JP2002532501A - Quinoline derivatives - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel quinoline derivatives having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of CNS diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to novel quinoline derivatives, processes for their production, and pharmaceutical compositions containing them.

[0002] US Pat. No. 5,703,072 discloses bicyclic nonane and decane compounds having dopamine receptor affinity and are claimed to be useful in the treatment of schizophrenia. WO98 / 50358, WO98 / 50346, WO98 / 47
868, WO 98/47855 and WO 98/50343 all claim to have mixed 5-HT _1A , 5-HT _1B and 5-HT _1D receptor antagonist activity and are useful for treatment of various CNS diseases A series of novel compounds are disclosed. WO 97/36867 and WO 98/14433 both disclose a series of lactam derivatives that are claimed to be selective agonists or antagonists of one or both of the 5-HT _1A and 5-HT _1D receptors.

[0003] This time, structurally different classes of compounds have been identified as mixed 5-HT _1A , 5-H
It was divided showing a T _1B and _{5-HT 1D} receptor affinity. Such compounds are expected to be useful for treating and preventing various diseases. Therefore, the first
In an embodiment, the present invention provides a compound of formula (I):

Embedded image (I) [wherein, ^{R a} is selected from the group of formula (i) or (ii); the group of formula (i)

(Equation 1) (i) (where P¹Is phenyl, bicyclic aryl, C_3-6Cycloalkyl, oxygen, nitrogen
5- to 7-membered compound containing 1 to 3 heteroatoms selected from silicon and sulfur
An elementary ring or one to three hetero atoms selected from oxygen, nitrogen and sulfur
R is a bicyclic heterocycle containing¹Is halogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_1-6Al
Coxy, hydroxy, hydroxy C_1-6Alkyl, hydroxy C_1-6Arco
Kissi, C_1-6Alkoxy C_1-6Alkoxy, C_1-6Alkanoyl, NO₂ , CF₃, CN, SR⁹, SOR⁹, SO₂R⁹, SO₂NR¹⁰R¹¹, CO ₂ R¹⁰, CONR¹⁰R¹¹, CONR¹⁰(CH₂)_cCO₂R¹¹, (C
H₂)_cNR¹⁰R¹¹, (CH₂)_cCONR¹⁰R¹¹, (CH₂)_cNR ¹⁰ COR¹¹, (CH₂)_cCO₂C_1-6Alkyl, CO₂(CH₂)_cO
R¹⁰, NR¹⁰R¹¹, NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹¹ , CR¹⁰= NOR¹¹Or CNR¹⁰= NOR¹¹And R⁹, R¹⁰ And R¹¹Is independently hydrogen or C_1-6Alkyl and c is 1 to 4
A is 0, 1, 2 or 3);Group of formula (ii)

Embedded image (ii) wherein P ² and P ³ are independently a phenyl, bicyclic aryl, 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur;
Or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; A is a bond, O, S (O) _n (n is 0 to 2), carbonyl, CH ₂ or N
R ⁴ (R ⁴ is hydrogen or C _1-6 alkyl); R ¹ and R ² are independently the same as R ¹ in formula (i) as defined above; a and b are independently L represents the formula -YC (= O) -DG- or -C (= O) -DG- or -DG-C (= O
Wherein Y is NH, NR ⁵ and R ⁵ is C _1-6 alkyl, or Y is CH ₂ , O, CH ＝ CH or OCH ₂ ; D is nitrogen, carbon Or G when D is a nitrogen or CH group.
Is hydrogen or C _1-6 alkyl, or G together with R ^b1 is a group W
Forming a, W is _{^{(CR 16 R 17) t,}} t is 2, 3 or ^4, or ^{R 1 6} and ^{R 17} are independently hydrogen or _{C 1-6} alkyl, or W is (CR ¹⁶ R ¹⁷ ) _u- J, wherein u is 0, 1, 2, or 3, J is oxygen,
^{Sulfur, CR 16 = CR 17, CR} 16 = N, = CR 16 O, a = ^{CR 16} S or ⁼ CR 16 ^{-NR 17,} when J is oxygen or sulfur u is not 0; ^{R b1} Is hydrogen or, together with G, forms said group W; X is nitrogen, carbon or CH;

Embedded image Is a single bond when X is nitrogen or CH; a double bond when X is carbon; m represents 1, 2 or 3] or a salt thereof. provide.

A C _1-6 alkyl group, alone or as part of another group, may be straight-chain or branched. The term “halogen” as used herein, unless otherwise specified, is a group selected from fluorine, chlorine, bromine or iodine. Bicyclic aryl group represented by P ^1, P ² or P ³ may be obtained by partially saturated, preferably naphthyl. As used herein, the term naphthyl refers to naphth-1-yl and naphth-2-yl groups unless otherwise specified.

When R ^a is of formula (i) When P ¹ is C _3-6 cycloalkyl, preferred examples are cyclopentyl and cyclohexyl. When P ¹ is a 5- to 7-membered heterocycle, suitable examples include 5 such as thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidinyl, pyrazinyl and pyridyl. Or a 6-membered heteroaryl ring. Non-aromatic 5- to 7-membered heterocycles include pyrrolidinyl, piperidinyl or piperazinyl. When P ¹ is a bicyclic heterocycle, suitable examples are quinolinyl, isoquinolinyl, indolyl, benzofuryl,
Includes benzo-fused rings such as benzothienyl and benzo [1,3] dioxolyl. The heterocyclic and bicyclic groups may be attached to the remainder of the molecule via a carbon atom or, if present, via a suitable nitrogen atom. Preferably, P ¹ is phenyl, naphthyl, quinolyl, pyridyl or thienyl. If a is greater than 1, the groups R ¹ may be the same or different. Preferably, a is 0, 1 or 2. Preferred R ¹ groups are allogens (especially chlorine)
, C _1-6 alkyl groups (especially methyl), CN, CF ₃ or C _1-6 alkoxy groups (especially methoxy or ethoxy).

When R ^a is Formula (ii) When P ² and / or P ³ is a heterocyclic or bicyclic heterocyclic group, suitable examples include those mentioned above for P ¹ . Preferably, P ² is phenyl, naphthyl, pyridyl, thienyl or furyl. The preferred substituent configuration for the naphthyl group is 1,4, more preferably 1,5, ie, a naphth-1-yl group in which group A is attached at the 4- or 5-position. Preferably, R ³ is phenyl, pyridyl, thienyl, pyrazolyl or oxazolyl. When a and / or b is 2, the groups R ¹ and / or R ² may be the same or different, respectively. Preferred R ¹ and / or R ² groups include halogen (especially chlorine), C _1-6 alkyl groups (especially methyl), CN, CF ₃ or C _1-6 alkoxy groups (especially methoxy or ethoxy). . Preferably, A is a bond or oxygen, most preferably a bond. Preferably, L is the formula: a -Y-C (= O) -DG- or -C (= O) groups represented by -DG-, preferably, Y is NH or CH _2, preferably,
D is nitrogen, preferably G is a hydrogen atom, or together with R ^b1 forms a further group W, preferably W is (CH ₂ ) ₂ , (CH ₂ ) ₃ or CH ＣＨCH, most preferably (CH ₂ ) ₂ . Preferably, R ^b1 is hydrogen or, together with G, forms said group W. Preferably, X is a nitrogen atom, preferably, m is 1 or 2, most preferably 1.

Particularly preferred compounds of the present invention are: (S)-(-)-N- [4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinolin-6-yl]-
3,4-dichlorobenzamide, (S)-(-)-N- [4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinolin-6-yl]-
3,4-dichlorobenzamide, (S)-(-)-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylcarbonyl] -8- (octa Hydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-6- [5- (5-methylpyridin-2-yl) naphtho- 1-oilamino] -4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline, (S)-(-)-6- (2,3-dichlorobenzoylamino] -4- ( Octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline, (S)-(-)-1- (2,3-dichlorobenzoyl) -2,3-dihydro-8- (octahydropyrrolo [ 1,
2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) naphtho -1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (5 -Methylpyridin-2-yl) naphth-1-oil] -8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline trifluoroacetate, (S)-(-)-2,3-dihydro-1- [5- ( 2,5-dimethylpyridin-4-yl) naphth-1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (6 -Methylpyridin-2-yl) naphth-1-oil] -8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-8- (octahydropyrrolo [1,2 -a] pyrazin-2-yl) -1- (quinolin-4-ylcarbonyl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- ( 2-methyloxazol-5-yl) naphth-1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (3 -Methylisoxazol-5-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline,
(S)-(-)-1- [5- (6-methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-1- (4-chlorobenzoyl) -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3 -g] quinoline, (S)-(-)-2,3-dihydro-1- [2- (4-chlorophenyl) -3-trifluoromethylpyrazole-4-carbonyl] -8- (octahydropyrrolo [1 , 2-a] pyrazin-2-yl) pyrrolo [2,
3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (2-methyl-5-trifluoromethylpyrazol-3-yl) -thiophen-2-carbonyl] -8 -(Octahydropyrrolo [1,2-a] pyrazin-2-yl
) Pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- (5-chlorothiophen-2-carbonyl) -8- (octahydropyrrolo [1,2-a ] Pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [1-methyl-7- (2-methylpyridin-6-yl) Indole-3
-Carbonyl] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [ 5- (5-methyloxazol-2-yl) naphth-1-ylacetyl] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S )-(-)-2,3-Dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -8- (octahydropyrrolo [1,2-a ] Pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline or a pharmaceutically acceptable salt thereof.

[0008] Other preferred compounds of the invention are E6-E9, E25-E72 and E75-E
80 (shown later in the table) or their pharmaceutically acceptable salts. A particularly preferred compound of the invention is E23. Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate and p-toluenesulfonate. And acid addition salts. Certain compounds of formula (I) may exist as stereoisomers. The present invention relates to a compound of the formula (I)
Those skilled in the art will understand that they encompass all geometric and optical isomers and mixtures of isomers, including racemates, of the compounds of

[0009] The compounds of the invention can be prepared using methods known in the art. In a further aspect, the present invention provides a process for preparing a compound of formula (I) comprising the following process: (a) L is -C (= O) -DG- or -DG- (C = O)- In some cases, the expression (
II): A compound represented by R ^a -L ¹ (II) is converted to a compound represented by the formula (III):

Embedded image (III) wherein R ^a , R ^b1 , X and m are the same as defined in formula (I), and L ¹ and L ² are a suitable function capable of reacting together to form an L moiety Or (b) when L is -Y-C (= O) -DG, D is nitrogen and Y is NH, the formula (IV): R ^a —NC (＝ O) (IV) wherein R ^a is the same as defined in formula (I) or a protected derivative thereof.

Embedded image (V) wherein R ^b1 , X, m and G are the same as defined in formula (I) or are protected derivatives thereof; or (c) L is -Y-C (= O) -DG- , D is nitrogen, Y is NH or NR ^5, wherein ^(VI): R a -NH ₂ or ^R a ^-NR 5 H ( VI) reacting a compound of the formula (V) with a compound of the formula (V) together with a suitable urea generator, wherein R ^a and R ⁵ are as defined in the formula (I); There is a -Y-C (= O) -DG , D is nitrogen, Y is CH ₂ or O, wherein ^{(VII): R a -Y- (} C = O) -L 3 (VII ) in [wherein, ^{R a} is as defined in formula (I), ^{L 3} is a suitable leaving group (E) when L is -YC (= O) -DG, D is CH and Y is NH, _{^{VI): R a -NH 2 (}} VI) [ wherein, ^{R a} is as defined in formula (I)] with a compound of formula (VIII):

Embedded image (VIII) [wherein D, G, R^b1, X and m are the same as defined in formula (I), ³ Is a suitable leaving group]; and the following steps:-removing the protecting group-obtaining a pharmaceutically acceptable salt.

