WO2007097697A1

WO2007097697A1 - Therapeutic quinoline compounds that are 5ht1b modulators

Info

Publication number: WO2007097697A1
Application number: PCT/SE2007/000164
Authority: WO
Inventors: David Nugiel; Margaret Schooler; Babu Sundar
Original assignee: Astrazeneca Ab
Priority date: 2006-02-23
Filing date: 2007-02-22
Publication date: 2007-08-30

Abstract

The present invention provides compounds having formula (I): wherein the compounds are useful for the treatment of anxiety disorders, cognitive disorders, and/or mood disorders. The compounds are 5HT1B modulators.

Description

THERAPEUTIC QUINOLINE COMPOUNDS THAT ARE 5HT1 B MODULATORS.

FIELD OF THE INVENTION

The present invention is directed, in part, to novel quinolone compounds and pharmaceutical compositions comprising the same, methods for their preparation, and methods of using novel quinolone compounds in therapy.

BACKGROUND OF THE INVENTION

Serotonin (5-HT) has been implicated in many psychiatric disorders including but not limited to depression, generalized anxiety, eating disorders, dementia, panic disorder, and sleep disorders. Serotonin has also been implicated in gastrointestinal disorders, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors have been subdivided into at least 14 subtypes, see Barnes and Sharp, Neuropharmacology, 1999, 38, 1083-1152. These various subtypes are responsible for serotonin's action in many pathophysicogical conditions. The 5-HT1 family of receptors has high affinity for serotonin and consists of five related receptors. This family includes the 5-HT1B receptor subtypes. Compounds that interact with the 5-HT1 families are known to have therapeutic potential in the above-mentioned disorders and diseases. In particular, compounds that are 5HT IB antagonists have been known to be antidepressant and anxiolytic agents.

Quinolone compounds and related compounds are reported in, for example, Internationals Application Publications WO/2002/055012, WO/2002/055014, WO/2003/037871, and WO/2003/037872.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by formula (I):

wherein:

R¹ is hydrogen or halogen;

R is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, -OCH₃, -OCH₂CH₃, -O(CH₂)₂CH₃, and -OCH(CH₃)₂; provided that R¹ and R² are not both hydrogen, and when R¹ is halogen then R² is hydrogen; n is 1 or 2;

R is methyl, provided that when n is 2 the nitrogen has a positive charge; R¹⁰ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl; R¹ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl; R is selected from phenyl, pyridyl or indole and is substituted with one or two substituents selected from R⁹;

R⁹ is selected from -OCH₃, halogen, -O(CH₂)₂OCH₃, -N(CH₂)₂OCH₃, morpholino, pyran, piperidine- R¹², and piperazin-R¹², wherein R¹² is selected from methyl, - C(=O)N(CH₃)₂, -C(=O)OCH₃, -SO₂CH₃, -SO₂CH₂CH₃, -C(=O)CH₂CH₃, and -C(O)CH₃; or a pharmaceutically acceptable salt.

In some embodiments, R¹ is halogen and R² is hydrogen; R¹ is fluorine and R² is hydrogen; R² is halogen and R¹ is hydrogen; or R² is fluorine and R¹ is hydrogen. In some embodiments, R² is halogen, methyl, or -OCH₃. In some embodiments, n is 1; or n is 2. In some embodiments, R¹⁰ is hydrogen or methyl. In some embodiments, R¹¹ is hydrogen or methyl. In some embodiments, R⁷ is phenyl or pyridyl.

5 In some embodiments, R⁹ is -OCH₃; -O(CH₂)₂OCH₃; -N(CH₂)₂OCH₃; morpholino; or piperazin-R¹². In some embodiments, R¹² is methyl; -C(=O)N(CH₃)₂; -C(=O)OCH₃; -SO₂CH₃; -SO₂CH₂CH₃; -C(=O)CH₂CH₃; or -CC=O)CH₃.

In some embodiments, a compound is: 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo-l,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide; 5-Methoxy-8- 0 (4-methyl-ρiperazin-l -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- dimethylcarbamoyl-piperazin-1 -yl)-phenyl]-amide; 4-(5- {[5-Methoxy~8-(4-methyl-piperazm- 1 -yl)-4-oxo- 1 ,4-dihydro-quinolme-2-carbonyl]-amino} -pyridin-2-yl)-piperazine-l -carboxylic acid methyl ester; 4-(4-{[5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro- quinoline-2-carbonyl]amino}-phenyl)-piperazine-l-carboxylic acid methyl ester; 5-Methoxy- 5 8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy- ethoxy)-pyridin-3-yl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl] -amide; 5- Methoxy~8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- ethanesulfonyl-piperazin-l-yl)-phenyl]-amide); 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4- 0 oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy-ethylamino)~pyridin-3-yl]- amide; 5-Methoxy-8-(4-methyl-piρerazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [6-(4-propionyl-piperazin-l-yl)-pyridin-3-yl]-amide; 5-Methoxy-8-(4-methyl-piperazin- l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(4-acetyl-piperazin-l-yl)-pyridin-3- yl]-amide; 5-Methoxy-8-(4-methyl-ρiperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic 5 acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo- 1 ,4-dihydro-quinoline-2 -carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-l ,4-dihydro-quinoline-2-carboxylic acid (6- morpholin-4-yl-pyridin-3-yl)-amide; l,l-Dimethyl-4-[5-methyl-2-(4-morpholin-4-yl- • phenylcarbamoyl)-4-oxo- 1 ,4-dihydf o-quinolin-8-yl]-piperazin- 1 -ium; 5-Fluoro- 1 -methyl-8- O (4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid methyl-(4- morpholin-4-yl-phenyl)-amide; 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline- 2-carboxylic acid (4-methoxy-phenyl)-arnide; 4-Hydroxy-5-memoxy-8-(4-methyϊ-piperazin- l-yl)-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide; 5-Fluoro~8-(4-methyl- piperazin-l-yl)-4-oxo-l,4-dihydro-qumoline-2-carboxylic acid (4-methoxy-phenyl)-amide; 5- Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-qumoline-2-carboxylic acid (6- methoxy-pyridin-3-yi)-amide; 5-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide; 4-Hydroxy-5-methyl-8-(4- methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide; 4- Hydroxy-5-methyl-8-(4-methyl-piperazin-l -yl)-quinoline-2-carboxylic acid [4-(4-methyl- piperazin-l-yl)-phenyl]-amide; 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline- 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4- oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-methyl-piperazin-l-yl)-phenyl]-amide; 6- Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline~2-carboxylic acid (6- methoxy-pyridin-3-yl)-amide; or 6-Fluoro-8-(4-methyl-piperazm-l-yl)-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide. In some embodiments, a composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or carrier is provided.

In some embodiments, use of any of the compounds described herein in the treatment of an anxiety disorder, cognitive disorder, or mood disorder is provided. In some embodiments, the anxiety disorder is selected from panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, and generalized anxiety disorder due to a general medical condition. In some embodiments, the cognitive disorder is selected from Alzheimer's disease, dementia, and dementia due to Alzheimer's disease, and dementia due to Parkinson's disease. In some embodiments, the mood disorder is a depressive disorder, such as, for example, major depressive disorder, dysthymic disorder, bipolar depression and/or bipolar mania, cyclothymic disorder, mood disorder due to a general medical condition, manic episode associated with bipolar disorder, and mixed episode associated with bipolar disorder. In some embodiments, the bipolar depression and/or bipolar mania is bipolar II, or bipolar I with or without manic, depressive or mixed episodes. In some embodiments, methods of treating an animal suffering from an anxiety disorder, cognitive disorder, or mood disorder comprising administering to such animal an effective amount of any compound described herein or a pharmaceutically acceptable salt of the compound are provided. In some embodiments, use of any one of the compounds described herein in the preparation of a medicament for the treatment of an anxiety disorder, a cognitive disorder, or a mood disorder is provided herein. DESCRIPTION OF EMBODIMENTS

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine radicals.

As used herein, the term "animal" refers to any animal including but not limited to humans.

