrated under reduced pressure to give the crude title compound (480.0 mg, 2.01 mmol, 99.8% yield) as a brown solid. MS (ESP): m / z = 240.2 [M+H] + .

[0627] Steps 3 to 6: tert-butyl N-[(4-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0628] The title compound was prepared analogously to Intermediate 29, steps 2-5, and obtained as a light brown oil. MS (ESP): m / z = 293.2 [M+H-tBu] + .

[0629] Intermediate 81 tert-Butyl N-[(5-fluoro-7-formyl-7,8-dihydro-6H-cyclopenta[e][1,3]benzoxazol-2-yl)methyl]-N-methyl-carbamate [ka]

[0630] The title compound was prepared from ethyl 7-fluoro-4-hydroxy-5-nitro-indan-2-carboxylate; ethyl 7-fluoro-5-hydroxy-4-nitro-indan-2-carboxylate (Intermediate 80, Step 1) as in Intermediate 80, Steps 2-6, and obtained as a light brown gum. MS (ESP): m / z = 349.4 [M+H] + .

[0631] Intermediate 82 tert-Butyl N-[(1S)-1(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)ethyl]carbamate [ka]

[0632] The title compound was prepared analogously to Intermediate 77 using BOC-ALA-OH instead of BOC-D-ALA-OH and was obtained as a pale yellow gum. MS (ESP): m / z=349.11 [M+H] + .

[0633] Intermediate 83 2-[[3-[tert-Butyl(dimethyl)silyl]oxyazetidin-1-yl]methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carbaldehyde [ka]

[0634] Step 1: Ethyl 2-(chloromethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0635] Ethyl 2-chloroethanimidate hydrochloride (660.5 mg, 4.18 mmol, 1.0 equiv.) was added to a solution of ethyl 6-amino-4-fluoro-5-hydroxy-indan-2-carboxylate (Intermediate 29, Step 1, 1000.0 mg, 4.18 mmol, 1.0 equiv.) in DCM (15 mL) at 0° C. The mixture was stirred at 20° C. for 12 h. The mixture was diluted with DCM (5 mL), filtered, and the filtrate was concentrated to give the title compound (1100.0 mg, 3.69 mmol, 88.4% yield) as a yellow oil, which was used directly in the next step. MS (ESP): m / z=298.3 [M+H] + .

[0636] Step 2: Ethyl 8-fluoro-2-[(3-hydroxyazetidin-1-yl)methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0637] To a solution of 3-hydroxyazetidine hydrochloride (294.4 mg, 2.69 mmol, 2.0 equiv.) and DIPEA (0.59 mL, 3.36 mmol, 2.5 equiv.) in DMF (5 mL) was added ethyl 2-(chloromethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate (400.0 mg, 1.34 mmol, 1.0 equiv.) in 0.2 mL of DMF at 30° C., and the mixture was stirred at 30° C. for 2 hours. The mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated to give the title compound (449.0 mg, 1.34 mmol, 99.9% yield) as a yellow oil, which was used directly in the next step. MS (ESP): m / z = 335.4 [M+H] + .

[0638] Step 3: Ethyl 2-[[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0639] To a solution of ethyl 8-fluoro-2-[(3-hydroxyazetidin-1-yl)methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate (400.0 mg, 1.2 mmol, 1.0 equiv.) in DMF (5 mL), DIPEA (0.32 mL, 1.79 mmol, 1.5 equiv.) and tert-butylchlorodimethylsilane (215.4 mg, 1.44 mmol, 1.2 equiv.) were added at 20° C., and the mixture was stirred for 2 hours at 20° C. The mixture was poured into water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue which was purified by flash column chromatography (petroleum ether / EtOAc 10:1) to give the title compound (500.0 mg, 1.11 mmol, 93.2% yield) as a yellow oil. MS (ESP): m / z = 449.3 [M+H] + .

[0640] Steps 4-5: 2-[[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carbaldehyde [ka]

[0641] The title compound was prepared analogously to Intermediate 71, steps 3 and 4, and obtained as a yellow oil. MS (ESP): m / z=405.3 [M+H] + .

