JP2010502618A - Benzofuran derivatives as modulators of serotonin 5-HT2A receptors - Google Patents

Abstract

The present invention relates to benzofuran derivatives of formula I that are modulators of serotonin 5-HT _2A receptors and are useful in the treatment of various diseases and disorders associated with 5-HT _2A receptors. In one embodiment, the present invention provides a 5-HT _2A receptor, by contacting the compound or a pharmaceutically acceptable salt of formula I, also provides a method of modulating 5-HT _2A receptor . In another embodiment, the present invention provides a method for administering a 5-HT _2A receptor related disease in a patient by administering to the patient a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Or provide a method of treating a disorder.

Description

(Field of Invention)
The present invention is a benzofuran derivative, which is a modulator of serotonin 5-HT _2A receptor, thrombus formation, asthma or symptoms thereof, excitement or symptoms thereof, behavioral disorder, drug-induced psychosis, excitable psychosis, La Tourette syndrome, gonorrhea, organic or NOS psychosis, mental disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetes related disorders, progressive multifocal leukoencephalopathy And derivatives useful in the treatment of various diseases and disorders associated with, for example, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, atrial fibrillation.

(Background of the Invention)
G protein-coupled receptors G protein-coupled receptors share a common structural motif of seven α-helices (22-24 hydrophobic amino acids) each penetrating the cell membrane. The transmembrane helix is connected by a strand of amino acids with a large loop between the fourth and fifth transmembrane helices outside the membrane. Other large loops, composed primarily of hydrophilic amino acids, connect the fifth and sixth transmembrane helices outside the membrane. The carboxy terminus of the receptor lies intracellularly with the amino terminus in the extracellular space. The loops connecting the helix 5 and 6 and the carboxy terminus are thought to interact with the G protein. Currently, Gq, Gs, Gi and Go are G proteins that have been identified.

  Under physiological conditions, G protein-coupled receptors exist in the cell membrane in equilibrium between two different states or forms, an “inactive” state and an “active” state. Inactive receptors cannot link with intracellular transduction pathways to generate biological responses. By changing the receptor configuration to the active state, it is possible to link to the transduction pathway and generate a biological response.

  The receptor can be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recently, it has been discovered that, for example (but not limited to) modifications to the amino acid sequence of the receptor provide a way to stabilize forms of the active state other than the ligand. These methods effectively stabilize the active receptor by mimicking the effect of the ligand binding to the receptor. Stabilization by such ligand-dependent methods is referred to as “structural receptor activation”.

Serotonin Receptors Serotonin receptors (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behavior, appetite, neurodegenerative regulation and biological rhythms. Of course, serotonin has been linked to pathophysiological conditions such as anxiety, depression, obsessive compulsive disorder, schizophrenia, suicide, autism, migraine, nausea, alcoholism and neurodegenerative disorders. With respect to anti-neuropathic therapeutic approaches that focus on serotonin receptors, these types can generally be divided into two classes, “typical” and “non-typical”. Both have anti-neuropathic effects but typically also include collateral movement-related side effects (extra pyramidal syndromes such as making loud noises on the lips, sticking out or retracting, spontaneous motor behavior, etc.). Such side effects are thought to be associated with compounds that interact with other receptors such as the human dopamine D2 receptor in the nigrostriatal pathway. Thus, atypical treatment is preferred. Haloperidol is a typical antipsychotic and clozapine is considered an atypical antipsychotic.

Serotonin receptors are classified into seven subfamilies and are referred to as 5-HT ₁ to 5-HT ₇ (inclusive). These subfamilies are further classified into subtypes. For example, 5-HT ₂ subfamily is three receptor subtypes _are classified into _{5-HT 2A, 5-HT} 2B and _{5-HT 2C.} The human 5-HT _2C receptor was first isolated and cloned in 1987, and the human 5-HT _2A receptor was first isolated and cloned in 1990. These two receptors are thought to be in the active site of hallucinogens. In addition, antagonists to 5-HT _2A and 5-HT _2C receptors are believed to be useful in the treatment of depression, anxiety, psychosis and eating disorders.

U.S. Patent No. 6,057,031 describes the isolation, characterization and expression of a functional cDNA clone encoding the entire human 5-HT _1C receptor (now known as the 5-HT _2C receptor). Patent Documents 2 and 3 describe the isolation, characterization and expression of a functional cDNA clone encoding the entire 5-HT _2A receptor in humans.

5-HT _2A receptor The 5-HT _2A receptor has been shown to be associated with numerous diseases and disorders, and its modulation is believed to have therapeutic potential.

