RU2409582C2 - Condensed tricyclic derivatives for treating psychotic disorders - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R⁷)(R⁸) or C(R⁷), where if the bond between B and Y is a single bond, B denotes C(R⁷)(R⁸), and when the bond between B and Y is a double bond, B denotes C(R⁷); Y denotes C(R⁷), C(R⁷)(R⁸) or O, where if the bond between B and Y is a single bond, Y denotes C(R⁷)(R⁸) or O, and when the bond between B and Y is a double bond, B denotes C(R⁷); Z¹ denotes -CH₂-, -(CH₂)₂-, -CH₂CH-CH₃-, where Z¹ is bonded on the left side to a nitrogen atom or -(CH₂)₃-; X denotes C(R¹) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C_1-6-alkyl, halogen-C_1-6-alkyl, C(O)N(R³)(R⁴), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C_1-6-alkyl; when R is present, each independently denotes halogen, C_1-6-alkyl; each R¹ denotes hydrogen or methyl; each R² denotes cyano, C_1-6-alkyl, C_1-6-alkoxy, halogen-C_1-6-alkyl, =O, -C(O)N(R³)(R⁴), -C(O)N(R³)-C_1-6-alkoxy, -C(NOR⁵)R⁶, -C(O)R⁶, -C(O)OR⁷, -C(O)NHNHC(O)R⁶, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C_1-6-alkyl; R³ and R⁴ independently denote hydrogen; C_1-6-alkyl; C_3-7-cycloalkyl; C_3-7-cycloalkyl-C_1-6-alkyl; or when R³ and R⁴ are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R⁵ denotes C_1-4-alkyl; R⁶ denotes C_3-7-cycloalkyl or C_1-6-alkyl; R⁷ and R⁸ independently denote hydrogen or C_1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT₁ receptor mediated activity.

23 cl, 195 ex

Description

The present invention relates to new condensed tricyclic derivatives, methods for their preparation, pharmaceutical compositions containing such compounds, and their use as medicines, inter alia, for the treatment of psychotic disorders, depressive disorders, anxiety disorders and sexual dysfunctions.

WO 2004/046124 discloses a number of benzoxazinones, compounds with affinity for 5-HT ₁ receptors and / or having serotonin reuptake inhibitory activity.

A new series of compounds with high affinity for 5-HT ₁ receptors and / or serotonin reuptake inhibitors has been established.

In a first aspect, the invention relates to a compound of formula (I)

its salt or prodrug,

Where

---- represents, independently, a single or double bond;

the Q cycle is a 5-membered heteroaromatic ring or a 5-membered heterocyclic ring, each of which contains at least one nitrogen atom in the ring, as seen in formula (I), and, optionally, 1-3 additional heteroatoms in the ring independently selected from oxygen, nitrogen and sulfur;

B represents C (R ⁷ ) (R ⁸ ) or C (R ⁷ ), where in the case where the bond connecting B and Y is a single bond, B represents C (R ⁷ ) (R ⁸ ), and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ), O or S (O) _t , where when the bond connecting B and Y is a single bond, Y is C (R ⁷ ) (R ⁸ ), O or S (O) _t , and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Z ¹ represents a linker group of the formula (A)

Where

W represents - (CH = CH) -; -C (= O) -; -C (= CH ₂ ) -; -C (R ⁷ ) (R ⁸ ) -; -C (R ⁷ ) (R ⁸ ) -S (O) _t -; -C (R ⁷ ) (R ⁸ ) -O- or 3-7-membered cycloalkylene group or 3-7-membered cycloalkenylene group, any of which is optionally substituted by 1-3 substituents, which may be the same or different, selected from halogen, hydroxy, cyano, C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkanoyl and C _1-6 alkoxy; and

n and m are independently 0, 1 or 2;

X represents C (R ¹ ), N or C; where in the case where the dotted bond attached to X is a single bond, X is C (R ¹ ) or N, and when the dotted bond attached to X is a double bond, X is C;

A is indolyl, quinolyl, quinazolinyl, benzofuranyl or benzothienyl, any of which is optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-7 -cycloalkyl, aryl-C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy , C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-4 alkoxy, C _2-6 alkenyl, C _3-6 alkynyl, halo-C _2-6 - alkenyl, —C (O) N (R ³ ) (R ⁴ ), —C (O) N (R ³ ) —C _1-6 alkoxy, —S (O) ₂ N (R ³ ) (R ⁴ ) , -N (R ³ ) (R ⁴ ), -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), —C (O) R ⁶ , —C (O) OR ⁷ , a heterocyclic ring, aroyl and aryl; where the heterocyclic ring, aroyl and aryl groups are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halo-C _{1- 6-} alkyl, C _1-6 alkoxy and halogen-C _1-6 alkoxy;

when R is present, each is independently halogen, C _1-6 alkyl, cyano, halo-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxy or trifluoromethoxy;

each R ¹ represents hydrogen, halogen, C _1-6 alkyl, cyano, halogen-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxy or C _1-6 alkoxy C _1-6 alkyl;

each R ² represents hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen-C _1-6 alkyl, C _3-7 cycloalkyl, aryl C _1-6 alkoxy, C _{1- 6} -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6- alkoxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-4 -alkoxy, C _{2 -6-} alkenyl, C _3-6 -alkynyl, halogen-C _2-6 -alkenyl, = O, -C (O) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) - C _1-6 alkoxy, -S (O) ₂ N (R ³ ) (R ⁴ ), -N (R ³ ) (R ⁴ ), -C (NOR ⁵ ) R ⁶ , --N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), -C (O) R ⁶ , -C (O) OR ⁷ , -C (O) NHNHC (O) R ⁶ is a heterocyclic ring, aroyl or aryl; where the heterocyclic ring, aroyl or aryl groups are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halo-C _{1- 6-} alkyl, C _1-6 alkoxy and halogen-C _1-6 alkoxy;

R ³ and R ⁴ are independently hydrogen; C _1-6 alkyl; aryl; C _3-7 cycloalkyl; C _3-7 cycloalkyl-C _1-6 alkyl; or when R ³ and R ^{4 are} connected to the same nitrogen atom, they together with the nitrogen atom form a 4-, 5-, 6- or 7-membered ring, optionally containing one additional O, N or S atom in the ring;

R ⁵ represents C _1-4 alkyl, C _3-7 cycloalkyl-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁶ represents hydrogen, halogen, cyano, C _3-7 cycloalkyl-C _1-6 alkyl, C _3-7 cycloalkyl or C _1-6 alkyl;

R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-6 alkyl, cyano, halo-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxyl, halogen or C _{1 -6-} alkoxy-C _1-6 -alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3; and

t is 0, 1 or 2.

The term “5-membered heteroaromatic ring” means a 5-membered aromatic ring containing at least one nitrogen atom in the cycle and, optionally, containing in addition 1-3 additional heteroatoms selected from oxygen, nitrogen and sulfur. Examples of 5 membered heteroaromatic rings are pyrrole, imidazole, pyrazole, triazole, oxadadiazole and tetrazole.

The term “5 membered heterocyclic ring” means a 5 membered heterocyclic ring partially or fully saturated, i.e. non-aromatic, containing at least one nitrogen atom in the cycle and, optionally, containing in the cycle an additional 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of such cycles that are partially saturated include oxazoline, isoxazoline, imidazoline, pyrroline and pyrazoline. Examples of such rings which are fully saturated include pyrrolidine, imidazolidine and oxadiazoline.

The term “heterocyclic ring” means a 5- or 6-membered mononuclear ring, partially or fully saturated, where up to 5 carbon atoms are replaced by heteroatoms independently selected from O, S and N. Examples of heterocyclic rings that are fully saturated 5- or 6-membered mononuclear rings are pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, dioxolane, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrothiophene, dioxane, tetrahydro-2H-pyran and dithian. Examples of heterocyclic rings that are partially saturated 5- or 6-membered mononuclear rings are oxazoline, isoxazoline, imidazoline, pyrazoline, 1,2,3,6-tetrahydropyridine and 3,6-dihydro-2H-pyran.

The term "aryl", as an independent or as part of another group, is intended, unless otherwise indicated, to mean an aromatic carbocyclic ring or heteroaromatic ring. Examples of aryl groups are phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, isothiazolyl, oxazolyl, thiazolyl, thiazinyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, azepinyl and naphthyl.

The term “C _1-6 -alkyl”, as an independent or as part of another group, is intended to mean an alkyl group with one to six carbon atoms in all isomeric forms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The term “halogen” is used herein to describe, unless otherwise indicated, a group selected from fluoro, chloro, bromo and iodo.

The term “halo-C _1-6 alkyl” means a C _1-6 alkyl group which is substituted with one or more halogen, for example CF ₃ .

The term “C _1-6 alkanoyl” means an alkanoyl group with 1-6 carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”), propanoyl, butanoyl, pentanoyl and hexanoyl.

The term “C _1-6 alkoxy” denotes a linear or branched alkoxy (or “alkyloxy”) group with one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy, tert-pentoxy and hexyloxy.

The term "3-7 membered cycloalkylene group" refers to cycloalkylene groups with 3-7 carbon atoms, such as cyclohexylene.

The term “3-7 membered cycloalkenylene group” refers to cycloalkenylene groups with 3-7 carbon atoms, such as cyclohexenylene.

The term “C _1-6 alkylthio” means a linear or branched alkylthio group with one to six carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio, pentylthio , n-pentylthio, isopentylthio, tert-pentylthio and hexylthio.

The term "aryl-C _1-6 alkoxy" refers to an aryl group connected to a C _1-6 alkoxy group. Examples include phenylmethoxy, phenylethoxy, naphthylmethoxy, naphthylethoxy, phenylpropoxy, naphthylpropoxy, phenylbutoxy and naphthylpentoxy.

The term “C _3-7 cycloalkyl” refers to a cycloalkyl group of 3-7 carbon atoms, for example cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

The term "aroyl" refers to a group of the formula aryl-CO, where aryl has the meanings indicated above.

The term “C _2-6 alkenyl” refers to an unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, with two to six carbon atoms in all isomeric forms, such as ethenyl, propenyl, butenyl, pentenyl and hexenyl.

The term “C _2-6 alkynyl” refers to an unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds, with two to six carbon atoms in all isomeric forms, such as propynyl, butylidine, penteninyl and pentylidine.

In one embodiment, cycle Q is imidazole, triazole (e.g., 1,2,3-triazole or 1,3,4-triazole) or tetrazole. In another embodiment, cycle Q is imidazole.

In one embodiment, Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ) or O, where in the case where the bond connecting B and Y is a single bond, Y is C (R ⁷ ) ( R ⁸ ) or O, and when the bond connecting B and Y is a double bond, B is C (R ⁷ ). In another embodiment, when Y is C (R ⁷ ), C (R ⁷ ) (R ⁸ ) or O, R ⁷ and R ⁸ are independently hydrogen or C _1-6 alkyl (in particular methyl or ethyl). In another embodiment, R ⁷ and R ⁸ are hydrogen.

In one embodiment, Z ¹ is —CH ₂ -, - (CH ₂ ) ₂ -, —CH ₂ CH (CH ₃ ) - (where the left side of the Z ¹ bond is attached to a nitrogen atom) or - (CH ₂ ) ₃ -. In another embodiment, Z ¹ represents - (CH ₂ ) ₂ -.

In one embodiment, X is C (R ¹ ) or N. In another embodiment, when X is C (R ¹ ), R ¹ is hydrogen, halogen, or C _1-6 alkyl (such as methyl or ethyl). In another embodiment R ¹ represents hydrogen or methyl. In another embodiment, X represents N or CH.

In one embodiment, A is quinolyl or quinazolinyl, any of which is optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen-C _1-6 -alkyl, C _3-7 -cycloalkyl, aryl-C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _{1 -6-} alkoxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-4 -alkoxy, C _2-6 -alkenyl, C _3-6 -alkynyl, halogen-C _2-6 -alkenyl, - C (O) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) -C _1-6 alkoxy, -S (O) ₂ N (R ³ ) (R ⁴ ), -N (R ³ ) (R ⁴ ), -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), - C (O) R ⁶ , -C (O) OR ⁷ , a heterocyclic ring, aroyl and aryl; where the heterocyclic ring, aroyl and aryl groups are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halo-C _{1- 6} -alkyl, C _1-6 alkoxy and halogen-C _1-6 alkoxy. In another embodiment, the substituents on A are selected from the group consisting of halogen, cyano, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halogen-C _1-6 alkoxy, -C (O) N (R ³ ) (R ⁴ ) and —C (O) R ⁶ . In another embodiment, the substituents on A are selected from the group consisting of halogen (such as fluorine or chlorine), C _1-6 alkyl (such as methyl, ethyl and propyl), cyano, trifluoromethyl, C _1-6 alkoxy (such as methoxy, ethoxy or isopropoxy) and —C (O) R ⁶ . In yet another embodiment, A is quinolyl, and the substituents on A are selected from the group consisting of halogen, cyano, C _1-6 alkyl, halogen-C _1-6 alkyl, C _1-6 alkoxy, halogen-C _{1 -6} alkoxy and -C (O) N (R ³ ) (R ⁴ ). In another embodiment, A is 5-quinolyl, and the substituents on A are selected from the group consisting of halogen, cyano, C _1-6 alkyl, halogen-C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy and -C (O) N (R ³ ) (R ⁴ ). In yet another embodiment, A is 2-methyl-5-quinolyl.

In one embodiment, R, when present, is halogen (such as fluorine or chlorine) or C _1-6 alkyl (such as methyl or ethyl).

In one embodiment, R ¹ , when present, is hydrogen or C _1-6 alkyl (such as methyl or ethyl).

In one embodiment, each R ² is hydrogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, halogen-C _1-6 alkyl, = O, —C (O) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) -C _1-6 alkoxy, -S (O) ₂ N (R ³ ) (R ⁴ ), -N (R ³ ) (R ⁴ ), -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), -C (O) R ⁶ , -C (O ) OR ⁷ , —C (O) NHNHC (O) R ⁶ , a heterocyclic ring or aryl; wherein the heterocyclic ring or aryl groups are optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, nitro, amino, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy and halo C _1-6 alkoxy. In another embodiment, each R ² is hydrogen, cyano, C _1-6 alkyl, = O, —C (O) N (R ³ ) (R ⁴ ), —C (O) N (R ³ ) —C _{1 -6-} alkoxy, -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -C (O) R ⁶ ,

—C (O) OR ⁷ , —C (O) NHNHC (O) R ⁶ , a heterocyclic ring or aryl; wherein the heterocyclic ring or aryl groups are optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, nitro, amino, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy and halo C _1-6 alkoxy. In another embodiment, each R ² is C _1-6 alkyl, —C (O) N (R ³ ) (R ⁴ ), or —C (O) R ⁶ .

In one embodiment, s is 1 or 2.

In one embodiment, the invention relates to a compound of formula (I), a salt or prodrug thereof, wherein

---- represents, independently, a single bond or a double bond;

cycle Q is imidazole, triazole (for example, 1,2,3-triazole or 1,3,4-triazole) or tetrazole;

B represents C (R ⁷ ) (R ⁸ ) or C (R ⁷ ), where in the case where the bond connecting B and Y is a single bond, B represents C (R ⁷ ) (R ⁸ ), and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ) or O, where in the case where the bond connecting B and Y is a single bond, Y represents C (R ⁷ ) (R ⁸ ) or O, and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Z ¹ represents —CH ₂ -, - (CH ₂ ) ₂ -, —CH ₂ CH (CH ₃ ) - (where the left side of the Z ¹ bond is attached to a nitrogen atom) or - (CH ₂ ) ₃ -;

X represents C (R ¹ ) or N;

A is quinolyl or quinazolinyl, any of which is optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen-C _1-6 -alkyl, C _3-7 -cycloalkyl, aryl-C _1-6 -alkoxy, C _1-6 -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 - alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-4 alkoxy, C _2-6 alkenyl, C _3-6 alkynyl, halo-C _2-6 alkenyl, -C (O ) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) -C _1-6 alkoxy, -S (O) ₂ N (R ³ ) (R ⁴ ), -N (R ³ ) (R ⁴ ), -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), -C (O ) R ^6, -C (O) OR ^7, geterotsiklich Skog ring, aroyl and aryl; where the heterocyclic ring, aroyl and aryl groups are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halo-C _{1- 6-} alkyl, C _1-6 alkoxy and halogen-C _1-6 alkoxy;

R, when present, is halogen (such as fluorine or chlorine) or C _1-6 alkyl (such as methyl or ethyl);

R ¹ , when present, is hydrogen or C _1-6 alkyl (such as methyl or ethyl);

each R ² represents hydrogen, cyano, C _1-6 -alkyl, C _1-6 -alkoxy, halogen-C _1-6 -alkyl, = O, -C (O) N (R ³ ) (R ⁴ ), —C (O) N (R ³ ) —C _1-6 alkoxy, —S (O) ₂ N (R ³ ) (R ⁴ ), —N (R ³ ) (R ⁴ ), —C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -N (R ³ ) S (O) ₂ (R ⁶ ), -C (O) R ⁶ , -C (O) OR ⁷ , -C (O) NHNHC (O) R ⁶ , a heterocyclic ring or aryl; wherein the heterocyclic ring or aryl groups are optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, nitro, amino, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy and halo-C _1-6 alkoxy;

R ³ and R ⁴ are independently hydrogen; C _1-6 alkyl; aryl; C _3-7 cycloalkyl; C _3-7 cycloalkyl-C _1-6 alkyl; or when R ³ and R ^{4 are} connected to the same nitrogen atom, they together with the nitrogen atom form a 4-, 5-, 6- or 7-membered ring, optionally containing one additional O, N or S atom in the ring;

R ⁵ represents C _1-4 alkyl, C _3-7 cycloalkyl-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁶ represents hydrogen, halogen, cyano, C _3-7 cycloalkyl-C _1-6 alkyl, C _3-7 cycloalkyl or C _1-6 alkyl;

R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-6 alkyl, cyano, halo-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxyl, halogen or C _{1 -6-} alkoxy-C _1-6 -alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3;

s is 0, 1 or 2; and

t is 0, 1 or 2.

In one embodiment, the invention relates to a compound of formula (I), a salt or prodrug thereof, wherein

---- represents, independently, a single bond or a double bond;

cycle Q is imidazole, triazole (for example, 1,2,3-triazole or 1,3,4-triazole) or tetrazole;

B represents C (R ⁷ ) (R ⁸ ) or C (R ⁷ ), where in the case where the bond connecting B and Y is a single bond, B represents C (R ⁷ ) (R ⁸ ), and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ) or O, where in the case where the bond connecting B and Y is a single bond, Y represents C (R ⁷ ) (R ⁸ ) or O, and when the bond connecting B and Y is a double bond, B is C (R ⁷ );

Z ¹ represents - (CH ₂ ) ₂ -;

X represents CH or N;

A is quinolyl or quinazolinyl, any of which is optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, cyano, C _1-6 alkyl, halo-C _1-6 - alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, -C (O) N (R ³ ) (R ⁴ ) and -C (O) R ⁶ ;

R, when present, is halogen (such as fluorine or chlorine) or C _1-6 alkyl (such as methyl or ethyl);

R ¹ , when present, is hydrogen or C _1-6 alkyl (such as methyl or ethyl);

each R ² represents hydrogen, cyano, C _1-6 -alkyl, = O, -C (O) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) -C _1-6 - alkoxy, -C (NOR ⁵ ) R ⁶ , -N (R ³ ) C (O) (R ⁶ ), -C (O) R ⁶ , -C (O) OR ⁷ , -C (O) NHNHC (O ) R ⁶ , a heterocyclic ring or aryl; wherein the heterocyclic ring or aryl groups are optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, nitro, amino, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy and halo-C _1-6 alkoxy;

R ³ and R ⁴ are independently hydrogen; C _1-6 alkyl; aryl; C _3-7 cycloalkyl; C _3-7 cycloalkyl-C _1-6 alkyl; or when R ³ and R ^{4 are} connected to the same nitrogen atom, they together with the nitrogen atom form a 4-, 5-, 6- or 7-membered ring, optionally containing one additional O, N or S atom in the ring;

R ⁵ represents C _1-4 alkyl, C _3-7 cycloalkyl-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁶ represents hydrogen, halogen, cyano, C _3-7 cycloalkyl-C _1-6 alkyl, C _3-7 cycloalkyl or C _1-6 alkyl;

R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3; and

s is 0, 1, or 2.

In one embodiment, the compounds of formula (I) are selected from

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (Example 14) ;

N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (example 15);

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinyl glycarbonyl) -4H-imidazo [5,1-c] [1,4] benzoxazine dihydrochloride (example 24);

N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 83 );

N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 89);

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 91);

6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} tetrazolo [1,5-a] quinoline dihydrochloride (Example 94);

ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate dihydrochloride (Example 97 );

dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (3-methyl-1,2,4-oxadiazole-5 -yl) imidazo [1,5-a] quinoline (Example 105);

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 109);

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 122);

dihydrochloride N, 7-dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3 -carboxamide (example 124) and

7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (example 125);

or their pharmaceutically acceptable salts or free bases.

In another embodiment, the compound is 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 dihydrochloride -carboxamide (example 14).

In another embodiment, the compound is 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazin-3- carboxamide (example 14, free base).

In another embodiment, the compound is 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 91).

In another embodiment, the compound is 6- {2- [4- (2-methyl-5-quinolininyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinolin-3- dihydrochloride carboxamide (Example 109).

According to another aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Where

A is indolyl, quinolyl, quinazolinyl, benzofuranyl or benzothienyl, where these groups are optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-6 alkyl , halogen-C _1-6 -alkyl, C _3-7 -cycloalkyl, aryl-C _1-6 -alkoxy, C _1-6 -alkanoyl, C _1-6 -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-4 alkoxy, C _2-6 alkenyl, C _3-6 alkynyl, halogen C _2-6 alkenyl, C (O) N (R ³ ) (R ⁴ ), C (O) N (R ³ ) -C _1-6 alkoxy, S (O) ₂ N (R ³ ) (R ⁴ ), N (R ³ ) (R ⁴ ); C (NOR ⁵ ) R ⁶ , N (R ³ ) C (O) (R ⁴ ), N (R ³ ) S (O) ₂ (R ⁴ ), C (O) R ⁷ , C (O) OR ⁷ , heterocycle, aroyl or aryl, where the aroyl or heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halogen-C _{1 -6} alkyl, C _1-6 alkoxy and halogen C _1-6 alkoxy;

B represents C (R ⁷ ) (R ⁸ ) or C (R ⁷ );

X represents C (R ¹ ), N or C;

Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ), O or S (O) _t ;

Z ¹ represents a group

where n and m are independently, 0, 1 or 2, and W is a 3-7 membered cycloalkylene group or a 3-7 membered cycloalkenylene group, optionally substituted with 1-3 substituents, which may be the same or different and which are selected from halogen, hydroxy, cyano, C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkanoyl or C _1-6 alkoxy; or W represents - (CH = CH) -; -C (= O) -; -C (= CH ₂ ) -; -C (R ⁷ ) (R ⁸ ) -; —C (R ⁷ ) (R ⁸ ) —S (O) _t - or —C (R ⁷ ) (R ⁸ ) —O—;

the Q cycle is a 5-membered heteroaromatic ring or a 5-membered heterocyclic ring containing at least one nitrogen atom, and optionally containing an additional 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

---- represents, independently, a single bond or a double bond, provided that when

(a) X represents N or C (R ¹ ), the bond ---- connected to X represents a single bond;

(b) Y is C (R ² ) (R ³ ), N (R ² ), O or S (O) _t , the bond ---- connected to Y is a single bond;

R is independently halogen, C _1-6 alkyl, cyano, halo-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxy or trifluoromethoxy;

R ¹ (a) represents hydrogen, C _1-6 alkyl, cyano, halogen-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxy or C _1-6 alkoxy C _1-6 alkyl;

R ² represents hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 -alkyl, halogen-C _1-6 -alkyl, C _3-7 -cycloalkyl, aryl-C _1-6 -alkoxy, C _1-6 -alkanoyl, C _1-6 -alkylthio, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkoxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _{1- 4-} alkoxy, C _1-6 alkenyl, C _3-6 alkenyl, halogen-C _1-6 alkenyl, = O, C (O) N (R ³ ) (R ⁴ ), C (O) N ( R ³ ) -C _1-6 alkoxy, S (O) ₂ N (R ³ ) (R ⁴ ), N (R ³ ) (R ⁴ ); C (NOR ⁵ ) R ⁶ , N (R ³ ) C (O) (R ⁴ ), N (R ³ ) S (O) ₂ (R ⁴ ), C (O) R ⁷ , C (O) OR ⁷ , heterocycle, aroyl or aryl, where the aroyl or heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, halogen-C _{1 -6} alkyl, C _1-6 alkoxy and halogen C _1-6 alkoxy;

R ³ and R ⁴ are independently hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl or, together with N, NR ³ R ⁴ or form a 4-, 5-, 6- or 7-membered azacyclic group, optionally containing one additional O, N or S atom in the azacycle and containing 3-8 carbon atoms (including carbon atoms contained in any of the optional ( s) substituent (s) of azacycle);

R ⁵ represents C _1-4 alkyl, C _3-7 cycloalkyl-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁶ represents hydrogen, halogen, cyano, C _3-7 -cycloalkyl-C _1-6 -alkyl or C _3-7 -cycloalkyl or C _1-6 -alkyl;

R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl or halo-C _1-6 alkyl;

R ⁹ and R ¹⁰ are independently hydrogen, C _1-6 alkyl, cyano, halo-C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkoxy, hydroxyl, halogen or C _{1 -6-} alkoxy-C _1-6 -alkyl;

p is 0, 1 or 2;

r is 1, 2 or 3;

s is 1, 2 or 3;

t is 0, 1 or 2.

The term “substituted” means substitution with one or more groups. In the case where groups can be selected from a number of alternative groups, the selected groups may be the same or different.

The term “independently” means that when multiple substituents are selected from a number of possible substituents, such substituents may be the same or different.

The compounds of formula (I) can form acid or base addition salts. It should be borne in mind that for use in medicine, salts must be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are apparent to those skilled in the art and include those described in Berge et al., J. Pharm. Sci., 1977, 66, 1-19. When the compounds of formula (I) contain a basic center, they can form acid addition salts with suitable inorganic or organic acids. Examples of suitable inorganic acids are hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric or phosphoric acid. Examples of suitable organic acids are succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfonic, isotionic, mucus, gentisic, isonic glucanoic, , ascorbic, anthranilic, salicylic, phenylacetic, almond, embonic (pamova), ethanesulfonic, pantothenic, stearic, sulfinyl, alginic, galacturonic acid and arylsulfonic acids (n for example, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid). When the compounds of formula (I) contain an acid center, they can form base addition salts with alkali metals, alkaline earth metals and suitable organic bases. Examples of suitable organic bases are N, N-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine. Some compounds of formula (I) can form acid addition salts with less than one equivalent, one equivalent, or more than one equivalent of an acid (e.g., dihydrochloride salt). Salts of the compounds of formula (I) include all possible stoichiometric and non-stoichiometric forms. Salts with a physiologically unacceptable anion or cation are included in the scope of the invention, so they themselves may be useful intermediates for the preparation of physiologically acceptable salts and / or used for non-therapeutic purposes, for example in vitro situations. In one embodiment, the salt is a physiologically acceptable salt.

Specialists in this field should be borne in mind that some protective groups containing derivatives of the compounds of formula (I), which can be obtained before the final stage by removal of the protective group, may not have pharmacological activity as such, but in some cases can be introduced and subsequently metabolized an organism to form compounds of the invention that are pharmacologically active. Therefore, such derivatives can be described as prodrugs. In addition, some compounds of formula (I) may act as prodrugs of other compounds of formula (I). All protecting groups derivatives and prodrugs of the compounds of formula (I) are included within the scope of the invention. Examples of suitable prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp. 499-538, in Topics in Chemistry, Chapter 31, pp. 306-316, and in Design of Prodrugs, H. Bundgaard, Elsevier, 1985, Chapter 1 (incorporated herein by reference). Those skilled in the art should also bear in mind that some groups known to those skilled in the art as progroups, such as those described by H. Bundgaard in Design of Prodrugs (incorporated by reference herein), may be replaced by corresponding functional groups when such functional groups are present in the compounds of the invention. In one embodiment, the prodrugs for the compounds of the invention include esters, carbonate esters, half esters, phosphate esters, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

Hereinafter, in the description of the compounds of formula (I), their salts and prodrugs, defined in any aspect of the invention (with the exception of intermediates in chemical methods), are called compounds of the invention.

Compounds of the invention can be obtained in crystalline and non-crystalline form. If the compounds are in crystalline form, they can be hydrated or solvated. Stoichiometric hydrates or solvates are included in the scope of the invention, as well as compounds containing varying amounts of water and / or solvent.

The compounds of the invention may also exist in various polymorphic forms.

Some compounds of the invention are capable of existing in stereoisomeric forms (for example, geometric or ("cis-trans") isomers, diastereomers and enantiomers), and the invention extends to each of these stereoisomeric forms and mixtures thereof, including racemates. The various stereoisomeric forms can be separated by methods known to those skilled in the art of chemistry, or any given isomer can be obtained by asymmetric synthesis.

The invention also extends to any tautomeric forms and mixtures thereof. All such isomers, including mixtures, are included within the scope of the present invention.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic embodiment of a compound of the invention is defined as an embodiment in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass commonly found in nature. Examples of isotopes that can be included in the compounds of the invention include isotopes of hydrogen, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² N, ³ N, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Some isotopic variants of the invention, for example, variants in which a radioactive isotope is included, such as ³ N or ¹⁴ C, are applicable in a drug and / or in the study of distribution in a tissue substrate. Tritium isotopes, i.e. ³ N, and carbon-14, i.e. ¹⁴ C are suitable by virtue of their easy acquisition and detection. Further, substitution with isotopes such as deuterium, i.e. ² N may provide some therapeutic benefits resulting from a greater resistance to metabolism, such as an increased in vivo half-life or reduced dosage requirement, and therefore may be appropriate in some circumstances. Isotopic variations of the compounds of the invention can typically be obtained by conventional procedures, such as the methods described, or by the preparation methods described in the examples and descriptions below, using appropriate isotopic variations of suitable reagents.

In the description, the general formulas are denoted by the Latin numbers (I), (II), (III), (IV), etc. Subgroups of such general formulas are designated as (Ia), (Ib), (Ic), etc., ... (IVa), (IVb), (IVc), etc.

Compounds of formula (Ia), i.e. compounds of formula (I), where Z ¹ is —CH (R ⁷ ) - [CH (R ⁹ )] _m - (where m is 0, 1 or 2) can be prepared according to reaction scheme 1. Compounds of formula (II) reacted with compounds of formula (III) in the presence of a suitable reducing agent, such as sodium triacetoxyborohydride. The reaction is typically carried out in an aprotic solvent (such as an ether, for example tetrahydrofuran, a halogenated hydrocarbon, for example 1,2-dichloroethane, N, N-dimethylformamide or acetonitrile) at room temperature.

Scheme 1

Some compounds of formula (III) are known (see published international patent application WO2004 / 046124), or they can be obtained by procedures similar to those described in WO2004 / 046124. Other compounds of formula (III) can be obtained using procedures similar to those described in descriptions 47, 116, 142, 143, 146, 150, 151 and 163.

Compounds of formula (II) can be obtained by oxidative cleavage of compounds of formula (IV) according to reaction scheme 2. Oxidative cleavage can be carried out using catalytic osmium tetroxide in aqueous tetrahydrofuran followed by sodium periodate at room temperature. Other methods include ozone using ozone, followed by treatment with a suitable reducing agent (such as dimethyl sulfide).

Scheme 2

Compounds of formula (IVa) can be prepared from compounds of formula (V) by reaction with diethyl chlorophosphate in the presence of a base (e.g. potassium tert-butoxide) at a low temperature (such as 120 ° C) followed by addition of a C _1-6 alkyl isocyanoacetate and a base (e.g. tert β-potassium butoxide) (see reaction scheme 3). Such an interaction is usually carried out in an aprotic solvent such as N, N-dimethylformamide.

Scheme 3

Compounds of formula (IVb) can be prepared according to Reaction Scheme 4. Compounds of formula (V) are treated with a suitable base (e.g. sodium hydride) in a suitable solvent (e.g. DMF) and then treated with R ² C (O) CHR ² Cl with cooling ( for example, at 0 ° C), and get the compounds of formula (VI). Treatment of compounds of formula (VI) with ammonium acetate in acetic acid under the influence of microwave radiation gives compounds of formula (IVb).

Scheme 4

Compounds of formula (IVc) can be prepared according to Reaction Scheme 5. Compounds of formula (V) are reacted with Laesson's reagent (Lawesson) in toluene at an elevated temperature (for example, toluene / reflux) to give compounds of formula (VIIa). Treatment of (VIIa) with methyl iodide in acetone in the presence of a suitable base (e.g. potassium hydroxide) followed by treatment with aminoacetaldehyde dimethyl acetal in dry ethanol gives the compounds of formula (VIII). Cyclization in an acidic medium (for example, concentrated hydrochloric acid in methanol) gives compounds of formula (IVc).

Scheme 5

Compounds of formula (IVd) can be prepared from compounds of formula (VII) according to reaction scheme 6. Treatment of (VII) with hydrazine monohydrate in ethanol at elevated temperature (for example, 80 ° C) followed by treatment of (MeO) ₃ R ² under the influence of microwave radiation gives formulas (IVd).

Scheme 6

Compounds of formula (IVe) can be prepared according to reaction scheme 7. Compounds of formula (VII) are treated with hydroxylamine hydrochloride and sodium acetate in dry ethanol to give compounds of formula (IX). The compounds of formula (IX) are then treated with carbonyldiimidazole in dry tetrahydrofuran to give compounds of formula (IVe).

Scheme 7

Compounds of formula (IVf) can be prepared by an intramolecular 1,3-bipolar cycloaddition of compounds of formula (X) according to reaction scheme 8. The reaction is usually carried out in an organic solvent (eg, toluene).

Scheme 8

Compounds of formula (X) can be prepared by procedures similar to those described in descriptions 2, 37, 38 and 39.

Compounds of formula (IVg) can be prepared according to reaction scheme 9 from compounds of formula (VIIa). Typical interaction conditions are described in descriptions 19, 131, 133 and 135.

Scheme 9

Compounds of formula (IVh) can be prepared according to Reaction Scheme 10 from compounds of formula (XI). Typical interaction conditions are described in descriptions 87, 88, 89, 90, 107 and 108.

Pattern 10

Compounds of formula (IVi) can be prepared according to reaction scheme 11 from compounds of formula (XI). Typical interaction conditions are described in descriptions 88 and 92.

Scheme 11

Compounds of formula (IVj) can be prepared according to reaction scheme 12 from compounds of formula (XI). Typical interaction conditions are described in descriptions 88, 94, 95 and 96.

Pattern 12

Compounds of formula (IVk) can be prepared according to reaction scheme 13 from compounds of formula (XI). Typical interaction conditions are described in descriptions 101, 102 and 103.

Pattern 13

Compounds of formula (XI) can be prepared according to procedures similar to the procedure described in description 88.

Compounds of formula (V) (see Reaction Schemes 3, 4, and 5) can be prepared according to Reaction Scheme 14 from compounds of formula (XII). Typical reaction conditions include heating (XII) in the presence of iron powder and ammonium chloride. The interaction is typically carried out in a solvent or mixture of solvents at a temperature in the range of 60-100 ° C. Suitable solvents are a mixture of water and an alcohol (e.g., methanol or ethanol).

Scheme 14

Compounds of formula (Va) can be prepared according to Reaction Scheme 15. Typical reaction conditions for the first step are reaction with BrCH (R ⁷ ) C (= O) NH ₂ in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone ) Typical interaction conditions for the second stage are the interaction in the presence of copper iodide and N, N-dimethylethylenediamine and a suitable base (such as potassium carbonate) in a suitable solvent (such as NMP) at elevated temperatures (such as 150 ° C).

Scheme 15

Compounds of formula (Vb) can be prepared according to reaction scheme 16 from compounds of formula XIII. Typical interaction conditions are described in descriptions 71 and 72.

Pattern 16

The compounds of formula (XIII) are commercially available, or can be obtained using procedures known to those skilled in the art from readily available starting materials.

Compounds of formula (XIIa) can be prepared according to reaction scheme 17 by reacting compounds of formula (XIV) with a suitable base (such as sodium hydride) followed by treatment with a compound of formula (Hal) —CH ₂ —C (O) OC _1-4 -alkyl, where Hal is halogen (such as bromine).

Scheme 17

The compounds of formula (XIV), where m is 1, can be obtained by procedures similar to those described in descriptions 1 and 2.

Compounds of general formula (I) can be prepared according to reaction scheme 18, when compounds of formula (XV) (wherein Hal is halogen, such as chloro, bromo) are reacted with compounds of formula (III). Reaction conditions include heating in the presence of a base (e.g., sodium carbonate or potassium carbonate) and, optionally, a catalyst, such as sodium iodide, in a suitable solvent (such as 1-methyl-2-pyrrolidone or methyl isobutyl ketone).

Scheme 18

Compounds of formula (Ib), i.e. compounds of formula (I), where Y is O or —CH ₂ -, and B is —CH ₂ -, can be prepared from compounds of formula (XVI) according to reaction scheme 19. Compounds of formula (XVI) can be reacted under conditions similar to those described for reaction schemes 3 and 4, and to obtain a compound of formula (Ib).

Scheme 19

Compounds of formula (XVI) can be prepared by reacting compounds of formula (III) with compounds of formula (XVII) according to reaction scheme 20. Reaction conditions are as described for reaction scheme 18.

Scheme 20

It should be borne in mind that the compounds of formula (I) or (IV) can be converted into other compounds of formula (I) or (IV) by synthetic methods known to those skilled in the art. Examples of such transformations are described below.

a) Compounds of formula (I) or (IV), where one or more of R ² is CO ₂ H, can be obtained by hydrolysis of the corresponding compounds in which R ² is CO ₂ R ⁷ . Typically, hydrolysis is carried out in the presence of a base (for example sodium hydroxide) in aqueous methanol at high temperature and / or using microwave radiation.

b) Compounds of formula (I) or (IV), wherein R ² is C (O) N (R ³ ) (R ⁴ ), can be prepared by reacting the corresponding compounds in which R ² is a suitable activated carboxyl group with a compound formula NH (R ³ ) (R ⁴ ). Suitable activated carboxyl groups include acyl halides, mixed anhydrides, activated ester (such as thioether) groups or a derivative group formed between the carboxyl group and a coupling agent (such as tetrafluoroborate O-benzotriazol-1-yl-N, N, N ′, N ′ Tetramethyluronium). Typically, the reaction is carried out at room temperature and in an aprotic solvent, such as a hydrocarbon solvent, a halogenated hydrocarbon solvent (such as dichloromethane) or an ether (such as tetrahydrofuran), in the presence of a suitable base (such as diisopropylethylamine or dimethylamine).

c) Compounds of formula (I) or (IV), where R ² is —C (O) N (C _1-6 alkyl) O — C _1-6 alkyl, can be prepared by reacting the corresponding compounds in which R ² represents -CO ₂ R ⁷ , with trimethylaluminum and N, O-di-C _1-6 -alkylhydroxylamine hydrochloride at room temperature.

d) Compounds of formula (I) or (IV) where R ² is —C (O) R ⁶ can be prepared by reacting the corresponding compounds in which R ² is —C (O) N (C _1-6 alkyl ) O-C _1-6 -alkyl, with a suitable Grignard reagent in an organic solvent at low temperature.

e) The compounds of formula (I) or (IV), where R ² is 3-methyl-5-isoxazolyl, can be obtained in two stages, first by reacting the corresponding compounds in which R ² is —C (O) R ⁶ , with N, N-dimethylacetamide dimethyl acetal at elevated temperatures (such as 150 ° C), and then treating with hydroxylamine hydrochloride in a suitable solvent (such as ethanol) at elevated temperatures (such as 150 ° C).

f) Compounds of formula (I) or (IV), where R ² is 3-methyl-1H-pyrazol-5-yl, can be obtained in two stages, first by reacting the corresponding compounds in which R ² is —C (O ) R ⁶ , with N, N-dimethylacetamide dimethyl acetal at elevated temperatures (such as 150 ° C), and then treating with hydrazine monohydrate in a suitable solvent (such as ethanol) at elevated temperatures (such as 150 ° C).

g) Compounds of formula (I) or (IV) where R ² is cyano can be prepared by reacting the corresponding compounds in which R ² is —C (O) NH ₂ with trifluoroacetic acid anhydride in the presence of an organic base (e.g. pyridine). The interaction usually occurs in an aprotic solvent, such as tetrahydrofuran, at 0 ° C.

h) Compounds of formula (I) or (IV), where R ² is hydrogen, can be obtained by decarboxylation of a compound of formula (I) or (IV), in which R ² is CO ₂ N. The reaction can be carried out by heating in an organic solvent ( such as a halogenated aromatic hydrocarbon).

i) Compounds of formula (I) or (IV), where R ² is 3-methyl-1,2,4-oxadiazol-5-yl, can be prepared by reacting the corresponding compound of formula (I) or (IV), in which R ² represents CO ₂ R ⁷ , with a methylcarboxyamide oxime in the presence of a suitable base (such as sodium hydride).

j) Compounds of formula (I) or (IV), where R ² is —C (= NOMe) R ⁶ , can be prepared in two stages by reacting the corresponding compounds of formula (I) or (IV), in which R ² is C (O) R ⁶ , with methoxylamine hydrochloride in a suitable solvent (such as ethanol) at elevated temperature.

k) Compounds of formula (I) or (IV), where R ² is —C (O) NH — NHC (O) Me, can be prepared by reacting the corresponding compounds of formula (I) or (IV) in which R ² is CO ₂ R ⁷ , with acetohydrazide in a suitable solvent (such as DCM) at low temperature (such as 0 ° C).

l) Compounds of formula (I) or (IV), where R ² is 5-methyl-1,3,4-oxadiazol-2-yl, can be prepared by reacting the corresponding compounds of formula (I) or (IV) in which R ² represents —C (O) NH — NHC (O) Me (see k), with trifluoroacetic anhydride in a suitable solvent (such as pyridine) at low temperature (such as 0 ° C).

m) Compounds of formula (I) or (IV), where R ² is 1,3-oxazol-5-yl, can be obtained in two stages from the corresponding compounds of formula (I) or (IV), in which R ² represents CO ₂ R ⁷ . In a first step, ether is reduced to an aldehyde using lithium aluminum hydride at low temperature (such as 0 ° C) in a suitable solvent (such as THF). In a second step, the aldehyde is treated with p-toluenesulfonylmethylisocyanide.

Specialists in this field should be borne in mind that it may be necessary to protect certain reactive substituents during some of the above procedures. You can use standard methods of introducing and removing protective groups, such as those described in Greene T.W., Protective groups in organic synthesis, New York, Wiley (1981). For example, primary amines can be protected as phthalimide, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or tritylcarbonyl derivatives. Carboxyl groups can be protected as ester groups. Aldehyde or keto groups can be protected as acetals, ketals, thioacetals or thioketals. Removal of such protecting groups is achieved using conventional procedures well known in the art. For example, protecting groups such as tert-butoxycarbonyl can be removed using an acid, such as hydrochloric or trifluoroacetic acid, in a suitable solvent, such as dichloromethane, diethyl ether, isopropanol, or mixtures thereof.

Pharmaceutically acceptable salts can be prepared in the usual manner by reaction with an appropriate acid or acid derivative.

Other details of the preparation of compounds of formula (I) are provided hereinbelow in the examples section.

As indicated above, the compounds of the invention have high affinity for receptors of type 5-HT ₁ and / or are inhibitors of reuptake of serotonin and, accordingly, are applicable in the treatment or prevention of diseases and conditions mediated by modulation of receptor type 5-HT ₁ and / or receptor re absorption of serotonin.

Therefore, according to another aspect, the invention relates to a compound of the invention for use as a medicine, respectively, a medicine for humans.

According to another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor.

In one embodiment, diseases or conditions that can be mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor are selected from the list of diseases or conditions listed below [the numbers in parentheses after the diseases listed below are classified code in the Diagnostic and Statistical Manual of Mental Disorders, 4 ^th Edition, published by American Psychiatric Assotiation (DSM-IV), and / or in the International Classification of Diseases, 10 ^th Edition (ICD-10)].

i) Psychotic disorders, such as schizophrenia (including subtypes of the paranoid type (295.30), destructive type (295.10), catatonic type (295.20), undifferentiated type (295.90) and residual type (295.60)); disorder of the schizophrenic form (295.40); schizoaffective disorder (295.70) (including subtypes of the bipolar type and depressive type); delusional disorder (297.1) (including subtypes of erotomania, megalomania, jealousy, persecution, somatic type, mixed type and unknown type); short-term psychotic disorder (298.8); distributed psychotic disorder (297.3); psychotic disorder due to the General Treatment Condition (including subtypes with delusions and hallucinations); psychotic disorder caused by substances (including subtypes with delusions (293.81) and hallucinations (293.82)), and psychotic disorder that has no other definition (298.9).

ii) Depression and mood disorders, such as depressive episodes (including major depressive episode, manic episode, mixed episode and hypomanic episode); depressive disorders (including major depressive disorder, dysthymic disorder (300.4), depressive disorder without other definitions (311)); bipolar disorder (including bipolar disorder I, bipolar disorder II (i.e. recurring major depressive episodes with hypomanic episodes) (296.89), cyclothymic disorder (301.13), and bipolar disorder that have no other definition (296.80)); other mood disorders (including mood disorder due to the general treatment regimen (293.83), which includes subtypes with depressive symptoms, with an episode resembling a major depressive, with manic symptoms and with mixed symptoms); mood disorder caused by substances (including subtypes with depressive symptoms, manic symptoms and mixed symptoms), and mood disorder that has no other definition (296.90).

iii) Anxiety disorders, such as a social anxiety disorder; panic attack; agoraphobia, panic disorder; agoraphobia without a history of panic disorder (300.22); specific phobia (300.29) (including subtypes of animal type, such as the natural environment, such as damage by blood injection (Blood-Injection-Injury), psychogenic type, and other type); social phobias (300.23); obsessive-compulsive disorder (300.3); post-traumatic stress (309.81); acute stress (308.3); generalized anxiety disorder (300.02); anxiety disorder due to the general treatment regimen (293.84); anxiety disorder caused by substances, and anxiety disorder that has no other definition (300.00).

iv) Disorders caused by substances, such as disorders in the use of substances (including substance dependence, addiction to substances and substance abuse); substance-induced disorders (including intoxication, cessation syndrome, substance-induced delirium, substance-induced persistent dementia, substance-related persistent amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced anxiety disorder, sexual dysfunction, substance-induced sleep disorder and hallucinogenic persistent preceptive disorder (“still images”); alcohol-related disorders (including I am addicted to alcohol (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), alcohol withdrawal syndrome (291.81), delirium alcohol intoxication, delirium withdrawal from alcohol, alcohol-induced persistent dementia, alcohol-induced persistent amnestic psychotic disorder caused by alcohol alcohol-related disorder mood disorder alcohol-induced anxiety disorder alcohol-induced sexual dysfunction alcohol-induced sleep disorder p sstroystvo having no other definition (291.9)); amphetamine-related disorders (or amphetamine-like substances) (e.g. amphetamine addiction (304.40), amphetamine abuse (305.70), amphetamine intoxication (292.89), amphetamine withdrawal syndrome (292.0), amphetamine-induced delirium amphetamine intoxication caused by amphetamine addiction amphetamine-induced mood disorder amphetamine-induced anxiety disorder sexual dysfunction, amphetamine-induced sleep disorder and amphetamine-related disorder not having other definition (292.9)); caffeine-related disorders (including caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise defined (292.9)); cannabis-related disorders (including dependence on cannabis preparations (304.30), abuse of cannabis preparations (305.20), hemp drugs intoxication (292.89), delirium intoxication with hemp drugs, hemp-induced psychotic disorder, caused by hemp drugs anxiety and cannabis-related disorder that has no other definition (292.9)); cocaine-related disorders (including cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), cocaine withdrawal syndrome (292.0), delirium cocaine intoxication caused by cocaine psychotic disorder caused by cocaine cocaine mood disorder caused by cocaine anxiety caused by cocaine; sexual dysfunction; cocaine-induced sleep disorder; and cocaine-related disorder that has no other definition (292.9)); hallucinogen-related disorders (including addiction to hallucinogen (304.50), abuse of hallucinogens (305.30), hallucinogenic intoxication (292.89), hallucinogenic persistent preceptive disorder (“freeze frames”) (292.89); delirium hallucinogenic psychotoxicity hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder, not otherwise defined (292.9)); disorders associated with volatile drugs (including dependence on a volatile drug (304.60), abuse of volatile drugs (305.90), intoxication with a volatile drug (292.89), delirium intoxication with a volatile drug caused by a volatile drug, persistent dementia caused by a volatile drug, psychotic disorder caused by a volatile drug mood disorder caused by a volatile drug anxiety disorder and a volatile drug related disorder that has no other definition (292.9)); nicotine-related disorders (including nicotine addiction (305.1), nicotine weaning syndrome (292.0) and nicotine-related disorder that have no other definition (292.9)); opioid-related disorders (including opioid dependence (304.00), opioid abuse (305.50), opioid intoxication (292.89), opioid withdrawal syndrome (292.0), delirium opioid intoxication, opioid-induced psychotic disorder, opioid-induced opioid disorder, dysfunction, opioid-induced sleep disorder and opioid-related disorder, not otherwise defined (292.9)); disorders associated with phencyclidine (or phencyclidine-like substances) (including phencyclidine addiction (304.60), abuse of phencyclidine (305.90), phencyclidine intoxication (292.89), delirium phencyclidine intoxication, phencyclidine-induced psychotic disorder, phencyclidine-induced anxiety disorder caused by phencyclidine with phencyclidine, a disorder that has no other definition (292.9)); disorders associated with sedative, hypnotic or anxiolytic agents (including dependence on sedative, hypnotic or anxiolytic agents (304.10), abuse of sedative, hypnotic or anxiolytic agents (305.40), intoxication with sedative, hypnotic or anxiolytic agents (292.89), sedative withdrawal syndrome from sedatives hypnotics or anxiolytic drugs (292.0), delirium intoxication sedatives, hypnotics or anxiolytic drugs, delirium of the syndrome of weaning from sedatives, hypnotics or anxiolytic agents caused by sedative, hypnotic or anxiolytic agents, persistent dementia caused by sedative, hypnotic or anxiolytic agents, persistent amnestic disorder caused by sedative, hypnotic or anxiolytic agents, psychotic disorder caused by sedative, hypnotic or anxiolytic agents, mood disorder anxiolytic drugs anxiety disorder caused by sedatives, hypnotics or anxiolytic agents sexual dysfunction caused by sedative, hypnotic or anxiolytic agents sleep disorder and associated with sedative, hypnotic or anxiolytic agents disorder that has no other definition (292.9)); disorders related to several substances (including dependence on several substances (304.80)), and disorders associated with other (or unknown) substances (including anabolics, steroids, volatile nitrates and nitric oxide).

v) Sleep disorders, such as primary sleep disorders such as dysomnia (including primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep-related breathing disorders (780.59), circadian sleep rhythm disorder (307.45) and dissomnia that has no other definition (307.47)); primary sleep disorders such as parasomnia (including nightmare disorder (307.47), sleep fear disorder (307.46), sleep walking disorder (307.46), and parasomnia not otherwise defined (307.47)); sleep disorders associated with another mental disorder (including insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder (307.44)); sleep disorder due to the general treatment regimen and substance-induced sleep disorder (including subtypes of the insomnia type, hypersomnic type, parasomnic type and mixed type).

vi) Eating disorders such as anorexia nervosa (307.1) (including subtypes of the restrictive type and type of overeating / bowel cleansing (Binge-Eating / Purging Type); bulimia nervosa (307.51) (including laxative subtypes and non-laxative type); obesity; compulsive eating disorder; overeating and eating disorder, which have no other definition (307.50).

vii) Autism disorders, including autistic disorder (299.00), Asperger disorder, Rett disorder, childhood disintegrative disorder, and a common developing disorder that have no other definition.

viii) Attention deficit / hyperactivity disorder (including the subtypes Attention Deficit Disorder / Hyperactivity Disorder of the Combined Type (314.01), Attention Deficit Disorder / Hyperactivity Type of Preferential Inattention (314.00), Attention Deficit Disorder / Hyperactivity Disorder Type Hyperactivity Disorder (314.01) and Attention Deficit Disorder, Hyperactive Impaired / Attention Deficit / not having another definition (314.9)); hyperkinetic disorder; a destructive behavior disorder such as a behavioral disorder (including subtypes of the onset of the disorder in childhood (321.81), the onset of the disorder in adolescence (321.82) and the undetermined occurrence of the disorder (312.89), oppositional demonstrative disorder (313.81) and a destructive behavioral disorder not having another definitions); and tick disorders, such as Tourette disorder (307.23).

ix) Personality disorders, including subtypes of paranoid personality disorder (301.0), schizoid personality disorder (301.20), personality disorder for schizophrenia (301.22), antisocial personality disorder (301.7), borderline personality disorder (301.83), facial personality disorder (301.50) narcissism (301.81), avoidance (301.82), addiction (301.86), obsessive-compulsive personality disorder (301.4), and personality disorder that has no other definition (301.9).

x) Improving perception, including treatment of impaired perception in other diseases, such as schizophrenia, bipolar disorder, depression, other mental disorders and psychotic conditions associated with impaired perception, such as Alzheimer's disease.

xi) Sexual dysfunctions such as sex drive disorders (including hypoactive sex drive disorder (302.71) and sexual aversion (302.79)); sexual arousal disorders (including sexual arousal disorder in women (302.72) and erectile dysfunction in men (302.72)); orgasmic disorders (including orgasmic disorder in women (302.73), orgasmic disorder in men (302.74) and premature ejaculation (302.75)); pain during sexual intercourse (including dyspareunia (302.76) and vaginismus (306.51)); sexual dysfunction that has no other definition (302.70); paraphilia (including exhibitionism (302.4), fetishism (302.81), frothage (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transvestite fetishism (302.3), voyeurism (302.82) and paraphilia another definition (302.9)); gender identity disorders (including gender identity disorder in children (302.6) and gender identity disorder in adolescents or adults (302.85)) and sexual disorder that has no other definition (302.9).

In another embodiment of the disease or condition, which can be mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor, are selected from group i), ii), iii) and xi) above.

In another embodiment, sexual dysfunction is premature ejaculation.

It should be borne in mind that in this description the instructions for "treatment" apply to the prevention, prevention of relapse and the suppression or alleviation of symptoms (mild, moderate or severe), as well as the treatment of established conditions. A compound of the invention can be administered as a chemical, but the active ingredient is usually presented in the form of a pharmaceutical composition.

The compounds of the invention can be used to treat or prevent psychotic disorders in combination with the following agents: i) antipsychotic drugs; ii) drugs for extrapyramidal side effects, such as anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenidramine) and dopaminergic drugs (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) sensory enhancers, for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine, and galantamine).

The compounds of the invention can be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of the invention can be used to treat or prevent bipolar disease in combination with the following agents: i) mood stabilizers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention can be used to treat or prevent anxiety disorders in combination with the following agents: i) anxiolytics and ii) antidepressants.

The compounds of the invention can be used to treat or prevent sexual dysfunction in combination with the following agents: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists / dopamine transfer inhibitors, for example apomorphine and buproprion; iii) alpha adrenergic antagonists, for example phenotolamine; iv) prostaglandin agonists, for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transfer inhibitors, for example, serotonin reuptake inhibitors; vii) norepinephrine transfer inhibitors, for example reboxetine, and viii) 5-HT1A agonists, for example fibanserin.

The compounds of the invention can be used to treat or prevent sexual dysfunction in women in combination with the same means as those defined for sexual dysfunction in men, as well as an estrogen agonist such as estradiol.

Antipsychotic drugs include typical antipsychotics (e.g., chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazin, thiotixin, haloperidol, molindone and loxapine, e.g. and amisulpride).

Antidepressant medicines include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpin and zimeldine); dual serotonin / norepinephrine reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran): norepinephrine reuptake inhibitors (such as reboxetine and venlafaxine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine) and other agents (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabilizer drugs include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabin.

