HK1122279A - New tricyclic compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Tricyclic compounds, process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel tricyclic compounds, processes for their preparation and pharmaceutical compositions containing them.

The compounds of the invention are novel and possess valuable pharmacological properties in the fields of apoptosis and cancerology.

Apoptosis, otherwise known as programmed cell death, is an important physiological process in embryonic development and in maintaining homeostasis in tissues.

Apoptotic cell death results in morphological changes such as nuclear condensation, DNA fragmentation and biochemical phenomena such as caspase activation, which causes damage to critical structural components of the cell, inducing its breakdown and death. The control of the apoptotic process is complex, involving the activation or inhibition of several intracellular signaling pathways (Cory s. et al, Nature Review Cancer, 2002,2，647-656)。

disorders in which apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as parkinson's disease, alzheimer's disease and ischemia. In contrast, insufficient execution of apoptosis plays an important role in the development of cancer and its chemoresistance, in autoimmune diseases, inflammatory diseases and viral infections. Thus, a lack of apoptosis is one of the phenotypic characteristics of cancer (Hanahan d. et al, Cell 2000, 100, 57-70).

In addition to being novel, the compounds of the present invention also have pro-apoptotic (pro-apoptotic) properties, which means that they are useful in disorders including a lack of apoptosis, for example, in the treatment of cancer.

The invention relates more particularly to compounds of formula (I), the enantiomers and diastereomers and to addition salts with a pharmaceutically acceptable acid or base thereof:

wherein:

a represents a 5-, 6-or 7-membered aromatic or nonaromatic ring which may contain 1 or 2 heteroatoms selected from oxygen, sulphur and nitrogen, where for the nitrogen heteroatom it is linear or branched (C)₁-C₆) Alkyl substitution is possible, it being understood that the defined a ring cannot contain 2 sulfur atoms or 2 oxygen atoms and that one of the ring members may be a C ═ O group,

n and n ', which may be the same or different, represent 0, 1 or 2, where 0 < n + n' < 4,

◆R₃represents an aryl group or a heteroaryl group,

x represents a straight or branched alkylene chain having 1 to 6 carbon atoms, in which 1 or 2 carbon atoms may be replaced by an oxygen atom, a cycloalkylene group, an arylene group, a heteroarylene group, or SO₂The radical(s) is (are),

◆R₁and R₂One of the radicals represents a hydrogen atom and the other represents a group of formula (II):

wherein:

-Y represents C ═ O or CH₂The radical(s) is (are),

-R₅represents a hydrogen atom, in which case R₆Represents a hydrogen atom or-NR₇R′₇or-CH₂-NR₇R′₇Group, wherein R₇And R'₇Each of which may be the same or different, independently represents a hydrogen atom or a linear or branched (C) chain substituted by one or more groups₁-C₆) Alkyl groups: aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or-NR₁₀R′₁₀A group wherein:

^＊R₁₀and R'₁₀Can be used forSame or different, selected from hydrogen, linear or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, aryl and heteroaryl, or

^＊R₁₀And R'₁₀Forming a saturated or unsaturated cyclic or bicyclic group which may be replaced by a heteroatom selected from oxygen, nitrogen and sulphur, it being understood that one or more ring members may represent a C ═ O group or may be substituted as described in the definition of heterocycloalkyl below,

or R₅And R₆Together with the two carbon atoms bearing them, form an aromatic or non-aromatic ring containing 5 or 6 ring members, one nitrogen atom being in SO₂Para to the radical, the ring containing, in addition to the nitrogen atom, a further nitrogen atom and/or SO₂The radicals, the rings being defined by R as defined above₇The substitution of the group(s),

-R₄represents a halogen atom or NO₂、R₈、SO₂-R₉Straight or branched chain (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) Alkoxy radical, wherein R₈May have R as defined above₇Any of the meanings of (a), (b), (c), (d,

-R₉represents amino or linear or branched (C) optionally substituted by one or more halogen atoms₁-C₆) An alkyl group, a carboxyl group,

it should be understood that:

- "aryl" is understood to mean phenyl, naphthyl or biphenyl,

"heteroaryl" is understood to mean any monocyclic or bicyclic group having at least one aromatic moiety and containing from 5 to 10 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, such as, for example, the following groups: furan, thiophene, pyrrole, imidazoline, pyridine, quinoline, isoquinoline, chroman, indole, benzothiophene, benzofuran, 1, 3-benzodioxole and 2, 3-dihydro-1, 4-benzodioxin,

- "heterocycloalkyl" is understood to mean any monocyclic or bicyclic nonaromatic radical containing from 4 to 10 ring members which may contain from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen,

"cycloalkyl" is understood to mean any monocyclic or bicyclic nonaromatic radical containing from 4 to 10 ring members,

for aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups as defined, it is possible to substitute from 1 to 3 groups selected from: straight or branched chain (C) optionally substituted by hydroxy or amino₁-C₆) Alkyl, straight or branched (C)₁-C₆) Alkoxy, hydroxy, carboxy, formyl, nitro, cyano, amino, straight or branched polyhalogen (C)₁-C₆) An alkyl group, an alkoxycarbonyl group, and a halogen atom,

- "arylene", "heteroarylene" and "cycloalkylene" are understood to mean, respectively, an aryl, heteroaryl or cycloalkyl radical as defined above, inserted in place of a carbon atom of the alkylene chain.

Among the pharmaceutically acceptable acids, mention may be made, by way of non-limiting example, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, and the like.

Among the pharmaceutically acceptable bases, mention may be made, by way of non-limiting example, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

Y advantageously represents a C ═ O group.

Preferred values for n and n' are 1.

Preferred R₄The radical being NO₂And SO₂CF₃。

Preferred X-R₃The radicals being optionally substituted by one or more radicals selected from the group consisting of halogen, cyano, amino, aminomethyl and trifluoromethyl ([1, 1' -biphenyl)]-2-yl) methyl.

R₅Preferably represents a hydrogen atom.

Preferred R₇The radicals being 1- (N, N-dimethylamino) -4- (phenylsulfanyl) -butan-3-yl and 1- (NR)₁₀R′₁₀) -4- (phenylsulfanyl) -butan-3-yl, R₁₀And R'₁₀Forming a saturated or unsaturated cyclic or bicyclic group optionally replaced by a heteroatom selected from oxygen, nitrogen and sulphur.

R′₇Advantageously represents a hydrogen atom.

It is preferable thatIs a group

More particularly, the present invention relates to compounds of formula (I):

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bistrifluoroacetate,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -3-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -3-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide hydrochloride,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -4-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-a ] quinolin-8-ylcarbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -4-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide hydrochloride,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- { [ (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha ] quinolin-8-yl ] carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide,

n- { [ (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha ] quinolin-8-yl ] carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide hydrochloride,

3-nitro-N- ({ (4aS, R) -3- [2- (2-phenylethyl) benzyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- { [2- (phenylsulfanyl) ethyl ] amino } -benzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-a ] quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -3-nitro-4- [ (2-phenoxyethyl) amino ] benzenesulfonamide,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinolin-8-yl ] carbonyl } -3-nitro-4- [ (3-phenylpropyl) amino ] benzenesulfonamide,

4- [ (2-anilinoethyl) amino ] -N- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl ] carbonyl } -3-nitrobenzenesulfonamide,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- { [3- (dimethylamino) propyl ] [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- { [3- (dimethylamino) propyl ] [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide hydrochloride,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-a ] quinolin-8-yl } carbonyl) -4- { [3- (dimethylamino) propyl ] amino } -3-nitrobenzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) benzenesulfonamide,

4- { [ (2-aminoethyl) (2-phenylethyl) amino ] methyl } -N- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } -carbonyl) benzenesulfonamide,

4- { [ (2-aminoethyl) (2-phenylethyl) amino ] methyl } -N- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } -carbonyl) benzenesulfonamide tris (trifluoroacetate),

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-7-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-7-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [2- ([1, 1' -biphenyl ] -2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2- α ] indol-8-yl ] -carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [2- ([1, 1' -biphenyl ] -2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2- α ] indol-8-yl ] -carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- ({2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4-tetrahydropyrazino [1, 2- α ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- ({ (10aS, R) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydro-pyrazino [1, 2- α ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- { [ (4aS) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [ (4aS) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride),

n- { [ (4aR) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- { [ (4aR) -3- ([1, 1' -biphenyl ] -2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl ] carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide tris (hydrochloride),

n- { [ (4aS, R) -3- ([1, 1' -biphenyl ] -2-ylsulfonyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinolin-8-yl ] carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- { (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide,

n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- { (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } -4H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide,

n- ({ (10 a. alpha.) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (10a β) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2- α ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (10a α) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2- α ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (10a α) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2- α ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide dihydrochloride,

n- [ ((4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) -sulfonyl ] benzenesulfonamide dihydrochloride,

n- [ ((10a β) -2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. -indol-8-yl) carbonyl ] -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) -sulfonyl ] benzenesulfonamide dihydrochloride,

n- [ ((4aR) -3- { [4- (4-chlorophenyl) -3-pyridinyl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinolin-8-yl) carbonyl ] -4- ({ (1R) -2- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] ethyl } amino) -3-nitrobenzenesulfonamide trihydrochloride,

n- ({ (4aR) -3- [ (4-amino-4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide trihydrochloride,

n- [ ((4aR) -3- { [4- (aminomethyl) -4 '-chloro- [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide trihydrochloride,

n- [ ((4aR) -3- { [3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- [ ((4aR) -3- { [4 '- (trifluoromethyl) - [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- [ ((4aR) -3- { [4 '-cyano- [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [2- (1, 3-benzodioxol-5-yl) benzyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-methyl-1-piperazinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-pyrrolidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (3, 6-dihydro-1 (2H) -pyridinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-azepanyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- ((1R, 5S) -3-azabicyclo [3.1.0] hex-in-3-yl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide sodium.

Enantiomers, diastereomers and pharmaceutically acceptable acid or base addition salts of preferred compounds of the invention form part of the invention.

The invention also relates to a process for the preparation of compounds of formula (I), characterized in that compounds of formula (III):

wherein Y is as defined for formula (I) and Cy represents a fused tricyclic ring system of formula (IV):

wherein A, X, n' and R₃As defined in formula (I), a-Y-Cl group is attached at the a-or b-position of the defined tricyclic system,

condensing a compound of formula (III) with a compound of formula (V) in an alkaline medium in the presence or absence of a coupling agent, wherein R₄As defined in formula (I),

to give a compound of the formula (VI) in which Cy, Y and R₄As defined above, in the above-mentioned manner,

reacting a compound of formula (VI) with a compound of formula HNR₇R′₇By condensation of a compound of (1), wherein R₇And R'₇As defined in formula (I), a compound of formula (I/a), which is a particular case of the compound of formula (I), is obtained,

wherein Cy, Y, R₄、R₇And R'₇As defined above, in the above-mentioned manner,

the compound of formula (I/a) may be purified according to conventional separation techniques, the compound of formula (I/a) may be converted into a pharmaceutically acceptable acid or base addition salt thereof, if necessary, and the compound of formula (I/a) may be optionally separated into its isomers according to conventional separation techniques.

The compounds of formulae (III) and (V) are commercially available compounds or can be obtained by the person skilled in the art by means of conventional chemical reactions described in the literature.

An advantageous variant relates to a process for the preparation of the compounds of the formula (I), characterized in that a compound of the formula (III') is used as starting material:

wherein Y is as defined for formula (I) and Cy represents a fused tricyclic ring system of formula (IV):

a, X, R therein₃N and n' are as defined in formula (I), -the Y-OH group is attached at the a or b position of the defined tricyclic system,

condensing a compound of formula (III') with a compound of formula (VII) in an alkaline medium in the presence of a coupling agent, wherein R₄、R₅And R₆As defined in formula (I),

obtaining the compound of formula (I), which can be purified according to conventional separation techniques, converting the compound of formula (I) into a pharmaceutically acceptable acid or base addition salt thereof, if desired, and optionally separating the compound of formula (I) into its isomers according to conventional separation techniques.

The compounds of formulae (III') and (VII) are commercially available or can be obtained by the person skilled in the art by means of conventional chemical reactions described in the literature.

Pharmacological studies carried out on the compounds of the invention have shown that they have pro-apoptotic properties. The ability to reactivate apoptotic processes in cancer cells has major therapeutic benefit in cancer therapy.

More particularly, the compounds of the present invention are useful for the treatment of chemo-or radiation-resistant cancers as well as hematologic malignancies and small cell lung cancer.

Among the treatments of cancer of interest, mention may be made, without any limitation, of bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, primitive lymphocytic leukemia, follicular lymphoma, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer.

The invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) by itself or in combination with one or more pharmaceutically acceptable carriers.

Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral, nasal, transdermal or transdermal, rectal, lingual, ocular or respiratory administration, in particular tablets or sugar-coated tablets, sublingual tablets, sachets, packs (packets), gelatin capsules, glossettes (sublingual or rectal dosage form), lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.

The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any concomitant therapy, and ranges from 0.01mg to 1g per 24 hours, administered in single or multiple administrations.

Furthermore, the present invention relates to the combination of a compound of formula (I) with an anti-cancer agent selected from the group consisting of gene poisons, mitotic inhibitors (mitotic poison), anti-metabolites, proteasome inhibitors and kinase inhibitors, and the use of a combination of this type for the preparation of a medicament for the treatment of cancer.

The compounds of the invention may also be used in combination with radiation therapy for the treatment of cancer.

The following preparations and examples illustrate the invention, but do not limit it in any way.

Preparation example 1: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

Step A: 6-methoxy-2-quinolinecarboxaldehyde

Selenium oxide was added portionwise to 6-methoxy-2-methylquinoline (42g) in 400ml dioxane/H₂O (5%) in a mixture, and the whole was then heated at reflux overnight. The mixture was left to cool, filtered to remove metals and concentrated to dryness. The resulting dark brown solid was purified by chromatography over a silica column (heptane/AcOEt 80/20) to give the title compound as a white solid.