5-HT _2A receptors are expressed in vascular smooth muscle and 5-HT secreted by activated platelets causes vasoconstriction and additional platelet activation during blood clotting. There is evidence that 5-HT _2A inverse agonists inhibit platelet aggregation and are therefore a potential treatment for antiplatelet therapy (see Non-Patent Document 1; and Non-Patent Document 2).

5-HT _2A inverse agonists are, for example, intermittent claudication or peripheral arterial disease and cardiovascular complications (see Non-Patent Document 3), arterial thrombosis (Non-Patent Document 4), and atherosclerosis (Non-Patent Document). 5) Can be used to treat vasoconstriction caused by serotonin (see Non-Patent Document 6), restenosis of an artery after angiogenesis, or stent placement (Non-Patent Document 7). It can also be used alone or in combination with thrombolytic therapy such as tPA (see Non-Patent Document 8), cardioprotection after MI or post-ischemic myocardial dysfunction (Non-Patent Document 9), or transdermal Protection from ischemic injury during coronary angioplasty (see Non-Patent Document 10), and protection from complications caused by them.

5-HT _2A reverse antagonists can increase the patient's circulating adiponectin, because the antagonist is against patients with indication diseases associated with adiponectin such as myocardial ischemia-reperfusion injury and atherosclerosis This suggests that it is useful for the protection (Non-patent Document 11).

Excitement is a well-recognized behavioral symptom with various symptoms, including hostility, extreme excitement, poor impulse control, tension and lack of coordination (see Non-Patent Document 12). Excitement is often treated with antipsychotic drugs such as haloperidol in nursing homes and other auxiliary care facilities. There is new evidence that drugs that act on 5-HT _2A receptors in the brain have the effect of reducing excitement in patients with Alzheimer's dementia (see Non-Patent Document 13; and Non-Patent Document 14).

US Pat. No. 4,985,352 US Pat. No. 5,661,024 US Pat. No. 6,541,209

Satimura, K, et al., Clin Cardiol, January 25, 2002 (1): 28-32. Wilson, H.C. C et al., Thromb Haemost September 2, 1991; 66 (3): 355-60 Br. Med. J. et al. 298: 424-430, 1989 Pawlak, D.C. Et al., Thrombosis Research 90: 259-270, 1998. Hayashi, T .; Et al., Atherosclerosis 168: 23-31, 2003. Fujiwara, T .; And Chiba, S .; Journal of Cardiovascular Pharmacology 26: 503-510, 1995. Fujita, M .; Et al., Am Heart J. et al. 145: e16 2003 Yamashita, T .; Et al., Haemostasis 30: 321-332,2000. Muto, T .; Et al., Mol. Cell. Biochem. 272: 119-132,2005 Horive, E .; Circulation Research 68: 68-72,2004 Nomura, Shosaku, et al., Blood Coagulation and Fibrinolysis 2005, 16, 423-428 Cohen-Mansfield J, and Billig, N .; (1986), Aggregated Behaviors in the Elderly. I. A Conceptual Review. J Am Geriatr Soc34 (10): 711-721 Katz, I.K. R. , Et al., J Clin Psychiatry February 1999, 60 (2): 107-115. Street, J. et al. S. , Et al., Arch Gen Psychiatry October 2000, 57 (10): 968-976.

5-HT _2A receptor dysfunction has also been associated with various sleep disorders, diabetes-related conditions, glaucoma, progressive multifocal leukoencephalopathy (PML), hypertension and pain. Thus, new compounds that act as 5-HT _2A receptor modulators are certainly needed to develop new drugs for the treatment of previously described and other diseases. The compounds, compositions and methods described herein proceed for this purpose.

(Summary of Invention)
The present invention specifically relates to Formula I:

（式中、構成要素は本明細書に記載される）の化合物、またはその医薬的に許容しうる塩を提供する。

Provided is a compound of the formula (wherein the components are described herein), or a pharmaceutically acceptable salt thereof.

  The present invention further provides a composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

  Furthermore, the present invention provides a pharmaceutical composition of the present invention by mixing at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. It also provides a way to do this.

The present invention further receptor, by contacting the compound or a pharmaceutically acceptable salt of formula I, also provides a method of modulating 5-HT _2A receptor.

The present invention further treats a patient's 5-HT _2A receptor related disease or disorder by administering to the patient a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Provide a method.