Anxiolytics include benzodiazepines such as alprozolam and lorazepam.

In addition, the compounds of the invention can be administered in combination with 5-HT ₃ antagonists (such as ondansetron, granisetron and metoclopramide); serotonin agonists (such as sumatriptan, rauwolscin, yohimbine and metoclopramide) and NK-1 antagonists.

It should be borne in mind that the combination or composition of the compounds of the invention can be administered simultaneously (either in one or in different dosage forms), separately or sequentially.

According to another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention in combination with one or more pharmaceutically acceptable carriers, diluents and / or excipients. The carrier, diluent and / or excipient should be acceptable in the sense of being compatible with other ingredients of the composition and not be irritating to their recipient.

The compounds of the invention can be administered in conventional dosage forms prepared by combining the compounds of the invention with standard pharmaceutical carriers or diluents according to the usual procedures well known in the art. Such procedures may include mixing, granulating and compressing or dissolving the ingredients, respectively, for the desired preparation.

The pharmaceutical compositions of the invention can be formulated for administration by any route and include compositions in a form adapted for oral, local or parenteral administration to mammals, including humans.

The composition can be obtained for administration in any way. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral solutions or suspensions or sterile parenteral solutions or suspensions.

The topical compositions of the present invention can be presented in the form of, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives, such as preservatives, solvents to facilitate drug penetration and emollients in ointments and creams.

The compositions may also contain conventional carriers such as a cream or ointment base, and ethanol or oleyl alcohol in the case of lotions. Such carriers may represent from about 1% to about 98% of the composition. More often they will make up to about 80% of the composition.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silicon dioxide; spattering aids such as potato starch; or acceptable wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well known in ordinary pharmaceutical practice. Liquid preparations for oral administration may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitan monooleate or gum arabic; non-aqueous media (which may include edible oils), such as almond oil, esters of fatty acids and, for example, glycerol, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

Suppositories will contain conventional suppository bases, for example cocoa butter or other glyceride.

For parenteral administration, liquid unit dosage forms are prepared using a compound and a sterile medium, with water being typical. The compound, depending on the medium used and the concentration, can either be suspended or dissolved in the medium. In preparing solutions, the compound can be dissolved in water for injection, sterilized by filtration before filling in a suitable vial or ampoule, and closed hermetically.

Advantageously, substances such as a local anesthetic, preservative or buffering agents can be dissolved in the medium. In order to improve stability, the composition can be frozen after filling the bottle and remove water in a vacuum. The dry lyophilized powder is then sealed in a vial and an accompanying vial of water for injection can be provided to reconstitute the liquid composition before use. Parenteral suspensions are prepared essentially in the same manner, except that the compound is suspended in the medium instead of being dissolved, and sterilization cannot be carried out by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in sterile water. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1 wt.%, Respectively, 10-60 wt.%, Of the active material, depending on the method of administration. When the compositions are in unit dosage forms, each unit will contain, respectively, 50-500 mg of the active ingredient. The dosage used to treat adults will, accordingly, range from 10 to 3000 mg per day, for example, will be 1500 mg per day, depending on the method and frequency of administration. This dosage corresponds to 0.1-50 mg / kg per day.

Specialists in this field should keep in mind that the optimal number and intervals between administrations of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, method and place of administration and the specific type of mammal being treated, and that their optimums can be determined conventional methods. Specialists in this field should also bear in mind that the optimal course of treatment, i.e. the number of doses of the compounds of the invention given per day for a certain number of days can be established by specialists in this field using conventional therapeutic analytical tests.

All publications, including patents and patent applications, and other works cited in this description are included in it by reference.

It should be borne in mind that the invention includes additional aspects listed below. The embodiments described for the first aspect also apply to such additional aspects. The diseases and conditions described above, as appropriate, relate to such additional aspects.

i) A compound of the invention for use in the treatment or prevention of a disease or condition mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor.

ii) A method for treating or preventing a disease or condition in a mammal mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor, comprising administering an effective amount of a compound of the invention.

Examples

The invention is illustrated by the examples described below.

In the procedures described below, after the name of each starting material, a description is typically given. Such a link is provided solely to assist a chemist. The starting material need not be obtained from the batch to which reference is made.

The compounds are named using the chemical name software ACD / Name PRO 6.02 (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Proton magnetic resonance spectra (NMR) are recorded either on a Varian instrument at 300, 400 or 500 MHz, or on a Bruker instrument at 300 MHz. Chemical shifts are indicated in ppm. (δ) using the residual solvent line as an internal standard. The splitting spectrogram is displayed in the notation with - singlet, d - doublet, t - triplet, k - quartet, m - multiplet, wide. - broadened. NMR spectra are recorded in the temperature range from 25 to 90 ° C. When several conformers are detected, chemical shifts result for the most abundant conformer.

Mass spectra (MS) are obtained on a quadrupole mass spectrometer 4 II (Micromass UK) or on an Agilent MSD 1100 mass spectrometer operating according to the type of ionization ES (+) and ES (-), or on an Agilent LC / MSD mass spectrometer 1100, operating according to the type of ionization ES (+) and ES (-), in combination with an Agilent 1100 Series HPLC instrument [LC / MS - ES (+): analysis is performed on Supelcosil ABZ + Plus (33 × 4.6 mm, 3 μm) (mobile phase 100% [water + 0.1% HCO ₂ N] for 1 min, then from 100% [water + 0.1% HCO ₂ N] to 5% [water + 0.1% HCO ₂ H] and 95% [CH ₃ CN] in 5 min, finally under these conditions for 2 min; T = 40 ° C, flow rate = 1 mL / min; LC / MS - ES (-): analysis osuschest lyayut on Supelcosil ABZ + Plus (33 × 4,6 mm, 3 mm) (mobile phase 100% [water + 0,05% NH _3] for 1 min, then from 100% [water + 0,05% NH ₃ ] up to 5% [water + 0.05% NH ₃ ] and 95% [CH ₃ CN] for 5 minutes, finally, under the indicated conditions for 2 minutes; T = 40 ° C, flow rate = 1 ml / min]. Mass spectra show only one peak in a cluster of molecular ions.

Flash chromatography on silica gel is carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), or on pre-packed Varian Mega Be-Si cartridges, or on pre-packed Biotage silica cartridges.

SPE-SCX cartridges are solid-state ion-exchange extraction columns supplied by Varian. The eluent used with the SPE-SCX cartridges is methanol followed by the use of a 2 N solution of ammonia in methanol.

In some production methods, purification is carried out using either an automated flash chromatography apparatus (Flash +) Biotage or automated flash chromatography systems (Horizon). All of these instruments work with the Biotage Silica cartridge.

SPE-Si cartridges are solid phase extraction columns of silica supplied by Varian.

(+/-) - BINAP - racemic 2,2- (diphenylphosphino) -1,1-binaphthyl 1,2-DCE and DCE - 1,2-dichloroethane CH - cyclohexane DAST - sulfur trifluoride (diethylamino) DBU - 1,8- diazabicyclo [5.4.0] undec-7-ene DCM - dichloromethane DEOXOFLUOR - bis (2-methoxymethyl) amino sulfur trifluoride Dipa - N, N-diisopropylethylamine DMF - N, N'-dimethylformamide EDC × HCl - 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDTK - ethylenediaminetetraacetic acid Nmp - 1-methyl-2-pyrrolidone rt - room temperature TBTU - tetrafluoroborate O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium TEM - triethylamine TFK trifluoroacetic acid THF - tetrahydrofuran Triton B - benzyltrimethylammonium hydroxide

Description 1. 2-Nitrophenyl-2-propen-1-yl ester (D1)

Allyl bromide (68.5 ml, 791.4 mmol, 1.1 eq.) And K ₂ CO ₃ are added to a solution of 2-nitrophenol (100 g, 719.4 mmol) in acetone (1.4 L) under N ₂ atmosphere. (110 g, 791.4 mmol, 1.1 equiv.). The heterogeneous mixture is heated at the boil under reflux and stirred for 16 hours. The mixture was cooled to room temperature, and the solids were filtered and washed with Et ₂ O. The combined organic phases were concentrated in vacuo to give the title compound (132 g, 737.4 mmol) as a pale orange viscous oil, which was used in the next step no additional cleaning. MS (ES) m / z: 180.10 [MH ⁺ ]. C ₉ H ₉ NO ₃ requires 179.17. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.76 (m, 1H), 7.43 (m, 1H), 7.01-6.92 (m, 2H), 5.94 (m, 1H), 5.42 (m, 1H), 5.26 (m, 1H), 4.64-4.59 (m, 2H).

Description 2. 2-Nitro-6- (2-propen-1-yl) phenol (D2)

2-Nitrophenyl-2-propen-1-yl ester (D1) (132 g, 737.4 mmol) was stirred and heated in a sand bath under reflux at 200 ° C (internal temperature 180-160 ° C) for 26 hours. After cooling, the crude reaction product was purified by filtration through a pad of silica (1 kg), eluting with a gradient of cyclohexane / ethyl acetate (100: 0 - 80:20), to give the title compound as a pale yellow oil (89 g, 68% ) MS (ES) m / z: 180.10 [MH ⁺ ]. C ₉ H ₉ NO ₃ requires 179.17. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.86 (s, 1H), 7.91 (m, 1H), 7.38 (m, 1H), 6.84 (m, 1H), 5 94 (m, 1H); 5.07-5.01 (m, 2H); 3.43-3.40 (m, 2H).

Description 3. Methyl - {[2-nitro-6- (2-propen-1-yl) phenyl] oxy} acetate (D3)

To a solution of 2-nitro-6- (2-propen-1-yl) phenol (D2) (76 g, 424.6 mmol) in acetone (600 ml), methyl bromoacetate (42, 2 ml, 445.8 mmol, 1.05 equiv.) And K ₂ CO ₃ (61.6 g, 445.8 mmol, 1.05 equiv.). The mixture is heated at 60 ° C and stirred for 3.5 hours. The mixture was cooled, the solid was filtered off and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (1 L) and extracted with 1 N NaOH solution (3 × 200 ml), water (1 × 200 ml) and brine (1 × 200 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a viscous pale yellow oil, which was used in the next step without further purification. MS (ES) m / z: 252.10 [MH ⁺ ]. C ₁₂ H ₁₃ NO ₅ requires 251.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.66 (m, 1H), 7.39 (m, 1H), 7.14 (m, 1H), 5.88 (m, 1H), 5 10-4.95 (m, 2H); 4.56 (s, 2H); 3.75 (s, 3H); 3.49-3.46 (m, 2H).

Description 4. 8- (2-Propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4)

To a solution of methyl - {[2-nitro-6- (2-propen-1-yl) phenyl] oxy} acetate (D3) (109 g, 434 mmol) in a mixture of MeOH / H ₂ O) (1: 1, 1 , 8 L) iron powder (145 g, 2.6 mol, 6 eq.) And NH ₄ Cl (232 g, 4.34 mol, 10 eq.) Are added with stirring. The mixture is heated at 80 ° C and stirred for 3.5 hours and then cooled to about 40 ° C. The mixture was filtered through celite using a MeOH / DCM mixture (1: 1, 1 L) as eluent. The solvent was evaporated to dryness and then DCM (2 L) was added. The organic phase is washed with a saturated aqueous solution of ammonium chloride, water and brine. The mixed organic phase is dried (Na ₂ SO ₄ ) and discolored by adding carbon powder. The mixture was filtered, the filtrate was evaporated in vacuo to give a residue, which was purified on a silica layer using a gradient of cyclohexane / ethyl acetate (4: 1 - 1: 1), and the title compound (70 g, 86%) was obtained as white solid. MS (ES) m / z: 190.10 [MH ⁺ ]. C ₁₁ H ₁₁ NO ₂ requires 189.21. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.10-7.85 (br s, 1H), 6.91-6.84 (m, 2H), 6.66 (m, 1H), 5.95 (m, 1H), 5.10-5.00 (m, 2H), 4.61 (s, 2H), 3.40-3.36 (m, 2H).

Description 5. Ethyl-6- (2-propen-1-yl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (D5)

To a solution of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4) (170 mg, 0.9 mmol) and potassium tert-butoxide (110 mg, 0 , 9 mmol) in dry DMF (5 ml) at 0 ° C, diethyl chlorophosphate (0.15 ml, 1.8 mmol) is added. After 10 minutes, a solution of ethyl isocyanoacetate (0.15 ml, 1.35 mmol) and potassium tert-butoxide (152 mg, 1.35 mmol) in dry DMF (2 ml) was added. The reaction mixture was stirred at 60 ° C for 6 hours, then cooled and quenched with water (5 ml). DMF was evaporated in vacuo, the crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 30% ethyl acetate in cyclohexane to give the title compound as a white solid (132 mg, 52%). MS (ES) m / z: 285.2 [MH ⁺ ]. C ₁₆ H ₁₆ N ₂ O ₃ requires 284.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.2 (s, 1H), 7.55 (d, 1H), 7.3 (d, 1H), 7.2 (t, 1H), 6 25 (m, 1H), 5.7 (s, 2H), 5.2-5.3 (m, 2H), 4.65 (q, 2H), 3.65 (d, 2H), 1, 6 (t, 3H).

Description 6. Ethyl 6- (2-oxoethyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D6)

To a solution of ethyl 6- (2-propen-1-yl) -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (D5) (77 mg, 0.27 mmol) in a mixture THF / water (2: 1, 1.5 ml) osmium tetroxide (0.2 ml of a 4 wt.% Solution in water, 0.125 equiv.) Is added with stirring. After 10 minutes, sodium periodate (145 mg, 0.68 mmol) was added and the reaction mixture was stirred for 2 hours. After evaporation of THF, the residue was partitioned between water (10 ml) and DCM (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge eluting with a mixture of 4% methanol in DCM to give the title compound as a white solid (52 mg, 67%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.8 (s, 1H), 8 (s, 1H), 7.4 (t, 1H), 7-7.1 (m, 2H), 5 5 (s, 2H); 4.35 (q, 2H); 3.8 (s, 2H); 1.4 (t, 3H).

Description 7. 6- (2-Propen-1-yl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylic acid (D7)

A solution of ethyl 6- (2-propen-1-yl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (D5) (900 mg, 3.17 mmol) in a mixture of methanol and 1 M sodium hydroxide solution (1: 1, 60 ml) was stirred at 60 ° C for 30 minutes. The cooled reaction mixture is neutralized with acetic acid and then cooled to 0 ° C. The crude reaction product was collected by filtration, washed with methanol and dried to give the title compound as a white solid (570 mg, 70%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.55 (s, 1H), 7.75 (d, 1H), 7.05-7.15 (m, 2H), 5.8 (m, 1H), 5.5 (s, 2H), 5.0-5.1 (m, 2H), 3.45 (d, 2H).

Description 8. N, N-Dimethyl-6- (2-propen-1-yl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (D8)

1-Hydroxybenzotriazole (80 mg, 0.59 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) are added to a solution of 6- (2-propen-1-yl) -4H -imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (D7) (150 mg, 0.59 mmol) and dimethylamine (0.35 ml of a 2 M solution in THF, 0.7 mmol) in DMF / DCM solution (2: 1, 6 ml). The reaction mixture was stirred at room temperature for 4 hours, DMF was removed on a SPE-SCX cartridge (eluting with methanol, then with 2 N ammonia in methanol). The crude reaction product is then purified on an SPE-Si cartridge eluting with a mixture of 5% methanol in DCM to give the title compound as a white solid (68 mg, 41%). MS (ES) m / z: 284.2 [MH ⁺ ]. C ₁₆ H ₁₆ N ₂ O ₃ requires 283.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.85 (s, 1H), 7.35 (d, 1H), 7.05 (d, 1H), 6.95 (t, 1H), 5 95 (m, 1H), 5.5 (s, 2H), 5.05 (m, 2H), 3.6 (s, 3H), 3.45 (d, 2H), 3.1 (s, 3H).

Description 9. N, N-Dimethyl-6- (2-oxoethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (D9)

4-Methylmorpholine N-oxide (50 mg, 0.42 mmol) and osmium tetroxide (50 μl of a 4 wt.% Solution in water, 0.035 equiv.) Are added to the solution of N, N-dimethyl-6- (2-propene-1 -yl) -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxamide (D8) (60 mg, 0.21 mmol) in acetone / water mixture (8: 1, 2.25 ml ) The reaction mixture was stirred for 4 hours and then the reaction was quenched with saturated aqueous sodium sulfite (10 ml). After 30 minutes stirring, the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the intermediate 6- (2,3-hydroxypropyl) -N, N-dimethyl-4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (40 mg, 0.14 mmol, 60%), which is dissolved in a mixture of THF / water (1: 1, 2 ml) without further purification. Sodium periodate (43 mg, 0.21 mmol) was added and the mixture was stirred for 1 hour. After evaporation of THF, the residue was treated with water (10 ml) and DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material is purified by chromatography eluting with a 2% solution of methanol in DCM to give the corresponding 6- [2,2-bis (methyloxy) ethyl] -N, N-dimethyl-4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxamide (25 mg). Hydrolysis of acetal HCl (0.15 ml, 1 M solution in diethyl ether) and subsequent evaporation of the volatiles gave the title compound (20 mg) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.75 (s, 1H), 7.8 (s, 1H), 7.45 (t, 1H), 7.05 (d, 1H), 6 75 (d, 1H), 5.5 (s, 2H), 3.55 (s, 3H), 3.8 (s, 2H), 3.1 (s, 3H).

Description 10. N-Cyclopentyl-6- (2-propen-1-yl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (D10)

The title compound was obtained in 21% yield according to the general procedure for Description 8, starting from 6- (2-propen-1-yl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylic acid (D7) (150 mg, 0.59 mmol) and cyclopentylamine (70 μl, 0.07 mmol). MS (ES) m / z: 324 [MH ⁺ ]. C ₁₉ H ₂₁ N ₃ O ₂ requires 323.4. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.85 (s, 1H), 7.3 (d, 1H), 6.9-7.1 (m, 3H), 5.95 (m, 1H), 5.55 (s, 2H), 5.05 (m, 2H), 4.35 (q, 1H), 3.45 (d, 2H), 2-2.1 (m, 2H), 1.45-1.8 (m, 6H).

Description 11. N-Cyclopentyl-6- (2-oxoethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (D11)

4-methylmorpholine N-oxide (28 mg, 0.24 mmol) and osmium tetroxide (29 μl of a 4 wt.% Solution in water, 0.035 equiv.) Are added to the solution of N-cyclopentyl-6- (2-propen-1-yl ) -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxamide (D10) (37 mg, 0.12 mmol) in acetone / water mixture (8: 1, 2.25 ml). The reaction mixture was stirred for 4 hours and then the reaction was quenched with saturated aqueous sodium sulfite (10 ml). After 30 minutes stirring, the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the intermediate 6- (2,3-hydroxypropyl) -N-cyclopentyl-4H-imidazo [5,1-c] [1,4] benzoxazine- 3-carboxamide (38 mg, 0.14 mmol, 90%), which is dissolved in a mixture of THF / water (1: 1, 2 ml) without further purification. Sodium periodate (34 mg, 0.16 mmol) was added and the mixture was stirred for 1 hour. After evaporation of THF, the residue was treated with water (10 ml) and DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a white solid (25 mg), which was used without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.8 (s, 1H), 7.8 (s, 1H), 7.45 (t, 1H), 6.7-7.1 (m, 3H), 5.5 (s, 2H), 4.4 (q, 1H), 3.8 (s, 2H), 1.4-1.9 (m, 8H).

Description 12. 6- (2-Propen-1-yl) -4H-imidazo [5.1-c] [1.4] benzoxazine (D12)

A mixture of 6- (2-propen-1-yl) -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (D7) (120 mg, 0.47 mmol) and 1.2 -dichlorobenzene (1.5 ml) is irradiated in a microwave reactor (PersonalChemistry ErmysTM Optimiser, 300 W, 250 ° C, 10 minutes). The solvent was removed on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give the title compound as a white solid (61 mg, 100%). MS (ES) m / z: 213.2 [MH ⁺ ]. C ₁₃ H ₁₂ N ₂ O requires 212.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.6 (s, 1H), 7.6 (d, 1H), 7.2-7.35 (m, 3H), 6.25 (m, 1H), 5.5 (s, 2H), 5.35 (m, 2H), 3.65 (d, 2H).

Description 13. 4H-Imidazo [5.1-c] [1.4] benzoxazin-6-yl-acetaldehyde (D13)

The title compound was prepared in 30% yield according to the procedure for Description 11, starting from 6- (2-propen-1-yl) -4H-imidazo [5.1-c] [1.4] benzoxazine (D12) (60 mg 0.28 mmol). The reaction mixture was stirred for 3 days, and for the good conversion of 3- (4H-imidazo [5,1-c] [1,4] benzoxazin-6-yl) -1,2-propanediol to the intermediate, an additional amount of osmium tetroxide was required (50 μl, 0.026 equiv.) And 4-methylmorpholine N-oxide (66 mg, 0.56 mmol). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.8 (s, 1H), 8.15 (s, 1H), 7.7 (d, 1H), 7.3-7.45 (m, 3H), 5.5 (s, 2H), 3.75 (s, 2H).

Description 14. 8- (3-Hydroxypropyl) -2H-1,4-benzoxazin-3 (4H) -one (D14)

To a solution of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4) (2.5 g, 13.2 mmol) in dry THF (45 ml) at 0 ° C, a 1.6 M solution of disiamylborane in THF (18 ml, 29 mmol) is added dropwise. The solution was stirred for 4 hours at 0 ° C and then overnight at room temperature. The reaction mixture was diluted with ethanol (8.7 ml) and then an aqueous solution of sodium hydroxide (6 M, 3 ml) and hydrogen peroxide (aqueous 35 wt.% Solution, 6 ml) were added dropwise. The mixture was stirred at 50 ° C for 2 hours and then cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (3 × 300 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 40% cyclohexane in ethyl acetate, to give the title compound as a white solid (1.9 g, 69%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.1 (br s, 1H), 6.9 (m, 2H), 6.65 (d, 1H), 4.6 (s, 2H) 3.6 (t, 2H); 2.7 (t, 2H); 1.8 (dd, 2H).

Description 15. 8- (3 - {[tert-Butyl (dimethyl) silyl] oxy} propyl) -2H-1,4-benzoxazin-3 (4H) -one (D15)

To a solution of 8- (3-hydroxypropyl) -2H-1,4-benzoxazin-3 (4H) -one (D14) (0.5 g, 2.4 mmol) in dry DMF (35 ml), imidazole (1, 6 g, 24 mmol) and tert-butyldimethylsilyl chloride (3.5 g, 24 mmol). The reaction mixture was stirred at room temperature for 4 hours, then the reaction was quenched with saturated aqueous NaHCO ₃ solution (200 ml) and the mixture was extracted with ethyl acetate (3 × 200 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 30% cyclohexane in ethyl acetate to give the title compound (containing ~ 50% DMF). The compound is used in the next step without further purification. MS (ES) m / z: 322.2 [MH ⁺ ]. C ₁₇ H ₂₇ NO ₃ Si requires 321.5. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.3 (s, 1H), 8 (s, 1H DMF), 6.9 (m, 2H), 6.7 (d, 1H), 4, 6 (s, 2H), 3.7 (t, 2H), 2.95 (3H, DMF), 2.8 (3H, DMF), 2.65 (t, 2H), 1.9 (m, 2H ), 0.9 (s, 9H), 0 (s, 6H).

Description 16. Ethyl 6- (3-hydroxypropyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D16)

The title compound was obtained in 24% yield according to the procedure for Description 5, starting from 8- (3 - {[tert-butyl (dimethyl) silyl] oxy} propyl) -2H-1,4-benzoxazin-3 (4H) -one (D15) (2.4 mmol). The crude reaction product is purified on an SPE-SCX cartridge (eluting with methanol, then with 2 N ammonia in methanol). MS (ES) m / z: 303.2 [MH ⁺ ]. C ₁₆ H ₁₈ N ₂ O ₄ requires 302.3. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 8 (s, 1H), 7.3 (d, 1H), 7.1 (d, 1H), 6.9 (t, 1H), 5 5 (s, 2H), 4.3 (q, 2H), 3.7 (t, 2H), 2.8 (t, 2H), 1.8 (m, 2H), 1.4 (t, 3H).

Description 17. Ethyl 6- (3-oxopropyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D17)

To a solution of ethyl 6- (3-hydroxypropyl) -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (D16) (170 mg, 0.56 mmol) in DCM (5 ml) Dess-Martin periodan (263 mg, 0.56 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 hours, filtered, the reaction was quenched with water (10 ml) and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (160 mg, 100%), which was used without further purification. MS (ES) m / z: 301.2 [MH ⁺ ]. C ₁₆ H ₁₆ N ₂ O ₄ requires 300.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.8 (s, 1H), 8.2 (m, 1H), 7.6-8 (m, 3H), 5.5 (s, 2H) 4.35 (q, 2H); 3 (m, 2H); 2.7 (m, 2H) 1.4 (t, 3H).

Description 18. 8- (2-Propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -thion (D18)

A mixture of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4) (2 g, 10.5 mmol) and Lausson's reagent (2.2 g, 5, 3 mmol) in dry toluene (35 ml) is heated at the boil under reflux for 1 hour. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude material was purified by silica gel chromatography eluting with a mixture of 10% cyclohexane in ethyl acetate to give the title compound as a white solid (1.9 g, 88%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.6 (s, 1H), 6.85 (m, 2H), 6.75 (m, 1H), 5.8 (m, 1H), 5 05 (m, 2H); 4.75 (s, 2H); 3.35 (d, 2H).

Description 19. 3- (Methylthio) -8- (2-propen-1-yl) -2H-1,4-benzoxazine (D19)

To a mixture of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -thione (D18) (100 mg, 0.49 mmol) and potassium hydroxide (69 mg, 1.23 mmol) in acetone (2 ml) add methyl iodide (46 μl, 0.74 mmol) in two doses with an interval of 15 minutes. The reaction mixture is heated at the boil under reflux for 2 hours, cooled, filtered to remove potassium iodide and evaporated in vacuo. The crude material was purified by silica gel chromatography eluting with a mixture of 10% cyclohexane in ethyl acetate to give the title compound as a colorless oil (70 mg, 65%). MS (ES) m / z: 220.2 [MH ⁺ ]. C ₁₂ H ₁₃ NOS requires 219.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.2 (m, 1H), 6.9 (br s, 2H), 5.9 (m, 1H), 5 (m, 2H), 4 5 (s, 2H); 3.3 (d, 2H); 2.5 (s, 3H).

Description 20. N- [2,2-Bis (methyloxy) ethyl] -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3-amine (D20)

A mixture of 3- (methylthio) -8- (2-propen-1-yl) -2H-1,4-benzoxazine (D19) (180 mg, 0.82 mmol) and aminoacetaldehyde dimethyl acetal (134 μl, 1.23 mmol) in dry ethanol (5 ml) is heated at the boil under reflux for 9 hours. Volatiles were evaporated in vacuo, the crude reaction product was purified by silica gel chromatography eluting with a mixture of 40% ethyl acetate in cyclohexane to give the title compound as a colorless oil (93 mg, 41%). MS (ES) m / z: 277.3 [MH ⁺ ]. C ₁₅ H ₂₀ N ₂ O ₃ requires 276.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.2 (m, 1H), 6.9 (br s, 2H), 5.9 (m, 1H), 5 (m, 2H), 4 5 (s, 2H); 3.3 (d, 2H); 2.5 (s, 3H).

Description 21. 6- (2-Propen-1-yl) -4H-imidazo [2,1-c] [1,4] benzoxazine (D21)

Mixture of N- [2,2-bis (methyloxy) ethyl] -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3-amine (D20) (90 mg, 0.33 mmol) and concentrated hydrochloric acid (0.8 ml) in methanol (1 ml) was heated at the boil under reflux for 3 hours. After concentration in vacuo, the residue was dissolved in DCM (20 ml), the solution was washed with aqueous saturated NaHCO ₃ solution (15 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude material was purified by silica gel chromatography eluting with a mixture of 35% ethyl acetate in cyclohexane to give the title compound as a yellow solid (65 mg, 92%). MS (ES) m / z: 213.3 [MH ⁺ ]. C ₁₃ H ₁₂ N ₂ O requires 212.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.4 (broad s, 1H), 7.2 (broad s, 2H), 7.05 (broad s, 2H), 5.95 ( m, 1H), 5.3 (s, 2H), 5.1 (m, 2H), 3.45 (d, 2H).

Descriptions 22 and 23

4H-Imidazo [2,1-c] [1,4] benzoxazin-6-yl-acetaldehyde (D22)

4H-Imidazo [2,1-c] [1,4] benzoxazine-6-carbaldehyde (D23)

The title compounds were prepared using the procedure described in description 11, starting from 6- (2-propen-1-yl) -4H-imidazo [2,1-c] [1,4] benzoxazine (D21) (200 mg , 0.94 mmol). The reaction mixture was stirred for 2 days, and additional osmium tetroxide (200 μl, 0.03 equiv.) And 4-methylmorpholine N-oxide (250 mg, 2.1 mmol) were required. The reaction gives a mixture of two aldehydes D22 and D23 (~ 7: 3), which is used in the next step. MS (ES) m / z: for D22 215.3 [MH ⁺ ], C ₁₂ H ₁₀ N ₂ O ₂ requires 214.3; for D23 201.3 [MH ⁺ ], C ₁₁ H ₈ N ₂ O ₂ requires 200.2. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.5 (s, 1H D23), 9.8 (s, 1H D22), 7.7 (m, 1H D23), 7.5 (m, 1H D23), 7-7.4 (m, 5H D22 + 3H D23), 5.4 (s, 2H D23), 5.25 (s, 2H D22), 3.8 (s, 2H D22).

Description 24. 1-Methyl-6- (2-propen-1-yl) -4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazine (D24)

A solution of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -thione (D18) (1.38 g, 6.71 mmol) in absolute ethanol (50 ml) was added dropwise over 1 hour at 80 ° C to a solution of hydrazine monohydrate (8 ml) in absolute ethanol (50 ml). The resulting reaction mixture was stirred at reflux (80 ° C) for another 40 minutes and concentrated in vacuo to give the intermediate hydrazone (3E) -8- (2-propen-1-yl) -2H-1,4-benzoxazin- 3 (4H) -one, which is immediately used in the next step without any further purification. Hydrazone is mixed with trimethylorthoacetate (15 ml) and heated with stirring at 150 ° C for 10 minutes when exposed to microwave radiation. The resulting reaction mixture was evaporated in vacuo, the residue was purified by flash chromatography on silica gel eluting with a mixture of 5% methanol in DCM to give the title compound as a pale yellow solid (0.78 g, 51%). MS (ES) m / z: 228.20 [MH ⁺ ]; C ₁₃ H ₁₃ N ₃ O requires 227.27. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 (d, 1H), 7.11-7.03 (m, 2H), 6.01-5.84 (m, 1H), 5, 25 (s, 2H), 5.08-5.01 (m, 2H), 3.43 (d, 2H), 2.76 (s, 3H).

Description 25. (1-Methyl-4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-6-yl) acetaldehyde (D25)

4-methylmorpholine N-oxide (145 mg, 1.24 mmol) and osmium tetroxide (0.20 ml of a 4 wt.% Solution in water) are added to a solution of 1-methyl-6- (2-propen-1-yl) - 4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazine (D24) (142 mg, 0.62 mmol) in acetone / water (8: 1, 9 ml). The resulting reaction mixture was stirred at room temperature overnight, evaporated in vacuo, and then the residue was purified by flash chromatography on silica gel eluting with 5% methanol in DCM to give intermediate 3- (1-methyl-4H- [1,2 , 4] triazolo [3,4-c] [1,4] benzoxazin-6-yl) -1,2-propanediol (97 mg, 60%) as a white solid. The resulting substance was dissolved in a mixture of THF / water (1: 1, 3 ml), sodium periodate (197 mg, 0.92 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. After evaporation of THF, the residue was treated with water (10 ml) and DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a white solid (50 mg, 35%), which could be used without further purification. MS (ES) m / z: 230.20 [MH ⁺ ]. C ₁₂ H ₁₁ N ₃ O ₂ requires 229.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.78 (s, 1H), 7.49 (d, 1H), 7.15-7.12 (m, 2H), 5.28 (s, 2H); 3.82 (s, 2H); 2.79 (s, 3H).

Description 26. 4- (2-Oxopropyl) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D26)

Sodium hydride (159 mg 60%, w / w, suspension in mineral oil, 3.98 mmol) at 0 ° C is added in portions to a solution of 8- (2-propen-1-yl) -2H-1,4-benzoxazine -3 (4H) -one (D4) (500 mg, 2.65 mmol) and 1-chloro-2-propanone (253 μl, 3.17 mmol) in dry DMF (6 ml). The reaction mixture was allowed to warm to room temperature and stirred for 7 hours, and then the reaction was quenched with water (10 ml), and the mixture was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude reaction product which was purified by flash chromatography on silica gel eluting with DCM / acetone (95/5) to give the title compound as a white solid (314 mg, 49%). MS (ES) m / z: 246.20 [MH ⁺ ]. C ₁₄ H ₁₅ NO ₃ requires 245.28. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.95-6.85 (m, 2H), 6.49 (m, 1H), 5.95 (m, 1H), 5.08-5, 01 (m, 2H), 4.67 (s, 4H), 3.39 (m, 2H), 2.54 (s, 3H).

Description 27. 2-Methyl-6- (2-propen-1-yl) -4H-imidazo [2,1-c] [1,4] benzoxazine (D27)

To a solution of 4- (2-oxopropyl) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D26) (63 mg, 0.257 mmol) in glacial acetic acid (1 ml) ammonium acetate (396 mg, 5.14 mmol) was added. The mixture is irradiated in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 ° C, 10 min), then diluted with ethyl acetate (10 ml), poured into a mixture of ice water (10 ml) and made basic with an aqueous solution of ammonium hydroxide (3 ml). The mixture was extracted with ethyl acetate (3 × 20 ml), the combined organic layers were dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with DCM / acetone (95/5) to give the title compound (47 mg, 81%). MS (ES) m / z: 227.10 [MH ⁺ ]. C ₁₄ H ₁₄ N ₂ O requires 226.28. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.09-6.94 (m, 4H), 5.95 (m, 1H), 5.19 (s, 2H), 5.06-5, 00 (m, 2H), 3.39 (m, 2H), 2.26 (s, 3H).

Description 28. (2-Methyl-4H-imidazo [2,1-c] [1,4] benzoxazin-6-yl) acetaldehyde (D28)

The title compound was prepared according to the procedure for Description 6, starting from 2-methyl-6- (2-propen-1-yl) -4H-imidazo [2,1-c] [1,4] benzoxazine (D27). The reaction product was recovered in 36% flash chromatography on silica gel using ethyl acetate / cyclohexane (1/1) as an eluent. MS (ES) m / z: 229.20 [MH ⁺ ]. C ₁₃ H ₁₂ N ₂ O ₂ requires 228.25. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.77 (s, 1H), 7.22-6.91 (m, 4H), 5.24 (s, 2H), 3.77 (s, 2H), 2.31 (s, 3H).

Description 29. 4- (1-Methyl-2-oxopropyl) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D29)

Mixture of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4) (500 mg, 2.65 mmol), 3-chloro-2-butanone (294 μl , 2.91 mmol, 1.1 eq.) And K ₂ CO ₃ (402 mg, 2.91 mmol, 1.1 eq.) In dry acetone (15 ml) are heated under reflux for 4 hours. Another 3-chloro-2-butanone (294 μl, 2.91 mmol, 1.1 eq.) And K ₂ CO ₃ (402 mg, 2.91 mmol, 1.1 eq.) Were added, and the reaction mixture was heated at refluxing for 18 hours. The mixture was cooled to room temperature, the solids were filtered and washed with acetone (50 ml), and the combined filtrates were concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with DCM / acetone 95/5) to give the title compound (626 mg, 91%) as a pale yellow viscous oil. MS (ES) m / z: 260.2 [MH ⁺ ]. C ₁₅ H ₁₇ NO ₃ requires 259.31. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.96-6.85 (m, 2H), 6.66-6.58 (m, 1H), 5.93 (m, 1H), 5, 16-5.00 (m, 3H), 4.70-4.52 (m, 2H), 3.38 (m, 2H), 2.12 (s, 3H), 1.51 (m, 3H) .

Description 30. [4- (1-Methyl-2-oxopropyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl] acetaldehyde (D30)

The title compound was obtained in 64% yield according to the procedure for Description 6, starting from 4- (1-methyl-2-oxopropyl) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 ( 4H) -one (D29) (195 mg, 0.753 mmol). The reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (1/1) as eluent. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.72 (s, 1H), 6.93 (m, 1H), 6.85 (m, 1H), 6.68 (m, 1H), 5 12 (m, 1H), 4.59 (m, 2H), 3.71 (s, 2H), 2.11 (s, 3H), 1.50 (m, 3H).

Description 31. 4- (1-Methyl-2-oxopropyl) -8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 ( 4H) -one (D31)

The title compound was obtained as a white solid in 92% yield according to the general procedure described in Example 1, starting from [4- (1-methyl-2-oxopropyl) -3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-8-yl] acetaldehyde (D30) (127 mg, 0.487 mmol). The reaction product is purified by flash chromatography on silica gel eluting with a gradient of DCM / methanol mixtures (99 / 1-98 / 2). MS (ES) m / z: 473.40 [MH ⁺ ]. C ₂₈ H ₃₂ N ₄ O ₃ requires 472.59. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.36 (d, 1H), 7.60 (m, 2H), 7.40 (d, 1H), 7.12 (dd, 1H) 7.04 (m, 3H), 4.95 (quart, 1H), 4.7 (dd, 2H), 3.05 (br s, 4H), 2.85 (t, 2H), 2, 75 (br s, 4H), 2.65 (m, 5H), 2.08 (s, 3H), 1.41 (d, 3H).

Description 32. Methyl [3-oxo-8- (2-propen-1-yl) -2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate (D32)

The title compound was obtained in 95% yield according to the general procedure of description 26. Accordingly, 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D4) (1 , 0 g, 5.29 mmol) in DMF (15 ml) was treated with methyl bromoacetate (651 μl, 6.88 mmol, 1.3 eq.) And sodium hydride (318 mg 60% w / w suspension in oil, 7 , 94 mmol, 1.5 equiv.). The mixture was stirred for 6 hours and the crude reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (1/4) as eluent. MS (ES) m / z: 262.2 [MH ⁺ ]. C ₁₄ H ₁₅ NO ₄ requires 261.28. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.96-6.90 (m, 2H), 6.65-6.60 (m, 1H), 5.95 (m, 1H), 5, 10-5.01 (m, 2H), 4.67 (s, 2H), 4.66 (s, 2H), 3.78 (s, 3H), 3.39 (m, 2H).

Description 33. Methyl [3-oxo-8- (2-oxoethyl) -2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate (D33)

The title compound was obtained in 66% yield according to the general procedure for Description 6, starting from methyl- [3-oxo-8- (2-propen-1-yl) -2,3-dihydro-4H-1,4-benzoxazine- yl] acetate (D32) (1.0 g, 3.83 mmol). The reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (3/7) as eluent. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.74 (m, 1H), 6.98 (m, 1H), 6.88 (m, 1H), 6.71 (m, 1H), 4 68 (s, 2H); 4.67 (s, 2H); 3.79 (s, 3H); 3.74 (m, 2H).

Description 34. Methyl- (8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4 -yl) acetate (D34)

The title compound was prepared in 90% yield according to the procedure of Example 1, starting from methyl [3-oxo-8- (2-oxoethyl) -2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate ( D33) (300 mg, 1.14 mmol). The reaction product is purified by flash chromatography on silica gel eluting with a gradient of DCM / methanol mixtures (99 / 1-98 / 2). MS (ES) m / z: 475.20 [MH ⁺ ]. C ₂₇ H ₃₀ N ₄ O ₄ requires 474.56. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.37 (m, 1H), 7.71 (m, 1H), 7.58 (m, 1H), 7.24 (m, 1H), 7 07 (m, 1H), 6.95 (m, 2H), 6.64 (m, 1H), 4.70 (s, 2H), 4.66 (s, 2H), 3.79 (s, 3H), 3.16 (br s, 4H), 2.98-2.74 (br m, 8H), 2.73 (s, 3H).

Description 35. (8- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl ) acetic acid (D35)

To a suspension of methyl- (8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4- il) acetate (D34) (300 mg, 0.633 mmol) in methanol (5 ml), a 2 N solution of NaOH in methanol (5 ml) was added. The mixture was stirred at room temperature for 4 hours and then water (10 ml) was added. Methanol was evaporated under reduced pressure and the residue was acidified with 6 N hydrochloric acid (5 ml). The resulting mixture was added to an SPE-SCX cartridge (elution with 1: 1 water / methanol, then 2 N ammonia in methanol) to give the title compound as a white solid (290 mg, 99%). MS (ES) m / z: 461.2 [MH ⁺ ]. C ₂₆ H ₂₈ N ₄ O ₄ requires 460.54. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.30 (m, 1H), 7.58-7.52 (m, 2H), 7.34 (m, 1H), 7.07 ( m, 1H), 6.90-6.80 (m, 2H), 6.75 (m, 1H), 4.60 (s, 2H), 4.21 (s, 2H), 3.01 (broad s, 4H), 2.84-2.53 (br m, 11H).

Description 36. 8- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4- (3,3,3-trifluoro-2-oxopropyl) -2H-1,4- benzoxazin-3 (4H) -one (D36)

To a suspension of (8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) acetic acid (D35) (115 mg, 0.25 mmol) in toluene (10 ml) was added oxalyl chloride (64 μl, 0.75 mmol, 3 equiv.) and a drop of DMF at room temperature. The suspension is heated at 60 ° C for 3 hours. Removal of the solvent under reduced pressure gives the crude acid chloride which is used directly in the subsequent reaction. To a suspension of the resulting crude acid chloride (120 mg, 0.25 mmol) in DCM (10 ml) at room temperature, trifluoroacetic anhydride (315 μl, 1.5 mmol, 6 eq.) And pyridine (162 μl, 2 mmol, 8 eq. .). After stirring for 2 hours, water (15 ml) was added and then the reaction mixture was made alkaline by adding NaHCO ₃ (saturated aqueous solution, 10 ml). The organic phase is separated, and the remaining aqueous phase is extracted with DCM (3 × 50 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give a crude reaction product which was flash column chromatographed on silica gel eluting with DCM / methanol (97/3) to give the title compound D36 (ketone hydrate) ) as a yellow solid (79 mg, 60%). MS (ES) m / z: 531.1 [MH ⁺ ]. C ₂₇ H ₂₉ F ₃ N ₄ O ₄ requires 530.55. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.37 (m, 1H), 7.70 (m, 1H), 7.58 (m, 1H), 7.23 (m, 1H) 7.08-6.81 (m, 4H), 5.15-4.20 (m, 4H), 3.14 (br s, 4H), 2.95-2.60 (br m, 11H).

Description 37. 2- (2-Butyn-1-yloxy) -1-nitro-3- (2-propen-1-yl) benzene (D37)

A mixture of 2-nitro-6- (2-propen-1-yl) phenol (D2) (500 mg, 2.79 mmol), 1-bromo-2-butine (269 μl, 3.07 mmol, 1.1 eq. .) and K ₂ CO ₃ (424 mg, 3.07 mmol, 1.1 eq.) in acetone (20 ml) are heated at the boil under reflux for 4 hours. The mixture was cooled to room temperature, and then the solids were filtered off and washed with acetone (30 ml). The combined organic phases were concentrated in vacuo, the crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/9) to give the title compound (640 mg, 99%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.65 (m, 1H), 7.39 (m, 1H), 7.13 (m, 1H), 5.90 (m, 1H), 5 11-5.02 (m, 2H); 4.60 (m, 2H); 3.49 (m, 2H); 1.77 (s, 3H).

Description 38. [2- (2-Butyn-1-yloxy) -3- (2-propen-1-yl) phenyl] amine (D38)

To a solution of 2- (2-butyn-1-yloxy) -1-nitro-3- (2-propen-1-yl) benzene (D37) (640 mg, 2.77 mmol) in glacial acetic acid (10 ml) iron powder (619 mg, 11.1 mmol, 4 equiv.) was added at room temperature and the mixture was stirred for 16 hours. The solvent was evaporated in vacuo and ethyl acetate (50 ml) was added to the residue. The precipitated substance was removed by filtration, and the filtrate was sequentially extracted with 1 N NaOH solution (10 ml) and brine (10 ml), then dried (MgSO ₄ ) and evaporated in vacuo to give the title compound (540 mg, 97%). MS (ES) m / z: 202.10 [MH ⁺ ]. C ₁₃ H ₁₅ NO requires 201.27. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.86 (m, 1H), 6.61-6.53 (m, 2H), 5.94 (m, 1H), 5.10-5, 01 (m, 2H), 4.44 (m, 2H), 3.82 (br s, 2H), 3.40 (m, 2H), 1.87 (m, 3H).

Description 39. 1-Azido-2- (2-butyn-1-yloxy) -3- (2-propen-1-yl) benzene (D39)

A solution of sodium nitrite (72 mg, 1.05 mmol, 1.05 equiv.) In water (1 ml) with vigorous stirring and cooling with ice / water was added dropwise to a suspension of [2- (2-butyn-1-yloxy) -3- (2-propen-1-yl) phenyl] amine (D38) (201 mg, 1 mmol) in 4 N HCl (3 ml). The mixture is then neutralized by adding an aqueous solution of NaHCO ₃ and a solution of sodium azide (65 mg, 1 mmol, 1 equiv.) In water (1 ml) is gradually added at 5 ° C. After 30 minutes, the mixture was extracted with diethyl ether (3 × 20 ml), and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to obtain the title azide (222 mg, 98%), which was used in the next step without further cleaning up. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.02 (m, 1H), 6.96-6.87 (m, 2H), 5.90 (m, 1H), 5.10-4, 95 (m, 2H), 4.55 (s, 2H), 3.45 (m, 2H), 1.80 (s, 3H).

Description 40. 3-Methyl-6- (2-propen-1-yl) -4H- [1,2,3] triazolo [5,1-c] [1,4] benzoxazine (D40)

A solution of 1-azido-2- (2-butyn-1-yloxy) -3- (2-propen-1-yl) benzene (D39) (222 mg, 0.98 mmol) in toluene (8 ml) is heated by boiling under reflux for 2.5 hours. Then, the solvent was evaporated under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/4) to give the title compound (183 mg, 82%). MS (ES) m / z: 228.20 [MH ⁺ ]. C ₁₃ H ₁₃ N ₃ O requires 227.27. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.86 (m, 1H), 7.10-7.00 (m, 2H), 5.90 (m, 1H), 5.25 (s, 2H), 5.05-4.98 (m, 2H), 3.39 (m, 2H), 2.33 (s, 3H).

Description 41. (3-Methyl-4H- [1,2,3] triazolo [5,1-c] [1,4] benzoxazin-6-yl) acetaldehyde (D41)

The title compound was obtained in 66% yield according to the procedure for Description 6, starting from 3-methyl-6- (2-propen-1-yl) -4H- [1,2,3] triazolo [5,1-c] [ 1,4] benzoxazine (D40) (183 mg, 0.806 mmol). The reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (2/3) as eluent. MS (ES) m / z: 230.10 [MH ⁺ ]. C ₁₂ H ₁₁ N ₃ O ₂ requires 229.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.72 (s, 1H), 7.97 (m, 1H), 7.1 (m, 2H), 5.26 (s, 2H), 3 74 (s, 2H); 2.33 (s, 3H).

Description 42. Oxime (3E) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D42)

A mixture of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -thione (D18) (108 mg, 0.53 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol 1.5 equivalents) and sodium acetate (65 mg, 0.79 mmol, 1.5 equivalents) in dry ethanol (5 ml) are heated at the boil under reflux for 40 minutes. Water (15 ml) was added, ethanol was removed under reduced pressure and the aqueous layer was extracted with DCM (3 × 30 ml). The combined organic layers were dried (MgSO ₄ ) and the solvent removed under reduced pressure. Silica gel flash column chromatography (ethyl acetate / cyclohexane, 1/4) gave the title compound as a white solid (105 mg, 97%). MS (ES) m / z: 205.10 [MH ⁺ ]. C ₁₁ H ₁₂ N ₂ O ₂ requires 204.23. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.82 (m, 1H), 6.70 (m, 1H), 6.63 (m, 1H), 6.16 (s, 1H), 5 90 (m, 1H); 5.02-4.95 (m, 2H); 4.51 (s, 2H); 3.32 (m, 2H).

Description 43. 6- (2-Propen-1-yl) -4H- [1,2,4] oxadiazole [3,4-c] [1,4] benzoxazin-1-one (D43)

Oxime (3E) -8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D42) (108 mg, 0.529 mmol) in dry THF (4 ml) is treated with carbonyldiimidazole (94 mg, 0.582 mmol, 1.1 eq.) At reflux for 1 hour and then further treated with carbonyldiimidazole (94 mg, 0.582 mmol). After refluxing for 2 hours, the solvent was removed under reduced pressure, the residue was dissolved in DCM (20 ml), the solution was washed with water (10 ml), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/4) to give the title compound (115 mg, 94%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.98 (m, 1H), 7.32 (m, 1H), 7.12 (m, 1H), 5.97 (m, 1H), 5 20-5.00 (m, 4H); 3.43 (m, 2H).

Description 44. (1-Oxo-4H- [1,2,4] oxadiazole [3,4-c] [1,4] benzoxazin-6-yl) acetaldehyde (D44)

The title compound was obtained in 71% yield according to the procedure for Description 6, starting from 6- (2-propen-1-yl) -4H- [1,2,4] oxadiazole [3,4-c] [1,4] benzoxazin-1-one (D43) (115 mg, 0.50 mmol). The reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (1/4) as eluent. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.72 (s, 1H), 8.00 (m, 1H), 7.14-7.02 (m, 2H), 5.05 (s, 2H), 3.76 (s, 2H).

Description 45. 2- (Trifluoromethyl) -5-quinolinyl trifluoromethanesulfonate (D45)

To a solution of 2- (trifluoromethyl) -5-quinolinol (1.07 g, 5.03 mmol) and pyridine (2.05 ml, 25.1 mmol) in dry DCM (20 ml), trifluoromethanesulfonic acid anhydride ( 1.34 ml, 8.05 mmol). The mixture was warmed to room temperature and stirring was continued for 2 hours. Water (15 ml) was added and the mixture was extracted with DCM (3 × 20 ml). The combined organic layers were dried (MgSO ₄ ) and evaporated in vacuo to give the title compound as a yellowish oil (1.61 g, 93%). MS (ES) m / z: 346 [MH ⁺ ]. C ₁₁ H ₅ F ₆ NO ₃ S requires 345.22. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.70 (d, 1H), 8.33 (d, 1H), 8.20 (d, 1H), 8.03 (2H, m) .

Description 46. 1,1-Dimethylethyl-4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinecarboxylate (D46)

A mixture of 2- (trifluoromethyl) -5-quinolinyl trifluoromethanesulfonate (D45) (1.61 g, 4.68 mmol), Cs ₂ CO ₃ (2.29 g, 7.02 mmol), Pd (OAc) ₂ (147 mg, 0.655 mmol) (+/-) - BINAP (436 mg, 0.702 mmol) and N-Boc-piperazine (1.39 g, 7.48 mmol) in dry toluene (20 ml) were stirred at 90 ° C. overnight. After cooling to room temperature, aqueous saturated NH ₄ Cl solution (25 ml) was added and the mixture was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of cyclohexane / ethyl acetate (9: 1-0: 1), and the title compound was obtained as a yellow oil (1.27 g, 71%). MS (ES) m / z: 382 [MH ⁺ ]. C ₁₉ H ₂₂ F ₃ N ₃ O ₂ requires 381.40. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.65 (d, 1H), 7.9 (d, 1H), 7.7 (m, 2H), 7.2 (d, 1H), 3 6-3.8 (m, 4H); 3.0-3.1 (m, 4H); 1.5 (s, 9H).

Description 47. 5- (1-piperazinyl) -2- (trifluoromethyl) quinoline (D47)

A solution of 1,1-dimethylethyl-4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinecarboxylate (D46) (1.27 g, 3.33 mmol) in a mixture of TFA / THF (1: 3, 20 ml ) stirred at room temperature overnight. After evaporation, the crude material is purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give the title compound (888 mg, 95%) as a yellow solid. MS (ES) m / z: 282 [MH ⁺ ]. C ₁₄ H ₁₄ F ₃ N ₃ requires 281.28. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.7 (d, 1H), 7.9 (d, 1H), 7.7 (m, 2H), 7.2 (m, 1H), 3 2-3.0 (m, 9H).

Description 48. (2-E, Z) -2-Butene-1-yl-2-nitrophenyl ether (D48)

To a solution of 2-nitrophenol (5.1 g, 363 mmol) in acetone (45 ml), crotyl chloride (3.9 ml, 40.0 mmol, 1.1 eq.) And K ₂ CO ₃ (5.5 g, 40.0 mmol, 1.1 equiv.). The heterogeneous mixture is heated at the boil under reflux for 18 hours. The mixture was cooled and concentrated in vacuo. To the concentrated reaction mixture was added 1 M NaOH solution (200 ml) and the reaction product was extracted with ethyl acetate (2 × 100 ml). The combined organic extracts were washed with 1 M NaOH solution (2 × 100 ml), water (1 × 100 ml) and brine (1 × 100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to dryness. A mixture of 8/2 stereoisomers of the title compound is obtained as an orange oil, which can be used in the next step without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81 (m, 1H), 7.45 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 5 92-5.58 (m, 2H), 4.74 (m, 2H, stereoisomer 1), 4.60 (m, 2H, stereoisomer 2), 1.74 (m, 3H).

Description 49. 2- (1-Methyl-2-propen-1-yl) -6-nitrophenol (D49)

(2-E, Z) -2-Buten-1-yl-2-nitrophenyl ether (D48) (6.0 g, 31.1 mmol) was stirred and refluxed in a sand bath at 200 ° C for 5 hours. After cooling, the crude reaction product was purified on an SPE-Si cartridge, eluting with cyclohexane / ethyl acetate (100: 0-80: 20), to give the title compound (964 mg, 16%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 11.04 (s, 1H), 7.98 (d, 1H), 7.47 (d, 1H), 6.90 (t, 1H), 6 02 (m, 1H); 5.11-5.05 (m, 2H); 4.00 (m, 1H); 1.33 (d, 3H).

Description 50. Methyl {[2- (1-methyl-2-propen-1-yl) -6-nitrophenyl] oxy} acetate (D50)

To a stirred solution of 2- (1-methyl-2-propen-1-yl) -6-nitrophenol (D49) (343 mg, 1.77 mmol) in acetone (10 ml), methyl bromoacetate (0.18 ml) was added at room temperature , 1.95 mmol) and K ₂ CO ₃ (269 mg, 1.95 mmol). The mixture is heated at the boil under reflux for 3 hours and the reaction is quenched with water (20 ml). The reaction product was extracted with ethyl acetate (2 × 20 ml), the extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge (cyclohexane / ethyl acetate, 90:10) to give the title compound (486 mg, quant.) As a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.71 (d, 1H), 7.48 (d, 1H), 7.23 (m, 1H + CDCl ₃ ), 5.96 (m, 1H ), 5.14-4.92 (m, 2H), 4.75-4.48 (d + d, 2H), 4.09 (m, 1H), 3.82 (s, 3H), 1, 38 (d, 3H).

Description 51. 8- (1-Methyl-2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D51)

To a solution of methyl {[2- (1-methyl-2-propen-1-yl) -6-nitrophenyl] oxy} acetate (D50) (486 mg, 1.83 mmol) in a mixture of MeOH / H ₂ O (1: 1, 8 ml), iron powder (614 mg, 11.0 mmol) and NH ₄ Cl (979 mg, 18.3 mmol) are added with stirring. The mixture is heated at 80 ° C and stirred for 4 hours, and then filtered through celite using MeOH / DCM (1: 1, 1 L) as eluent. Volatile organic matter was removed in vacuo and the remaining aqueous solution was extracted with DCM (2 × 50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (280 mg, 80%) as a light brown solid, which could be used in the next step without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (br s, 1H), 7.00-6.82 (m, 2H), 6.61 (m, 1H), 6.00 ( m, 1H), 5.11-4.96 (m, 2H), 4.58 (s, 2H), 3.82 (m, 1H), 1.31 (d, 3H).