Step B: 2- { [ (6-methoxy-2-quinolyl) methyl]Amino } ethanol

9.5ml of 3-aminopropanol were added to a suspension of the compound obtained in step A (28g) in 200ml of EtOH and the whole was refluxed overnight with a dean-Stark apparatus. The reaction mixture was then concentrated to dryness and added to 200ml of 0 ℃ EtOH; 14g of NaBH were then added in portions₄. Then heating the whole bodyReflux overnight. The reaction mixture is then concentrated to dryness with H₂Hydrolysis of O with CH₂Cl₂And (4) extracting. Over MgSO₄Dried and concentrated to dryness to give a gradually crystallizing oil. The crystals were then triturated in diisopropyl ether, filtered and dried to give the title compound as light brown crystals.

Step C: 2- { [ (6-methoxy-1, 2, 3, 4-tetrahydro-2-quinolinyl) methyl]Amino } ethanol

To a solution of the compound from step B (33g) in 50/50MeOH/KOH 1M (1.21) mixture was added in portions 169g of Raney nickel. The whole was then stirred at ambient temperature overnight. After which the metal was removed by filtration and the filtrate was concentrated to dryness. The residue is then added to CH₂Cl₂In (1), with H₂Hydrolysis of O followed by CH₂Cl₂The extraction was performed several times. The extracts were then combined over MgSO₄Dried, filtered and concentrated to dryness. The resulting crystals were triturated in diisopropyl ether, filtered and dried to give the title compound as white crystals.

Step D: (4aS, R) -8-methoxy-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolines

Will P₂O₅(18g) A suspension of the compound obtained in step C (10g) in 200ml of o-xylene is added. The whole was then heated at 150 ℃ overnight. The mixture was left to cool, concentrated to dryness, then taken with H₂O slowly undergoes cold hydrolysis followed by slow addition of 5n naoh without heating and the whole is stirred at ambient temperature for 30 minutes. By CH₂Cl₂The reaction mixture was extracted several times over MgSO₄Dried and concentrated to dryness to give a brown oil, the title product, which was used directly in the next step without purification.

Step E: (4aS, R) -3-benzyl-8-methoxy-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolines

Dissolving the compound (7g) obtained in step D in 100ml of DMF, then 8.85g of K are added in turn₂CO₃4.2ml of benzyl bromide and 100mg of NaI, the whole is heated at 80 ℃ for 2 hours. Concentrate to dryness and add the residue to AcOEt. By H₂O, then the organic phase was washed with saturated LiCl solution, then with saturated NaCl solution. The organic phase is passed over MgSO₄Dried and concentrated to dryness. The residue was purified by chromatography on a silica column (heptane/AcOEt 95/5) to give the title product as a milk white solid.

Step F: (4aS, R) -3-benzyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl trifluoromethanesulfonate salt

1M BBr₃/CH₂Cl₂The solution is added to the compound obtained in step E (5g) in 100ml CH₂Cl₂Then the whole was stirred while gradually returning to ambient temperature. The temperature was maintained and stirring was continued overnight. The mixture was then returned to 0 ℃, 50ml of MeOH was slowly added, and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated to dryness and added several times to diisopropyl ether. The resulting light brown crystals are then filtered off and dried. The crystals were dissolved in 100ml of CH₂Cl₂In (1), 11.6ml Et was added dropwise₃N and triflate donor (8.84g), the whole was stirred at ambient temperature. By H₂Hydrolysis of O followed by CH₂Cl₂The extraction was performed twice. The combined organic extracts were then dried over MgSO₄Drying and concentrating to dryness. The residue was then purified by chromatography on a silica column (heptane/AcOEt 9/1) to give the title product in the form of milk white crystals.

Step G: (4aS, R) -3-benzyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The compound from step F (3.6g) was dissolved in 100ml of a DMSO/MeOH (3/2) mixture and then 2.6ml of Et was added sequentially₃N、0.19g Pd(OAc)₂And 0.935g dppf ligand. The mixture was degassed under argon for 20 minutes and then carbon monoxide was passed for 30 minutesThe mixture was then saturated with carbon monoxide for 15 minutes. Subsequently, the whole was sealed and heated at 65 ℃ for 3 hours. The mixture was allowed to cool and carbon monoxide was removed with argon. The reaction mixture is then washed with H₂O was hydrolyzed and extracted with AcOEt. The combined organic extracts were then dried over MgSO₄Drying and concentrating to dryness. The residue was purified by chromatography on a silica column to give the title product as an oil which crystallized.

Step H: (4aS, R) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

0.64g of 10% Pd/C and 2.4g of NH₄COOH was added successively to a solution of the compound from step G (3.2G) in 100ml of a THF/MeOH (50/50) mixture and the whole was heated at 50 ℃ for 4 hours. The reaction mixture was then cooled and filtered, and the filtrate was concentrated to dryness. The resulting solid was added to diisopropyl ether, triturated, filtered and concentrated to dryness to give the title product as a white solid.

Step I: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The compound obtained in step H (7g) is dissolved in 100ml DMF and then 8.85g K is added₂CO₃4.2ml of 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl and 100mg of NaI, the whole was heated at 80 ℃ for 2 hours. Concentrated to dryness, then the residue is taken up in AcOEt and washed with H₂O, saturated LiCl solution, then washed with saturated NaCl solution. Over MgSO₄The organic phase was dried and concentrated to dryness. The residue was purified by chromatography on a silica column (heptane/AcOEt 95/5) to give the title product as an off-white solid.

Step J: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

9ml of 6N HCl are added to a solution of 0.5g of the compound obtained in step I in 9ml of dioxane. The whole was then heated to reflux for 4 hours and then concentrated to dryness. The resulting solid was triturated in diisopropyl ether, filtered and dried to give the title compound as a pale-blue solid.

Preparation example 2: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure was as described in preparation example 1, wherein 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl was replaced in step I by 4-chloro-3 '- (chloromethyl) -1, 1' -biphenyl.

Preparation example 3: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-4-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

The procedure was as described in preparation example 1, wherein 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl was replaced in step I by 4-chloro-4 '- (chloromethyl) -1, 1' -biphenyl.

Preparation example 4: (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinoline-8-carboxylic acid hydrochloride

The procedure is as described in preparation example 1, wherein 2- (chloromethyl) -1, 1 ' -biphenyl is used in place of 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl in step I.

Preparation example 5: (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

The procedure was as described in preparation example 1, wherein 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl was replaced in step I with 1-benzyl-2- (chloromethyl) benzene.

Preparation example 6: (4aS, R) -3- [2- (2-phenylethyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

The procedure was as described in preparation example 1, wherein 1- (chloromethyl) -2- (2-phenylethyl) benzene was used instead of 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl in step I.

Preparation example 7: (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-7-carboxylic acid hydrochloride

The procedure is as described in preparation 1, where 5-methoxy-2-methylquinoline is used instead of 6-methoxy-2-methylquinoline in step A.

Preparation example 8: (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinoline-7-carboxylic acid hydrochloride

The procedure is as described in preparation example 1, where 5-methoxy-2-methylquinoline is used instead of 6-methoxy-2-methylquinoline in step A and 2- (chloromethyl) -1, 1 ' -biphenyl is used instead of 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl in step I.

Preparation example 9: 2- ([1, 1' -Biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indole-8-carboxylic acid hydrochloride

Step A: 5-methoxy-1H-indole-2-carboxylic acid ethyl ester

14.5ml of thionyl chloride were added dropwise to a suspension of 20g of 5-methoxy-1H-indole-2-carboxylic acid in 100ml of absolute ethanol at 0 ℃ using a dropping funnel. Once the addition was complete, the mixture was gradually returned to ambient temperature and then heated under slow reflux for 4 hours. The reaction mixture was then concentrated and the resulting solid was triturated with diisopropyl ether, filtered and dried. The title product is obtained in the form of a dark brown solid.

Step B: 1- (cyanomethyl) -5-methoxy-1H-indole-2-carboxylic acid ethyl ester

20.8g of the compound obtained in step A dissolved in 150ml of anhydrous DMF are added dropwise to a suspension of 5.7g of NaH (60%) in 100ml of anhydrous DMF via a dropping funnelThe mixture was stirred at ambient temperature for 30 minutes, then 12ml of chloroacetonitrile were added and the whole was stirred at ambient temperature overnight. The reaction mixture was then concentrated to dryness, added to AcOEt, and washed with H₂O was hydrolyzed and then extracted twice with AcOEt. The organic phases are then combined, washed with saturated LiCl solution and then with saturated NaCl solution, over MgSO₄Dried, filtered and concentrated to dryness. The solid was then purified by silica gel chromatography (heptane/AcOEt 95/5) to give the title product as a light yellow solid.

Step C: 8-methoxy-1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indoles

A solution of 57ml of commercial 1M aluminum hydride in THF was added dropwise to a solution of 7.35g of the compound obtained in step B in 150ml of anhydrous THF at 0 ℃ using a dropping funnel. The mixture was gradually returned to ambient temperature and then heated under slight reflux for 3 hours. The mixture was allowed to cool and then returned to 0 ℃ and slowly hydrolyzed with saturated rochelle salt solution. The reaction mixture was then extracted with AcOEt. The combined organic extracts were washed with saturated NaCl solution and MgSO₄Drying and concentrating to dryness. 5.7g of the title product are obtained in the form of a brown oil.

Step D: 2- ([1, 1' -Biphenyl)]-2-ylmethyl) -8-methoxy-1, 2, 3, 4-tetrahydropyrazino [1, 2- α]Indoles

The procedure is as described in preparation 1, step I, starting from the compound obtained in step C and substituting 2- (chloromethyl) -1, 1 ' -biphenyl for 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl. The title product was obtained as a light yellow solid.

Step E: 2- ([1, 1' -Biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indol-8-yl trifluoromethanesulfonate salt

The procedure is as described in step F of preparation 1. The title product was obtained as an orange-yellow solid.

Step F: 2- ([1, 1' -Biphenyl)]-2-ylmethyl) -1, 2, 3,4-tetrahydropyrazino [1, 2-alpha ] s]Indole-8-carboxylic acid methyl ester

The procedure is as described in step G of preparation 1. The title product was obtained as a light yellow solid.Step by step Procedure G: 2- ([1, 1' -Biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indole-8-carboxylic acid hydrochloride

The procedure is as described in preparation example 1, step J. The title product was obtained as a light yellow solid.

Preparation example 10: 2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indole-8-carboxylic acid hydrochloride

The procedure was as described in preparation 9, wherein 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl was used instead of 2- (chloromethyl) -1, 1 ' -biphenyl in step D.

Preparation example 11: (10aS, R) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indole-8-carboxylic acid hydrochloride

Step A: 2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indole-8-carboxylic acid methyl ester

The procedure is as described in preparation 9, steps a to F, wherein 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl is used instead of 2- (chloromethyl) -1, 1 ' biphenyl in step D.

Step B: (10aS, R) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indole-8-carboxylic acid methyl ester

0.158g NaBH at ambient temperature₃CN was added to a solution of 0.2g of the compound obtained in step A in 5ml of acetic acid. The reaction mixture was stirred for 48 hours. The mixture was saturated NaHCO₃The solution was hydrolyzed and then extracted with AcOEt. The organic phases were combined and then washed with saturated NaCl solution and then MgSO₄Dried, filtered and evaporated to dryness. The title compoundPurifying by silica gel chromatography.

Step C: (10aS, R) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indole-8-carboxylic acid hydrochloride

The procedure is as described in preparation 1, step J, starting from the compound obtained in step B.

Preparation example 12: (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

Step A: (4aS) -8-methoxy-3- [ (2S) -2-methoxy-2-phenylacetyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolines

First, 36.5ml of thionyl chloride was added to 4.94g S-methoxyphenylacetic acid in 100ml of CH₂Cl₂In the solution of (1). The reaction mixture was heated at 40 ℃ for half a day and then cooled to ambient temperature. Evaporate to dryness to obtain an oil. Secondly, it will be in 120ml CH₂Cl₂To the resulting oil was added 6.18g of the compound obtained in step D of preparation 1 in 120ml of CH₂Cl₂And 240ml of 1N NaOH. The whole was stirred vigorously at ambient temperature for 1 hour. Separating the two phases with CH₂Cl₂And extracting once. Washed with saturated NaCl solution and MgSO₄After drying, concentrate to dryness. The mixture was purified by flash chromatography on silica gel (petroleum ether/AcOEt 80/20) to give a mixture of the two diastereomers as an oil.

The diastereomers were then separated by optical preparative liquid chromatography (optical preparative chromatography) on Chiralpak AD using EtOH as solvent and eluent.

Step B: (4aS) -8-methoxy-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolines

9.6g of KOtBu were added to 3.91g of the reaction mixtureThe compound obtained in step A is dissolved in 150ml of THF. The reaction mixture was stirred at ambient temperature for half a day and then overnight. THF is removed by evaporation, and the reaction mixture is then washed with H₂Hydrolysis of O and extraction with AcOEt. Washed with saturated NaCl solution and then MgSO₄After drying, concentrate to dryness. The mixture was purified by flash chromatography on silica gel (CH)₂Cl₂/MeOH/NH₄OH (95/5/0.5)) to give the title product as an oil.

Step C: (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

The procedure is as described in preparation 1, steps E to J, starting from the compound obtained in step B.

Preparation example 13: (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

The procedure is as described in preparation example 12, where the other diastereomer obtained is used in step A.

Preparation example 14: (4aS) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinoline-8-carboxylic acid hydrochloride

The procedure was as described in preparation 12, wherein 2- (chloromethyl) -1, 1 ' -biphenyl was used instead of 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl in step I of preparation 1.