As used herein, "anxiety disorder" includes, but is not limited to, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive- compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, and generalized anxiety disorder due to a general medical condition.

As used herein, "cognitive disorder" includes, but is not limited to, Alzheimer's disease, dementia, and dementia due to Alzheimer's disease, and dementia due to Parkinson's disease.

As used herein, "mood disorder" includes depressive disorders such as, for example, major depressive disorder, dysthymic disorder, bipolar depression and/or bipolar mania, cyclothymic disorder, mood disorder due to a general medical condition, manic episode associated with bipolar disorder, and mixed episode associated with bipolar disorder. Examples of bipolar depression and/or bipolar mania include, but are not limited to, bipolar II, or bipolar I with or without manic, depressive or mixed episodes.

As used herein, the phrase "or any subset thereof means any subset of the group described. For example, the phrase "X is selected from A, B, C, and D, or any subset thereof, X includes the following groups: 1) A, B, C, and D; 2) A, B, and C; 3) A, B, and D; 4) B, C, and D; 5) A and B; 6) A and C; 7) A and D; 8) B and C; 9) B and D; 10) C and D; H) A; 12) B; 13) C; and 14) D. The present invention provides compounds represented by formula (I):

wherein:

R¹ is hydrogen or halogen; R² is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, -OCH₃,

-OCH₂CH₃, -O(CH₂)₂CH₃, and -OCH(CH₃)₂, or any subgroup thereof; provided that R¹ and R² are not both hydrogen, and when R¹ is halogen then R² is hydrogen; n is 1 or 2; R³ is methyl, provided that when n is 2 the nitrogen has a positive charge;

R¹⁰ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, or any subgroup thereof;

R¹¹ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, or any subgroup thereof; R⁷ is selected from phenyl, pyridyl or indole and is substituted with one or two substituents selected from R⁹;

R⁹ is selected from -OCH₃, halogen, -O(CH₂)₂OCH₃, -N(CH₂)₂OCH₃, morpholino, pyran, piperidine-R¹², and piperazin-R¹², or any subgroup thereof, wherein R¹² is selected from methyl, -C(=O)N(CH₃)₂, -C(=O)OCH₃, -SO₂CH₃, -SO₂CH₂CH₃, -C(=O)CH₂CH₃, and - C(=O)CH₃, or any subgroup thereof; or a pharmaceutically acceptable salt.

In some embodiments, R¹ is hydrogen or halogen, such as F, Cl, Br, and I, or any subgroup thereof. In some embodiments, R² is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, -OCH₃, -OCH₂CH₃, -O(CH₂)₂CH₃, and -OCH(CH₃)₂, or any subgroup thereof. In other embodiments, R² is halogen, methyl, or -OCH₃, or any subgroup thereof. In other embodiments, R² is halogen. In other embodiments, R² is methyl. In other embodiments, R² is -OCH₃.

R¹ and R² are not both hydrogen. When R¹ is halogen, then R² is hydrogen.

In some embodiments, R is halogen and R is hydrogen. In other embodiments, R is fluorine and R² is hydrogen. In yet other embodiments, R² is halogen and R¹ is hydrogen. In yet other embodiments, R² is fluorine and R¹ is hydrogen. In some embodiments, n is 1 or 2.

In some embodiments, R³ is methyl, provided that when n is 2, the nitrogen has a positive charge.

In some embodiments, R¹⁰ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, or any subgroup thereof. In some embodiments, R¹⁰ is hydrogen or methyl. In some embodiments, R¹⁰ is hydrogen. In other embodiments, R¹⁰ is methyl.

In some embodiments, R¹¹ is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, or any subgroup thereof. In some embodiments, R¹¹ is hydrogen or methyl. In some embodiments, R¹¹ is hydrogen. In other embodiments, R¹¹ is methyl.

In some embodiments, R⁷ is phenyl or pyridyl and is substituted with one substitutent selected from R⁹.

In some embodiments, R⁹ is selected from -OCH₃, -O(CH₂)₂OCH₃, -N(CH₂)₂OCH₃, morpholino, and piperazin-R¹², or any subgroup thereof, wherein R¹² is selected from methyl, -C(=O)N(CH₃)_2? -C(=O)OCH₃, -SO₂CH₃, -SO₂CH₂CH₃, -C(^O)CH₂CH₃, and -CC=O)CH₃, or any subgroup thereof. In some embodiments, R⁹ is -OCH₃. In other embodiments, R⁹ is -O(CH₂)₂OCH₃. In other embodiments, R⁹ is -N(CH₂)₂OCH₃. In other embodiments, R⁹ is morpholino. In other embodiments, R⁹ is piperazin-R¹².

In some embodiments, R¹² is selected from methyl, -C(=O)N(CH₃)₂, -C(=O)OCH₃, -SO₂CH₃, -SO₂CH₂CH₃, -CC=O)CH₂CH₃, and -C(=O)CH₃, or any subgroup thereof. In some embodiments, R¹² is methyl. In other embodiments, R¹² is -C(=O)N(CH₃)₂. In other embodiments, R¹² is -C(=O)OCH₃. In other embodiments, R¹² is -SO₂CH₃. In other embodiments, R¹² is -SO₂CH₂CH₃. In other embodiments, R¹² is -C(=O)CH₂CH₃. In other embodiments, R¹² is -C(=O)CH₃.

In some embodiments, the compound is selected from: 5-Methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)- amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-qumoline-2-carboxylic acid [4-(4-dimethylcarbamoyl-piperazin-l-yl)-phenyl]-amide; 4-(5-{[5-Methoxy-8-(4- methyl-piperazin- 1 -yl)-4-oxo-l ,4-dihydro-quinoline-2-carbonyl]-amino} -pyridin-2-yl)- piperazine-1-carboxylic acid methyl ester; 4-(4-{[5-Methoxy-8-(4-methyl-piperazin-l_^yl)-4- oxo- 1 ,4-dihydτo-quinolme-2-carbonyl] amino} -phenyl)-piperazine- 1 -carboxylic acid methyl ester; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3 -yl]-amide; 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l -yl)-phenyl]- amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-qumoline-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin-l -yl)-phenyl]-amide); 5-Methoxy-8-(4-methyl-piperazin- l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3- yl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(4-propionyl-piperazin-l -yl)-pyridin-3-yl]-amide; 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [6-(4-acetyl-piperazin- 1 -yl)-pyridin-3- yl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]-amide; 5-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (6- morpholin-4-yl-pyridin-3-yl)-amide; l,l-Dimethyl-4-[5-methyl-2-(4-moφholin-4-yl- phenylcarbamoyl)-4-oxo-l,4-dih.ydro-quiriolin-8-yl]-piperazin-l-ium; 5-Fluoro-l-methyl-8- (4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid methyl-(4- morρholin-4-yl-phenyl)-amide; 4-Hydroxy-5-methyl-8-(4-methyl-ρiperazin- 1 -yl)-quinoline- 2-carboxylic acid (4-methoxy-phenyl)-amide; 4-Hydroxy-5-methoxy-8-(4-methyl-piperazin- l-yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-Fluoro-8-(4-methyl- piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide; 5- Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (6- methoxy-pyridin-3 -yl)-amide; 5-Fluoro-8-(4-methyl-piρerazin- 1 -yl)-4-oxo- 1 ,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 4-Hydroxy-5-methyl-8-(4- methyl~piperazm-l-yl)-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yϊ)-amide; 4- Hydroxy-5-methyl-8-(4-methyl~piperazin- 1 -yl)-quinoline-2-carboxylic acid [4-(4-methyl- piperazin-l-yl)-phenyl]-amide; 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline- 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-Fluoro-8~(4-methyl-piperazin-l-yl)-4- oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-methyl-piperazin-l-yl)-phenyl]-amide; 6- Fluoro-8-(4-methyl-piperazin-l -yl)-4-oxo-l ,4-dihydro-quinoline-2-carboxylic acid (6- methoxy-pyridm-3-yl)-amide; or 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide, or any subgroup thereof. The compounds provided herein are useful in the form as a free base, but may also be provided in the form of a pharmaceutically acceptable salt, and/or in the form of a pharmaceutically acceptable hydrate. For example, pharmaceutically acceptable salts of compounds of Formula I include those derived from mineral acids such as, for example: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, or any subgroup thereof. Pharmaceutically acceptable salts may also be developed with organic acids including, but not limited to, aliphatic mono and dicarboxylates and aromatic acids, or any subgroup thereof. Other pharmaceutically acceptable salts of compounds of the present invention include, for example, hydrochloride, sulfate, pyrosulfate, bisulfate, bisulfite, nitrate, and phosphate, or any subgroup thereof.