In the reaction of compounds of formulas (II) and (III), suitable examples of groups L ¹ and L ² include: L ¹ is COL ^a and L ² is NH ₂ L ¹ There is NH _{2, L 2} is here COL ^a, a ^{L a} suitable leaving group. Suitably, ^one of L ¹ and L ² is an activated carboxylic acid derivative, such as an acyl chloride or an acid anhydride, and the other is an amine group. Formulas (II) and (I)
The activated compounds of II) can also be prepared by reacting the corresponding carboxylic acids with a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylhistolyl azide. Preferably, ^{L 1} or ^{L 2} is a group COL ^{a, L a} is halo, in particular chloro. Typically, in an inert solvent such as dimethylformamide, tetrahydrofuran or dichloromethane, in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine at ambient or elevated temperature, the compounds of formulas (II) and (III) ) Are reacted together.

In process (b), the reaction is conveniently carried out in an organic solvent such as dichloromethane. In process (c), the urea-forming agent may be carbonyldiimidazole, triphosgene or phosgene, at ambient temperature or in an inert solvent such as dimethylformamide, tetrahydrofuran or dichloromethane in the presence of a base such as triethylamine or pyridine. Perform the reaction by warming. In process (d), the leaving group L ³ is a halogen, for example a chloro group;
The reaction may be carried out in an organic solvent such as tetrahydrofuran or dichloromethane in the presence of a base such as triethylamine or pyridine at ambient or elevated temperature. In process (e), the leaving group L ³ is a halogen, for example a chloro group,
The reaction may be carried out in an organic solvent such as tetrahydrofuran or dichloromethane in the presence of a base such as triethylamine or pyridine at ambient or elevated temperature.

The intermediate compounds of formulas (II) to (VIII) are commercially available and may be obtained according to literature methods or by analogous methods to those described in the literature. Those skilled in the art will appreciate that certain reactive substituents need to be protected during the above process. Standard protection and deprotection methods can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional methods well known in the art. Carboxylic acids can be protected as esters. Aldehyde or ketone groups can be protected as acetal, ketal, thioacetal or thioketal. Deprotection is performed using standard conditions.

[0013] The involvement of serotonin receptors in many pharmacological effects has been described by RA Glennon in "
Serotonin Receptors: Clinical Implications ", Neuroscience and Behavior
l Reviews, 1990, 14 , 35 and by LOWilkinson and CT Dourish in "Seroto
nin Receptor Subtypes: Basic and Clinical Aspects "S. Peroutka Ed., Jo
hn Wiley and Sons, New York, 1991 p.147. Serotonin (5-hydroxytryptamine; 5-HT) receptors are depressants, mood disorders including seasonal affective disorder and dysthymia, general anxiety, panic disorder, phobia, social phobia, obsessive-compulsive Anxiety disorders, including idiopathic disorders and posttraumatic stress disorders, dementia, memory disorders, including memory loss disorders associated with aging, and eating disorders, including anorexia nervosa and bulimia nervosa. Disturbance of eating behavior,
Includes sleep disorders (including disruption of diurnal rhythms), Parkinson's disease, dementia in Parkinson's disease, motor disorders such as neuroleptic-induced Parkinson's disease and tardive ataxia, and other psychiatric disorders Involved in many pharmacological effects. Serotonin receptor ligands have been shown to be useful in treating nausea and vomiting, including hyperlactinemia, vasospasm (particularly in the cerebrovascular system),
It can also be used in endocrine disorders such as cerebellar ataxia and hypertension, and in diseases of the gastrointestinal tract where motility and secretion are involved. They can also be used to treat sexual dysfunction and hypothermia.

[0014] Ligands with high affinity for the 5-HT ₁ receptor are well recognized as having a therapeutic effect on the above conditions. For example, WO95 / 31
988 refers to the use of a combination of a 5-HT _1A receptor antagonist and a 5-HT _1D receptor antagonist to treat diseases of the CNS (central nervous system), endocrine system and GI (gastrointestinal). K. Rasmussen (Annual Reports in Me
dicinal Chemistry, (1995) 30, 1) states that there are 5-5-
The utility of HT1A receptor agonists and incomplete agonists has been described.
P. Trouillas (Progress in Brain Research, CI de Zeeuw, P. Stara and J.
Voogd, Eds. 1997, 144 , 589 and G. Maura (J. Neurochemistry, 1996, 66 ,
202) is a 5-HT _1A receptor selective agonist ligand or 5-HT _1A receptor.
It has been proposed to provide an effective treatment of cerebellar ataxia in humans by administration of agonist ligands selective for both the HT _1A and 5-HT _1D receptors.

The present invention also provides a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in treating the above diseases. In a further aspect, the present invention provides a method for treating a disease, comprising administering to a patient in need of treatment for the disease an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof. A method of treatment is provided. In particular, the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of depression.

The affinity of the compounds of the invention for the 5-HT _1A , 5-HT _1B and 5-HT _1D receptors can be determined according to the radioligand binding assay described below. HEK29 expressing 5-HT _1A receptor (4 × 10 ⁷ cells / ml)
Homogenize the 3 cells in Tris buffer, aliquot into 1 ml and save. 5
CHO cells expressing HT _1B receptor (4 × 10 ⁷ cells / ml) are homogenized in Tris buffer, aliquoted into 1.5 ml and stored. CHO cells expressing the 5-HT _1D receptor (0.563 × 10 ⁸ cells / ml) are homogenized in Tris buffer, aliquoted into 1 ml, and stored. 0.4 ml of the cell suspension is treated with the test agent as well as [ ³ H] -5-HT (4 nM) in the case of the 5-HT _{1B / 1D} receptor.
In addition, in the case of the 5-HT _1A receptor, [ ³ H] -8-OH-DPAT (1n
M) with Tris Mg HCl buffer (pH 7.7)
Incubate at 7 ° C for 45 minutes. Each test drug was prepared at 10 concentrations (0.01 m
M to 0.3 nM) and non-specific binding is determined using 0.01 mM 5-HT. The assay volume is 0.5 ml in total. Packard Filtermate (
The incubation is stopped by rapid filtration using 0.3% polyethyleneimine (pre-soaked filter) and the radioactivity is measured by Topcount scintillation counting. I obtained by the least squares curve fitting program
Calculating a pKi value from C _50.

The intrinsic activity of the compound of the present invention can be determined according to the following method. Hi
To 5-HT_1AHEK293 cell membrane stably expressing the receptor and human 5-HT _1B A CHO cell membrane stably expressing a receptor is converted into a HEPES / EDTA buffer.
And homogenize in aliquots and store in 1 ml aliquots, essentially Lazareno et al. (Life
 Sci., 1993, 52, 449), but with a slight modification of this method [
[35S] GTPγS binding test is performed. MgCl₂(3 mM), NaCl (100
mM), 20 mM HEP in the presence of GDP (10 μM) and ascorbic acid.
In ES buffer (pH 7.4), 10⁶Compounds from membranes obtained from individual cells
With (or without compound) for 30 minutes at 30 ° C
. 10 μl of [³⁵S] Addition of GTPγS (assay concentration 100 pM)
To start the reaction, followed by further incubation at 30 ° C. for 30 minutes.
Unlabeled GTPγS (20 μM) added prior to membrane addition
To determine non-specific binding. Quick filtration through Whatman GF / B grade filters
To stop the reaction, then add ice-cold HEPES (20 mM) / MgC
l₂Wash 5 times with 1 ml of (3 mM) buffer. Liquid scintillation spec
Radioactivity is measured by the torr measurement method. Hereafter, this procedure is referred to as [³⁵S] GTPγS
It is called a functional assay.

The compounds of formula (I) show a high affinity for the 5-HT _1A , 5-HT _1B and 5-HT _1D receptors. Using the [ ³⁵ S] GTPγS functional assay, certain compounds of formula (I) were found to exhibit varying levels of efficacy, and 1
. Defined by a scale ranging from 0 to 0. The difficulty in explaining the intrinsic activity of drugs acting on receptors coupled to G proteins has been recognized in the art (Hoyer and Boddeke, Trends in Pharmacological Sciences, Jul.
y 1993, [Vol.14], pages 270-275). However, we believe that this functional assay classifies these ligands and that the compounds of the invention are useful antidepressants in vivo. Preferred compounds of the invention are 5-
It exhibits HT _1A , 5-HT _1B and 5-HT _1D antagonist activity and believes that such compounds are rapidly acting. The rapid action is partly advantageous for antidepressants. By "rapid" onset is meant that a response is seen within 7 days of the first administration of the compound, as opposed to a period of about 21 days typical for SSRIs, tricyclic antidepressants and buspirone. I do.

Compounds of formula (I) having an intrinsic activity of 0.5 or less in the [ ³⁵ S] GTPγS functional assay are particularly preferred since they may be complete antagonists in vivo. As disclosed in WO 95/31988, concomitant antagonism of the presynaptic 5-HT _{1A / 1B / 1D} receptor increases the release of 5-HT in vivo, thereby improving 5-HT neurotransmission. There will be. Advantageously, the compounds of the present invention may be used in conjunction with one or more therapeutic agents, such as selective serotonin uptake inhibitor (SSRI) antidepressants.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical compositions of the present invention can be prepared by mixing, suitably at ambient temperature and atmospheric pressure, and are usually adapted for oral, parenteral or rectal administration, such as tablets, Capsules, oral liquid preparations, powders, granules, sweetened tablets, reconstitutable powders, injectable or infusible solutions or suspensions, or suppositories may be used. Generally, orally administrable compositions are preferred. Tablets and capsules for oral administration may be in unit dosage form and may contain binders, fillers, tableting lubricants, disintegrants, and acceptable wetting agents. Tablets may be coated by methods well known in normal pharmaceutical practice. Oral liquid formulations include, for example, aqueous or oily suspensions, solutions, emulsions,
It may be in the form of a syrup or elixir, or it may be in the form of a dry product for reconstitution with water or another suitable carrier before use. Such liquid preparations may contain suspending agents, emulsifying agents, non-aqueous carriers (including edible oils), preservatives, and if desired, conventional flavors or colorings. For parenteral administration, liquid unit dosage forms are prepared utilizing a compound of the present invention or pharmaceutically acceptable salt thereof and a sterile carrier. Depending on the carrier and concentration used,
The compound can be suspended or dissolved in a carrier. When preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents are dissolved in the carrier. To improve stability,
The composition can be frozen after being placed in a vial and the water removed under reduced pressure.
The parenteral suspension is prepared in substantially the same manner except that the compound is suspended in the carrier without dissolving it and sterilization is not performed by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile carrier. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. Depending on the method of administration, the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient. The dose of the compound used in the treatment of the above diseases will be varied in the usual way according to the severity of the disease, the weight of the patient and other similar factors. However, as a general guide, a suitable unit dose is 0.05 to 1000 mg, more suitably 1
. 0-200 mg, and such unit doses may be administered more than once a day, for example, two or three times a day. Such treatment may be continued for weeks or months.

The following Descriptions and Examples illustrate the preparation of the compounds of the present invention. Description Example 1 (S)-(-)-6-nitro-4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (D1) 4-chloro-6-nitroquinoline in toluene (D1) J. Org. Chem. 1944, 9, 302
) (750 mg, 3.69 mmole) was added to the stirred solution of (S)-(-
) -Octahydropyrrolo [1,2-a] pyrazine (J. Med. Chem., 1993, 36, 2).
311J. Med. Chem., 1993, 36, 2311) (500 mg, 3.97 mmole) and heated at reflux for 48 hours, then cooled, concentrated in vacuo and evaporated to dryness.
Silica gel chromatography (DCM / MeOH 19: 1) gave the title compound as a yellow oil (620 mg, 56%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.98 (d, 1H), 8.84 (d, 1H), 8.41 (dd,
1H), 8.14 (d, 1H), 6.98 (d, 1H), 3.74-3.56 (m, 2H), 3.26-3.17 (m, 3H), 2
.88 (t, 1H), 2.70 (td, 1H), 2.55-2.45 (m, 1H), 2.43-2.32 (m, 1H), 2.03-1
.80 (m, 3H), 1.65-1.51 (m, 1H). MS: m / z (MH) = 299.

