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WO2020183011A1 - Htr1d inhibitors and uses thereof in the treatment of cancer - Google Patents

Htr1d inhibitors and uses thereof in the treatment of cancer Download PDF

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Publication number
WO2020183011A1
WO2020183011A1 PCT/EP2020/056957 EP2020056957W WO2020183011A1 WO 2020183011 A1 WO2020183011 A1 WO 2020183011A1 EP 2020056957 W EP2020056957 W EP 2020056957W WO 2020183011 A1 WO2020183011 A1 WO 2020183011A1
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Prior art keywords
methyl
phenyl
piperazin
methoxy
methylpiperazin
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PCT/EP2020/056957
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French (fr)
Inventor
Sergio Roman Roman
Alice PINHEIRO
Fabien Reyal
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Institut Curie
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Institut Curie
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • the present invention relates to the treatment of cancer.
  • the present invention relates to the use of 5-hydroxytryptamine receptor ID inhibitors in the prevention and treatment of cancer.
  • the present invention further relates to the use of 5 -hy droxytryptamine receptor ID inhibitors in combination with one or several 5 -hy droxytryptamine receptor IB inhibitor(s) in the prevention and treatment of cancer.
  • the present invention further pertains to diagnosis, stratification and/or prognosis methods based on the measure of HTRID and/or HTR1B gene expression level.
  • Breast cancer is a cancer that develops from breast tissue. Most breast cancers are invasive, i.e., the proliferation of cell has expanded into surrounding breast tissues, beyond the wall of the glands or ducts where they originate from. The extent of the spread of the cancer at the time of diagnosis is used in the TNM (Tissue, Node, Metastasis) staging system, that distinguishes between five stages of advancement, from noninvasive (stage 0) to metastasized cancer (stage IV).
  • TNM tissue, Node, Metastasis
  • the four types of breast cancer are:
  • HR HER2 + This type of cancer, called “HER2-enriched breast cancer”, accounts for about 1 to 5% of all diagnosed breast cancers. Despite the tendency of cancer in this group to grow and spread aggressively, the use of targeted therapies has reversed much of the adverse prognosis impact of HER2 overexpression. Because of the absence of hormone receptors, HER2-enriched breast cancers do not respond to hormonal therapy. Targeted therapies are therefore used, such as Herceptin (trastuzumab), Perjeta (pertuzumab), Tykerb (lapatinib) or Kadcyla (T-DM1 or ado-trastuzumab emtansine).
  • Herceptin tacuzumab
  • Perjeta pertuzumab
  • Tykerb lapatinib
  • Kadcyla T-DM1 or ado-trastuzumab emtansine
  • Luminal A breast cancer This type of breast cancers, called“luminal A breast cancer”, is the most common form of breast cancer. It accounts for around 70 to 75% of all diagnosed breast cancers. Luminal A breast cancers have low levels of proliferation marker Ki-67, which helps control how fast cancer cells grow. Luminal A cancers tend to be slow-growing, low-grade and thus less aggressive. They are thus associated with favorable prognosis and good response to hormonal therapy.
  • This type of breast cancers is further defined by being highly positive for the proliferation marker Ki-67. It accounts for around 10% of all diagnosed breast cancers and tends to be higher- grade and more aggressive than luminal A breast cancers.
  • 5-HT serotonin (5-hydroxytryptamine or 5-HT) has emerged as an important regulator of cell proliferation and tumor growth in a variety of tissues.
  • 5-HT well studied for its function in the nervous system as neurotransmitter, has numerous important peripheral functions.
  • 5-HT has been shown to function as a growth factor regulating normal cell (e.g., vascular smooth muscle cells, lung fibroblasts, mammary epithelial cells or renal mesangial cells) and cancer cell (e.g., in cholangiocarcinoma, breast cancer, bladder cancer or pancreatic cancer) proliferation in various tissues (Nemecek et al, 1986. Proc Natl Acad Sci U S A.
  • 5-HT can exert its action through a repertoire of more than 15 G protein-coupled receptors or ligand-gated ion channels, collectively named 5-HT receptors, and belonging to seven families: 5-HTR1 to 7.
  • Another major player in the 5-HT system primarily terminating the action of 5-HT, is the 5-HT reuptake transporter (SERT, encoded by the SLC6A4 gene).
  • SERT 5-HT reuptake transporter
  • another 5-HT transporter has been identified, which may account for a significant percentage of 5-HT clearance although having a low serotonergic affinity (Zhou et al., 2007. Biochem Pharmacol. 73(1): 147-54).
  • the Inventors show that the expression of the gene coding for 5-HTR1D, HTRID, is upregulated in breast cancer patient with poor prognosis. From this finding, the Inventors further demonstrate that inhibiting 5-HTR1D signaling, either by using a selective 5-HTR1D antagonist or a specific silencing RNA (siRNA), decreases breast cancer cell viability. Moreover, they show that this decrease in breast cancer cell viability is even sharper when both 5-HTR1D and 5-HTR1B signaling are inhibited. Together, these observations unveil a novel therapeutic strategy for breast cancer patients, i.e., the inhibition of 5-HTR1D signaling alone or in combination with the inhibition of 5-HTR1B signaling.
  • siRNA silencing RNA
  • liver cancer lung cancer
  • brain lower grade glioma mesothelioma
  • mesothelioma head and neck squamous cell carcinoma
  • renal clear cell carcinoma renal chromophobe cell carcinoma
  • renal papillary cell carcinoma gastric cancer and cervical squamous cell carcinoma.
  • the invention deals with a 5-hydroxytryptamine receptor ID (5-HTR1D) inhibitor, for use in the prevention and/or treatment of cancer in a subject in need thereof.
  • 5-HTR1D 5-hydroxytryptamine receptor ID
  • the 5-HTR1D inhibitor is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides. In a further embodiment of the invention, the 5-HTR1D inhibitor is a selective 5-HTR1D inhibitor.
  • the invention deals with a combination of at least one 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) for use in the prevention and/or treatment of cancer in a subj ect in need thereof wherein said 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
  • the invention deals with a composition for use in the prevention and/or treatment of cancer in a subject in need thereof comprising a 5-HTR1D inhibitor as above described
  • composition for use further comprises at least one inhibitor of 5 -hy droxytryptamine receptor IB (5-HTR1B).
  • the 5-HTR1B inhibitor of said composition for use is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
  • the composition for use is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.
  • the 5-HTR1D inhibitor, the combination, the composition is for use in the treatment and/or prevention of cancer, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer.
  • said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer and mesothelioma.
  • said cancer cells overexpress the gene coding for 5-HTR1D.
  • said cancer cells overexpress the gene coding for 5-HTR1B.
  • said 5-HTR1D inhibitor, the combination, the composition is for use in the treatment and/or prevention of breast cancer preferably triple negative, HER2-enriched, luminal B or luminal A breast cancer
  • the present invention also deals with a medicament comprising the 5-HTR1D inhibitor, the combination, the composition of the present invention, for use in the treatment and/or prevention of cancer, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer, more particularly breast cancer and preferably triple negative, HER2-enriched, luminal B or luminal A breast cancer
  • the present invention also deals with an in vitro cancer diagnosis, stratification and/or prognosis method comprising a step of measuring the expression level of 5-HTR1D and/or 5-HTR1B in a sample previously obtained from a subject.
  • 5-hydroxytryptamine receptor IB or“5-HTR1 B ”, as used herein, have their general meaning in the art and refer to a seven-pass transmembrane G protein-coupled receptor. Its natural ligand is serotonin (5-HT), and its principal signal transduction pathway is cyclic- AMP. Briefly, upon binding of serotonin to 5-HTR1B, a conformational change allows it to act as a guanin nucleotide exchange factor. The receptor can then activate the associated Goa protein by exchanging the GDP bound to the G protein for a GTP, thereby inhibiting cyclic AMP synthesis by the adenylate cyclase.
  • 5-HT serotonin
  • 5-HTR1B is a 390-amino acid protein with SEQ ID NO: 33, encoded by the HTR1B gene. It shares 60.6% global identity with SEQ ID NO: 34 (5-HTR1D) as assessed by EMBOSS Needle and 67.1% local identity with SEQ ID NO: 34 (5-HTR1D) as assessed by EMBOSS Water.
  • 5-hydroxytryptamine receptor ID or“5-HTR1 D ”, as used herein, have their general meaning in the art and refer to a seven-pass transmembrane G protein-coupled receptor. Its natural ligand is serotonin (5-HT), and its principal signal transduction pathway is cyclic- AMP. Briefly, upon binding of serotonin to 5-HTR1D, a conformational change allows it to act as a guanin nucleotide exchange factor. The receptor can then activate the associated Goa protein by exchanging the GDP bound to the G protein for a GTP hereby inhibiting cyclic AMP synthesis by the adenylate cyclase.
  • 5-HT serotonin
  • 5-HTR1D inhibitor and“5-HTR1 B inhibitor”, as used herein, both refer to any molecule, compound or substance that, when administered to a subject, leads to a partial or complete reduction of the normal physiological activity of 5-HTR1D and 5-HTR1B, respectively.
  • normal physiological activity of 5-HTR1D and 5-HTR1B is meant the physiological activity of these receptors which is observed upon binding of their natural ligand, 5-HT.
  • 5-HTR1D and 5-HTR1B also refer to any molecule, compound or substance that, when administered to a subject, leads to a reversal of the normal physiological activity of 5-HTR1D and 5-HTR1B, respectively (i.e., to a physiological activity which is opposite to the normal physiological activity of these receptors which is observed upon binding of their natural ligand, 5-HT).
  • inhibition can be achieved by preventing the binding of 5-HT to 5-HTR1D or 5-HTR1B using a receptor antagonist; by preventing the synthesis of 5-HTR1D or 5-HTR1B; or by inducing a physiological activity which is opposite to the normal physiological activity which is observed upon binding of 5-HT, using a receptor inverse agonist.
  • Antibody encompasses intact polyclonal antibodies, intact monoclonal antibodies, single-domain antibodies, nanobodies, antibody fragments (such as Fab, Fab’, F(ab’)2 and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies (such as bispecific antibodies generated from at least two intact antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site, so long as the antibodies exhibit the desired biological activity.
  • An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as a (alpha), d (delta), e (epsilon), g (gamma) and m (mu), respectively.
  • the different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations.
  • Antibodies can be naked, or conjugated to other molecules such as toxins, radioisotopes, or any of the other specific molecules recited herein.
  • A“monoclonal antibody” refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to“polyclonal antibodies” that typically include different antibodies directed against different antigenic determinants.
  • monoclonal antibody encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site.
  • monoclonal antibody refers to such antibodies made in any number of ways including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.
  • humanized antibody refers to an antibody derived from a non human (e.g., murine) immunoglobulin, which has been engineered to contain minimal non-human (e.g., murine) sequences.
  • humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, or hamster) that have the desired specificity, affinity, and capability (Jones et al, 1986 Nature. 321(6069):522-5; Riechmann et al, 1988 Nature. 332(6162):323-7; Verhoeyen et al., 1988 Science.
  • CDR complementary determining region
  • humanized antibodies will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non- human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • Humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region or domain
  • “Aptamer”, as used herein, refers to a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk et al. (1990. Science. 249(4968): 505- 10). The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence.
  • Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli thioredoxin A, that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996. Nature. 380(6574):548-50).
  • Cancer refers to any member of a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis. Metastasis is defined as the stage in which cancer cells are transported through the bloodstream or lymphatic system. Cancers are classified by the type of cell that the tumor resembles and, therefore, the tissue presumed to be the origin of the tumor. For example, carcinomas are malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung, and colon cancer. Lymphomas and leukemias include malignant tumors derived from blood and bone marrow cells.
  • Sarcomas are malignant tumors derived from connective tissue or mesenchymal cells.
  • Mesotheliomas are tumors derived from the mesothelial cells lining the peritoneum and the pleura.
  • Gliomas are tumors derived from glia, the most common type of brain cell.
  • Germinomas are tumors derived from germ cells, normally found in the testicle and ovary.
  • Choriocarcinomas are malignant tumors derived from the placenta.
  • breast cancer including HER2-enriched breast cancer, luminal A breast cancer, luminal B breast cancer and triple negative breast cancer
  • liver cancer including liver hepatocellular carcinoma
  • lung cancer including lung adenocarcinoma
  • pancreas cancer include brain cancer (including brain lower-grade glioma), mesothelioma, head and neck squamous cell carcinoma, kidney cancer (including clear renal cell carcinoma, chrom
  • “Expression”, as used herein, refers to the expression of a gene. Expression of a gene may be determined at the protein level by ways of, e.g., immunohistochemistry, Multiplex methods (Luminex), western blot, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, fluorescent-linked immunosorbent assay (FLISA), enzyme immunoassay (EIA), radi oimmunoas say (RIA) and the like.
  • Luminex Multiplex methods
  • ELISA enzyme-linked immunosorbent assay
  • FLISA fluorescent-linked immunosorbent assay
  • EIA enzyme immunoassay
  • RIA radi oimmunoas say
  • expression of a gene may be determined at the mRNA level, by ways of, e.g., RT-PCR, RT-qPCR (wherein qPCR stands for quantitative PCR), hybridization techniques such as, for example, Northern Blot, use of microarrays, and combination thereof including but not limited to, hybridization of amplicons obtained by RT-PCR, sequencing such as, for example, next-generation DNA sequencing (NGS) or RNA-seq (also known as“Whole Transcriptome Shotgun Sequencing”) and the like.
  • NGS next-generation DNA sequencing
  • RNA-seq also known as“Whole Transcriptome Shotgun Sequencing”
  • “Overexpression” as used herein, refers to the expression of a gene being higher in a sample when compared to a“reference expression level”.
  • the reference expression level can be the typical level of expression observed in a similar population of cancer cell among a large group of subjects (typically more than 10, preferably at least 50 or more subjects).
  • the reference expression level can also refer to the level of expression in healthy cells of the same tissue of origin in the same subject or derived from a large group of subjects.
  • the reference expression level can also refer also the level of expression in the cancer cells of a subject at different time points. The person of the art is familiar with the techniques allowing the comparison of gene expression level.
  • Receptor antagonist refers to any molecule, compound or substance that binds to a receptor and thereby prevents the normal physiological activity which is observed upon binding of its activating ligand (i.e ., the receptor agonist).
  • a receptor antagonist can, for instance, compete with the binding of the agonist to the receptor.
  • Receptor inverse agonist refers to any molecule, compound or substance that binds to the same receptor as the receptor agonist but exerts the opposite effect. Receptor inverse agonists have the ability to decrease the constitutive activity of the receptor, i.e., the basal receptor activity observed in absence of receptor agonist.
  • Response to chemotherapy refers to the effectiveness of a chemotherapy in treating a cancer. Methods to measure the effectiveness of a chemotherapy as known in the art and includes, but is not limited to, determining the size of a solid tumor, metabolites level reflecting the function of the organ(s) affected by cancer, measuring the level of a cancer marker and cell counting techniques.
  • a subject having cancer can be“resistant to chemotherapy” or“unresponsive to chemotherapy” if, after chemotherapy, said cancer as progressed, remained stable or insufficiently decreased.
  • a subject having cancer can be“responsive to chemotherapy” if, after chemotherapy, said cancer has become undetectable or has significantly decreased.
  • Treatment refers to both therapeutic and prophylactic (or preventive) measures, whose object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • a subject or mammal is successfully“treated” if, after receiving a therapeutic amount of the inhibitor or composition according to the present invention, the patient shows one or more of the following observable and/or measurable changes: amelioration related to one or more of the symptoms associated with the specific disease or condition, reduction of morbidity and mortality and improvement in quality of life issues.
  • Example of observable or measurable changes includes, but are not limited to, a reduction of the cancer cells proliferation, a decrease in the size or a disappearance of the tumor, the prevention of metastasis or recurrence, a reduction in the appearance of tumors and an increase of cancer cell death.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • “Therapeutically effective amount”, as used herein, refers to the level or amount of the inhibitor or composition according to the present invention, that is aimed at (but without causing significant negative or adverse side effects to the subject): (1) delaying or preventing the onset of the targeted condition or disorder; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the targeted condition or disorder; (3) bringing about ameliorations of the symptoms of the targeted condition or disorder; (4) reducing the severity or incidence of the targeted condition or disorder; and/or (5) curing the targeted condition or disorder.
  • a therapeutically effective amount of the inhibitor or composition according to the present invention may be administered prior to the onset of the targeted condition or disorder, for a prophylactic or preventive action. Alternatively or additionally, the therapeutically effective amount of the inhibitor or composition according to the present invention may be administered after initiation of the targeted condition or disorder, for a therapeutic action.
  • Subject refers to a warm-blooded animal, preferably a human, a pet or livestock.
  • the terms“pet” and“livestock” include, but are not limited to, dogs, cats, guinea pigs, rabbits, pigs, cattle, sheep, goats, horses and poultry.
  • the subject is a male or female subject.
  • the subject is an adult (for example, a subject above the age of 18 (in human years) or a subject after reproductive capacity has been attained).
  • the subject may be a “patient”, i.e., a subject who/which is awaiting the receipt of or is receiving medical care or was/is/will be the obj ect of a medical procedure according to the methods of the present invention or is monitored for the development of a disease.
  • a patient i.e., a subject who/which is awaiting the receipt of or is receiving medical care or was/is/will be the obj ect of a medical procedure according to the methods of the present invention or is monitored for the development of a disease.
  • the present invention relates to a 5-hydroxytryptamine receptor ID (5-HTR1D) inhibitor, for use in the prevention and/or treatment of cancer in a subject in need thereof.
  • 5-HTR1D 5-hydroxytryptamine receptor ID
  • 5-HTR1D inhibitors according to the present invention include, but are not limited to, small organic molecules, antibodies, aptamers and polynucleotides.
  • the 5-HTR1D inhibitor according to the present invention is a selective 5-HTR1D inhibitor.
  • selective it is meant that the affinity of the antagonist for 5-HTR1D is at least 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more higher than the affinity for the other human 5-HT receptor (5-HTR1A, 5-HTR1B, 5-HTRlc, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6, 5-HTR7).
  • the affinity of a 5-HTR1D inhibitor may be quantified by measuring the activity of 5-HTR1D in the presence of a range of concentrations of said inhibitor in order to establish a dose-response curve. From that dose response curve, an IC50 value may be deduced which represents the concentration of inhibitor necessary to inhibit 50% of the response to an agonist (e.g., 5-HT) in defined concentration.
  • the IC5 0 value may be readily determined by the one skilled in the art by fitting the dose-response plots with a dose- response equation as described in De Lean A. & Rodbard D. (1979) Kinetics of cooperative binding. In: O’Brien R.D. (eds) General Principles and Procedures.
  • a selective 5-HTR1D inhibitor is a compound for which at least one of the ratios:
  • 5-HTR1-7 ⁇ 5-HTR1D means all 5-HT receptors except 5 -HTR ID, i.e., 5 -HTR 1A, 5-HTR1B, 5-HTR1C, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6 and 5-HTR7.
  • a selective 5 -HTR ID inhibitor is a compound for which at least one of the ratios:
  • Ki(5 -HTR 1B) Ki(5 -HTR ID), and/or
  • the 5 -HTR ID inhibitor is a small organic molecule.
  • Small organic molecule refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules such as protein and nucleic acids. Preferred small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • Exemplary 5-HTR1D inhibitors that are contemplated by the present invention include, but are not limited to, those described in European patents EP0533268, EP0701819, EP0712397, EP0714389, EP0716650, EP0736023, EP0736025, EP0752982,
  • 5-HTR1D inhibitors which may be contemplated by the present invention include, but are not limited to:
  • naphthalene derivatives such as those described in EP0701819 and US5, 821, 245;
  • biphenylamide and biphenylethanone derivatives such as those described in EP0736025, US5,801,170, US5,919,932, US5,972,935 and WO1995030675;
  • indole, indoline, quinolone and quinoline derivatives such as those described in EP0716650, EP0736023, EP0777650, US7,432,282, US20050085457,
  • spiropiperidine derivatives such as those described in US6, 166,034;
  • 2-pyrrolidones derivatives such as those described in EP0894085, EP1113015 and US6,924,289;
  • heterocyclic lactam and imide derivatives such as those described in US6,403,592;
  • azabicyclic derivatives such as those described in EP1070065, EP 1140931 and US6,887,905;
  • diazabicyclooctane derivatives such as those described in EiS6,107,321;
  • 1,4-thiazines derivatives such as those described in E1S20060009448.
  • arylpiperazine derivatives such as those described in EiS6,342,498;
  • piperazine and piperidine derivatives such as the ones described in US20030064995;
  • chromone derivatives such as those described in EiS7,026,314;
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0533268, including, without limitation, 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)[l,r- biphenyl]-4-carboxamide; 7V-[4-chl oro-3-(4-methyl-l-piperazinyl)phenyl]-2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)[l,l’-biphenyl]-4-carboxamide; 2’-chloro-/V-[4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]-4’ -(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)[ 1,1’- biphenyl]-4-carboxamide
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0701819, including, without limitation, 7-(imidazolo[4,5- &]pyridin-l-yl)-l(l-methylpyrrolidin-3-yl)naphthalene; 7-(4-chlorobenzamido)-l- (pyrrolidin-2-(i?)-ylmethyl)naphthalene; 2-[8-(4-methylpiperazin-l-yl)naphthalen-2- y 1 oxy ] ni cotinonitril e ; l-(4-methylpiperazin-l-yl)-7-pyrimidin-5-yl)naphthalene; 7-(5- cyanopyridin-3 -yl)- 1 -4-methylpiperazin- 1 -yl)naphthalene; 1 -(piperazin- 1 -yl)-7-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0712397, including, without limitation, 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)furan-2-carboxamide; 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)furan-3-carboxamide; A/-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)thiophene-2-carboxamide; A/-[4-methoxy-3- (4-methyl- l-piperazinyl)phenyl]-2-(4-pyridyl)pyridine-5-carboxamide; A/-[4-methoxy- 3 -(4-methyl- l-piperazinyl)phenyl
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0714389, including, without limitation, 7V-[4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl]-4-bromophenylacetamide; 7V-(4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-bromocinnamide; 7V-[4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl]-3-(thien-3-yl)acrylamide; 7V-(4-m ethoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-(4-pyridyl)cinnamide; 7V-(4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-phenylcinnamide; N-(4-m ethoxy-3
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0716650, including, without limitation, l-[3-methyl-4-(4- pyridyl)benzoyl]-2,3-dihydro-5-methoxy-6-(4-methyl-l-piperazinyl)]-lif-indole; l-(4- bromo-3-methylbenzoyl)-2,3-dihydro-5-methoxy-6-(4-methyl-l-piperazinyl)-lif- indole; l-(4-bromo-3-methylbenzoyl)-5-methoxy-6-(4-methyl-l -piperazinyl) lif-indole; 2,3 -dihydro-5-methoxy-6-(4-methyl- 1 -piperazinyl)- 1 -[2’ -bromo-3’ -methoxythiophene- 4’-ylcarbony
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0736023, including, without limitation, 5-chloro-2,3-dihydro- 6-(2-dimethylaminoethoxy)- 1 -[4-(2-methyl-4-(5-methyl- 1 ,2,4-oxadiazol-3 - yl)phenyl)benzoyl] l//-indole; 2,3-dihydro-6-(3-dimethylaminopropyl)-5-methoxy-l-[4- (2-methyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)benzoyl] 1 //-indole; 2-3-dihydro-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0736025, including, without limitation, N-[ 7-[(2- dimethylaminoethyl)amino]-2,3-dihydrobenzofuran-5-yl]-2’ -methyl-4’ -(5-methyl- 1,2, 4- oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-[7-(2-dimethylamino)ethoxy-2,3- dihy drobenzofiiran-5-yl]-2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-[7-(3-dimethylaminopropyl)-2,3-dihydrobenzofuran-5-yl]-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0752982, including, without limitation, N-[ 3-(2- dimethylaminoethoxy)4-methoxyphenyl]-4’-methoxy carbonyl-2’ -methylbiphenyl-4- carboxamide; A/-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2’-methyl-4’-A/- methylcarboxamidobiphenyl-4-carboxamide; A/-[3-(2-dimethylaminoethoxy)-4- methoxyphenyl]-2’ -methyl-4’ -N, 7V-dimethylcarboxamidobiphenyl-4-carboxamide; N- [3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2’ -methyl-4’ -carboxamidobiphenyl-4- carboxamide; A/-[3-(2-dimethylaminoethoxy
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0777650, including, without limitation, l-(4’- acetamidomethyl-2’-methylbiphenyl-4-carbonyl)-5-chloro-2,3-dihydro-6-(2- dimethylaminoethoxy)- 177-indole; l-(4’-cyano-2’-methylbiphenyl-4-carbonyl)-2,3- dihydro-6-(2-dimethylaminoethoxy)-5-methoxy- 177-indole; l-(4’-acetyl-3’- methylbiphenyl-4-carbonyl)-2,3-dihydro-6-(2-dimethylaminoethoxy)-5-methoxy-177- indole; l-(4’-acetyl-2’-methylbiphenyl-4-carbonyl)-6-(2-dimethylamino-e
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0799226, including, without limitation, l’-methyl-5-(2’- methyl-4’-(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0894085, including, without limitation, 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 6-chloro-3-(2-(4- methylpiperazin-l-yl)-benrylidene]-l,3-dihydro-indol-2-one; 5-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; l-methyl-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-benzylidene]- 1 -phenyl- 1 ,3
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1070065, including, without limitation, (7R,9as)-trans- 1 - ⁇ 3 - [2-(5-fluoro-benzo[ ⁇ i]isoxazol-3-yl)-octahydropyrido[l,2-u]pyrazin-7-ylmethoxy]- benzyl ⁇ -azetidin-3-ol; (7i?,9uS)-/ra «s-2-(5-fluoro-benzo[ ⁇ i]isoxazol-3-yl)-7-(3- morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (' 7S,9aS)-cis - 1 - [3-(2-benzo[ ⁇ i]isoxazol-3-yl-octahydro-pyrido[l
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1113015, including, without limitation, (-)-3(S)-[[2-(4-methyl- lpiperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2-pyrrolidinone; (+)-3 (R)-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1140931, including, without limitation, (7R,9aS)-trans-(2- benzo[ ⁇ i]isoxazol-3-yl-octahydro-pyrido[l,2-u]pyrazin-7-ylmethyl)-(5-methyl- pyrimidin-2-yl)-amine; (7S,9uS)-czs-(2-benzo[ ⁇ i]isoxazol-3-yl-octahydro-pyrido[l,2- u]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)-amine; (7R,9aS)-trans-(2- benzo[ ⁇ i]isoxazol-3-yl-octahydro-pyrido[l,2-u]pyrazin-7-ylmethyl)-(5-chloro- pyrimidin-2-yl)-amine
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1186318, including, without limitation, 3-(4-chlorophenyl)-5- [2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)- 5-[2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 3-(4- chlorobenzyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 4- benzyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorobenzyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,356,893, including, without limitation, 7V-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl-2-methyl-4’ -(methyl sulphinyl)- 1 , G -biphenyl-4- carboxamide; 4’-acetyl-A/-4-methoxy-3-(4-methyl-l-piperazinyl)phenyl-2-methyl-l, G- biphenyl-4-carboxamide; A/-4-methoxy-3-(4-methyl-l-piperazinyl)phenyl-2’-methyl-4’- methylamino- 1 , G -biphenyl-4-carboxamide; methyl-4’ -4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenylaminocarbonyl-2-methyl-(l,r-biphenyl-4-yl)methyl
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,358,948, including, without limitation, 7V-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl-4-(4-pyridinyl)benzamide; 7V-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-4-(4-methyl-3-pyridinyl)benzamide; A/-4-methoxy-3 -(4-methyl- 1- piperazinyl)phenyl-3-methyl-4-(4-pyridinyl)benzamide; A/-4-methoxy-3 -(4-methyl- 1- piperazinyl)phenyl-2-methyl-4-(4-pyridinyl)benzamide; /V-4-methyl-3 -(4-methyl- 1 - piperazinyl)phenyl-4-(4-pyridinyl)benzamide; A/-4-chloro-3 -(4-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,436,246, including, without limitation, 4-4-(2-phenylethyl)- 1 -piperazinyl-benzo[Z?]thiophene-2-methanol monohydrochloride; 4-4-(2-phenylethyl)-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,756,496, including, without limitation, N- 1-(2- dimethylaminoethyl)-li7-indol-6-yl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; /V-2,3-dihydro-l-(2-dimethylaminoethyl)-l.i/-indol-6-yl-2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-4-(2- dimethylaminoethyl)-3,4-dihydro-2.i/-l,4-benzoxazin-6-yl-2’ -methyl-4’ -(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,801,170, including, without limitation, 77-3- (dimethylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-3-(2-diethylaminoethoxy)-4-methoxyphenyl-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- 3-(2- diisopropylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide; 7V-3-(2-dimethylamino-l-methylethoxy)-4-methoxyphenyl- 2’ -methyl-4
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,821,245, including, without limitation, 7-benzamido- 1 -(4- methyl- 1 -piperazinyl)-naphthalene; 7-( 1 -naphthyl carb oxami do)- 1 -(4-methyl- 1 - piperazinyl)-naphthalene; 7-benzamido- 1 -( 1 -piperazinyl)-naphthalene; 7-acetamido- 1 - (4-methyl- 1 -piperazinyl)-naphthalene; 7-hexanamido- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 7-(phenylaminocarbonylamino)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(benzyloxycarbonylamino)-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,919,932, including, without limitation, 7V-3-(8-azabicyclo- 3.2. l-octan-3-yl)-4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-4-methoxy-3-(8-methyl-8-azabicyclo-3.2.
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,952,325, including, without limitation, 7V-(2, 3 -dihydro- G- methylspiro-4if-benzopyran-6-yl-4, 4’ -piperidine)-2’-methyl-4’ -(5-methyl- 1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-(2,3-dihydrospiro-4i7-benzopyran-6-yl-4,4’- piperidine)-2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,972,935, including, without limitation, 4-(2- dimethylaminoethyl)-2,3,6,7,8,9-hexahydro-6- ⁇ 2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carbonyl ⁇ -4.i/-pyrido[2,3-g][l,4]benzoxazine; 2 -(N,N- dimethyl-3,4,6,7,8,9-hexahydro-6-[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- y ⁇ biphenyM-carbonylJ ⁇ if-pyranoP ⁇ -gJquinolin ⁇ -y ⁇ ethanamine; 2-(7V,/V-dimethyl- 2, 3, 5,6,7, 8-hexahydro-5-[2’-methyl-4’ -(5-methyl- 1,
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 107,321, including, without limitation, 3-benzyl-7-[3-(5- (l,2,4-triazol-4-yl)-17/-indol-3-yl)propyl]-5-3,7-diazabicyclo[3.3.0]octane; 3-(pyridin-3- yl)methyl-7-[3-(5-(l,2,4-triazol-4-yl)-li7-indol-3-yl)propyl]-c/5-3,7- diazabicyclo[3.3.0]octane; 3-[2-(4-(acetylamino)phenyl)ethyl]-7-[3-(5-(l,2,4-triazol-4- yl)-lif-indol-3-yl)propyl]-c/5-3,7-diazabicyclo[3.3.0]o
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 124,283, including, without limitation, (R)-N- 8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-(trifluoroacetyl)benzamide; (R) ⁇
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 159,962, including, without limitation, 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-phenyl)-l-piperazinyl)ethylthieno[2,3- ⁇ i]pyrimidin-4-one; 3, 4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(l -naphthyl)- 1- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-methyl-l-napththyl)-l-piperazinyl)ethylthieno-[2,3- ⁇ i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-d
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 159,979, including, without limitation, 7V-4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl-4-bromonaphth- 1 -ylcarboxamide; 5-bromo-7V-4-methoxy-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 166,034, including, without limitation, 5-4- ⁇ 5-(5-methyl- l,3,4-oxadiazol-2-yl)-l-naphthyl ⁇ benzoyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- )indole-3,4’-piperidine; 5-4- ⁇ 5-(5-methyl-l,3,4-oxadiazol-2-yl)-l-naphthyl ⁇ benzoyl- 2,3,5,6,7,8-methylspirofuro[2,3-g]quinoline-3,4 , -piperidine; 5-4- ⁇ 5-(5-methyl-l,3,4- oxadiazol -2 -yl)-l -naphthyl ⁇ -3-methylbenzoyl- r-methyl-2, 3,6,7- tetrahydrospir
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 197,773, including, without limitation, 3,4-dichloro- V-(2-2- (4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 4-fluoro-7V-(2-2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl)-benzamide; 7V-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3,4-dichloro-/V-(l-methyl-2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3 ,4-dichloro-/V-(l -methyl-2-2-(4-methylpiperazin- 1 -yl)-phenyl-propyl)- benzamide; 3,4-dichloro-A/-methyl-A/
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,342,498, including, without limitation, N-( 2-(4-(2- methoxyphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6-fluoroindol-3 -yl)-piperidin- 1 - yl)propenamide; A/-(2-(4-(2-methoxyphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6- fluoroindol-3-yl-l,2,3,6-tetrahydropyridin-l-yl)propenamide; N-( 2-(4-(2- methoxphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6-chloroindol-3 -yl)-l, 2,3,6- te
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,346,622, including, without limitation, 3 , 3 -dimethyl-2-3 -(4- (5-tetralinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-3 -(4-(2-phenyl-4-quinazolinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3, 3 -dimethyl-2-3 -(4-(2-quinolinyl)- 1 -piperazinyl)-prop- 1 - yl-2, 3 -dihydro- 1 ,2-benzoisothi azole-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,355,647, including, without limitation, 3,4, 5,7-tetrahydro- 6-carbethoxy-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- ⁇ i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- ⁇ i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-(l-naphthyl)-l-piperazinyl)ethyl- pyrrolo[3’,4’ :4,5]thieno[2,3- ⁇ i]pyrimidin-4-one
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,403,592, including, without limitation, 3-(4-chlorophenyl)- 5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)- 5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 509,340, including, without limitation, 7V-2-(5-fluoro-3- indolyl)ethyl-A/’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenylurea; 4-(5-cyano-3- indolyl)-/V-4-methoxy-3-(4-methylpiperazin-l-yl)phenylpiperidine-l -carboxamide; 4- (6-fluoro-3 -indolyl)-7V-4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 - carboxamide; 3- ⁇ l-4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl-4- piperidyl ⁇ indole-5-carboxamide; 4-(5-fluoro-3-indolyl
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,537,995, including, without limitation, 5-2-(4- methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 4-chlorobenzylamide; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-furan-2-carboxylic acid 4-chlorophenylamide; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid 4-chlorophenylamide; 5-2-(4- methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 2-(4-chlorophenyl)ethyl-amide; 4- 2-(4-methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 4-chlorobenzylamide; 5-2-(4- methylpiperazin-l
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,887,905, including, without limitation, (7R, 9as)-trans- 1 - ⁇ 3 -
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 924,289, including, without limitation, 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 6-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 5-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 1 -methyl-3 -[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-benzylidene]- 1 -phenyl- 1
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,026,314, including, without limitation, 8-(4-methyl-l- piperazinyl)-A/-[4-(4-morpholinyl)phenyl]-4-oxo-4if-chromene-2-carboxamide; 2- ⁇ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one, 2- ⁇ l-[4-(l-acetyl-2,3-dihydro-lif-indol-6-yl)-piperazin-l-yl]- methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chl oro-5-(4- ⁇ l-[8-(4- methyl-piperazin-l-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,425,574, including, without limitation, 4- ⁇ 2-[4-(5-cyano- lif-indol-3-yl)butylamino]ethoxy ⁇ benzofuran-2-carboxylic acid methyl ester; 5- ⁇ 2-[4- (5-cyano-lif-indol-3-yl)butylamino]ethoxy ⁇ benzofuran-2-carboxylic acid ethyl ester; 6- ⁇ 2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy ⁇ benzofuran-2-carboxylic acid ethyl ester; 4- ⁇ 2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy ⁇ benzofuran-2-carboxylic acid amide; 7- ⁇ 2-[4-(5-cyano-lif-indo
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,432,282, including, without limitation, 3- ⁇ 4-[(5- bromopyridin-3 -ylmethyl)amino]butyl ⁇ -l//-indole-5-carbonitrile; 3 - ⁇ 4-[(pyridin-3 - ylmethyl)amino]butyl ⁇ -lf7-indole-5-carbonitrile; 3- ⁇ 4-[(pyridin-2- ylmethyl)amino]butyl ⁇ -l//-indole-5-carbonitrile; 3- ⁇ 4-[(pyridin-4- ylmethyl)amino]butyl ⁇ -l//-indole-5-carbonitrile; 3-(4- ⁇ [5-(4-fluorophenyl)pyridin-3 - ylmethyl]amino ⁇ butyl)-lf7-indole-5-carbonitrile; 3- ⁇
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,776,860, including, without limitation, 3-amino-8-(l- piperazinyl)-2//-l-benzopyran-2-one; and pharmaceutically acceptable salts or esters thereof.
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US9,938,277, including, without limitation, 3-((6aR,9S,l0aR)-5- cyclopropyl-7-methyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinolin-9-yl)-l,l- diethylurea; (6ui?,9i?)-5-cyclopropyl-A/-((5')-l-hydroxybutan-2-yl)-4,7-dimethyl-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US20030064995, including, without limitation, A/-[2-(5-fluoro- 3-indolyl)ethyl]-A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4-(5-cyano-3- indolyl)-A/-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (6-fluoro-3-indolyl)-A/-[4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]piperidine-l- carboxamide; 3- ⁇ l-[4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl]-4- piperidyl ⁇ indole-5-carboxamide; 4-(
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US20030212109, including, without limitation, 3, 3 -dimethyl- 1- (2-[4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl ⁇ - 1 ,3 -dihydro-2if-indol-2-one; 1 - (2-[4- (4-fluorobenzoyl)-l-piperidinyl]-l-ethylU-3-methyl-3-methylthio-l,3-dihydro-2if- indol-2-one; 1 - ⁇ 2- [4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl ⁇ -3 -methyl- 1 ,3-dihydro-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US20050085457, including, without limitation, 8-(4-methyl-l- piperazinyl)-7V-[4-(4- morpholinyl)phenyl]-4-oxo-47f-chromene-2-carboxamide; 2- ⁇ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one; 2- ⁇ l-[4-(l -acetyl-2,3 -dihydro- 17/-indol-6-yl)-piperazin-l-yl]- methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chloro-5-(4- ⁇ l-[8-(4- methyl-piperazin-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US20060009448, including, without limitation, 4-(3,4-dichloro- phenyl)-2-[2-(4-methyl-piperazin-l-yl)-benzylidene]-thiomorpholin-3-one; and pharmaceutically acceptable salts or esters thereof.
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in US20070010526, including, without limitation, l-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-(4-piperi din-l-ylmethyl- phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3,4-dihydro- 1 H-[ soquinolin-2-yl] -ethanone; 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methoxy-8-phenyl-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in WO 1994015920, including, without limitation, TV- [4-m ethoxy-3 - (4-methyl- 1 -piperazinyl)phenyl] -2-m ethyl-4’ -( 1 -methyl- lif-pyrazol-3 -yl)[ 1 , G - biphenyl]-4-carboxamide; 7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’ -methyl-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1995011243, including, without limitation, 4-bromo-3- methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide; 4- bromo-3-methyl-A/-[7-(piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide; 4- bromo-3-methyl-A/-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benzamide; 4-(4- pyridyl)-3-methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yljbenzamide; 4-(4-pyridyl)-3-methyl-A/-[5-(4-methylpiperazin-l-y
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1995030675, including, without limitation, /V-[3-((S)-l- methylpyrrolidin-2-ylmethoxy)-4-methoxyphenyl]-2’-methyl-4’-(5-methyl-r,4- oxadiazol-3-yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-((i?)-l-methylpyrrolidin-2- ylmethoxy)phenyl]-2’ -methyl-4, -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-[4-methoxy-3-((i?)-pyrrolidin-2-ylmethoxy)phenyl]-2’-methyl-4’-(5- methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-[4-[4-
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1999029666, including, without limitation, 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-5-yl)aminocarbonyl]indoline; 5-chloro-6-(4- ethylpiperazin-l-yl)-l -[(5,6,7, 8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -[( 1 - oxoindan-5-yl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -
  • the 5-HTR1D inhibitor according to the present invention is selected from those described in WO 1999031086, including, without limitation, 7V-[3-chloro-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N- ⁇ 4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)naphth-l-yl]-urea; N- ⁇ 4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[5-(pyridin-4-yl)naphth-l-yl]
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • BRL-15,572 (3-[4-(3-chlorophenyl)-l-piperazinyl]-l,l-diphenyl-2-propanol); LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-27f-indol-2-one);
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2 , -methyl-4 , -(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • methiothepin (l-methyl-4-[8-(methylsulfanyl)-10, 1 l-dihydrodibenzo[A
  • metergoline (benzyl ⁇ [(8P)-l,6-dimethylergolin-8-yl]methyl ⁇ carbamate);
  • ritanserin (6-(2- ⁇ 4-[bis(4-fluorophenyl)methylene]-l-piperidinyl ⁇ ethyl)-7- methyl-57/-[l,3]thiazolo[3,2-u]pyrimidin-5-one);
  • ziprasidone (5- ⁇ 2-[4-(l,2-benzothiazol-3-yl)-l-piperazinyl]ethyl ⁇ -6-chloro-l,3- dihydro-27f-indol-2-one);
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-2i7-indol-2-one);
  • metergoline (benzyl ⁇ [(8P)-l,6-dimethylergolin-8-yl]methyl ⁇ carbamate);
  • ritanserin (6-(2- ⁇ 4-[bis(4-fluorophenyl)methylene]-l-piperidinyl ⁇ ethyl)-7- methyl-5i7-[l,3]thiazolo[3,2-a]pyrimidin-5-one);
  • ziprasidone (5- ⁇ 2-[4-(l,2-benzothiazol-3-yl)-l-piperazinyl]ethyl ⁇ -6-chloro-l,3- dihydro-27f-indol-2-one);
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-27f-indol-2-one);
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2 , -methyl-4 , -(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • - LY-393558 (1 - ⁇ 2-[4-(6-fluoro- lH-indol-3-yl)-3, 6-dihydro- 1 (2/7)- pyridinyl]ethyl ⁇ -3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-l//-2,l,3- benzothiadiazine-2, 2-dioxide); and
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-2//-indol-2-one);
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2 , -methyl-4 , -(5- methyl- 1 ,2,4-oxadiazol-3 -yl)-4-biphenylcarboxamide);
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • BRL-15,572 (3-[4-(3-chlorophenyl)-l-piperazinyl]-l,l-diphenyl-2-propanol); LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-2//-indol-2-one); and
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • LY-310762 (l- ⁇ 2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl ⁇ -3,3-dimethyl-l,3- dihydro-2//-indol-2-one);
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2 , -methyl-4 , -(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide); and pharmaceutically acceptable salts or esters thereof.
  • the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
  • the 5-HTR1D inhibitor according to the present invention is an antibody that blocks 5-HTR1D activation (i.e ., a 5-HTR1D blocking antibody).
  • the 5-HTR1D blocking antibodies contemplated in the present invention may, for instance, impair the binding of 5-HT to the receptor by binding to said receptor.
  • the 5-HTR1D inhibitor according to the present invention is a polyclonal antibody, preferably a 5-HTR1D polyclonal blocking antibody.
  • Polyclonal antibodies can be produced by various procedures well-known in the art. For example, a host animal such as a rabbit, mouse, rat, etc., can be immunized by injection with an antigen to induce the production of sera containing polyclonal antibodies specific for the antigen.
  • the antigen can include a natural, synthesized, or expressed protein, or a derivative (e.g., fragment) thereof.
  • the 5-HTR1D inhibitor according to the present invention is a monoclonal antibody, preferably a 5-HTR1D monoclonal blocking antibody.
  • monoclonal antibodies can be prepared using hybridoma methods, including, but not limited to, the hybridoma technique originally described by Kohler and Mil stein (1975. Nature. 256(5517):495-7); the human B-cell hybridoma technique (Cote et al., 1983. Proc Natl Acad Sci U S A. 80(7):2026-30); and the EBV-hybridoma technique (Cole et al., 1985. J Immunol Methods. 78(2):271-8).
  • a mouse, hamster, or any other appropriate host animal is immunized as described above to elicit the production by lymphocytes of antibodies that will specifically bind to an immunizing antigen.
  • Lymphocytes can also be immunized in vitro. Following immunization, the lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol, to form hybridoma cells that can then be selected away from unfused lymphocytes and myeloma cells.
  • Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen as determined by immunoprecipitation, immunoblotting, or by an in vitro binding assay (e.g., radi oimmunoas say (RIA) or enzyme-linked immunosorbent assay (ELISA)) can then be propagated either in in vitro culture using standard methods (Goding J. W. (1986). Monoclonal antibodies: Principles and practice (2nd ed.). London: Academic Press) or in vivo as ascites tumors in an animal. The monoclonal antibodies can then be purified from the culture medium or ascites fluid.
  • monoclonal antibodies can be made using recombinant DNA methods, as described in US patents US4, 816,567 and US4,946,778.
  • the polynucleotides encoding a monoclonal antibody are isolated from mature B-cells or hybridoma cells, such as by RT- PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using conventional procedures.
  • the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors, which when transfected into host cells such as Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells or myeloma cells that do not otherwise produce immunoglobulin protein, monoclonal antibodies are generated by the host cells.
  • host cells such as Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells or myeloma cells that do not otherwise produce immunoglobulin protein
  • monoclonal antibodies or antigen-binding fragments thereof of the desired species can be isolated from phage display libraries expressing CDRs of the desired species as described (McCafferty et al, 1990. Nature. 348(6301) 552-4; Clackson et al. , 1991 Nature.
  • the 5-HTR1D inhibitor according to the present invention is a humanized antibody, preferably a 5-HTR1D humanized blocking antibody.
  • the 5-HTR1D inhibitor according to the present invention is an aptamer that can block 5-HTR1D activation.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition.
  • Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk et al. (1990. Science. 249(4968): 505- 10).
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA.
  • each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena (1999. Clin Chem. 45(9): 1628-50).
  • Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as Escherichia coifs thioredoxin A, that are selected from combinatorial libraries by two hybrid methods (Colas etal. , 1996. Nature. 380(6574): 548-50). Then, after raising aptamers directed against 5-HTR1D as described above, the skilled man in the art can easily select those blocking 5-HTR1D activation.
  • the 5-HTR1D inhibitor according to the present invention is a polynucleotide.
  • polynucleotide refers to a series of nucleotide bases (also called“nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides.
  • the polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded.
  • the oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, e.g., to improve stability of the molecule, its hybridization parameters, etc.
  • the antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, b-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine,
  • a nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and complementary DNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as“protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids.
  • PNAs protein nucleic acids
  • Exemplary DNAs include, but are not limited to, single-stranded DNA (ssDNA), double- stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.
  • ssDNA single-stranded DNA
  • dsDNA double- stranded DNA
  • pDNA genomic DNA
  • cDNA complementary DNA
  • antisense DNA antisense DNA
  • chloroplast DNA ctDNA or cpDNA
  • microsatellite DNA mitochondrial DNA
  • mtDNA or mDNA mitochondrial DNA
  • kDNA kinetoplast DNA
  • provirus provirus
  • lysogen repetitive DNA
  • satellite DNA satellite DNA
  • RNAs include, but are not limited to, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and
  • Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.).
  • a number of methods have been developed for delivering antisense DNA or RNA to cells, e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically.
  • RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule.
  • DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.
  • a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter.
  • a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA.
  • Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA.
  • Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells.
  • Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site.
  • the polynucleotides may be flanked by natural regulatory (expression control) sequences or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5'- and 3’ -non-coding regions and the like.
  • the nucleic acids may also be modified by many means known in the art.
  • Non-limiting examples of such modifications include methylation,“caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and internucleotide modifications, such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.).
  • uncharged linkages e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.
  • charged linkages e.g., phosphorothioates, phosphorodithioates, etc.
  • Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly- 1 -lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators.
  • the polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage.
  • polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly.
  • exemplary labels include radioisotopes, fluorescent molecules, isotopes (e.g., radioactive isotopes), biotin and the like.
  • the 5-HTR1D inhibitor according to the present invention is a polynucleotide which interferes with 5-HTR1D synthesis.
  • the synthesis of 5-HTR1D may be blocked at the transcriptional level. In one embodiment, the synthesis of 5-HTR1D may be blocked at the translational level.
  • the 5-HTR1D inhibitor according to the present invention is an antisense oligonucleotide.
  • Antisense oligonucleotides including antisense RNA molecules and antisense DNA molecules, would act to directly block the translation of 5-HTR1D mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of 5-HTR1D, and subsequently, 5-HTR1D activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding 5-HTR1D can be synthesized, e.g., by conventional phosphodiester techniques and administered by, e.g., intravenous injection or infusion.
  • the 5-HTR1D inhibitor according to the present invention is a ribozyme.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
  • Engineered hairpin- or hammerhead-motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of 5-HTR1D mRNA sequences are thereby useful within the scope of the present invention.
  • Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU and GUC.
  • RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable.
  • the suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • Both antisense oligonucleotides and ribozymes useful as inhibitors of 5-HTR1D gene expression can be prepared by known methods. These include, without limitation, techniques for chemical synthesis such as, e.g., solid phase phosphoramadite chemical synthesis.
  • RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • modifications to the oligonucleotides according to the present invention can be introduced as a means of increasing intracellular stability and half-life.
  • Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxy rib onucl eoti des to the 5’ and/or 3’ ends of the molecule, or the use of phosphorothioate or 2’ -O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
  • the 5-HTR1D inhibitor according to the present invention is an interference RNA (RNAi).
  • RNAi include, without limitation, small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs) and microRNAs (miRNAs), targeted to a 5-HTR1D transcript; as well as RNAi vectors whose presence within a cell results in the production of an siRNA, shRNA or miRNA targeted to the target 5-HTR1D transcript.
  • siRNA, shRNA or miRNA comprises a portion of RNA that is complementary to a region of the target 5-HTR1D transcript.
  • the RNAi contemplated in the present invention downregulates expression of 5-HTR1D via RNA interference.
  • RNA interference is a multi step process and is generally activated by double-stranded RNA (dsRNA) that is homologous in sequence to the targeted 5-HTR1D gene.
  • dsRNA double-stranded RNA
  • Introduction of long dsRNA into the cells of organisms leads to the sequence-specific degradation of homologous gene transcripts.
  • the long dsRNA molecules are metabolized to small (e.g., 21-23 nucleotide) interfering RNAs (siRNAs, shRNAs or miRNAs) by the action of an endogenous ribonuclease known as Dicer.
  • the interfering RNAs bind to a protein complex, termed RNA-induced silencing complex (RISC), which contains a helicase activity and an endonuclease activity.
  • RISC RNA-induced silencing complex
  • RNAi is an antisense mechanism of action, as a single stranded (ssRNA) RNA molecule binds to the target 5-HTR1D RNA molecule and recruits a ribonuclease that degrades the 5-HTR1D RNA.
  • ssRNA single stranded
  • the 5-HTR1D inhibitor according to the present invention is an siRNA.
  • siRNAs inhibiting 5-HTR1D include, but are not limited to, the siRNA purchased from Dharmacon used in the example section.
  • identity when used in a relationship between the sequences of two or more polypeptides or of two or more polynucleotides, refers to the degree of sequence relatedness between polypeptides or polynucleotides, as determined by the number of matches between strings of two or more amino acid or nucleotide residues.“Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e.,“algorithms”). Identity of related polypeptides or polynucleotides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Lesk A. M. (1988).
  • Preferred methods for determining identity are designed to give the largest match between the sequences tested. Methods of determining identity are described in publicly available computer programs. Preferred computer program methods for determining identity between two sequences include the GCG program package, including GAP (Genetics Computer Group, University of Wisconsin, Madison, WI; Devereux et al, 1984 Nucleic Acids Res. 12(1 Pt l):387-95), BLASTP, BLASTN, and FASTA (Altschul et al, 1990 J Mol Biol. 215(3):403-10). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al. N CB/NLM/NIH Bethesda, Md. 20894). The well-known Smith Waterman algorithm may also be used to determine identity.
  • GAP Genetics Computer Group, University of Wisconsin, Madison, WI; Devereux et al, 1984 Nucleic Acids Res. 12(1 Pt l):38
  • the 5-HTR1D inhibitor according to the present invention is polynucleotide for targeted gene editing.
  • gene editing methods contemplated in the present invention include, but are not limited to, transcription activator-like effector nucleases (TALEN)-based editing system, clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9), meganucleases, zinc-finger nucleases (ZFNs) and the like.
  • TALEN transcription activator-like effector nucleases
  • CRISPR-Cas9 clustered regularly interspaced short palindromic repeats-Cas9
  • ZFNs zinc-finger nucleases
  • any of the polynucleotide according to the present invention may be delivered in vivo alone or in association with a vector.
  • a "vector” is any vehicle capable of facilitating the transfer of the polynucleotides according to the present invention to the cells, and preferably to cells expressing 5-HTR1D and in a cell-specific manner.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the polynucleotide according to the present invention.
  • Viral vectors are a preferred type of vector and include, but are not limited to, nucleic acid sequences from the following viruses: retrovirus, such as Moloney murine leukemia virus (MMLV), Harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus (AAV); SV40-type viruses; Polyoma viruses; Epstein-Barr viruses; papilloma viruses; Herpes virus; Vaccinia virus; Polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as Moloney murine leukemia virus (MMLV), Harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • retrovirus such as Moloney murine leukemia virus (MMLV), Harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • adenovirus adeno
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are repli cati on-defi ci ent ( i.e ., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • Standard protocols for producing replication-deficient retroviruses including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided by Kriegler (1990. Methods Enzymol. 185:512-27).
  • Preferred viruses for certain applications are the adeno-viruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in gene therapy.
  • the adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species.
  • the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection.
  • wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event.
  • the adeno-associated virus can also function in an extrachromosomal fashion.
  • Other vectors include plasmid vectors.
  • Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See, e.g., Sambrook I, Fritsch E. F. & Maniatis T. (1989). Molecular cloning: A laboratory manual. New York, NY: Cold Spring Harbor Laboratory Press. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid.
  • Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally.
  • the plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and mi croencap sul ati on .
  • the 5-HTR1D inhibitor according to the present invention can be further identified by screening methods described in the state of the art.
  • the screening methods according to the present invention can be carried out according to known methods.
  • the screening method may measure the binding of a candidate compound to 5-HTR1D, or to cells or membranes bearing 5-HTR1D, or a fusion protein thereof by means of a label directly or indirectly associated with the candidate compound.
  • a screening method may involve measuring or, qualitatively or quantitatively, detecting the competition of binding of a candidate compound to 5-HTR1D with a labelled competitor (e.g., antagonist or agonist). Further, screening methods may test whether the candidate compound results in a signal generated by an antagonist of the receptor, using detection systems appropriate to cells bearing the receptor.
  • a labelled competitor e.g., antagonist or agonist
  • Antagonists can be assayed in the presence of a known agonist (e.g., 5-HT) and an effect on activation by the agonist by the presence of the candidate compound is observed.
  • a known agonist e.g., 5-HT
  • Competitive binding using known agonist such as 5-HT is also suitable.
  • the antagonistic activity of compounds towards 5-HTR1D may be determined by using various methods well-known in the art. For example, 5-HTR1D antagonistic activity may be evaluated in a radioligand binding assay and in the 5-HT -induced von Bezold-Jarisch reflex (BJR) in rats, such as described by Turconi et al. (1990. J Med Chem. 33(8):2101-8).
  • BJR 5-HT -induced von Bezold-Jarisch reflex
  • composition, pharmaceutical composition or medicament according to the present invention further comprises 5 -hy droxytryptamine receptor IB (5-HTR1B) inhibitor.
  • 5-HTR1B 5 -hy droxytryptamine receptor IB
  • 5-HTR1B inhibitors according to the present invention include, but are not limited to, small organic molecules, antibodies, aptamers and polynucleotides.
  • the 5-HTR1B inhibitor according to the present invention is a selective 5-HTR1B inhibitor.
  • selective it is meant that the affinity of the inhibitor for 5-HTR1B is at least 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more higher than the affinity for the other human 5-HT receptor (5-HTR1A, 5-HTR1 C, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6, 5-HTR7).
  • the affinity of a 5 -HTR 1B inhibitor may be quantified by measuring the activity of 5-HTR1B in the presence of a range of concentrations of said inhibitor in order to establish a dose-response curve. From that dose response curve, an ICso value may be deduced which represents the concentration of inhibitor necessary to inhibit 50% of the response to an agonist (e.g., 5-HT) in defined concentration.
  • the ICso value may be readily determined by the one skilled in the art by fitting the dose-response plots with a dose- response equation as described in De Lean A. & Rodbard D. (1979) Kinetics of cooperative binding. In: O’Brien R.D. (eds) General Principles and Procedures.
  • a selective 5-HTR1B inhibitor is a compound for which at least one of the ratios:
  • 5 -HTR 1 -7 ⁇ 5 -HTR 1 B means all 5-HT receptors except 5-HTR1B, i.e., 5 -HTR 1A, 5-HTR1 C, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6 and 5-HTR7.
  • a selective 5-HTR1B inhibitor is a compound for which at least one of the ratios:
  • Ki(5 -HTR ID) Ki(5 -HTR 1B)
  • the 5 -HTR 1B inhibitor is a small organic molecule.
  • Exemplary 5-HTR1B inhibitors that are contemplated by the present invention include, but are not limited to, those described in US patents US6, 197,773, US9,938,277, US6, 509,340, US6, 107,328, US6,346,622, US6,291,458, US7, 101,881, US7,026,314, US6,747,030; US patent applications US20070010526, US20050085457,
  • 5-HTR1B inhibitors which may be contemplated by the present invention include, but are not limited to:
  • N-acyl and N-aroyl aralkyl amides derivatives such as the ones described in US patent 6,197,773; isoquinoline derivatives such as the ones described in US patent application 2007010526; ergoline compounds, such as the ones described in US patent 9,938,277; amide and urea derivatives, such as the ones described US patent 6,509,340; benzanilide derivatives, such as the ones described in US patent 6,107,328;
  • 2-substituted 1,2-benzisothi azole derivatives such as the ones described in US patent 6,346,622; arylpiperazine and arylpiperidine derivatives such as the one described in international patent application W09929666; quinolinepiperazine and quinolinepiperidine derivatives, such as the ones described in international patent application WO9931086; 8-amino derivatives, such as the ones described in US patent application 2005085457 and US patent 7,026,314; morpholinobenzamide salts, such as the ones described in US Patent 6,291,458; tetrahydroquinoline derivatives, such as the ones described in US patent 7, 101,881; piperazine derivatives, such as the ones described in US patent 6,747,030; pyridyl piperazine derivatives such as the ones described in US patent application 2006025421; aminomethy lpy ri dy 1 oxy methy 1/b enzi soxazol e substituted azabi
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US5,965,575, including, without limitation, TV- 1 -(2,3- dihydro[ 1 ,4]benzodioxin-5-yl)piperid-4-yl- V-2-(indan- 1 -yl)ethylamine; N- 1 -(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-yl- V-(indan-l-yl-methyl)amine; N- 1-(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-yl- V-3-(indan-l-yl)-propylamine; N-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US5,968,954, including, without limitation, l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4- V-(indan-2-yl)aminopiperidine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4-A/-(indan-2-yl)-A/-methylaminopieridine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4-A/-(5,6-methylenedioxyindan-2-yl)amino-piperidine;
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,066,644, including, without limitation, 1’ -(2-hydroxyethyl)- 5-(2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; G -(2-hydroxy ethyl)-5-(2’ -methyl-4’ - (5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospirofuro[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 100,272, including, without limitation, 5-2’-methyl-4’-(2- oxo-l-pyrrolidinyl)biphenyl-4-carbonyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3, 4’ -piperidine; 1’-methyl-5-2’ -methyl-4’-(2-oxo-l-piperidinyl)biphenyl-4- carbonyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; 5-4’-(4,5-dihydro-2- oxooxazol-3-yl)-2’ -methylbiphenyl-4-carbonyl- -methyl-2, 3,6,7- tetrahydrospirofuro[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 107,328, including, without limitation, 4-(hydroxymethyl)- 1 -methyl-1, 2, 3, 6-tetrahydropyri dine; 4-(2-iodophenoxymethyl)- 1 -methyl- 1 ,2,3 ,6- tetrahydropyridine; 2,3-dihydro-l’-methylspirobenzofuran-3,4’-piperidine; 2, 3 -dihydro- l’-methyl-5-nitrospirobenzofuran-3, 4’ -piperidine; 5 -amino-2, 3 -dihydro- - methylspirobenzofuran-3, 4’ -piperidine; 6-(cyanomethyl)-2,3-dihydro-l’-methyl-5- nitrospirobenzofuran-3,4’-piperidine; 2,3-dihydro-l’-methylspirofuro[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 159,962, including, without limitation, 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-phenyl)-l-piperazinyl)ethylthieno[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 159,970, including, without limitation, (/?)- V-8-(piperazin- l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (/?)-7V-8-(4-ethylpiperazin-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 197,773, including, without limitation, 3,4-dichloro- V-(2-2- (4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 4-fluoro-7V-(2-2-(4-methylpiperazin-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,291,458, including, without limitation, (i?)- V-5-methyl-8- (4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide hydrogen (2S,3S)-tartrate; (/?)-lV-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydro-2-naphthyl-4-morpholinobenzamide hydrogen (2i?,3i?)-tartrate; (R)-N- 5- methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide benzenesulfonate; (i?)-7V-5-methyl-8-(4-methylpiperazin-l-yl)-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,346,622, including, without limitation, 3 , 3 -dimethyl-2-3 -(4- (5-tetralinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,355,647, including, without limitation, 3,4, 5,7-tetrahydro- 6-carbethoxy-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- ⁇ i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 509,340, including, without limitation, 7V-2-(5-fluoro-3- indolyl)ethyl-A/’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenylurea; 4-(5-cyano-3- indolyl)-/V-4-methoxy-3-(4-methylpiperazin-l-yl)phenylpiperidine-l -carboxamide; 4- (6-fluoro-3 -indolyl)-A/-4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 - carboxamide; 3- ⁇ l-4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl-4- piperidyl ⁇ indole-5-carboxamide; 4-(5-fluoro-3-indoly
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,747,030, including, without limitation, ds-5-methoxy-l-[4-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US7,026,314, including, without limitation, 8-(4-methyl-l- piperazinyl)-7V-[4-(4-morpholinyl)phenyl]-4-oxo-4if-chromene-2-carboxamide; 2- ⁇ l- [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one, 2- ⁇ l-[4-(l-acetyl-2,3-dihydro-lif-indol-6-yl)-piperazin-l-yl]- methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chl oro-5-(4- ⁇ l-[8-(4- methyl-piperazin-l-y
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US7, 101,881, including, without limitation, N- ⁇ 4- chlorophenylacetyl)-8-(4-methylpiperazinyl)-tetrahydroisoquinoline; 3-(4-chloro- phenyl)- l-[8-(4-methyl-piperazin- 1 -yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-propan- 1 -one;
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US7, 109,201, including, without limitation, l-acetyl-6-bromo-5- methoxyindoline; c/5-l-acetyl-6-(3,5-dimethylpiperazin-l-yl)-5-methoxyindoline; cis- 6- (3,5-dimethylpiperazin-l-yl)-5-methoxyindoline; 6-bromo-5-fluoroindoline; l-acetyl-6- bromo-5 -fluoroindoline; cis-6-(3 , 5 -dimethylpiperazin- 1 -yl)-5 -fluoroindoline; methyl-4- (6-acetamido-2-methylpyridin-3-yl)benzoate; methyl-4-[6-(methanesulfonamido)-2- m ethylpyri
  • the at least one 5-HTR1B receptor inhibitor is selected from those described in US7,345,038: (7i?,9uS)-/ra «s-cyclohexyl- ⁇ 6-[2-(5-fluoro-benzo[ ⁇ i]isoxazol- 3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl ⁇ -amine;
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US7,479,559, including, without limitation, 3-[5-fluoro-2-(4- methyl-piperazin- 1 -yl)-benzyl]- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2- one; 4- ⁇ 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-2-oxo-pyrrolidin-l-yl ⁇ -benzoic acid ethyl ester; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(6-morpholin-4-yl-pyridin-3-yl)- pyrrolidin-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 - yl)
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US8,859,534, including, without limitation, 7V,7V-dimethyl-7-(4-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US9,938,277, including, without limitation, 3-((6aR,9S,l0aR)-5- cyclopropyl-7-methyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinolin-9-yl)-l,l- diethylurea; (6ui?,9i?)-5-cyclopropyl-A/-((5')-l-hydroxybutan-2-yl)-4,7-dimethyl-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20030064995, including, without limitation, 7V-[2-(5-fluoro- 3-indolyl)ethyl]-A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4-(5-cyano-3- indolyl)-7V-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (6-fluoro-3-indolyl)-A/-[4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]piperidine-l- carboxamide; 3- ⁇ l-[4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl]-4- piperidyl ⁇ indole-5-carboxamide; 4-(5
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20040132720, including, without limitation, c/5-A/-[3-chloro- 2-fluorophenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N-[ 2- fluoro-3-(trifluoromethyl)phenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3- carboxamide; c/5-A/-[2,3-dichlorophenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran- 3 -carboxamide; czs-A/-[2 , -methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenyl]-5- (3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; c
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050085457, including, without limitation, 8-(4-m ethyl- 1- piperazinyl)-7V-[4-(4- morpholinyl)phenyl]-4-oxo-4//-chromene-2-carboxamide; 2- ⁇ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one; 2- ⁇ l-[4-(l -acetyl-2, 3-dihy dro-l//-indol-6-yl)-piperazin-l-yl]- methanoyl ⁇ -8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chloro-5-(4- ⁇ l-[8-(4-(4-
  • 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methyl-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]- amide; 6-methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- fluoro-4-morpholin-4-yl-phenyl)-amide; 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methyl-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-morpholin-4-yl- phenyl)-amide
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050165025, including, without limitation, /V-[3-[3- (dimethylamino)ethoxy]-4-methoxyphenyl-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)-[l,r-biphenyl]-4-carboxamide; r-methyl-5-[(2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050282816, including, without limitation, l-(4-tert- butylphenyl)-3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro-2if- [1,2’ ]bipyrazinyl-3’ -ylmethyl)- pyrrolidin-2-one; 3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2 , ]bipyrazinyl-3’-ylmethyl)-l- [4-(tetrahydropyran-4-yl)-phenyl]-pyrrolidin-2-one; 4-(4-tert-butylphenyl)-2-(4-methyl-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20051710985, including, without limitation, 4-benzyl-2-[2- (4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050182049, including, without limitation, 4-benzyl-2-[2- (4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050288304, including, without limitation, 7V- ⁇ 8-[(2- dimethylamino-ethyl)-ethyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl ⁇ -4- trifluoromethyl-benzamide; A/- ⁇ 8-[(2-dimethylamino-ethyl)ethyl-amino]-5, 6,7,8- tetrahydro-naphthalen-2-yl ⁇ -4-fluoro-benzamide; 4-tert-butyl-/V- ⁇ 8-[(2-dimethylamino- ethyl)-ethyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl ⁇ -benzamide; l-[7-(4-benzyl- phenyl) l,2,3,4-tetrahydro-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20060025421, including, without limitation, l-[4-(3,5- dimethyl-isoxazol-4-yl)phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethylene]- piperidin-2-one; 2-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethylene]-4-[4-[4-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070010526, including, without limitation, l-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-(4-piperi din-l-ylmethyl- phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3,4-dihydro-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070135442, including, without limitation, 6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(2-oxopyrrolidin- 1 -yl)phenyl)chroman-2-carboxamide; (+)- 6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2-oxopyrrolidin- 1 -yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(2-oxopyrrolidin- 1 - yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(2- oxotetrahydropyrimidin- 1 (2H)-yl)phen
  • A/-(4-morpholinophenyl)chroman-2-carboxamide (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(piperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-2- methyl-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide;
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070185107, including, without limitation, 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-7V-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; 7V-(4-(4-acetylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)- V-(4-(4-acetylpiperazin- 1 -yl)phenyl)-6-fluoro-8-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in US20080318926, including, without limitation, (7 R, 9aS)-trans-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in WO1999029666, including, without limitation, 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-5-yl)aminocarbonyl]indoline; 5-chloro-6-(4- ethylpiperazin-l-yl)-l -[(5,6,7, 8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -[( 1 - oxoindan-5-yl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in WO 1999031086, including, without limitation, 7V-[3-chloro-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N- ⁇ 4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)naphth-l-yl]-urea; N- ⁇ 4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-A/’ -[5-(pyridin-4-yl)naphth- 1 -ylj-urea ; N- ⁇ 4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-6-yl]-urea; N
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in W02006048727, including, without limitation, l- ⁇ 2-[2-(4- methyl-piperazin- 1 -yl)-phenyl]-ethyl ⁇ -3 -(4-trifluoromethy 1-phenyl)- 1 , 3 -dihydro- imidazol-2-one; l-(4-isopropoxy-phenyl)-3- ⁇ 2-[2-(4-methyl-piperazin-l-yl)-pyridin-3- yl]-ethyl ⁇ -l,3-dihydro-imidazol-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3- ⁇ 2-[3- (4-methyl-piperazin- 1 -yl)-pyri din-2 -yl]-ethyl ⁇ - 1 ,3 -dihydro-imidazol-2-
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007026219, including, without limitation, elzasonan; 3-(4- chlorobenzyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 3 -(4- chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 3-(4- trifluoromethylphenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4- dione; 3-(3,4-dichlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidin-4- one; 5-[2-(4-methylpiperazin-l-yl)-benzylidene]
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007026224, including, without limitation, 3-[5-fluoro-2-(4- methyl-piperazin- 1 -yl)-benzyl]- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2- one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(6-morpholin-4-yl-pyridin-3-yl)- pyrrolidin-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 - yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(4-morpholin-4- yl-phenyl)-pyrrolidin
  • the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007053093, including, without limitation, 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-fluoro-
  • (4-morpholinobenzyl)chroman-2-carboxamide (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)- A/-(4-morpholinobenzyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - (ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-A/-(4-(ethyl)
  • the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
  • SB-224289 ((r-methyl-6,7-dihydro-5if-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- ⁇ 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl ⁇ -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • AR-A000002 ((i?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
  • GR-55562 (3-[3-(dimethylarnino)propyl]-4-hydroxy-/V-[4-(4- pyridinyl)phenyl]benzamide);
  • NAS-181 ((2i?)-2-( ⁇ [3-(4-morpholinylmethyl)-2if-chromen-8- yl] oxy ⁇ methyl)morpholine methanesulfonate (1 :2));
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • alprenolol (l-(2-allylphenoxy)-3-(isopropylamino)-2-propanol);
  • oxprenolol (l-[2-(allyloxy)phenoxy]-3-(isopropylamino)-2-propanol);
  • cyanopindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-17/-indole- 2-carbonitrile);
  • pindolol (l-(17/-indol-4-yloxy)-3-(isopropylamino)-2-propanol);
  • metergoline (benzyl ⁇ [(8P)-l,6-dimethylergolin-8-yl]methyl ⁇ carbamate); methiothepin (l-methyl-4-[8-(methylsulfanyl)-10, 1 l-dihydrodibenzo[/? ]thiepin- 10-yl]piperazine);
  • the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
  • SB-224289 ((r-methyl-6,7-dihydro-5//-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- ⁇ 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl ⁇ -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • AR-A000002 ((/?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
  • GR-55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-A/-[4-(4- pyridinyl)phenyl]benzamide);
  • NAS-181 ((2/?)-2-( ⁇ [3-(4-morpholinylmethyl)-2//-chromen-8- yl]oxy ⁇ methyl)morpholine methanesulfonate (1 :2));
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • alprenolol (l-(2-allylphenoxy)-3-(isopropylamino)-2-propanol);
  • oxprenolol (l-[2-(allyloxy)phenoxy]-3-(isopropylamino)-2-propanol);
  • cyanopindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-l//-indole- 2-carbonitrile); pindolol (l-(l//-indol-4-yloxy)-3-(isopropylamino)-2-propanol);
  • the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
  • SB-224289 ((r-methyl-6,7-dihydro-5i7-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- ⁇ 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl ⁇ -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • AR-A000002 ((i?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
  • GR-55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-/V-[4-(4- pyridinyl)phenyl]benzamide);
  • NAS-181 ((2i?)-2-( ⁇ [3-(4-morpholinylmethyl)-2if-chromen-8- yl]oxy ⁇ methyl)morpholine methanesulfonate (1 :2));
  • GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
  • the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
  • SB-224289 ((l’-methyl-6,7-dihydro-5.f/-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- ⁇ 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl ⁇ -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide); AR-A000002 ((i?)-A/-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide); and
  • the 5-HTR1B inhibitor according to the present invention is an antibody that blocks 5-HTR1B activation (i.e ., a 5-HTR1B blocking antibody).
  • the 5-HTR1B blocking antibodies contemplated in the present invention may, for instance, impair the binding of 5-HT to the receptor by binding to said receptor.
  • the 5-HTR1B inhibitor according to the present invention is a polyclonal antibody, preferably a 5-HTR1B polyclonal blocking antibody.
  • the 5-HTR1B inhibitor according to the present invention is a monoclonal antibody, preferably a 5-HTR1B monoclonal blocking antibody.
  • the 5-HTR1B inhibitor according to the present invention is a humanized antibody, preferably a 5-HTR1B humanized blocking antibody.
  • the 5-HTR1B inhibitor according to the present invention is an aptamer that can block 5-HTR1B activation.
  • the 5-HTR1B inhibitor according to the present invention is a polynucleotide.
  • the 5-HTR1B inhibitor according to the present invention is a polynucleotide which interferes with 5-HTR1B synthesis.
  • the synthesis of 5-HTR1B may be block at the transcriptional level. In one embodiment, the synthesis of 5-HTR1B may be block at the translational level.