Preparation example 15: (4aR) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinoline-8-carboxylic acid hydrochloride

The procedure was as described in preparation 13, wherein 2- (chloromethyl) -1, 1 ' -biphenyl was used instead of 4-chloro-2 ' - (chloromethyl) -1, 1 ' -biphenyl in step I of preparation 1.

Preparation example 16：(4aS，R)-3- ([1, 1' -biphenyl)]-2-ylsulfonyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ] -]Quinoline-8-carboxylic acid hydrochloride

Step A: 3- ([1, 1' -Biphenyl)]-2-ylsulfonyl) -8-methoxy-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolines

The procedure was as described in preparation 1, step E, wherein benzyl bromide was replaced with [1, 1' -biphenyl ] -2-sulfonyl chloride.

Step B: 3- ([1, 1' -Biphenyl)]-2-ylsulfonyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ] -]Quinoline-8-carboxylic acid hydrochloride

The procedure is as described in preparation 1, steps F, G and J, starting from the compound obtained in step a.

Preparation example 17: 3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-carboxylic acid

Step A: 6-methoxy-3, 4-dihydro-1 (2H) -naphthalenone O-methyl-oximes

28.93g of Na₂HPO₄·2H₂O and 27.15g MeONH₂HCl was added to a solution of 28.64g 6-methoxy-3, 4-dihydro-1 (2H) -naphthalenone in 500ml methanol. The reaction mixture was then stirred at ambient temperature for 2 hours. After concentration, the residue was added to CH₂Cl₂/H₂To the O mixture, the organic phase was washed with water, dried over magnesium sulfate and concentrated to give the expected product.

Step B: n- (6-methoxy-1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -O-methyl-hydroxylamine

17.2ml of BH₃The pyridine complex is added to a solution of 10g of the compound obtained in step A in 100ml of ethanol. AOnce the reaction mixture reached 0 ℃, 200ml of 2.5n hcl solution was added dropwise over 3 hours. The mixture was returned to ambient temperature, stirred for 1 hour, and then saturated NaHCO was added dropwise at 0 deg.C₃The solution was brought to pH 5. By CH₂Cl₂The aqueous phase is extracted, and the organic phase is then dried over magnesium sulfate, concentrated and purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step C: 7-methoxy-2-vinyl-2, 3, 4, 5-tetrahydro-1H-1-benzazepine

A solution of 145mmol of vinylmagnesium bromide in 145ml of THF is added to a solution of 10g of the aforementioned compound in 100ml of THF. The addition was carried out at 0 ℃ over 40 minutes, and then the reaction mixture was returned to ambient temperature. After stirring for 1 hour, the mixture was hydrolyzed by dropwise addition of water at 0 ℃ and then treated with CH₂Cl₂The aqueous phase is extracted. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step D: 7-methoxy-2-vinyl-2, 3, 4, 5-tetrahydro-1H-1-benzazepine-1-Carboxylic acid tert-butyl ester

2.45g Boc₂O and 1.55g K₂CO₃A solution of 1.52g of the compound of step C in 15ml of THF is added. The reaction mixture was heated to 60 ℃ and stirred for 16 hours. With AcOEt/H₂After dilution of the O mixture, the aqueous phase was extracted with AcOEt, then the organic phases were combined, washed with water and saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step E: 7-methoxy-2, 3, 4, 5-tetrahydro-1H-1-benzazepine-2-Carboxylic acid methyl ester

12ml of a 2.5N NaOH solution in methanol are added to 1g of the above-mentioned compound in 50ml of CH₂Cl₂In the solution of (1). The whole was cooled to-78 ℃ and an ozone stream was passed. Once a characteristic blue color appeared, the reaction mixture was hydrolyzed and extracted with AcOEt. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is dissolved in a solution of 4N HCl solution in dioxane. After neutralization with CH₂Cl₂The aqueous phase was extracted, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Step F: 1- ({ (benzyloxy) carbonyl]Amino } acetyl) -7-methoxy-2, 3, 4, 5-tetrahydro-1H-1-benzazepine-2-Carboxylic acid methyl ester

14.2g of PCl are added at 0 DEG₅14.3g of [ (benzyloxy) carbonyl group are added in portions]Aminoacetic acid in 300ml of THF. The whole was then stirred at the same temperature for 2 hours. A solution of 10g of the compound of step E in 100ml of THF and 50ml of pyridine is added dropwise at 0 ℃ over 2 hours to the reaction mixture. The mixture was then returned to ambient temperature and stirred for 16 hours. The resulting heterogeneous mixture was hydrolyzed dropwise at 0 ℃ and then extracted with AcOEt. The organic phases were combined and washed with saturated NaHCO₃And saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step G: 9-methoxy-2, 3, 4a, 5, 6, 7-hexahydropyrazino [1, 2-alpha ] pyrazine][1]Benzazepine compounds-1, 4-diketones

To a solution of 10g of the compound from step F in 400ml of a THF/MeOH (1/3) mixture were added 2g of 10% Pd/C followed by 4.1g of NH₄COOH. The whole was heated at 50 ℃ for 10 hours. The reaction mixture was then cooled, filtered and concentrated to dryness. The resulting solid was added to diisopropyl ether, triturated, filtered and concentrated to dryness to give the expected compound.

Step H: 3-benzyl-9-methoxy-2, 3, 4a, 5, 6, 7-hexahydropyrazino [1, 2-alpha ]][1]Benzazepine compounds-1, 4-diketones

A solution of 7G of the compound of step G in 450ml of DMF was added dropwise over 2 hours at 0 ℃ to a heterogeneous solution of 1.6G 60% NaH in 50ml of DMF. After returning to ambient temperature, 4ml of benzyl bromide were added over 30 minutes and the reaction mixture was stirred for 16 hours. After concentration, the residue was added with AcOEt and saturated NaHCO at 0 deg.C₃In a mixture of solutions. The aqueous phase was extracted with AcOEt, then the organic phases were combined, washed with saturated LiCl solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected compound.

Step I: 3-benzyl-9-methoxy-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-alpha ]][1]Benzazepine compounds

2.27g of NaBH is added at 0 deg.C₄7g of the compound of step H in 150ml of THF are added portionwise. The reaction mixture was then stirred at the same temperature for 30 minutes. Followed by dropwise addition of 11.4ml BF at 0 ℃ over 1 hour₃·Et₂And (3) an O complex. After having been returned to the ambient temperature,the reaction mixture was refluxed for 16 hours and 50ml of 5N HCl solution was added dropwise at 0 ℃. The reaction mixture was then heated to reflux for 1 hour, followed by hydrolysis with 50ml of 5N NaOH until pH 5. The aqueous phase was extracted with AcOEt, then the organic phases were combined and saturated NaHCO was used₃The solution was washed, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step J: 3-benzyl-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-alpha ] -alpha][1]Benzazepine compounds-9-yl trifluoromethanesulfonate salt

The procedure was as described in preparation 1, step F.

Step K: 3-benzyl-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-alpha ] -alpha][1]Benzazepine compounds-9-Carboxylic acid methyl ester

The procedure was as described in preparation example 1, step G.

Step L: 1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-alpha ] octahydropyrazino][1]Benzazepine compounds-9-Carboxylic acid methyl ester hydrochloride

300mg of palladium catalyst were added to a solution of 1.5g of the aforementioned compound in 35ml of 1N HCl in methanol. The heterogeneous solution was then hydrogenated at a pressure of 2 bar for 48 hours. The reaction mixture was filtered and washed with methanol to give the title compound as the hydrochloride salt.

Step M: 3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-Carboxylic acid methyl ester

The procedure is as described in preparation 1, step I.

Step N: 3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-carboxylic acid

387mg LiOH were added to 850mg of the compound of step M in 15ml dioxane/H₂O (4/1) mixture. The whole was then stirred for 4 hours and concentrated to dryness. After dilution in 0.5N HCl, the aqueous phase was extracted with AcOEt. The organic phases are then combined with saturated NaHCO₃The solution was washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated. The obtained solid is placed in ACN/H₂The title compound was obtained by freeze-drying the mixture of O.

Preparation example 18: (10a alpha) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indole-8-carboxylic acid (α ═ R or S)

This compound was obtained by separation of the racemic mixture obtained in preparation 11 on Chiralpak AD using methanol, acetonitrile and diethylamine as eluents.

Retention time: 8,7 minutes

Preparation example 19: (10a beta) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indole-8-carboxylic acid (β ═ R or S)

This compound was obtained by separation of the racemic mixture obtained in preparation 11 on Chiralpak AD using methanol, acetonitrile and diethylamine as eluents.

Retention time: 9,6 minutes

Preparation example 20: 6- (tert-Butoxycarbonyl) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-8-carboxylic acid

Step A: 4- [ (benzyloxy) carbonyl]-1- (2-nitrophenyl) -2-piperazinecarboxylic acid

To a solution of 5g of 2-piperazinecarboxylic acid dihydrochloride in 20ml of water was added 19.5ml of a 2.5N NaOH solution, followed by a solution of 2.07g of copper sulfate in 40ml of water. The resulting blue solution was cooled to 5 ℃ and then 2.5g Na was added in one portion₂CO₃Then a solution of 3.85ml benzyl chloroformate in 20ml dioxane was added dropwise. After returning to ambient temperature, the reaction mixture was stirred for 24 hours. The precipitate was filtered to give 4- [ (benzyloxy) carbonyl groups chelated with copper]-2-piperazinecarboxylic acid. The compound was dissolved in 375ml of water and 4.5g of EDTA was added. The reaction mixture was heated at 80 ℃ for 3 hours and then concentrated to dryness. The residue was added to 75ml DMSO. Then 3.43g 2-fluoro-nitrobenzene and 15ml Et were added₃N, and then the reaction mixture was heated at 60 ℃ for 48 hours. After returning to ambient temperature, the solution was adjusted to pH 3 with 5N HC1, then diluted with 250ml water and extracted with AcOEt. The organic phase is washed with water, dried over magnesium sulfate, concentrated and chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Step B: 5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1, 2-alpha ]]Quinoxaline-3-carboxylic acid benzyl ester

8g of iron powder are added in portions to a solution of 5.7g of the compound of step A in 100ml of acetic acid. The mixture was heated at 60 ℃ for 3 hours, then after returning to ambient temperature, 50ml of 1n hcl was added. The solution was extracted with dichloromethane and the organic phases were combined, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step C: 8-bromo-5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1, 2-alpha ]]Quinoxaline-3-carboxylic acid benzyl ester

A solution of 2.55g N-bromosuccinimide in 30ml of DMF is added to a solution of 4.4g of the compound of step B in 40ml of DMF at 0 ℃ over a period of 25 minutes. The orange solution was stirred at the same temperature for 1.5 hours and then diluted in H₂O/AcOEt (1/1) mixture. The aqueous phase was extracted with AcOEt, then the organic phases were combined, washed with water, then with saturated LiCl solution, then dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica column (heptane/AcOEt) to give the expected product.

Step D: 8-bromo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1, 2-alpha ]]Quinoxaline-3-carboxylic acid benzyl ester

The procedure was as described in preparation 17, step I, wherein the compound obtained in the preceding step was used.

Step E: 8-bromo-4 a, 5-dihydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-3, 6(2H, 4H) -dicarboxylic acid 3-benzyl ester 6-tert-butyl ester

The procedure was as described in preparation 17, step D, using the compound obtained in the previous step.

Step F: 4a, 5-dihydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-3, 6, 8(2H, 4H) -tricarboxylic acid 3-benzyl ester 6-tert-butyl ester 8-methyl ester

The procedure was as described in preparation 1, step G, using the compound obtained in the previous step.

Step G: 1, 2, 3, 4, 4a, 5-hexahydro-6H-pyrazino [1, 2-alpha ] pyrazine]Quinoxaline-6, 8-dicarboxylic acid 6-tert-butyl ester 8-methyl ester

To a solution of 1.1g of the compound obtained in step F in 40ml of a THF/MeOH (1/1) mixture was added 0.22g of 10% Pd/C followed by 144mg of NH₄COOH. Heating the whole body at 50 deg.C for 4 hrThen (c) is performed. The reaction mixture was then cooled, filtered and concentrated to dryness. The resulting solid was added to diisopropyl ether, triturated, filtered and concentrated to dryness to give the title compound.

Step H: 3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5-hexahydro-6H-pyrazino [1, 2-alpha ]]Quinoxaline-6, 8-dicarboxylic acid 6-tert-butyl ester 8-methyl ester

The procedure was as described in preparation 1, step I, wherein the compound obtained in the preceding step was used.

Step I: 6- (tert-Butoxycarbonyl) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-8-carboxylic acid

The procedure was as described in preparation 17, step N, using the compound obtained in the previous step.

Preparation example 21: 6- (tert-Butoxycarbonyl) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-5-oxo-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-8-carboxylic acid

The title compound was obtained following the same procedure as preparation 20 with two differences, namely: step D is omitted, while in step E, at HNa (instead of K)₂CO₃) The addition of the Boc group was performed in DMF (instead of THF).

Preparation example 22: 1-bromo-2- (bromomethyl) -4, 4-dimethyl-1-cyclohexene

Step A: 4, 4-dimethyl-cyclohexanone

1g of 5% Pd/C was added portionwise to a solution of 4, 4-dimethyl-2-cyclohexen-1-one (0.0805mol, 10.6ml) in 110ml of AcOEt, and the whole was stirred at ambient temperature under hydrogen atmosphere for 2 hours. The palladium was filtered off and concentrated to dryness. The resulting oil gradually crystallized. The title compound was thus obtained in the form of a white solid.