Description 52. Ethyl 6- (1-methyl-2-propen-1-yl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D52)

To a solution of 8- (1-methyl-2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D51) (545 mg, 2.68 mmol) and potassium tert-butoxide ( 300 mg, 2.68 mmol) in dry DMF (8 ml) at 0 ° C, diethyl chlorophosphate (0.80 ml, 5.36 mmol) is added. After 20 minutes, a solution of ethyl isocyanoacetate (0.44 ml, 4.02 mmol) and potassium tert-butoxide (451 mg, 4.02 mmol) in dry DMF (3.2 ml) was added. The reaction mixture was stirred at 60 ° C for 8 hours, then cooled and quenched with water (20 ml). The reaction product was extracted with ethyl acetate (2 × 20 ml), the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 30% ethyl acetate in cyclohexane to give the title compound as a white solid (200 mg, 25%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.98 (s, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 7.01 (t, 1H), 5 98 (m, 1H), 5.53 (s, 2H), 5.14-5.01 (m, 2H), 4.40 (q, 2H), 3.91 (m, 1H), 1, 41 (t, 3H); 1.32 (d, 3H).

Description 53. Ethyl 6- (1-methyl-2-oxoethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (D53)

4-methylmorpholine N-oxide (196 mg, 1.68 mmol) and osmium tetroxide (50 μl of a 4 wt.% Solution in water) are added to a solution of ethyl 6- (1-methyl-2-propen-1-yl) - 4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (D52) (200 mg, 0.67 mmol) in acetone / water (8: 1, 16.7 ml). The reaction mixture was stirred for 18 hours and then the reaction was quenched with saturated aqueous sodium sulfite (20 ml). After 30 minutes stirring, the mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give ethyl 6- (2,3-dihydroxy-1-methylpropyl) -4H-imidazo [5,1-c] [1,4] benzoxazine- 3-carboxylate (200 mg, 0.60 mmol, 90%), which is dissolved in a mixture of THF / water (1: 1, 17 ml) without further purification. Sodium periodate (272 mg, 1.27 mmol) was added and the mixture was stirred for 2 hours. After evaporation of THF, the residue is treated with water (30 ml) and ethyl acetate (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (151 mg, 84%) as a white solid, which was used in the next step without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.70 (s, 1H), 7.98 (s, 1H), 7.40 (d, 1H), 7.15-7.0 (d + t, 2H), 5.61-5.39 (d + d, 2H), 4.38 (q, 2H), 3.89 (m, 1H), 1.49-1.31 (t + d, 6H).

Description 54. 2-Bromo-5-fluorophenyl-2-propen-1-yl ether (D54)

2-Bromo-5-fluorophenol (10 mmol), allyl bromide (1 ml, 1.1 eq.) And K ₂ CO ₃ (1.5 g, 1.1 eq.) In acetone (100 ml) are stirred at 60 ° C in overnight. Then the reaction mixture was concentrated under reduced pressure, washed with an aqueous solution of NH ₄ Cl (100 ml) and extracted with Et ₂ O (3 × 75 ml). The combined organic phases were washed with 1 M aqueous NaOH solution (100 ml), dried over Na ₂ SO ₄ and concentrated to give the title compound as a yellow oil (1.50 g, 90%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35-7.30 (m, 1H), 6.50-6.30 (m, 2H), 5.95-5.75 (m, 1H ), 5.25 (d, 1H), 5.15 (d, 1H), 4.40 ppm. (d, 2H).

Description 55. 1-Bromo-4-fluoro-2- (2-propen-1-yloxy) benzene (D55)

To a solution of 2-bromo-5-fluorophenyl-2-propen-1-yl ester (D54) (213 mg, 1 mmol) in heptane (100 ml), cooled to 0 ° C, 2 ml of a 1 M solution of diethylaluminium chloride was added dropwise with stirring (2.0 equiv.) In hexane. The resulting mixture was warmed to room temperature and stirred for 1 hour. Then the mixture is cooled to 0 ° C and 1 M hydrochloric acid (50 ml) is added. The reaction mixture was extracted with Et ₂ O (3 × 50 ml), and the collected organic phases were washed with H ₂ O (75 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The resulting crude material was purified by flash chromatography on silica gel using a mixture of cyclohexane / ethyl acetate (98: 2) to give the title compound (120 mg, 60%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.25 (t, 1H), 6.55 (t, 1H), 6.00-5.70 (m, 1H), 5.60 (s, 1H), 5.10-4.95 (m, 2H), 3.40 ppm. (d, 2H).

Description 56. (3-Bromo-6-fluoro-2-hydroxyphenyl) acetaldehyde (D56)

Sodium periodate (7.4 g, 34.7 mmol) was added with stirring at room temperature to 1-bromo-4-fluoro-2- (2-propen-1-yloxy) benzene (D55) (4.0 g, 17 , 3 mmol) in THF (70 ml) and H ₂ O (70 ml). After 5 minutes, add 4 wt.% Solution of OsO ₄ in H ₂ About (6.3 ml, 5 mol.%). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with Et ₂ O (100 ml), H ₂ O (100 ml) and an aqueous solution of Na ₂ S ₂ O ₃ (100 ml) and then dried over Na ₂ SO ₄ . The resulting crude material was purified by silica gel chromatography using a cyclohexane / ethyl acetate mixture (95: 5) to give the title compound as a colorless solid (2.0 g, 50%). Based on the NMR spectra, the resulting substance is identified as a mixture of approximately 30/70 of the title product and 7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-ol. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.7 (s, 1H), 7.38 (dd, 1H), 6.65 (t, 1H), 5.78 (br s, 1H) 3.80 ppm (s, 2H). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20-7.30 (m, 1H), 6.65 (t, 1H), 6.2 (br s, 1H), 3.55 ( d, 1H), 3.45 (dd, 1H), 3.20 ppm. (dd, 1H).

Description 57. 6-Bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenol (D57)

2-Methyl-5- (1-piperazinyl) quinoline (1.46 g, 6.4 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl) acetaldehyde (D56) (1.50 g, 6.4 mmol) was stirred at room temperature in DCM (10 ml) for 30 minutes and then Na ₂ SO ₄ (0.91 g, 6.4 mmol) was added. The resulting mixture was stirred at room temperature for another 30 minutes, then sodium triacetoxyborohydride (1.35 g, 6.4 mmol) was added and the mixture was stirred overnight. The reaction mixture was poured into an aqueous solution of NH ₄ Cl (50 ml) and extracted with DCM (3 × 50 ml). The collected organic phases are washed with an aqueous solution of NH ₄ Cl (75 ml) and H ₂ O (75 ml), then dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography using a DCM / MeOH mixture (98: 2) to give the title compound as a yellow solid (2.0 g, 70%). MS (ES / +) m / z: 444 [MH ⁺ ]. C ₂₂ H ₂₄ FBrN ₃ O requires 443. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.40-7.25 (m, 2H), 7.15 (d, 1H), 6.50 (t, 1H), 3.30-2.25 (m, 12H), 2.75 ppm (s, 3H).

Description 58. 2 - [(2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy] acetamide (D58)

2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenol (D57) (444 mg, 1 mmol), 2-bromoacetamide (151 mg, 1.1 mmol) and K ₂ CO ₃ (145 mg, 1.1 mmol) are dissolved in acetone (10 ml) and stirred at 60 ° C overnight. After evaporation under reduced pressure, H ₂ O (50 ml) was added and the resulting mixture was extracted with DCM (3 × 50 ml). The combined organic phases are washed with H ₂ O (50 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography using a DCM / MeOH mixture (96: 4) to give the title compound as a colorless solid (400 mg, 86%). MS (ES / +) m / z: 503 [MH ⁺ ]. C ₂₄ H ₂₆ BrFN ₄ O ₂ requires 502. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7, 55 (t, 1H), 7.40 (dd, 1H), 7.30-7.20 (m, 1H), 7.05 (d, 1H), 6.85 (t, 1H), 4.5 (s, 2H); 3.5 (br s, 2H); 3.10-2.6 (m, 15H).

Description 59. 7-Fluoro-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D59)

2 - [(2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy] acetamide (D58) (400 mg, 0.80 mmol), CuI (152 mg, 0.80 mmol), N, N'-dimethylethylenediamine (71 mg, 0.80 mmol) and K ₂ CO ₃ (220 mg, 1.6 mmol) are suspended in NMP (5 ml) and stirred at 150ºС for 1 hour. The resulting reaction mixture was purified on an SPE- (SCX) cartridge and then silica gel chromatography using a DCM / MeOH mixture (96: 4) to give the title compound as a colorless solid (200 mg, 60%). MS (ES / +) m / z: 421 [MH ⁺ ]. C ₂₄ H ₂₅ FN ₄ O ₂ requires 420. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (d, 1H), 7.9 (s, 1H), 7, 7 (d, 1H), 7.6 (t, 1H), 7.2 (m, 1H), 7.0 (d, 1H), 6.5-6.7 (m, 2H), 4.6 (s, 2H), 3.2 (br s, 4H), 3.0-2.6 ppm. (m, 11H).

Description 60. 2 - [(2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy] propanamide (D60)

Sodium hydride (37 mg, 60% w / w dispersion in mineral oil) is carefully added to 6-bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinolinyl) -1- piperazinyl] ethyl} phenol (D57) (400 mg, 0.93 mmol) in dioxane (3 ml). The resulting yellow solution was stirred at room temperature for 10 minutes, and then 2-bromopropionamide (140 mg, 1.05 mmol) was added. The reaction mixture was heated at 120 ° C. under microwave irradiation for 30 minutes, then diluted with MeOH (1 ml) and purified on SPE- (SCX) to give the title compound (100%). MS (ES / +) m / z: 498 [MH ⁺ ]. C ₂₅ H ₂₉ BrN ₄ O ₂ requires 498. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7, 55 (t, 1H), 7.40 (d, 1H), 7.30-6.85 (m, 4H), 4.85 (q, 1H), 3.5 (br s, 2H), 3 10-2.6 (m, 15H); 1.45 (d, 3H).

Description 61. 2-Methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D61)

2 - [(2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy] propanamide (D60) (370 mg, 0.74 mmol), CuI (141 mg, 0.74 mmol), N, N'-dimethylethylenediamine (65 mg, 0.74 mmol) and K ₂ CO ₃ (195 mg, 1.5 mmol) are suspended in NMP (5 ml) and stirred at 150ºС for 1 hour. The resulting reaction mixture was purified on SPE- (SCX) and then silica gel chromatography using a DCM / MeOH mixture (97: 3) to give the title compound as a colorless solid (150 mg, 50%). MS (ES / +) m / z: 417 [MH ⁺ ]. C ₂₅ H ₂₈ N ₄ O ₂ requires 416. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.61 (br s, 1H), 8.41 (d, 1H), 7.35 (d, 1H), 7.60 (t, 1H), 7.35-7.25 (m, 1H), 7.10 (d, 1H), 7.96-6.86 (m, 2H), 6.76-6.66 (m, 1H), 4.7 (m, 1H), 3.1-2.6 (m, 15H), 1.63 (d, 3H).

Description 62. 6-Bromo-3-fluoro-2- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) phenol (D62)

5- (1-piperazinyl) -2- (trifluoromethyl) quinoline (D47) (211 mg, 1 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl) acetaldehyde (D56) (231 mg, 1 mmol) are mixed at room temperature in DCM (3 ml) for 30 min, and then Na ₂ SO ₄ (142 mg, 1 mmol) was added. The resulting mixture was stirred at room temperature for another 30 minutes, then sodium triacetoxyborohydride (212 mg, 1 mmol) was added and the mixture was stirred overnight. The reaction mixture was poured into an aqueous solution of NH ₄ Cl (50 ml) and extracted with DCM (3 × 50 ml). The combined organic phases are washed with an aqueous solution of NH ₄ Cl (50 ml) and H ₂ O (50 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography using DCM / MeOH (99: 1) and the title compound was obtained as a yellow solid (298 mg, 60%). MS (ES / +) m / z: 499 [MH ⁺ ]. C ₂₂ H ₂₀ BrF ₄ N ₃ O requires 498. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 7.96 (d, 1H), 7 8-7.7 (m, 2H), 7.4-7.3 (m, 2H), 6.48 (t, 1H), 3.1-2.9 (m, 12H).

Description 63. 2 - {[6-Bromo-3-fluoro-2- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) phenyl] oxy} acetamide (D63)

6-Bromo-3-fluoro-2- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) phenol (D62) (285 mg, 0.57 mmol), 2- bromoacetamide (86 mg, 0.63 mmol) and K ₂ CO ₃ (226 mg, 1.71 mmol) in acetone (10 ml) are stirred at 40 ° C for 48 hours. After removing the solvent under reduced pressure, H ₂ O (20 ml) was added and the mixture was extracted with DCM (3 × 25 ml). The combined organic phases are washed with H ₂ O (40 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography using a DCM / MeOH mixture (96: 4) to give the title compound as a colorless solid (200 mg, 63%). MS (ES / +) m / z: 556 [MH ⁺ ]. C ₂₄ H ₂₃ BrF ₄ N ₄ O ₂ requires 555. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 7.90 (m, 1H), 7.7 (m, 2H), 7.4 (m, 1H), 7.20 (d, 1H), 7.0 (br s, 1H), 6.85 (t, 1H), 6.65 (broad s, 1H), 4.5 (s, 2H), 3.1-2.6 (m, 12H).

Description 64. 7-Fluoro-8- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -2H-1,4-benzoxazin-3 (4H) -one (D64 )

2 - {[6-Bromo-3-fluoro-2- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) phenyl] oxy} acetamide (D63) (200 mg, 0.36 mmol), CuI (68 mg, 0.36 mmol), N, N'-dimethylethylenediamine (32 mg, 0.36 mmol) and K ₂ CO ₃ (100 mg, 0.72 mmol) are suspended in NMP ( 5 ml) and stirred at 150 ° C for 1 hour. The resulting reaction mixture was purified on SPE- (SCX) and then silica gel chromatography using a DCM / MeOH mixture (96: 4) to give the title compound as a solid (165 mg, 100%). MS (ES / +) m / z: 475 [MH ⁺ ]. C ₂₄ H ₂₂ F ₄ N ₄ O ₂ requires 474. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 7.70 (m, 1H), 7.8-7.6 (m, 3H), 7.2 (m, 1H), 6.7-6.6 (m, 2H), 4.6 (s, 2H), 3.1-2, 6 (m, 12H).

Description 65. 6-Bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} phenol (D65)

2-Methyl-5- (1-piperazinyl) quinazoline (180 mg, 0.79 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl) acetaldehyde (D56) (180 mg, 0.79 mmol) are stirred at room temperature in DCM (10 ml) over 30 min, and then Na ₂ SO ₄ (112 mg, 0.79 mmol) was added. The resulting mixture was stirred at room temperature for another 30 minutes, then sodium triacetoxyborohydride (167 mg, 0.79 mmol) was added and the mixture was stirred overnight. The reaction mixture was poured into an aqueous solution of NH ₄ Cl (50 ml) and then extracted with DCM (3 × 40 ml). The combined organic phases are washed with an aqueous solution of NH ₄ Cl (30 ml) and H ₂ O (30 ml), then dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography using DCM / MeOH (98: 2) and the title compound was obtained as a yellow solid (210 mg, 60%). MS (ES / +) m / z: 445 [MH ⁺ ]. C ₂₁ H ₂₂ BrFN ₄ O requires 444. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.5 (s, 1H), 7.78 (t, 1H), 7.62 (d, 1H), 7.34-7.25 (m, 2H), 7.13 (d, 1H), 6.47 (t, 1H), 3.4-2.8 (m, 15H).

Description 66. 2 - [(6-Bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} phenyl) oxy] acetamide (D66)

6-Bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} phenol (D65) (210 mg, 0.47 mmol), 2-bromoacetamide ( 74 mg, 0.52 mmol) and K ₂ CO ₃ (186 mg, 1.41 mmol) in acetone (10 ml) were stirred at 40 ° C for 48 hours. After removing the solvent under reduced pressure, H ₂ O (30 ml) was added and the resulting mixture was extracted with DCM (3 × 25 ml). The combined organic phases are washed with H ₂ O (40 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude reaction product was purified by silica gel chromatography using a DCM / MeOH mixture (95: 5) to give the title compound as a solid (200 mg, 85% yield). MS (ES / +) m / z: 502 [MH ⁺ ]. C ₂₃ H ₂₅ BrFN ₅ O ₂ requires 501. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.5 (s, 1H), 7.75 (t, 1H), 7, 55 (t, 1H), 7.4 (m, 1H), 7.05 (d, 1H), 6.9 (br s, 1H), 6.8 (t, 1H), 5.75 (br s, 1H), 4.5 (s, 2H), 3.1-2.6 (m, 15H).

Description 67. 7-Fluoro-8- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D67)

2 - [(6-Bromo-3-fluoro-2- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} phenyl) oxy] acetamide (D66) (200 mg, 0, 40 mmol), CuI (76 mg, 0.40 mmol), N, N'-dimethylethylenediamine (35 mg, 0.40 mmol) and K ₂ CO ₃ (105 mg, 0.80 mmol) are suspended in NMP (5 ml ) and stirred at 150 ° C for 1 hour. The resulting reaction mixture was purified on SPE- (SCX) and then silica gel chromatography using a DCM / MeOH mixture (96: 4) to give the title compound as a solid (90 mg, 53%). MS (ES / +) m / z: 422 [MH ⁺ ]. C ₂₃ H ₂₄ FN ₅ O ₂ requires 421. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.5 (s, 1H), 7.8-7.7 (m, 2H ), 7.55 (d, 1H), 7.05 (d, 1H), 6.7-6.5 (m, 2H), 4.6 (s, 1H), 3.1-2.6 ( m, 15H).

Description 68. 1,1-Dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D68)

To a solution of 1,1-dimethylethyl-4- (2-methyl-5-quinolinyl) -1-piperazinecarboxylate (D165) (4.51 g, 13.8 mmol) in dioxane (20 ml) was added selenium dioxide (1.83 g, 16.5 mmol). The mixture was stirred at 90 ° C for 1.5 hours, cooled to room temperature, filtered and evaporated. The residue was purified by flash column chromatography eluting with a cyclohexane / ethyl acetate mixture (9: 1-1: 1) to give the title compound as a yellow solid (3.35 g, 71%). MS (ES; m / z): 342 [MH ⁺ ]. C ₁₉ H ₂₃ N ₃ O ₃ requires 341.41. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.20 (s, 1H), 8.63 (d, 1H), 7.98 (q, 2H), 7.71 (t, 1H), 7 21 (d, 1H), 3.69 (br s, 4H), 3.03 (br s, 4H), 1.48 (s, 9H).

Description 69. 1,1-Dimethylethyl-4- (2-cyano-5-quinolinyl) -1-piperazinecarboxylate (D69)

To a solution of 1,1-dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D68) (522 mg, 1.52 mmol) in a 20% aqueous solution of ammonia (15 ml) and THF (3 ml) ) add iodine (427 mg, 1.68 mmol). The mixture was stirred at room temperature for 1 hour. An aqueous solution of Na ₂ S ₂ O ₃ (5%, 10 ml) was then added and the reaction product was extracted with DCM (3 × 15 ml). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with cyclohexane / ethyl acetate (8: 2-0: 1) mixtures to give the title compound as a yellow solid (265 mg, 51%). MS (ES; m / z): 339 [MH ⁺ ]. C ₁₉ H ₂₂ N ₄ O ₂ requires 338.41. NMR ( ¹ H, 300 MHz, DMSO-d ₆ ) δ: 8.70 (d, 1H), 7.97 (d, 1H), 7.79 (m, 2H), 7.36 (m, 1H), 3.57 (br s, 4H), 2.95 (m, 4H), 1.40 (s, 9H).

Description 70. 5- (1-piperazinyl) -2-quinolinecarbonitrile (D70)

A solution of 1,1-dimethylethyl-4- (2-cyano-5-quinolinyl) -1-piperazinecarboxylate (D69) (1.04 g, 3.06 mmol) in a mixture of TFA / DCM (20 ml, 1: 3) is stirred at room temperature overnight. After evaporation, the crude material is purified by SPE-SCX to give a yellow solid (633 mg, 87%). HPLC / MS analysis showed a second product (28%, m / z 312). The resulting substance can be used in the next step without further purification. MS (ES; m / z): 239 [MH ⁺ ]. C ₁₄ H ₁₄ N ₄ requires 238.29.

Description 71. 2-Oxo-1,2,3,4-tetrahydro-5-quinolinyl trifluoromethanesulfonate (D71)

1,1,1-Trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide (1.21 g, 3.39 mmol) is added portionwise with stirring at 0 ° C to a suspension of 5-hydroxy-3,4-dihydro -2 (1H) -quinolinol (Davos, commercially available) (460 mg, 2.82 mmol) in CH ₃ CN (25 ml) and triethylamine (492 μl, 3.53 mmol). The reaction mixture was stirred for 15 hours at room temperature, then the reaction was quenched with water (20 ml) and the mixture was extracted with DCM (3 × 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a cyclohexane / ethyl acetate mixture (7: 3) to give the title compound (812 mg, 97%). MS (ES) m / z: 296.00 [MH ⁺ ]. C ₁₀ H ₈ F ₃ NO ₄ S requires 295.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.92 (br s, 1H), 7.28 (m, 1H), 6.97 (m, 1H), 6.76 (m, 1H) 3.08 (t, 2H); 2.68 (t, 2H).

Description 72. 5- (2-Propen-1-yl) -3,4-dihydro-2 (1H) -quinolinone (D72)

To a solution of 2-oxo-1,2,3,4-tetrahydro-5-quinolinyl trifluoromethanesulfonate (D71) (919 mg, 3.12 mmol) in dry DMF (9 ml), allyl tributyl stannane (1.16 ml, 3 was added at room temperature , 74 mmol), LiCl (3 mg, 2%) and tetrakis (triphenylphosphine) palladium (0) (361 mg, 10%). The reaction mixture was stirred at 100 ° C for 2 hours, then cooled, quenched with water (10 ml) and the mixture was extracted with DCM (3 × 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude reaction product, which was purified by flash chromatography on silica gel eluting with cyclohexane / ethyl acetate (7: 3) to give the title compound (496 mg, 85% ) MS (ES) m / z: 188.10 [MH ⁺ ]. C ₁₂ H ₁₃ NO requires 187.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.93 (br s, 1H), 7.13 (t, 1H), 6.88 (d, 1H), 6.65 (d, 1H) 6.00-5.87 (m, 1H), 5.11-4.95 (m, 2H), 3.42-3.38 (m, 2H), 2.94 (t, 2H), 2 62 (t, 2H).

Description 73. (2-Oxo-1,2,3,4-tetrahydro-5-quinolyl) acetaldehyde (D73)

The title compound was obtained in 63% yield according to the procedure for Description 6, starting from 5- (2-propen-1-yl) -3,4-dihydro-2 (1H) -quinolinone (D72) (380 mg, 2.03 mmol). The reaction product was purified by flash chromatography on silica gel using ethyl acetate / cyclohexane (1: 1) as an eluent. MS (ES) m / z: 190.1 [MH ⁺ ]. C ₁₁ H ₁₁ NO ₂ requires 189.21. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.73 (t, 1H), 7.68 (br s, 1H), 7.19 (t, 1H), 6.90 (d, 1H) 6.71 (d, 1H); 3.77 (d, 2H); 2.88 (t, 2H); 2.63 (d, 2H).

Description 74. 5- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3,4-dihydro-1 (1H) -quinolinone (D74)

The title compound was obtained in 75% yield according to the general procedure of Example 1, starting from (2-oxo-1,2,3,4-tetrahydro-5-quinolyl) acetaldehyde (D73) (242 mg, 1.28 mmol). The crude reaction product was purified by flash chromatography on silica gel with a methanol gradient in DCM (1-3%) to give the title compound (384 mg, 75%). MS (ES) m / z: 401.20 [MH ⁺ ]. C ₂₅ H ₂₈ N ₄ O requires 400.52. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.01 (s, 1H), 8.34 (br s, 1H), 7.58 (m, 2H), 7.37 ( d, 1H), 7.09 (m, 1H), 7.07 (t, 1H), 6.84 (d, 1H), 6.72 (dd, 1H), 3.03 (br s, 4H ), 2.89 (t, 2H), 2.80 (m, 2H), 2.74 (br s, 4H), 2.54 (m, 2H), 2.44 (t, 2H), 2 63 (br s, 3H).

Description 75. 5-Methyl-2-nitrophenyl-2-propen-1-yl ether (D75)

The title compound was obtained in quantitative yield (2.5 g), following the procedure for Description 1, starting from 5-methyl-2-nitrophenol (2.0 g, 13 mmol). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.71 (d, 1H), 6.77-6.72 (m, 2H), 5.95 (m, 1H), 5.46-5, 23 (m, 2H); 4.61-4.58 (m, 2H); 2.33 (s, 3H).

Description 76. 3-Methyl-6-nitro-2- (2-propen-1-yl) phenol (D76)

The title compound was obtained in 68% yield (1.7 g), following the procedure for Description 2, starting from 5-methyl-2-nitrophenyl-2-propen-1-yl ester (D75) (2.5 g, 13 mmol) ) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 11.06 (s, 1H), 7.89 (d, 1H), 6.78 (d, 1H), 5.95 (m, 1H), 5 05-4.93 (m, 2H); 3.52-3.49 (m, 2H); 2.37 (s, 3H).

Description 77. Methyl {[3-methyl-6-nitro-2- (2-propen-1-yl) phenyl] oxy} acetate (D77)

The title compound was prepared following the procedure for Description 3, starting from 3-methyl-6-nitro-2- (2-propen-1-yl) phenol (D76) (1.7 g, 8.81 mmol). MS (ES) m / z: 266.1 [MH ⁺ ]. C ₁₃ H ₁₅ NO ₅ requires 265.26. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.71 (d, 1H), 7.08 (d, 1H), 5.95 (m, 1H), 5.10-4.81 (m, 2H), 4.61 (s, 2H), 3.81 (s, 3H), 3.59-3.55 (m, 2H), 2.36 (s, 3H).

Description 78. 7-Methyl-8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -one (D78)

The title compound was obtained in 48% yield (860 mg), following the procedure for Description 4, starting from methyl {[3-methyl-6-nitro-2- (2-propen-1-yl) phenyl] oxy} acetate (D77 ) (2.33 g, 8.81 mmol). MS (ES) m / z: 204.1 [MH ⁺ ]. C ₁₂ H ₁₃ NO ₂ requires 203.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (br s, 1H), 6.77 (d, 1H), 6.56 (d, 1H), 5.89 (m, 1H) 5.02-4.88 (m, 2H); 4.58 (s, 2H); 3.42-3.39 (m, 2H); 2.25 (s, 3H).

Description 79. (7-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl) acetaldehyde (D79)

The title compound was obtained in 48% yield (860 mg), following the procedure for Description 6, starting from 7-methyl-8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) - she (D78) (2.33 g, 8.81 mmol). MS (ES) m / z: 206.1 [MH ⁺ ]. C ₁₁ H ₁₁ NO ₃ requires 205.21. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.70 (s, 1H), 7.79 (br s, 1H), 6.81 (d, 1H), 6.66 (d, 1H) 4.56 (s, 2H); 3.75 (s, 2H); 2.38 (s, 3H).

Description 80. 7-Methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D80)

The title compound was prepared following the general reductive amination procedure of Example 1, starting from (7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl) acetaldehyde (D79) (242 mg 1.28 mmol). The crude reaction product was purified by flash chromatography on silica gel with a methanol gradient in DCM (1-3%) to give the title compound (384 mg, 75%). MS (ES) m / z: 417.20 [MH ⁺ ]. C ₂₅ H ₂₈ N ₄ O ₂ requires 416.52. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.52 (s, 1H), 8.33 (d, 1H), 7.57 (m, 2H), 7.35 (d, 1H), 7 09 (m, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 4.53 (s, 2H), 3.04 (br.m, 4H), 2.81- 2.64 (m, 6H), 2.62 (s, 3H), 2.38-2.57 (m 2H), 2.24 (s, 3H).

Description 81. 5 - {[(1,1-Dimethylethyl) (dimethyl) silyl] oxy} -3,4-dihydro-2 (1H) -quinolinone (D81)

To a solution of 5-hydroxy-3,4-dihydro-2 (1H) -quinolinone (640 mg, 3.93 mmol) in DMF (3.5 ml), tert-butyldimethylsilyl chloride (651 mg, 4, 32 mmol) and imidazole (321 mg, 4.71 mmol). After 4 hours, water (10 ml) was added and the mixture was extracted with DCM (3 × 70 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated in vacuo to give the title compound (997 mg, 91%), which was used in the next step without further purification. MS (ES) m / z: 278.2 [MH ⁺ ]. C ₁₅ H ₂₃ NO ₂ Si requires 277.44. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.62 (br s, 1H), 7.03 (t, 1H), 6.52 (d, 1H), 6.36 (d, 1H) 2.95 (t, 2H); 2.61 (t, 2H); 1.03 (s, 9H); 0.25 (s, 6H).

Description 82. Ethyl-6 - {[(1,1-dimethylethyl) (dimethyl) silyl] oxy} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D82)

The title compound was prepared according to the procedure of Example 80, starting from 5 - {[(1,1-dimethylethyl) (dimethyl) silyl] oxy} -3,4-dihydro-2 (1H) -quinolinone (D81) (997 mg, 3.6 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (4: 6) to give the title compound (992 mg, 74%). MS (ES) m / z: 373.2 [MH ⁺ ]. C ₂₀ H ₂₈ N ₂ O ₃ Si requires 372.54. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.99 (s, 1H), 7.21 (t, 1H), 7.09 (d, 1H), 6.77 (d, 1H), 4 41 (q, 2H), 3.31 (t, 2H), 2.93 (t, 2H), 1.44 (t, 3H), 1.05 (s, 9H), 0.27 (s, 6H).

Description 83. Ethyl-6-hydroxy-4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D83)

To a solution of ethyl 6 - {[(1,1-dimethylethyl) (dimethyl) silyl] oxy} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D82) (642 mg, 1.73 mmol) in THF (20 ml) was added tetrabutylammonium fluoride (3.45 ml of a 1 M solution in THF, 3.45 mmol) and the resulting solution was stirred at room temperature. After 2 hours, a saturated solution of ammonium chloride (10 ml) was added, THF was removed in vacuo and the resulting mixture was extracted with DCM (4 × 100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated in vacuo to give the title compound (446 mg, 100%), which can be used in the next step without further purification. MS (ES) m / z: 259.1 [MH ⁺ ]. C ₁₄ H ₁₄ N ₂ O ₃ requires 258.28. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 10.07 (br s, 1H), 8.72 (s, 1H), 7.27 (d, 1H), 7.17 (t, 1H), 6.84 (d, 1H), 4.26 (q, 2H), 3.18 (t, 2H), 2.82 (t, 2H), 1.30 (t, 3H).

Description 84. Ethyl-6 - {[(trifluoromethyl) sulfonyl] oxy} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D84)

The title compound was prepared according to the procedure for description 71, starting from ethyl 6-hydroxy-4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D83) (446 mg, 1.73 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97: 3), then on an SCX cartridge to give the title compound (491 mg, 73%). MS (ES) m / z: 391.0 [MH ⁺ ]. C ₁₅ H ₁₃ F ₃ N ₂ O ₅ S requires 390.34. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.03 (s, 1H), 7.55-7.40 (m, 2H), 7.26 (m, 1H), 4.41 (q, 2H), 3.39 (t, 2H), 3.06 (t, 2H), 1.43 (t, 3H).

Description 85. Ethyl 6- (2-propen-1-yl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D85)

The title compound was obtained in quantitative yield according to the procedure for description 72, starting from ethyl 6 - {[(trifluoromethyl) sulfonyl] oxy} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D84) ( 491 mg, 1.26 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (7: 3) to give the title compound (354 mg, quant.). MS (ES) m / z: 283.2 [MH ⁺ ]. C ₁₇ H ₁₈ N ₂ O ₂ requires 282.34. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.99 (s, 1H), 7.40-7.28 (m, 2H), 7.13 (d, 1H), 5.95 (m, 1H), 5.13-4.95 (m, 2H), 4.40 (q, 2H), 3.47 (m, 2H), 3.30 (t, 2H), 2.89 (t, 2H) ), 1.43 (t, 3H).

Description 86. Ethyl-6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D86)

The title compound was obtained in 85% yield (305 mg), following the procedure for Description 6, starting from ethyl 6- (2-propen-1-yl) -4,5-dihydroimidazo [1,5-a] quinolin-3 -carboxylate (D85) (354 mg, 1.25 mmol). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.77 (t, 1H), 8.01 (s, 1H), 7.46 (d, 1H), 7.35 (t, 1H), 7 14 (d, 1H), 4.39 (q, 2H), 3.86 (d, 2H), 3.32 (t, 2H), 2.83 (t, 2H), 1.43 (t, 3H).

Description 87. 5- (2-Propen-1-yl) quinoline (D87)

To a mixture of 5-bromoquinoline (1.5 g, 7.24 mmol), tris (dibenzylideneacetone) dipalladium (0) (331 mg, 0.36 mmol) and triphenylphosphine (760 mg, 2.9 mmol) in toluene (50 ml ) add allyl tributyl stannane (2.4 ml, 8 mmol). The reaction mixture was stirred overnight at 120 ° C and then the reaction was quenched with water (30 ml) and 1 N hydrochloric acid (10 ml). The organic layer was extracted with 1 M hydrochloric acid (3 × 20 ml), then the combined aqueous phases were made basic with solid NaHCO ₃ and then extracted with DCM (3 × 50 ml). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The crude material is purified on an SPE-Si cartridge, eluting with a mixture of 5% ethyl acetate in cyclohexane to give the title compound as a pale yellow solid (1 g, 81%). MS (ES) m / z: 170.1 [MH ⁺ ]. C ₁₂ H ₁₁ N requires 169.23. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.75 (t, 1H), 8.20 (d, 1H), 7.85 (d, 1H), 7.45 (t, 1H), 5 95-5.8 (m, 1H); 5.0-4.8 (m, 2H); 3.65 (d, 2H).

Description 88. 5- (2-Propen-1-yl) Quinoline N-Oxide (D88)

To a solution of 5- (2-propen-1-yl) quinoline (D87) (6 g, 35.5 mmol) in DCM (100 ml) at 0 ° C, 3-chloroperbenzoic acid (55%, 13.4 g, 42, 6 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then the reaction was quenched with saturated aqueous NaHCO ₃ solution (100 ml). The mixture was extracted with DCM (3 × 50 ml), and the combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 40% ethyl acetate in cyclohexane to give the title compound as a pale brown solid (5.4 g, 82%). MS (ES) m / z: 186.2 [MH ⁺ ]. C ₁₂ H ₁₁ NO requires 185.24. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.7 (br s, 1H), 8.50 (br s, 1H), 7.9 (br s, 1H), 7.7 ( broad s, 1H), 7.5 (broad s, 1H), 7.3 (broad s, 1H), 6 (broad s, 1H), 5.1 (d, 1H), 5.0 (d, 1H); 3.8 (br s, 2H).

Description 89. Ethyl nitro [5- (2-propen-1-yl) -2-quinolinyl] acetate (D89)

Ethyl nitroacetate (1.3 ml, 11.9 mmol) is added dropwise to a mixture of 5- (2-propen-1-yl) quinoline N-oxide (D88) (2 g, 10.8 mmol) and acetic anhydride (5 ml) ) After 30 minutes of stirring, precipitate formation is observed, the reaction is quenched with water (10 ml) and the mixture is filtered. The solid was washed with methanol (10 ml) and dried in vacuo to give the title compound as a yellow solid (1.4 g, 43%). MS (ES) m / z: 301.1 [MH ⁺ ]. C ₁₆ H ₁₆ N ₂ O ₄ requires 300.31. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.2 (brd, 1H), 7.7-7.4 (m, 3H), 7.3 (brd, 1H), 6, 1-5.9 (br.m, 1H), 5.2-4.9 (br.m, 2H), 4.5-4.3 (br.m, 2H), 3.7 (br.s , 2H), 1.4-1.3 (br.m, 3H).

Description 90. Ethyl 6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate (D90)

Zinc powder (720 mg, 11 mmol) was added to a mixture of ethyl nitro [5- (2-propen-1-yl) -2-quinolinyl] acetate (D89) (550 mg, 1.83 mmol) and glacial acetic acid (15 ml) ) The reaction mixture was stirred at room temperature for 4 hours, then the reaction was quenched with water (50 ml), the mixture was diluted with DCM (50 ml), cooled to 0 ° C and neutralized with solid NaHCO ₃ . The aqueous layer was separated and extracted with DCM (2 × 50 ml), and then the combined organic phases were washed with saturated aqueous NaHCO ₃ (3 × 50 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The intermediate ethylamino [5- (2-propen-1-yl) -2-quinolinyl] acetate is rapidly treated with triethylorthoformate (5 ml) and heated with stirring at 150 ° C for 7 minutes under the influence of microwave radiation. The resulting reaction mixture was passed through an SCX cartridge to remove triethylorthoformate and then purified on an SPE-Si cartridge, eluting with a mixture of 50% ethyl acetate in cyclohexane to give the title compound as a pale yellow solid (245 mg, 48%). MS (ES) m / z: 281.20 [MH ⁺ ]. C ₁₇ H ₁₆ N ₂ O ₂ requires 280.33. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.6 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.5-7.6 (m, 2H), 7.3 (d, 1H), 6.0-5.9 (m, 1H), 5.1 (d, 1H), 5.0 (d, 1H), 4.45 (q, 2H ), 3.8 (d, 2H), 1.4 (t, 3H).

Description 91. Ethyl 6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D91)

To a solution of ethyl 6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate (D90) (245 mg, 0.88 mmol) in a THF / water mixture (2: 1, 9 ml) osmium tetroxide (0.63 ml of a 4 wt.% Solution in water) is added with stirring. After 10 minutes, sodium periodate (470 mg, 2.2 mmol) was added and the reaction mixture was stirred for another 20 minutes. After evaporation of THF, the residue was treated with water (10 ml) and ethyl acetate (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (220 mg). The crude reaction product can be used without further purification in the next step. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.8 (s, 1H), 8.7 (s, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7 65 (t, 1H), 7.3 (m, 2H), 4.45 (q, 2H), 4.15 (s, 2H), 1.4 (t, 3H).

Description 92. 6- (2-Propen-1-yl) tetrazolo [1,5-a] quinoline (D92)

A mixture of 5- (2-propen-1-yl) quinoline N-oxide (D88) (500 mg, 2.7 mmol) and methanesulfonyl chloride (0.22 ml, 2.7 mmol) in dry acetonitrile (5 ml) is stirred in for 3 hours at room temperature. Trimethylsilyl azide (0.36 ml, 2.7 mmol) was added dropwise to the suspension, and then the mixture was heated under reflux for 24 hours. Evaporation of the volatiles in vacuo and purification on an SPE-Si cartridge eluting with DCM afforded the title compound (318 mg, 56%). MS (ES) m / z: 211.1 [MH ⁺ ]. C ₁₂ H ₁₀ N ₄ requires 210.2. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.6 (d, 1H), 8.1 (d, 1H), 7.9-7.7 (m, 2H), 7.6 (d, 1H), 6.1-5.9 (m, 1H), 5.15 (d, 1H), 5.0 (d, 1H), 3.8 (d, 2H).

Description 93. Tetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D93)

To a solution of 6- (2-propen-1-yl) tetrazolo [1,5-a] quinoline (D92) (100 mg, 0.48 mmol) in a THF / water mixture (2: 1, 4.5 ml) at osmium tetroxide (0.34 ml of a 4 wt.% solution in water) is added with stirring. After 10 minutes, sodium periodate (256 mg, 1.2 mmol) was added and the reaction mixture was stirred for another 15 minutes. After evaporation of THF, the residue was treated with water (10 ml) and ethyl acetate (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Treatment of the crude material with DCM / ethyl acetate (1: 1, 2 ml) gave the title compound (62 mg, 61%). MS (ES) m / z: 213.1 [MH ⁺ ]. C ₁₁ H ₈ N ₄ O requires 212.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 9.8 (s, 1H), 8.6 (d, 1H), 8.3 (d, 1H), 8.1 (d, 1H) 7.95 (t, 1H); 7.7 (d, 1H); 4.5 (s, 2H).

Description 94. 5- (2-Propen-1-yl) -2 (1H) -quinolinone (D94)

To a solution of 5- (2-propen-1-yl) quinoline N-oxide (D88) (670 mg, 3.62 mmol) in DMF (12 ml), trifluoroacetic anhydride (5.1 ml, 36.2 mmol) was added with stirring ) The mixture was stirred at room temperature overnight, then the reaction was quenched with saturated aqueous NaHCO ₃ (20 ml) and the mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic phases are dried over Na ₂ SO ₄ and then evaporated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 30% cyclohexane in ethyl acetate to give the title compound as a white solid (360 mg, 54%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 13.4 (s, 1H), 8.2 (d, 1H), 7.5 (t, 1H), 7.4 (d, 1H), 7 3 (d, 1H), 6.8 (d, 1H), 6.1-5.9 (m, 1H), 5.2 (d, 1H), 5.0 (d, 1H), 3, 7 (d, 2H).

Description 95. 5- (2-Propen-1-yl) -2 (1H) -quinolinthione (D95)

A mixture of 5- (2-propen-1-yl) -2 (1H) -quinolinone (D94) (1.1 g, 6 mmol) and Lausson's reagent (1.2 g, 3 mmol) in dry toluene (30 ml) heated at the boil under reflux for 30 minutes The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 30% ethyl acetate in cyclohexane to give the title compound as a white solid (0.96 g, 80%). MS (ES) m / z: 202.1 [MH ⁺ ]. C ₁₂ H ₁₁ NS requires 201.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 12.5 (s, 1H), 7.8 (d, 1H), 7.6-7.3 (m, 3H), 7.1 (d, 1H), 6.0-5.8 (m, 1H), 5.05 (d, 1H), 4.95 (d, 1H), 3.7 (d, 2H).

Description 96. 1-Methyl-6- (2-propen-1-yl) [1,2,4] triazolo [4,3-a] quinoline (D96)

A solution of 5- (2-propen-1-yl) -2 (1H) -quinolinthione (D95) (150 mg, 0.75 mmol) in absolute ethanol (1 ml) at 100 ° C is added dropwise to a solution of hydrazine monohydrate (1 ml ) in absolute ethanol (1 ml). The resulting reaction mixture was stirred at 100 ° C for 6 hours and concentrated in vacuo to give the intermediate 5- (2-propen-1-yl) -2 (1H) -quinoline hydrazone, which was used immediately in the next step without further purification. Hydrazone is mixed with trimethylorthoacetate (2 ml) and heated with stirring at 150 ° C for 10 min under the influence of microwave radiation. The resulting reaction mixture was purified on an SCX cartridge and then chromatography (SPE-Si cartridge), eluting with a mixture of 10% methanol in DCM. The title compound was obtained after treatment with diethyl ether (110 mg, 65%). MS (ES) m / z: 224.1 [MH ⁺ ]. C ₁₄ H ₁₃ N ₃ requires 223.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.2 (d, 1H), 7.8-7.5 (m, 3H), 7.4 (d, 1H), 6.2-6, 0 (m, 1H), 5.2 (d, 1H), 5.0 (d, 1H), 3.8 (d, 2H), 3.2 (s, 3H), 1.6 (d, 3H) )

Description 97. (1-Methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) acetaldehyde (D97)

4-methylmorpholine N-oxide (98 mg, 0.28 mmol) and osmium tetroxide (106 μl of a 4 wt.% Solution in water, 0.035 equiv.) Are added to the solution of 1-methyl-6- (2-propen-1-yl ) [1,2,4] triazolo [4,3-a] quinoline (D96) (94 mg, 0.42 mmol) in acetone / water (8: 1, 4.5 ml). The reaction mixture was stirred for 4 hours and then the reaction was quenched with saturated aqueous sodium sulfite (15 ml). After 30 minutes stirring, the mixture was extracted with DCM (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the intermediate 3- (1-methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) -1,2 -propanediol (80 mg), which is dissolved in a mixture of THF / water (1: 1, 2 ml) without further purification. Sodium periodate (133 mg, 0.62 mmol) and acetone (1 ml) were added and the mixture was stirred for 10 minutes. After evaporation of THF, the residue is treated with water (10 ml) and DCM (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo (using methanol to improve dissolution in DCM) to give the title compound as a white solid. ( ¹ H-NMR analysis shows a mixture of compounds - 40% (1-methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) acetaldehyde plus 60% 1- (methyloxy) -2- (1-methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) ethanol; 35 mg). The mixture is used without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) (1-methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) acetaldehyde: δ 9.9 (s, 1H), 8, 3 (d, 1H), 7.8-7.4 (m, 4H), 4.0 (d, 2H), 3.2 (s, 3H); and 1- (methyloxy) -2- (1-methyl [1,2,4] triazolo [4,3-a] quinolin-6-yl) ethanol: δ 8.2 (d, 1H), 7.8 ( d, 1H), 7.8-7.4 (m, 3H), 5.9 (br s, 1H), 3.4 (s, 3H), 3.3 (br s, 2H), 3 , 1 (s, 3H).

Description 98. Ethyl-6- (2-propen-1-yl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D98)

Following the procedure for describing 90, ethyl nitro [5- (2-propen-1-yl) -2-quinolinyl] acetate (D89) (1.2 g, 4 mmol) in glacial acetic acid (15 ml) was reacted with zinc powder (1.57 g, 24 mmol) for 2 hours. A portion of the crude intermediate ethylamino [5- (2-propen-1-yl) -2-quinolinyl] acetate (200 mg) was quickly dissolved in hydrochloric acid (2.5 ml, 37%), and after 5 minutes stirring, was added dropwise sodium nitrite solution (62 mg in 1.5 ml of water). After reacting for 2 hours, the precipitated material was filtered off and purified on an SPE-Si cartridge, eluting with a mixture of 50% ethyl acetate in cyclohexane to give the title compound (68 mg). MS (ES) m / z: 282.20 [MH ⁺ ]. C ₁₆ H ₁₅ N ₃ O ₂ requires 281.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.8 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6 2-6.0 (m, 1H), 5.2 (d, 1H), 5.1 (d, 1H), 4.6 (q, 2H), 3.9 (d, 2H), 1, 5 (t, 3H).

Description 99. Ethyl 6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D99)

To a solution of ethyl 6- (2-propen-1-yl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D98) (64 mg, 0.23 mmol) in a mixture of THF / water (2: 1, 3 ml) with stirring add osmium tetroxide (0.16 ml of a 4 wt.% solution in water). After 15 minutes, sodium periodate (122 mg, 0.57 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with water (5 ml) and extracted with DCM (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 40% cyclohexane in ethyl acetate to give the title compound (37 mg, 57%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.85 (s, 1H), 8.9 (d, 1H), 8.15 (d, 1H), 7.9-7.7 (m, 2H), 4.5 (q, 2H), 4.2 (s, 2H), 1.5 (t, 3H).

Description 100. 1,1-Dimethylethyl-4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinecarboxylate (D100)

To a solution of 1,1-dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D68) (1.015 g, 2.97 mmol) in DCM (10 ml), sulfur trifluoride (diethylamino) is added at room temperature (DAST) (428 μl, 3.27 mmol). After 4 hours, another DAST (194 μl, 1.49 mmol) was added and stirring was continued for another 1 hour. The reaction was quenched with water (30 ml) and the mixture was extracted with DCM (3 × 30 ml). The organic layer was dried (MgSO ₄ ) and evaporated in vacuo to a residue, which was purified by flash column chromatography eluting with cyclohexane / ethyl acetate (9: 1-8: 2) to give the title compound (886 mg, 82%) in as a yellow solid. MS (ES; m / z): 364 [MH ⁺ ]. C ₁₉ H ₂₃ F ₂ N ₃ O ₂ requires 363.41. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.65 (d, 1H), 7.84 (d, 1H), 7.67 (m, 2H), 7.17 (d, 1H), 6 75 (t, 1H); 3.68 (broad m, 4H); 3.02 (broad m, 4H); 1.49 (s, 9H).

Description 101. Methyl-3-oxo-2- [5- (2-propen-1-yl) -2-quinolinyl] butanoate (D101)

Methylacetoacetate (1.3 ml) was added to a mixture of 5- (2-propen-1-yl) quinoline N-oxide (D88) (2.0 g, 10.81 mmol) and acetic anhydride (5 ml), keeping the internal temperature at a level below 30ºС. The reaction mixture was stirred at 30 ° C. overnight and then poured into a mixture of ice water. The precipitated substance is filtered off, washed with water and then dried in vacuo at 40 ° C, and the title compound is obtained as a yellow solid (2.94 g, 96%). MS (ES) m / z: 284 [MH ⁺ ]. C ₁₇ H ₁₇ NO ₃ requires 283.3.

Description 102. Methyl [5- (2-propen-1-yl) -2-quinolinyl] acetate (D102)

Methyl-3-oxo- [5- (2-propen-1-yl) -2-quinolinyl] butanoate (D101) (2.83 g, 10 mmol) is added portionwise over 10 minutes to a 10% HCl solution (10 ml). After stirring for another 20 minutes at room temperature, the reaction mixture was made basic with a 10% solution of potassium carbonate in water (35 ml) and then extracted with DCM (3 × 50 ml). The organic layer was dried over Na ₂ SO ₄ and then evaporated in vacuo. The residue was purified by flash chromatography eluting with mixtures of 10% cyclohexane in ethyl acetate to 25% cyclohexane in ethyl acetate to give the title compound as an orange liquid (1.62 g, 67%). MS (ES) m / z: 242 [MH ⁺ ]. C ₁₅ H ₁₅ NO ₂ requires 241.3.

Description 103. Methyl-6- (2-propen-1-yl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D103)

To a mixture of methyl [5- (2-propen-1-yl) -2-quinolinyl] acetate (D102) (620 mg) and ethyl [5- (2-propen-1-yl) -2-quinolinyl] acetate (100 mg, obtained according to the procedure described above for D102, but starting from ethyl acetoacetate in description 101) (2.96 mmol total) in dry acetonitrile (15 ml) at 0 ° C, DBU (0.464 ml, 3.1 mmol) and p-acetamidobenzenesulfonylazide are added (768 mg, 3.1 mmol). The reaction mixture was stirred for 20 minutes and then quenched at 0 ° C with a solution of ammonium chloride (20 ml). The mixture was extracted with DCM (3 × 20 ml), and the organic layer was dried over Na ₂ SO ₄ and then evaporated in vacuo. The residue was purified by flash chromatography eluting with mixtures of 10% cyclohexane in ethyl acetate to 20% cyclohexane in ethyl acetate to give the title compound as a white solid (500 mg, 63%). MS m / z: 268 [MH ⁺ ]. C ₁₅ H ₁₃ N ₃ O ₂ requires 267.3. HPLC detected the presence of ≈10% ethyl 6- (2-propen-1-yl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate.

Description 104. Methyl-6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D104)

To a solution of methyl 6- (2-propen-1-yl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D103) (450 mg, 1.68 mmol) in a THF mixture / water (2: 1, 21 ml) with stirring add osmium tetroxide (1.9 ml of a 4 wt.% solution in water). After 30 minutes, sodium periodate (900 mg, 4.21 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3 × 30 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 50% cyclohexane in ethyl acetate to give the title compound (360 mg, 80%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.9 (s, 1H), 8.9 (d, 1H), 8.2 (d, 1H), 7.8 (m, 2H), 7 6 (br s, 1H); 4.2 (s, 2H); 4.1 (s, 3H).

Description 105. Ethyl-1-methyl-6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate (D105)

Zinc powder (1.4 g) was added to a mixture of ethyl nitro [5- (2-propen-1-yl) -2-quinolinyl] acetate (D89) (1 g) and glacial acetic acid (25 ml). The reaction mixture was stirred at room temperature for 2 hours and then filtered. Triethylorthoacetate (10 ml) was added to 14 ml of the filtered solution and heated with stirring at 150 ° C for 7 minutes under the influence of microwave radiation (Personal Chemistry EmrysTM Optimiser, 300 W). The resulting reaction mixture was evaporated in vacuo, and then the residue was purified on an SPE-Si cartridge, eluting with a mixture of 50% ethyl acetate in cyclohexane to give the title compound as a pale yellow solid (210 mg). MS (ES) m / z: 295.1 [MH] ⁺ . C ₁₈ H ₁₈ N ₂ O ₂ requires 294.4.

Description 106. Ethyl 1-methyl-6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D106)

To a solution of ethyl 1-methyl-6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate (D105) (205 mg, 0.7 mmol) in a THF / water mixture ( 2: 1, 6 ml) osmium tetroxide (0.5 ml of a 4 wt.% Solution in water) is added with stirring. After 10 minutes, sodium periodate (372 mg, 1.74 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3 × 15 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with a mixture of 30% cyclohexane in ethyl acetate to give the title compound as a white solid (90 mg, 43%). MS (ES) m / z: 297.2 [MH] ⁺ . C ₁₇ H ₁₆ N ₂ O ₃ requires 296.3.

Description 107. 5-Bromo-6-methylquinoline (D107)

The title compound was obtained in 86% yield following the procedure described in Chem. Heterocycl. Compd (Engl. Transl.), 1988, vol. 24 (8), 892. MS (ES) m / z: 222.0 [MH ⁺ ]. C ₁₀ H ₈ BrN requires 221.08.

Description 108. 6-Methyl-5- (2-propen-1-yl) quinoline (D108)

To a solution of 5-bromo-6-methylquinoline (D107) (5.6 g, 25.2 mmol) in dry toluene (40 ml), allylbutyl stannane (8.5 ml, 27.7 mmol) and tetrakis (triphenylphosphine) are added at room temperature ) palladium (0) (1.4 g, 5%). The reaction mixture was stirred at 125 ° C for 5 hours, then cooled, quenched with water (40 ml) and the mixture was extracted with DCM (3 × 100 ml). The organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude reaction product, which was purified on a SPE-Si cartridge eluting with cyclohexane / ethyl acetate (15: 5) to give the title compound (3.74 g, 81%). MS (ES) m / z: 184.10 [MH ⁺ ]. C ₁₃ H ₁₃ N requires 183.25.

Description 109. 6-Methyl-5- (2-propen-1-yl) quinoline (D109)

The title compound was obtained in 82% yield according to the procedure used to prepare the compound in description 88, starting from 6-methyl-5- (2-propen-1-yl) quinoline (D108). MS (ES / +) m / z: 200.1 [MH ⁺ ]. C ₁₃ H ₁₃ NO requires 199.25.

Description 110. Ethyl [6-methyl-5- (2-propen-1-yl) -2-quinolinyl] (nitro) acetate (D110)

The title compound was obtained in 36% yield according to the synthesis procedure used to prepare the compound in description 89, starting from 6-methyl-5- (2-propen-1-yl) quinoline (D109). The crude material is purified on an SPE-Si cartridge, eluting with a mixture of 0.5% MeOH in DCM. MS (ES / +) m / z: 315.0 [MH ⁺ ]. C ₁₇ H ₁₈ N ₂ O ₄ requires 314.34.

Description 111. Ethyl-7-methyl-6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate (D111)

To an ice-cooled suspension of ethyl [6-methyl-5- (2-propen-1-yl) quinolinyl] (nitro) acetate (D110) (300 mg, 0.95 mmol) in glacial acetic acid (4 ml) was added parts zinc (374 mg, 5.7 mmol). After adding zinc, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The zinc is filtered off and washed with water (30 ml). The solution was poured into a 1 M EDTA solution (50 ml) and made basic to pH 8 with a 1 M NaOH solution. Then the whole solution was adjusted to pH 6 and extracted with EtOAc (2 × 30 ml). The combined organic phases are washed with 1 M NaOH solution (40 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The intermediate ethylamino [6-methyl-5- (2-propen-1-yl) -2-quinolinyl] acetate is quickly treated with triethylorthoformate (4 ml) and heated with stirring at 150 ° C for 10 minutes under the influence of microwave radiation. The light yellow solid precipitated from the reaction mixture was collected by filtration and washed with ether to give 80 mg of the title compound as a pale yellow solid. The filtrate was passed through an SCX cartridge to remove triethyl orthoformate and then purified on an SPE-Si cartridge, eluting with a mixture of 20% ethyl acetate in cyclohexane to give the title compound (100 mg, 35.8%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.5 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 7 6 (d, 1H), 7.3 (d, 1H), 6.1-5.9 (m, 1H), 5.1 (d, 1H), 4.8 (d, 1H), 4, 45 (q, 2H), 3.8 (d, 2H), 2.45 (s, 3H), 1.4 (t, 3H).