  • the 5-HTR1B inhibitor according to the present invention is an antisense oligonucleotide.
  • Antisense oligonucleotides including antisense RNA molecules and antisense DNA molecules, would act to directly block the translation of 5-HTR1B mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of 5-HTR1B, and subsequently, 5-HTR1B activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding 5-HTR1B can be synthesized, e.g., by conventional phosphodiester techniques and administered by, e.g., intravenous injection or infusion.
  • the 5-HTR1B inhibitor according to the present invention is a ribozyme.
  • the 5-HTR1B inhibitor according to the present invention is an interference RNA (RNAi).
  • RNAi include, without limitation, small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs) and microRNAs (miRNAs), targeted to a 5-HTR1B transcript; as well as RNAi vectors whose presence within a cell results in the production of an siRNA, shRNA or miRNA targeted to the target 5-HTR1B transcript.
  • siRNA, shRNA or miRNA comprises a portion of RNA that is complementary to a region of the target 5-HTR1B transcript.
  • the RNAi contemplated in the present invention downregulates expression of 5-HTR1B via RNA interference.
  • the 5-HTR1B inhibitor according to the present invention is an siRNA.
  • Exemplary siRNA inhibiting 5-HTR1B include, but are not limited to, the siRNA purchased from Dharmacon used in the example section.
  • the 5-HTR1B inhibitor according to the present invention is polynucleotide for targeted gene editing.
  • any of the polynucleotide according to the present invention may be delivered in vivo alone or in association with a vector.
  • the 5-HTR1B inhibitor according to the present invention can be further identified by screening methods described in the state of the art and already mentioned hereinabove.
  • the present invention further relates to a combination of a 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) for use in the prevention and/or treatment of cancer in a subject in need thereof wherein said 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
  • 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
  • the present invention further relates to a composition comprising a 5-HTR1D inhibitor according to the present invention, for use in the prevention and/or treatment of cancer.
  • the present invention relates to a composition comprising a 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) according to the present invention, for use in the prevention and/or treatment of cancer.
  • the present invention further relates to a pharmaceutical composition comprising a 5-HTR1D inhibitor according to the present invention, and at least one pharmaceutically acceptable excipient, for use in the prevention and/or treatment of cancer.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a 5-HTR1D inhibitor, at least one inhibitor of 5 -hy droxytryptamine receptor IB (5-HTR1B) according to the present invention, and at least one pharmaceutically acceptable excipient, for use in the prevention and/or treatment of cancer.
  • the pharmaceutical composition comprises the 5-HTR1D inhibitor according to the present invention in a therapeutically effective amount.
  • the pharmaceutical composition comprises the 5-HTR1D inhibitor, at least one 5-HTR1B according to the present invention in a therapeutically effective amount.
  • a“pharmaceutically acceptable excipient” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • Pharmaceutically acceptable excipients that may be used in the compositions according to the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorb ate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances ( e.g ., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes,
  • the pharmaceutical composition according to the present invention may further comprise antioxidant agents, including, but not limited to, ascorbic acid, ascorbyl palmitate, BHT, potassium sorbate or Rosmarinus officinalis extracts.
  • antioxidant agents including, but not limited to, ascorbic acid, ascorbyl palmitate, BHT, potassium sorbate or Rosmarinus officinalis extracts.
  • composition according to the present invention may further comprise flavour agents, including, but not limited to, sugars, fruit or tea flavourings.
  • flavour agents including, but not limited to, sugars, fruit or tea flavourings.
  • the pharmaceutical composition according to the present invention may further comprise pharmaceutically acceptable salts, including, but not limited to, acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the excipient can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils such as oleic acid.
  • a coating such as lecithin (i.e., soy lecithin or de-greased soy lecithin), by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • agents delaying absorption can be added, including, but not limited to, aluminium monostearate and gelatine.
  • the present invention further relates to a medicament comprising a 5-HTR1D inhibitor according to the present invention, for use in the prevention and/or treatment of cancer.
  • present invention further relates to a medicament comprising the 5-HTR1D inhibitor, at least one 5-HTR1B according to the present invention in a therapeutically effective amount.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: gynecological cancer, liver cancer, lung cancer, gastrointestinal cancer, nervous system cancer, mesotheliomas, head and neck cancer, genitourinary tract cancer, sarcoma, cardiac cancer, bone cancer, hematologic and lymphoid cancer, skin cancer, thyroid gland cancer and adrenal glands cancer.
  • cancer selected from the group comprising or consisting of: gynecological cancer, liver cancer, lung cancer, gastrointestinal cancer, nervous system cancer, mesotheliomas, head and neck cancer, genitourinary tract cancer, sarcoma, cardiac cancer, bone cancer, hematologic and lymphoid cancer, skin cancer, thyroid gland cancer and adrenal glands cancer.
  • Examples of gynecological cancers include, but are not limited to, breast cancer, cervical cancer, ovarian cancer, uterine cancer, vulvar cancer and vaginal cancer.
  • Examples of breast cancers include, but are not limited to, triple negative breast cancer; luminal A breast cancer; luminal B breast cancer; and HER-2-enriched breast cancer.
  • ovarian cancers include, but are not limited to, dysgerminoma; granulosa- theca cell tumors; Sertoli-Leydig cell tumors;
  • Examples of uterine cancers include, but are not limited to, endometrial cancer such as endometrial carcinomas, endometrial stromal sarcomas and malignant mixed Mullerian tumors; uterine sarcomas; leiomyosarcomas; and gestational trophoblastic disease.
  • Examples of vulvar cancers include, but are not limited to, squamous cell vulvar carcinoma; verrucous vulvar carcinoma; vulvar melanoma; basal cell vulvar carcinoma; Bartholin gland carcinoma; vulvar adenocarcinoma; and erythroplasia of Queyrat.
  • vaginal cancers include, but are not limited to, squamous-cell vaginal carcinoma; vaginal adenocarcinoma; clear cell vaginal adenocarcinoma; vaginal germ cell tumors; vaginal sarcoma botryoides; and vaginal melanoma.
  • liver cancers include, but are not limited to, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma.
  • lung cancers include, but are not limited to, adenocaminoma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, lymphoma, chondromatous hamartoma and pleural mesothelioma.
  • gastrointestinal cancers include, but are not limited to, pancreatic cancer (such as, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors or vipoma), esophageal cancer (such as, e.g., squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma or lymphoma), stomach or gastric cancer (such as, e.g., carcinoma, lymphoma or leiomyosarcoma), small bowel or small intestines cancer (such as, e.g., adenocarcinoma lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma or fibroma), large bowel or large intestines cancer (such as, e.g., adeno
  • mesotheliomas include, but are not limited to, pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and end stage mesothelioma.
  • nervous system cancers include, but are not limited to, brain cancer (such as, e.g., astrocytoma, medulloblastoma, glioma, lower grade glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, glioma or sarcoma), skull cancer (such as, e.g., osteoma, hemangioma, granuloma, xanthoma or osteitis deformans) and meninges cancer (such as, e.g., meningioma, meningiosarcoma or gliomatosis).
  • brain cancer such as, e.g., astrocytoma, medulloblastoma, glioma,
  • head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma and oral cancer (such as, e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer or pharynx cancer).
  • oral cancer such as, e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer or pharynx cancer.
  • kidney cancer such as, e.g., clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, adenocarcinoma, Wilm’s tumor, nephroblastoma, lymphoma or leukemia
  • bladder and urethra cancer such as, e.g., squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma
  • prostate cancer such as, e.g., adenocarcinoma or sarcoma
  • testis cancer such as, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors or lipoma).
  • sarcomas include, but are not limited to, Askin' s tumor; sarcoma botryoides; chondrosarcoma; Ewing's sarcoma; malignant hemangioendothelioma; malignant schwannoma; osteosarcoma; and soft tissue sarcomas.
  • soft tissue sarcomas include, but are not limited to, alveolar soft part sarcoma; angiosarcoma; cystosarcoma phyllodes; dermatofibrosarcoma protuberans; desmoid tumor; desmoplastic small round cell tumor; epithelioid sarcoma; extraskeletal chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; gastrointestinal stromal tumor (GIST); hemangiopericytoma; hemangiosarcoma; Kaposi's sarcoma; leiomyosarcoma; liposarcoma; lymphangiosarcoma; lymphosarcoma; malignant peripheral nerve sheath tumor (MPNST); neurofibrosarcoma; plexiform fibrohistiocytic tumor; rhabdomyosarcoma; synovial sarcoma; and undifferentiated pleomorphic sarcoma.
  • cardiac cancers include, but are not limited to, sarcoma (such as, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma or liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma.
  • sarcoma such as, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma or liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma
  • lipoma lipoma
  • teratoma teratoma
  • bone cancers include, but are not limited to, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma and reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxoflbroma, osteoid osteoma and giant cell tumors.
  • hematologic and lymphoid cancers include, but are not limited to, blood cancer (such as, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma or myelodysplasia syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma and hairy cell and lymphoid disorders.
  • blood cancer such as, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma or myelodysplasia syndrome
  • Hodgkin’s disease non-Hodgkin’s lymphoma and hairy cell and lymphoid disorders.
  • Examples of skin cancers include, but are not limited to, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles, dysplastic nevi, lipoma, angioma and dermatofibroma.
  • Examples of thyroid gland cancers include, but are not limited to, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2 A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma and paraganglioma.
  • adrenal glands cancers include, but are not limited to, neuroblastoma and pheochromocytoma.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer, cervical cancer, ovarian cancer, uterine cancer, vulvar cancer, vaginal cancer, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, lung lymphoma, lung chondromatous hamartoma, lung mesothelioma, pancreatic cancer, esophageal cancer, stomach (or gastric) cancer, small bowel or small intestines cancer, large bowel or large intestines cancer, colorectal cancer, brain cancer, skull cancer, meninges
  • cancer
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer, cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
  • breast cancer including, but not limited to,
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer, cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • lung cancer including, but not limited to, lung
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • liver cancer including, but not limited to, liver hepatocellular carcinoma
  • lung cancer including, but not limited to, lung adenocarcinoma
  • brain cancer including, but not limited to, brain lower grade glioma
  • mesothelioma mesot
  • the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • lung cancer including, but not limited to, lung adenocarcinoma
  • brain cancer including, but not limited to, brain lower grade glioma
  • mesothelioma mesothelioma
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma) and lung cancer (including, but not limited to, lung adenocarcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • liver cancer including, but not limited to, liver hepatocellular carcinoma
  • lung cancer including, but not limited to, lung adenocarcinoma
  • the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched, luminal A breast cancer and luminal B breast cancer) and lung cancer (including, but not limited to, lung adenocarcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched, luminal A breast cancer and luminal B breast cancer
  • lung cancer including, but not limited to, lung adenocarcinoma
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein said cancer is selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer) and mesothelioma.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: triple negative breast cancer, luminal A breast cancer, luminal B breast cancer, liver cancer (including, but not limited to, liver hepatocellular carcinoma), mesothelioma and sarcoma.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: triple negative breast cancer, luminal A breast cancer, luminal B breast cancer, mesothelioma and sarcoma.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D or the high expression of 5-HTR1D and of 5-HTR1B in said cancer is associated with a lower survival of said subject.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D in said cancer is associated with a lower survival of said subject.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1B in said cancer is associated with a lower survival of said subject.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D and of 5-HTR1B in said cancer is associated with a lower survival of said subject.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D and low expression of 5-HTR1B in said cancer is associated with a lower survival of said subject.
  • Association between the level of expression of 5-HTR1D and/or 5-HTR1B, and life expectancy of a subject can be determined using methods well-known in the art, such as the method described hereinafter.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D or overexpress the gene coding for 5-HTR1D and overexpress the gene coding for 5-HTR1B.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D and 5-HTR1B.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D but do not overexpress the gene coding for 5-HTR1B.
  • the Inventors have demonstrated that a high level of 5-HTR1D and/or 5-HTR1B expression is particularly associated with a lower survival of breast cancer patients. These observations suggest that the inhibition of the activity of these receptors is particularly effective in the treatment of breast cancer.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of breast cancer in a subject.
  • Routinely evaluated markers of breast cancer cells such as the presence or absence of the hormone receptors (HR) for estrogen and progesterone, the level of human epidermal growth factor receptor 2 (HER2), and the cell proliferation markers Ki67, are used to classify breast cancer into 4 molecular subtypes:
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative, HER2-enriched, luminal A breast cancer or luminal B breast cancer in a subject.
  • the Inventors have demonstrated that a high level of 5-HTR1D or 5-HTR1B expression is particularly associated with a lower survival of triple negative breast cancer patient. Moreover, the inhibition of 5-HTR1D and/or 5-HTR1B is particularly efficient in inhibiting proliferation and survival of triple negative breast cancer cell lines. The Inventors have also demonstrated that a high level of 5-HTR1D expression is particularly associated with a lower survival of luminal A breast cancer patient. These observations suggest that inhibiting the activity of these receptors is particularly effective for the treatment of triple negative breast cancer, luminal A breast cancer patients, and/or luminal B breast cancer.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative, HER2-enriched, luminal A or luminal B breast cancer in a subject.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative breast cancer in a subject.
  • Triple negative breast cancers have been classified into different subtype by Lehmann et al, J Clin Invest. 2011 Jul;121(7):2750-67.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative breast cancer in a subject wherein said triple negative breast cancer is of the type TNBC-BL1, TNBC-M and TNBC-UNS.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of luminal A breast cancer in a subject.
  • the Inventors have demonstrated that a level of 5-HTR1D receptor or 5-HTR1B receptor expression is particularly high in tumor samples not responding to chemotherapy.
  • chemotherapies include, but are not limited to:
  • alkylating agents that act mainly by forming covalent bonds between DNA bases, including, but not limited to, nitrogen mustards (e.g., cyclophosphamide), aziridines and epoxides ( e.g ., thiopeta), alkyl sulfonates ( e.g ., busulfan), nitrosureas (e.g., BCNU and CCNU), hydrazine and triazine derivatives (e.g., procarbazine and temozolomide);
  • nitrogen mustards e.g., cyclophosphamide
  • aziridines and epoxides e.g ., thiopeta
  • alkyl sulfonates e.g ., busulfan
  • nitrosureas e.g., BCNU and CCNU
  • hydrazine and triazine derivatives e.g., procarbazine and temozolomide
  • cisplatin and its analogs that act by forming DNA adducts which lead to intra strand and inter-strand linking leading to the formation of DNA filaments including, but not limited to, carboplatin, cisplatin and oxaliplatin;
  • c. antimetabolites including but not limited to folate metabolism inhibitors (e.g., methotrexate, trimetrexate, tomudex), 5-fluoropyrimidines (e.g., 5-FU), oral fluoropyramidines (e.g., tegafur, uracil, capecitabine), necleoside analogs (e.g., cytarabine), gemcitabine and 6-thiopurines (e.g., 6-MP and 6-TG);
  • folate metabolism inhibitors e.g., methotrexate, trimetrexate, tomudex
  • 5-fluoropyrimidines e.g., 5-FU
  • oral fluoropyramidines e.g., tegafur, uracil, capecitabine
  • necleoside analogs e.g., cytarabine
  • gemcitabine e.g., 6-MP and 6-TG
  • 6-MP and 6-TG 6-thiopurines
  • topoisomerase-interactive agents that affect the topologic states of DNA by interfering or modulating DNA cleavage, strand passage and re-ligation, including, but not limited to, epipodophyllotoxins (e.g., etoposide and teniposide), camptothecin analogs, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), mitoxantrone and losoxantrone, and dactinomycin;
  • epipodophyllotoxins e.g., etoposide and teniposide
  • camptothecin analogs e.g., camptothecin analogs
  • anthracyclines e.g., doxorubicin, daunorubicin, epirubicin, idarubicin
  • mitoxantrone and losoxantrone dactinomycin
  • antimicrotubule agents which interfere with the proper polymerization/depolymerization of microtubules, including, but not limited to, vinca alkaloids (e.g., vincristine, vinorelbine and vinblastine), taxanes (e.g., paclitaxel, docetaxel) and estramustine phosphate; and
  • miscellaneous agents exist which cannot be classified into any of the above groups, including but not limited to suramin, bleomycin, L-asparaginase and amifostine.
  • the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of breast cancer (preferably, of triple negative or luminal A breast cancer) unresponsive to chemotherapy in a subject.
  • said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a first-line chemotherapy.
  • First-line chemotherapy refers to an initial chemotherapy treatment given to a subject for the treatment of cancer.
  • said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a second-line chemotherapy.
  • Second-line chemotherapy refers a chemotherapy treatment given when the first-line chemotherapy treatment did not work or stopped working.
  • said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a third-line chemotherapy or more.
  • “Third-line chemotherapy”, as used herein, refers a chemotherapy treatment given when both the first-line chemotherapy treatment and the second-line chemotherapy treatment did not work or stopped working.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered system! cally or locally.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered orally, buccally, by injection, by percutaneous administration, parenterally, intraperitoneal, by endoscopy, topically, transdermally, transmucosally, nasally, by inhalation spray, rectally, vaginally, intratracheally, or via an implanted reservoir.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be orally administered.
  • formulations adapted to oral administration include, but are not limited to, solid forms, liquid forms and gels.
  • solid forms adapted to oral administration include, but are not limited to, pill, tablet, capsule, soft gelatin capsule, hard gelatin capsule, dragees, granules, caplet, compressed tablet, cachet, wafer, sugar-coated pill, sugar coated tablet, or dispersing/or disintegrating tablet, powder, solid forms suitable for solution in, or suspension in, liquid prior to oral administration and effervescent tablet.
  • liquid form adapted to oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, sealed phial, potion, drench, syrup, liquor and sprays.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be injected, preferably systemically injected.
  • formulations adapted to systemic injections include, but are not limited to, liquid solutions or suspensions, solid forms suitable for solution in, or suspension in, liquid prior to injection.
  • systemic inj ections include, but are not limited to, intravenous, intratumoral, intracranial, intralymphatic, intraperitoneal, intramuscular, subcutaneous, intradermal, intraarticular, intrasynovial, intrastemal, intrathecal, intravesical, intrahepatic, intralesional, intracavemous, infusion techniques and perfusion.
  • the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is sterile.
  • Methods for obtaining a sterile composition, pharmaceutical composition, medicament or nutraceutical composition include, but are not limited to, GMP synthesis (GMP stands for“Good manufacturing practice”).
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be topically administered.
  • formulations adapted to topical administration include, but are not limited to, lubricants, sticks, lipsticks, waxes, creams, lotions, ointments, balms, gels, glosses, sunscreen preparations, cosmetics, masks, leave-on washes or cleansers, depilatory preparations and/or the like.
  • Topical administration characterizes the delivery, administration or application of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention directly to the site of interest for a localized effect (generally onto one or more exposed or outer surfaces thereof, such as the outermost layer of the epidermis, which is exposed and visually observable), e.g., using hands, fingers or a wide variety of applicators (rollup, roll-on or other stick container, tube container, cotton ball, powder puff, Q-tip, pump, brush, mat, cloth and/or the like).
  • the application may be made, e.g., by laying, placing, rubbing, sweeping, pouring, spreading and/or massaging into, or onto, the skin, or by any other convenient or suitable method.
  • topical administration is effected without any significant absorption of components of the composition into the subject’s blood stream (to avoid a systemic effect).
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, e.g., benzyl alcohol 1% or 2% (w/w) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution.
  • the compositions can contain polyethylene glycol 400 (PEG 400).
  • ointments can be mixed to form ointments with, e.g., benzyl alcohol 2% (w/w) as preservative, white petrolatum, emulsifying wax and tenox II (butyl ated hydroxy ani sole, propyl gallate, citric acid, propylene glycol).
  • Woven pads or rolls ofbandaging material e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
  • the combination, the composition, pharmaceutical composition or medicament according to the present invention may be used in conjunction with delivery systems that facilitate delivery of the agents to the central nervous system.
  • delivery systems that facilitate delivery of the agents to the central nervous system.
  • various blood brain barrier (BBB) permeability enhancers may be used to transiently and reversibly increase the permeability of the blood brain barrier to a treatment agent.
  • BBB blood brain barrier
  • Such BBB permeability enhancers include, but are not limited to, leukotrienes, bradykinin agonists, histamine, tight junction disruptors (e.g., zonulin, zot), hyperosmotic solutions (e.g., mannitol), cytoskeletal contracting agents, and short chain alkylglycerols (e.g., 1 -0-pentylglycerol).
  • Oral, sublingual, parenteral, implantation, nasal and inhalational routes can provide delivery of the active agent to the central nervous system.
  • the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention may be administered to the central nervous system with minimal effects on the peripheral nervous system.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in an immediate release form.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in a mixed-release form. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in an enterically-coated form.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in a sustained-release form.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention comprises a delivery system that controls the release of the active ingredients.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered at a dose determined by the skilled artisan and personally adapted to each subject.
  • the total daily usage of the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective amount for any particular subject will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, the duration of the treatment; drugs used in combination or coincidental with the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention; and like factors well known in the medical arts.
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered at least once a day, at least twice a day, at least three times a day. In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered every two, three, four, five, six days.
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered twice a week, every week, every two weeks, every three weeks, once a month.
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered every month, every two months, every three months, every four months, every five months, every six months, once a year.
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered for a period of time of about one day, two days, three days, four days, five days, six days, a week, two weeks, three weeks, a month, two months, three months, six months, a year, or over longer periods such as, e.g., for several years or for the rest of the life of the subject.
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered until treatment or alleviation of cancer, preferably selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer and luminal A breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including but not limited to brain lower grade glioma), mesothelioma, head and neck squamous cell carcinoma, kidney cancer (including but not limited to clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma) and cervix cancer (including but not limited to cervical squamous cell carcinoma); more preferably breast cancer, even more preferably triple negative or luminal A breast cancer.
  • breast cancer including but not limited to triple negative breast cancer and luminal A breast cancer
  • liver cancer including, but not limited to, liver hepatocellular
  • a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered until the tumor(s) size has decreased, preferably the decrease of the tumor in size is of at least 50%, more preferably of at least 60 %, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, at least 99% or more, of the size of the tumor before administration of the treatment.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said cancer is metastasized. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said cancer is metastasized and wherein said chemotherapy comprises the administration of taxanes, preferably of paclitaxel.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said chemotherapy comprises the administration of taxanes, preferably of paclitaxel.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the sensitization to chemotherapy in a subject in need thereof. In one embodiment said cancer is unresponsive to chemotherapy.
  • the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with an immune checkpoint inhibitor.
  • immune checkpoint inhibitor refers to any compound, small molecule, coding or antisense nucleic acids, protein, antibody and fragment or functional equivalent thereof, having, intrinsically or via the protein encoded by said coding nucleic acids, the ability to antagonize the inhibition of the immune response by an immune checkpoint.
  • immune checkpoint inhibitor antagonizes at least partially (e.g., more than 50%) the activity of inhibitory immune checkpoints, in particular those mediated by any of the following: programmed death- 1 (PD-1), programmed death ligand- 1 (PD-L1), programmed death ligand-2 (PD-L2), lymphocyte- activation gene 3 (LAG3), T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3), B- and T-lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and killer immunoglobulin-like receptors (KIR).
  • PD-1 programmed death- 1
  • PD-L1 programmed death ligand- 1
  • PD-L2 programmed death ligand-2
  • LAG3 lymphocyte- activation gene 3
  • immune checkpoint inhibitors include, but are not limited to, antibodies such as pembrolizumab (a.k.a. MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda), nivolumab (a.k.a. ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), cemiplimab (a.k.a. REGN2810 or REGN-2810), tislelizumab (a.k.a. BGB-A317), spartalizumab (a.k.a. PDR001 or PDR-001), ABBV-181,
  • pembrolizumab a.k.a. MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda
  • nivolumab a.k.a. ONO-4538, BMS-936558, MDX1106, GTPL7335 or
  • the immune checkpoint inhibitor gene has, or encodes, a protein having a PD-1/PD-L1 inhibitory activity. In one embodiment, the immune checkpoint inhibitor gene encodes an antibody, a mimetics thereof or a fragment thereof having a PD-1/PD-L1 immune checkpoint inhibitory activity.
  • the immune checkpoint inhibitor gene encodes an antibody, a mimetic thereof or a fragment thereof, that specifically binds to PD-1 or PD-L1.
  • Example of anti -PD 1 antibodies include, but are not limited to, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab, pembrolizumab and antibodies described in International patent applications W02004004771, W02004056875, W02006121168, WO2008156712, W02009014708, W02009114335, WO2013043569 and W02014047350.
  • Example of anti-PD-Ll antibodies include, but are not limited to, LY3300054, atezolizumab, durvalumab and avelumab.
  • VISTA also designated PD-1H or PD-L3
  • PD-1H a member of the PD-L1 family.
  • anti-VISTA antibodies are described in US patent application US20130177557.
  • CTLA-4 Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the CTLA-4 protein, and especially an antibody (or mimetic or fragment thereof) that recognizes human CTLA-4.
  • CTLA4 also known as CD 152, is encoded by the CTLA4 gene.
  • CTLA4 is a member of the immunoglobulin superfamily of receptors. It is expressed on the surface of helper T cells where it primarily regulates the amplitude of the early stages of T cell activation. Recent work has suggested that CTLA-4 may function in vivo by capturing and removing B7.1 and B7.2 from the membranes of antigen-presenting cells, thus making these unavailable for triggering T-cell proliferation through CD28.
  • anti-CTLA-4 antibodies are available in the art (see, e.g., those described in US patent US8,491,895).
  • Other anti-CTLA-4 antibodies that can be considered in the context of this invention are FDA-approved or under advanced clinical development.
  • Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the LAG3 receptor (see e.g. US patent US5,773,578).
  • KIR2L3 and KIR3DL2 Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the KIR proteins (KIR2L3 and KIR3DL2).
  • KIR proteins are expressed by NK cells and T cells and promote self-tolerance by dampening lymphocyte activation, cytotoxic activity and cytokine release.
  • Exemplary molecule targeting KIR that can be considered in the context of the present invention is IPH4102 targeting KIR3DL2.
  • the subject is an animal, preferably a mammal, more preferably a primate, even more preferably a human.
  • the subject is a male. In one embodiment, the subject is a female.
  • the subject is a child. In one embodiment, the subject is a teenager. In one embodiment, the subject is an adult.
  • the subject is over 20 years old. In one embodiment, the subject is over 30 years old. In one embodiment, the subject is over 40 years old. In one embodiment, the subject is over 50 years old. In one embodiment, the subject is over 55 years old. In one embodiment, the subject is over 60 years old.
  • the subject i s/was diagnosed with cancer In one embodiment, the subject is/was diagnosed with breast cancer. In one embodiment, the subject i s/was diagnosed with triple negative breast cancer. In one embodiment, the subject is/was diagnosed with luminal A breast cancer. In one embodiment, the subject is/was diagnosed with breast cancer unresponsive to chemotherapy. In one embodiment, the subject is/was diagnosed with metastasized cancer.
  • the subject is/was diagnosed with cancer, wherein said cancer is characterized by the overexpression of 5-HTR1D and/or overexpression of 5-HTR1B.
  • the Inventors have demonstrated that high expression of 5-HTR1D is associated with a lower survival of subjects affected with breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • the present invention hence relates to cancer prognosis methods, comprising a step of measuring the expression level of 5-HTR1D in a sample from the subject.
  • the term“prognosis” refers to the likelihood of a given outcome in the development of a disease.
  • Exemplary outcomes include, but are not limited to, improvement or worsening of the symptoms, death, survival, expectation of quality of life, potential complications and associated health issues.
  • the outcome may include survival, long-term survival (i.e ., survival for at least 3, preferably at least 5, 8, 10 years or more), survival without recurrence, survival without metastasis and responsiveness to chemotherapy.
  • the Inventors have further demonstrated that high level of expression of 5-HTR1D are characteristic of certain cancers.
  • the present invention hence relates to cancer diagnostic methods, comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • diagnosis refers to a technique or method to facilitate the identification of the nature and/or cause(s) of a medical condition or disease.
  • the Inventors have further demonstrated that the level of expression of 5-HTR1D allows the stratification of breast cancers, in particular in terms of response to chemotherapy. Indeed, the Inventors have surprisingly been able to correlate the high level of expression of 5-HTR1D with tumor unresponsiveness to chemotherapy.
  • the present invention hence relates to cancer stratification methods, comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • cancer stratification refers to the identification of a group of subjects with shared biological characteristics. These ad hoc defined groups can then be used in the design of clinical trials or to choose an appropriate course for the management of the cancer.
  • the measure of the expression level of 5-HTR1D in a sample of a subject is therefore indicative of stratification, diagnostic and prognosis, which can be combined accordingly in a single method.
  • the present invention hence relates to diagnostic and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • the present invention hence relates to diagnostic and stratification methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • the present invention hence relates to stratification and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • the present invention hence relates to cancer diagnostic, stratification and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
  • 5-HTR1B may also be associated with a lower survival of patient with breast cancer (including, but not limited to, triple negative breast cancer and luminal A breast cancer) and mesothelioma. Furthermore, the Inventors have demonstrated that the expression level of 5-HTR1B is also useful in the context of stratification and diagnostic methods.
  • the present invention hence relates to cancer diagnosis, stratification and/or prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample.
  • the cancer diagnosis, stratification and/or prognosis methods of the present invention comprise a step of measuring the expression levels of both 5-HTR1D and 5-HTR1B in a sample.
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma and cholangiocarcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer, gastric cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer, sarcoma, thyroid cancer, colon cancer, bladder cancer and gastrointestinal cancer
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma) and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • liver cancer including
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
  • breast cancer including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • liver cancer including, but not limited to, liver hepatocellular carcinoma
  • lung cancer including, but not limited to, lung adenocarcinoma
  • brain cancer including, but not limited to, brain lower grade glioma
  • mesothelioma including, but not limited to, mesothelioma.
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma) and lung cancer (including, but not limited to, lung adenocarcinoma).
  • breast cancer including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • liver cancer including, but not limited to, liver hepatocellular carcinoma
  • lung cancer including, but not limited to, lung adenocarcinoma
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer) and mesothelioma.
  • breast cancer including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • mesothelioma including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer
  • the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, luminal B breast cancer, liver cancer (including, but not limited to, liver hepatocellular carcinoma), mesothelioma and sarcoma.
  • the cancer diagnosis, stratification and/or prognosis methods according to the invention comprise a step of measuring the expression level of 5-HTR1D or measuring the expression level of 5-HTR1D and of 5-HTR1B in a sample of the subject.
  • the cancer diagnosis, stratification and/or prognosis methods according to the present the invention comprise a step of providing a sample from the subject.
  • the sample is a body tissue sample.
  • body tissues include, but are not limited to, breast, mesothelioma, liver, lung, brain, cervix, kidney, pancreas, ovary, skin, nerve, spleen, thymus, esophagus, stomach, intestine, testis, hair, skin, bone, uterus, bladder and spinal cord.
  • the sample is a biopsy sample, preferably a cancer biopsy sample.
  • the sample is a fine-needle aspirate sample, preferably a cancer fine- needle aspirate sample.
  • the sample is a resection sample, preferably a cancer resection sample.
  • the sample is a bodily fluid.
  • bodily fluids include, but are not limited to, blood, plasma, serum, lymph, ascetic fluid, cystic fluid, urine, bile, nipple exudate, synovial fluid, bronchoalveolar lavage fluid, sputum, amniotic fluid, peritoneal fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, semen, saliva, sweat and alveolar macrophages.
  • the sample preferably the cancer tissue sample
  • the methods according to the present invention do not comprise a step of recovering a sample from the subject. Consequently, according to this embodiment, the methods according to the present invention are non-invasive methods, i.e., in vitro methods.
  • the step of measuring the expression level of 5-HTR1D and/or of 5-HTR1B can be carried out using methods well-known to the one skilled in the art.
  • measuring the expression level comprises a sub -step of extracting total RNAs from the sample.
  • measuring the expression level comprises a sub -step of retro- transcribing total RNAs extracted from the sample, thereby obtaining total cDNAs.
  • measuring the expression level comprises a sub -step of amplifying, such as, e.g., by PCR, preferably by qPCR, the cDNAs corresponding to 5-HTR1D and/or 5-HTR1B.
  • the expression level of 5-HTR1D and/or 5-HTR1B is measured using a DNA microarray.
  • the expression level of 5-HTR1D and/or 5-HTR1B is measured using RNAseq.
  • the cancer diagnostic, stratification and/or prognosis methods according to the present invention comprise a step of comparing the expression level of 5-HTR1D and/or 5-HTR1B determined in the sample of the subject, with a reference expression level.
  • the reference expression level may be either implemented in the software or an overall median or other arithmetic mean across measurements may be built.
  • the reference expression level is relative to an expression level derived from population studies, including without limitation, such subjects having similar age range, subjects in the same or similar ethnic group, similar cancer history and the like.
  • the reference expression level is derived from the measurement of the expression levels of 5-HTR1D and/or 5-HTR1B, in a reference population.
  • the reference population comprises subjects diagnosed with a given cancer, preferably at least 100, more preferably at least 250, even more preferably at least 500 subjects diagnosed with said cancer.
  • the reference population comprises subjects substantially healthy in respect to a given cancer, preferably at least 100, more preferably at least 250, even more preferably at least 500 subjects substantially healthy in respect to said cancer.
  • the reference expression level corresponds to the mean expression levels of 5-HTR1D and/or 5-HTR1B, measured in the reference population. In one embodiment, the reference expression level corresponds to the median expression levels 5-HTR1D and/or 5-HTR1B measured in the reference population.
  • 5-HTR1D and/or 5-HTR1B is considered as differentially expressed (, i.e ., overexpressed or underexpressed) in the sample from the subject as compared to the reference expression level if expression levels differ (positively or negatively) by a factor of at least 1.1, preferably of at least 1.5, more preferably of at least 2 and even more preferably of at least 5.
  • 5-HTR1D and/or 5-HTR1B expression level is considered as substantially unchanged in the sample from the subject as compared to the reference expression level if expression levels do not differ (positively or negatively) by a factor of more than 1.2, preferably 1.15, more preferably 1.1, even more preferably 1.05 or less.
  • the cancer diagnostic, stratification and/or prognosis methods according to the present invention comprise a step of assigning the subject to a group based on the relation of the expression of 5-HTR1D and/or 5-HTR1B with their reference expression level.
  • the subject may be assigned to a short survival group.
  • short survival group refers to a group of subjects having cancer and who are likely to die from said cancer within about 2, 3, 5, 8, 10 or more years.
  • the subject is assigned to the short survival group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
  • the subject may be assigned to a long survival group.
  • long survival group refers to a group of subjects having cancer who are not likely to die from said cancer within about 2, 3, 5, 8, 10 or more years.
  • the subject is assigned to the long survival group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to the reference expression level.
  • an outcome is considered as“not likely” if its probability is inferior to 0.5, preferably inferior to 0.4, 0.3, 0.2, 0.1 or less.
  • an outcome is considered as“likely” if its probability is superior to 0.5, preferably superior to 0.6, 0.7, 0.8, 0.9 or more.
  • the subject may be assigned to a short metastasis-free survival group.
  • short metastasis-free survival group refers to a group of subjects having cancer and wherein said cancer is likely to metastasize within about 2, 3, 5, 8, 10 or more years.
  • the subject is assigned to the short metastasis-free survival group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
  • the subject may be assigned to a long metastasis-free survival group.
  • the term“long metastasis-free survival group” refers to a group of subjects having cancer who are likely to survive without said cancer having metastasized for at least about 2, 3, 5, 8, 10 or more years.
  • the subject is assigned to the long metastasis-free survival group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to the reference expression level.
  • the subject is assigned to a chemotherapy-resi stant group.
  • chemotherapy-resistant group refers to a group of subjects having cancer and whose cancer is likely to be unresponsive to chemotherapy. In one embodiment said subject has been previously treated with a chemotherapy. In one embodiment, the subject is assigned to a chemotherapy-resi stant group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
  • the subject is assigned to a chemotherapy-responsive group.
  • chemotherapy-responsive group refers to a group of subjects having cancer and whose cancer is likely to be responsive to chemotherapy. In one embodiment said subject has been previously treated with a chemotherapy.
  • the subject is assigned to a chemotherapy-responsive group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to their reference expression level.
  • the subject is diagnosed with cancer.
  • the subject is diagnosed with cancer if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
  • the cancer prognosis method according to the present invention comprises the steps of:
  • the cancer stratification method according to the present invention comprises the steps of:
  • cancer diagnostic methods according to the present invention comprise the steps of:
  • the present invention further relates to a method for preventing and/or treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition, pharmaceutical composition or medicament according to the invention.
  • Figure 1 is a graph showing the metastasis free survival (MFS) of breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both.
  • Figure 2 is a graph showing the metastasis free survival (MFS) of luminal A breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both.
  • HR hormone receptor
  • ERBB2 Erb-B2 receptor tyrosine kinase 2 (HER2).
  • Figure 3 is a graph showing the metastasis free survival (MFS) of triple negative breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both.
  • Figure 4 is a graph showing the survival of pancreatic cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • Figure 5 is a graph showing the survival of liver cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • LIHC liver hepatocellular carcinoma.
  • Figure 6 is a graph showing the survival of lung cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • LUAD lung adenocarcinoma.
  • Figure 7 is a graph showing the survival of brain cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • LGG lower grade glioma.
  • Figure 8 is a graph showing the survival of mesothelioma patients wherein said cancers have different level of expression of (A) 5-HTR1B and (B) 5-HTR1D.
  • MESO mesothelioma.
  • Figure 9 is a graph showing the survival of head and neck squamous cell carcinoma patients wherein said cancers have different level of expression of 5-HTR1D.
  • Figure 10 is a graph showing the survival of kidney cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • KIRP kidney renal papillary cell carcinoma
  • KIRC kidney renal clear cell carcinoma
  • KICK kidney chromophobe renal cell carcinoma.
  • Figure 11 is a graph showing the survival of cervical squamous cell carcinoma (CESC) patients wherein said cancer have different level of expression of 5-HTR1D.
  • Figure 12 is a graph showing the survival of gastric cancer patients wherein said cancers have different level of expression of 5-HTR1D.
  • Figure 13 is a box plot showing the expression level of 5-HTR1D in normal and kidney renal papillary cell carcinoma tissues (KIRP).
  • TCGA the cancer genome atlas.
  • Figure 14 is a box plot showing the expression level of 5-HTR1D in normal and lung adenocarcinoma tissues (LUAD).
  • TCGA the cancer genome atlas.
  • Figure 15 is a box plot showing the expression level of 5-HTR1D in normal and pancreatic adenocarcinoma tissues (PA AD).
  • TCGA the cancer genome atlas.
  • Figure 16 is a box plot showing the expression level of 5-HTR1D in normal and cervical squamous cell carcinoma tissues (CESC).
  • TCGA the cancer genome atlas.
  • Figure 17 is a box plot showing the expression level of 5-HTR1D in normal and liver hepatocellular carcinoma tissues (LIHC).
  • TCGA the cancer genome atlas.
  • Figure 18 is a box plot showing the expression level of 5-HTR1D in normal and head and neck squamous cell carcinoma tissues (HNSC).
  • TCGA the cancer genome atlas.
  • Figure 19 is a box plot showing the expression level of 5-HTR1D in normal and rectum adenocarcinoma tissues (READ).
  • TCGA the cancer genome atlas.
  • Figure 20 is a box plot showing the expression level of 5-HTR1D in normal and colon adenocarcinoma tissues (COAD).
  • TCGA the cancer genome atlas.
  • Figure 21 is a box plot showing the expression level of 5-HTR1D in normal and Cholangiocarcinoma tissues (CHOL).
  • TCGA the cancer genome atlas.
  • Figure 22 is a box plot showing the expression level of 5-HTR1D in normal and esophageal carcinoma tissues (ESCA).
  • TCGA the cancer genome atlas.
  • Figure 23 is a box plot showing the expression level of 5-HTR1D in normal and thyroid carcinoma tissues (THCA).
  • TCGA the cancer genome atlas.
  • Figure 24 is a box plot showing the expression level of 5-HTR1D in normal and uterine corpus endometrial carcinoma tissues (UCEC).
  • TCGA the cancer genome atlas.
  • Figure 25 is a box plot showing the expression level of 5-HTR1D in normal and bladder urothelial carcinoma tissues (BLCA).
  • TCGA the cancer genome atlas.
  • Figure 26 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in luminal breast cancer, HER2-enriched breast cancer, triple negative breast cancer and normal tissues.
  • Figure 27 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in breast cancer tissues.
  • Figure 28 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in tissues of Luminal, HER2-enriched and triple-negative breast cancer.
  • Figure 29 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in tissues of different type of triple negative breast cancer as defined by Lehmann et al, J Clin Invest. 2011 Jul;121(7):2750-67.
  • Figure 30 shows histograms illustrating (A) the effect of BRL-15,572 treatment on the viability triple negative breast cancer cell lines; (B) the effect of BRL-15,572 treatment on apoptosis in the triple negative breast cancer cell line BT549; and (C) the effect of BRL-15,572 treatment on proliferation of the triple negative breast cancer cell line BT549.
  • Figure 31 shows histograms illustrating (A) the effect of GR- 127935 treatment on the viability triple negative breast cancer cell lines; (B) the effect of GR- 127935 treatment on apoptosis in the triple negative breast cancer cell line BT549; and (C) the effect of GR- 127935 treatment on the proliferation of the triple negative breast cancer cell line BT549.
  • Figure 32 is a histogram illustrating the effect of HTR1D silencing on the viability of BT549 cells alone or with the combined silencing of HTR1B. ( ⁇ p ⁇ 0.001; Student’s t- test).
  • HR hormone receptor
  • Table 1 clinical characteristics of the cohort
  • Negative 181 (34.4) 76 (42.0) 0.096 (NS) Positive 345 (65.6) 133 (38.6)
  • RNA quality was determined by electrophoresis through agarose gels, staining with ethidium bromide, and visualization of the 18S and 28S RNA bands under ultraviolet light.
  • Quantitative values were obtained from the cycle number (Ct value) at which the increase in the fluorescence signal associated with exponential growth of PCR products started to be detected by the laser detector of the ABI Prism 7900 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA), using PE Biosystems analysis software according to the manufacturer’ s manuals.
  • the TBP gene (Genbank accession NM_003194) encoding the TATA box-binding protein (a component of the DNA-binding protein complex TFIID) was quantified as an endogenous RNA control, and each sample was normalized on the basis of its TBP content.
  • Ntarget 2ACtsample, where the ACt value of the sample was determined by subtracting the average Ct value of the target gene from the average Ct value of the TBP gene.
  • the median target gene value of normal breast tissues (14 samples) was used as a reference to normalize the data.
  • Primers’ sequences are indicated below in Table 2. The conditions of cDNA synthesis and PCR have been described previously (Bieche et al, Clin Chem. 1999; 45: 1148-56). Table 2: list of primers used in the RT-PCR experiments
  • the metastasis-free survival (MFS) of breast cancer patients with a low level of HTR1D expression was longer than the MFS of breast cancer patients with a high level of HTR1D expression (Fig. 1 A).
  • the MFS of breast cancer patients with a low level of HTR1B expression was longer than the MFS of breast cancer patients with a high level of HTR1B expression (Fig. 1 B).
  • Breast cancer patients expressing both genes at a low level showed a longer MFS than breast cancer patients expressing both genes at a high level (Fig. 1C).
  • FIG. 2 is a graph showing the metastasis free survival (MFS) of luminal A breast cancer patients wherein said cancers have different level of expression of (Fig. A) 5-HTR1D, (Fig. B) 5- HTRIB or (Fig. C) both.).
  • MFS In breast cancer patient of the triple negative (TN) group, MFS also negatively correlated with the expression level of the HTR1D gene (Fig. 3 A), HTR1B gene (Fig. 3 B) or HTR1D and HTR1B genes (Fig. 3 C).
  • the MFS of breast cancer patients correlates negatively with the expression level of the HTR1D and/or HTR1B gene(s) in breast cancer patients, breast cancer patient of the luminal A group and breast cancer patient of the TN group.
  • HTR1D and/or HTR1B gene(s) might be used in the diagnosis, prognosis and stratification of breast cancer patient. They also support the hypothesis that the inhibition of 5-HTR1D and / 5-FFTRIB could be useful in the treatment of breast cancer, in particular the triple negative and luminal A subtype.
  • Kaplan-Meier curves illustrating the survival probability in different cancers based on transcriptomic levels of HTR1D or HTR1B were obtained using the current release of Ualcan web -tool. Transcriptomic data were also obtained using the current release of Ualcan web -tool, interrogating the database using HTR1D or HTR1B and selecting the different tumors types and molecular subtypes when indicated. (Chandrashekar et at, Neoplasia. 2017 Aug;19(8):649-658). For gastric cancer, data were obtained using KM plot web -tool (www.kmplot.com) interrogating the database using probe ID“207368_at”.
  • Table 3 cancers wherein lower expression of HTR1D and/or HTR1B expression correlates with longer survival and corresponding analysis of HTR1D expression level.
  • HTR1D and/or HTR1B gene(s) might be used in the diagnosis, prognosis and stratification of several cancer, in particular mesothelioma, glioma, gastric cancer, kidney cancer, liver cancer, lung cancer, head and neck squamous cell carcinoma, pancreas cancer and cervical cancer. Furthermore, in view of these results, the treatment of said cancer by the inhibition of 5-HTR1D and/or 5-HTR1B might be considered.
  • Example 3 HTR1D is overexpressed in several cancers Material and Methods
  • Transcriptomic data were obtained using the current release of Ualcan web -tool, interrogating the database using HTR1D and selecting the different tumors types and molecular subtypes when indicated. (Chandrashekar et at, Neoplasia. 2017 Aug;19(8): 649-658).
  • data were obtained using KM plot web -tool (www.kmplot.com) interrogating the database using probe ID“207368_at”.
  • HTR1D gene might be used in the diagnosis, prognosis and stratification of cancer, in particular kidney cancer, liver cancer, lung cancer, head and neck squamous cell carcinoma, pancreas cancer, cervical cancer, rectum cancer, colon cancer, choliangiocarcinoma, Esophageal cancer thyroid cancer, endometrial cancer and bladder cancer. They also support the hypothesis that the inhibition of 5-HTR1D and / 5-HTR1B could be useful in the treatment of said cancer.
  • Microarray data (Affymetrix human exon 1.0 ST DNA array) of breast cell lines from Institut Curie comprising different breast cancer histological subtypes were queried for HTR1D and HTR1B transcripts. Boxplots illustrating each subtype and compared to non- tumorigenic breast cell lines were displayed.
  • Reverse transcription was performed with 2pg of total RNA, with the High-Capacity cDNA reverse transcription kit (Applied Biosystems).
  • the seventeen 5-HT receptors (HTRs) and GAPDH were amplified by Q-PCR in a Roche LightCycler 480 real-time thermal cycler, with the Roche Taqman master mix (Roche) with couples of primers and probes designed with the Roche Assay Center tool (available online at https://www.lifescience.roche.com/en_fr/brands/universal-probe-library.html#assay- design-center) or ready-to-use assay (encompassing primers and Taqman probes) purchased from Applied LifeTechnologies. Primers and probes sequences or reference are listed in Table 5.
  • Transcriptomic expression levels for each HTR gene were calculated with the 2-ACt method normalized to GAPDH as housekeeping gene and displayed as UAE (Arbitrary Unit of Expression).
  • HTR1D (Fig. 26 A) was found overexpressed in triple negative breast cancer tissues from the patient cohort described in Example 1 while it was not the case for HTR1B (Fig. 26 B).
  • HTR1D (Fig. 27 A) was found overexpressed in breast cancer tissues while it was not the case for HTR1B (Fig. 27 B) using the Cancer Genome Atlas (TCGA) transcriptome data.
  • HTR1D was found overexpressed in tissues of Luminal, HER2-(Fig. 28 A) enriched and triple-negative breast cancers while it was not the case for HTR1B (Fig. 28 B).
  • TCGA Cancer Genome Atlas
  • Table 6 HTR receptor expression in cancer cell lines (Arbitrary Unit of Expression).
  • HTR1D gene(s) might be used in the diagnosis, prognosis and stratification of breast cancer and in particular breast cancer of the luminal, HER-2 enriched and triple negative type. Furthermore, in view of these results, the treatment of said cancer by the inhibition of 5-HTR1D appear as a promising approach.
  • Example 5 effect of the inhibition of 5-HTRln and 5-HTR1B on breast cancer cell lines
  • TNBC cell lines were treated with different doses of BRL-15,572 (selective antagonist of 5-HTR1D) or GR- 127935 (potent and dual antagonist of 5-HTR1D and 5-HTR1B) for 72h and cell viability was assessed using the CellTiter-Glo® assay from Promega according to according to the manufacturer’s protocol. Proliferation assay were performed at 72h with the different compounds indicated using the colorimetric BrDU assay from Cell Signaling. Induction of cell apoptosis were detected after 6 hours of treatment using the RealTime-GloTM Annexin V Apoptosis assay (Promega).
  • siRNA Ctrl siRNA HTR1D
  • siRNA Ctrl and SiRNA HTR1B+HTR1D in the presence of Dhermafect I reagent (Dharmacon), in accordance with the manufacturer’ s protocol. All siRNAs were purchased from Dharmacon. Cell viability was assessed with the CellTiter-Glo assay (Promega) 120 h after transfection.
  • Treatment of triple negative cancer cell lines with BRL-15,572 comprised their viability in a dose-dependent manner (Fig.30A). Treatment of cells from the BT549 triple negative cancer cell line with BRL-15,572 inducted their apoptosis and inhibited their proliferation in a dose-dependent manner (Fig. 30B-C).
  • Treatment of triple negative cancer cell lines with GR- 127935 comprised their viability in a dose-dependent manner (Fig.31A). Treatment of cells from the BT549 triple negative cancer cell line with GR- 127935 inducted their apoptosis and inhibited their proliferation in a dose-dependent manner (Fig. 31B-C).

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Abstract

The present invention deals with a 5 -hydroxytryptamine receptor 1D (5-HTR1D) inhibitor and with a combination of a 5-HTR1D inhibitor and at least one inhibitor of 5 -hydroxytryptamine receptor 1B (5-HTR1B) for use in the prevention and/or treatment of cancer in a subject in need thereof. According to the invention the cancer may be selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer.

Description

HTRID INHIBITORS AND USES THEREOF IN THE TREATMENT OF
CANCER
FIELD OF INVENTION
The present invention relates to the treatment of cancer. In particular, the present invention relates to the use of 5-hydroxytryptamine receptor ID inhibitors in the prevention and treatment of cancer. The present invention further relates to the use of 5 -hy droxytryptamine receptor ID inhibitors in combination with one or several 5 -hy droxytryptamine receptor IB inhibitor(s) in the prevention and treatment of cancer. The present invention further pertains to diagnosis, stratification and/or prognosis methods based on the measure of HTRID and/or HTR1B gene expression level.
BACKGROUND OF INVENTION
Breast cancer is a cancer that develops from breast tissue. Most breast cancers are invasive, i.e., the proliferation of cell has expanded into surrounding breast tissues, beyond the wall of the glands or ducts where they originate from. The extent of the spread of the cancer at the time of diagnosis is used in the TNM (Tissue, Node, Metastasis) staging system, that distinguishes between five stages of advancement, from noninvasive (stage 0) to metastasized cancer (stage IV).
In addition to the TNM classification, several molecular markers have recently been identified, allowing the distinction of four main types of cancer. This classification is based on the presence or absence of hormone receptors for progesterone and estrogen (HR+ vs HR ) and of epidermal growth factor receptor 2 (HER2+ vs HER2 ).
The four types of breast cancer are:
HR HER2+. This type of cancer, called “HER2-enriched breast cancer”, accounts for about 1 to 5% of all diagnosed breast cancers. Despite the tendency of cancer in this group to grow and spread aggressively, the use of targeted therapies has reversed much of the adverse prognosis impact of HER2 overexpression. Because of the absence of hormone receptors, HER2-enriched breast cancers do not respond to hormonal therapy. Targeted therapies are therefore used, such as Herceptin (trastuzumab), Perjeta (pertuzumab), Tykerb (lapatinib) or Kadcyla (T-DM1 or ado-trastuzumab emtansine).
- HR+/HER2 . This type of breast cancers, called“luminal A breast cancer”, is the most common form of breast cancer. It accounts for around 70 to 75% of all diagnosed breast cancers. Luminal A breast cancers have low levels of proliferation marker Ki-67, which helps control how fast cancer cells grow. Luminal A cancers tend to be slow-growing, low-grade and thus less aggressive. They are thus associated with favorable prognosis and good response to hormonal therapy.
HR+/HER2+. This type of breast cancers, called“luminal B breast cancer”, is further defined by being highly positive for the proliferation marker Ki-67. It accounts for around 10% of all diagnosed breast cancers and tends to be higher- grade and more aggressive than luminal A breast cancers.
HR/HER2 . This last group of breast cancers, called“triple negative breast cancer” (as they are negative for both hormone receptors and HER2), accounts for about 12 to 15% of all diagnosed breast cancers. They have the poorest short-term prognosis as they are the most aggressive subtype, associated with a large risk for early distant metastasis and for which there is currently no targeted therapy.
Interestingly, this type of cancer is more common in women with BRCA1 gene mutations. It has also been shown that it is the most common type ofbreast cancers among young women.
Recently, serotonin (5-hydroxytryptamine or 5-HT) has emerged as an important regulator of cell proliferation and tumor growth in a variety of tissues. 5-HT, well studied for its function in the nervous system as neurotransmitter, has numerous important peripheral functions. Of particular interest in the context of cancer, 5-HT has been shown to function as a growth factor regulating normal cell (e.g., vascular smooth muscle cells, lung fibroblasts, mammary epithelial cells or renal mesangial cells) and cancer cell (e.g., in cholangiocarcinoma, breast cancer, bladder cancer or pancreatic cancer) proliferation in various tissues (Nemecek et al, 1986. Proc Natl Acad Sci U S A. 83(3):674-8; Takuwa et al, 1989 Am J Physiol. 257(3 Pt 2):F431-9; Soil et al, 2010 Hepatology. 51(4): 1244-54; Pai et al., 2009. Breast Cancer Res. 11(6):R81; Gurbuz et al., 2014. PLoS One. 9(9):el 10067).
5-HT can exert its action through a repertoire of more than 15 G protein-coupled receptors or ligand-gated ion channels, collectively named 5-HT receptors, and belonging to seven families: 5-HTR1 to 7. Another major player in the 5-HT system, primarily terminating the action of 5-HT, is the 5-HT reuptake transporter (SERT, encoded by the SLC6A4 gene). Of note, another 5-HT transporter has been identified, which may account for a significant percentage of 5-HT clearance although having a low serotonergic affinity (Zhou et al., 2007. Biochem Pharmacol. 73(1): 147-54).
In short, the large number of potential receptors and the numerous physiological processes in which the 5-HT machinery is involved has hampered the identification of target(s) that would be of interest in the treatment of cancer.
In an attempt to circumvent this limitation, International patent application WO2013063492 reports the downregulation of cell proliferation, colony formation and the induction of apoptosis in breast cancer cell models using the selective 5-HTR1B receptor antagonists SB224289 and SB216641. Curiously however, the same disclosure shows a similar antiproliferative effect of 5 -nonylytryptamine (5 -NT), a triptan ( i.e ., a class of molecules known as 5-HTR1B agonists), on breast cancer cell models. In view of these observations, it remains unclear whether an efficient therapeutic approach in the treatment of breast cancer requires to downregulate or upregulate 5-HTR1B signaling activity. While these observations point toward a role for serotonin and associated signaling pathways in the regulation of breast tissues homeostasis in normal and pathological conditions, there is a lack of evidence allowing to choose the best target and the best approach for the treatment of breast cancer.
Here, the Inventors show that the expression of the gene coding for 5-HTR1D, HTRID, is upregulated in breast cancer patient with poor prognosis. From this finding, the Inventors further demonstrate that inhibiting 5-HTR1D signaling, either by using a selective 5-HTR1D antagonist or a specific silencing RNA (siRNA), decreases breast cancer cell viability. Moreover, they show that this decrease in breast cancer cell viability is even sharper when both 5-HTR1D and 5-HTR1B signaling are inhibited. Together, these observations unveil a novel therapeutic strategy for breast cancer patients, i.e., the inhibition of 5-HTR1D signaling alone or in combination with the inhibition of 5-HTR1B signaling.
Interestingly, the association of higher level of HTR1D expression and poor prognosis seen in breast cancer has also been observed by the Inventors in several other cancers: liver cancer, lung cancer, brain lower grade glioma, mesothelioma, head and neck squamous cell carcinoma, renal clear cell carcinoma, renal chromophobe cell carcinoma, renal papillary cell carcinoma, gastric cancer and cervical squamous cell carcinoma. This suggests a more global therapeutic effect of 5-HTR1D signaling inhibition for the treatment of cancers, beyond breast cancer.
SUMMARY According to a first aspect, the invention deals with a 5-hydroxytryptamine receptor ID (5-HTR1D) inhibitor, for use in the prevention and/or treatment of cancer in a subject in need thereof.
In a first embodiment of the invention, the 5-HTR1D inhibitor is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides. In a further embodiment of the invention, the 5-HTR1D inhibitor is a selective 5-HTR1D inhibitor.
According to another aspect, the invention deals with a combination of at least one 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) for use in the prevention and/or treatment of cancer in a subj ect in need thereof wherein said 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides. According to another aspect, the invention deals with a composition for use in the prevention and/or treatment of cancer in a subject in need thereof comprising a 5-HTR1D inhibitor as above described
According to further aspect, the composition for use further comprises at least one inhibitor of 5 -hy droxytryptamine receptor IB (5-HTR1B).
In a further embodiment of the invention, the 5-HTR1B inhibitor of said composition for use is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
In a further embodiment of the invention, the composition for use is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.
In a further embodiment of the invention, the 5-HTR1D inhibitor, the combination, the composition is for use in the treatment and/or prevention of cancer, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer.
In a still further embodiment, said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer and mesothelioma.
In a still further embodiment, said cancer cells overexpress the gene coding for 5-HTR1D.
In a still further embodiment, said cancer cells overexpress the gene coding for 5-HTR1B. In a still further embodiment the 5-HTR1D inhibitor, the combination, the composition is for use in the treatment and/or prevention of breast cancer preferably triple negative, HER2-enriched, luminal B or luminal A breast cancer
The present invention also deals with a medicament comprising the 5-HTR1D inhibitor, the combination, the composition of the present invention, for use in the treatment and/or prevention of cancer, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer, more particularly breast cancer and preferably triple negative, HER2-enriched, luminal B or luminal A breast cancer
The present invention also deals with an in vitro cancer diagnosis, stratification and/or prognosis method comprising a step of measuring the expression level of 5-HTR1D and/or 5-HTR1B in a sample previously obtained from a subject.
DEFINITIONS
In the present invention, the following terms have the following meanings:
“ 5-hydroxytryptamine receptor IB” or“5-HTR1B”, as used herein, have their general meaning in the art and refer to a seven-pass transmembrane G protein-coupled receptor. Its natural ligand is serotonin (5-HT), and its principal signal transduction pathway is cyclic- AMP. Briefly, upon binding of serotonin to 5-HTR1B, a conformational change allows it to act as a guanin nucleotide exchange factor. The receptor can then activate the associated Goa protein by exchanging the GDP bound to the G protein for a GTP, thereby inhibiting cyclic AMP synthesis by the adenylate cyclase. In human, 5-HTR1B is a 390-amino acid protein with SEQ ID NO: 33, encoded by the HTR1B gene. It shares 60.6% global identity with SEQ ID NO: 34 (5-HTR1D) as assessed by EMBOSS Needle and 67.1% local identity with SEQ ID NO: 34 (5-HTR1D) as assessed by EMBOSS Water.
“5-hydroxytryptamine receptor ID” or“5-HTR1D”, as used herein, have their general meaning in the art and refer to a seven-pass transmembrane G protein-coupled receptor. Its natural ligand is serotonin (5-HT), and its principal signal transduction pathway is cyclic- AMP. Briefly, upon binding of serotonin to 5-HTR1D, a conformational change allows it to act as a guanin nucleotide exchange factor. The receptor can then activate the associated Goa protein by exchanging the GDP bound to the G protein for a GTP hereby inhibiting cyclic AMP synthesis by the adenylate cyclase. It shares 60.6% global identity with SEQ ID NO: 33 (5-HTR1B) as assessed by EMBOSS Needle and 67.1% local identity with SEQ ID NO: 33 (5-HTR1B) as assessed by EMBOSS Water. “5-HTR1D inhibitor” and“5-HTR1B inhibitor”, as used herein, both refer to any molecule, compound or substance that, when administered to a subject, leads to a partial or complete reduction of the normal physiological activity of 5-HTR1D and 5-HTR1B, respectively. By normal physiological activity of 5-HTR1D and 5-HTR1B is meant the physiological activity of these receptors which is observed upon binding of their natural ligand, 5-HT. These terms also refer to any molecule, compound or substance that, when administered to a subject, leads to a reversal of the normal physiological activity of 5-HTR1D and 5-HTR1B, respectively (i.e., to a physiological activity which is opposite to the normal physiological activity of these receptors which is observed upon binding of their natural ligand, 5-HT). For example, but without limitation, inhibition can be achieved by preventing the binding of 5-HT to 5-HTR1D or 5-HTR1B using a receptor antagonist; by preventing the synthesis of 5-HTR1D or 5-HTR1B; or by inducing a physiological activity which is opposite to the normal physiological activity which is observed upon binding of 5-HT, using a receptor inverse agonist.
“Antibody”, as used herein, encompasses intact polyclonal antibodies, intact monoclonal antibodies, single-domain antibodies, nanobodies, antibody fragments (such as Fab, Fab’, F(ab’)2 and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies (such as bispecific antibodies generated from at least two intact antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site, so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as a (alpha), d (delta), e (epsilon), g (gamma) and m (mu), respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked, or conjugated to other molecules such as toxins, radioisotopes, or any of the other specific molecules recited herein. A“monoclonal antibody” refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to“polyclonal antibodies” that typically include different antibodies directed against different antigenic determinants. The term “monoclonal antibody” encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, “monoclonal antibody” refers to such antibodies made in any number of ways including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals. The term“humanized antibody” refers to an antibody derived from a non human (e.g., murine) immunoglobulin, which has been engineered to contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, or hamster) that have the desired specificity, affinity, and capability (Jones et al, 1986 Nature. 321(6069):522-5; Riechmann et al, 1988 Nature. 332(6162):323-7; Verhoeyen et al., 1988 Science. 239 4847 1534-6). In some instances, the Fv framework region (FW) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity and capability. Humanized antibodies can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or capability. In general, humanized antibodies will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non- human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. Humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in US Patents US5,225,539 and US5,639,641.
“Aptamer”, as used herein, refers to a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk et al. (1990. Science. 249(4968): 505- 10). The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed by Jayasena (1999. Clin Chem. 45(9): 1628-50). Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli thioredoxin A, that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996. Nature. 380(6574):548-50).
“Cancer”, as used herein, refers to any member of a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis. Metastasis is defined as the stage in which cancer cells are transported through the bloodstream or lymphatic system. Cancers are classified by the type of cell that the tumor resembles and, therefore, the tissue presumed to be the origin of the tumor. For example, carcinomas are malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung, and colon cancer. Lymphomas and leukemias include malignant tumors derived from blood and bone marrow cells. Sarcomas are malignant tumors derived from connective tissue or mesenchymal cells. Mesotheliomas are tumors derived from the mesothelial cells lining the peritoneum and the pleura. Gliomas are tumors derived from glia, the most common type of brain cell. Germinomas are tumors derived from germ cells, normally found in the testicle and ovary. Choriocarcinomas are malignant tumors derived from the placenta. Specific, non-limiting examples of cancer cells whose proliferation is reduced by the inhibitors or composition of the present invention include breast cancer (including HER2-enriched breast cancer, luminal A breast cancer, luminal B breast cancer and triple negative breast cancer), liver cancer (including liver hepatocellular carcinoma), lung cancer (including lung adenocarcinoma), pancreas cancer, brain cancer (including brain lower-grade glioma), mesothelioma, head and neck squamous cell carcinoma, kidney cancer (including clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer and cervical cancer.
“Expression”, as used herein, refers to the expression of a gene. Expression of a gene may be determined at the protein level by ways of, e.g., immunohistochemistry, Multiplex methods (Luminex), western blot, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, fluorescent-linked immunosorbent assay (FLISA), enzyme immunoassay (EIA), radi oimmunoas say (RIA) and the like. Alternatively, expression of a gene may be determined at the mRNA level, by ways of, e.g., RT-PCR, RT-qPCR (wherein qPCR stands for quantitative PCR), hybridization techniques such as, for example, Northern Blot, use of microarrays, and combination thereof including but not limited to, hybridization of amplicons obtained by RT-PCR, sequencing such as, for example, next-generation DNA sequencing (NGS) or RNA-seq (also known as“Whole Transcriptome Shotgun Sequencing”) and the like.
“Overexpression” as used herein, refers to the expression of a gene being higher in a sample when compared to a“reference expression level”. The reference expression level can be the typical level of expression observed in a similar population of cancer cell among a large group of subjects (typically more than 10, preferably at least 50 or more subjects). The reference expression level can also refer to the level of expression in healthy cells of the same tissue of origin in the same subject or derived from a large group of subjects. The reference expression level can also refer also the level of expression in the cancer cells of a subject at different time points. The person of the art is familiar with the techniques allowing the comparison of gene expression level.
“Receptor antagonist”, as used herein, refers to any molecule, compound or substance that binds to a receptor and thereby prevents the normal physiological activity which is observed upon binding of its activating ligand ( i.e ., the receptor agonist). A receptor antagonist can, for instance, compete with the binding of the agonist to the receptor.
“Receptor inverse agonist”, as used herein refers to any molecule, compound or substance that binds to the same receptor as the receptor agonist but exerts the opposite effect. Receptor inverse agonists have the ability to decrease the constitutive activity of the receptor, i.e., the basal receptor activity observed in absence of receptor agonist. “Response to chemotherapy”, as used herein refers to the effectiveness of a chemotherapy in treating a cancer. Methods to measure the effectiveness of a chemotherapy as known in the art and includes, but is not limited to, determining the size of a solid tumor, metabolites level reflecting the function of the organ(s) affected by cancer, measuring the level of a cancer marker and cell counting techniques. A subject having cancer can be“resistant to chemotherapy” or“unresponsive to chemotherapy” if, after chemotherapy, said cancer as progressed, remained stable or insufficiently decreased. Alternatively, a subject having cancer can be“responsive to chemotherapy” if, after chemotherapy, said cancer has become undetectable or has significantly decreased.
“Treatment”, as used herein, refers to both therapeutic and prophylactic (or preventive) measures, whose object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully“treated” if, after receiving a therapeutic amount of the inhibitor or composition according to the present invention, the patient shows one or more of the following observable and/or measurable changes: amelioration related to one or more of the symptoms associated with the specific disease or condition, reduction of morbidity and mortality and improvement in quality of life issues. Example of observable or measurable changes includes, but are not limited to, a reduction of the cancer cells proliferation, a decrease in the size or a disappearance of the tumor, the prevention of metastasis or recurrence, a reduction in the appearance of tumors and an increase of cancer cell death. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
“Therapeutically effective amount”, as used herein, refers to the level or amount of the inhibitor or composition according to the present invention, that is aimed at (but without causing significant negative or adverse side effects to the subject): (1) delaying or preventing the onset of the targeted condition or disorder; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the targeted condition or disorder; (3) bringing about ameliorations of the symptoms of the targeted condition or disorder; (4) reducing the severity or incidence of the targeted condition or disorder; and/or (5) curing the targeted condition or disorder. A therapeutically effective amount of the inhibitor or composition according to the present invention may be administered prior to the onset of the targeted condition or disorder, for a prophylactic or preventive action. Alternatively or additionally, the therapeutically effective amount of the inhibitor or composition according to the present invention may be administered after initiation of the targeted condition or disorder, for a therapeutic action.
“Subject”, as used herein, refers to a warm-blooded animal, preferably a human, a pet or livestock. As used herein, the terms“pet” and“livestock” include, but are not limited to, dogs, cats, guinea pigs, rabbits, pigs, cattle, sheep, goats, horses and poultry. In some embodiments, the subject is a male or female subject. In some embodiments, the subject is an adult (for example, a subject above the age of 18 (in human years) or a subject after reproductive capacity has been attained). In some embodiments, the subject may be a “patient”, i.e., a subject who/which is awaiting the receipt of or is receiving medical care or was/is/will be the obj ect of a medical procedure according to the methods of the present invention or is monitored for the development of a disease.
DETAILED DESCRIPTION
The present invention relates to a 5-hydroxytryptamine receptor ID (5-HTR1D) inhibitor, for use in the prevention and/or treatment of cancer in a subject in need thereof.
In one embodiment, 5-HTR1D inhibitors according to the present invention include, but are not limited to, small organic molecules, antibodies, aptamers and polynucleotides.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is a selective 5-HTR1D inhibitor. By“selective”, it is meant that the affinity of the antagonist for 5-HTR1D is at least 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more higher than the affinity for the other human 5-HT receptor (5-HTR1A, 5-HTR1B, 5-HTRlc, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6, 5-HTR7). The affinity of a 5-HTR1D inhibitor may be quantified by measuring the activity of 5-HTR1D in the presence of a range of concentrations of said inhibitor in order to establish a dose-response curve. From that dose response curve, an IC50 value may be deduced which represents the concentration of inhibitor necessary to inhibit 50% of the response to an agonist (e.g., 5-HT) in defined concentration. The IC50 value may be readily determined by the one skilled in the art by fitting the dose-response plots with a dose- response equation as described in De Lean A. & Rodbard D. (1979) Kinetics of cooperative binding. In: O’Brien R.D. (eds) General Principles and Procedures. The Receptors (A Comprehensive Treatise), Vol. 1. Springer, Boston, MA. IC50 values can be converted into affinity constant (Ki) using the assumptions of Cheng & Prusoff (1973. Biochem Pharmacol. 22(23):3099-108).
Accordingly, a selective 5-HTR1D inhibitor is a compound for which at least one of the ratios:
(i) Ki(5 -HTR 1 -7\5 -HTR ID): Ki(5 -HTR ID), and/or
(ii) IC5O(5 -HTRl -7\5 -HTR 1 D) : ICso(5 -HTR 1 D),
is above 2: 1, 5: 1, 10: 1, 15: 1, 20:1, 25: 1, 50: 1, 100: 1 or above,
wherein “5-HTR1-7\5-HTR1D” means all 5-HT receptors except 5 -HTR ID, i.e., 5 -HTR 1A, 5-HTR1B, 5-HTR1C, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6 and 5-HTR7. Accordingly, a selective 5 -HTR ID inhibitor is a compound for which at least one of the ratios:
(i) Ki(5 -HTR 1B): Ki(5 -HTR ID), and/or
(ii) IC5O(5 -HTRl B) : ICso(5 -HTRl D),
is above 2: 1, 5: 1, 10: 1, 15: 1, 20:1, 25: 1, 50: 1, 100: 1 or above. In a first embodiment, the 5 -HTR ID inhibitor is a small organic molecule.
“Small organic molecule”, as used herein, refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules such as protein and nucleic acids. Preferred small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
Exemplary 5-HTR1D inhibitors that are contemplated by the present invention include, but are not limited to, those described in European patents EP0533268, EP0701819, EP0712397, EP0714389, EP0716650, EP0736023, EP0736025, EP0752982,
EP0777650, EP0799226, EP0894085, EP1070065, EP1113015, EP1140931; European patent application EP1186318; EiS patents EiS5,356,893, US5,358,948, US5,436,246, US5,756,496, US5,801,170, US5,821,245, US5,919,932, US5,952,325, US5,972,935, US6, 107,321, US6, 107,328, US6, 124,283, US6, 159,962, US6, 159,979, US6, 166,034, US6, 197,773, US6,342,498, US6,346,622, US6,355,647, US6,403,592, US6,509,340, US6,537,995, US6, 887,905, US6,924,289, US7,026,314, US7,425,574, US7,432,282, US7,776,860, US9,938,277; US patent applications US20030064995, US20030212109, US20050085457, US20060009448, US20070010526; International patent applications WO 1994015920, WO1995011243, WO1995030675, WO 1999029666 and WO1999031086; the content of all of which is hereby incorporated by reference.