It will be appreciated by those skilled in the art that certain compounds of the present invention contain for example asymmetrically substituted carbon and/or sulfur atoms, and accordingly may exist in and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism, thus it is to be understood that the present invention encompasses racemic, optically active, polymorphic or stereoisomeric forms, or mixtures thereof, which forms possess properties useful in the treatment of the disorders set forth below. Preparation of optically active forms is well known in the art how (for example by resolution of racemic forms by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the treatment of the disorder described above. Processes for the manufacture of the compounds of Formula I are provided as further features of the invention. Many of the compounds described herein can be made by processes known in the chemical arts for the production of structurally analogous compounds. Accordingly, the compounds of this invention maybe prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates.

Compounds of the present invention are prepared via the synthetic route depicted in METHOD A. l-(4-Methoxy-2-nitro-phenyl)-4-methyl-piperazine

l-Chloro-4-methoxy-2-nitrobenzene (20 g, 107 mM) in N-methylpiperazine (30 mL, 267.5 mM) is heated to 12O⁰C for 3 hours. The mixture is cooled, diluted with water, extracted with EtOAc, dried, and concentrated. The residue is taken up in EtOAc and treated with 4N HCl in dioxane (1.2 eq.) to generate the HCl salt. The product is collected by filtration, washed with additional EtOAc and dried overnight on a vacuum pump (18.5 g, 61%). LC/MS 1.23 min. 252 (M+H, 100%); IH-NMR (300 MHz, CDC13) 57.60 (s, IH), 7.45 (d, J=I 1 Hz, IH), 7.15 (d, J=I l Hz, IH), 3.95 (s, 3H).

2-[5-Methoxy-2-(4-methyl-piperazin-l-yl)-phenylamino]-but-2-enedioic acid diethyl ester

l-(4-Methoxy-2-nitro-phenyl)-4-methyl-piperazine hydrochloride (5 g, 17.4 mM) in MeOH treated with 10% Pd/C (0.5 g) and hydrogenated at 50 psi for 3 hours. The solution is filtered and the solvent removed at reduced pressure. The residue is dissolved in EtOH and treated with diethylacetylenedicarboxylate (2.96 mL, 17.4 mM) via syringe over 1 minute. After 1 hour, the solvent is removed at reduced pressure and the residue chromatographed (silica, 0 to 10% MeOH/DCM gradient) to give the product as a yellow oil (4.75 g, 70%). LC/MS 2.05 min. 392 (M+H, 100%); IH-NMR (300 MHz, CDC13) δ 8.52 (bs, IH), 7.30 (d, J=8.6 Hz, 1 H)₃ 6.70 (s, IH), 6.49 (d, J=8.6 Hz, 1 H), 5.06 (s, IH), 4.30 (m, 2H), 4.13 (m, 2H), 3.80 (s, 3H)₃ 3.13 (m,2H), 2.72 (m,2H), 2.34 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H).

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid ethyl ester

A three-neck flask equipped with a thermometer, Dean-Stark trap and septum is charged with Dowtherm (40 mL) and heated to reflux (245⁰C). A solution of 2-[5-Methoxy-2-(4-methyl- piperazin-l-yl)-phenylamino]-but-2-enedioic acid diethyl ester (5 g, 12.8 mM) in Dowtherm (5 mL) is added to the boiling reaction via syringe at such a rate as to keep the internal temperature above 24O⁰C. The addition takes about 4 minutes. The reaction is allowed to reach reflux again and the heating source is removed. After cooling to room temperature the reaction mixture is diluted with DCM (10 mL) and applied directly to a silica gel column and chromatographed (0 to 10 % MeOH/DCM) to give the product as a brown solid. Recrystallization from ethyl ether gives the product as a yellow solid (2.2 g, 50%). LC/MS 1.22 min. 346 (M+H, 100%); IH-NMR (300 MHz, CDC13) δ 10.68 (bs, IH), 7.49 (d, J=8.6 Hz, 1 H), 6.60 (d, J=8.6 Hz, 1 H), 6.43 (s, IH), 4.44 (q, J=7.1 Hz, 2H) 3.91 (s, 3H), 3.14 (m, 2H), 2.68 (m, 2H), 2.34 (s, 3H), 1.36 (t, J=7.1 Hz, 3H).

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (6- methoxy-pyridin-3 -yl)-amide

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l ,4-dihydro-quinoline-2-carboxylic acid ethyl ester (0.5g, 1.45 mM) is dissolved in EtOH and treated with 2N LiOH (0.83 mL, 1.67 mM) in one portion. The reaction mixture is heated to 5O⁰C for 30 minutes. The reaction is cooled and the solvent evaporated at reduced pressure. Additional EtOH is added and the solvent removed at reduced pressure. The residue is triturated with AcN and the solid product collected by filtration. The solid is dried on a vacuum pump for several hours. The solid is suspended in DMF and treated with DIPEA (0.4 mL, 2.02 mM) and then HATU (0.66 g, 1.74 mM). The solid dissolves upon addition of HATU and the mixture turns deep red. After 30 minutes 2-amino-6-methoxypyridine (0.18 g, 1.45 mM), is added in one portion and the reaction mixture stirred for 3 hours. The product begins to precipitate after 1 hour. The reaction is diluted with AcN and the product filtered. The solid is rinsed with additional AcN and air-dried. The product is recrystallized form EtOH to give a yellow powder (0.3 g, 50%). LC/MS 1.57 min. 424 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 2H)₃ 8.45 (s, IH), 8.36 (d, J=8.0Hz, IH)₅ 7.52 (d, J=8.5Hz, IH)₃ 6.75 (s₃ IH), 6.74 (d, J=8.0Hz, IH), 6.62 (d, J=8.5Hz, IH), 3.91 (s, 3H), 3.82 (s, 3H), 3.17 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

5-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid ethyl ester

This compound is synthesized from l-(4-methyl-2-nitrophenyl)-4-methyl-piperazine using the same synthetic procedures as described in method A. LC/MS 1.43 min. 330 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.68 (bs, IH), 7.46 (d, J=8.6 Hz, 1 H), 6.93 (d, J=8.6 Hz, 1 H), 6.42 (s, IH), 4.44 (q, J=7.1 Hz, 2H) 3.16 (s, 3H), (m, 4H), 2.68 (m, 4H)₅ 2.60 (s, 3H), 2.34 (s, 3H), 1.36 (t, J=7.1 Hz, 2H).

5-Fluoro-8-(4~methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinolme-2-carboxylic acid ethyl ester

This compound is synthesized from l-(4-fluoro-2-nitrophenyl)-4-methyl-piperazine using the same synthetic procedures as described in method A. LC/MS 1.47 min. 334 (M+H, 100%); IH-NMR (300 MHz, DMSO-dό) δ 10.68 (bs, IH), 7.75 (d, J=8.6 Hz₃ 1 H), 7.19 (d, J=8.6 Hz₅ 1 H), 6.50 (s, IH)₃ 4.44 (q, J=7.1 Hz, 2H)₅ 3.15 (m, 4H)₅ 2.68 (m, 4H), 2.34 (s, 3H), 1.36 (t, J=7.1 Hz, 2H).