[0642] Intermediate 84 tert-Butyl 3-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)azetidine-1-carboxylate [ka]

[0643] The title compound was prepared analogously to Intermediate 29, steps 2-5, using 1-BOC-azetidine-3-carboxylic acid instead of BOC-SAR-OH, and obtained as a brown solid. MS (ESP): m / z = 383.3 [M + Na] + .

[0644] Intermediate 85 tert-Butyl N-[2-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)ethyl]carbamate [ka]

[0645] Steps 1 and 2: Ethyl 2-[2-(tert-butoxycarbonylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0646] The title compound was prepared analogously to Intermediate 29, steps 2 and 3, using BOC-β-ALA-OH instead of BOC-SAR-OH, and obtained as a yellow oil. MS (ESP): m / z = 337.2 [M + H-tBu] + .

[0647] Step 3: tert-butyl N-[2-[8-fluoro-6-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]ethyl]carbamate [ka]

[0648] To a solution of ethyl 2-[2-(tert-butoxycarbonylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate (3.5 g, 8.92 mmol, 1.0 equiv.) and lithium chloride (3781 mg, 89.19 mmol, 10.0 equiv.) in methanol (56 mL) was added sodium borohydride (3374 mg, 89.2 mmol, 10.0 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched by the addition of ice-cold NH4Cl (1 M, 100 mL), and then the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography (60% petroleum ether / ethyl acetate) to give the title compound (800.0 mg, 2.28 mmol, 24.4% yield) as a yellow oil. MS (ESP): m / z = 351.2 [M+H] + .

[0649] Step 4: tert-butyl N-[2-(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)ethyl]carbamate [ka]

[0650] The title compound was prepared analogously to Intermediate 29, step 5, and obtained as a yellow oil. MS (ESP): m / z=293.2 [M+H-tBu] + .

[0651] Intermediate 86 tert-Butyl N-[(8-fluoro-6-formyl-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl)methyl]carbamate [ka]

[0652] Step 1: Ethyl 2-(azidomethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0653] To a solution of ethyl 2-(chloromethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate (Intermediate 83, Step 1, 900.0 mg, 3.02 mmol, 1.0 equiv.) in DMF (12 mL), sodium azide (738.0 mg, 11.35 mmol, 3.76 equiv.) was added at 10° C., and the mixture was stirred at 15° C. for 16 hours. Water was added to the mixture, which was then extracted with EtOAc (20 mL×3) to give the crude title compound (919.86 mg, 3.02 mmol, quantitative yield), which was used directly in the next step. MS (ESP) m / z=305.1 [M+H] + .

[0654] Step 2: Ethyl 2-[(tert-butoxycarbonylamino)methyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazole-6-carboxylate [ka]

[0655] To a solution of ethyl 2-(azidomethyl)-8-fluoro-6,7-dihydro-5H-cyclopen...