Typically, 5-HTR1D inhibitors which may be contemplated by the present invention include, but are not limited to:
naphthalene derivatives, such as those described in EP0701819 and US5, 821, 245;
- tetrahydronaphthalene derivatives, such as those described in US6, 124,283; carboxamide derivatives, such as those described in EP0712397, EP0752982 and US5,756,496;
- biphenylamide and biphenylethanone derivatives, such as those described in EP0736025, US5,801,170, US5,919,932, US5,972,935 and WO1995030675;
- benzanilide derivatives, such as those described in EP0533268, US5,356,893, US5,358,948, WO 1994015920 and WO1995011243;
- /V-acyl and TV-aroyl aralkyl amides derivatives, such as those described in US6, 197,773;
indole, indoline, quinolone and quinoline derivatives, such as those described in EP0716650, EP0736023, EP0777650, US7,432,282, US20050085457,
US20070010526, WO 1999029666 and WO1999031086; - tricyclic spiro derivatives, such as those described in US5,952,325;
- tetracyclic spiro derivatives, such as the one described in EP0799226;
spiropiperidine derivatives, such as those described in US6, 166,034;
2-pyrrolidones derivatives, such as those described in EP0894085, EP1113015 and US6,924,289;
2,5-pyrrolidine-dione derivatives, such as those described in EiS6,537,995;
heterocyclic lactam and imide derivatives, such as those described in US6,403,592;
azabicyclic derivatives, such as those described in EP1070065, EP 1140931 and US6,887,905;
diazabicyclooctane derivatives, such as those described in EiS6,107,321;
- benzothiophene derivatives, such as those described in EiS5,436,246;
- benzisothi azole derivatives, such as those described in EiS6,346,622;
- benzofuranoxyethylamines derivatives, such as those described in EiS7,425,574;
- benzo[Z?]pyran derivatives, such as those described in EiS7,776,860;
1,4-thiazines derivatives, such as those described in E1S20060009448.
arylpiperazine derivatives, such as those described in EiS6,342,498;
4-methylpiperazine derivatives, such as those described in EP0714389, US6, 159,979 and US6, 509,340;
- thieno[2,3-i ]pyrimidine derivatives, such as those described in US6, 159,962 and US6,355,647;
piperazine and piperidine derivatives, such as the ones described in US20030064995;
chromone derivatives, such as those described in EiS7,026,314; and
ergoline derivatives, such as those described in EiS9,938,277.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0533268, including, without limitation, 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)[l,r- biphenyl]-4-carboxamide; 7V-[4-chl oro-3-(4-methyl-l-piperazinyl)phenyl]-2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)[l,l’-biphenyl]-4-carboxamide; 2’-chloro-/V-[4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]-4’ -(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)[ 1,1’- biphenyl]-4-carboxamide; A/-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl- 4’ -(1 ,2,3 -thiadiazol-4-yl)[ 1 , 1’ -biphenyl]-4-carboxamide; 2’-methyl- V-[4-methyl-3-(4- methyl-l-piperazinyl)phenyl]-4’-(5-methyl-l,3,4-oxadiazol-2-yl)[l, -biphenyl]-4- carboxamide; 2-chloro-A/-[4-methoxy-3 -(4-methyl- l-piperazinyl)phenyl]-4’-(5-methyl- 1 ,2,4-oxadiazol-3 -yl)[ 1 , G -biphenyl]-4-carboxamide; /V-[4-chloro-3 -(4-methyl- 1 - piperazinyl)phenyl]-2’-methyl-4’ -(5-methyl- 1,3, 4-oxadiazol-2-yl)[l, -biphenyl]-4- carboxamide; A/-[4-bromo-3-(4-methyl-l-piperazinyl)phenyl]-2’methyl-4’-[5-methyl- 1 ,2,4-oxadiazol-3 -yl] [ 1 , G -biphenyl]-4-carboxamide; 7V-[4-methoxy-3 -(4-methyl- 1 - piperazinyl]-2’-methyl-4’-(l,3,4-oxadiazol-2-yl)[l, -biphenyl]-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0701819, including, without limitation, 7-(imidazolo[4,5- &]pyridin-l-yl)-l(l-methylpyrrolidin-3-yl)naphthalene; 7-(4-chlorobenzamido)-l- (pyrrolidin-2-(i?)-ylmethyl)naphthalene; 2-[8-(4-methylpiperazin-l-yl)naphthalen-2- y 1 oxy ] ni cotinonitril e ; l-(4-methylpiperazin-l-yl)-7-pyrimidin-5-yl)naphthalene; 7-(5- cyanopyridin-3 -yl)- 1 -4-methylpiperazin- 1 -yl)naphthalene; 1 -(piperazin- 1 -yl)-7-
(py rimi din- 5 -y l)naphthal ene ; 7-(4-chlorobenzamido-l -(4-methylpiperazin- 1- yl)naphthalene; 7 -(3 -methoxyphenyl)- 1 -(4-methylpiperazin- 1 -yl)naphthalene; 7-
(imidazolo[4,5-Z?]pyridin-l-yl)-l-(4-methylpiperazin-l-yl)naphthalene; 8-(4- methylpiperazin-l-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide; 7-(4- methoxyphenyl)- 1 -(4-methylpiperazin- 1 -yl)-naphthalene; 7-pyrimidin-2-yloxy- 1 -(4- methylpiperazin- 1 -yl)naphthalene; 7-(b enzimi dazor- 1 -yl)- 1 -(4-methylpiperazin- 1 - yl)naphthalene; 8-(l-methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4- chl orob enzyl ami de; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0712397, including, without limitation, 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)furan-2-carboxamide; 7V-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)furan-3-carboxamide; A/-[4-methoxy-3-(4- methyl-l-piperazinyl)phenyl]-5-(4-pyridyl)thiophene-2-carboxamide; A/-[4-methoxy-3- (4-methyl- l-piperazinyl)phenyl]-2-(4-pyridyl)pyridine-5-carboxamide; A/-[4-methoxy- 3 -(4-methyl- l-piperazinyl)phenyl]-2-(4-pyridyl)-3-methoxythiophene-4-carboxamide; 7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-5-(2-pyridyl)thiophene-2- carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0714389, including, without limitation, 7V-[4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl]-4-bromophenylacetamide; 7V-(4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-bromocinnamide; 7V-[4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl]-3-(thien-3-yl)acrylamide; 7V-(4-m ethoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-(4-pyridyl)cinnamide; 7V-(4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-4-phenylcinnamide; N-(4-m ethoxy-3 -(4-methyl- 1 - piperazinyl)phenyl)-5-phenylpenta-2,4-dienamide; A/-(4-bromophenyl)-N’-[4-methoxy- 3 -(4-methyl- l-piperazinyl)phenyl]urea; A/-(4-bromo-3-methylphenyl)-N’-[4-methoxy-3- (4-methyl- 1 -piperazinyl)phenyl]urea; A/-[3-methyl-4-(4-pyridyl)phenyl]-N’-[4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]urea; A/-(4-methoxy-3 -( 1 - piperazinyl)phenyl)-4-(4-pyridyl)cinnamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0716650, including, without limitation, l-[3-methyl-4-(4- pyridyl)benzoyl]-2,3-dihydro-5-methoxy-6-(4-methyl-l-piperazinyl)]-lif-indole; l-(4- bromo-3-methylbenzoyl)-2,3-dihydro-5-methoxy-6-(4-methyl-l-piperazinyl)-lif- indole; l-(4-bromo-3-methylbenzoyl)-5-methoxy-6-(4-methyl-l -piperazinyl) lif-indole; 2,3 -dihydro-5-methoxy-6-(4-methyl- 1 -piperazinyl)- 1 -[2’ -bromo-3’ -methoxythiophene- 4’-ylcarbonyl]indole; 2,3 -dihydro-5-methoxy-6-(4-methyl- 1 -piperazinyl)- 1 -[4’ - phenoxybenzoyljindole; 2,3-dihydro-5-methoxy-l-[4-(2-methyl-4-(5-methyl-l,2,4- oxadiazol-3 -yl)phenyl)benzoyl]-6-(4-methyl- 1 -piperazinyl)- l//-indole; 5-methoxy- 1-[4-
(2-methyl-4-(5-methyl- 1 ,2,4-oxadiazol-3 -yl)phenyl)benzoyl]-6-(4-m ethyl- 1 - piperazinyl)- l//-indole; 2,3-dihydro-5-methoxy-l-[4-(2-methyl-4-(5-methyl-l,2,4- oxadiazol-3-yl)phenyl)benzoyl]-6-(l-piperazinyl)-lif-indole; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0736023, including, without limitation, 5-chloro-2,3-dihydro- 6-(2-dimethylaminoethoxy)- 1 -[4-(2-methyl-4-(5-methyl- 1 ,2,4-oxadiazol-3 - yl)phenyl)benzoyl] l//-indole; 2,3-dihydro-6-(3-dimethylaminopropyl)-5-methoxy-l-[4- (2-methyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)benzoyl] 1 //-indole; 2-3-dihydro-
6(2-(dimethylaminoethoxy)-5-methoxy-l-[4-2-methyl-4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)benzoyl]-l//-indole; 6-(2-(dimethylaminoethoxy)-5-methoxy-l-[4-(2-methyl- 4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)benzoyl]-l//-indole; [7-(2- dimethylaminoethoxy)-6-methoxy-3,4-dihydro-2//-quinolin-l-yl]-[2’-methyl-4’(5- methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-yl]methanone; [7-(3-dimethylaminopropyl)-6- methoxy-3,4-dihydro-2//-quinolin-l-yl]-[2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-yl]methanone; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0736025, including, without limitation, N-[ 7-[(2- dimethylaminoethyl)amino]-2,3-dihydrobenzofuran-5-yl]-2’ -methyl-4’ -(5-methyl- 1,2, 4- oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-[7-(2-dimethylamino)ethoxy-2,3- dihy drobenzofiiran-5-yl]-2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-[7-(3-dimethylaminopropyl)-2,3-dihydrobenzofuran-5-yl]-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0752982, including, without limitation, N-[ 3-(2- dimethylaminoethoxy)4-methoxyphenyl]-4’-methoxy carbonyl-2’ -methylbiphenyl-4- carboxamide; A/-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2’-methyl-4’-A/- methylcarboxamidobiphenyl-4-carboxamide; A/-[3-(2-dimethylaminoethoxy)-4- methoxyphenyl]-2’ -methyl-4’ -N, 7V-dimethylcarboxamidobiphenyl-4-carboxamide; N- [3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2’ -methyl-4’ -carboxamidobiphenyl-4- carboxamide; A/-[3-(2-dimethylaminoethoxy)4-methoxyphenyl]-2’-methyl4’- cyanobiphenyl-4-carboxamide; A/-[3-(2-dimethylaminoethoxy)4-methoxyphenyl]-4’- acetyl-2’ -methylbiphenyl-4-carboxamide; A/-[3-(2-dimethylaminoethoxy)-4- methoxyphenyl]-4,-[l-(methoxyimino)ethyl]-2’-methylbiphenyl-4-carboxamide; N-[3- (2-dimethylaminoethoxy)-4-methoxyphenyl]-4,-[l-(hydroxyimino)ethyl]-2’- methylbiphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0777650, including, without limitation, l-(4’- acetamidomethyl-2’-methylbiphenyl-4-carbonyl)-5-chloro-2,3-dihydro-6-(2- dimethylaminoethoxy)- 177-indole; l-(4’-cyano-2’-methylbiphenyl-4-carbonyl)-2,3- dihydro-6-(2-dimethylaminoethoxy)-5-methoxy- 177-indole; l-(4’-acetyl-3’- methylbiphenyl-4-carbonyl)-2,3-dihydro-6-(2-dimethylaminoethoxy)-5-methoxy-177- indole; l-(4’-acetyl-2’-methylbiphenyl-4-carbonyl)-6-(2-dimethylamino-ethoxy)-5- methoxy- 177-indole; 1 -(4’ -acetyl-3’ -methylbiphenyl-4-carbonyl)-6-(2-dimethylamino ethoxy)-5-methoxy-177-indole; l-(4’-cyano-2’-methylbiphenyl-4-carbonyl)-6-(2- dimethylaminoethoxy)-5-methoxy- 177-indole; 6-(2-dimethylaminoethoxy)-5-methoxy- 1 -(4’ -( 1 -(methoxyimino) ethyl)-2’-methylbiphenyl-4-carbonyl)- 177-indole; 2, 3 -dihydro- 6-(2-dimethylaminoethoxy)-5-methoxy-l-(5,-methoxy-carbonyl-2’-methylbiphenyl-4- carbonyl)- 177-indole; 6-(2-dimethylaminoethoxy)-5-methoxy-l-(2-methylbiphenyl-4- carbonyl)- 177-indole; l-(4’-acetamidomethyl-2’-methylbiphenyl-4-carbonyl)-2,3- dihydro-6-(3-dimethylaminopropyl)-5-ethoxy-177-indole; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0799226, including, without limitation, l’-methyl-5-(2’- methyl-4’-(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 2,3,5,6,7,8-hexahydro-l’-methyl-5- (2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)spiro[furo[2,3- gJquinoline-3, 4’ -piperidine]; 5-(2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-
4-carbonyl)-2, 3, 6, 7-tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; l’-ethyl-5-(2’- methyl-4’-(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3-/’]indole-3,4’-piperidine]; 1’ -methyl - 5 -(2’ -methyl -4’ -(5 - methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- /]indole-3 ,4’ -piperidine] ; 5-(4’-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2’- methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4’- piperidine]; l’-methyl-5-[4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl]-
2.3.6.7 -tetrahy drospiro[furo[2, 3 - |indole-3 ,4’ -piperidine] ; 2,3-dihydro-r-methyl-5-(2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)spiro[furo[2,3- |indole- 3, 4’ -piperidine]; 5-[4’-cy ano-2’-methylbiphenyl-4-carbonyl]- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5 -(4’ -acetyl-2’ -methylbiphenyl-4- carbonyl)- -rnethyl-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5-(4’-(l- (methoxyamino)ethyl)-2’-methylbiphenyl-4-carbonyl)- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5 -(4’ -acetamidomethyl-2’ - methylbiphenyl-4-carbonyl)- -methyl-2,3,6,7-tetrahydrospiro[furc>[2,3- ]indole-3,4’- piperidine]; 3,5,6,7,8,9-hexahydro- -methyl-5-(2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carbonyl)spiro[27/-furo[2,3- z]benzazepine-3,4’-piperidine]; -methyl-5-(2’-methyl-4’-(3-methyl-l,2,4-oxadiazol-5-yl)biphenyl-4-carbonyl)-
2.3.6.7-tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 1’ -methyl - 5 -(2’ -methyl -4’ -
(l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-
3, 4’ -piperidine]; 5-[4’-(5-ethyl-l,3,4-oxadiazol-2-yl)-2’-methylbiphenyl-4-carbonyl]-r- methyl-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5-[2’-methyl-4’-(5- methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3 ,4’ -piperidine] ; 2,3-dihydro- -methyl-5-(2’-methyl-4’-(5-methyl-l,3,4- oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3- ]indole-3,4’-piperidine]; 5-(2,2’- dimethyl-4’-(5-methyl-l, 3, 4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5-(2,3’ -dimethyl-4’ -(5-m ethyl- 1,3,4- oxadiazol-2-yl)biphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3, 4’ -piperidine]; -methyl-5-(2’-methyl-4’-(4-methylthiazol-2-yl)biphenyl-4- carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5-(4’- methoxycarbonyl-2’-methylbiphenyl-4-carbonyl)- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 5-(5’-methoxycarbonyl-2’- methylbiphenyl-4-carbonyl)- -methyl-2,3,6,7-tetrahydrospiro[furc>[2,3- ]indole-3,4’- piperidine]; 5-[4’-(methanesulphonamino)-2’-methylbiphenyl-4-carbonyl]- -methyl-
2.3.6.7 -tetrahy drospiro[furo[2, 3 - |indole-3 ,4’ -piperidine] ; 5 -(4’ -hy drazinocarbonyl-2’ - methylbiphenyl-4-carbonyl)- -methyl-2,3,6,7-tetrahydrospiro[furc>[2,3- ]indole-3,4’- piperidine]; l’-ethyl-5-(2’ -methyl-4’ -(5-methyl- 1, 3, 4-oxadiazol-2-yl)biphenyl-4- carbonyl)-2, 3, 6, 7-tetrahydrospiro[furo[2,3- ]indole-3,4, -piperidine]; -methyl-5-(2’- methyl-5’-(5-methyl- 1,3, 4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-(4’-carboxamido-2’- methylbiphenyl-4-carbonyl)- -methyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4,- piperidine]; 5-(4’-acetamido-2’-methylbiphenyl-4-carbonyl)- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 2,3,5,6,7,8-hexahydro- -methyl-5- (2,-methyl-4’-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3- g]quinoline-3,4,-piperidine]; 2,3 , 5 ,6, 7, 8-hexahy dro-5 -(4’ -methanesulphonamino-2’ - methylbiphenyl^-carbony^-r-methylspirotfuroP^-^quinoline-S^’-piperidine]; - methyl-5-[2,-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[thiopheno[2,3- |indole-3,4, -piperidine]; 1,2,3,5,6,7-hexahydro- - methyl-l-(2,-methyl-4,-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4- carbonyl)spiro[indeno[5,6-ri]pyrrole-7,4’-piperidine]; 5-[4’-(A/-methanesulphonyl-A/- methylamino)-2’ -methylbiphenyl-4-carbonyl]- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-[4’-
(dimethylaminosulphonyl)biphenyl-4-carbonyl]- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-[4’-(methanesulphonyl)biphenyl-4- carbonyl]- -methyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-[4’- (A/,A/-dimethylcarbamoylamino)-2-methylbiphenyl-4-carbonyl]- -methyl, 2, 3,6,7- tetrahydrospiro[furo[2,3- )indole-3,4’-piperidine]; 5-[4’-(ethoxycarbonylamino)-2’- methylbiphenyl-4-carbonyl]- -methyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4,- piperidine]; 5-[4,-(4,5-dimethyl-l,2,4-triazol-3-yl)-2’-methylbiphenyl-4-carbonyl]-l- methyl-2, 3, 6, 7-tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; -methyl-6-[2’- methyl-4’-(5-methyl- 1,3, 4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2, 3,7,8- tetrahydrospiro[4H-pyrano[2,3- |indole-4,4, -piperidine]; -methyl-5-(2’-methyl-4’-(5- methyl-l,3,4-thiadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3 ,4’ -piperidine] ; 5-(2’-methyl-4’-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4- carbonyl)-l’-iV-propyl-2, 3, 6, 7-tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; - methyl-5-(2’-methyl-4’-(5-methyloxazol-2-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 1’ -methyl - 5 -(2’ -methyl -4’-(3- methylisoxazol-5-yl)biphenyi-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- |indole- 3, 4’ -piperidine]; l’-methyl-5-(2’ -methyl-4’ -(5-methylisoxazol-3-yl)biphenyl-4- carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3,4’-piperidine]; 2,3,5,6,7,8- hexahydro- -methyl-5-(4’-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2’-methylbiphenyl-
4-carbonyl)spiro[furo[2,3-g]quinoline-3,4’-piperidine]; 2,3,5,6,7,8-hexahydro-l’- methyl-5-(4’-(5-ethyl-l,3,4-oxadiazol-2-yl)-2’-methylbiphenyl-4- carbonyl)spiro[furo[2,3-g]quinoline-3,4’-piperidine]; 2,3,5,6,7,8-hexahydro-l’-methyl-
5-(4’-methoxycarbonyl-2’-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4- piperidine]; 2,3,5,6,7,8-hexahydro- -methyl-5-(4’-hydrazinocarbonyl-2’- methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4’-piperidine]; 2, 3, 5, 6,7,8- hexahydro-1’-methyl-5-(2’ -methyl-4’ -(1, 3, 4-oxadiazol-2-yl)biphenyl-4- carbonyl)spiro[furo[2,3-g]quinoline-3,4’-piperidine]; 1’ -methyl - 5 -(2’ -methyl -4’- pyrazinylbiphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4’- piperidine]; l’-methyl-5-[2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazolyl-3-yl)biphenyl-4- carbonyl]-l-oxo-2,3,6,7-tetrahydrospiro[thiopheno[2,3- ]indole-3,4’-piperidine]; - ethyl-5-[2’-methyl-4’ -(5-methyl- 1,3, 4-oxadiazol -2 -yl)biphenyl-4-carbonyl]-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; -methyl-5-[2’-methyl-4’-(l- methylimidazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-
3, 4’ -piperidine]; 1’ -methyl-5 - [2’ -methyl-4’ -( 1 -methylimidazol-5-yl)biphenyl-4- carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; 5-[4’-(5- hy droxymethyl-1, 2, 4-oxadiazol-3-yl)-2’-methylbiphenyl-4-carbonyl]- -methyl-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; -methyl-5-(2’-methyl-4’-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-l’-oxo-2,3,6,7-tetrahydrospiro[furc>[2,3- |indole-3 ,4’ -piperidine] ; -methyl-5-[2’-methyl-4’-(l,2,4-triazin-3-yl)biphenyl-4- carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; 2, 3, 6, 7,8,9- hexahydro- 1’ -methyl-6-(2’ -methyl-4’ -(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)biphenyl-4- carbonyl)spiro[4//-pyrano[2,3-g]quinoline-4,4’ piperidine]; l’-ethyl-5-(2’ -methyl-4’ -(5- methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)- -oxo-2,3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; l’-ethyl-5-[4’-(5-methyl-l,3,4- oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4’- piperidine]; l’-ethyl-5-(4’-hydrazinocarbonyl-2’-methylbiphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospiro[furo[2,3- |indole-3,4’-piperidine]; 5 -[4’ -(acetylhy drazinocarbonyl)-2’ - methylbiphenyl-4-carbonyl]-l’-ethyl-2, 3,6, 7-tetrahydrospiro[furo[2,3- |indole-3, 4’- piperidine]; 5-[4’-(5-methoxymethyl-l,2,4-oxadiazol-3-yl)-2’-methylbiphenyl-4- carbonyl]-G-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- ]indole-3,4, -piperidine]; 5-[4’- (4,5-dihydrooxazol-2-yl)-2’-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3- ]indole-3,4, -piperidine]; 5-[4’-(2 -(N,N- dimethylamino^cetamido^’-methylbiphenyM-carbonylJ-r-methyl^^e^- tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-[4’-(ethoxycarbonylamino)-2- methylbiphenyl-4-carbonyl]- -ethyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4,- piperidine]; S-fd’^acetylhydrazinocarbonyl^’-methylbiphenyM-carbonyl]-!’ -methyl- 2, 3, 6, 7-tetrahydrospiro[furo[2,3- |indole-3,4, -piperidine]; 5-(4’-(5-methylfuran-2-yl)-2- methylbiphenyl-4-carbonyl)- -methyl-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4,- piperidine]; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP0894085, including, without limitation, 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 6-chloro-3-(2-(4- methylpiperazin-l-yl)-benrylidene]-l,3-dihydro-indol-2-one; 5-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; l-methyl-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-benzylidene]- 1 -phenyl- 1 ,3 -dihydro-indol-2-one; l-(3,4-dichlorophenyl)-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(3,4-dichlorobenzyl)-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; l-(4-chlorobenzyl)-3-[2- (4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(4-chlorobenzyl)-3-[5- fluoro-2-(4-methylpiperazin- 1 -yl)-benzylidene]-pyrrolidin-2-one; 1 -(3 ,4- difluorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(2,4- dichlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(3,4- dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; 1 -(3,4- dichlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; l-(4- chlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; 1- (3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2- one; 3 -[2-(4-methylpiperazin- 1 -yl)-benrylidene]- 1 -phenyl-pyrrolidin-2-one; 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l-(4-trifluoromethylphenyl)-pyrrolidin-2-one; 1-
(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benryl]-pyrrolidin-2-one; 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; 3 - [5 -fluoro-2-(4-methylpiperazin- l-yl)-benzylidene]-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-benzylidene]- piperidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benzyl]- piperidin-2-one; l-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzyl]- piperidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-benzyl]-l-phenyl-pyrrolidin-2-one; 3-[2-
(4-methylpiperazin-l-yl)-benrylidene]-l-(p-tolyl)-pyrrolidin-2-one; 3-[4-fluoro-2-(4- methylpiperazin- 1 -yl)-benzylidene]- 1 -phenyl-pyrrolidin-2-one; l-(3,4-dichlorophenyl)- 3-[2-fluoro-6-(4-methylpiperazin-l-yl)-benrylidene]-pyrrolidin-2-one; l-(3,4- difluorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-piperine-2-one; 1- [2-(4-chlorophenyl)ethyl]-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]- piperidin-2-one; 3-[2-(4-methylpiperazin-l-yl)benzyl]-l-(4-trifluoromethylphenyl)- pyrrolidin-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1070065, including, without limitation, (7R,9as)-trans- 1 - { 3 - [2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydropyrido[l,2-u]pyrazin-7-ylmethoxy]- benzyl}-azetidin-3-ol; (7i?,9uS)-/ra«s-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(3- morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (' 7S,9aS)-cis - 1 - [3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy)-benzyl]- azetidin-3-ol; (7i?,9u5,)-/ra«5-2-(4-fluoro-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l- ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-uJpyrazine; (' 7S,9aS)-cis-2 - benzo[i ]isoxazol-3-yl-7-(3-pyrrolidin-l-ylmethylphenoxymethyl)-octahydro-pyrido- [l,2-u]pyrazine; (75,9u5)-cw-l-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- u]pyrazin-7-ylmethoxy)-benzyl]pyrrolidine-3,4-diol; (7R, 9aS)-trans-2-(5-fluoro- benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethylphenoxymethyl)- octahydropyrido[l,2-u]pyrazine; (75,9u5)-c/5-2-benzo[<i]isoxazol-3-yl-7-(2-methyl-5- pyrimidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (' 7S,9aS)-cis-2 - benzo[<7]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-l-ylmethylphenoxymethyl)- octahydro-pyrido[ 1 ,2-uJpyrazine; (7S,9uS)-czs-2-benzo[<i]isoxazol-3-yl-7-(4-chloro-3- pyrrolidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-uJpyrazine; (' 7S,9aS)-cis-2 - benzo[<i]isoxazol-3-yl-7-(4-pyrrolidin-l-ylmethylphenoxymethyl)-octahydro- pyrido[ 1 ,2-u]pyrazine; (7S,9aS)-cis-7-(3 -azetidin- 1 -ylmethyl-phenoxymethyl)-2- benzo[i ]isoxazol-3-yl-octahydro-pyrido[l,2-3]pyrazine; (7S,9aS)-cis-[3-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-benzyl]- cyclopropylmethyl-amine; (7 ,9a5)-d,s-2-benzo[<i]isoxazol-3-yl-7-[3-(2- methoxymethyl-pyrrolidin- 1 -ylmethyl)-phenoxymethyl)-octahydro-pyrido[ 1 ,2- ajpyrazine; (75,,9a5,)-c/5-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-benzyl]-cyclopropyl-amine; (7 ,9a5)-d,s-2-benzo[<i]isoxazol-3-yl-7-[3-(4- ethyl-piperazin- 1 -ylmethyl)-phenoxymethyl]-octahydro-pyrido[ 1 ,2-a]pyrazine;
(75,9«5)-cd-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-i3]pyrazin-7- ylmethoxy)-benzyl]-cyclohexyl-amine; (7S,9aS)-ds-l-[3-(2-benzo[<i]isoxazol-3-yl- octahydro-pyridol[l,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidin-3-ol; (' 7S,9aS)-cis-2 - benzo[<i]isoxazol-3-yl-7-[3-(2,5-dimethyl-[pyrrolidin-l-ylmethyl)-phenoxymethyl- octahydro-pyrido[l,2-a]pyrazine; (75,9«5)-cd-[3-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-benzyl]-isobutyl -amine; (' 7S,9aS)-cis-2 - benzo[<i]isoxazol-3-yl-7-(2-morpholin-4-ylmethylphenoxymethyl)-octahydro- pyrido[ 1 ,2-a]pyrazine; (75,9«5)-cd-2-benzo[<i]isoxazol-3 -yl-7-(2-pyrrolidin- 1 - ylmethylphenoxymethyl)-octahydro-pyridol[l,2-a]pyrazine; (' 7S,9aS)-cis-2 - benzo[<i]isoxazol-3-yl-7-(4-morpholin-4-ylmethylphenoxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9a5,)-/ra«5-2-(7-fluoro-benzo[<i]isoxazol-3-yl)-7-(3- pyrrolidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7R,9aS)~ /ra«5-2-(6-fluoro-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethylphenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9a5,)-/ra«5-2-(6,7-difluoro-benzodisoxazol-3-yl)- 7-(3 -pyrrolidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7R,9aS)~ ira«5-3-{3-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy]-benzyl}-3-aza-bicyclo[3.2.2]nonane; (7R, 9aS)-trans-2-(5 -fluoro- benzo[<i]isoxazol-3-yl)-7-[3-cd-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]- octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)-ds-4-(2-benzo[<7]isoxazol-3-yl-octahydro- pyrido-l,2-a]pyrazin-7-ylmethoxy)-benzylamine; (75, 9aS)-trans-2-(5-fluoro- benzo[<i]isoxazol-3-yl)-7-(2-pyrrolidin-l-ylmethylphenoxymethlthyl)-octahydro- pyrido[l,2-a]pyrazine; (7 ,9a5)-/ra«5-2-(5-chloro-benzo[<i]isoxazol-3-yl)-7-(3- pyrrolidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7S,9aS)-trans-
2-(5-methyl-benzo[<7]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethylphenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (75,9a5)-ira«5-2-benzo[<i]isoxazol-3-yl)-7-(2- pyrrolidin- 1 -ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7R,9aS)-cis-2- benzo[<i]isoxazol-3-yl)-7-(2-pyrrolidin-l-ylmethylphenoxymethyl)-octahydro- pyrido[ 1 ,2-u]pyrazine; (7S,9uS)-/rans-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(2- morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7S,9aS)~ /rans-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(4-morpholin-4-ylmethylphenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9uS)-irans-2-(2-methoxy-benzo[<i]isoxazol-3-yl)- 7-(3-pyrrolidin-l-ylmethylphenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)~ c/5-2-(5-methoxy-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethylphenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9a5,)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7- (3-(2-methoxymethylpyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2- ajpyrazine; (77?,9aS)-/rans-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-[3-(2- methoxymethylpyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2- ajpyrazine; (7i?,9a5,)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-[3-(2- methoxymethylpiperidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7i?,9a5,)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-[3-(3-methoxymethylpiperidin-l- ylmethyl)-phenoxymethyl]-octahydro-pyrido[l,2-a]; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1113015, including, without limitation, (-)-3(S)-[[2-(4-methyl- lpiperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2-pyrrolidinone; (+)-3 (R)-
[[2-(4-methyl-l-piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2- pyrrolidinone; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1140931, including, without limitation, (7R,9aS)-trans-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-u]pyrazin-7-ylmethyl)-(5-methyl- pyrimidin-2-yl)-amine; (7S,9uS)-czs-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- u]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)-amine; (7R,9aS)-trans-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-u]pyrazin-7-ylmethyl)-(5-chloro- pyrimidin-2-yl)-amine; (75,9u5)-cz5-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- u]pyrazin-7-ylmethyl)-5-chloro-pyrimidin-2-yl)-amine; (7R,9aS)-trans-(5-ch\oro- pyrimidin-2-yl)-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-i3]pyrazin-7- ylmethyl]-amine; (7S,9aS)-ds-(5-chloro-pyrimidin-2-y))-[2-(5-fluoro-benzo[<i]isoxazol- 3-yl)-octahydropyrido[l,2-a]pyrazin-7-ylmethy)]-amine; (7R, 9aS)-trans- [2-(5 -fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazin-7-ylmethyl]-(5-methyl- pyrimidin-2-yl)amine; (75,9a5)-cd-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro- pyrido[l,2-a]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)amine; (7R, 9aS)-trans-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyridin-2- yl)-amine; (75,,9«5')-c/5-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethyl)-(5-fluoro-pyridin-2-yl)-amine; (7i?,9a5,)-/ra«5-[2-(5-fluoro-benzo[<i]isoxazol- 3-ylyoctahydro-pyrido[l,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyridin-2-yl)-amine;
(75,9a5)-cd-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)octahydro-pyrido[l,2-i3]pyrazin-7- ylmethyl]-(5-fluoro-pyridin-2-yl)-amine; (7i?,9«5')-ira«5-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (75,9«5)-cd-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-i3]pyrazin-7-ylmethyl)-(5- fluoro-3-methyl-pyridin-2-yl)-amine; (7R, 9aS)-trans-\2-(5 -fluoro-benzo[<i]i soxazol-3 - yl)-octahydro-pyrido[l,2-a]pyrazin-7-ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)amine; (75,9«5)-cd-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-i3]pyrazin-7- ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7R,9aS)-trans-(2-benzo[d]isoxazo\- 3yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyrimidin-2-yl)-amine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in EP1186318, including, without limitation, 3-(4-chlorophenyl)-5- [2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)- 5-[2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 3-(4- chlorobenzyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 4- benzyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorobenzyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 3-(4- chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 3-(4- trifluoromethylphenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4- dione; 2-[2-(4-methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)- thiomorpholin-3-one; 2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)- benzylidene]-morpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l- yl)-benzyl]-thiomorpholin-3-one; 4-methyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-(2-piperazin-l-ylbenzylidene)- thiomorpholin-3 -one; 4-benzyl-2-[2-(4-methylpiperazin- 1 -yl)-benzylidene]-l , 1 - dioxothiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[5-fluoro-2-(4- methylpiperazin- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-(3 ,4-dichlorophenyl)- 1-[2-
(4-methylpiperazin-l-yl)-5-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-l-yl]-benzylidene}-thiomorpholin- 3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-ethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-chloro-6-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin- l-yl)-4-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2- (4-methylpiperazin- 1 -yl)-benzylidene]-l -oxo-thiomorpholin-3 -one; 4-(3,4- dichlorophenyl)-2-(5-fluoro-2-piperazin-l-yl-benzylidene)-thiomorpholin 3 -one; 4-(3,4- dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-phenyl-2-[2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2-[5-fluoro-2-(4-methylpiperazin-l-yl)- benzylidene]-4-phenyl-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4-tert-butylpiperazin- 1 -yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3 -one; 3 -(3 ,4- dichlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidin 4-one; 3-[4- (3,4-dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino 2-(4- methylpiperazin- 1 -yl)-benzonitrile; 5-[2-(4-methylpiperazin-l-yl)-benzylidene]-2- phenylthiazolidin-4-one; 4-(3,4-dichlorophenyl)-2-[2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[5-methyl-2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[4-chloro-2-(4- methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4- (3,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(2,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 2-[4-bromo-2-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin- 2-ylmethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3 , 5 -dichlorophenyl)-2-[2-(3 , 5 - dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2- [2-(3,4,5-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(octahydropyrido[l,2-3]pyrazin-2-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-pyridin-3-yl- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4- difluorophenyl)-thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]- 4-(3,5-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2-[2-(2,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,5-dichlorophenyl)-2- [2-(2,5-dimethylpiperazin-l-yl)-benzylidene)-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2- [2-(3 , 5 -dimethylpiperazin- 1 -yl)-benzylidene] -4- (4-fluorophenyl)-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(2,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-4-phenylthiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-
(3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-
[ 1 ,4]diazepan- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-[2- (2,4,6-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 2-[2,4-dibromo-6- (4-methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-
(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-[l,4]oxazepan-3-one; 4- (4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-[l,4,5]oxadiazepan-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-[l,4]thiazepan-3-one; 4- (3,4-dichlorophenyl)-2-{2-[(2-dimethylaminoethyl)-methyl-amino]-benzylidene}- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpiperidin-4-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l,4-dimethylpiperidin- 4-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholine-3,5-dione; 4-(3,4-dichlorophenyl)- 2-[2-(2-dimethylaminoethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-isopropylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin-3-ylmethyl)-benzylidene]-thiomorpholin
3 -one; 4-(3,4-dichlorophenyl)-2-{2-[methyl-(l-methylpyrrolidin-2-ylmethyl)-amino]- benzylidene} -thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin-2- ylmethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3 ,4-dichlorophenyl)-2- {2-[2-( 1 - methylpyrrolidin-2-yl)-ethyl]-benzylidene}-thiomorpholin-3-one; l-(3,4- dichlorophenyl)-4-methyl-3-(2-(4-methylpiperazin-l-yl)-benzylidene]-piperazin-2-one;
4-methyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-l-(4-trifluoromethylphenyl)- piperazin-2-one; l-(4-chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-l-yl)- benzylidene]-piperazin-2-one; 2-[2-(4-methylpiperazin-l-yl)-benzylidene]-4-(4- trifluoromethylphenyl)-morpholin-3-one; 2-[4-fluoro-2-(4-methylpiperazin-l-yl)- benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 2-[5-fluoro-2-(4- methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 2-{ l-[2-(4-methylpiperazin-l-yl)-phenyl]-ethylidene}-4-(4-trifluoromethylphenyl)- thiomorpholin-3 -one; 2-[2-(4-methylpiperazin-l-yl)-benzyl]-4-(4- trifluoromethylphenyl)-thiomorpholin-3-one; 4-(4-chlorophenyl)-6-methyl-2-[2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 3-(4-chlorophenyl)-2,2- dimethyl-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidin-4-one; 4-(4- chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-[l,4]oxazepan-3-one; 4-(4- chlorophenyl)-2-[2-(4-methylpiperazin- 1 -yl)-benzylidene]-4 -[l ,4]thiazin-3 -one; 1 -(4- chlorophenyl)-4,6,6-trimethyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperazin-2- one; l-(4-chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]- piperazin-2-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- morpholin-3 -one; 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]- oxazolidin-4-one; 3-(4-chlorophenyl)-2,2-dimethyl-5-[2-(4-methylpiperazin-l-yl)- benzylidenej-imidazolidin 4-one; 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)- benzylidene]-imidazolidin-4-one; 5-[2-(4-methylpiperazin-l-yl)-phenyl]-furan-2- carboxylic acid 4-chlorobenzylamide; 5-[2-(4-methylpiperazin-l-yl)-phenyl]-furan-2- carboxylic acid 4-chlorophenylamide; 5-[2-(4-methylpiperazin-l-yl)-phenyl]-thiophene- 2-carboxylic acid 4-chlorophenylamide; 5-[2-(4-methylpiperazin-l-yl)-phenyl]-furan-2- carboxylic acid [2-(4-chlorophenyl)ethyl]-amide; 4-[2-(4-methylpiperazin-l-yl)- phenyl]-furan-2-carboxylic acid 4-chlorobenzylamide; 5-[2-(4-methylpiperazin-l-yl)- phenyl]-thiophene-2-carboxylic acid benzyl amide; 5-[2-(4-methylpiperazin-l-yl)- phenyl]-thiophene-2-carboxylic acid 4-fluorobenzylamide; 5-[2-(4-methylpiperazin-l- yl)-phenyl]-thiophene-2-carboxylic acid 4-methoxybenzylamide; 5-[2-(4- methylpiperazin- 1 -y 1 -phenyl ] -thi ophene-2-carb oxy li c acid [2-(4-chlorophenyl)ethyl]- amide; 3-methyl-5-[2-(4-methylpiperazin-l-yl)-phenyl]-thiophene-2-carboxylic acid 4- chlorobenzylamide; 5 - [5 -fluoro-2-(4-methylpiperazin- 1 -yl)-phenyl] -thiophene-2- carboxylic acid 4-chlorobenzylamide; 5-(2-(4-methylpiperazin- 1 -yl)-phenyl]- 1 - pyrrole-2-carboxylic acid 4chlorobenzylamide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,356,893, including, without limitation, 7V-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl-2-methyl-4’ -(methyl sulphinyl)- 1 , G -biphenyl-4- carboxamide; 4’-acetyl-A/-4-methoxy-3-(4-methyl-l-piperazinyl)phenyl-2-methyl-l, G- biphenyl-4-carboxamide; A/-4-methoxy-3-(4-methyl-l-piperazinyl)phenyl-2’-methyl-4’- methylamino- 1 , G -biphenyl-4-carboxamide; methyl-4’ -4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenylaminocarbonyl-2-methyl-(l,r-biphenyl-4-yl)methyl carbamate; 4’-4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenylaminocarbonyl-2’ -methyl- 1 , G -biphenyl-4- dimethylcarbamate; 4’-(methoxyacetyl)methylaminomethyl-A/-4-methoxy-3-(4-methyl- 1 -piperazinyl)phenyl-2’ -methyl- 1 , G -biphenyl-4-carboxamide; 4’-acetyl -2’- trifluoromethyl-A/-4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl- 1,1’ -biphenyl-4- carboxamide; A/-4-bromo-3 -(4-methyl- 1 -piperazinyl)phenyl-7V’ ,N’ ,2’ -trimethyl- 1,1’- biphenyl-4, 4’ -dicarboxamide; 4’ -hydroxy -/V-4-m ethoxy-3 -(4-methyl- 1 - piperazinyl)phenyl- 1 , -biphenyl-4-carboxamide; 4’ -acetyl-/V-4-m ethoxy-3 -(4-methyl- 1 -piperazinyl)phenyl-2’ -methyl- 1 , G -biphenyl-4-carboxamide; A/-4-methoxy-3 -(4- methyl- 1 -piperazinyl)phenyl-2’ -methyl-4’ -(4-morpholinylcarbonyl)- 1 , G -biphenyl-4- carboxamide; 4’ -acetyl-2’ -methoxy -7V-4-m ethoxy-3 -(4-methyl- l-piperazinyl)phenyl-
1 , 1’ -biphenyl-4-carboxamide; N-4-m ethoxy-3 -(4-methyl- l-piperazinyl)phenyl-A/’, TV’ - dimethyl- 1,1’ -biphenyl-4,4’ -dicarboxamide; 7V-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-2’ methyl-4’ -( 1 -pyrrolidinyl)carbonyl- 1,1’ -biphenyl-4-carboxamide; A/,A/-diethyl-A/-4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl-2-methyl- 1,1’ -biphenyl- 4,4’ -dicarboxamide; 7V-4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl-2’ -methyl-4’ -
(methylsulphonyl)amino-l, 1’-biphenyl-4-carboxamide; 7V-butyl-7V’-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl-7V, 2-dimethyl 1,1’ -biphenyl-4,4’ -dicarboxamide; N-4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl-A/’ ,7V’ -dipropyl 1,1’ -biphenyl-4,4’ - dicarboxamide; 4’ -(2-methoxyethoxy)methyl-7V-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-2’ -methyl- 1,1’ -biphenyl-4-carboxamide; 4’ -cyano-/V-4-m ethoxy-3 -
(4-methyl- 1 -piperazinyl)phenyl-2’ -methyl- 1,1’ -biphenyl-4-carboxamide; V-4-methoxy- 3 -(4-methyl- 1 -piperazinyl)phenyl-7V’ ,7’ ,2’ -trimethyl- 1,1’ -biphenyl-4,4’ -dicarboxamide; 4’-(dimethylamino)-7V-4-methoxy-3-(4-methyl- 1 -piperazinyl)phenyl-2’ -methyl- 1,1’- biphenyl-4-carboxamide; 2-chloro-7V’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenyl- A/,A/-dimethyl-l, G -biphenyl-4,4’ -dicarboxamide; A/-4-chloro-3 -(4-methyl- 1- piperazinyl)phenyl-A/’ ,2’ -trimethyl- 1,1’ -biphenyl-4, 4’-dicarboxamide; N-( 1,1- dimethylethyl)-A/’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenyl-2-m ethyl 1,1’-biphenyl- 4, 4’ -dicarboxamide; 4’ -(1 -azetidinyl)carbonyl-7V-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-2’ -methyl 1,1’ -biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,358,948, including, without limitation, 7V-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenyl-4-(4-pyridinyl)benzamide; 7V-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-4-(4-methyl-3-pyridinyl)benzamide; A/-4-methoxy-3 -(4-methyl- 1- piperazinyl)phenyl-3-methyl-4-(4-pyridinyl)benzamide; A/-4-methoxy-3 -(4-methyl- 1- piperazinyl)phenyl-2-methyl-4-(4-pyridinyl)benzamide; /V-4-methyl-3 -(4-methyl- 1 - piperazinyl)phenyl-4-(4-pyridinyl)benzamide; A/-4-chloro-3 -(4-methyl- 1- piperazinyl)phenyl-4-(4-pyridinyl)benzamide; 7V-4-fluoro-3 -(4-methyl- 1- piperazinyl)phenyl-4-(4-pyridinyl)benzamide; N-4-m ethoxy-3 -(4-methyl- 1-piperazinyl- 4-(3.-methyl-4-pyridinyl)benzamide; 7V-6-fluoro-4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl-3-methyl-4-(4-pyridinyl)benzamide; A/-4-bromo-3 -(4-methyl- 1- piperazinyl)phenyl-3-methyl-4-(4-pyridinyl)benzamide; N-3 -(4-methyl- 1- piperazinyl)phenyl-4-(4-pyridinyl)benzamide; 4-(4-pyridinyl)-2-methoxy-A/-4-methoxy- 3 -(4-methyl- 1 -piperazinyl)phenylbenzamide; A/-4-hydroxy-3 -(4-methyl- 1 - piperazinyl)phenyl4-(4-pyridinyl) benzamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,436,246, including, without limitation, 4-4-(2-phenylethyl)- 1 -piperazinyl-benzo[Z?]thiophene-2-methanol monohydrochloride; 4-4-(2-phenylethyl)-
1-piperazinyl-benzo[Z?]thiophene-2-carboxamide; 4-4-(2-phenylethyl)-l-piperazinyl- benzo[Z?]thiophene-2-nitrile; 4-4-(3-phenylpropyl)-l-piperazinyl-benzo[Z?]thiophene-2- m ethanol; 4-4-(3-phenylpropyl)-l-piperazinyl-benzo[Z?]thiophene-2-carboxamide; 4-4-
2-(4-methoxyphenyl)ethyl-l-piperazinyl-benzo[Z?]thiophene-2-methanol; 4-4-2-(4- chlorophenyl)ethyl-l-piperazinyl-benzo[Z?]thiophene-2-carboxamide; 4-4-2-(4- chlorophenyl)ethyl-l-piperazinyl-benzo[/?]thiophene-2-methanol; 4-4-2-(4- methylphenyl)ethyl-l-piperazinyl-benzo[/?]thiophene-2-methanol; 4-4-(2-phenylethyl)- l-piperazinyl-benzo[/?]thiophene-2-(N-methyl)-carboxamide; 4-4-(2-phenylethyl)-l- piperazinyl-benzo[/?]thiophene-2-(N,N-dimethyl)-carboxamide; 4-4-2-(4- methylphenyl)ethyl-l-piperazinyl-benzo[/?]thiophene-2-carboxamide; 4-4-2-(4- fluorophenyl)ethyl-l-piperazinyl-benzo[Z?]thiophene-2-methanol; 4-4-2-(4- fluorophenyl)ethyl- 1 -piperazinyl-benzo[Z?]thiophene-2-carboxamide; 4-(4-propyl)- 1 - piperazinylbenzo[Z?]thiophene-2-carboxylate hydrochloride; 4-(4-propyl)- 1 - piperazinylbenzo[Z?]thiophene-2-m ethanol hydrochloride; 4-4-(2-phenylethyl)- 1 - piperazinyl-benzo[Z?]thiophene-2-(7V-ethyl)carboxamide hydrochloride; 4-4-(2- phenylethyl)- 1 -piperazinyl-benzo[/?]thiophene-2-(0-methyl)-methanol hydrochloride; 4- 4-propyl- l-piperazinyl-benzo[/?]thiophene-2-A/-methylcarboxamide hydrochloride; 4-4- methyl- 1 -piperazinyl-benzo[Z?]thiophene-2-methanol hydrochloride; 4-4-(2- phenylethyl)-l-piperazinyl-benzo[&]thiophene-2-(A/-methyl-A/-methoxy)-carboxamide hydrochloride; 2-4-4-(2-phenylethyl)- 1 -piperazinylbenzo[Z?]thiophene-2-(2-propanol) hydrochloride; 1 -4-(4-phenethyl-piperazin- 1 -yl)-benzo[Z?]thiophen-2-yl-ethanone hydrochloride; 1 -4-(4-phenethyl-piperazin- 1 -yl)-benzo[Z?]thiophen-2-yl-ethanol hydrochloride; 4-4-phenylmethyl-l-piperazinyl-benzo[&]thiophene-2-methoxymethyl hydrochloride; 4-(l-piperazinyl)-benzo[&]thiophene-2-methoxymethyl hydrochloride; 4- 4-(2-(4-fluorophenyl)-ethyl)-l-piperazinylbenzo[/?]thiophene-2-methoxymethyl hydrochloride; 4-4-(2-phenylethyl)- 1 -piperazinly-benzo[Z?]thiopene-2-carboxaldehyde; 4-4-(4-phenylcarbomoyl-butyl)-piperazin-l-yl-benzo[fr]thiopen-2-carboxylic acid ethyl ester hydrochloride; 4-(l-piperazinyl)benzo[fr]thiophene-2-(7V-methyl)carboxamide; 4-
4-2-(4-nitrophenyl)ethyl- 1 -piperazinyl-benzo[&]thiophene-2-methanol hydrochloride dihydrochloride; 4-(l-piperazinyl)benzo[&]thiophene-2-methanol hydrochloride; 4-4-2- (4-nitrophenyl)ethyl-l-piperazinyl-benzo[Z?]thiophene-2-carboxylate hydrochloride; 5-4- (2-hydroxymethyl-benzo[/?]thiophen-4-yl)-piperazin-l-yl)-pentanoic acid phenyl amide hydrochloride; 2-4-(4-phenethyl-piperazin-l-yl)-benzo[fr]thiophen-2-ylmethyl- i soindole- 1 , 3 -dione hydrochloride; 4-4-(2-phenylethyl)- 1 -piperazinyl- benzo[fr]thiophene-2-methanamine dihydrochloride; 4-(4-phenethyl-piperazin- 1 -yl)- benzo[/?]thiophen-2-yl-piperidin-l-yl methanone hydrochloride; 4-(4-phenethyl- piperazin- 1 -yl)-benzo[fr]thiophen-2-ylpyrrolidin- 1 -yl methanone hydrochloride; 3-4-(4- phenethyl-piperazin-l-yl)-benzo[/?]thiophen-2-yl-acrylic acid ethyl ester hy drochl ori de : y 1 -aery li c acid ethyl ester hydrochloride; 3 -4-(4-phenethyl-piperazin- 1 - yl)-benzo[/?]thiophen-2-yl-prop-2-en- 1 -ol hydrochloride; 3 -4-(4-phenethyl-piperazin- 1 - yl)-benzo[/?]thiophen-2-yl-acrylonitrile hydrochloride; 3 -4-(4-phenethyl-piperazin- 1 -yl)- benzo[/?]thiophen-2-yl-acrylamide hydrochloride; 3 -4-(4-phenethyl-piperazin- 1 -yl)- b enzo [/?] thi ophen-2-y 1 -propi oni c acid ethyl ester hydrochloride; 3-4-(4-phenethyl- piperazin- 1 -yl)-benzo[/?]thiophen-2-yl-propan- 1 -ol hydrochloride; 3 -4-(4-phenethyl- piperazin- 1 -yl)-benzo[^]thiophen-2-yl-propionitrile hydrochloride; 3-4-(4-phenethyl- piperazin- 1 -yl)-benzo[Z?]thiophen-2-yl-propionamide hydrochloride; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,756,496, including, without limitation, N- 1-(2- dimethylaminoethyl)-li7-indol-6-yl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; /V-2,3-dihydro-l-(2-dimethylaminoethyl)-l.i/-indol-6-yl-2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-4-(2- dimethylaminoethyl)-3,4-dihydro-2.i/-l,4-benzoxazin-6-yl-2’ -methyl-4’ -(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethyl)-l -indol-5- yl-2’ -methyl-4’-(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-4-(2- dimethylaminoethyl)-3, 4-dihydro-3-oxo-2 -l,4-benzoxazin-6-yl-2’ -methyl-4’ -(5- m ethyl- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-carboxamide; A/-4-(2-dimethylaminoethyl)-3,4- dihy dro-3-methyl-2//-l, 4-benzoxazin-6-yl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-4-(2-dimethylaminoethyl)-3,4-dihydro-2 - benzo[Z?]pyran-6-yl-2’ -methyl-4’-(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-3-(2-dimethylaminoethyl)-2-oxo-2(3 )-benzoxazol-5-yl-2’ -methyl-4’ - (5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-5-(2-dimethylaminoethyl)- 2, 3,4, 5-tetrahydro-l, 5-benzoxazepin-7-yl-2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,801,170, including, without limitation, 77-3- (dimethylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-3-(2-diethylaminoethoxy)-4-methoxyphenyl-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- 3-(2- diisopropylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide; 7V-3-(2-dimethylamino-l-methylethoxy)-4-methoxyphenyl- 2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3-(2- dimethylaminopropoxy)-4-methoxyphenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamnide; A/-3-(2-Methylaminoethoxy)-4-methoxyphenyl-2’-methyl- 4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3 -(2-Aminoethoxy)-4- methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-3-(2 -piperi din- l-ylethoxy)-4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4- oxadiazol-3-yl)biphenyl-4-carboxamide; A/-3-(2-morpholin-4-ylethoxy)-4- methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2’ -methyl-4’ -(3-methyl-l, 2,4- oxadiazol-5-yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4- methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 3, 4-oxadiazol -2 -yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’-(l,3,4-oxadiazol-2- yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)phenyl-2’ -methyl-4’ -(5- methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-5-(2-dimethylaminoethoxy)-
2.4-diiodophenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-3-(2-dimethylaminoethyl)amino-4-methoxyphenyl-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide; /V-3 -(3 -dimethylaminopropoxy)- 4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-3-(3-dimethylaminopropyl)-4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-
1.2.4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3 -(3 -dimethylaminoprop- 1 -enyl)-4- methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-4-(3-dimethylaminopropoxy)phenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; N-3 -(2-pyrrolidin- 1 -ylethoxy)-4-methoxyphenyl-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- 3-(2- dimethylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’ -(5-ethyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2’- methyl-4’-(5-dimethylamino-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3-(2- dimethylaminoethoxy)-4-methoxyphenyl-2’ -methyl-4’ -(4-methylthiazol-2-yl)biphenyl- 4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2’-methyl-4’- pyrazinyl biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethylthio)-4-methoxyphenyl- 2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3-(2- dimethylaminoethylsulphinyl)-4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2,4- oxadiazol-3-yl)biphenyl-4-carboxamide; A/-5-(2-dimethylaminoethoxy)-2-chlorophenyl- 2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-3-(2- dimethylaminoethoxy)-4-chlorophenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-bromophenyl-2’-methyl- 4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- 3-(2- dimethylaminoethoxy)-4-iodophenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-ethylphenyl-2’-methyl-4’- (5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- 3-(2- dimethylaminoethoxy)-4-isopropylphenyl-2’ -methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; 7V-3-(2-dimethylaminoethoxy)-4-methoxyphenyl4’-(l,2,4- triazol- 1 -yl)-2’ -methyl-(l , 1’ -biphenyl)-4-carboxamide; 7V-3-(2-dimethylaminoethoxy)- 4-methoxyphenyl-4’ -(5-methyl- 1 ,2,4-oxadiazol-3 -yl)- 1 , G -biphenyl-4-carboxamide; N- 3 -(2-dimethylaminoethoxy)-4-methoxyphenyl-4’ -(1 ,2,4-triazol- 1 -yl)- 1 , G -bipheny-4- carboxamide; N-3 -(2-dimethylaminoethoxy)-4-methoxyphenyl-4’ -(tetrazol-2-yl)- 1 , G - biphenyl-4-carboxamide; 7V-3-(2-dirnethylaminoethoxy)-4-methoxyphenyl-2-methyl-4’- (5-methyl-l,2,4-oxadiazol-3-yl)-l, -biphenyl-4-carboxamide; N- 3-(2- dimethylaminoethoxy)-4-methoxyphenyl-2-methyl-4’-(2-pyridyl)-l, -biphenyl-4- carboxamide; 7V-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2-methyl-4’-(3-pyridyl)- 1 , -biphenyl)-4-carboxamide; 7V-3-(2-dimethylaminoethoxy)-4-methoxyphenyl-2’- ethy 1 -4’ -(5 -methyl - 1 ,2,4-oxadiazol-3 -yl)- 1 , G -biphenyl-4-carboxamide; 7V-3 -(2- dimethylarminoethoxy)-4-methoxyphenyl-2,2’dimethyl-4’-(5-methyl-l,2,4-oxadiazol-
3-yl)-l, 1’-biphenyl -4-carboxamide; A/-3-(N’-(2-dimethylaminoethyl)-A/’-methylamino)-
4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)-l,r -biphenyl-4- carboxamide; A/-3 -(N’ -(2-dimethylaminoethoxy)-/V’-phenethylamino)-4- methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)-l, l’-biphenyl-4- carboxamide; A/-3-(A/’-(2-dimethylaminoethoxy)-A/’-butylamino)-4-methoxyphenyl-2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-l,l’-biphenyl-4-carboxamide; N-3-(2- dimethylaminoethoxy)-4-methoxyphenol-4’-(l,2,4-triazol-l-yl)-(l,l’-biphenyl)-4- carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenol-4’-(tetrazol-2-yl)-(l,l’- biphenyl)-4-carboxamide; A/-3-(2-dimethylaminoethoxy)-4-methoxyphenol-2’-methyl- 4’ -(1 ,2,4-triazol- 1 -yl)-( 1,1’ -biphenyl)-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,821,245, including, without limitation, 7-benzamido- 1 -(4- methyl- 1 -piperazinyl)-naphthalene; 7-( 1 -naphthyl carb oxami do)- 1 -(4-methyl- 1 - piperazinyl)-naphthalene; 7-benzamido- 1 -( 1 -piperazinyl)-naphthalene; 7-acetamido- 1 - (4-methyl- 1 -piperazinyl)-naphthalene; 7-hexanamido- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 7-(phenylaminocarbonylamino)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(benzyloxycarbonylamino)- 1 -(4-methyl- 1 -piperazinyl)-napthalene; 7-(3 -nitro-2- pyridinylamino)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(5-nitro-2-pyridylamino)- 1 - (4-methyl- 1 -piperazinyl)-naphthalene; 7-(3 -hydroxy-3 -methyl- 1 -butynyl)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(2-ethylsulfonyl)ethenyl-l-(4-methyl-l-piperazinyl)- napthalene; 7-(3-methylaminosulfonylphenyl)-l-(4-methyl-l-piperazinyl)naphthalene; 7 -benzoyl- 1 -(4-methyl- 1 -piperazinyl)naphthalene; 7 -(3 -methoxy carbonylphenyl)- 1 -(4- methyl- 1 -piperazinyl)-napthalene; 7 -(3 -fluorophenyl)- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 7-(benzyloxy)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(4- chlorobenzoyloxy)-l -(4-methyl- l-piperazinyl)-naphthalene; 7-(imidazole[4,5-Z?]pyridin- 1 -yl)- 1 -(4-methyl- 1 -piperazinyl)-naphthalene; 7-(benzimidazol- 1 -yl)- 1 -(4-methyl- 1 - piperazinyl)-naphthalene; 7-(5-cyanobenzimidazol- 1 -yl)- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 7-(5-trifluoromethylbenzimidazol- 1 -yl)- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 7-(6, 7-di chi orob enzimi dazol - 1 -yl)- 1 -(4-methyl- 1 -piperazinyl)- naphthalene; 2-8-(4-methylpiperazin- 1 -yl)naphthalen-2-yloxymethylquinoline; 1 - methyl-4-{7-2-(4-chlorophenyl)thiazol-5-ylmethoxynaphthalen-l-yl (piperazine; 1- methyl-4-7-(5-chloro-thiophen-2-ylmethoxy)naphthalen-l-ylpiperazine; 8-(4- methylpiperazin- 1 -yl)naphthalene-2-carboxylic acid phenyl amide; 7-amino-l-(l- methyl-4-piperidinyl)-naphthalene; 7 -(3 -nitro-2-pyridy lamino)- 1 -( 1 -methyl-4- piperidinyl)-naphthalene; 7-(imidazolo4,5-bpyridin-l-yl)-l-(l-methyl-4-piperidinyl)- naphthalene; 7-(4-chlorobenzamido- 1 -( 1 -methyl-4-piperidinyl)-naphthalene; 7-amino- 1 - (1 -methyl-3 -piperidinyl)-naphthalene; 7-(3 -nitro-2-pyridylamino)- 1 -( 1 -methyl-3 - piperidinyl)-naphthalene; 7-(imidazole[4, 5-Z?]pyridin- 1 -yl)- 1 -( 1 -methyl -3 -piperidinyl)- naphthalene; 7-benzamido-l-(l-methyl-3-piperidinyl)-naphthalene; 7-(4- chlorobenzamido)- 1 -(4-methoxy ethyl- 1 -piperazinyl)-naphthalene; 7-(4- chlorobenzamido)- 1 -(4-propyl- 1 -piperazinyl)-naphthalene; 7-(4-chlorobenzamido)- 1 - (4-ethyl- 1 -piperazinyl)-naphthalene; 7-amino- 1 -( 1 -piperazinyl)-naphthalene; 7- (imidazolo-[4,5-Z?]-pyridin-l-yl)-l-(l-piperazinyl)-naphthalene; 7-(l,2,3-triazolo-4,5-b- pyridin- 1 -yl)- 1 -( 1 -piperazinyl)-naphthalene; 1 - { 7-5 -(2-methoxyphenyl)- 1,2,4- oxadiazol-3 -ylmethoxy-naphthalen- 1 -yl } -4-methylpiperazine; 1 -7 -(5-tert-butyl- 1 ,2,4- oxadiazol-3-ylmethoxy)-naphthalen-l-yl-4-methylpiperazine; l-methyl-4-7-(3-phenyl-
1.2.4-oxadiazol-5-ylmethoxy)-naphthalen- 1 -yl-piperazine; l-methyl-4-7-(5-phenyl- 1 ,2,4-oxadiazol-3 -ylmethoxy)-naphthalen- 1 -yl-piperazine; l-{7-5-(3 -methoxyphenyl)-
1.2.4-oxadiazol-3 -ylmethoxy-naphthalen- 1 -yl } -4-methylpiperazine; l-{7-5-(3,5- dimethylisoxazol-4-yl)-l,2,4-oxadiazol-3-ylmethoxy-naphthalen-l-yl}-4- methylpiperazine; l-{7-3-(4-methoxyphenyl)-l,2,4oxadiazol-5-ylmethoxy-naphthalen- 1 -yl } -4-methylpiperazine; 2-8-(l-methylpiperidin-4-yl)-naphthalen-2-yloxy -pyrimidine; l-methyl-4-7-(3-pyridin-3-ylmethyl-l,2,4-oxadiazol-5-yl)-naphthalen-l-yl-piperazine;
1 -methyl-4-7-(pyri din-2 -ylmethoxy)-naphthalen- 1 -yl-piperazine; 7-(imidazole[4,5- Z?]pyridin- 1 -yl)- 1 -(l-methylpyrrolidin-3 -yl)naphthalene; 2-8-(4-methylpiperazin- 1 - yl)naphthalen-2-yloxynicotinonitrile; 1 -(4-methylpiperazin- 1 -yl)-7-pyrimidin-5- yl)naphthalene; 7-(4-chlorobenzamido- 1 -(4-methylpiperazin- 1 -yl)naphthalene; 7-(3- methoxyphenyl) 1 -(4-methylpiperazin- 1 -yl)naphthalene; 8-(4-methylpiperazin- 1 - yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide; 7-pyrimidin-2-yloxy-l-(4- methylpiperazin- 1 -yl)naphthalene; 7-(4-methoxyphenyl)- 1 -(4-methylpiperazin- 1 -yl)- naphthalene; 8-(l-methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4- chlorobenzylamide; l-{7-3-(4-chloro-benzyl)-l,2,4-oxadiazol-5-yl-naphthalen-l-yl}-4- methyl-piperazine; 4-{7-3-(4-chloro-benzyl)-l,2,4-oxadiazol-5-yl-naphthalen-l-yl}-l- methyl-piperidine; 7-(3-methoxyphenyl)-l-(l-methylpiperidin-4-yl)-naphthalene; 7-(4- methoxyphenyl)- 1 -( 1 -methylpiperidin-4-yl)-naphthalene; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,919,932, including, without limitation, 7V-3-(8-azabicyclo- 3.2. l-octan-3-yl)-4-methoxyphenyl-2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-4-methoxy-3-(8-methyl-8-azabicyclo-3.2. l-octan-3- yl)phenyl-2’-methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; 3,4- dihydro-6-methoxy-7-(8-methyl-8-azabicyclo-3.2.1-octan-3-yl)-27/-quinolin-l-yl-2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-ylmethanone; 7-(8- azabicyclo3.2.1 octan-3-yl)-3,4-dihydro-6-methoxy-2if-quinolin-l-yl-2’ -methyl-4’ -(5- methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-ylmethanone; 7V-3-(8-methyl-8- azabicyclo3.2.1octan-3-yl)phenyl-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,952,325, including, without limitation, 7V-(2, 3 -dihydro- G- methylspiro-4if-benzopyran-6-yl-4, 4’ -piperidine)-2’-methyl-4’ -(5-methyl- 1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-(2,3-dihydrospiro-4i7-benzopyran-6-yl-4,4’- piperidine)-2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N-
(2,3-dihydro- -methylspirobenzofuran-5-yl-3,4’-piperidine)-2’-methyl-4’-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; /V-(2,3-dihydro-l’- methylspirobenzothiophen-5-yl-3,4’-piperidine)-2’ -methyl-4’ -(5-methyl- 1,2, 4- oxadiazol-5-yl)biphenyl-4-carboxamide; /V-( 1 , 2, 3 , 5 , 6, 7 -hexahy dro- 1 -methyl spiro-4 - azepine-4,3’ (2H -b enzofuran- 5’ -yl)-2’ -methyl-4’ -(5 -methyl- 1 ,2,4-oxadiazol-3 - yl)biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US5,972,935, including, without limitation, 4-(2- dimethylaminoethyl)-2,3,6,7,8,9-hexahydro-6-{2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carbonyl}-4.i/-pyrido[2,3-g][l,4]benzoxazine; 2 -(N,N- dimethyl-3,4,6,7,8,9-hexahydro-6-[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- y^biphenyM-carbonylJ^if-pyranoP^-gJquinolin^-y^ethanamine; 2-(7V,/V-dimethyl- 2, 3, 5,6,7, 8-hexahydro-5-[2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carbonyl]furo[2,3-g]quinolin-3-yl)ethanamine; 4-(2-dimethylaminoethyl)-2,3,4,6,7,8- hexahydro-6-[2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl]pyrrolo [2,3-g][l,4]benzoxazine; 3-(2-dimethylaminoethyl)-5-[2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrofuro[2,3- |indole; 4-(2- dimethylaminoethyl)-2,3,6,7,8,9-hexahydro-6-[2’-methyl-4’-(2-oxopyrrolidin-l- yl)biphenyl-4-carbonyl]-4if-pyrido[2,3-g][l,4]benzoxazine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 107,321, including, without limitation, 3-benzyl-7-[3-(5- (l,2,4-triazol-4-yl)-17/-indol-3-yl)propyl]-5-3,7-diazabicyclo[3.3.0]octane; 3-(pyridin-3- yl)methyl-7-[3-(5-(l,2,4-triazol-4-yl)-li7-indol-3-yl)propyl]-c/5-3,7- diazabicyclo[3.3.0]octane; 3-[2-(4-(acetylamino)phenyl)ethyl]-7-[3-(5-(l,2,4-triazol-4- yl)-lif-indol-3-yl)propyl]-c/5-3,7-diazabicyclo[3.3.0]octane; 3-benzoyl-7-[3-(5-(l,2,4- triazol-4-yl)-li7-indol-3-yl)propyl]-c/5-3,7-diazabicyclo[3.3.0]octane; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 107,328, including, without limitation, 4-(hydroxymethyl)-
1 -methyl-1, 2, 3, 6-tetrahydropyri dine; 4-(2-iodophenoxymethyl)- 1 -methyl- 1 ,2,3 ,6- tetrahydropyridine; 2,3-dihydro- -methylspirobenzofuran-3,4’-piperidine; 2,3-dihydro- -methyl-5-nitrospirobenzofuran-3, 4’ -piperidine; 5 -amino-2, 3 -dihydro- - methylspirobenzofuran-3, 4’ -piperidine; 6-(cyanomethyl)-2,3-dihydro- -methyl-5- nitrospirobenzofuran-3,4’-piperidine; 2,3-dihydro- -methylspirofuro[2,3- ]indole-3,4’- piperidine; G -methyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- ]indole-3,4’ -piperidine; - methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; -methyl-5-(2’- methyl-4’ -(5-methyl- 1,3, 4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 124,283, including, without limitation, (R)-N- 8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-(trifluoroacetyl)benzamide; (R)~
7V-8-(l-methylpiperidin-4-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (7?)-7V-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- piperidinobenzamide; (5)-A/-8-(4-methylpiperazin-l-yl)- 1,2,3, 4-tetrahy dro-2-naphthyl- 4-7V,7V-diethylaminobenzamide; (i?)-A/-8-(4-propylpiperazin-l-yl)- 1,2,3, 4-tetrahydro-2- naphthyl-4-morpholinobenzamide; (i?)-A/-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-
2-naphthyl-4-ethylbenzamide; (i?)-A/-8-(4-methylpiperazin-l-yl)- 1,2,3, 4-tetrahydro-2- naphthyl-4-morpholinocarbonylbenzamide; (i?)-7V-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4- tetrahydro-2-naphthyl-4-morpholinobenzamide; (i?)-A/-8-(4-methylpiperazin- 1 -yl)- l,2,3,4-tetrahydro-2-naphthyl-4-butoxybenzamide; (i?)-A/-8-(4-methylpiperazin-l-yl)- 1,2, 3, 4-tetrahydro-2-naphthyl-4-( 177-pyrrol- l-yl)benzamide; (R)-N-S-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-3-methyl-4-morpholinobenzamide; (7?)-A/-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4-(4- ethylphenyl)benzamide; (7?)-A/-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2- naphthy 1 -4-trifluoromethy lb enzami de; (7?)-A/-8-(4-methylpiperazin- l-yl)-l, 2,3,4- tetrahydro-2-naphthyl-4-(7V,/V-dipropylamninosulphonyl)benzamide; (R)-N-S-(4- ethylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (7?)-A/-8-( 1 - methylpiperidin-4-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-trifluoromethylbenzamide; (R)- 7V-8-(l-methylpiperidin-4-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-butoxybenzamide; (R)-N- 8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-cyclohexylbenzamide; (R)- A/-8-(methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-(4-piperidon- 1 - yl)benzamide; (i?)- V-8-(piperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide; A/-(4-morpholinocarbonylphenyl)-8-4-(methylpiperazin- 1 -yl)-
1.2.3.4-tetrahydronaphthalene-2-carboxamide; (i?)- V-8-(4-methylpiperazin-l-yl)-
1.2.3.4-tetrahydro-2-naphthyl-4-(4-morpholinomethyl)benzamide; (R)-N-S-(4- methylpiperazin-l-yl)- 1,2,3, 4-tetrahydro-2-naphthyl-4-(A/,A/- dimethylaminocarbonyl)benzamide; (i?)-7V-8-(4-methylpiperazin- 1 -yl)- 1, 2,3,4- tetrahydro-2-naphthyl-4-morpholinocarbonylbenzamide; (i?)-7V-8-(4-methylpiperazin- 1 - yl)-l,2,3,4-tetrahydro-2-naphthyl-4-thiomorpholinobenzamide; (R)-N-S-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-2-methylbenzamide; (R)-N-S-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-cyanobenzamide; (R)-N- 8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-fluorobenzamide; (R)-N- 8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-(4-hydroxyphenyl)benzamide; (i?)-A/-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-3-phenoxybenzamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 159,962, including, without limitation, 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-phenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3, 4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(l -naphthyl)- 1- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-methyl-l-napththyl)-l-piperazinyl)ethylthieno-[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-l- naphthyl)-l-piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-methylphenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(3-tri- fluoromethylphenyl)-l-piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-chloro-phenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3, 4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-pyrimi din-2- ylpiperazin-l-yl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-pyridin-2-ylpiperazin-l-yl)ethylthieno[2,3-<i]pyrimi din-4- one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-quinolin-2-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-(3,5-dichlorophenyl)-l-piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-
5-methyl-6-dimethylcarbamoyl-3-2-(4-tetralin-5-ylpiperazin-l-yl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-indan-4- ylpiperazin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-cyanophenyl)-l-piperazinyl)ethylthieno[2,3-i ]pyrimidin- 4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-isoquinolin-4-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-3- (4-pyrimidin-2-ylpiperazin-l-yl)propylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxyphenyl)-l-piperidinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(2- methoxyphenyl)-3,4-dihydro-l-piperidinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4- dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-naphth-l-ylpiperidin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-(2-methoxy-l-naphthyl)-3, 4-dehydro- l-piperidinyl)ethylthieno[2, 3 -<i]pyrimidin-4- one; 3 ,4-dihydro-5-methyl-6-dimethylcarbamoyl-3 -2-(4-naphth- 1-yl-l ,4-hexahydro- 1 ,4- diazepin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-carbamoyl-3-
2-(4-(l -naphthyl)- l-piperazinyl)ethylthieno[2, 3 -<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-carbamoyl-3-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethylthieno[2,3-<i]pyrimidin- 4-one; 3,4-dihydro-5-methyl-6-diethylcarbamoyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-Dihydro-5-methyl-6- diethylcarbamoyl-3-2-(4-(l -naphthyl)- l-piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one;
3,4-dihydro-5-methyl-6-diethylcarbamoyl-3-2-(4-pyrimidin-2-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-quinazolin-4-ylpiperazin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2,4-dimethoxyphenyl)-l- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2,5-dimethylphenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-naphth-l-yl-3,4- dehydro-l-piperidinyl)ethylthieno[2,3-<i]pyrimidin-4-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 159,979, including, without limitation, 7V-4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl-4-bromonaphth- 1 -ylcarboxamide; 5-bromo-7V-4-methoxy-
3-(4-methylpiperazin-l-yl)phenylnaphth-l-ylcarboxamide; 7V-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylquinolin-4-ylcarboxamide; 7V-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-5-(pyridin-4-yl)naphth- 1 -ylcarboxamide; 7V-4-methoxy-3 - (4-methylpiperazin-l-yl)phenyl-4-(pyridin-4-yl)naphth-l -ylcarboxamide; N-(4- methoxy-3 -(4-methylpiperazin- 1 -yl)phenyl-A/’ -naphth- 1 -ylurea; 7V-4-bromonaphth- 1 -yl-
7V’ -(4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenylurea; A/-4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl-7V’ -4-(pyridin-4-yl)naphth- 1 -ylurea; A/-4-methoxy-3 -(4- methylpiperizin- 1 -yl)phenyl-4-bromonaphth- 1 -ylacetamide; 7V-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-4-(pyridin-4-yl)naphth- 1 -ylacetamide; A/-4-chloro-3 -(4- methylpiperazin- 1 -yl)phenyl-7V’ -4-(pyridin-4-yl)naphth- 1 -ylurea; A/-4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl-A/’ -naphth- 1 -ylthiourea; 7V-4-methoxy-3 -(1- methylpiperidin-4-yl)phenyl-A/’-4-(pyridin-4-yl)naphth-l -ylurea; 7V-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl- V’ -5,6,7,8-tetrahydronaphth- 1 -ylurea; N- benzo-2, 1,3- thiadiazol-4-yl-A/’-4-methoxy-3 -(4-methylpiperazin- l-yl)phenylurea; A/-indol-4-yl-N’- 4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenylurea; N-4-m ethoxy-3 -(4-methylpiperazin-
1 -yl)phenyl-A/’ -3 ,4-methylenedioxyphenylurea; A/-5-bromonaphth- 1 -yl-7V’ -4-methoxy-
3 -(4-methylpiperazin- 1 -yl)phenylurea; 5 -bromo-A/-4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenylnaphth- 1 -ylacetamide; N-4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl-A/’ -2- methylquinolin-6-ylurea; A/-isoquinolin-5-yl-A/’-4-methoxy-3-(4-methylpiperazin-l- yl)phenylurea; A/-benzothiazol-6-yl-A/’-4-methoxy-3 -(4-methylpiperazin- 1- yl)phenylurea; A/-4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl-A/-quinolin-3 -ylurea; N-
4-Methoxy-3 -(4-methylpiperazin- 1 -yl)phenyl-7V’ -quinolin-6-ylurea; A/-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-7V’ -quinolin-5-ylurea; A/-2,3-dihydrobenzofuran-5-yl-A/’-4- methoxy-3 -(4-methylpiperazin- 1 -yl)phenylurea; A/-4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-4-(pyridin-3-yl)naphth-l -ylacetamide; A/-4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-A/’-5-(pyridin-3-yl)naphth-lylurea; 4-(4-Acetylphenyl)-A/-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylnaphth- 1 -ylacetarnide; 4-(3 - Acety lphenyl)-A -methoxy-3 - (4-methylpiperazin- 1 -yl)phenylnaphth- 1 -ylacetarnide; 5-(3 - Acetylphenyl)-7V-4- methoxy-3-(4-methylpiperazin-l-yl)phenylnaphth-l -ylacetarnide; 7V-4-Methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-A/’ -5-phenylnaphth- 1 -ylurea; 7V-4-Methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl-5-(pyri din-3 -yl)naphth- 1 -ylacetarnide; 7V-4-Methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-5-phenylnaphth- 1 -ylacetarnide; 5-(4-Acetylphenyl)-7V-4- methoxy-3 -(4-methylpiperazin- l-yl)phenylnaphth-l -ylacetarnide; 7V-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl-5-(2-methylphenyl)naphth- 1 -ylacetarnide; 7V-4-bromo-3 - (4-methylpiperazin- 1 -yl)phenyl-4-(pyridin-4-yl)naphth- 1 -ylacetarnide; 5 -(3, 4- dimethoxypheny l)-7V-4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenylnaphth- 1 - ylacetarnide; N-5-(3 -acetylphenyl)naphth- 1 -yl-TV’ -4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenylurea; 7V-4-chloro-3 -(1 -methylpiperidin-4-yl)phenyl-4-(pyridin-4-yl)naphth- 1 - ylacetarnide; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -5-(pyridin-4-yl)naphth- 1 - ylcarbonyl-l -indole; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 166,034, including, without limitation, 5-4-{5-(5-methyl- l,3,4-oxadiazol-2-yl)-l-naphthyl}benzoyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- )indole-3,4’-piperidine; 5-4-{5-(5-methyl-l,3,4-oxadiazol-2-yl)-l-naphthyl}benzoyl- 2,3,5,6,7,8-methylspirofuro[2,3-g]quinoline-3,4,-piperidine; 5-4-{5-(5-methyl-l,3,4- oxadiazol -2 -yl)-l -naphthyl }-3-methylbenzoyl- r-methyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-4-{5-(5-methyl-l,3,4-oxadiazol-2- yl)- 1 -naphthyl }-3-methylbenzoyl-2, 3, 5,6,7, 8-hexahydro- -methylspirofuro[2, 3- ,g]quinoline-3, 4’ -piperidine; r-methyl-5-4-(2-methyl-6-(2-oxopyrrolidin-l-yl)pyridin-3- yl)benzoyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-4-(2-methyl-6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)benzoyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4,- piperidine; -methyl-5-6-(2-methyl-4-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl)nicotinoyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 197,773, including, without limitation, 3,4-dichloro- V-(2-2- (4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 4-fluoro-7V-(2-2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl)-benzamide; 7V-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3,4-dichloro-/V-(l-methyl-2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3 ,4-dichloro-/V-(l -methyl-2-2-(4-methylpiperazin- 1 -yl)-phenyl-propyl)- benzamide; 3,4-dichloro-A/-methyl-A/-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; A/-benzyl-A/-(2-2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl)-benzamide; N-(4- chlorobenzyl)-A/-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 3,4-dichloro- /V-(2-{2-methyl-(l-methylpyrolidin-2-ylmethyl)-amino-phenyl}-ethyl)-benzamide; 3,4- dichloro- V-{2-2-(l-methyl-octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl-ethyl}- benzamide; 3,4-dichloro-/V-{2-2-(hexahydro-pyrrolo[l,2-i3]pyrazin-2-yl)-phenyl-ethyl}- benzamide; 3,4-dichloro-/V-{2-2-(l-methylpiperidin-4-yl)-phenyl-ethyl)-benzamide; 3,4-dichloro-/V-{2-2-(2-dimethylaminoethoxy)-phenyl-ethyl}-benzamide; 3,4-dichloro- 7V-{2-2-(2-dimethylamino-ethylsulfanyl)-phenyl-ethyl}-benzamide; 3,4-dichloro- V-{2- 2-(2-pyrrolidin- 1 -yiethoxy)-phenyl-ethyl } -benzamide; 4-chloro-/V- { 2-2-(3 - dimethylamino-pyrrolidin-l-yl)-phenyl-ethyl} -benzamide; 4-chloro-A/-(2-{2-methyl-(2- morpholin-4-yl-ethyl)-amino-phenyl}-ethyl)-benzamide; 2-(4-chlorophenyl)-A/-{2-2-(4- methylpiperazin-l-yl)-phenyl-ethyl} -acetamide; A/-{2-2-(4-methylpiperazin-l-yl)- phenyl-ethyl } -7V-pheny 1 acetami de; 7V-{2-2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl } - isonicotinamide; A/-{2-2-(l-azabicyclo[2.2.2]oct-4-yl)-phenyl-ethyl}-A/- methylbenzamide; N-{2-2-( 1 ,4-dimethylpiperidin-4-yl)-phenyl-ethyl } -4- fluorobenzamide; 4-fluoro-A/-{2-2-(9-methyl-3,9-diazabicyclo[3.3.1]non-3-yl)-phenyl- ethy 1 } -b enzami de ; 7V-(2-2-(l,4-diazabicyclo[3.3.1]non-4-yl)-phenyl-ethyl}- V- methylbenzamide; N-{ l-methyl-2-2-(5-methyl-2,5-diazabicyclo[2.2. l]hept-2-yl)- pheny 1 -ethyl } -b enzami de; 2, 4-di chi oro-A/-methyl-7V-{ l-methyl-2-2-(3 -methyl-3,8- di azabi cy cl o [3.2.1 ] oct- 8 -y l)-pheny 1 ethyl } -b enzami de; 7V-{2-2-(4-methyl- octahydroquinoxalin- 1 -yl)-phenyl-ethyl } -benzamide; A/-{2-2-(l-ethylpyrrolidin-2- ylmethoxy)-phenyl-ethyl} -benzamide; 5-phenyloxazole-2-carboxylic acid{2-2-(4- methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 5-phenylthiophene-2-carboxylic acid{2-2- (4-methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 5-methylthiophene-2-carboxylic acid{2- 2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 4-fluoronaphthalene- 1 -carboxylic acid{2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl}-amide; 5 -fluoro- 1 -indole-2- carboxylic acid{2-2-(4-methyl-piperazin-l-yl)-phenyl-ethyl}-amide; 4-chloro-A/-{2-2- (3,4,5-trimethylpiperazin-l-yl)-phenyl-ethyl}-benzamide; 3,4-dichloro-7V-{2-2-(2,4,5- trimethylpiperazin-l-yl)-phenyl-ethyl}-benzamide; 3,4-dichloro-/V-{2-2-(2,4,6- trimethylpiperazin-l-yl)-phenyl-ethyl}-benzamide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,342,498, including, without limitation, N-( 2-(4-(2- methoxyphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6-fluoroindol-3 -yl)-piperidin- 1 - yl)propenamide; A/-(2-(4-(2-methoxyphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6- fluoroindol-3-yl-l,2,3,6-tetrahydropyridin-l-yl)propenamide; N-( 2-(4-(2- methoxphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6-chloroindol-3 -yl)-l, 2,3,6- tetrahydropyridin- 1 -yl)propenamide; l-(2-methoxyphenyl)-4-(6-(4-(6-chloroindole-3- yl)- 1,2,3,6-tetrahydropyridin- 1 -yl)hex- 1 -yl)piperazine; N-( 2-(4-(2- methoxyphenyl)piperazin- 1 -yl)eth- 1 -yl)-3 -(4-(6-chloroindol-3 -yl)-piperidin- 1 - yl)propenamide; 1 -(2-methoxyphenyl)-4-(6-(4(6-fluoroindole-3 -yl)-piperidin- 1 -yl)hex- l-yl)piperazine; l-(2-methoxypheny)-4-(6-(4-(6-chloroindole-3-yl)-piperidin-l-yl)hex- l-yl)piperazine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,346,622, including, without limitation, 3 , 3 -dimethyl-2-3 -(4- (5-tetralinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-3 -(4-(2-phenyl-4-quinazolinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3, 3 -dimethyl-2-3 -(4-(2-quinolinyl)- 1 -piperazinyl)-prop- 1 - yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 - diazepanyl)-prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3, 3 -dimethyl-2-3 - (4-(4-chloro- 1 -phthalazinyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1, 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-2-methyleneprop- 1 -yl-2, 3 - dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-2-(4-(4-quinazolinyl)- 1 - piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3-dimethyl-2-2- (4-(l -naphthyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
3 , 3 -dimethyl-2-2-(4-i soquinolin-4-yl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1,2- benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-prop- 1 - yl-6-(l-pyrrolyl)-2,3-dihydro-l,2-benzoisothi azole-1, 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 - naphthyl)- 1 -piperazinyl)-prop- 1 -yl-6-benzoylamido-2, 3 -dihydro- 1 ,2-benzoisothiazole- 1 , 1 -dioxide; 3, 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-prop- 1 -yl-6-nitro-2, 3 - dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-2-(4-(2,3 -dimethylphenyl)- 1 - piperazinyl)eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-2-(4-
(4-indanyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -di-hydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3- dimethyl-2-3 -(4-(4-chloro- 1 -naphthyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-(2-pyrimidinyl)- 1 -piperazinyl)-prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-2-(4-(4- methoxyphenyl)- 1 -piperazinyl)eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
3 , 3 -dimethyl-2-3 -(4-(2 -methoxyphenyl)- 1 -piperazinyl)-2-hy droxy-prop- 1 -yl-2, 3- dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -diethyl-2-3 -(4-( 1 -naphthyl)- 1 - piperazinyl)-prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3-dimethyl-2-3- (4-(2, 5-dimethylphenyl)-l-piperazinyl)prop-l-yl-2, 3-dihydro-l,2-benzoisothi azole-1, 1- dioxide; 3 ,3 -dimethyl-2-2-(4-(2-cyanophenyl)- 1 -piperazinyl)eth- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl -2-2-(4-( 1 -naphthyl)- 1 -piperazinyl)-eth- 1 -yl- 4-chloro-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,355,647, including, without limitation, 3,4, 5,7-tetrahydro- 6-carbethoxy-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-(l-naphthyl)-l-piperazinyl)ethyl- pyrrolo[3’,4’ :4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(l- naphthyl)-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3, 4,5,7- tetrahydro-6-acetyl-3-2-(4-(l-naphthyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-6-benzyl-3 -2-(4-( 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- (4-chlorophenyl-2-ethyl)-3 -2-(4-( 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(l -naphthyl)- l-piperazinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-methyl-l-naphthyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3 -2-(4-(2-methoxy- 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-pyrimidin-2-yl-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-6-carbethoxy-3 -2-(4-(2-methoxyphenyl)- 1 - piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2- (4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3,,4’:4,5]thieno[2,3-<i]pyrimidin-4- one; 3,4,5,7-tetrahydro-3-2-(4-naphth- 1 -ylhexahydro- 1 ,4-diazepin- 1 - yl)ethylpynOlo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2-(4-(2- methylphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-tetralin-5-yl-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2-(4-indan- 1-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2-