Description Example 2 (S)-(−)-6-amino-4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (D2) EtOH (36 ml) and water (18 ml) (S)-(-)-6-nitro-4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (D
1600 mg, 2.01 mmole) was stirred with iron powder (0.72
g, 12.9 mmol) and NH ₄ Cl (86 mg, 1.6 mmole) and heated at reflux for 4 hours. After cooling, the mixture was filtered over diatomaceous earth, and the filtrate was concentrated under reduced pressure to dryness. The residue was taken up in DCM (50ml) and washed with water. The organic phase was dried (over MgSO ₄ ), filtered, and concentrated in vacuo to dryness to give the title compound as a yellow crystalline solid (300 mg, 56%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.50 (d, 1H), 7.90 (d, 1H), 7.14-7.10
(m, 2H), 6.82 (d, 1H), 3.99 (br.s, 2H), 3.65-3.50 (m, 2H), 3.22-3.17 (m
, 2H), 3.05 (td, 1H), 2.72 (t, 1H), 2.62 (td, 1H), 2.50-2.40 (m, 1H), 2.
40-2.29 (m, 1H), 2.01-1.80 (m, 3H), 1.62-1.47 (m, 1H). MS: m / z (MH) = 269.

Description Example 3 1-Benzyl-5-nitroindoline (D3) 5-Nitroindoline (50 g, 0.30 mol) in acetone (500 ml)
e) To the stirred solution of e), add anhydrous K ₂ CO ₃ (55.3 g 0.40 mole)
Was added, and benzyl bromide (42 ml, 0.35 mole) was added dropwise over 45 minutes. The mixture was stirred at room temperature for 24 hours. Further, benzyl bromide (10.0
ml, 0.08 mole) and K ₂ CO ₃ (12.0 g, 0.09 mole)
Was added and the mixture was heated at reflux for 3 days. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure to give a dark red oil. Trituration with hexane gave the title compound as an orange crystalline solid (79.0 g, 100%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.05 (d, 1H), 7.91 (s, 1H), 7.40-7.25
(m, 5H), 6.35 (d, 1H), 4.35 (s, 2H), 3.63 (t, 2H), 3.09 (t, 2H) .MS: m /
z (MH) = 255.

Description 4 5-Amino-1-benzylindoline (D4) 1-benzyl-5-nitroindoline (D3,2) in MeOH (400 ml)
0.0g, 0.08 mole), tin (II) chloride (60.0 g, 0.32 mole)
le) and concentrated hydrochloric acid (40 ml) were heated at reflux for 16 hours. After cooling, the mixture was evaporated under reduced pressure to give a red oil which was partitioned between DCM and water, made basic with 40% NaOH solution and the insoluble tin residue was removed by filtration. The filtrate was extracted with DCM (twice) and evaporated under reduced pressure to give the title compound as a dark green oil (10.5 g, 60%). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.41-7.23 (m, 5H), 6.58 (s, 1H), 6.45
(dd, 1H), 6.37 (d, 1H), 4.13 (s, 2H), 3.31 (br.s, 2H), 3.18 (t, 2H), 2.
87 (t, 2H). MS: m / z (MH) = 225.

Description 5 Diethyl (1-benzylindoline-5-ylamino) methylenemalonate (D5
) 5-Amino-1-benzylindoline (D4.1) in toluene (500 ml).
0.5 g, 0.05 mole) of diethyl ethoxymethylenemalonate (9
. 45 ml, 0.05 mole) and heated under argon under reflux for 1.5 hours. After cooling, the solvent was removed in vacuo to give a brown oil (19.6 g). Purification by silica gel chromatography, eluting with hexane: EtOAc (70:30), gave the title compound as a yellow crystalline solid (14.3 g, 77%).
). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.42 (d, 1H), 7.38-7.28 (m, 5H), 6.93
(s, 1H), 6.83 (dd, 1H), 6.44 (d, 2H), 4.33-4.17 (m, 6H), 3.36 (t, 2H), 2
.99 (t, 2H), 1.40-1.25 (m, 6H). MS: m / z (MH) = 395.

Description Example 6 1-benzyl-8-chloro-2,3-dihydropyrrolo [2,3-g] quinoline-
Ethyl 7-ylcarboxylate (D6) Diethyl (1-benzylindoline-5-ylamino) methylenemalonate (D5, 10.0 g, 25.3 mmole) in phosphorus oxychloride (40 ml) under argon under reflux 2. Heat for 5 hours. After cooling, the mixture was concentrated under reduced pressure and the residual oil was treated with 10% aqueous Na ₂ CO ₃ until basic. Extraction with DCM gave a red gum, which was purified using silica gel chromatography, eluting with hexane: EtOAc (70:30) to give the title compound as a yellow crystalline solid (6.3 g) , 68%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.81 (s, 1H), 7.69 (s, 1H), 7.40-7.27
(m, 5H), 7.02 (s, 1H), 4.51 (s, 2H), 4.46 (q, 2H), 3.59 (t, 2H), 3.24 (t
, 2H), 1.44 (t, 3H). MS: m / z (MH) = 367.

Description Example 7 (S)-(−)-1-benzyl-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g Ethyl quinoline-7-carboxylate (D7) Ethyl 1-benzyl-8-chloro-2,3-dihydropyrrolo [2,3-g] quinolin-7-ylcarboxylate (D6,4. 0 g, 10.
9 mmole) and a mixture of (S)-(-)-octahydropyrrolo [1,2-a] pyrazine (J. Med. Chem., 1993, 36, 2311) (6.0 g, 47.6 mmole). 20 ml) and the mixture is brought to 90 ° C. under argon.
For 40 hours. After cooling, DMF was removed under reduced pressure and EtOAc: MeOH (1
The residue was purified by silica gel chromatography, eluting with 9: 1) to give the title compound as a dark orange crystalline solid (4.5 g, 90%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.56 (s, 1H), 7.67 (s, 1H), 7.41-7.26
(m, 5H), 6.79 (s, 1H), 4.49-4.37 (m, 4H), 3.60 (t, 2H), 3.35-3.06 (m, 6H
), 2.99-2.89 (m, 2H), 2.26-2.09 (m, 2H), 1.86-1.64 (m, 4H), 1.43-1.37 (m
, 4H). MS: m / z (MH) = 457.

Description Example 8 (S)-(−)-1-benzyl-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g ] Quinolin-7-ylcarboxylic acid (D8) (S)-(-)-1-benzyl-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazine-2 in EtOH (36 ml) -Yl) pyrrolo [2,
3-g] ethyl quinoline-7-carboxylate (D7, 1.8 g, 4.1 mmole
) Was treated with a solution of NaOH (0.35 g, 8.8 mmole) in water (7 ml) and the mixture was heated at reflux for 16 hours. The EtOH was removed under reduced pressure and the residue was diluted with water and treated with 2M HCl solution to pH7. The water was removed under reduced pressure to give the title compound as a yellow solid (1.7g, 100%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.69 (s, 1H), 7.85 (s, 1H), 7.41-7.27 (
m, 5H), 6.50 (s, 1H), 4.47 (s, 2H), 4.10-3.78 (br.s, 2H), 3.70 (t, 2H),
3.66-3.28 (br.m, 3H), 3.27-3.03 (br.m, 3H), 2.85-2.38 (br.s, 3H), 2.1
3 (br.s, 1H), 1.97 (br.s, 1H), 1.86 (br.s, 2H). No acid protons were observed. MS: m / z (MH) = 427.

Description Example 9 (S)-(−)-1-benzyl-2,3-dihydro-8- (octahydropyrrolo
[1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D9) (S)-(−)-1-benzyl-2,3-dihih in Dowtherm A (200 ml)
Dro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [
2,3-g] quinolin-7-ylcarboxylic acid (D81.7 g, 4.0 mmole
) Was heated at reflux for 30 minutes. After cooling, the mixture was taken up in hexane (600 ml).
Poured and extracted with 2M HCl solution (3 times). Combine the acidic extracts and add K₂CO
₃And extracted with EtOAc (3 times). Organic extracts together
And dried (MgSO 4₄), Filter and concentrate under reduced pressure to give the title compound an orange
Obtained as an oil (1.4 g, 90%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.41 (d, 1H), 7.69 (s, 1H), 7.42-7.26 (
m, 5H), 6.75 (d, 1H), 6.63 (s, 1H), 4.40 (s, 2H), 3.59-3.47 (m, 3H), 3.3
6 (dd, 1H), 3.22-2.88 (m, 5H), 2.58 (t, 1H), 2.37 (dt, 1H), 2.24-2.17 (m
, 2H), 1.95-1.73 (m, 3H), 1.47-1.34 (m, 1H) .MS: m / z (MH) = 385.

Description Example 10 (S)-(−)-2,3-dihydro-8- (octahydropyrrolo [1,2-a]
(Pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D10) (S)-(-)-in EtOH (100 ml) and 2M HCl (4 ml).
A solution of 1-benzyl-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D9) was treated with 10% palladium on activated carbon. Was hydrogenated at 50 psi at room temperature for 32 hours.
The mixture was then filtered over diatomaceous earth and concentrated in vacuo. The residue was treated with DCM and 10
% Na ₂ CO ₃ is partitioned between an aqueous solution, the organic phase was separated, dried (MgSO ₄
) And concentrated in vacuo to dryness to give the title compound as an orange solid (0.6
6g, 62%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.45 (d, 1H), 7.72 (s, 1H), 6.98 (s, 1H
), 6.79 (d, 1H), 4.13 (br.s, 1H), 3.68 (t, 2H), 3.58 (dd, 1H), 3.47 (dd
, 1H), 3.25-3.15 (m, 3H), 2.99 (dt, 1H), 2.67-2.56 (m, 2H), 2.39-2.24 (m
, 2H), 1.97-1.45 (m, 5H). MS: m / z (MH) = 295.

Description 11 5-Carboxynaphth-1-ylboronic acid (D11) 5-bromo- in dry THF (1000 ml) at -60 ° C under argon.
1-Naphthoic acid (Bull. Soc. Chim. Fr., 1968, 7, 2957) (22.3 g, 0.089 mole)
To a stirred solution of 1.6 M n-butyllithium in hexane (125 m
1, 0.20 mole) was added dropwise. Upon addition of the first equivalent, the brown solution initially produced a beige precipitate, and upon addition of an additional equivalent, the precipitate dissolved. The resulting solution was stirred at −60 ° C. for 40 minutes, then triisopropyl borate (51 ml, 0.22 mole) was added and the mixture was further cooled at −60 ° C. for 1 more hour.
Stirred for an hour and then gradually warmed to -10 <0> C. NH ₄ Cl saturated aqueous solution (3
00 ml), then water (400 ml) and 5M HCl solution (2
00 ml) was added. The resulting mixture was concentrated in vacuo to a volume of about 1000 ml, then made basic by the addition of 40% aqueous NaOH and washed with EtOAc. The aqueous phase was added to an excess of 5M HCl solution and the precipitated solid was filtered off, washed with water and dried to give a white solid (9.67 g) containing about 50% of the title compound with 1-naphthoic acid. I got

Description 12 2,6-Dimethyl-4-iodopyridine (D12) 4-Chloro-2,6-dimethylpyridine (Ch) in 2-butanone (250 ml)
em. Abs. 1952, 46, 4541) (2.6 g, 18 mmole) was treated with sodium iodide (17.6 g, 120 mmole) and 4-toluenesulfonic acid (3.4 g, 18 mmole). The mixture was heated at reflux under argon for 72 hours. The reaction mixture was cooled then concentrated in vacuo and the residue was treated with water (200ml) and extracted with EtOAc. The extract was washed with aqueous sodium thiosulfate solution, then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a white solid, which was converted to its hydrochloride salt from acetone as a white solid (3.44 g, 69%). 1H NMR (free base) (250 MHz, CDCl3) δ (ppm): 7.37 (s, 2H), 2.46 (s, 6H)
MS: m / z (MH) = 234.