Step B: 2-bromo-5, 5-dimethyl-1-cyclohexene-1-carbaldehyde

20.1ml of phosphorus tribromide were added dropwise to 110ml of CH in an ice bath at 0 deg.C₂Cl₂And 18.7ml DMF. The whole was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0 ℃ and dissolved in 90ml of CH₂Cl₂10.5g of the compound of step A. The whole was then stirred for 4 hours and gradually returned to ambient temperature, then ice/saturated NaHCO was poured in₃In a mixture of solutions. It was then stirred for 1 hour and Et₂And (4) extracting. The organic phases are then combined, washed with saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. The residue was purified with a silica column (heptane AcOEt gradient 0% to 5% AcOEt). The title compound was obtained as a colorless oil.

Step C: (2-bromo-5, 5-dimethyl-1-cyclohexen-1-yl) -methanol

3.23g of sodium borohydride are added in portions to a solution of 12.48g of the compound of step B in 120ml of methanol at 0 ℃. The whole was stirred for 5 hours and gradually returned to ambient temperature. The reaction mixture was then cooled to 0 ℃ and then hydrolyzed with CH₂Cl₂And (4) extracting. The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and finally concentrated to dryness. The title compound was obtained as a colorless oil which was purified by chromatography on a silica column (heptane/AcOEt).

Step D: 1-bromo-2- (bromomethyl) -4, 4-dimethyl-1-cyclohexene

3.96g of the compound of step C are dissolved in 70ml Et₂In O, the whole was maintained at 0 ℃. Then 1.7ml of phosphorus tribromide was added dropwise thereto. The whole is stirred at this temperature for 1 hour 30 minutes. The reaction mixture was then hydrolyzed, followed by Et₂And (4) extracting. The organic phases were combined and washed with saturated NaHCO₃The solution was then washed with saturated NaCl solution, dried over magnesium sulfate and finally concentrated to dryness. The title compound is obtained in the form of a colorless oilIt was purified by chromatography on a silica (heptane/AcOEt) column.

Preparation example 23: (4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl } methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -pyrazine]Quinoline-8-carboxylic acid hydrochloride

Step A: (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The procedure is as described in preparation example 12, Steps A and B, with the other diastereomer being selected. The resulting compound was then subjected to the same treatment as described in steps E, F, G and H of production example 1.

Step B: (4aR) -3- [ (2-bromo-5, 5-dimethyl-1-cyclohexen-1-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

0.98ml of Et₃N, 0.1g NaI and 1.06g of the compound from preparation 22 are added in succession to a solution of 0.76g of the compound from step A in 20ml of DMF. The whole was then heated at 80 ℃ for 3 hours. After cooling to ambient temperature, the reaction mixture was hydrolyzed and then extracted with AcOEt. The organic phases are combined, washed with a saturated LiCl solution and then with a saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. The resulting solid was then added to diisopropyl ether, triturated and then filtered. The title compound was obtained as a white solid in sufficient purity for the next step.

Step C: (4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

To 1.33g of the compound of step B in DME/H₂To a suspension in a mixture of O/EtOH (15ml/6ml/4ml) was added 0.14g of PdCl in succession₂(Ph₃)₂0.697g of 4-chlorophenylboronic acid and 2.4ml of 2M Na₂CO₃An aqueous solution. The whole was degassed under argon for 15 minutes and then at 80 deg.CThe mixture was heated for 16 hours. The reaction mixture was then filtered at ambient temperature. Hydrolyzing the filtrate with CH₂Cl₂And (4) extracting. The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. The resulting green oil was purified by silica gel chromatography (heptane/AcOEt: 95/5) to give the title compound as a white solid.

Step D: (4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid hydrochloride

A suspension of 0.910g of the compound of step C in dioxane/6N HC1(10ml/15ml) was heated at 70 ℃ for 20 hours. The mixture was then returned to ambient temperature. The resulting precipitate was filtered off, then washed with diisopropyl ether and dried. The title compound was obtained as a pale green solid.

Preparation example 24: (10a β) -2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] -l]Indole-8-carboxylic acid (β ═ S or R)

Step A: 2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -8-methoxy-1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ] s]Indoles

The compound obtained in step C of preparation 9 was subjected to the operations of steps B and C of preparation 23.

Step B: 2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indole-8-carboxylic acid methyl ester

The compound of step A was subjected to the procedures of preparation 9, steps E and F.

Step C: 2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] -l]Indole-8-carboxylic acid hydrochloride

The compound of the previous step was subjected to the procedures of preparation example 11, steps B and C.

Step D: (10a β) -2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] -l]Indole-8-carboxylic acid (β ═ S or R)

The compound is obtained by separating the mixture of enantiomers obtained in step C.

Preparation example 25: (4aR) -3- { [4- (4-chlorophenyl) -3-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

Step A: (4-bromo-3-pyridyl) methanol

0.2g of sodium borohydride was added in portions to a solution of 1g of 4-bromonicotinaldehyde (nicotinaldehyde) in 50ml of MeOH at 0 ℃. The whole was then stirred for 6 hours and gradually returned to ambient temperature. The reaction mixture was cooled to 0 ℃ and then saturated NH was used₄Hydrolysis with Cl solution, using CH₂Cl₂And (4) extracting. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness. The title compound was obtained as a light brown gel which was used directly in the following step.

Step B: [4- (4-chlorophenyl) -3-pyridyl]Methanol

0.335g Pd (Ph)₃)₄0.453g of 4-chlorophenylboronic acid and 2.9ml of 2M Na₂CO₃The aqueous solution was added in turn to a suspension of 0.545g of the compound of step A in a DME/EtOH (7.5ml/3ml) mixture. The whole was degassed under argon for 15 minutes and then heated at 80 ℃ for 18 hours. The reaction mixture was filtered at ambient temperature. Then hydrolyzing the filtrate with CH₂Cl₂And (4) extracting. The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. Finally, the solid obtained is chromatographed on silica gel (CH)₂Cl₂MeOH) to afford the title compound.

Step C: 3- (chloromethyl) -4- (4-chlorophenyl) pyridine

0.590ml of thionyl chloride (0.008mol) in 5ml of CH at 0 deg.C₂Cl₂0.176g of the compound of step B in 5ml of CH is added dropwise₂Cl₂In the solution of (1). The whole was stirred for 2 hours and gradually returned to ambient temperature. The reaction mixture was then concentrated to dryness. The resulting solid was washed with heptane and dried. The title compound was obtained as a light brown solid which was used directly in the following step.

Step D: (4aR) -3- { [4- (4-chlorophenyl) -3-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The procedure is as described in preparation 23, step B, wherein the compound of preparation 23, step a, is reacted with the compound of the preceding step C.

Step E: (4aR) -3- { [4- (4-chlorophenyl) -3-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The foregoing compound was subjected to the procedure of preparation example 17, step N. Amorphous compound was obtained, which was purified by reverse phase chromatography (C-18) (gradient H)₂O，CH₃CN, 0.1% TFA). After lyophilization, the title product was obtained as a TFA salt.

Preparation example 26: (4aR) -3- { [2- (4-chlorophenyl) -3-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 25, replacing 4-bromonicotinaldehyde with 2-bromonicotinaldehyde.

Preparation example 27: (4aR) -3- { [3- (4-chlorophenyl) -2-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 25, replacing 4-bromonicotinaldehyde with 3-bromo-2-pyridinecarboxaldehyde.

Preparation example 28: (4aR) -3- { [3- (4-chlorophenyl) -4-pyridinyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure is as described in preparation 25, wherein 3-bromo-isonicotinaldehyde is used instead of 4-bromonicotinaldehyde.

Preparation example 29: (4aR) -3- [ (4- [ (tert-butoxycarbonyl) amino group]-4 '-chloro- [1, 1' -biphenyl]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

Step A: 4-nitro-4 '-chloro- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

This compound was obtained using the coupling procedure described in preparation 25, step B, substituting methyl 2-bromo-5-nitrobenzoate for (4-bromo-3-pyridinyl) methanol. The expected product is obtained after a purification step on silica gel (petroleum ether/AcOEt) in the form of a yellow solid.

Step B: 4-Nitro-4 '-chloro- [1, 1' -biphenyl-2-yl]Methanol

0.617g of sodium borohydride are added portionwise to a solution of 2.38g of the compound of step A in 20ml of MeOH at 0 ℃. The whole was stirred for 6 hours while gradually returning to ambient temperature, and then heated under reflux for 24 hours. The reaction mixture was then cooled to 0 ℃ with saturated NH₄Hydrolysis with Cl solution, using CH₂Cl₂And (4) extracting. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the expected product is obtained in the form of a yellow solid.

Step C: 4-amino-4 '-chloro- [1, 1' -biphenyl-2-yl]Methanol

3.8g of tin chloride (SnCl)₂) 0.890g of the compound of step B in a THF (15ml)/MeOH (20ml) mixture are added in portions. Gradually stir the whole bodyReflux for 3 hours. The reaction mixture was then concentrated to dryness and CH was added₂Cl₂Cooling to 0 deg.C, hydrolyzing with 5N NaOH solution, and hydrolyzing with CH₂Cl₂And (4) extracting. The organic phases are then combined, washed with saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. The expected product was obtained as a yellow solid and used directly in the next step.

Step D: 4- [ (tert-Butoxycarbonyl) amino group]-4 '-chloro-2- (hydroxymethyl) -1, 1' -biphenyl

0.71g of Boc₂O is added to a solution of 0.76g of the compound of step C in 25ml of ethanol. The whole was stirred for 20 hours gradually to 35 ℃. The reaction mixture was then concentrated to dryness and Et was added₂In O, then hydrolyzed and treated with Et₂And (4) extracting. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the title compound is obtained in the form of a light brown solid.

Step E: 4- [ (tert-Butoxycarbonyl) amino group]-4 '-chloro-2- (chloromethyl) -1, 1' -biphenyl

0.532ml Et at 0 ℃₃N and 0.22ml of methanesulfonyl chloride (0.00284mol) were added successively to a solution of 0.634g of the compound of step D in 15ml of THF. The whole was then stirred for 96 hours gradually back to ambient temperature. The reaction mixture was then concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the expected compound is obtained in the form of a yellow oil which crystallizes.

Step F: (4aR) -3- ({4- [ (tert-Butoxycarbonyl) amino group]-4 '-chloro- [1, 1' -biphenyl]-2-yl } methyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha]Quinoline-8-carboxylic acid methyl ester

The procedure is as described in preparation 23, step B, where the compound of preparation 23, step a, is reacted with the compound of the preceding step E.

Step G: (4aR) -3- [ (4- [ (tert-butoxycarbonyl) amino group]-4' -chloro- [1,1' -Biphenyl]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The foregoing compound was subjected to the procedure of preparation example 17, step N.

Preparation example 30: (4aR) -3- [ (4- { [ (tert-Butoxycarbonyl) amino group]Methyl } -4 '-chloro- [1, 1' -biphenyl]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

Step A: 4-methoxy-4 '-chloro- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

This compound was obtained using the coupling procedure described in preparation 25, step B, substituting methyl 2-bromo-5-methoxybenzoate for (4-bromo-3-pyridinyl) methanol. After purification on silica gel (heptane/AcOEt), the expected product is obtained in solid form.

Step B: 4 '-chloro-4-hydroxy- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

1M BBr at-78 deg.C₃In 42ml CH₂Cl₂To the solution was slowly added 1.6g of the compound of step A in 20ml CH₂Cl₂In the solution of (1). The whole is stirred at this temperature for 1 hour 30 minutes. Then H is added₂O/MeOH (40ml/10ml) mixture. The whole was still stirred at-78 ℃ for 45 minutes and then with CH₂Cl₂And (4) extracting. The organic phases were combined, dried over magnesium sulfate and concentrated to dryness. A brown foam was obtained and used directly in the following step.

Step C: 4 '-chloro-4-trifluoromethanesulfonyl- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

4ml of Et are added at 0 ℃₃N (0.029mol) and 3.1g N-phenyl-bis (trifluoromethanesulfonamide) were added sequentially to 1.5g of the compound of step B in 20ml CH₂Cl₂In the solution of (1). The whole was then stirred for 20 hours gradually returning to ambient temperature. The reaction mixture was then concentrated to dryness, added to AcOEt, and washed successively with 1N HCl solution, saturated NaHCO₃The solution was washed with saturated NaCl solution and dried over magnesium sulfate. After purification on silica gel (heptane/AcOEt), the expected compound is obtained in the form of a colorless oil.

Step D: 4 '-chloro-4-cyano- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

0.44g Pd₂(dba)₃0.066g dppf and 0.422g Zn (CN)₂A solution of 1.2g of the compound of step C in 50ml of DMF is added in succession. The whole was then stirred for 3 hours and gradually warmed to 90 ℃. The reaction mixture was concentrated, added to AcOEt, washed with a saturated LiCl solution and a saturated NaCl solution in this order, and then dried over magnesium sulfate. After purification on silica gel (heptane/AcOEt), the expected compound is obtained in the form of a colorless oil which gradually crystallizes.

Step E: 4-aminomethyl-4 '-chloro- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

1.68g of NiCl are added at 0 DEG C₂And 1.47g of sodium borohydride were added portionwise to a suspension of 3.52g of the compound of step D in 40ml of MeOH. The whole was then stirred for 6 hours gradually returning to ambient temperature. The reaction mixture was filtered and the filtrate was diluted with AcOEt and then hydrolyzed. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate and then concentrated. The title compound was obtained as a white foam and used directly in the following step.

Step F: 4- { [ (tert-Butoxycarbonyl) amino]Methyl } -4 '-chloro- [1, 1' -biphenyl]-2-Carboxylic acid methyl ester

2.82g Boc₂O3.02 g of the compound of step E in 60ml CH₂Cl₂In the solution of (1). The whole was then stirred at ambient temperature for 20 hours. The reaction mixture was concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the title compound is obtained in the form of a white solid.