(4-(2-methoxyphenyl)-3, 4-dehydro- l-piperidinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-naphth- 1 -yl- 1 -piperidinyl)- ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-(2- methoxy-1 -naphthyl-3, 4-dehydro-l-piperidinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-(2,3-dimethylphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-chlorophenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-pyrimidin-2-yl-l-piperazinyl)ethylpyrrolo[3,,4’:4,5]thieno[2,3-
<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-pyridin-2-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-quinolin-2-yl-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin- 4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-methoxyphenyl)-l- piperidinyl)ethylpyrrolo[3’,4’ :4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-S-S^-pyrimidin^-yl-l-piperaziny^propylpyrrolofS’^’^^JthienoP^- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-methyl-3-2-(4-(3-trifluoromethyl-phenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- methyl-3-2-(4-(2-cyano-phenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-methyl-3-2-(4-isoquinolin-4-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyriinidin-4-one; 3,4,5,7-tetrahydro-6- methyl-3-2-(4-naphth-l-yl-3,4-dehydro-l-piperidinyl)ethylpyrrolo[3,,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-acetyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyriinidin-4-one; 3,4,5,7-tetrahydro-6- acetyl-3-2-(4-(2-methyl-l-naphthyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-benzyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-
(4-nitrophenyl-2-ethyl)-3 -2-(4-( 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- (4-aminobenzyl)-3-2-(4-(2-methyl-l-naphthyl)-l- iperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methylphenyl)-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3-
<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-chlorophenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-phenyl-l-piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-naphth- 1-yl-l- piperidinyl)ethylpyrrolo[3’,4’ :4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-naphth-l-yl-3,4-dehydro-l-piperidinyl)ethyl- pyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-3-(4- (2-cyanophenyl)-l-piperazinyl)propylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-indan-4-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,403,592, including, without limitation, 3-(4-chlorophenyl)- 5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)- 5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidine-2,4-dione; 3-(4-chlorobenzyl)-
5-2-(4-methylpiperazin-l-yl)-benzylidene-thiazolidine-2,4-dione; 4-benzyl-2-2-(4- methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-2-(4- methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 3-(4-chlorophenyl)-5-2-(4- methylpiperazin- 1 -yl)-benzylidene-thiazolidine-2,4-dione; 3 -(4-trifluoromethylphenyl)- 5-2-(4-methylpiperazin-l-yl)-benzylidene-thiazolidine-2,4-dione; 2-2-(4- methylpiperazin-l-yl)-benzylidene-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 2-
2-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2- 2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(4-methylpiperazin-l-yl)-benzylidene-morpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(4-methylpiperazin-l-yl)-benzyl-thiomorpholin-3-one; 4-methyl-2-
2-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2- (2-piperazin-l-ylbenzylidene)-thiomorpholin-3-one; 4-benzyl-2-2-(4-methylpiperazin- 1 -yl)-benzylidene- 1 , 1 -dioxothiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-3 -fluoro-2- (4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-5- fluoro-2-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(4-methylpiperazin-l-yl)-5-trifluoromethyl-benzylidene- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{2-4-(2-methoxyethyl)piperazin-l-yl- benzylidene} -thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-2-(4-isopropylpiperazin-l- yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(4-ethylpiperazin-l- yl)-benzylidene-thiomorpholin-3-one; 4-(4-chlorophenyl)-2-2-(4-methylpiperazin- 1 -yl)- benzylidene-thiomorpholin-3-one; 4-(3-chlorophenyl)-2-2-(4-methylpiperazin-l-yl)- benzylidene-thiomorpholin-3-one; 2-2-chloro-6-(4-methylpiperazin- 1 -yl)-benzylidene- 4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(4- methylpiperazin-l-yl)-4-trifluoromethyl-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(4-methylpiperazin- 1 -yl)-benzylidene- 1 -oxo-thiomorpholin-3 -one;
4-(3,4-dichlorophenyl)-2-(5-fluoro-2-piperazin-l-yl-benzylidene)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-3,6-difluoro-2-(4-methylpiperazin-l-yl)-benzylidene- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(3,5-dimethylpiperazin-l-yl)- benzylidene-thiomorpholin-3-one; 4-phenyl-2-2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene-thiomorpholin-3-one; 2-5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene-
4-phenyl-thiomorpholin-3-one; 4-benzol, 3-di oxol-5-yl-2-2-(3, 5-dimethylpiperazin- 1- yl)-benzylidene-thiomorpholin-3-one; 2-2-(4-tert-butylpiperazin- 1 -yl)-benzylidene-4- (3,4-dichlorophenyl)-thiomorpholin-3-one; 3-(3,4-dichiorophenyl)-5-2-(4- methylpiperazin- 1 -yl)-benzylidene-thiazolidin-4-one; 3 -4-(3 ,4-dichlorophenyl)-3 -oxo- thiomorpholin-2-ylidenemethyl-6-dimethylamino-2-(4-methylpiperazin-l-yl)- benzonitrile; 5-2-(4-methylpiperazin-l-yl)-benzylidene-2-phenylthiazolidin-4-one; 4- (3,4-dichlorophenyl)-2-2-(3,4,5-trimethylpiperazin-l-yl)-benzylidene-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-5-methyl-2-(4-methylpiperazin-l-yl)-benzylidene- thiomorpholin-3-one; 2-4-chloro-2-(4-methylpiperazin-l-yl)-benzylidene-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3 ,4-difluorophenyl)-2-2-(3 , 5 - dimethylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(2,4-difluorophenyl)-2-2- (3,5 -dimethylpiperazin- 1 -yl)-benzylidene-thiomorpholin-3 -one; 2-4-bromo-2-(4- methylpiperazin-l-yl)-benzylidene-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(l-methylpyrrolidin-2-ylmethoxy)-benzylidene-thiomorpholin-3- one; 4-(3,5-dichlorophenyl)-2-2-(3,5-dimethylpiperazin-l-yl)-benzylidene- thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2-2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(octahydropyrido-[l,2- a]pyrazin-2-yl)-benzylidene-thiomorpholin-3-one; 2-2-(4-cy clopropylpiperazin- 1 -yl)- benzylidene-4-pyridin-3-yl-thiomorpholin-3-one; 2 -2-(4-cy clopropylpiperazin- 1 -yl)- benzylidene-4-(3 ,4-difluorophenyl)-thiomorpholin-3 -one; 2-2-(4-cyclopropylpiperazin- l-yl)-benzylidene-4-(3,5-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-diflourophenyl)- 2-2-(2,5-dimethylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,5- dichlorophenyl)-2-2-(2,5-dimethylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-2-(3-methylaminopyrrolidin-l-yl)-benzylidene-thiomorpholin-3- one; 4-(3,4-difluorophenyl)-2-2-(2,4,5-trimethylpiperazin-l-yl)-benzylidene- thiomorpholin-3 -one; 4-benzo- 1 ,3-dioxol-5-yl-2-2-(4-cy clopropylpiperazin- 1 -yl)- benzylidene-thiormorpholin-3-one; 2-2-(3,5-dimethylpiperazin-l-yl)-benzylidene-4-(4- fluorophenyl)-thiomorpholin-3-one; 4-benzo-l,3-dioxol-5-yl-2-2-(2,5- dimethylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 2-2-(3 , 5 -dimethylpiperazin- l-yl)-benzylidene-4-phenylthiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(4- methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(3- dimethylaminopynOlidin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-2-(3-dimethylaminopyrrolidin-l-yl)-benzylidene-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-2-(4-methyl-l,4-diazepan-l-yl)-benzylidene- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(2,4,6-trimethylpiperazin-l-yl)- benzylidene-thiomorpholin-3-one; 2-2-(4-cyclopropylpiperazin- 1 -yl)-benzylidene-4-
(3,4-dichlorophenyl)-thiomorpholin-3-one; 5-2-(4-methylpiperazin-l-yl)-benzylidene- thiazolidine-2,4-dione; 2-2,4-dibromo-6-(4-methylpiperazin-l-yl)-benzylidene-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(4-chlorophenyl)-2-2-(4-methylpiperazin-l-yl)- benzylidene-l,4oxazepan-3-one; 4-(4-chlorophenyl)-2-2-(4-methylpiperazin- 1 -yl)- benzylidene-l,4,5oxadiazepan-3-one; 4-(4-chlorophenyl)-2-2-(4-methylpiperazin- 1 -yl)- benzylidene-l,4thiazepan-3-one; 4-(3,4-dichlorophenyl)-2-{2-(2-dimethylaminoethyl)- methyl-amino-benzylidene}-thiomorpholin-3-one; 4-(3 ,4-dichlorophenyl)-2-2-( 1 - methylpiperidin-4-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-
(l,4-dimethylpiperidin-4-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)- 2-2-(4-methylpiperazin-l-yl)-benzylidene-thiomorpholine-3,5-dione; 4-(3,4- dichlorophenyl)-2-2-(2-dimethylaminoethoxy)-benzylidene-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-2-(4-isopropylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-2-(l-methylpyrrolidin-3-ylmethyl)-benzylidene- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{2-methyl-(l-methylpyrrolidin-2- ylmethyl)-amino-benzylidene}-thiomorpholin-3-one; 4-(3 ,4-dichlorophenyl)-2-2-( 1 - methylpyrrolidin-2-ylmethoxy)-benzylidene-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-{2-2-(l-methylpyrrolidin-2-yl)-ethyl-benzylidene}-thiomorpholin-3- one; l-(3,4-dichlorophenyl)-4-methyl-3-2-(4-methylpiperazin-l-yl)-benzylidene- piperazin-2-one; 4-methyl-3-2-(4-methylpiperazin-l-yl)-benzylidene-l-(4- trifluoromethylphenyl)-piperazin-2-one; l-(4-chlorophenyl)-4-methyl-3-2-(4- methylpiperazin- 1 -yl)-benzylidene-piperazin-2-one; 2-2-(4-methylpiperazin-l-yl)- benzylidene-4-(4-trifluoromethylphenyl)-morpholin-3-one; 2-4-fluoro-2-(4- methylpiperazin-l-yl)-benzylidene-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 2-
5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene-4-(4-trifluoromethylphenyl)- thiomorpholin-3 -one; 2- { 1 -2-(4-methylpiperazin- 1 -yl)-phenyl-ethylidene}-4-(4- trifluoromethylphenyl)-thiomorpholin-3-one; 2-2-(4-methylpiperazin- 1 -yl)-benzyl-4-(4- trifluoromethylphenyl)-thiomorpholin-3-one; 4-(4-chlorophenyl)-6-methyl-2-2-(4- methylpiperazin-l-yl)-benzylidene-thiomorpholin-3-one; 3-(4-chlorophenyl)-2,2- dimethyl-5-2-(4-methylpiperazin-l-yl)-benzylidene-thiazolidin-4-one; 4-(4- chlorophenyl)-2-2-(4-methylpiperazin- 1 -yl)-benzylidene- 1 ,4-oxazepan-3 -one; 4-(4- chlorophenyl)-2-2-(4-methylpiperazin-l-yl)-benzylidene-4if-l,4-thiazin-3-one; l-(4- chlorophenyl)-4,6,6-trimethyl-3-2-(4-methylpiperazin-l-yl)-benzylidene-piperazin-2- one; l-(4-chlorophenyl)-4-methyl-3-2-(4-methylpiperazin-l-yl)-benzylidene-piperazin-
2-one; 4-(4-chlorophenyl)-2-2-(4-methylpiperazin-l-yl)-benzylidene-morpholin-3-one; 3-(4-chlorophenyl)-5-2-(4-methylpiperazin-l-yl)-benzylidene-oxazolidin-4-one; 3 -(4- chlorophenyl)-2,2-dimethyl-5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidin-4- one; 3-(4-chiorophenyl)-5-2-(4-methylpiperazin-l-yl)-benzylidene-imidazolidin-4-one; and pharmaceutically acceptable salts thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 509,340, including, without limitation, 7V-2-(5-fluoro-3- indolyl)ethyl-A/’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenylurea; 4-(5-cyano-3- indolyl)-/V-4-methoxy-3-(4-methylpiperazin-l-yl)phenylpiperidine-l -carboxamide; 4- (6-fluoro-3 -indolyl)-7V-4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 - carboxamide; 3-{ l-4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl-4- piperidyl}indole-5-carboxamide; 4-(5-fluoro-3-indolyl)-A/-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylpiperidine- 1 -carboxamide; 4-2-(3-indolyl)ethyl-7V-4- m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 -carboxamide; 4-(3-indolyl)-/V- 4-methoxy-3 -(4-methylpiperazin- l-yl)phenylpiperidine-l -carboxamide; 4-(4-fluoro-3- indolyl)-/V-4-methoxy-3 -(4-methylpiperazin- l-yl)phenylpiperidine-l -carboxamide; 4- (7-methoxyindol-3-yl)piperidine-l-carboxylic acid 4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-amide; 4-4-(5-fluoro-3-indolyl)butylpiperazine-l-carboxylic acid 4-methoxy- 3 -(4-methylpiperazin- 1 -yl)phenylamide; 4-(5-cyanoindol-3-yl)-3,6-dihydro-2if- pyridine[/ucMuu] 1 -carboxylic acid 4-methoxy-3 -(4-methylpiperazin- l-yl)phenylamide;
3-(5-fluoroindol-3-yl)pyrrolidine-l -carboxylic acid 4-m ethoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-amide; 4-(5-fluoroindol-3-yl)cyclohexanecarboxylic acid 4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylamide; A/-2-(5-hydroxy-3-indolyl)ethyl-A/’-4-methoxy-3-(4- methyl- 1 -piperazinyl)phenylurea; N- (2-4-(6-fluoro-3 -indolyl)piperidin- 1 -yl ethyl } -A/’ -4- m ethoxy-3 -(4-methyl- l-piperazinyl)phenyl-urea; A/-4-(5 -cy ano-3 -indolyl)butyl-A/’ -4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenylurea; 4-4-(5 -cy ano-3 - indolyl)butylpiperazine- 1 -carboxylic acid 4-m ethoxy-3 -(4-methyl- 1 -piperazinyl)- phenylamide; 4-(5-fluoroindol-3-yl)piperidine-l-carboxylic acid (2, 3 -dihydro- - methylspiro(benzofuran)-3,4-piperidin)amide; N- { 2-4-(6-fluoro-3 -indolyl)piperidin- 1 - ylethyl}-2,3-dihydro-l-methylspiro(benzofuran)-3,4-piperidinurea; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,537,995, including, without limitation, 5-2-(4- methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 4-chlorobenzylamide; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-furan-2-carboxylic acid 4-chlorophenylamide; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid 4-chlorophenylamide; 5-2-(4- methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 2-(4-chlorophenyl)ethyl-amide; 4- 2-(4-methylpiperazin-l-yl)-phenyl-furan-2-carboxylic acid 4-chlorobenzylamide; 5-2-
(4-methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid benzyl amide; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid 4-fluorob enzy 1 ami de ; 5-2-(4- methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid 4-methoxybenzylamide; 5-2- (4-methylpiperazin- 1 -yl)-phenyl-thiophene-2-carboxylic acid 2-(4-chlorophenyl)ethyl- amide; 3-methyl-5-2-(4-methylpiperazin-l-yl)-phenyl-thiophene-2-carboxylic acid 4- chlorobenzylamide; 5-5-fluoro-2-(4-methylpiperazin-l-yl)-phenyl-thiophene-2- carboxylic acid 4-chlorobenzylamide; 5-2-(4-methylpiperazin-l-yl)-phenyl-lH-pyrrole- 2-carboxylic acid 4-chlorobenzylamide; and pharmaceutically acceptable salts thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6,887,905, including, without limitation, (7R, 9as)-trans- 1 - { 3 -
[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydropyrido[l,2-u]pyrazin-7-ylmethoxy]- benzyl}-azetidin-3-ol; (7 ?,9u5)-/rau5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(3- morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (' 7S,9as)-cis - 1 - (3-{ l-[2-(benzo[i ]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperi din-3- ylmethoxy}-benzyl)-azetidin-3-ol; (7 ?,9u5)-/rau5-2-(4-fluoro-benzo[<i]isoxazol-3-yl)-7-
(3-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-u]pyrazine; (7S,9aS)~ c/5-2-benzo[<i]isoxazol-3-yl-7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro- pyrido-[l,2-u]pyrazine; (75,9u5)-c/5-l-[3-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-u]pyrazin-7-ylmethoxy)-benzyl]pyrrolidine-3,4-diol; (7R,9aS)-trans-2-(5- fluoro-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)- octahydropyrido[l,2- 3]pyrazine; (7S,9aS)-ds-2-benzo[rf]isoxazol-3-yl-7-(2-methyl-5- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7S,9aS)-cis- 2-benzo[<i]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-l-ylmethyl-phenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (75,9«5)-cd-2-benzo[<i]isoxazol-3-yl-7-(4-chloro-3- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (' 7S,9aS)-cis -
2-benzo[<i]isoxazol-3-yl-7-(4-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro- pyrido[ 1 ,2-a]pyrazine; (7S,9aS)-cis-7-(3 -azetidin- 1 -ylmethyl-phenoxymethyl)-2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)-cis-[3-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-benzyl]- cyclopropylmethyl-amine; (75,9«5)-d5-2-benzo[<i]isoxazol-3-yl-7-[3-(2- methoxymethyl-pyrrolidin- 1 -ylmethyl)-phenoxymethyl]-octahydro-pyrido[ 1 ,2- ajpyrazine; (75,,9a5’)-cd-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-benzyl]-cyclopropyl-amine; (75,9«5)-cd-2-benzo[<i]isoxazol-3-yl-7-(3- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (' 7S,9aS)-cis - 2-benzo[<i]isoxazol-3-yl-7-[3-(4-ethyl-piperazin-l-ylmethyl)-phenoxymethyl]- octahydro-pyrido[l,2-a]pyrazine; (75,9«5)-cd-[3-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclohexyl-amine; (7S,9aS)-cis-l-[3-(2- benzo[<i]isoxazol-3-yl-octahydro-pyridol[l,2-a]pyrazin-7-ylmethoxy)-benzyl]- pyrrolidin-3-ol; (7S,9aS)-ds-2-benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-[pyrrolidin-l- ylmethyl)-phenoxymethyl-octahydro-pyrido[ 1 ,2-a]pyrazine; (' 7S,9aS)-cis-2 - benzo[<i]isoxazol-3-yl-7-[3-(2,5-dimethyl-pyrrolidin-l-ylmethyl)-phenoxymethyl]- octahydro-pyridol [ 1 ,2-a]pyrazine; (75,9«5)-d5-l-[3-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidine-3,4-diol; (7S,9aS)~ cd-l-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)- benzyl]-pyrrolidin-3-ol; (75,9«5)-cd-[3-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-benzyl]-isobutyl-amine; (7S,9aS)-ds-benzo[<i]isoxazol-3-yl- methyl-{2-[2-methyl-5-(2-morpholin-4-ylmethyl-phenoxymethyl)-piperidin-l-yl]- ethyl} -amine; (75,9«5)-cd-2-benzo[<i]isoxazol-3-yl-7-(2-pyrrolidin-l-ylmethyl- phenoxymethyl)-octahydro-pyridol[l,2-a]pyrazine; (75,9«5)-cd-2-benzo[<i]isoxazol-3- yl-7-(4-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine;
(75,9«5)-cd-2-benzo[<i]isoxazol-3-yl-7-(4-pyrrolidin-l-ylmethyl-phenoxymethyl)- octahydro-pyridol [ 1 ,2-a]pyrazine; (7i?,9a5,)-/ra«5-2-(7-fluoro-benzo[<i]isoxazol-3-yl)-7- (3-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-3]pyrazine; (7R,9aS)~ /ra«5-2-(6-fluoro-benzo[<i]isoxazol-3-yl)-7-(3-pynOlidin-l-ylmethyl-phenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9a5')-ira«5-2-(6,7-difluoro-benzo[<i]isoxazol-3- yl)-7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine;
(7i?,9aS)-ira«s-3-{3-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydiO-pyrido[l,2- a]pyrazin-7-ylmethoxy]-benzyl}-3-aza-bicyclo[3.2.2]nonane; (7R,9aS)-trans-2-(5- fluoro-benzo[<i]isoxazol-3-yl)-7-[3-c/5-octahydro-isoindol-2-ylmethyl)- phenoxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (75, 9aS)-trans-2-(5-fluoro- benzo[<i]isoxazol-3-yl)-7-(2-pyrrolidin-l-ylmethyl-phenoxymethlthyl)-octahydro- pyrido[l,2-a]pyrazine; (7 ,9u5)-/rans-2-(5-chloro-benzo[<i]isoxazol-3-yl)-7-(3- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (7S,9aS)~ /ra«5-2-(5-methyl-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (75,9«5)-/ra«5-2-benzo[<i]isoxazol-3-yl)-7-(2- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (7R,9aS)-c/5- 2-benzo[i ]isoxazol-3-yl)-7-(2-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (75,9a5)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(2- morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)~ irans-2-(5-fluoro-benzo[rf]isoxazol-3-yl)-7-(4-morpholin-4-ylmethyl-phenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9u5)-irans-2-(2-rnethoxy-benzo[<i]isoxazol-3-yl)- 7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)~ c/5-2-(5-methoxy-benzo[<i]isoxazol-3-yl)-7-(3-pyrrolidin-l-ylmethyl-phenoxymethyl)- octahydro-pyrido[l,2-a]pyrazine; (7i?,9a5)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7- (3 -(2-methoxymethyl-pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2- ajpyrazine; (7i?,9a5)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-[3-(2-methoxymethyl- pyrrolidin- 1 -ylmethyl-phenoxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7R,9aS)~
/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-[3-(2-methoxymethyl-piperidin-l-ylmethyl- phenoxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7R, 9aS)-trans-2-{5 -fluoro- benzo[i ]isoxazol-3-yl)-7-[3-(3-methoxymethyl-piperidin-l-ylmethyl)-phenoxymethyl]- octahydro-pyrido[ 1 ,2-a] ; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US6, 924,289, including, without limitation, 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 6-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 5-chloro-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 1 -methyl-3 -[2-(4- methylpiperazin-l-yl)-benzylidene]-l,3-dihydro-indol-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-benzylidene]- 1 -phenyl- 1 , 3 -dihy dro-indol-2-one; 1 -(3,4-dichlorophenyl)-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(3,4-dichlorobenzyl)-3-[2-(4- methylpiperazin- 1 -yl)-benzylidene]- 1 ,3 -dihydro-indol-2-one; 1 -(4-chlorobenzyl)-3-[2- (4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(4-chlorobenzyl)-3-[5- fluoro-2-(4-methylpiperazin- 1 -yl)-benzylidene] -pyrrolidin-2-one; l-(3,4- difluorophenyl)-3-[2-(4-methylpiperazin- 1 -yl)-benzylidene]-pyrrolidin-2-one; 1 -(2,4- dichlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(3,4- dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; l-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; 1 -(3,4- dichlorobenzyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; l-(4- chlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2-one; 1-
(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-piperidin-2- one; 3-[2-(4-methylpiperazin-l-yl)-benzylidene]-l-phenyl-pyrrolidin-2-one; 3-[2-(4- methylpiperazin- 1 -yl)-benzylidene]-l -(4-trifluoromethylphenyl)-pyrrolidin-2-one; 1 - (3,4-difluorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4- methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2-one; 3 - [5 -fluoro-2-(4-methylpiperazin- l-yl)-benzylidene]-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-benzylidene]- piperidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benzyl]- piperidin-2-one; l-(4-methoxyphenyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-3,4- dihydro-liif-quinolin -2-one; l-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin- 1 -yl)-benzyl)-piperidin-2-one; 3-[2-(4-methylpiperazin- 1 -yl)-benzyl]- 1 -phenyl- pyrrolidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-benzylidene]-l-(p-tolyl)-pyrrolidin-2- one; 3-[4-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-l-phenyl-pyrrolidin-2-one; 1- (3,4-dichlorophenyl)-3-[2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene]-pyrrolidin-2- one; l-(3,4-difluorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]- piperine-2-one; l-[2-(4-chlorophenyl)ethyl]-3-[5-fluoro-2-(4methylpiperazin-l-yl)- benzylidene]-piperidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethoxy)- benzylidene]-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-benzyl]-l-(4- trifluoromethylphenyl)-pyrrolidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-azetidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(4- methylpiperazin-l-yl)-benzylidene]-azepin-2-one; l-(3,4-dichlorophenyl)-3-{ l-[2-(4- methylpiperazin-l-yl)phenyl]ethyl}-pyrrolidin-2-one; l-(3,4-dichlorophenyl)-3-{ l-[2- (4-methylpiperazin-l-yl)phenyl]ethyl-piperidine-2-one; l-(3,4-dichlorophenyl)-3-{ l-[2-
(4-methylpiperazin-l-yl)phenyl]-ethylidene}-pyrrolidin-2-one; l-(3,4-dichlorophenyl)- 3-{ l-[2-(4-methylpiperazin-l-yl)phenyl]-ethylidene}-piperidin-2-one; l-(3,4- dichlorophenyl)-3-{[2-(4-methylpiperazin-l-yl)phenyl]-phenylmethylene}-pyrrolidin-2- one; l-(3,4-dichlorophenyl)-3-{2-[(2-dimethylaminoethyl)-methylamino]-benzylidene}- pyrrolidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-l-ylethoxy)-benzylidene]- pyrrolidin-2-one; l-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethylamino)- benzylidene]-pyrrolidin-2-one; 2-(3,4-dichlorophenyl)-3-[2-(2- dimethylaminoethylamino)-benzylidene]-pyrrolidin-2-one; 2-(3,4-dichlorophenyl)-4-[2- (4-methylpiperazin-l-yl)-benzylidene]-octahydro-isoquinolin-3-one; l-(3,4- dichlorophenyl)-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-octahydro-quinolin-2-one; l-(3,4-dichlorophenyl)-3-[2-(4methylpiperazin-l-yl))-benzylidene]-octahydro-indol-2- one; l-(3,4-dichlorophenyl)-5,5-dimethyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]- pyrrolidin-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,026,314, including, without limitation, 8-(4-methyl-l- piperazinyl)-A/-[4-(4-morpholinyl)phenyl]-4-oxo-4if-chromene-2-carboxamide; 2-{ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl } -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one, 2-{ l-[4-(l-acetyl-2,3-dihydro-lif-indol-6-yl)-piperazin-l-yl]- methanoyl }-8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chl oro-5-(4- { l-[8-(4- methyl-piperazin-l-yl)-4-oxo-4if-chromen-2-yl]-methanoyl}-piperazin-l-yl)- benzonitrile; 2- { 1 -[4-(4-methoxyphenyl)-piperazin- 1 -yl]-methanoyl }-8-(4-methyl- piperazin- 1 -yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2- carboxylic acid (5-furan-2-yl-lif-pyrazol-3-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4- oxo-4if-chromene-2-carboxylic acid (4-imidazol-l-yl-phenyl)-amide; 8-(4-methyl- piperazin-l-yl)-4-oxo-4if-chromene-2-carboxylic acid (4-[l,2,3]thiadiazol-5-yl-phenyl)- amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2-carboxylic acid 4- [ 1 ,2,3 ]thiadiazol-5-yl-benzylamide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 8-(4-methyl-piperazin-l-yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]- amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (2-methoxy- 4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)- 4-oxo-4 -chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-1 -yl)-4-oxo-4iif-chromene-2-carboxylic acid (2,5-diethoxy-4- morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-cyanomethyl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid(l -indol-5-yl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4if-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(2,6-dimethyl- morpholin-4-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide; 8-(4-methyl-piperazin-l-yl)-2-(6- morpholin-4-yl-benzooxazol-2-yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (2-hydroxy-4-morpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (5-ethoxy -benzothiazol- 2-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- bromo-phenyl)-amide; 8-(4-methylpiperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 8- (4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (3-fluoro-4- morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-piperazin- 1 -yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)- phenyl]-amide; 6-methoxy-8-(4-Methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(2,6-dimethyl-morpholin-4-yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2- hydroxy-ethyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- cyano-4-morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid tert-butyl ester; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 -yl)- phenyl]-amide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid dimethylamide; 4-[4-({ l- [6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)- phenylj-piperazine- 1 -carboxylic acid ethylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 -chromen-2-yl]-methanoyl } -amino)-phenyl]-piperazine- 1 - carboxylic acid cyclohexylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid cyclopentylamide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid {4-[4-(l-pyrrolidin-l-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4- (propane-2-sulfonyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazin-l- yl]-phenyl}-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid {4-[4-(l-morpholin-4-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-acetyl- piperazin- 1 -yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4- methyl-piperazin-1 -yl)-4-oxo-4iif-chromene-2-carboxylic acid (3 -fluoro-4-morpholin-4- yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4if-chromene-2-carboxylic acid [4-(l -morpholin-4-yl- methanoyl)-phenyl]-amide; 6-methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene- 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methyl-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]- amide; 6-methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- fluoro-4-morpholin-4-yl-phenyl)-amide; 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4if-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methyl-8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (4-morpholin-4-yl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]- phenyl } -amide; 4-[4-({ 1 -[6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 4-[4-({l- [6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- piperazin- 1 -yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}- amide; A/-[8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-4-morpholin-4-yl- benzamide; 8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid(4-morpholin-4-yl- phenyl)-amide; (+)-8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; (-)-8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; racemic-8-(4-methyl-piperazin-l-yl)-4-oxo- chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer); 8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide (slower running isomer); 4-[4-({ l-[6-fluoro-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid ethylamide; 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-
8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(4-propionyl- piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-4-oxo-8-piperazin- 1 -yl-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-hydroxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-[ 1 ,4]diazepan- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid(4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy- 8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-
(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 8-[(2-dimethylamino-ethyl)-methyl-amino]-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 8-[(3-dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-l, 4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((3i?)-(+)-3- dimethylamino-pyrrolidin-l-yl)-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((35)-(-)-3 -dimethylamino-pyrrolidin- 1 -yl)-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 6-methoxy-8-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-[ethyl-(l-ethyl- pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 4-dimethylamino-6-methoxy-8-(4-methyl-piperazin- 1 - yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-4- methylamino-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide; 6-fluoro-4-methoxy-8-(4-methyl-piperazin- 1 -yl)-quinoline-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-4-oxo-8-piperazin-l-yl-4 H- chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,425,574, including, without limitation, 4-{2-[4-(5-cyano- lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid methyl ester; 5-{2-[4- (5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid ethyl ester; 6- {2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid ethyl ester; 4-{2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid amide; 7-{2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid ethyl ester; 7-{2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2- carboxylic acid methyl ester; 7-{2-[4-(5-cyano-lif-indol-3- yl)butylamino]ethoxy}benzofuran-2-carboxylic acid amide; 7-{2-[4-(5-cyano-lif-indol- 3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid; 5-{2-[4-(5-cyano-lif-indol-3- yl)butylamino]ethoxy}benzofuran-2-carboxylic acid amide; 5 - { 2- [2-(5 -fluoro- 177-indol- 3-yl)ethylamino]ethoxy}benzofuran-2-carboxylic acid amide; 6-{2-[4-(5-cyano-177- indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid amide; 5-bromo-7-{2-[4- (5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid methyl ester; 5-bromo-7-{2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}benzofuran-2-carboxylic acid amide; 7 - { 2- [2-(5 -fluoro- 1 //-indol-3 -yl)ethylamino] ethoxy }benzofuran-2- carboxylic acid amide; 7-{2-[4-(5-cyano-lif-indol-3-yl)butylamino]ethoxy}-5- nitrobenzofuran-2-carboxylic acid amide; 7-{2-[2-(5-cyano-lif-indol-3- yl)ethylamino]ethoxy}benzofuran-2-carboxylic acid amide; 7- { 3 - [2-(5 -cyano- 177-indol- 3-yl)ethylamino]propoxy}benzofuran-2-carboxylic acid amide; 7- { 3 - [2-(5 -fluoro- 1 H- indol-3-yl)ethylamino]propoxy}benzofuran-2-carboxylic acid amide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,432,282, including, without limitation, 3-{4-[(5- bromopyridin-3 -ylmethyl)amino]butyl } -l//-indole-5-carbonitrile; 3 - {4-[(pyridin-3 - ylmethyl)amino]butyl}-lf7-indole-5-carbonitrile; 3-{4-[(pyridin-2- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(pyridin-4- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-(4-{ [5-(4-fluorophenyl)pyridin-3 - ylmethyl]amino}butyl)-lf7-indole-5-carbonitrile; 3-{4-[(quinolin-3- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 -[4-(2-pyridin-4- ylethylamino]butyl]-l//-indole-5-carbonitrile; 3-{4-[(2,6-dichloropyridin-4- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile, 3-{4-[(2-chloro-6-methylpyridin-4- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - {4-[(2-chloropyridin-4- ylmethyl)amino]butyl}-lf7-indole-5-carbonitrile; 3-{4-[(2-methylpyridin-3- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - {4-[(6-chloropyri din-3 - ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-(4-{[2-(4-chlorophenoxy)pyridin-3- ylmethyl]amino}butyl)-l//-indole-5-carbonitrile; 3-{4-[(2-methylsulfanylpyridin-3- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - { 4- [(2, 5 -dichloropyridin-3 - ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(2,6-dichloropyridin-3- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(5-methylpyridin-3- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - { 4-[(6-trifluoromethylpyri din-3 - ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(quinolin-2- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(4-phenylpyridin-2- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(quinolin-4- ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - {4-[(4-phenylpyri din-3 - ylmethyl)amino]butyl}-lf7-indole-5-carbonitrile; 3-{4-[(5-cyano-6- methylsulfanylpyridin-2-ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(5- phenylpyridin-3-ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3-{4-[(5- phenylpyridin-2-ylmethyl)amino]butyl}-l//-indole-5-carbonitrile; 3 - [4-(methylpyridin- 3-ylmethylamino)butyl]-lf7-indole-5-carbonitrile; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US7,776,860, including, without limitation, 3-amino-8-(l- piperazinyl)-2//-l-benzopyran-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US9,938,277, including, without limitation, 3-((6aR,9S,l0aR)-5- cyclopropyl-7-methyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinolin-9-yl)-l,l- diethylurea; (6ui?,9i?)-5-cyclopropyl-A/-((5')-l-hydroxybutan-2-yl)-4,7-dimethyl-
4,6,6u,7,8,9-hexahydroindolo[4,3-/g]quinoline-9-carboxamide; (6ui?,9i?)-5-cyclopropyl- /V-((S)-l-hydroxybutan-2-yl)-4,7-dimethyl-4,6,6u,7,8,9-hexahydroindolo[4,3- /g]quinoline-9-carboxamide; (6aR,9R, 10aS)-N-((S)~ 1 -hy droxybutan-2-yl)- 1 Ou-methoxy- 4,7-dimethyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinoline-9-carboxamide; (aR,9R, 10 aS)-N-((S)~ 1 -hydroxybutan-2-yl)- 10u-methoxy-4,7-dimethyl- 4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinoline-9-carboxamide; (6aR,9R,l0aS)~ N-((S)- 1 -hydroxybutan-2-yl)- 10u-methoxy-4,7-dimethyl-4,6,6u,7, 8,9, 10,10 a- octahydroindolo[4,3-/g]quinoline-9-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US20030064995, including, without limitation, A/-[2-(5-fluoro- 3-indolyl)ethyl]-A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4-(5-cyano-3- indolyl)-A/-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (6-fluoro-3-indolyl)-A/-[4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]piperidine-l- carboxamide; 3-{ l-[4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl]-4- piperidyl}indole-5-carboxamide; 4-(5 -fluoro-3 -indolyl)-A/- [4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4-[2-(3-indolyl)ethyl]-A/-[4- methoxy-3 -(4-methylpiperazin- l-yl)phenyl]piperidine-l -carboxamide; 4-(3-indolyl)-7V- [4-methoxy-3 -(4-methylpiperazin- l-yl)phenyl]piperidine-l -carboxamide; 4-(4-fluoro-3- indolyl)-A/-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (7-methoxyindol-3-yl)piperidine-l -carboxylic acid [4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl]amide; 4-[4-(5-fluoro-3-indolyl)butyl]piperazine-l-carboxylic acid [4- m ethoxy-3 -(4-methylpiperazin- l-yl)phenyl]amide; 4-(5-cyanoindol-3-yl)-3,6-dihydro- 2H-pyridme[lacuna] 1 -carboxylic acid [4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl]amide; 3 -(5-fluoroindol-3 -yl)pyrrolidine- 1 -carboxylic acid [4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl]amide; 4-(5-fluoroindol-3-yl)-cyclohexanecarboxylic acid [4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]amide; 7V-[2-(5-hydroxy-3-indolyl)ethyl]- A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; N- { 2- [4-(6-fluoro-3 - indolyl)piperidin- 1 -yl] ethyl } -TV’ -[4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]urea; N-
[4-(5-cyano-3-indolyl)butyl]- V,-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4- [4-(5-cyano-3 -indolyl)butyl]piperazine- 1 -carboxylic acid [4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl]amide; 4-(5-fluoroindol-3-yl)piperidine-l-carboxylic acid (2,3- dihydro- -methylspiro(benzofuran)-3,4-piperidin) amide; N- { 2-[4-(6-fluoro-3 - indolyl)piperidin- 1 -yl] ethyl }- [2, 3 -dihydro- 1 -methylspiro(benzofuran)-3 ,4- piperidinjurea; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US20030212109, including, without limitation, 3, 3 -dimethyl- 1- (2-[4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}- 1 ,3 -dihydro-2if-indol-2-one; 1 - (2-[4- (4-fluorobenzoyl)-l-piperidinyl]-l-ethylU-3-methyl-3-methylthio-l,3-dihydro-2if- indol-2-one; 1 - { 2- [4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}-3 -methyl- 1 ,3-dihydro-
2if-indol-2-one; 1 - (2-[4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}-3 -methylthio-3 - phenylmethyl- 1 ,3 -dihydro-2if-indol-2-one; 1 - { 2- [4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 - ethyl}-3-phenylmethyl-l,3-dihydro-2if-indol-2-one; l-{2-[4-(4-fluorobenzoyl)-l- piperidinyl]- 1 -ethyl}-3 -methyl-3 -phenylmethyl- 1 ,3 -dihydro-2if-indol-2-one; 3 -Ethyl- 1 -
{ 2- [4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}-3 -methyl- 1 ,3 -dihydro-2if-indol-2-one;
1-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]-l-ethyl}-3-(l-methylethyl)-3-methylthio-l,3- dihydro-2if-indol-2-one; 1 - (2-[4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}-3-( 1 - methylethyl)-l,3-dihydro-2if-indol-2-one; 5-bromo-3,3-dimethyl-l-{2-[4-(4- fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}- 1 ,3 -dihydro-2/ -indol-2-one; 3 ,3 -dimethyl- 1 - { 2-
[4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl } - 5 -methanesulfony 1 - 1 ,3 -dihydro-2if-indol-
2-one; 3, 3-dimethyl-5-fluoro-l-{2-[4-(4-fluorobenzoyl)-l -piperidinyl]- 1 -ethyl}- 1,3- dihydro-2if-indol-2-one; 5,6-difluro-3,3-dimethyl-l-{2-[4-(4-fluorobenzoyl)-l- piperidinyl]- 1 -ethyl}- 1 ,3 -dihydro-2/ -indol-2-one; 3,3-dimethyl-l-{2-[4-(4- fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}-4-methoxy- 1 ,3 -dihydro-2if-indol-2-one; 1 -{2-[4-
(4-fluorobenzoyl)-l -piperidinyl]-! -ethyl}-3, 3, 5-trimethyl-l,3-dihydro-2if-indol-2-one; 5-chloro-3, 3-dimethyl- l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]-l -ethyl}- 1,3-dihydro- 2 -indol-2-one; l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]-l-ethyl}-3, 3, 7-trimethyl- 1,3- dihydro-27f-indol-2-one; 3, 3 -dimethyl- 1 - { 2- [4-(4-fluorobenzoyl)- 1 -piperidinyl]- 1 - ethyl}-5-methoxy-l,3-dihydro-27f-indol-2-one; 1 - (2-[4-(4-fluorobenzoyl)- 1 - piperidinyl]- 1 -ethyl}-3 ,3 ,4-trimethyl-indol-2(3f7)-one; 1 -(2-[4-(4-fluorobenzoyl)- 1 - piperidinyl]- 1 -ethyl}-3, 3, 6-trimethyl- l,3-dihydro-2f7-indol-2-one; l-{2-[4-(4- fluorobenzoyl)- 1 -piperidinyl]- 1 -ethyl}- 1 ,3 -dihydro-2f7-indol-2-one; 1 -{2-[4-(4- fluorobenzoyl)-l-piperidinyl]-l-ethyl}-5-fluoro-l,3-dihydro-2//-indol-2-one; l-{2-[4- (4-fluorobenzoyl)-l-piperidinyl]-l-ethyl}-3,3-difluoro-l,3-dihydro-2//-indole-2-one; 1- {2-[4-(4-fluorobenzoyl)-l-piperidinyl]-l-ethyl}-3,3,5-trifluoro-l,3-dihydro-2//-indole- 2-one; 1 -(2-(4-(4-fluorobenzoyl)- 1 -piperidinyl)- 1 -ethyl)- 1 ,3 -dihydro-3 -spiro- 1 - cyclopropyl-2f7-indole-2-one; 1 -(2-(4-(4-fluorobenzoyl)- 1 -piperidinyl)- 1 -ethyl)-3 - methyl-3-phenyl-l,3-dihydro-2f7-indol-2-one; l-(2-(4-(4-fluorobenzoyl)-l-piperidinyl)- 1 -ethyl)- l//-indol-2,3 -dione monohydrochloride; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US20050085457, including, without limitation, 8-(4-methyl-l- piperazinyl)-7V-[4-(4- morpholinyl)phenyl]-4-oxo-47f-chromene-2-carboxamide; 2-{ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl } -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one; 2-{ l-[4-(l -acetyl-2,3 -dihydro- 17/-indol-6-yl)-piperazin-l-yl]- methanoyl }-8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chloro-5-(4- { l-[8-(4- methyl-piperazin-l-yl)-4-oxo-47f-chromen-2-yl]-methanoyl)-piperazin-l-yl)- benzonitrile; 2-{ l-[4-(4-methoxy-phenyl)-piperazin-l-yl]-methanoyl}-8-(4-methyl- piperazin- 1 -yl)-chromen-4-one; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-47/-chromene-2- carboxylic acid (5-furan-2-yl-li7-pyrazol-3-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4- oxo-4H-chromene-2-carboxylic acid (4-imidazol- 1 -yl-phenyl)-amide; 8-(4-methyl- piperazin- 1 -yl)-4-oxo-47/-chromene-2-carboxylic acid (4-[l,2,3]thiadiazol-5-yl-phenyl)- amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4i7-chromene-2-carboxylic acid 4- [ 1 ,2,3 ]thiadiazol-5-yl-benzylamide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-47f-chromene-2- carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-
4-oxo-47f-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]- amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (2-methoxy- 4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4 /-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid (2,5-diethoxy-4- morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-cyanomethyl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /- chromene-2-carboxylic acid (l /-indol-5-yl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 8-(4- methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(2,6-dimethyl- morpholin-4-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2- carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-2-(6- morpholin-4-yl-benzooxazol- 2-yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (2-hydroxy-4-morpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin- l-yl)-4-oxo-4 -chromene-2-carboxylic acid (5-ethoxy -benzothiazol- 2-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- bromo-phenyl)-amide; 8-(4-methylpiperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 8- (4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (3-fluoro-4- morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-piperazin- 1 -yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)- phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (3 -fluoro-4-morpholin-4-yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4if-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2-carboxylic acid [4-(2, 6-dimethyl- morpholin-4-yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2- hydroxy-ethyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- cyano-4-morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid tert-butyl ester; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin-
1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 -yl)- phenyl]-amide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid dimethylamide; 4-[4-({ l- [6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)- phenylj-piperazine- 1 -carboxylic acid ethylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 -chromen-2-yl]-methanoyl } -amino)-phenyl]-piperazine- 1 - carboxylic acid cyclohexylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-caxboxylic acid cyclopentylamide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid {4-[4-(l -pyrrolidin- 1 -yl- methanoyl)-piperazin- 1 -yl]- phenyl} -amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (4-(4- (propane-2-sulfonyl)-piperazin-l-yl]-phenyl} -amide; 6-methoxy-8-(4-methyl-piperazin- l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazin-l- yl]-phenyl}-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-(4-(l-morpholin-4-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 H- chromene-2-carboxylic acid [4-(4- methanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-acetyl- piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3 -fluoro-4-morpholin-4- yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4if-chromene-2-carboxylic acid [4-(l -morpholin-4-yl- methanoyl)-phenyl]-amide; 6-methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene- 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methyl-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4if-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]- amide; 6-methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- fluoro-4-morpholin-4-yl-phenyl)-amide; 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methyl-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-morpholin-4-yl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4if-chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]- phenyl } -amide; 4-[4-({ 1 -[6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 4-[4-({l-
[6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- piperazin- 1 -yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4-ethane sulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-
4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}- amide; A/-[8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-4-morpholin-4-yl- benzamide; 8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl - phenyl)-amide; (+)-8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; (-)-8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; racemic-8-(4-methyl-piperazin-l-yl)-4-oxo- chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer); 8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide (slower running isomer); 4-[4-({ l-[6-fluoro-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid ethylamide; 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy- 8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(4-propionyl- piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-4-oxo-8-piperazin- 1 -yl-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-hydroxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-[ 1 ,4]diazepan- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy- 8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8- (4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 8-[(2-dimethylamino-ethyl)-methyl-amino]-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 8-[(3-dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((3i?)-(+)-3- dimethylamino-pyrrolidin- 1 -yl)-6-methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((35)-(-)-3 -dimethylamino-pyrrolidin- 1 -yl)-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 6-methoxy-8-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-[ethyl-(l-ethyl- pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 4-dimethylamino-6-methoxy-8-(4-methyl-piperazin- 1 - yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-m ethoxy -4- methylamino-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide; 6-fluoro-4-methoxy-8-(4-methyl-piperazin- 1 -yl)-quinoline-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-4-oxo-8-piperazin-l-yl-4.fi- chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US20060009448, including, without limitation, 4-(3,4-dichloro- phenyl)-2-[2-(4-methyl-piperazin-l-yl)-benzylidene]-thiomorpholin-3-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in US20070010526, including, without limitation, l-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-(4-piperi din-l-ylmethyl- phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3,4-dihydro- 1 H-[ soquinolin-2-yl] -ethanone; 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methoxy-8-phenyl-
3.4-dihydro-lif-isoquinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; l-[5- benzyloxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-(4- isopropyl-phenyl)-ethanone; l-[5-hydroxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinolin-2-yl]-2-(4-isopropyl-phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-(5- methoxy-8-pyridin-4-yl-3,4-dihydro-lif-isoquinolin-2-yl)-ethanone; 2-(4-isopropyl- phenyl)-l-[5-methoxy-8-(l-methyl-l,2,3,6-tetrahydro-pyridinyl)-3,4-dihydro-lif- isoquinolin-2-yl]-ethanone; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-6-propyl-3,4- dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}-A/-propyl-benzenesulfonamide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo-ethyl}- /V-propyl-benzenesulfonamide; A/-isopropyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; A/-tert-butyl-4- {2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo- ethyl}-benzenesulfonamide; A/-benzyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; 7V-(2-methoxy- benzyl)-4-{2-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- lif-isoquinolin-2- yl]-2-oxo-ethyl}-benzenesulfonamide; A/-(3-methoxy-benzyl)4-{2-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo-ethyl}- benzenesulfonamide; 7V-(4-methoxy-benzyl)4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2 -yl]-2-oxo-ethyl }- //-(2-methoxy-phenyl)-benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-oxo-ethyl}-//-(3-methoxy-phenyl)- benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- IH- isoquinolin-2-yl]-2-oxo-ethyl}-//-(4-methoxy-phenyl)-benzenesulfonamide; N- cyclopropyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin- 2-yl]-2-oxo-ethyl}-benzenesulfonamide; 7V-cyclobutyl-4-{2-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; 4-
{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo- ethyl} -benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l//-isoquinolin-2-yl]-2-oxo-ethyl}-A/-methyl-benzenesulfonamide; 4-{2-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-oxo-ethyl}-A/-ethyl- benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- 1//- isoquinolin-2-yl]-2-oxo-ethyl}- V,/V-dimethyl-benzenesulfonamide; 7V-ethyl-4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}- A/-methyl-benzenesulfonamide; /V,/V-diethyl-4-{2-[S-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; /V,/V-dipropyl- 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-2-oxo- ethyl} -benzenesulfonamide; /V-benzyl-4-{2-[S-methoxy-8-(4-methyl-piperazin-l-yl)- 3,4-dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}- V-methyl-benzenesulfonamide; N- benzyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- lff-isoquinolin-2-yl]- 2-oxo-ethyl}-A/-ethyl-benzenesulfonamide; 7V-benzyl-4-{2-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinolin-2-yl] -2-oxo-ethyl } -N-i sopropyl- benzenesulfonamide; 2-[4-(azetidine-l-sulfonyl)-phenyl]-l-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinolin-2-yl] -2- [4-(pyrrolidine- 1 -sulfonyl)-phenyl] - ethanone; A/-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2- yl]-2-oxo-ethyl}-isonicotinamide; A/-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l//-isoquinolin-2-yl]-4-oxo-butyl}-isonicotinamide; 7V-{5-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-5-oxo-pentyl}- isonicotinamide; quinoline-5-carboxylic acid {2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-amide; quinoline-5-carboxylic acid {4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-4-oxo- butyl} -amide; quinoline-5-carboxylic acid (5-[5-methoxy-8-(4-methyl-piperazin-l-yl)- 3 ,4-dihydro- 1 -isoquinolin-2-yl]-5-oxo-pentyl } -amide; 7V-{2-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H- i soquinolin-2-yl] -2-oxo-ethyl } -benzamide; 7V-{3-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-3-oxo-propyl}- benzamide; A/-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin- 2-yl]-4-oxo-butyl} -benzamide; A/-{5-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro- l//-isoquinolin-2-yl]-5-oxo-pentyl}-benzamide; 4-methoxy-7V-{2-[5-methoxy- 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-benzamide; 4-methoxy-A/-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin- 2-yl]-4-oxo-butyl}-benzamide; 4-methoxy-A/-{5-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l//-isoquinolin-2-yl]-5-oxo-pentyl}-benzamide; (4-butylamino-phenyl)- [5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-methanone; (4-cy cl ohexyl-phenyl)-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- 1 - isoquinolin-2-yl]-methanone; (4-benzyl-phenyl)-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-methanone; (4’-ethyl-biphenyl-4-yl)-[5-methoxy- 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-methanone; (4’ -hydroxy - biphenyl-4-yl)-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2- yl]-methanone; [5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinolin-2- yl]-(4-phenoxy-phenyl)-methanone; (4-benzoyl-phenyl)-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-\ soquinolin-2-yl] -methanone; 5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid [4-(4-methoxy- phenylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid (4-phenylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(2-methoxy- phenylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid [4-(3-methoxy-phenylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4- benzylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid [4-(2-methoxy-benzylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinoline-2-carboxylic acid [4- (3-methoxy-benzylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro-l//-isoquinoline-2-carboxylic acid [4-(4-methoxy-benzylsulfamoyl)- phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-propylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-i sopropyl sulfamoyl-phenyl)- amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-cyclopropylsulfamoyl-phenyl)-amide; 5 -methoxy- 8 -(4-methy 1 - piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid (4-tert-butylsulfamoyl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-methylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-
1-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-ethylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-cyclobutylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro- lif-isoquinoline-2-carboxylic acid [4-(thiazol-2-ylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4- acetylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid (4-butyrylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(methyl- phenyl-sulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid [4-(acetyl-methyl-sulfamoyl)-phenyl]-amide; l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-(4- morpholin-4-yl-phenyl)-ethanone; 2-(4-bromo-phenyl)-l-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-(4-dimethylamino- phenyl)- l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-
2-(3-morpholin-4-yl-phenyl)-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-(4-piperidin-l-yl-phenyl)-ethanone; l-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-[4-(4-methyl-piperazin-l- yl)-phenyl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinolin-2-yl]-2-[4-(4-propyl-piperidin-l-yl)-phenyl]-ethanone; 2-{4-[4-(2-methoxy- ethyl)-piperidin- 1 -yl] -phenyl } - 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4-dihydro- lif-isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-[4-(4-methyl-piperidin-l-yl)-phenyl]-ethanone; 2-[4-(4- hydroxy-piperidin- 1 -yl)-phenyl]-l-[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3,4- dihydro-l//-isoquinolin-2-yl]-ethanone; 2-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]- phenyl }-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; 2-(4-amino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-ethanone; 2-(4-isopropyl-phenoxy)-l-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-[4-(4-benzyl-piperazin- 1 - yl)-phenyl]-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-li7-isoquinolin-2- yl]-ethanone; 2-(4-isopropyl-phenyl)-l-[S-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l//-isoquinolin-2-yl]-ethanone; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-liif-isoquinoline-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 4- amino-A/-(4-{2-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- l -isoquinolin-2- yl]-2-oxo-ethyl}-phenyl)-butyramide; 2-(4-dibutylamino-phenyl)-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-ethanone; 2-(4-butylamino- phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl)- ethanone; 2-(4-diphenethylamino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro-l -isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro- 17f-i soquinolin-2-yl] -2-(4-phenethylamino-phenyl)-ethanone; 2- { 4- [Bi s-(2- benzyloxy-ethyl)-amino]-phenyl } - 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4- dihydro-l//-isoquinolin-2-yl]-ethanone; 2-[4-(2-benzyloxy-ethylamino)-phenyl]-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone;
biphenyl-4-yl-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2- yl]-methanone; 2-biphenyl-4-yl-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-ethanone; l-(5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l//-isoquinolin-2-yl]-2-(4-methoxy-phenyl)-ethanone; 2-benzo[l,3]dioxol-5-yl-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2- (3, 4-dimethoxy -phenyl)- l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- 1/7- isoquinolin-2-yl]-ethanone; 2-(4-fluoro-phenyl)- 1 -[5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l//-isoquinolin-2-yl]-ethanone; 2-(4-chloro-phenyl)-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-(4-methyl- phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; 2-phenyl-l -[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif- isoquinolin-2-yl]-ethanone; 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4-dihydro- IH- isoquinolin-2-yl]-2-(4-methylsulfanyl-phenyl)-ethanone; 2-(4-methanesulfinyl-phenyl)- l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; A/-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2- oxo-ethyl}-phenyl)-methanesulfonamide; 2-[4-(2-methoxy-benzylamino)-phenyl]-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-(4- benzylamino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinolin-2-yl]-ethanone; 2-[4-(3-methoxy-benzylamino)-phenyl]-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-[4-(4-methoxy- benzylamino)-phenyl]-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- 1/7- isoquinolin-2-yl]-ethanone; 2-(4-isopropyl-phenyl)-l-[5-methoxy-8-(4-methyl- piperazine-l-carbonyl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3’,4-dihydro-l -isoquinoline-2-carboxylic acid (4-isopropyl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-cyclohexyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(5-methoxy-pyrimidin-2- ylsulfamoyl)-phenyl]-amide; (4-{[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinoline-2-carbonyl]-amino)-benzyl)-phosphonic acid diethyl ester; 5-methoxy- 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2-carboxylic acid [4-(3,4- dimethyl-isoxazol-5-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(6-methyl-benzothiazol-2-yl)- phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-tert-butyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-sulfamoyl-phenyl)-amide; 5-methoxy-
8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(2- phenyl-2 -pyrazol-3-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(pyrrolidine-l-sulfonyl)-phenyl]- amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid [4-(5-methyl-[l,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4- (4,5-dimethyl-oxazol-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- l-yl)-3,4-dihydro-lif-isoquinoline-2-carboxylic acid [4-(2-phenyl-2i7-pyrazol-3- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//- isoquinoline-2-carboxylic acid [4-(4-methyl-pyrimidin-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinoline-2-carboxylic acid [4-(2,6-dimethyl-pyrimidin-4-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid [4-(pyrimidin-2- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//- isoquinoline-2-carboxylic acid [4-(2,6-dimethoxy-pyrimidin-4-ylsulfamoyl)-phenyl]- amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- liif-isoquinoline-2- carboxylic acid [4-(6-methoxy-pyridazin-3-ylsulfamoyl)-phenyl)-amide; 5-methoxy-8-
(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(4,6- dimethyl-pyrimidin-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(6-methoxy-pyrimidin-4- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinoline-2-carboxylic acid [4-(pyridin-2-ylsulfamoyl)-phenyl]-amide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}- benzoic acid methyl ester; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-A/-methyl-benzamide; 8-(4-ethyl-piperazin- 1 -yl)-5- methoxy-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-propylsulfamoyl-phenyl)- amide; 8-(4-cyclohexyl-piperazin-l-yl)-5-methoxy-3,4-dihydro-l -isoquinoline-2- carboxylic acid (4-propylsulfamoyl-phenyl)-amide; 2-(4-isopropyl-phenyl)-l-(5- methoxy-8-piperazin-l-yl-3,4-dihydro-l -isoquinolin-2-yl)-ethanone; /V-(4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}- phenyl)-2-phenyl-acetamide; 7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-3-phenyl-propionamide; N-(4-{2-
[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo- ethyl}-phenyl)-benzamide; 7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-benzenesulfonamide; l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-(4- phenylmethanesulfonyl-methyl-phenyl)-ethanone; 4-chloro-/V-(4-{2-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)- benzenesulfonamide; 4-tert-butyl-7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-benzenesulfonamide; TV-benzyl-TV- (4-{2-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- liif-isoquinolin-2 -yl]-2-oxo- ethyl}-phenyl)-benzenesulfonamide; l-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro- 1 if-i soquinolin-2-yl] -2-oxo-ethyl } -phenyl)-3 -(4-methoxy-phenyl)-urea; 1 - (4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo- ethyl } -phenyl)-3 -(3 -methoxy-phenyl)-urea; [5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro-l//-isoquinolin-2-yl]-[2’-methyl-4’-(5-methyl-[l,2,4]oxadiazol-3-yl)- biphenyl-4-yl]-methanone; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- IH- isoquinoline-2-carboxylic acid (4-piperidin-l-yl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(4-methyl- piperazin- 1 -yl)-phenyl]-amide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in WO 1994015920, including, without limitation, TV- [4-m ethoxy-3 - (4-methyl- 1 -piperazinyl)phenyl] -2-m ethyl-4’ -( 1 -methyl- lif-pyrazol-3 -yl)[ 1 , G - biphenyl]-4-carboxamide; 7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’ -methyl-
4’-(2-methyl-4- thiazolyl)[ 1 , 1’ -biphenyl]-4-carboxamide; 7V-[4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl]-2’-methyl-4’-(2-oxazolyl)[l,r-biphenyl]-4-carboxamide; N-[4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]-2’ -methyl-4’ -(5-methyl-2-oxazolyl)[ 1 , G - biphenyl]-4-carboxamide; A/-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’ -methyl- 4’ -(1 ,3 -oxathiolan-2-yl)[ 1 , -biphenyl]-4-carboxamide; 4’-(4,5-dihydro-2-oxazolyl)-/V-
[4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl] -2’ -methyl [ 1 , G -biphenyl]-4- carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1995011243, including, without limitation, 4-bromo-3- methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide; 4- bromo-3-methyl-A/-[7-(piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide; 4- bromo-3-methyl-A/-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benzamide; 4-(4- pyridyl)-3-methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yljbenzamide; 4-(4-pyridyl)-3-methyl-A/-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan- 7-yl]benzamide; A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5-yl]- 2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-[7-(4- methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; /V-[7-(piperazin-l-yl)-2,3- dihy dro-2,2-dimethylbenzofuran-5-yl]-2’-methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; 4-bromo-3-methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3- dihydro-2,2-dimethylbenzofuran-5-yl]benzamide; N- [7-(piperazin- 1 -yl)-2,3-dihydro-2- methylbenzofuran-5-yl]-2’-methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; 4-bromo-3-methyl-A/-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2- methylbenzofuran-5-yl]benzamide; A/-[7-(4-methylpiperazin-l-yl)-2,3- dihy drobenzofuran-5-yl]-2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/- [7-(piperazin- 1 -yl)-2, 3 -dihy drobenzofuran-5 -yl] -2’ -methyl-4’ -(5 - methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1995030675, including, without limitation, /V-[3-((S)-l- methylpyrrolidin-2-ylmethoxy)-4-methoxyphenyl]-2’-methyl-4’-(5-methyl-r,4- oxadiazol-3-yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-((i?)-l-methylpyrrolidin-2- ylmethoxy)phenyl]-2’ -methyl-4, -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-[4-methoxy-3-((i?)-pyrrolidin-2-ylmethoxy)phenyl]-2’-methyl-4’-(5- methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; 7V-[4-methoxy-3-(l- methylazetidin-2-ylmethoxy)phenyl]-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-[3-(azeti din-2 -ylmethoxy)-4-methoxyphenyl]-2’-methyl- 4’ -(5-methyl- 1 ,2,4-oxadiazol- 3-yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-(l- methylpiperidin-2-ylmethoxy)phenyl]-2’ -methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-(l-methylazepin-3-yloxy)phenyl]-2’- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-(l- methylpiperidin-3-ylmethoxy)phenyl]-2’ -methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; N- [4-m ethoxy-3 -( 1 -methylpiperi din-3 -yloxy)phenyl] -2’ - methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carboxamide; N- [4-methoxy-3 -( 1 - methylpyrrolidin-3-yloxy)phenyl]-2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3- yl)biphenyl-4-carboxamide; A/-[4-methoxy-3-(3-quinuclidinyloxy)phenyl]-2’-methyl-4’- (5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide; 4-oxadiazol-3-yl)biphenyl-4- carboxamide; A/-[4-chloro-3-(l-methylpyrrolidin-2-ylmethoxy)phenyl]-2,-methyl-4’-(5- methyl- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-carboxamide; 7V-[4-(l -methylpiperi din-3 - ylmethoxy)phenyl]-2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4- carboxamide; 5-chloro-2,3-dihydro-l-[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-carbonyl]-6-(l-methylpyrrolidin-2-ylmethoxy)-l -indole; 2,3-dihydro-5- methoxy-1 -[2’ -methyl-4’ -(5-methyl- 1, 2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl]-6-[2-(l- methylpyrrolidin-2-yl)ethyl]-l -indole; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in WO1999029666, including, without limitation, 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-5-yl)aminocarbonyl]indoline; 5-chloro-6-(4- ethylpiperazin-l-yl)-l -[(5,6,7, 8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -[( 1 - oxoindan-5-yl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -
[(5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-6-yl)aminocarbonyl]indoline; 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(l-oxoindan-6-yl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin-l-yl)-l-[(5,6,7,8-tetrahydro-8-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-chloro-6-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-8-oxo-2-naphthalenyl)aminocarbonyl]indoline; 5-chloro- 1 -(9-oxo-9H- fluoren-2-ylaminocarbonyl)-6-(4-methylpiperazin- 1 -yl)indoline; 5-chloro- 1 -(9-oxo-9H- fluoren-3-ylaminocarbonyl)-6-(4-methylpiperazin-l-yl)indoline; 5-methoxy-6-(4- methylpiperazin-l-yl)-l-[(5,6,7,8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-chloro-6-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-5-oxo-l-naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin- 1 -yl)-l-[(5,6,7,8-tetrahydro-5-oxo- 1 - naphthalenyl)aminocarbonyl]indoline; 5-methoxy-6-(4-methylpiperazin- 1 -yl)- 1 -
[(5,6,7,8-tetrahydro-5-oxo-l-naphthalenyl)aminocarbonyl]indoline; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from those described in WO 1999031086, including, without limitation, 7V-[3-chloro-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)naphth-l-yl]-urea; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[5-(pyridin-4-yl)naphth-l-yl]-urea ; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-6-yl]-urea; 4-bromo-7V-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth- 1 -ylacetamide; 5-bromo-7V-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth- 1 -ylacetamide; 7V-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-4-(pyridin-4-yl)naphth-l -ylacetamide; 7V-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-5-(pyridin-4-yl)naphth-l -ylacetamide; 7V-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)-3-trifluoromethylphenyl]-urea; 7V-[3-cyano-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-5-yl]-urea; 7V-[4-(4-methylpiperazin- l-yl)quinolin-6-yl]-A/’-[quinolin-8-yl]-urea; A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yl]-A/’-[quinolin-3-yl]-urea; 2/-dichloro-A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yljphenylacetamide; 5-(4-acetylphenyl)-A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yljnaphth- 1 -ylacetamide; 7V-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]- V,-[quinolin-4- yl]-urea; A/-[3-chloro-4-(pyridin-4-yl)phenyl]-A/’-[4-(l-methylpiperidin-4-yl)quinolin-6- yl]-urea; A/-[3-methyl-4-(6-methylpyridin-2-yl)phenyl]-A/’-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-urea; A/-[4-(2,6-dimethylpyridin-4-yl)-3-methylphenyl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[5-cyanonaphth-l-yl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; 7V-[5-(5-methyl-l,2,4-oxadiazol-3-yl)naphth- l-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-A/’-[5-(pyrimidin-2-yloxy)naphth-l-yl]-urea; A/-[5-acetylnaphth-l-yl]- A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[5-bromonaphth-l-yl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[5-(6-methylpyridin-2-yl)naphth- 1 -yl]-7V’ - [4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[5-(2-methylpyridin-5-yl)naphth-l- yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[5-(2-methylpyridin-3- yl)naphth- 1 -ylJ-NP -[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-urea; N-\4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-A/’ -[5-(pyrimidin-2-yl)naphth- 1 -yl]-urea; N-[5- bromonaphth-l-yl]-/V’-[4-(piperazin-l-yl)quinolin-6-yl]-urea; 2,3-dihydro-8-(4- methylpiperazin- 1 -yl)- 1 -[4-(pyridin-4-yl)naphth- 1 -y 1 aminocarb ony 1 ]py rrol o \2J- gjquinoline; 2/-dihydro-8-(4-methylpiperazin- 1 -yl)- 1 -[5-(5-methyl- 1 ,2,4-oxadiazol-3 - yl)naphth-l-ylaminocarbonyl]pyrrolo[2/-g]quinoline; 2/-dihydro-8-(4-methylpiperazin-
1-yl)-l-[5-(pyrimidin-2-yloxy)naphth-l-ylaminocarbonyl]pyrrolo[2/-g]quinoline; 9-(4- methylpiperazin- 1 -yl)- 1 -[4-(pyridin-4-yl)naphth- 1 -y 1 aminocarb ony 1 ] - 1 ,2,3,4- tetrahydropyrido[2,3 -g] quinoline; 9-(4-methylpiperazin- 1 -yl)- 1 -[5-(pyrimidin-2- yloxy)naphth-l-ylaminocarbonyl]-l,2,3,4-tetrahydropyrido[2.3-g]quinoline; N-[ 8- bromoquinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; 7V-[8-(2- fluorophenyl)quinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; 7V-[8-(2- methoxyphenyl)quinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[2- biphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N- [2 -di chi oropheny 1 ] -A/’ - [4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/’-[4-biphenyl]-A/-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[3,4-dichlorophenyl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-chlorophenyl]-A/’-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[3-cyanophenyl]-7V,-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-N’ -[4- phenoxy phenyl ] -urea; A/-[4-bromophenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6- yl]-urea; A/-[4-acetylphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 2- bromophenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[3,5- bis(trifluoromethyl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 3- acetylphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 2,6- difluorophenyI]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[3-bromophenyl]- A/’-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-urea; 7V-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-A/’ -[naphth- 1 -yl]-urea; A/-[2,6-dichlorophenyl]-A/’-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-chloro-2-methylphenyl]-A/’-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-bromo-3-methylphenyl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-
2-nitrophenylacetamide; 4-bromo-A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yljphenylacetamide; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-4-biphenylacetamide; 3,4-dichloro-A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]benzamide; N-\4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth-2-ylacetamide; 4-dimethylamino-A/-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]phenylacetamide; 3,4-difluoro-A/-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]phenylacetamide; A/-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-3-phenoxyphenylacetamide; 7V-[4-(4-methylpiperazin-l-yl)quinolin-6- yljnaphth- 1 -ylcarboxamide; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-4- phenoxyb enzami de; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-A/’-[5,6,7,8- tetrahy dro- 5 -oxo-2-naphthal eny 1 ] - urea; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]- TV’ - [5 -oxoindan-2-yl] -urea; 2,3-dihydro-8-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-5-oxo-2-naphthalenyl)aminocarbonyl]pyrrolo[2/-g]quinoline; 9-(4- methylpiperazin-l-yl)-l-[(5-oxo-5,6,7,8-tetrahydronaphth-6-yl)aminocarbonyl]-l,2,3,4- tetrahydropyrido[2,3-g]quinoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
BRL-15,572 (3-[4-(3-chlorophenyl)-l-piperazinyl]-l,l-diphenyl-2-propanol); LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-27f-indol-2-one);
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2,-methyl-4,-(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-lfJ-indol-3-yl)-3,6-dihydro-l(2fl)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-17/-2,l,3- benzothiadiazine-2, 2-dioxide);
methiothepin (l-methyl-4-[8-(methylsulfanyl)-10, 1 l-dihydrodibenzo[A |thiepin- 10-yl]piperazine);
metergoline (benzyl {[(8P)-l,6-dimethylergolin-8-yl]methyl} carbamate);
methysergide ((8b)-A/-[(25)- 1 -hydroxy-2-butanyl]- 1 ,6-dimethyl-9, 10- di dehydroergoline- 8 -carboxamide);
- yohimbine (methyl(16a, 17a)- 17-hydroxyyohimban- 16-carboxylate);
- ritanserin (6-(2-{4-[bis(4-fluorophenyl)methylene]-l-piperidinyl}ethyl)-7- methyl-57/-[l,3]thiazolo[3,2-u]pyrimidin-5-one);
risperidone (3-{2-[4-(6-fluoro-l,2-benzoxazol-3-yl)-l-piperidinyl]ethyl}-2- methyl-6,7,8,9-tetrahydro-47/-pyrido[l,2-u]pyrimidin-4-one);
ziprasidone (5-{2-[4-(l,2-benzothiazol-3-yl)-l-piperazinyl]ethyl}-6-chloro-l,3- dihydro-27f-indol-2-one); and
pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-2i7-indol-2-one);
- GR- 127935 (A/-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-lfJ-indol-3-yl)-3,6-dihydro-l(2fl)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-17/-2,l,3- benzothiadiazine-2, 2-dioxide);
- methiothepin (l-methyl-4-[8-(methylsulfanyl)-10,l l-dihydrodibenzo[Z? ]thiepin-
10-yl]piperazine);
metergoline (benzyl {[(8P)-l,6-dimethylergolin-8-yl]methyl} carbamate);
methysergide ((8b)-A/-[(25)- 1 -hydroxy-2-butanyl]- 1 ,6-dimethyl-9, 10- di dehydroergoline- 8 -carboxamide);
- yohimbine (methyl(l 6a, 17a)- 17-hydroxyyohimban-l 6-carboxylate);
ritanserin (6-(2-{4-[bis(4-fluorophenyl)methylene]-l-piperidinyl}ethyl)-7- methyl-5i7-[l,3]thiazolo[3,2-a]pyrimidin-5-one);
risperidone (3-{2-[4-(6-fluoro-l,2-benzoxazol-3-yl)-l-piperidinyl]ethyl}-2- methyl-6,7,8,9-tetrahydro-4i7-pyrido[l,2-a]pyrimidin-4-one);
- ziprasidone (5-{2-[4-(l,2-benzothiazol-3-yl)-l-piperazinyl]ethyl}-6-chloro-l,3- dihydro-27f-indol-2-one); and
pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
- BRL-15,572 (3-[4-(3-chlorophenyl)-l-piperazinyl]-l,l-diphenyl-2-propanol);
LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-27f-indol-2-one);
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2,-methyl-4,-(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide); - LY-393558 (1 -{2-[4-(6-fluoro- lH-indol-3-yl)-3, 6-dihydro- 1 (2/7)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-l//-2,l,3- benzothiadiazine-2, 2-dioxide); and
pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-2//-indol-2-one);
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2,-methyl-4,-(5- methyl- 1 ,2,4-oxadiazol-3 -yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-l//-indol-3-yl)-3,6-dihydro-l(2//)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-l//-2,l,3- benzothiadiazine-2, 2-dioxide); and
pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
BRL-15,572 (3-[4-(3-chlorophenyl)-l-piperazinyl]-l,l-diphenyl-2-propanol); LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-2//-indol-2-one); and
- pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
LY-310762 (l-{2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl}-3,3-dimethyl-l,3- dihydro-2//-indol-2-one); and
- pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2,-methyl-4,-(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide); and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is selected from the group comprising or consisting of:
BRL- 15,572 (3-[4-(3 -chlorophenyl)- 1 -piperazinyl]- 1 , 1 -diphenyl-2-propanol); and
pharmaceutically acceptable salts or esters thereof.