Claims

1. The following general formula (I) 【Chemical 1】 (In the formula, A １ is -N-; A ２ teeth, i) -N-, and ii) —CH— Selected from: A ３ is —CH—; A ４ teeth, i) —O—, and ii) -S- Selected from: A ５ is —CH—; A ６ is —O—; W is a ring system: 【Chemistry 2】 Selected from: R ２ is H; R ３ and R ４ teeth, i) H, ii) C １～６ - alkyl, iii) halogens, iv) OH, and v) Cyano are independently selected from L is -L １ -NR １０ -L ２ - and; L １ (CH ２ ) ｘ (wherein x represents an integer of 1 to 6); L ２ (CH ２ ) ｙ (wherein y represents an integer of 1 to 5); R １ is H and R １０ teeth, i) H, and ii) C １～６ -Alkyl Selected from; Or, R １ , R １０ and L ２ and the atoms to which they are attached form a 4-6 membered heterocycle containing a single N heteroatom, or Or, R １ and L ２ and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R １１ teeth, i)NH ２ 、 ii) C １～６ - alkyl, iii) heterocycloalkyl, iv) heterocycloalkylalkyl, v) substituted cycloalkyl, vi) substituted heterocycloalkyl; vii) substituted heterocycloalkylalkyl; viii) aminoalkyl, ix) alkylaminoalkyl, x) (dialkylamino)alkyl, xi) alkylaminoacetamides, xii) aminohydroxyalkyl, xiii) hydroxyalkyl, xiv) hydroxy(alkylamino)alkyl, xv)-(CH ２ ) ｎ NR ａ R ｂ , and xvi)-CH ２ -O-(CH ２ ) ｎ NR ａ R ｂ 、 xvii) (dialkylamino)hydroxyalkyl, and xviii) H is selected from n is an integer of either 1 or 2; Substituted cycloalkyl, substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, OH, oxo and dioxo; R ａ teeth, 【Chemistry 3】 Selected from: R ｂ is H or C １～６ - selected from alkyl; R １２ teeth, i) H, ii) C １～６－ Alkyl, iii) aminoalkyl, iv) (alkylamino)acetamidoalkyl, and v)-(CH ２ ) ２ NR ｃ R ｄ 、 vi) cycloalkylalkyl substituted by amino; vii) cyclopropylaminoalkyl, viii) heterocycloalkyl; ix) alkylaminoalkyl, and x) (dialkylamino) alkyl is selected from R ｃ teeth, 【Chemistry 4】 Selected from: R ｄ is H or C １～６ - selected from alkyl; Or, R １１ and R １２ together form a 6-membered heterocycle containing 1 or 2 N heteroatoms; R １３ teeth, i) H, and ii) aminoalkyl Selected from: R １４ is aminoalkyl; R １５ teeth, i) NH ２ , and ii) (alkylamino) alkylamino Selected from: R ２０ is alkylaminoalkyl; R ２１ is aminoalkyl, alkylaminoalkyl, or (dialkylamino)alkyl; R ２２ is aminoalkyl) or a pharmaceutically acceptable salt thereof.

2. A ４ The compound of claim 1 , wherein is —O—.

3. A ２ The compound according to claim 1 or 2, wherein is -N-.

4. R ３ and R ４ but, i) H, and ii) halogen 3. The compound of claim 1 or 2, independently selected from:

5. 3. The compound of claim 1 or 2, wherein W is selected from the ring systems A, B, C, D, G, H and I.

6. 3. The compound of claim 1, wherein W is selected from the ring systems A, B, C, D and I.

7. R １１ but, i)NH ２ 、 ii) C １～６ - alkyl, iii) a 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iv) a 6-membered heterocycloalkylalkyl containing one N atom and one O atom; v) a 5-6 membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; vi) a 6-membered substituted heterocycloalkylalkyl containing one N atom and one S atom; vii) aminoalkyl, viii) alkylaminoalkyl, ix) (dialkylamino)alkyl, x) alkylaminoacetamides, xi) aminohydroxyalkyl, xii) hydroxyalkyl, and xiii) hydroxy(alkylamino)alkyl, xiv) H, xv) (dialkylamino)hydroxyalkyl, and xvi)-(CH ２ ) ｎ NR ａ R ｂ is selected from n is an integer of either 1 or 2, R ａ but, 【Chemistry 5】 Selected from: R ｂ is H; 3. The compound of claim 1 or 2, wherein the substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, OH, oxo, and dioxo.

8. R １１ but, i) a 4-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5-6 membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, vi) alkylaminoacetamides, vii) aminohydroxyalkyl, and viii) hydroxy(alkylamino)alkyl is selected from 3. The compound of claim 1 or 2, wherein the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH.

9. R １１ but, i) a 5-membered substituted heterocycloalkyl containing one N atom; ii) a 4-membered heterocycloalkyl containing one N atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, and vi) aminohydroxyalkyl is selected from 3. The compound of claim 1 or 2, wherein the substituted heterocycloalkyl is substituted with OH.

10. R １２ but, i) H, ii) C １～６－ Alkyl, iii) aminoalkyl, iv) a 4-membered heterocycloalkyl containing one N atom; v) alkylaminoalkyl, and vi) (dialkylamino)alkyl 3. The compound of claim 1 or 2, selected from:

11. R １２ 3. The compound of claim 1 or 2, wherein is selected from H, alkylaminoalkyl, aminoalkyl, or a 4-membered heterocycloalkyl ring containing one N atom.

12. R １２ 3. The compound of claim 1 or 2, wherein is H.

13. R １１ and R １２ The compound of claim 1 or 2, wherein together form a 6-membered heterocycle containing two N heteroatoms.