Description 112. Ethyl-7-methyl-6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D112)

The title compound is prepared according to the synthesis procedure used to prepare the compound in Description 91, starting from ethyl 7-methyl-6- (2-propen-1-yl) imidazo [1,5-a] quinoline-3-carboxylate ( D111). The crude material is purified on an SPE-Si cartridge, eluting with mixtures of 50-100% ethyl acetate in cyclohexane to give the title compound in 75% yield. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.85 (s, 1H), 8.65 (s, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7 5 (d, 1H), 7.4 (d, 1H), 4.5 (q, 2H), 4.2 (s, 2H), 2.5 (s, 3H), 1.4 (t, 3H).

Description 113. (2Z) -3- (Dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5,1-c ] [1,4] benzoxazin-3-yl) -2-buten-1-one (D113)

1- (6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3-yl) ethanone (free base E114) (75.01 mg, 0.16 mmol) are suspended in N, N-dimethylacetamide dimethyl acetal (1.50 ml) and heated with stirring at 150 ° C under the influence of microwave radiation for 5 minutes. Then for another 5 minutes. The precipitate was filtered off from the reaction mixture and washed with diethyl ether to obtain the title compound (7.30 mg, 0.10 mmol, 63% yield) as a yellow solid. MS (ES) m / z: 536.3 [MH ⁺ ]. C ₃₃ H ₃₇ N ₅ O ₂ requires 535.69.

Description 114. 2- (5-Methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl trifluoromethanesulfonate (D114)

1,1,1-Trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide (2.54 g, 7.11 mmol) is added portionwise with stirring to an ice-cooled suspension of 2- (5-methyl-1 , 3,4-oxadiazol-2-yl) -1-benzofuran-4-ol (WO 2000071517) (1.28 g, 5.92 mmol) and triethylamine (1.10 ml, 7.89 mmol) in dry CH ₃ CN (40 ml). The reaction mixture was stirred overnight at room temperature, then the reaction was quenched with water (30 ml) and the mixture was extracted with EtOAc (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction mixture was purified on Horizon-Si, eluting with a mixture of 30% EtOAc in c-hexane to give the title compound (1.60 g, 4.60 mmol, 78% yield) as a white solid. MS (ES) m / z: 349.1 [MH ⁺ ]. C ₁₂ H ₇ F ₃ N ₂ O ₅ S requires 348.26.

Description 115. 1,1-Dimethylethyl-4- [2- (5-methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl] -1-piperazinecarboxylate (D115)

A mixture of 2- (5-methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl trifluoromethanesulfonate (D114) (1.31 g, 3.76 mmol), Cs ₂ CO ₃ (1, 84 g, 5.64 mmol), Pd (OAc) ₂ (84.41 g, 0.38 mmol), (+/-) - BINAP (0.35 g, 0.56 mmol) and N-Boc-piperazine (0.91 g, 4.88 mmol) in dry toluene (40 ml) was stirred at 100 ° C for 4 hours. After cooling to room temperature, an aqueous saturated solution of NH ₄ Cl (30 ml) was added and the mixture was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified on Biotage-Si, eluting with a cyclohexane / ethyl acetate 70/30 mixture to give the title compound (0.94 g, 2.44 mmol, 65% yield) as a yellow oil. ¹ H-NMR (300 MHz, DMSO) δ: 7.8 (s, 1H), 7.4 (m, 2H), 7.8 (d, 1H), 3.5-3.4 (br.m , 4H), 3.3 (s, 3H), 3.2-3.1 (br.m, 4H), 1.4 (s, 9H).

Description 116. 1- [2- (5-Methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl] piperazine (D116)

A solution of 1,1-dimethylethyl-4- [2- (5-methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl] -1-piperazinecarboxylate (D115) (0.83 g , 2.16 mmol) in a mixture of TFA / THF (1: 3, 12 ml) was stirred at room temperature overnight. After evaporation, the crude material is purified on an SCX cartridge (eluting with methanol and then with 2 N ammonia in methanol) to give the title compound (0.77 g, yield 92%) as a yellow solid. MS (ES; m / z): 285.1 [MH ⁺ ]. C ₁₅ H ₁₆ N ₄ O ₂ requires 284.32.

Description 117. Ethyl 2- [8- (2-propen-1-yl) -2H-1,4-benzoxazin-3-yl] hydrazinecarboxylate (D117)

A mixture of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -thione (D18) (1 mmol, 203 mg) and ethyl carbazate (3 mmol, 312 mg) in anhydrous ethanol ( 4 ml) was refluxed for 4.5 hours. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and treated with ethyl ether. The title compound was obtained in 75% yield (210 mg). MS (ES) m / z: 276.2 [MH ⁺ ]. C ₁₄ H ₁₇ N ₃ O ₃ requires 275.3.

Description 118. 6- (2-Propen-1-yl) -2,4-dihydro-1H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-1-one (D118 )

A solution of ethyl 2- [8- (2-propen-1-yl) -2H-1,4-benzoxazin-3-yl] hydrazinecarboxylate (D117) (80 mg, 0.291 mmol) in DMF (1 ml) is heated with stirring at 200ºС for 10 minutes under the influence of microwave radiation. The solution was concentrated, the resulting solid was treated with diethyl ether to give the title compound (50 mg, 74%). MS (ES) m / z: 230.0 [MH ⁺ ]. C ₁₂ H ₁₁ N ₃ O ₂ requires 229.2.

Description 119. 2-Methyl-6- (2-propen-1-yl) -2,4-dihydro-1H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-1 -one (D119)

To a solution of 6- (2-propen-1-yl) -2,4-dihydro-1H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-1-one (D118) (60 mg, 0.26 mmol) and iodomethane (20 μl, 0.31 mmol) in dry DMF (3 ml) at 0 ° C add sodium hydride (15 mg 60% w / w, suspension in mineral oil, 0, 37 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, then the reaction was quenched with water (5 ml) and the mixture was extracted with DCM (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (66 mg), which can be used in the next step without further purification. MS (ES) m / z: 244.0 [MH ⁺ ]. C ₁₃ H ₁₃ N ₃ O ₂ requires 243.2.

Description 120. (2-Methyl-1-oxo-2,4-dihydro-1H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-6-yl) acetaldehyde (D120)

The title compound was prepared according to the procedure for Description 6, starting from 2-methyl-6- (2-propen-1-yl) -2,4-dihydro-1H- [1,2,4] triazolo [3,4-c ] [1,4] benzoxazin-1-one (D119) (64 mg, 0.26 mmol). The crude reaction product is used in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.77 (s, 1H), 8.24 (m, 1H), 7.14 (m, 1H), 7.05 (m, 1H), 5 03 (s, 2H); 3.78 (s, 2H); 3.54 (s, 3H).

Description 121. 7-Methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D121)

The title compound was obtained in 92% yield following the general procedure of Example 1, starting from (7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl) acetaldehyde (D79) ( 100 mg, 0.488 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (165 mg, 0.732 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a gradient of methanol mixtures in DCM (2-3%) to give the title compound (186 mg, 92%). MS (ES) m / z: 416.10 [MH ⁺ ]. C ₂₆ H ₂₉ N ₃ O ₂ requires 415.53.

Description 122. 6-Methyl-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl trifluoromethanesulfonate (D122)

The title compound was prepared following the procedure for Description 71, starting from 5-hydroxy-6-methyl-3,4-dihydro-2 (1H) -quinolinone [see Organic Preparations and Procedures International, 25 (2), 223-8, 1993] (2.0 g, 11.3 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (7/3) to give the title compound (3.9 g). MS (ES) m / z: 310.00 [MH ⁺ ]. C ₁₁ H ₁₀ F ₃ NO ₄ S requires 309.26.

Description 123. 6-Methyl-5- (2-propen-1-yl) -3,4-dihydro-2 (1H) -quinolinone (D123)

The title compound was prepared following the procedure for Description 72 from 6-methyl-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl trifluoromethanesulfonate (D122) (3.5 g, 11.3 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (7/3) and diethyl ether to give the title compound (1.97 g, 85%). MS (ES) m / z: 202.10 [MH ⁺ ]. C ₁₃ H ₁₅ NO requires 201.27.

Description 124. Ethyl-7-methyl-6- (2-propen-1-yl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D124)

The title compound was prepared following the procedure of Example 80 using 6-methyl-5- (2-propen-1-yl) -3,4-dihydro-2 (1H) -quinolinone (D123) (700 mg, 3, 48 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/1) to give the title compound (863 mg, 84%). MS (ES) m / z: 297.10 [MH ⁺ ]. C ₁₈ H ₂₀ N ₂ O ₂ requires 296.37.

Description 125. Ethyl-7-methyl-6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D125)

The title compound was prepared following the procedure in the preparation of D6 using ethyl 7-methyl-6- (2-propen-1-yl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D124) (863 mg, 2.92 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate to give the title compound (602 mg, 69%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: ppm 1.43 (t, 3H), 2.35 (s, 3H), 2.85 (t, 2H), 3.32 (t, 2H), 3.91 (s, 2H), 4.40 (q , 2H), 7.22 (d, 1H), 7.36 (d, 1H), 8.02 (s, 1H), 9.78 (s, 1H).

Description 126. 6- (2-Propen-1-yl) -4H-tetrazolo [5.1-s] [1.4] benzoxazine (D126)

A solution of hydrazine hydrate (380 μl, 12.2 mmol) in dry THF (2 ml) was treated at 20 ° C, adding a solution of 8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) dropwise thione (D18) (500 mg, 2.44 mmol) in THF (25 ml). After stirring for 1.5 hours, the solvent was removed under reduced pressure to obtain an intermediate hydrazone, which was used in the next step without further purification. A solution of sodium nitrite (252 mg, 3.66 mmol) in water (2 ml) is added dropwise to a suspension of hydrazone (495 mg, 2.44 mmol) in 0.5 N HCl (15 ml) at 5 ° C. After stirring for 4 hours, the mixture was neutralized with saturated NaHCO ₃ solution and extracted with DCM (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (2/8) to give the title compound (235 mg, 45%). MS (ES) m / z: 215.10 [MH ⁺ ]. C ₁₁ H ₁₀ N ₄ O requires 214.23.

Description 127. 5- (2-Propen-1-yl) -3,4-dihydro-2 (1H) -quinolinthione (D127)

The title compound was prepared following the procedure for Description 18 using 5- (2-propen-1-yl) -3,4-dihydro-2 (1H) quinolinone (D72) (404 mg, 2.16 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (4/6) to give the title compound (290 mg, 66%). MS (ES) m / z: 204.10 [MH ⁺ ]. C ₁₂ H ₁₃ NS requires 203.31.

Description 128. 6- (2-Propen-1-yl) -4,5-dihydrotetrazolo [1,5-a] quinoline (D128)

The title compound was prepared following the procedure for Description 126, starting from 5- (2-propen-1-yl) -3,4-dihydro-2 (1H) -quinolinethione (D127) (290 mg, 1.43 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (3/7) to give the title compound D128 (225 mg, 74%). MS (ES) m / z: 213.10 [MH ⁺ ]. C ₁₂ H ₁₂ N ₄ requires 212.25.

Description 129. 4H-Tetrazolo [5.1-c] [1.4] benzoxazin-6-yl-acetaldehyde (D129)

The title compound was prepared following the procedure for describing the preparation of D6 using 6- (2-propen-1-yl) -4H-tetrazolo [5,1-a] quinoline (D126) (235 mg, 1.09 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (4/6) to give the title compound (144 mg, 61%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm 3.77 (s, 2H); 5.56 (s, 2H); 7.14 (d, 2H); 7.90 (t, 1H); 9.72 (s, 1H).

Description 130. 4,5-Dihydrotetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D130)

The title compound was prepared following the procedure for Description 6 using 6- (2-propen-1-yl) -4,5-dihydrotetrazolo [1,5-a] quinoline (D128) (225 mg, 1.06 mmol) . The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (4 / 6-10 / 0) mixtures to give the title compound (132 mg, 58%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm 2.95 (t, 2H), 3.27 (t, 2H), 3.82 (s, 2H), 7.19 (m, 1H), 7.38 (t, 1H), 7.97 (d , 1H); 9.72 (s, 1H).

Description 131. 2- (Methylthio) -5- (2-propen-1-yl) -3,4-dihydroquinoline (D131)

The title compound was prepared following the procedure for Description 19 using 5- (2-propen-1-yl) -3,4-dihydro-2 (1H) -quinolithione (D127) (150 mg, 0.74 mmol). The crude reaction product is used in the next step without further purification. MS (ES) m / z: 218.10 [MH ⁺ ]. C ₁₃ H ₁₅ NS requires 217.33.

Description 132. Ethyl (2E / Z) -nitro [8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -ilidene] ethanoate (D132)

To a mixture of 3- (methylthio) -8- (2-propen-1-yl) -2H-1,4-benzoxazine (D19) (441 mg, 2.01 mmol) and ethyl nitroacetal (2.23 ml, 20.1 mmol) at room temperature and in a nitrogen atmosphere add triton-B (40% solution in methanol, 841 μl, 2.01 mmol). The reaction mixture was heated at 50 ° C for 2 hours, then the reaction was quenched with water (10 ml), and the mixture was extracted with DCM (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude reaction product which was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/9) to give the title compound (411 mg, 67 %) as a mixture of E / Z isomers. MS (ES) m / z: 305.10 [MH ⁺ ]. C ₁₅ H ₁₆ N ₂ O ₅ requires 304.30.

Description 133. Ethyl (2E / Z) -nitro [5- (2-propen-1-yl) -3,4-dihydro-2 (1H) quinolinylidene] ethanoate (D133)

The title compound was prepared following the procedure for Description 132 using 2- (methylthio) -5- (2-propen-1-yl) -3,4-dihydroquinoline (D131) (261 mg, 1.20 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1/9) to give the title compound (264 mg, 73%) as a mixture of E / Z isomers. MS (ES) m / z: 303.20 [MH ⁺ ]. C ₁₆ H ₁₈ N ₂ O ₄ requires 302.33.

Description 134. Ethyl 6- (2-propen-1-yl) -4H- [1,2,3] triazolo [5,1-c] benzoxazine-3-carboxylate (D134)

To a solution of ethyl (2E / Z) -nitro [8- (2-propen-1-yl) -2H-1,4-benzoxazin-3 (4H) -ilidene] ethanoate (D132) (280 mg, 0.921 mmol) in glacial acetic acid (3 ml) at 0 ° C, zinc (356 mg, 5.53 mmol) is added. The reaction mixture was warmed to room temperature and stirred for 45 minutes, then cooled to 5 ° C, and trichloroacetic acid (30 mg, 0.184 mmol) and amyl nitrite (151 mg, 1.28 mmol) were added. The reaction mixture was warmed to room temperature and stirred for another 1.5 hours, then the reaction was quenched with water (10 ml), and the mixture was extracted with DCM (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude reaction product, which was first purified on an SCX cartridge and then flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (2/8) gave the title the title compound (154 mg, 58%). MS (ES) m / z: 286.00 [MH ⁺ ]. C ₁₅ H ₁₅ N ₃ O ₃ requires 285.30.

Description 135. Ethyl 6- (2-propen-1-yl) -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D135)

The title compound was prepared following the procedure for Description 134 using ethyl (2E / Z) -nitro [5- (2-propen-1-yl) -3,4-dihydro-2 (1H) quinolinylidene] ethanoate (D133 ) (200 mg, 0.662 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (2/8) to give the title compound (97 mg, 52%). MS (ES) m / z: 284.00 [MH ⁺ ]. C ₁₆ H ₁₇ N ₃ O ₂ requires 283.33.

Description 136. Ethyl 6- (2-oxoethyl) -4H- [1,2,3] triazolo [5,1-s] [1,4] benzoxazine-3-carboxylate (D136)

The title compound was prepared following the procedure for Description 6 using ethyl 6- (2-propen-1-yl) -4H- [1,2,3] triazolo [5,1-c] [1,4] benzoxazine -3-carboxylate (D134) (154 mg, 0.540 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (2/8) to give the title compound (96 mg, 62%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm 1.37 (t, 3H), 3.76 (s, 2H), 4.40 (q, 2H), 5.57 (s, 2H), 7.12 (m, 2H), 8.01 (m , 1H); 9.72 (s, 1H).

Description 137. Ethyl 6- (2-oxoethyl) -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D137)

The title compound was prepared following the procedure for describing the preparation of D6 using ethyl 6- (2-propen-1-yl) -4,5-dihydro [1,2,3] triazolo [1,5-a] quinolin- 3-carboxylate (D135) (97 mg, 0.343 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (2 / 8-4 / 6) mixtures to give the title compound (71 mg, 73%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm 1.40 (t, 3H), 2.87 (t, 2H), 3.33 (t, 2H), 3.83 (s, 2H), 4.41 (q, 2H), 7.18 (m , 1H), 7.38 (t, 1H), 8.12 (d, 1H), 9.73 (s, 1H).

Description 138. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carbaldehyde (D138 )

To a solution of N-methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1, 4] benzoxazine-3-carboxamide (E25) (120 mg, 0.234 mmol) in dry THF (1 ml), cooled to 0 ° C, LiAlH ₄ (0.117 ml of a 1 M solution in THF, 0.117 mmol) was added with stirring, and the resulting mixture stirred for 1 hour at 0 ° C. The reaction was quenched with water and then the reaction mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, and the resulting crude oil was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 2% methanol in DCM to give the title compound as a white solid ( 77 mg, 75%). MS (ES) m / z: 454.4 [MH ⁺ ]. C ₂₇ H ₂₇ N ₅ O ₃ requires 453.54.

Description 139. (2Z) -3- (Dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c ] [1,4] benzoxazin-3-yl) -2-buten-1-one (D139)

The free base of 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- hydrochloride il) ethanone (E35) (85 mg, 0.182 mmol) is suspended in N, N-dimethylacetamide dimethyl acetal and the mixture is exposed in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 ° C, 5 min + 5 min). The creamy solid which precipitated from the reaction mixture was collected by filtration and treated with ethyl ether, to give the title compound (67 mg, 69%). MS (ES) m / z: 537.3 [MH ⁺ ]. C ₃₂ H ₃₆ N ₆ O ₂ requires 536.68.

Description 140. 1,1-Dimethylethyl-4-hydroxy-4- (5-quinolinyl) -1-piperidinecarboxylate (D140)

5-Bromoquinoline (2 g, 0.0096 mol) in an atmosphere of N ₂ at -70 ° C is added with stirring to a solution of n-BuLi (12 ml of a 1.6 M solution in hexane, 0.0192 mmol) in 20 ml of a mixture of dry THF: diethyl ether (1: 1). The reaction mixture was stirred for 30 minutes, then a solution of 1,1-dimethylethyl-4-oxo-1-piperidinecarboxylate (1.9 g, 0.0095 mol) in THF (20 ml) was added and the reaction mixture was stirred for another 30 minutes. The reaction mixture was heated to 0 ° C, then the reaction was quenched with water and the mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 2 g of a crude substance. The resulting mixture was purified on a Horizon column (40 M), eluting with a mixture of 10% ethyl acetate in cyclohexane to give the title compound as a cream solid (1.9 g, 60%). MS (ES) m / z: 329.2 [MH ⁺ ]. C ₁₉ H ₂₄ N ₂ O ₃ requires 328.41.

Description 141. 1,1-Dimethylethyl-4-fluoro-4- (5-quinolinyl) -1-piperidinecarboxylate (D141)

1,1-Dimethylethyl-4-hydroxy-4- (5-quinolinyl) -1-piperidinecarboxylate (D140) (100 mg, 0.3 mmol) dissolved in dry DCM (3 ml) was added at -78 ° C with stirring to a solution of DEOXOFLUOR (0.144 ml of a 50% solution in THF, 0.335 mmol) in dry DCM (3 ml). The reaction mixture was stirred for 2 hours at -78 ° C and then for 1 hour at room temperature. The reaction was quenched with saturated NH ₄ Cl solution and the reaction mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a crude material. The resulting mixture was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 2% methanol in DCM to give the title compound as a white foam (85 mg, 83%). MS (ES) m / z: 331.2 [MH ⁺ ]. C ₁₉ H ₂₃ FN ₂ O ₂ requires 330.4.

Description 142. 5- (4-Fluoro-4-piperidinyl) quinoline (D142)

1,1-Dimethylethyl-4-fluoro-4- (5-quinolinyl) -1-piperidinecarboxylate (D141) (170 mg, 0.51 mmol) was dissolved in TFA / DCM (3: 1, 6.2 ml) and stirred overnight at room temperature. The solvent was evaporated in vacuo and the crude mixture was purified on an SPE-SCX cartridge (2 g) (eluting with methanol, then 2 N ammonia in methanol) to give the title compound as a white solid (90 mg, 76%). MS (ES) m / z: 231.1 [MH ⁺ ]. C ₁₄ H ₁₅ FN ₂ requires 230.28.

Description 143. 2- (Difluoromethyl) -5- (1-piperazinyl) quinoline (D143)

A solution of 1,1-dimethylethyl-4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinecarboxylate (D100) (886 mg, 2.438 mmol) in a TFA / DCM mixture (10 ml, 1: 1) was stirred at room temperature temperature during the night. After evaporation, the crude material was purified by extraction on SCX to give the title compound (616 mg, 96%) as a yellow solid. MS (ES) m / z: 264 [MH ⁺ ]. C ₁₄ H ₁₅ F ₂ N ₃ requires 263.29. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.65 (d, 1H), 7.80 (d, 1H), 7.66 (m, 2H), 7.17 (d, 1H), 6 74 (t, 1H); 3.1 (m, 9H).

Description 144. 1,1-Dimethylethyl-4- [2- (hydroxymethyl) -5-quinolinyl] -1-piperazinecarboxylate (D144)

A solution of 1,1-dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D68) (1.505 g, 4.41 mmol) and sodium borohydride (834 mg, 22.05 mmol) in ethanol (20 ml) was stirred for 5 hours at room temperature. The mixture was evaporated in vacuo and the residue was dissolved in water (100 ml). The suspension was extracted with DCM (3 × 100 ml) and the extract was washed with brine (100 ml). The organic layer was dried (MgSO ₄ ) and evaporated to give the title compound (1.515 g, quant.). MS (ES) m / z: 344 [MH ⁺ ]. C ₁₉ H ₂₅ N ₃ O ₃ requires 343.42. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.4 (m, 1H), 7.7 (m, 1H), 7.6 (m, 1H), 7.2 (m, 1H), 7 , 1 (m, 1H), 4.9 (m, 2H), 4.4 (s, 1H), 3.7 (br.m, 4H), 3.0 (br.m, 4H), 1, 4 (s, 9H).

Description 145. 1,1-Dimethylethyl-4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazinecarboxylate (D145)

DAST (636 μl, 782 mg, 4.852 mmol) was added to a cooled (-78 ° C) solution of 1,1-dimethylethyl-4- [2- (hydroxymethyl) -5-quinolinyl] -1-piperazinecarboxylate (D144) (1.515 g, 4 , 41 mmol) in DCM (20 ml). After 1.5 hours, additional DAST (289 μl, 355 mg, 2.20 mmol) was added and stirring was continued for another 3 hours while the reaction mixture was warmed to room temperature. The reaction was quenched with water (100 ml) and the mixture was extracted with DCM (100 ml). The organic layer was dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified by flash column chromatography (cyclohexane: EtOAc, 9: 1-8: 2) to give the title compound (1.087 g, 71%) as a yellow solid. MS (ES) m / z: 346 [MH ⁺ ]. C ₁₉ H ₂₄ FN ₃ O ₂ requires 345.42. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.56 (d, 1H), 7.74 (d, 1H), 7.6 (m, 2H), 7.09 (d, 1H), 5 62 (d, 2H), 3.68 (br.m, 4H), 3.0 (br.m, 4H), 1.48 (s, 9H).

Description 146. 2- (Fluoromethyl) -5- (1-piperazinyl) quinoline (D146)

A solution of 1,1-dimethylethyl-4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazine carboxylate (D145) (1.087 g, 3.147 mmol) in a TFA / DCM mixture (15 ml, 1: 2) was stirred at room temperature temperature during the night. After evaporation, the crude material was purified by extraction on SCX to give the title compound (725 mg, 94%) as a yellow solid. MS (ES) m / z: 246 [MH ⁺ ]. C ₁₄ H ₁₆ FN ₃ requires 245.30. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.56 (d, 1H), 7.72 (d, 1H), 7.6 (m, 2H), 7.10 (d, 1H), 5 62 (d, 2H); 3.1 (br.m, 9H).

Description 147. 5- (4 - {[(1,1-Dimethylethyl) oxy] carbonyl} -1-piperazinyl) -2-quinolinecarboxylic acid (D147)

1,1-Dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D68) (1.0 g, 2.93 mmol, 1 equiv.) Was dissolved in DMSO (12 ml) and the mixture was cooled to 5ºС. A buffer solution (3 ml; pH 3, citric acid / sodium hydroxide / hydrochloric acid) is added. To the resulting yellow suspension at 5 ° C, a 1 M aqueous solution of NaClO ₂ (4 ml, 1.36 equiv.) Was added dropwise over 1 hour. Then the mixture is stirred at 25 ° C for 1 hour. TLC analysis shows an incomplete reaction. Another 1 M aqueous solution of NaClO ₂ (12 ml) and DMSO (2 ml) were added dropwise. After stirring for 1 hour at 25 ° C, the mixture was diluted with water (10 ml) and extracted with AcOEt (2 × 10 ml). The organic layer was dried (Na ₂ SO ₄ ), evaporated and the residue was chromatographed on silica gel (230-400 mesh) eluting with DCM / methanol 9/1 to give the title compound (0.876 g, 83%) as yellow oils. C ₁₉ H ₂₃ N ₃ O ₄ requires 357.41. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.62 (d, 1H), 8.06 (d, 1H), 7.85 (d, 1H), 7.69 (t, 1H), 7 25 (d, 1H), 3.59 (br.m, 4H), 2.98 (br.m, 4H), 1.43 (s, 9H).

Description 148. 1,1-Dimethylethyl-4- {2 - [(dimethylamino) carbonyl} -5-quinolinyl} -1-piperazinecarboxylate (D148)

Solution 5- (4 - {[((1,1-dimethylethyl) oxy] carbonyl} -1-piperazinyl) -2-quinolinecarboxylic acid (D147) (219 mg, 0.753 mmol), EDC × HCl (216 mg, 1.129 mmol) , HOBt (173 mg, 1.129 mmol) and dimethylamine (2.0 M solution in THF, 1.88 ml, 3.765 mmol) in dry DMF (5 ml) were stirred at room temperature for 20 hours. The reaction mixture was diluted with DCM (20 ml) and washed with saturated NaHCO ₃ solution (20 ml). The organic layer was dried (MgSO ₄ ) and evaporated in vacuo to give the title compound (171 mg, 75%). The product can be used crude in the next step.

Description 149. 1,1-Dimethylethyl-4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinecarboxylate (D149)

The title compound (296 mg, 87%) was obtained by the 148 procedure using 5- (4 - {[(1,1-dimethylethyl) oxy] carbonyl} -1-piperazinyl) -2-quinolinecarboxylic acid (D147) (376 mg, 1.052 mmol) and methylamine (2.0 M / THF). The title compound was used in the next step without further purification.

Description 150. N, N-Dimethyl-5- (1-piperazinyl) 2-quinolinecarboxamide (D150)

A solution of 1,1-dimethylethyl-4- {2 - [(dimethylamino) carbonyl] -5-quinolinyl} -1-piperazinecarboxylate (D148) (171 mg, 0.444 mmol) in a mixture of DCM with 10% TFA contained therein (5 ml ) stirred at room temperature overnight. After evaporation, the crude material was purified by extraction on SCX to give the title compound (102 mg, 81%). MS (ES; m / z): 285 [MH ⁺ ]. C ₁₆ H ₂₀ N ₄ O requires 284.36.

Description 151. N-Methyl-5- (1-piperazinyl) -2-quinolinecarboxamide (D151)

A solution of 1,1-dimethylethyl-4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinecarboxylate (D149) (296 mg, 0.770 mmol) in a mixture of DCM with 10% TFA contained therein (5 ml ) stirred at room temperature overnight. After evaporation, the crude material is purified by extraction on SCX to give the title reaction product (96 mg, 46%). MS (ES; m / z): 271 [MH ⁺ ]. C ₁₅ H ₁₈ N ₄ O requires 270.33.

Descriptions 152 and 153. 2-Methyl-2 - [(1S) -1-phenylethyl] -4-piperidinone (D152 and D153)

The title compounds D152 and D153 were prepared according to the experimental procedure described in WO2004 / 094380. The crude mixture was purified on a Biotage column (65M), eluting with a mixture of 15% ethyl acetate in cyclohexane to give the diastereoisomers D152 and D153 as pale yellow oils. Diastereoisomer 1 (D152): ¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.15 (d, J = 5.86 Hz, 3H), 1.34 (d, J = 6.83 Hz, 3H), 2.16-2.39 (m, 3H), 2.60-2 80 (m, 3H), 3.35-3.42 (m, 1H), 4.02 (q, 1H), 7.24-7.28 (m, 1H), 7.34 (t, 2H) ), 7.45 (d, J = 6.83 Hz, 2H); Diastereoisomer 2 (D153): ¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J = 6.83 Hz, 3H), 1.43 (d, J = 6.83 Hz, 3H), 2.10-2.12 (m, 1H), 2.29-2 36 (m, J = 12.69 Hz, 1H), 2.51-2.60 (m, 2H), 2.92-3.00 (m, 2H), 3.14-3.20 (m , 1H); 3.92 (q, 1H); 7.24-7.29 (m, 1H); 7.31-7.38 (m, 4H).

Description 154. Acetate of 2-methyl-4-piperidinone (D154)

2-Methyl-1 - [(1S) -1-phenylethyl] -4-piperidinone (diastereomer 1) (D152) (18 g, 0.083 mol) was dissolved in acetic acid (90 ml) in a nitrogen atmosphere in a hydrogenation flask. 10% Pd / C (900 mg, 5%, w / w) was added, and the reaction mixture was vigorously stirred in a Parr apparatus at a pressure of H ₂ 4 atm for 2 days. The catalyst was filtered off, the solution was evaporated in vacuo to give the title salt of acetate as a pale yellow oil (14 g, 97%). MS (ES) m / z: 114.1 [MH ⁺ ]. C ₆ H ₁₁ NO requires 113.16.

Description 155. 2-Methyl-4-piperidinone acetate (D155)

The title compound was prepared in 100% yield according to the experimental production procedure described in 154, starting from 2-methyl-2 - [(1S) -1-phenylethyl] -4-piperidinone (diastereomer 2) (D153). MS (ES) m / z: 114.1 [MH ⁺ ]. C ₆ H ₁₁ NO requires 113.16.

Description 156. 1,1-Dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D156)

To a solution of 2-methyl-4-piperidinone acetate (D154) (14 g, 0.081 mol) in a 1 M NaOH solution (30 ml) was added di-tert-butyl carbonate (18 g, 0.081 mol) and the reaction mixture was stirred overnight at 20ºС. The reaction mixture was diluted with ethyl acetate (50 ml) and extracted several times (50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a crude oil, which was purified on a silica layer eluting with a mixture of 11% ethyl acetate in cyclohexane to give the title compound (6.95 g, 40%) as a pale yellow oil. MS (ES) m / z: 214.1 [MH ⁺ ]. C ₁₁ H ₁₉ NO ₃ requires 213.28.

Description 157. 1,1-Dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D157)

The title compound was prepared according to the experimental production procedure in Description 56, starting from 2-methyl-4-piperidinone acetate (D155). MS (ES) m / z: 214.1 [MH ⁺ ]. C ₁₁ H ₁₉ NO ₃ requires 213.28.

Description 158. 1,1-Dimethylethyl-2-methyl-4 - {[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydro-1 (2H) -pyridinecarboxylate (D158)

To a solution of 1,1-dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D156) (6.95 g, 0.0325 mol) in dry THF (60 ml), LiHDMS is added under cooling at -78 ° C (35, 8 μl of a 1 M solution in hexane, 0.0358 mol), and then a solution of 1,1,1-trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide (11.5 g, 0.0325) is added dropwise. mol) in THF (60 ml). After 30 minutes at -78 ° C, the reaction mixture was warmed to room temperature and then stirred for 4 hours. A saturated solution of NH ₄ Cl (200 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 10 g of a crude substance. The resulting mixture was purified on a Horizon column (65M), eluting with a mixture of 3% ethyl acetate in cyclohexane to give a 1: 1 mixture of the regioisomers in the double bond as a cream solid. MS (ES) m / z: 246.1, 290.0, 346.0 [MH ⁺ ]. C ₁₂ H ₁₈ F ₃ NO ₅ S requires 345.3.

Description 159. 1,1-Dimethylethyl-6-methyl-4 - {[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydro-1 (2H) -pyridinecarboxylate (D159)

The title compound was prepared according to the experimental procedure for Description 158, starting from 1,1-dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D157). MS (ES) m / z: 246.1, 290.0, 346.0 [MH ⁺ ]. C ₁₂ H ₁₈ F ₃ NO ₅ S requires 345.3.

Description 160. 2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline (D160)

A mixture of 2-methyl-5-quinolinyl trifluoromethanesulfonate (preparation is described in WO 2004/046124 A1) (13.5 g, 0.046 mol), bis (pinacolato) dibor (13 g, 0.051 mol), complex [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (1.88 g, 0.0023 mol), 1,1'-bis (diphenylphosphino) ferrocene (1.27 g, 0.0023 mol) and potassium acetate (13.5 g, 0.138 mol) in dry 1,4-dioxane (120 ml) is heated overnight at 80 ° C. The solvent was evaporated to dryness and the crude material was purified on a Horizon column (65M), eluting with a mixture of 10% ethyl acetate in cyclohexane to give the title compound as a cream solid (10 g, 81%). MS (ES) m / z: 270.2 [MH ⁺ ]. C ₁₆ H ₂₀ BNO ₂ requires 269.15.

Description 161 (racemic mixture). 1,1-Dimethylethyl-6-methyl-4- (2-methyl-5-quinolinyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate (D161)

A mixture of regioisomers in the double bond of 1,1-dimethylethyl-2-methyl-4 - {[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydro-1 (2H) -pyridinecarboxylate (D158) (1.65 g, 4.778 mmol ), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline (D160) (1.35 g, 5.017 mmol), complex [1.1 'bis (diphenylphosphino) ferrocene] dichloropalladium (0.39 g, 0.4778 mol) and potassium acetate (2 g, 14.33 mmol) in dry DMF (100 ml) are heated at the boil under reflux for 4 hours. The solvent was evaporated to dryness and the crude material was purified on a Horizon column (40M), eluting with a linear gradient, starting with a mixture of 10% ethyl acetate in cyclohexane and a mixture of 30% ethyl acetate in cyclohexane to give the title compound as a cream solid (736 mg, 45%). MS (ES) m / z: 339.2 [MH ⁺ ]. C ₂₁ H ₂₆ N ₂ O ₂ requires 338.45.

Description 162 (racemic mixture of enantiomers). 1,1-Dimethylethyl-2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinecarboxylate (D162)

1,1-Dimethylethyl-6-methyl-4- (2-methyl-5-quinolinyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate (D161) (736 mg, 2.17 mmol) was dissolved in 95% ethanol (8.5 ml) in a hydrogenation flask. 10% Pd / C (84 mg) was added and the reaction mixture was vigorously stirred at atmospheric pressure of hydrogen for 9 days. The catalyst was filtered off and the solution was evaporated in vacuo. The crude material was purified on a Horizon column (40M) with linear gradient elution, starting with 100% cyclohexane and a mixture of 20% ethyl acetate in cyclohexane to give the title compound as a white solid (350 mg, 47%). MS (ES) m / z: 341.3 [MH ⁺ ]. C ₂₁ H ₂₈ N ₂ O ₂ requires 340.46.

Description 163 (racemic mixture of enantiomers). 2-Methyl-5- (2-methyl-4-piperidinyl) quinolinyl (D163)

1,1-Dimethylethyl-2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinecarboxylate (D162) (350 mg, 1.03 mmol) was dissolved in a mixture of TFA / DCM (3: 1, 3, 1 ml) and stirred overnight at room temperature. The solvent was evaporated in vacuo and the crude mixture was purified on an SPE-SCX cartridge (2 g) (eluting with methanol, then 2 N ammonia in methanol) to give the title compound as a white solid (212 mg, 86%). MS (ES) m / z: 241.2 [MH ⁺ ]. C ₁₆ H ₂₀ N ₂ requires 240.36.

Description 164. 1,1-Dimethylethyl-4- (2-methyl-5-quinolinyl) -1-piperazinecarboxylate (D164)

To a solution of 2-methyl-5- (1-piperazine) quinoline (3.00 g, 13.19 mmol) in dioxane (10 ml) and saturated aqueous NaHCO ₃ solution (10 ml) was added BOC ₂ O (3.17 g , 14.52 mmol) and stirred at room temperature overnight. Water was added and the reaction product was extracted with ethyl acetate (2 ×). The organic layer was dried (MgSO ₄ ), filtered and evaporated in vacuo to give the title compound (4.51 g, quant.). MS (ES) m / z: 328 [MH ⁺ ]. C ₁₉ H ₂₅ N ₃ O ₂ (327.43). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.36 (d, 1H), 7.72 (d, 1H), 7.56 (t, 1H), 7.26 (d, 1H), 7 02 (d, 1H), 3.68 (m, 4H), 3.00 (m, 4H), 2.72 (s, 3H), 1.48 (s, 9H).

Description 165. 1,1-Dimethylethyl-4- (2-formyl-5-quinolinyl) -1-piperazinecarboxylate (D165)

To a solution of intermediate 164 (4.51 g, 13.77 mmol) in dioxane (20 ml) was added SeO ₂ (1.83 g, 16.52 mmol). The mixture was stirred at 90 ° C for 1.5 hours, then cooled to room temperature and then filtered and evaporated. The residue was purified by flash column chromatography (cyclohexane: EtOAc, 9: 1-1: 1) to give the title compound (3.35 g, 71%) as a yellow solid. MS (ES) m / z: 342 [MH ⁺ ]. C ₁₉ H ₂₃ N ₃ O ₃ (341.41). ¹ H NMR (300 MHz, CDCl ₃ ) δ: 10.20 (s, 1H), 8.63 (d, 1H), 7.98 (q, 2H), 7.71 (t, 1H), 7, 21 (d, 1H), 3.69 (br s, 4H), 3.03 (br s, 4H), 1.48 (s, 9H).

Description 166. 2-Bromophenyl-2-propenyl ether (D166)

In a round bottom flask equipped with a refrigerator, o-bromophenol (500 g), acetone (5000 ml) and K ₂ CO ₃ (440 g) were charged. Allyl bromide (385 g) is then added dropwise (over 30 minutes). The mixture is heated at the boil under reflux for 2 hours. The reaction mixture was cooled and the solid was filtered. The solution was concentrated in vacuo to 1500 ml and then 5000 ml of cyclohexane was added. The solution was again concentrated to 1500 ml and then 5000 ml of cyclohexane was added. Finally, the mixture was concentrated to 1500 ml and 1500 ml of cyclohexane was added.

Description 167. 2-Bromo-6- (2-propen-1-yl) phenol

Et ₂ AlCl in hexanes (2885 ml) was added dropwise to the product of the reaction mixture of description 166, adjusting the temperature to below 30 ° C (internal temperature). The reaction is monitored by HPLC. Upon completion of the reaction, the reaction mixture was cooled to 5 ° C (internal temperature) and 1 N HCl (3000 ml) was added dropwise, controlling the onset of gas evolution (pH control). Water (50 ml) is then added dropwise. The phases are separated and the organic phase is extracted with cyclohexane (2500 ml). The solution was concentrated to 1500 ml in vacuo and then 5000 ml of THF were added. The solution is again concentrated to 1500 ml and then 5000 ml of THF are added. Finally, the mixture was concentrated to 3075 ml.

Description 168. (3-Bromo-2-hydroxyphenyl) acetaldehyde

A solution of sodium periodate (1537.5 g) in water (11375 ml) was obtained and stirred overnight. The solution is filtered. To a solution of 2-bromo-6- (2-propen-1-yl) phenol (D167) in THF was added water (920 ml) and then K ₂ OsO ₄ .2H ₂ O (1.18 g). The mixture was stirred at room temperature for 30 minutes. Then an aqueous solution of sodium periodate is added dropwise over 3 hours, adjusting the temperature so that the internal temperature remains below 20-25 ° C. The reaction is monitored by HPLC. Upon completion of the reaction, water (5000 ml) and DCM (4000 ml) were added to the reaction mixture. The mixture is stirred for 15 minutes. The phases are separated and the organic phase is washed with water (5000 ml). Si-thiol resin (28.5 g, heavy metal acceptor) was added to the organic phase, and the solution was refluxed for 2 hours. After cooling to room temperature, the solution is passed through a CUNO filter to remove metal contaminants. Then the solution is concentrated in vacuo to a volume of 2500 ml.

Description 169. 2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenol

Piperazine (314 g), DCM (2590 ml) and sodium triacetoxyborohydride (399.6 g) were charged to the reactor. The mixture is stirred for 15 minutes at room temperature (a thick solution forms). (3-Bromo-2-hydroxyphenyl) acetaldehyde (D168) in DCM (370 g in 2500 ml of DCM) was added dropwise to adjust the internal temperature. The reaction is monitored by HPLC. A 10% NaOH solution was added to the reaction mixture until the pH was alkaline (approximately 1110 ml) (pH was monitored using paper strips or a pH meter). Then the phases are separated, and the organic phase is washed with water (3700 ml). 3700 ml of THF are added to the organic phase, then the mixture is concentrated to 3700 ml at atmospheric pressure (T = 45-55 ° C). Then add 3700 ml of THF, and the mixture is again concentrated to 3330 ml at atmospheric pressure (T = 55-57 ° C). The reaction mixture was gradually cooled to room temperature (approximately 1 hour). The mixture was seeded and heptane (5550 ml) was added dropwise. The mixture was stirred overnight at room temperature. The solid is filtered off and the filter residue washed with 925 ml of a THF / heptane mixture, 1: 2. The solid is dried in a vacuum oven at 40 ° C.

Description 170. 1 - [(2-Bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy] -2-propanone

The reactor is charged with 2-bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenol (D169), phenol (550 g), methyl ethyl ketone (5500 ml), chloroacetamide ( 302.5 g), potassium carbonate (325 mesh) (550 mg) and 18.6-crown ether (17.05 g). The mixture was refluxed for 90 minutes (heterogeneous solution). The reaction is monitored by HPLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. DCM (8250 ml) and then water (8250 ml) are added. The organic phase is separated. The aqueous phase is checked by HPLC if there is still some reaction product in it, then the aqueous phase is re-extracted with 5500 ml of DCM. 5500 ml of THF are added to the organic phase and the mixture is concentrated to 5500 ml at atmospheric pressure (T = 45-55 ° C). Then 5500 ml of THF are added and the mixture is again concentrated to 4950 ml at atmospheric pressure (T = 55-57 ° C). The reaction mixture was gradually cooled to room temperature (approximately 1 hour). The mixture was seeded and heptane (8250 ml) was added dropwise. The mixture was stirred overnight at room temperature. The solid is filtered off and the filter residue washed with 1375 ml of a THF / heptane mixture, 1: 2. The solid is dried in a vacuum oven at 40 ° C.

Description 171. 8- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one

DMF (4750 ml), CuI (75.05 g) and N, N'-dimethylethylenediamine (97.85 g) are charged to the reactor under nitrogen atmosphere. The reaction mixture was stirred under N ₂ until the mixture turned dark blue (approximately 2 hours). Potassium carbonate (325 mesh) (306 g) and 1 - [(2-bromo-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} phenyl) oxy are added to the reaction mixture. ] -2-propanone (D170) (475 g). The heterogeneous mixture is heated at 110 ° C (internal temperature) for 16 hours. The reaction is monitored by HPLC. The reaction mixture was cooled to room temperature and water (9500 ml) and DCM (9500 ml) were added. The reaction mixture is stirred at 30 ° C (internal temperature) for 1 hour. Then the mixture was cooled to room temperature and the phases were separated. The aqueous phase is checked by HPLC if there is still some reaction product present, then the aqueous phase is re-extracted with 4750 ml of DCM. The organic phase is washed first with a 3.5% solution of NH ₄ OH (4750 ml) and then with water (4750 ml) four times (until HPLC no longer detects DMF). The organic phase is passed through a CUNO filter to remove metal contaminants. 4750 ml of THF are added to the organic phase, and then the mixture is concentrated to 4750 ml at atmospheric pressure (T = 45-55 ° C). Then 4750 ml of THF are added and the mixture is again concentrated to 4750 ml at atmospheric pressure (T = 55-57 ° C). The mixture was gradually cooled to room temperature (approximately 1 hour). The mixture was seeded and heptane (7125 ml) was added dropwise. The mixture was stirred overnight at room temperature. The solid is filtered off and the filter residue washed with 1187 ml of a THF / heptane mixture, 1: 2. The solid is dried in a vacuum oven at 40 ° C.

Examples

Example 1. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- dihydrochloride carboxylate (E1)

A mixture of ethyl 6- (2-oxoethyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D6) (50 mg, 0.17 mmol) and 2-methyl-5- piperazin-1-ylquinoline (58 mg, 0.21 mmol) in dry 1,2-dichloroethane (4 ml) was stirred at room temperature under nitrogen for 15 minutes. Then sodium triacetoxyborohydride (44 mg, 0.21 mmol) was added and the resulting reaction mixture was stirred for 3 hours, the reaction was quenched with a saturated aqueous solution of ammonium chloride, and the mixture was extracted with DCM (× 3). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE cartridge (silica gel) eluting with a mixture of 4% methanol in DCM to give the free base of the title compound as a white solid (61 mg, 70%). MS (ES) m / z: 498.5 [MH ⁺ ]. C ₁₆ H ₁₆ N ₂ O ₃ requires 497.6. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.4 (d, 1H), 8 (s, 1H), 7.7 (d, 1H), 7.55 (t, 1H), 7.3 (d, 1H), 7.2 (m, 1H), 7.1 (d, 1H), 6.95-7.05 (m, 2H), 5.55 (s, 2H), 4.4 ( q, 2H), 2.7-3.15 (m, 12H), 3.7 (s, 3H), 1.4 (t, 3H). The free base (20 mg, 0.04 mmol) was dissolved in dry methanol (1 ml) and treated with HCl (0.068 ml of a 1.25 M solution in methanol, 0.084 mmol) at 0 ° C. The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (20 mg, 87%) as a yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.67 (br s, 1H), 8.8-8.6 (br s, 1H), 7.89 (dd, 1H), 7.82 (s, 2H), 7.64 (br s, 1H), 7.35 (s, 1H), 7.29 (dd, 1H), 7.2 (d, 1H), 4.3 (q, 2H), 3.76 (dd, 2H), 3.6-3.3 (m, 8H), 2.8 (s, 3H), 1.33 (t, 3H).

The compound of example 1 is also obtained as follows.

8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D171) (274 g) was charged to the reactor; and THF (2740 ml). The mixture was cooled to 0 ° C and a 1 M solution of t-BuOK in THF (748 ml) was added dropwise, adjusting the temperature to 0 ° C. At 0 ° C, diethyl chlorophosphate (126 ml) was added and the reaction mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was cooled to -5 ° C and ethylisocyanoacetate (87.7 ml) and a 1 M solution of tert-BuOK in THF (811 ml) were added, keeping the temperature below 0 ° C. The reaction mixture was stirred at -5 ° C for 1.5 hours. The reaction is monitored by HPLC. The reaction was quenched by adding a solution of ammonium chloride (20%, 4250 ml), and then THF was evaporated to 4658 ml. DCM (5480 ml) was added and the mixture was heated to 30 ° C. After stirring for 30 minutes, the phases are separated and the aqueous phase is re-extracted with DCM (2740 ml) if the reaction product is still present (after checking by HPLC). The organic phases are combined and washed with water (2740 ml). The organic phase is passed through a CUNO filter to remove metal contaminants. The organic phase is concentrated to 822 ml (P = 1000 mbar, T = 66 ° C), 2740 ml of acetone is added to it, and the mixture is concentrated to 2192 ml (P = 950 mbar, T = 45-55 ° C). Then another 274 ml of acetone is added and the mixture is again concentrated to 1370 ml (P = 950 mbar, T = 55-57 ° C). After cooling, a sample is taken for NMR monitoring of the amount of DCM. If DCM remains, the solvent is exchanged until the amount of DCM is ≤2.25%. Then the mixture was cooled to room temperature and stirred overnight. The solid is filtered off and the filter residue washed with 685 ml of acetone. The solid is dried in a vacuum oven at 40 ° C.

Example 2. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid ( E2)

To a solution of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate ( E1) (220 mg, 0.44 mmol) in methanol (3 ml), NaOH (3 ml of a 10% aqueous solution) is added and the resulting white suspension is heated for 5 minutes when exposed to microwave radiation at 120 ° C. The resulting pale yellow solid was filtered off, suspended in water (15 ml) and the solution was neutralized (pH 7) with an aqueous solution of acetic acid. The resulting precipitated off-white solid was filtered off and washed with diethyl ether (3 × 20 ml) to give the title compound (0.168 g, 81%). MS (ES) m / z: 470.3 [MH ⁺ ]. C ₂₇ H ₂₇ N ₅ O ₃ requires 469.54. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.49 (br s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.55 (br. s, 1H), 7.35 (d, 1H), 7.2 (d, 1H), 7.07 (br.m, 2H), 5.5 (s, 2H), 3.05-2.75 (very broad m, 15H).

The potassium salt of the compound of Example 2 was prepared as follows.

Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate dihydrochloride (E1 ) (115 g) are suspended in a 1.5 M solution of KOH in methanol (805 ml). The suspension is heated at the boil under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with methanol (287.5 ml). The white solid is dried in a vacuum oven at 40 ° C.

Example 3. N-cyclopentyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E3)

The title compound was obtained in 40% yield following the general procedure of Example 1, starting from N-cyclopentyl-6- (2-oxoethyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (D11) (25 mg, 0.08 mmol) and 2-methyl-5-piperazin-1-ylquinoline (20 mg, 0.09 mmol) (WO 2004/046124). MS (ES) m / z: 537.3 [MH ⁺ ]. C ₃₂ H ₃₆ N ₆ O ₂ requires 536.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.79 (br s, 1H), 8.67 (br s, 1H), 8.58 (s, 1H), 7.9 (d, 1H), 7.8 (d + br s, 3H), 7.6 (br s, 1H), 7.32 (br s, 1H), 7, 24 (d, 1H), 7.15 (t, 1H), 5.59 (s, 2H), 4.18 (m, 1H), 3.7-3 (species m, 12H), 2.78 (broad s, 3H), 1.83 (m, 2H), 1.67 (m, 2H), 1.52 (m, 4H).

Example 4. Dihydrochloride of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine (E4)

The title compound was prepared in 40% yield following the general reductive amination procedure of Example 1 starting from 4H-imidazo [5,1-c] [1,4] benzoxazin-6-yl-acetaldehyde (D13) (20 mg, 0.08 mmol) and 2-methyl-5-piperazin-1-ylquinoline (20 mg, 0.1 mmol). MS (ES) m / z: 426.3 [MH ⁺ ]. C ₂₆ H ₂₇ N ₅ O requires 425.5. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.64 (br s, 1H), 8.64 (s, 1H), 8.47 (d, 1H), 7.81 (d, 1H), 7.7 (s, 2H), 7.48 (d, 1H), 7.3-7.1 (m, 3H), 7.07 (s, 1H), 5.35 (s, 2H ), 3.8-3.1 (very broad m, 12H), 2.68 (s, 3H).

Example 5. Ethyl-6- {3- [4- (2-methylquinolin-5-yl) piperazin-1-yl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 dihydrochloride -carboxylate (E5)

The title compound was prepared in 40% yield following the general reductive amination procedure of Example 1 starting from ethyl 6- (3-oxopropyl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (D17) (20 mg, 0.08 mmol) and 2-methyl-5-piperazin-1-ylquinoline (20 mg, 0.1 mmol). MS (ES) m / z: 512.4 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.92 (br s, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 7.83 (m, 3H), 7.67 (br s, 2H), 7.33 (br s, 1H), 7.26 (d, 1H), 7.15 (t, 1H), 5.6 (s, 2H) ), 4.3 (q, 2H), 3.64 (br.s. 2H), 3.0-3.3 (br.s. 8M), 2.81 (br s, 3H), 2.77 (dd, 2H); 2.12 (br s, 2H); 1.33 (s, 3H).

Example 6. 6- {3- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid ( E6)

Ethyl 6- {3- [4- (2-methylquinolin-5-yl) piperazin-1-yl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate dihydrochloride ( E5) (100 mg, 0.2 mmol) was dissolved in methanol (1 ml) and sodium hydroxide (1 ml of a 1 M aqueous solution) was added. The reaction mixture is exposed in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 120 ° C., 5 minutes). The crude material is purified on an SPE-SCX cartridge and then treated with trifluoroacetic acid (0.2 mmol) to give the title compound. MS (ES) m / z: 484.3 [MH ⁺ ]. C ₂₈ H ₂₉ N ₅ O ₃ requires 483.6. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 9.6 (br s, 1H), 8.6 (s, 1H), 8.4 (d, 1H), 7.8 (d, 1H), 7.65 (m, 1H), 7.4 (d, 1H), 7-7.2 (m, 4H), 5.55 (s, 2H), 3.0-3.7 (pts) br.m, 10H), 2.81 (m, 2H), 2.77 (s, 3H), 2.12 (br s, 2H).

Example 7. 6- {3- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazine dihydrochloride

6- {3- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid (E6) ( 30 mg, 0.06 mmol) in 1,2-dichlorobenzene (1.5 ml) was exposed in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 250 ° C, 10 min). The solvent was removed on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give the free base of the title compound as a white solid (20 mg, 72%). The free base is dissolved in dry methanol (1 ml) and HCl is gradually added at 0 ° C (80 μl of a 1.25 M solution in methanol, 0.1 mmol). The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (20 mg). MS (ES) m / z: 440.4 [MH ⁺ ]. C ₂₇ H ₂₉ N ₅ O requires 439.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.4 (br s, 1H), 8.4 (s, 1H), 8.3 (d, 1H), 7.6-7, 75 (m, 3H), 7.4 (d, 1H), 7.1-7.2 (m, 3H), 7 (br s, 1H), 5.3 (s, 2H), 3.1 -3.6 (br.m, 10H), 2.7 (m, 2H), 2.6 (br s, 3H), 2.1 (m, 2H).

Examples 8 and 9. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [2,1-c] [1,4] benzoxazine (E8) and 6- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] methyl} -4H-imidazo [2,1-c] [1,4] benzoxazine dihydrochloride (E9)

The title compounds were obtained as a mixture following the general reductive amination procedure of Example 1, starting from a mixture of 4H-imidazo [2,1-c] [1,4] benzoxazin-6-yl-acetaldehyde and 4H-imidazo [2,1- c] [1,4] benzoxazine-6-carbaldehyde (D22 and D23) (50 mg, 0.2 mmol). The free bases of the title compounds E8 and E9 (13.8 mg and 14 mg, 20%) were separated by silica gel chromatography, eluting with a mixture of 2% methanol in DCM. Free bases were dissolved in dry methanol (0.5 ml) and HCl (2.2 eq. 1.25 M solution in methanol) was gradually added at 0 ° C. The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compounds as yellow solids.