6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid ethyl ester

This compound is synthesized from l-(5-fluoro-2-nitrophenyl)-4-methyl-piperazine using the same synthetic procedures asdescribed in method A. LC/MS 1.41 min. 334 (M+H₃ 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.68 (bs, IH), 7.32 (d, J=8.6 Hz, 1 H)₅ 7.28 (m, IH), 6.66 (s, IH)₅ 4.44 (q, 1=1.1 Hz₅ 2H)₅ 3.16 (m, 4H), 2.67 (m, 4H), 2.34 (s, 3H), 1.36 (t, J=7.1 Hz₅ 2H).

Aniline Synthesis

2-Chloro-6-morpholin-4-yl-pyridrn-3-ylamine

A solution of 2-chloro-4-nitropyridine (2.0 g, 12.6 mM) in EtOH is treated with morpholine (2.4 mL, 27.8 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in EtOH and treated with 4N HCl in dioxane. Then 10% Pd/C (0.2 g) is added and the reaction hydrogenated on a Parr Shaker at 50 psi for 2h. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a tan solid (2.0 g, 75%). LC/MS 0.65 min. 214 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 57.10 (d, J=9.0 Hz₃ IH), 6.60 (d, J=9.0 Hz, IH), 5.44 (bs, 2H), 3.74 (m, 4H)₃ 3.67 (m, 4H).

2-(Methoxyethylamino)-4-aminopyridme

A solution of 2-chloro-4-nitropyridine (1.5 g, 9.5 mM) in EtOH is treated with 2- methoxylethylamine (2.1 mL, 23.5 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a dark tan solid (1.8 g, 95%). LC/MS 0.41 min. 168 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 57.60 (s, IH), 6.93 (d, J=9.0 Hz, IH), 6.37 (d, J=9.0 Hz, IH), 5.72 (bs, 3H), 3.70 (t, J=13.0 Hz, IH), 3.45 (t, J=13.0 Hz, IH), 3.43 (s, 3H).

2-(Methoxyethoxy)-4-aminopyridine

2-Methoxyethanol (5 ml) is treated with NaH (0.57 g, 14.3 mM) at room temperature in several portions over 10 minutes. The reaction is exothermic. After stirring at room temperature for 20 minutes, 2-chloro-4-nitropyridine (1.5 g, 9.5 mM) is added in two portions. After stirring at room temperature for 20 minutes, the reaction is poured into water and the product is filtered off and air-dried. This solid is suspended in MeOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as an off white solid (1.8 g, 95%). LC/MS 0.26 min. 169 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 58.12 (s, IH)₃ 7.14 (d, J=8.6 Hz, IH), 6.66 (d, J=8.6 Hz, IH), 5.50 (bs, IH), 4.47 (d, J=8.4 Hz, IH)₃ 3.74 (d, J=8.4 Hz₃ IH), 3.44 (s, 3H). 1 -[4-(5-Amino-pyridin-2-yl)-piperazin- 1 -yl] -propan- 1 -one

A solution of 2~chloro-4-nitropyridine (1.5 g, 9.5 mM) in EtOH is treated with piperazine (2.0 g, 23.5 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in DCM and treated with DIPEA (2.3 mL, 12.4 mM) followed by neat propionyl chloride (0.88 g, 12.4 mM). The reaction is stirred at room temperature for 12 hours. The reaction is quenched with MeOH and the solvent removed at reduced pressure. The product is recrystallized from EtOH. This solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a gray solid (1.4 g, 90%). LC/MS 0.60 min. 235 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 57.56 (s, IH), 6.98 (d, J-9.0 Hz, IH)₇6.86 (d, J=9.0 Hz, IH), 5.51 (bs, 2H), 3.88 (m, 4H), 3.15 (m, 4H), 2.34 (q, J=7.4 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H).

4-(4-Amino-phenyl)-piperazine-l-carboxylic acid dimethylamide

A solution of 4-fluoronitrobenzene (2.7 mL, 25 mM) in EtOH is treated with piperazine (4.7 g, 55 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in DCM and treated with DIPEA (1.7 mL, 9.4 mM) followed by neat N₃N- dimethylcarbamoylchloride (0.71 mL, 7.9 mM). The reaction is stirred at reflux for 1 hour. The reaction is quenched with MeOH and the solvent removed at reduced pressure. The product is recrystallized from EtOH. This solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a gray solid (0.8 g, 13%). LC/MS 0.46 min. 249 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 7.03 (d, J=9.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 2H), 3.75 (m, 4H)₃ 3.72 (bs₃ 2H), 3.24 (m, 4H), 2.83 (s, 3H)₅ 2.73 (s, 3H).

2-(5-Amino-2,3-dihydro-indol-l -yl)-N,N-diethyl-acetamide

A solution of 5-nitro-2,3-dihydro-lH-mdole (1.0 g, 6.1 mM) in DMF is treated with CsCO₃ (3.0 g, 9.1 mM) and 2-Chloro-N,N-diethyl-acetamide (1.1 g, 7.3 mM) and heated to 8O⁰C for 16 hours. The solution Is cooled, poured into water, extracted with EtOAc, the organic layer separated, dried (MgSO₄) and the solvent removed at reduced pressure. The residue is recrystallized from EtOH. This solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a gray solid (0.8 g, 13%). LC/MS 0.46 min. 249 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 6.56 (m, IH), 6.51 (m, IH), 6.45 (s, IH), 3.80 (bs, 2H)₅ 3.62 (s, 2H), 3.30 (m, 2H), 3.26 (m, 4H), 2.91 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H).

4-(4-Amino-phenyl)-piperazine-l-carboxylic acid methyl ester

A solution of 4-fluoronitrobenzene (2.7 mL, 25 mM) in EtOH is treated with piperazine (4.7 g, 55 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in DCM and treated with DIPEA (1.7 mL, 9.4 mM) followed by neat methyl chloroformate (0.62 mL, 7.9 mM). The reaction is stirred at reflux for 1 hour. The reaction is quenched with MeOH and the solvent removed at reduced pressure. The product is recrystallized from EtOH. This solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a gray solid (0.8 g, 13%). LC/MS 0.49 min. 236 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 57.03 (d, J=9.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 2H)₅ 3.75 (m, 4H)₅ 3.72 (bs, 2H)₅ 3.56 (s, 3H)₅ 3.24 (m, 4H).

The present invention also provides compositions comprising any one or more of the compounds described herein and a pharmaceutically acceptable diluent or carrier. Suitable compositions are pharmaceutical compositions.

Compounds of Formula I have been found by the inventors to be useful as 5-HT1B modulators, including as antagonists. The present invention also provides for use of any one or more of the compounds described herein in the treatment of an anxiety disorder, cognitive disorder, or mood disorder as defined herein. In some embodiments, the use is in the treatment of an anxiety disorder. In other embodiments, the use is in the treatment of a cognitive disorder. In other embodiments, the use is in the treatment of a mood disorder.

The present invention also provides methods of treating an animal including a human suffering from an anxiety disorder, cognitive disorder, or mood disorder comprising administering to such animal an effective amount of any of the compounds described herein or a pharmaceutically acceptable salt of the compound. The treatment of these disorders comprises administering to a warm-blooded animal, such as a mammal, or a human, an effective amount of a compound of Formula I₅ or a pharmaceutically acceptable salt of the compound.

The present invention also provides for use of any one of the compounds described herein in the preparation of a medicament for the treatment of an anxiety disorder, a cognitive disorder, or a mood disorder.

The present invention also relates to combination therapies for the treatment of anxiety disorder(s), cognitive disorder(s), and/or mood disorder(s), wherein a compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following: (i) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, mirtazapine, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (ii) atypical antipsychotics including for example quetiapine and lithium and pharmaceutically active isomer(s) and metabolite(s) thereof; (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (v) anticonvulsants including for example carbamazepine, topiramate, valproate, lamotrigine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (vi) Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (ix) stroke therapies including for example abciximab, activase, (NXY-059), citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (x) urinary incontinence therapies including for example darifenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, trypium, tolterodine and equivalents thereof; (xi) neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents thereof; (xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents thereof; (xiii) insomnia therapies including for example allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, eszopiclone, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, roletamide, triclofos₃secobarbital, zaleplon, Zolpidem and equivalents thereof.

Such combination products employ the compounds of the present invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.