14. R １ and R １０ is H or or R １ , R １０ and L ２ and the atoms to which they are bonded are: 【Chemistry 6】 or R １ and L ２ and the atoms to which they are bonded are: 【Chemistry 7】 3. The compound according to claim 1 or 2, wherein the compound forms a four-membered cycloalkyl ring such as:

15. R １ , R １０ and L ２ and the atoms to which they are bonded are: 【Chemistry 8】 The compound according to claim 1 or 2, which forms a piperidine ring as follows:

16. A １ is -N-; A ２ but, i) -N-, and ii) —CH— Selected from: A ３ is —CH—; A ４ is —O—; A ５ is —CH—; A ６ is —O—; W is a ring system: 【Chemistry 9】 Selected from: R ２ is H; R ３ and R ４ is independently selected from H and halogen; L is -L １ -NR １０ -L ２ - and; L １ But (CH ２ ) ｘ (wherein x represents an integer of 1 to 6); L ２ But (CH ２ ) ｙ (wherein y represents an integer of 1 to 5); R １ is H and R １０ but, i) H, and ii) C １～６ -Alkyl Selected from; Or, R １ , R １０ and L ２ and the atoms to which they are attached form a 4-6 membered heterocycle containing a single N heteroatom, or Or, R １ and L ２ and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R １１ but, i)NH ２ 、 ii) C １～６ - alkyl, iii) a 5-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iv) a 6-membered heterocycloalkylalkyl containing one N atom and one O atom; v) a 5-6 membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; vi) a 6-membered substituted heterocycloalkylalkyl containing one N atom and one S atom; vii) aminoalkyl, viii) alkylaminoalkyl, ix) (dialkylamino)alkyl, x) alkylaminoacetamides, xi) aminohydroxyalkyl, xii) hydroxyalkyl, and xiii) hydroxy(alkylamino)alkyl, xiv) H, xv) (dialkylamino)hydroxyalkyl, and xvi)-(CH ２ ) ｎ NR ａ R ｂ is selected from n is an integer of either 1 or 2, R ａ but, 【Chemistry 10】 Selected from: R ｂ is H; substituted heterocycloalkyl and substituted heterocycloalkylalkyl are substituted with 1 to 2 substituents independently selected from alkyl, alkoxy, amino, alkylamino, OH, oxo, and dioxo; R １２ but, i) H, ii) C １～６－ Alkyl, iii) aminoalkyl, iv) (alkylamino)acetamidoalkyl, v)-(CH ２ ) ２ NR ｃ R ｄ 、 vi) cycloalkylalkyl substituted by amino; vii) cyclopropylaminoalkyl, viii) heterocycloalkyl; ix) alkylaminoalkyl, and x) (dialkylamino) alkyl is selected from R ｃ but, 【Chemistry 11】 Selected from: R ｄ is H or C １～６ - selected from alkyl; Or, R １１ and R １２ together form a 6-membered heterocycle containing 1 or 2 N heteroatoms; R １３ is selected from H and aminoalkyl; R １４ is aminoalkyl; R １５ But NH ２ and (alkylamino)alkylamino; R ２０ is alkylaminoalkyl; R ２１ is aminoalkyl or alkylaminoalkyl; R ２２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is aminoalkyl.

17. A １ is -N-; A ２ but, i) -N-, and ii) —CH— Selected from: A ３ is —CH—; A ４ is —O—; A ５ is —CH—; A ６ is —O—; W is selected from ring systems A, B, C, D, G, H and I; R ２ is H; R ３ and R ４ but, i) H, and ii) halogen are independently selected from L is -L １ -NR １０ -L ２ - and; L １ But (CH ２ ) ｘ wherein x is 1; R １ , R １０ and L ２ and the atoms to which they are bonded are: 【Chemistry 12】 and forming a piperidine ring such as R １１ but, i) a 4-6 membered heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; ii) a 5-6 membered substituted heterocycloalkyl containing one N atom, one O atom, or both one N atom and one O atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, vi) alkylaminoacetamides, vii) aminohydroxyalkyl, and viii) hydroxy(alkylamino)alkyl is selected from the substituted heterocycloalkyl is substituted with alkoxy, amino, or OH; R １２ but, i) H, ii) C １～６－ Alkyl, iii) aminoalkyl, iv) a 4-membered heterocycloalkyl containing one N atom; v) aminoalkyl, vi) alkylaminoalkyl, and vii) (dialkylamino)alkyl is selected from R ２０ is alkylaminoalkyl; R ２１ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is alkylaminoalkyl or aminoalkyl.