Example 8. MS (ES) m / z: 426.3 [MH ⁺ ]. C ₂₆ H ₂₇ N ₅ O requires 425.5. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.07 (br s, 1H), 8.78 (br.m, 1H), 8.05 (s, 1H), 7.88 ( br.m, 2H), 7.7 (br.m, 2H), 7.38 (br.m, 1H), 7.25 (br.s, 1H), 7.24 (d, 1H), 7 18 (t, 1H), 5.43 (s, 2H), 3.8-3.2 (very broad m, 12H), 2.84 (s, 3H).

Example 9. MS (ES) m / z: 412.4 [MH ⁺ ]. C ₂₅ H ₂₅ N ₅ O requires 411.5. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.64 (broad s, 1H), 8.8 (broad s, 1H), 8.0 (broad m, 1H), 7, 9 (br s, 3H), 7.8 (br s, 1H), 7.7 (d, 1H), 7.1-7.4 (br.m, 3H), 5.5 (s, 2H), 4.5 (s, 2H), 3.8-3.1 (very broad m, 8H), 2.7 (s, 3H).

Example 10. 1-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H- [1,2,4] triazolo [3,4-c] dihydrochloride [1,4] benzoxazine (E10)

The title compound was obtained in 71% yield following the general reductive amination procedure of Example 1, starting from (1-methyl-4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazin-6 -yl) acetaldehyde (D25) (45 mg, 0.2 mmol) and 2-methyl-5-piperazin-1-ylquinoline (54 mg, 0.24 mmol). MS (ES) m / z: 441.3 [MH ⁺ ]. C ₂₆ H ₂₈ N ₆ O requires 440.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.21 (br s, 1H), 8.92 (br s, 1H), 7.97 (br s, 2H), 7, 81 (broad d, 1H), 7.72 (d, 1H), 7.45 (broad d, 1H), 7.34 (d, 1H), 7.25 (t, 1H), 5.46 (s, 2H), 3.75 (d, 2H), 3.3-3.6 (br.m, 8H), 3.24 (m, 2H), 2.91 (s, 3H), 2, 74 (s, 3H).

Example 11. 1-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,4] triazolo [3,4-c] dihydrochloride [1,4] benzoxazine (E11)

The title compound was obtained in 35% yield following the general reductive amination procedure of Example 1, starting from (1-methyl-4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazine-6 -yl) acetaldehyde (D25) (50 mg, 0.22 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (54.77 mg, 0.24 mmol). MS (ES) m / z: 440.10 [MH ⁺ ]. C ₂₇ H ₂₉ N ₅ O requires 439.57. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.3 (br s, 1H), 8.02 (br s, 1H), 8.06 (br s, 1H), 7, 95 (br s, 1H), 7.82 (br s, 1H), 7.74 (d, 1H), 7.64 (br s, 1H), 7.34 (d, 1H), 7 25 (t, 1H), 5.46 (s, 2H), 3.76 (d, 2H), 3.80-3.10 (very broad m, 6H), 2.86 (broad s , 3H); 2.74 (s, 3H); 2.3-2.1 (m, 5H).

Example 12. 1-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H- [1,2,4] dihydrochloride triazolo [3,4-c] [1,4] benzoxazine (E12)

The title compound was obtained in 47% yield following the general reductive amination procedure of Example 1, starting from (1-methyl-4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazine-6 -yl) acetaldehyde (D25) (26 mg, 0.11 mmol) and 2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (40 mg, 0.16 mmol) (WO 2004 / 046124). MS (ES) m / z: 455.70 [MH ⁺ ]. C ₂₇ H ₃₀ N ₆ O requires 454.58. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.85 (broad s, 1H), 8.85 (broad s, 1H), 7.88 (broad s, 2H), 7, 72 (br s, 1H), 7.7-7.6 (br s, 1H), 7.4-7.3 (br s, 1H), 7.38 (d, 1H), 7, 25 (t, 1H), 5.48 (s, 2H), 4-3.2 (br s, 11H), 2.85 (br s, 3H), 2.74 (s, 3H) 1.46-1.6 (2d, 3H).

Example 13. Dihydrochloride 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -1-methyl-4H- [1,2,4] triazolo [3, 4-c] [1.4] benzoxazine (E13)

The title compound was obtained in 53% yield following the general reductive amination procedure of Example 1, starting from (1-methyl-4H- [1,2,4] triazolo [3,4-c] [1,4] benzoxazine-6 -yl) acetaldehyde (D25) (25 mg, 0.11 mmol) and 7-fluoro-2-methyl-5- (1-piperazinyl) quinoline (38 mg, 0.15 mmol) (WO 2004/046124). MS (ES) m / z: 459.30 [MH ⁺ ]. C ₂₆ H ₂₇ N ₆ OF requires 458.54. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.44 (br s, 1H), 8.44 (br s, 1H), 7.73 (d, 1H), 7.47 ( d, 1H), 7.43 (m, 1H), 7.34 (d, 1H), 7.32 (t, 1H), 7.22 (m, 1H), 5.46 (s, 2H), 3.74 (d, 2H), 3.6-3.1 (m, 10H), 2.69 (br s, 3H), 2.74 (s, 3H).

Examples 14-24. General procedure for producing amides

To a solution of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid (E2 ) (1 equiv.) And DIPEA (1.1 equiv.) In DMF, TBTU (1.1 equiv.) Was added with stirring, and the resulting solution was stirred for 1 hour at room temperature. The desired amine (1.1 equiv.) Was added and the solution was stirred for 1 hour. The crude solution was added to the SPE-SCX cartridge (eluted with methanol, then with 2 N ammonia in methanol). After evaporation of the solvent from the ammonia fractions and treatment with diethyl ether, the free base of the desired compound is recovered in pure form. The free base is dissolved in dry methanol and treated with HCl (2.1 eq. 1 M solution in diethyl ether) at 0 ° C. Evaporation of the solvent and treatment with diethyl ether afforded the final compounds in pure form.

Example 14. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide ( E14)

To a solution of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid (E2 ) (30 mg, 0.06 mmol) and DIPEA (0.012 mmol) in DMF (1 ml) were added with stirring TBTU (22.6 mg, 0.07 mmol) and the resulting solution was stirred for 1 hour at room temperature. Hexamethyldisilazane (0.013 ml, 0.07 mmol) was added and the solution was stirred for 1 hour. The excess amine is removed using a PS-isocyanate resin, and after filtering off the resin and evaporating the solvent, the crude reaction product is purified on an SPE cartridge (silica gel) eluting with 3% methanol in DCM to give the free base of the title compound as a white solid. The free base is dissolved in dry methanol and treated with HCl (2.1 eq. 1 M solution in diethyl ether) at 0 ° C. Evaporation of the solvent and treatment with diethyl ether afforded the final compound in pure form (22 mg, 65%). MS (ES) m / z: 469.4 [MH ⁺ ]. C ₂₇ H ₂₈ N ₆ O ₂ requires 468.56. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.4 (br s, 1H), 9.05 (d, 1H), 8.59 (s, 1H), 8.08 (d, 1H), 8.01 (t, 1H), 7.91 (d, 1H), 7.84 (dd, 1H), 7.51-7.49 (broad d, 2H), 7.33 (broad s, 1H), 7.26 (d, 1H), 7.15 (t, 1H), 5.59 (s, 2H), 3.81-3.72 (broad d, 2H), 3, 53-3.49 (broad d, 4H), 3.43-3.39 (broad d, 4H), 3.22-3.17 (m, 2H), 2.97 (s, 3H).

The free base of the compound of Example 14 is also prepared as follows.

6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] potassium benzoxazine-3-carboxylate (E2) ( 63.5 g) was suspended in DMF (952.5 ml) in an atmosphere of N ₂ . The suspension was stirred for 15 minutes at room temperature and then DIPEA (23.5 ml) and TBTU (45.72 g) were added. The suspension becomes orange-brown and after 45 minutes at room temperature it becomes a clear orange-brown solution. HMDS (28.5 ml) was added to the clear reaction mixture at room temperature. A white precipitate forms during the addition and the suspension is stirred for another 2 hours at room temperature. Water (127 ml) was added to the reaction mixture, the suspension was stirred for 30 minutes and then filtered (filtration was very slow). The filter residue was washed with water / THF (2/1, 315 ml) and then MTBE (63 ml). The resulting solid is dried in a vacuum oven at 40 ° C for 24 hours.

The compound of Example 14 (i.e. the dihydrochloride salt) is also prepared from the free base as follows.

6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (250.13 mg ) are suspended in a mixture of THF / H ₂ O 90:10, vol./about. (15 ml). The mixture is heated to a temperature slightly below the boiling point under reflux and allowed to cool to about room temperature. Then, concentrated hydrochloric acid (89 μl) was added to the suspension, which immediately turned yellow, and substantial dissolution of the solid was stimulated. Several large agglomerates of deep yellow / orange solid remain in solution, but they break down with stirring. The mixture is again heated almost to the boiling temperature under reflux, and almost all of the solid substance goes into solution, and a homogeneous yellow solution remains. Upon cooling, a solid yellow substance in a significant amount begins to precipitate from the solution. Then the mixture is transferred to an apparatus with a cyclic temperature regime and subjected to a cycle of 0-40 ° C during the weekend for maximum crystallization of the sample. The solid is recovered by filtration and dried for 48 hours in vacuo at 40 ° C.

The free base of the compound of Example 14 is also prepared as follows.

6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (250.52 mg ) suspended in a mixture of Meon / N ₂ About 90:10, vol./about. (15 ml). The mixture is heated to a temperature slightly below the boiling point under reflux and allowed to cool to about room temperature. The mixture was reheated to near reflux and allowed to cool again. Then the mixture is transferred to an apparatus with a cyclic temperature regime and subjected to a cycle of 0-40 ° C during the weekend for maximum crystallization of the sample. The solid is recovered by filtration and dried for 48 hours in vacuo at 40 ° C.

The free base of the compound of Example 14 is also prepared as follows.

6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (E14) ( 6 g) was suspended in DCM (25 ml) and sodium bicarbonate solution (30 ml) was added. The color of the suspension changes from yellow to white and the mixture is stirred for another 30 minutes. The solid is filtered off and washed with water (15-20 ml). The filter residue was dried in an oven at 40 ° C for 12 hours to give the title product (4 g).

The 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide salt mesylate is prepared as follows .

6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (250.77 mg ) suspended in a mixture of Meon / N ₂ About 90:10, vol./about. (15 ml). The mixture is heated to a temperature slightly below the boiling point under reflux and allowed to cool to about room temperature. Then methanesulfonic acid (70 μl) is added to the suspension, which immediately turns yellow. The mixture is again heated to a temperature slightly below the boiling point under reflux, at which all the solid goes into solution, and a homogeneous yellow solution remains. Upon cooling, significant amounts of a yellow solid begin to precipitate out of solution. Then the mixture is transferred to a device with a cyclic temperature regime and subjected to a cycle of 0-40 ° C for maximum crystallization of the sample. The solid is recovered by filtration and dried for 120 hours in vacuo at 40 ° C.

Example 15. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E15)

The title compound was obtained in 44% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using methylamine (2 M solution in THF). MS (ES) m / z: 483.4 [MH ⁺ ]. C ₂₈ H ₃₀ N ₆ O ₂ requires 482.58. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.29 (br s, 1H), 9.045 (d, 1H), 8.60 (s, 1H), 8.07-7.97 ( m, 2H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.37 (br s, 1H), 7.24 (t, 1H) ), 7.15 (t, 1H), 5.59 (s, 2H), 3.70-3.38 (broad m, 10H), 3.22-3.15 (m, 2H), 2, 96 (s, 3H); 2.74 (d, 3H).

Example 16. Dihydrochloride N- (1-methylethyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1, 4] benzoxazine-3-carboxamide (E16)

The title compound was obtained in 83% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using isopropylamine. MS (ES) m / z: 511.4 [MH ⁺ ]. C ₃₀ H ₃₄ N ₆ O ₂ requires 510.64. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.41 (br s, 1H), 9.07 (d, 1H), 8.61 (s, 1H), 8.09 (d, 1H), 8.02 (t, 1H), 7.92 (d, 1H), 7.87 (s, 1H), 7.85 (dd, 1H), 7.51 (d, 1H), 7, 25 (d, 1H), 7.14 (t, 1H), 5.59 (s, 2H), 4.11-4.01 (m, 1H), 3.75-3.71 (broad d, 2H), 3.53-3.49 (broad d, 4H), 3.43-3.39 (broad d, 4H), 3.22-3.15 (m, 2H), 2.98 ( s, 3H), 1.15 (d, 6H).

Example 17. N-cyclopropyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E17)

The title compound was obtained in 60% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using cyclopropylamine. MS (ES) m / z: 509.4 [MH ⁺ ]. C ₃₀ H ₃₂ N ₆ O ₂ requires 508.62. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.24 (br s, 1H), 9.06 (d, 1H), 8.58 (s, 1H), 8.18 (d, 1H), 8.05 (s, 1H), 8.01 (t, 1H), 7.91 (d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7, 25 (d, 1H), 7.14 (t, 1H), 5.59 (s, 2H), 4.11-3.71 (br.m, 2H), 3.50-3.45 (br. d, 4H), 3.42-3.38 (brd. 4H), 3.22-3.15 (m, 2H), 2.98 (s, 3H), 2.82 (m, 1H) 0.65-0.62 (broad d, 6H).

Example 18. N-cyclobutyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E18)

The title compound was obtained in 83% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using cyclobutylamine. MS (ES) m / z: 523.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₂ requires 522.65. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.39 (br s, 1H), 9.07 (d, 1H), 8.62 (s, 1H), 8.37 (d, 1H), 8.11 (d, 1H), 8.01 (t, 1H), 7.91 (d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7, 25 (d, 1H), 7.14 (t, 1H), 5.59 (s, 2H), 4.46-4.35 (m, 1H), 3.78-3.71 (br.m, 2H), 3.56-3.49 (broad d, 4H), 3.43-3.39 (broad d, 4H), 3.22-3.15 (m, 2H), 2.98 ( s, 3H), 2.17-2.10 (m, 4H), 1.65-1.58 (m, 2H).

Example 19. Dihydrochloride (cyclopropylmethyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- 3-carboxamide (E19)

The title compound was obtained in 60% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using cyclopropanemethylamine. MS (ES) m / z: 523.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₂ requires 522.65. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.50 (br s, 1H), 9.05 (d, 1H), 8.60 (s, 1H), 8.21 (br. s, 1H), 8.01 (t, 1H), 7.91 (d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7.25 (d, 1H), 7.14 (t, 1H), 5.59 (s, 2H), 3.74 (broad d, 2H), 3.53-3.49 (broad d, 4H), 3.42-3, 38 (broad d, 4H), 3.22-3.15 (m, 2H), 3.10 (t, 2H), 2.97 (s, 3H), 1.04-1.00 (m, 1H), 0.40 (d, 2H), 0.22 (d, 2H).

Example 20. N-methyl-N- (1-methylethyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] dihydrochloride ] [1,4] benzoxazine-3-carboxamide (E20)

The title compound was obtained in 57% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using N-methylisopropylamine. MS (ES) m / z: 525.4 [MH ⁺ ]. C ₃₁ H ₃₆ N ₆ O ₂ requires 524.67. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.37 (br s, 1H), 9.05 (d, 1H), 8.61 (s, 1H), 8.08 (d, 1H), 8.01 (t, 1H), 7.90 (d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7.24 (dd, 1H), 7, 15 (t, 1H), 5.52 (s, 2H), 4.11-4.01 (m, 1H), 3.71 (broad d, 2H), 3.52-3.49 (broad. d, 4H), 3.42-3.38 (brd. 4H), 3.22-3.15 (m, 2H), 2.97 (s, 3H), 2.50-2.47 ( broad s, 3H), 1.22-1.16 (broad m, 6H).

Example 21. Dihydrochloride 3- (1-azetidinylcarbonyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1, 4] benzoxazine (E21)

The title compound was obtained in 48% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using cyclobutylamine. MS (ES) m / z: 509.4 [MH ⁺ ]. C ₃₀ H ₃₂ N ₆ O ₂ requires 508.62. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 10.98 (broad s, 1H), 8.98 (broad s, 1H), 8.57 (s, 1H), 7.98- 7.96 (broad d, 2H), 7.87-7.81 (broad m, 2H), 7.47 (broad t, 1H), 7.24 (dd, 1H), 7.15 ( t, 1H), 5.59 (s, 2H), 4.54 (t, 2H), 4.00 (t, 2H), 3.75-3.34 (broad m, 10H), 3.20 -3.15 (br.m, 2H), 2.92 (s, 3H), 1.96 (m, 2H).

Example 22. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (1-pyrrolidinylcarbonyl) -4H-imidazo [5,1-c] [1, 4] benzoxazine (E22)

The title compound was obtained in 81% yield of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using pyrrolidine. MS (ES) m / z: 523.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₂ requires 522.65. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.56 (br s, 1H), 9.06 (d, 1H), 8.57 (s, 1H), 8.10 (d, 1H), 8.02 (t, 1H), 7.91 (d, 1H), 7.82 (dd, 1H), 7.51 (d, 1H), 7.24 (dd, 1H), 7, 15 (t, 1H), 5.59 (s, 2H), 4.01 (t, 2H), 3.72 (br.s.d, 2H), 3.53-3.35 (br.s. 10H), 3.21-3.17 (br.m, 2H), 2.98 (s, 3H), 1.94-1.75 (m, 4H).

Example 23. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (1-piperidinylcarbonyl) -4H-imidazo [5,1-c] [1, 4] benzoxazine (E23)

The title compound was obtained in 94% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for the preparation of amides described above using piperidine. MS (ES) m / z: 537.4 [MH ⁺ ]. C ₃₂ H ₃₆ N ₆ O ₂ requires 536.68. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.55 (br s, 1H), 9.06 (d, 1H), 8.57 (s, 1H), 8.10 (d, 1H), 8.02 (t, 1H), 7.91 (d, 1H), 7.82 (dd, 1H), 7.51 (d, 1H), 7.24 (dd, 1H), 7, 15 (t, 1H), 5.53 (s, 2H), 4.46-4.05 (very broad m, 2H), 3.72 (broad d, 2H), 3.53-3, 49 (br.s.d, 4H), 3.44-3.35 (br.s., 6H), 3.21-3.17 (br.m, 2H), 2.98 (s, 3H), 1, 63-1.62 (broad d, 2H); 1.54-1.53 (broad d, 4H).

Example 24. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo [5,1-c] [1, 4] benzoxazine (E24)

The title compound was obtained in 33% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E2), following the general procedure for producing amides described above using morpholine. MS (ES) m / z: 537.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₃ requires 538.65. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.46 (br s, 1H), 9.04 (d, 1H), 8.59 (s, 1H), 8.06 (d, 1H), 8.00 (t, 1H), 7.90-7.83 (m, 2H), 7.48 (d, 1H), 7.26 (d, 1H), 7.15 (t, 1H) ), 5.56 (s, 2H), 4.31 (broad m, 4H), 3.93-3.56 (very broad m, 6H), 3.53-3.49 (broad d) , 4H), 3.42-3.38 (broad d, 4H), 3.22-3.17 (broad m, 2H), 2.95 (s, 3H).

Example 25. N-Methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1 , 4] benzoxazine-3-carboxamide (E25)

To a solution of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid (E2 ) (54 mg, 0.115 mmol) and DIPEA (0.24 ml, 0.138 mmol) in DMF (1 ml) were added TBTU (41 mg, 0.12 mmol) with stirring at room temperature. After stirring for 1 hour, N, O-dimethylhydroxylamine hydrochloride (13.5 mg, 0.138 mmol) was added and the reaction mixture was stirred for another 1 hour. The reaction mixture was added to an SPE-SCX cartridge (eluted with methanol, then with a 2 N solution of ammonia in methanol), and after treatment with diethyl ether, the title compound (40 mg, 68%) was obtained. MS (ES) m / z: 513.4 [MH ⁺ ]. C ₂₉ H ₃₂ N ₅ O ₃ requires 512.61. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.38 (d, 1H), 7.93 (s, 1H), 7.72 (d, 1H), 7.57 (t, 1H) 7.32 (d, 1H), 7.26 (brd, 1H), 7.15 (d, 1H), 7.09-6.99 (m, 2H), 5.53 (s, 2H) ), 3.84 (broad s, 3H), 3.55 (broad s, 3H), 3.15 (broad s, 4H), 2.99-2.94 (broad m, 2H), 2.85 (br.m, 4H), 2.75-2.72 (br.m, 5H).

Example 26. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carbonitrile ( E26)

To a solution of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide (free base E14) (23 mg, 0.049 mmol) in THF (0.5 ml) and pyridine (0.008 ml, 0.098 mmol) under ice-cooling and stirring, trifluoroacetic anhydride (0.008 ml, 0.054 mmol) was added and the resulting solution was stirred at 0 ° C for 1 hours. The crude reaction mixture was added to an SPE-SCX cartridge (eluted with methanol, then with 2 N ammonia in methanol). After evaporation of the solvent from the ammonia fractions, the resulting mixture was further purified on an SPE cartridge (silica gel, 2 g), eluting with DCM / methanol (98: 2), and the free base of the title compound (7 mg, 32%) was obtained as an off-white solid matter. The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 451.3 [MH ⁺ ]. C ₂₇ H ₂₆ N ₆ O requires 450.54. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.93 (very broad s, 1H), 8.92 (very broad s, 1H), 8.79 (s, 1H), 7.95 (br s, 2H), 7.91 (d, 1H) 7.83 (br s, 1H), 7.46 (br s, 1H), 7.34 (d, 1H), 7.24 (t, 1H), 5.56 (s, 2H), 4-3 (br s, 12H), 2.91 (br s, 3H).

Example 27. 2-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [2,1-c] [1,4] benzoxazine dihydrochloride ( E27)

A mixture of (2-methyl-4H-imidazo [2,1-c] [1,4] benzoxazin-6-yl) acetaldehyde (D28) (42 mg, 0.18 mmol) and 2-methyl-5-piperazin-1 -ilquinoline (63 mg, 0.28 mmol, 1.5 equiv.) in dry 1,2-dichloroethane (4 ml) was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (58 mg, 0.28 mmol) was added. , 1.5 equiv.). The resulting mixture was stirred for 3 hours, the reaction was quenched with NaHCO ₃ (10 ml of a saturated aqueous solution), and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on a SPE-Si cartridge eluting with a gradient of DCM / methanol (99 / 1-97 / 3) and the corresponding free base of the title compound E27 was obtained as a white solid (21 mg, 26%). To a solution of the free base (21 mg, 0.05 mmol) in a MeOH / DCM mixture (3: 1, 4 ml), HCl (84 ml of a 1.25 M solution in methanol) is gradually added at 0 ° C. After stirring at room temperature for 2 hours, evaporation of the volatiles afforded the title compound E27 as a yellow solid. MS (ES) m / z: 440.30 [MH ⁺ ]. C ₂₇ H ₂₉ N ₅ O requires 439.57. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.47 (broad s, 1H), 8.55 (broad s, 1H), 7.75 (broad s, 2H), 7, 68 (s, 1H), 7.60 (m, 2H), 7.29 (br s, 1H), 7.2 (m, 2H), 5.36 (s, 2H), 3.75-3 00 (br.p.m, 12H), 2.74 (s, 3H), 2.21 (s, 3H).

Example 28. 1,2-Dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [2,1-c] dihydrochloride [1,4] benzoxazine (E28)

To a solution of 4- (1-methyl-2-oxopropyl) -8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H ) -one (D31) (50 mg, 0.106 mmol) in glacial acetic acid (1 ml) ammonium acetate (163 mg, 2.12 mmol, 20 eq.) is added. The mixture was exposed in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 ° C, 10 min), then diluted with ethyl acetate (10 ml), poured into a mixture of ice water (10 ml) and made basic with an aqueous solution of ammonium hydroxide (3 ml). The mixture was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (44 mg, 92%). The free base (44 mg) was dissolved in MeOH / DCM (3: 1, 4 ml) and treated with HCl (2.2 equiv. 1.25 M solution in methanol) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours. Evaporation of the volatiles afforded the title compound (44 mg) as a yellow solid. MS (ES) m / z: 454.40 [MH ⁺ ]. C ₂₈ H ₃₁ N ₅ O requires 453.59. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.65 (br s, 1H), 8.64 (br s, 1H), 7.79 (br s, 2H ), 7.68 (d, 1H), 7.61 (broad s, 1H), 7.32 (broad s, 1H), 7.27 (d, 1H), 7.20 (t, 1H) , 5.27 (s, 2H), 3.75 (d, 2H), 3.70-3.00 (br.p.m, 10H), 2.77 (s, 3H), 2.48 (s , 3H), 2.18 (s, 3H).

Example 29. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2- (trifluoromethyl) -4H-imidazo [2,1-c] [1,4] benzoxazine (E29)

The title compound was obtained in 58% yield as a yellow solid in a similar manner to that in Example 28, from 8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4- (3,3,3-trifluoro-2-oxopropyl) -2H-1,4-benzoxazin-3 (4H) -one (D36) (79 mg, 0.149 mmol) and ammonium acetate (230 mg, 2.98 mmol, 20 equiv.) In acetic acid (2 ml). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-2%) to give the free base of the title compound (42 mg, 58%). The resulting free base was treated with HCl (2.2 equiv. 1.25 M solution in MeOH) to give the title compound. MS (ES) m / z: 494.30 [MH ⁺ ]. C ₂₇ H ₂₆ F ₃ N ₅ O requires 493.54. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.52 (br s, 1H), 8.74 (s, 1H), 8.63 (br s, 1H), 7.79 (m, 3H), 7.61 (br s, 1H), 7.30 (m, 2H), 7.22 (t, 1H), 5.47 (s, 2H), 3.75 (d, 2H), 3.70-3.10 (very broad m, 10H), 2.77 (s, 3H).

Example 30. 3-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H- [1,2,3] triazolo [5,1-c] dihydrochloride [1,4] benzoxazine (E30)

The title compound was obtained in 81% yield following the general reductive amination procedure of Example 1, starting from (3-methyl-4H- [1,2,3] triazolo [5,1-c] [1,4] benzoxazin-6 -yl) acetaldehyde (D41) (60 mg, 0.262 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (93 mg, 81%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (4: 1, 5 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 441.20 [MH ⁺ ]. C ₂₆ H ₂₈ N ₆ O requires 440.55. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.51 (br s, 1H), 8.62 (br s, 1H), 7.93 (d, 1H), 7.78 (br s, 2H), 7.60 (br s, 1H), 7.37 (d, 1H), 7.32 (br s, 1H), 7.24 (t, 1H), 5.58 (s, 2H), 3.75-3.10 (very broad m, 12H), 2.76 (s, 3H), 2.34 (s, 3H).

Example 31. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H- [1,2,4] oxadiazolo [3,4-c] [1,4 ] benzoxazin-1-one (E31)

The title compound was obtained in 81% yield (46 mg) following the general reductive amination procedure of Example 1, starting from (1-oxo-4H- [1,2,4] oxadiazolo [3,4-c] [1,4 ] benzoxazin-6-yl) acetaldehyde (D44) (30 mg, 0.129 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-2%) to give the free base of the title compound (46 mg, 81%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (5: 1, 5 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 444.20 [MH ⁺ ]. C ₂₅ H ₂₅ N ₅ O ₃ requires 443.51. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.50 (br s, 1H), 8.51 (br s, 1H), 7.81 (d, 1H), 7.68 (br s, 2H), 7.50 (br s, 1H), 7.21-7.10 (m, 3H), 5.32 (s, 2H), 3.66- 3.05 (br.m, 12H); 2.67 (s, 3H).

Example 32. 3-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5,1-c] dihydrochloride [1,4] benzoxazine (E32)

The title compound was obtained in 45% yield (25 mg) following the general reductive amination procedure of Example 1, starting from (3-methyl-4H- [1,2,3] triazolo [5,1-c] [1,4 ] benzoxazin-6-yl) acetaldehyde (D41) (25 mg, 0.109 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (30 mg, 0.130 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (22 mg, 45%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (4: 1, 5 ml) at 0 ° C gave the title compound as a solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.33 (br s, 1H), 9.01 (br s, 1H), 8.06 (br s, 1H ), 7.93 (m, 2H), 7.82 (broad s, 1H), 7.62 (broad s, 1H), 7.23 (t, 1H), 5.58 (s, 2H) 3.39-3.10 (br s, 9H); 2.86 (br s, 3H); 2.34 (s, 3H); 2.20 (m, 4H).

Example 33. Hydrochloride 1-methyl-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl) -1-piperazinyl] ethyl} -4H- [1,2,4] triazolo [3,4- c] [1.4] benzoxazine (E32)

To a mixture of 5- (1-piperazinyl) -2- (trifluoromethyl) quinoline (D47) (39 mg, 0.137 mmol) and (1-methyl-4H- [1,2,4] triazolo [3,4-c] [ 1,4] benzoxazin-6-yl) acetaldehyde (D25) (21 mg, 0.092 mmol), sodium triacetoxyborohydride (42 mg, 0.84 mmol) was added to DCM (5 ml). After the mixture was stirred at room temperature overnight, water (10 ml) was added and the mixture was extracted with DCM (3 × 15 ml). The combined organic layers were dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified on a reverse phase preparative mass-directed HPLC system to give the free base of the title compound as a colorless oil (14 mg, 30%). The free base is dissolved in dry DCM / diethyl ether and treated with HCl (1.1 eq. 1 M solution in diethyl ether). Evaporation of the solvent and treatment in diethyl ether gave the title compound. MS (ES; m / z): 495 [MH ⁺ ]. C ₂₆ H ₂₅ F ₃ N ₆ O requires 494.52. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.85 (br s, 1H), 8.86 (d, 1H), 7.99 (d, 1H), 7.94 (d, 1H), 7.9 (d, 1H), 7.73 (dd, 1H), 7.48 (d, 1H), 7.35 (d, 1H), 7.25 (t, 1H), 5, 47 (s, 2H), 3.77 (broad d, 2H), 3.6-3.45 (m, 4H), 3.32 (t, 2H), 3.47 (m, 2H), 3 32 (m, 2H); ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ: -66.04.

Example 34. N, N-dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo dihydrochloride [5.1-c] [1.4] benzoxazine-3-carboxamide (E34)

The title compound was obtained in 60% yield following the general procedure described in Example 1, starting from N, N-dimethyl-6- (2-oxoethyl) -4H-imidazo [5.1-c] [1.4] benzoxazin-3-carboxamide (D9) (20 mg, 0.07 mmol) and 2-methyl-5-piperazin-1-ylquinoline (19 mg, 0.084 mmol). MS (ES) m / z: 497.3 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O ₂ requires 496.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11 (very broad s, 1H), 8.77 (very broad s, 1H), 8.57 (s, 1H), 7, 9 (br s + d, 3H), 7.69 (br s, 1H), 7.36 (br s, 1H), 7.25 (d, 1H), 7.15 (t, 1H) 5.54 (s, 2H), 3.7-3.2 (br.p.m, 12H), 2.96-2.82 (2s, 6H), 2.5 (m, 3H).

Example 35. Hydrochloride 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 -yl) ethanone (E35)

To a solution of N-methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1, 4] benzoxazine-3-carboxamide (E25) (40 mg, 0.078 mmol) in THF (1 ml) while cooling with ice and stirring, methyl magnesium bromide (0.03 ml of a 3 M solution in diethyl ether, 0.09 mmol) was added, and the obtained the solution is stirred for 1 hour at 0 ° C. The reaction mixture was poured into cold hydrochloric acid (2 ml of a 2.5 M solution), then treated with a solution of NaHCO ₃ (15 ml) and extracted with DCM (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a brown oil, which was purified on an SPE cartridge (silica gel, 2 g) eluting with DCM / methanol (98: 2) to give the free base of the title compound (22 mg, 60%) as a white solid. The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 468.4 [MH ⁺ ]. C ₂₈ H ₂₉ N ₅ O ₃ requires 467.57. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.41 (br s, 1H), 9.08 (d, 1H), 8.66 (d, 1H), 8.2-7, 08 (m, 4H) 7.52 (dd, 1H), 7.3 (dd, 1H), 7.19 (t, 1H), 5.62 (s, 2H), 4.2-3.2 ( very broad m, 12H), 2.99 (s, 3H), 2.5 (s, 3H).

Example 36. Dihydrochloride N, N-dimethyl-6- {3- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] propyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (E36)

To a solution of 6- {3- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] propyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid (E6 ) (32 mg, 0.07 mmol) and DIPEA (23 μl, 0.13 mmol) in DMF (1 ml) while adding TBTU (24 mg, 0.075 mmol) with stirring. The reaction mixture was stirred at room temperature for 1 hour, then dimethylamine in THF (37 μl of a 2 M solution, 0.075 mmol) was added, and the solution was stirred for 1 hour. The crude solution was purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol), then treated with diethyl ether to give the corresponding free base of the title compound as a solid (20 mg, 59%). The free base is dissolved in dry methanol (1 ml) and HCl (68 μl of a 1.25 M solution in methanol, 0.09 mmol) is gradually added at 0 ° C. The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles afforded the title compound as a yellow solid (22 mg). MS (ES) m / z: 511.4 [MH ⁺ ]. C ₃₀ H ₃₄ N ₆ O ₂ requires 510.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.4 (br s, 1H), 8.6 (s, 1H), 8.4 (d, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 2H), 7.4 (br s, 1H), 7.0-7.2 (m, 3H), 5.5 (s, 2H), 3 1-3.6 (br.m, 10H), 2.9 (s, 3H), 2.5-2.8 (br.m, 8H), 2.1 (br s, 2H).

Example 37. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E37)

A mixture of ethyl 6- (2-oxoethyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (D6) (62 mg, 0.27 mmol) and 2-methyl-5- piperidin-1-ylquinoline (70 mg, 0.31 mmol) in dry 1,2-dichloroethane (10 ml) was stirred at room temperature under nitrogen for 40 minutes. Then sodium triacetoxyborohydride (65 mg, 0.31 mmol) was added, and the resulting reaction mixture was stirred for 3 hours, the reaction was quenched with saturated aqueous NaHCO ₃ solution (10 ml) and the mixture was extracted with DCM (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified by silica gel column chromatography, eluting with 1% methanol in DCM, to give the title compound as a pale yellow solid (68 mg, 50%). MS (ES) m / z: 497.4 [MH ⁺ ]. C ₃₀ H ₃₂ N ₄ O ₃ requires 496.5. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 8.30 (d, 1H), 7.98 (s, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 7 34 (dd, 1H), 7.28 (d, 1H), 7.15 (dd, 1H), 7.03 (t, 1H), 5.53 (s, 2H), 4.39 (q, 2H), 3.23 (m, 3H), 2.92 (dd, 2H), 2.73 (s, 3H), 2.65 (dd, 2H), 2.29 (m, 2H), 1, 95 (m, 4H); 1.41 (t, 3H).

Example 38. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E38)

A solution of trimethylaluminum (2.0 M in hexanes, 150 μl, 0.3 mmol) and methylamine (2.0 M solution in THF, 150 μl, 0.3 mmol) in DCM (1 ml) was stirred at room temperature for 15 min Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E37) was added ) (30 mg, 0.061 mmol) and stirring is continued for another 3 hours at 40 ° C. Upon completion of the reaction, water is added dropwise until the gas is no longer evolved and the final added volume reaches approximately 3 ml. Aqueous 1 M NaOH solution (5 ml) was added and the aqueous solution was extracted with DCM (3 × 20 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated, the residue was purified by Si gel chromatography eluting with DCM / MeOH mixtures (98: 2-96: 4) to give the free base of the title compound as a pale yellow solid substances (22 mg, 76%). The free base was dissolved in dry methanol (3 ml), 2.1 equiv. hydrochloric acid (1.25 M solution in MeOH) and the resulting suspension was stirred for 2 hours. Evaporation of the solvent and treatment in diethyl ether afforded the desired dihydrochloride salt (26 mg) as a yellow solid. MS (ES) m / z: 481.2 [MH ⁺ ]. C ₂₉ H ₃₁ N ₅ O ₂ requires 480.5. ¹ H-NMR (500 MHz, DMSO) δ: 10.67 (br s, 1H), 9.24 (br s, 1H), 8.60 (s, 1H), 8.21 (dd, 1H ), 8.17 (q, 1H), 8.06 (t, 1H), 7.96 (d, 1H), 7.85 (dd, 1H), 7.71 (m, 1H), 7.28 (d, 1H), 7.17 (t, 1H), 5.62 (s, 2H), 3.84 (m, 1H), 3.7-3.2 (m, 4H), 3.2 ( d, 2H), 2.95 (s, 3H), 2.77 (d, 3H), 2.25 (q, 2H), 2.11 (d, 2H).

Example 39. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo [5,1-c] [1, 4] benzoxazine (E39)

A solution of trimethylaluminum (2.0 M in hexanes, 150 μl, 0.3 mmol) and morpholine (30 μl, 0.3 mmol) in DCM (1 ml) was stirred at room temperature for 15 minutes. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E37) was added ) (30 mg, 0.061 mmol) and stirring is continued for another 3 hours at 40 ° C. Upon completion of the reaction, water is added dropwise until the gas is no longer evolved and the final volume reaches approximately 3 ml. Aqueous 1 M NaOH solution (5 ml) was added and the aqueous solution was extracted with DCM (3 × 15 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated, the residue was purified by Si gel chromatography eluting with DCM / MeOH mixtures (98: 2-96: 4) to give the free base of the title compound as a pale yellow solid substances (24 mg, 75%). The free base was dissolved in dry MeOH (3 ml), 2.1 equiv. hydrochloric acid (1.25 M solution in methanol), and the resulting suspension was stirred for 2 hours. Evaporation of the solvent and treatment in diethyl ether afforded the desired dihydrochloride salt (28 mg) as a yellow solid. MS (ES) m / z: 538 [MH ⁺ ]. C ₃₂ H ₃₇ N ₅ O ₃ requires 537.66. ¹ H-NMR (500 MHz, DMSO) δ: 10.7 (br s, 1H), 9.2 (br s, 1H), 8.60 (s, 1H), 8.2 (dd, 1H ), 8.0 (t, 1H), 7.96 (d, 1H), 7.85 (dd, 1H), 7.71 (m, 1H), 7.28 (d, 1H), 7.17 (t, 1H), 5.52 (s, 2H), 4.3 (m, 2H), 3.84 (m, 1H), 3.7-3.2 (m, 4H), 3.2 ( d, 2H), 2.95 (s, 3H), 2.25 (q, 2H), 2.11 (d, 2H).

Example 40. 6- (2- {4- [2- (Trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (E40)

6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid ethyl ester solution acid (E56) (32 mg, 0.058 mmol) and a catalytic amount of potassium cyanide in a 7 M solution of NH ₃ in MeOH (20 ml) was stirred at room temperature for 3 days. The reaction mixture was filtered, the filtrate was evaporated under high vacuum and the title compound (18 mg, 59%) was obtained as a solid. MS (ES; m / z): 523 [MH ⁺ ]. C ₂₇ H ₂₅ F ₃ N ₆ O ₂ requires 522.53. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (d, 1H), 8.54 (s, 1H), 7.95 (d, 1H), 7.84 (m, 2H), 7.76 (d, 1H), 7.51 (dd, 1H), 7.37 (t, 1H), 7.33 (br s, 1H), 7.24 (dd, 1H), 7.1 (t, 1H), 5.54 (s, 2H), 3.31 (br s, 4H), 2.89 (t, 2H), 2.79 (br s, 4H), 2.7 ( m, 2H); ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ: -66.05.

Example 41. N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] dihydrochloride salt [1,4] benzoxazine-3-carboxamide (E41)

A solution of trimethylaluminum (2.0 M in hexane, 2.4 ml, 4.82 mmol) and methoxylamine hydrochloride (402 mg, 4.82 mmol) in DCM (8 ml) were stirred at room temperature for 30 minutes. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E1 ) (400 mg, 0.803 mmol) and stirring is continued for another 4 hours at 54 ° C. Upon completion of the reaction, water is added dropwise until the gas is no longer released and the final volume reaches approximately 20 ml. The aqueous solution was extracted with DCM (3 × 30 ml). In the case where the organic and inorganic phases are not well separated, an aqueous 1 M NaOH solution is added. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated. The residue was taken up in Et ₂ O to give the free base of the desired compound (284 mg, 71%). The free base (25 mg) was dissolved in dry MeOH (1 ml) and 2.1 equivalents were added gradually at 0 ° C. hydrochloric acid (1 M solution in ethyl ether). The resulting suspension is stirred for 2 hours at 0 ° C. Evaporation of the solvent and work-up in ethyl ether gave the title compound as a yellow solid (31 mg). MS (ES) m / z: 499.6 [MH ⁺ ]. C ₂₈ H ₃₀ N ₆ O ₃ requires 498.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.62 (br s, 1H), 11.37 (br s, 1H), 9.06 (d, 1H), 8.62 ( s, 1H), 8.09 (d, 1H), 8.03 (t, 1H), 7.92 (d, 1H), 7.86 (dd, 1H), 7.52 (d, 1H), 7.28 (dd, 1H), 7.18 (t, 1H), 5.62 (s, 2H), 4-3.3 (very broad m, 10H), 3.69 (s, 3H) 3.22 (dd, 2H); 2.98 (s, 3H).

Example 42. Ethyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1 , 4] benzoxazine-3-carboxylate (E42)

To a solution of 2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (WO 2004/046124) (200 mg, 0.84 mmol) and ethyl 6- (2-oxoethyl) -4H- imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (D6) (200 mg, 0.69 mmol) in DCM (10 ml) sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added. After the mixture was stirred at room temperature overnight, water (15 ml) was added and the reaction product was extracted with DCM (3 × 20 ml). The organic layer was dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (98: 2), and the title compound was obtained as a white foam (212 mg, 60%). MS (ES) m / z: 512.2 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.44 (d, 1H), 8.03 (s, 1H), 7.76 (d, 1H), 7.62 (t, 1H) 7.4 (d, 1H), 7.3 (m, 1H), 7.2 (d, 1H), 7.1 (m, 2H), 5.59 (s, 2H), 4.45 ( quart, 2H), 3, -2.7 (br.s. m, 11H), 2.77 (s, 3H), 1.46 (t, 3H), 1.2 (m, 3H).

Example 43. Ethyl-6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E43)

The title compound was obtained in 62% yield following the procedure of Example 1 using 7-fluoro-2-methyl-5- (1-piperazinyl) quinoline (see WO 2004/046124) (205 mg, 0.84 mmol) . MS (ES) m / z: 516.6 [MH ⁺ ]. C ₂₉ H ₃₀ FN ₅ O ₃ requires 515.59. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.33 (d, 1H), 8.03 (s, 1H), 7.39 (dd, 1H), 7.36 (dd, 1H) , 7.23 (d, 1H), 7.2 (dd, 1H), 7.08 (t, 1H), 6.87 (dd, 1H), 5.58 (s, 2H), 4.44 ( quart., 2H), 3.18 (br s, 4H), 2.99 (dd, 2H), 2.86 (br s, 4H), 2.76 (m, 5H), 1.46 ( t, 3H).

Example 44. Ethyl 6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (E44)

The title compound was obtained in 74% yield following the procedure of Example 42 using 2-methyl-5- (1-piperazinyl) quinazoline (see WO 2004/046124) (228 mg, 0.84 mmol). MS (ES) m / z: 499.1 [MH ⁺ ]. C ₂₉ H ₃₀ FN ₅ O ₃ requires 498.58. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 9.61 (s, 1H), 8.03 (s, 1H), 7.79 (t, 1H), 7.62 (d, 1H) 7.4 (dd, 1H), 7.2 (dd, 1H), 7.1 (m, 2H), 5.58 (s, 2H), 4.44 (q, 2H), 3.25 (broad s, 4H), 3 (dd, 2H), 2.91 (s, 3H), 2.87 (broad s, 4H), 2.76 (dd, 2H), 1.46 (t, 3H).

Example 45. 6- {2 - [(2R) -2-Methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4 ] benzoxazine-3-carboxylic acid (E45)

To a solution of ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1, 4] benzoxazine-3-carboxylate (E42) (212 mg, 0.45 mmol) in MeOH (4 ml) was added NaOH (4 ml of a 10% aqueous solution), and the resulting white suspension was heated for 5 minutes under the influence of microwave radiation at 120ºС. The resulting pale yellow solid is filtered off, suspended in water and the solution is neutralized (pH 7) with acetic acid. The precipitated substance is filtered off and washed with diethyl ether (3 × 20 ml) to obtain the title compound (164 mg, 81%) as an off-white solid. MS (ES) m / z: 484.6 [MH ⁺ ]. C ₂₈ H ₂₉ N ₅ O ₃ requires 482.57. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.53 (s, 1H), 8.37 (d, 1H), 7.74 (dd, 1H), 7.58 (m, 2H) 7.4 (d, 1H), 7.21 (dd, 1H), 7.08 (m, 2H), 5.52 (s, 2H), 3.2-2.5 (m, 11H), 2.63 (s, 3H); 1.10 (d, 3H).

Example 46. Ethyl-6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E46)

The title compound was prepared following the procedure of Example 45, starting from ethyl-6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5, 1-c] [1.4] benzoxazine-3-carboxylate (E43) (223 mg, 0.43 mmol). MS (ES) m / z: 488.6 [MH ⁺ ]. C ₂₇ H ₂₆ FN ₅ O ₃ requires 487.53. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.63 (d, 1H), 7.42 (s, 1H), 6.78 (d, 1H), 6.57 (d, 1H) 6.5-6.0 (m, 4H), 4.74 (s, 2H), 2.49 (s, 3H), 2.37 (m, 4H), 2.2 (dd, 2H), 2.12 (m, 4H); 2.0 (dd, 2H).

Example 47. 6- {2- [4- (2-Methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylic acid ( E47)

The title compound was prepared following the procedure of Example 45, starting from ethyl 6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (E44) (255 mg, 0.512 mmol). MS (ES) m / z: 488.6 [MH ⁺ ]. C ₂₇ H ₂₆ FN ₅ O ₃ requires 487.53. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.8 (s, 1H), 7.47 (s, 1H), 7.06 (t, 1H), 6.77 (d, 2H) 6.46 (d, 1H), 6.41 (d, 1H), 6.25 (t, 1H), 4.7 (s, 2H), 2.55 (m, 4H), 2.49 ( s, 3H), 249 (m, 4H), 2.36 (dd, 2H), 2.30 (dd, 2H).

Examples 48-53. General procedure for producing amides

To a suspension of carboxylic acid (0.1 mmol) in DMF (1.5 ml) and DIPEA (0.11 mmol), TBTU (0.11 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The corresponding amine (0.11 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was loaded into an SCX cartridge (5 g), the ammonia fractions were evaporated in vacuo to give the desired amide in pure form. The free base is dissolved in dry MeOH and 2.1 equiv. hydrochloric acid (1 M solution in diethyl ether) at 0ºС. The resulting suspension is stirred for 2 hours at 0 ° C. Filtration or evaporation of the solvent and treatment with diethyl ether afforded the desired dihydrochloride salt as a yellow solid.

Example 48. N-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo dihydrochloride [5,1-c ] [1,4] benzoxazine-3-carboxamide (E48)

The title compound was obtained in 52% yield according to the general procedure for the preparation of amides, starting from 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} - 4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E45) (48.3 mg, 0.1 mmol) and methylamine (0.055 ml of a 2 M solution in THF, 0.11 mmol ) MS (ES) m / z: 497.7 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O ₂ requires 496.61. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.51 (br s, 1H), 9.14 (d, 1H), 8.60 (s, 1H), 8.16 (m, 1H), 8.11 (d, 1H), 8.03 (t, 1H), 7.92 (d, 1H), 78.4 (d, 1H), 7.5 (d, 1H), 7, 3 (d, 1H), 7.15 (t, 1H), 5.62 (s, 2H), 4.0-2.9 (m, 11H), 2.99 (s, 3H), 2.74 (d, 3H); 1.48 (d, 3H).

Example 49. Dihydrochloride 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -N-methyl-4H-imidazo [5,1-c] [1, 4] benzoxazine-3-carboxamide (E49)

The title compound was obtained in 61% yield according to the general procedure for the preparation of amides, starting from ethyl 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H- imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (E46) (48.7 mg, 0.1 mmol) and methylamine (0.055 ml of a 2 M solution in THF, 0.11 mmol). MS (ES) m / z: 501.6 [MH ⁺ ]. C ₂₈ H ₂₉ FN ₆ O ₂ requires 500.58. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.39 (br s, 1H), 8.94 (d, 1H), 8.60 (s, 1H), 8.16 (br. m, 1H), 7.82 (m, 3H), 7.43 (d, 1H), 7.25 (d, 1H), 7.15 (t, 1H), 5.59 (s, 2H), 3.75-3.40 (m, 10H), 3.2 (t, 2H), 2.93 (s, 3H), 2.74 (d, 3H).

Example 50. N-methyl-6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxamide (E50)

The title compound was obtained in 72% yield according to the general procedure for the preparation of amides starting from ethyl 6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5, 1-c] [1,4] benzoxazine-3-carboxylate (E47) (47 mg, 0.1 mmol) and methylamine (0.055 ml of a 2 M solution in THF, 0.11 mmol). MS (ES) m / z: 484.6 [MH ⁺ ]. C ₂₇ H ₂₉ N ₇ O ₂ requires 483.57. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.95, 11.14 (s, 1H), 9.69 (d, 1H), 8.62 (s, 1H), 8.17 ( d, 1H), 7.97 (t, 1H), 7.84 (d, 1H), 7.67 (d, 1H), 7.33 (d, 1H), 7.25 (dd, 1H), 7.16 (t, 1H), 5.60 (s, 2H), 3.71 (d, 2H), 3.6 (d, 2H), 3.52, 3.4, 3.19 (form. m, 8H), 3.15 (s, 3H), 2.75 (d, 3H).

Example 51. 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo dihydrochloride [5 , 1-c] [1,4] benzoxazine (E51)

The title compound was obtained in 52% yield according to the general procedure for the preparation of amides, starting from 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} - 4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylic acid (E45) (48.3 mg, 0.1 mmol) and morpholine (0.01 ml, 0.11 mmol). MS (ES) m / z: 553.6 [MH ⁺ ]. C ₃₂ H ₃₆ N ₆ O ₃ requires 552.68. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.7 (br s, 1H), 9.15 (d, 1H), 8.61 (s, 1H), 8.16 (d, 1H), 8.03 (t, 1H), 7.92 (d, 1H), 7.86 (d, 1H), 7.51 (d, 1H), 7.31 (d, 1H), 7, 15 (t, 1H), 5.57 (s, 2H), 4.0-2.9 (m, 19H), 2.99 (s, 3H), 1.48 (d, 3H).

Example 52. Dihydrochloride 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo [5,1-c ] [1,4] benzoxazine (E52)

The title compound was obtained in 61% yield according to the general procedure for the preparation of amides, starting from 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [ 5.1-c] [1.4] benzoxazine-3-carboxylate (E46) (49 mg, 0.1 mmol) and morpholine (0.01 ml, 0.11 mmol). MS (ES) m / z: 557.6 [MH ⁺ ]. C ₃₁ H ₃₃ FN ₆ O ₂ requires 556.64.

Example 53. Dihydrochloride 6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo [5,1-c] [1, 4] benzoxazine (E53)

The title compound was obtained in 72% yield according to the general procedure for the preparation of amides, starting from 6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1- c] [1,4] benzoxazine-3-carboxylic acid (E47) (47 mg, 0.1 mmol) and morpholine (0.055 ml, 0.11 mmol). MS (ES) m / z: 540.6 [MH ⁺ ]. C ₃₀ H ₃₃ N ₇ O ₃ requires 539.64.

Example 54. 3- (3-Methyl-1,2,4-oxadiazol-5-yl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H dihydrochloride -imidazo [5.1-c] [1.4] benzoxazine (E54)

To a suspension of sodium hydride (85 mg of a 60% suspension in oil, 0.22 mmol) in dry THF (5 ml) was added methylcarboxyamide oxime (17 mg, 0.22 mmol), and then after 10 minutes ethyl 6- {2 - [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E1) (100 mg, 0, 2 mmol). After 10 minutes, DMF (1 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 ml) and the reaction mixture was extracted with ethyl acetate (3 × 15 ml). After drying and evaporation of the organic solvents, the crude material is treated with diethyl ether to give the free base of the title compound as a yellow solid (77 mg, 0.15 mmol). The resulting material was dissolved in dry methanol and 2.1 equiv. hydrochloric acid (1 M solution in diethyl ether) at 0ºС. The resulting suspension is stirred for 2 hours at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid in pure form (87 mg). MS (ES) m / z: 508.6 [MH ⁺ ]. C ₂₉ H ₂₉ N ₇ O ₂ requires 507.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.22 (s, 1H), 8.92 (d, 1H), 8.81 (s, 1H), 7.96 (m, 3H) 7.8 (broad d, 1H), 7.45 (d, 1H), 7.31 (d, 1H), 7.20 (t, 1H), 5.7 (s, 2H), 3, 74 (d, 2H), 3.6-3.4 (species m, 8H), 3.21 (m, 2H), 2.90 (s, 3H), 2.40 (s, 3H).

Example 55. Ethyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinolin-3- dihydrochloride carboxylate (E55)

A mixture of ethyl 6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D91) (73 mg, 0.26 mmol) and 2-methyl-5 - [(3R) -3-methyl -1-piperazinyl] quinoline (WO 2004/046124) (75 mg, 0.31 mmol) in 1,2-dichloroethane (4 ml) was stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (66 mg, 0.31 mmol) was added and the resulting mixture was stirred overnight. The crude reaction mixture was evaporated in vacuo and then the residue was purified on an SPE-Si cartridge eluting with 4% MeOH in DCM to give the free base of the title compound as a white solid (95 mg, 72%). The free base (15 mg, 0.03 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.053 ml of a 1.25 M solution in MeOH) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (11 mg, 63%) as a yellow solid. MS (ES) m / z: 508.3 [MH ⁺ ]. C ₃₁ H ₃₄ N ₅ O ₂ requires 507.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.7 (br s, 1H), 9.33 (s, 1H), 9.05 (br s, 1H), 8.5 ( d, 2H), 8.03 (m, 4H), 7.9 (d, 1H), 7.79 (t, 1H), 7.64 (dd, 1H), 7.52 (m, 1H), 4.37 (q, 2H), 3.64 (br.m + water, 11H), 2.95 (s, 3H), 1.50 (d, 2H), 1.37 (t, 3H).

Example 56. Ethyl ester 6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-s] [1,4] benzoxazine- 3-carboxylic acid (E56)

To a solution of 5- (1-piperazinyl) -2- (trifluoromethyl) quinoline (D47) (235 mg, 0.84 mmol) and ethyl 6- (2-oxoethyl) -4H-imidazo [5.1-s] [ 1,4] benzoxazine-3-carboxylate (D6) (200 mg, 0.69 mmol) in dichloroethane (10 ml) sodium triacetoxyborohydride (178 mg, 0.84 mmol) is added. After the mixture was stirred at room temperature overnight, water (15 ml) was added and the reaction product was extracted with DCM (3 × 20 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with DCM / MeOH (98: 2) to give the title compound as a yellow solid (204 mg, 54%). MS (ES; m / z): 552 [MH ⁺ ]. C ₂₉ H ₂₈ F ₃ N ₅ O ₃ requires 551.57. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.69 (d, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.73-7.67 (m, 2H), 7.36 (d, 1H), 7.33 (m, 1H), 7.14 (d, 1H), 7.02 (t, 1H), 5.55 (s, 2H), 4, 40 (q, 2H), 3.15 (m, 4H), 2.98-2.68 (m, 8H), 1.39 (t, 3H).