In a second embodiment, the 5-HTR1D inhibitor according to the present invention is an antibody that blocks 5-HTR1D activation ( i.e ., a 5-HTR1D blocking antibody). The 5-HTR1D blocking antibodies contemplated in the present invention may, for instance, impair the binding of 5-HT to the receptor by binding to said receptor.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is a polyclonal antibody, preferably a 5-HTR1D polyclonal blocking antibody.
Polyclonal antibodies can be produced by various procedures well-known in the art. For example, a host animal such as a rabbit, mouse, rat, etc., can be immunized by injection with an antigen to induce the production of sera containing polyclonal antibodies specific for the antigen. The antigen can include a natural, synthesized, or expressed protein, or a derivative (e.g., fragment) thereof. Various adjuvants may be used to increase the immunological response, depending on the host species, and include, but are not limited to, Freund’s (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacillus Calmette-Guerin) and Corynebacterium parvum. Such adjuvants are also well-known in the art. Antibodies can be purified from the host’s serum. In a preferred embodiment, the 5-HTR1D inhibitor according to the present invention is a monoclonal antibody, preferably a 5-HTR1D monoclonal blocking antibody.
In particular, monoclonal antibodies can be prepared using hybridoma methods, including, but not limited to, the hybridoma technique originally described by Kohler and Mil stein (1975. Nature. 256(5517):495-7); the human B-cell hybridoma technique (Cote et al., 1983. Proc Natl Acad Sci U S A. 80(7):2026-30); and the EBV-hybridoma technique (Cole et al., 1985. J Immunol Methods. 78(2):271-8). Using the hybridoma method, a mouse, hamster, or any other appropriate host animal is immunized as described above to elicit the production by lymphocytes of antibodies that will specifically bind to an immunizing antigen. Lymphocytes can also be immunized in vitro. Following immunization, the lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol, to form hybridoma cells that can then be selected away from unfused lymphocytes and myeloma cells. Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen as determined by immunoprecipitation, immunoblotting, or by an in vitro binding assay (e.g., radi oimmunoas say (RIA) or enzyme-linked immunosorbent assay (ELISA)) can then be propagated either in in vitro culture using standard methods (Goding J. W. (1986). Monoclonal antibodies: Principles and practice (2nd ed.). London: Academic Press) or in vivo as ascites tumors in an animal. The monoclonal antibodies can then be purified from the culture medium or ascites fluid.
Alternatively, monoclonal antibodies can be made using recombinant DNA methods, as described in US patents US4, 816,567 and US4,946,778. The polynucleotides encoding a monoclonal antibody are isolated from mature B-cells or hybridoma cells, such as by RT- PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using conventional procedures. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors, which when transfected into host cells such as Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells or myeloma cells that do not otherwise produce immunoglobulin protein, monoclonal antibodies are generated by the host cells. Also, recombinant monoclonal antibodies or antigen-binding fragments thereof of the desired species can be isolated from phage display libraries expressing CDRs of the desired species as described (McCafferty et al, 1990. Nature. 348(6301) 552-4; Clackson et al. , 1991 Nature. 352(6336) 624-8; Marks et al. , 1991 J Mol Biol. 222(3):581-597). In one embodiment, the 5-HTR1D inhibitor according to the present invention is a humanized antibody, preferably a 5-HTR1D humanized blocking antibody.
In a third embodiment, the 5-HTR1D inhibitor according to the present invention is an aptamer that can block 5-HTR1D activation. Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk et al. (1990. Science. 249(4968): 505- 10). The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena (1999. Clin Chem. 45(9): 1628-50). Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as Escherichia coifs thioredoxin A, that are selected from combinatorial libraries by two hybrid methods (Colas etal. , 1996. Nature. 380(6574): 548-50). Then, after raising aptamers directed against 5-HTR1D as described above, the skilled man in the art can easily select those blocking 5-HTR1D activation. In a fourth embodiment, the 5-HTR1D inhibitor according to the present invention is a polynucleotide.
The terms“polynucleotide”,“nucleotide sequence”,“nucleic acid”,“nucleic acid molecule”,“nucleic acid sequence” and“oligonucleotide” refer to a series of nucleotide bases (also called“nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded.
The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, e.g., to improve stability of the molecule, its hybridization parameters, etc. The antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, b-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine,
2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, b-D-mannosylqueosine, 5’ -methoxycarboxymethyluracil, 5-methoxyuracil,
2-methylthio-N6-isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5 -methyl -2-thi ouracil , 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxy acetic acid, 5-methyl-2-thiouracil,
3 -(3 -amino-3 - V-2-carboxypropyl) uracil, a thio-guanine and 2, 6-diaminopurine .
A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and complementary DNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as“protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids.
Exemplary DNAs include, but are not limited to, single-stranded DNA (ssDNA), double- stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.
Exemplary RNAs include, but are not limited to, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA.
Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.). A number of methods have been developed for delivering antisense DNA or RNA to cells, e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines. However, it is often difficult to achieve intracellular concentrations of the antisense sufficient to suppress translation of endogenous mRNAs. Therefore, a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter. The use of such a construct to transfect target cells in the patient will result in the transcription of sufficient amounts of single stranded RNAs that will form complementary base pairs with the endogenous target gene transcripts and thereby prevent translation of the target gene mRNA. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site. The polynucleotides may be flanked by natural regulatory (expression control) sequences or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5'- and 3’ -non-coding regions and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation,“caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and internucleotide modifications, such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.). Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly- 1 -lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. The polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, isotopes (e.g., radioactive isotopes), biotin and the like.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is a polynucleotide which interferes with 5-HTR1D synthesis. In one embodiment, the synthesis of 5-HTR1D may be blocked at the transcriptional level. In one embodiment, the synthesis of 5-HTR1D may be blocked at the translational level.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is an antisense oligonucleotide. Antisense oligonucleotides, including antisense RNA molecules and antisense DNA molecules, would act to directly block the translation of 5-HTR1D mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of 5-HTR1D, and subsequently, 5-HTR1D activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding 5-HTR1D can be synthesized, e.g., by conventional phosphodiester techniques and administered by, e.g., intravenous injection or infusion.
Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well-known in the art (see, e.g., see US patents US5,981,732, US6,046,321, US6, 107,091, US6,365,354, US6,410,323, US6,566,131 and US6,566,135).
In one embodiment, the 5-HTR1D inhibitor according to the present invention is a ribozyme.
Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Engineered hairpin- or hammerhead-motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of 5-HTR1D mRNA sequences are thereby useful within the scope of the present invention. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
Both antisense oligonucleotides and ribozymes useful as inhibitors of 5-HTR1D gene expression can be prepared by known methods. These include, without limitation, techniques for chemical synthesis such as, e.g., solid phase phosphoramadite chemical synthesis. Alternatively, asRNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides according to the present invention can be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxy rib onucl eoti des to the 5’ and/or 3’ ends of the molecule, or the use of phosphorothioate or 2’ -O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is an interference RNA (RNAi). The term RNAi, as used herein, include, without limitation, small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs) and microRNAs (miRNAs), targeted to a 5-HTR1D transcript; as well as RNAi vectors whose presence within a cell results in the production of an siRNA, shRNA or miRNA targeted to the target 5-HTR1D transcript. Such siRNA, shRNA or miRNA comprises a portion of RNA that is complementary to a region of the target 5-HTR1D transcript. Essentially, the RNAi contemplated in the present invention downregulates expression of 5-HTR1D via RNA interference. RNA interference is a multi step process and is generally activated by double-stranded RNA (dsRNA) that is homologous in sequence to the targeted 5-HTR1D gene. Introduction of long dsRNA into the cells of organisms leads to the sequence-specific degradation of homologous gene transcripts. The long dsRNA molecules are metabolized to small (e.g., 21-23 nucleotide) interfering RNAs (siRNAs, shRNAs or miRNAs) by the action of an endogenous ribonuclease known as Dicer. The interfering RNAs bind to a protein complex, termed RNA-induced silencing complex (RISC), which contains a helicase activity and an endonuclease activity. The helicase activity unwinds the two strands of RNA molecules, allowing the antisense strand to bind to the targeted 5-HTR1D RNA molecule. The endonuclease activity hydrolyzes the 5-HTR1D RNA at the site where the antisense strand is bound. Therefore, RNAi is an antisense mechanism of action, as a single stranded (ssRNA) RNA molecule binds to the target 5-HTR1D RNA molecule and recruits a ribonuclease that degrades the 5-HTR1D RNA.
Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well-known in the art for genes whose sequence is known (see, e.g., Tuschl et al, 1999. Genes Dev. 13(24):3191-7; Elbashir et al, 2001 Nature. 411(6836) 494-8; Hannon, 2002.
Nature. 418(6894):244-51; McManus & Sharp, 2002. Nat Rev Genet. 3(10):737-47; McManus et al, 2002. RNA. 8(6):842-50; Brummelkamp et al, 2002. Science. 296(5567):550-3; US patents US6,573,099 and US6,506,559; and International patent applications WO1999032619, W02001036646 and W02001068836). In one embodiment, the 5-HTR1D inhibitor according to the present invention is an siRNA.
Exemplary siRNAs inhibiting 5-HTR1D include, but are not limited to, the siRNA purchased from Dharmacon used in the example section.
The term“identity”, when used in a relationship between the sequences of two or more polypeptides or of two or more polynucleotides, refers to the degree of sequence relatedness between polypeptides or polynucleotides, as determined by the number of matches between strings of two or more amino acid or nucleotide residues.“Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e.,“algorithms”). Identity of related polypeptides or polynucleotides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Lesk A. M. (1988). Computational molecular biology: Sources and methods for sequence analysis. New York, NY: Oxford University Press; Smith D. W. (1993). Biocomputing: Informatics and genome projects. San Diego, CA: Academic Press; Griffin A. M. & Griffin H. G. (1994). Computer analysis of sequence data, Part 1. Totowa, NJ: Humana Press; von Heijne G. (1987). Sequence analysis in molecular biology: treasure trove or trivial pursuit. San Diego, CA: Academic press; Gribskov M. R. & Devereux J. (1991). Sequence analysis primer. New York, NY: Stockton Press; Carillo etal, 1988. SIAM J Appl Math. 48(5): 1073-82. Preferred methods for determining identity are designed to give the largest match between the sequences tested. Methods of determining identity are described in publicly available computer programs. Preferred computer program methods for determining identity between two sequences include the GCG program package, including GAP (Genetics Computer Group, University of Wisconsin, Madison, WI; Devereux et al, 1984 Nucleic Acids Res. 12(1 Pt l):387-95), BLASTP, BLASTN, and FASTA (Altschul et al, 1990 J Mol Biol. 215(3):403-10). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al. N CB/NLM/NIH Bethesda, Md. 20894). The well-known Smith Waterman algorithm may also be used to determine identity.
In one embodiment, the 5-HTR1D inhibitor according to the present invention is polynucleotide for targeted gene editing.
Examples of gene editing methods contemplated in the present invention include, but are not limited to, transcription activator-like effector nucleases (TALEN)-based editing system, clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9), meganucleases, zinc-finger nucleases (ZFNs) and the like.
In one embodiment, any of the polynucleotide according to the present invention may be delivered in vivo alone or in association with a vector.
In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the polynucleotides according to the present invention to the cells, and preferably to cells expressing 5-HTR1D and in a cell-specific manner. Preferably, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the polynucleotide according to the present invention.
Viral vectors are a preferred type of vector and include, but are not limited to, nucleic acid sequences from the following viruses: retrovirus, such as Moloney murine leukemia virus (MMLV), Harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus (AAV); SV40-type viruses; Polyoma viruses; Epstein-Barr viruses; papilloma viruses; Herpes virus; Vaccinia virus; Polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known in the art. Preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the gene of interest. Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are repli cati on-defi ci ent ( i.e ., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided by Kriegler (1990. Methods Enzymol. 185:512-27). Preferred viruses for certain applications are the adeno-viruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in gene therapy. The adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion. Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See, e.g., Sambrook I, Fritsch E. F. & Maniatis T. (1989). Molecular cloning: A laboratory manual. New York, NY: Cold Spring Harbor Laboratory Press. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid. Some commonly used plasmids include pBR322, pUC18, pUC19, pRC/CMV, SV40 and pBlueScript. Other plasmids are well-known to those of ordinary skill in the art. Additionally, plasmids may be custom-designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes. For example, the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun. The plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and mi croencap sul ati on .
In a fifth embodiment, the 5-HTR1D inhibitor according to the present invention can be further identified by screening methods described in the state of the art. The screening methods according to the present invention can be carried out according to known methods. The screening method may measure the binding of a candidate compound to 5-HTR1D, or to cells or membranes bearing 5-HTR1D, or a fusion protein thereof by means of a label directly or indirectly associated with the candidate compound. Alternatively, a screening method may involve measuring or, qualitatively or quantitatively, detecting the competition of binding of a candidate compound to 5-HTR1D with a labelled competitor (e.g., antagonist or agonist). Further, screening methods may test whether the candidate compound results in a signal generated by an antagonist of the receptor, using detection systems appropriate to cells bearing the receptor. Antagonists can be assayed in the presence of a known agonist (e.g., 5-HT) and an effect on activation by the agonist by the presence of the candidate compound is observed. Competitive binding using known agonist such as 5-HT is also suitable. The antagonistic activity of compounds towards 5-HTR1D may be determined by using various methods well-known in the art. For example, 5-HTR1D antagonistic activity may be evaluated in a radioligand binding assay and in the 5-HT -induced von Bezold-Jarisch reflex (BJR) in rats, such as described by Turconi et al. (1990. J Med Chem. 33(8):2101-8).
In one embodiment, the composition, pharmaceutical composition or medicament according to the present invention further comprises 5 -hy droxytryptamine receptor IB (5-HTR1B) inhibitor.
In one embodiment, 5-HTR1B inhibitors according to the present invention include, but are not limited to, small organic molecules, antibodies, aptamers and polynucleotides.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is a selective 5-HTR1B inhibitor. By“selective”, it is meant that the affinity of the inhibitor for 5-HTR1B is at least 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more higher than the affinity for the other human 5-HT receptor (5-HTR1A, 5-HTR1 C, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6, 5-HTR7).
The affinity of a 5 -HTR 1B inhibitor may be quantified by measuring the activity of 5-HTR1B in the presence of a range of concentrations of said inhibitor in order to establish a dose-response curve. From that dose response curve, an ICso value may be deduced which represents the concentration of inhibitor necessary to inhibit 50% of the response to an agonist (e.g., 5-HT) in defined concentration. The ICso value may be readily determined by the one skilled in the art by fitting the dose-response plots with a dose- response equation as described in De Lean A. & Rodbard D. (1979) Kinetics of cooperative binding. In: O’Brien R.D. (eds) General Principles and Procedures. The Receptors (A Comprehensive Treatise), Vol. 1. Springer, Boston, MA. ICso values can be converted into affinity constant (Ks) using the assumptions of Cheng & Prusoff (1973. Biochem Pharmacol. 22(23):3099-108).
Accordingly, a selective 5-HTR1B inhibitor is a compound for which at least one of the ratios:
(i) Ki(5 -HTR 1 -7\5 -HTR 1B): Ki(5 -HTR 1B), and/or (ii) IC5O(5 -HTRl -7\5 -HTR 1 B) : ICso(5 -HTR1 B),
is above 2: 1, 5: 1, 10: 1, 15: 1, 20:1, 25: 1, 50: 1, 100: 1 or above,
wherein “5 -HTR 1 -7\5 -HTR 1 B” means all 5-HT receptors except 5-HTR1B, i.e., 5 -HTR 1A, 5-HTR1 C, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2, 5-HTR3, 5-HTR4, 5-HTR5, 5-HTR6 and 5-HTR7.
Accordingly, a selective 5-HTR1B inhibitor is a compound for which at least one of the ratios:
(i) Ki(5 -HTR ID): Ki(5 -HTR 1B), and/or
(ii) IC5O(5-HTR1D):IC5O(5-HTR1B),
is above 2: 1, 5: 1, 10: 1, 15: 1, 20:1, 25: 1, 50: 1, 100: 1 or above.
In a first embodiment, the 5 -HTR 1B inhibitor is a small organic molecule.
Exemplary 5-HTR1B inhibitors that are contemplated by the present invention include, but are not limited to, those described in US patents US6, 197,773, US9,938,277, US6, 509,340, US6, 107,328, US6,346,622, US6,291,458, US7, 101,881, US7,026,314, US6,747,030; US patent applications US20070010526, US20050085457,
US20050171095, US20060025421, US20080318926; International patent applications WO1999029666 and WO1999031086; the content of all of which is hereby incorporated by reference.
Typically, 5-HTR1B inhibitors which may be contemplated by the present invention include, but are not limited to:
N-acyl and N-aroyl aralkyl amides derivatives such as the ones described in US patent 6,197,773; isoquinoline derivatives such as the ones described in US patent application 2007010526; ergoline compounds, such as the ones described in US patent 9,938,277; amide and urea derivatives, such as the ones described US patent 6,509,340; benzanilide derivatives, such as the ones described in US patent 6,107,328;
2-substituted 1,2-benzisothi azole derivatives, such as the ones described in US patent 6,346,622; arylpiperazine and arylpiperidine derivatives such as the one described in international patent application W09929666; quinolinepiperazine and quinolinepiperidine derivatives, such as the ones described in international patent application WO9931086; 8-amino derivatives, such as the ones described in US patent application 2005085457 and US patent 7,026,314; morpholinobenzamide salts, such as the ones described in US Patent 6,291,458; tetrahydroquinoline derivatives, such as the ones described in US patent 7, 101,881; piperazine derivatives, such as the ones described in US patent 6,747,030; pyridyl piperazine derivatives such as the ones described in US patent application 2006025421; aminomethy lpy ri dy 1 oxy methy 1/b enzi soxazol e substituted azabicyclic compounds, such as the ones described in US patent application 20083118926; which are incorporated by reference.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US5,965,575, including, without limitation, TV- 1 -(2,3- dihydro[ 1 ,4]benzodioxin-5-yl)piperid-4-yl- V-2-(indan- 1 -yl)ethylamine; N- 1 -(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-yl- V-(indan-l-yl-methyl)amine; N- 1-(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-yl- V-3-(indan-l-yl)-propylamine; N-
(benzocyclobuten- 1 -ylmethyl)- V- 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5-yl)piperid-4- ylamine; N- 3 -(benzocyclobuten- 1 -yl)propyl- V- 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5- yl)piperid-4-ylamine; /V-2-(benzocyclobuten- 1 -yl)ethyl- V- 1 -(2,3 - dihydro[ 1 ,4]benzodioxin-5-yl)piperid-4-ylamine; 7V-4-(benzocyclobuten- 1 -yl)butyl- V- 1 - (2,3-dihydro[l,4]benzodioxin-5-yl)piperid-4-ylamine; N- 1-(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-yl- V-(4,5-dimethoxybenzocyclobuten-l- ylmethyl)amine; 7V-2-(adamant- 1 -yl)ethyl- V- 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5-yl)- piperid-4-ylamine; N- adamant- 1 -ylmethyl)- V- 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5-yl)- piperid-4-ylamine; 5,6-dihydro-8,9-dimethoxy-2-{2-{ l-(2,3-dihydro[l,4]benzodioxin-5- yl)-piperid-4-ylaminoethyl} }pyrrolo[2,l-u]isoquinoline; 5 , 6-dihy dro-2- { 2- { l-(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-ylaminoethyl} }pyrrolo[2,l-u]isoquinoline; 5,6- dihydro-9-methoxy-2-{2-{ l-(2,3-dihydro[l,4]benzodioxin-5-yl)piperid-4- ylaminoethyl} }pyrrolo[2, l-u]isoquinoline; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4-{A/- benzyl-2-(indan-l-yl)ethylamino}piperidine; 5,6-dihydro-8,9-dimethoxy-2-{ l-(2,3- dihydro[l,4]benzodioxin-5-yl)piperid-4-ylaminomethyl}pyrrolo[2,l-u]isoquinoline; N- 2-(adamant-2-yl)ethyl-A/-l-(2,3-dihydro[l,4]benzodioxin-5-yl)piperid-4-ylamine; 77-2- (adamant-2-yl)ethyl- V- 1 -(chroman-8-yl)piperid-4-ylamine; 5,6-dihydro-8,9-dimethoxy- 2-+2- 1 -(chroman-8-yl)piperid-4-ylamino-ethyl }pyrrolo[2, 1 -ujisoquinoline; 5, 6-dihy dro- 8,9-dimethoxy-2-{2-l-(6-fluorochroman-8-yl)piperid-4-ylaminoethyl}pyrrolo[2,l- ajisoquinoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US5,968,954, including, without limitation, l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4- V-(indan-2-yl)aminopiperidine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4-A/-(indan-2-yl)-A/-methylaminopieridine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)-4-A/-(5,6-methylenedioxyindan-2-yl)amino-piperidine;
4-A/-(indan-2-yl)aminol-(thiochroman-8-yl)piperidine; l-(2,3-dihydro[l,4]benzodioxin-
5-yl)-4-A/-(5,6-dimethoxyindan-2yl)aminopiperidine; 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5- yl)-4-A/-(5-methylindan-2-yl)aminopiperidine; 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5-yl)-4- A/-(chloroindan-2-yl)aminopiperidine; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4- V-(5- methoxyindan-2-yl)aminopiperidine; 1 -(2,3 -dihydro[ 1 ,4]benzodioxin-5-yl)-4-A/-(5,6- dimethylindan-2-yl)aminopiperidine; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4- V-(5- trifluoromethylindan-2-yl)-aminopiperidine; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4-A/- (4,7-dimethoxyindan-2-yl)aminopiperidine; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4- V- (5-fluoroindan-2-yl)aminopiperidine; 4-IV-(indan-2-yl)-IV-methylamino-l-(2,3-dihydro- l,4-dioxino[2,3-/?]pyridin-8-yl)-piperidine; 1 -(2,3 -dihydro[ 1 ,4]benzoxathiin-5-yl)-4- (indan-2-ylamino)piperidine; l-(chroman-8-yl)-4-(indan-2-ylamino)piperidine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)-3-(indan-2-ylamino)pyrrolidine; l-(6-fluorochroman-8- yl)-4-(indan-2-ylamino)piperidine; l-(2,3-dihydro[l,4]benzodioxin-5-yl)-4-(5- nitroindan-2-ylamino)piperidine; l-(chroman-8-yl)-4-5-(l,2,4-triazol-4-yl)indan-2- ylaminopiperidine; l-(chroman-8-yl)-4-(cyclopenta[/-2,l,3]benzoxadiazol-6- yl)aminopiperidine; l-(chroman-8-yl)-4-(5-fluoroindan-2-yl)aminopiperidine; l-(2,3- dihydrobenzofuran-7-yl)4-(5-fluoroindan-2-yl)aminopiperidine; l-(chroman-8-yl)-4- (5,6-methylenedioxyindan-2-yl)aminopiperidine; 1 -(benzofuran-7 -yl)-4-(5 -fluoroindan- 2-yl)aminopiperidine; l-(chroman-8-yl)-4-(5-methoxyindan-2-yl)aminopiperidine; l-(4- hydroxychroman-8-yl)-4-(5,6-methylenedioxyindan-2-yl)aminopiperidine; l-(2,3- dihydro[l,4]benzodioxin-5-yl)4-(indan-2-ylamino)-4-methylpiperidine; 1 -(2,3- dihydro(l,4-benzodioxin-5-yl)-4-A/-(5-hydroxyindan-2-yl)aminopiperidine; l-(chroman- 8-yl)-4-A/-(5-hydroxyindan-2-yl)aminopiperidine; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,066,644, including, without limitation, 1’ -(2-hydroxyethyl)- 5-(2’-methyl-4’ -(5-methyl- 1,2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; G -(2-hydroxy ethyl)-5-(2’ -methyl-4’ - (5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3 ,4’ -piperidine; -(2-dimethylaminoethyl)-5-(2’ -methyl-4’ -(5-methyl-l, 3, 4- oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospirofiiro[2,3- ]indole-3,4’- piperidine; l’-(2-methoxyethyl)-5-(2’ -methyl-4’ -(5-methyl-l, 3, 4-oxadiazol-2- yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospirofiiro[2,3- ]indole-3,4’-piperidine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 100,272, including, without limitation, 5-2’-methyl-4’-(2- oxo-l-pyrrolidinyl)biphenyl-4-carbonyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3, 4’ -piperidine; 1’-methyl-5-2’ -methyl-4’-(2-oxo-l-piperidinyl)biphenyl-4- carbonyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; 5-4’-(4,5-dihydro-2- oxooxazol-3-yl)-2’ -methylbiphenyl-4-carbonyl- -methyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-(4’-acetamido-2’-methylbiphenyl-4- carbonyl)-l’-methyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; -methyl- 5-2’ -methyl-4’-(2-thi oxo-1 -pyrrolidinyl)biphenyl-4-carbonyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-4’-(l, l-dioxo-2,3,4,5- tetrahydroisothiazol-2-yl)-2’-methylbiphenyl-4-carbonyl- -methyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-4’-(4,5-dihydro-2-oxoimidazol-l-yl)- 2,-methylbiphenyl-4-carbonyl- -methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4,- piperidine; 5 -4’ -(4, 5 -dihydro-3 -methyl-2-oxoimidazol- 1 -yl)-2’ -methylbiphenyl-4- carbonyl- -methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; G-methyl-
5-2’ -methyl-4’ -(3-methyl-2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 5-4’-(3,3-dimethyl-2-oxopyrrolidin-l- yl)-2’-methylbiphenyl-4-carbonyl- -methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole- 3,4’-piperidine; 5 -4’ -(2, 3 -dihydro- 1 -oxoi soindol-2-yl)-2’ -methylbiphenyl-4-carbonyl- l’-methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 5-2,3’-dimethyl-4’-
(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3, 4’ -piperidine; 1’ -methyl-5-4’ -(2-oxo- 1 -pyrrolidinyl)-2’- trifluoromethylbiphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3,4’- piperidine; 5-2’ -chi oro-4’ -(2-oxo- 1 -pyrrolidinyl)biphenyl-4-carbonyl-r -methyl-2, 3,6,7- tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; 5-4-(l-acetyl-l,2,3,4- tetrahydroquinolin-6-yl)-3-methylbenzoyl-r-methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; 5-4-(l-acetyl-2,3-dihydroindol-5-yl)-3-methylbenzoyl- - methyl-2,3,6,7-tetrahydrospirofuro[2,3- ]indole-3,4’-piperidine; l’-methyl-5-(2’- methyl-4’-(2-oxo-li7-pyrazin-l-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4, -piperidine; 5-2’ -methyl-4’ -(2-oxopyrrolidin- 1 - yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; - ethyl-5-2’-methyl-4’ -(2-oxopyrrolidin- l-yl)biphenyl-4-carbonyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 5-2’ -methyl-4’ -(2-oxopyrrolidin- 1 - yl)biphenyl-4-carbonyl-l’-/V-propyl-2,3,6,7-tetrahydrospirofuro[2,3-/]indole-3,4’- piperidine; l’-isopropyl-5-2’-methyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl- 2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 1’ -A/-buty 1 - 5 -2’ -methyl -4’-(2- oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’- piperidine; -cyclopropylmethyl-5-2’-methyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-l’- cy cl opropylmethyl-5-2’ -methyl-4’ -(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; l’-allyl-5-2’-methyl-4’-(2- oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’- piperidine; l’-cyclopentyl-5-2’-methyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl- 2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 2,3,5,6,7,8-hexahydro-l’- methyl-5-2’-methyl-4’ -(2-oxopyrrolidin- l-yl)biphenyl-4-carbonylspirofiiro[2, 3- ,g]quinoline-3,4’-piperidine; 2,3,5,6,7,8-hexahydro-5-2’-methyl-4’-(2-oxopyrrolidin-l- yl)biphenyl-4-carbonylspirofuro[2,3-g]quinoline-3,4’-piperidine; c/5-2’,6’-dimethyl isomer of 5-2’-methyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydro- l’,2’,6’-trimethylspirofuro[2,3- |indole-3,4’-piperidine; 5 -2’ -methoxy carb ony 1 -4’-(2- oxopyrrolidin-l-yl)biphenyl-4-carbonyl-l’-methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3, 4’ -piperidine; 5-2’-hydroxymethyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-4- carbonyl-l’-methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 5-2’- methoxymethyl-4’-(2-oxopyrrolidin- l-yl)biphenyl-4-carbonyl-l’-methyl-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; 1’ -tert-buty 1 - 5 -2’ -methyl -4’ -(2- oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’- piperidine; 2,3 -dihydro- 1’ -methyl-5-2’ -methyl-4’ -(2-ox opyrrolidin- 1 -yl)biphenyl-4- carbonylspirofuro[3,2- ]indole-3,4’-piperidine; 5-2’ -methyl -4’ -(2-oxo- 1 - pyrrolidinyl)biphenyl-4-carbonyl-l’-methyl-2, 3, 6, 7-tetrahydrospirofiiro[2,3- ]indole- 3 ,4’ -piperidine; 1’ -methyl-5-2’ -methyl -4’-(3 -methyl-2-oxopyrrolidin- 1 -yl)biphenyl-4- carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; l’-isopropyl-5-2’- methyl-4’-(2-oxopyrrolidin-l-yl)biphenyl-4-carbonyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3 ,4’ -piperidine; 2,3 -dihydro- 1’ -methyl-5-2’ -methyl-4’ -(2-oxopyrrolidin- 1 - yl)biphenyl-4-carbonylspirofuro[3,2- |indole-3,4’-piperidine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 107,328, including, without limitation, 4-(hydroxymethyl)- 1 -methyl-1, 2, 3, 6-tetrahydropyri dine; 4-(2-iodophenoxymethyl)- 1 -methyl- 1 ,2,3 ,6- tetrahydropyridine; 2,3-dihydro-l’-methylspirobenzofuran-3,4’-piperidine; 2, 3 -dihydro- l’-methyl-5-nitrospirobenzofuran-3, 4’ -piperidine; 5 -amino-2, 3 -dihydro- - methylspirobenzofuran-3, 4’ -piperidine; 6-(cyanomethyl)-2,3-dihydro-l’-methyl-5- nitrospirobenzofuran-3,4’-piperidine; 2,3-dihydro-l’-methylspirofuro[2,3- |indole-3,4’- piperidine; 1’-methyl-2, 3, 6, 7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; - methyl-2,3,6,7-tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; l’-methyl-5-(2’- methyl-4’ -(5-methyl- 1,3, 4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2, 3,6,7- tetrahydrospirofuro[2,3- |indole-3,4’-piperidine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 159,962, including, without limitation, 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-phenyl)-l-piperazinyl)ethylthieno[2,3-
<i]pyrimidin-4-one; 3, 4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(l -naphthyl)- 1- piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-methyl-l-napththyl)-l-piperazinyl)ethylthieno-[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxy-l- naphthyl)- l-piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-methylphenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(3-tri- fluoromethylphenyl)-l-piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-chloro-phenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-pyrimidin-2- ylpiperazin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-pyridin-2-ylpiperazin-l-yl)ethylthieno[2,3-<i]pyrimi din-4- one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-quinolin-2-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-(3,5-dichlorophenyl)-l-piperazinyl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-
5-methyl-6-dimethylcarbamoyl-3-2-(4-tetralin-5-ylpiperazin-l-yl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-indan-4- ylpiperazin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2-cyanophenyl)-l-piperazinyl)ethylthieno[2,3-i ]pyrimidin- 4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-isoquinolin-4-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-3- (4-pyrimidin-2-ylpiperazin-l-yl)propylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2-methoxyphenyl)-l-piperidinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-(2- methoxyphenyl)-3,4-dihydro-l-piperidinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4- dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-naphth-l-ylpiperidin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-(2-methoxy-l-naphthyl)-3, 4-dehydro- l-piperidinyl)ethylthieno[2, 3 -<i]pyrimidin-4- one; 3 ,4-dihydro-5-methyl-6-dimethylcarbamoyl-3 -2-(4-naphth- 1-yl-l ,4-hexahydro- 1 ,4- diazepin-l-yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-carbamoyl-3-
2-(4-(l -naphthyl)- l-piperazinyl)ethylthieno[2, 3 -<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-carbamoyl-3-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethylthieno[2,3-<i]pyrimidin- 4-one; 3,4-dihydro-5-methyl-6-diethylcarbamoyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-Dihydro-5-methyl-6- diethylcarbamoyl-3-2-(4-(l-naphthyl)-l-piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one;
3,4-dihydro-5-methyl-6-diethylcarbamoyl-3-2-(4-pyrimidin-2-ylpiperazin-l- yl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2- (4-quinazolin-4-ylpiperazin-l-yl)ethylthieno[2,3-<i]pyrimidin-4-one; 3,4-dihydro-5- methyl-6-dimethylcarbamoyl-3-2-(4-(2,4-dimethoxyphenyl)-l- piperazinyl)ethylthieno[2,3-i ]pyrimidin-4-one; 3,4-dihydro-5-methyl-6- dimethylcarbamoyl-3-2-(4-(2,5-dimethylphenyl)-l-piperazinyl)ethylthieno[2,3- <i]pyrimidin-4-one; 3,4-dihydro-5-methyl-6-dimethylcarbamoyl-3-2-(4-naphth-l-yl-3,4- dehydro-l-piperidinyl)ethylthieno[2,3-i ]pyrimidin-4-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 159,970, including, without limitation, (/?)- V-8-(piperazin- l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (/?)-7V-8-(4-ethylpiperazin-
1-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (R)-N-S-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (R)-N-5- methoxy-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide; (/?)-7V-5-ethyl-8-(4-methylpiperazin-l-yl)- 1 ,2,3, 4-tetrahydro-2- naphthyl-4-morpholinobenzamide; (i?)-A/-5-ethyl-8-(4-methylpiperazin-l -yl)-l, 2,3,4- tetrahydro-2-naphthyl-(4-morpholinocarbonyl)benzamide; (i?)-A/-5-methoxy-8-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinocarbonylbenzamide; (i?)-A/-5-bromo-8-(piperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide; 7V-5-bromo-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2- naphthyl-4-morpholinobenzamide; (i?)-A/-5-bromo-8-(4-methylpiperazin- 1 -yl)- 1, 2,3,4- tetrahydro-2-naphthyl-4-trifluoromethylbenzamide; (i?)-A/-5-methyl-8-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; N-(4- morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy- 1,2,3, 4-tetrahydronaphthalene-
2-carboxamide; (i?)-A/-(4-morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy- l,2,3,4-tetrahydronaphthalene-2-carboxamide; (5)-A/-(4-morpholinophenyl)-8-(4- methylpiperazinyl)-5-methoxy-l,2,3,4-tetrahydronaphthalene-2-carboxamide; (R)-N- (morpholinocarbonylphenyl)-8-(4-methylpiperazin- 1 -yl)-5-m ethoxy- 1 ,2,3,4- tetrahydronaphthalene-2-carboxamide; (S)- V-5-(4-methylpiperazin-l-yl)-3,4-dihydro- 2if-l-benzopyran-3-yl-4-morpholinobenzamide; (5)-A/-5-(4-methylpiperazin-l-yl)-3,4- dihydro-2//- l-benzopyran-3-yl-4-(4-piperidon-l-yl)benzamide; (5)-A/-8-methyl-5-(4- methyl-piperazin-l-yl)-3,4-dihydro-2//-l-benzopyran-3-yl-4- (dimethylaminocarbonyl)benzamide; 7V-4-(4-morpholinyl)phenyl-8-methoxy-5-(4- methyl-piperazin-l-yl)-3,4-dihydro-2 -l-benzopyran-3 -carboxamide; (R)-N-S-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide; (R)-N-5- methoxy-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide; (i?)-7V-5-methyl-8-(4-methylpiperazin-l -yl)- 1 ,2,3, 4-tetrahydro-
2-naphthyl-4-morpholinobenzamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 197,773, including, without limitation, 3,4-dichloro- V-(2-2- (4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 4-fluoro-7V-(2-2-(4-methylpiperazin-
1 -yl)-phenyl-ethyl)-benzamide; 7V-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3,4-dichloro-/V-(l-methyl-2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 3 ,4-dichloro-/V-(l -methyl-2-2-(4-methylpiperazin- 1 -yl)-phenyl-propyl)- benzamide; 3,4-dichloro-7V-methyl-.V-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)- benzamide; 7V-benzyl-7V-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; N-(4- chlorobenzyl)-A/-(2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl)-benzamide; 3,4-dichloro- 7V-(2-{2-methyl-(l-methylpyrolidin-2-ylmethyl)-amino-phenyl}-ethyl)-benzamide; 3,4- dichloro-A/-{2-2-(l-methyl-octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl-ethyl}- benzamide; 3,4-dichloro-A/-{2-2-(hexahydro-pyrrolo[l,2-u]pyrazin-2-yl)-phenyl-ethyl}- benzamide; 3,4-dichloro-7V-{2-2-(l-methylpiperidin-4-yl)-phenyl-ethyl)-benzamide;
3,4-dichloro-A/-{2-2-(2-dimethylaminoethoxy)-phenyl-ethyl}-benzamide; 3,4-dichloro- 7V-{2-2-(2-dimethylamino-ethylsulfanyl)-phenyl-ethyl}-benzamide; 3,4-dichloro-A/-{2- 2-(2-pyrrolidin- 1 -yiethoxy)-phenyl-ethyl } -benzamide; 4-chloro-A/- (2-2-(3- dimethylamino-pyrrolidin-l-yl)-phenyl-ethyl} -benzamide; 4-chloro-7V-(2-{2-methyl-(2- morpholin-4-yl-ethyl)-amino-phenyl}-ethyl)-benzamide; 2-(4-chlorophenyl)-A/-{2-2-(4- methylpiperazin-l-yl)-phenyl-ethyl} -acetamide; 7V-{2-2-(4-methylpiperazin-l-yl)- phenyl-ethyl } -A/-pheny 1 acetami de; A/-{2-2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl } - isonicotinamide; 7V-{2-2-(l-azabicyclo[2.2.2]oct-4-yl)-phenyl-ethyl}- V- methylbenzamide; N-{2-2-( 1 ,4-dimethylpiperidin-4-yl)-phenyl-ethyl } -4- fluorobenzamide; 4-fluoro-A/-{2-2-(9-methyl-3,9-diazabicyclo[3.3. l]non-3-yl)-phenyl- ethy 1 } -b enzami de ; 7V-(2-2-(l,4-diazabicyclo[3.3.1]non-4-yl)-phenyl-ethyl}- V- methylbenzamide; N-{ l-methyl-2-2-(5-methyl-2,5-diazabicyclo[2.2. l]hept-2-yl)- pheny 1 -ethyl } -b enzami de; 2,4-dichloro-A/-methyl-7V-{ l-methyl-2-2-(3-methyl-3,8- di azabi cy cl o [3.2.1 ] oct- 8 -y l)-pheny 1 ethyl } -b enzami de; 7V-{2-2-(4-methyl- octahydroquinoxalin- 1 -yl)-phenyl-ethyl } -benzamide; 7V-{2-2-(l-ethylpyrrolidin-2- ylmethoxy)-phenyl-ethyl} -benzamide; 5-phenyloxazole-2-carboxylic acid{2-2-(4- methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 5-phenylthiophene-2-carboxylic acid{2-2- (4-methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 5-methylthiophene-2-carboxylic acid{2- 2-(4-methylpiperazin- 1 -yl)-phenyl-ethyl } -amide; 4-fluoronaphthalene- 1 -carboxylic acid{2-2-(4-methylpiperazin-l-yl)-phenyl-ethyl}-amide; 5 -fluoro- 1 -indole-2- carboxylic acid{2-2-(4-methyl-piperazin-l-yl)-phenyl-ethyl}-amide; 4-chloro-/V-{2-2-
(3,4,5-trimethylpiperazin-l-yl)-phenyl-ethyl}-benzamide; 3 ,4-dichloro-/V- { 2-2-(2,4, 5 - trimethylpiperazin-l-yl)-phenyl-ethyl} -benzamide; 3,4-dichloro-/V-{2-2-(2,4,6- trimethylpiperazin-l-yl)-phenyl-ethyl} -benzamide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,291,458, including, without limitation, (i?)- V-5-methyl-8- (4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide hydrogen (2S,3S)-tartrate; (/?)-lV-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydro-2-naphthyl-4-morpholinobenzamide hydrogen (2i?,3i?)-tartrate; (R)-N- 5- methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide benzenesulfonate; (i?)-7V-5-methyl-8-(4-methylpiperazin-l-yl)- l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzarnide hydrogen 1,2-ethanedi sulfonate; (i?)-A/-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide hydrogen maleate; (i?)-A/-5-methyl-8-(4-methylpiperazin-l-yl)- l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzarnide hydrogen sulfate; (R)-N- 5- methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydro-2-naphthyl-4- morpholinobenzamide Z -gluconate; (i?)-A/-5-methyl-8-(4-methylpiperazin-l -yl)-l, 2,3,4- tetrahydro-2-naphthyl-4-morpholinobenzamide hydrogen succinate; (i?)- V-5-methyl-8- (4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide methanesulfonate; (i?)- V-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl-4-morpholinobenzamide hydrogen (5)-maleate; (i?)-A/-5-methyl-8-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide dihydrogen citrate; (i?)- V-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl-4-morpholinobenzamide hydrochloride; (i?)-7V-5-methyl-8-(4-methylpiperazin- l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide L-lactate, (i?)- V- 5 -methyl - 8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2-naphthyl-4-morpholinobenzamide dihydrobromide; (/?)-IV-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2- naphthyl-4-morpholinobenzamide monohydrobromide; (i?)-7V-5-methyl-8-(4- methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydro-2-naphthyl-4-morpholinobenzamide dihydrochloride; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,346,622, including, without limitation, 3 , 3 -dimethyl-2-3 -(4- (5-tetralinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
3 , 3 -dimethyl-2-3 -(4-(2-phenyl-4-quinazolinyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3, 3 -dimethyl-2-3 -(4-(2-quinolinyl)- 1 -piperazinyl)-prop- 1 - yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 - diazepanyl)-prop- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-3 - (4-(4-chloro- 1 -phthalazinyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1, 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-2-methyleneprop- 1 -yl-2, 3 - dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-2-(4-(4-quinazolinyl)- 1 - piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3-dimethyl-2-2-
(4-(l -naphthyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
3 , 3 -dimethyl-2-2-(4-i soquinolin-4-yl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -dihydro- 1,2- benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-prop- 1 - yl-6-(l-pyrrolyl)-2,3-dihydro-l,2-benzoisothiazole-l, l-dioxide; 3 , 3 -dimethyl-2-3 -(4-( 1 - naphthyl)- 1 -piperazinyl)-prop- 1 -yl-6-benzoylamido-2, 3 -dihydro- 1 ,2-benzoisothiazole-
1 , 1 -dioxide; 3, 3 -dimethyl-2-3 -(4-( 1 -naphthyl)- 1 -piperazinyl)-prop- 1 -yl-6-nitro-2, 3 - dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-2-(4-(2,3 -dimethylphenyl)- 1 - piperazinyl)eth- 1 -yl-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-2-(4- (4-indanyl)- 1 -piperazinyl)-eth- 1 -yl-2, 3 -di-hydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3- dimethyl-2-3 -(4-(4-chloro- 1 -naphthyl)- 1 -piperazinyl)prop- 1 -yl-2, 3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -dimethyl-2-3 -(4-(2-pyrimidinyl)- 1 -piperazinyl)-prop- 1 -yl-2,3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3-dimethyl-2-2-(4-(4- methoxyphenyl)- 1 -piperazinyl)eth- 1 -yl-2,3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide;
3 , 3 -dimethyl-2-3 -(4-(2-methoxyphenyl)- 1 -piperazinyl)-2-hy droxy-prop- 1 -yl-2,3 - dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3 , 3 -diethyl-2-3 -(4-( 1 -naphthyl)- 1 - piperazinyl)-prop- 1 -yl-2,3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; 3,3-dimethyl-2-3-
(4-(2,5-dimethylphenyl)-l-piperazinyl)prop-l-yl-2, 3-dihydro-l,2-benzoisothi azole-1, 1- dioxide; 3 ,3 -dimethyl-2-2-(4-(2-cyanophenyl)- 1 -piperazinyl)eth- 1 -yl-2,3 -dihydro- 1 ,2- benzoisothi azole- 1 , 1 -dioxide; 3 ,3 -dimethyl -2-2-(4-( 1 -naphthyl)- 1 -piperazinyl)-eth- 1 -yl- 4-chloro-2, 3 -dihydro- 1 ,2-benzoisothi azole- 1 , 1 -dioxide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,355,647, including, without limitation, 3,4, 5,7-tetrahydro- 6-carbethoxy-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-
<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-(l-naphthyl)-l-piperazinyl)ethyl- pyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(l- naphthyl)-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3, 4,5,7- tetrahydro-6-acetyl-3-2-(4-(l-naphthyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-6-benzyl-3 -2-(4-( 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- (4-chlorophenyl-2-ethyl)-3-2-(4-(l-naphthyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(l -naphthyl)- l-piperazinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-methyl-l-naphthyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3 -2-(4-(2-methoxy- 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-S^^-pyrimidin^-yl-l-piperaziny^ethylpyrrolo ’^’^^JthienoP^- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-6-carbethoxy-3 -2-(4-(2-methoxyphenyl)- 1 - piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2- (4-(2-methoxyphenyl)-l-piperazinyl)ethylpyrrolo[3,,4, :4,5]thieno[2,3-<i]pyriinidin-4- one; 3,4,5,7-tetrahydro-3-2-(4-naphth- 1 -ylhexahydro- 1 ,4-diazepin- 1 - yl)ethylpyirolo[3’,4’:4,5]thieno[2,3-<i]pyriinidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2-(4-(2- methylphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-tetralin-5-yl-l-piperazinyl)ethylpynOlo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2-(4-indan- 1-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4, 5 ,7-tetrahy dro-3 -2- (4-(2-methoxyphenyl)-3,4-dehydro-l-piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-naphth- 1 -yl- 1 -piperidinyl)- ethylpyrrolo[3’,4’ :4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-3-2-(4-(2- methoxy-1 -naphthyl-3, 4-dehydro-l-piperidinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-(2,3-dimethylphenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-chlorophenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-pyrimidin-2-yl-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-pyridin-2-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-2-(4-quinolin-2-yl-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-
4-one; 3,4,5,7-tetrahydro-6-ethyl-3-2-(4-(2-methoxyphenyl)-l- piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- ethyl-3-3-(4-pyrimidin-2-yl-l-piperazinyl)propylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-methyl-3-2-(4-(3-trifluoromethyl-phenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- methyl-3-2-(4-(2-cyano-phenyl)-l-piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-methyl-3-2-(4-isoquinolin-4-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- methyl-3-2-(4-naphth-l-yl-3,4-dehydro-l-piperidinyl)ethylpyrrolo[3,,4’:4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-acetyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- acetyl-3-2-(4-(2 -methyl- 1 -naphthyl)-! -piperazinyl)ethylpyrrolo[3’, 4’ :4,5]thieno[2, 3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-benzyl-3-2-(4-(2-methoxyphenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- (4-nitrophenyl-2-ethyl)-3 -2-(4-( 1 -naphthyl)- 1 - piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- (4-aminobenzyl)-3-2-(4-(2-methyl-l-naphthyl)-l- iperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-methylphenyl)-l-piperazinyl)ethylpyrrolo[3,,4, :4,5]thieno[2,3- <i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-chlorophenyl)-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-phenyl-l-piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-
<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-(2-naphth- 1 -yl- 1 - piperidinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6- carbethoxy-3-2-(4-(2-naphth-l-yl-3,4-dehydro-l-piperidinyl)ethyl- pyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; 3,4,5,7-tetrahydro-6-carbethoxy-3-3-(4- (2-cyanophenyl)-l-piperazinyl)propylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one;
3,4,5,7-tetrahydro-6-carbethoxy-3-2-(4-indan-4-yl-l- piperazinyl)ethylpyrrolo[3’,4’:4,5]thieno[2,3-<i]pyrimidin-4-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6, 509,340, including, without limitation, 7V-2-(5-fluoro-3- indolyl)ethyl-A/’-4-methoxy-3 -(4-methyl- l-piperazinyl)phenylurea; 4-(5-cyano-3- indolyl)-/V-4-methoxy-3-(4-methylpiperazin-l-yl)phenylpiperidine-l -carboxamide; 4- (6-fluoro-3 -indolyl)-A/-4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 - carboxamide; 3-{ l-4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl-4- piperidyl}indole-5-carboxamide; 4-(5-fluoro-3-indolyl)-A/-4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylpiperidine- 1 -carboxamide; 4-2-(3-indolyl)ethyl-A/-4- m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenylpiperidine- 1 -carboxamide; 4-(3-indolyl)-A/- 4-methoxy-3 -(4-methylpiperazin- l-yl)phenylpiperidine-l -carboxamide; 4-(4-fluoro-3- indolyl)-A/-4-methoxy-3 -(4-methylpiperazin- l-yl)phenylpiperidine-l -carboxamide; 4- (7-methoxyindol-3-yl)piperidine-l-carboxylic acid 4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-amide; 4-4-(5-fluoro-3-indolyl)butylpiperazine-l-carboxylic acid 4-methoxy- 3 -(4-methylpiperazin- 1 -yl)phenylamide; 4-(5-cyanoindol-3-yl)-3,6-dihydro-2if- pyridine[ 3CM«i3]l -carboxylic acid 4-methoxy-3 -(4-methylpiperazin- l-yl)phenylamide; 3-(5-fluoroindol-3-yl)pyrrolidine-l -carboxylic acid 4-m ethoxy-3 -(4-methylpiperazin- 1 - yl)phenyl-amide; 4-(5-fluoroindol-3-yl)cyclohexanecarboxylic acid 4-methoxy-3-(4- methylpiperazin- 1 -yl)phenylamide; 7V-2-(5 -hydroxy-3 -indolyl)ethyl-A/’ -4-methoxy-3 -(4- methyl- 1 -piperazinyl)phenylurea; N- (2-4-(6-fluoro-3 -indolyl)piperidin- 1 -yl ethyl } -TV’ -4- m ethoxy-3 -(4-methyl- l-piperazinyl)phenyl-urea; 7V-4-(5 -cy ano-3 -indolyl)butyl-A/’ -4- methoxy-3 -(4-methyl- 1 -piperazinyl)phenylurea; 4-4-(5 -cy ano-3 - indolyl)butylpiperazine- 1 -carboxylic acid 4-m ethoxy-3 -(4-methyl- 1 -piperazinyl)- phenylamide; 4-(5-fluoroindol-3-yl)piperidine-l-carboxylic acid (2, 3 -dihydro- - methylspiro(benzofuran)-3,4-piperidin)amide; N- { 2-4-(6-fluoro-3 -indolyl)piperidin- 1 - ylethyl}-2,3-dihydro-l-methylspiro(benzofuran)-3,4-piperidinurea; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US6,747,030, including, without limitation, ds-5-methoxy-l-[4-
(6-methylpyridin-2-yl)-l-naphthoyl]-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 5- methoxy-l-[5-(6-methylpyridin-2-yl)-l-naphthoyl]-6-(3,4,5-trimethylpiperazin-l- yl)indoline; cd-5-methoxy-l-[5-(2-methyloxazol-5-yl)-l-naphthoyl]-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cd-l-(2,3-dichlorobenzoyl)-5-methoxy-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cd-5-methoxy-l-[2,-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carbonyl]-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 5- m ethoxy- 1- [(3 -nitrophenyl)acetyl]-6-(3, 4, 5 -trimethylpiperazin- l-yl)indoline; cis- 6- methoxy- 1 -[4-(6-methylpyridin-2-yl)- 1 -naphthoyl]- 1 ,2,3 ,4-tetrahydro-7-(3 ,4,5- trimethylpiperazin-l-yl)quinoline; cd-l-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6- (3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1 -[(2,3 -dichlorophenyl)acetyl]-6-(3 , 5- dimethylpiperazin-l-yl)-5-methoxyindoline; cd-l-[(3-chloro-2-fluorophenyl)acetyl]-6- (3,4,5 -trimethylpiperazin- 1 -yl)indoline; cis- 1-[(2,3 -difluorophenyl)acetyl] -6-(3 ,4,5- trimethylpiperazin- 1 -yl)indoline; cis- 1 - [(2, 3 -dichlorophenyl)acetyl] -6-(3 ,4,5- trimethylpiperazin- 1 -yl)indoline; cd-l-[(2-trifluoromethylphenyl)acetyl]-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cd-l-[(2,3-dichlorophenyl)acetyl]-5-methoxy-6-
(3,4,5-trimethylpiperazin-l-yl)indoline; cd-l-[(2-trifluoromethylphenyl)acetyl]-5- methoxy-6-(3 ,4,5 -trimethylpiperazin- 1 -yl)indoline; cis- 1-[(3 -chloro-2- fluorophenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; ds-l-[(2,3- difluorophenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 5- methoxy- l-[4-(6-methylpyridin-2-yl)- 1 -naphthylacetyl]-6-(3 ,4,5-trimethylpiperazin- 1 - yl)indoline; cd-5-chloro-l-[4-(6-methylpyridin-2-yl)-l-naphthoyl]-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cis- 1 -[4-(2,6-dimethylpyri din-3 -yl)- 1 -naphthoyl]-5- methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; c/5-l-[4-(3,6-dimethylpyrazin-2-yl)- l-naphthoyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; ds-5-methoxy-l-[4- ( 1 -methyl-6-oxo- 1 , 6-dihy dropyridin-3 -yl)- 1 -naphthoyl] -6-(3 ,4,5 -trimethylpiperazin- 1 - yl)indoline; ds-l-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-methyl-6-(3,4,5- trimethylpiperazin- l-yl)indoline; cw-l-[(2-chloro-3-fluorophenyl)acetyl]-5-methoxy-6- (3,4,5-trimethylpiperazin-l-yl)indoline; ds-l-[(2-bromo-3-fluorophenyl)acetyl]-5- methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1 -[(2-bromo-3 - chlorophenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; ds-l-[(2- fluoro-3-trifluoromethylphenyl)acetyl]-6-(3,5-dimethylpiperazin-l-yl)-5- methoxyindoline; ds-l-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,5- dimethylpiperazin-l-yl)-5-methoxyindoline; cis-l -[(3-chl oro-2-fluorophenyl)acetyl]-6- (3 , 5 -dimethylpiperazin- 1 -yl)-5 -methoxyindoline; cis- 1 -[(2-chloro-3 - trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- l-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-l- yl)indoline; c/5-l-[(3-fluoro-2-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5- trimethylpiperazin-l-yl)indoline; c/5-l-[(3-chloro-2-cyanophenyl)acetyl]-5-methoxy-6- (3,4,5-trimethylpiperazin-l-yl)indoline; c/5-l-[(2-acetyl-3-chlorophenyl)acetyl]-5- methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1 -[(3 -bromo-2- methylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; c/5-l-[(3- cyano-2-methylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; c/5-5-bromo-l-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin- 1 -yl)indoline; cis-5 -acetyl- 1 - [(2-chloro-3 -trifluoromethylphenyl)acetyl] -6-(3 ,4, 5 - trimethylpiperazin- 1 -yl)indoline; c/5-5-methoxy- l-[(2-phenyl-3 - (trifluoromethyl)pyrazol-4-ylcarbonyl]-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis-6-
(3,5-dimethylpiperazin-l-yl)-l-[(4-(2,5-dimethylpyridin-4-yl)benzoyl]-5- methoxyindoline; c/s-6-(3,5-dimethylpiperazin-l-yl)-5-methoxy-l-[2,-methyl-4,-(2- oxopyrrolidin- 1 -yl)biphenyl-4-carbonyl]indoline; cis-6-(3 , 5 -dimethylpiperazin- 1 -yl)-5 - methoxy-1 -[2’ -methyl-4’ -(5-methyl-l, 2, 4-oxadiazol-3-yl)biphenyl-4-carbonyl]indoline; cis- 6-(3 ,5 -dimethylpiperazin- 1 -yl)-5-m ethoxy- 1 -[4-(2-methyl-6-(2-oxopyrrolidin- 1 - yl)pyri din-3 -yl)benzoyl] -indoline; cis- 6-(3 , 5 -dimethylpiperazin- 1 -yl)-5 -methoxy- 1-[4- (6-methylpyridin-2-yl)-l-naphthoyl]indoline; cis- 1 -[(2-chloro-3 - trifluoromethylphenyl)acetyl]-5-cyano-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1- [(3-aminocarbonyl-2-methylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l- yl)indoline; c/5-5-methoxy-l-[4-(l-methylpiperidin-4-yl)-l-naphthoyl]-6-(3,4,5- trimethylpiperazin-l-yl)indoline; c/5-5-methoxy-l-[4-(piperidin-4-yl)-l-naphthoyl]-6- (3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1 -[(2-chloro-3 - trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-l-yl)indole; 5-l-[(2-fluoro- 3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indole; cis- l-(2,3-dichlorophenylaminocarbonyl)-5-methoxy-(3,4,5-trimethylpiperazin-l-yl)indole; cd-5-methoxy-l-[4-(6-methylpyridin-2-yl)-l-naphthylacetyl]-6-(3,4,5- trimethylpiperazin-l-yl)indole; cis- 1 - [(3 -chloro-2-fluorophenyl)acetyl] -6-(3 , 5 - dimethylpiperazin- l-yl)-5-methoxyindole; cis- 1 - [(2,3 -dichlorophenyl)acetyl] -6-(3 , 5 - dimethylpiperazin- l-yl)-5-methoxyindole; cd-l-[(2-fluoro-3- trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-l-yl)indole; cis-5- methoxy-l-[4-(6-methylpyridin-2-yl)-l-naphthylaminocarbonyl]-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cis-5 -methoxy- 1 -[5-(6-methylpyridin-2-yl)- 1 - naphthylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cd-5-methoxy-l-[5- (2-methyloxazol-5-yl)-l-naphthylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-l- yl)indoline; cd-l-(2,3-dichlorophenylaminocarbonyl)-5-methoxy-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cis- 1 -(3 -chloro-2-fluorophenylaminocarbonyl)-5- methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cd-l-[3-fluoro-2-
(trifluoromethyl)phenylaminocarbonyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l- yl)indoline; cd-l-[2-chloro-3-(trifluoromethyl)phenylaminocarbonyl]-5-methoxy-6- (3,4,5-trimethylpiperazin-l-yl)indoline; cd-l-[2-chloro-3-methylphenyl)amiocarbonyl]- 5 -methoxy-6-(3, 4, 5 -trimethylpiperazin- l-yl)indoline; cd-l-[2-chloro-3- (trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin-l- yl)indoline; cd-l-(2,3-dichlorophenylaminocarbonyl)-6-(3,4,5-trimethylpiperazin-l- yl)indoline; cd-l-(2,3-dichlorophenylaminocarbonyl)-5-chloro-6-(3,4,5- trimethylpiperazin-l-yl)indoline; c/s-l-(2,3-dichlorophenylaminocarbonyl)-5-bromo-6- (3,4,5-trimethylpiperazin-l-yl)indoline; c/5-l-(2,3-dichlorophenylaminocarbonyl)-5- ethyl-6-(3,4,5-trimethylpiperazin-l-yl)indoline; ds-5-methoxy-l-[2-
(trifluoromethyl)phenylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-l-yl)indoline; cis- 1- [2-fluoro-3-(trifluoromethyl)phenylaminocarbonyl]-5-methoxy-6-(3,4,5- trimethylpiperazin- 1 -yl)indoline; cis- 1 - [2-chloro-3 -
(trifluoromethyl)phenylaminocarbonyl]-3,3-dimethyl-5-methoxy-6-(3,4,5- trimethylpiperazin-l-yl)indoline; cis-l -[(2-chl oro-3-trifluoromethyl)phenoxy carbonyl]- 5-methoxy-6-(3 ,4,5-trimethylpiperazin- 1 -yl)indoline; cis- 1 -[(2-chl oro-3 - trifluoromethylphenyl)acetyl]-6-(3 ,4,5-trimethylpiperazin- 1 -yl)indole; cis- 1 -[(2-fluoro-
3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-l-yl)indoline; c/5-l-[(2,3dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-l-yl)-5-methoxyindoline; cis- 6-(3 ,5-dimethylpiperazin- 1 -yl)-5-m ethoxy- 1 -[4-(2-methyl-6-(2-oxopyrrolidin- 1 - yl)pyridin-3-yl)benzoyl]indoline; cis- 1 -[(3 -chloro-2-fluorophenyl)acetyl]-6-(3 , 5- dimethylpiperazin-l-yl)-5-methoxyindole; cis- 1 - [(2-fluoro-3 - trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-l-yl)indole; cis- 1-[2- chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin- l-yl)indoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US7,026,314, including, without limitation, 8-(4-methyl-l- piperazinyl)-7V-[4-(4-morpholinyl)phenyl]-4-oxo-4if-chromene-2-carboxamide; 2-{ l- [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl } -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one, 2-{ l-[4-(l-acetyl-2,3-dihydro-lif-indol-6-yl)-piperazin-l-yl]- methanoyl }-8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chl oro-5-(4- { l-[8-(4- methyl-piperazin-l-yl)-4-oxo-4if-chromen-2-yl]-methanoyl}-piperazin-l-yl)- benzonitrile; 2- { 1 -[4-(4-methoxyphenyl)-piperazin- 1 -yl]-methanoyl }-8-(4-methyl- piperazin- 1 -yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2- carboxylic acid (5-furan-2-yl-lif-pyrazol-3-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4- oxo-4if-chromene-2-carboxylic acid (4-imidazol-l-yl-phenyl)-amide; 8-(4-methyl- piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid (4-[l,2,3]thiadiazol-5-yl-phenyl)- amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4if-chromene-2-carboxylic acid 4- [ 1 ,2,3 ]thiadiazol-5-yl-benzylamide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 8-(4-methyl-piperazin-l-yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]- amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (2-methoxy- 4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)- 4-oxo-4 -chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-1 -yl)-4-oxo-4iif-chromene-2-carboxylic acid (2,5-diethoxy-4- morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-cyanomethyl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid(l -indol-5-yl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4if-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(2,6-dimethyl- morpholin-4-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide; 8-(4-methyl-piperazin-l-yl)-2-(6- morpholin-4-yl-benzooxazol-2-yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (2-hydroxy-4-morpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (5-ethoxy -benzothiazol- 2-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- bromo-phenyl)-amide; 8-(4-methylpiperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 8- (4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (3-fluoro-4- morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-piperazin- 1 -yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)- phenyl]-amide; 6-methoxy-8-(4-Methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4if-chromene-2- carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(2,6-dimethyl-morpholin-4-yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2- hydroxy-ethyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- cyano-4-morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid tert-butyl ester; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 -yl)- phenyl]-amide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid dimethylamide; 4-[4-({ l- [6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)- phenylj-piperazine- 1 -carboxylic acid ethylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 -chromen-2-yl]-methanoyl } -amino)-phenyl]-piperazine- 1 - carboxylic acid cyclohexylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid cyclopentylamide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid {4-[4-(l-pyrrolidin-l-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4- (propane-2-sulfonyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazin-l- yl]-phenyl}-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid {4-[4-(l-morpholin-4-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-acetyl- piperazin- 1 -yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4- methyl-piperazin-1 -yl)-4-oxo-4iif-chromene-2-carboxylic acid (3 -fluoro-4-morpholin-4- yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4if-chromene-2-carboxylic acid [4-(l -morpholin-4-yl- methanoyl)-phenyl]-amide; 6-methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene- 2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methyl-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]- amide; 6-methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- fluoro-4-morpholin-4-yl-phenyl)-amide; 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4if-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methyl-8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (4-morpholin-4-yl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]- phenyl } -amide; 4-[4-({ 1 -[6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 4-[4-({l- [6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4- piperazin- 1 -yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4-ethanesulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}- amide; A/-[8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromen-2-yl]-4-morpholin-4-yl- benzamide; 8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid(4-morpholin-4-yl- phenyl)-amide; (+)-8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; (-)-8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; racemic-8-(4-methyl-piperazin-l-yl)-4-oxo- chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer); 8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide (slower running isomer); 4-[4-({ l-[6-fluoro-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid ethylamide; 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-
8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(4-propionyl- piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-4-oxo-8-piperazin- 1 -yl-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-hydroxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-[ 1 ,4]diazepan- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid(4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy- 8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-
(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 8-[(2-dimethylamino-ethyl)-methyl-amino]-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 8-[(3-dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-l, 4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((3i?)-(+)-3- dimethylamino-pyrrolidin-l-yl)-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((35)-(-)-3 -dimethylamino-pyrrolidin- 1 -yl)-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 6-methoxy-8-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-[ethyl-(l-ethyl- pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 4-dimethylamino-6-methoxy-8-(4-methyl-piperazin- 1 - yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-4- methylamino-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide; 6-fluoro-4-methoxy-8-(4-methyl-piperazin- 1 -yl)-quinoline-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-4-oxo-8-piperazin-l-yl-4 H- chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US7, 101,881, including, without limitation, N-{ 4- chlorophenylacetyl)-8-(4-methylpiperazinyl)-tetrahydroisoquinoline; 3-(4-chloro- phenyl)- l-[8-(4-methyl-piperazin- 1 -yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-propan- 1 -one;
2-(4-methoxy-phenyl)-l -[8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2- yl]-ethanone; l-[8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-p- tolyl-ethanone; 2-(4-chloro-phenoxy)- 1 -[8-(4-methyl-piperazin- 1 -yl)-3 ,4-dihydro- IH- isoquinolin-2-yl]-ethanone; 2-(2,4-dichloro-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3,4- dihydro- lif-isoquinolin-2-yl]-ethanone; 2-(2-chloro-phenyl)-l-[8-(4-methyl-piperazin- l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-ethanone; 2-cyclopropyl-l-[8-(4-methyl- piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-ethanone; 1 -[8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-pyridin-3-yl-ethanone; (4-chloro-phenyl)-[8-(4- methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-methanone; [8-(4-methyl- piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-(4-morpholin-4-yl-phenyl)- methanone; 2-(3,4-dichloro-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinolin-2-yl]-ethanone; 2-(4-chloro-benzenesulfonyl)-8-(4-methyl-piperazin- 1 -yl)- 1,2,3,4-tetrahydroisoquinoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US7, 109,201, including, without limitation, l-acetyl-6-bromo-5- methoxyindoline; c/5-l-acetyl-6-(3,5-dimethylpiperazin-l-yl)-5-methoxyindoline; cis- 6- (3,5-dimethylpiperazin-l-yl)-5-methoxyindoline; 6-bromo-5-fluoroindoline; l-acetyl-6- bromo-5 -fluoroindoline; cis-6-(3 , 5 -dimethylpiperazin- 1 -yl)-5 -fluoroindoline; methyl-4- (6-acetamido-2-methylpyridin-3-yl)benzoate; methyl-4-[6-(methanesulfonamido)-2- m ethylpyri din-3 -yljbenzoate; methyl-4-[6-(A/-acetyl-A/-methyl)amino-2-methylpyri din- 3-yl]benzoate; methyl-4-[6-(A/-methanesulfonyl-7V-methylarnino)-2-methylpyri din-3- yljbenzoate; methyM’-acetamido^’-methylbiphenyM-carboxylate; methyl-4’- (methanesulfonamido)-2’-methylbiphenyl-4-carboxylate; ds-5-chloro-6-(3,5- dimethylpiperazin- 1 -yl)indoline; cis- 6-(3 , 5-dimethylpiperazin- 1 -yl)-5 -methylindoline; cis- 1 -acetyl-5-methoxy-6-(3 ,4, 5-trimethylpiperazin- 1 -yl)indoline; 5-methoxy-6-(3,4,5- trimethylpiperazin-l-yl)indoline; A/-[5-(4-{[6-[(3 ?,55)-3,5-dimethyl-l-piperazinyl]-5- (methoxy)-2,3-dihydro-l//-indol-l-yl]carbonyl}phenyl)-6-methyl-2- pyridinyljacetamide; A/-[4’-({6-[(3 ?,55)-3,5-dimethyl-l-piperazinyl]-5-fluoro-l -indol- l-yl}carbonyl)-2-methyl-4-biphenylyl]acetamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the at least one 5-HTR1B receptor inhibitor is selected from those described in US7,345,038: (7i?,9uS)-/ra«s-cyclohexyl-{6-[2-(5-fluoro-benzo[<i]isoxazol- 3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine;
(7i?,9uS)-ira«s-2-(ethyl-{6-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2- u]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amino)-ethanol; (7R,9aS)-trans-7-[6-(2,6- dimethyl-piperidin-l-ylmethyl)-pyridin-2-yloxymethyl]-2-(5-fluoro-benzo[<i]isoxazol- 3 -yl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (7 R,9aS)-trans- 1 -( 1 - { 6-[2-(5-fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl}-4-phenyl-piperidin-4-yl)ethenone; (7R,9aS)-trans-( 1 , 2-dimethyl -propyl)- { 6- [2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyridol[l,2-u]pyrazin-7-ylmethoxyl- pyridin-2-ylmethyl} -amine; (7R,9aS)-trans-cyc\opropy\- { 6- [2-(5 -fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl} -amine; (7i?,9u5')-ira«5-cyclopropylmethyl-{6-[2-(5-fluoro-benzo[<i]isoxazol- 3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine;
(7 ?,9u5)-/ran5-(4-chloro-benzyl)-{6-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro- pyrido[l,2-u]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine; (7R,9aS)-trans-{6-[2- (5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-u]pyrazin-7-ylmethoxy]- pyridin-2-ylmethyl}-[2-(l-methyl-pyrrolidin-2-yl)-ethyl]-amine; (7R,9aS)-trans-2-(5- fluoro-benzo[<i]isoxazol-3-yl)-7-[6-(4-methyl-piperazin-l -ylmethyl)-pyri din-2- yloxymethyl]-octahydro-pyrido[ 1 ,2-u]pyrazine; (7R, 9aS)-trans-2-(5-f[uoro- benzo[i ]isoxazol-3-yl)-7-(6-piperidin-l -ylmethyl-pyri din-2 -yloxymethyl)-octahydro- pyrido[ 1 ,2-a]pyrazine; (7R,9aS)-trans-{6-[2-(5-fluoro-henzo[d]isoxazol-3-yl)- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-dimethyl-amine; (7i?,9a5')-ira«5-{6-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazin- 7-ylmethoxy]-pyridin-2-ylmethyl}-(tetrahydro-furan-2-ylmethyl)-amine; (7R,9aS)~ /ra«5-7-[6-(2,5-dimethyl-pyrrolidin-l-ylmethyl)-pyridin-2-yloxymethyl]-2-(5-fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans- { 6-[2-(5- fluoro-benzo[<7]isoxazol-3-yl)-octahydro-pyrido[l,2- 3]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl}-(2,2,2-trifluoro-ethyl)-amine; (7R,9aS)-trans-{6-[2-(5-fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl } - [3 -(4-methyl-piperazin- 1 -yl)-propyl] -amine; (7R,9aS)-trans-{ 6-[2-(5-fluoro- benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl } -pyrrolidin- 1 -yl-amine; (7R,9aS)-trans-7-(6-azepm- 1 -ylmethyl-pyridin-2- yloxymethyl)-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro-pyrido[l,2-a]pyrazine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-(3-methyl-isoxazol-4-yl)-amine; (7R, 9aS)-trans- [6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-thiazol-2 -yl-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(3-methyl-isoxazol-5-yl)- amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-(3-methyl-pyridin-4-yl)-amine; (7R,9aS)-trans-\6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(5-methyl-27f-pyrazol-3-yl)-amine; (7R,9aS)-trans-[6-(2-benzo[d]isoxazol-3- yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(5-methyl- pyridin-2-yl)-amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(li7-pyrazol-3-yl)-amine; (7R,9aS)-trans- [6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl-(6-methyl-pyridin-2-yl)-amine; (7 ?,9a5)-/ra«5-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-pyridin-2-yl-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-cyclopropylmethyl-amine; (7R, 9aS)-trans- [6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(2-morpholin-4-yl-ethyl)-amine; (7 ?,9a5)-/ra«5-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-pyrimidin-4-yl- amine; (7i?,9aS)-/rans-[6-(2-benzo[rf]isoxazol-3-yl-octahydiO-pyrido[l,2- 2]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-cyclopropyl-amine; (7R,9aS)-trans-\6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(6-methoxy-pyridin-3-yl)-amine; (7i?,9aS)-/rans-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-pyrrolidin-l-yl- ethyl)-amine; (7 ?,9a5)-/ra«5-2-benzo[<i]isoxazol-3-yl-7-[5-(4-methyl-[1.4]diazepan-l- ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-[6- (2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(tetrahydro-furan-2-ylmethyl)-amine; (7R,9aS)-trans-[6-(2-benzo[d\isoxazo\- 3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(l-phenyl- ethyl)-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(l-phenyl-ethyl)-amine; (7R,9aS)-trans-[6- (2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-pyridin-3-ylmethyl-amine; (7 ?,9aS)-/rans-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-pyridin-3-yl-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-thiazol-2-yl-amine; (7R,9aS)-trans-\6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-thiazol-2-yl-amine; (7 ?,9aS)-/rans-[6-(2-benzo[<i]isoxazol-3-yl-octahydiO- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(3-methyl-pyridin-4-yl)-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl-(5-methyl-27/-pyrazol-3-yl)-amine; (7R,9aS)-trans-[6- (2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-(5-methyl-pyridin-2-yl)-amine; (7i?,9aS)-/rans-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(li7-pyrazol-3-yl)- amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-(6-methyl-pyridin-2-yl)-amine; (7R,9aS)-trans-\6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-pyridin-2-yl-amine; (7 ?,9aS)-/rans-[6-(2-benzo[<i]isoxazol-3-yl-octahydiO- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-cyclopropylmethyl-amine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-(2-morpholin-4-yl-ethyl)-amine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-pyrimidin-4-yl-amine; (7 ?,9a5)-/ra«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyri din-2 -ylmethyl]-(6-methoxy-pyridin-3-yl)- amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-(2-pyrrolidin-l-yl-ethyl)-amine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-diethyl-amine; (7i?,9a5,)-ira«5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-pyrrolidin-3-ol; (7R,9aS)-trans- l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-pyrrolidin-3-ol; (7i?,9a5,)-/ran5-7-(5-azetidin-l-ylmethyl-pyridin-2- yloxymethyl)-2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)~ ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)- pyridin-3-ylmethyl]-(2-methoxy-ethyl)-methyl-amine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-cyclopentyl-methyl-amine; (' 7R,9aS)-trans-N-\6-(2-benzo[d]isoxazol-3-yl - octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl-A/,A/’-dimethyl- ethane- 1 ,2-diamine; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methyl-aziridin-l- ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-7- (5-azepan-l-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazine; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methoxymethyl- pyrrolidin-l-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine;