  The present invention further relates to the administration of a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient to form thrombus, asthma or symptoms thereof, excitement or symptoms thereof, behavioral disorder. , Drug-induced psychosis, excitable psychosis, Gilles de la Tourette syndrome, mania, organic or NOS psychosis, mental disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders Reduce the risk of diabetes-related disorders, progressive multifocal leukoencephalopathy, for example, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation Methods of treating diseases and disorders are provided.

(Detailed explanation)
The present invention particularly relates to compounds that modulate the 5-HT _2A receptor, which have the formula I:

（式中、
Ａは、存在しない、あるいはＯまたはＮＲ^８であり；
Ｄは、存在しない、あるいはＣ_１−４アルキレン、Ｃ_２−４アルケニレン、Ｃ_２−４アルキニレン、Ｏ、Ｓ、ＮＲ^９、ＣＯ、ＣＯＯ、ＣＯＮＲ^９、ＳＯ、ＳＯ_２、ＳＯＮＲ^９またはＮＲ^９ＣＯＮＲ^１０であり；
Ｙは、Ｃ_１−１０アルキル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、シクロアルキルアルキル、ヘテロアリールアルキルまたはヘテロシクロアルキルアルキルであり、それぞれ、場合によっては、Ｃｙ、ハロ、、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６ハロアルキル、ＣＮ、ＮＯ_２、ＯＲ^ａ、ＳＲ^ａ、Ｃ（Ｏ）Ｒ^ｂ、Ｃ（Ｏ）ＮＲ^ｃＲ^ｄ、Ｃ（Ｏ）ＯＲ^ａ、ＯＣ（Ｏ）Ｒ^ｂ、ＯＣ（Ｏ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（Ｏ）Ｒ^ｂ、ＮＲ^ｃＣ（Ｏ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（Ｏ）ＯＲ^ａ、Ｃ（＝ＮＲ^ｅ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（＝ＮＲ^ｅ）ＮＲ^ｃＲ^ｄ、Ｓ（Ｏ）Ｒ^ｂ、Ｓ（Ｏ）ＮＲ^ｃＲ^ｄ、Ｓ（Ｏ）_２Ｒ^ｂ、ＮＲ^ｃＳ（Ｏ）_２Ｒ^ｂおよびＳ（Ｏ）_２ＮＲ^ｃＲ^ｄから独立して選択される１、２、３、４または５個の置換基で置換され；
Ｚは、Ｈ、Ｃ_１−１０アルキル、ＮＲ’Ｒ’’、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、シクロアルキルアルキル、ヘテロアリールアルキルまたはヘテロシクロアルキルアルキルであり、それぞれ、場合によっては、ハロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６ハロアルキル、ＣＮ、ＮＯ_２、ＯＲ^ａ１、ＳＲ^ａ１、Ｃ（Ｏ）Ｒ^ｂ１、Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、Ｃ（Ｏ）ＯＲ^ａ１、ＯＣ（Ｏ）Ｒ^ｂ１、ＯＣ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（Ｏ）Ｒ^ｂ１、ＮＲ^ｃ１Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（Ｏ）ＯＲ^ａ１、Ｃ（＝ＮＲ^ｅ１）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（＝ＮＲ^ｅ１）ＮＲ^ｃ１Ｒ^ｄ１、Ｓ（Ｏ）Ｒ^ｂ１、Ｓ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、Ｓ（Ｏ）_２Ｒ^ｂ１、ＮＲ^ｃ１Ｓ（Ｏ）_２Ｒ^ｂ１およびＳ（Ｏ）_２ＮＲ^ｃ１Ｒ^ｄ１から独立して選択される１、２、３、４または５個の置換基で置換され；
Ｒ^１は、ＨまたはＣ_１−６アルキルであり；
Ｒ^２およびＲ^３は、独立して、Ｈ、ハロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６ハロアルキル、ＣＮ、ＮＯ_２、ＯＲ^ａ２、ＳＲ^ａ２、Ｃ（Ｏ）Ｒ^ｂ２、Ｃ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、Ｃ（Ｏ）ＯＲ^ａ２、ＯＣ（Ｏ）Ｒ^ｂ２、ＯＣ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ（Ｏ）Ｒ^ｂ２、ＮＲ^ｃ２Ｃ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ（Ｏ）ＯＲ^ａ２、Ｃ（＝ＮＲ^ｅ２）ＮＲ^ｃ２Ｒ^ｄ２、ＮＲ^ｃ２Ｃ（＝ＮＲ^ｅ２）ＮＲ^ｃ２Ｒ^ｄ２、Ｓ（Ｏ）Ｒ^ｂ２、Ｓ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、Ｓ（Ｏ）_２Ｒ^ｂ２、ＮＲ^ｃ２Ｓ（Ｏ）_２Ｒ^ｂ２およびＳ（Ｏ）_２ＮＲ^ｃ２Ｒ^ｄ２から選択され；