AU compounds described herein demonstrate binding affinities (observed Ki values), in an assay described below, of less than about lOμM. Further, some compounds of the present invention not only demonstrate 5HT1B antagonist activity by reversing 5HT1B agonist-induced hypothermia in the guinea pig, some of these compounds are considered to be orally active.

The compounds described herein may be provided or delivered in a form suitable for oral use, for example in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. The compounds may be also be provided for topical administration, for example, as a cream, ointment, gel, spray, or aqueous solutions, oily solutions, emulsions or suspensions. The compounds described herein may also be provided in a form suitable for nasal administration for example, as a nasal spray, nasal drops, or dry powder. The compositions may also be administered to the vagina or rectum in the form of a suppository. The compounds described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion. The compounds may be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingualis

The compositions of the invention may accordingly be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

The amount of active ingredient that, is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. Various assays and in vivo tests are known for determining the utility of the compounds in the disorders noted above and specifically as modulators of 5HT1B and 5HT1D. A utility of the compounds for example to treat depression may be shown via a learned helplessness test in guinea pigs, which is used extensively as correlative to antidepressant activity in humans. The learned helplessness test may be carried out as follows: Seventy male Hartley guinea pigs, each weighing about 350-425 gm are fed ad lib, and are housed under a 12-hour light/dark cycle. The procedure consists of two phases: The induction phase and the avoidance-training phase. In the induction phase, subjects are placed into standard shuttle cages (20 L X 16 W X 21 centimeters H ) which are fitted with a grid floor. Electrical stimulation (1.25 mA, 10 sec duration) is delivered to the floor of the cage every 90-sec during 1 hour daily sessions. Subjects have no opportunity to escape or to avoid shocks. Induction is conducted for 2 consecutive days. In avoidance training, testing may also be conducted in the shuttle cages, except that the subjects are not returned to the same chamber in which induction had occurred. Additionally, all cages are fitted with a partition with an arch in the center of the cage, through which animals can pass between the left and right halves of the cage. The procedure employed is a standard shuttle avoidance procedure in which a compound, conditioned stimulus (a 10-second presentation of a tone and turning on of a lamp on the side of the cage that the guinea pig is occupying) serves to indicate presentation of electrical current to the floor of the cage. Shock is presented for a 5 second period, 5 seconds after initiation of the conditioned stimulus. Entry into the opposite side of the shuttle cage via the arched partition prior to shock onset results in the end of the trial (avoidance response). If shock is delivered, entry into the opposite side of the cage results in termination of the shock and CS (escape). Reversal of learned helplessness in the induction subjects correlates to antidepressant activity of the test compound.

Avoidance training, 45-minute in duration, is conducted on 2 consecutive days, beginning 48 hours after the final induction session. Seventy subjects are assigned to 1 of 6 groups of 11-12 animals. The groups are as follows: 1) No induction group. The subjects are placed into the shuttle cages but are not given inescapable shock, the animals are subsequently trained in the avoidance procedure and the vehicle is administered;

2) Induction vehicle control group;

3) Imipramine 17. S mg/kg; 4) 0.3 mg/kg compounds;

5) 1 mg/kg compounds; and

6) 5 mg/kg compounds.

Groups 2-6 are given induction and avoidance training sessions. Injections are administered immediately following induction sessions and 1 hour prior to avoidance training sessions. A second inj ection is administered 7-8 hours following the first injection, for a total of 9 injections administered over 5 days. No injections are administered following the final avoidance training session.

Compounds of the present invention may be administered in a volume of 1 mL/kg bwt. Imipramine is dissolved in DI water. The compounds are dissolved in DI water, to which is added a few drops of lactic acid (pH 5.5). The vehicle control is DI water prepared with lactic acid to the same pH as the-treated groups.

The primary dependent variable is escape failure during avoidance training. 2-way analysis of variance (ANOVA) is used to assess overall treatment effect, with Dunn's post hoc analysis used to compare the vehicle-treated group with the drug-treated groups. The no- induction group is used to gauge whether learned helplessness is established, by comparison to the vehicle treated group. An alternative method for determining the utility of the compounds of the present invention is to investigate the in vivo activity of the compounds using a guinea pig hypothermia test (J. Med. Chem., 41 : 1218-1235 (1998)).

Assays that may be used to measure for example affinity of compounds of the present invention for 5HT1B receptors are described in J. Med. Chem 41:1218-1235, 1228 (1998) and J. Med. Chem 42:4981-5001, (1999). These assays may be used with some modifications: Frozen membrane preparations of a stably transfected Chinese hamster ovary (CHO) cell line expressing 5-rHTlB receptors and 5-HT1D receptors are thawed rapidly, briefly vortexed, and diluted in assay buffer (AB) containing 50 mM Tris-HCl, 4 mM MgCl₂, 4 mM CaCl₂, 1 mM EDTA, and adjusted to pH 7.4 with NaOH. Final protein concentrations are - 0.185 mg/ml for 5-HT1B, and 0.4 mg/ml for 5-HT1D membranes. Test compounds are evaluated in competition assays using [³H]-GRl 25743 (Amersham). The ligand concentration in both assays is 0.27nM. Kd for [³H]-GRl 25743 may vary from 0.15 nM to 0.25 nM. The 5-HT1B and 5-HT1D assays are performed simultaneously on one 96-well assay plate, one drug/compound per plate. Ten serial dilutions (1 μM to 4 pM, final concentration) of compound are prepared in DMSO from 10 mM stock solutions. Incubation mixtures are prepared in quadruplicate in 96-deep well assay plates (Matrix 1 ml). Final assay volumes per well are 10 μl compound/nonspecific; 100 μl membranes; 100 μl [³H]- GR125743; and 790 μl AB. Specific binding is defined by using 10 μM Methiothepine. The assay plates are shaken for 5 minutes, and then incubated for an additional 55 minutes. Then the assay plates are filtered through Beckman GF/B filters (soaked > 2 hours in PEI) using a Packard Filtermate 196. Filters are washed 2x with 1 ml ice-cold wash buffer (5 mM Tris- HCl - pH7.4 with NaOH). After the filters are dried, 35 μl of Microscint20 is added to each well. The plates are then counted on a Packard TopCount to determine CPM's per well. Ki values are determined for each test compound utilizing the graphic and analytical software package, GraphPad Prism. Compounds are then ranked in order of potency, and selectivity for 5-HT1B over 5-HT1D receptors. Ki values for compounds of the present invention range from InM-IO μM.

A method that may be used to determine a compound's affinity for 5-HT1B and 5HT1D receptors is a guinea pig cortical test. This assay is described in detail by Roberts, et al, Br. J. Pharmacol., 1996, 117, 384-388, which is incorporated by reference herein. The test is carried out as follows: Guinea pigs are decapitated and the cortici is dissected out, weighed and homogenized in 50 mM Tris-HCl, pH 7.7 with an Ultra-Turrax followed by centrifugation for 10 min at 48000 x g and 5⁰C. The pellet is resuspended and recentrifuged. The final pellet is suspended in 0.32 M sucrose buffer to a concentration of 0.5g original wet weight per mL and stored frozen at -7O⁰C. The radioligand binding assay is carried out as follows: [³H]GR125743 saturation studies are tested in duplicate with 3-4 mg w.w. per tube in 5 mL buffer (50 mM Tris, 4 mM CaCl₂, 4 mM MgCl₂ and 1 mM EDTA at pH 7.7), and a concentration range of 0.012 to 2 nM (10-12 concentrations) for the radioligand. Nonspecific binding is determined in the presence of 10 mM methiothepin. In competition experiments 4-8 mg w.w. per tube and a radioligand concentration of 0.2 nM are used with 10-12 concentrations of the competing drug. The assays are run for 2-4 hours at 30⁰C and terminated by rapid filtration through Whatman GF/B filters (pretreated with 0.1% polyethyleneimine) using a Brandel cell harvester. Bovine serum albumin (0.1%) is added to the washing buffer to reduce non-specific binding. Data from the experiments may be analyzed using the iterative non-linear curve-fitting program LIGAND. The Kd values obtained from the saturation studies are used in the calculation of the Ki values by the LIGAND program. The Kd value of [³H]GR125743 may result in a measurement of 46 ± 4 pM and the Bmax in a measurement of 4.9 ± 0.2 pmol/g w.w. Kd values for compounds of the present invention range from InM-IO μM. A GTPγS binding assay may used to determine whether a compound is a 5HT1B or