(7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-tert-butyl-amine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-tert-butyl-methyl-amine; (7R,9aS)-trans-2-benzo[d\isoxazo\-3-y\-7-(5- thiazolidin-3-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine;
(7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-(5-imidazol-l-ylmethyl-pyridin-2- yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (' 7R,9aS)-trans-[6-(2-benzo[d\isoxazo\ - 3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclohexyl- methyl-amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-dimethyl-amine; (7R, 9aS)-trans- [6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-ethyl-methyl-amine; (7i?,9aS)-ira/M-[6-(2-benzo[rf]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-l-methyl-ethyl)- amine; (7 ?,9a5)-/ra«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methyl-pyrrolidin-l-ylmethyl)- pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (7S,9aS)-cis-2- benzo[<i]isoxazol-3-yl-7-(5-piperidin-l -ylmethyl-pyri din-2 -yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (75,9«5)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-dimethyl-amine; (7S,9aS)-cis-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-ethyl-methyl-amine; (75,9«5)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclopentyl-methyl-amine; (75,,9a5,)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-ethyl)-methyl-amine; (7S,9aS)-cis-7-(5- azetidin-l-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazine; (7S,9aS)-cz's-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methyl-aziridin-l- ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-[6- (2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-(2-methoxy-ethyl)-methyl-amine; (7i?,9a5,)-irara-l-[6-(2-benzo[<i]isoxazol-3- yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-pyrrolidin-3-ol; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-dimethyl-amine; (7R,9aS)-trans-\6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-cyclohexyl-methyl-amine; (75,9a5)-cz'5-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-cyclohexyl-methyl- amine; (75,,9a5,)-c«-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-dimethyl-amine; (75,9a5)-cz'5-[6-(2-benzo[<i]isoxazol- 3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(2-methoxy- ethyl)-methyl-amine; (7i?,9a5,)-ira«5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(i?)-pyrrolidin-3-ol; (7R,9aS)~ ira«5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)- pyridin-2-ylmethyl]-(5)-pyrrolidin-3-ol; (7S,9aS)-cz's-[6-(2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclohexyl-methyl- amine; (7S,9aS)-ds-l-[6-(2-benzo[rf]isoxazol-3-yl-octahydiO-pyrido[l,2-i2]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-pyrrolidin-(5 -3-ol; (7R,9aS)-trans-2-benzo[d]isoxazol- 3-yl-7-(5-pyrrolidin-l -ylmethyl-pyri din-2-yloxymethyl)-octahydro-pyrido[l, 2- ajpyrazine; (7i?,9a5,)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(5-pyrrolidin-l- ylmethyl-pyri din-2 -yloxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine; (7R,9aS)-trans- 1 -
[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-piperidin-4-ol; (75,9«5)-c/5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-pynOlidin-(i?)-3-ol; (lR,9aS)~ /ra«5-7-(5-azetidin-l-ylmethyl-pyridin-2-yloxymethyl)-2-(5-fluoro-benzo[<i]isoxazol-3- yl)-octahydro-pyrido[l,2-a]pyrazine; (7R, 9aS)-trans-{ 6-[2-(5-fluoro-benzo[<i]isoxazol-
3-yl)-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-3-ylmethyl}-dimethyl- amine; (7i^9aS)-irans-ethyl-{6-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-3-ylmethyl}-methyl-amine; (7R,9aS)-trans- 2-benzo[i ]isoxazol-3-yl-7-(6-pyrrolidin- 1 -ylmethyl-pyri din-2-yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-benzyl-amine; (7R,9aS)-trans- 2-benzo[i ]isoxazol-3-yl-7-(6-morpholin-4-ylmethyl-pyridin-2-yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9«5')-ira«5-2-benzo[<i]isoxazol-3-yl-7-(5-morpholin-4- ylmethyl-pyri din-2 -yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-2- benzo[<i]isoxazol-3-yl-7-(5-piperidin-l -ylmethyl-pyri din-2 -yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9«5')-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-diisopropyl-amine; (7R,9aS)~ ira«5-2-benzo[i ]isoxazol-3-yl-7-[5-(4-methyl-piperazin-l-ylmethyl)-pyridin-2- yloxymethyl]-octahydro-pyrido[ 1 ,2a]pyrazine; (75,9«5)-c/5-2-benzo[<i]isoxazol-3-yl-7- (5-pyrrolidin-l -ylmethyl-pyri din-2 -yloxymethyl)-octahydro-pyrido[l,2-3]pyrazine;
(75,9«5)-c/5-2-Benzo[<i]isoxazol-3-yl-7-(6-morpholin-4-ylmethyl-pyridin-2- yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (75,9«5)-c/5-2-benzo[<i]isoxazol-3-yl-7- (6-pyrrolidin-l -ylmethyl-pyri din-2-yloxymethyl)-octahydro-pyrido[l,2-3]pyrazine; (7 ?,9a5)-/ra«5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(6-pyrrolidin-l -ylmethyl-pyri din- 2-yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-2-(5-f[uoro- benzo[i ]isoxazol-3-yl)-7-(6-morpholin-4-ylmethyl-pyridin-2-yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9a5')-ira«5-{6-[2-(5-fluoro-benzo[<i]isoxazol-3-yl)- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-(2-morpholin-4-yl- ethyl)-amine; (7 ?,9a5)-/ra«5-2-benzo[<i]isoxazol-3-yl-7-(6-morpholin-4-ylmethyl- pyri din-2 -yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-2- benzo[<i]isoxazol-3-yl-7-(5-piperidin-l -ylmethyl-pyri din-2 -yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; (7i?,9a5,)-/ran5-2-(5-fluoro-benzo[<i]isoxazol-3-yl)-7-(5- pyrrolidin- 1 -ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[ 1 ,2-a]pyrazine;
(7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-di ethyl-amine; (7R,9aS)-trans-\6-(2-benzo[d]isoxazol- 3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-dimethyl- amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(2-methoxy-l-methyl-ethyl)-amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3- yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy- ethyl)-methyl-amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclopentyl-methyl-amine; (7R,9aS)~ /ran5-7-(5-azetidin-l-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-2-benzo[d]isoxazci[-3-yl-7-[5-(2- methyl-aziridin- 1 -ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[ 1 ,2-a]pyrazine; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methoxymethyl-pyrrolidin-l-ylmethyl)- pyridin-2-yloxymethyl]-octahydro-pyrido[l,2-a]pyrazine; (7R, 9aS)-trans- [6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-tert-butyl-amine; (75,9«5)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine; (7S,9aS)~ c/5-7-(5-azeti din- 1 -ylmethyl-pyri din-2-yloxymethyl)-2-benzo[<i]isoxazol-3-yl- octahydro-pyrido[l,2-a]pyrazine; (7R,9aS)-trans-[6-(2-benzo[d]isoxazci[-3-yl- octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-dimethyl-amine; (7i?,9a5,)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-(2-methoxy-ethyl)-methyl-amine; (7R,9aS)-trans-l-[6- (2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-(5)-pyrrolidin-3-ol; (7i?,9a5,)-ira«5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(i?)-pyrrolidin-3-ol; (7R,9aS)~ ira«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methyl-pyrrolidin-l-ylmethyl)-pyri din-2- y 1 oxy methyl ] -octahy dro-py ri do [ 1 ,2-u]pyrazine; (7R,9aS)-trans- 1 -[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-piperidin-4-ol; (75,9«5)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydro- pyrido[l,2-u]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclohexyl-methyl-amine; (7i?,9a5,)-ira«5-l-[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl]-(5)-pyrrolidin-3-ol; (7R,9aS)-trans- 1 -[6-(2- benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-(R)-pyrrolidin-3-ol; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-(6-pynOlidin- 1 -ylmethyl-pyri din-2 -yloxymethyl)-octahydro-pyrido[l ,2-u]pyrazine; (7R,9aS)-trans-
[6-(2-benzo[<i]isoxazol-3-yl-octahydro-pyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-benzyl-amine; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-(5-pynOlidin-l- ylmethyl-pyri din-2 -yloxymethyl)-octahydro-pyrido[ 1 ,2-u]pyrazine; (' 7S,9aS)-cis-2 - benzo[<7]isoxazol-3-yl-7-(5-pyrrolidin-l-yl methyl-pyridin-2-yloxymethyl)-octahydro- pyrido[l,2-a]pyrazine; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US7,479,559, including, without limitation, 3-[5-fluoro-2-(4- methyl-piperazin- 1 -yl)-benzyl]- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2- one; 4-{3-[2-(4-methyl-piperazin-l-yl)-benzyl]-2-oxo-pyrrolidin-l-yl}-benzoic acid ethyl ester; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(6-morpholin-4-yl-pyridin-3-yl)- pyrrolidin-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 - yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(4-morpholin-4- yl-phenyl)-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclohexyl)-phenyl]-3-[2-(4- methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-(l -ethyl- 1 -hydroxy-propyl)- phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 1 - [3 -( 1 -hydroxy- 1 - methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(2- hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one; 1 -[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; l-[4-(l-methoxy-l-methyl-ethyl)-phenyl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(2-methoxy-2-methyl-propyl)-phenyl]-3- [2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-( 1 -methoxy-cyclobutyl)- phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl- piperazin-l-yl)-benzyl]-l-(4-pyridin-4-yl-phenyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclopentyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclobutyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclohexyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-ethyl-l- hydroxy-propyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l- hydroxy- 1 -methyl-ethyl)-phenyl]-3 -(2-piperazin- 1 -yl-benzyl)-pyrrolidin-2-one; l-[4-( 1 - hydroxy- l-methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzylidene]- pyrrolidin-2-one; 3-[2-(4-ethyl-piperazin- 1 -yl)-benzyl]-l -[4-(l -hydroxy- 1 -methyl - ethyl)-phenyl]-pyrrolidin-2-one; 3 - [2-(2, 5 -dimethyl-piperazin- 1 -yl)-benzyl]- 1 - [4-( 1 - hydroxy-cyclopentyl)-phenyl]-pyrrolidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]- l-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-pyrrolidin-2-one; 1 -[6-(l -hydroxy - cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 1- [4-(l-hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one; l-[5-(l -hydroxy- 1 -methyl-ethyl)-pyri din-2 -yl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; l-[5-(l-hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-3-[5-fluoro-2-(4-methyl-piperazin-l-yl)- benzyl]- 1 -[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2-one; (i?)-4-{3-[2-(4- methyl-piperazin- 1 -yl)-benzyl]-2-oxo-pyrrolidin- 1 -yl } -benzoic acid ethyl ester; (R)- 3- [2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -(6-morpholin-4-yl-pyri din-3 -yl)-pyrrolidin-2- one; (R)- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; (i?)-3 -[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(4-morpholin-4- yl-phenyl)-pyrrolidin-2-one; (i?)-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1-[4-( 1 -hydroxy-cyclohexyl)-phenyl]-3 -
[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1 -[4-(l -ethyl- 1 -hydroxy- propyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- l-[3-(l-
Hydroxy-l-methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one; (R)- 1 -[4-(2-hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; (R)- 1 -[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3-[2-(4- methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (5)-3-[5-fluoro-2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -[4-(l -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2-one; (5)-4-{3-[2- (4-methyl-piperazin- 1 -yl)-benzyl]-2-oxo-pyrrolidin- 1 -yl } -benzoic acid ethyl ester; ( S)-3 - [2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -(6-morpholin-4-yl-pyridin-3 -yl)-pyrrolidin-2- one; ( S )- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; (S)-3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(4-morpholin-4- yl-phenyl)-pyrrolidin-2-one; (S)-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- 1-[4-( 1 -hydroxy-cyclohexyl)-phenyl]-3 -
[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- 1 -[4-(l -ethyl- 1 -hydroxy- propyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- l-[3-(l- hydroxy-l-methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one; ( S )- 1 -[4-(2-hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; ( S )- 1 -[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3-[2-(4- methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US8,859,534, including, without limitation, 7V,7V-dimethyl-7-(4-
(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; 7-(4-(2-(pyridin-2- yl)ethyl)piperazin-l-yl)-A/-(pyridin-2-ylmethyl)benzofuran-2-carboxamide; N-( 4- morpholinophenyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; A/-(l -phenylpiperi din-4-yl)-7-(4-(2-(pyri din-2 -yl)ethyl)piperazin-l - yl)benzofuran-2-carboxamide; A/-(4-(methylsulfonyl)benzyl)-7-(4-(2-(pyridin-2- yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; A/-((l -methyl- lH-imidazol-4- yl)methyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; N-( 1- acetylpiperidin-4-yl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; N-( 1 -(pyridin-2-yl)ethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin- 1 - yl)benzofuran-2-carboxamide; 7V-(l-(3-chloropyridin-2-yl)piperidin-4-yl)-7-(4-(2-
(pyri din-2 -yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; A/-(4-cyanobenzyl)-7-(4- (2-(pyri din-2 -yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; N-
(benzo[i ][l,3]dioxol-5-ylmethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-carboxamide; A/-methyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-carboxamide; A/-cyclopropyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-carboxamide; A/-(3,3-difluorocyclobutyl)-7-(4-(2-(pyridin-2- yl)ethyl)piperazin- 1 -yl)b enzofuran-2 -carb oxami de ; azetidin- 1 -yl(7-(4-(2-(pyridin-2- yl)ethyl)piperazin- 1 -yl)benzofuran-2-yl)methanone; (7-(4-(2-(pyridin-2- yl)ethyl)piperazin-l-yl)benzofuran-2-yl)(pyrrolidin-l-yl)methanone; TV-(4-
(methylsulfonylmethyl)benzyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran- 2-carboxamide; 7V-(3-methoxyphenethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-carboxamide; TV-methyl-TV-(3-(methylsulfbnyl)benzyl)-7-(4-(2-
(pyri din-2 -yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; TV-((6-cyanopyridin-3- yl)methyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; N- methyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)-TV-(pyridin-3-ylmethyl)benzofuran-2- carboxamide; TV-(3-cyanobenzyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-
2-carboxamide; (7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-yl)(4-(thiazol- 2-yl)piperazin- 1 -yl)methanone; 7V-(l-(3-methoxypyridin-2-yl)piperidin-4-yl)-7-(4-(2- (pyri din-2 -yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; 7V-methyl-7-(4-(2-
(pyridin-2-yl)ethyl)piperazin-l-yl)-A/-(pyridin-2-ylmethyl)benzofuran-2-carboxamide; A/-(3-methoxybenzyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; 7V-(l-(pyridin-2-yl)cyclopropyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-carboxamide; A/-(4-methoxybenzyl)-7-(4-(2-(pyridin-2- yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; A/-(2-(4-methylpyrimidin-2- yl)ethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; N-( 2-(l- methyl- 17/-imidazol-4-yl)ethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l -yl)benzofuran-
2-carboxamide; 7-(4-(2-(pyri din-2 -yl)ethyl)piperazin- 1 -yl)-A/-((tetrahydro-27/-pyran-4- yl)methyl)benzofuran-2-carboxamide; 7V-(1-(1 -methyl- l//-pyrazol-5-yl)ethyl)-7-(4-(2 - (pyri din-2 -yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; N-( 1 -(6-methylpyri din-3 - yl)ethyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; N-(( 2- methylpyrimidin-5-yl)methyl)-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)-A/-(pyridin-3- ylmethyl)benzofuran-2-carboxamide; (7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l- yl)benzofuran-2-yl)(3 -(pyri din-3 -yloxy)azeti din- l-yl)methanone; A/-(3-hydroxybenzyl)- 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; 7-(4-(2-(4- methoxypyridin-2-yl)ethyl)piperazin-l-yl)-A/,A/-dimethylbenzofuran-2-carboxamide;
A/,A/-dimethyl-7-(4-(2-(5-methylpyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; 7-(4-(2-(4-cyanopyridin-2-yl)ethyl)piperazin-l-yl)- V, TV- dimethylbenzofuran-2-carboxamide; A//V-dirnethyl-7-(4-(2-(6-(trifluoromethyl)pyridin- 2-yl)ethyl)piperazin- 1 -yl)benzofuran-2-carboxamide; 7-(4-(2-(5-acetylpyridin-2- yl)ethyl)piperazin-l-yl)- V,.V-dimethylbenzofuran-2-carboxamide; 7-(4-(2-(5- acetamidopyridin-2-yl)ethyl)piperazin-l-yl)-A/,A/-dimethylbenzofuran-2-carboxamide; azeti din-l-yl(7-(4-(2-(6-methoxypyri din-2 -yl)ethyl)piperazin-l-yl)benzofuran-2- yl)methanone; 7-(4-(2-(6-methoxypyri din-2 -yl)ethyl)piperazin- 1 -y\)-N,N- dimethylbenzofuran-2-carboxamide; 7-(4-(2-(5 -fluoropyri din-2 -yl)ethyl)piperazin- 1 - yl)- V,/V-dimethylbenzofuran-2-carboxamide; 7-(4-(2-(3-methoxy-2- pyridyl)ethyl)piperazin- 1 -yl)-A/,A/-dimethylbenzofuran-2-carboxamide; 1 -(5-(2-(4-(2- (azetidine-l-carbonyl)benzofuran-7-yl)piperazin-l-yl)ethyl)indolin-l-yl)ethanone; 5- fluoro-A/, A/-dimethyl-7-(4-(2-(pyri din-2 -yl)ethyl)piperazin-l-yl)benzofuran-2- carboxamide; 7-(4-(2-(l-acetylindolin-5-yl)ethyl)piperazin-l-yl)-5-fluoro- V,.V- dimethylbenzofuran-2-carboxamide; 5-methoxy-A/7V-dimethyl-7-(4-(2-(pyridin-2- yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; 4-bromo- V,.V-dirnethyl-7-(4-(2- (pyridin-2-yl)ethyl)piperazin-l-yl)benzofuran-2-carboxamide; 7 -(4-(2-( 1 -acety lindolin- 5-yl)ethyl)piperazin-l-yl)- V,.V-dimethylbenzofuran-2-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US9,938,277, including, without limitation, 3-((6aR,9S,l0aR)-5- cyclopropyl-7-methyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinolin-9-yl)-l,l- diethylurea; (6ui?,9i?)-5-cyclopropyl-A/-((5')-l-hydroxybutan-2-yl)-4,7-dimethyl-
4,6,6u,7,8,9-hexahydroindolo[4,3-/g]quinoline-9-carboxamide; (6ui?,9i?)-5-cyclopropyl- /V-((S)-l-hydroxybutan-2-yl)-4,7-dimethyl-4,6,6u,7,8,9-hexahydroindolo[4,3- /g]quinoline-9-carboxamide; (6aR,9R, 10aS)-N-((S)~ 1 -hy droxybutan-2-yl)- 1 Ou-methoxy- 4,7-dimethyl-4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinoline-9-carboxamide; (aR,9R, 10 aS)-N-((S)~ 1 -hydroxybutan-2-yl)- 10u-methoxy-4,7-dimethyl- 4,6,6u,7,8,9,10,10u-octahydroindolo[4,3-/g]quinoline-9-carboxamide; (6aR,9R,l0aS)~ N-((S)- 1 -hydroxybutan-2-yl)- 10u-methoxy-4,7-dimethyl-4,6,6u,7, 8,9, 10,10 a- octahydroindolo[4,3-/g]quinoline-9-carboxamide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20030064995, including, without limitation, 7V-[2-(5-fluoro- 3-indolyl)ethyl]-A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4-(5-cyano-3- indolyl)-7V-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (6-fluoro-3-indolyl)-A/-[4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]piperidine-l- carboxamide; 3-{ l-[4-methoxy-3-(4-methyl-l-piperazinyl)phenylaminocarbonyl]-4- piperidyl}indole-5-carboxamide; 4-(5 -fluoro-3 -indolyl)- V- [4-methoxy-3 -(4- methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4-[2-(3-indolyl)ethyl]-7V-[4- methoxy-3 -(4-methylpiperazin- l-yl)phenyl]piperidine-l -carboxamide; 4-(3-indolyl)-/V- [4-methoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4-(4-fluoro-3 - indolyl)-7V-[4-m ethoxy-3 -(4-methylpiperazin- 1 -yl)phenyl]piperidine- 1 -carboxamide; 4- (7-methoxyindol-3-yl)piperidine-l -carboxylic acid [4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl]amide; 4-[4-(5-fluoro-3-indolyl)butyl]piperazine-l-carboxylic acid [4- m ethoxy-3 -(4-methylpiperazin- l-yl)phenyl]amide; 4-(5-cyanoindol-3-yl)-3,6-dihydro- 2//-pyridine[/ucMuu] 1 -carboxylic acid [4-methoxy-3 -(4-methylpiperazin- 1 - yl)phenyl]amide; 3 -(5-fluoroindol-3 -yl)pyrrolidine- 1 -carboxylic acid [4-methoxy-3-(4- methylpiperazin- 1 -yl)phenyl]amide; 4-(5-fluoroindol-3-yl)-cyclohexanecarboxylic acid [4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]amide; 7V-[2-(5-hydroxy-3-indolyl)ethyl]- A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; N- { 2- [4-(6-fluoro-3 - indolyl)piperidin- 1 -yl] ethyl } -TV’ -[4-methoxy-3 -(4-methyl- 1 -piperazinyl)phenyl]urea; N-
[4-(5-cyano-3-indolyl)butyl]-A/’-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]urea; 4- [4-(5-cyano-3 -indolyl)butyl]piperazine- 1 -carboxylic acid [4-methoxy-3 -(4-methyl- 1 - piperazinyl)phenyl]amide; 4-(5-fluoroindol-3-yl)piperidine-l-carboxylic acid (2,3- dihydro-r-methylspiro(benzofuran)-3,4-piperidin) amide; N- { 2-[4-(6-fluoro-3 - indolyl)piperidin- 1 -yl] ethyl } - [2, 3 -dihydro- 1 -methyl spiro(benzofiiran)-3 ,4- piperidinjurea; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20040132720, including, without limitation, c/5-A/-[3-chloro- 2-fluorophenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N-[ 2- fluoro-3-(trifluoromethyl)phenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3- carboxamide; c/5-A/-[2,3-dichlorophenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran- 3 -carboxamide; czs-A/-[2,-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenyl]-5- (3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N- [2’ -methyl -4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenyl]-5-(3,5-dimethylpiperazin-l-yl)benzofuran-3- carboxamide; czs- V-[3-chloro-2-fluorophenyl]-6-fluoro-5-(3,4,5-trimethylpiperazin-l- yl)benzofuran-3 -carboxamide; cis-N-[ 3 -chi oro-2-fluoropheny 1 ] 5 -(3 ,5- dimethylpiperazin-l-yl)-6-fluorobenzofiiran-3 -carboxamide; cd-A/-[3-methyl-4-(6- methylpyridin-2-yl)phenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3- carboxamide; cd-A/-[3-methyl-4-(6-methylpyridin-2-yl)phenyl]-5-(3,4,5- trimethylpiperazin-l-yl)-6-fluorobenzofiiran-3 -carboxamide; cd-A/-[4-(imidazol- 1 -yl)- 3-methylphenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N-[4- (imidazol-l-yl)-3-methylphenyl]-6-fluoro-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran- 3 -carboxamide; ds-7V-[3-chloro-4-(pyridin-4-yl)phenyl]-5-(3,4,5-trimethylpiperazin-l- yl)benzofuran-3 -carboxamide; cd-A/-[3-chloro-4-(pyridin-4-yl)phenyl]-6-fluoro-5- (3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N-[ 4-(4- methoxycarbonylpiperazin-l-yl)-3-methylphenyl]-5-(3,4,5-trimethylpiperazin-l- yl)benzofuran-3 -carboxamide; cd-A/-[2-(4-cyanophenyl)-3-methylpyridin-5-yl]-6- fluoro-5-(3,4,5-trimethylpiperazin-l-yl)benzofuran-3-carboxamide; cis-N-[ 4-(4- methoxycarbonylpiperazin-l-yl)-3-methylphenyl]-5-(3,4,5-trimethylpiperazin-l- yl)benzothiophene-3-carboxamide; cd-A/-[2,3-dichlorophenyl]-5-(3,4,5- trimethylpiperazin-l-yl)benzothiophene-3 -carboxamide; cw-A/-[4-(imidazol-2-yl)-3- methylphenyl]-5-(3,4,5-trimethylpiperazin-l-yl)benzothiophene-3-carboxamide; cis-N- [indol-5-yl]-5-(3,4,5-trimethylpiperazin-l-yl)benzothiophene-3-carboxamide; cis-N-[ T- methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenyl]-5-(3,4,5-trimethylpiperazin-l- yl)benzothiophene-3-carboxamide; cd-A/-[2,3-dichlorophenyl]-5-(3,5- dimethylpiperazin-l-yl)benzothiophene-3 -carboxamide; cis-N- [2’ -methyl -4’ -(5 -methyl - l,2,4-oxadiazol-3-yl)-4-biphenyl]-5-(3,5-dimethylpiperazin-l-yl)benzothiophene-3- carboxamide; cis-3 -\T -methyl-4’ -(5-m ethyl- 1 ,2,4-oxadiazol-3 -yl)- 1 , G -biphenyl-4- carbonyl]-5-(3,4,5-trimethylpiperazin-l-yl)-l -indole; cis- 1 -methyl-3 -[2’ -methyl-4’ -(5- methyl- 1 ,2,4-oxadiazol-3 -yl)- 1 , G -biphenyl-4-carbonyl]-5-(3 ,4,5-trimethylpiperazin- 1 - yl)-l -indole; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050085457, including, without limitation, 8-(4-m ethyl- 1- piperazinyl)-7V-[4-(4- morpholinyl)phenyl]-4-oxo-4//-chromene-2-carboxamide; 2-{ 1 - [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-methanoyl } -8-(4-methyl-piperazin- 1 -yl)- chromen-4-one; 2-{ l-[4-(l -acetyl-2, 3-dihy dro-l//-indol-6-yl)-piperazin-l-yl]- methanoyl } -8-(4-methyl-piperazin- 1 -yl)-chromen-4-one; 2-chloro-5-(4-{ l-[8-(4- methyl-piperazin- 1 -yl)-4-oxo-4//-chromen-2-yl]-methanoyl)-piperazin- 1 -yl)- benzonitrile; 2-{ l-[4-(4-methoxy-phenyl)-piperazin-l-yl]-methanoyl}-8-(4-methyl- piperazin- 1 -yl)-chromen-4-one; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2- carboxylic acid (5-furan-2-yl-lf7-pyrazol-3-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4- oxo-4H-chromene-2-carboxylic acid (4-imidazol- 1 -yl-phenyl)-amide; 8-(4-methyl- piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid (4-[l,2,3]thiadiazol-5-yl-phenyl)- amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid 4- [ 1 ,2,3 ]thiadiazol-5-yl-benzylamide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2- carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4//-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]- amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid (2-methoxy- 4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4//-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid (2,5-diethoxy-4- morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4//-chromene-2- carboxylic acid (4-cyanomethyl-phenyl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4f7- chromene-2-carboxylic acid (l//-indol-5-yl)-amide; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4//-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4//-chromene-2-carboxylic acid [4-(2,6-dimethyl- morpholin-4-yl)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2- carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide; 8-(4-methyl-piperazin- 1 -yl)-2-(6- morpholin-4-yl-benzooxazol- 2-yl)-chromen-4-one; 8-(4-methyl-piperazin-l-yl)-4-oxo- 4//-chromene-2-carboxylic acid (2-hydroxy-4-morpholin-4-yl-phenyl)-amide; 8-(4- methyl-piperazin-l-yl)-4-oxo-4//-chromene-2-carboxylic acid (5-ethoxy -benzothiazol- 2-yl)-amide; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4//-chromene-2-carboxylic acid (4- bromo-phenyl)-amide; 8-(4-methylpiperazin- 1 -yl)-4-oxo-4if-chromene-2-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)amide; 8-(4-methyl-piperazin-l-yl)-4-oxo-4 /- chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-4if-chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 8- (4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-fluoro-4- morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /- chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-piperazin- 1 -yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)- phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2- carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl- phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2- carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(2, 6-dimethyl- morpholin-4-yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2- hydroxy-ethyl)-piperazin- 1 -yl] -phenyl } -amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)- 4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- cyano-4-morpholin-4-yl-phenyl)-amide; 4-[4-({ 1 -[6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid tert-butyl ester; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]- amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid
[4-(4-ethanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 -yl)- phenyl]-amide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid dimethylamide; 4-[4-({ l- [6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromen-2-yl]-methanoyl}-amino)- phenylj-piperazine- 1 -carboxylic acid ethylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 /-chromen-2-yl]-methanoyl } -amino)-phenyl]-piperazine- 1 - carboxylic acid cyclohexylamide; 4-[4-({ l-[6-methoxy-8-(4-methyl-piperazin-l-yl)-4- oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-caxboxylic acid cyclopentylamide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid {4-[4-(l -pyrrolidin- 1 -yl- methanoyl)-piperazin- 1-yl]- phenyl} -amide; 6- methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-(4-
(propane-2-sulfonyl)-piperazin-l-yl]-phenyl} -amide; 6-methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazin-l- yl]-phenyl}-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-(4-(l-morpholin-4-yl-methanoyl)-piperazin-l-yl]-phenyl}-amide; 6- fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 - chromene-2-carboxylic acid [4-(4- methanesulfonyl-piperazin- 1 -yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(4-acetyl- piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 - chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4- methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3 -fluoro-4-morpholin-4- yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2- carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide; 6-fluoro-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(l -morpholin-4-yl- methanoyl)-phenyl]-amide; 6-methyl-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-
2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methyl-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 -chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]- amide; 6-methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (3- fluoro-4-morpholin-4-yl-phenyl)-amide; 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 -chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methyl-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4 -chromene-2-carboxylic acid (4-morpholin-4-yl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l- yl)-4-oxo-4 -chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]- phenyl } -amide; 4-[4-({ 1 -[6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromen-2- yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester; 4-[4-({l- [6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4 -chromene-2-carboxylic acid (4- piperazin- 1 -yl-phenyl)-amide; 6-fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /- chromene-2-carboxylic acid [4-(4-ethane sulfonyl-piperazin-l-yl)-phenyl]-amide; 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- 4 /-chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}- amide; 7V-[8-(4-methyl-piperazin-l-yl)-4-oxo-4.i/-chromen-2-yl]-4-morpholin-4-yl- benzamide; 8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl - phenyl)-amide; (+)-8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; (-)-8-(4-methyl-piperazin- 1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; racemic-8-(4-methyl-piperazin-l-yl)-4-oxo- chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-(4-methyl-piperazin- 1 - yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer); 8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide (slower running isomer); 4-[4-({ l-[6-fluoro-8-(4-methyl-piperazin-l- yl)-4-oxo-4 /-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l -carboxylic acid ethylamide; 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-ethoxy- 8-(4-methyl-piperazin-l-yl)-4-oxo-4 /-chromene-2-carboxylic acid [4-(4-propionyl- piperazin- 1 -yl)-phenyl]-amide; 6-methoxy-4-oxo-8-piperazin- 1 -yl-4 /-chromene-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-hydroxy-8-(4-methyl-piperazin- 1 - yl)-4-oxo-4 /-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6- methoxy-8-(4-methyl-[ 1 ,4]diazepan- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy- 8-(4-methyl-piperazin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide; 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo- l,4-dihydro-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- propionyl-piperazin-l-yl)-phenyl]-amide; 8-[(2-dimethylamino-ethyl)-methyl-amino]-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 8-[(3-dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-l,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((3i?)-(+)-3- dimethylamino-pyrrolidin- 1 -yl)-6-methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-((3S)-(-)-3 -dimethylamino-pyrrolidin- 1 -yl)-6- methoxy-4-oxo- 1 ,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)- amide; 6-methoxy-8-[methyl-( 1 -methyl-pyrrolidin-3 -yl)-amino]-4-oxo- 1 ,4-dihydro- quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 8-[ethyl-(l-ethyl- pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide; 4-dimethylamino-6-methoxy-8-(4-methyl-piperazin- 1 - yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-methoxy-4- methylamino-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide; 6-fluoro-4-methoxy-8-(4-methyl-piperazin- 1 -yl)-quinoline-2- carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6-fluoro-4-oxo-8-piperazin-l-yl-4 H- chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050165025, including, without limitation, /V-[3-[3- (dimethylamino)ethoxy]-4-methoxyphenyl-2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)-[l,r-biphenyl]-4-carboxamide; r-methyl-5-[(2’-methyl-4’-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- |indole-3,4,- piperidine; 3-[3-dimethylamino)propyl]-4-hydroxy-A/-[4-(4-pyridinyl)phenyl]benzamide
(Z)-4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)benzylidene]thiomorpholin-3- one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050282816, including, without limitation, l-(4-tert- butylphenyl)-3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro-2if- [1,2’ ]bipyrazinyl-3’ -ylmethyl)- pyrrolidin-2-one; 3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2,]bipyrazinyl-3’-ylmethyl)-l- [4-(tetrahydropyran-4-yl)-phenyl]-pyrrolidin-2-one; 4-(4-tert-butylphenyl)-2-(4-methyl-
3.4.5.6-tetrahydro-2//-[l,2,]bipyrazinyl-3,-ylmethyl)-morpholin-3-one; l-(4-tert- butylphenyl)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl-3’-ylmethyl)- piperidin-2-one; 3-(4-methyl-3,4,5,6-tetrahydro-2if-[l,2,]bipyrazinyl-3,-ylmethyl)-l-[4- (tetrahydropyran-4-yl)-phenyl]-piperidin-2-one; 3-(4-methyl-3,4,5,6-tetrahydro-2 - [ 1 ,2’ ]bipyrazinyl-3’ -ylmethylene)-piperidin-2-one; 3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro-2//- [ 1 ,2’ ]bipyrazinyl-3’ -ylmethyl)-piperidin-2-one; 3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro-2//-
[ 1 ,2’]bipyrazinyl-3’ -ylmethyl)- 1 -[4-(4-methyl-tetrahydro-pyran-4-yl)-phenyl]piperidin-
2-one; (+)-l-(4-tert-butylphenyl)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl- 3’ -ylmethyl)-pyrrolidin-2-one; (+)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl- 3’-ylmethyl)-l-[4-(tetrahydropyran-4-yl)-phenyl]-pyrrolidin-2-one; (+)-4-(4-tert-butyl- phenyl)-2-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl-3’-ylmethyl)-morpholin-
3 -one; (+)-l-(4-tert-butyl-phenyl)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl- 3’ -ylmethyl)-piperidin-2-one; (+)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2’]bipyrazinyl- 3’ -ylmethyl)- l-[4-(tetrahydropyran-4-yl)-phenyl]-piperidin-2-one; (+)-3-(4-methyl-
3.4.5.6-tetrahydro-2 -[l,2’]bipyrazinyl-3’-ylmethyl)-piperidin-2-one; (+)-3-(4-m ethyl-
3.4.5.6-tetrahydro-2 -[l,2’]bipyrazinyl-3’-ylmethyl)-l-[4-(4-methyltetrahydropyran-4- yl)-phenyl]piperidin-2-one; (-)-l-(4-tert-butylphenyl)-3-(4-methyl-3,4,5,6-tetrahydro- 2H-[\ ,2’ ]bipyrazinyl-3’ -ylmethyl)-pyrrolidin-2-one; (-)-3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro- 2H-\l ,2’]bipyrazinyl-3’ -ylmethyl)- 1 -[4-(tetrahydropyran-4-yl)-phenyl]-pyrrolidin-2- one; (-)-4-(4-tert-butylphenyl)-2-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2,]bipyrazinyl-3’- ylmethyl)-morpholin-3 -one; (-)-l-(4-tert-butyl-phenyl)-3-(4-methyl-3,4,5,6-tetrahydro- 2H-[l ,2’ ]bipyrazinyl-3’ -ylmethyl)-piperidin-2-one; (-)-3 -(4-methyl-3 ,4, 5 ,6-tetrahy dro- 2H-[l ,2’]bipyrazinyl-3’ -ylmethyl)- 1 -[4-(tetrahydropyran-4-yl)-phenyl]-piperidin-2-one; (-)-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2,]bipyrazinyl-3’-ylmethyl)-piperidin-2-one; (- )-3-(4-methyl-3,4,5,6-tetrahydro-2 -[l,2,]bipyrazinyl-3’-ylmethyl)-l-[4-(4- methyltetrahydropyran-4-yl)-phenyl]piperidin-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20051710985, including, without limitation, 4-benzyl-2-[2- (4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-
[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;
2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-
3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzyl]-thiomorpholin-3- one; 4-methyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-(2-piperazin-l-ylbenzylidene)-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methyl-(4-piperazin-l-yl)-benzylidene]-l-oxo thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-4-oxy-piperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 10-[4(3,4-dichlorophenyl)-3-oxo-thiomorpholin-2-yl]-2-methyl- 3,42-dihydro-pyrazino[l,2-a]indol-2-ium; 4-benzyl-2-[2-(4-methylpiperazin-l-yl)- benzylidene]-l,l-dioxothiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[3-fluoro-2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[5- fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-5-trifluoromethyl-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-l-yl]- benzylidene}thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-ethylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3-chlorophenyl)-2-[2-(4-methylpiparazin-l- yl)-benzylidene]-thiomorpholin-3-one; 2-[2-chloro-6-(4-methylpiperazin-l-yl)- benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2- (4-methylpiperazin-l-yl)-4-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-l-oxo-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-(5-fluoro-2-piperazin-l-yl-benzylidene)-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-phenyl-2-[2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2-[5-fluoro-2-(4-methylpiperazin-l-yl)- benzylidene]-4-phenyl-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4-tert-butylpiperazin- 1 -yl)-benzylidene]-4-(3 ,4-dichlorophenyl)-thiomorpholin-3 -one; 3-[4-(3 ,4- dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-2-(4- methylpiperazin- 1 -yl)-benzonitrile; 4-(3 ,4-dichlorophenyl)-2- [2-(3 ,4,5- trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-
[5-methyl-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[4-chloro-2- (4-methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4- (3,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(2,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 2-(4-bromo-2-(4-muthylpiperazin-l-yl)-benzylidene]-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin- 2-ylmethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3 , 5 -dichlorophenyl)-2-[2-(3 , 5 - dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2- [2-(3,4,5-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(octahydropyrido[l,2-3]pyrazin-2-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-pyridin-3-yl- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4- difluorophenyl)-thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]- 4-(3,5-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2-[2-(2,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,5-dichlorophenyl)-2-
[2-(2,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2- [2-(3 , 5 -dimethylpiperazin- 1 -yl)-benzylidene] -4-
(4-fluorophenyl)-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(2,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-4-phenylthiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl- [ 1 ,4]diazepan- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-[2- (2,4,6-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; (-)-3(5)-[[2-(4-methyl-l-piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2- pyrrolidinone; enantiomeric mixture of (-)-3 (S)-[[2-(4-m ethyl- 1 - piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2-pyrrolidinone and (+)-3 (R)- [[2-(4-methyl-l-piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2- pyrrolidinone; 3,4-dichloro-/V-{2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl}- benzamide; 4-fluoro-7V-{2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl}-benzamide; N- {2-[2-(4-methylpiperazin- 1 -y l)-pheny 1 ] -ethyl } -benzamide; 3 ,4-dichloro-7V-( 1 -methyl-2-
[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl)-benzamide; 3,4-dichloro-A/-(l-methyl-2-[2- (4-methylpiperazin-l-yl)-phenyl]-propyl)-benzamide; 3,4-dichloro-A/-methyl-7V-{2-[2- (4-methylpiperazin- 1 -yl)-phenyl]-ethyl } -benzamide; /V-benzyl-7V-(2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; iV-(4-chlorobenzyl)-iV-(2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; 3,4-dichloro-7V-2-{2-[methyl-(l- methylpyrolidin-2-ylmethyl)-amino]-phenyl}-ethyl)-benzamide; 3,4-dichloro-/V-{2-[2- (l-methyl-octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl]-ethyl}-benzamide; 3,4- dichloro-A/-{2-[2-(hexahydro-pyrrolo[l,2-u]pyrazin-2-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-A/-{2-[2-(l-methylpiperidin-4-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro- A/-{2-[2-(2-dimethylaminoethoxy)-phenyl]-ethyl}-benzamide; 3 ,4-dichloro-/V- { 2- [2-(2- dimethylamino-ethylsulfanyl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-A/-{2-[2-(2- pyrrolidin- 1 -ylethoxy)-phenyl] -ethyl } -benzamide; 4-chloro-A/-{2-[2-(3-dimethylamino- pyrrolidin- 1 -yl)-phenyl]-ethyl } -benzamide; 4-chloro-7V-(2-{2-[methyl-(2-morpholin-4- yl-ethyl)-amino]-phenyl}-ethyl)-benzamide; 2-(4-chloro-phenyl)-A/-{2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl } -acetamide; A/-{2-[2-(4-methylpiperazin- 1 -yl)- pheny 1 ] -ethyl } - V-phenyl acetami de; N- { 2-[2-(4-methylpiperazin- 1 -yl)-phenyl] -ethyl } - isonicotinamide; /V-{2-[2-(l-azabicyclo[2.2.2]oct-4-yl)-phenyl]-ethyl}- V- methylbenzamide; A/-{2-[2-(l,4-dimethylpiperidin-4-yl)-phenyl]-ethyl}-4- fluorobenzamide; 4-fluoro-A/-{2-[2-(9-methyl-3,9-diazabicyclo[3.3.1]non-3-yl)-phenyl]- ethyl} -benzamide; A/-(2-[2-(l,4-diazabicyclo[3.3.1]non-4-yl)-phenyl]-ethyl}-A/- methylbenzamide; N-{ l-methyl-2-[2-(5-methyl-2,5-diazabicyclo[2.2. l]hept-2-yl)- pheny 1 ] -ethyl } -b enzami de; 2,4-dichloro-A/-methyl-A/-{ l-methyl-2-[2-(3-methyl-3,8- diazabicyclo[3.2.1]oct-8-yl)-phenyl]-ethyl}-benzamide; /V-{2-[2-(4-methyl- octahydroquinoxalin- 1 -yl)-phenyl]-ethyl } -benzamide; A/-{2-[2-(l-ethylpyrrolidin-2- ylmethoxy)-phenyl]-ethyl}-benzamide; 5-phenyloxazole-2-carboxylic acid {2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 5 -pheny lthi ophene-2-carb oxy li c acid {2- [2-(4-methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 5-methylthiophene-2-carboxylic acid
{2-[2-(4-methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 4-fluoronaphthalene- 1 -carboxylic acid {2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl}-amide; 5-fluoro-l -indole-2- carboxylic acid {2-[2-(4-methyl-piperazin-l-yl)-phenyl]-ethyl}-amide; 4-chloro- V-{2- [2-(3,4,5-trimethylpiperazin-l-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-/V-{2-[2- (2,4,5-trimethylpiperazin-l-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-/V-{2-[2-(2,4,6- trimethylpiperazin-l-yl)-phenyl]-ethyl} -benzamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050182049, including, without limitation, 4-benzyl-2-[2- (4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-
[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;
2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-
3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzyl]-thiomorpholin-3- one; 4-methyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-(2-piperazin-l-ylbenzylidene)-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methyl-(4-piperazin-l-yl)-benzylidene]-l-oxo-thiomorpholin- 3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-4-oxy-piperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 10-[4(3,4-dichlorophenyl)-3-oxo-thiomorpholin-2-yl]-2-methyl- 3,42-dihydro-pyrazino[l,2-u]indol-2-ium; 4-benzyl-2-[2-(4-methylpiperazin-l-yl)- benzylidene]-l,l-dioxothiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[3-fluoro-2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[5- fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-5-trifluoromethyl-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-l-yl]- benzylidene}thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-ethylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3-chlorophenyl)-2-[2-(4-methylpiparazin-l- yl)-benzylidene]-thiomorpholin-3-one; 2-[2-chloro-6-(4-methylpiperazin-l-yl)- benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2- (4-methylpiperazin-l-yl)-4-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-l-oxo-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-(5-fluoro-2-piperazin-l-yl-benzylidene)-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-phenyl-2-[2-(3,4,5-trimethylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2-[5-fluoro-2-(4-methylpiperazin-l-yl)- benzylidene]-4-phenyl-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4-tert-butylpiperazin- 1 -yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3 -one; 3-[4-(3 ,4- dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-2-(4- methylpiperazin- 1 -yl)-benzonitrile; 4-(3 ,4-dichlorophenyl)-2- [2-(3 ,4,5- trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-
[5-methyl-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[4-chloro-2- (4-methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4- (3,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(2,4-difluorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 2-(4-bromo-2-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin- 2-ylmethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3 , 5 -dichlorophenyl)-2-[2-(3 , 5 - dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2- [2-(3,4,5-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(octahydropyrido[l,2-3]pyrazin-2-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-pyridin-3-yl- thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4- difluorophenyl)-thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]- 4-(3,5-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2-[2-(2,5- dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,5-dichlorophenyl)-2- [2-(2,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-l-yl)- benzylidene]-thiomorpholin-3-one; 2- [2-(3 , 5 -dimethylpiperazin- 1 -yl)-benzylidene] -4- (4-fluorophenyl)-thiomorpholin-3-one; 4-benzo[l,3]dioxol-5-yl-2-[2-(2,5- dimethylpiperazin- l-yl)-benzylidene]-thiomorpholin-3 -one; 2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-4-phenylthiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-
[ 1 ,4]diazepan- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-[2- (2,4,6-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; (-)-3(5)-[[2-(4-methyl-l-piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2- pyrrolidinone; enantiomeric mixture of (-)-3 (S)-[[2-(4-m ethyl- 1 - piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2-pyrrolidinone and (+)-3 (R)- [[2-(4-methyl-l-piperazinyl)phenyl]methyl]-l-[4-(trifluoromethyl)phenyl]-2- pyrrolidinone; 3,4-dichloro-A/-(2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl)-benzamide; 4-fluoro-A/-(2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl)-benzamide; A/-(2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; 3,4-dichloro-A/-(l-methyl-2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; 3,4-dichloro-7V-(l-methyl-2-[2-(4- methylpiperazin-l-yl)-phenyl]-propyl)-benzamide; 3,4-dichloro-A/-methyl-A/-(2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; A/-benzyl-A/-(2-[2-(4-methylpiperazin- 1 -yl)-phenyl]-ethyl)-benzamide; A/-(4-chlorobenzyl)-A/-(2-[2-(4-methylpiperazin-l-yl)- phenyl]-ethyl)-benzamide; 3,4-dichloro-A/-(2-{2-[methyl-(l-methylpyrolidin-2- ylmethyl)-amino]-phenyl}-ethyl)-benzamide; 3,4-dichloro-A/-{2-[2-(l-methyl- octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl]-ethyl}-benzamide; 3 , 4-di chi oro-N- { 2- [2- (hexahydro-pyrrolo[l,2-a]pyrazin-2-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro- V-{2- [2-(l-methylpiperidin-4-yl)-phenyl]-ethyl)-benzamide; 3 ,4-dichl oro-N- { 2- [2-(2- dimethylaminoethoxy)-phenyl]-ethyl}-benzamide; 3,4-dichloro-7V-{2-[2-(2- dimethylamino-ethylsulfanyl)-phenyl]-ethyl}-benzamide; 3,4-dichloro- V-{2-[2-(2- pyrrolidin- 1 -ylethoxy)-phenyl] -ethyl } -benzamide; 4-chloro-/V-{2-[2-(3-dimethylamino- pyrrolidin- 1 -yl)-phenyl]-ethyl } -benzamide; 4-chloro-7V-(2-{2-[methyl-(2-morpholin-4- yl-ethyl)-amino]-phenyl}-ethyl)-benzamide; 2-(4-chloro-phenyl)-7V-{2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl } -acetamide; /V-{2-[2-(4-methylpiperazin- 1 -yl)- pheny 1 ] -ethyl } - V-phenyl acetami de; N- { 2-[2-(4-methylpiperazin- 1 -yl)-phenyl] -ethyl } - isonicotinamide; /V-{2-[2-(l-azabicyclo[2.2.2]oct-4-yl)-phenyl]-ethyl}- V- methylbenzamide; 7V-{2-[2-(l,4-dimethylpiperidin-4-yl)-phenyl]-ethyl}-4- fluorobenzamide; 4-fluoro- V-{2-[2-(9-methyl-3,9-diazabicyclo[3.3.1]non-3-yl)-phenyl]- ethy 1 } -b enzami de ; 7V-(2-[2-(l,4-diazabicyclo[3.3.1]non-4-yl)-phenyl]-ethyl}- V- methylbenzamide; A/-{ l-methyl-2-[2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)- phenyl ] -ethyl } -b enzami de; 2,4-dichloro-A/-methyl-7V-{ l-methyl-2-[2-(3-methyl-3,8- di azabi cy cl o [3.2.1 ] oct- 8 -y l)-pheny 1 ] -ethyl } -b enzami de; 7V-{2-[2-(4-methyl- octahydroquinoxalin- 1 -yl)-phenyl]-ethyl } -benzamide; /V-{2-[2-(l-ethylpyrrolidin-2- ylmethoxy)-phenyl]-ethyl} -benzamide; 5 -phenyl oxazol e-2-carb oxy li c acid {2-[2-(4- methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 5 -pheny lthi ophene-2-carb oxy li c acid {2- [2-(4-methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 5-methylthiophene-2-carboxylic acid
{2-[2-(4-methylpiperazin- 1 -yl)-phenyl]-ethyl } -amide; 4-fluoronaphthalene- 1 -carboxylic acid {2-[2-(4-methylpiperazin-l-yl)-phenyl]-ethyl}-amide; 5 -fluoro- 1 -indole-2- carboxylic acid {2-[2-(4-methyl-piperazin- 1 -yl)-phenyl]-ethyl } -amide; 4-chloro- V-{2- [2-(3,4,5-trimethylpiperazin-l-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-A/-{2-[2- (2,4,5-trimethylpiperazin-l-yl)-phenyl]-ethyl}-benzamide; 3,4-dichloro-A/-{2-[2-(2,4,6- trimethylpiperazin-l-yl)-phenyl]-ethyl} -benzamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20050288304, including, without limitation, 7V-{8-[(2- dimethylamino-ethyl)-ethyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl}-4- trifluoromethyl-benzamide; A/-{8-[(2-dimethylamino-ethyl)ethyl-amino]-5, 6,7,8- tetrahydro-naphthalen-2-yl}-4-fluoro-benzamide; 4-tert-butyl-/V-{8-[(2-dimethylamino- ethyl)-ethyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl}-benzamide; l-[7-(4-benzyl- phenyl) l,2,3,4-tetrahydro-naphthalen-l-yl]-4-methyl-piperazine; l-[7-(4-benzyloxy- phenyl)- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl]-4-methyl-piperazine; l-methyl-4-(7- phenyl- 1 ,2,3 , 4-tetrahy dro-naphthal en- 1 -yl)-piperazine; 1 -[7-(4-fluoro-phenyl)- 1, 2,3,4- tetrahydro-naphthalen- 1 -yl]-4-methyl-piperazine; l-[7-(3, 5-dichloro-phenyl)-l, 2,3,4- tetrahy dro-naphthal en- 1 -yl]-4-methyl-piperazine; 1 -[7-(2-methoxy-phenyl)-l, 2,3,4- tetrahy dro-naphthal en- 1 -yl]-4-methyl-piperazine; 1 -methyl-4-[7-(4-trifluoromethyl- phenyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-piperazine; l-[7-(3,4-dimethoxy-phenyl)- 1 ,2,3 , 4-tetrahy dro-naphthal en- 1 -yl]-4-m ethyl-piperazine; 1 -(7-biphenyl-4-yl- 1 ,2,3,4- tetrahydro-naphthalen- 1 -yl)-4-m ethyl-piperazine; l-[7-(2,3-dihydro-benzo[l,4]dioxin-6- yl)- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl]-4-m ethyl-piperazine; 8-(4-methyl-piperazin- 1 - yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid [l-(4-methoxy-phenyl)ethyl]- amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4- tert-buty 1 -b enzy 1 ami de ; 8-(4-methyl-piperazin-l-yl)-5, 6, 7, 8-tetrahy dro-naphthal ene-2- carboxylic acid 4-trifluoromethy 1 -b enzy 1 ami de; 8-(4-methyl-piperazin-l -yl)-5, 6,7,8- tetrahydro-naphthalene-2-carboxylic acid (1,2,3 , 4-tetrahy dro-naphthal en- 1 -yl)-amide; 8- (4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]-amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro- naphthal ene-2-carb oxy li c acid 4-chloro-benzylamide; 8-(4-methyl-piperazin-l-yl)- 5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-fluoro-benzylamide; 8-(4-methyl- piperazin-l-yl)-5, 6, 7, 8-tetrahy dro-naphthal ene-2-carboxylic acid (furan-2-ylmethyl)- amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2- chloro-benzylamide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2- carboxylic acid 3 -trifluoromethy 1 -b enzy 1 ami de; 8-(4-methyl-piperazin-l-yl)-5, 6,7,8- tetrahydro-naphthalene-2-carboxylic acid 3 -fluoro-b enzy 1 ami de; 8-(4-methyl-piperazin- l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2-methyl-benzylamide; 8-(4- methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2-methoxy- b enzy 1 amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 3-methoxy-benzylamide; 8-(4-methyl-piperazin-l-yl)-5, 6, 7, 8-tetrahy dro- naphthalene-2-carboxylic acid (2,5-dimethyl-2i7-pyrazol-3-yl)-amide; 8-(4-methyl- piperazin-l-yl)-5, 6, 7, 8-tetrahy dro-naphthal ene-2-carboxylic acid (5-tert-butyl-2-methyl- 2i7-pyrazol-3-yl)-amide; 8-(4-methyl-piperazin-l-yl)-5, 6, 7, 8-tetrahy dro-naphthal ene-2- carboxylic acid [l-(4-chloro-phenylyethyl]-amide; 8-(4-methyl-piperazin-l-yl)-5, 6,7,8- tetrahydro-naphthalene-2-carboxylic acid 3-chloro-benzylamide; 8-(4-methyl-piperazin- l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (pyridin-2-ylmethyl)-amide; 8- (4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (4-chloro- phenyl)amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (5-methyl-[l,3,4]thiadiazol-2-yl)-amide; 8-(4-methyl-piperazin-l-yl)-5, 6,7,8- tetrahydro-naphthalene-2-carboxylic acid 3,4-difluoro-benzylamide; 8-(4-methyl- piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-methoxy- benzyl amide; 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid pyridin-2-ylamide; 1 -methyl -4-(7-C>-tolyl- 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl)- piperazine; l-[7-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-4-methyl- piperazine; l-[7-(3 -methoxy-phenyl)- 1 ,2,3 , 4-tetrahy dro-naphthal en- 1 -yl]-4-methyl- piperazine; 4-tert-butyl- V-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2- yl]-benzamide; 2 -methoxy-A/-[8-(4-methyl-piperazin-l-yl)-5, 6,7, 8-tetrahy dro- naphthal en-2-yl]-4-morpholin-4-yl-benzamide; 4-Isopropoxy-7V-[8-(4-methyl-piperazin- l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide; 4-benzyloxy- V-[8-(4-methyl- piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide; benzo[l,3]dioxole-5- carboxylic acid [8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-amide; 4-(cy cl ohex-l-enyloxy -A/-[8-(4-methyl-piperazin-l-yl)-5, 6,7, 8-tetrahy dro-naphthal en-2- yl]-benzamide; A/-{8-[(2-dimethylamino-ethyl)methyl-amino]-5,6,7,8-tetrahydro- naphthalen-2-yl}2-fluoro-4-morpholin-4-yl-benzamide; A/-[8-(4-methyl-piperazin-l-yl)-
5.6.7.8-tetrahydro-naphthalen-2-yl]-4-trifluoromethoxy-benzamide; l-methyl-4-(7- pyridin-4-yl- 1 ,2, 3, 4-tetrahy dro-naphthal en- 1 -yl)-piperazine; 1 -methyl-4-[7-(4-methyl- pyri din-3 -yl)- 1,2, 3, 4-tetrahy dro-naphthalen-l-yl]-piperazine; l-methyl-4-[7-(6-methyl- pyri din-3 -yl)- 1,2, 3, 4-tetrahy dro-naphthalen-l-yl]-piperazine; 1 - [7-(6-methoxy-pyridin- 3-yl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-4-methyl-piperazine; l-methyl-4-(7-pyri din-2 - yl- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-piperazine; 4- { 5-[8-(4-methyl-piperazin- 1 -yl)-
5.6.7.8-tetrahy dro-naphthal en-2-yl]-pyridin-2-yl}-morpholine; (+)- 1 -methyl-4- [7-(4- methyl-pyridin-3 -yl)- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl]-piperazine; (-)- 1 -methyl-4-[7- (4-methyl-pyridin-3-yl)- 1,2, 3, 4-tetrahy dro-naphthalen-l-yl]-piperazine; l-methyl-4-[6- (4-methyl-pyridin-3-yl)-chroman-4-yl]-piperazine; 1 -methyl-4-(6-pyridin-4-yl- chroman-4-yl)-piperazine; 4-{5-[4-(4-methyl-piperazin-l-yl)-chroman-6-yl]-pyridin-3- yl} -morpholine; l-[4-(4-methyl-piperazin-l-yl)-chroman-6-yl]-l -pyrrolo[2,3-
Z?]pyridine; l-methyl-4-[6-(4-methyl-pyridin-3-yl)-chroman-4-yl]-piperazine; 1 -methyl - 4-[7-(4-trifluoromethyl-benzyloxy)-l,2,3,4-tetrahydro-naphthalen-l-yl]-piperazine; 1- [7-(4-tert-butyl-benzyloxy)-l,2,3,4-tetrahydro-naphthalen-l-yl]-4-methyl-piperazine; 6- morpholin-4-yl-nicotinic acid 8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro- naphthalen-2-yl ester; 7V-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2- yl]-6-morpholin-4-yl-nicotinamide; {4-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro- naphthal en-2-y 1 carb amoy 1 ] -b enzy 1 } -carb ami c acid tert-butyl ester; 7V-[8-(4-methyl- piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-trifluoromethyl-benzamide; N-[ 8-
(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-trifluoromethyl- benzamide; 2-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-6- morpholin-4-yl-3 ,4-dihy dro-2//-i soquinolin- 1 -one; l-methyl-4-(7-piperidin-4-yl-
1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl)-piperazine; l-methyl-4-(7-piperidin-3-yl-l, 2,3,4- tetrahydro-naphthalen- 1 -yl)-piperazine; 1 -methyl-4- [7-( 1 -methyl-piperidin-4-yl)-
1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl]-piperazine; (5 -fluoro-pyrimidin-2-yl)- { 2- [8-(4- methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}amine; 7V-{2-[8- (4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}4- trifluoromethyl-benzamide; A/-{2-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro- naphthalen-2-yloxy]-ethyl}-4-trifluoromethyl-benzamide; {4-[8-(4-methyl-piperazin- 1 - yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-piperidin-l-yl}(4-trifluoromethyl-phenyl)- methanone; {3-[8-(4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]- piperidin- 1 -yl } (4-trifluoromethyl-phenyl)methanone; 4-aminomethyl-A/-[8-(4-methyl- piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide; (+)-l-methyl-4-(7- pyridin-4-yl- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-piperazine; (-)- 1 -methyl-4-(7-pyridin-
4-yl- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)piperazine; 4-( 1 -hydroxy- 1 -methyl-ethyl)- V-[8- (4-methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide; 3-[8-(4- methyl-piperazin-l-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-6’-morpholin-4-yl-3,4,5,6- tetrahydro-27/-[l,2’]bipyridinyl; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20060025421, including, without limitation, l-[4-(3,5- dimethyl-isoxazol-4-yl)phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethylene]- piperidin-2-one; 2-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethylene]-4-[4-
(tetrahy dropyran-4-yl)-phenyl] -morpholin-3 -one; 1 - [4-(3 , 5-dimethylisoxazol-4- yl)phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]-piperidin-2-one; 2-[2-(4- methylpiperazin-l-yl)-pyridin-3-ylmethyl]-4-[4-(tetrahydropyran-4-yl)-phenyl]- morpholin-3 -one; l-[4-(2-methyloxazol-4-yl)-phenyl]-3-[2-(4-methylpiperazin-l-yl)- pyri din-3 -ylmethyl]-piperidin-2-one; l-[4-(2-tert-butyloxazol-4-yl)phenyl]-3-[2-(4- methylpiperazin- l-yl)-pyri din-3 -ylmethyl]-piperidin-2-one; l-[4-(2-isopropyl-oxazol-4- yl)phenyl]-3-[2-(4-methylpiperazin-l-yl)pyridin-3-ylmethyl]-piperidin-2-one; l-[4-(2,5- dimethyloxazol-4-yl)-phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]- piperidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]-l-[4-
(tetrahydropyran-4-yl)-phenyl]-piperidin-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-pyridin- 3-ylmethyl]-l-[4-(tetrahydropyran-4-yl)-phenyl]-pyrrolidin-2-one; 3-[2-(4- methylpiperazin- 1 -yl)-pyridin-3 -ylmethyl]- 1 -(4-oxazol-2-ylphenyl)-pyrrolidin-2-one; 3- [2-(4-methylpiperazin-l -yl)-pyri din-3 -ylmethyl]- l-(4-oxazol-4-ylphenyl)pyrrolidin-2- one; 3-[2-(4-methylpiperazin-l -yl)-pyri din-3 -ylmethyl]- l-(4-oxazol-5-ylphenyl)- pyrrolidin-2-one; l-[4-(2-methyloxazol-4-yl)phenyl]-3-[2-(4-methylpiperazin-l-yl)- pyridin-3-ylmethyl]-pyrrolidin-2-one; l-[4-(l-methoxycyclobutyl)-phenyl]-3-[2-(4- methylpiperazin-l-yl)-pyridin-3-ylmethyl]-piperidin-2-one; 3 -[2-(4-methylpiperazin- 1 - yl)-pyridin-3-ylmethyl]-l-(4-trifluoromethylphenyl)-pyrrolidin-2-one; l-[4-(l- hydroxycyclopentyl)phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]- pyrrolidin-2-one; 1 -[4-(l -hydroxy- 1 -methylethyl)-phenyl]-3-[2-(4-methylpiperazin- 1 - yl)pyridin-3-ylmethyl]-pyrrolidin-2-one; l-(4-tert-butylphenyl)-3-[2-(4- methylpiperazin- 1 -yl)-pyri din-3 -ylmethyl]-pyrrolidin-2-one; 1 -[4-(l -hydroxy - cy cl opentyl)-phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyri din-3-ylmethyl]-piperi din-2 - one; l-(4-tert-butylphenyl)-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]- piperidin-2-one; 3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]-l-phenylpiperidin- 2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-pyri din-3 -ylmethyl]- 1 -(4- trifluoromethoxyphenyl)-piperidin-2-one; 1 -[4-(l -hydroxy- 1 -methylethyl)phenyl]-3-[2- (4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]-piperidin-2-one; 1 -[4- 1- hydroxycyclobutyl)-phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3-ylmethyl]- piperidin-2-one; 1 -(4-tert-butylphenyl)-3 - [2-(4-methylpiperazin- 1 -yl)-pyri din-3 - ylmethyl]-pyrrolidin-2-one; l-(4-tert-butylphenyl)-3-[2-(4-methylpiperazin-l-yl)- pyridin-3-ylmethyl]-piperidin-2-one; 3 - [2-(4-methylpiperazin- 1 -yl)-pyri din-3 - ylmethyl]- 1 -(4-tetrahydropyran-4-yl)-phenyl]-piperidin-2-one; l-[4-( 1 -hydroxy- 1 - methylethyl)-phenyl]-3-[2-(4-methylpiperazin-l-yl)pyridin-3-ylmethyl]-piperi din-2- one; l-[4-(l-hydroxy-l-methylethyl)phenyl]-3-[2-(4-methylpiperazin-l-yl)-pyridin-3- ylmethyl]-pyrrolidin-2-one; and pharmaceutically acceptable salts or ester thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070010526, including, without limitation, l-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-(4-piperi din-l-ylmethyl- phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-[8-(4-methyl-piperazin-l-yl)-3,4-dihydro-
1 H-[ soquinolin-2-yl] -ethanone; 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 5-methoxy-8-phenyl-
3.4-dihydro-lif-isoquinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; l-[5- benzyloxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-(4- isopropyl-phenyl)-ethanone; l-[5-hydroxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif- isoquinolin-2-yl]-2-(4-isopropyl-phenyl)-ethanone; 2-(4-isopropyl-phenyl)-l-(5- methoxy-8-pyridin-4-yl-3,4-dihydro-lif-isoquinolin-2-yl)-ethanone; 2-(4-isopropyl- phenyl)-l-[5-methoxy-8-(l-methyl-l,2,3,6-tetrahydro-pyridinyl)-3,4-dihydro-lif- isoquinolin-2-yl]-ethanone; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-6-propyl-3,4- dihydro-l//-isoquinolin-2-yl]-2-oxo-ethyl}-A/-propyl-benzenesulfonamide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo-ethyl}- A/-propyl-benzenesulfonamide; A/-isopropyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; A/-tert-butyl-4- {2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo- ethyl }-benzenesulfonamide; A/-benzyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; A/-(2-methoxy- benzyl)-4-{2-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- lif-isoquinolin-2- yl]-2-oxo-ethyl}-benzenesulfonamide; A/-(3-methoxy-benzyl)4-{2-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- lif-isoquinolin-2-yl]-2-oxo-ethyl}- benzenesulfonamide; A/-(4-methoxy-benzyl)4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-2-oxo-ethyl}- -(2-methoxy-phenyl)-benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3, 4-dihydro- l /-isoquinolin-2-yl]-2-oxo-ethyl}- /-(3-methoxy-phenyl)- benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- IH- isoquinolin-2-yl]-2-oxo-ethyl}- -(4-methoxy-phenyl)-benzenesulfonamide; N- cy cl opropyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin- 2-yl]-2-oxo-ethyl}-benzenesulfonamide; 7V-cyclobutyl-4-{2-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; 4- {2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo- ethyl }-benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-A/-methyl-benzenesulfonamide; 4-{2-[5-methoxy-8- (4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-A/-ethyl- benzenesulfonamide; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- 1 - isoquinolin-2-yl]-2-oxo-ethyl}-A/,A/-dimethyl-benzenesulfonamide; /V-ethyl-4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-2-oxo-ethyl}-
A/-methyl-benzenesulfonamide; /V,/V-diethyl-4-{2-[S-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-benzenesulfonamide; /V,/V-dipropyl- 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-2-oxo- ethyl}-benzenesulfonamide; /V-benzyl-4-{2-[S-methoxy-8-(4-methyl-piperazin-l-yl)- 3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-A/-methyl-benzenesulfonamide; N- benzyl-4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]- 2-oxo-ethyl}-A/-ethyl-benzenesulfonamide; A/-benzyl-4-{2-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H- i soquinolin-2-yl] -2-oxo-ethyl } -N-Ϊ sopropyl- benzenesulfonamide; 2-[4-(azetidine-l-sulfonyl)-phenyl]-l-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H- i soquinolin-2-yl] -2- [4-(pyrrolidine- 1 -sulfonyl)-phenyl] - ethanone; A/-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2- yl]-2-oxo-ethyl}-isonicotinamide; 7V-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-4-oxo-butyl}-isonicotinamide; 7V-{5-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-5-oxo-pentyl}- isonicotinamide; quinoline-5-carboxylic acid {2-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-amide; quinoline-5-carboxylic acid {4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l//-isoquinolin-2-yl]-4-oxo- butyl} -amide; quinoline-5-carboxylic acid {5-[5-methoxy-8-(4-methyl-piperazin-l-yl)- 3,4-dihydro-l//-isoquinolin-2-yl]-5-oxo-pentyl}-amide; A/-{2-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H- i soquinolin-2-yl] -2-oxo-ethyl } -benzamide; 7V-{3-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-3-oxo-propyl}- benzamide; A/-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin- 2-yl]-4-oxo-butyl}-benzamide; A/-{5-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-5-oxo-pentyl}-benzamide; 4-methoxy-/V-{2-[5-methoxy- 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l//-isoquinolin-2-yl]-2-oxo-ethyl}-benzamide; 4-methoxy-A/-{4-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-
2-yl]-4-oxo-butyl}-benzamide; 4-methoxy-/V-{5-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l//-isoquinolin-2-yl]-5-oxo-pentyl}-benzamide; (4-butylamino-phenyl)- [5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-methanone; (4-cyclohexyl-phenyl)-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- IH- isoquinolin-2-yl]-methanone; (4-benzyl-phenyl)-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l -isoquinolin-2-yl]-methanone; (4’-ethyl-biphenyl-4-yl)-[5-methoxy- 8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-methanone; (4’-hydroxy- biphenyl-4-yl)-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2- yl]-methanone; [5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinolin-2- yl]-(4-phenoxy-phenyl)-methanone; (4-benzoyl-phenyl)-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-\ soquinolin-2-yl] -methanone; 5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid [4-(4-methoxy- phenylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid (4-phenylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(2-methoxy- phenylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid [4-(3-methoxy-phenylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4- benzylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinoline-2-carboxylic acid [4-(2-methoxy-benzylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4- (3-methoxy-benzylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro-lif-isoquinoline-2-carboxylic acid [4-(4-methoxy-benzylsulfamoyl)- phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- liif-isoquinoline-2- carboxylic acid (4-propylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-i sopropyl sulfamoyl-phenyl)- amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-cyclopropylsulfamoyl-phenyl)-amide; 5 -methoxy- 8 -(4-methy 1 - piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid (4-tert-butylsulfamoyl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-methylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-ethylsulfamoyl-phenyl)-amide;
5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-cyclobutylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-liif-isoquinoline-2-carboxylic acid [4-(thiazol-2-ylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4- acetylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid (4-butyrylsulfamoyl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(methyl- phenyl-sulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- liif-isoquinoline-2-carboxylic acid [4-(acetyl-methyl-sulfamoyl)-phenyl]-amide; l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-(4- morpholin-4-yl-phenyl)-ethanone; 2-(4-bromo-phenyl)-l-[5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinolin-2-yl] -ethanone; 2-(4-dimethylamino- phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]- 2-(3-morpholin-4-yl-phenyl)-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-(4-piperidin-l-yl-phenyl)-ethanone; l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-[4-(4-methyl-piperazin-l- yl)-phenyl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinolin-2-yl]-2-[4-(4-propyl-piperidin-l-yl)-phenyl]-ethanone; 2-{4-[4-(2-methoxy- ethyl)-piperidin- 1 -yl] -phenyl } - 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4-dihydro- l -isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-[4-(4-methyl-piperidin-l-yl)-phenyl]-ethanone; 2-[4-(4- hydroxy-piperidin- 1 -yl)-phenyl]- 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3,4- dihydro-l -isoquinolin-2-yl]-ethanone; 2-{4-[4-(2-hydroxy-ethyl)-piperazin-l-yl]- phenyl}-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; 2-(4-amino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-ethanone; 2-(4-isopropyl-phenoxy)-l-[5-methoxy-8-(4-methyl- piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-[4-(4-benzyl-piperazin- 1 - yl)-phenyl]-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2- yl]-ethanone; 2-(4-isopropyl-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-ethanone; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro- lif-isoquinoline-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide; 4- amino-A/-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2- yl]-2-oxo-ethyl}-phenyl)-butyramide; 2-(4-dibutylamino-phenyl)-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; 2-(4-butylamino- phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl)- ethanone; 2-(4-diphenethylamino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro-l -isoquinolin-2-yl]-ethanone; l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-
3.4-dihydro- 1 H-i soquinolin-2-yl] -2-(4-phenethylamino-phenyl)-ethanone; 2- { 4- [Bi s-(2- benzyloxy-ethyl)-amino]-phenyl } - 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4- dihydro- l /-isoquinolin-2-yl]-ethanone; 2-[4-(2-benzyloxy-ethylamino)-phenyl]-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone;
biphenyl-4-yl-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2- yl]-methanone; 2 -biphenyl-4-yl-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-ethanone; l-(5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-(4-methoxy-phenyl)-ethanone; 2-benzo[l,3]dioxol-5-yl-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; 2-