Step G: 4- { [ (tert-Butoxycarbonyl) amino]Methyl } -4 '-chloro-2- (hydroxymethyl) -1, 1' -biphenyl

A solution of 2.4M LAH in THF was added dropwise to a solution of 1.6g of the compound of step F in 60ml of THF at 0 ℃. The whole was stirred at ambient temperature for 2 hours. The reaction mixture was then hydrolyzed with saturated rochelle salt solution at ambient temperature for 1 hour 30 minutes. It was then extracted with AcOEt. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the title compound is obtained as a clear oil.

Step H: 4- { [ (tert-Butoxycarbonyl) amino]Methyl } -4 '-chloro-2- (chloromethyl) -1, 1' -biphenyl

1.26ml of Et at 0 ℃₃N (0.00896mol) and 0.52ml methanesulfonyl chloride (0.00672mol) were added successively to a solution of 1.56G of the compound of step G in 50ml THF. The whole was then stirred for 96 hours gradually back to ambient temperature. The reaction mixture was concentrated to dryness. After purification on silica gel (petroleum ether/AcOEt), the expected compound is obtained in the form of an oil which crystallizes.

Step I: (4aR) -3- [ (4- { [ (tert-Butoxycarbonyl) amino group]Methyl } -4 '-chloro- [1, 1' -biphenyl]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The process is as described in preparation 23, step B, wherein the compound of preparation 23, step a, is reacted with the compound of the preceding step H. After purification on silica gel (heptane/AcOEt), the title compound is obtained.

Step J: (4aR) -3- { (4- { [ (tert-Butoxycarbonyl) amino]Methyl } -4 '-chloro- [1, 1' -biphenyl]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The foregoing compound was subjected to the procedure of preparation example 17, step N. The expected product is obtained in the form of a white solid.

Preparation example 31: (4aR) -3- [ (3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino[1，2-α]Quinoline-8-carboxylic acid

Step A: (4aR) -3- (2-bromobenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The procedure is as described in preparation 23, step B, wherein the compound of preparation 23, step A, is reacted with 1-bromo-2- (bromomethyl) benzene.

Step B: (4aR) -3- [ (3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The procedure was as described in preparation 25, step B, substituting 3-fluoro-4-chlorophenylboronic acid for 4-chlorophenylboronic acid.

Step C: (4aR) -3- [ (3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The foregoing compound was subjected to the procedure of preparation example 17, step N.

Preparation example 32: (4aR) -3- [ (4 '-cyano- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure is as described in preparation 31, where in step B4-cyanoboronic acid is used instead of 3-fluoro-4-chlorophenylboronic acid.

Preparation example 33: (4aR) -3- [ (4 '-trifluoro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure is as described in preparation 31, where in step B4-trifluoromethylboronic acid is used instead of 3-fluoro-4-chlorophenylboronic acid.

Preparation example 34: (4aR) -3- [2- (1, 3-benzodioxol-5-yl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure is as described in preparation 31, where 1, 3-benzodioxol-5-ylboronic acid is used in place of 3-fluoro-4-chlorophenylboronic acid in step B.

Preparation example 35: (4aR) -3-benzhydryl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

Step A: (4aR) -3-benzhydryl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

The procedure is as described in preparation 23, step B, wherein the compound of preparation 23, step a, is reacted with [ bromo (phenyl) methyl ] benzene.

Step B: (4aR) -3-benzhydryl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The foregoing compound was subjected to the procedure of preparation example 17, step N.

Preparation example 36: (4aS, R) -3- { [4- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure is as described in preparation 25, where the compound of preparation 23, step A, is replaced in step D by the enantiomeric mixture of preparation 1, step H.

Preparation example 37: (4aS, R) -3- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 26, substituting the compound of preparation 1, step H for the compound of preparation 23, step a, in step D.

Preparation example 38: (4aS, R) -3- { [3- (4-chlorophenyl) -2-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 27, wherein the compound of preparation 23, step a, was replaced in step D with the compound of preparation 1, step H.

Preparation example 39: (4aS, R) -3- { [3- (4-chlorophenyl) -4-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 28, substituting the compound of preparation 1, step H for the compound of preparation 23, step a, in step D.

Preparation example 40: (4aS, R) -3- [ (2- (4-pyridyl) -3-pyridyl) methyl group]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure was as described in preparation 25, using 2-bromo-nicotinaldehyde in step a, 4-pyridylboronic acid in step B and the enantiomeric mixture of preparation 1, step H, as tricyclic synthon in step D.

Preparation example 41: (4aS, R) -3- [ ((6-chloro-pyridin-3-yl) -3-pyridinyl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure is as described in preparation 25, using 2-bromo-nicotinaldehyde in step a, 6-chloro-3-pyridylboronic acid in step B and the enantiomeric mixture of preparation 1, step H, as tricyclic synthon in step D.

Preparation example 42: (4aS, R) -3- [ (2- (6-hydroxy-pyridin-3-yl) -3-pyridinyl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid trifluoroacetic acid salt

The procedure is as described in preparation 25, using 2-bromo-nicotinaldehyde in step a, 6-hydroxy-3-pyridylboronic acid in step B and the enantiomeric mixture of preparation 1, step H, as tricyclic synthon in step D.

Preparation example 43: 2- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indole-8-carboxylic acid trifluoroacetate salt

The procedure was as described in preparation 25, using 2-bromo-nicotinaldehyde in step A, 4-chlorophenylboronic acid in step B and the compound of preparation 9, step F, as the tricyclic synthon in step D.

Preparation example 44: 2- { [2- (6-chloro-pyridin-3-yl) -3-pyridinyl]Methyl } -1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indole-8-carboxylic acid trifluoroacetate salt

The procedure is as described in preparation 25, using 2-bromo-nicotinaldehyde in step a, 6-chloro-3-pyridylboronic acid in step B and the compound of preparation 9, step F, as the tricyclic synthon in step D.

Preparation example 45: (4aS, R) -3- [ (4 '-tert-butyl- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure was aS described in preparation 31, where 4-tert-butyl-phenylboronic acid was used in place of 3-fluoro-4-chlorophenylboronic acid in step B and a mixture of (4aS, R) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylic acid methyl ester (preparation 1, step H) was used in place of (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylic acid methyl ester in step C (preparation 23, step a).

Preparation example 46: (4aS, R) -3- [2- (4-chlorobenzyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

The procedure was as described in preparation example 1, wherein 4-chloro-2 '- (chloromethyl) -1, 1' -biphenyl was replaced in step I with 1-chloro-2- (4-chlorobenzyl) benzene.

Preparation example 47: 3- (2-phenoxybenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid

Step A: 3- (2-phenoxybenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carboxylic acid methyl ester

By reaction with 2-phenoxybenzaldehyde in NaBH (OAc)₃The compound of preparation 1, step H, is subjected to a reductive amination reaction in the presence of a catalyst. The reaction mixture was then treated with acetic acid and then CH₂Cl₂And (4) extracting.

Step B: 3- (2-phenoxybenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]The quinoline-8-carboxylic acid procedure was as described in preparation 1, step J.

Example 1: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bistrifluoroacetate salt

Step A: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

2.05ml of DIEA and then 1.5g of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl) are added at ambient temperature]Propyl } amino) -3-nitrobenzenesulfonamide, 0.783g EDC and 0.5g DMAP are then added to 1.26g of the compound from preparation 1 in 50ml CH₂Cl₂In solution in a mixture of/THF (1/1). The reaction mixture was stirred at ambient temperature for 2 days. Evaporated to dryness and the residue obtained is then taken up in saturated NH₄In Cl solution, with CH₂Cl₂The extraction was performed twice. The organic phase was washed with saturated NaCl solution and MgSO₄Dried, filtered and evaporated to dryness. The oil was purified by flash chromatography on silica gel (CH)₂Cl₂/MeOH/NH₄OH 84/16/1.6) and then freeze-dried to give the title product as a yellow solid.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 62.955.6410.017.64

Found value 63.205.629.787.22

Step B: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bistrifluoroacetate salt

The compound obtained in step A (0.3g) was dissolved in 10ml of CH at 0 deg.C₂Cl₂Trifluoroacetic acid (56 μ l) was then added dropwise. The whole was then stirred at ambient temperature for 30 minutes and concentrated to dryness. Adding the obtained solid into H₂In O, CH is added dropwise₃CN until the reaction mixture was completely dissolved, and then lyophilized at low temperature for 24 hours. A cotton wool-like yellow solid was obtained as the title product.

Example 2: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

Step A: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 2 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Step B: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

The compound obtained in step A (0.3g) was dissolved in 10ml of CH at 0 deg.C₂Cl₂Then hydrochloric acid in Et is added dropwise₂Solution in O (2M) (375. mu.l). The whole was then stirred at ambient temperature for 30 minutes and concentrated to dryness. Adding the obtained solid into H₂In O, CH is added dropwise₃CN until the reaction mixture was completely dissolved, and then lyophilized at low temperature for 24 hours.

Example 3: n- ({ ((4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-4-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

Step A: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-4-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 3 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Step B: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-4-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

The procedure is as described in example 2, step B.

Example 4: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 4 replacing the compound of preparation 1.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 65.656.0110.447.97

Found value 65.245.9410.247.89

Step B: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 59.215.699.427.19

Found value 58.545.929.066.50

Example 5: n- { [ (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ]]Quinolin-8-yl]Carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

Step A: n- { [ (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ]]Quinolin-8-yl]Carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 5 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Step B: n- { [ (4aS, R) -3- (2-benzylbenzyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ]]Quinolin-8-yl]Carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

The procedure is as described in example 2, step B.

Example 6: 3-nitro-N- ({ (4aS, R) -3- [2- (2-phenylethyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 6 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 66.215.699.198.42

Found value 65.985.938.898.08

Example 7: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure was as described in example 1, step A, substituting 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 62.534.989.118.35

Found value 62.535.128.708.12

Example 8: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- [ (2-phenoxyethyl) amino]Benzenesulfonamides

The procedure was as described in example 1, step A, substituting 3-nitro-4- [ (2-phenoxyethyl) amino ] benzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 63.865.099.314.26

Found value 63.825.238.983.82

Example 9: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -3-nitro-4- [ (3-phenylpropyl) -amino]Benzenesulfonamides

The procedure is as described in example 1, step A, where the compound from preparation 4 is used instead of the compound from preparation 1 and 3-nitro-4- [ (3-phenylpropyl) amino ] benzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 68.795.779.784.48

Found value 68.155.859.763.63

Example 10: 4- [ (2-anilinoethyl) amino group]-N- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -3-nitrophenylsulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 4 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- [ (2-anilinoethyl) amino ] -3-nitrobenzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 67.025.6211.724.47

Found value 65.935.8011.613.72

Example 11: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- { [3- (dimethylamino) propyl group]- [2- (Phenylthio) ethyl group]Amino } -3-nitrobenzenesulfonamide hydrochloride

Step A: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- { [3- (dimethylamino) propyl group][2- (Phenylthio) ethyl group]Amino } -3-nitrobenzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 4 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- { [3- (dimethylamino) propyl ] [2- (phenylthio) ethyl ] amino } -3-nitrobenzenesulfonamide.

Step B: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- { [3- (dimethylamino) propyl group][2- (Phenylthio) ethyl group]Amino } -3-nitrobenzenesulfonamide hydrochloride

The procedure is as described in example 2, step B.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 64.556.0810.047.66

Found value 64.675.9910.037.47

Example 12: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [3- (dimethylamino) propyl]Amino } -3-nitrobenzenesulfoneAmides of carboxylic acids

The procedure was as described in example 1, step A, substituting 4- { [3- (dimethylamino) propyl ] amino } -3-nitrobenzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis：

％C ％H ％N ％S

Calculated value 61.965.7611.724.47

Found value 62.366.0811.504.94

Example 13: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) benzenesulfonamides

The procedure is as described in example 1, step A, where 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced with benzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 67.185.297.345.60

Found value 66.745.227.195.48

Example 14: 4- { [ (2-aminoethyl) (2-phenylethyl) amino]Methyl } -N- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) benzenesulfonamide tris (trifluoroacetate salt)

Step A: 4- { [ (2-aminoethyl) (2-phenylethyl) amino]Methyl } -N- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) benzenesulfonamides

The procedure was as described in example 1, step A, substituting 4- { [ (2-aminoethyl) (2-phenylethyl) amino ] methyl } benzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Step B: 4- { [ (2-aminoethyl) (2-phenylethyl) amino]Methyl } -N- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) benzenesulfonamide tris (trifluoroacetate salt)

The procedure is as described in example 1, step B.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.974.536.422.94

Found value 53.224.786.202.46

Example 15: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-7-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 7 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 62.955.6410.017.64

Found value 62.075.609.477.34

Example 16: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-7-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 8 replacing the compound of preparation 1.

Theoretical m/z: 805.3206

Actually measured m/z: 805.3207

Example 17: n- { [2- ([1, 1' -biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indol-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- { [2- ([1, 1' -biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indol-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 9 replacing the compound of preparation 1.

Step B: n- { [2- ([1, 1' -biphenyl)]-2-ylmethyl) -1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Indol-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Example 18: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethyl)Amino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step A, with the compound obtained in preparation 10 replacing the compound of preparation 1.

Step B: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Example 19: n- ({ (10aS, R) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 11 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.495.279.357.14

Found value 57.315.479.066.95

Example 20: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 13 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 62.955.6410.017.64

Found value 62.305.599.667.40

Step B: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.925.419.217.03

Found value 58.445.219.196.14

Example 21: n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]2, 3, 4, 4a, 5, 6-hexaHydrogen-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 12 replacing the compound of preparation 1.

Step B: n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.925.419.217.03

Found value 57.585.298.756.97

Example 22: n- { [ (4aS) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide tris (hydrochloride)

Step A: n- { [ (4aS) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 14 replacing the compound of preparation 1.