Description Example 13 5- (2,6-Dimethylpyridin-4-yl) -1-naphthoic acid (D13) Na₂CO₃1,2-Dimethate containing (2.27 g, 21.4 mmole)
2,6-Dimethyl-4-io in xyethane (60 ml) and water (15 ml)
Dopyridine (D12, 1.66 g, 7.1 mmole) and 5-carboxyna
Fut-1-ylboronic acid (D11, 1.54 g, 7.1 mmole)
Argon was passed through the stirred suspension of for 20 minutes. Tetrakis (Trifeni
(Phosphine) palladium (0) (0.41 g, 0.36 mmole) was added.
The mixture was heated at reflux under argon for 18 hours. 1,2-dimethoxy eta
The solvent was removed in vacuo and the residue was diluted with 2M NaOH solution and washed with EtOAc.
Acidify the aqueous phase to pH 1 with concentrated hydrochloric acid, wash with EtOAc, then add K₂CO ₃ And extracted with DCM (3 times). Combine the DCM extracts and dry.
(Na₂SO₄) And concentrated under reduced pressure to give the title compound as a white solid (1.3
8g, 70%). 1H NMR (250 MHz, d6DMSO) δ (ppm): 8.75 (d, 1H), 7.99 (dd, 1H), 7.80 (d,
 1H), 7.60-7.52 (m, 1H), 7.50-7.32 (m, 2H), 7.00 (s, 2H), 2.36 (s, 6H). No acid protons observed. MS: m / z (MH) = 276.

Description Example 14 5- (2,6-Dimethylpyridin-4-yl) -1-naphthoyl chloride (D14) 5- (2,6-Dimethylpyridin-4-yl) -1 in DCM (10 ml). −
A suspension of naphthoic acid (D13, 200 mg, 0.72 mmole) was treated with oxalyl chloride (0.13 ml, 1.49 mmole) and stirred at room temperature for 16 hours.
It was then concentrated in vacuo to dryness to give the title compound as a cream solid, which was used directly in the next step.

Description 15 5- (2,6-Dimethylpyridin-4-yl) naphth-1-ylisocyanate (D15) 5- (2,6-Dimethylpyridin-4-yl)-in DCM (10 ml) 1-
A suspension of naphthoic acid (D13, 250 mg, 0.91 mmole) was treated with oxalyl chloride (0.16 ml, 1.81 mmole) and stirred at room temperature for 18 hours.
Then, it was concentrated under reduced pressure to dryness. The residue was dissolved in DCM (20 ml) and ice-cold N
Shake quickly with aHCO ₃ saturated aqueous solution (10 ml). The organic phase was immediately separated and, at 5 ° C., sodium azide (111 mg, 1.10 g) in water (10 ml).
71 mmole) and a stirred solution of tetrabutylammonium iodide (22 mg). Shake the mixture vigorously for 1.5 hours at 0-5 ° C.
It was then diluted with water (10 ml), the DCM layer separated, dried (Na ₂ SO ₄ ) and carefully concentrated under reduced pressure at room temperature to a volume of about 10 ml. The solution was then treated with toluene (10 ml) and heated at reflux under argon for 1.5 hours. The reaction mixture was allowed to cool and the isocyanate solution was used directly for the next step.

Description Example 16 5- (5-Methylpyridin-2-yl) -1-naphthoic acid (D16) Using a procedure similar to that of Description Example 13, 2-iodo-5-methylpyridine and 5
-Carboxynaphth-1-ylboronic acid (D11) gave the title compound as a beige solid (64%). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 13.3 (br s, 1H), 8.94 (d, 1H), 8.55 (s
, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.89 7.70 (m, 2H), 7.707.50 (m, 2H),
7.45 (d, 1H), 2.60 (s, 3H).

Description Example 17 5- (6-Methylpyridin-2-yl) -1-naphthoic acid (D17) Using a procedure similar to that of Description Example 13, 2-bromo-6-methylpyridine and 5
-The title compound was obtained as a beige solid from -carboxynaphth-1-ylboronic acid (D11) (46%). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 8.90 (d, 1H), 8.13 (d, 1H), 8.06 (dd,
1H), 7.84 (t, 1H), 7.67 (t, 1H), 7.62-7.46 (m, 2H), 7.41 (d, 1H), 7.32 (
d, 1H), 2.55 (s, 3H). No acid protons were observed.

Description Example 18 4-Bromo-N-propargyl-1-naphthylcarboxamide (D18) 4-Bromo-1-naphthoic acid (J. Chem. Soc. 1958) in DCM (180 ml).
, 1426) (3.30 g, 13 mmole) was treated with oxalyl chloride (3.4 ml, 39 mmole). After 5 hours, the mixture was concentrated in vacuo to dryness, the residue was dissolved in DCM (120 ml) and propargylamine (0.83 g, 15 mmole) and triethylamine (50 ml) in DCM (50 ml)
2 ml, 15 mmole) was added over a period of 30 minutes. The mixture was stirred at room temperature overnight, then 2M HCl solution (50 ml), 20% aqueous K ₂ CO ₃ (
2 × 50 ml), and washed sequentially with brine (50ml), dried _(Na 2 SO _4), concentrated under reduced pressure until dryness. The residue was triturated with _Et 2 O / n-hexane to give the title compound as a cream powder (2.62g, 70%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.30 (dd, 2H), 7.78 (d, 1H), 7.64 (m,
2H), 7.43 (d, 1H), 6.21 (s, 1H), 4.32 (q, 2H), 2.31 (t, 1H).

Description 19 1-Bromo-4- (5-methyloxazol-2-yl) naphthalene (D19) 4-Bromo-N-propargyl-1-naphthylcarboxamide (D18,2) in glacial acetic acid (40 ml). .60 g, 9.0 mmole) and mercury acetate (0.0
2 g, 0.06 mmole) of the stirred mixture was heated at reflux for 3 hours. The cooled mixture was concentrated in vacuo to dryness and the residue was taken up in EtOAc (100 ml)
And washed sequentially with 20% aqueous K ₂ CO ₃ ( ₂ × 25 ml), water (50 ml), and brine (25 ml), dried (over Na ₂ SO ₄ ) and concentrated in vacuo to dryness. The residue was purified by flash chromatography on silica gel eluting with DCM to give the title compound as a cream powder (2.03 g,
78%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.32 (m, 1H), 8.34 (m, 1H), 7.97 (d, 1
H), 7.83 (d, 1H), 7.65 (m, 2H), 6.99 (s, 1H), 2.46 (s, 3H).

Description Example 20 1-cyano-4- (5-methyloxazol-2-yl) naphthalene (D20) 1-bromo-4- (5-methyloxazol-2-yl) naphthalene (D19)
, 2.00 g, 6.9 mmole), copper (I) cyanide (1.11 g, 12.4).
mmole) and N-methylpyrrolidinone (20 ml) under argon for 16 hours.
Stir at 0 ° C. for 3 hours. The cooled mixture was combined with water (200 ml) and EtOAc (
150 ml) and the resulting suspension was added to KCN (2.00 g, 30 mmole).
) Was added. After stirring at room temperature for 1.5 hours, the layers were separated and the aqueous layer was extracted with EtOAc (2 ×
50 ml). The combined organic extracts were washed with water, dried (Na₂SO ₄ ) And concentrated under reduced pressure to dryness. The residue was triturated in EtOAc / n-hexane
To give the title compound as a pale colored fluffy solid (1.24 g, 76%
). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.46 (q, 1H), 8.31 (q, 1H), 8.18 (d, 1
H), 7.96 (d, 1H), 7.77 (q, 2H), 7.03 (s, 1H), 2.49 (s, 3H).

Description 21 4- (5-Methyloxazol-2-yl) -1-naphthoic acid (D21) 1-cyano-4- (5-methyloxazol-2-yl) naphthalene (D20)
, 1.00 g, 4.0 mmole), KOH (2.24 g, 40.0 mmole)
), PrOH (70 ml) and water (10 ml) were stirred at reflux for 48 hours. The colored mixture was concentrated in vacuo to dryness and the residue was partitioned between EtOAc (50ml) and water (70ml). After stirring for 15 minutes, the mixture was filtered, the aqueous layer was separated,
Wash with EtOAc (25 ml), acidify with 5M HCl solution, pH 1
And The precipitate was collected, washed with water and dried under reduced pressure to give the title compound as a colorless solid (
0.64 g, 59%). 1H NMR (250 MHz, d6-DMSO) δ (ppm): 13.46 (s, 1H), 9.39 (m, 1H), 8.91 (m
, 1H), 8.20 (s, 2H), 7.75 (m, 2H), 7.22 (s, 1H), 2.47 (s, 3H).

Description Example 22 5- (2,5-Dimethylpyridin-4-yl) -1-naphthoic acid (D22) Using a procedure similar to that of Description Example 13, 4-bromo-2,5-dimethylpyridine and The title compound was obtained from 5-carboxynaphth-1-ylboronic acid (D11) as a white solid (47%). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 13.3 (br s, 1H), 8.90 (d, 1H), 8.45 (s
, 1H), 8.17-8.10 (m, 1H), 7.75-7.66 (m, 1H), 7.57-7.47 (m, 2H), 7.41 (d, 1H), 7.12 (s, 1H), 2.50 (s, 3H ), 1.86 (s, 3H).

Description Example 23 5- (3-Methylpyridin-2-yl) -1-naphthoic acid (D23) Using a procedure similar to that of Description Example 13, 2-bromo-3-methylpyridine and 5
-The title compound was obtained as a beige solid from carboxynaphth-1-ylboronic acid (D11) (46%) ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 8.92 (d, 1H), 8.56 (dd, 1H), 8.15 (dd,
1H), 7.83 (d, 1H), 7.74 (dd, 1H), 7.55-7.40 (m, 4H), 2.00 (s, 3H). No acid protons were observed.

Description 24 24-Bromo-N-propargyl-1-naphthylcarboxamide (D24) Using a procedure similar to that described in Description 18, 5-bromo-1-naphthoic acid (Bull. Soc.
Chim. Fr., 1968, 7, 2957) to give the title compound as a light yellow solid (5.
48 g, 70%). 1H NMR (250 MHz, CDCl3) δ (ppm) 8.35 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H
), 7.66 (d, 1H), 7.58 (t, 1H), 7.38 (t, 1H), 6.24 (s, 1H), 4.33 (q, 2H),
2.31 (t, 1H).

Description 25 25-Bromo-5- (5-methyloxazol-2-yl) naphthalene (D25) (D24, 5.45 g, 18.9 mmole) gave the title compound as a light yellow solid (2.80 g, 50%). 1H NMR (250 MHz; CDCl3) δ (ppm): 9.30 (d, 1H), 8.38 (d, 1H), 8.18 (d, 1
H), 7.84 (d, 1H), 7.64 (t, 1H), 7.45 (t, 1H), 6.99 (s, 1H), 2.46 (s, 3H)

Description Example 26 Diethyl 5- (2-methyloxazol-2-yl) -1-naphthylmalonate (
D26) Diethyl malonate (3.42 g, 21.4 m) in dry dioxane (100 ml)
sodium hydride (0.86 g, 60% in oil)
(Dispersion) was added dropwise. After 15 minutes, copper (I) bromide (3.07 g, 21.4)
mmole) and 1-bromo-5- (5-methyloxazol-2-yl) naphthalene (D25, 3.09 g, 10.7 mmole) were added sequentially. The mixture was then heated at reflux under argon for 8 hours. The cooled mixture was filtered through celite (diatomaceous earth), concentrated in vacuo to dryness. The residue was treated with EtOAc (100
ml), washed sequentially with 2M HCl solution (2 × 30 ml), water (30 ml), and brine (30 ml), dried (over Na ₂ SO ₄ ), and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with DCM-MeOH (0-2% MeOH gradient elution) to give the title compound as a yellow oil (1.70 g, 43%). 1H NMR (250 MHz, d6DMSO) δ (ppm): 9.28 (d, 1H), 8.18 (m, 2H), 7.70 (m,
2H), 7.55 (dd, 1H), 7.16 (s, 1H), 4.26-4.07 (m, 5H), 2.45 (s, 3H), 1.17
(t, 6H).

Description Example 27 5- (5-Methyloxazol-2-yl) -1-naphthylacetic acid (D27) Diethyl 5- (2-methyloxazol-2-yl) -1-naphthylmalonate (D26,1. 70 g, 4.6 mmol), glacial acetic acid (10 ml) and concentrated hydrochloric acid (
10 ml) was refluxed and stirred for 7 hours. The cooled mixture was concentrated in vacuo to dryness, the residue was triturated in water (25 ml), the solid was filtered off and dried in vacuo to give the title compound as a pale gray powder (0.90 g, 73%). . 1H NMR (250 MHz, d6 DMSO) δ (ppm): 9.06 (d, 1H), 8.02 (d, 2H), 7.58-7
.40 (m, 3H), 7.02 (s, 1H), 4.03 (s, 2H), 2.33 (s, 3H). No acid protons were observed.