(3,4-dimethoxy-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /- isoquinolin-2-yl]-ethanone; 2-(4-fluoro-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l- yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; 2-(4-chloro-phenyl)-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; 2-(4-methyl- phenyl)- l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- liif-isoquinolin-2-yl]- ethanone; 2 -phenyl-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- 1 - isoquinolin-2-yl]-ethanone; 1 -[5-methoxy-8-(4-methyl-piperazin- 1 -yl)-3 ,4-dihydro- IH- isoquinolin-2-yl]-2-(4-methylsulfanyl-phenyl)-ethanone; 2-(4-methanesulfmyl-phenyl)- l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-ethanone; /V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-2- oxo-ethyl}-phenyl)-methanesulfonamide; 2-[4-(2-methoxy-benzylamino)-phenyl]-l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; 2-(4- benzylamino-phenyl)-l-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinolin-2-yl]-ethanone; 2-[4-(3-methoxy-benzylamino)-phenyl]-l-[5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinolin-2-yl]-ethanone; 2-[4-(4-methoxy- benzylamino)-phenyl]-l -[5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- 1 - isoquinolin-2-yl]-ethanone; 2-(4-isopropyl-phenyl)-l-[5-methoxy-8-(4-methyl- piperazine-l-carbonyl)-3,4-dihydro-l /-isoquinolin-2-yl]-ethanone; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3’,4-dihydro-l -isoquinoline-2-carboxylic acid (4-isopropyl- phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-cyclohexyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro- l -isoquinoline-2-carboxylic acid [4-(5-methoxy-pyrimidin-2- ylsulfamoyl)-phenyl]-amide; (4-{[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinoline-2-carbonyl]-amino)-benzyl)-phosphonic acid diethyl ester; 5-methoxy- 8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(3,4- dimethyl-isoxazol-5-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(6-methyl-benzothiazol-2-yl)- phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid (4-tert-butyl-phenyl)-amide; 5-methoxy-8-(4-methyl-piperazin- 1 -yl)- 3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-sulfamoyl-phenyl)-amide; 5-methoxy- 8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(2- phenyl-2 -pyrazol-3-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(pyrrolidine-l-sulfonyl)-phenyl]- amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinoline-2- carboxylic acid [4-(5-methyl-[l,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-amide; 5- methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4- (4,5-dimethyl-oxazol-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(2-phenyl-2 -pyrazol-3- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinoline-2-carboxylic acid [4-(4-methyl-pyrimidin-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-lif-isoquinoline-2-carboxylic acid [4-(2,6-dimethyl-pyrimidin-4-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl- piperazin- 1 -yl)-3 ,4-dihydro- 1 H-i soquinoline-2-carboxylic acid [4-(pyrimidin-2- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l /- isoquinoline-2-carboxylic acid [4-(2,6-dimethoxy-pyrimidin-4-ylsulfamoyl)-phenyl]- amide; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- liif-isoquinoline-2- carboxylic acid [4-(6-methoxy-pyridazin-3-ylsulfamoyl)-phenyl)-amide; 5-methoxy-8- (4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(4,6- dimethyl-pyrimidin-2-ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin- 1 - yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(6-methoxy-pyrimidin-4- ylsulfamoyl)-phenyl]-amide; 5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l - isoquinoline-2-carboxylic acid [4-(pyridin-2-ylsulfamoyl)-phenyl]-amide; 4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}- benzoic acid methyl ester; 4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-A/-methyl-benzamide; 8-(4-ethyl-piperazin- 1 -yl)-5- methoxy-3,4-dihydro-l -isoquinoline-2-carboxylic acid (4-propylsulfamoyl-phenyl)- amide; 8-(4-cyclohexyl-piperazin-l-yl)-5-methoxy-3,4-dihydro-l -isoquinoline-2- carboxylic acid (4-propylsulfamoyl-phenyl)-amide; 2-(4-isopropyl-phenyl)-l-(5- methoxy-8-piperazin-l-yl-3,4-dihydro-l -isoquinolin-2-yl)-ethanone; /V-(4-{2-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}- phenyl)-2-phenyl-acetamide; 7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-3-phenyl-propionamide; N-(4-{2- [5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo- ethyl }-phenyl)-benzamide; 7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-benzenesulfonamide; l-[5- methoxy-8-(4-methyl-piperazin-l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-(4- phenylmethanesulfonyl-methyl-phenyl)-ethanone; 4-chloro-/V-(4-{2-[5-methoxy-8-(4- methyl-piperazin-1 -yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)- benzenesulfonamide; 4-tert-butyl-7V-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4- dihydro-l -isoquinolin-2-yl]-2-oxo-ethyl}-phenyl)-benzenesulfonamide; 7V-benzyl- V- (4-{2-[5-methoxy-8-(4-methyl-piperazin- l-yl)-3, 4-dihydro- l -isoquinolin-2-yl]-2-oxo- ethyl }-phenyl)-benzenesulfonamide; l-(4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)- 3, 4-dihydro- 1 if-i soquinolin-2-yl] -2-oxo-ethyl } -phenyl)-3 -(4-methoxy-phenyl)-urea; 1 - (4-{2-[5-methoxy-8-(4-methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinolin-2-yl]-2-oxo- ethyl } -phenyl)-3 -(3 -methoxy-phenyl)-urea; [5-methoxy-8-(4-methyl-piperazin-l-yl)- 3,4-dihydro-l -isoquinolin-2-yl]-[2,-methyl-4’-(5-methyl-[l,2,4]oxadiazol-3-yl)- biphenyl-4-yl]-methanone; 5-methoxy-8-(4-methyl-piperazin-l -yl)-3, 4-dihydro- IH- isoquinoline-2-carboxylic acid (4-piperidin-l-yl-phenyl)-amide; 5-methoxy-8-(4- methyl-piperazin-l-yl)-3,4-dihydro-l -isoquinoline-2-carboxylic acid [4-(4-methyl- piperazin- 1 -yl)-phenyl]-amide; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070135442, including, without limitation, 6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(2-oxopyrrolidin- 1 -yl)phenyl)chroman-2-carboxamide; (+)- 6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2-oxopyrrolidin- 1 -yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(2-oxopyrrolidin- 1 - yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(2- oxotetrahydropyrimidin- 1 (2H)-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(2- oxotetrahydropyrimidin- 1 (2/ )-yl)phenyl)chroman-2-carboxamide; 6-methoxy-/V-(4-(3 - methyl-2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamide; (+)-6-methoxy-/V-(4-(3-methyl-2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy-A/- (4-(3 -methyl-2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamide; 6-fluoro-A/-(4-(3-methyl-2-oxotetrahydropyrimidin-l(2if)- yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(3 - methyl-2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamide; (-)-6-fluoro-A/-(4-(3-methyl-2-oxotetrahydropyrimidin- 1 (2if)-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3-yl)phenyl)chroman-2-carboxamide; (+)- 6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3-yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3- yl)phenyl)chroman-2-carboxamide; 6-methoxy-7V-(4-(3-methyl-2,5-dioxoimidazolidin- l-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-/V-(4- (3-methyl-2,5-dioxoimidazolidin-l-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-6-methoxy-/V-(4-(3-methyl-2,5-dioxoimidazolidin-l-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 7V-(4-(2, 5-dioxoimidazolidin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-/V-(4- (2, 5-dioxoimidazolidin- l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)- V-(4-(2,5-dioxoimidazolidin-l-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-(2-oxooxazolidin-3-yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3-yl)phenyl)chroman-2-carboxamide; (-)- 6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2-oxopyrrolidin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(2- oxopyrrolidin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin-
1 -yl)-/V-(4-(2-oxopyrrolidin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-/V-(4-(3 - methyl-2, 5-dioxoimidazolidin-l-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro- V-(4-(3-methyl-2,5-dioxoimidazolidin-l-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-fluoro-/V-(4-(3 -methyl-2, 5 - dioxoimidazolidin- 1 -yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-
(4-(2, 5-dioxoimidazolidin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (+)-A/-(4-(2,5-dioxoimidazolidin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(2, 5-dioxoimidazolidin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(2-oxotetrahydropyrimidin- 1 (2 )-yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2-oxotetrahydropyrimidin- l(2 )-yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4- (2-oxotetrahydropyrimidin- 1 (2 )-yl)phenyl)chroman-2-carboxamide; 6-methoxy-A/-(4- (3-(methoxymethyl)-l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; (+)-6-methoxy-7V-(4-(3-(methoxymethyl)-l,2,4-oxadiazol-5-yl)phenyl)-
8-(4-methylpiperazin- 1 -yl)chroman -2-carboxamide; (-)-6-m ethoxy -A/-(4-(3 -
(methoxymethyl)- 1 ,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; 6-fluoro- V-(4-(3-(methoxymethyl)-l,2,4-oxadiazol-5-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(3-(methoxymethyl)- l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-6- fluoro-/V-(4-(3-(methoxymethyl)-l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; 6-methoxy-/V-(4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)-8-
(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-m ethoxy -/V-(4-(3 -methyl- 1,2, 4- oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-6- methoxy-/V-(4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; 6-fluoro- V-(4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-7V-(4-(3 -methyl- 1 ,2,4- oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-6- fluoro-/V-(4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamide; /V-(4-(4-ethoxypiperidin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-/V-(4-(4-ethoxypiperidin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-N-(4-(4- ethoxypiperidin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; 6-methoxy-A/-(4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(5-m ethyl- 1 ,2,4- oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-6- methoxy-7V-(4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; A/-(4-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)-6-methoxy-8- (4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)- V-(4-(5 -ethyl- 1 ,2,4-oxadiazol-3 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-7V-(4-(5- ethyl-l,2,4-oxadiazol-3-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; A/-(4-(5-isopropyl-l,2,4-oxadiazol-3-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(5-isopropyl-l,2,4-oxadiazol-3- yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-7V-(4-(5- isopropyl-l,2,4-oxadiazol-3-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; 6-methoxy-A/-(4-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(5-
(methoxymethyl)- 1 ,2,4-oxadiazol-3 -yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (-)-6-methoxy-A/-(4-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)-8- (4-methylpiperazin-l-yl)chroman-2-carboxamide; 6-fluoro-/V-(4-(5-methyl-l,2,4- oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6- fluoro-/V-(4-(5-methyl- 1 ,2,4-oxadiazol-3 -yl)phenyl)-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamide; (-)-6-fluoro- V-(4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)- 8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; 7V-(4-(5-ethyl- 1 ,2,4-oxadiazol-3 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-/V-(4-(5- ethyl- 1 ,2,4-oxadiazol-3 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (-)- V-(4-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-7V-(4-(5-isopropyl-l,2,4- oxadiazol-3 -yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6- fluoro-/V-(4-(5-isopropyl-l,2,4-oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (-)-6-fluoro- V-(4-(5-isopropyl-l,2,4-oxadiazol-3- yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-(4-(4- ethoxypiperidin- 1 -yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (-)-7V-(4-(4-ethoxypiperidin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-/V-(4-(4-ethoxypiperidin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy- A/-(4-(4-methyloxazol-2-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(4-methyloxazol-2-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; (-)-6-methoxy-A/-(4-(4-methyloxazol-2-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-A/-(4-morpholinophenyl)-8- (4-(2,2,2-trifluoroethyl)piperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(4-(2,2,2-trifluoroethyl)piperazin- 1 -yl)chroman-2-carboxamide; (- )-6-methoxy-/V-(4-morpholinophenyl)-8-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)chroman-2-carboxamide; 6-methoxy-8-(4-(2 -m ethoxy ethyl)piperazin-l-yl)-A/-(4- morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-(2- methoxyethyl)piperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6- methoxy-8-(4-(2-methoxyethyl)piperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; 8-(4-butylpiperazine- 1 -yl)-6-m ethoxy -A/-(4-morpholinophenyl)chroman- 2-carboxamide; (+)-8-(4-butylpiperazine- 1 -yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-butylpiperazine- 1 -yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-A/-(4-morpholinophenyl)- 8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-7V-(4- morpholinophenyl)-8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy- A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; 8-(4- isopropylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2- carboxamide; (-)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; 8-(4-ethylpiperazin- 1 -yl)-6-m ethoxy -7V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-ethylpiperazin- 1 -yl)-6- m ethoxy -7V-(4-morpholinophenyl)chroman-2-carboxamide; 6-m ethoxy -7V-(4- morpholinophenyl)-8-(piperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-/V-(4- morpholinophenyl)-8-(piperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy-/V-(4- morpholinophenyl)-8-(piperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-2-methyl-8- (4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6- methoxy-2-methyl-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; (-)-6-methoxy-2-methyl-8-(4-methylpiperazin-l-yl)-A/-(4- morpholinophenyl)chroman-2-carboxamide; 6-hydroxy-8-(4-methylpiperazin-l-yl)-A/- (4-morpholinophenyl)chroman-2-carboxamide; (+)-6-hydroxy-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-hydroxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(2-oxopyrrolidin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2- oxotetrahydropyrimidin- 1 (2H)-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-A/- (4-(3-methyl-2-oxotetrahydropyrimidin-l-(2 )-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(3-methyl-2-oxotetrahydropyrimidin-
1 (2 )-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8- (4-methylpiperazin-l-yl)-A/-(4-(2-oxooxazolidin-3-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(3-methyl-2,5-dioxoimidazolidin-l-yl)phenyl)-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(2,5-dioxoimidazolidin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-fluoro-
8-(4-methylpiperazin- l-yl)-A/-(4-(2-oxooxazoh din-3 -yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(2-oxopyrrolidin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(3-methyl-2,5-dioxoimidazolidin- l-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-/V-(4-(2,5- dioxoimidazolidin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)- V-(4-(2-oxotetrahydropyrimidin- l(2 )-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(3-(methoxymethyl)- l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6- fluoro-/V-(4-(3-(methoxymethyl)-l,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)-6-methoxy- V-(4-(3-methyl-l,2,4-oxadiazol-5- yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-/V-(4-(3 - methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (+)-/V-(4-(4-ethoxypiperidin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-7V-(4-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(5-ethyl- 1 ,2,4- oxadiazol-3-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-/V-(4-(5-isopropyl-l,2,4-oxadiazol-3-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-(5-(methoxymethyl)-l,2,4-oxadiazol- 3-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(5- methyl-l,2,4-oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-A/-(4-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-A/-(4-(5-isopropyl-l,2,4- oxadiazol-3-yl)phenyl)-8-(4-methylpiperazin-l-yl)chroman -2-carboxamide; (+)-N-(4- (4-ethoxypiperidin- 1 -yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (+)-6-methoxy-A/-(4-(4-methyloxazol-2-yl)phenyl)-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-morpholinophenyl)-8-(4-(2,2,2- trifluoroethyl)piperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-(2- methoxyethyl)piperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8- (4-butylpiperazine-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2- carboxamide; (+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy-
A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(piperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-2- methyl-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide;
(+)-6-hydroxy-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20070185107, including, without limitation, 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-7V-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; 7V-(4-(4-acetylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)- V-(4-(4-acetylpiperazin- 1 -yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)- V-(4-(4-acetylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l- yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (- )-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-7V-(4-(4- (ethylsulfonyl)piperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; 6-methoxy-7V-(4-morpholinophenyl)-8-(4-(2,2,2- trifluoroethyl)piperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-7V-(4- morpholinophenyl)-8-(4-(2,2,2-trifluoroethyl)piperazin- 1 -yl)chroman-2-carboxamide; (- )-6-methoxy-/V-(4-morpholinophenyl)-8-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)chroman-2-carboxamide; 6-methoxy-8-(4-(2 -m ethoxy ethyl)piperazin-l-yl)-A/-(4- morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-(2- methoxyethyl)piperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6- methoxy-8-(4-(2-methoxyethyl)piperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; 8-(4-butylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2- carboxamide; (+)-8-(4-butylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-butylpiperazin- 1 -yl)-6-methoxy-A/-
(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-A/-(4-morpholinophenyl)-8- (4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy- A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; 8-(4- isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide;
(+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2- carboxamide; (-)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; 8-(4-ethylpiperazin- 1 -yl)-6-m ethoxy -A/-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-ethylpiperazin- 1 -yl)-6- methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-A/-(4- morpholinophenyl)-8-(piperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(piperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy-A/-(4- morpholinophenyl)-8-(piperazin-l-yl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 4-(4-(6-methoxy-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (-)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; 4-(4-(6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; (-)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; 4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)- V V-dimethylpiperazine-l -carboxamide; (-)-4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; 6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-
(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-A/-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy- 8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-A/-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman -2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)- 6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4-butylpiperazin- 1 -yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-m ethoxy -7V-
(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4- isopropylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)- V,7V-dimethylpiperazine-l -carboxamide; (+)-4-(4- (6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/- dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l- yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6- methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-A/-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)-
A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l- yl)phenyl)chroman -2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (- )-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-N-(4-(4- (ethylsulfonyl)piperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; 8-(4-butylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman- 2-carboxamide; (+)-8-(4-butylpiperazin-l-yl)-6-methoxy-A/-(4- morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-butylpiperazin- 1 -yl)-6-methoxy-A/- (4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-A/-(4-morpholinophenyl)-8- (4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-A/-(4- morpholinophenyl)-8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy- A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; 8-(4- isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2- carboxamide; (-)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; 8-(4-ethylpiperazin- 1 -yl)-6-m ethoxy -7V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-ethylpiperazin- 1 -yl)-6- methoxy-7V-(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman -2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 4-(4-(6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/ 7V-dimethylpiperazine- 1 - carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (-)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/ 7V-dimethylpiperazine- 1 - carboxamide; 4-(4-(6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-methoxy-8-
(4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; (-)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; 4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l-carboxamide; (-)-4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-
(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-(methyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-7V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy- 8-(4-methylpiperazin-l-yl)-A/-(4-(4-propanoylpiperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman -2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; /V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman -2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)- 6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4-butylpiperazin- l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-A/- (4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4- isopropylpiperazin-l-yl)-6-methoxy-7V-(4-morpholinophenyl)chroman-2-carboxamide;
(+)-8-(4-ethylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)-N,N-dimethylpiperazine- 1 -carboxamide; (+)-4-(4- (6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-N,N- dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)- V,/V-dimethylpiperazine- 1 -carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l- yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6- methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-A/-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)- A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin-
1-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l- yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (- )-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-N-(4-(4-
(ethylsulfonyl)piperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-
2-carboxamide; 8-(4-butylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman- 2-carboxamide; (+)-8-(4-butylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-butylpiperazin- 1 -yl)-6-methoxy-/V- (4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-/V-(4-morpholinophenyl)-8- (4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-/V-(4- morpholinophenyl)-8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy- A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; 8-(4- isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2- carboxamide; (-)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; 8-(4-ethylpiperazin- 1 -yl)-6-m ethoxy -7V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-ethylpiperazin- 1 -yl)-6- methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 4-(4-(6-methoxy-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (-)-4-(4-(6-methoxy-8-
(4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; 4-(4-(6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; (-)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l-carboxamide; 4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; (-)-4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; 6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-7V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy- 8-(4-methylpiperazin-l-yl)-A/-(4-(4-propanoylpiperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman -2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; /V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-7V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)- 6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4-butylpiperazin- l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-A/- (4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4- isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; (+)-4-(4- (6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/- dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l- yl)phenyl)chroman-2-carboxamide; (+)-7V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6- methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-/V-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-8-(4-methylpiperazin-l-yl)- A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)- V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide;
(+)-6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l- yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-
)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-methylpiperazin-l-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-7V-(4-(4- (ethylsulfonyl)piperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman- 2-carboxamide; 8-(4-butylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman- 2-carboxamide; (+)-8-(4-butylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-butylpiperazin- 1 -yl)-6-methoxy-7V-
(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-7V-(4-morpholinophenyl)-8- (4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-7V-(4- morpholinophenyl)-8-(4-propylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-6-methoxy- A/-(4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; 8-(4- isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide;
(+)-8-(4-isopropylpiperazin-l-yl)-6-methoxy-A/-(4-morpholinophenyl)chroman-2- carboxamide; (-)-8-(4-isopropylpiperazin-l-yl)-6-methoxy- V-(4- morpholinophenyl)chroman-2-carboxamide; 8-(4-ethylpiperazin- 1 -yl)-6-m ethoxy -A/-(4- morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy- A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-8-(4-ethylpiperazin- 1 -yl)-6- methoxy-A/-(4-morpholinophenyl)chroman-2-carboxamide; 6-methoxy-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; 4-(4-(6-methoxy-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (-)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; 4-(4-(6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-methoxy-8- (4-methylpiperazin- 1 -yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine- 1 - carboxamide; (-)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; 4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamido)phenyl)-A/,A/-dimethylpiperazine-l -carboxamide; (-)-4-(4-(6-fluoro-8-(4- methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/-dimethylpiperazine-l- carboxamide; 6-methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; N-(4-(4- ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-7V-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-/V-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-methoxy-
8-(4-methylpiperazin-l-yl)-7V-(4-(4-propanoylpiperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (-)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4- propanoylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-A/-(4-(4-ethanoylpiperazin- 1 -yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-A/-(4-(4-ethanoylpiperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - ethanoylpiperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4- methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-(4-methylpiperazin- 1 -yl)phenyl)chroman-2-carboxamide;
(+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)- 6-methoxy-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-8-(4-butylpiperazin-
1-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-methoxy-/V- (4-morpholinophenyl)-8-(4-propylpiperazin-l-yl)chroman-2-carboxamide; (+)-8-(4- isopropylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2-carboxamide; (+)-8-(4-ethylpiperazin-l-yl)-6-methoxy-/V-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-methoxy-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-propanoylpiperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-4-(4-(6-methoxy-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)- V,.V-dimethylpiperazine-l -carboxamide; (+)-4-(4- (6-methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamido)phenyl)-A/,A/- dimethylpiperazine- 1 -carboxamide; (+)-4-(4-(6-fluoro-8-(4-methylpiperazin- 1 - yl)chroman-2-carboxamido)phenyl)- V,/V-dimethylpiperazine- 1 -carboxamide; (+)-6- methoxy-8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l- yl)phenyl)chroman-2-carboxamide; (+)-7V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6- methoxy-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-methoxy-8-(4- methylpiperazin- 1 -yl)-7V-(4-(4-propanoylpiperazin- 1 -yl)phenyl)chroman-2- carboxamide; (+)-7V-(4-(4-ethanoylpiperazin-l-yl)phenyl)-6-methoxy-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in US20080318926, including, without limitation, (7 R, 9aS)-trans-
2-benzo[i ]isoxazol-3-yl-7-(6-morpholin-4-ylmethylpyri din-2 -yloxymethyl)- octahydropyrido[l,2-u]pyrazine; (7 ?,9u5)-/rau5-2-benzo[<i]isoxazol-3-yl-7-(5- piperidin- 1 -ylmethylpyridin-2-yloxymethyl)-octahydropyrido[ 1 ,2-u]pyrazine; (7R, 9 aS)~ /rau5-2-(5-fluorobenzo[<i]isoxazol-3-yl)-7-(5-pynOlidin-l -ylmethylpyri din-2- yloxymethyl)-octahydropyrido[l,2-u]pyrazine; (7R,9aS)-trans-[6-(2-benzo[d]isoxazo\-
3-yl-octahydropyrido[l,2-u]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-diethylamine;
(7 ?,9u5)-/rau5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-u]pyrazin-7- ylmethoxy)-pyridin-3-ylmethyl]-dimethylamine; (7R,9aS)-trans-[6-(2- benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-u]pyrazin-7-ylmethoxy)-pyridin-3- ylmethylj-ethylmethylamine; (7i?,9u5,)-irara-[6-(2-benzo[<i]isoxazol-3-yl- octahydropyrido[l,2-u]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-l- methylethyl)-amine; (7 ?,9a5)-/ra«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxyethyl)-methylamine; (7R,9aS)~ ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)- pyridin-3-ylmethyl]-cyclopentylmethylamine; (7 ?,9a5)-/ra«5-7-(5-azetidin-l-ylmethyl- pyridin-2-yloxymethyl)-2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazine;
(7 ?,9a5)-/ra«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methylaziridin- l-ylmethyl)-pyri din-2- yloxymethyl]-octahydropyrido[l,2-a]pyrazine; (7R,9aS)-trans-2-benzo[d\isoxazo\-3-y\- 7-[5-(2-methoxymethylpyrrolidin-l-ylmethyl)-pyridin-2-yloxymethyl]- octahydropyrido[l,2-a]pyrazine; (7R,9aS)-trans-[6-(2-benzo[d\isoxazo\-3-y\- octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-tert-butylamine; (75, 9«5)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)- pyridin-3-ylmethyl]-ethylmethylamine; (75,9«5)-c/5-7-(5-azetidin-l-ylmethylpyridin-2- yloxymethyl)-2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazine; (7R,9aS)-trans- [6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethylj-dimethylamine; (7i?,9a5)-/ran5-cyclohexyl-{6-[2-(5-fluoro-benzo[<i]isoxazol- 3-yl)-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine;
(7i?,9a5)-/ran5-2-(ethyl-{6-[2-(5-fluorobenzo[<i]isoxazol-3-yl)-octahydropyrido[l,2- a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amino)-ethanol; (7 R, 9 aS)-trans -7 -\6-(2, 6- dimethylpiperidin-1 -ylmethyl)-pyri din-2 -yloxymethyl]-2-(5-fluorobenzo[<i]isoxazol-3- yl)-octahydropyrido[l,2-a]pyrazine; (7i?,9a5)-/rans-(l,2-dimethylpropyl)-{6-[2-(5- fluorobenzo[<7]isoxazol-3-yl)-octahydropyrido[l,2- 3]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl} -amine; (7i?,9a5)-ira«5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(2-methoxyethyl)-methylamine; (7R,9aS)~ ira«5-l-[6-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)- pyridin-3-ylmethyl]-(5)-pyrrolidin-3-ol; (7i?,9a5)-ira«5-l-[6-(2-benzo[<i]isoxazol-3- yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(i?)-pyrrolidin-3-ol; (7i?,9a5)-ira«5-2-benzo[<i]isoxazol-3-yl-7-[5-(2-methylpyrrolidin-l-ylmethyl)-pyridin-
2-y 1 oxy methyl ] -octahy dropy ri do [ 1 ,2-a]pyrazine; (7R,9aS)-trans- 1 -[6-(2- benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3- ylmethyl]-piperidin-4-ol; (7i?,9a5)-/ran5-cyclopropyl-{6-[2-(5-fluorobenzo[<i]isoxazol-
3-yl)-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine;
(7i?,9a5)-irans-cyclopropylmethyl-{6-[2-(5-fluorobenzo[<i]isoxazol-3-yl)- octahydropyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine; (7R,9aS)~ /ra«5-2-(5-fluorobenzo[<i]isoxazol-3-yl)-7-[6-(4-methylpiperazin-l-ylmethyl)-pyridin-
2-yloxymethyl]-octahydropyrido[l,2-a]pyrazine; (' TR,9aS)-trans-2-(5 - fluorobenzo[<i]isoxazol-3-yl)-7-(6-piperi din-l-ylmethylpyri din-2 -yloxymethyl)- octahydropyrido[l,2-a]pyrazine; (7i?,9a5,)-/ran5-{6-[2-(5-fluorobenzo[<i]isoxazol-3-yl)- octahydropyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-dimethylamine; (7i?,9a5,)-/ran5-{6-[2-(5-fluorobenzo[<i]isoxazol-3-yl)-octahydropyrido[l,2-a]pyrazin-7- ylmethoxy]-pyridin-2-ylmethyl}-(tetrahydrofuran-2-ylmethyl)-amine; (7 R,9aS)-trans-l - [6-(2,5-dimethylpyrrolidin-l-ylmethyl)-pyri din-2 -yloxymethyl]-2-(5- fluorobenzo[<7]isoxazol-3-yl)-octahydropyrido[l,2-3]pyrazine; (7R,9aS)-trans- { 6-[2-(5- fluorobenzo[<7]isoxazol-3-yl)-octahydropyrido[l,2-3]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl } - [3 -(4-methylpiperazin- 1 -yl)-propyl] -amine; (7 R, 9aS)-trans- {6-[2-(5- fluorobenzo[<7]isoxazol-3-yl)-octahydropyrido[l,2-3]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl } -pyrrolidin- 1 -ylamine; (7 R, 9 aS)-trans -7 -(6-azepan- 1 -ylmethylpyridin-2- yloxymethyl)-2-(5-fluorobenzo[<i]isoxazol-3-yl)-octahydropyrido[l,2-a]pyrazine;
(75,,9«5,)-c/5-[6-(2-benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)- pyri din-3 -ylmethyl]-cyclohexyl-m ethyl-amine; (7R,9aS)-trans- 1 -[6-(2- benzo[<i]isoxazol-3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2- ylmethyl]-(5)-pyrrolidin-3-ol; (7 R, 9aS)-trans- 1 -[6-(2-benzo[<i]isoxazol-3 - yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(i?)-pyrrolidin-3-ol; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-(6-pyrrolidin-l-ylmethylpyridin-2- yloxymethyl)-octahydropyrido[l,2-a]pyrazine; (7R,9aS)-trans-[6-(2-benzo[d\isoxazo\-
3-yl-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-benzylamine; (7i?,9a5,)-ira«5-2-benzo[<i]isoxazol-3-yl-7-(5-pyrrolidin-l-ylmethylpyridin-2- yloxymethyl)-octahydropyrido[l,2-a]pyrazine; (75,9«5 - 5-2-benzo[<i]isoxazol-3-yl-7- (5-pyrrolidin-l-ylmethypyridin-2-yloxymethyl)-octahydro-pyrido[l,2-a]pyrazine;
(7i?,9a5,)-ira«5-6-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7- ylmethoxy)-nicotinic acid methyl ester; (7R,9aS)-trans-6-(2-benzo[d\isoxazo\-3- yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-3-yl]-methanol; (7R,9aS)-trans- methanesulfonic acid 6-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7- ylmethyoxy)-pyridin-2-ylmethyl ester; (' 7R,9aS)-trans-methanesu\fonic acid 6-[2-(5- fluorobenzo[<7]isoxazol-3-yl)-octahydropyrido[l,2-3]pyrazin-7-ylmethoxy]-pyridin-2- ylmethyl ester; (7i?,9aS)-ira/M-6-(2-benzo[rf]isoxazol-3-yloctahydropyrido[l,2- a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester; (7R,9aS)-trans-6-(2- benzo[i ]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]- m ethanol; (7i?,9a5,)-/ran5-{6-[2-(5-fluorobenzo[<i]isoxazol-3-yl)-octahydropyrido[l,2- a]pyrazin-7-ylmethoxy]-pyridin-2-yl}-methanol; (7R,9aS)-trans-6-[2-(5- fluorobenzo[<i]isoxazol-3-yl)-octahydropyrido[l,2-a]pyrazin-7-ylmethoxy]-pyridine-2- carboxylic acid ester; (7i?,9aS)-c/s-6-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2- u]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester; (7R, 9aS)-cis-6-(2- benzo[i ]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]- methanol; (7i?,9«5')-c/5-methanesulfonic acid 6-(2-benzo[<i]isoxazol-3- yloctahydropyrido[l,2-a]pyrazin-7-ylmethyoxy)-pyridin-2 -ylmethyl ester; (7R,9aS)~ ira«5-5-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridine- 2-carboxylic acid methyl ester; (7i?,9a5,)-ira«5-[5-(2-benzo[<i]isoxazol-3- yloctahydropyrido[l,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol; (7R,9aS)-trans- methanesulfonic acid 5-(2-benzo[<i]isoxazol-3-yloctahydropyrido[l,2-a]pyrazin-7- ylmethoxy)-pyridin-2-ylmethyl ester; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in WO1999029666, including, without limitation, 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-5-yl)aminocarbonyl]indoline; 5-chloro-6-(4- ethylpiperazin-l-yl)-l -[(5,6,7, 8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -[( 1 - oxoindan-5-yl)aminocarbonyl]indoline; 5-bromo-6-(4-methylpiperazin- 1 -yl)- 1 -
[(5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin- 1 -yl)- 1 -[(1 -oxoindan-6-yl)aminocarbonyl]indoline; 5-chloro-6-(4- methylpiperazin- 1 -yl)- 1 -[(l-oxoindan-6-yl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin-l-yl)-l-[(5,6,7,8-tetrahydro-8-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-chloro-6-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-8-oxo-2-naphthalenyl)aminocarbonyl]indoline; 5-chloro- 1 -(9-oxo-9H- fluoren-2-ylaminocarbonyl)-6-(4-methylpiperazin- 1 -yl)indoline; 5-chloro- 1 -(9-oxo-9H- fluoren-3-ylaminocarbonyl)-6-(4-methylpiperazin-l-yl)indoline; 5-methoxy-6-(4- methylpiperazin-l-yl)-l-[(5,6,7,8-tetrahydro-5-oxo-2- naphthalenyl)aminocarbonyl]indoline; 5-chloro-6-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-5-oxo-l-naphthalenyl)aminocarbonyl]indoline; 5-bromo-6-(4- methylpiperazin- 1 -yl)-l-[(5,6,7,8-tetrahydro-5-oxo- 1 - naphthalenyl)aminocarbonyl]indoline; 5-methoxy-6-(4-methylpiperazin- 1 -yl)- 1 -
[(5,6,7,8-tetrahydro-5-oxo-l-naphthalenyl)aminocarbonyl]indoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in WO 1999031086, including, without limitation, 7V-[3-chloro-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)naphth-l-yl]-urea; N-\4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-A/’ -[5-(pyridin-4-yl)naphth- 1 -ylj-urea ; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-6-yl]-urea; 4-bromo-7V-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth- 1 -ylacetamide; 5-bromo-7V-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth- 1 -ylacetamide; 7V-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-4-(pyridin-4-yl)naphth-l -ylacetamide; 7V-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-5-(pyridin-4-yl)naphth-l -ylacetamide; 7V-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-A/’-[4-(pyridin-4-yl)-3-trifluoromethylphenyl]-urea; 77-[3-cyano-4- (pyridin-4-yl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-\4-(4- methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-5-yl]-urea; A/-[4-(4-methylpiperazin- l-yl)quinolin-6-yl]-A/’-[quinolin-8-yl]-urea; 7V-[4-(4-methylpiperazin-l-yl)quinolin-6- yl]-A/’-[quinolin-3-yl]-urea; 2/-dichloro-A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yljphenylacetamide; 5-(4-acetylphenyl)-A/-[4-(4-methylpiperazin-l-yl)quinolin-6- yljnaphth- 1 -ylacetamide; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-A/’-[quinolin-4- yl]-urea; A/-[3-chloro-4-(pyridin-4-yl)phenyl]-A/’-[4-(l-methylpiperidin-4-yl)quinolin-6- yl]-urea; A/-[3-methyl-4-(6-methylpyridin-2-yl)phenyl]-A/’-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]-urea; A/-[4-(2,6-dimethylpyridin-4-yl)-3-methylphenyl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[5-cyanonaphth-l-yl]-A/’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[5-(5-methyl-l,2,4-oxadiazol-3-yl)naphth- l-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin-l- yl)quinolin-6-yl]- V,-[5-(pyrimidin-2-yloxy)naphth-l-yl]-urea; A/-[5-acetylnaphth-l-yl]- A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[5-bromonaphth-l-yl]-7V’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[5-(6-methylpyridin-2-yl)naphth- 1 -yl]- V’ - [4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; 7V-[5-(2-methylpyridin-5-yl)naphth-l- yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; 7V-[5-(2-methylpyridin-3- yl)naphth- 1 -ylJ-NP -[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-urea; N-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-A/’ -[5-(pyrimidin-2-yl)naphth- 1 -yl]-urea; N-[5- bromonaphth-l-yl]-/V’-[4-(piperazin-l-yl)quinolin-6-yl]-urea; 2,3-dihydro-8-(4- methylpiperazin- 1 -yl)- 1 -[4-(pyridin-4-yl)naphth- 1 -y 1 aminocarb ony 1 ]py rrol o \2J- gjquinoline; 2/-dihydro-8-(4-methylpiperazin- 1 -yl)- 1 -[5-(5-methyl- 1 ,2,4-oxadiazol-3 - yl)naphth- 1 -ylaminocarbonyl]pyrrolo[2/-g]quinoline; 2/-dihydro-8-(4-methylpiperazin- l-yl)-l-[5-(pyrimidin-2-yloxy)naphth-l-ylaminocarbonyl]pyrrolo[2/-g]quinoline; 9-(4- methylpiperazin- 1 -yl)- 1 -[4-(pyridin-4-yl)naphth- 1 -y 1 aminocarb ony 1 ] - 1 ,2,3,4- tetrahydropyrido[2,3 -g] quinoline; 9-(4-methylpiperazin- 1 -yl)- 1 -[5-(pyrimidin-2- yloxy)naphth-l-ylaminocarbonyl]-l,2,3,4-tetrahydropyrido[2.3-g]quinoline; N-[ 8- bromoquinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; 7V-[8-(2- fluorophenyl)quinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[8-(2- methoxyphenyl)quinolin-4-yl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[2- biphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N- [2 -di chi oropheny 1 ] -A/’ - [4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/’-[4-biphenyl]-A/-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; N-[3 ,4-dichlorophenyl]-A/’ -[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-chlorophenyl]-7V,-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[3-cyanophenyl]-A/’-[4-(4-methylpiperazin- l-yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-N’-[4- phenoxyphenyl]-urea; A/-[4-bromophenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6- yl]-urea; A/-[4-acetylphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 2- bromophenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[3,5- bis(trifluoromethyl)phenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 3- acetylphenyl]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; N-[ 2,6- difluorophenyI]-A/’-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[3-bromophenyl]- A/’-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-A/’ -[naphth- 1 -yl]-urea; A/-[2,6-dichlorophenyl]-A/’-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-chloro-2-methylphenyl]-7V,-[4-(4- methylpiperazin-l-yl)quinolin-6-yl]-urea; A/-[4-bromo-3-methylphenyl]-7V’-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]-urea; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]- 2-nitrophenylacetamide; 4-bromo-/V-[4-(4-methylpiperazin-l-yl)quinolin-6- yljphenylacetamide; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-4-biphenylacetamide; 3,4-dichloro-7V-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]benzamide; N-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]naphth-2-ylacetamide; 4-dimethylamino-A/-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]phenylacetamide; 3,4-difluoro- V-[4-(4- methylpiperazin- 1 -yl)quinolin-6-yl]phenylacetamide; A/-[4-(4-methylpiperazin- 1 - yl)quinolin-6-yl]-3-phenoxyphenylacetamide; 7V-[4-(4-methylpiperazin-l-yl)quinolin-6- yljnaphth- 1 -yl carboxamide; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]-4- phenoxyb enzami de; A/-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-A/’-[5,6,7,8- tetrahy dro- 5 -oxo-2-naphthal eny 1 ] - urea; A/-[4-(4-methylpiperazin- 1 -yl)quinolin-6-yl]- /V’ - [5 -oxoindan-2-yl] -urea; 2,3-dihydro-8-(4-methylpiperazin-l-yl)-l-[(5,6,7,8- tetrahydro-5-oxo-2-naphthalenyl)aminocarbonyl]pyrrolo[2/-g]quinoline; 9-(4- methylpiperazin-l-yl)-l-[(5-oxo-5,6,7,8-tetrahydronaphth-6-yl)aminocarbonyl]-l,2,3,4- tetrahydropyrido[2,3-g]quinoline; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in W02006048727, including, without limitation, l-{2-[2-(4- methyl-piperazin- 1 -yl)-phenyl]-ethyl } -3 -(4-trifluoromethy 1-phenyl)- 1 , 3 -dihydro- imidazol-2-one; l-(4-isopropoxy-phenyl)-3-{2-[2-(4-methyl-piperazin-l-yl)-pyridin-3- yl]-ethyl}-l,3-dihydro-imidazol-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-{2-[3- (4-methyl-piperazin- 1 -yl)-pyri din-2 -yl]-ethyl } - 1 ,3 -dihydro-imidazol-2-one; l-[4-(l- hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-3,4,5,6-tetrahydro-27/-[l,2’]bipyrazinyl- 3’ -yl)-ethyl]- 1 ,3 -dihydro-imidazol-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3 - {2-[2-(4-methyl-piperazin-l-yl)-phenyl]-ethyl}-imidazolidin-2-one; l-[4-(l-hydroxy- cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-pyridin-3-yl]-imidazolidin-2-one; l-[4-(l-hydroxy-cyclobutyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-l-yl)-phenyl]-ethyl}- tetrahydro-pyrimidin-2-one; 1 -[4-(l -hydroxy- 1 -methyl-ethyl)-phenyl]-3-{2-[2-(4- methyl-piperazin-l-yl)-phenyl]-ethyl}-l,3-dihydro-benzoimidazol-2-one; l-[4-(l- hydroxy-cyclopentyl)-phenyl]-3-{2-[2-(4-methyl-piperazin-l-yl)-phenyl]-ethyl}-l,3- dihydro-imidazo[4,5-/?]pyridin-2-one; 3-{2-[2-(4-methyl-piperazin-l-yl)-phenyl]- ethyl}-7-phenyl-lif-quinazoline-2,4-dione; 5-tert-butyl-2-{2-[2-(4-methyl-piperazin-l- yl)-phenyl]-ethyl } -isoindole- 1 ,3 -dione; 2-[2-(4-methyl-piperazin-l-yl)-benzyl]-7- phenyl-3 ,4-dihydro-27/-isoquinolin- 1 -one; 2- { 2- [2-(4-methyl-piperazin- 1 -yl)-phenyl] - ethyl } -5-phenyl-2,3 -dihydro-isoindol- 1 -one; 2- { 2- [2-(4-methyl-piperazin- 1 -yl)-phenyl] - ethyl } -6-phenyl-3,4-dihydro-2//-isoquinolin- 1 -one; 2-{2-[2-(4-methyl-piperazin- 1 -yl)- phenyl]-ethyl}-6-phenyl-l,2,3,4-tetrahydro-isoquinoline; 2-{2-[2-(4-methyl-piperazin- l-yl)-phenyl]-ethyl}-5-phenyl-2,3-dihydro-lif-isoindole; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007026219, including, without limitation, elzasonan; 3-(4- chlorobenzyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 3 -(4- chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4-dione; 3-(4- trifluoromethylphenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidine-2,4- dione; 3-(3,4-dichlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidin-4- one; 5-[2-(4-methylpiperazin-l-yl)-benzylidene]-2-phenylthiazolidin-4-one; 5-[2-(4- methylpiperazin- 1 -yl)-benzylidene]-thiazolidine-2,4-dione; 3-(4-chlorophenyl)-2,2- dimethyl-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiazolidin-4-one; 3-(4- chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 3- (4-chlorobenzyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]-imidazolidine-2,4-dione; 4-benzyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorobenzyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2- (4-methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3- one; 2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-morpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin- 3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzyl]-thiomorpholin-3- one; 4-methyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-(2-piperazin-l-ylbenzylidene)-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(4-methyl-4-piperazin-l-yl)-benzylidene]- 1-oxo- thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-4-oxy-piperazin-l-yl)-benzylidene]- thiomorpholin-3 -one; 4-benzyl-2-[2-(4-methylpiperazin- 1 -yl)-benzylidene]-l , 1 - dioxothiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-l- yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[5-fluoro-2-(4- methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2- (4-methylpiperazin-l-yl)-5-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-l-yl]-benzylidene}-thiomorpholin-
3 -one; 4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-ethylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3 -one; 4-(3-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-chloro-6-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4- dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin- l-yl)-4-trifluoromethyl-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-(5- fluoro-2-piperazin-l-yl-benzylidene)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2- [3,6-difluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one;
4-phenyl-2-[2-(3,4,5-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[5- fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-4-phenyl-thiomorpholin-3-one; 4- benzo[l,3]dioxol-5-yl-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 2-[2-(4-tert-butylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)- thiomorpholin-3-one; 3-[4-(3,4-dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]- 6-dimethylamino-2-(4-methylpiperazin-l-yl)-benzonitrile; 4-(3,4-dichlorophenyl)-2-[2- (3,4,5-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[5-methyl-2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 2-[4-chloro-2-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)- thiomorpholin-3 -one; 4-(3 ,4-difiuorophenyl)-2-[2-(3 , 5 -dimethylpiperazin- 1 -yl)- benzylidene]-thiomorpholin-3-one; 4-(2,4-difIuorophenyl)-2-[2-(3,5-dimethylpiperazin- l-yl)-benzylidene]-thiomorpholin-3-one; 2-[4-bromo-2-(4-methylpiperazin-l-yl)- benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2- (l-methylpyrrolidin-2-ylmethoxy)-benzylidene]-thiomorpholin-3-one; 4-(3,5- dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3 ,4-difluorophenyl)-2- [2-(3 ,4,5 -trimethylpiperazin- 1 -yl)-benzylidene] - thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(octahydropyrido[l,2-3]pyrazin-2- yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4-cyclopropylpiperazin- 1 -yl)- benzylidene]-4-pyridin-3-yl-thiomorpholin-3-one; 2- [2-(4-cy clopropylpiperazin- 1 -yl)- benzylidene]-4-(3,4-difluorophenyl)-thiomorpholin-3-one; 2-[2-(4- cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,5-dichlorophenyl)-thiomorpholin-3-one;
4-(3,4-difluorophenyl)-2-[2-(2,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin- 3 -one; 4-(3 , 5 -dichlorophenyl)-2- [2-(2, 5 -dimethylpiperazin- 1 -yl)-benzylidene] - thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-difluorophenyl)-2-[2-(2,4)5- trimethylpiperazin- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-benzo[ 1 ,3]dioxol-5-yl-2-
[2-(4-cyclopropylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(3,5- dimethylpiperazin-l-yl)-benzylidene]-4-(4-fluorophenyl)-thiomorpholin-3-one; 4- benzo[l,3]dioxol-5-yl-2-[2-(2,5-dimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3- one; 2-[2-(3,5-dimethylpiperazin-l-yl)-benzylidene]-4-phenylthiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-l-yl)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methyl-
[ 1 ,4]diazepan- 1 -yl)-benzylidene]-thiomorpholin-3 -one; 4-(3,4-dichlorophenyl)-2-[2- (2,4,6-trimethylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 2-[2-(4- cyclopropylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;
2-[2,4-dibromo-6-(4-methylpiperazin-l-yl)-benzylidene]-4-(3,4-dichlorophenyl)- thiomorpholin-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- [ 1 ,4]oxazepan-3 -one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin- 1 -yl)-benzylidene]- [l,4,5]oxadiazepan-3-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)- benzylidene]-[ 1 ,4]thiazepan-3 -one; 4-(3,4-dichlorophenyl)-2-{2-[(2- dimethylaminoethyl)-methyl-amino]-benzylidene}-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-[2-(l-methylpiperidin-4-yl)-benzylidene]-thiomorpholin-3-one; 4- (3,4-dichlorophenyl)-2-[2-(l,4-dimethylpiperidin-4-yl)-benzylidene]-thiomorpholin-3- one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- thiomorpholine-3,5-dione; 4-(3,4-dichlorophenyl)-2-[2-(2-dimethylaminoethoxy)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin- l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3 ,4-dichlorophenyl)-2-[2-(l - methylpyrrolidin-3-ylmethyl)-benzylidene]-thiomorpholin-3-one; 4-(3,4- dichlorophenyl)-2-{2-[methyl-(l-methylpyrrolidin-2-ylmethyl)-amino]-benzylidene}- thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(l-methylpyrrolidin-2-ylmethoxy)- benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{2-[2-(l-methylpyrrolidin- 2-yl)-ethyl]-benzylidene}-thiomorpholin-3-one; l-(3,4-dichlorophenyl)-4-methyl-3-[2-
(4-methylpiperazin-l-yl)-benzylidene]-piperazin-2-one; 4-methyl-3-[2-(4- methylpiperazin- 1 -yl)-benzylidene]-l -(4-trifluoromethylphenyl)-piperazin-2-one; 1 -(4- chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperazin-2-one; 2- [2-(4-methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-morpholin-3- one; 2-[4-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-4-(4-trifluoromethylphenyl)- thiomorpholin-3-one; 2-[5-fluoro-2-(4-methylpiperazin-l-yl)-benzylidene]-4-(4- trifluoromethylphenyl)-thiomorpholin-3-one; 2- { 1 - [2-(4-methylpiperazin- 1 -yl)-phenyl] - ethylidene}-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 2-[2-(4-methylpiperazin- l-yl)-benzyl]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one; 4-(4-chlorophenyl)-6- methyl-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(4- chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]-[l,4]oxazepan-3-one; 4-(4- chlorophenyl)-2-[2-(4-methylpiperazin- 1 -yl)-benzylidene]-4 -[l ,4]thiazin-3 -one; 1 -(4- chlorophenyl)-4,6,6-trimethyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]-piperazin-2- one; l-(4-chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-l-yl)-benzylidene]- piperazin-2-one; 4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-l-yl)-benzylidene]- morpholin-3 -one; 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)-benzylidene]- oxazolidin-4-one; 3-(4-chlorophenyl)-2,2-dimethyl-5-[2-(4-methylpiperazin-l-yl)- benzylidene]-imidazolidin-4-one; 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-l-yl)- benzylidene]-imidazolidin-4-one; and pharmaceutically acceptable salts or esters thereof. In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007026224, including, without limitation, 3-[5-fluoro-2-(4- methyl-piperazin- 1 -yl)-benzyl]- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2- one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(6-morpholin-4-yl-pyridin-3-yl)- pyrrolidin-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 - yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(4-morpholin-4- yl-phenyl)-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclohexyl)-phenyl]-3-[2-(4- methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-(l -ethyl- 1 -hydroxy-propyl)- phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 1 - [3 -( 1 -hydroxy- 1 - methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(2- hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yI)-benzyl]-pyrrolidin- 2-one; 1 -[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; l-[4-(l-methoxy-l-methyl-ethyl)-phenyl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(2-methoxy-2-methyl-propyl)-phenyl]-3- [2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-( 1 -methoxy-cyclobutyl)- phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl- piperazin-l-yl)-benzyl]-l-(4-pyridin-4-yl-phenyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclopentyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclobutyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclohexyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l-ethyl-l- hydroxy-propyl)-phenyl]-3-(2-piperazin-l-yl-benzyl)-pyrrolidin-2-one; l-[4-(l- hydroxy- 1 -methyl-ethyl)-phenyl]-3 -(2-piperazin- 1 -yl-benzyl)-pyrrolidin-2-one; l-[4-( 1 - hydroxy- l-methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzylidene]- pyrrolidin-2-one; 3 - [5 -fluoro-2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -[4-( 1 -hydroxy- cyclopentyl)-phenyl]-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[5- methyl-2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; 1 - [4-( 1 -hydroxy- 1 - methyl-ethyl)-phenyl]-3-[5-methyl-2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- piperidin-2-one; 1 -[4-( 1 -hydroxy- 1 -methyI-ethyl)-phenyl]-3-[2-(4-methyl-piperazin- 1 - yl)-benzyl]-piperidin-2-one; 1 -[4-(l -hydroxy- 1 -methyl-ethyl)-phenyl]-3-[5-methoxy-2- (4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)- phenyl]-3-[5-methoxy-2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 3-[2- fluoro-6-(4-methyl-piperazin- 1 -yl)-benzyl]-l -[4-( 1 -hydroxy-cyclopentyl)-phenyl]- pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-(l -hydroxy- l-methyl-ethyl)-phenyl]-3-[2-(3, 4,5- trimethyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-(4-hydroxy-tetrahydro-pyran- 4-yl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(4- hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- piperidin-2-one; 1 - [4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl] -3 - [2-(3 ,4, 5 -trimethyl- piperazin-l-yl)-benzyl]-piperidin-2-one; 3 - [5 -fluoro-2-(3 ,4,5 -trimethyl-piperazin- 1 -yl)- benzyl]- 1 -[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-piperidin-2-one; 3-[5-fluoro-2-(3,4,5- trimethyl-piperazin- 1 -yl)-benzyl]- 1-[4-( 1 -hydroxy-cy cl opentyl)-phenyl]-piperi din-2 - one; 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-l-[4-(2-oxo-pyrrolidin- 1 -ylmethyl)- phenyl]-piperidin-2-one; 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(3 -oxo- 1 ,3-dihydro- isobenzofuran-5-yl)-piperidin-2-one; 3-[5-fluoro-2-(4-methyl-piperazin-l-yl)-benzyl]-l- [4-(l -hydroxy-cy clobutyl)-phenyl]-piperidin-2-one; 3 - [2-(4-methyl-piperazin- 1-yl)- benzyl]-l-(3-[l,3,4]oxadiazol-2-yl-phenyl)-pyrrolidin-2-one; 6-( 1 -hydroxy- 1 -methyl- ethyl)-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-3,4,5,6-tetrahydro-[l,3’]bipyridinyl-2- one; 3-[5-fluoro-2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -[6-( 1 -hydroxy- 1 -methyl-ethyl)- pyri din-3 -yl]-pyrrolidin-2-one; 3-[2-fluoro-6-(4-methyl-piperazin-l-yl)-benzyl]-l-[6-(l- hydroxy-l-methyl-ethyl)-pyridin-3-yl]-pyrrolidin-2-one; 1 - [6-( 1 -hydroxy- 1 -methyl- ethyl)-pyridin-3-yl]-3-[2-(3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 6- (1 -hydroxy- l-methyl-ethyl)-3-[2-(3, 4, 5-trimethyl-piperazin-l-yl)-benzyl]-3, 4,5,6- tetrahydro-[ 1,3’ ]bi-pyridinyl-2-one; 3-[5-fluoro-2-(3,4,5-trimethyl-piperazin-l-yl)- benzyl]-6’ -( 1 -hydroxy- 1 -methyl-ethyl)-3 ,4, 5,6-tetrahydro-[ 1 ,3’ ]bipyridinyl-2-one; 3-[5- fluoro-2-(4-methyl-piperazin-l-yl)-benzyl]-6’-(l -hydroxy-l-methyl-ethyl)-3, 4,5,6- tetrahydro-[ 1,3’ ]bipyridinyl-2-one; 1 -[4-( 1 -hydroxy-cyclopentyl)-phenyl]-3-[2-(4- methyl-[ 1 ,4]diazepan- 1 -yl)-benzyl]-pyrrolidin-2-one; l-[4-( 1 -hydroxy- 1 -methyl-ethyl)- phenyl]-3-[2-(4-methyl-[l,4]diazepan-l-yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-ethyl- piperazin- 1 -yl)-benzyl]-l-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2-one; 3 - [2-(2,5-dimethyl-piperazin-l-yl)-benzyl]-l-[4-(l -hydroxy-cy cl opentyl)-phenyl]- pyrrolidin-2-one; l-[6-(l -ethyl- l-hydroxy-propyl)-pyri din-3-yl]-3-[2-(4-methyl - piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one, 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1-[6-
(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-pyrrolidin-2-one; l-[6-(l -hydroxy- cy cl opentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; 1- [4-(l -hydroxy-cy clobutyl)-phenyl]-3-[2-(4-methyl-piperazin- l-yl)-benzyl]-pyrrolidin-2- one; l-[5-(l -hydroxy- 1 -methyl-ethyl)-pyri din-2 -yl]-3-[2-(4-methyl-piperazin- 1 -yl)- benzyl]-pyrrolidin-2-one; l-[5-(l -hydroxy-cy clopentyl)-pyridin-2-yl]-3-[2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -(4- oxazol-4-yl-phenyl)-piperidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-(4- pyrazol- 1 -yl-phenyl)-piperidin-2-one; l-[4-(2-methyl-oxazol-4-yi)-phenyl]-3-[2-(4- methyI-piperazin-l-yl)-benzyl]-piperidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)- benzyl]-l-(4-oxazol-5-yl-phenyl)-piperidin-2-one; 3-[2-(4-methyl-piperazin-l-yl)- benzyl]-l-[4-(morpholine-4-carbonyl)-phenyl]-pyrrolidin-2-one; l-[4-(4-methyl- piperazine-l-carbonyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2- one, 3 -[2-(4-methyl-piperazin- 1 -yl)-benzyl]- l-[4-(piperidine- 1 -carbonyl)-phenyl]- pyrrolidin-2-one; l-[4-(l-hydroxy-cyclobutyl)-phenyl]-3-[2-(l-methyl-piperidin-4-yl)- benzyl]-pyrrolidin-2-one; 1 -[4-(l-hydroxy-cy cl ohexyl)-phenyl]-3-[2-(l -methyl - piperidin-4-yl)-benzyl]-pyrrolidin-2-one; 1 -[4-(l -hydroxy- 1 -methyl-ethyl)-phenyl]-3 - [2-(l-methyl-piperidin-4-yl)-benzyl]-pyrrolidin-2-one; l-[4-(l-hydroxy-cyclopentyl)- phenyl]-3-[2-(l-methyl-piperidin-4-yl)-benzyl]-pyrrolidin-2-one; l-[4-(l-hydroxy- cyclopentyl)-phenyl]-3-[2-((3i?,55,)-3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin- 2-one; l-[4-(l -hydroxy- l-methyl-ethyl)-phenyl]-3-[2-((3 ?,55)-3, 4, 5-trimethyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[4-(4-hydroxy-tetrahydro-pyran-4-yl)- phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; l-[6-(l- hydroxy-l-methyl-ethyl)-pyridin-3-yl]-3-[2-((3 ?,55)-3,4,5-trimethyl-pipera2in-l-yl)- benzyl]-pyrrolidin-2-one; (R)-3 -[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(6-morpholin-4- yl-pyridin-3-yl)-pyrrolidin-2-one; (R)- 1 -[4-(l -hydroxy- 1 -methyl-ethyl)-phenyl]-3 -[2-(4- methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-3-[2-(4-methyl-piperazin-l-yl)- benzyl]- 1 -(4-morpholin-4-yl-phenyl)-pyrrolidin-2-one; (R)- 1 -[4-(l-hydroxy- cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-l-[4- (2-hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- pyrrolidin-2-one; (R)- 1 -[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3 -2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1 -[4-(l -methoxy- 1 -methyl -ethy l)-pheny 1 ] - 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1 -[4-(l -hydroxy- 1 -methyl- ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-piperidin-2-one; (i?)-3-[2-fluoro- 6-(4-methyl-piperazin-l-yl)-benzyl]-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-pyrrolidin- 2-one; (i?)-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-((3i?,55')-3,4,5-trimethyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]- 3-[2-((3 ?,55)-3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-l-[4-(4- hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3i?,55’)-3,4,5-trimethyl-piperazin-l-yl)- benzyl]-pyrrolidin-2-one; (i?)-6’-(l -hydroxy- l-methyl-ethyl)-3-[2-(4-methyl-piperazin- l-yl)-benzyl]-3,4,5,6- tetrahydro-[ 1,3’ Jbipyridinyl-2-one; (i?)-3-[2-fluoro-6-(4-methyl- piperazin- 1 -yl)-benzyl]-l -[6-(l -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-pyrrolidin-2- one; (i?)-l-[6-(l-hydroxy-l-methyl-ethyl)-pyridin-3-yl]-3-[2-((3i?,55')-3,4,5-trimethyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)-3 -[2-(4-ethyl-piperazin- 1 -yl)-benzyl]-l - [4-(l -hydroxy- 1 -methyl -ethyl -phenyl ] -pyrroli din-2 -one ; (R)- 1-[6-( 1 -ethyl- 1 -hydroxy- propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-3-[2- (4-methyl-piperazin- 1 -yl)-benzyl]-l -[6-(tetrahydro-pyran-4-yloxy)-pyri din-3 -yl]- pyrrolidin-2-one; (i?)-l-[6-(l-hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1 -[4-( 1 -hydroxy-cyclobutyl)-phenyl]-3 - [2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (R)- 1 -[5-(l -Hydroxy - cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (i?)-l-[4-(2-methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- piperidin-2-one; (i?)-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-l-[4-(piperidine-l- carbonyl)-phenyl]-pyrrolidin-2-one; (S)-3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- 1 -(6- morpholin-4-yl-pyri din-3 -yl)-pyrrolidin-2-one; ( S )- 1 -[4-( 1 -hydroxy- 1 -methyl-ethyl)- phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (S)-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-l-(4-morpholin-4-yl-phenyl)-pyrrolidin-2-one; (S)-l-[4-(l- hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (5)-l-[4-(2-hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- pyrrolidin-2-one; (S)- 1-[6-( 1 -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-3-[2-(4-methyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- 1 -[4-(l -methoxy- 1 -methyl -ethy l)-pheny 1 ] - 3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- 1 -[4-(l -hydroxy- 1 -methyl- ethyl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]- piperidin-2-one; (5)-3-[2-fluoro- 6-(4-methyl-piperazin-l-yl)-benzyl]-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-pyrrolidin- 2-one; (5)-l-[4-(l-hydroxy-cyclopentyl)-phenyl]-3-[2-((3 ?,55)-3,4,5-trimethyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; ( S )- 1-[4-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]- 3-[2-((3i?,55’)-3,4,5-trimethyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (5)-l-[4-(4- hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3i?,55’)-3,4,5-trinnethyl-piperazin-l-yl)- benzyl]-pyrrolidin-2-one; (5)-6’-(l -hydroxy- l-methyl-ethyl)-3-[2-(4-methyl-piperazin- l-yl)-benzyl]-3,4,5,6-tetrahydro-[l,3’]bipyridinyl-2-one; (5)-3-[2-fluoro-6-(4-methyl- piperazin- 1 -yl)-benzyl]-l -[6-(l -hydroxy- 1 -methyl-ethyl)-pyri din-3 -yl]-pyrrolidin-2- one; (5)-l-[6-(l-hydroxy-l-methyl-ethyl)-pyridin-3-yl]-3-[2-((3 ?,55)-3,4,5-trimethyl- piperazin- 1 -yl)-benzyl]-pyrrolidin-2-one; (S)-3-[2-(4-ethyl-piperazin- 1 -yl)-benzyl]- l-[4- ( 1 -hydroxy- 1 -methyl-ethyl)-phenyl]-pyrrolidin-2-one; ( S )- 1 -[6-(l -ethyl- 1 -hydroxy- propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (5)-3-[2- (4-methyl-piperazin- 1 -yl)-benzyl]-l -[6-(tetrahydro-pyran-4-yloxy)-pyri din-3 -yl]- pyrrolidin-2-one; (S)-l-[6-(l-hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl- piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (5)-l-[4-(l-hydroxy-cyclobutyl)-phenyl]-3-[2- (4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (5)- 1 - [5 -( 1 -hydroxy-cy cl openly 1)- pyridin-2-yl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-pyrrolidin-2-one; (S)-l-[4-(2- methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-l-yl)-benzyl]-piperidin-2-one; (S)-3 - [2-(4-methyl-piperazin- 1 -yl)-benzyl]-l -[4-(piperidine- 1 -carbonyl)-phenyl]- pyrrolidin-2-one; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from those described in W02007053093, including, without limitation, 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6-fluoro-
8-(4-methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; 6-fluoro- 8-(4-methylpiperazin- 1 -yl)-A/-(4-morpholinoben-2-yl)chroman-2-carboxamide; (+)-6- fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; (-)- 6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; N-(4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l- yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro- 8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (-)-A/-(4-(4-
(ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l- yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin-l-yl)- V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-morpholinobenzyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin- l-yl)-A/-(4-(4-(m ethyl sulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-/V-(4- morpholmophenyl)chroman-2-carboxamide; (+)-6-fiuoro-8-(4-methylpiperazin-l-yl)-A/- (4-morpholinoben-2-yl)chroman-2-carboxamide; ( +)-N-(4-(4 - (ethyl sulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-6-fluoro-
8-(4-methylpiperazin-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin-l-yl)- V-(4- morpholinophenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-morpholinophenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin-l-yl)-A/-
(4-morpholinobenzyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)- A/-(4-morpholinobenzyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - (ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (-)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin- l-yl)-A/-(4-(4-(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2- carboxamide; (-)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; ( +)-N-(4-(4 - (ethyl sulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-(4-
(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; 6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)cliroman-2-carboxamide; (4-)-6-fluoro- 8-(4-methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (-)-6- fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; 6- fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide;
(+)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2- carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-morpholinobenzyl)chroman- 2-carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; (-)-N-(4-(4- (ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-(4-(methylsulfonyl)piperazin- 1 - yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-iV-(4-(4- (m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4- methylpiperazm-l-yl)-A/-(4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin-l-yl)- V-(4- morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-N-
(4-morpholinobenzyl)chroman-2-carboxamide; (+)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 - yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin- l-yl)-A/-(4-(4-(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2- carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin-l-yl)-A/-(4- morpholinophenyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-morpholinophenyl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin-l-yl)-A/- (4-morpholinobenzyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -yl)- A/-(4-morpholinobenzyl)chroman-2-carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 - yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; A/-(4-(4-(ethylsulfonyl)piperazin-
1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2-carboxamide; ( +)-N-(4-(4 - (ethyl sulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4-methylpiperazin- 1 -yl)chroman-2- carboxamide; (-)-A/-(4-(4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)-6-fluoro-8-(4- methylpiperazin- 1 -yl)chroman-2-carboxamide; 6-fluoro-8-(4-methylpiperazin- 1 -yl)-N- (4-(4-(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-
(4-methylpiperazin- l-yl)-A/-(4-(4-(m ethyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2- carboxamide; (-)-6-fluoro-8-(4-methylpiperazin- 1 -y\)-N-(4-(4-
(methylsulfonyl)piperazin-l-yl)phenyl)chroman-2-carboxamide; (+)-6-fluoro-8-(4- methylpiperazin- 1 -yl)-A/-(4-morpholinophenyl)chroman-2-carboxamide; (+)-6-fluoro-8- (4-methylpiperazin-l-yl)-A/-(4-morpholinobenzyl)chroman-2-carboxamide; ( +)-N-(4-(4 -
(ethylsulfonyl)piperazin-l-yl)phenyl)-6-fluoro-8-(4-methylpiperazin-l-yl)chroman-2- carboxamide; (+)-6-fluoro-8-(4-methylpiperazin- 1 -y\)-N-(4-(4- (methyl sulfonyl)piperazin- 1 -yl)phenyl)chroman-2-carboxamide; and pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
SB-224289 ((r-methyl-6,7-dihydro-5if-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- { 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl } -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
AR-A000002 ((i?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
GR-55562 (3-[3-(dimethylarnino)propyl]-4-hydroxy-/V-[4-(4- pyridinyl)phenyl]benzamide);
NAS-181 ((2i?)-2-({[3-(4-morpholinylmethyl)-2if-chromen-8- yl] oxy } methyl)morpholine methanesulfonate (1 :2));
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl- 1, 2, 4-oxadiazol-3-yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-lfJ-indol-3-yl)-3,6-dihydro-l(2fl)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-lif-2,l,3- benzothiadiazine-2, 2-dioxide);
alprenolol (l-(2-allylphenoxy)-3-(isopropylamino)-2-propanol);
oxprenolol (l-[2-(allyloxy)phenoxy]-3-(isopropylamino)-2-propanol);
isamoltane ( 1 -(isopropylamino)-3 - [2-( 1 H- pyrrol- 1 -yl)phenoxy]-2-propanol hydrochloride (1 : 1));
cyanopindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-17/-indole- 2-carbonitrile);
pindolol (l-(17/-indol-4-yloxy)-3-(isopropylamino)-2-propanol);
(S)-(-)-pindolol ((25)-l-(17/-indol-4-yloxy)-3-(isopropylamino)-2-propanol); carpindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-17/-indole-2- carboxylic acid 1-methylethyl ester);
metergoline (benzyl {[(8P)-l,6-dimethylergolin-8-yl]methyl} carbamate); methiothepin (l-methyl-4-[8-(methylsulfanyl)-10, 1 l-dihydrodibenzo[/? ]thiepin- 10-yl]piperazine);
- yohimbine (methyl(16a, 17a)- 17-hydroxyyohimban- 16-carboxylate);
asenapine ((3 aS, 12/?S)-5-chloro-2-methyl-2,3,3u, 12/?-tetrahy dro- 1 H- dibenzo[2,3 : 6, 7] oxepino[4, 5 -cjpyrrole);
methysergide ((8b)-A/-[(25)- 1 -hydroxy-2-butanyl]- 1 ,6-dimethyl-9, 10- di dehydroergoline- 8 -carboxamide); and
pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
SB-224289 ((r-methyl-6,7-dihydro-5//-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- { 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl } -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
AR-A000002 ((/?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
GR-55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-A/-[4-(4- pyridinyl)phenyl]benzamide);
NAS-181 ((2/?)-2-({[3-(4-morpholinylmethyl)-2//-chromen-8- yl]oxy}methyl)morpholine methanesulfonate (1 :2));
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-l//-indol-3-yl)-3,6-dihydro-l(2//)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-l//-2,l,3- benzothiadiazine-2, 2-dioxide);
alprenolol (l-(2-allylphenoxy)-3-(isopropylamino)-2-propanol);
oxprenolol (l-[2-(allyloxy)phenoxy]-3-(isopropylamino)-2-propanol);
isamoltane ( 1 -(isopropylamino)-3 - [2-( 1 //-pyrrol- 1 -yl)phenoxy]-2-propanol hydrochloride (1 : 1));
cyanopindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-l//-indole- 2-carbonitrile); pindolol (l-(l//-indol-4-yloxy)-3-(isopropylamino)-2-propanol);
(S)-(-)-pindolol ((25)-l-(l -indol-4-yloxy)-3-(isopropylamino)-2-propanol); carpindolol (4-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-l -indole-2- carboxylic acid 1-methylethyl ester); and
- pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
SB-224289 ((r-methyl-6,7-dihydro-5i7-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- { 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl } -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
AR-A000002 ((i?)-7V-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide);
GR-55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-/V-[4-(4- pyridinyl)phenyl]benzamide);
NAS-181 ((2i?)-2-({[3-(4-morpholinylmethyl)-2if-chromen-8- yl]oxy}methyl)morpholine methanesulfonate (1 :2));
GR- 127935 (7V-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2’-methyl-4’-(5- methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide);
- LY-393558 (l-{2-[4-(6-fluoro-lfJ-indol-3-yl)-3,6-dihydro-l(2fl)- pyridinyl]ethyl}-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-li/-2,l,3- benzothiadiazine-2, 2-dioxide); and
pharmaceutically acceptable salts or esters thereof.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is selected from the group comprising or consisting of:
SB-224289 ((l’-methyl-6,7-dihydro-5.f/-spiro[furo[2,3- ]indole-3,4’-piperidin]- 5-yl)[2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylyl]methanone); SB-216641 (TV- { 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl } -2’ -methyl-4’ - (5-methyl-l,2,4-oxadiazol-3-yl)-4-biphenylcarboxamide); AR-A000002 ((i?)-A/-[5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydro-2- naphthyl]-4-morpholinobenzamide); and
pharmaceutically acceptable salts or esters thereof.