Step B: n- { [ (4aS) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide tris (hydrochloride)

The procedure is as described in example 2, step B.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.215.699.427.19

Found value 58.56.059.126.48

Example 23: n- { [ (4aR) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride)

Step A: n- { [ (4aR) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in preparation A of example 1, with the compound of preparation 15 replacing the compound of preparation 1.

Step B: n- { [ (4aR) -3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino group) -3-Nitrobenzenesulfonamide bis (hydrochloride)

The procedure is as described in example 2, step B.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.735.679.347.13

Found value 58.785.99.177.29

Example 24: n- { [ (4aS, R) -3- ([1, 1' -Biphenyl)]-2-ylsulfonyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ] -]Quinolin-8-yl]Carbonyl } -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 16 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.754.768.9312.27

Found value 60.024.988.4111.81

Example 25: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide

The procedure was as described in example 1, step A, where 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide was replaced with 4- { (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.

Example 26: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } -4H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide

The procedure was as described in example 1, step A, where 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide was replaced with 4- { (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } -4H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.

Example 27: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 17 replacing the compound of preparation 1.

Example 28: n- ({ (4aS) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The enantiomeric mixture described in preparation 17 was separated on a column. The title compound was obtained by subjecting the selected enantiomer to the procedure of example 1, step a.

Example 29: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 28, where the other enantiomer is used.

Example 30: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 17 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Example 31: n- ([3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 4a, 5, 6, 7-octahydropyrazino [1, 2-a ] and pharmaceutically acceptable salts thereof][1]Benzazepine compounds-9-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3- [ (trifluoromethyl) sulfonyl]Benzenesulfonamides

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 17 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Example 32: n- ({ (10 a. alpha. -) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride (α ═ R or S)

The title compound was obtained by the method of example 1, step a, substituting the compound of preparation 18 for the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.495.279.357.14

Found value 57.724.579.407.46

Example 33: n- ({ (10 a. beta. -) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride (β ═ S or R)

The title compound was obtained by following the procedure of example 1, step a, substituting the compound of preparation 19 for the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.495.279.357.14

Found value 57.314.299.487.87

Example 34: n- ({ (10 a. alpha. -) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride (α ═ R or S)

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 18 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.475.258.946.82

Found value 57.565.149.166.31

Example 35: n- ({ (10 a. alpha. -) -2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-alpha ] pyrazine]Indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3- [ (trifluoromethyl) sulfonyl]Benzenesulfonamide dihydrochloride (α ═ R or S)

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 18 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.774.816.829.36

Found value 53.634.827.288.79

Example 36: n- ({3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-5-oxo-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxalin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 21 replacing the compound of preparation 1. This was followed by a deprotection step, in which the residue which had separated was dissolved in a solution of 4N HCl in dioxane. After neutralization with CH₂Cl₂The aqueous phase was extracted, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Example 37: n- ({3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxalin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 20 replacing the compound of preparation 1. This was followed by a deprotection step, in which the residue which had separated was dissolved in a solution of 4N HCl in dioxane. After neutralization with CH₂Cl₂The aqueous phase was extracted, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Example 38: n- ({3- [ (4 '-chloro- [1, 1' -biphenyl)]-3-yl) methyl]-6-methyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxalin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

Deprotection of the 6-position of the tricyclic moiety of compound of step H, preparative example 20 was performed using a solution of 4N HCl in dioxane. After neutralization, extraction and purification, the residue obtained is taken up in methyl iodide and K₂CO₃In the presence of an alkylation catalyst. After treatment with LiOH, 3- [ (4 '-chloro- [1, 1' -biphenyl) is obtained]-2-yl) methyl]-6-methyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoxaline-8-carboxylic acid. The latter was subjected to the procedure of example 1, step a, to obtain the title compound.

Example 39: n- [ ((4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]-methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-a]Quinolin-8-yl) carbonyl]-4- ({ (1R) -2- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Ethyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 23 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.506.088.906.79

Found value 58.065.948.846.85

Example 40: n- [ ((4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]-methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-a]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3- [ (trifluoromethyl) sulfonyl]Benzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 23 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.825.546.528.96

Found value 54.565.136.678.45

EXAMPLE 41: n- [ ((10a β) -2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]-methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-a ] as]Indol-8-yl) carbonyl]-4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3- [ (trifluoromethyl) sulfonyl]Benzenesulfonamide dihydrochloride (β ═ S or R)

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 24 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.415.426.619.08

Found value 53.665.516.508.71

Example 42: n- [ ((4aR) -3- { [4- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -2- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Ethyl } amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 25 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.375.2010.326.75

Found value 54.705.1210.356.71

Example 43: n- [ ((4aR) -3- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 26 replacing the compound of preparation 1.

Example 44: n- [ ((4aR) -3- { [3- (4-chlorophenyl) -2-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 27 replacing the compound of preparation 1.

Example 45: n- [ ((4aR) -3- { [3- (4-chlorophenyl) -4-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 28 replacing the compound of preparation 1.

Example 46: n- ({ (4aR) -3- [ (4-amino-4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 29 replacing the compound of preparation 1. This was followed by a deprotection step, in which the residue which had separated was dissolved in a solution of 4N HCl in dioxane. After neutralization with CH₂Cl₂The aqueous phase was extracted, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.835.3310.176.65

Found value 54.975.2510.076.62

Example 47: n- [ ((4aR) -3- { [4- (aminomethyl) -4 '-chloro- [1, 1' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 30 replacing the compound of preparation 1. Thereafter proceed withA deprotection step, in which the residue which has been separated off is dissolved in a solution of 4N HCl in dioxane. After neutralization with CH₂Cl₂The aqueous phase was extracted, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue obtained is chromatographed on a silica Column (CH)₂Cl₂MeOH) to give the expected product.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.275.4610.036.56

Found value 55.985.559.826.31

Example 48: n- [ ((4aR) -3- { [3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 31 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 56.805.209.036.89

Found value 56.065.209.086.55

Example 49: n- [ ((4aR) -3- { [4 '-cyano- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 32 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.865.4710.867.10

Found value 59.865.1910.866.72

Example 50: n- [ ((aR) -3- { [4 '- (trifluoromethyl) - [1, 1' -biphenyl ]]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 33 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.145.228.886.78

Found value 57.725.108.836.34

Example 51: n- [ ((4aS, R) -3- { [4 '- (trifluoromethyl) - [1, 1' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is aS in example 50, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate (preparation 23 step a).

Example 52: n- ({ (4aR) -3- [2- (1, 3-benzodioxol-5-yl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 34 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.625.479.126.96

Found value 58.765.259.196.83

Example 53: n- ({ (4aS, R) -3- [2- (1, 3-benzodioxol-5-yl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [2- (phenylsulfanyl) ethyl]Amino }) -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is aS described in example 52, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate (preparation 23 step A) and 4- { [2- (phenylthio) ethyl ] amino } -3-nitrobenzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.644.387.46.78

Found value 55.424.377.356.87

Example 54: n- { [ (4aR) -3-Diphenylmethyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ]]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide

The procedure is as described in example 1, step a, with the compound of preparation 35 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 65.656.0110.447.97

Found value 64.635.9110.117.81

Example 55: n- [ ((4aR) -3- { 2-bromobenzyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The compound obtained in step A of preparation 31 was subjected to the procedure of preparation 17, step N. The product was then subjected to the procedure of example 1, step a.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 51.825.159.547.28

Found value 51.335.149.667.08

Example 56: n- [ ((4aS, R) -3- { 2-bromobenzyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ([2- (phenylsulfanyl) ethyl)]Amino) -3-nitrobenzenesulfonamide hydrochloride

The procedure is aS described in example 55, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate (preparation 23 step A) and 4- { [2- (phenylthio) ethyl ] amino } -3-nitrobenzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 52.824.569.068.29

Found value 52.924.488.848.47

Example 57: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.895.398.816.72

Found value 57.115.068.487.46

Example 58: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is aS described in example 57, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate (preparation 23 step a).

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.895.398.816.72

Found value 57.385.228.806.57

Example 59: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3- [ (trifluoromethyl) sulfonyl]Benzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.204.946.729.24

Found value 54.314.586.758.90

Example 60: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1S) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is aS described in example 59, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate (preparation 23 step A) and 4- ({ (1S) -3- (4-morpholinyl) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide is used instead of 4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylthio) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide An amide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.895.398.816.72

Found value 57.695.329.056.54

Example 61: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-methyl-1-piperazinyl) -1- [ (phenylsulfanyl) methyl]Propyl radicalAmino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (4-methyl-1-piperazinyl) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Example 62: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.275.618.826.73

Found value 59.235.218.756.78

Example 63: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is aS described in example 62, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinoline-8-carboxylate (preparation 23 step a).

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.275.618.826.73

Found value 58.655.488.566.37

Example 64: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1S) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure was as described in example 63, substituting 4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide with 4- ({ (1S) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.275.618.826.73

Found value 59.005.398.586.70

Example 65: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-pyrrolidinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (1-pyrrolidinyl) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.885.488.966.83

Found value 58.535.048.816.60

Example 66: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (3, 6-dihydro-1 (2H) -pyridinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (3, 6-dihydro-1 (2H) -pyridinyl) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Example 67: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-azepanyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (1-azepanyl) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.655.748.706.64

Found value 60.015.608.406.39

Example 68: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- ((1R, 5S) -3-azabicyclo [3.1.0]Hexane-3-yl) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 13 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 4- ({ (1R) -3- ((1R, 5S) -3-azabicyclo [3.1.0] hex-3-yl) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.395.418.846.75

Found value 59.515.178.906.43

The following examples 69 to 78 were obtained by coupling the tricyclic compound described in preparation example 1 with the appropriate benzenesulfonamide compound according to the method described in step A of example 1.

Example 69: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- [ (4-Phenylbutyl) amino]-3-Nitrobenzenesulfonamide bistrifluoroacetate salt

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.244.737.583.47

Found value 58.614.877.542.97

Example 70: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [2- (1-methyl-1H-benzimidazol-2-yl) ethyl]Amino } -3-nitrobenzenesulfonamide tris (trifluoroacetate salt)

Elemental microanalysis

％C ％H ％N ％S

Calculated value 50.913.838.662.83

Found value 51.194.038.762.34

Example 71: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [2- (1H-benzimidazol-2-yl) ethyl]Amino } -3-nitrobenzenesulfonamide tris (trifluoroacetate salt)

Elemental microanalysis

％C ％H ％N ％S

Calculated value 52.063.859.243.02

Found value 52.13.99.12.38

Example 72: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({2- [ (4-methoxyphenyl) thio]Ethyl } amino) -3-nitrobenzenesulfonamide trifluoroacetate salt

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.524.317.226.62

Found value 53.914.517.156.32

Example 73: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { (1H-benzimidazol-2-yl) methylamino } -3-nitrobenzenesulfonamide bistrifluoroacetate

Elemental microanalysis

％C ％H ％N ％S

Calculated value 52.293.779.573.13

Found value 52.663.8910.132.6

Example 74: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({2- [ (2-methoxyphenyl) thio]Ethyl } amino) -3-nitrobenzenesulfonamide hydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.994.958.397.68

Found value 59.144.928.457.45

Example 75: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({2- [ (2-pyridyl) thio]Ethyl } amino) -3-nitrobenzenesulfonamide hydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.134.7510.437.96

Found value 57.624.239.967.55

Example 76: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [2- (2-nitroanilino) ethyl]Amino } -3-nitrobenzenesulfonamide hydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.694.7211.773.85

Found value 58.144.5411.814.01

Example 77: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- [ (2- { [2- (hydroxymethyl) phenyl]Thio } ethyl) amino]-3-nitrobenzenesulfonamide hydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.994.958.397.68

Found value 59.004.648.227.27

Example 78: n- ({ (4aS, R) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1S, R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide

Elemental microanalysis

％C ％H ％N ％S

Calculated value 62.955.6410.017.64

Found value 63.375.5010.007.76

The following examples 79 to 90 were obtained by coupling the tricyclic compound described in preparation example 10 with the appropriate benzenesulfonamide compound according to the method described in step a of example 1.

Example 79: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- (4-methyl-1-piperazinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide tris (trifluoroacetate salt)

Elemental microanalysis

％C ％H ％N ％S

Calculated value 50.354.127.815.11

Found value 50.264.227.914.72

Example 80: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [3- (dimethylamino) -1- (2-phenylethyl) propyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 60.175.399.573.65

Found value 59.555.69.642.58

Example 81: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- ((3aR, 6aS) -hexahydrocyclopenta [ c]Pyrrol-2 (1H) -yl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.95.348.736.66

Found value 59.665.478.466.3

Example 82: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [1- [ (phenylsulfanyl) methyl]-3- (1-piperidinyl) propyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.005.278.976.85

Found value 58.955.48.686.59

Example 83: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [1- [ (phenylsulfanyl) methyl]-3- (1-pyrrolidinyl) propyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.065.159.187.01

Found value 59.315.219.087.43

Example 84: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [3- (dimethylamino) -1- (phenoxymethyl) propyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.675.159.553.64

Found value 58.654.999.443.31

Example 85: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- (4-morpholinyl) -1- [ (phenyl)Thio) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.65.058.966.83

Found value 58.455.038.786.61

Example 86: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [1- (anilinomethyl) -3- (dimethylamino) propyl]Amino } -3-nitrobenzenesulfonamide bistrifluoroacetate salt

It should be noted that the nitrogen atom of the anilinomethyl group of the benzenesulfonamide compound is protected by a Boc functional group when coupled to a tricyclic ring. The deprotection step was carried out in the presence of 6N HCl and dioxane to give the title product.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 51.864.198.712.85

Found value 52.174.59.552.29

Example 87: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- (dimethylamino) -1- [2- (2-furyl) ethyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.105.229.683.69

Found value 57.854.909.663.70

Example 88: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- { [1- [ (phenylsulfanyl) methyl]-3- (4-Thiomorpholinyl) propyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 56.634.968.8110.08

Found value 56.444.718.8210.10

Example 89: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- [ methoxy (methyl) amino]-1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide hydrochloride

Example 90: n- ({2- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-1, 2, 3, 4-tetrahydropyrazino [1, 2-a [ ]]Indol-8-yl } carbonyl) -4- ({3- (4, 4-difluoro-1-piperidinyl) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 56.824.878.646.60

Found value 56.884.658.646.49

Example 91: n- [ ((4aS, R) -3- { [4- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide hydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 36 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzene is replaced by 4- { [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.134.7510.437.96

Found value 57.154.3610.207.46

Example 92: n- [ ((4aS, R) -3- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide bistrifluoroacetate salt

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 37 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzene is replaced by 4- { [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 51.783.948.436.43

Found value 52.384.128.476.68

Example 93: n- [ ((4aS, R) -3- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 37 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.375.2010.326.75

Found value 53.745.2310.155.97

Example 94: n- [ ((4aS, R) -3- { [3- (4-chlorophenyl) -2-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino-benzenesulfonamide hydrochloride

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.134.7510.437.96

Found value 57.504.4610.207.94

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 38 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzene is replaced by 4- { [2- (phenylsulfanyl) ethyl ] amino } 3-nitrobenzenesulfonamide.