Example 57. N-Methyl-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxamide (E57)

A solution of trimethylaluminum (2.0 M in hexanes, 226 μl, 0.45 mmol) and methylamine (2.0 M solution in THF, 226 μl, 0.45 mmol) in DCM (1 ml) was stirred at room temperature for 15 minutes. 6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-3- ethyl ester is added carboxylic acid (E56) (45 mg, 0.081 mmol) and stirring is continued for another 3 hours at 40 ° C. Upon completion of the reaction, water is added dropwise until the gas is no longer evolved and the final added volume reaches approximately 3 ml. The aqueous solution was extracted with DCM (3 × 10 ml). In the case where the organic and inorganic phases are not well separated, an aqueous 1 M NaOH solution is added. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by silica gel chromatography eluting with DCM / MeOH mixtures (98: 2-96: 4) to give the title compound as a colorless solid (36 mg, 83%). MS (ES; m / z): 537 [MH ⁺ ]. C ₂₈ H ₂₇ F ₃ N ₆ O ₂ requires 536.56. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (d, 1H), 8.56 (s, 1H), 8.14 (q, 1H), 7.95 (d, 1H) 7.84 (m, 2H), 7.75 (dd, 1H), 7.37 (quint, 1H), 7.24 (dd, 1H), 7.1 (t, 1H), 5.55 ( s, 2H), 3.1 (br s, 4H), 2.89 (t, 2H), 2.8 (m, 4H), 2.76 (d, 3H), 2.67 (t, 2H) ); ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ: -66.05.

Example 58. N, N-Dimethyl-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-c] [1,4 ] benzoxazine-3-carboxamide (E58)

The title compound (12 mg, 40%) was obtained as a colorless solid using the procedure of Example 57 using 6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl ethyl ester } ethyl) -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylic acid (E56) (30 mg, 0.054 mmol) and dimethylamine. MS (ES; m / z): 551 [MH ⁺ ]. C ₂₉ H ₂₉ F ₃ N ₆ O ₂ requires 550.59. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (d, 1H), 8.55 (s, 1H), 7.65 (d, 1H), 7.84 (d, 2H) 7.76 (dd, 1H), 7.37 (quint, 1H), 7.24 (dd, 1H), 7.1 (t, 1H), 5.48 (s, 2H), 3.49 ( broad s, 3H), 3.1 (broad s, 4H), 2.98 (broad s, 3H), 2.89 (t, 2H), 2.78 (broad s, 4H), 2 66 (t, 2H); ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ: -66.05.

Example 59. 3- (4-Morpholinylcarbonyl) -6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5,1-c] [1 , 4] benzoxazine (E59)

The title compound (29 mg, 78%) was obtained as a colorless solid using the procedure of Example 57 using 6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl ethyl ester } ethyl) -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylic acid (E56) (35 mg, 0.063 mmol) and morpholine. MS (ES; m / z): 593 [MH ⁺ ]. C ₃₁ H ₃₁ F ₃ N ₆ O ₃ requires 592.62. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (d, 1H), 8.56 (s, 1H), 7.95 (d, 1H), 7.84 (m, 2H) 7.77 (dd, 1H), 7.37 (quint, 1H), 7.24 (dd, 1H), 7.11 (t, 1H), 5.51 (s, 2H), 4.3 ( very broad s, 2H), 3.66 (m, 4H), 3.6 (very broad s, 2H), 3.1 (broad s, 4H), 2.89 (t, 2H) 2.78 (br s, 4H); 2.68 (t, 2H); ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ: -66.05.

Example 60. Ethyl ester 6- (2- {4- [2-cyano-5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-3- carboxylic acid (E60)

To a solution of 5- (1-piperazinyl) -2-quinolinecarbonitrile (D70) (200 mg, 0.839 mmol) and ethyl 6- (2-oxoethyl) -4H-imidazo [5.1-s] [1,4] benzoxazine -3-carboxylate (D6) (250 mg, 0.873 mmol) in DCM (10 ml) sodium triacetoxyborohydride (266 mg, 1.26 mmol) was added. After the mixture was stirred at room temperature overnight, water (15 ml) was added and the mixture was extracted with DCM (3 × 20 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with ethyl acetate / MeOH mixtures (1: 0-9: 1), to give a yellow solid that contained the title compound (373 mg, HPLC / MS purity 75%). A portion of the resulting material (20 mg) was purified by mass-directed preparative HPLC. MS (ES; m / z): 509 [MH ⁺ ]. C ₂₉ H ₂₈ N ₆ O ₃ requires 508.58. ¹ H-NMR (400 MHz, DMSO-d ₆ ) 5: 8.71 (d, 1H), 8.61 (s, 1H), 8.02 (d, 1H), 7.9-7.7 ( m, 3H), 7.39 (dd, 1H), 7.26 (dd, 1H), 7.12 (t, 1H), 5.56 (s, 2H), 4.28 (quart, 2H), 3.09 (br s, 4H), 2.89 (t s, 2H), 2.78 (br s, 4H), 2.66 (m, 2H), 1.33 (t, 3H); IR (cm ^-1 ): 2230.65 (CN), 1728.58 (CO).

Example 61. Ethyl-7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E61)

To a solution of 7-fluoro-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D59) (200 mg, 0.48 mmol) in THF (5 ml) at 0 ° C add potassium tert-butoxide (57 mg, 0.50 mmol). After stirring at the indicated temperature for 30 minutes, the reaction mixture was cooled to -20 ° C and diethyl chlorophosphate (83 μl, 0.58 mmol) was added. After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to -78 ° C and ethyl isocyanoacetate (57 μl, 0.50 mmol) was added, followed by potassium tert-butoxide (57 mg, 0.50 mmol). The reaction mixture was warmed to room temperature and then stirred overnight. The mixture was then poured into brine (15 ml) and extracted with DCM (3 × 20 ml). The combined organic phases are dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by silica gel chromatography eluting with DCM / MeOH (96: 4) to give the title compound (120 mg, 50%). MS (ES / +) m / z: 516 [MH ⁺ ]. C ₂₉ H ₃₀ FN ₅ O ₃ requires 515. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.4 (d, 1H), 7.9 (s, 1H), 7, 55 (d, 1H), 7.6 (t, 1H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.08 (d, 1H), 6.85 (t, 1H) ), 5.6 (s, 2H), 4.4 (q, 2H) 3.2-2.6 (m, 15H), 1.4 (t, 3H).

Example 62. Dihydrochloride 7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4H-imidazo [5,1-c ] [1,4] benzoxazine (E62)

The title compound was prepared according to the procedure for Example 57 starting from ethyl-7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1 -c] [1,4] benzoxazine-3-carboxylate (E61 free base) and morpholine. MS (ES / +) m / z: 557 [MH ⁺ ]. C ₃₁ H ₃₃ FN ₆ O ₃ requires 556. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.43 (br s, 1H), 8.61 (s, 1H), 8 60 (br s, 1H), 7.95 (dd, 1H), 7.78 (br s, 2H), 7.60 (br s, 1H), 7.32 (br s, 1H ), 7.15 (t, 1H), 5.63 (s, 2H), 4.34 (br s, 2H), 3.79 (d, 2H), 3.7-3.0 (m, 16H), 2.77 (br s, 3H).

Example 63. 7-Fluoro-N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] dihydrochloride [1, 4] benzoxazine-3-carboxamide (E63)

The title compound was prepared according to the procedure for Example 57 starting from ethyl-7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1 -c] [1,4] benzoxazine-3-carboxylate (E61) and N-methylamine. MS (ES / +) m / z: 501 [MH ⁺ ]. C ₂₈ H ₂₉ FN ₆ O ₂ requires 500. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.64 (br s, 1H), 8.93 (br s, 1H) 8.60 (s, 1H), 8.2 (q, 1H), 7.9 (m, 3H), 7.82 (br s, 1H), 7.46 (br.s. 1H), 7.15 (t, 1H), 7.15 (t, 1H), 5.67 (s, 2H), 3.8 (d, 2H), 3.7-3.0 (m, 8H), 3 22 (m, 2H), 2.9 (br s, 3H), 2.78 (d, 3H).

Examples 64 and 65

7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (E64) and

7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carbonitrile dihydrochloride (E64)

A mixture of ethyl 7-fluoro-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 -carboxylate (E61) (47 mg, 0.09 mmol), trimethylaluminium (230 μl of a 2 M solution in hexanes, 0.45 mmol) and ammonia (0.91 ml of a 0.5 M solution in 1,4-dioxane, 0 , 45 mmol) in DCM (3 ml) is exposed to microwave radiation at 100 ° C for 1 hour. The reaction mixture was dissolved in MeOH (1 ml) and purified on SPE- (SCX) and then using silica gel column chromatography eluting with DCM / MeOH (97: 3) to give the title compounds E64 (9 mg) and E65 ( 17 mg).

Example 64. MS (ES / +) m / z: 487 [MH ⁺ ]. C ₂₇ H ₂₇ FN ₆ O ₂ requires 486. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.4 (broad s, 1H), 8.8 (broad s, 1H) 8.59 (s, 1H); 7.94 (dd, 1H); 7.85 (broad s, 2H); 7.72 (broad s, 1H); 7.57 (broad s, 1H) ), 7.39 (br s, 1H), 7.36 (br s, 1H), 7.15 (t, 1H), 5.66 (s, 2H), 3.8 (m, 2H) 3.7-3 (m, 10H); 2.83 (br s, 3H).

Example 65. MS (ES / +) m / z: 469 [MH ⁺ ]. C ₂₇ H ₂₅ FN ₆ O requires 468. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.51 (br 1H), 8.79 (s, 1H), 8.8 ( broad s, 1H), 7.99 (dd, 1H), 7.85 (broad s, 2H), 7.71 (broad s, 1H), 7.38 (broad s, 1H), 7 21 (t, 1H); 5.61 (s, 2H); 3.79 (m, 2H); 3.6-3.1 (m, 10H); 2.83 (br s, 3H).

Example 66. Ethyl-4-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E66)

To a solution of 2-methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D61) (150 mg, 0.36 mmol) in THF (5 ml) at 0 ° C add potassium tert-butoxide (42 mg, 0.37 mmol). After stirring at the indicated temperature for 30 minutes, the mixture was cooled to -20 ° C and diethyl chlorophosphate (62 μl, 0.43 mmol) was added. After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to -78 ° C and ethyl isocyanoacetate (42 μl, 0.37 mmol) was added, followed by potassium tert-butoxide (42 mg, 0.37 mmol). The reaction mixture was warmed to room temperature and then stirred overnight. The mixture was then poured into brine (15 ml) and extracted with DCM (3 × 20 ml). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to give a crude reaction product, which was purified using silica gel chromatography eluting with DCM / MeOH (97: 3) to give the title compound (60 mg, 30%) . MS (ES / +) m / z: 512 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7, 55 (t, 1H), 7.3-7-0 (m, 6H), 6.15 (q, 1H), 3.2-2.6 (m, 15H), 1.5 ppm. (d, 3H).

Example 67. Dihydrochloride N, 4-dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1,4] benzoxazine-3-carboxamide (E67)

The title compound was obtained in 42% yield according to the procedure of Example 57, starting from ethyl-4-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (E66) and methylamine. MS (ES / +) m / z: 497 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O ₂ requires 496. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.72 (broad s, 1H), 8.88 (broad s, 1H) 8.6 (s, 1H), 8.17 (q, 1H), 7.91 (br s, 2H), 7.87 (d, 1H), 7.8 (m, 1H), 7, 44 (m, 1H), 7.28 (d, 1H), 7.17 (t, 1H), 6.18 (q, 1H), 3.78 (m, 2H), 3.6-3.1 (m, 8H), 3.19 (m, 2H), 2.88 (br s, 3H), 2.77 (d, 3H), 1.51 (d, 3H).

Example 68. Ethyl-7-fluoro-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-c] [1,4 ] benzoxazine-3-carboxylate (E68)

To a solution of 7-fluoro-8- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -2H-1,4-benzoxazin-3 (4H) -one (D64) (165 mg, 0.35 mmol) in THF (5 ml) at 0 ° C add potassium tert-butoxide (350 μl of a 1 M solution in THF, 0.35 mmol). After stirring at the indicated temperature for 30 minutes, the mixture was cooled to -20 ° C and diethyl chlorophosphate (60 μl, 0.42 mmol) was added. After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to -78 ° C and ethyl isocyanoacetate (40 μl, 0.35 mmol) was added, followed by potassium tert-butoxide (350 μl of a 1 M solution in THF, 0.35 mmol). The reaction mixture was warmed to room temperature and then stirred overnight. The mixture was then poured into brine (15 ml) and extracted with DCM (3 × 20 ml). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to a residue which was purified using silica gel column chromatography eluting with DCM / MeOH (97: 3) to give the title compound (50 mg, 25%). MS (ES / +) m / z: 570 [MH ⁺ ]. C ₂₉ H ₂₇ F ₄ N ₅ O ₃ requires 569. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 7.70 (m, 1H), 7.8-7.6 (m, 3H), 7.2 (m, 1H), 6.7-6.6 (m, 2H), 5.6 (s, 2H), 4.4 (q, 2H), 3.1-2.6 (m, 12H), 1.4 (t, 3H).

Example 69. Hydrochloride 7-fluoro-N-methyl-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5,1-c] [ 1,4] benzoxazine-3-carboxamide (E69)

The title compound was prepared in 50% yield according to the procedure of Example 57, starting from ethyl-7-fluoro-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H -imidazo [5,1-c] [1,4] benzoxazine-3-carboxylate (E68) and methylamine. MS (ES / +) m / z: 555 [MH ⁺ ]. C ₂₈ H ₂₆ F ₄ N ₆ O ₂ requires 554. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 7.95 (d, 1H), 7.9 (s, 1H), 7.8-7.7 (m, 3H), 7.35-7.25 (m, 2H), 6.85 (t, 1H), 5.6 (s, 2H), 3.1-2.6 (m, 15H).

Example 70. 7-Fluoro-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo hydrochloride [5.1-c] [1.4] benzoxazine-3-carbonitrile (E70)

A mixture of ethyl 7-fluoro-6- (2- {4- [2- (trifluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E68) (25 mg, 0.043 mmol), trimethylaluminum (110 μl of a 2 M solution in hexanes, 0.213 mmol) and ammonia (0.43 ml of a 0.5 M solution in 1,4-dioxanes, 0.213 mmol) in DCM (3 ml) is exposed to microwave radiation at 100 ° C for 1 hour. The reaction mixture was dissolved in MeOH (1 ml) and purified on SPE- (SCX), and then the title compound (4 mg, 18%) was obtained using mass-directed preparative HPLC. MS (ES / +) m / z: 523 [MH ⁺ ]. C ₂₇ H ₂₂ F ₄ N ₆ O requires 522. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.7 (d, 1H), 8 (s, 1H), 7.95 (d, 1H), 7.8-7.7 (m, 2H), 7.4-7.25 (m, 2H), 6.9 (t, 1H), 5.6 (s, 2H), 3.1-2.6 (m, 12H).

Example 71. Ethyl-7-fluoro-6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine -3-carboxylate (E71)

To a solution of 7-fluoro-8- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D67) (90 mg, 0.21 mmol) in THF (5 ml) at 0 ° C add potassium tert-butoxide (215 μl of a 1 M solution in THF, 0.22 mmol). After stirring at the indicated temperature for 30 minutes, the mixture was cooled to -20 ° C and diethyl chlorophosphate (45 μl, 0.25 mmol) was added. After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to -78 ° C and ethyl isocyanoacetate (29 μl, 0.21 mmol) was added, followed by potassium tert-butoxide (215 μl of a 1 M solution in THF, 0.22 mmol). The reaction mixture was warmed to room temperature and then stirred overnight. The mixture was then poured into brine (15 ml) and extracted with DCM (3 × 20 ml). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to a residue which was purified using silica gel chromatography eluting with DCM / MeOH (96: 4) to give the title compound (20 mg, 20%). MS (ES / +) m / z: 517 [MH ⁺ ]. C ₂₈ H ₂₉ FN ₆ O ₃ requires 516. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.5 (s, 1H), 8.0 (s, 1H), 7, 75 (t, 1H), 7.6 (d, 1H), 7.4-7.3 (m, 1H), 7.05 (d, 1H), 6.85 (t, 1H), 5.6 (s, 2H), 4.4 (q, 2H), 3.4-2.6 (m, 15H), 1.45 (t, 3H).

Example 72. Dihydrochloride 7-fluoro-N-methyl-6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5,1-c] [1, 4] benzoxazine-3-carboxamide (E72)

The title compound was prepared in 50% yield according to the procedure of Example 57, starting from ethyl-7-fluoro-6- {2- [4- (2-methyl-5-quinazolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1.4] benzoxazine-3-carboxylate (E71) and methylamine. MS (ES / +) m / z: 502 [MH ⁺ ]. C ₂₇ H ₂₈ FN ₇ O ₂ requires 501. ¹ H-NMR (400 MHz, DMSO) δ (ppm): 10.5 (br s, 1H), 9.63 (s, 1H), 8 60 (s, 1H), 8.18 (q, 1H), 7.9 (m, 2H), 7.62 (d, 1H), 7.30 (d, 1H), 7.14 (t, 1H), 5.66 (s, 2H), 3.78 (d, 2H), 3.61 (t, 2H), 3.5-3.3 (m, 4H), 3.30 (t, 2H) ), 3.19 (dd, 2H), 2.79 (s, 3H), 2.77 (d, 3H).

Example 73. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- dihydrochloride carboxylate (E73)

A mixture of ethyl 6- (1-methyl-2-oxoethyl) -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (D53) (151 mg, 0.50 mmol) and 2- methyl 5-piperazin-1-ylquinoline (WO 2004/046124) (108 mg, 0.48 mmol) in dry 1,2-dichloroethane (12.5 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added and the resulting mixture was stirred for 18 hours, then the reaction was quenched with water (30 ml) and the mixture was extracted with ethyl acetate (3 × 25 ml). The combined organic phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product is purified on an SPE cartridge (silica gel) eluting with a mixture of 2% MeOH in DCM to give the title compound as a colorless oil (200 mg, 78%). MS (ES) m / z: 512.4 [MH ⁺ ]. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.36 (d, 1H), 7.98 (s, 1H), 7.69 (d, 1H), 7.54 ( t, 1H), 7.33 (d, 1H), 7.25-7.22 (m, 1H + CDCl ₃ ), 7.17 (d, 1H), 7.12-6.96 (m, 2H ), 5.52 (s, 2H), 4.39 (q, 2H), 3.51 (m, 1H), 3.10-3.0 (m, 4H), 2.76-2.5 ( m, 9H), 1.41 (t, 3H), 1.30 (d, 3H).

Examples 74 and 75

N-methyl-6- {1-methyl-2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine dihydrochloride -3-carboxamide:

enantiomer 1 (E74),

enantiomer 2 (E75)

A mixture of trimethylaluminum (214 μl of a 2.0 M solution in hexanes, 0.43 mmol) and methylamine (214 μl of a 2.0 M solution in THF, 0.43 mmol) in DCM (1.7 ml) was stirred at room temperature for 15 minutes. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (free base E73) (44 mg, 0.086 mmol) and stirring is continued for another 2 hours at 54 ° C. Upon completion of the reaction, water is added dropwise until the gas is no longer evolved and the final added volume reaches approximately 4 ml. The aqueous solution was extracted with DCM (3 × 10 ml). In the case where the organic and inorganic phases are not well separated, an aqueous 1 M NaOH solution is added. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to give the free base of the title compound (30 mg). The racemic mixture was then separated by SFC (Gilson) semi-preparative chromatography [CHIRALCEL AD-H, 25 × 2.1 cm; modifier 30% (ethanol + 0.1% isopropylamine), flow rate = 22 ml / min; pressure 192 bar; T = 36ºС; UV wavelength 220 nm; loop = 1 ml, and enantiomer 1 (5 mg) and enantiomer 2 (8 mg) are obtained. The enantiomeric excess of both enantiomers is confirmed by analytical SFC (Berger) under the following conditions: CHIRALCEL AD-H chiral column, 25 × 0.46 cm; modifier 30% (ethanol + 0.1% isopropylamine), flow rate = 2.5 ml / min; pressure 180 bar; T = 35ºС; UV wavelength 220 nm; loop = 10 μl.

Enantiomer 1 (E74) - (a / a UV 100%, retention time 17.5 min, e.i. (ee) = 100%).

Enantiomer 2 (E75) - (a / a UV 100%, retention time 25.6 min, e.i. = 100%).

Free base E74 was dissolved in dry methanol (1 ml) and HCl (8 μl of a 1.25 M solution in MeOH, 0.1 mmol) was gradually added at 0 ° C. The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (4 mg).

The free base E75 is dissolved in dry methanol (1 ml) and HCl (13 μl of a 1.25 M solution in MeOH, 0.1 mmol) is gradually added at 0 ° C. The resulting suspension is stirred at 0 ° C for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (5.3 mg).

Enantiomer 1 (E74): ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 9.70 (br s, 1H), 8.58 (s, 1H), 8.42 (br s, 1H ), 8.15 (br s, 1H), 7.84 (d, 2H), 7.67 (br s, 2H), 7.46 (br s, 1H), 7.34 (d, 1H), 7.19 (m, 1H), 5.62 (s, 2H), 3.8-3.1 (br.m, 11H + water), 2.74 (d, 3H), 2.67 (s, 3H); 1.37 (d, 3H).

Enantiomer 2 (E75): ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 9.48 (br s, 1H), 8.58 (s, 1H), 8.36 (m, 1H), 8.14 (d, 1H), 7.84 (d, 2H), 7.64 (m, 2H), 7.42 (m, 1H), 7.34 (d, 1H), 7.17 (m , 1H), 5.62 (s, 2H), 3.8-3.1 (br.m, 11H + water), 2.98 (s, 3H), 2.74 (d, 3H), 1, 37 (d, 3H).

Example 76. Dihydrochloride 6- {2- [4- (7-fluoro-2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3-methyl-4H- [1,2,3] triazolo [5, 1-c] [1.4] benzoxazine (E76)

The title compound was prepared following the general reductive amination procedure of Example 1, starting from (3-methyl-4H- [1,2,3] triazolo [5.1-s] [1,4] benzoxazin-6-yl) acetaldehyde (D41) (20 mg, 0.087 mmol) and 7-fluoro-2-methyl-5- (1-piperazinyl) quinoline (WO 2004/046124) (32 mg, 0.131 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-3%) to give the free base of the title compound (27 mg, 68%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (4: 1, 5 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 459.20 [MH ⁺ ]. C ₂₆ H ₂₇ FN ₆ O requires 458.54. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.57 (broad s, 1H), 8.52 (broad d, 1H), 7.93 (dd, 1H), 7.53 ( d, 1H), 7.47 (d, 1H), 7.36 (dd, 1H), 7.24 (m, 2H), 5.57 (s, 2H), 3.75 (d, 2H), 3.60-3.10 (br.p.m, 10H), 2.73 (s, 3H), 2.34 (s, 3H).

Example 77. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate dihydrochloride (E77 )

To a solution of 5- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3,4-dihydro-2 (1H) -quinolinone (D74) (334 mg, 0.835 mmol) and Potassium tert-butoxide (140 mg, 1.25 mmol) in dry DMF (15 ml) was added diethyl chloroformate (0.24 ml, 1.67 mmol) at -5 ° C. After 20 minutes, a solution of ethyl isocyanoacetate (0.14 ml, 1.25 mmol) and potassium tert-butoxide (140 mg, 1.25 mmol) in dry DMF (2 ml) was added. The reaction mixture was stirred at room temperature for 24 hours, then the reaction was quenched with water (5 ml) and the mixture was extracted with DCM (3 × 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated in vacuo, and the crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (116 mg , 28%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 4 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 496.2 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₂ requires 495.62. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.87 (br s, 1H), 8.66 (br s, 1H), 8.57 (s, 1H), 7.81 ( m, 3H), 7.63 (br s, 1H), 7.43 (t, 1H), 7.35 (br s, 1H), 7.29 (d, 1H), 4.29 (q , 2H), 3.78 (d, 2H), 3.52-3.35 (m, 6H), 3.40-3.20 (m, 6H), 3.05 (m, 2H), 2, 79 (s, 3H); 1.33 (t, 3H).

Example 78. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E78)

The title compound was prepared according to the procedure for Example 57, starting from ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a ] quinoline-3-carboxylate (E77 free base) (53 mg, 0.107 mmol) and methylamine. The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-3%) to give the free base of the title compound (33 mg, 65%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (3: 1, 4 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 481.20 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O requires 480.61. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.52 (br s, 1H), 8.55 (br s, 1H), 8.49 (s, 1H), 8.00 ( q, 1H), 7.79 (d, 1H), 7.76 (br s, 2H), 7.58 (br s, 1H), 7.41 (t, 1H), 7.32 (br s, 1H), 7.27 (d, 1H), 3.79 (d, 2H), 3.52-3.30 (m, 6H), 3.40-3.20 (m, 6H), 3.00 (m, 2H); 2.77 (2s, 6H).

Example 79. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinylcarbonyl) -4,5-dihydroimidazo [1,5-a] quinoline (E79)

The title compound was obtained in 82% yield according to the procedure of Example 57, starting from ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1 , 5-a] quinoline-3-carboxylate (E77 free base) (53 mg, 0.107 mmol) and morpholine. The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-5%) to give the free base of the title compound (47 mg, 82%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (4: 1, 5 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 537.40 [MH ⁺ ]. C ₃₂ H ₃₆ N ₆ O ₂ requires 536.68. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.65 (br s, 1H), 8.57 (br s, 1H), 8.50 (s, 1H), 7.79 ( d, 1H), 7.77 (br s, 2H), 7.58 (br s, 1H), 7.42 (t, 1H), 7.31 (br s, 1H), 7.28 (d, 1H), 4.18 (br s, 2H), 3.78 (d, 2H), 3.66 (m, 6H), 3.52-3.30 (m, 6H), 3, 40-3.20 (m, 6H), 3.00 (m, 2H), 2.77 (s, 3H).

Example 80. Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine -3-carboxylate (E80)

To a solution of 7-methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2H-1,4-benzoxazin-3 (4H) -one (D80) (50 mg, 0.120 mmol) in THF (3 ml) at 0 ° C add potassium tert-butoxide (132 μl of a 1 M solution in THF, 0.132 mmol). After stirring at 0 ° C for 20 minutes, the reaction mixture was cooled to -20 ° C and diethyl chlorophosphate (22 μl, 0.156 mmol) was gradually added. After stirring at 0 ° C for 30 minutes, the reaction mixture was cooled to -78 ° C and ethyl isocyanoacetate (15 μl, 0.132 mmol) was added, followed by potassium tert-butoxide (132 μl of a 1 M solution in THF, 0.132 mmol). After stirring at ambient temperature for 4 hours, the reaction was quenched with a saturated aqueous solution of NH ₄ Cl (4 ml) and the mixture was extracted with DCM (3 × 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated in vacuo, the crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-3%) to give the title compound (29 mg, 48%) . MS (ES) m / z: 512.40 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511.62.

Example 81. N, 7-Dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo dihydrochloride [5.1-s] [1.4] benzoxazine-3-carboxamide (E81)

The title compound was prepared according to the procedure for Example 57, starting from ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1 -c] [1,4] benzoxazine-3-carboxylate (E80) (29 mg, 0.06 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-3%) to give the free base of the title compound (24 mg, 86%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (4: 1, 5 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 497.20 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O ₂ requires 496.61. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.50 (br s, 1H), 8.70 (br s, 1H), 8.53 (s, 1H), 8.14 (q, 1H), 7.80 (br s, 2H), 7.72 (d, 1H), 7.64 (br s, 1H), 7.35 (br s, 1H), 7.03 (d, 1H), 5.58 (s, 2H), 3.79 (d, 2H), 3.60-3.10 (m, 8H), 3.15 (m, 2H ), 2.78 (s, 3H), 2.74 (d, 3H), 2.39 (s, 3H).

Example 82. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate dihydrochloride (E82 )

The title compound was prepared following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D86) (50 mg, 0.18 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (WO 2004/046124) (60 mg, 0.26 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-3%) to give the free base of the title compound (75 mg, 84%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in MeOH / DCM mixture (4: 1, 5 ml) at 0 ° C gives the title compound as a solid. MS (ES) m / z: 495.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₄ O ₂ requires 494.64. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.07 (br.s, 1H), 9.29 (br.s, 1H), 8.66 (s, 1H), 8.23 ( d, 1H), 8.09 (t, 1H), 7.98 (d, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.43 (t, 1H), 7.32 (d, 1H), 4.29 (q, 2H), 3.85 (m, 1H), 3.80 (broad d, 2H), 3.7-3.2 (broad m, 8H), 3.06 (t, 2H), 2.97 (s, 3H), 2.30 (m, 2H), 2.12 (broad d, 2H), 1.33 (t, 3H).

Example 83. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E83)

The title compound was prepared according to the procedure for Example 57, starting from ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a ] quinoline-3-carboxylate (E82 free base) (33 mg, 0.07 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a MeOH gradient in DCM (1-5%) to give the free base of the title compound (25 mg, 78%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a MeOH / DCM mixture (1: 1, 2 ml) at 0 ° C gives the title compound as a solid. MS (ES) m / z: 480.3 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O requires 479.62. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.25 (br s, 1H), 8.72 (br s, 1H), 8.47 (s, 1H), 7.97 ( d, 1H), 7.92 (broad s, 1H), 7.80 (broad s, 1H), 7.77 (d, 1H), 7.61 (broad s, 1H), 7.50 (broad s, 1H), 7.38 (t, 1H), 7.26 (d, 1H), 3.78 (d, 2H), 3.72 (m, 1H), 3.6-3, 1 (br.m, 8H), 2.98 (t, 2H), 2.74 (m, 6H), 2.12 (m, 4H).

Example 84. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (E84)

The title compound was obtained in 70% yield from 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3 -carboxylate (E180) (122 mg, 0.261 mmol), following the general procedure for the preparation of amides (see examples 48-53), using hexamethyldisilazane (1.1 eq.). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in a MeOH / DCM mixture (1: 1, 6 ml) at 0 ° C gives the title compound as a solid. MS (ES) m / z: 467.30 [MH ⁺ ]. C ₂₈ H ₃₀ N ₆ O requires 466.59. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.50 (br s, 1H), 8.50 (br s, 1H), 8.46 (s, 1H), 7.77 ( d, 1H), 7.72 (s, 2H), 7.52 (br s, 1H), 7.40 (t, 1H), 7.35 (s, 1H), 7.26 (br s , 1H), 7.25 (d, 1H), 7.14 (s, 1H), 3.76 (d, 2H), 3.50 (d, 4H), 3.4-3.1 (br. m, 8H), 2.98 (t, 2H), 2.71 (s, 3H).

Example 85. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate dihydrochloride (E85)

A mixture of ethyl 6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D91) (30 mg, 0.11 mmol) and 2-methyl-5-piperazin-1-ylquinoline (WO 2004 / 046124) (30 mg, 0.13 mmol) in 1,2-dichloroethane was stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (27.5 mg, 0.13 mmol) was added and the resulting reaction mixture was stirred for 8 hours, the reaction was quenched with saturated aqueous NaHCO ₃ solution (10 ml) and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with 2% MeOH in DCM to give the free base of the title compound as a white solid (17 mg, 31%). The free base (16 mg, 0.032 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.057 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (17 mg, 94%) as a yellow solid. MS (ES) m / z: 494.20 [MH ⁺ ]. C ₃₀ H ₃₁ N ₅ O ₂ requires 493.61. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 10.8 (br s, 1H), 9.3 (s, 1H), 8.6-8.4 (m, 2H), 7, 9-7.8 (m, 2H), 7.9-7.6 (m, 3H), 7.6-7.4 (m, 2H), 7.25 (br s, 1H), 4, 3 (q, 2H), 3.9-3.2 (br.m + water, 12H), 2.8 (s, 3H), 1.35 (t, 3H).

Example 86. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate dihydrochloride (E86)

A mixture of ethyl 6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D91) (115 mg, 0.41 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (WO 2004/046124) (111 mg, 0.49 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (104 mg, 0.49 mmol) was then added and the resulting reaction mixture was stirred for 6 hours and then concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 5% MeOH in DCM to give the free base of the title compound as a white solid (105 mg, 52%). The free base (15 mg, 0.03 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.054 ml of a 1.25 M solution in MeOH) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (16 mg, 94%) as a pale yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.12 (br s, 1H), 9.32 (s, 1H), 8.86 (br s, 1H), 8.52 ( d, 1H), 8.1-8.0 (dd + broad m, 3H), 7.88 (broad m, 1H), 7.79 (t, 1H), 7.68 (broad m, 1H), 7.61 (d, 1H), 7.60 (br.m, 1H), 4.38 (q, 2H), 3.81 (m, 3H), 3.63 (m, 3H), 3.3 (m + water, 4H), 2.8 (s, 3H), 2 28 (q, 2H), 2.14 (d, 2H), 1.39 (t, 3H).

Example 87. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E87)

A solution of trimethylaluminum (0.19 ml of a 2.0 M solution in hexanes, 0.37 mmol) and methylamine (0.19 ml of a 2.0 M solution in THF, 0.37 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E85 free base) was added (35 mg, 0.074 mmol) in dry DCM (1 ml) and stirring is continued for an additional 6 hours at 56 ° C. Upon completion of the reaction at 0 ° C, water is added dropwise, followed by a 1 M NaOH solution until the organic and aqueous phases are separated. The mixture was extracted with DCM (3 × 10 ml), and the combined organic phases were dried (Na ₂ SO ₄ ) and then evaporated in vacuo. The residue was taken up in diethyl ether to give the free base of the title compound as a white solid (29 mg, 76%). The free base (22.5 mg, 0.047 mmol) was dissolved in dry MeOH (1 ml) and treated with HCl (0.083 ml of a 1.25 M solution in MeOH) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (22 mg, 85%) as a yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.19 (br s, 1H), 9.26 (s, 1H), 8.7 (br s, 1H), 8.47 ( d, 1H), 8.23 (q, 1H), 8.13 (d, 1H), 7.87 (d, 1H), 7.9-7.6 (broad m, 3H), 7.75 (t, 1H), 7.55 (d, 1H), 7.38 (br.s, 1H), 3.84 (br.s, 2H), 3.7-3.2 (br.m + water , 10H); 2.83 (s, 3H); 2.80 (s, 3H).

Example 88. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide (E88)

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E85 free base) (31 mg, 0.063 mmol) and potassium hydroxide (0.4 ml of a 1 M solution in MeOH) is stirred at 80 ° C for 2 hours. After purification on SPE-SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-ammonium carboxylate (0.063 mmol) was recovered and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.016 ml, 1.1 eq.). Then the reaction mixture was evaporated in vacuo and the residue was purified by SCX. The free base (15 mg, 0.032 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.071 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (16 mg, overall yield 47%). MS (ES) m / z: 465.2 [MH ⁺ ]. C ₂₈ H ₂₈ N ₆ O requires 464.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.42 (br s, 1H), 9.23 (s, 1H), 8.88 (br s, 1H), 8.46 ( d, 1H), 8.1 (br.s.d, 1H), 7.93 (br.s, 2H), 7.87 (d, 1H), 7.8 (br.s, 1H), 7.73 (t, 1H), 7.58 (br s, 1H), 7.54 (d, 1H), 7.45 (br s, 1H), 7.25 (br s, 1H), 3, 82 (d, 2H), 3.6 (dd, 2H), 3.54 (d, 2H), 3.5-3.2 (m + water, 6H), 2.88 (s, 3H).

Example 89. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E89)

A solution of trimethylaluminum (0.1 ml of a 2.0 M solution in hexanes, 0.2 mmol) and methylamine (0.1 ml of a 2.0 M solution in THF, 0.2 mmol) in dry DCM (0.5 ml) is stirred at room temperature for 15 minutes Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E86 free base) (20 mg, 0 , 04 mmol) in dry DCM (1 ml) and stirring is continued for an additional 8 hours at 60 ° C. Upon completion of the reaction at 0 ° C, water is added dropwise, followed by a 1 M NaOH solution until the organic and aqueous phases are separated. The mixture was extracted with DCM (3 × 10 ml), and the combined organic phases were dried (Na ₂ SO ₄ ) and then evaporated in vacuo. The residue was taken up in diethyl ether to give the free base of the title compound as a white solid (19 mg, 98%). The free base (18 mg, 0.038 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.067 ml of a 1.25 M solution in MeOH) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (18 mg, 86%) as a pale yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.93 (br s, 1H), 9.23 (s, 1H), 8.69 (br s, 1H), 8.44 ( d, 1H), 8.21 (d, 1H), 8.1 (d, 1H), 7.86 (d, 1H), 7.72 (t, 1H), 7.54 (d, 1H), 8.0-7.4 (br.m, 4H), 3.82 (d, 2H), 3.74 (t, 1H), 3.58 (t, 2H), 3.5-3.2 ( m + water, 4H), 2.81 (d, 3H), 2.71 (s, 3H), 2.23 (q, 2H), 2.11 (d, 2H).

Example 90. N- (Cyclopropylmethyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E90)

A solution of trimethylaluminum (0.15 ml of a 2.0 M solution in hexanes, 0.3 mmol) and cyclopropanemethylamine (0.021 ml, 0.3 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E86 free base) (30 mg, 0.061) was added mmol) in dry DCM (1 ml) and stirring is continued for another 8 hours at 60 ° C. Upon completion of the reaction at 0 ° C, water is added dropwise, followed by a 1 M aqueous NaOH solution until the organic and aqueous phases are separated. The aqueous mixture was extracted with DCM (3 × 10 ml), and the combined organic phases were dried (Na ₂ SO ₄ ) and then evaporated in vacuo. The residue was taken up in diethyl ether to give the free base of the title compound as a white solid (31 mg, 100%). The free base (30 mg, 0.061 mmol) was dissolved in dry MeOH (1 ml) and treated with HCl (0.107 ml of a 1.25 M solution in MeOH) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (30 mg, 83%) as a pale yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.04 (br s, 1H), 9.25 (s, 1H), 8.74 (br s, 1H), 8.46 ( d, 1H), 8.25 (t, 1H), 8.1 (d, 1H), 7.87 (d, 1H), 8.0-7.4 (br.m, 4H), 7.72 (t, 1H), 7.54 (d, 1H), 3.82 (d, 2H), 3.75 (t, 1H), 3.59 (m, 2H), 3.5-3.1 ( broad m + water, 4H), 3.17 (t, 2H), 2.73 (s, 3H), 2.25 (q, 2H), 2.11 (d, 2H), 1.08 (m , 1H), 0.42 (d, 2H), 0.26 (d, 2H).

Example 91. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E91)

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E86 free base) (40 mg, 0.081 mmol) and potassium hydroxide (0.49 ml of a 1 M solution in MeOH) is stirred at 80 ° C for 2 hours. After purification on SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-ammonium carboxylate is recovered and used without further purification to obtain the free base of the title compound following the general procedure for preparing amides using hexamethyldisilazane (0.021 ml, 1.1 eq.). The reaction was then evaporated in vacuo and the residue purified by SCX to give the title compound as a free base (20 mg, 0.043 mmol), which was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.076 ml 1.25 M solution in ethanol) at 0ºС. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a pale yellow solid (20 mg, 46% overall yield). MS (ES) m / z: 464.2 [MH ⁺ ]. C ₂₉ H ₂₉ N ₅ O requires 463.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.43 (br s, 1H), 9.3 (br s, 1H), 9.22 (s, 1H), 8.45 ( d, 1H), 8.26 (broad d, 1H), 8.08 (d, 2H), 7.96 (broad d, 1H), 7.91 (d, 1H), 7.73 (m , 2H), 7.58 (br s, 1H), 7.55 (d, 1H), 7.25 (br s, 1H), 3.82 (d, 2H), 3.61 (dd, 2H), 3.6-3.2 (m + water, 5H), 2.96 (s, 3H), 2.32 (q, 2H), 2.11 (d, 2H).

Example 92. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} tetrazolo [1,5-a] quinoline (E92)

A mixture of tetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D93) (50 mg, 0.24 mmol) and 2-methyl-5-piperazin-1-yl-quinoline (WO 2004/046124) (60 mg, 0, 29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was then added, and the resulting reaction mixture was stirred overnight and then concentrated in vacuo. The residue was purified on an SPE-Si cartridge eluting from DCM to a mixture of 4% MeOH in DCM to give the free base of the title compound as a white solid (83 mg, 81%). The free base (80 mg, 0.19 mmol) was dissolved in dry MeOH (1.5 ml) and treated with HCl (0.33 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (82 mg, 87%) as a yellow solid. MS (ES) m / z: 424.0 [MH] ⁺ . C ₂₅ H ₂₅ N ₇ requires 423.5. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.88 (br s, 1H), 8.92 (br s, 1H), 8.71 (d, 1H), 8.63 ( d, 1H), 8.20 (d, 1H), 8.0 (t, 1H), 8.0 (m, 2H), 7.8 (d, 1H), 7.8 (m, 1H), 7.47 (broad d, 1H), 3.83 (d, 2H), 3.77 (dd, 1H), 3.7-3.3 (broad m + water, 8H), 2.91 ( s, 3H).

Example 93. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} tetrazolo [1,5-a] quinoline (E93)

A mixture of tetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D93) (50 mg, 0.24 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (WO 2004/046124) (66 mg, 0 , 29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was then added, and the resulting reaction mixture was stirred overnight and then concentrated in vacuo. The residue was purified on an SPE-Si cartridge eluting from DCM to a mixture of 4% MeOH in DCM to give the free base of the title compound as a white solid (66 mg, 65%). The free base (60 mg, 0.14 mmol) was dissolved in dry MeOH (1.5 ml) and treated with HCl (0.25 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (62 mg, 89%) as a pale yellow solid. MS (ES) m / z: 423.0 [MH] ⁺ . C ₂₆ H ₂₆ N ₆ requires 422.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.14 (br s, 1H), 8.84 (br s, 1H), 8.68 (d, 1H), 8.63 ( d, 1H), 8.20 (d, 1H), 8.0 (t, 1H), 8.1-7.8 (broad m, 2H), 7.82 (d, 1H), 7.69 (broad s, 1H), 7.56 (broad s, 1H), 3.83 (d, 2H), 3.74 (dd, 2H), 3.5-3.2 (broad m + water 5H), 2.78 (s, 3H), 2.26 (q, 2H), 2.12 (d, 2H).

Example 94. 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} tetrazolo [1,5-a] quinoline dihydrochloride (E94)

A mixture of tetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D93) (50 mg, 0.24 mmol) and 2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (WO 2004 / 046124) (70 mg, 0.29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was then added, and the resulting reaction mixture was stirred overnight and then concentrated in vacuo. The residue was purified on an SPE-Si cartridge eluting from DCM to a mixture of 4% MeOH in DCM to give the free base of the title compound as a white solid (64 mg, 61%). The free base (60 mg, 0.14 mmol) was dissolved in dry MeOH (1.5 ml) and treated with HCl (0.24 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 4 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (64 mg, 90%) as a yellow solid. MS (ES) m / z: 438.0 [MH] ⁺ . C ₂₆ H ₂₇ N ₇ requires 437.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.70 (br s, 1H), 8.8 (br s, 1H), 8.69 (d, 1H), 8.63 ( d, 1H), 8.20 (d, 1H), 8.0 (t, 1H), 7.9-7.8 (br s, 2H), 7.85 (d, 1H), 7.69 (broad s, 1H), 7.38 (broad s, 1H), 3.96 (d, 2H), 3.9-3.1 (m + water, 8H), 3.82 (m, 1H ), 2.82 (s, 3H), 1.47 (d, 3H).

Example 95. 6- (2- {4- [2- (Difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) tetrazolo [1,5-a] quinoline dihydrochloride (E95)

A mixture of tetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D93) (50 mg, 0.24 mmol) and 2- (difluoromethyl) -5- (1-piperazinyl] quinoline (D143) (76 mg, 0, 29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes, then Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added, the resulting reaction mixture was stirred overnight and then concentrated in vacuo. purified on a SPE-Si cartridge eluting from DCM to a mixture of 4% MeOH in DCM to give the free base of the title compound as a white solid (48 mg, 44%). base (45 mg, 0.098 mmol) was dissolved in dry MeOH (1.5 ml) and treated with HCl (0.172 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 4 hours. treatment with diethyl ether gave the title compound (46 mg, 83%) as a white solid. MS (ES) m / z: 460.0 [MH] ⁺ . C ₂₅ H ₂₃ F ₂ N ₇ required 459.5. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.88 (br s, 1H), 8.75 (d, 1H), 8.64 (m, 2H), 8.24 (d, 1H), 8.01 (t, 1H), 7.9-7.6 (m, 4H), 7.43 (d, 1H), 7.13 (t, 1H), 3.84 (d, 2H) ), 3.71 (m, 2H), 3.55 (m, 6H), 3.3 (m + water, 2H).

Example 96. 1-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,4] triazolo [4,3-a] quinoline dihydrochloride (E96 )

A mixture of (1-methyl) [1,2,4] triazolo [4,3-a] quinolin-6-yl) acetaldehyde and 1- (methyloxy) -2- (1-methyl [1,2,4] triazolo [ 4,3-a] quinolin-6-yl) ethanol (see D97) (30 mg, 0.13 mmol) and 2-methyl-5-piperazin-1-ylquinoline (WO 2004/046124) (36 mg, 0 , 16 mmol) and drops of glacial acetic acid in a mixture of 1,2-dichloroethane / acetonitrile (3: 1, 4 ml) were stirred at room temperature under nitrogen for 30 minutes. Then sodium triacetoxyborohydride (34 mg, 0.16 mmol) was added, the resulting reaction mixture was stirred for 6 hours, the reaction was quenched with saturated aqueous NaHCO ₃ solution (10 ml) and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified on an SPE cartridge (silica gel) eluting with a mixture of 5% MeOH in DCM to give the free base of the title compound as a white solid (32 mg, 55%). The free base (30 mg, 0.07 mmol) was dissolved in dry MeOH (2 ml) and treated with HCl (0.123 ml of a 1.25 M solution in MeOH, 0.15 mmol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (30 mg, 87%) as a yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.4 (br s, 1H), 8.53 (br s, 1H), 8.36 (d, 1H), 8.11 ( d, 1H), 7.75 (m, 4H), 7.59 (d, 1H), 7.54 (br s, 1H), 7.29 (br s, 1H), 3.82 (m , 2H), 3.64 (m, 2H), 3.52 (m, 6H), 3.2 (m, 2H), 3.09 (s, 3H), 2.72 (br s, 3H) .

Example 97. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate dihydrochloride (E97)

A mixture of ethyl 6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D99) (36 mg, 0.13 mmol) and 2-methyl-5-piperazine -1-ylquinoline (36 mg, 0.16 mmol) in 1,2-dichloroethane (2 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (34 mg, 0.16 mmol) was then added, and the resulting reaction mixture was stirred overnight and then concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 30% cyclohexane in ethyl acetate and then with a mixture of 2% MeOH in DCM to give the free base of the title compound (60 mg, 93%). A part of the obtained substance (15 mg) was dissolved in dry MeOH (1 ml) and treated with HCl (0.055 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.64 (br s, 1H), 8.92 (br s, 1H), 8.77 (d, 1H), 8.58 ( d, 1H), 8.09 (d, 1H), 7.98 (t, 1H), 7.95 (br s, 2H), 7.82 (d, 1H), 7.47 (br s , 1H), 3.83 (d, 2H), 3.74 (dd, 1H), 3.7-3.5 (br.m + water, 6H), 3.39 (t, 2H), 2, 90 (s, 3H); 1.41 (t, 3H).

Example 98. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide (E98 )

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (free base E97) (25 mg, 0.081 mmol) and potassium hydroxide (0.3 ml of a 1 M solution in MeOH) was stirred at 80 ° C for 2 hours. After SCX purification, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-ammonium carboxylate is recovered and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.009 ml, 1.1 eq.). Then the reaction mixture was evaporated in vacuo and the residue was purified by SCX and then on SPE-Si, eluting with a mixture of 2% MeOH in DCM. The free base (9 mg, 0.019 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.034 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (10 mg, overall yield 23%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.76 (br s, 1H), 8.75 (d, 1H), 8.55 (br s, 1H), 8.36 ( d, 1H), 8.21 (d, 1H), 8.2 (br s, 2H), 7.96 (t, 1H), 7.77 (d, 1H), 7.74 (br s , 2H), 7.69 (s, 1H), 7.56 (br s, 1H), 7.31 (br s, 1H), 3.84 (d, 2H), 3.68 (m, 2H), 3.56 (m + water, 5H), 3.3 (m, 2H), 2.73 (s, 3H).

Example 99. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate dihydrochloride (E99)

A mixture of ethyl 6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D99) (41 mg, 0.14 mmol) and 2-methyl-5- ( 4-piperidinyl) quinoline (WO 2004/046124) (39 mg, 0.17 mmol) in 1,2-dichloroethane (2 ml) was stirred at room temperature under nitrogen for 30 minutes. Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was then added, and the resulting reaction mixture was stirred for 6 hours and then concentrated in vacuo. The crude reaction product is purified on an SPE-Si cartridge, eluting with a mixture of 20% cyclohexane in ethyl acetate to give the free base of the title compound (65 mg, 94%). The free base (15 mg) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.053 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension was stirred at room temperature for 2 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (16 mg, 93%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.58 (br s, 1H), 8.76 (d, 1H), 8.58 (d, 1H), 8.49 (d, 1H), 8.10 (d, 1H), 7.97 (t, 1H), 7.84 (d, 1H), 7.80 (d, 1H), 7.72 (t, 1H), 7, 49 (d, 1H), 7.44 (d, 1H), 4.43 (q, 2H), 3.84 (d, 2H), 3.71 (m, 3H), 3.45 (m, 2H) ), 3.33 (m, 2H), 2.67 (s, 3H), 2.18 (m, 4H), 1.41 (t, 3H).

Example 100. Ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} dihydrochloride} [1,2,3] triazolo [1,5 -a] quinoline-3-carboxylate (E100)

A mixture of ethyl 6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D99) (41 mg, 0.14 mmol) and 2-methyl-5- [ (3R) -3-methyl-1-piperazinyl] quinoline (WO 2004/046124) (41 mg, 0.17 mmol) in 1,2-dichloroethane (2 ml) was stirred at room temperature under nitrogen for 30 minutes. Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was then added, and the resulting reaction mixture was stirred for 6 hours and then concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with a mixture of 20% cyclohexane in ethyl acetate to give the free base of the title compound (55 mg, 77%). The free base (15 mg) was dissolved in dry methanol (0.5 ml) and treated with HCl (0.052 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension was stirred at room temperature for 2 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (15 mg, 90%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.94 (br s, 1H), 8.77 (d, 1H), 8.52 (d, 1H), 8.45 (d, 1H), 8.12 (d, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.67 (m, 2H), 7.45 (d, 1H), 7, 23 (br s, 1H), 4.45 (q, 2H), 3.83 (m, 1H), 3.69 (m, 4H), 3.49 (m, 3H), 3.30 (m , 2H), 3.08 (m, 1H), 2.66 (s, 3H), 1.46 (d, 3H), 1.41 (t, 3H).

Example 101. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate dihydrochloride (E101)

Mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-ammonium carboxylate (E181) ( 20 mg) and 1,2-dichlorobenzene (1 ml) are exposed in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 250 ° C, 10 minutes). The solvent was removed on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give the free base of the title compound as a white solid (12.3 mg). The free base is dissolved in dry methanol (0.5 ml) and treated with HCl (0.073 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension was stirred at room temperature for 2 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (14 mg, 96%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.52 (br s, 1H), 8.69 (d, 1H), 8.6 (br s, 1H), 8.34 ( s, 1H), 8.13 (d, 1H), 7.95 (d, 1H), 7.87 (m, 2H), 7.74 (m, 2H), 7.52 (br s, 1H ), 7.46 (d, 1H), 3.83 (d, 1H), 3.74 (d, 2H), 3.64 (m, 2H), 3.43 (m, 2H), 3.35 (m, 2H); 2.69 (s, 3H); 2.16 (m, 4H).

Example 102. Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate ( E102)

Methyl 6- (2-oxoethyl) [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D104) (355 mg, 1.32 mmol) and 2-methyl-5- (4 -piperidinyl) quinoline (328 mg, 1.45 mmol) (WO 2004/046124) in 1,2-dichloroethane (15 ml) was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Sodium triacetoxyborohydride (306 mg, 1.45 mmol) was then added, the resulting reaction mixture was stirred overnight, then the reaction was quenched with NaHCO ₃ solution (100 ml) and the mixture was extracted with DCM (3 × 100 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified on an SPE-Si cartridge, eluting with 2% MeOH in DCM to give the title compound as a white solid (501 mg, 79%). MS (ES) m / z: 480.3 [MH ⁺ ]. C ₂₉ H ₂₉ N ₅ O ₂ requires 479.6.

Example 103. 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} dihydrochloride} [1,2,3] triazolo [1,5-a ] quinoline-3-carboxamide (E103)

A mixture of ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (E100 free base) (40 mg, 0.078 mmol) and KOH (1 M solution in MeOH, 0.5 ml) are stirred at reflux for 2 hours. The solution was cooled to room temperature, the precipitated substance was dissolved by adding H ₂ O, and then the solution was purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give 38 mg 6- {2 - [( 2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-ammonium carboxylate. 20 mg (0.04 mmol) of the obtained intermediate are used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.01 ml, 1.1 eq.) (See Example 14 ) Then the reaction mixture was evaporated in vacuo, and the residue was purified by SCX. The free base (18 mg, 0.038 mmol) was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.083 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (20 mg, 90%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.56 (br s, 1H), 8.74 (d, 1H), 8.48 (br s, 1H), 8.36 ( m, 2H), 8.2 (m, 2H), 7.95 (t, 1H), 7.8 (d, 1H), 7.68 (m, 2H), 7.48 (d, 1H), 7.25 (d, 1H), 3.86 (m, 1H), 3.61 (m, 9H), 3.06 (t, 1H), 2.68 (s, 3H), 1.44 (d , 3H).

Example 104. N-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline dihydrochloride 3-carboxamide (E104)

A solution of trimethylaluminum (0.113 ml of a 2.0 M solution in hexanes, 0.226 mmol) and methylamine (0.91 ml of a 2.0 M solution in THF, 0.226 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 min Ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (free base E55) (20.7 mg, 0.041 mmol), and stirring is continued for an additional 8 hours at 56 ° C. Upon completion of the reaction at 0 ° C, water is added dropwise, followed by a 1 M NaOH solution until the organic and aqueous phases are separated. The mixture was extracted with DCM (3 × 10 ml), and the combined organic phases were dried (Na ₂ SO ₄ ) and then evaporated in vacuo. The residue was purified by chromatography eluting with 0.25% NH ₃ (2 M in MeOH) in DCM to give the free base of the title compound as a white solid (13 mg, 64%). The resulting substance was dissolved in a mixture of Meon: DCM (1: 1, 0.5 ml) and treated with HCl (0.047 ml of a 1.25 M solution in Meon) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (13 mg). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 10.8 (br s, 1H), 9.25 (s, 1H), 8.55 (m, 1H), 8.46 (d, 1H), 8.22 (d, 1H), 8.12 (d, 1H), 7.82 (d, 1H), 7.72 (br.m, 3H), 7.58 (d, 1H), 7.51 (br s, 1H), 7.27 (br s, 1H), 3.94 (d, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 3 42 (m, 7H), 3.08 (m, 1H), 2.81 (s, 3H), 2.7 (s, 3H), 1.45 (d, 3H).

Example 105. Dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (3-methyl-1,2,4- oxadiazol-5-yl) imidazo [1,5-a] quinoline (E105)

To a suspension of sodium hydride (2.1 mg of a 60% suspension in oil, 0.054 mmol) in dry THF (1 ml), methylcarboxamide oxime (4 mg, 0.054 mmol) was added, and then after 10 minutes ethyl 6- {2- [ (2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E55 free base) (25 mg, 0.049 mmol ) After 30 minutes, DMF (0.2 ml) was added and the reaction mixture was stirred at room temperature overnight. The conversion of the starting material did not complete, therefore, NaH (4.2 mg, 0.108 mmol) and methylcarboxamide oxime (8 mg, 0.108 mmol) were added and the reaction mixture was stirred for another 3 hours. The reaction was quenched with water (5 ml) and the mixture was extracted with ethyl acetate (3 × 5 ml). After drying and evaporation of the organic solvents, the crude material is purified by chromatography eluting with 0.25% NH ₃ (2 M in MeOH) in DCM to give the free base of the title compound as a white solid (11 mg). The resulting substance was dissolved in a mixture of Meon: DCM (1: 1, 0.5 ml) and treated with HCl (0.038 ml of a 1.25 M solution in Meon) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (11 mg). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.44 (d, 3H), 2.69 (s, 3H), 3.08 (t, 1H), 3.19-3.49 (m, 5H), 3.52 (d, 2H), 3 61 (s, 3H), 3.69-3.79 (m, 1H), 3.79-3.88 (m, 1H), 3.95 (d, 1H), 7.26 (br s , 1H), 7.49 (br s, 1H), 7.64 (d, 1H), 7.67-7.74 (m, 2H), 7.82 (t, 1H), 8.08 ( d, 1H), 8.14 (d, 1H), 8.49 (br s, 1H), 8.55 (d, 1H), 9.43-9.51 (m, 1H), 10.75 (broad s, 1H).