In a second embodiment, the 5-HTR1B inhibitor according to the present invention is an antibody that blocks 5-HTR1B activation ( i.e ., a 5-HTR1B blocking antibody). The 5-HTR1B blocking antibodies contemplated in the present invention may, for instance, impair the binding of 5-HT to the receptor by binding to said receptor.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is a polyclonal antibody, preferably a 5-HTR1B polyclonal blocking antibody. In a preferred embodiment, the 5-HTR1B inhibitor according to the present invention is a monoclonal antibody, preferably a 5-HTR1B monoclonal blocking antibody.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is a humanized antibody, preferably a 5-HTR1B humanized blocking antibody.
In a third embodiment, the 5-HTR1B inhibitor according to the present invention is an aptamer that can block 5-HTR1B activation.
In a fourth embodiment, the 5-HTR1B inhibitor according to the present invention is a polynucleotide.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is a polynucleotide which interferes with 5-HTR1B synthesis. In one embodiment, the synthesis of 5-HTR1B may be block at the transcriptional level. In one embodiment, the synthesis of 5-HTR1B may be block at the translational level.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is an antisense oligonucleotide. Antisense oligonucleotides, including antisense RNA molecules and antisense DNA molecules, would act to directly block the translation of 5-HTR1B mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of 5-HTR1B, and subsequently, 5-HTR1B activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding 5-HTR1B can be synthesized, e.g., by conventional phosphodiester techniques and administered by, e.g., intravenous injection or infusion.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is a ribozyme.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is an interference RNA (RNAi). The term RNAi, as used herein, include, without limitation, small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs) and microRNAs (miRNAs), targeted to a 5-HTR1B transcript; as well as RNAi vectors whose presence within a cell results in the production of an siRNA, shRNA or miRNA targeted to the target 5-HTR1B transcript. Such siRNA, shRNA or miRNA comprises a portion of RNA that is complementary to a region of the target 5-HTR1B transcript. Essentially, the RNAi contemplated in the present invention downregulates expression of 5-HTR1B via RNA interference. In one embodiment, the 5-HTR1B inhibitor according to the present invention is an siRNA.
Exemplary siRNA inhibiting 5-HTR1B include, but are not limited to, the siRNA purchased from Dharmacon used in the example section.
In one embodiment, the 5-HTR1B inhibitor according to the present invention is polynucleotide for targeted gene editing.
In one embodiment, any of the polynucleotide according to the present invention may be delivered in vivo alone or in association with a vector.
In a fifth embodiment, the 5-HTR1B inhibitor according to the present invention can be further identified by screening methods described in the state of the art and already mentioned hereinabove.
The present invention further relates to a combination of a 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) for use in the prevention and/or treatment of cancer in a subject in need thereof wherein said 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
The present invention further relates to a composition comprising a 5-HTR1D inhibitor according to the present invention, for use in the prevention and/or treatment of cancer.
In another embodiment, the present invention relates to a composition comprising a 5-HTR1D inhibitor and at least one inhibitor of 5-hydroxytryptamine receptor IB (5-HTR1B) according to the present invention, for use in the prevention and/or treatment of cancer. The present invention further relates to a pharmaceutical composition comprising a 5-HTR1D inhibitor according to the present invention, and at least one pharmaceutically acceptable excipient, for use in the prevention and/or treatment of cancer.
The present invention further relates to a pharmaceutical composition comprising a 5-HTR1D inhibitor, at least one inhibitor of 5 -hy droxytryptamine receptor IB (5-HTR1B) according to the present invention, and at least one pharmaceutically acceptable excipient, for use in the prevention and/or treatment of cancer.
In one embodiment, the pharmaceutical composition comprises the 5-HTR1D inhibitor according to the present invention in a therapeutically effective amount.
In one embodiment, the pharmaceutical composition comprises the 5-HTR1D inhibitor, at least one 5-HTR1B according to the present invention in a therapeutically effective amount.
As used herein, a“pharmaceutically acceptable excipient” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Pharmaceutically acceptable excipients that may be used in the compositions according to the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorb ate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances ( e.g ., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical composition according to the present invention may further comprise antioxidant agents, including, but not limited to, ascorbic acid, ascorbyl palmitate, BHT, potassium sorbate or Rosmarinus officinalis extracts.
The pharmaceutical composition according to the present invention may further comprise flavour agents, including, but not limited to, sugars, fruit or tea flavourings.
The pharmaceutical composition according to the present invention may further comprise pharmaceutically acceptable salts, including, but not limited to, acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
The excipient can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils such as oleic acid. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin (i.e., soy lecithin or de-greased soy lecithin), by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
For a prolonged absorption of the pharmaceutical composition according to the present invention, agents delaying absorption can be added, including, but not limited to, aluminium monostearate and gelatine.
The present invention further relates to a medicament comprising a 5-HTR1D inhibitor according to the present invention, for use in the prevention and/or treatment of cancer.
In one embodiment, present invention further relates to a medicament comprising the 5-HTR1D inhibitor, at least one 5-HTR1B according to the present invention in a therapeutically effective amount.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: gynecological cancer, liver cancer, lung cancer, gastrointestinal cancer, nervous system cancer, mesotheliomas, head and neck cancer, genitourinary tract cancer, sarcoma, cardiac cancer, bone cancer, hematologic and lymphoid cancer, skin cancer, thyroid gland cancer and adrenal glands cancer.
Examples of gynecological cancers include, but are not limited to, breast cancer, cervical cancer, ovarian cancer, uterine cancer, vulvar cancer and vaginal cancer. Examples of breast cancers include, but are not limited to, triple negative breast cancer; luminal A breast cancer; luminal B breast cancer; and HER-2-enriched breast cancer.
Examples of ovarian cancers include, but are not limited to, dysgerminoma; granulosa- theca cell tumors; Sertoli-Leydig cell tumors;
Examples of uterine cancers include, but are not limited to, endometrial cancer such as endometrial carcinomas, endometrial stromal sarcomas and malignant mixed Mullerian tumors; uterine sarcomas; leiomyosarcomas; and gestational trophoblastic disease. Examples of vulvar cancers include, but are not limited to, squamous cell vulvar carcinoma; verrucous vulvar carcinoma; vulvar melanoma; basal cell vulvar carcinoma; Bartholin gland carcinoma; vulvar adenocarcinoma; and erythroplasia of Queyrat.
Examples of vaginal cancers include, but are not limited to, squamous-cell vaginal carcinoma; vaginal adenocarcinoma; clear cell vaginal adenocarcinoma; vaginal germ cell tumors; vaginal sarcoma botryoides; and vaginal melanoma.
Examples of liver cancers include, but are not limited to, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma. Examples of lung cancers include, but are not limited to, adenocaminoma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, lymphoma, chondromatous hamartoma and pleural mesothelioma.
Examples of gastrointestinal cancers include, but are not limited to, pancreatic cancer (such as, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors or vipoma), esophageal cancer (such as, e.g., squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma or lymphoma), stomach or gastric cancer (such as, e.g., carcinoma, lymphoma or leiomyosarcoma), small bowel or small intestines cancer (such as, e.g., adenocarcinoma lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma or fibroma), large bowel or large intestines cancer (such as, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma or leiomyoma) and colorectal cancer.
Examples of mesotheliomas include, but are not limited to, pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and end stage mesothelioma.
Examples of nervous system cancers include, but are not limited to, brain cancer (such as, e.g., astrocytoma, medulloblastoma, glioma, lower grade glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, glioma or sarcoma), skull cancer (such as, e.g., osteoma, hemangioma, granuloma, xanthoma or osteitis deformans) and meninges cancer (such as, e.g., meningioma, meningiosarcoma or gliomatosis).
Examples of head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma and oral cancer (such as, e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer or pharynx cancer).
Examples of genitourinary tract cancers include, but are not limited to, kidney cancer (such as, e.g., clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, adenocarcinoma, Wilm’s tumor, nephroblastoma, lymphoma or leukemia), bladder and urethra cancer (such as, e.g., squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate cancer (such as, e.g., adenocarcinoma or sarcoma) and testis cancer (such as, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors or lipoma).
Examples of sarcomas include, but are not limited to, Askin' s tumor; sarcoma botryoides; chondrosarcoma; Ewing's sarcoma; malignant hemangioendothelioma; malignant schwannoma; osteosarcoma; and soft tissue sarcomas.
Examples of soft tissue sarcomas include, but are not limited to, alveolar soft part sarcoma; angiosarcoma; cystosarcoma phyllodes; dermatofibrosarcoma protuberans; desmoid tumor; desmoplastic small round cell tumor; epithelioid sarcoma; extraskeletal chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; gastrointestinal stromal tumor (GIST); hemangiopericytoma; hemangiosarcoma; Kaposi's sarcoma; leiomyosarcoma; liposarcoma; lymphangiosarcoma; lymphosarcoma; malignant peripheral nerve sheath tumor (MPNST); neurofibrosarcoma; plexiform fibrohistiocytic tumor; rhabdomyosarcoma; synovial sarcoma; and undifferentiated pleomorphic sarcoma.
Examples of cardiac cancers include, but are not limited to, sarcoma (such as, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma or liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma. Examples of bone cancers include, but are not limited to, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma and reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxoflbroma, osteoid osteoma and giant cell tumors.
Examples of hematologic and lymphoid cancers include, but are not limited to, blood cancer (such as, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma or myelodysplasia syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma and hairy cell and lymphoid disorders.
Examples of skin cancers include, but are not limited to, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles, dysplastic nevi, lipoma, angioma and dermatofibroma. Examples of thyroid gland cancers include, but are not limited to, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2 A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma and paraganglioma.
Examples of adrenal glands cancers include, but are not limited to, neuroblastoma and pheochromocytoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer, cervical cancer, ovarian cancer, uterine cancer, vulvar cancer, vaginal cancer, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, lung lymphoma, lung chondromatous hamartoma, lung mesothelioma, pancreatic cancer, esophageal cancer, stomach (or gastric) cancer, small bowel or small intestines cancer, large bowel or large intestines cancer, colorectal cancer, brain cancer, skull cancer, meninges cancer, head and neck squamous cell carcinoma, oral cancer, kidney cancer, bladder and urethra cancer, prostate cancer, testis cancer, cardiac sarcoma, cardiac myxoma, cardiac rhabdomyoma, cardiac fibroma, cardiac lipoma and cardiac teratoma, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma and reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxoflbroma, osteoid osteoma, giant cell tumors, blood cancer, Hodgkin’s disease, non-Hodgkin’s lymphoma, hairy cell and lymphoid disorders, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles, dysplastic nevi, lipoma, angioma, dermatofibroma, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2 A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma, neuroblastoma and pheochromocytoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer, cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer, cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), gastric cancer and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
In one embodiment, the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma) and lung cancer (including, but not limited to, lung adenocarcinoma). In one embodiment, the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched, luminal A breast cancer and luminal B breast cancer) and lung cancer (including, but not limited to, lung adenocarcinoma).
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein said cancer is selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer) and mesothelioma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: triple negative breast cancer, luminal A breast cancer, luminal B breast cancer, liver cancer (including, but not limited to, liver hepatocellular carcinoma), mesothelioma and sarcoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer selected from the group comprising or consisting of: triple negative breast cancer, luminal A breast cancer, luminal B breast cancer, mesothelioma and sarcoma.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D or the high expression of 5-HTR1D and of 5-HTR1B in said cancer is associated with a lower survival of said subject.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D in said cancer is associated with a lower survival of said subject. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1B in said cancer is associated with a lower survival of said subject. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D and of 5-HTR1B in said cancer is associated with a lower survival of said subject. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein high expression of 5-HTR1D and low expression of 5-HTR1B in said cancer is associated with a lower survival of said subject. Association between the level of expression of 5-HTR1D and/or 5-HTR1B, and life expectancy of a subject can be determined using methods well-known in the art, such as the method described hereinafter.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D or overexpress the gene coding for 5-HTR1D and overexpress the gene coding for 5-HTR1B.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D and 5-HTR1B.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of cancer in a subject, wherein cells of said cancer overexpress the gene coding for 5-HTR1D but do not overexpress the gene coding for 5-HTR1B.
The Inventors have demonstrated that a high level of 5-HTR1D and/or 5-HTR1B expression is particularly associated with a lower survival of breast cancer patients. These observations suggest that the inhibition of the activity of these receptors is particularly effective in the treatment of breast cancer.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of breast cancer in a subject. Routinely evaluated markers of breast cancer cells, such as the presence or absence of the hormone receptors (HR) for estrogen and progesterone, the level of human epidermal growth factor receptor 2 (HER2), and the cell proliferation markers Ki67, are used to classify breast cancer into 4 molecular subtypes:
HER2-enriched breast cancer (HR/HER2+),
- luminal A breast cancer (HR+/HER2 ),
luminal B breast cancer (HR+/HER2+/Ki67+), and
- triple negative breast cancer (HR/HER2 ).
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative, HER2-enriched, luminal A breast cancer or luminal B breast cancer in a subject.
Notably, the Inventors have demonstrated that a high level of 5-HTR1D or 5-HTR1B expression is particularly associated with a lower survival of triple negative breast cancer patient. Moreover, the inhibition of 5-HTR1D and/or 5-HTR1B is particularly efficient in inhibiting proliferation and survival of triple negative breast cancer cell lines. The Inventors have also demonstrated that a high level of 5-HTR1D expression is particularly associated with a lower survival of luminal A breast cancer patient. These observations suggest that inhibiting the activity of these receptors is particularly effective for the treatment of triple negative breast cancer, luminal A breast cancer patients, and/or luminal B breast cancer.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative, HER2-enriched, luminal A or luminal B breast cancer in a subject.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative breast cancer in a subject. Triple negative breast cancers have been classified into different subtype by Lehmann et al, J Clin Invest. 2011 Jul;121(7):2750-67.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of triple negative breast cancer in a subject wherein said triple negative breast cancer is of the type TNBC-BL1, TNBC-M and TNBC-UNS.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of luminal A breast cancer in a subject.
The Inventors have demonstrated that a level of 5-HTR1D receptor or 5-HTR1B receptor expression is particularly high in tumor samples not responding to chemotherapy.
Examples of chemotherapies include, but are not limited to:
a. alkylating agents that act mainly by forming covalent bonds between DNA bases, including, but not limited to, nitrogen mustards (e.g., cyclophosphamide), aziridines and epoxides ( e.g ., thiopeta), alkyl sulfonates ( e.g ., busulfan), nitrosureas (e.g., BCNU and CCNU), hydrazine and triazine derivatives (e.g., procarbazine and temozolomide);
b. cisplatin and its analogs that act by forming DNA adducts which lead to intra strand and inter-strand linking leading to the formation of DNA filaments, including, but not limited to, carboplatin, cisplatin and oxaliplatin;
c. antimetabolites including but not limited to folate metabolism inhibitors (e.g., methotrexate, trimetrexate, tomudex), 5-fluoropyrimidines (e.g., 5-FU), oral fluoropyramidines (e.g., tegafur, uracil, capecitabine), necleoside analogs (e.g., cytarabine), gemcitabine and 6-thiopurines (e.g., 6-MP and 6-TG);
d. topoisomerase-interactive agents that affect the topologic states of DNA by interfering or modulating DNA cleavage, strand passage and re-ligation, including, but not limited to, epipodophyllotoxins (e.g., etoposide and teniposide), camptothecin analogs, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), mitoxantrone and losoxantrone, and dactinomycin;
e. antimicrotubule agents, which interfere with the proper polymerization/depolymerization of microtubules, including, but not limited to, vinca alkaloids (e.g., vincristine, vinorelbine and vinblastine), taxanes (e.g., paclitaxel, docetaxel) and estramustine phosphate; and
f. numerous miscellaneous agents exist which cannot be classified into any of the above groups, including but not limited to suramin, bleomycin, L-asparaginase and amifostine.
In one embodiment, the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the prevention and/or treatment of breast cancer (preferably, of triple negative or luminal A breast cancer) unresponsive to chemotherapy in a subject.
In one embodiment, said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a first-line chemotherapy.“First-line chemotherapy”, as used herein, refers to an initial chemotherapy treatment given to a subject for the treatment of cancer. In one embodiment, said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a second-line chemotherapy.“Second-line chemotherapy”, as used herein, refers a chemotherapy treatment given when the first-line chemotherapy treatment did not work or stopped working. In one embodiment, said breast cancer (preferably, triple negative or luminal A breast cancer) is unresponsive to a third-line chemotherapy or more. “Third-line chemotherapy”, as used herein, refers a chemotherapy treatment given when both the first-line chemotherapy treatment and the second-line chemotherapy treatment did not work or stopped working. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered system! cally or locally.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered orally, buccally, by injection, by percutaneous administration, parenterally, intraperitoneal, by endoscopy, topically, transdermally, transmucosally, nasally, by inhalation spray, rectally, vaginally, intratracheally, or via an implanted reservoir.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be orally administered.
Examples of formulations adapted to oral administration include, but are not limited to, solid forms, liquid forms and gels.
Examples of solid forms adapted to oral administration include, but are not limited to, pill, tablet, capsule, soft gelatin capsule, hard gelatin capsule, dragees, granules, caplet, compressed tablet, cachet, wafer, sugar-coated pill, sugar coated tablet, or dispersing/or disintegrating tablet, powder, solid forms suitable for solution in, or suspension in, liquid prior to oral administration and effervescent tablet. Examples of liquid form adapted to oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, sealed phial, potion, drench, syrup, liquor and sprays.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be injected, preferably systemically injected.
Examples of formulations adapted to systemic injections include, but are not limited to, liquid solutions or suspensions, solid forms suitable for solution in, or suspension in, liquid prior to injection. Examples of systemic inj ections include, but are not limited to, intravenous, intratumoral, intracranial, intralymphatic, intraperitoneal, intramuscular, subcutaneous, intradermal, intraarticular, intrasynovial, intrastemal, intrathecal, intravesical, intrahepatic, intralesional, intracavemous, infusion techniques and perfusion.
In another embodiment, when injected, the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is sterile. Methods for obtaining a sterile composition, pharmaceutical composition, medicament or nutraceutical composition include, but are not limited to, GMP synthesis (GMP stands for“Good manufacturing practice”).
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be topically administered.
Examples of formulations adapted to topical administration include, but are not limited to, lubricants, sticks, lipsticks, waxes, creams, lotions, ointments, balms, gels, glosses, sunscreen preparations, cosmetics, masks, leave-on washes or cleansers, depilatory preparations and/or the like.
Topical administration characterizes the delivery, administration or application of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention directly to the site of interest for a localized effect (generally onto one or more exposed or outer surfaces thereof, such as the outermost layer of the epidermis, which is exposed and visually observable), e.g., using hands, fingers or a wide variety of applicators (rollup, roll-on or other stick container, tube container, cotton ball, powder puff, Q-tip, pump, brush, mat, cloth and/or the like). The application may be made, e.g., by laying, placing, rubbing, sweeping, pouring, spreading and/or massaging into, or onto, the skin, or by any other convenient or suitable method. Preferably, topical administration is effected without any significant absorption of components of the composition into the subject’s blood stream (to avoid a systemic effect). The 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, e.g., benzyl alcohol 1% or 2% (w/w) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions can contain polyethylene glycol 400 (PEG 400). They can be mixed to form ointments with, e.g., benzyl alcohol 2% (w/w) as preservative, white petrolatum, emulsifying wax and tenox II (butyl ated hydroxy ani sole, propyl gallate, citric acid, propylene glycol). Woven pads or rolls ofbandaging material, e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
In one embodiment, the combination, the composition, pharmaceutical composition or medicament according to the present invention may be used in conjunction with delivery systems that facilitate delivery of the agents to the central nervous system. For example, various blood brain barrier (BBB) permeability enhancers may be used to transiently and reversibly increase the permeability of the blood brain barrier to a treatment agent. Such BBB permeability enhancers include, but are not limited to, leukotrienes, bradykinin agonists, histamine, tight junction disruptors (e.g., zonulin, zot), hyperosmotic solutions (e.g., mannitol), cytoskeletal contracting agents, and short chain alkylglycerols (e.g., 1 -0-pentylglycerol). Oral, sublingual, parenteral, implantation, nasal and inhalational routes can provide delivery of the active agent to the central nervous system. In some embodiments, the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention may be administered to the central nervous system with minimal effects on the peripheral nervous system.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in an immediate release form.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in a mixed-release form. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in an enterically-coated form.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered in a sustained-release form.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention comprises a delivery system that controls the release of the active ingredients.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered at a dose determined by the skilled artisan and personally adapted to each subject.
It will be understood that the total daily usage of the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective amount for any particular subject will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, the duration of the treatment; drugs used in combination or coincidental with the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a therapeutic compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved; but, at the opposite, it can be equally useful to start with a loading dose, a manner to reach steady- state plasma concentration more quickly, and then to follow with a maintenance dose calculated to exactly compensate the effect of the elimination process.
In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered at least once a day, at least twice a day, at least three times a day. In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered every two, three, four, five, six days.
In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered twice a week, every week, every two weeks, every three weeks, once a month.
In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered every month, every two months, every three months, every four months, every five months, every six months, once a year.
In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered for a period of time of about one day, two days, three days, four days, five days, six days, a week, two weeks, three weeks, a month, two months, three months, six months, a year, or over longer periods such as, e.g., for several years or for the rest of the life of the subject.
In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered until treatment or alleviation of cancer, preferably selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer and luminal A breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including but not limited to brain lower grade glioma), mesothelioma, head and neck squamous cell carcinoma, kidney cancer (including but not limited to clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma) and cervix cancer (including but not limited to cervical squamous cell carcinoma); more preferably breast cancer, even more preferably triple negative or luminal A breast cancer. In one embodiment, a therapeutically effective amount of the 5-HTR1D inhibitor, the composition, the pharmaceutical composition or the medicament according to the present invention is to be administered until the tumor(s) size has decreased, preferably the decrease of the tumor in size is of at least 50%, more preferably of at least 60 %, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 98%, at least 99% or more, of the size of the tumor before administration of the treatment.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said cancer is metastasized. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said cancer is metastasized and wherein said chemotherapy comprises the administration of taxanes, preferably of paclitaxel.
In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with chemotherapy, wherein said chemotherapy comprises the administration of taxanes, preferably of paclitaxel. In one embodiment, the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the sensitization to chemotherapy in a subject in need thereof. In one embodiment said cancer is unresponsive to chemotherapy.
In one embodiment the 5-HTR1D inhibitor, the combination, the composition, the pharmaceutical composition or the medicament according to the present invention is for use in the treatment of cancer in combination with an immune checkpoint inhibitor.
As used herein, the term“immune checkpoint inhibitor” refers to any compound, small molecule, coding or antisense nucleic acids, protein, antibody and fragment or functional equivalent thereof, having, intrinsically or via the protein encoded by said coding nucleic acids, the ability to antagonize the inhibition of the immune response by an immune checkpoint. In one embodiment, immune checkpoint inhibitor antagonizes at least partially (e.g., more than 50%) the activity of inhibitory immune checkpoints, in particular those mediated by any of the following: programmed death- 1 (PD-1), programmed death ligand- 1 (PD-L1), programmed death ligand-2 (PD-L2), lymphocyte- activation gene 3 (LAG3), T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3), B- and T-lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and killer immunoglobulin-like receptors (KIR). Examples of immune checkpoint inhibitors include, but are not limited to, antibodies such as pembrolizumab (a.k.a. MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda), nivolumab (a.k.a. ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), cemiplimab (a.k.a. REGN2810 or REGN-2810), tislelizumab (a.k.a. BGB-A317), spartalizumab (a.k.a. PDR001 or PDR-001), ABBV-181,
JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, avelumab, atezolizumab, durvalumab, LY3300054, ipilimumab, tremelimumab and GRH4102.
In one embodiment, the immune checkpoint inhibitor gene has, or encodes, a protein having a PD-1/PD-L1 inhibitory activity. In one embodiment, the immune checkpoint inhibitor gene encodes an antibody, a mimetics thereof or a fragment thereof having a PD-1/PD-L1 immune checkpoint inhibitory activity.
In one embodiment, the immune checkpoint inhibitor gene encodes an antibody, a mimetic thereof or a fragment thereof, that specifically binds to PD-1 or PD-L1. Example of anti -PD 1 antibodies include, but are not limited to, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab, pembrolizumab and antibodies described in International patent applications W02004004771, W02004056875, W02006121168, WO2008156712, W02009014708, W02009114335, WO2013043569 and W02014047350.
Example of anti-PD-Ll antibodies include, but are not limited to, LY3300054, atezolizumab, durvalumab and avelumab.
One may further consider as an immune checkpoint inhibitor in the context of the present invention the VISTA protein, which was shown to negatively regulate T cells. VISTA, also designated PD-1H or PD-L3, resembles members of the PD-L1 family. For example, anti-VISTA antibodies are described in US patent application US20130177557.
Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the CTLA-4 protein, and especially an antibody (or mimetic or fragment thereof) that recognizes human CTLA-4. CTLA4, also known as CD 152, is encoded by the CTLA4 gene. CTLA4 is a member of the immunoglobulin superfamily of receptors. It is expressed on the surface of helper T cells where it primarily regulates the amplitude of the early stages of T cell activation. Recent work has suggested that CTLA-4 may function in vivo by capturing and removing B7.1 and B7.2 from the membranes of antigen-presenting cells, thus making these unavailable for triggering T-cell proliferation through CD28. A number of anti-CTLA-4 antibodies are available in the art (see, e.g., those described in US patent US8,491,895). Other anti-CTLA-4 antibodies that can be considered in the context of this invention are FDA-approved or under advanced clinical development. One may cite more particularly ipilimumab (see, e.g., US patents US6,984,720 and US8,017,114), tremelimumab (see, e.g., US patents US7, 109,003 and US8, 143,379) and single chain anti-CTLA4 antibodies (see, e.g., International patent applications WO1997020574 and WO2007123737).
Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the LAG3 receptor (see e.g. US patent US5,773,578).
Another group to be considered as an immune checkpoint inhibitor is represented by inhibitors of the KIR proteins (KIR2L3 and KIR3DL2). KIR proteins are expressed by NK cells and T cells and promote self-tolerance by dampening lymphocyte activation, cytotoxic activity and cytokine release. Exemplary molecule targeting KIR that can be considered in the context of the present invention is IPH4102 targeting KIR3DL2.
In one embodiment, the subject is an animal, preferably a mammal, more preferably a primate, even more preferably a human.
In one embodiment, the subject is a male. In one embodiment, the subject is a female.
In one embodiment, the subject is a child. In one embodiment, the subject is a teenager. In one embodiment, the subject is an adult.
In one embodiment, the subject is over 20 years old. In one embodiment, the subject is over 30 years old. In one embodiment, the subject is over 40 years old. In one embodiment, the subject is over 50 years old. In one embodiment, the subject is over 55 years old. In one embodiment, the subject is over 60 years old.
In one embodiment, the subject i s/was diagnosed with cancer. In one embodiment, the subject is/was diagnosed with breast cancer. In one embodiment, the subject i s/was diagnosed with triple negative breast cancer. In one embodiment, the subject is/was diagnosed with luminal A breast cancer. In one embodiment, the subject is/was diagnosed with breast cancer unresponsive to chemotherapy. In one embodiment, the subject is/was diagnosed with metastasized cancer.
In one embodiment, the subject is/was diagnosed with cancer, wherein said cancer is characterized by the overexpression of 5-HTR1D and/or overexpression of 5-HTR1B.
The Inventors have demonstrated that high expression of 5-HTR1D is associated with a lower survival of subjects affected with breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma.
The present invention hence relates to cancer prognosis methods, comprising a step of measuring the expression level of 5-HTR1D in a sample from the subject.
As used herein, the term“prognosis” refers to the likelihood of a given outcome in the development of a disease. Exemplary outcomes include, but are not limited to, improvement or worsening of the symptoms, death, survival, expectation of quality of life, potential complications and associated health issues. In the context of cancer, the outcome may include survival, long-term survival ( i.e ., survival for at least 3, preferably at least 5, 8, 10 years or more), survival without recurrence, survival without metastasis and responsiveness to chemotherapy.
The Inventors have further demonstrated that high level of expression of 5-HTR1D are characteristic of certain cancers. The present invention hence relates to cancer diagnostic methods, comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
As used herein, the term“diagnostic” refers to a technique or method to facilitate the identification of the nature and/or cause(s) of a medical condition or disease.
The Inventors have further demonstrated that the level of expression of 5-HTR1D allows the stratification of breast cancers, in particular in terms of response to chemotherapy. Indeed, the Inventors have surprisingly been able to correlate the high level of expression of 5-HTR1D with tumor unresponsiveness to chemotherapy.
The present invention hence relates to cancer stratification methods, comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject. As used herein, the term“cancer stratification” refers to the identification of a group of subjects with shared biological characteristics. These ad hoc defined groups can then be used in the design of clinical trials or to choose an appropriate course for the management of the cancer.
The measure of the expression level of 5-HTR1D in a sample of a subject is therefore indicative of stratification, diagnostic and prognosis, which can be combined accordingly in a single method.
The present invention hence relates to diagnostic and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
The present invention hence relates to diagnostic and stratification methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject. The present invention hence relates to stratification and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
The present invention hence relates to cancer diagnostic, stratification and prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample of a subject.
The Inventors have further unveiled that high expression of 5-HTR1B may also be associated with a lower survival of patient with breast cancer (including, but not limited to, triple negative breast cancer and luminal A breast cancer) and mesothelioma. Furthermore, the Inventors have demonstrated that the expression level of 5-HTR1B is also useful in the context of stratification and diagnostic methods.
Together, the expression levels of both 5-HTR1D and 5-HTR1B strengthen the effectiveness of the methods of diagnosis, prognosis and/or stratification according to the present invention.
The present invention hence relates to cancer diagnosis, stratification and/or prognosis methods comprising a step of measuring the expression level of 5-HTR1D in a sample.
In one embodiment, the cancer diagnosis, stratification and/or prognosis methods of the present invention comprise a step of measuring the expression levels of both 5-HTR1D and 5-HTR1B in a sample.
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma and cholangiocarcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer, gastric cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer, sarcoma, thyroid cancer, colon cancer, bladder cancer and gastrointestinal cancer.
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma), cervical cancer (including, but not limited to, cervical squamous cell carcinoma), ovarian cancer and sarcoma. In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), pancreas cancer, brain cancer (including, but not limited to, brain lower grade glioma), mesothelioma, head and neck cancer (including, but not limited to, head and neck squamous cell carcinoma), kidney cancer (including, but not limited to, clear renal cell carcinoma, chromophobe renal cell carcinoma and papillary renal cell carcinoma) and cervical cancer (including, but not limited to, cervical squamous cell carcinoma).
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma), lung cancer (including, but not limited to, lung adenocarcinoma), brain cancer (including, but not limited to, brain lower grade glioma) and mesothelioma.
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including, but not limited to, triple negative breast cancer, HER-2 enriched breast cancer, luminal A breast cancer and luminal B breast cancer), liver cancer (including, but not limited to, liver hepatocellular carcinoma) and lung cancer (including, but not limited to, lung adenocarcinoma).
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of breast cancer (including but not limited to triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer and luminal B breast cancer) and mesothelioma.
In one embodiment, the invention relates to cancer diagnosis, stratification and/or prognosis methods, wherein said cancer is selected from the group comprising or consisting of triple negative breast cancer, HER2-enriched breast cancer, luminal A breast cancer, luminal B breast cancer, liver cancer (including, but not limited to, liver hepatocellular carcinoma), mesothelioma and sarcoma.
In one embodiment, the cancer diagnosis, stratification and/or prognosis methods according to the invention comprise a step of measuring the expression level of 5-HTR1D or measuring the expression level of 5-HTR1D and of 5-HTR1B in a sample of the subject.
In one embodiment, the cancer diagnosis, stratification and/or prognosis methods according to the present the invention comprise a step of providing a sample from the subject. In one embodiment, the sample is a body tissue sample. Examples of body tissues include, but are not limited to, breast, mesothelioma, liver, lung, brain, cervix, kidney, pancreas, ovary, skin, nerve, spleen, thymus, esophagus, stomach, intestine, testis, hair, skin, bone, uterus, bladder and spinal cord. In one embodiment, the sample is a biopsy sample, preferably a cancer biopsy sample. In one embodiment, the sample is a fine-needle aspirate sample, preferably a cancer fine- needle aspirate sample. In one embodiment, the sample is a resection sample, preferably a cancer resection sample. In one embodiment, the sample is a bodily fluid. Examples of bodily fluids include, but are not limited to, blood, plasma, serum, lymph, ascetic fluid, cystic fluid, urine, bile, nipple exudate, synovial fluid, bronchoalveolar lavage fluid, sputum, amniotic fluid, peritoneal fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, semen, saliva, sweat and alveolar macrophages. In one embodiment, the sample, preferably the cancer tissue sample, was previously taken from the subject, i.e., the methods according to the present invention do not comprise a step of recovering a sample from the subject. Consequently, according to this embodiment, the methods according to the present invention are non-invasive methods, i.e., in vitro methods. In one embodiment, the step of measuring the expression level of 5-HTR1D and/or of 5-HTR1B can be carried out using methods well-known to the one skilled in the art.
In one embodiment, measuring the expression level comprises a sub -step of extracting total RNAs from the sample.
In one embodiment, measuring the expression level comprises a sub -step of retro- transcribing total RNAs extracted from the sample, thereby obtaining total cDNAs.
In one embodiment, measuring the expression level comprises a sub -step of amplifying, such as, e.g., by PCR, preferably by qPCR, the cDNAs corresponding to 5-HTR1D and/or 5-HTR1B.
In one embodiment, the expression level of 5-HTR1D and/or 5-HTR1B is measured using a DNA microarray.
In one embodiment, the expression level of 5-HTR1D and/or 5-HTR1B is measured using RNAseq. In one embodiment, the cancer diagnostic, stratification and/or prognosis methods according to the present invention comprise a step of comparing the expression level of 5-HTR1D and/or 5-HTR1B determined in the sample of the subject, with a reference expression level. The reference expression level may be either implemented in the software or an overall median or other arithmetic mean across measurements may be built.
In one embodiment, the reference expression level is relative to an expression level derived from population studies, including without limitation, such subjects having similar age range, subjects in the same or similar ethnic group, similar cancer history and the like.
In one embodiment, the reference expression level is derived from the measurement of the expression levels of 5-HTR1D and/or 5-HTR1B, in a reference population.
In one embodiment, the reference population comprises subjects diagnosed with a given cancer, preferably at least 100, more preferably at least 250, even more preferably at least 500 subjects diagnosed with said cancer.
In one embodiment, the reference population comprises subjects substantially healthy in respect to a given cancer, preferably at least 100, more preferably at least 250, even more preferably at least 500 subjects substantially healthy in respect to said cancer.
By implying a multitude of samples from the reference population, it is conceivable to calculate a median and/or mean expression level for 5-HTR1D and/or 5-HTR1B. In relation to these results, 5-HTR1D and/or 5-HTR1B expression value can be monitored as upregulated (or overexpressed), downregulated (or underexpressed) or substantially unchanged. In one embodiment, the reference expression level corresponds to the mean expression levels of 5-HTR1D and/or 5-HTR1B, measured in the reference population. In one embodiment, the reference expression level corresponds to the median expression levels 5-HTR1D and/or 5-HTR1B measured in the reference population.
In one embodiment, 5-HTR1D and/or 5-HTR1B is considered as differentially expressed (, i.e ., overexpressed or underexpressed) in the sample from the subject as compared to the reference expression level if expression levels differ (positively or negatively) by a factor of at least 1.1, preferably of at least 1.5, more preferably of at least 2 and even more preferably of at least 5.
In one embodiment, 5-HTR1D and/or 5-HTR1B expression level is considered as substantially unchanged in the sample from the subject as compared to the reference expression level if expression levels do not differ (positively or negatively) by a factor of more than 1.2, preferably 1.15, more preferably 1.1, even more preferably 1.05 or less.
In one embodiment, the cancer diagnostic, stratification and/or prognosis methods according to the present invention comprise a step of assigning the subject to a group based on the relation of the expression of 5-HTR1D and/or 5-HTR1B with their reference expression level.
It will be understood - and it is part of the knowledge of the one skilled in the art - that the assignment of a subject to a group or another, based on the relation between the measured level of expression of 5-HTR1D and/or 5-HTR1B with regard to their reference expression level, will depend on the reference expression level itself, i. e. , on the reference population used to determine the reference level of expression of 5-HTR1D and/or 5-HTR1B.
In one embodiment, the subject may be assigned to a short survival group. As used herein, the term“short survival group” refers to a group of subjects having cancer and who are likely to die from said cancer within about 2, 3, 5, 8, 10 or more years.
In one embodiment, the subject is assigned to the short survival group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
In one embodiment, the subject may be assigned to a long survival group. As used herein, the term“long survival group” refers to a group of subjects having cancer who are not likely to die from said cancer within about 2, 3, 5, 8, 10 or more years. In one embodiment, the subject is assigned to the long survival group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to the reference expression level.
In one embodiment, an outcome is considered as“not likely” if its probability is inferior to 0.5, preferably inferior to 0.4, 0.3, 0.2, 0.1 or less.
In one embodiment an outcome is considered as“likely” if its probability is superior to 0.5, preferably superior to 0.6, 0.7, 0.8, 0.9 or more.
In one embodiment, the subject may be assigned to a short metastasis-free survival group. As used herein, the term“short metastasis-free survival group” refers to a group of subjects having cancer and wherein said cancer is likely to metastasize within about 2, 3, 5, 8, 10 or more years.
In one embodiment, the subject is assigned to the short metastasis-free survival group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level. In one embodiment, the subject may be assigned to a long metastasis-free survival group. As used herein, the term“long metastasis-free survival group” refers to a group of subjects having cancer who are likely to survive without said cancer having metastasized for at least about 2, 3, 5, 8, 10 or more years.
In one embodiment, the subject is assigned to the long metastasis-free survival group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to the reference expression level.
In one embodiment, the subject is assigned to a chemotherapy-resi stant group. As used herein, the term“chemotherapy-resistant group” refers to a group of subjects having cancer and whose cancer is likely to be unresponsive to chemotherapy. In one embodiment said subject has been previously treated with a chemotherapy. In one embodiment, the subject is assigned to a chemotherapy-resi stant group if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
In one embodiment, the subject is assigned to a chemotherapy-responsive group. As used herein, the term“chemotherapy-responsive group” refers to a group of subjects having cancer and whose cancer is likely to be responsive to chemotherapy. In one embodiment said subject has been previously treated with a chemotherapy.
In one embodiment, the subject is assigned to a chemotherapy-responsive group if 5-HTR1D and/or 5-HTR1B is underexpressed or substantially unchanged with respect to their reference expression level.
In one embodiment, the subject is diagnosed with cancer.
In one embodiment, the subject is diagnosed with cancer if 5-HTR1D and/or 5-HTR1B is substantially unchanged or overexpressed with respect to their reference expression level.
In one embodiment, the cancer prognosis method according to the present invention comprises the steps of:
a) measuring the expression level of 5-HTR1D and/or 5-HTR1B, in a sample previously obtained from a subject,
b) comparing the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level obtained from a reference population, and c) assigning the subject to a survival group based on the comparison of the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level,
thereby prognosing survival in said subject.
In one embodiment, the cancer stratification method according to the present invention comprises the steps of:
a) measuring the expression level of 5-HTR1D and/or 5-HTR1B, in a sample previously obtained from a subject, b) comparing the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level obtained from a reference population, and
c) assigning the subject to a chemotherapy response group based on the comparison of the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level,
thereby classifying said subject.
In one embodiment, the cancer diagnostic methods according to the present invention comprise the steps of:
a) measuring the expression level of 5-HTR1D and/or 5-HTR1B, in a sample previously obtained from a subject,
b) comparing the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level obtained from a reference population, and
c) diagnosing cancer in said subject on the basis of on the comparison of the expression level of 5-HTR1D and/or 5-HTR1B with their reference expression level.
The present invention further relates to a method for preventing and/or treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition, pharmaceutical composition or medicament according to the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the metastasis free survival (MFS) of breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both. Figure 2 is a graph showing the metastasis free survival (MFS) of luminal A breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both. HR: hormone receptor; ERBB2: Erb-B2 receptor tyrosine kinase 2 (HER2). Figure 3 is a graph showing the metastasis free survival (MFS) of triple negative breast cancer patients wherein said cancers have different level of expression of (A) 5-HTR1D, (B) 5-HTR1B or (C) both.
Figure 4 is a graph showing the survival of pancreatic cancer patients wherein said cancers have different level of expression of 5-HTR1D.
Figure 5 is a graph showing the survival of liver cancer patients wherein said cancers have different level of expression of 5-HTR1D. LIHC: liver hepatocellular carcinoma.
Figure 6 is a graph showing the survival of lung cancer patients wherein said cancers have different level of expression of 5-HTR1D. LUAD: lung adenocarcinoma. Figure 7 is a graph showing the survival of brain cancer patients wherein said cancers have different level of expression of 5-HTR1D. LGG: lower grade glioma.
Figure 8 is a graph showing the survival of mesothelioma patients wherein said cancers have different level of expression of (A) 5-HTR1B and (B) 5-HTR1D. MESO: mesothelioma. Figure 9 is a graph showing the survival of head and neck squamous cell carcinoma patients wherein said cancers have different level of expression of 5-HTR1D.
Figure 10 is a graph showing the survival of kidney cancer patients wherein said cancers have different level of expression of 5-HTR1D. (A) KIRP: kidney renal papillary cell carcinoma; (B) KIRC: kidney renal clear cell carcinoma; (C) KICK: kidney chromophobe renal cell carcinoma.
Figure 11 is a graph showing the survival of cervical squamous cell carcinoma (CESC) patients wherein said cancer have different level of expression of 5-HTR1D.
Figure 12 is a graph showing the survival of gastric cancer patients wherein said cancers have different level of expression of 5-HTR1D. Figure 13 is a box plot showing the expression level of 5-HTR1D in normal and kidney renal papillary cell carcinoma tissues (KIRP). TCGA: the cancer genome atlas. Figure 14 is a box plot showing the expression level of 5-HTR1D in normal and lung adenocarcinoma tissues (LUAD). TCGA: the cancer genome atlas.
Figure 15 is a box plot showing the expression level of 5-HTR1D in normal and pancreatic adenocarcinoma tissues (PA AD). TCGA: the cancer genome atlas.
Figure 16 is a box plot showing the expression level of 5-HTR1D in normal and cervical squamous cell carcinoma tissues (CESC). TCGA: the cancer genome atlas.
Figure 17 is a box plot showing the expression level of 5-HTR1D in normal and liver hepatocellular carcinoma tissues (LIHC). TCGA: the cancer genome atlas.
Figure 18 is a box plot showing the expression level of 5-HTR1D in normal and head and neck squamous cell carcinoma tissues (HNSC). TCGA: the cancer genome atlas.
Figure 19 is a box plot showing the expression level of 5-HTR1D in normal and rectum adenocarcinoma tissues (READ). TCGA: the cancer genome atlas.
Figure 20 is a box plot showing the expression level of 5-HTR1D in normal and colon adenocarcinoma tissues (COAD). TCGA: the cancer genome atlas.
Figure 21 is a box plot showing the expression level of 5-HTR1D in normal and Cholangiocarcinoma tissues (CHOL). TCGA: the cancer genome atlas.
Figure 22 is a box plot showing the expression level of 5-HTR1D in normal and esophageal carcinoma tissues (ESCA). TCGA: the cancer genome atlas.
Figure 23 is a box plot showing the expression level of 5-HTR1D in normal and thyroid carcinoma tissues (THCA). TCGA: the cancer genome atlas.
Figure 24 is a box plot showing the expression level of 5-HTR1D in normal and uterine corpus endometrial carcinoma tissues (UCEC). TCGA: the cancer genome atlas.
Figure 25 is a box plot showing the expression level of 5-HTR1D in normal and bladder urothelial carcinoma tissues (BLCA). TCGA: the cancer genome atlas. Figure 26 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in luminal breast cancer, HER2-enriched breast cancer, triple negative breast cancer and normal tissues.
Figure 27 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in breast cancer tissues.
Figure 28 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in tissues of Luminal, HER2-enriched and triple-negative breast cancer.
Figure 29 is a box plot showing the expression level of (A) 5-HTR1D and (B) 5-HTR1B in tissues of different type of triple negative breast cancer as defined by Lehmann et al, J Clin Invest. 2011 Jul;121(7):2750-67.
Figure 30 shows histograms illustrating (A) the effect of BRL-15,572 treatment on the viability triple negative breast cancer cell lines; (B) the effect of BRL-15,572 treatment on apoptosis in the triple negative breast cancer cell line BT549; and (C) the effect of BRL-15,572 treatment on proliferation of the triple negative breast cancer cell line BT549. *p < 0.05, ** 0.001 < p < 0.005 and ***p < 0.001 Students t-test, in B and C.
Figure 31 shows histograms illustrating (A) the effect of GR- 127935 treatment on the viability triple negative breast cancer cell lines; (B) the effect of GR- 127935 treatment on apoptosis in the triple negative breast cancer cell line BT549; and (C) the effect of GR- 127935 treatment on the proliferation of the triple negative breast cancer cell line BT549. *p < 0.05, ** 0.001 < p < 0.005 and ***p < 0.001, Student’s t-test, in B and C.
Figure 32 is a histogram illustrating the effect of HTR1D silencing on the viability of BT549 cells alone or with the combined silencing of HTR1B. (■ p < 0.001; Student’s t- test). EXAMPLES
The present invention is further illustrated by the following examples.
Example 1: relation between expression of HTR1D and HTR1B and breast cancer patient’s survival Material and Methods
Patients
Primary breast tumor samples were obtained from 526 women treated at Institut Curie - Hopital Rene Huguenin (Saint-Cloud, France) between 1978 and 2008. All patients treated at Institut Curie before 2007 were informed that their tumor samples might be used for scientific purposes and had the opportunity to decline. Since 2007, patients treated at Institut Curie have given their approval by signing an informed consent. This study was approved by the local ethics committee (Breast Group of Institut Curie - Rene Huguenin Hospital). The samples were immediately stored in liquid nitrogen until RNA extraction. A tumor sample was considered suitable for this study if the proportion of tumor cells exceeded 70%. All patients (mean age 60.9 years, range 29 - 91 years) met the following criteria: primary unilateral non-metastatic breast carcinoma for which complete clinicopathological data and follow-up were available; no radiotherapy or chemotherapy before surgery; and full follow-up at Institut Curie - Hopital Rene Huguenin. Adjuvant therapy was administered to 367 patients, consisting of chemotherapy alone in 95, hormone therapy alone in 177, and both treatments in 95 patients. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2) statuses were determined at the protein level by biochemical methods (Dextran-coated charcoal method, enzyme immunoassay or immunohi stochemi stry) and confirmed by real-time quantitative RT-PCR. The population was divided into four groups according to hormone receptor (HR) ( estrogen receptor - ER and progesterone receptor PR) and HER2/ERBB2 statuses as follows: two luminal subtypes [HR+ (ERa+ or PR+)/ERBB2+ (n=58)] and [HR+ (ERa+ or PR+)/ERBB2- (n=294)]; an ERBB2+ subtype [HR- (ERa- and PR-)/ERBB2+ (n=73)] and a triple-negative subtype [HR- (ERa- and PR-)/ERBB2- (n=101)]. Within a median follow-up of 9.4 years (range 1 month to 33.2 years), 210 patients developed distant metastasis. Clinical characteristics of the cohort are described in Table 1.
Table 1: clinical characteristics of the cohort
Number of patients (%) Number with metastases p-valuea
(%)
Total 526 (100) 209 (39.7)
Age
<50 125 (23.8) 52 (41.6) 0.51 (NS)
>50 401 (76.2) 157 (39.2)
60 (11.7) 12 (20.0) 0.0018
241 (47.2) 100 (41.5)
Figure imgf000243_0001
210 (41.1) 93 (44.3)
Lymph node status d
0 160 (30.7) 48 (30.0) <0.0001
1-3 248 (47.6) 87 (35.1)
>3 113 (21.7) 72 (63.7)
Macroscopic tumor size e
<25mm 248 (48.1) 76 (30.6) <0.0001
>25mm 268 (51.9) 132 (49.3)
ERa status
Negative 181 (34.4) 76 (42.0) 0.096 (NS) Positive 345 (65.6) 133 (38.6)
PR status
Negative 254 (48.3) 109 (42.9) 0.028
Positive 272 (51.7) 100 (36.8)
ERBB2 status
Negative 395 (75.1) 152 (38.5) 0.19 (NS) Positive 131 (24.9) 57 (43.5)
Molecular subtypes
HR- ERBB2- 101 (19.2) 38 (37.6) 0.072 (NS)
73 (13.9) 36 (49.3)
HR- ERBB2+ 294 (55.9) 114 (38.8)
HR+ ERBB2- 58 (11.0) 21 (36.2)
HR+ ERBB2+
PIK3CA mutation status ^
wild type 354 (68.1) 145 (41.0) 0.21 (NS) mutated 166 (31.9) 61 (36.7) a Log-rank test. NS: not significant
b Scarff Bloom Richardson classification
c Information available for 511 patients
d Information available for 521 patients
e Information available for 516 patients
f Information available for 520 patients
RNA extraction
Total RNA was extracted from breast tumor samples by using acid-phenol guanidium. RNA quality was determined by electrophoresis through agarose gels, staining with ethidium bromide, and visualization of the 18S and 28S RNA bands under ultraviolet light.
Real-time RT-PCR
Quantitative values were obtained from the cycle number (Ct value) at which the increase in the fluorescence signal associated with exponential growth of PCR products started to be detected by the laser detector of the ABI Prism 7900 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA), using PE Biosystems analysis software according to the manufacturer’ s manuals. The TBP gene (Genbank accession NM_003194) encoding the TATA box-binding protein (a component of the DNA-binding protein complex TFIID) was quantified as an endogenous RNA control, and each sample was normalized on the basis of its TBP content. Results, expressed as N-fold differences in target gene expression relative to the TBP gene and termed“Ntarget”, were determined as Ntarget = 2ACtsample, where the ACt value of the sample was determined by subtracting the average Ct value of the target gene from the average Ct value of the TBP gene. The median target gene value of normal breast tissues (14 samples) was used as a reference to normalize the data. Primers’ sequences are indicated below in Table 2. The conditions of cDNA synthesis and PCR have been described previously (Bieche et al, Clin Chem. 1999; 45: 1148-56). Table 2: list of primers used in the RT-PCR experiments
Figure imgf000245_0001
Results
The metastasis-free survival (MFS) of breast cancer patients with a low level of HTR1D expression was longer than the MFS of breast cancer patients with a high level of HTR1D expression (Fig. 1 A). Similarly, the MFS of breast cancer patients with a low level of HTR1B expression was longer than the MFS of breast cancer patients with a high level of HTR1B expression (Fig. 1 B). Breast cancer patients expressing both genes at a low level showed a longer MFS than breast cancer patients expressing both genes at a high level (Fig. 1C). Considering HR+ERBB2 breast cancer patients, similar results were obtained: Fig. 2 is a graph showing the metastasis free survival (MFS) of luminal A breast cancer patients wherein said cancers have different level of expression of (Fig. A) 5-HTR1D, (Fig. B) 5- HTRIB or (Fig. C) both.).
In breast cancer patient of the triple negative (TN) group, MFS also negatively correlated with the expression level of the HTR1D gene (Fig. 3 A), HTR1B gene (Fig. 3 B) or HTR1D and HTR1B genes (Fig. 3 C).
Conclusion
The MFS of breast cancer patients correlates negatively with the expression level of the HTR1D and/or HTR1B gene(s) in breast cancer patients, breast cancer patient of the luminal A group and breast cancer patient of the TN group.
These results suggest that the measure of the expression level of HTR1D and/or HTR1B gene(s) might be used in the diagnosis, prognosis and stratification of breast cancer patient. They also support the hypothesis that the inhibition of 5-HTR1D and / 5-FFTRIB could be useful in the treatment of breast cancer, in particular the triple negative and luminal A subtype.
Example 2: relation between expression of HTR1D and HTR1B and cancer patient’s survival
Material and Methods
Kaplan-Meier curves illustrating the survival probability in different cancers based on transcriptomic levels of HTR1D or HTR1B were obtained using the current release of Ualcan web -tool. Transcriptomic data were also obtained using the current release of Ualcan web -tool, interrogating the database using HTR1D or HTR1B and selecting the different tumors types and molecular subtypes when indicated. (Chandrashekar et at, Neoplasia. 2017 Aug;19(8):649-658). For gastric cancer, data were obtained using KM plot web -tool (www.kmplot.com) interrogating the database using probe ID“207368_at”.
Results Lower expression level of HTR1D was found associated with a longer survival of patients for several cancer type. Lower expression level of HTR1B was found associated with a longer survival of mesothelioma patients. The results of the analysis of cancer patient’s survival are indicated in Table 3 hereinafter.
Table 3: cancers wherein lower expression of HTR1D and/or HTR1B expression correlates with longer survival and corresponding analysis of HTR1D expression level.
Figure imgf000246_0001
Figure imgf000247_0001
Conclusion
These results suggest that the measure of the expression level of HTR1D and/or HTR1B gene(s) might be used in the diagnosis, prognosis and stratification of several cancer, in particular mesothelioma, glioma, gastric cancer, kidney cancer, liver cancer, lung cancer, head and neck squamous cell carcinoma, pancreas cancer and cervical cancer. Furthermore, in view of these results, the treatment of said cancer by the inhibition of 5-HTR1D and/or 5-HTR1B might be considered.
Example 3 HTR1D is overexpressed in several cancers Material and Methods
Transcriptomic data were obtained using the current release of Ualcan web -tool, interrogating the database using HTR1D and selecting the different tumors types and molecular subtypes when indicated. (Chandrashekar et at, Neoplasia. 2017 Aug;19(8): 649-658). For gastric cancer, data were obtained using KM plot web -tool (www.kmplot.com) interrogating the database using probe ID“207368_at”.
Results
Overexpression of HTR1D was found associated with several cancer type. The results of the analysis of cancer patient’s survival are indicated in Table 4 hereinafter. Table 4: cancers wherein overexpression of HTR1D is observed
Figure imgf000248_0001
Conclusion These results suggest that the measure of the expression level of HTR1D gene might be used in the diagnosis, prognosis and stratification of cancer, in particular kidney cancer, liver cancer, lung cancer, head and neck squamous cell carcinoma, pancreas cancer, cervical cancer, rectum cancer, colon cancer, choliangiocarcinoma, Esophageal cancer thyroid cancer, endometrial cancer and bladder cancer. They also support the hypothesis that the inhibition of 5-HTR1D and / 5-HTR1B could be useful in the treatment of said cancer.
Example 4: 5-HT receptors expression in breast cancer
Material and Methods
RNA extraction from breast cell lines
RNA was isolated from cell lines at 80% confluency with miRNeasy Mini kits (Qiagen, Courtaboeuf, France) following the manufacturer’ s instructions. Affvmetrix arrays
Microarray data (Affymetrix human exon 1.0 ST DNA array) of breast cell lines from Institut Curie comprising different breast cancer histological subtypes were queried for HTR1D and HTR1B transcripts. Boxplots illustrating each subtype and compared to non- tumorigenic breast cell lines were displayed.
Real-time reverse transcription- quantitative PCR
Reverse transcription was performed with 2pg of total RNA, with the High-Capacity cDNA reverse transcription kit (Applied Biosystems). The seventeen 5-HT receptors (HTRs) and GAPDH were amplified by Q-PCR in a Roche LightCycler 480 real-time thermal cycler, with the Roche Taqman master mix (Roche) with couples of primers and probes designed with the Roche Assay Center tool (available online at https://www.lifescience.roche.com/en_fr/brands/universal-probe-library.html#assay- design-center) or ready-to-use assay (encompassing primers and Taqman probes) purchased from Applied LifeTechnologies. Primers and probes sequences or reference are listed in Table 5.
Table 5: Primer used in the qPCR experiments
Figure imgf000249_0001
Figure imgf000250_0001
Transcriptomic expression levels for each HTR gene were calculated with the 2-ACt method normalized to GAPDH as housekeeping gene and displayed as UAE (Arbitrary Unit of Expression).
Analysis of expression using U ale an web-tool Transcriptomic data were obtained using the current release of Ualcan web -tool, interrogating the database using HTR1D or HTR1B and selecting the different tumors types and molecular subtypes when indicated. (Chandrashekar et al, Neoplasia. 2017 Aug; 19(8):649-658).
Results HTR1D ((Fig. 26 A) was found overexpressed in triple negative breast cancer tissues from the patient cohort described in Example 1 while it was not the case for HTR1B (Fig. 26 B). Similarly, HTR1D (Fig. 27 A) was found overexpressed in breast cancer tissues while it was not the case for HTR1B (Fig. 27 B) using the Cancer Genome Atlas (TCGA) transcriptome data. Using the same dataset, HTR1D was found overexpressed in tissues of Luminal, HER2-(Fig. 28 A) enriched and triple-negative breast cancers while it was not the case for HTR1B (Fig. 28 B). Detailed analysis revealed that HTR1D (Fig. 29 A) was overexpressed in the following type of triple-negative breast cancer (defined by Lehmann etal, J Clin Invest. 2011 Jul;121(7):2750-67): TNBC-BL1, TNBC- M and TNBC-UNS while HTR1B was found underexpressed in the following type of triple negative breast cancer: TNBC-BL1, TNBC-LAR (Fig. 29 B). Furthermore, HTR1D was also found highly expressed in several triple negative cancer cell lines (Table 6).
Table 6: HTR receptor expression in cancer cell lines (Arbitrary Unit of Expression).
Figure imgf000252_0001
BT20 BT549 HCC38 HCC70 HCC1143 HCC1187 HCC1937 Hs578T 157 231 436 468 Cal51 1A 6,2618E-06 3,1703E-05 2,522 IE-05 l,7407E-05 l,6185E-05 3,604 IE-05 6,4602E-06 9,2833E-05 6,7813E-06 6,972E-06 6,3492E-06 l,1766E-05 l,5365E- 1B 0,00042124 0,00054555 0,00011914 0,00032891 0,00017144 0,00019023 0,00048659 9,6775E-05 0,0002118 7,0354E-05 4,6417E-05 0,00010964 7,6192E- 1D 0,00135734 0,0094859 0,00213729 0,00459729 0,00699238 0,00019762 0,00172403 0,00111403 0,00060452 0,00191957 0,00072236 0,00096312 0,006066 1E NA NA NA NA NA 3,2301E-06 NA NA NA NA 4,762E-06 NA 5,924E- 1F NA 3,0664E-06 0,00012377 NA NA l,3723E-06 NA 4,5839E-06 3,1594E-05 NA NA NA NA2A NA 0,0105618 0,00340059 4,3971E-06 NA NA NA 0,00056479 0,00020601 NA NA 0,00002958 NA 2B NA 6,141 IE-07 1,984 IE-07 NA NA NA 7,2372E-08 l,4226E-07 l,3885E-07 6,776E-08 2,2216E-2C NA NA NA NA NA NA NA NA NA NA NA NA NA 3A NA NA 3,1418E-06 0,00011194 2,5786E-06 l,1326E-05 3,4739E-06 NA 4,5522E-06 NA 5,7222E-06 2,8022E-06 NA 3B NA NA NA NA NA NA NA NA NA NA NA NA NA 3C 2,5289E-07 NA NA NA NA NA l,9033E-07 9,0103E-06 l,9815E-06 3,4307E-07 NA NA NA 3D 4,5425E-07 3,9032E-05 7,7524E-05 9,8467E-05 0,00003073 0,00010336 l,9033E-07 0,00016276 3,344E-06 6,4826E-06 3,1788E-07 6,876E-06 NA 3E 2,6567E-05 7 793E-05 0,00018761 0,00018375 0,00011549 0,00012903 0,00010019 0,00022779 3,9032E-05 l,7589E-05 l,5312E-05 3,8628E-05 5,7743E-R4 6,4602E-06 NA NA NA 5,0793E-05 2,887 IE-05 2,0204E-05 NA 3,9084E-06 NA NA 8,9171E-06 NA 5A NA NA NA NA NA NA NA 4,795 IE-06 NA NA NA NA NAR6 9,8599E-06 0,00002411 3,7833E-05 l,8021E-05 l,3752E-05 3,9852E-05 l,5962E-05 4,7887E-05 0,00026166 l,5259E-05 3,2595E-05 0,00003328 l,9381E-R7 8,3778E-06 2,2526E-06 4,664E-06 2,284E-06 l,1905E-06 2,431E-06 6,2268E-07 5,4063E-05 9,1166E-07 2,8972E-05 l,9474E-06 2,5608E-06 l,344E-
Conclusion
These results suggest that the measure of the expression level of HTR1D gene(s) might be used in the diagnosis, prognosis and stratification of breast cancer and in particular breast cancer of the luminal, HER-2 enriched and triple negative type. Furthermore, in view of these results, the treatment of said cancer by the inhibition of 5-HTR1D appear as a promising approach.
Example 5: effect of the inhibition of 5-HTRln and 5-HTR1B on breast cancer cell lines
Material and Methods Drug treatment
TNBC cell lines were treated with different doses of BRL-15,572 (selective antagonist of 5-HTR1D) or GR- 127935 (potent and dual antagonist of 5-HTR1D and 5-HTR1B) for 72h and cell viability was assessed using the CellTiter-Glo® assay from Promega according to according to the manufacturer’s protocol. Proliferation assay were performed at 72h with the different compounds indicated using the colorimetric BrDU assay from Cell Signaling. Induction of cell apoptosis were detected after 6 hours of treatment using the RealTime-Glo™ Annexin V Apoptosis assay (Promega).
All the experiments were done in three independent replicates and relatively compared to the vehicle control. Values are expressed as means and standard deviation (SD). Statistical analysis (Student’s t-test was conducted using Graphpad Prism software version 7.0 and the difference was considered significant when *p < 0.05. siRNA experiments
Cells were transfected with 50 (siRNA Ctrl, siRNA HTR1D) or 100 nM siRNA (SiRNA Ctrl and SiRNA HTR1B+HTR1D in the presence of Dhermafect I reagent (Dharmacon), in accordance with the manufacturer’ s protocol. All siRNAs were purchased from Dharmacon. Cell viability was assessed with the CellTiter-Glo assay (Promega) 120 h after transfection.
Results
Treatment of triple negative cancer cell lines with BRL-15,572 comprised their viability in a dose-dependent manner (Fig.30A). Treatment of cells from the BT549 triple negative cancer cell line with BRL-15,572 inducted their apoptosis and inhibited their proliferation in a dose-dependent manner (Fig. 30B-C).
Treatment of triple negative cancer cell lines with GR- 127935 comprised their viability in a dose-dependent manner (Fig.31A). Treatment of cells from the BT549 triple negative cancer cell line with GR- 127935 inducted their apoptosis and inhibited their proliferation in a dose-dependent manner (Fig. 31B-C).
Silencing the expression of HTR1D in BT549 cells compromised their viability (Fig. 32). The silencing of both HTR1D and HTR1B lead to a stronger decrease of BT549 cell viability (Fig. 32). Conclusion
These results suggest the use or 5-HTR1D inhibitors alone or in combination with 5-HTR1B inhibitors in the treatment of cancer, in particular breast cancer and triple negative breast cancer.

Claims

1. A 5 -hy droxytryptamine receptor ID (5-HTR1D) inhibitor, for use in the prevention and/or treatment of cancer in a subject in need thereof.
2. The 5-HTR1D inhibitor of claim 1, wherein said 5-HTR1D inhibitor is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
3. The 5-HTR1D inhibitor for use according to claim 1 or 2, wherein said 5-HTR1D inhibitor is a selective 5-HTR1D inhibitor.
4. A combination of a 5-HTR1D inhibitor and at least one inhibitor of
5 -hy droxytryptamine receptor IB (5-HTR1B) for use in the prevention and/or treatment of cancer in a subject in need thereof wherein said 5-HTR1D inhibitor and/or 5-HTR1B is preferably selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides. 5. A composition for use in the prevention and/or treatment of cancer in a subject in need thereof comprising a 5 -HTR 1 D inhibitor according to any one of claims 1 to 3.
6. The composition for use according to claim 5 further comprising at least one inhibitor of 5 -hy droxytryptamine receptor IB (5 -HTR 1B).
7. The composition for use according to claim 6, wherein said 5-HTR1B inhibitor is selected from the group comprising small organic molecules, antibodies, aptamers and polynucleotides.
8. The composition for use according to any one of claims 5 to 7 being a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.
9. The 5 -HTR ID inhibitor for use according to any one of claims 1 to 3, the combination for use according to claim 4, the composition for use according to any one of claims 5 to 8, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer, mesothelioma, head and neck squamous cell carcinoma, kidney cancer, gastric cancer and cervix cancer.
10. The 5-HTR1D inhibitor for use, the combination for use or the composition for use according to any one of claims 1 to 9, wherein said cancer is selected from the group comprising breast cancer, liver cancer, lung cancer, brain cancer and mesothelioma.
11. The 5-HTR1D inhibitor for use, the combination for use or the composition for use according to any one of claims 1 to 10, wherein cancer cells overexpress the gene coding for 5-HTR1D.
12. The 5-HTR1D inhibitor for use, the combination for use or the composition for use according to any one of claims 1 to 11, wherein cancer cells overexpress the gene coding for 5-HTR1B.
13. The 5-HTR1D inhibitor for use, the combination for use or the composition for use according to any one of claims 1 to 12, wherein said cancer is breast cancer preferably triple negative, HER2-enriched, luminal B or luminal A breast cancer.
14. A medicament comprising the 5-HTR1D inhibitor according to any one of claims 1 to 3, the combination according to claim 4, the composition according to any one of claims 5 to 8, for use according to any one of claims 10 to 13.
15. An in vitro cancer diagnosis, stratification and/or prognosis method comprising a step of measuring the expression level of 5-HTR1D and/or 5-HTR1B in a sample previously obtained from a subject.
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CN118308475A (en) * 2024-03-18 2024-07-09 安徽医科大学第一附属医院 Application of HTR1B as a diagnostic marker and therapeutic target for embryonic developmental arrest
WO2024256646A1 (en) * 2023-06-16 2024-12-19 Leukos Biotech Sl 5-htr1b modulator for use in the treatment of solid tumours

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