Example 95: n- [ ((4aS, R) -3- { [3- (4-chlorophenyl) -4-pyridyl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 39 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzene is replaced by 4- { [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.624.679.987.71

Found value 56.494.5010.067.32

Example 96: n- [ ((4aS, R) -3- [ (2- (4-pyridyl) -3-pyridyl) methyl group]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 40 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.985.3411.996.86

Found value 53.345.4812.685.78

Example 97: n- [ ((4aS, R) -3- [ (2- (6-chloro-pyrazine)Pyridin-3-yl) -3-pyridyl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carbonyl]-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl amino) -3-nitrobenzenesulfonamide trihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 41 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.055.0911.786.74

Found value 52.695.2511.595.99

Example 98: n- [ ((4aS, R) -3- [ (2- (6-hydroxy-pyridin-3-yl) -3-pyridinyl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinoline-8-carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 42 replacing the compound of preparation 1.

Example 99: n- [ ((4aS, R) -2- { [2- (4-chlorophenyl) -3-pyridyl]Methyl } -1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indole-8-carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 43 replacing the compound of preparation 1.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.324.9110.757.03

Found value 54.794.8510.476.71

Example 100: n- [ ((4aS, R) -2- { [2- (6-chloro-pyridin-3-yl) -3-pyridinyl]Methyl } -1, 2, 3, 4-tetrahydropyrazino [1, 2-alpha ]]Indole-8-carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide dihydrochloride

The procedure is as described in example 1, step a, with the compound of preparation 44 replacing the compound of preparation 1.

Example 101: n- [ ((4aS, R) -3- { [4 '-cyano- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is aS described in example 49, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate (preparation 23 step A) and 4- { [2- (phenylthio) ethyl ] amino } -3-nitrobenzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzene.

Example 102: n- [ ((4aS, R) -3- { [4 '- (trifluoromethyl) - [1, 1' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is aS described in example 50, where methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate mixture (preparation 1 step H) is used instead of methyl (4aR) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinoline-8-carboxylate (preparation 23 step A) and 4- { [2- (phenylthio) ethyl ] amino } -3-nitrobenzenesulfonamide is used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzene.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 54.914.157.336.71

Found value 55.124.137.026.63

Example 103: n- [ ((4aS, R) -3- { [3 '- (trifluoromethyl) - [1, 1' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 102, 3-trifluoromethylphenylboronic acid being used instead of 4-trifluoromethylboronic acid in the synthesis.

Example 104: n- [ ((4aS, R) -3- { [4 '- (tert-butyl) - [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The compound of preparation 45 was subjected to the procedure of example 1, step A, substituting 4- { [2- (phenylsulfanyl) ethyl ] amino } -3-nitrobenzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzene.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 61.125.357.757.09

Found value 61.175.177.856.84

Example 105: n- [ ((4aS, R) -3- { [3 ', 5 ' -dimethyl- [1, 1 ' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, substituting 3, 5-dimethylphenylboronic acid for 4-tert-butylphenyl-boronic acid in preparation 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.414.897.496.86

Found value 57.464.877.326.77

Example 106: n- [ ((4aS, R) -3- { [2 ', 4 ' -dimethoxy- [1, 1 ' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, preparation 45 being replaced by 2, 4-dimethoxyphenylboronic acid instead of 4-tert-butylphenyl-boronic acid.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.434.727.236.62

Found value 55.54.747.136.21

Example 107: n- [ ((4aS, R) -3- { [3 ', 4 ' -dimethoxy- [1, 1 ' -biphenyl]-2-yl]A mixture of methyl } -2, 3, 4,4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, preparation 45 being replaced by 3, 4-dimethoxyphenylboronic acid instead of 4-tert-butylphenyl-boronic acid.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 58.204.887.717.06

Found value 57.254.897.687.66

Example 108: n- [ ((4aS, R) -3- { [2 ', 3 ' -dimethoxy- [1, 1 ' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, preparation 45 replacing 4-tert-butylphenyl-boronic acid with 2, 3-dimethoxyphenylboronic acid.

Example 109: n- [ ((4aS, R) -3- { [4 '-fluoro- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide hydrochloride

The procedure is as described in example 104, 4-tert-butylphenyl-boronic acid is replaced by 4-fluorophenyl-boronic acid in preparation example 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 60.944.998.888.13

Found value 61.425.188.57.48

Example 110: n- [ ((4aS, R) -3- { [3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, wherein 3-fluoro-4-chlorophenylboronic acid was used instead of 4-tert-butylphenyl-boronic acid in preparation example 45.

Example 111: n- [ ((4aS, R) -3- { [3 ', 4 ' -dichloro- [1, 1 ' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, substituting 3, 4-dichlorophenyl boronic acid for 4-tert-butylphenyl boronic acid in preparation example 45.

Example 112: n- [ ((4aS, R) -3- { [4 '-methyl- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, substituting 4-tert-butylphenyl boronic acid with 4-methylphenyl boronic acid in preparation example 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.924.918.137.44

Found value 58.774.928.076.78

Example 113: n- [ ((4aS, R) -3- { [3 '-chloro- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, where 3-chlorophenylboronic acid is used instead of 4-tert-butylphenyl-boronic acid in preparation 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 57.174.457.947.27

Found value 56.374.507.816.67

Example 114: n- [ ((4aS, R) -3- { [3 '-fluoro- [1, 1' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide bistrifluoroacetate salt

The procedure is as described in example 104, preparation 45 being carried out using 3-fluorophenylboronic acid instead of 4-tert-butylphenyl-boronic acid.

Example 115: n- [ ((4aS, R) -3- { [3 ', 4 ' -difluoro- [1, 1 ' -biphenyl)]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as in example 104, where 3, 4-difluorophenylboronic acid is used in place of 4-tert-butylphenyl-boronic acid in preparation 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 534.17.126.52

Found value 53.214.296.976.29

Example 116: n- [ (4aS, R) -3- { [3 ' -chloro-4 ' -fluoro- [1, 1 ' -biphenyl]-2-yl]Methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl) carbonyl]-4- { [2- (phenylsulfanyl) ethyl]Amino } -3-nitrobenzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, preparation 45 replacing 4-tert-butylphenyl-boronic acid with 3-chloro-4-fluorophenyl-boronic acid.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.374.007.196.58

Found value 53.74.097.16.16

Example 117: n- ((4aS, R) - {3- [2- (2, 2-difluoro-1, 3-benzodioxol-4-yl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } benzenesulfonamide trifluoroacetate salt

The procedure is as in example 104, where 2, 2-difluoro-1, 3-benzodioxol-4-ylboronic acid is used in preparation 45 instead of 4-tert-butylphenyl-boronic acid.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.664.137.556.91

Found value 54.953.927.517.44

Example 118: n- ((4aS, R) - {3- [2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } benzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, wherein 2, 3-dihydro-1, 4-benzodioxin-6-ylboronic acid was used in preparation example 45 instead of 4-tert-butylphenyl boronic acid.

Example 119: n- ((4aS, R) - {3- [2- (1-naphthyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } benzenesulfonamide trifluoroacetate salt

The procedure is as described in example 104, where 1-naphthylboronic acid is used in place of 4-tert-butylphenyl-boronic acid in preparation 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.074.628.416.78

Found value 58.924.717.26.34

Example 120: n- ((4aS, R) - {3- [2- (2-naphthyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } benzenesulfonamide trifluoroacetate salt

The procedure was as described in example 104, substituting 2-naphthalene boronic acid for 4-tert-butylphenyl boronic acid in preparation example 45.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.424.657.486.85

Found value 59.574.767.236.83

Example 121：N¹- ((4aS, R) - {3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- [ (2-phenoxyethyl) amino]-1, 3-benzene-disulfonamide trifluoroacetate

The procedure is as described in example 1, step A, replacing 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide with 4- [ (2-phenoxyethyl) amino ] -1, 3-benzene-disulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.564.337.236.62

Found value 53.954.387.216.28

Example 122: n- ((4aS, R) - {3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [3- (2-oxo-1-azepanyl) propyl]Amino } benzenesulfonamide bistrifluoroacetate salt

The procedure was as described in example 1, step A, substituting 3-nitro-4- { [3- (2-oxo-1-azepanyl) propyl ] amino } benzenesulfonamide for 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Example 123: n- { (4aS, R) - [3- ([1, 1' -Biphenyl)]-2-ylmethyl) -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α]Quinolin-8-yl]Carbonyl } -6-chloro-2-[2- (Phenylthio) ethyl group]-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide trifluoroacetate salt

The procedure is as described in example 4, step A, where 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced with 6-chloro-2- [2- (phenylsulfanyl) ethyl ] -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 53.824.267.159.82

Found value 53.524.207.109.86

Example 124: n- ((4aS, R) - {3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- (2-phenoxyethyl) -4H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide trifluoroacetate salt

The procedure is as described in example 1, step A, replacing 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide with 4- (2-phenoxyethyl) -4H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 55.864.237.506.87

Found value 55.014.307.236.76

Example 125: n- { (4aS, R) - [3- (2-benzylbenzyl) -2,3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ] pyrazine]Quinolin-8-yl]Carbonyl } -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl group]Propyl } amino) -3-nitrobenzenesulfonamide hydrochloride

The procedure was as described in example 5, step A, substituting 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide for 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 60.595.889.427.19

Found value 60.505.889.436.59

Example 126: n- ((4aS, R) - {3- [2- (4-chlorobenzyl) benzyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } -benzenesulfonamide hydrochloride

The procedure is as described in example 5, step a, with the compound of preparation 46 replacing the compound of preparation 5.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 60.145.058.557.83

Found value 59.474.858.397.55

Example 127: n- ((4aS, R) - {3- [ 2-phenoxybenzyl)]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- { [2- (phenylsulfanyl) ethyl]Amino } -benzenesulfonamide hydrochloride

The procedure is as described in example 1, step A, where the compound of preparation 1 is replaced by the compound of preparation 47 and 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide is replaced by 3-nitro-4- { [2- (phenylsulfanyl) ethyl ] amino } benzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 61.105.138.918.16

Found value 61.464.968.927.83

Example 128: n- ((4aS, R) - {3- [ 2-phenoxybenzyl)]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -3-nitro-4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) dihydrochloride

The procedure is as described in example 1, step a, wherein the compound of preparation 1 is replaced by the compound of preparation 47.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 59.125.649.407.17

Found value 59.305.349.347.23

Example 129: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- { [ (3R) -3-amino-4- (phenylsulfanyl) butyl]Amino } -3-nitrobenzenesulfonamide tris (trifluoroacetate salt)

The procedure is as described in example 20, 4- { [ (3R) -3-amino-4- (phenylsulfanyl) butyl ] amino } -3-nitrobenzenesulfonamide being used instead of 4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

Elemental microanalysis

％C ％H ％N ％S

Calculated value 49.984.027.295.56

Found value 48.893.996.925.24

Example 130: n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl)]-2-yl) methyl]-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-alpha ]]Quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl]Propyl } amino) -3-nitrobenzenesulfonamide sodium salt

This compound was obtained starting from the di (hydrochloride) salt solution described in example 20 by reacting it with three equivalents of NaOH.

Pharmacological study

Example A: induction of caspase activity in vitro

This study was performed in three human tumor cell lines:

-1 small cell lung cancer, H146

-1 acute myeloid leukemia, MV 4; 11,

-1 leukemia, RS 4; 11.

cell lines were incubated at 37 ℃ in 5% CO₂Culturing in an incubator in the presence of oxygen. H146 and RS 4; 11 cells were cultured in complete RPMI 1640 medium containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50. mu.g/ml streptomycin, and 10mM Hepes buffer (pH 7.4).

MV 4; 11 cells were cultured in similar medium supplemented with 5ng/ml GM-CSF.

Cells were distributed in 6-well plates and exposed to test compounds for 6 hours. The cells were then harvested and lysed and the caspase activity in the cell lysate was determined. This enzyme assay was performed by measuring the appearance of fluorescently generated cleavage products (Pharmacia, Inc.)

The results show that the compounds of the invention are potent apoptosis inducers, which were evaluated by measuring caspase 3 activity in three tumor cells tested.

For example, the activity of the compound of example 20 was 22000IU at 3 μ M in H146 cells, at MV 4; activity at 0.1 μ M in 11 cells is 20000IU, at RS 4; the activity in 11 cells at 1. mu.M was 23000 IU.