Example 106. Dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide ( E106)

A mixture of ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (free base E55) (28 mg, 0.055 mmol) and potassium hydroxide (0.33 ml of a 1 M solution in MeOH) was stirred at 80 ° C for 3 hours. After purification on SCX, 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate is recovered ammonium and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.014 ml, 1.1 eq.) (see Example 14). Then the reaction mixture was evaporated in vacuo and the residue was purified on SCX and then on SPE-Si, eluting with a mixture of 2% MeOH in DCM. The free base (10 mg, 0.021 mmol) was dissolved in a mixture of dry MeOH: DCM (1: 1, 0.5 ml) and treated with HCl (0.037 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.44 (d, 3H), 2.77 (br s, 3H), 3.00-3.16 (m, 2H), 3.19-3.66 (m, 6H), 3.69- 3.80 (m, 1H), 3.80-3.91 (m, 1H), 3.91-4.00 (m, 1H), 7.26 (br s, 1H), 7.33 ( broad s, 1H), 7.48-7.65 (m, 3H), 7.80 (broad s, 2H), 7.71-7.79 (m, 1H), 7.82 (d, 1H), 8.12 (d, 1H), 8.64 (br s, 1H), 8.47 (d, 1H), 9.15-9.33 (m, 1H), 10.71 (br .s, 1H).

Example 107. Ethyl 1-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate dihydrochloride (E107)

A mixture of ethyl 1-methyl-6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D106) (85 mg, 0.29 mmol) and 2-methyl-5- (4-piperidinyl ) quinoline (77 mg, 0.34 mmol) (WO 2004/046124) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (34 mg, 0.16 mmol) was then added, and the resulting reaction mixture was stirred overnight and then concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with 2% MeOH in DCM to give the free base of the title compound (70 mg, 48%). A part of the obtained substance (10 mg) was dissolved in dry MeOH (0.3 ml) and treated with HCl (0.035 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound E107 as a white solid (10 mg, 91%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.36 (t, 3H), 2.06-2.17 (m, 2H), 2.16-2.33 (m, 2H), 2.81 (s, 3H), 3.07 (s, 3H), 3.24-3.34 (m, 2H), 3.32-3.41 (m, 2H), 3.56-3.67 (m, 2H), 3.73-3.89 ( m, 3H), 4.27-4.39 (m, 2H), 7.54-7.63 (m, 2H), 7.73 (t, 1H), 7.77-7.94 (m, 2H), 7.93-8.00 (m, 1H), 7.99-8.07 (m, 2H), 8.43 (d, 1H), 8.91 (br s, 1H), 10 93 (br s, 1H).

Example 108. 1-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E108)

A mixture of ethyl 1-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (free base E107) ( 55 mg, 0.108 mmol) and potassium hydroxide (0.65 ml of a 1 M solution in MeOH) are stirred at 80 ° C for 3 hours. After purification on SPE-SCX, 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinolin-3 is recovered ammonium β-carboxylate and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.097 ml, 1.2 eq.), Then the reaction mixture was evaporated in vacuo and the residue was purified on SCX, and then on SPE-Si with elution with mixtures of 2% MeOH in DCM to 5% MeOH in DCM (20 mg, 39%). The resulting substance was dissolved in dry MeOH (0.5 ml) and treated with HCl (0.075 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a white solid (18 mg, 82%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.05-2.18 (m, 2H), 2.20-2.32 (m, 2H), 2.84 (s, 3H), 3.06 (s, 3H), 3.24-3, 51 (m, 4H), 3.53-3.64 (m, 2H), 3.70-3.90 (m, 3H), 7.14-7.25 (m, 1H), 7.43- 7.52 (m, 1H), 7.54 (d, 1H), 7.57-7.66 (m, 1H), 7.69 (t, 1H), 7.72-7.86 (m, 2H), 7.84-8.00 (m, 1H), 8.00-8.12 (m, 1H), 8.15 (d, 1H), 8.38 (d, 1H), 8.63 -9.35 (m, 1H); 11.07 (br s, 1H).

Example 109. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide (E109 )

Methyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (free base E102 ) (100 mg, 0.42 mmol) is treated with 2.5 ml of a 7 M solution of NH ₃ in MeOH and introduced into the interaction in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W) at 145 ° C for 1 hour. In order to improve the conversion of the starting material, another 7 M solution of NH ₃ in MeOH (2 ml) was added and the reaction mixture was reacted in a microwave reactor at 145 ° C for 1 hour. The crude product was evaporated in vacuo, and then the residue was purified by silica gel chromatography to give a certain amount of the title reaction product in low yield. The reaction is repeated on the same scale and under the same conditions. The crude material obtained from this second reaction is combined with the impurity-containing fractions from the first reaction and purified by silica gel chromatography eluting with mixtures of 2% MeOH in DCM to 4% MeOH in DCM to give the free base of the title compound (80 mg, 41%). The free base (77 mg, 0.166 mmol) was dissolved in dry MeOH (3 ml) and treated with HCl (0.292 ml of a 1.25 M solution in ethanol) at 0 ° C. The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a yellow solid (79 mg, 88.5%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.1-2.2 (m, 4H), 2.67 (s, 3H), 3.32-3.40 (m, 2H), 3.42-3.52 (m, 2H), 3, 61-3.69 (m, 2H), 3.69-3.77 (m, 1H), 3.85 (d, 2H), 7.4-8.0 (m, 7H), 8.34 ( d, 1H), 8.7 (br s, 1H), 8.75 (d, 1H), 10.4 (br s, 1H).

Example 110. Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E110)

A mixture of ethyl 7-methyl-6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D112) (75 mg, 0.25 mmol) and 2-methyl-5- (4-piperidinyl ) quinoline (WO 2004/046124) (67 mg, 0.30 mmol) in 1,2-dichloroethane (2.5 ml) was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added and after stirring at room temperature for 18 hours the reaction was quenched with water (10 ml), the mixture was extracted with ethyl acetate (3 × 15 ml) and then the extracts were concentrated in vacuo. The crude reaction product was purified on an SPE-Si cartridge, eluting with 5% MeOH in DCM to give the title compound as a white solid (60 mg, 47%). MS (ES / +) m / z: 507.3 [MH ⁺ ]. C ₃₂ H ₃₅ N ₄ O ₂ requires 506.65.

Example 111. 7-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E111)

A mixture of ethyl 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxylate (E110) (60 mg , 0.12 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) is stirred at 80 ° C for 2 hours. After purification on SCX, 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-ammonium carboxylate is recovered and used without further purification to obtain the free base of the title compound following the general procedure for the preparation of amides using hexamethyldisilazane (0.002 ml, 1.1 eq.). The white solid precipitated from the reaction mixture was collected by filtration and treated with a mixture of CH ₃ OH / CH ₂ Cl ₂ , 9/1, and 16 mg of the free base were obtained as a white solid, which was dissolved in dry CH ₃ OH (0.5 ml) and treated with HCl (0.059 ml of a 1.25 M solution in ethanol). The resulting suspension was stirred at room temperature for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound as a white solid (13 mg, overall yield 27%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 10.23 (br s, 1H), 9.17 (s, 1H), 8.55 (d, 1H), 8.36 (d, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.78 (d, 1H), 7.72 (t, 1H), 7.62 (d, 1H), 7.57 (s, 1H), 7.49 (d, 1H) 7.45 (d, 1H), 7.22 (s, 1H), 3.18-3.39 (m, 4H), 3.17-3.95 (m, 5H), 2.66 (s , 3H); 2.55 (s, 3H); 2.00-2.26 (m, 4H).

Example 112. 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxamide dihydrochloride ( E112)

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylate (free base E37) (89 mg, 0.18 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) was stirred at 90 ° C for 2 hours. After purification on SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylate is recovered ammonium and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.042 ml, 1.10 eq.) (see Example 14). The free base of the title compound precipitated from the reaction mixture is separated by filtration from the reaction mixture and treated with diethyl ether. Then the free base (38 mg, 0.082 mmol, 45% yield) was suspended in dry DCM (2 ml) and treated with HCl (0.165 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension is stirred at 0 ° C for 2 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (40 mg, 0.074 mmol) as a white solid. MS (ES) m / z: 468.2 [MH ⁺ ]. C ₂₈ H ₂₉ N ₅ O ₂ requires 467.57. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.05-2.15 (m, 2H), 2.19-2.34 (m, 2H), 2.95 (s, 3H), 3.15-3.22 (m, 2H), 3, 24-3.32 (m, 2H), 3.30-3.37 (m, 2H), 3.70-3.79 (m, 1H), 3.79-3.89 (m, 1H), 5.58 (s, 2H), 7.16 (t, 1H), 7.26 (d, 1H), 7.36 (br s, 1H), 7.54 (br s, 1H), 7 74 (d, 1H), 7.84 (d, 1H), 7.99 (d, 1H), 8.04-8.13 (m, 1H), 8.28 (d, 1H), 8, 57 (s, 1H), 9.31 (br s, 1H), 10.89 (br s, 1H).

Example 113. 3- (3-Methyl-1,2,4-oxadiazol-5-yl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H dihydrochloride -imidazo [5.1-s] [1.4] benzoxazine (E113)

To a suspension of sodium hydride (5.60 mg of a 60% suspension in oil, 0.14 mmol) in dry THF (3.50 ml) was added methyl carboxamide oxime (10.6 mg, 0.14 mmol), and then after 10 minutes, add ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylate (free base E37) (66 mg, 0.13 mmol). After 10 minutes, DMF (0.50 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified on SCX and then on SPE-Si, eluting with a mixture of 3% MeOH in DCM to give the free base of the title compound as a white foam (13.8 mg, 0.027 mmol, 19% yield). Then the free base is suspended in dry DCM (2 ml) and treated with HCl (0.054 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension is stirred at 0 ° C for 2 hours. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (13 mg, 0.022 mmol) as a white solid. MS (ES) m / z: 507.3 [MH ⁺ ]. C ₃₀ H ₃₀ N ₆ O ₂ requires 506.61. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.04-2.13 (m, 2H), 2.13-2.28 (m, 2H), 2.40 (s, 3H), 2.79 (s, 3H), 3.13-3, 25 (m, 2H), 3.22-3.47 (m, 4H), 3.66-3.85 (m, 3H), 5.68 (s, 2H), 7.20 (t, 1H) , 7.31 (d, 1H), 7.47-7.61 (m, 1H), 7.61-7.78 (m, 1H), 7.78-7.89 (m, 1H), 7 91 (d, 1H), 7.93-8.08 (m, 1H), 8.85 (br s, 1H), 8.80 (s, 1H), 10.53 (br s, 1H )

Example 114. 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 dihydrochloride -yl) ethanone (E114)

To a solution of N-methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1, 4] benzoxazine-3-carboxamide (E182) (0.39 g, 0.76 mmol) in anhydrous THF (5 ml) while cooling with ice and stirring, methyl magnesium bromide (0.30 ml of a 3 M solution in diethyl ether, 0.90 mmol) and the resulting solution was stirred for 1 hour at 0 ° C. The reaction mixture was poured into cold 1 N hydrochloric acid (5 ml), then treated with a solution of NaHCO ₃ (15 ml) and extracted with EtOAc (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, and the residue was purified on SPE-Si eluting with 3% methanol in DCM to give the free base of the title compound (175 mg, 0.38 mmol, yield 50 %) as a white solid. Then the free base (19.8 mg, 0.042 mmol) is suspended in dry DCM (2 ml) and treated with HCl (0.085 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension is stirred at 0 ° C for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (17.5 mg, 0.032 mmol) as a white solid. MS (ES) m / z: 467.3 [MH ⁺ ]. C ₂₉ H ₃₀ N ₄ O ₂ requires 466.58. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.08 (d, 2H), 2.16-2.31 (m, 2H), 2.48 (s, 3H), 2.85 (s, 3H), 3.11-3.24 (m, 2H), 3.24-3.50 (m, 2H), 3.27-3.35 (m, 2H), 3.63-3.87 (m, 3H), 5.59 (s, 2H) 7.16 (t, 1H), 7.28 (d, 1H), 7.50-7.65 (m, 1H), 7.72-7.84 (m, 1H), 7.86 (d) , 1H), 7.88-7.99 (m, 1H), 8.01-8.17 (m, 1H), 8.63 (s, 1H), 8.72-9.24 (m, 1H ), 10.78 (br s, 1H).

Example 115. 3- (3-Methyl-5-isoxazolyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo dihydrochloride [5.1-s ] [1,4] benzoxazine (E115)

A mixture of (2Z) -3- (dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [ 1,4] benzoxazin-3-yl) -2-buten-1-one (D113) (57 mg, 0.16 mmol) and hydroxylamine hydrochloride (16.68 mg, 0.24 mmol) in EtOH (1.50 ml) is heated with stirring at 150 ° C under the influence of microwave radiation for 5 minutes The precipitate was filtered off from the reaction mixture and washed with diethyl ether to give the title compound (54 mg, 0.10 mmol, 65% yield) as a white solid. MS (ES) m / z: 506.3 [MH ⁺ ]. C ₃₁ H ₃₁ N ₅ O ₂ requires 505.62. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.02-2.20 (m, 2H), 2.18-2.40 (m, 2H), 2.31 (s, 3H), 2.99 (s, 3H), 3.13-3, 51 (m, 4H), 3.41-3.89 (m, 5H), 5.63 (s, 2H), 6.62 (s, 1H), 7.20 (t, 1H), 7.31 (d, 1H), 7.75 (d, 1H), 7.90 (d, 1H), 8.00 (d, 1H), 8.10 (t, 1H), 8.28 (d, 1H) 8.73 (s, 1H); 9.31 (d, 1H); 10.87 (br s, 1H).

Example 116. 3- (3-Methyl-1H-pyrazol-5-yl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo dihydrochloride [5 , 1-s] [1,4] benzoxazine (E116)

A mixture of (2Z) -3- (dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [ 1,4] benzoxazin-3-yl) -2-buten-1-one (D113) (33 mg, 0.062 mmol) and hydrazine monohydrate (0.003 ml, 0.096 mmol) in EtOH (1.5 ml) are heated with stirring 150ºС under the influence of microwave radiation for 5 minutes. The precipitated free base of the title compound is filtered off from the reaction mixture and treated with diethyl ether. Then the free base (29 mg, 0.058 mmol, 60% yield) was suspended in dry DCM (2 ml) and treated with HCl (0.116 ml of a 1.25 M solution in methanol) at 0 ° C. The resulting suspension is stirred at 0 ° C for 1 hour. Evaporation of the volatiles and treatment with diethyl ether gave the title compound (28 mg, 0.048 mmol) as a pale yellow solid. MS (ES) m / z: 505.3 [MH ⁺ ]. C ₃₁ H ₃₂ N ₆ O requires 504.63. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.01-2.36 (m, 4H), 2.30 (s, 3H), 2.92 (s, 3H), 3.12-4.01 (m, 9H), 5.62 (s, 2H), 6.43 (s, 1H), 7.20 (t, 1H), 7.33 (d, 1H), 7.61-7.77 (m, 1H), 7.80-7.96 (m, 2H), 7.96-8.08 (m, 1H), 8.07-8.22 (m, 1H), 8.96 (s, 1H), 9.04-9.24 (m , 1H); 10.52 (br s, 1H).

Example 117. Ethyl-6- (2- {4- [2- (5-methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl] -1-piperazinyl} ethyl hydrochloride) imidazo [1,5-a] quinoline-3-carboxylate (E117)

The title compound was obtained in 20% yield following the general procedure described in Example 1, starting from ethyl 6- (2-oxoethyl) imidazo [1,5-a] quinoline-3-carboxylate (D91) (44 mg, 0.15 mmol) and 1- [2- (5-methyl-1,3,4-oxadiazol-2-yl) -1-benzofuran-4-yl] -1-piperazine (D116) (55 mg, 0, 19 mmol). MS (ES) m / z: 551.2 [MH ⁺ ]. C ₃₁ H ₃₀ N ₆ O ₄ requires 550.62. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.37 (t, J = 6.83 Hz, 3H), 2.63 (s, 3H), 3.24-3.52 (m, 6H), 3.60 (dd, 2H), 3.80 (d, J = 10.74 Hz, 2H), 3.86 (d, J = 12.69 Hz, 2H), 4.36 (q, 2H), 6.92 (d, J = 7.81 Hz , 1H), 7.37-7.47 (m, 2H), 7.58 (d, J = 6.83 Hz, 1H), 7.79 (t, 1H), 8.01-8.04 ( m, 3H), 8.52 (d, J = 7.81 Hz, 1H), 9.32 (s, 1H), 11.01 (br s, 1H).

Example 118. Ethyl-6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4H-imidazo [5,1- c] [1,4] benzoxazine-3-carboxylate (E118)

A mixture of ethyl 6- (2-oxoethyl) -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (D6) (83 mg, 0.28 mmol) and 7-fluoro-2- methyl 5 - [(3R) -3-methyl-1-piperazinyl] quinoline (90 mg, 0.35 mmol) (obtained by a similar procedure to that described in WO 2004/046124) in dry 1,2-dichloroethane (10 ml) was stirred at room temperature in a nitrogen atmosphere for 40 minutes. Then sodium triacetoxyborohydride (74 mg, 0.35 mmol) was added, the resulting reaction mixture was stirred for 3 hours, the reaction was quenched with saturated aqueous NaHCO ₃ solution (10 ml), and the mixture was extracted with DCM (3 × 10 ml). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude reaction product was purified by column chromatography on silica eluting with a mixture of 1% methanol in DCM to give the title compound as a white foam (63 mg, 34%). MS (ES) m / z: 530.1 [MH ⁺ ]. C ₃₀ H ₃₂ FN ₅ O ₃ requires 529.61. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 8.34 (d, 1H), 8.03 (s, 1H), 7.76 (d, 1H), 7.4 (d, 1H), 7 , 3 (m, 1H), 7.2 (d, 1H), 7.1 (m, 2H), 5.59 (s, 2H), 4.45 (quart, 2H), 3, -2.7 (broad m, 11H), 2.77 (s, 3H), 1.46 (t, 3H), 1.2 (m, 3H).

Example 119. Dihydrochloride 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4H-imidazo [5.1-s ] [1,4] benzoxazine-3-carboxamide (E119)

The title compound was obtained in 45% yield according to the general procedure for the preparation of amides (see Example 14), starting from 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2 -methyl-1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylic acid (E183) (38 mg, 0.07 mmol) and hexamethyldisilazane (1.1 eq. .). MS (ES) m / z: 501.5 [MH ⁺ ]. C ₂₈ H ₂₉ N ₆ O ₂ requires 500.58. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.20 (br s, 1H), 9.1 (d, 1H), 8.58 (s, 1H), 8.16 (m, 1H), 8.11 (d, 1H), 7.92 (d, 1H), 78.4 (d, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 7, 15 (t, 1H), 5.62 (s, 2H), 4.0-2.9 (m, 11H), 2.99 (s, 3H), 2.74 (d, 3H).

Example 120. 2-Methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -2,4-dihydro-1H- [1,2,4] triazolo [ 3,4-s] [1,4] benzoxazin-1-one (E120)

The title compound was obtained in 61% yield following the general amination procedure of Example 1, starting from (2-methyl-1-oxo-2,4-dihydro-1H- [1,2,4] triazolo [3,4-s ] [1,4] benzoxazin-6-yl) acetaldehyde (D120) (64 mg, 0.261 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-2%) to give the free base of the title compound (72 mg, 61%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 4 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 457.00 [MH ⁺ ]. C ₂₆ H ₂₈ N ₆ O ₂ requires 456.55. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.69 (s, 3H), 3.11-3.17 (m, 2H), 3.22 (t, 2H), 3.26-3.39 (m, 4H), 3.40 (s, 3H), 3.41 3.54 (m, 2H), 3.66-3.76 (m, 2H), 5.24 (s, 2H), 7.08-7.34 (m, 3H), 7.37-7.58 (m, 1H), 7.58-7.84 (m, 2H), 8.06 (d, 1H), 8.26-8.61 (m, 1H), 10, 45 (br s, 1H).

Example 121. 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3-yl) dihydrochloride) ethanone (E121)

The title compound was prepared following the procedure of Example 35 using methyl magnesium bromide (0.081 ml of a 3 M solution in diethyl ether, 0.243 mmol) and N-methyl-N- (methyloxy) -6- {2- [4- (2-methyl -5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (E184) (105 mg, 0.206 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-5%) to give the free base of the title compound (24 mg, 25%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a white solid. MS (ES) m / z: 465.00 [MH ⁺ ]. C ₃₀ H ₃₂ N ₄ O requires 464.61. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.05-2.23 (m, 4H), 2.46 (s, 3H), 2.77 (s, 3H), 3.00 (t, 2H), 3.07-3.61 (m, 6H), 3.28 (t, 2H), 3.66-3.83 (m, 3H), 7.29 (d, 1H), 7.41 (t, 1H), 7.47-7.59 (m, 1H), 7.60-7.76 (m, 1H), 7.80 (d, 1H), 7.82-7.90 (m, 1H), 7.90-8.03 (m , 1H), 8.53 (s, 1H), 8.66-8.99 (m, 1H), 10.39 (br s, 1H).

Example 122. 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (E122)

The mixture of the free base of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E82) (32 mg, 0.065 mmol) and potassium hydroxide (5 ml of a 1 M solution in MeOH) are stirred at the boil under reflux for 2.5 hours. After purification on SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylic acid (0.065) is recovered mmol) and used without further purification according to the general procedure for producing amides using hexamethyldisilazane (0.015 ml, 0.071 mmol) (see example 14). The precipitated free base is filtered off and treated with ethyl ether (12 mg, 40%) and then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C and get named in the title compound as a white solid. MS (ES) m / z: 466.00 [MH ⁺ ]. C ₂₉ H ₃₁ N ₅ O requires 465.60. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.08-2.24 (m, 4H), 2.75 (br s, 3H), 2.99 (t, 2H), 3.18-3.49 (m, 8H), 3.71- 3.77 (m, 1H), 3.78 (d, 2H), 7.15 (br s, 1H), 7.27 (d, 1H), 7.36 (br s, 1H), 7 40 (t, 1H), 7.51 (br s, 1H), 7.62 (br s, 1H), 7.78 (d, 1H), 7.81 (br s, 1H), 7.93 (br s, 1H), 8.47 (s, 1H), 8.72 (br s, 1H), 10.38 (br s, 1H).

Example 123. Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] dihydrochloride salt [1,4] benzoxazine-3-carboxylate (E123)

The title compound was prepared following the procedure of Example 80, starting from 7-methyl-8- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -2H-1,4-benzoxazine- 3 (4H) -one (D121) (173 mg, 0.417 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (87 mg, 41%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a white solid. MS (ES) m / z: 511.00 [MH ⁺ ]. C ₃₁ H ₃₄ N ₄ O ₃ requires 510.63. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, 3H), 2.03-2.24 (m, 4H), 2.40 (s, 3H), 2.69 (s, 3H), 3.03-3.25 (m, 4H), 3.25-3.51 (m, 2H), 3.64-3.77 (m, 1H), 3.80 (d, J = 11.35 Hz, 2H), 4.27 (q , 2H), 5.57 (s, 2H), 7.06 (d, J = 8.42 Hz, 1H), 7.49 (broad s, 1H), 7.61 (broad s, 1H) 7.76 (d, J = 8.06 Hz, 1H), 7.81 (broad s, 1H), 7.90 (broad s, 1H), 8.58 (s, 1H), 8, 80 (br s, 1H); 10.17 (br s, 1H).

Example 124. Dihydrochloride N, 7-dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxamide (E124)

The title compound was prepared following the procedure of Example 38 using trimethylaluminum (2.0 M solution in hexanes, 392 μl, 0.784 mmol), methylamine (2.0 M solution in THF, 392 μl, 0.784 mmol) and ethyl free base -7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate (E123) (40 mg, 0.078 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (25 mg, 64%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a white solid. MS (ES) m / z: 496.00 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₂ requires 495.62. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.10-2.18 (m, 4H), 2.40 (s, 3H), 2.71 (s, 3H), 2.76 (d, 3H), 3.11-3.24 (m, 2H), 3.24-3.62 (m, 4H), 3.67-3.75 (m, 1H), 3.81 (d, 2H), 5.60 (s, 2H), 7.05 (d, 1H), 7.47 (br s, 1H), 7.58 (br s, 1H), 7.72 (d, 1H), 7.75-7.84 (m, 1H), 7.83-7.98 (m, 1H), 8.13 (q, 1H), 8.55 (s, 1H), 8.68 (br s, 1H), 10.21 (br s, 1H).

Example 125. Dihydrochloride 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine- 3-carboxamide (E125)

Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine free base mixture -3-carboxylate (E123) (36 mg, 0.071 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) are stirred at reflux for 2 hours. After purification on SCX, 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine is recovered -3-carboxylic acid (24 mg, 0.050 mmol, 71%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.023 ml, 0.108 mmol). The free base of the title compound precipitated during the reaction is filtered off and treated with ethyl ether (10.3 mg, 26%). The free base is then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C to give the title compound as a white solid. MS (ES) m / z: 482.00 [MH ⁺ ]. C ₂₉ H ₃₁ N ₅ O ₂ requires 481.60. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.07-2.18 (m, 4H), 2.38 (s, 3H), 2.73 (s, 3H), 3.10-3.24 (m, 4H), 3.24-3, 52 (m, 2H), 3.69-3.77 (m, 1H), 3.80 (d, 2H), 5.57 (s, 2H), 7.03 (d, 1H), 7.31 (s, 1H), 7.45-7.56 (m, 2H), 7.60 (br s, 1H), 7.73 (d, J = 8.18 Hz, 1H), 7.79 ( broad s, 1H), 7.91 (broad s, 1H), 8.52 (s, 1H), 8.69 (broad s, 1H), 10.03 (broad s, 1H).

Example 126. Ethyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a dihydrochloride ] quinoline-3-carboxylate (E126)

The title compound was obtained in 72% yield following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D86) (103 mg, 0.363 mmol) and 2-methyl-5 [(3R) -3-methyl-1-piperazinyl] quinoline (131 mg, 0.544 mmol) (WO 2004/046124). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-3%) to give the free base of the title compound (134 mg, 72%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 510.10 [MH ⁺ ]. C ₃₁ H ₃₅ N ₅ O ₂ requires 509.65. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.30 (t, 3H), 1.43 (s, 3H), 2.74 (s, 3H), 3.03 (t, 2H), 3.17-3.91 (m, 6H), 3 , 20-3.37 (m, 2H), 3.26 (t, 2H), 3.40-3.56 (m, 2H), 3.85 (d, 1H), 4.26 (q, 2H) ), 7.23-7.30 (m, 1H), 7.32 (d, 1H), 7.40 (t, 1H), 7.46-7.65 (m, 1H), 7.69- 7.78 (m, 2H), 7.80 (d, 1H), 8.52 (s, 1H), 8.53-8.69 (m, 1H), 10.94 (br s, 1H) .

Example 127. Dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline -3-carboxamide (E127)

Ethyl 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] free base mixture quinoline-3-carboxylate (E126) (122 mg, 0.24 mmol) and potassium hydroxide (5 ml of a 1 M solution in MeOH) are stirred at reflux for 4 hours. After purification on SCX, 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] is recovered quinoline-3-carboxylic acid (114 mg, 0.24 mmol, 100%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.055 ml, 0.261 mmol) (cm .example 14). The free base of the title compound precipitated during the reaction is filtered off and treated with ethyl ether (89 mg, 78%). The free base is then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 4 ml) at 0 ° C to give the title compound as a yellow solid. MS (ES) m / z: 481.30 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O requires 480.61. ¹ H NMR (500 MHz, DMSO-d ₆ ), δ ppm 1.43 (s, 3H), 2.70 (s, 3H), 2.99 (t, 2H), 3.16-3.82 (m, 6H), 3.27 (t, 2H), 3 , 26-3.36 (m, 2H), 3.43-3.53 (m, 2H), 3.86 (d, 1H), 7.14 (s, 1H), 7.20-7.27 (m, 1H), 7.30 (d, 1H), 7.35 (s, 1H), 7.40 (t, 1H), 7.43-7.56 (m, 1H), 7.65- 7.75 (m, 2H), 7.78 (d, 1H), 8.46 (s, 1H), 8.46-8.60 (m, 1H), 10.41 (br s, 1H) .

Example 128. Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3 dihydrochloride -carboxylate (E128)

The title compound was obtained in 62% yield following the general reductive amination procedure of Example 1, starting from ethyl-7-methyl-6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinolin-3- carboxylate (D125) (110 mg, 0.369 mmol) and 2-methyl-5- (1-piperazinyl) quinoline (101 mg, 0.443 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (117 mg, 62%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol (1 ml) at 0 ° C gives the title compound as a yellow solid. MS (ES) m / z: 510.10 [MH ⁺ ]. C ₃₁ H ₃₅ N ₅ O ₂ requires 509.65. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, 3H), 2.41-2.46 (m, 3H), 2.78 (br s, 3H), 2.99-3.09 (m, 2H), 3.21- 3.43 (m, 8H), 3.44-3.61 (m, 4H), 3.80 (d, 2H), 4.25 (q, 2H), 7.28 (d, 1H), 7 35 (br s, 1H), 7.58 (br s, 1H), 7.70 (d, 1H), 7.84 (br s, 2H), 8.47-8.53 (m , 1H), 8.68 (br s, 1H), 10.89 (br s, 1H).

Example 129. Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3 dihydrochloride -carboxylate (E129)

The title compound was obtained in 88% yield following the general reductive amination procedure of Example 1, starting from ethyl-7-methyl-6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinolin-3- carboxylate (D125) (110 mg, 0.369 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (100 mg, 0.443 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (166 mg, 88%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol (1 ml) at 0 ° C gives the title compound as a white solid. MS (ES) m / z: 509.10 [MH ⁺ ]. C ₃₂ H ₃₆ N ₄ O ₂ requires 508.66. ¹ H NMR (500 MHz, DMSO-d ₆ ), δ ppm 1.30 (t, 3H), 2.03-2.29 (m, 4H), 2.39-2.46 (m, 3H), 2.81 (br s, 3H), 2.97- 3.09 (m, 2H), 3.11-3.54 (m, 8H), 3.69-3.78 (m, 1H), 3.80-3.92 (m, 2H), 4, 26 (q, 2H), 7.27 (d, 1H), 7.46-8.10 (m, 4H), 7.70 (d, 1H), 8.47-8.54 (m, 1H) 8.95 (br s, 1H); 10.65 (br s, 1H).

Example 130. Ethyl-7-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo dihydrochloride [1 , 5-a] quinoline-3-carboxylate (E130)

The title compound was obtained in 89% yield following the general reductive amination procedure of Example 1, starting from ethyl-7-methyl-6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinolin-3- carboxylate (D125) (110 mg, 0.369 mmol) and 2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (107 mg, 0.443 mmol) (WO 2004/046124). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (172 mg, 89%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol (1 ml) at 0 ° C gives the title compound as a yellow solid. MS (ES) m / z: 524.10 [MH ⁺ ]. C ₃₂ H ₃₇ N ₅ O ₂ requires 523.68. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, 3H), 1.45 (d, 3H), 2.41-2.46 (m, 3H), 2.80 (br s, 3H), 2.97-3.12 ( m, 2H), 3.19-3.44 (m, 8H), 3.47-3.60 (m, 2H), 3.68-3.85 (m, 2H), 3.87-3, 99 (m, 1H), 4.25 (q, 2H), 7.26-7.30 (m, 1H), 7.36 (br s, 1H), 7.61 (br s, 1H) 7.68-7.73 (m, 1H), 7.86 (br s, 2H), 8.46-8.54 (m, 1H), 8.76 (br s, 1H), 10 99 (br s, 1H).

Example 131. N, 7-Dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3 dihydrochloride -carboxamide (E131)

The title compound was prepared following the procedure for Example 38 using ethyl 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5- free base. dihydroimidazo [1,5-a] quinoline-3-carboxylate (E128) (50 mg, 0.098 mmol). The crude reaction product is purified on an SCX cartridge to give the free base of the title compound (30 mg, 61%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 495.10 [MH ⁺ ]. C ₃₀ H ₃₄ N ₆ O requires 494.64. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.44 (s, 3H), 2.72 (s, 3H), 2.76 (d, 3H), 3.02 (t, 2H), 3.17-3.44 (m, 8H), 3 , 45-3.63 (m, 4H), 3.74-3.90 (m, 2H), 7.21-7.33 (m, 2H), 7.54 (br s, 1H), 7 68 (d, 1H), 7.71-7.80 (m, 2H), 7.93-8.02 (m, 1H), 8.45 (s, 1H), 8.53 (br s , 1H), 11.12 (br s, 1H).

Example 132. N, 7-Dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3 dihydrochloride -carboxamide (E132)

The title compound was prepared following the procedure of Example 38 using the free base of ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5- dihydroimidazo [1,5-a] quinoline-3-carboxylate (E129) (60 mg, 0.118 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-2%) to give the free base of the title compound (40 mg, 69%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a white solid. MS (ES) m / z: 494.10 [MH ⁺ ]. C ₃₁ H ₃₅ N ₅ O requires 493.65. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.07-2.20 (m, 2H), 2.18-2.36 (m, 2H), 2.43 (s, 3H), 2.76 (d, 3H), 2.76 (s, 3H), 3.02 (t, 2H), 3.11-3.52 (m, 8H), 3.66-3.79 (m, 1H), 3.77-3.91 (m, 2H) 7.25 (d, 1H), 7.45-7.59 (m, 1H), 7.59-7.74 (m, 2H), 7.76-7.89 (m, 1H), 7 92-8.05 (m, 2H), 8.39-8.49 (m, 1H), 8.78 (br s, 1H), 11.02 (br s, 1H).

Example 133. N, 7-Dimethyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo dihydrochloride [1 , 5-a] quinoline-3-carboxamide (E133)

The title compound was prepared following the procedure of Example 38 using ethyl 7-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl free base. ] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E130) (70 mg, 0.134 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (1-2%) to give the free base of the title compound (55 mg, 79%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 509.10 [MH ⁺ ]. C ₃₁ H ₃₆ N ₆ O requires 508.67. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.49 (d, 3H), 2.45 (s, 3H), 2.76 (s, 3H), 2.79 (s, 3H), 2.96-3.10 (m, 2H), 3 , 13-3.57 (m, 12H), 3.67-3.86 (m, 1H), 7.26 (d, 1H), 7.29-7.38 (m, 1H), 7.57 -7.66 (m, 1H), 7.69 (d, 1H), 7.75-7.89 (m, 2H), 7.92-8.02 (m, 1H), 8.45 (s , 1H), 8.70 (br s, 1H), 11.64 (br s, 1H).

Example 134. Dihydrochloride 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (E134)

Ethyl 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3- free base mixture carboxylate (E128) (57 mg, 0.112 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) are stirred at reflux for 4 hours. After purification on SCX, 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3- is recovered carboxylic acid (54 mg, 0.112 mmol, 100%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.031 ml, 0.146 mmol). The precipitated free base is filtered off and treated with ethyl ether (24 mg, 50%). The free base is then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (2: 1, 3 ml) at 0 ° C. and the title compound is obtained as a yellow solid. MS (ES) m / z: 481.30 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O requires 480.61. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.42 (s, 3H), 2.71 (s, 3H), 2.99 (t, 2H), 3.10-3.60 (m, 12H), 3.74-3.90 (m, 2H), 7.01 (s, 1H), 7.24 (d, 1H), 7.24-7.33 (m, 2H), 7.54 (br s, 1H), 7.66 (d , 1H), 7.71-7.80 (br.m, 2H), 8.41 (s, 1H), 8.53 (br s, 1H), 10.71 (br s, 1H).

Example 135. Dihydrochloride 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (E135)

Ethyl-7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3- free base mixture carboxylate (E129) (96 mg, 0.189 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) are stirred at reflux for 4 hours. After purification on SCX, 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinolin-3- is recovered carboxylic acid (91 mg, 0.189 mmol, 100%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.052 ml, 0.246 mmol). The precipitated free base of the title compound is filtered off and treated with diethyl ether (46 mg, 50%). The free base is then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (2: 1, 3 ml) at 0 ° C, and the title compound is obtained as a white solid. MS (ES) m / z: 480.30 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O requires 479.62. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.10-2.29 (m, 4H), 2.44 (s, 3H), 2.76 (s, 3H), 3.01 (t, 2H), 3.13-3.52 (m, 8H), 3.68-3.79 (m, 1H), 3.80-3.90 (m, 2H), 7.14 (s, 1H), 7.28 (d, 1H), 7.35 (s, 1H), 7.54 (br.m, 1H), 7.59-7.68 (br.m, 1H), 7.69 (d, 1H), 7.84 (br.m, 1H ), 7.98 (broad s, 1H), 8.44 (s, 1H), 8.75 (broad s, 1H), 10.59 (broad s, 1H).

Example 136. Dihydrochloride 7-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5 -a] quinoline-3-carboxamide (E136)

A mixture of ethyl 7-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5- a] quinoline-3-carboxylate (E130 free base) (92 mg, 0.176 mmol) and potassium hydroxide (4 ml of a 1 M solution in MeOH) are stirred at reflux for 4 hours. After purification on SCX, 7-methyl-6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1, 5-a] quinoline-3-carboxylic acid (87 mg, 0.176 mmol, 100%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.048 ml, 0.228 mmol) (see example 14). The precipitated free base of the title compound is filtered off and treated with ethyl ether (26 mg, 30%). The free base is then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (2: 1, 3 ml) at 0 ° C. and the title compound is obtained as a yellow solid. MS (ES) m / z: 495.30 [MH ⁺ ]. C ₃₀ H ₃₄ N ₆ O requires 494.64. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.47 (d, 3H), 2.45 (s, 3H), 2.75 (s, 3H), 3.03 (t, 2H), 3.13-3.57 (m, 12H), 3 , 67-3.86 (m, 1H), 7.14 (s, 1H), 7.26-7.36 (m, 3H), 7.57 (br.m, 1H), 7.70 (d , 1H), 7.77 (s, 1H), 8.45 (s, 1H), 8.62 (br s, 1H), 10.89 (br s, 1H).

Example 137. Dihydrochloride of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-tetrazolo [5.1-s] [1,4] benzoxazine (E137)

The title compound was obtained in 77% yield following the general reductive amination procedure of Example 1, starting from 4H-tetrazolo [5.1-s] [1,4] benzoxazin-6-yl-acetaldehyde (D129) (47 mg, 0.218 mmol) and 2-methyl-5- (1-piperazinyl) quinoline (74 mg, 0.326 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (72 mg, 77%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 428.00 [MH ⁺ ]. C ₂₄ H ₂₅ N ₇ O requires 427.51. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.72 (s, 3H), 3.18-3.56 (m, 10H), 3.66-3.78 (m, 2H), 5.84-5.97 (m, 2H), 7, 22-7.32 (m, 2H), 7.43 (d, 1H), 7.47-7.63 (m, 1H), 7.67-7.83 (m, 2H), 7.89 ( dd, 1H), 8.36-8.75 (m, 1H), 11.24 (br s, 1H).

Example 138. 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-tetrazolo [5,1-s] [1,4] benzoxazine dihydrochloride (E138)

The title compound was obtained in 86% yield following the general reductive amination procedure of Example 1, starting from 4H-tetrazolo [5.1-s] [1,4] benzoxazin-6-yl-acetaldehyde (D129) (50 mg, 0.231 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (78 mg, 0.347 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (86 mg, 86%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (3: 1, 4 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 427.10 [MH ⁺ ]. C ₂₅ H ₂₆ N ₆ O requires 426.52. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.02-2.24 (m, 4H), 2.71 (s, 3H), 3.15-3.25 (m, 2H), 3.23-3.41 (m, 4H), 3, 65-3.82 (m, 3H), 5.91 (s, 2H), 7.27 (t, 1H), 7.37-7.49 (m, 2H), 7.49-7.63 ( m, 1H), 7.68-7.82 (m, 1H), 7.83-7.95 (m, 2H), 8.44-8.83 (m, 1H), 10.32 (br. s, 1H).

Example 139. Dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-tetrazolo [5.1-s] [1, 4] benzoxazine (E139)

The title compound was obtained in 77% yield following the general reductive amination procedure of Example 1, starting from 4H-tetrazolo [5.1-s] [1,4] benzoxazin-6-yl-acetaldehyde (D129) (47 mg, 0.217 mmol) and 2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (79 mg, 0.326 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (74 mg, 77%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 442.00 [MH ⁺ ]. C ₂₅ H ₂₇ N ₇ O requires 441.54. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.45 (d, 3H), 2.70 (s, 3H), 3.08-3.86 (m, 11H), 5.91 (s, 2H), 7.17-7.32 (m, 2H), 7.39-7.58 (m, 2H), 7.63-7.81 (m, 2H), 7.88 (d, 1H), 8.42-8.71 (m, 1H) 11.47 (br s, 1H).

Example 140. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydrotetrazolo [1,5-a] quinoline (E140)

The title compound was obtained in 82% yield following the general reductive amination procedure of Example 1, starting from 4,5-dihydrotetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D130) (41 mg, 0.192 mmol) and 2- methyl 5- (1-piperazinyl) quinoline (65 mg, 0.287 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (67 mg, 82%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 426.10 [MH ⁺ ]. C ₂₅ H ₂₇ N ₇ requires 425.54. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.72 (s, 3H), 3.19-3.43 (m, 10H), 3.42-3.58 (m, 4H), 3.67-3.82 (m, 2H), 7, 21-7.31 (m, 1H), 7.41 (d, 1H), 7.45-7.59 (m, 1H), 7.51 (t, 1H), 7.67-7.82 ( m, 2H), 7.88 (d, 1H), 8.37-8.70 (m, 1H), 11.69 (br s, 1H).

Example 141. 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydrotetrazolo [1,5-a] quinoline dihydrochloride (E141)

The title compound was obtained in 86% yield following the general reductive amination procedure of Example 1, starting from 4,5-dihydrotetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D130) (50 mg, 0.234 mmol) and 2- methyl 5- (4-piperidinyl) quinoline (79 mg, 0.350 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (86 mg, 86%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (3: 1, 4 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 425.10 [MH ⁺ ]. C ₂₆ H ₂₈ N ₆ requires 424.55. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.02-2.27 (m, 4H), 2.72 (s, 3H), 3.17-3.46 (m, 10H), 3.64-3.85 (m, 3H), 7, 43 (d, 1H), 7.44-7.49 (m, 1H), 7.51 (t, 1H), 7.53-7.63 (m, 1H), 7.71-7.84 ( m, 1H), 7.84-7.94 (m, 2H), 8.31-8.91 (m, 1H), 10.56 (br s, 1H).

Example 142. 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydrotetrazolo [1,5-a] quinoline dihydrochloride (E142)

The title compound was prepared in 90% yield following the general reductive amination procedure of Example 1, starting from 4,5-dihydrotetrazolo [1,5-a] quinolin-6-yl-acetaldehyde (D130) (41 mg, 0.192 mmol) and 2- methyl 5 - [(3R) -3-methyl-1-piperazinyl) quinoline (69 mg, 0.287 mmol) (WO 2004/046124). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (76 mg, 90%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (2: 1, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 440.10 [MH ⁺ ]. C ₂₆ H ₂₉ N ₇ requires 439.56. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.46 (d, 3H), 2.71 (s, 3H), 3.10-3.60 (m, 12H), 3.60-3.73 (m, 1H), 3.73-3, 81 (m, 1H), 3.81-3.89 (m, 1H), 7.20-7.35 (m, 1H), 7.46 (d, 1H), 7.51 (t, 1H) 7.53-7.62 (m, 1H), 7.68-7.83 (m, 2H), 7.90 (d, 1H), 8.41-8.77 (m, 1H), 11 53 (br s, 1H).

Example 143. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5,1-c] dihydrochloride salt [1 , 4] benzoxazine-3-carboxylate (E143)

The title compound was obtained in 88% yield following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4H- [1,2,3] triazolo [5,1-s] [1, 4] benzoxazine-3-carboxylate (D136) (96 mg, 0.33 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (113 mg, 0.50 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (144 mg, 88%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 498.30 [MH ⁺ ]. C ₂₉ H ₃₁ N ₅ O ₃ requires 497.60. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.34 (t, 3H), 2.03-2.13 (m, 2H), 2.12-2.28 (m, 2H), 2.75 (s, 3H), 3.16-3, 23 (m, 2H), 3.23-3.48 (m, 4H), 3.66-3.82 (m, 3H), 4.35 (q, 2H), 5.78 (s, 2H) 7.24 (t, 1H), 7.42 (d, 1H), 7.45-7.55 (m, 1H), 7.54-7.72 (m, 1H), 7.73-7 87 (m, 1H), 7.87-7.97 (m, 1H), 7.99 (dd, 1H), 8.43-9.08 (m, 1H), 10.49 (br s , 1H).

Example 144. N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5.1-s] dihydrochloride [1,4] benzoxazine-3-carboxamide (E144)

The title compound was prepared following the procedure of Example 38 using the free base of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3 ] triazolo [5.1-s] [1.4] benzoxazine-3-carboxylate (E143) (44 mg, 0.089 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (34 mg, 79%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (2: 1, 3 ml) at 0 ° C gives the title compound as a solid. MS (ES) m / z: 509.10 [MH ⁺ ]. C ₂₈ H ₃₀ N ₆ O ₂ requires 482.58. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.98-2.15 (m, 4H), 2.67 (s, 3H), 2.76 (d, 3H), 3.08-3.18 (m, 2H), 3.18-3, 38 (m, 4H), 3.58-3.78 (m, 3H), 5.74 (s, 2H), 7.20 (t, 1H), 7.35 (d, 1H), 7.39 -7.46 (m, 1H), 7.45-7.62 (m, 1H), 7.66-7.78 (m, 1H), 7.78-7.89 (m, 1H), 7 93 (d, 1H), 8.51-8.67 (m, 1H), 8.71 (d, 1H), 10.05 (br s, 1H).

Example 145. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5,1-s] [1,4 ] benzoxazine-3-carboxamide (E145)

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5,1-s] [1,4] benzoxazine-3-carboxylate (E143 free base) (90 mg, 0.181 mmol) and lithium hydroxide (30 mg, 0.724 mmol) in a mixture of THF / H ₂ O (3/1, 8 ml) was stirred at room temperature for 2 hours . After purification on SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H- [1,2,3] triazolo [5.1-s] [1, 4] benzoxazine-3-carboxylic acid (80 mg, 0.171 mmol, 94%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.040 ml, 0.188 mmol). The precipitated free base is filtered off and treated with ethyl ether (31 mg, 39%) and then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 4 ml) at 0 ° C and get named in the title compound as a white solid. MS (ES) m / z: 469.00 [MH ⁺ ]. C ₂₇ H ₂₈ N ₆ O ₂ requires 468.56. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.03-2.15 (m, 2H), 2.14-2.31 (m, 2H), 2.78 (s, 3H), 3.03-3.59 (m, 6H), 3, 65-3.86 (m, 3H), 5.77 (s, 2H), 7.21 (t, 1H), 7.40 (d, 1H), 7.47-7.58 (m, 1H) 7.58-7.72 (m, 1H); 7.74 (s, 1H); 7.78-7.91 (m, 1H); 7.91-8.07 (m, 1H); 7 96 (d, 1H), 8.15 (s, 1H), 8.56-9.08 (m, 1H), 10.64 (br s, 1H).

Example 146. Ethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a dihydrochloride ] quinoline-3-carboxylate (E146)

The title compound was obtained in 92% yield following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline 3-carboxylate (D137) (71 mg, 0.249 mmol) and 2-methyl-5- (4-piperidinyl) quinoline (84 mg, 0.374 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound (113 mg, 92%). Treatment of HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gave the title compound as a solid. MS (ES) m / z: 496.10 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₂ requires 495.62. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.35 (t, 3H), 2.04-2.29 (m, 4H), 2.75 (s, 3H), 3.14 (t, 2H), 3.21-3.49 (m, 8H), 3.68-3.84 (m, 3H), 4.36 (q, 2H), 7.42 (d, 1H), 7.45-7.55 (m, 1H), 7.49 (t, 1H), 7.55-7.69 (m, 1H), 7.74-7.87 (m, 1H), 7.87-7.99 (m, 1H), 8.01 (d , 1H), 8.45-9.05 (m, 1H), 10.55 (br s, 1H).

Example 147. 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline dihydrochloride -3-carboxamide (E147)

A mixture of ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline- 3-carboxylate (E146 free base) (103 mg, 0.208 mmol) and lithium hydroxide (35 mg, 0.832 mmol) in a THF / H ₂ O mixture (3/1, 8 ml) were stirred at room temperature for 5 hours. After purification on SCX, 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] is recovered quinoline-3-carboxylic acid (88 mg, 0.188 mmol, 91%) and used without further purification to obtain the free base of the title compound, following the general procedure for the preparation of amides using hexamethyldisilazane (0.044 ml, 0.207 mmol) (see example fourteen). The precipitated free base is filtered off and treated with ethyl ether and methanol (30.9 mg, 35%) and then treated with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C and the title compound is obtained as a white solid. MS (ES) m / z: 467.30 [MH ⁺ ]. C ₂₈ H ₃₀ N ₆ O requires 466.59. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.04-2.24 (m, 4H), 2.71 (s, 3H), 3.10 (t, 2H), 3.20-3.47 (m, 8H), 3.64-3, 87 (m, 3H), 7.40 (d, 1H), 7.43-7.51 (m, 2H), 7.52-7.59 (m, 2H), 7.68-7.82 ( m, 1H), 7.82-7.93 (m, 1H), 7.94 (s, 1H), 8.00 (d, 1H), 8.45-8.80 (m, 1H), 10 34 (br s, 1H).

Example 148. Cyclopropyl dihydrochloride (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3- sludge) methanone (E148)

To a solution of N-methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1, 4] benzoxazine-3-carboxamide (E25) (150 mg, 0.292 mmol) in THF (2.5 ml), while cooling with ice and stirring, cyclopropyl magnesium bromide (0.72 ml of a 0.5 M solution in THF, 0.351 mmol) was added and the resulting the solution is stirred first for 1 hour at 0 ° C and then 2 days at room temperature. The reaction mixture was poured into cold hydrochloric acid (4 ml of a 2.5M solution), then treated with saturated NaHCO ₃ solution (15 ml) and extracted with DCM (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, and the resulting crude brown oil was purified on an SPE-Si cartridge (2 g) eluting with diethyl ether to give the free base of the title compound (22 mg, 60%) in the form of a white solid. The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 494.4 [MH ⁺ ]. C ₃₀ H ₃₁ N ₅ O ₂ requires 493.61. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.05 (broad s, 1H), 9.02 (broad s, 1H), 8.70 (s, 1H), 8.02 ( m, 2H), 7.9 (m, 2H), 7.51 (m, 1H), 7.3 (d, 1H), 7.2 (t, 1H), 5.62 (s, 2H), 3.8-3.2 (m, 12H), 3.09 (m, 1H), 2.96 (s, 3H), 1.00 (m, 4H).

Example 149 (mixture of E / Z isomers). 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3 dihydrochloride -yl) ethanone (E148)

Solution 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3-yl) ethanone (E35 free base) (75 mg, 0.160 mmol), pyridine (4 ml) and methoxylamine hydrochloride (27 mg, 0.32 mmol) in 95% ethanol (4 ml) were stirred at reflux for 2 hours. The solvent was evaporated in vacuo, the residue was dissolved in water, and the solution was extracted with DCM (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, the resulting brown oil was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 4% methanol in DCM to give the free base of the title compound as a white solid (80 mg, 100%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid (85/15 E / Z mixture of isomers). MS (ES) m / z: 497.4 [MH ⁺ ]. C ₂₉ H ₃₂ N ₆ O ₂ requires 496.61. ¹ H-NMR (500 MHz, DMSO-d ⁶ ) δ: 11.29 (br.s, 1H), 8.95 (br.s, 1H), 8.58 (s, 1H), 7.99 ( m, 2H), 7.84 (m, 2H), 7.46 (broad d, 1H), 7.3-7.1 (m, 2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.8-3.1 (m, 12H), 2.92 (s, 3H), 2.2 (s, 3H).

Example 150 (mixture of E / Z isomers). O-methyloxime dihydrochloride cyclopropyl (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- sludge) methanone (E150)

The solution of cyclopropyl (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3-yl) methanone (E148 free base) (80 mg, 0.162 mmol), pyridine (4 ml) and methoxylamine hydrochloride (27 mg, 0.32 mmol) in 95% ethanol (4 ml) were stirred at reflux for 2 hours. The solvent was evaporated in vacuo, the residue was dissolved in water and the solution was extracted with DCM (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, the resulting brown oil was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 4% methanol in DCM to give the free base of the title compound E150 as a white solid substances (44 mg, 52%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid (65/15 E / Z isomer mixture). MS (ES) m / z: 523.4 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₂ requires 522.6. ¹ H-NMR (500 MHz, DMSO-d ₆ ), (given only for the prevailing isomer), δ: 11.58 (br s, 1H), 9.10 (d, 1H), 8.58 (s, 1H), 8.14 (d, 1H), 8.05 (t, 1H), 7.94 (d, 1H), 7.83 (dd, 1H), 7.53 (d, 1H), 7, 26 (m, 1H), 7.17 (m, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.77 (d, 2H), 3.6-3.4 (m, 8H), 3.23 (m, 2H), 3.01 (s, 3H), 2.41 (m, 1H), 1.42 (m, 2H), 0.89 (m, 2H) .

Example 151. The dihydrochloride of 2,2,2-trifluoroethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1, 4] benzoxazine-3-carboxylate (E151)

To a mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylic acid (E2 ) (50 mg, 0.106 mmol) and DMF (1 ml) add DIPEA (0.018 ml, 0.116 mmol) and the suspension gradually turns into a clear solution. TBTU (38 mg, 0.116 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hour. 2.2,2-trifluoro-1-ethanol (0.05 ml) was added and the resulting reaction mixture was stirred overnight at room temperature. The crude solution was purified on a SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) and then on an SPE-Si cartridge (2 g) eluting with 3% methanol in DCM to give the free base of the title compound as white solid (15 mg, 26%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 552.2 [MH ⁺ ]. C ₂₉ H ₂₈ F ₃ N ₅ O ₃ requires 551.57. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.35 (br s, 1H), 9.05 (d, 1H), 8.72 (s, 1H), 8.06 (d, 1H), 8.01 (t, 1H), 7.91 (d, 1H), 7.89 (d, 1H), 7.5 (d, 1H), 7.29 (d, 1H), 7, 19 (t, 1H), 5.6 (s, 2H), 4.97 (q, 2H), 3.73 (broad d, 2H), 3.5 (broad m, 4H), 3.39 (br.m, 4H), 3.21 (br, 2H), 2.97 (s, 3H).

Example 152. Dihydrochloride of 2,2,2-trifluoro-1-methylethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s ] [1,4] benzoxazine-3-carboxylate (E152)

To a mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylic acid (E2 ) (40 mg, 0.0852 mmol) and DMF (1 ml) add DIPEA (0.017 ml, 0.0938 mmol) and the suspension gradually turns into a clear solution. TBTU (30 mg, 0.0938 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 1 hour, then 1,1,1-trifluoro-2-propanol (0.05 ml) was added and the resulting reaction mixture was stirred in overnight at room temperature. The crude solution was purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) and then on an SPE-Si cartridge (2 g) eluting with 3% methanol in DCM to give the free base of the title compound as white solid (40 mg, 83%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 566.7 [MH ⁺ ]. C ₃₀ H ₃₀ F ₃ N ₅ O ₃ requires 565.59. ¹ H NMR (500 MHz, DMSO-d ₆ ), δ ppm 1.49 (d, 3H), 2.97 (s, 3H), 3.22 (dd, 2H), 3.35-3.47 (m, 4H), 3.47-3.57 (m, 4H), 3.75 (d, 2H), 5.61 (s, 2H), 5.66-5.74 (m, 1H), 7.20 (t, 1H), 7.30 (d, 1H ), 7.51 (d, 1H), 7.87-7.95 (m, 2H), 7.98-8.11 (m, 2H), 8.72 (s, 1H), 9.06 ( d, 1H), 11.34 (br s, 1H).