Description 28 Ethyl 5-bromo-1-naphthoate (D28) 5-Bromo-1-naphthoic acid (Bull. Soc. Chum.) In EtOH (150 ml).
Fr., 1968, 7, 2957) (10.0 g, 0.040 mole) was treated with concentrated sulfuric acid (7 ml) and heated at reflux for 24 hours. After cooling, E
The tOH was removed under reduced pressure and the residue was partitioned between EtOAc and 10% aqueous Na ₂ CO ₃ . The organic phase was separated, the aqueous phase was further extracted with EtOAc, the organic phases were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness to give the title compound as a white solid (10 .14 g, 91%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.88 (d, 1H), 8.49 (d, 1H), 8.20 (dd,
1H), 7.84 (dd, 1H), 7.61 (dd, 1H), 7.43 (dd, 1H), 4.48 (q, 2H), 1.46 (t,
3H).

Description 29 Ethyl 5-acetyl-1-naphthoate (D29) Ethyl 5-bromo-1-naphthoate in dry 1,4-dioxane (D28,8.
98 g, 32.2 mmole) and tributyl (1-ethoxyvinyl) tin (
A stirred solution of 13.9 g, 38.5 mmole) was degassed by bubbling argon through for 20 minutes. Bis (triphenylphosphine) palladium (I
I) Dichloride was added and the mixture was heated at reflux under argon for 18 hours.
After cooling, a 2M HCl solution (20 ml) and water (50 ml) were added, and the mixture was preferably stirred vigorously at room temperature for 4 hours. The mixture was then concentrated in vacuo and the residue was partitioned between water and EtOAc and filtered through diatomaceous earth to remove catalyst residues. The organic phase was separated, dried (over MgSO ₄ ) and concentrated in vacuo to dryness to give a light yellow crystalline solid which was broken up and washed thoroughly with 60-80 petrol to remove the tin residue. Removed, then filtered and dried in vacuo to give the title compound as a light yellow solid (5.31 g, 68%). ¹ H NMR (250 MHz, CDCl3) δ (ppm): 9.10 (d, 1H), 8.89 (d, 1H), 8.20 (dd, 1
H), 7.97 (dd, 1H), 7.66-7.57 (m, 2H), 4.48 (q, 2H), 2.76 (s, 3H), 1.47 (
t, 3H). MS: m / z (MH) = 243.

Description 30 Ethyl 5-bromoacetyl-1-naphthoate (D30) 5-Acetyl-1 in a mixture of DC (80 ml) and MeOH (40 ml)
-A stirred solution of ethyl naphthoate (D29, 4.80 g, 17.2 mmole) was added to benzyltrimethylammonium tribromide (7.38 g, 18.9 mm).
ole) and stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure to give the title compound as an orange-brown solid (5.52 g,
100%). ^{1 H NMR (250MHz, CDCl3)} δ (ppm): 9.16 (d, 1H), 8.75 (d, 1H), 8.23 (dd, 1
H), 7.95 (dd, 1H), 7.68-7.61 (m, 2H), 4.58 (s, 2H), 4.49 (q, 2H), 1.47 (
s, 3H).

Description Example 31 Ethyl 5-aminoacetyl-1-naphthoate hydrochloride (D31) Ethyl 5-bromoacetyl-1-naphthoate (D30, 3.50 g, 10.9)
mmole) was dissolved in DCM (40 ml) and cooled to ５5 ° C. in an ice bath.
This solution was treated with tetrabutylammonium iodide (0.20 g, 0.54 mmole).
) And sodium azide (1.06 g, 16.3 mmole) in water (8 ml)
And stirred vigorously for 3 hours while warming to room temperature. Water (30ml)
Was added, the organic phase was separated, dried (over Na ₂ SO ₄ ) and carefully concentrated in vacuo to about 40 ml (to remove residual DCM). This solution was added to EtOH (20
0 ml) and treated with concentrated hydrochloric acid (5 ml) at room temperature under pressure for 48 hours.
Hydrogenated with 10% palladium on activated carbon. The mixture was then filtered over diatomaceous earth, concentrated in vacuo to dryness to give the title compound as a white solid (2.26 g, 7
1%). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 8.98 (d, 1H), 8.84 (d, 1H), 8.45 (br s
, 3H), 8.32 (dd, 1H), 8.19 (dd, 1H), 7.86-7.77 (m, 2H), 4.70 (s, 2H), 4.
44 (q, 2H), 1.40 (t, 3H). MS: m / z (MH) = 258.

Description Example 32 Ethyl 5-acetamidoacetyl-1-naphthoate (D32) Ethyl 5-aminoacetyl-1-naphthoate hydrochloride (D31, 2.26 g, 7
. 70 mmole) were suspended in DCM (60 ml) with stirring, triethylamine (1.2 ml, 8.50 mmole) and acetic anhydride (0.86 g, 8.30 g).
5 mmole). After 18 hours, the mixture was concentrated in vacuo to dryness, and the residue was partitioned between EtOAc and 10% aqueous Na ₂ CO ₃ . The organic phase was separated, dried (Na ₂ SO ₄ ), concentrated in vacuo to dryness and EtOAc
Purification by silica gel chromatography, eluting with, gave the title compound as a white solid (1.73 g, 60%). ¹ H NMR (250 MHz, CDCl3) δ (ppm): 9.17 (d, 1H), 8.90 (d, 1H), 8.23 (dd, 1
H), 8.02 (dd, 1H), 7.69-7.62 (m, 2H), 6.57 (br s, 1H), 4.82 (d, 2H), 4.4
9 (q, 2H), 2.15 (s, 3H), 1.47 (t, 3H). MS: m / z (MH) = 300.

Description Example 33 Ethyl (2-methyloxazol-5-yl) -1-naphthoate (D33) Ethyl 5-acetamidoacetyl-1-naphthoate (D32, 1.71 g, 5
. 72 mmole) was coated with polyphosphoric acid (〜48 g) and the resulting viscous mixture was heated with stirring under argon. Upon reaching 140 ° C., the mixture was cooled incompletely and poured into a beaker with crushed ice (〜50 ml) with stirring.
Water (50 ml) was added and the solution was extracted with EtOAc. The organic phase was separated, dried (Na 2 _{SO 4),} dryness and concentrated under reduced pressure to give a pale yellow solid. This material was analyzed by ¹ H NMR for the title compound and 5- (2-methyloxazol-5-yl).
It was shown to be a mixture of -1-naphthoic acid.

Description Example 34 Ethyl 5- (2-methyloxazol-5-yl) -1-naphthoate (D34) Ethyl 5- (2-methyloxazol-5-yl) -1-naphthoate (D33)
, 5.72 mmole) in EtOH (30 ml) and 2M NaOH solution (
30 ml) and stirred at reflux for 1 hour. The mixture was cooled incompletely and the EtOH was removed under reduced pressure. The residue was washed with Et ₂ O and the aqueous layer was acidified to pH 1 with concentrated hydrochloric acid. This was then added to EtOAc (3 × 200 ml
) And the organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness to give the title compound as a light yellow solid (1.19 g, 82 in 2 steps).
%). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 8.89 (d, 1H), 8.49 (d, 1H), 8.18 (dd,
1H), 7.82 (dd, 1H), 7.76-7.66 (m, 2H), 7.55 (s, 1H), 2.56 (s, 3H). No acid protons observed. MS: m / z (MH) = 252 .

Description Example 35 Ethyl 5- (3-methylisoxazol-5-yl) -1-naphthoate (D3
5) Ethyl 5-bromo-1-naphthoate in dry dioxane (D28, 2.59 g,
A stirred solution of 9.3 mmole) and 3-methyl-5- (tributylstannyl) isoxazole (Tetrahedron, 1991, 47, 5111) was degassed by bubbling argon through for 20 minutes. Bis (triphenylphosphine) palladium (II) dichloride was added and the mixture was heated at reflux for 24 hours. After cooling, 1,4-dioxane was removed under reduced pressure and the residue was partitioned between water and DCM.
The organic phase was separated, dried (over MgSO ₄ ) and concentrated in vacuo to dryness to give an orange-brown oil. Purification by silica gel chromatography, eluting with 60-80 petrol: Et ₂ O (2: 1) gave the title compound as a cream solid (857 mg, 33%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.03 (d, 1H), 8.46 (d, 1H), 8.21 (dd,
1H), 7.80 (dd, 1H), 7.66 (dd, 1H), 7.58 (dd, 1H), 6.43 (s, 1H), 4.50 (q,
2H), 2.44 (s, 3H), 1.47 (t, 3H). MS: m / z (MH) = 282.

Description Example 36 5- (3-Methylisoxazol-5-yl) -1-naphthoic acid (D36) Using a procedure similar to that of Description Example 34, 5- (3-methylisoxazol-5-yl)
The title compound was obtained as a white solid (638 mg, 87%) from ethyl yl) -1-naphthoate (D35, 815 mg, 2.90 mmole). ¹ H NMR (250 MHz, d ⁶ DMSO) δ (ppm): 13.38 (br s, 1H), 9.00 (d, 1H), 8.40 (
d, 1H), 8.21 (dd, 1H), 7.90 (dd, 1H), 7.80-7.69 (m, 2H), 6.90 (s, 1H), 2
.38 (s, 3H). MS: m / z (MH) = 252.

Description Example 37 (S)-(−)-8- (Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D37) in MeOH (15 ml) (S)-(-)-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D10,588 mg, 2 mmole) Was added to PdCl ₂ (354 mg, 2
mmol) and _Et 3 N (280ml, was treated with 2 mmole), it was heated for 15 hours at reflux. The suspension was filtered over diatomaceous earth and washed thoroughly with MeOH. The pH of the combined methanol phases was brought to 10 with K ₂ CO ₃ , water and EtOAc
Distributed in between. The organic phase was washed with brine, dried over MgSO _4, filtered,
Concentration under reduced pressure to dryness gave a brown solid (150 mg, 26%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.68 (d, 1H), 8.39 (s, 1H), 8.03 (s, 1
H), 7.48 (dd, 1H), 6.81 (d, 1H), 6.73 (s, 1H), 3.73-3.58 (m, 2H), 3.21-3
.03 (m, 3H), 2.78-2.56 (m, 2H), 2.43-2.24 (m, 3H), 1.96-1.79 (m, 3H), 1.
55-1.46 (m, 1H). MS: m / z (MH) = 293.

Description Example 38 5- (6-Methylpyridin-2-yl) -1-naphthoyl chloride (D38) 5- (6-Methylpyridin-2-yl) -1-naphthoic acid (20 ml) in DCM ( D17, 180 mg, 0.68 mmole) in oxalyl chloride (
0.15 ml, 1.8 mmole), stirred at room temperature for 2 hours, then concentrated in vacuo to dryness to give the title compound as a cream solid, which was used directly in the next step.