5HT ID agonist or antagonist. One assay available measures agonist stimulated GTP binding for example as set forth by Lazareno, S. (1999) Methods in Molecular Biology 106: 231-245. Membrane preparations of a stably transfected CHO cell line expressing human 5-HT1B receptors are purchased for example from Unisyn, Hopkinton, MA. Frozen membranes are thawed, briefly sonicated, and diluted to 167 μg/ml protein in assay buffer containing 20 mM HEPES₃ 100 mM NaCl, ImM MgCl₂ and 1 μM GDP₃ pH adjusted to 7.4 with NaOH. Diluted membranes are briefly homogenized with a Polytron and allowed to equilibrate at room temperature for at least 15 minutes before use. Serial dilutions (10 μM to 1 pM, final concentration) of test compounds are prepared in buffer with and without 100 nM 5-HT (final concentration) from 10 mM DMSO stock solutions. Incubation mixtures are prepared in quadruplicate in 96-well, deep-well plates and consisted of 180 μL of membranes (30 μg protein) and 40 μL of compound with or without 5-HT. After an incubation period of 15 minutes at room temperature, 20 μL of [35S]GTPγS (NEN; 100 pM final concentration) is added to begin the assay. Mixtures are shaken for 2 minutes and incubated at room temperature for an additional 28 minutes. The reaction is stopped by rapid filtration through Beckman GF/B glass fiber filters using a 96-well Packard cell harvester. Filters are washed four times with 1 mL ice-cold water. The filter plates are nominally dried and 30 μL of scintillation cocktail (MicroScint 40, Packard) is added to each well. CPMs for each well is determined using a TopCount Scintillation Counter (Packard). Maximum stimulation of [35S]GTPyS binding is defined in the presence of 10OnM 5-HT. Basal [³⁵S]GTPyS binding is defined in buffer alone. IC50 values are defined as the concentration of compound at which 50% of the 10OnM 5-HT response [is] obtained. Maximal intrinsic activity (IA) of a compound is defined as the percent maximal 5-HT-induced stimulation by 10 μM compound in the absence of 5-HT. As an inter-assay standard, a concentration response curve of 5-HT (1 μM to 1 pM final) in the absence of compounds is included in each assay and an EC50 is determined. EC50 values for compounds of the present invention range from lOnM-10 μM.

In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner. Throughout these examples, molecular cloning reactions, and other standard recombinant DNA techniques, were carried out according to methods described in Maniatis et al., Molecular Cloning - A Laboratory Manual, 2nd ed., Cold Spring Harbor Press (1989), using commercially available reagents, except where otherwise noted.

Compounds of the present invention include, but are not limited to, those disclosed in the following Examples. AU examples can be synthesized according to Method A starting from the appropriate quinolone ester core and the corresponding amine partner.

EXAMPLES

Example 1 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid (6-methoxy-pyridin-3-yl)-amide

LC/MS 1.57 min. 424 (MH-H₅ 100%); IH-NMR (300 MHz, DMSO-d6) δlθ.09 (bs, 2H), 8.45 (s, IH), 8.36 (d, J=8.0Hz, IH), 7.52 (d, J=8.5Hz, IH), 6.75 (s, IH), 6.74 (d, J=8.0Hz, IH), 6.62 (d, J=8.5Hz, IH), 3.91 (s, 3H), 3.82 (s, 3H), 3.17 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 2: 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinolme-2- carboxylic acid [4-(4-dimethylcarbamoyl-piperazin-l -yl)-phenyl]-amide

LCMS 1.65 min. 548 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 59.89 (bs, 2H), 7.59 (d, J=9.3Hz, 2H), 7.52 (d, J=8.5Hz, IH), 6.91 (d, J=9.3Hz, 2H), 6.62 (d, J=8.5Hz, IH), 6.62 (s, IH), 3.91 (s, 3H), 3.75 (m, 4H), 3.27 (m, 4H), 3.17 (m, 4H), 2.83 (s, 3H), 2.73 (s, 3H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 3 : 4-(5- {[5-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-l ,4-dihydro-quinoline-2- carbonyl]-amino} -pyridin-2-yl)-piperazine-l -carboxylic acid methyl ester

LC/MS 1.53 min. 536 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 2H), 8.70 (s, IH), 8.16 (d, J=8.2Hz, IH), 7.52 (d, J=8.5Hz, IH), 6.98 (d, J=8.2Hz, IH), 6.75 (s, IH), 6.62 (d, J-8.2Hz, IH), 3.91 (s, 3H), 3^67 (m, 4H)₃ 3.56 (s, 3H), 3.17 (m, 4H), 2.85 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 4: 4-(4- { [5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carbonyl]amino}-phenyl)-piperazine-l-carboxylic acid methyl ester

LC/MS 1.62 min. 535 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.59 (d, J=9.3Hz, 2H), 7.52 (d, J=8.5Hz, IH), 6.89 (d, J=9.3Hz, 2H), 6.62 (d, J=8.5Hz, IH), 6.61 (s, IH), 3.91 (s, 3H), 3.62 (m, 4H), 3.56 (s, 3H), 3.45 (m, 4H), 3.23 (m, 4H), 3.17 (m, 4H)₅ 3.03 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 5 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide

LCMS 1.59 min. 468 (M+H, 100%); IH-NMR (300 MHz, DMSO~d6) δ 10.09 (bs, 2H), 8.45 (s, IH), 8.36 (d, J=8.0Hz, IH)₅ 7.52 (d, J=8.5Hz, IH), 6.77 (d, J=8.0Hz, IH), 6.75 (s, IH)₃ 6.62 (d, J=8.0Hz, IH), 4.47 (m, 2H), 3.91 (s, 3H), 3.71 (m, 2H), 3.44 (s, 3H), 3.17 (m, 4H), 2.68 (m,'4H), 2.34 (s, 3H).

Example 6: 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l ,4-dihydro-quinoline-2- carboxylic acid [4-(4-methanesulfonyl-piperazin- 1 -yl)-ph.enyl]~amide

LC/MS 1.56 min. 555 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H)₃ 7.59 (d, J=9.3Hz. 2H), 7.52 (d, J=8.5Hz, IH), 6.95 (d, J=9.3Hz, 2H), 6.62 (d, J=8.5Hz, IH), 3.91 s, 3H), 3.65 (m, 4H), 3.59 (m, 4H), 3.17 (m, 4H)₅ 2.93 (s, 3H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 7 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid [4-(4-ethanesulfonyl-piperazin-l-yl)-phenyl]-amide

LCMS 1.65 min. 569 (M+H, 100%); IH-NMR (300 MHz₅ DMSO-d6) δ 9.89 (bs, 2H), 7.59 (d, J=9.3Hz₃ 2H), 7.52 (d, J=8.5Hz, IH), 6.95 (d, J=9.3Hz, 2H)₃ 6.62 (d, J=8.5Hz, IH), 3.91 s, 3H)₃ 3.65 (m, 4H)₃ 3.59 (m, 4H)₃ 3.17 (m, 4H), 3.13 (m, 2H), 2.93 (s, 3H)₃ 2.68 (m, 4H), 1.34.(t, J=7.6Hz, 3H).

Example 8: 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l ,4-dihydro-qumoline-2- carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide

LC/MS 1.20 min. 467 (M+H, 100%); IH-NMR (300 MHz₃ DMSO-d6) δ 8.77 (bs, 3H)₃ 8.71 (S₃ IH), 8.20 (d, J=8.2Hz, IH)₃ 7.52 (d, J=8.5 Hz₃ IH)₃ 6.75 (s, IH)₃ 6.72 (d, J=8.2Hz, IH)₃ 6.62 (d, J=8.5Hz, IH), 3.91 (s, 3H)₃ 3.70 (s, 2H)₃ 3.43 (s, 3H), 3.42 (s, 2H), 3.17 (m, 4H), 2.68 (m, 4H)₃ 2.34 (s, 3H).