Example B: in vitro cytotoxicity

Cytotoxicity studies were performed in the three tumor cell lines of example a. Cells were distributed on microplates and exposed to test compounds for 48 hours. Cell viability was then quantified by colorimetric Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).

Result in IC₅₀(concentration of compound that inhibits 50% of cell viability) indicates that the compounds of the invention are cytotoxic.

For example, IC of the Compound of example 20 in H146₅₀Is 3.05X 10^-7M, at MV 4; IC in 11₅₀Is 2.95X 10^-8M, at RS 4; IC in 11₅₀Is 1.65X 10^-8M。

Example C: induction of caspase activity in vivo

The ability of the compounds of the invention to activate caspase 3 was evaluated on a xenograft model of H146 small cell lung cancer cells.

Will be 5X 10⁶Immunosuppressive mice (NOD SCID strain) were implanted subcutaneously with individual H146 cells. Test compounds in tween 80/water mixture were injected by intraperitoneal route 25 to 30 days after transplantation. At 16 hours after treatment, the tumor mass was withdrawn and dissolved and caspase 3 activity was measured in the tumor lysate.

The results obtained show that the compounds of the invention are capable of inducing apoptosis of the H146 tumor cell line in vivo.

For example, the compounds of example 20 and example 23 achieved greater than 700% activation compared to the control.

Example D: in vivo antitumor Activity

The antitumor activity of the compounds of the present invention was evaluated on a xenograft model of H146 small cell lung cancer cells.

Will be 5X 10⁶Individual H146 cells were subcutaneously implanted into immunosuppressed mice (NOD SCID strain). When the tumor mass has reached about 150mm 25 to 30 days after transplantation³On occasion, test compounds (in tween 80/water mixture) were injected intraperitoneally daily for a total of 21 days. Tumor mass was measured twice weekly, starting from treatment.

The results obtained demonstrate that the compounds of the invention are capable of inducing tumor regression during the treatment period.

For example, the compound of example 20, when administered at a dose of 100mg/kg, induces almost complete tumor regression during the treatment period, the effect lasting at least 40 days after the end of the treatment.

Example E: toxicity of blood platelets

BDF1 mouse blood was drawn into citrated tubes, diluted in PBS and cultured in the presence of different concentrations of test product. After 4 hours of incubation at 37 ℃, 20 μ l fluorescent spheres (1036 spheres/. mu.l) were added to each sample. Platelets can be identified by morphological analysis by flow cytometry, and the absolute number of platelets per μ l of blood analyzed can be quantified by counting 200 fluorescent spheres. In parallel, the percentage of platelets in apoptosis can be determined by labeling with annexin V FITC and then analyzing by a cytometric instrument.

In studies for cancer indications, the compounds of the invention showed acceptable platelet toxicity.

Example F: the pharmaceutical composition comprises: tablet formulation

1000 tablets containing 5mg of N- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride) (example 20)

Was a

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Claims (22)

1. A compound of formula (I), enantiomers and diastereomers and addition salts of a pharmaceutically acceptable acid or base thereof:

wherein:

a represents a 5-, 6-or 7-membered aromatic or nonaromatic ring which may contain 1 or 2 heteroatoms selected from oxygen, sulphur and nitrogen, where for the nitrogen heteroatoms they are linear orBranched chain (C)₁-C₆) Alkyl substitution is possible, it being understood that the defined a ring cannot contain 2 sulfur atoms or 2 oxygen atoms and that one of the ring members may be a C ═ O group,

n and n ', which may be the same or different, represent 0, 1 or 2, where 0 < n + n' < 4,

◆R₃represents an aryl group or a heteroaryl group,

x represents a straight or branched alkylene chain having 1 to 6 carbon atoms, in which 1 or 2 carbon atoms may be replaced by an oxygen atom, a cycloalkylene group, an arylene group, a heteroarylene group, or SO₂The radical(s) is (are),

◆R₁and R₂One of the radicals represents a hydrogen atom and the other represents a group of formula (II):

wherein:

-Y represents C ═ O or CH₂The radical(s) is (are),

-R₅represents a hydrogen atom, in which case R₆Represents a hydrogen atom or-NR₇R′₇or-CH₂-NR₇R′₇Group, wherein R₇And R'₇Each of which may be the same or different, independently represents a hydrogen atom or a linear or branched (C) chain substituted by one or more groups₁-C₆) Alkyl groups: aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or-NR₁₀R′₁₀A group wherein:

^＊R₁₀and R'₁₀May be the same or different and is selected from hydrogen, straight or branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, aryl and heteroaryl, or

^＊R₁₀And R'₁₀Forming a saturated or unsaturated cyclic or bicyclic group, which may be replaced by a heteroatom selected from oxygen, nitrogen and sulfur, it being understood thatOne or more ring members may represent a C ═ O group or may be substituted as described in the definition of heterocycloalkyl below,

or R₅And R₆Together with the two carbon atoms bearing them, form an aromatic or non-aromatic ring containing 5 or 6 ring members, one nitrogen atom being in SO₂Para to the radical, the ring containing, in addition to the nitrogen atom, a further nitrogen atom and/or SO₂The radicals, the rings being defined by R as defined above₇The substitution of the group(s),

-R₄represents a halogen atom or NO₂、R₈、SO₂-R₉Straight or branched chain (C)₁-C₆) Alkyl or straight or branched chain (C)₁-C₆) Alkoxy radical, wherein R₈May have R as defined above₇Any of the meanings of (a), (b), (c), (d,

-R₉represents amino or linear or branched (C) optionally substituted by one or more halogen atoms₁-C₆) An alkyl group, a carboxyl group,

it should be understood that:

- "aryl" is understood to mean phenyl, naphthyl or biphenyl,

"heteroaryl" is understood to mean any monocyclic or bicyclic group having at least one aromatic moiety and containing from 5 to 10 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, such as, for example, the following groups: furan, thiophene, pyrrole, imidazoline, pyridine, quinoline, isoquinoline, chroman, indole, benzothiophene, benzofuran, 1, 3-benzodioxole and 2, 3-dihydro-1, 4-benzodioxin,

- "heterocycloalkyl" is understood to mean any monocyclic or bicyclic nonaromatic radical containing from 4 to 10 ring members which may contain from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen,

"cycloalkyl" is understood to mean any monocyclic or bicyclic nonaromatic radical containing from 4 to 10 ring members,

for aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups as defined, it is possible to substitute from 1 to 3 groups selected from: optionally substituted by hydroxy or ammoniaStraight-chain or branched (C) substituted by radicals₁-C₆) Alkyl, straight or branched (C)₁-C₆) Alkoxy, hydroxy, carboxy, formyl, nitro, cyano, amino, straight or branched polyhalogen (C)₁-C₆) An alkyl group, an alkoxycarbonyl group, and a halogen atom,

- "arylene", "heteroarylene" and "cycloalkylene" are understood to mean, respectively, an aryl, heteroaryl or cycloalkyl radical as defined above, inserted in place of a carbon atom of the alkylene chain.

2. A compound of formula (I), according to claim 1, wherein Y represents a C ═ O group, enantiomers and diastereomers thereof, and addition salts with a pharmaceutically acceptable acid or base.

3. A compound of formula (I) according to claim 1, wherein n and n' represent 1, its enantiomers and diastereomers and addition salts with a pharmaceutically acceptable acid or base.

4. A compound of formula (I) according to claim 1, wherein R is a salt with a pharmaceutically acceptable acid or base, its enantiomers and diastereomers₄Represents NO₂Or SO₂-CF₃A group.

5. A compound of formula (I) according to claim 1, wherein X-R are₃The radicals represent ([1, 1' -biphenyl) optionally substituted by one or more radicals selected from the group consisting of halogen, cyano, amino, aminomethyl and trifluoromethyl]-2-yl) methyl.

6. A compound of formula (I) according to claim 1, wherein R is a salt with a pharmaceutically acceptable acid or base, its enantiomers and diastereomers₅Represents a hydrogen atom.

7. According to claim 1A compound of formula (I), enantiomers and diastereomers and addition salts of a pharmaceutically acceptable acid or base thereof, wherein R is₇Represents 1- (N, N-dimethylamino) -4- (phenylsulfanyl) -butan-3-yl.

8. A compound of formula (I) according to claim 1, wherein R is a salt with a pharmaceutically acceptable acid or base, its enantiomers and diastereomers₇Represents 1- (NR)₁₀R′₁₀) -4- (phenylsulfanyl) -butan-3-yl, R₁₀And R'₁₀Forming a saturated or unsaturated cyclic or bicyclic group optionally replaced by a heteroatom selected from oxygen, nitrogen and sulphur.

9. A compound of formula (I) according to claim 1, wherein R ', the enantiomers and diastereomers thereof, and the addition salts with a pharmaceutically acceptable acid or base'₇Represents a hydrogen atom.

A compound of formula (I) and pharmaceutically acceptable acid or base addition salts thereof, wherein said compound is:

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (10 a. alpha.) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (10 a. beta) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (10 a. alpha.) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (10 a. alpha.) -2- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. ] indol-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide,

n- [ ((4aR) -3- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) -sulfonyl ] benzenesulfonamide,

n- [ ((10a β) -2- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl } -1, 2, 3, 4, 10, 10 a-hexahydropyrazino [1, 2-. alpha. -indol-8-yl) carbonyl ] -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) -sulfonyl ] benzenesulfonamide,

n- [ ((4aR) -3- { [4- (4-chlorophenyl) -3-pyridinyl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. ] quinolin-8-yl) carbonyl ] -4- ({ (1R) -2- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] ethyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4-amino-4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- [ ((4aR) -3- { [4- (aminomethyl) -4 '-chloro- [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide, the trihydrochloride,

n- [ ((4aR) -3- { [3 ' -fluoro-4 ' -chloro- [1, 1 ' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- [ ((4aR) -3- { [4 '- (trifluoromethyl) - [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- [ ((4aR) -3- { [4 '-cyano- [1, 1' -biphenyl ] -2-yl ] methyl } -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl) carbonyl ] -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [2- (1, 3-benzodioxol-5-yl) benzyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3- [ (trifluoromethyl) sulfonyl ] benzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (4-methyl-1-piperazinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-piperidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-pyrrolidinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (3, 6-dihydro-1 (2H) -pyridinyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (1-azepanyl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide,

n- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2-. alpha. -quinolin-8-yl } carbonyl) -4- ({ (1R) -3- ((1R, 5S) -3-azabicyclo [3.1.0] hex-ane-3-yl) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

11. A compound of formula (I) according to claim 1, wherein said compound is N- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide, and pharmaceutically acceptable acid or base addition salts thereof.

12. A compound of formula (I) according to claim 1, wherein said compound is N- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide bis (hydrochloride).

13. A compound of formula (I) according to claim 1, wherein said compound is sodium N- ({ (4aR) -3- [ (4 '-chloro- [1, 1' -biphenyl ] -2-yl) methyl ] -2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino [1, 2- α ] quinolin-8-yl } carbonyl) -4- ({ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl } amino) -3-nitrobenzenesulfonamide.

14. A process for the preparation of a compound of formula (I), characterized in that a compound of formula (III) is used as starting material:

wherein Y is as defined for formula (I) and Cy represents a fused tricyclic ring system of formula (IV):

wherein A, X, n' and R₃As defined in formula (I), a-Y-Cl group is attached at the a-or b-position of the defined tricyclic system,

condensing a compound of formula (III) with a compound of formula (V) in an alkaline medium in the presence or absence of a coupling agent, wherein R₄As defined in formula (I),

to give a compound of the formula (VI) in which Cy, Y and R₄As defined above, in the above-mentioned manner,

reacting a compound of formula (VI) with a compound of formula HNR₇R′₇By condensation of a compound of (1), wherein R₇And R'₇As defined in formula (I), a compound of formula (I/a), which is a particular case of the compound of formula (I), is obtained,

wherein Cy, Y, R₄、R₇And R'₇As defined above, in the above-mentioned manner,

the compound of formula (I/a) may be purified according to conventional separation techniques, the compound of formula (I/a) may be converted into a pharmaceutically acceptable acid or base addition salt thereof, if necessary, and the compound of formula (I/a) may be optionally separated into its isomers according to conventional separation techniques.

15. A process for the preparation of a compound of formula (I), characterized in that a compound of formula (III') is used as starting material:

wherein Y is as defined for formula (I) and Cy represents a fused tricyclic ring system of formula (IV):

a, X, R therein₃N and n' are as defined in formula (I), -the Y-OH group is attached at the a or b position of the defined tricyclic system,

condensing a compound of formula (III') with a compound of formula (VII) in an alkaline medium in the presence of a coupling agent, wherein R₄、R₅And R₆As defined in formula (I),

obtaining the compound of formula (I), which can be purified according to conventional separation techniques, converting the compound of formula (I) into a pharmaceutically acceptable acid or base addition salt thereof, if desired, and optionally separating the compound of formula (I) into its isomers according to conventional separation techniques.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable acid or base addition salt thereof and one or more pharmaceutically acceptable excipients.

17. A pharmaceutical composition according to claim 16 for the preparation of a medicament as a pro-apoptotic agent.

18. A pharmaceutical composition according to claim 16 for use in the manufacture of a medicament for the treatment of cancer.

19. A pharmaceutical composition according to claim 16 for use in the preparation of a medicament for the treatment of bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, follicular lymphoma, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer.

20. A compound of formula (I) according to any one of claims 1 to 13 in combination with an anti-cancer agent selected from gene poisons, mitotic inhibitors, antimetabolites, proteasome inhibitors and kinase inhibitors.

21. Use of a combination according to claim 20 in the manufacture of a medicament for the treatment of cancer.

22. Use of a compound of formula (I) according to any one of claims 1 to 13 in combination with radiotherapy in the treatment of cancer.