Description 39 7-Bromo-3-trifluoroacetylindole (D39) 7-Bromoindole (2.0 g, 10.2 mmole) in DMF (8 ml)
) Was added to a stirred ice-cold solution of trifluoroacetic anhydride (1.74 ml, 12.2).
mmole) was treated dropwise. The solution was warmed to room temperature over 2 hours and then poured into saturated aqueous NaHCO ₃ . The title compound precipitates as a white solid,
This was filtered off, washed with water and dried in a vacuum oven at 50 ° C. (2.55 g, 96
%). MS: m / z (MH) = 290,292

Description 40 7-Bromoindole-3-carboxylic acid (D40) 7-bromo-3-trifluoroacetylindole (D39, 2.88 g, 9
. 8 mmole) in 20% aqueous NaOH (30 ml) and heated at reflux for 1 hour, then cooled, diluted with water (30 ml) and EtOAc (40 ml)
). The aqueous phase was separated and acidified to pH 1 with 5M aqueous HCl.
The title compound precipitated as a white solid, which was filtered off, washed with water and dried under reduced pressure (2
. 10 g, 89%). NS: m / z (M−H) = 238,240

Description 41 Methyl 7-bromo-1-methylindole-3-carboxylate (D41) 7-Bromoindole-3-carboxylic acid (D40) in acetone (100 ml)
, 2.0 g, 8.3 mmole) in K ₂ CO ₃ (2.4 g, 17.5 mm).
ole) and MeI (1.1 ml, 17.5 mmole) and heated at 50 ° C. for 40 hours under an argon atmosphere. The mixture was then cooled and the solid was filtered off and washed with acetone. The filtrate was concentrated in vacuo to dryness, the residue was re-taken in DCM and the filtrate was concentrated in vacuo to dryness to give the title compound as a light yellow solid (1.
95 g, 87%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.16 (dd, 1H), 7.72 (s, 1H), 7.41 (dd,
1H), 7.07 (dd, 1H), 4.20 (s, 3H), 3.90 (s, 3H). MS: m / z (MH) = 268, 270

Description 42 1-Methyl-7- (6-methylpyridin-2-yl) indole-3-carboxylic acid
Acid methyl ester (D42) 7-bromo-1-methylindole-3-car in anhydrous toluene (10 ml)
A stirred solution of methyl borate (D41,500 mg, 1.87 mmole)
The solution was treated with hexamethylditin (730 mg, 2.24 mmole)
Degassed by blowing air for 20 minutes. Pd (PPh₃) Add the mixture
Was heated under argon at 110 ° C. for 18 hours. The mixture is then cooled and
Filter through sodium chloride, wash with EtOAc, concentrate the filtrate under reduced pressure and remove
The intermediate was obtained as a light yellow oil. The oil is stirred with anhydrous D
Dissolve in MF (5 ml) and add CuI (35 mg, 0.19 mmole) and anhydrous
2-Bromo-6-methylpyridine (449 mg, 2.61) in DMF (5 ml).
mmole) and degassed by bubbling argon through. Pd (PPh ₃ ) Cl₂Was added and the mixture was heated at 110 ° C. under argon for 18 hours. mixture
The material was cooled incompletely and DMF was removed under reduced pressure. Et₂Silica gel eluted with O
Purify the residue by chromatography to give the title compound as a yellow oil
(159 mg, 30%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.25 (d, 1H), 7.72-7.66 (m, 2H), 7.37-
7.18 (m, 4H), 3.92 (s, 3H), 3.41 (s, 3H), 2.64 (s, 3H) .MS: m / z (MH) =
281.

Example 1 (S)-(−)-N- [4- (octahydropyrrolo [1,2-a] pyrazine-2
-Yl) quinolin-6-yl] -3,4-dichlorobenzamide (E1)

Embedded image (S)-(-)-6-amino-4- (octahydropyrrolo [1,2] in DCM
-A] pyrazin-2-yl) quinoline (D2, 70 mg, 0.26 mmole)
Solution of dichlorobenzoyl chloride (113 mg, 0.54 mmole) and D
Treated with MAP (1 mg, 8 mmole). After 15 hours, the solution was diluted with DCM and washed with a saturated aqueous solution of NaHCO ₃ . The organic phase is dried (over MgSO ₄ )
Filter and concentrate under reduced pressure to dryness. Silica gel chromatography (DCM / M
MeOH 93: 7) gave the title compound as a white glass, which was taken up in acetone, treated with dry ethereal HCl and concentrated to dryness to give the hydrochloride salt as a white powder (60 mg, 52). %). 1H NMR (free base) (400 MHz, CDCl3) δ (ppm): 9.45 (s, 1H), 8.68 (s, 1H),
8.58 (d, 1H), 8.00 (s, 1H), 7.91 (d, 1H), 7.72-7.66 (m, 2H), 7.41 (d, 1
H), 6.83 (d, 1H), 3.68 (br.d, 1H), 3.61 (br.d, 1H), 3.12-3.00 (m, 3H),
2.72 (t, 1H), 2.56 (td, 1H), 2.38-2.30 (m, 1H), 2.20-2.14 (m, 1H), 1.90
-1.80 (m, 2H), 1.75-1.65 (m, 1H), 1.51-1.40 (m, 1H). MS: m / z (MH) = 441.

Example 2 (S)-(−)-1-[(3,4-dichlorophenyl) carbonyl] -2,3-
Dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E2)

Embedded image (S)-(-)-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (4 ml) in DCM (
D10, 100 mg, 0.34 mmole) in pyridine (0.5 ml),
3,4-dichlorobenzoyl chloride (161 mg, 0.77 mmole) and D
Treated with MAP (1.5 mg, 12 mmole) and heated to reflux under argon. After 17 hours, the solution was cooled and washed with a 5% citric acid solution. The organic phase was dried (over MgSO ₄ ), filtered, and concentrated in vacuo to dryness. Silica gel chromatography (DCM / MeOH 19: 1) gave the title compound (44 mg).
, 28%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.85-8.75 (br.s, 1H), 8.63 (d, 1H), 7
.87 (s, 1H), 7.76 (s, 1H), 7.56 (d, 1H), 7.45 (dd, 1H), 6.83 (d, 1H), 4.
17 (br.s, 2H), 3.64 (br.s, 2H), 3.40-3.27 (m, 2H), 3.18-3.02 (m, 4H),
2.71 (br.s, 2H), 2.32 (br.d, 1H), 1.93-1.79 (m, 3H), 1.49 (br.s, 1H).
MS: m / z (MH) = 467.

Example 3 (S)-(−)-2,3-dihydro-1- [5- (2,6-dimethylpyridine-
4-yl) naphth-1-ylcarbonyl] -8- (octahydropyrrolo [1,2
-A] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E3)

Embedded image Using the same procedure as in Example 2, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 100 mg, 0.34 mmole) and 5- (2,6
-Dimethylpyridin-4-yl) naphthoyl (D14, 150 mg, 0.51 m
Mole) afforded the title compound as a cream solid (31 mg, 16%).
1H NMR (400 MHz, CDCl3) δ (ppm): 9.09 (s, 1H), 8.64 (d, 1H), 8.00 (d, 1H
), 7.94 (d, 1H), 7.86 (s, 1H), 7.64-7.54 (m, 3H), 7.45 (d, 1H), 7.11 (s,
2H), 6.88 (d, 1H), 3.97-3.69 (br.m, 3H), 3.46-3.22 (br.m, 3H), 3.19-3
.10 (br.m, 2H), 2.81-2.76 (br.m, 2H), 2.64 (s, 6H), 2.62-2.46 (br.m,
2H), 2.33-2.28 (m, 1H), 2.00-1.87 (br.m, 2H), 1.84-1.76 (br.m, 1H), 1.
58-1.50 (br.m, 1H). MS: m / z (MH) = 554.

Example 4 (S)-(−)-6- [5- (5-Methylpyridin-2-yl) naphth-1-oilamino] -4- (octahydropyrrolo [1,2-a] Pyrazin-2-yl)
Quinoline (E4)

Embedded image (S)-(−)-6-amino-4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (D2, 85 μmole) in DCM (3 ml), 5
-(5-Methylpyridin-2-yl) naphthoic acid (D16, 255 μmole)
And a solution of 1-hydroxybenzotriazole (255 μmole) in 1,3
Treated with diisopropylcarbodiimide (255 μmole) and shaken at room temperature for 48 hours. The solution is passed through a solid phase cation exchange (SCX) cartridge and MeOH
And washed. Eluted with MeOH in 2M NH _3, then as a pale brown glassy material the title compound was evaporated under reduced pressure (46%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.81 (s, 1H), 8.66 (d, 1H), 8.57 (s, 1
H), 8.47 (d, 1H), 8.42 (d, 1H), 8.03 (d, 1H), 7.90 (d, 1H), 7.78 (d, 1H)
, 7.70-7.58 (m, 3H), 7.45 (d, 2H), 7.31 (d, H), 6.89 (d, 1H), 3.78 (br.
d, 1H), 3.69 (br.d, 1H), 3.22-3.05 (br.m, 3H), 2.81-2.65 (m, 1H), 2.6
7 (s, 1H), 2.51-2.43 (br.m, 1H), 2.26 (q, 1H), 1.99-1.70 (br.m, 3H), 1
.50 (m, 1H). MS: m / z (MH) = 514.

Example 5 (S)-(−)-6- (2,3-Dichlorobenzoylamino) -4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (E5)

Embedded image Using a procedure similar to that in Example 4, (S)-(−)-6-amino-4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline (D2, 85 μmo)
le) and 2,3-dichlorobenzoic acid (255 μmole) gave the title compound as a yellow glass (67%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.74 (d, 1H), 8.72 (d, 1H), 8.58 (d, 1
H), 7.97 (d, 1H), 7.61 (dd, 1H), 7.53-7.48 (m, 2H), 7.23 (t, 1H), 6.84 (
d, 1H), 3.74 (br.d, 1H), 3.66 (br.d, 1H), 3.19-3.02 (m, 3H), 2.72 (t,
1H), 2.62 (td, 1H), 2.44-2.33 (br.m, 1H), 2.22 (q, 1H), 1.95-1.74 (br.
m, 3H), 1.48 (m, 1H) .MS: m / z (MH) = 441, 442, 443, 444.

Example E6 to E9 were prepared using a procedure similar to that described in Example 4.

Embedded image

[Table 1]

Example 10 (S)-(−)-1- (2,3-dichlorobenzoyl) -2,3-dihydro-8
-(Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-
g] Quinoline (E10)

Embedded image Using the same procedure as in Example 4, (S)-(−)-2,3-dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g ] Quinoline (D10, 85 μmole) and 2,3-dichlorobenzoic acid (255 μm)
Mole) gave the title compound as a yellow glass (51%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.93 (s, 1H), 8.62 (d, 1H), 7.86 (s, 1
H), 7.57 (dd, 1H), 7.37 (m, 2H), 6.85 (d, 1H), 4.05-3.65 (br.m, 3H), 3.
34 (t, 2H), 3.24-3.11 (br.m, 2H), 2.74 (br.t, 2H), 2.52 (br.s, 1H), 2
.30 (q, 1H), 1.98-1.74 (m, 5H), 1.60-1.48 (br.m, 1H) .MS: m / z (MH) = 467, 468, 469, 470.

Example 11 (S)-(−)-2,3-dihydro-1- [4- (5-methyloxazole-2
-Yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E11)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 85 μmole) and 4- (5-methyloxazole-2)
-Yl) -1-Naphthoic acid (D21, 255 [mu] mole) gave the title compound as a brown glass (47%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.39 (d, 1H), 9.09 (s, 1H), 8.64 (d, 1H
), 8.24 (d, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.71-7.56 (m, 3H), 7.05 (s
, 1H), 6.88 (d, 1H), 3.90-3.67 (br.m, 3H), 3.26 (t, 2H), 3.19-3.09 (br.
m, 2H), 2.80 (br.t, 2H), 2.49 (s, 3H), 2.31 (br.m, 1H), 2.00-1.87 (br
m, 3H), 1.60-1.48 (br.m, 1H) .MS: m / z (MH) = 530.

Example 12 (S)-(−)-2,3-dihydro-1- [5- (5-methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1 , 2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinolinetrifluoroacetate (E12)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
The title compound was obtained from quinoline (D10, 85 μmole) and 5- (5-methylpyridin-2-yl) -1-naphthoic acid (D16, 255 μmole). The compound was further purified using reverse phase HPLC and isolated as a light brown glassy trifluoroacetate salt (20%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.01 (s, 1H), 8.83 (s, 1H), 8.71 (s, 1
H), 8.25 (s, 1H), 8.23 (dd, 1H), 8.02 (d, 1H), 7.88 (br.d, 1H), 7.64-7.
54 (m, 4H), 7.58 (d, 1H), 7.25 (d, H), 4.23 (br.d, 1H), 4.10-3.65 (br.
m, 10 H), 3.43 (t, 2H), 2.90 (s, 3H), 2.51-2.43 (br.m, 1H), 2.35-2.18 (
br.m, 3H). MS: m / z (MH) = 540.