Example 9 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid [6-(4-propionyl-piperazin- 1 -yl)-pyridin-3 -yl]-amide

LC/MS 1.47 min. 534 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 2H), 8.70 (s, IH), 8.16 (d, J=8.2Hz, IH), 7.52 (d, J=8.5 Hz₃ IH), 6.98 (s, IH), 6.75 (d, J=8.5 Hz, IH), 6.62 (d, J=8.2 Hz, IH), 3.91 (s, 3H), 3.88 (m, 4H), 3.18 (m, 4H), 3.17 (m, 4H), 2.68 (m, 4H), 2.35 (m,2H), 2.34 (s, 3H), 0.97 (t, J=7.4Hz, 3H).

Example 10 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid [6-(4-acetyl-piperazin-l-yl)-pyridin-3-yl]-amide

LCMS 1.32 min. 520 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 2H), 8.70 (s, IH), 8.16 (d, J=8.2Hz, IH), 7.52 (d, J=8.5 Hz, IH), 6.98 (s, IH), 6.75 (d, J=8.5 Hz, IH), 6.62 (d, J=8.2 Hz, IH), 3.91 (s, 3H), 3.88 (m, 4H), 3.18 (m, 4H), 3.17 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H), 2.13 (s, 3H).

Example 11: 5-Methoxy-8-(4-meth.yl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2- carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide

LCMS 1.45 min. 519 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.59 (d, J=9.3Hz, 2H), 7.52 (d, J=8.5 Hz, IH), 6.89 (d, J=9.3 Hz, 2H), 6.62 (d, J=8.2 Hz, IH), 3.91 (s, 3H), 3.82 (m, 4H)₃ 3.17 (m, 4H), 3.08 (m, 4H), 2.68 (m, 4H)₅ 2.34 (s, 3H), 2.07 (s, 3H).

Example 12 : 5~Methoxy-8-(4-methyl~piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-qumoline-2- carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl] -amide

LC/MS 1.65 min. 533 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H)₃ 7.59 (d, J=9.3Hz, 2H), 7.52 (d, J=8.5 Hz, IH), 6.89 (d, J=9.3 Hz, 2H), 6.62 (d, J=8.2 Hz, IH), 3.91 (s, 3H), 3.82 (m, 4H), 3.17 (m, 4H), 3.08 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H), 2.32 (m, 2H), 0.97 (t, J=7.4Hz, 3H).

Example 13 : 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

LC/MS 1.40 min. 479 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10.09 (bs, 2H), 8.70 (s, IH), 8.16 (d, J=8.2Hz, IH), 7.52 (d, J=8.5 Hz, IH)₅ 6.83 (s, IH)₃ 6.75 (d, J=8.5 Hz, IH), 6.62 (d, J=8.2 Hz, IH), 3.91 (s₅ 3H), 3.72 (m, 4H), 3.64 (m, 4H), 3.17 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 14: l,l-Dimethyl-4-[5-methyl-2-(4-morpholin-4-yl-phenylcarbamoyl)-4-oxo-l,4- dihydro-quinolin-8-yl]-piperazin- 1 -ium

LC/MS 1.53 min. 476 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.59 (d, J=9.3Hz, IH), 7.27 (d, J=8.0Hz, IH), 6.94 (d, J=9.3Hz, IH), 6.76 (d, J=8.0Hz, IH), 6.61 (s, IH), 3.74 (m, 4H), 3.69 (m, 4H), 3.30 (s, 6H), 3.27 (m, 4H), 3.13 (m, 4H), 2.58 (s, 3H).

Example 15 : 5-Fluoro- 1 -methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid methyl-(4-morpholin-4-yl-phenyl)-amide

LC/MS 1.34 min. 494 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=9.3Hz, IH), 7.42 (d, J=8.0Hz, IH), 7.23 (d, J=9.3Hz, IH), 6.94 (d_r J=8.0Hz, IH), 6.56 (s,lH), 3.69 (m, 4H), 3.50 (s, 3H)₇ 3.36 (s, 3H), 3.31 (m, 4H), 3.26 (m, 4H), 2.69 (m, 4H), 2.34 (s, 3H).

Example 16: 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-I-yl)-quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide

LC/MS 1.74 min. 407 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.57 (d, J=9.3Hz, IH), 7.49 (d, J=8.0Hz, IH), 6.95 (d, J=9.3Hz, IH)₃ 6.83 (d, J=8.0Hz, IH), 6.61 (s, IH), 3.78 (s, 3H), 3.19 (m, 4H), 2.68 (m, 4H), 2.58 (s, 3H), 2.34 (s, 3H).

Example 17: 4-Hydroxy-5-methoxy-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholm-4~yI-phenyl)-amide

LC/MS 1.47 min. 478 (M+H, 100%); IH-NMR (300 MHz, DMSO-dό) δ 11.87 (bs, 2H), 7.50 (d, J=9.3Hz, IH), 7.22 (d, J=8.0Hz, IH), 6.77 (d, J=9.3Hz, IH)₃ 6.57 (d, J=8.0Hz, IH)₅ 6.49 (s, IH), 3.90 (s, 3H)₃ 3.69 (m, 4H), 3.53 (m, 4H), 3.12 (m, 4H), 2.57 (m, 4H), 2.28 (s, 3H).

Example 18: 5-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dthydro-quinoline-2-carboxylic acid (4-methoxy-ph.enyl)-amide

LC/MS 1.49 min. 411 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.78 (d, J=9.3Hz, IH), 7.57 (d, J=8.0Hz, IH)₅ 7.21 (d, J=9.3Hz, IH), 6.83 (d, J=8.0Hz, IH), 6.69 (s, IH)₅ 3.78 (m, 4H), 3.18 (m, 4H)₃ 2.68 (m, 4H), 2.34 (s, 3H).

Example 19: 5-Fluoro-8-(4-methyl-piperazin-l -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide

LC/MS 1.40 min. 412 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 10:09 (bs, 2H), 8.45 (d, J=8.0Hz₃ IH), 8.36 (d, J=8.0Hz, IH), 7.78 (d, J=8.0Hz₃ IH), 7.21 (d, J=8.0Hz, IH)₃ 6.82 (s, IH), 6.74 (d, J=8.0Hz, IH)₃ 3.82 (s, 3H), 3.18 (m₃ 4H)₃ 2.68 (m, 4H)₃ 2.34 (s, 3H).

Example 20 : 5-Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morρholm-4-yl-phenyl)-amide

LC/MS 1.53 min. 466 (M+H, 100%); IH-NMR (300 MHz₃ DMSO-d6) δ 9.89 (bs₃ 2H)₃ 7.78 (d₃ J=8.0Hz, IH)₃ 7.59 (d₃ J=9.3Hz, IH), 7.21 (d, J=8.0Hz, IH), 6.76 (d₃ J=9.3Hz, IH), 6.69 (s₃ IH), 3.69 (m₃ 4H), 3.27 (m, 4H), 3.18 (m, 4H), 2.68 (m, 4H), 2.34 (s, 3H).

Example 21: 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide

LCMS 1.64 min. 408 (M+H, 100%); IH-NMR (300 MHz₃ DMSO-d6) δ 10.09 (bs, 2H), 8.45 (s, IH), 8.36 (d, J=8.0Hz, IH), 7.49 (d, J=8.0Hz, IH), 6.95 (d, J=8.0Hz, IH), 6.74 (d, J=8.0Hz, IH), 6.73 (s, IH), 3.82 (s, 3H), 3.19 (m, 4H), 2.68 (m, 4H), 2.58 (s, 3H), 2.34 (s, 3H).