18. A １ is -N-; A ２ is -N-; A ３ is —CH—; A ４ is —O—; A ５ is —CH—; A ６ is —O—; W is selected from ring systems A, B, C, D and I; R ２ is H; R ３ and R ４ but, i) H, and ii) Fluoro are independently selected from L is -L １ -NR １０ -L ２ - and; L １ But (CH ２ ) ｘ wherein x is 1; R １ , R １０ and L ２ and the atoms to which they are bonded are: 【Chemistry 13】 and forming a piperidine ring such as R １１ but, i) a 5-membered substituted heterocycloalkyl containing one N atom substituted with OH; ii) a 4-membered heterocycloalkyl containing one N atom; iii) aminoalkyl, iv) alkylaminoalkyl, v) (dialkylamino)alkyl, and vi) aminohydroxyalkyl is selected from R １２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from H, alkylaminoalkyl, aminoalkyl, or a 4-membered heterocycloalkyl ring containing one N atom.

19. 6-[5-[2-[(4,8-difluoro-2-methyl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[5-[2-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(1-hydroxy-1-methyl-ethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(4-methylmorpholin-2-yl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(morpholinomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3R)-morpholin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3R)-morpholin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-5-oxopyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-5-oxopyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[(10,16 difluoro-2,5,8 triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),7,10,15-tetraen-13-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-(methylamino)pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-4-hydroxy-2-piperidyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-4-hydroxy-2-piperidyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(1-amino-1-methyl-ethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S,4R)-4-aminotetrahydrofuran-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(2-amino-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-azabicyclo[2.1.1]hexan-1-yl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-2-(methylamino)acetamide; 6-[8-[[2-[(1S,2S)-1-amino-2-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-methoxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[5-[2-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[5-[2-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]ethyl]-2-oxo-oxazolidin-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-[[4,8-difluoro-2-[(2R,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methylamino]-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-3-hydroxy-2-(methylamino)propyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(methylamino)acetamide; 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

20. 6-[8-[[2-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-(dimethylamino)-3-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(dimethylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[2-(methylamino)ethyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2-methoxyethylamino)methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methylamino]-N-methyl-acetamide; 6-[8-[[1-(2-aminoethyl)-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-2-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(1-aminocyclopropyl)methyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(1R)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-1,6,7,8-tetrahydrocyclopenta[e]benzimidazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-7,8-dihydro-6H-cyclopenta[e][1,3]benzoxazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(3-hydroxyazetidin-1-yl)methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(aminomethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; Formic acid; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[2-oxo-8-[[3-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[3-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; formic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[2-(cyclopropylamino)ethyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; formic acid; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; hydrochloric acid; 6-[8-[[1-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[2-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; (2R)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)propanamide; (2R)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(dimethylamino)propanamide; (2R)-2-(dimethylamino)-N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]propanamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(dimethylamino)-N-methyl-acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-N-methyl-acetamide; (2R)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]pyrrolidine-2-carboxamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-2-(methylamino)acetamide; N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]-2-(methylamino)acetamide; 2,2,2-trifluoroacetic acid; N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl-2-(methylamino)acetamide; (2R)—N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]pyrrolidine-2-carboxamide; 2,2,2-trifluoroacetic acid; (2R)—N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]methyl]pyrrolidine-2-carboxamide; (2R)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]pyrrolidine-2-carboxamide; (2R,4S)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide; (2R,4S)—N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide; 2-amino-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; Formic acid; 2-amino-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-2-yl]ethyl]-N-methyl-acetamide; 2-amino-N-methyl-N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]acetamide; N-[2-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-1-yl]ethyl]-2-(dimethylamino)acetamide; (2R)—N-[[8-fluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-2-yl]methyl]-2-(methylamino)propanamide; 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

21. 6-[8-[[2-[(dimethylamino)methyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S)-pyrrolidin-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[(4,8-difluoro-2-morpholin-2-yl-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R)-pyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(1-amino-1-methyl-ethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(3S,4R)-4-aminotetrahydrofuran-3-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-1-methyl-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-azabicyclo[2.1.1]hexan-1-yl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; N-[4,8-difluoro-6-[[2-oxo-3-(3-oxo-4H-pyrazino[2,3-b][1,4]oxazin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]methyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-2-yl]-2-(methylamino)acetamide; 6-[8-[[2-[(1S,2S)-1-amino-2-hydroxy-propyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-methoxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,3S)-3-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1S)-2-hydroxy-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one 20. The compound of claim 1 or claim 19, selected from: or a pharmaceutically acceptable salt thereof.