Example 13 (S)-(−)-2,3-dihydro-1- [5- (2,5-dimethylpyridine-
4-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E13)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10,85 μmole) and 5- (2,5-dimethylpyridine-
4-yl) -1-Naphthoic acid (D22, 255 μmole) gave the title compound as a light brown glass (35%). MS: m / z (MH) = 554

Example 14 (S)-(−)-2,3-Dihydro-1- [5- (6-methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1 , 2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E14)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
The title compound was obtained from quinoline (D10,85 μmole) and 5- (6-methylpyridin-2-yl) -1-naphthoic acid (D17,255 μmole) as a yellow glass (46%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.07 (s, 1H), 8.63 (d, 1H), 8.16 (d, 1
H), 7.98 (d, 1H), 7.90 (s, 1H), 7.75 (t, 1H), 7.66-7.49 (m, 4H), 7.37 (d
, 1H), 7.25 (d, 1H), 6.90 (d, 1H), 3.87-3.76 (br.m, 3H), 3.37-3.19 (br.
m, 4H), 3.00-2.87 (br.m, 2H), 2.69 (s, 3H), 2.42 (q, 1H), 2.08-1.83 (b
r.m, 3H), 1.71-1.60 (br.m, 1H) .MS: m / z (MH) = 540.

Example 15 (S)-(−)-2,3-Dihydro-1- [5- (3-methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1 , 2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E15)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
The title compound was obtained from quinoline (D10,85 μmole) and 5- (3-methylpyridin-2-yl) -1-naphthoic acid (D23,255 μmole) as a light yellow glass (64%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.09 (s, 1H), 8.65-8.60 (m, 2H), 8.03
(d, 1H), 7.86 (s, 1H), 7.74-7.59 (m, 4H), 7.51 (s, 1H), 7.49 (d, 1H), 7.
32 (dd, 1H), 6.88 (d, 1H), 3.90-3.71 (br.m, 3H), 3.32-3.13 (br.m, 5H),
2.87-2.73 (br.m, 2H), 2.64-2.52 (m, 1H), 2.38-2.26 (m, 2H), 2.08-1.83
(br.m, 3H), 2.07 (s, 3H), 1.71-1.60 (br.m, 1H) .MS: m / z (MH) = 540.

Example 16 (S)-(−)-2,3-dihydro-8- (octahydropyrrolo [1,2-a]
Pyrazin-2-yl) -1- (quinolin-4-ylcarbonyl) pyrrolo [2,3
-G] quinoline (E16)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 85 μmole) and 4-quinolinecarboxylic acid (255 μm)
(mole) to give the title compound as a yellow glass (72%). MS: m
/ Z (MH) = 450

Example 17 (S)-(−)-2,3-dihydro-1- [5- (2-methyloxazole-5)
-Yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E17)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 85 μmole) and 5- (2-methyloxazole-5)
-Yl) -1-Naphthoic acid (D34, 255 [mu] mole) gave the title compound as a yellow glass (36%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.08 (s, 1H), 8.62 (d, 1H), 8.39 (m, 1
H), 7.97 (d, 1H), 7.84 (s, 1H), 7.78 (d, 1H), 7.66-7.55 (m, 3H), 7.31 (s
, 1H), 6.88 (d, 1H), 3.85-3.67 (br.m, 3H), 3.25 (t, 2H), 3.21-3.11 (br.
m, 2H), 2.79 (br.t, 2H), 2.62 (s, 3H), 2.30 (m, 1H), 1.98-1.75 (br.m,
3H), 1.60-1.45 (br.m, 1H). MS: m / z (MH) = 530.

Example 18 (S)-(−)-2,3-dihydro-1- [5- (3-methylisoxazol-5-yl) naphth-1-oil] -8- (octahydropyrrolo [ 1,2-a]
Pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E18)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 85 μmole) and 5- (3-methyloxazole-5)
-Yl) -1-Naphthoic acid (D36, 255 [mu] mole) gave the title compound as a yellow glass (26%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.06 (s, 1H), 8.63 (d, 1H), 8.41 (m, 1
H), 8.07 (d, 1H), 7.90 (s, 1H), 7.84 (d, 1H), 7.67-7.58 (m, 3H), 6.89 (d
, 1H), 6.49 (s, 1H), 3.90-3.69 (br.m, 3H), 3.35-3.15 (br.m, 4H), 2.79
(br.m, 2H), 2.46 (s, 3H), 2.40-2.30 (m, 1H), 2.02-1.80 (br.m, 3H), 1.7
1-1.55 (br.m, 1H). MS: m / z (MH) = 530.

Example 19 (S)-(−)-1- [5- (6-Methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazine -2-yl) pyrrolo [2,3-g] quinoline (E19)

Embedded image (S)-(−)-8- in dry DMF (15 ml) at 4 ° C. under argon
(Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g
A stirred solution of quinoline (D37, 150 mg, 510 μmole) was treated with NaH (18 mg, 0.77 mmole) and warmed to room temperature over 30 minutes. A solution of 5- (6-methylpyridin-2-yl) -1-naphthoyl chloride (D38, 190 mg, 0.77 mmole) in DMF (5 ml) was added and stirring was continued for 20 hours. The solution was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The organic phase is washed with a saturated aqueous solution of NaHCO ₃ , water and then brine,
Dried over O ₄ , filtered and concentrated in vacuo to dryness. DCM, then DCM / M
The product was obtained as a yellow gum after silica gel chromatography, eluting with MeOH 9: 1 (15 mg, 5%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.37 (s, 1H), 8.82 (d, 1H), 8.50 (d, 1
H), 8.31 (d, 1H), 7.94 (d, 1H), 7.78-7.57 (m, 4H), 7.40 (d, 1H), 7.27 (d
, 1H), 7.17 (d, 1H), 6.97 (d, 1H), 6.73 (d, 1H), 3.95-3.80 (m, 2H), 3.49
-3.24 (m, 5H), 3.07 (m, 2H), 2.71 (s, 3H), 2.14-1.94 (m, 4H). MS: m / z (MH) = 430.

Example 20 (S)-(−)-1- (4-chlorobenzoyl) -8- (octahydropyrrolo [
1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E20)

Embedded image (S)-(-)-8- (octahydropyrrolo [1,1] in dry DMF (15 ml)
2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D37,150
mg, 510 μmole) was treated with DMAP and 4-chlorobenzoyl chloride (0.38 mmole). After 18 hours, the solution was partitioned between DCM and saturated aqueous NaHCO ₃ . The organic phase is washed with brine,
Dried SO _4, filtered, concentrated under reduced pressure until dryness. DCM, then DCM /
The product was obtained as a yellow gum after silica gel chromatography, eluting with MeOH 9: 1 (19 mg, 21%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.10 (s, 1H), 8.76 (d, 1H), 8.28 (d, 1
H), 7.74 (d, 2H), 7.56 (d, 2H), 7.49 (dd, 1H), 6.90 (d, 1H), 6.82 (d, 1H)
), 3.73 (m, 2H), 3.16 (m, 2H), 2.78 (m, 2H), 2.36 (m, 2H), 1.90 (m, 4H),
1.54 (m, 1H). MS: m / z (MH) = 430.

Example 21 (S)-(−)-2,3-dihydro-1- [2- (4-chlorophenyl) -3-
Trifluoromethylpyrazole-4-carbonyl] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E21)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 170 μmole) and 2- (4-chlorophenyl) -3
The title compound was obtained from -trifluoromethylpyrazole-4-carboxylic acid (250 μmole) as a yellow glass (52%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.90 (s, 1H), 8.63 (d, 1H), 7.90 (s, 1
H), 7.86 (s, 1H), 7.51 (d, 2H), 7.44 (d, 2H), 6.85 (d, 1H), 4.18-4.06 (b
r.t, 2H), 3.78-3.63 (br.m, 2H), 3.37 (t, 2H), 3.20-3.05 (br.m, 3H), 2
.70-2.78 (br.t, 2H), 2.50-2.60 (br.m, 1H), 1.79-1.97 (br.m, 4H), 1.45
-1.57 (br.m, 1H). MS: m / z (MH) = 568.

Example 22 (S)-(−)-2,3-Dihydro-1- [5- (2-methyl-5-trifluoromethylpyrazol-3-yl) thiophen-2-carbonyl] -8- (Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E22)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 170 μmole) and 5- (2-methyl-5-trifluoromethylpyrazol-3-yl) -thiophen-2-carboxylic acid (250 μm
ole) to give the title compound as a yellow glass (80%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.64 (s, 1H), 8.60 (d, 1H), 7.83 (s, 1
H), 7.58 (d, 1H), 7.31 (d, 1H), 6.85 (s, 1H), 6.82 (d, 1H), 4.48 (t, 2H)
, 4.02 (s, 3H), 3.69-3.57 (br.m, 2H), 3.39 (t, 2H), 3.20-3.02 (m, 3H),
2.75-2.63 (m, 2H), 2.50-2.40 (br.m, 1H), 2.25-2.21 (br.m, 1H), 1.92-1.
76 (br.m, 3H), 1.44-1.55 (m, 1H) .MS: m / z (MH) = 553.

Example 23 (S)-(−)-2,3-Dihydro-1- (5-chlorothiophen-2-carbonyl) -8- (octahydropyrrolo [1,2-a] pyrazine-2- Yl) pyrrolo [2,3-g] quinoline (E23)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
The title compound was obtained as a yellow glass from quinoline (D10, 170 μmole) and 5-chlorothiophene-2-carboxylic acid (250 μmole) (6
6%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.62 (s, 1H), 8.60 (d, 1H), 7.83 (s, 1
H), 7.40 (d, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 4.42 (t, 2H), 3.68-3.56 (b
r.m, 2H), 3.39 (t, 2H), 3.20-3.00 (m, 3H), 2.76-2.64 (m, 2H), 2.47-2.39
(br.m, 1H), 1.98-1.79 (br.m, 4H), 1.46-1.59 (m, 1H) .MS: m / z (MH) = 438.

Example 24 (S)-(−)-2,3-Dihydro-1- [1-methyl-7- (2-methylpyridin-6-yl) indole-3-carbonyl] -8- (octa Hydropyrrolo [
1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E24)

Embedded image Under argon, (S)-(-)-2,3- in anhydrous toluene (5 ml)
A stirred solution of dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D10, 45 mg, 0.15 mmole) was added to anhydrous toluene (D 1-methyl-7- (6-methylpyridin-2-yl) indole-3-carboxylic acid (D42, 54 mg, 0.19) in 5 ml).
mmole). AlMe ₃ (0.15 ml, 0.29 mmol
e) was added via syringe and the mixture was heated at reflux under argon for 18 hours. The reaction mixture was cooled, poured directly onto a silica sep pak (5 g) and eluted with 5% MeOH / DCM. The fractions containing the product were combined, concentrated in vacuo to dryness and the residue was subjected to preparative tlc to 15% MeO
Elution with H / DCM gave the title compound as a yellow solid (20 mg, 24%).
1H NMR (250 MHz, CDCl3) δ (ppm): 8.58 (d, 1H), 8.39 (br.s, 1H), 7.98-7
.93 (m, 2H), 7.70 (dd, 1H), 7.51 (s, 1H), 7.37 (d, 1H), 7.26-7.19 (m, 3H
), 6.83 (d, 1H), 4.37 (br.t, 2H), 3.71 (br.d, 1H), 3.46 (s, 3H), 3.35
(br.t, 2H), 3.38-3.23 (br.m, 4H), 2.97 (br.s, 2H), 2.70-2.40 (br.s,
2H), 2.65 (s, 3H), 2.07-1.70 (br.m, 4H) .MS: m / z (MH) = 543.

Example E25-E72 were prepared in parallel using a procedure similar to that described in Example 4.