Example 153. Cyclopropylmethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- dihydrochloride carboxylate (E153)

To a mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylic acid (E2 ) (40 mg, 0.0852 mmol) and DMF (1 ml) add DIPEA (0.017 ml, 0.0938 mmol) and the suspension gradually turns into a clear solution. TBTU (30 mg, 0.0938 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hour, then cyclopropylmethanol (0.06 ml) was added, and the resulting reaction mixture was stirred overnight at room temperature. The crude solution was purified on an SPE-SCX cartridge (eluting with methanol and then 2 N ammonia in methanol) and then on an SPE-Si cartridge (2 g) eluting with a mixture of 3% methanol in DCM to give the free base of the title compound in as a white solid (40 mg, 83%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 524.3 [MH ⁺ ]. C ₃₁ H ₃₃ N ₅ O ₃ requires 523.63. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 0.35 (q, J = 5.86 Hz, 2H), 0.57 (q, J = 7.81 Hz, 2H), 1.15-1.27 (m, 1H), 2.99 (s , 3H), 3.22 (dd, J = 7.81 Hz, 2H), 3.41-3.44 (m, J = 10.74 Hz, 4H), 3.49-3.54 (m, J = 10.74 Hz, 4H), 3.74 (d, J = 10.74 Hz, 2H), 4.09 (d, J = 7.81 Hz, 2H), 5.62 (s, 2H) 7.18 (t, J = 7.81 Hz, 1H), 7.29 (d, J = 6.83 Hz, 1H), 7.52 (d, J = 7.81 Hz, 1H), 7 88 (d, J = 7.81 Hz, 1H), 7.93 (d, J = 8.79 Hz, 1H), 8.03 (t, J = 8.30 Hz, 1H), 8.10 (d, 1H), 8.67 (s, 1H), 9.08 (d, J = 8.79 Hz, 1H), 11.48 (br s, 1H).

Example 154. 1-Methylethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine- dihydrochloride 3-carboxylate (E154)

To a mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylic acid (E2 ) (40 mg, 0.0852 mmol) and DMF (1 ml) add DIPEA (0.017 ml, 0.0938 mmol) and the suspension gradually turns into a clear solution. TBTU (30 mg, 0.0938 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hour, then isopropanol (0.10 ml) was added, and the resulting reaction mixture was stirred overnight at room temperature. The crude solution was purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) and then on an SPE-Si cartridge (2 g) eluting with 3% methanol in DCM to give the free base of the title compound as white solid (40 mg, 92%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 512.3 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511.62. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.31 (d, J = 6.83 Hz, 6H), 2.99 (s, 3H), 3.22 (t, 2H), 3.42-3.44 (m, 4H), 3.51 -3.54 (m, J = 9.76 Hz, 4H), 3.74 (d, J = 9.76 Hz, 2H), 5.06-5.19 (m, 1H), 5.60 ( s, 2H), 7.17 (t, J = 7.81 Hz, 1H), 7.28 (d, J = 7.81 Hz, 1H), 7.52 (d, 1H), 7.87 ( d, J = 8.79 Hz, 1H), 7.93 (d, J = 8.79 Hz, 1H), 8.03 (t, J = 8.30 Hz, 1H), 8.09 (d, 1H), 8.65 (s, 1H), 9.07 (d, J = 8.79 Hz, 1H), 11.48 (br s, 1H).

Example 155. Cyclopentyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazin-3- dihydrochloride carboxylate (E155)

To a mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxylic acid (E2 ) (40 mg, 0.0852 mmol) and DMF (1 ml) add DIPEA (0.017 ml, 0.0938 mmol) and the suspension gradually turns into a clear solution. TBTU (30 mg, 0.0938 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hour, then cyclopentanol (0.10 ml) was added, and the resulting reaction mixture was stirred overnight at room temperature. The crude solution was purified on an SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) and then on an SPE-Si cartridge (2 g) eluting with 3% methanol in DCM to give the free base of the title compound as white solid (40 mg, 87%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 538.3 [MH ⁺ ]. C ₃₂ H ₃₅ N ₅ O ₃ requires 537.66. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.41 (br s, 1H), 9.07 (d, 1H), 8.65 (s, 1H), 8.08 (d, 1H), 8.02 (t, 1H), 7.92 (d, 1H), 7.87 (d, 1H), 7.5 (d, 1H), 7.27 (d, 1H), 7, 16 (t, 1H), 5.58 (s, 2H), 5.28 (m, 1H), 3.74 (broad d, 2H), 3.47 (m, 4H), 3.38 (m , 4H), 3.19 (m, 2H), 2.97 (s, 3H), 1.91 (m, 2H), 1.74 (m, 4H), 1.61 (broad m, 2H) .

Example 156. N'-Acetyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine dihydrochloride -3-carbohydrazide (E156)

To a solution of trimethylaluminum (0.9 ml of a 2 M solution in hexane, 1.8 mmol) in dry DCM (1.5 ml) at 0 ° C, acetohydrazide (134 mg, 1.8 mmol) was added, and the resulting mixture was stirred at room temperature in within 30 minutes. Ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxylate dihydrochloride ( E1) (150 mg, 0.3 mmol) in dry DCM (1.5 ml), and the resulting solution was stirred at 54 ° C for 4 hours. The reaction was quenched with water (carefully, the reaction was highly exothermic), then a 1 M NaOH solution (15 ml) was added and the reaction mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a pale yellow solid, which was treated with ethyl ether, and the free base of the title compound (116 mg, 74%) was obtained as a white solid. The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 527.2 [MH ⁺ ]. C ₂₉ H ₃₃ N ₇ O ₃ requires 526.6. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.88 (s, 3H), 2.94 (s, 3H), 3.16-3.25 (m, 2H), 3.32-3.40 (m, 2H), 3.40-3, 47 (m, 2H), 3.46-3.56 (m, 4H), 3.73 (d, 2H), 5.58 (s, 2H), 7.17 (t, 1H), 7.27 (d, 1H), 7.49 (d, 1H), 7.80-7.94 (m, 2H), 7.93-8.08 (m, 2H), 8.62 (s, 1H), 9.02 (br s, 1H), 9.77 (s, 1H), 9.89 (s, 1H), 11.11 (br s, 1H).

Example 157. Dihydrochloride 3- (5-methyl-1,3,4-oxadiazol-2-yl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H -imidazo [5.1-s] [1.4] benzoxazine (E157)

To a suspension of N'-acetyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3 β-carbohydrazide (E156 free base) and dry pyridine (0.015 ml, 0.19 mmol) in dry DCM, trifluoroacetic anhydride (0.029 ml, 1.71 mmol) was added with stirring at 0 ° C, and the resulting mixture was stirred for 1 hour at 0ºС and during the night at room temperature. The reaction mixture was basified to pH 8-9 with NaHCO ₃ and then extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, the resulting crude oil was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 4% methanol in DCM to give the free base of the title compound as a white solid (24 mg, 50%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 508.2 [MH ⁺ ]. C ₂₉ H ₂₉ N ₇ O ₂ requires 507.6. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 2.92 (s, 3H), 3.22 (t, 2H), 3.32-3.41 (m, 2H), 3.41-3.48 (m, 2H), 3.48-3.58 (m, 2H), 3.58-3.83 (m, 4H), 5.66 (s, 2H), 7.20 (t, 1H), 7.30 (d, 1H), 7.47 (d, 1H), 7.81-7.87 (m, 1H), 7.91 (d, 1H), 7.99 (br s, 2H), 8, 77 (s, 1H), 8.97 (br s, 1H), 11.13 (br s, 1H).

Example 158. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (1,3-oxazol-5-yl) -4H-imidazo [5.1 c] [1.4] benzoxazine (E158)

A mixture of 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carbaldehyde (D138) ( 50 mg, 0.11 mmol), K ₂ CO ₃ (31 mg, 0.22 mmol) and p-toluenesulfonylmethylisocyanide (21 mg, 0.11 mmol) in MeOH (1 ml) was stirred overnight at room temperature. The crude solution was purified on an SPE-SCX cartridge (eluted with methanol, then 2 N ammonia in methanol) and then treated with diethyl ether to give the corresponding free base of the title compound as a solid (51 mg, 100%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 493.4 [MH ⁺ ]. C ₂₉ H ₂₈ N ₆ O ₂ requires 492.58. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.99 (s, 3H), 3.19-3.28 (m, 2H), 3.37-3.48 (m, 4H), 3.47-3.60 (m, 4H), 3, 74 (d, 2H), 5.56 (s, 2H), 7.17 (t, 1H), 7.27 (d, 1H), 7.42 (s, 1H), 7.51 (d, 1H) ), 7.86 (d, 1H), 7.93 (d, 1H), 8.03 (t, 1H), 8.13 (d, 1H), 8.44 (s, 1H), 8.73 (s, 1H), 9.08 (d, 1H), 11.61 (br s, 1H).

Example 159. 3- (3-Methyl-5-isoxazolyl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo dihydrochloride [5.1-s ] [1,4] benzoxazine (E159)

(2Z) -3- (Dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1 , 4] benzoxazin-3-yl) -2-buten-1-one (D139) (33 mg, 0.0614 mmol) was dissolved in ethanol (2 ml) and hydroxylamine hydrochloride (6.5 mg, 0.0922 mmol) was added ) The reaction mixture is exposed to microwave radiation in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 ° C., 5 minutes). The solvent was evaporated, then a saturated aqueous solution of NH ₄ Cl (10 ml) was added and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the free base of the title compound as a cream solid (15 mg, 48%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 507.3 [MH ⁺ ]. C ₃₀ H ₃₀ N ₆ O ₂ requires 506.61. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.28 (s, 3H), 2.98 (s, 3H), 3.18-3.27 (m, 2H), 3.36-3.47 (m, 4H), 3.47-3, 57 (m, 4H), 3.74 (d, 2H), 5.61 (s, 2H), 6.60 (s, 1H), 7.18 (t, 1H), 7.27 (d, 1H) ), 7.51 (d, 1H), 7.87 (d, 1H), 7.93 (d, 1H), 8.02 (t, 1H), 8.10 (d, 1H), 8.72 (s, 1H), 9.07 (d, 1H), 11.48 (br s, 1H).

Example 160. 3- (3-Methyl-1H-pyrazol-5-yl) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo dihydrochloride , 1-s] [1,4] benzoxazine (E160)

(2Z) -3- (Dimethylamino) -1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1 , 4] benzoxazin-3-yl) -2-buten-1-one (D139) (33 mg, 0.0614 mmol) was dissolved in ethanol (2 ml) and hydrazine hydrate (0.003 mg, 0.0922 mmol) was added. The reaction mixture is exposed to microwave radiation in a microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 ° C., 5 min). The solvent was evaporated, then a saturated aqueous solution of NH ₄ Cl (5 ml) was added and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the free base of the title compound as a cream solid (16 mg, 48%). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 506.4 [MH ⁺ ]. C ₃₀ H ₃₁ N ₇ O requires 505.62.

Example 161. Ethyl-6- {2- [4-fluoro-4- (5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3- dihydrochloride carboxylate (E161)

Solution of 5- (4-fluoro-4-piperidinyl) quinoline (D142) (90 mg, 0.391 mmol) and ethyl 6- (2-oxoethyl) -4H-imidazo [5.1-s] [1,4] benzoxazine -3-carboxylate (D6) (100 mg, 0.365 mmol) in 1.2 DCE (2 ml) was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (75 mg, 0.355 mmol) was added and the resulting mixture was stirred at the same temperature during the night. The reaction was quenched with water (10 ml) and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo, the resulting mixture was purified on an SPE-Si cartridge (2 g), eluting with a mixture of 50% ethyl acetate in cyclohexane to give the free base of the title compound as a white foam (122 mg , 62%). MS (ES) m / z: 501.3 [MH ⁺ ]. C ₂₉ H ₂₉ FN ₄ O ₃ requires 500.57. ¹ H-NMR (400 MHz, CDCl ₃ -d ₆ ) δ: 9.07 (broad d, 2H), 8.15 (d, 1H), 8.05 (s, 1H), 7.7 (t , 1H), 75 (br.s.d, 1H), 7.4 (br.s.d, 2H), 7.27 (br.s., 1H), 7.16 (t, 1H), 5.58 (s, 2H), 4.4 (q, 2H), 3.3-2.0 (br.m, 12H), 1.4 (t, 3H). The free base is treated with HCl (2.1 eq. 1 M solution in diethyl ether) in dry methanol at 0 ° C. Evaporation of the solvent and treatment with diethyl ether gave the title compound as a yellow solid. MS (ES) m / z: 501.3 [MH ⁺ ]. C ₂₉ H ₂₉ FN ₄ O ₃ requires 500.57.

Example 162. Ethyl-6- (2- {4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-3 carboxylate (E162)

The title compound (118 mg, 54%) was obtained by the procedure described for the preparation of the compound of Example 56 using 2- (fluoromethyl) -5- (1-piperazinyl) quinoline (D146) (104 mg, 0.424 mmol). MS (ES; m / z): 516 [MH ⁺ ]. C ₂₉ H ₃₀ FN ₅ O ₃ requires 515.59. NMR ( ¹ H, 300 MHz, CDCl ₃ ) δ: 8.56 (d, 1H), 7.97 (s, 1H), 7.7 (d, 1H), 7.56 (m, 2H), 7 34 (d, 1H), 7.14 (m, 2H), 7.11 (t, 1H), 5.62 (d, 2H), 5.53 (s, 2H), 4.38 (q, 2H), 3.1 (m, 4H), 2.94 (m, 2H), 2.82 (m, 4H), 2.72 (m, 2H), 1.40 (t, 3H).

Example 163. Ethyl-6- (2- {4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-3 carboxylate (E163)

The title compound (211 mg, 95%) was obtained by the procedure of Example 56 using 2- (difluoromethyl) -5- (1-piperazinyl) quinoline (D143) (109 mg, 0.414 mmol). MS (ES; m / z): 534 [MH ⁺ ]. C ₂₉ H ₂₉ F ₂ N ₅ O ₃ requires 533.58. NMR ( ¹ H, 300 MHz, CDCl ₃ ) δ: 8.64 (d, 1H), 7.98 (s, 1H), 7.82 (d, 1H), 7.67 (m, 2H), 7 34 (m, 1H), 7.18 (m, 2H), 7.14 (t, 1H), 6.75 (t, 1H), 5.53 (s, 2H), 4.39 (q, 2H), 3.15 (m, 4H), 2.95 (m, 2H), 2.83 (broad m, 4H), 2.72 (m, 2H), 1.41 (t, 3H).

Example 164. Ethyl-6- [2- (4- {2 - [(dimethylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E164)

The title compound (152 mg, 76%) was obtained by the procedure of Example 56 using N, N-dimethyl-5- (1-piperazinyl) -2-quinolinecarboxamide (D150) (102 mg, 0.359 mmol). MS (ES; m / z): 555 [MH ⁺ ]. C ₃₁ H ₃₄ N ₆ O ₄ requires 554.66. NMR ( ¹ H, 300 MHz, CDCl ₃ ) δ: 8.58 (s, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.64 (m, 2H), 7 34 (d, 1H), 7.15 (m, 2H), 7.05 (t, 1H), 5.53 (s, 2H), 4.39 (q, 2H), 3.1 (m, 10H), 2.95 (m, 2H), 2.83 (br s, 4H), 2.70 (m, 2H), 1.40 (t, 3H).

Example 165. Ethyl-6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H-imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E165)

The title compound (133 mg, 69%) was obtained by the procedure of Example 56 using N-methyl-5- (1-piperazinyl) -2-quinolinecarboxamide (D151) (96 mg, 0.355 mmol). MS (ES; m / z): 541 [MH ⁺ ]. C ₃₀ H ₃₂ N ₆ O ₄ requires 540.62. NMR ( ¹ H, 300 MHz, CDCl ₃ ) δ: 8.62 (d, 1H), 8.25 (d, 1H), 8.2 (d, 1H), 7.97 (s, 1H), 7 74 (d, 1H), 7.67 (t, 1H), 7.34 (d, 1H), 7.15 (m, 2H), 7.04 (t, 1H), 5.53 (s, 2H), 4.39 (q, 2H), 3.1 (m, 7H), 2.95 (m, 2H), 2.90 (m, 4H), 2.72 (m, 2H), 1, 40 (t, 3H).

Example 166. 6- (2- {4- [2- (Fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -N-methyl-4H-imidazo [5.1-s] [1,4] benzoxazine -3-carboxamide (E166)

The title compound (21 mg, 74%) was obtained by the procedure of Example 57 using ethyl 6- (2- {4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E162) (29 mg, 0.057 mmol). Stirring is carried out at room temperature overnight. MS (ES; m / z): 501 [MH ⁺ ]. C ₂₈ H ₂₉ FN ₆ O ₂ requires 500.58. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.58 (d, 1H), 8.55 (s, 1H), 8.14 (q, 1H), 7.76 (dd, 1H) 7.7 (m, 2H), 7.64 (d, 1H), 7.22 (m, 2H), 7.10 (t, 1H), 5.66 (d, 2H), 5.55 ( s, 2H), 3.07 (br s, 4H), 2.89 (t, 2H), 2.8 (br s, 4H), 2.77 (d, 3H), 2.65 (t , 2H).

Example 167. 6- (2- {4- [2- (Fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -N, N-dimethyl-4H-imidazo [5.1-s] [1.4 ] benzoxazine-3-carboxamide (E167)

The title compound (24 mg, 82%) was obtained by the procedure of Example 58 using ethyl 6- (2- {4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E162) (29 mg, 0.057 mmol) and dimethylamine (2.0 M / THF). Stirring is carried out at room temperature overnight. MS (ES; m / z): 515 [MH ⁺ ]. C ₂₉ H ₃₁ FN ₆ O ₂ requires 514.61. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.58 (d, 1H), 8.58 (s, 1H), 7.76 (dd, 1H), 7.7 (m, 2H) 7.64 (d, 1H), 7.22 (m, 2H), 7.10 (t, 1H), 5.66 (d, 2H), 5.48 (s, 2H), 3.49 ( broad s, 3H), 3.07 (broad s, 4H), 2.98 (broad s, 3H), 2.89 (t, 2H), 2.78 (broad s, 4H), 2 66 (t, 2H).

Example 168. 6- (2- {4- [2- (Fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -3- (4-morpholinylcarbonyl) -4H-imidazo [5.1-s] [1 , 4] benzoxazine (E168)

The title compound (25 mg, 80%) was obtained by the procedure of Example 59 using ethyl-6- (2- {4- [2- (fluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E162) (29 mg, 0.057 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50 ° C. MS (ES; m / z): 557 [MH ⁺ ]. C ₃₁ H ₃₃ FN ₆ O ₃ requires 556.65. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.58 (d, 1H), 8.56 (s, 1H), 7.77 (dd, 1H), 7.7 (m, 2H) 7.64 (d, 1H), 7.22 (m, 2H), 7.11 (t, 1H), 5.66 (d, 2H), 5.51 (s, 2H), 4.3 ( broad s, 2H), 3.66 (m, 6H), 3.08 (broad s, 4H), 2.89 (broad t, 2H), 2.78 (broad s, 4H), 2 66 (broad t, 2H).

Example 169. 6- (2- {4- [2- (Difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -N-methyl-4H-imidazo [5.1-s] [1,4] benzoxazine -3-carboxamide (E169)

The title compound (40 mg, 78%) was obtained by the procedure of Example 57 using ethyl 6- (2- {4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E163) (53 mg, 0.099 mmol). Stirring is carried out at room temperature overnight. MS (ES; m / z): 519 [MH ⁺ ]. C ₂₈ H ₂₈ F ₂ N ₆ O ₂ requires 518.57. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.71 (d, 1H), 8.55 (s, 1H), 8.13 (q, 1H), 7.78 (m, 4H) , 7.30 (dd, 1H), 7.24 (dd, 1H), 7.1 (t, 1H), 7.12 (t, 1H), 5.55 (s, 2H), 3.09 ( broad s, 4H), 2.89 (t, 2H), 2.8 (broad s, 4H), 2.77 (d, 3H), 2.66 (t, 2H).

Example 170. 6- (2- {4- [2- (Difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -N, N-dimethyl-4H-imidazo [5.1-s] [1.4 ] benzoxazine-3-carboxamide (E170)

The title compound (47 mg, 90%) was obtained by the procedure of Example 58 using ethyl 6- (2- {4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E163) (53 mg, 0.099 mmol) and dimethylamine (2.0 M / THF). Stirring is carried out at room temperature overnight. MS (ES; m / z): 533 [MH ⁺ ]. C ₂₉ H ₃₀ F ₂ N ₆ O ₂ requires 532.60. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.71 (d, 1H), 8.55 (s, 1H), 7.78 (m, 4H), 7.30 (dd, 1H) , 7.25 (dd, 1H), 7.1 (t, 1H), 7.1 (t, 1H), 5.48 (s, 2H), 3.49 (br s, 3H), 3, 09 (br s, 4H), 2.98 (br s, 3H), 2.89 (t, 2H), 2.78 (br s, 4H), 2.66 (t, 2H).

Example 171. 6- (2- {4- [2- (Difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -3- (4-morpholinylcarbonyl) -4H-imidazo [5.1-s] [1 , 4] benzoxazine (E171)

The title compound (39 mg, 68%) was obtained by the procedure of Example 59 using ethyl 6- (2- {4- [2- (difluoromethyl) -5-quinolinyl] -1-piperazinyl} ethyl) -4H-imidazo [ 5.1-s] [1.4] benzoxazine-3-carboxylate (E163) (29 mg, 0.057 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50 ° C. MS (ES; m / z): 575 [MH ⁺ ]. C ₃₁ H ₃₂ F ₂ N ₆ O ₃ requires 574.64. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.71 (d, 1H), 8.56 (s, 1H), 7.8 (m, 4H), 7.31 (quint, 1H) 7.24 (d, 1H), 7.1 (m, 2H), 5.51 (s, 2H), 4.3 (br s, 2H), 3.7 (m, 6H), 3.09 (br s, 4H), 2.89 (t, 2H), 2.78 (br s, 4H), 2.66 (m, 2H).

Example 172. N-Methyl-6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H-imidazo [5.1-s] [1, 4] benzoxazine-3-carboxamide (E172)

The title compound (14 mg, 43%) was obtained by the procedure of Example 57 using ethyl 6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H -imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E165) (33 mg, 0.061 mmol). Stirring is carried out at room temperature overnight. MS (ES; m / z): 526 [MH ⁺ ]. C ₂₉ H ₃₁ N ₇ O ₃ requires 525.62. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.88 (q, 1H), 8.66 (d, 1H), 8.55 (s, 1H), 8.13 (dd, 1H) 8.13 (q, 1H); 7.78 (m, 3H); 7.29 (dd, 1H); 7.25 (dd, 1H); 7.1 (t, 1H); 5.55 ( s, 2H), 3.09 (br s, 4H), 2.9 (d, 3H), 2.88 (t, 2H), 2.8 (br s, 4H), 2.77 (d , 3H); 2.66 (t, 2H).

Example 173. N, N-Dimethyl-6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H-imidazo [5.1-s] [ 1,4] benzoxazine-3-carboxamide (E173)

The title compound (29 mg, 88%) was obtained by the procedure of Example 58 using ethyl 6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H -imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E165) (33 mg, 0.061 mmol) and dimethylamine (2.0 M / THF). Stirring is carried out at room temperature overnight. MS (ES; m / z): 540 [MH ⁺ ]. C ₃₀ H ₃₃ N ₇ O ₃ requires 539.64. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.88 (q, 1H), 8.66 (d, 1H), 8.55 (s, 1H), 8.13 (d, 1H) 7.78 (m, 3H), 7.28 (dd, 1H), 7.24 (dd, 1H), 7.1 (t, 1H), 5.48 (s, 2H), 3.49 ( broad s, 3H), 3.09 (broad s, 4H), 2.98 (broad s, 3H), 2.86 (t, 2H), 2.9 (d, 3H), 2.78 (broad s, 4H); 2.66 (t, 2H).

Example 174. N-Methyl-5- (4- {2- [3- (4-morpholinylcarbonyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-6-yl] ethyl} -1- piperazinyl) -2- quinolinecarboxamide (E174)

The title compound (24 mg, 70%) was obtained by the procedure of Example 59 using ethyl 6- [2- (4- {2 - [(methylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H -imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E165) (33 mg, 0.061 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50 ° C. MS (ES; m / z): 582 [MH ⁺ ]. C ₃₂ H ₃₅ N ₇ O ₄ requires 581.68. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.88 (quart, 1H), 8.66 (dd, 1H), 8.56 (s, 1H), 8.13 (d, 1H) 7.8 (m, 3H), 7.28 (dd, 1H), 7.24 (dd, 1H), 7.11 (t, 1H), 5.51 (s, 2H), 4.3 ( broad s, 2H), 3.7 (m, 6H), 3.09 (broad s, 4H), 2.9 (d, 3H), 2.9 (m, 2H), 2.78 (broad s, 4H), 2.66 (m, 2H).

Example 175. 6- [2- (4- {2 - [(Dimethylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -N, N-dimethyl-4H-imidazo [5.1-s] [ 1,4] benzoxazine-3-carboxamide (E175)

The title compound (35 mg, 92%) was obtained by the procedure of Example 58 using ethyl 6- [2- (4- {2 - [(dimethylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H -imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E164) (38 mg, 0.068 mmol) and dimethylamine (2.0 M / THF). Stirring is carried out at room temperature overnight. MS (ES; m / z): 554 [MH ⁺ ]. C ₃₁ H ₃₅ N ₇ O ₃ requires 553.67. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.58 (d, 1H), 8.55 (s, 1H), 7.76 (dd, 1H), 7.73 (m, 2H) 7.63 (d, 1H); 7.25 (m, 2H); 7.1 (t, 1H); 5.48 (s, 2H); 3.49 (br s, 3H); 3, 09 (br s, 4H), 3.08 (s, 3H), 3.0 (s, 3H), 2.98 (br s, 3H), 2.86 (t, 2H), 2.69 (broad s, 4H); 2.66 (t, 2H).

Example 176. N, N-Dimethyl-5- (4- {2- [3- (4-moroflininylcarbonyl) -4H-imidazo [5.1-s] [1,4] benzoxazin-6-yl] ethyl} - 1-piperazinyl) -2- quinolinecarboxamide (E176)

The title compound (37 mg, 92%) was obtained by the procedure of Example 59 using ethyl 6- [2- (4- {2 - [(dimethylamino) carbonyl] -5-quinolinyl} -1-piperazinyl) ethyl] -4H -imidazo [5.1-s] [1.4] benzoxazine-3-carboxylate (E164) (38 mg, 0.068 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50 ° C. MS (ES; m / z): 596 [MH ⁺ ]. C ₃₃ H ₃₇ N ₇ O ₄ requires 595.71. NMR ( ¹ H, 400 MHz, DMSO-d ₆ ) δ: 8.59 (d, 1H), 8.56 (s, 1H), 7.77 (dd, 1H), 7.7 (m, 2H) 7.63 (d, 1H), 7.25 (m, 2H), 7.11 (t, 1H), 5.51 (s, 2H), 4.3 (br s, 2H), 3, 7 (m, 6H), 3.08 (br s, 4H), 3.08 (s, 3H), 3.0 (s, 3H), 2.89 (t, 2H), 2.77 (br s, 4H), 2.66 (m, 2H).

Examples 177-179 (pure enantiomers). Ethyl 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E177 -179)

Solution of 2-methyl-5- (2-methyl-4-piperidinyl) quinoline (D163) (212 mg, 0.883 mmol) and ethyl 6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D86) (228 mg, 0.803 mmol) in 1.2 DCE (2 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (170 mg, 0.803 mmol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction was quenched with water (10 ml) and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified on a Horizon column (25M), eluting with a mixture of 3% methanol in DCM to give a racemic mixture of the title compounds as a white foam (340 mg, 77%). MS (ES) m / z: 509.3 [MH ⁺ ]. C ₃₂ H ₃₆ N ₄ O ₂ requires 508.66.

The racemic mixture was separated by semi-preparative chromatography on SFC (Gilson) [CHIRALCEL AD-H, 25 × 2.1 cm; modifier 27% (ethanol + 0.1% isopropylamine); flow rate = 22 ml / min; pressure 195 bar; T = 36ºС; UV wavelength 220 nm; loop = 1 ml] and get enantiomer 1 (E177) (21 mg), enantiomer 4 (E178) (13 mg); enantiomer 2 + 3 (E179) (110 mg). The enantiomeric excess of enantiomers 1 and 4 was confirmed by SFC analysis (Berger): CHIRALPAK AD-H chiral column, 25 x 0.46 cm; modifier 27% (ethanol + 0.1% isopropylamine); flow rate = 2.5 ml / min; pressure 180 bar; T = 35ºС; UV wavelength 220 nm; loop = 10 μl.

Enantiomer 1 E177 (a / a UV 100%, retention time min, e.i. = 100%).

Enantiomer 4 E178 (a / a UV 100%, retention time min, e.i. = 100%).

Enantiomer 2 + 3 E179.

Example 180. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E180)

To ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (free base E177) (138 mg, 0.379 mmol), KOH (1 M solution in MeOH, 10 ml) was added and the mixture was stirred at reflux. After 3 hours, the solution was cooled to room temperature, the solvent was removed in vacuo and the crude reaction product was purified on an SCX cartridge. The title compound was obtained as an ammonium salt in 94% yield (122 mg). MS (ES) m / z: 468.20 [MH ⁺ ]. C ₂₈ H ₂₉ N ₅ O ₂ requires 467.57. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.40 (s, 1H), 8.33 (d, 1H), 7.66 (d, 1H), 7.57 (m, 2H) 7.36 (d, 1H), 7.29 (t, 1H), 7.20 (d, 1H), 7.09 (q, 1H), 3.22 (broad t, 2H), 3, 03 (br.h., 4H), 2.91 (br., 4H), 2.76 (br., 4H), 2.62 (s, 3H), 2.62-2, 45 (m, 2H).

Example 181. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-ammonium carboxylate (E181 )

To ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (free base E99) (50 mg, 0.1 mmol), KOH (1 M solution in MeOH, 0.6 ml) was added and the mixture was stirred at reflux. After 2 hours, the solution was cooled to room temperature, the precipitated substance was completely dissolved by adding H ₂ O, and then the solution was purified on a SPE-SCX cartridge (eluting with methanol, then 2 N ammonia in methanol) to give the title compound. MS (ES) m / z: 466.2 [MH ⁺ ]. C ₂₈ H ₂₇ N ₅ O ₂ requires 465.5.

Example 182. N-Methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] benzoxazine- 3-carboxamide (E182)

A solution of trimethylaluminum (2.0 M solution in hexanes, 2.60 ml, 5.20 mmol) and N, O-dimethylhydroxylamine hydrochloride (0.51 g, 5.20 mmol) in dry DCM (20 ml) was stirred at room temperature within 30 minutes. Then ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] benzoxazine-3-carboxylate (free base E37) is gradually added. (0.43 g, 0.87 mmol) and the resulting reaction mixture was stirred at 40 ° C for 2 hours. Upon completion of the reaction, a 1 M aqueous NaOH solution (20 ml) was added dropwise until gas evolution ceased. The aqueous solution was extracted with DCM (3 × 20 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude reaction product was treated with diethyl ether to give the title compound (0.39 g, 0.76 mmol, 87% yield) as a pale yellow solid. MS (ES; m / z): 512.3 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O ₃ requires 511.62. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.95-2.05 (br.m, 4H), 2.34-2.42 (br.m, 2H), 2.63-2.70 (br.m, 1H), 2.75 (s , 3H), 2.95-3.08 (br.m, 2H), 3.30-3.37 (br.m, 4H), 3.61 (br s, 3H), 3.89 (s , 3H), 5.58 (s, 2H), 7.09 (t, 1H), 7.21 (d, 1H), 7.40-7.32 (m, 2H), 7.48 (d, 1H), 7.64 (t, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.31 (d, 1H).

Example 183. 6- {2 - [(2R) -4- (7-Fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4H-imidazo [5.1-s] benzoxazine-3-carboxylic acid (E183)

To a solution of ethyl 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4H-imidazo [5.1-s ] Benzoxazine-3-carboxylate (E118) (58 mg, 0.1 mmol) in MeOH (3 ml) was added NaOH (1 ml of a 10% aqueous solution) and the resulting white suspension was heated for 2 hours at 80 ° C. The mixture was evaporated and the crude reaction product was purified on an SCX column, eluting with a solution of ammonia in methanol, recovering 0.038 g of the title compound E183 as a pale yellow foam. MS (ES) m / z: 502.5 [MH ⁺ ]. C ₂₈ H ₂₈ FN ₅ O ₃ requires 501.56.

Example 184. N-Methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (E184)

The title compound was prepared following the procedure for Example 41 using methoxylamine hydrochloride (118 mg, 1.21 mmol) and ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl free base. ] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E82) (100 mg, 0.202 mmol). MS (ES) m / z: 510.1 [MH ⁺ ]. C ₃₁ H ₃₅ N ₅ O ₂ requires 509.65. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 2.06 (br.m, 3H), 2.40 (br.m, 2H), 2.60-2.85 (br.m, 2H), 2.77 (s, 3H), 2.90- 3.60 (m, 13H), 3.89 (s, 3H), 7.20-7.40 (m, 4H), 7.47 (d, 1H), 7.68 (t, 1H), 7 93 (d, 1H); 7.99 (s, 1H); 8.32 (d, 1H).

Example 185. Ethyl-6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydroimidazo [1, 5-a] quinoline-3-carboxylate

The title compound was obtained in 49% yield following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (D86) (91 mg, 0.32 mmol) and 7-fluoro-2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (obtained by a procedure similar to that described in WO 2004/046124) (100 mg, 0.39 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (1%) to give the free base of the title compound. MS (ES) m / z: 528.3 [MH ⁺ ]. C ₃₁ H ₃₄ FN ₅ O ₂ requires 527.64. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.39 (d, 1H), 8.00 (s, 1H), 7.37-7.56 (m, 4H), 7.3 (m, 1H), 6.9 (d, 1H), 4.45 (quart, 2H), 3, -2.7 (broad m, 11H), 2.77 (s, 3H), 1.46 (t, 3H), 1.25 (m, 3H).

Example 186. 6- {2 - [(2R) -4- (7-Fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5- a] quinoline-3-carboxylic acid (E186)

A mixture of the free base of ethyl 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydroimidazo [1, 5-a] quinoline-3-carboxylate (E185) (100 mg, 0.19 mmol) and KOH (1 M solution in MeOH, 1.2 ml) were stirred at reflux for 2 hours. The yellow solid was filtered off, collected and suspended in water (5 ml). Acetic acid was added to pH 7, and the resulting pale yellow solid was filtered off, washed with diethyl ether and dried in vacuo. The title compound (80 mg, 0.14 mmol, 84%) was recovered as a pale yellow foam. MS (ES) m / z: 500.3 [MH ⁺ ]. C ₂₉ H ₃₀ FN ₅ O ₂ requires 501.5.

Example 187. Ethyl-6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydro [1, 2,3] triazolo [1,5-a] quinoline-3-carboxylate (E187)

The title compound was obtained in 92% yield following the general reductive amination procedure of Example 1, starting from ethyl 6- (2-oxoethyl) -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (D137) (50 mg, 0.175 mmol) and 7-fluoro-2-methyl-5 - [(3R) -3-methyl-1-piperazinyl] quinoline (50 mg, 0.193 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (85 mg, 92%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol (1 ml) at 0 ° C gives the title compound as a yellow solid. MS (ES) m / z: 529.10 [MH ⁺ ]. C ₃₀ H ₃₃ FN ₆ O ₂ requires 528.63. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.34 (t, 3H), 1.45 (d, 3H), 2.70 (s, 3H), 2.97-3.67 (m, 4H), 3.15 (t, 2H), 3 20-3.54 (m, 4H), 3.39 (t, 2H), 3.48-3.94 (m, 3H), 4.26-4.45 (m, 2H), 7.20 (d, 1H), 7.37-7.56 (m, 4H), 8.02 (d, 1H), 8.39-8.62 (m, 1H), 10.96 (br s, 1H )

Example 188. 6- {2 - [(2R) -4- (7-Fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydro [1,2, 3] triazolo [1,5-a] quinoline-3-carboxylic acid (E188)

A mixture of ethyl 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydro [1,2, 3] triazolo [1,5-a] quinoline-3-carboxylate (E187 free base) (75 mg, 0.142 mmol) and KOH (1 M solution in MeOH, 2 ml) were stirred at reflux for 45 minutes. The mixture was purified on an SCX column eluting with a solution of NH ₃ in methanol to give the title compound (70 mg, 0.14 mmol, 99%) as a pale yellow foam. MS (ES) m / z: 501.3 [MH ⁺ ]. C ₂₈ H ₂₈ FN ₆ O ₂ requires 500.5.

Example 189. Dihydrochloride 6- {2 - [(2R) -4- (7-fluoro-2-methyl-5-quinolinyl) -2-methyl-1-piperazinyl] ethyl} -4,5-dihydro [1,2 , 3] triazolo [1,5-a] quinoline-3-carboxamide (E189)

The title compound was prepared following the general procedure for preparing amides (see Example 14), starting from 6- {2 - [(2R) -4- (7-Fluoro-2-methyl-5-quinolinyl) -2-methyl- 1-piperazinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxylic acid (E188) (70 mg, 0.14 mmol) using hexamethyldisilazane ( 0.033 ml, 0.154 mmol). The crude reaction product is purified on an SCX cartridge and flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound. Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (1: 2, 3 ml) at 0 ° C gave the title compound as a yellow solid. MS (ES) m / z: 500.10 [MH ⁺ ]. C ₂₈ H ₃₀ FN ₇ O requires 499.59. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.45 (d, 3H), 2.71 (s, 3H), 3.05-3.21 (m, 2H), 3.19-3.52 (m, 4H), 3.22-3, 33 (m, 2H), 3.23-3.63 (m, 6H), 3.58-3.84 (m, 1H), 7.22 (d, 1H), 7.43 (d, 1H) 7.47 (t, 1H), 7.45-7.54 (m, 1H), 7.45-7.53 (m, 1H), 7.57 (s, 1H), 7.96 (s , 1H), 8.00 (d, 1H), 8.36-8.69 (m, 1H), 11.19 (br s, 1H).

Example 190. N-Methyl-N- (methyloxy) -6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide (E190)

The title compound was prepared following the procedure of Example 184 using N, O-dimethylhydroxylamine hydrochloride (178 mg, 1.82 mmol) and ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1 -piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate (E146 free base) (150 mg, 0.303 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the title compound (106 mg, 69%). MS (ES) m / z: 511.3 [MH ⁺ ]. C ₃₀ H ₃₄ N ₆ O ₂ requires 510.64. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 2.03 (br.m, 3H), 2.40 (br.m, 2H), 2.61-2.82 (br.m, 2H), 2.75 (s, 3H), 2.95- 3.65 (m, 13H), 3.95 (s, 3H), 7.22-7.48 (m, 4H), 7.65 (t, 1H), 7.90 (d, 1H), 8 06 (d, 1H); 8.28 (d, 1H).

Example 191. Dihydrochloride 1- (6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydro [1,2,3] triazolo [1,5- a] quinolin-3-yl) ethanone (E191)

The title compound was prepared following the procedure in Example 121 using methyl magnesium bromide (0.082 ml of a 3 M solution in diethyl ether, 0.245 mmol) and E190 (106 mg, 0.208 mmol). The crude reaction product was purified by flash chromatography on silica gel eluting with a mixture of methanol in DCM (2%) to give the free base of the title compound (44 mg, 45%). Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 1, 2 ml) at 0 ° C gives the title compound as a white solid). MS (ES) m / z: 466.00 [MH ⁺ ]. C ₂₉ H ₃₁ N ₅ O requires 465.60. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.03-2.15 (m, 2H), 2.13-2.34 (m, 2H), 2.63 (s, 3H), 2.77 (s, 3H), 3.12 (t, 2H), 3.14-3.49 (m, 6H), 3.19-3.47 (m, 2H), 3.64-3.88 (m, 3H), 7.42 (d, 1H) 7.49 (t, 1H), 7.48-7.58 (m, 1H), 7.57-7.76 (m, 1H), 7.76-7.90 (m, 1H), 7 90-8.01 (m, 1H); 8.01 (d, 1H); 8.35-9.27 (m, 1H); 10.87 (br s, 1H).

Example 192. 6- {2- [2-Methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylic acid (E192)

Ethyl 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E177 , enantiomer 1) (45 mg, 0.08 mmol) and KOH (1 M solution in MeOH, 1.5 ml) are stirred at reflux for 1 hour. The mixture was then loaded onto a SCX column eluting with a solution of NH ₃ in methanol to give the title compound (43 mg, 0.089 mmol, 100%). MS (ES) m / z: 481.3 [MH ⁺ ]. C ₃₀ H ₃₂ N ₄ O ₂ requires 480.61.

Example 193. 6- {2- [2-Methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide

The title compound was prepared following the general procedure for producing amides (see Example 14), starting from 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4 , 5-dihydroimidazo [1,5-a] quinoline-3-carboxylic acid (E192) (43 mg, 0.089 mmol) using hexamethyldisilazane (0.02 ml, 0.098 mmol). The crude reaction product is purified on an SCX cartridge and flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound. Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in methanol / DCM (1: 2, 3 ml) at 0 ° C gave the title compound as a white solid (39 mg, 79%). MS (ES) m / z: 480.1 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O requires 479.62. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.19 (br s, 1H), 9.33 (br s, 1H), 8.64 (br s, 1H) 8.27 (br s, 1H), 8.09 (t, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.75 (d, 1H), 7, 46-7.41 (m, 2H), 7.37 (d, 1H), 7.26 (br s, 1H), 3.93-3.24 (br m, 8H), 3.02- 2.97 (m, 7H), 2.3 (m, 1H), 2.1 (broad m, 3H), 1.45 (d, 3H).

Example 194. 6- {2- [2-Methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylic acid (E194)

Ethyl 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxylate (E178 , enantiomer 4) (20 mg, 0.039 mmol) and KOH (1 M solution in MeOH, 1.5 ml) are stirred at reflux for 1 hour. The mixture was then loaded onto a SCX column eluting with a solution of NH ₃ in methanol to give the title compound (20 mg, 100%). MS (ES) m / z: 481.3 [MH ⁺ ]. C ₃₀ H ₃₂ N ₄ O ₂ requires 480.61.

Example 195. 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide ( E195)

The title compound was prepared following the general procedure for producing amides (see Example 14), starting from 6- {2- [2-methyl-4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4 , 5-dihydroimidazo [1,5-a] quinoline-3-carboxylic acid (E194) (20 mg, 0.039 mmol) using hexamethyldisilazane (0.015 ml, 0.068 mmol). The crude reaction product is purified on an SCX cartridge and flash chromatography on silica gel eluting with a methanol gradient in DCM (2-3%) to give the free base of the title compound. Treatment with HCl (2.2 equiv. 1.25 M solution in MeOH) in a methanol / DCM mixture (1: 2, 3 ml) at 0 ° C gave the title compound as a white solid (22 mg, 100%). MS (ES) m / z: 480.1 [MH ⁺ ]. C ₃₀ H ₃₃ N ₅ O requires 479.62. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.51 (br s, 1H), 9.41 (d, 1H), 8.82 (br s, 1H), 8 3 (d, 1H), 8.1 (t, 1H), 8.0 (d, 1H), 7.7 (t, 2H), 7.5 (d, 1H), 7.4 (m, 2H), 7.37 (d, 1H), 4.0 (m, 3H), 3.58 (broad d, 1H), 3.4 (broad d, 1H), 3.2 (wide m , 3H), 3.07-3.00 (m, 6H), 2.75 (t, 1H), 2.25 (m, 1H), 1.98 (t, 2H), 1.74 (d, 1H), 1.55 (d, 3H).

Biological tests

a) Functional ability - primary screening

Functionality can be determined using the following GTPγS binding protocol. The cells used in the study are CHO cells and human primary kidneys (HEK293). Cells are transfected with DNA encoding human receptors as follows: HEK293_5-HT _1A ; CHO_5-HT _1B and CHO_5-HT _1D . The test compounds are first dissolved in 100% dimethyl sulfoxide to a concentration of 10 mM. Serial dilution of the test compounds in 100% dimethyl sulfoxide was performed using Biomek FX in 384 well assay plates so that the final final concentration of the test compound in the assay was 3 μM. Test compound was added in an amount of 1.0% of the total assay volume (TAV) in a solid white 384-well assay plate (Costar). Add 50% TAV membranes (5 μg / well) pre-bound (for 90 min at RT) with pellets for Wheatgerm Agglutinin Polystirole Scintillation Proximity Assay analysis (RPNQ0260 Amersham International) (0.25 mg / well) in 20 mM HEPES, pH 7.4, 100 mM NaCl, 3 mM MgCl ₂ and 10 μM GDP. The third addition is the addition of 20% TAV or a final concentration concentration agonist or EC ₈₀ buffer in an analysis (FAC) of an agonist, 5HT antagonist obtained in the assay buffer. Analysis begins by adding 29% TAV GTPγS 0.38 nM FAC. After all additions, assay plates were incubated at RT for 2–3 hours. Counting on analytical plates was carried out on a Viewlux 613/55 filter for 5 minutes. Assay plates are read 2-6 hours after the last addition.

Using analysis a), the compounds of the examples typically show fpKi against 5-HT _1A above 6.0. Using analysis a), the compounds of Examples 14, 15, 24, 83, 89, 91, 94, 97, 105, 109, 122, 124 and 125 show fpKi values greater than 8.0 at the 5-HT _1A receptor. Some of these compounds show fpKi values for the 5-HT _1B and 5-HT _1D receptors, similar to those for the 5-HT _1A receptor. Using analysis a), the compound of Example 24 shows fpKi 9.7.

b) Receptor affinity

The affinity of the compounds of the invention for 5-HT _1A , 5-HT _1B and 5-HT _1D receptors can be determined using the following assay.

Cells of Chinese hamster ovary (CHO) are homogenized expressing 5-HT _1A receptors (4 × 10 ⁷ cells / ml) in Tris buffer and stored in 1 ml aliquots. Homogenize CHO cells expressing 5-HT _1B receptors (4 × 10 ⁷ cells / ml) in Tris buffer and store in 1.5 ml aliquots. Homogenize CHO cells expressing 5-HT _1D receptors (1 × 10 ⁸ cells / ml) in Tris buffer and store in 1 ml aliquots. Binding assays were performed in a total volume of 500 μl. For each test compound, seven solutions are obtained with concentrations ranging from 0.3 mM to 0.3 nM (100 × final concentrations). A solution containing the test compound was distributed at 5 μl per well, and 100 μl of radioligand was added at a concentration of 5 × the final concentration needed for analysis, i.e. [ ³ H] -5-HT 15 nM (final concentration for analysis 3 nM), in Tris-Mg-HCl buffer (pH 7.7) for 5-HT _{1B / 1D} receptors, and [ ³ H] -WAY100635 2, 5 nM (final concentration for analysis 0.5 nM), in Tris-Mg-HCl buffer (pH 7.7) containing 150 μM GPP (NH) p (final concentration in the analysis 30 μM) for 5-HT _1A receptors. Add 400 μl / well of a suspension of cell membranes in Tris-Mg-HCl buffer (pH 7.7) to give a total volume of 505 μl. Incubated at 37 ° C for 45 minutes. Non-specific binding was determined using 0.01 mM 5-HT for 5-HT _{1B / 1D} receptors and 0.01 mm WAY100635 for 5-HT _1A receptors. Interrupt incubation by rapid filtration using Packard Filtermate. Radioactivity is measured using a Topcount scintillation counter. The pKi values are calculated from the IC ₅₀ obtained by the iterative curve fitting program from the least squares points.

c) Binding Assay [ ³ H] -citalopram for human SERT

The affinity of the compounds for binding to the serotonin transporter reuptake site (SERT) can be assessed using [ ³ H] citalopram binding analysis performed in recombinant pig kidney epithelial cells stably transfected with human SERT (hSERT / LLCPK). Cells are grown in Petri dishes, 500 cm ² , and used to obtain membranes at 80% fusion. Cells are harvested in phosphate buffered saline (PBS) containing 5 mM EDTA and centrifuged at 900 g for 8 min at 4 ° C. Homogenize sediment at 30-50 vol. assay buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 10 μM pargyline, 0.1% ascorbate (pH 7.7)) and centrifuged at 48,000 g for 20 min at 4 ° C. Resuspend the cell pellet in the same volume and after incubation at 37 ° C for 20 min, centrifuge it as previously indicated and obtain final aliquots at ~ 0.2 mg protein / ml in cold assay buffer. To analyze the binding of [ ³ H] -citalopram, add 4 μl of a solution of the test compound (100-fold in pure DMSO) (to determine complete binding) or fluoxetine at a final concentration of 10 μM in DMSO (to determine non-specific binding), 200 μl of solution [ ³ H] -citalopram at a final concentration of 0.25 nM in assay buffer and 200 μl of membranes diluted in assay buffer at a concentration of 1 μg / ml protein (final assay volume 400 μl). Membranes were added to initiate the reaction, and the mixture was incubated at room temperature for 2 hours. Stop the reaction by rapid filtration through a GF / B 96 filter plate pre-soaked in 0.5% polyethyleneimine (PEI) using a Packard cell harvester. Wash the 96-well filter plate 3 times with 1 ml / well with a cold 0.9% NaCl solution and calculate the radioactivity in a Packard TopCount counter.

Claims (23)

1. The compound of formula (I)

its pharmaceutically acceptable salt
where ---- represents independently a single or double bond;
cycle Q is imidazole, triazole (for example, 1,2,3-triazole or 1,3; 4-triazole) tetrazole or oxadiazole;
B represents C (R ⁷ ) (R ⁸ ) or C (R ⁷ ), where in the case where the bond connecting B and Y is a single bond, B represents C (R ⁷ ) (R ⁸ ), and when the bond connecting B and Y is a double bond, B is C (R ⁷ );
Y represents C (R ⁷ ), C (R ⁷ ) (R ⁸ ) or O, where in the case where the bond connecting B and Y is a single bond, Y represents C (R ⁷ ) (R ⁸ ) or O, and when the bond connecting B and Y is a double bond, B is C (R ⁷ );
Z ¹ represents —CH ₂ -, - (CH ₂ ) ₂ -, —CH ₂ CH — CH ₃ -, where the left bond Z ^{1 is} attached to a nitrogen atom, or - (CH ₂ ) ₃ -;
X represents C (R ¹ ) or N;
A is quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, cyano, C _1-6 alkyl, halo-C _1-6 - alkyl, —C (O) N (R ³ ) (R ⁴ ), a 5-membered heterocyclic ring comprising 1-3 heteroatoms selected from N or O; wherein the heterocyclic ring is optionally substituted with C _1-6 alkyl;
when R are present, each is independently halogen, C _1-6 alkyl;
each R ¹ represents hydrogen or methyl;
each R ² represents cyano, C _1-6 alkyl,
C _1-6 -alkoxy, halo-C _1-6 -alkyl, = O, -C (O) N (R ³ ) (R ⁴ ), -C (O) N (R ³ ) -C _1-6 - alkoxy, -C (NOR ⁵ ) R ⁶ , -C (O) R ⁶ ,
—C (O) OR ⁷ , —C (O) NHNHC (O) R ⁶ , a 5-membered heterocyclic ring comprising 1-3 heteroatoms selected from N or O; wherein the heterocyclic ring is optionally substituted with C _1-6 alkyl;
R ³ and R ⁴ are independently hydrogen; C _1-6 alkyl; C _3-7 cycloalkyl; C _3-7 cycloalkyl-C _1-6 alkyl; or when R ³ and R ^{4 are} connected to the same nitrogen atom, they together with the nitrogen atom form a 4-, 5- or 6-membered ring, optionally containing one additional O atom in the ring;
R ⁵ represents C _1-4 alkyl;
R ⁶ is C _3-7 cycloalkyl or C _1-6 alkyl;
R ⁷ and R ⁸ are independently hydrogen or C _1-6 alkyl;
p is 0, 1 or 2;
r is 0, 1, 2 or 3;
s is 0, 1, 2, or 3. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the Q cycle is imidazole or triazole (for example, 1,2,3-triazole or 1,3,4-triazole). 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is imidazole. 4. The compound according to claim 1 or its pharmaceutically acceptable salt, where Z ¹ represents - (CH ₂ ) ₂ -. 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ² is C _1-6 alkyl, —C (O) N (R ³ ) (R ⁴ ), or —C (O) R ⁶ . 6. The compound according to claim 1 or its pharmaceutically acceptable salt, where X represents C (R ¹ ) or N. 7. The compound according to claim 1 or its pharmaceutically acceptable salt, where X represents CH or N. 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substituents on A are selected from the group consisting of halogen, cyano, C _1-6 alkyl, halogen-C _1-6 alkyl, and —C (O) N (R ³ ) (R ⁴ ). 9. The compound according to claim 1 or its pharmaceutically acceptable salt, where R, when present, is selected from the group consisting of fluorine, chlorine, methyl or ethyl. 10. The compound according to claim 1 or its pharmaceutically acceptable salt, where s is 1 or 2. 11. The compound according to claim 1 or its pharmaceutically acceptable salt selected from
6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (Example 14) ;
N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (example 15);
6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (4-morpholinyl glycarbonyl) -4H-imidazo [5.1-c] [1,4] benzoxazine dihydrochloride (example 24);
N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 83 );
N-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 89);
6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 91);
6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} tetrazolo [1,5-a] quinoline dihydrochloride (Example 94);
ethyl 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxylate dihydrochloride (Example 97 );
dihydrochloride 6- {2 - [(2R) -2-methyl-4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -3- (3-methyl-1,2,4-oxadiazole-5 -yl) imidazo [1,5-a] quinoline (Example 105);
6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 109);
6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide dihydrochloride (Example 122);
dihydrochloride N, 7-dimethyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazin-3 β-carboxamide (Example 124);
7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} -4H-imidazo [5.1-c] [1,4] benzoxazine-3-carboxamide dihydrochloride (example 125); and
7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide (Example 134)
or their other pharmaceutically acceptable salts or free bases. 12. 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4H-imidazo [5.1-s] [1,4] benzoxazine-3-carboxamide (free base , example 14). 13. Dihydrochloride 6- {2- [4- (2-Methyl-5-quinolinyl) -1-piperidinyl] ethyl} imidazo [1,5-a] quinoline-3-carboxamide (Example 91). 14. Dihydrochloride 6- {2- [4- (2-methyl-5-quinolinyl) -1-piperidinyl] ethyl} [1,2,3] triazolo [1,5-a] quinoline-3-carboxamide (Example 109 ) 15. Dihydrochloride 7-methyl-6- {2- [4- (2-methyl-5-quinolinyl) -1-piperazinyl] ethyl} -4,5-dihydroimidazo [1,5-a] quinoline-3-carboxamide ( Example 134). 16. The compound or its pharmaceutically acceptable salt according to any one of the preceding paragraphs, suitable as a medicine. 17. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16, suitable for the treatment or prevention of a disease or condition mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor. 18. The compound or its pharmaceutically acceptable salt according to 17, where the disease or condition is a state of anxiety or depression. 19. The compound or its pharmaceutically acceptable salt according to 17, where the disease or condition is premature ejaculation. 20. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by modulation of the 5-HT ₁ receptor and / or serotonin reuptake receptor. 21. The application of claim 20, where the disease or condition is a state of anxiety or depression. 22. The use of claim 20, wherein the disease or condition is premature ejaculation. 23. A pharmaceutical composition having activity mediated by modulation of the 5-HT ₁ receptor, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, in combination with one or more pharmaceutically acceptable carriers, diluents and / or excipients.