22. 6-[8-[[3-[2-(dimethylamino)ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-1-methyl-6,7-dihydro-5H-cyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[3-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-1,6,7,8-tetrahydrocyclopenta[e]benzimidazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-(methylaminomethyl)-7,8-dihydro-6H-cyclopenta[e][1,3]benzoxazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-aminoethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(aminomethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; Formic acid; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; formic acid; 6-[8-[[4,8-difluoro-2-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride 21. The compound of claim 1 or claim 20, selected from: or a pharmaceutically acceptable salt thereof.

23. 6-[8-[[2-[2-(dimethylamino)ethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-(methylaminomethyl)-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(aminomethyl)-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(1R)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-4,8-difluoro-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(1S)-1-(methylamino)ethyl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(2-aminoethyl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1R)-1-aminoethyl]-8-fluoro-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[4,8-difluoro-2-[(2R,4S)-4-hydroxypyrrolidin-2-yl]-3,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[2-oxo-8-[[(6S)-8-fluoro-2-(methylaminomethyl)-1,5,6,7-tetrahydrocyclopenta[f]benzimidazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one 20. The compound of claim 1 or 18, selected from: or a pharmaceutically acceptable salt thereof.

24. 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 2,2,2-trifluoroacetic acid; 6-[8-[[2-(2-aminoethyl)-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[5-fluoro-2-[2-(methylamino)ethyl]-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-5-fluoro-7,8-dihydro-6H-cyclopenta[e]benzotriazol-7-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-(methylaminomethyl)-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-keto-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[1-(azetidin-3-yl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[4,8-difluoro-1-[2-(methylamino)ethyl]-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[1-(azetidin-3-yl)-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; Formic acid; 6-[8-[[2-[(2S)-2-aminopropyl]-4,8-difluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one dihydrochloride; 6-[2-oxo-8-[[2-(2-aminoethyl)-8-fluoro-6,7-dihydro-5H-cyclopenta[f]benzotriazol-6-yl]methyl]-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(2R)-Azetidin-2-yl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[8-fluoro-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one; 6-[8-[[2-[(1S)-1-amino-2-hydroxy-ethyl]-8-fluoro-6,7-dihydro-5H-cyclopenta[f][1,3]benzoxazol-6-yl]methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl]-4H-pyrazino[2,3-b][1,4]oxazin-3-one 21. The compound of claim 1 or 20, selected from: or a pharmaceutically acceptable salt thereof.

25. 3. A compound according to claim 1 or 2 for use as a therapeutically active substance.

26. 10. A pharmaceutical composition comprising a compound of claim 1 or 2 and a therapeutically inert carrier.

27. 27. The pharmaceutical composition of claim 26 for use as an antibiotic.

28. 27. The pharmaceutical composition of claim 26 for treating or preventing a bacterial infection.

29. 27. The pharmaceutical composition of claim 26 for treating or preventing infections and resulting diseases caused by Escherichia coli.

30. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for treating or preventing a bacterial infection.

31. 10. Use of a compound according to claim 1 or 2 for preparing a medicament for treating or preventing infections and resulting diseases caused by Escherichia coli.

32. A process for preparing a compound of claim 1 or 2, comprising reacting a compound of formula III with a compound of formula II in the presence of xxx under conditions comprising sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as methanol, THF or 1,2-dichloroethane, optionally in the presence of an additive such as N,N-diisopropylethylamine or triethylamine or acetic acid or powdered molecular sieves, at a temperature such as room temperature to obtain a compound of formula I. 【Chemistry 14】 (In the formula, R １ , R ２ , A １ , A ２ , A ３ , A ４ , A ５ , A ６ , L and W are as above) A method comprising:

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