Embedded image

[Table 2]

[Table 3]

Example 73 (S)-(−)-2,3-dihydro-1- [5- (5-methyloxazole-2
-Yl) naphth-1-ylacetyl] -8- (octahydropyrrolo [1,2-a
] Pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E73)

Embedded image Using the same procedure as in Example 4, (S)-(-)-2,3-dihydro-8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g]
Quinoline (D10, 85 μmole) and 5- (5-methyloxazole-2)
-Yl) naphth-1-ylacetic acid (D27, 255 [mu] mole) gave the title compound as a light brown glass (70%). 1H NMR (250 MHz, CDCl3) δ (ppm): 9.24 (d, 1H), 8.87 (s, 1H), 8.60 (d, 1
H), 8.18 (d, 1H), 8.14 (d, 1H), 7.80 (s, 1H), 7.64-7.48 (m, 3H), 6.99 (s
, 1H), 6.82 (d, 1H), 4.37 (s, 2H), 4.17 (t, 3H), 3.68 (br.t, 2H), 3.34
(t, 2H), 3.20-2.99 (m, 3H), 2.71 (t, 2H), 2.47 (s, 3H), 2.31 (q, 1H), 1.
95-1.70 (br.m, 3H), 1.55-1.42 (br.m, 1H) .MS: m / z (MH) = 544.

Example 74 (S)-(−)-2,3-dihydro-1- [5- (2,6-dimethylpyridine-
4-yl) naphth-1-ylaminocarbonyl] -8- (octahydropyrrolo [
1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (E74)

Embedded image (S)-(-)-2,3-Dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline (D10) in DCM (10 ml) , 100 mg, 340 μmole) was added to 5- (
2,6-dimethylpyridin-4-yl) naphth-1-ylisocyanate (D1
5,0.38 mmole). The mixture was heated at reflux under argon for 16 hours, then concentrated in vacuo to give the crude product. DCM: MeOH (9
This was purified by silica gel chromatography, eluting with 3: 7) to give the title compound as a cream solid (80 mg, 41%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.56 (d, 1H), 8.47 (s, 1H), 8.03 (d, 1
H), 7.85 (d, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.55 (dd, 1H), 7.47 (dd, 1
H), 7.40 (d, 1H), 7.09 (s, 1H), 7.08 (s, 2H), 6.82 (d, 1H), 4.30 (t, 2H)
, 3.64 (d, 1H), 3.56 (d, 1H), 3.44 (t, 2H), 3.07-2.98 (m, 3H), 2.69 (t,
1H), 2.62 (s, 6H), 2.55 (dt, 1H), 2.32 (br.m, 1H), 2.14 (q, 1H), 1.87-1
.61 (br.m, 3H), 1.42-1.38 (m, 1H) .MS: m / z (MH) = 567.

Examples E75-E80 were prepared in parallel using a procedure similar to that described in Example 74.

Embedded image

[Table 4] (R)-(+)-Octahydropyrrolo [1] according to the procedure described in D7 to D10.
, 2-a] pyrazine (J) Med. Chem., 1993, 36, 2311).
(+)-2,3-Dihydro-8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline was prepared using the same procedure as in Example 4. Examples 23, 29, 33 and 3 by coupling with carboxylic acids
Five (R) -enantiomers were prepared.

Pharmacological Data The affinity of the compounds of the invention was determined using the radiolabel binding assay described above. 5-HT _1A , 5-HT _1B and 5-HT _1D receptor binding The compounds of all examples have pKi values greater than 7.5 at the 5-HT _1A , 5-HT _1B and 5-HT _1D receptors. Had.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/00 101 A61P 25/00 101 25/14 25/14 25/16 25/16 25/18 25 / 18 25/20 25/20 25/22 25/22 25/24 25/24 25/28 25/28 43/00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AE, AL, AM, AT, A , AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX , NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Tom Daniel Heightman UK, CM 19.5 Adabrew, Essex, Harlow, Third Avenue, New Frontiers Science Park South F-term (Reference) 4C050 AA01 BB04 CC08 EE02 FF01 GG01 HH03 HH04 4C086 AA01 AA02 AA03 AA04 CB05 MA01 MA04 NA14 ZA02 ZA03 ZA05 ZA12 ZA15 ZA18 ZA22 ZA42 ZA66 ZC41

Claims (10)

[Claims] (1) Formula (I): (I) [wherein, R^aIs selected from the group of formula (i) or (ii);Group of formula (i) (Equation 1) (i) (where P¹Is phenyl, bicyclic aryl, C_3-6Cycloalkyl, oxygen, nitrogen
5- to 7-membered compound containing 1 to 3 heteroatoms selected from silicon and sulfur
An elementary ring or one to three hetero atoms selected from oxygen, nitrogen and sulfur
R is a bicyclic heterocycle containing¹Is halogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_1-6Al
Coxy, hydroxy, hydroxy C_1-6Alkyl, hydroxy C_1-6Arco
Kissi, C_1-6Alkoxy C_1-6Alkoxy, C_1-6Alkanoyl, NO₂ , CF₃, CN, SR⁹, SOR⁹, SO₂R⁹, SO₂NR¹⁰R¹¹, CO ₂ R¹⁰, CONR¹⁰R¹¹, CONR¹⁰(CH₂)_cCO₂R¹¹, (C
H₂)_cNR¹⁰R¹¹, (CH₂)_cCONR¹⁰R¹¹, (CH₂)_cNR ¹⁰ COR¹¹, (CH₂)_cCO₂C_1-6Alkyl, CO₂(CH₂)_cO
R¹⁰, NR¹⁰R¹¹, NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹¹ , CR¹⁰= NOR¹¹Or CNR¹⁰= NOR¹¹And R⁹, R¹⁰ And R¹¹Is independently hydrogen or C_1-6Alkyl and c is 1 to 4
A is 0, 1, 2 or 3);Group of formula (ii) Embedded image (ii) (where P²And P³Are independently phenyl, bicyclic aryl, oxygen, nitrogen and
5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from sulfur and sulfur,
Or contains one to three heteroatoms selected from oxygen, nitrogen and sulfur
A is a bond, O, S (O)_n(N is 0 to 2), carbonyl, CH₂Or N
R⁴(R⁴Is hydrogen or C_1-6Alkyl); R¹And R²Is independently R in formula (i) as defined above.¹A and b independently represent 0, 1, 2 or 3); L is of the formula -YC (= O) -DG- or -C (= O) -DG- or- DG-C (= O
)-, Wherein Y is NH, NR⁵And R⁵Is C_1-6Is or is alkyl
Or Y is CH₂, O, CH = CH or OCH₂D is a nitrogen, carbon or CH group; G when D is a nitrogen or CH group
Is hydrogen or C_1-6Alkyl or G is R^b1Together with Ki W
And W is (CR¹⁶R¹⁷)_tAnd t is 2, 3 or 4, and R^{1 6} And R¹⁷Is independently hydrogen or C_1-6Alkyl or W is
(CR¹⁶R¹⁷)_u-J, u is 0, 1, 2, or 3, J is oxygen,
Sulfur, CR¹⁶= CR¹⁷, CR¹⁶= N, = CR¹⁶O, = CR¹⁶S also
Is = CR¹⁶-NR¹⁷And u is 0 when J is oxygen or sulfur
No; R^b1Is hydrogen or, together with G, forms the group W; X is nitrogen, carbon or CH;Is a single bond when X is nitrogen or CH; and when X is carbon
Is a double bond, and m represents 1, 2 or 3.] or a salt thereof. 2. The compound according to claim 1, wherein X is a nitrogen atom and m is 1. 3. In the definition of L, the group D is nitrogen and the group G is hydrogen,
Alternatively, a compound according to any of the preceding claims, wherein G together with R ^b1 forms a further group (CH ₂ ) ₂ . 4. The compound according to claim 1, wherein ^Ra is a group of formula (i) and P ¹ is a phenyl, naphthyl, quinolyl, pyridyl or thienyl group. 5. The compound according to claim 1, wherein ^Ra is a group represented by the formula (ii), and P ² is a phenyl, naphthyl, pyridyl, thienyl or furyl group. (6) (S)-(-)-N- [4- (octahydropyrrolo [1,2-a] pyrazin-2-yl
) Quinolin-6-yl] -3,4-dichlorobenzamide, (S)-(-)-N- [4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinolin-6-yl ]-
3,4-dichlorobenzamide, (S)-(-)-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylcarbonyl] -8- (octa Hydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-6- [5- (5-methylpyridin-2-yl) naphtho- 1-oilamino] -4- (octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline, (S)-(-)-6- (2,3-dichlorobenzoylamino] -4- ( Octahydropyrrolo [1,2-a] pyrazin-2-yl) quinoline, (S)-(-)-1- (2,3-dichlorobenzoyl) -2,3-dihydro-8- (octahydropyrrolo [ 1,
2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) naphtho -1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (5 -Methylpyridin-2-yl) naphth-1-oil] -8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline trifluoroacetate, (S)-(-)-2,3-dihydro-1- [5- ( 2,5-dimethylpyridin-4-yl) naphth-1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (6 -Methylpyridin-2-yl) naphth-1-oil] -8- (
Octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-8- (octahydropyrrolo [1,2 -a] pyrazin-2-yl) -1- (quinolin-4-ylcarbonyl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- ( 2-methyloxazol-5-yl) naphth-1-oil]-
8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (3 -Methylisoxazol-5-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline,
(S)-(-)-1- [5- (6-methylpyridin-2-yl) naphth-1-oil] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-1- (4-chlorobenzoyl) -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3 -g] quinoline, (S)-(-)-2,3-dihydro-1- [2- (4-chlorophenyl) -3-trifluoromethylpyrazole-4-carbonyl] -8- (octahydropyrrolo [1 , 2-a] pyrazin-2-yl) pyrrolo [2,
3-g] quinoline, (S)-(-)-2,3-dihydro-1- [5- (2-methyl-5-trifluoromethylpyrazol-3-yl) -thiophen-2-carbonyl] -8 -(Octahydropyrrolo [1,2-a] pyrazin-2-yl
) Pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- (5-chlorothiophen-2-carbonyl) -8- (octahydropyrrolo [1,2-a ] Pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [1-methyl-7- (2-methylpyridin-6-yl) Indole-3
-Carbonyl] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S)-(-)-2,3-dihydro-1- [ 5- (5-methyloxazol-2-yl) naphth-1-ylacetyl] -8- (octahydropyrrolo [1,2-a] pyrazin-2-yl) pyrrolo [2,3-g] quinoline, (S )-(-)-2,3-Dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -8- (octahydropyrrolo [1,2-a ] Pyrazin-2-yl) pyrrolo [2,3-g]
The compound according to claim 1, which is quinoline, or a pharmaceutically acceptable salt thereof. 7. (a) L is -C (= O) -DG- or -DG- (C = O)
If-, formula (II): R^a-L¹ A compound of the formula (III): (III) [wherein, R^a, R^b1, X and m are the same as defined in formula (I),¹ And L²Contains a suitable functional group that can react together to form the L moiety]; or (b) L is -Y-C (= O) -DG and D Is nitrogen and Y is NH
When the formula (IV) is:^a-NC (= O) (IV) wherein R^aIs the same as defined in formula (I), or its protected
A compound represented by the formula (V): (V) [wherein, R^b1, X, m and G are the same as defined in formula (I) or are
Or a protected derivative thereof]; or (c) L is -YC (= O) -DG-, D is nitrogen, and Y is NH or
NR⁵In the formula (VI): R^a-NH₂Or R^a-NR⁵H (VI) wherein R^aAnd R⁵Is the same as defined in formula (I)] with a compound of formula (V) together with a suitable urea generator.
Or (d) L is -YC (= O) -DG, D is nitrogen and Y is CH₂Or
When O, a compound of formula (VII): R^a-Y- (C = O) -L³ (VII) [wherein, R^aIs the same as defined in formula (I),³Is a suitable leaving group
Reacting a compound of formula (V) with a compound of formula (V); or (e) a reaction where L is -YC (= O) -DG, D is CH and Y is NH
When the formula (VI) is R^a-NH₂ (VI) [wherein, R^aIs the same as defined in the formula (I)] with a compound of the formula (VIII): (VIII) [wherein D, G, R^b1, X and m are the same as defined in formula (I), ³ Is a suitable leaving group]; and the following step: removing the protecting group; obtaining a pharmaceutically acceptable salt. ). 8. The compound according to claim 1, which is used for treatment. 9. The compound according to claim 1, which is used for treating depression. 10. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.