Example 22: 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid [4-(4-methyl-piperazin- 1 -yl)-phenyl]-amide

LC/MS 1.38 min. 475 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H)₅ 7.59 (d, J=9.3Hz, IH), 7.49 (d, J=8.0Hz, IH), 6.95 (d, J=8.0Hz, IH), 6.89 (d, J=9.3Hz, IH), 6.61 (s, IH), 3.19 (m, 4H), 3.07 (m, 4H), 2.68 (m, 4H), 2.58 (s, 3H), 2.54 (m, 4H), 2.34 (s, 3H), 2.31 (s, 3H).

Example 23 : 4-Hydroxy-5-methyl-8-(4-methyl-piperazin- 1 -yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

LCMS 1.71 min. 462 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) δ 9.89 (bs, 2H), 7.59 (d, J=9.3Hz, IH), 7.49 (d, J=8.0Hz, IH), 6.95 (d, J=8.0Hz, IH), 6.76 (d, J=9.3Hz, IH), 6.61 (s, IH), 3.69 (m, 4H), 3.27 (m, 4H), 3.19 (m, 4H), 2.68 (m, 4H), 2.58 (s, 3H), 2.34 (s, 3H).

Example 24 : 6-Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4-methyl-piperazin-l -yl)-phenyl]-amide

LCMS 1.32 min. 479 (M+H, 100%); IH -NMR (300 MHz, DMSO-d6, TFA shake) δ 7.78 (d, J = 8.8 Hz, 2H), 7.60 (s, IH), 7.47 (d, J = 9.0 Hz₅ IH), 7.26 (d, J = 10.9 Hz, IH), 7.08 (d, J = 8.8 Hz, 2H), 4.15 (d, J = 12.8 Hz, 2H), 3.84 (d, J = 13.0 Hz, 2H), 3.67 (d, J = 11.3 Hz, 2H), 3.62 - 3.41 (m, 4H), 3.33 - 3.13 (m, 4H), 3.07 - 2.83 (m, 8H).

Example 25 : 6-Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide

LC/MS 1.50 min. 412 (M+H, 100%); IH -NMR (300 MHz, DMSO-d6, TFA shake) δ 8.61 (d, J = 2.6 Hz, IH), 8.26 (dd, J = 8.9, 2.7 Hz, IH), 7.61 (s, IH), 7.47 (dd, J = 9.1, 2.6 Hz, IH), 7.25 (dd, J - 11.0, 2.7 Hz, IH), 6.93 (d, J = 8.9 Hz, IH), 4.17 (d, J = 13.3 Hz₅ 2H)₃ 3.89 (s, 3H)₅ 3.68 (d, J = 12.1 Hz, 2H), 3.53 (t, J = 10.7 Hz, 2H), 3.24 (t, J = 11.7 Hz, 2H), 2.98 (s, 3H).

Example 26: 6-Fluoro-8-(4-methyl-piperazm-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide

LC/MS 1.58 min. 411 (M+H, 100%); IH -NMR (300 MHz, DMSO-d6, TFA shake) δ 7.80 (d, J = 9.0 Hz, 2H), 7.61 (s, IH), 7.47 (dd, J = 9.2, 2.6 Hz, IH), 7.25 (dd, J = 10.8, 2.6 Hz, IH), 7.00 (d, J = 9.0 Hz, 2H), 4.15 (d, J - 13.0 Hz₃ 2H), 3.79 (s, 3H), 3.68 (d, J = 11.9 Hz, 2H), 3.53 (t, J = 10.7 Hz, 2H), 3.25 (t, J = 11.6 Hz, 2H), 2.98 (s, 3H).

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound selected from the following:

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide;

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4-dimethylcarbamoyl-piperazin-l-yl)-phenyl]-amide;

4-(5- {[5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carbonyl]-ammo}-pyridin-2-yl)-piperazme-l-carboxylic acid methyl ester; 4-(4- {[5-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo- 1 ,4-dihydro-quinoline~2- carbonyl]amino}-phenyl)-piperazine-l-carboxylic acid methyl ester;

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide;

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]-amide;

5-Methoxy-8-(4-methyl-piperazm-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin-l-yl)-phenyl]-amide);

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide; 5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1₃4-dihydro-quinoline-2-carboxylic acid [6-(4-propionyI-piρerazin-l -yl)-pyridin-3-yl]-amide;

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [6-(4-acetyl-piperazin-l-yl)-pyridin-3-yl]-amide;

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide;

5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]-amide;

5-Methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide; 1,1 -Dimethyl-4-[5-methyl-2-(4-morpholin-4-yl-phenylcarbamoyl)-4-oxo- 1 ,4- dihydro-quinolin-8-yl]-piperazin- 1 -ium; 5-Fluoro- 1 -methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2- carboxylic acid methyl-(4-morpholin-4-yl-phenyl)-amide;

4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4- methoxy-phenyl)-amide; 4-Hydroxy-5-methoxy-8-(4-methyl-piperazm-l-yl)-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide;

5-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide;

5-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (6~methoxy-pyridin-3-yl)-amide;

5-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide;

4-Hydroxy-5-methyl-8-(4-methyl-piperazm-l -yl)-quinoline-2-carboxylic acid (6- methoxy-pyridin-3-yl)-amide; 4-Hydroxy-5-methyl-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid [4-(4- methyl-piperazin- 1 -yl)-phenyl]-amide;

4-Hydroxy-5-methyl-8-(4-methyl-piperazin- 1 -yl)-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide;

6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-methyl-piperazin-l-yl)-phenyl]-amide;

6-Fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-l ,4-dihydro-quinoline-2-carboxylic acid (6-methoxy-pyxidin-3 -yl)-amide;

6-Fluoro-8-(4-methyl-piperazm-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-methoxy-phenyl)-amide or a pharmaceutically acceptable salt.

2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent or carrier.

3. The use of a compound according to claim 1 in the treatment of an anxiety disorder, cognitive disorder, and/or mood disorder.

4. The use of a compound according to claim 1 in the treatment of an anxiety disorder.

5. The use of a compound according to claim 1 in the treatment of panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive- compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, and/or generalized anxiety disorder due to a general medical condition.

6. The use of a compound according to claim 1 in the treatment of a cognitive disorder.

7. The use of a compound according to claim 1 in the treatment of Alzheimer's disease, dementia, dementia due to Alzheimer's disease, and/or dementia due to Parkinson's disease.

8. The use of a compound according to claim 1 in the treatment of a mood disorder.

9. The use of a compound according to claim 1 in the treatment of a depressive disorder.

10. The use of a compound according to claim 1 in the treatment of major depressive disorder, dysthymic disorder, bipolar depression, bipolar mania, cyclothymic disorder, mood disorder due to a general medical condition, manic episode associated with bipolar disorder, and/or mixed episode associated with bipolar disorder.

11. A method of treating an animal suffering from an anxiety disorder, cognitive disorder, and/or mood disorder comprising administering to such animal an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt of said compound.

12. The method according to claim 11 wherein the treatment is for an anxiety disorder.

13. The method according to claim 12 wherein the anxiety disorder is selected from panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, and/or generalized anxiety disorder due to a general medical condition.

14. The method according to claim 11 wherein the treatment is for a cognitive disorder.

15. The method according to claim 14 wherein the cognitive disorder is selected from Alzheimer's disease, dementia, and dementia due to Alzheimer's disease, and/or dementia due to Parkinson's disease.

16. The method according to claim 11 wherein the treatment is for a mood disorder.

17. The method according to claim 16 wherein the mood disorder is a depressive disorder.

18. The method according to claim 17 wherein the depressive disorder is selected from major depressive disorder, dysthymic disorder, bipolar depression and/or bipolar mania, cyclothymic disorder, mood disorder due to a general medical condition, manic episode associated with bipolar disorder, and mixed episode associated with bipolar disorder.

19. The method according to claim 18 wherein the bipolar depression and/or bipolar mania is bipolar II, or bipolar I with or without manic, depressive or mixed episodes.

20. The use of any one of the compounds according to claim 1 in the preparation of a medicament for the treatment of an anxiety disorder, a cognitive disorder, and/or a mood disorder.