Ｒ^４、Ｒ^５およびＲ^６は、独立して、Ｈ、ハロおよびＣ_１−４アルキルから選択され；
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０は、独立して、ＨおよびＣ_１−４アルキルから選択され；
Ｃｙは、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクロアルキルであり、それぞれ、場合によっては、ハロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６ハロアルキル、ＣＮ、ＮＯ_２、ＯＲ^ａ、ＳＲ^ａ、Ｃ（Ｏ）Ｒ^ｂ、Ｃ（Ｏ）ＮＲ^ｃＲ^ｄ、Ｃ（Ｏ）ＯＲ^ａ、ＯＣ（Ｏ）Ｒ^ｂ、ＯＣ（Ｏ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（Ｏ）Ｒ^ｂ、ＮＲ^ｃＣ（Ｏ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（Ｏ）ＯＲ^ａ、Ｃ（＝ＮＲ^ｅ）ＮＲ^ｃＲ^ｄ、ＮＲ^ｃＣ（＝ＮＲ^ｅ）ＮＲ^ｃＲ^ｄ、Ｓ（Ｏ）Ｒ^ｂ、Ｓ（Ｏ）ＮＲ^ｃＲ^ｄ、Ｓ（Ｏ）_２Ｒ^ｂ、ＮＲ^ｃＳ（Ｏ）_２Ｒ^ｂおよびＳ（Ｏ）_２ＮＲ^ｃＲ^ｄから独立して選択される１、２、３、４または５個の置換基で置換され；
Ｒ’およびＲ’’は、独立して、Ｈ、Ｃ（Ｏ）Ｒ^ｂ１、Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、Ｃ（Ｏ）ＯＲ^ａ１、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、該Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、ハロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６ハロアルキル、ＣＮ、ＮＯ_２、ＯＲ^ａ１、ＳＲ^ａ１、Ｃ（Ｏ）Ｒ^ｂ１、Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、Ｃ（Ｏ）ＯＲ^ａ１、ＯＣ（Ｏ）Ｒ^ｂ１、ＯＣ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（Ｏ）Ｒ^ｂ１、ＮＲ^ｃ１Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（Ｏ）ＯＲ^ａ１、Ｃ（＝ＮＲ^ｅ１）ＮＲ^ｃ１Ｒ^ｄ１、ＮＲ^ｃ１Ｃ（＝ＮＲ^ｅ１）ＮＲ^ｃ１Ｒ^ｄ１、Ｓ（Ｏ）Ｒ^ｂ１、Ｓ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、Ｓ（Ｏ）_２Ｒ^ｂ１、ＮＲ^ｃ１Ｓ（Ｏ）_２Ｒ^ｂ１およびＳ（Ｏ）_２ＮＲ^ｃ１Ｒ^ｄ１から独立して選択される１、２または３個の置換基で置換され；
Ｒ^ａ、Ｒ^ａ１およびＲ^ａ２は、独立して、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、該Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
Ｒ^ｂ、Ｒ^ｂ１およびＲ^ｂ２は、独立して、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルおよびヘテロシクロアルキルアルキルから選択され、該Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
Ｒ^ｃおよびＲ^ｄは、独立して、Ｈ、Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、該Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
あるいはＲ^ｃおよびＲ^ｄは、それらが結合するＮ原子と一緒になって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、それらはそれぞれ、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
Ｒ^ｃ１およびＲ^ｄ１は、独立して、Ｈ、Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、該Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
あるいはＲ^ｃ１およびＲ^ｄ１は、それらが結合するＮ原子と一緒になって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、それらはそれぞれ、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
Ｒ^ｃ２およびＲ^ｄ２は、独立して、Ｈ、Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルから選択され、該Ｃ_１−１０アルキル、Ｃ_１−６ハロアルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキルまたはヘテロシクロアルキルアルキルは、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；
あるいはＲ^ｃ２およびＲ^ｄ２は、それらが結合するＮ原子と一緒になって、４員、５員、６員または７員ヘテロシクロアルキル基またはヘテロアリール基を形成し、それらはそれぞれ、場合によっては、１、２または３個のＯＨ、ＣＮ、アミノ、ハロ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６ハロアルキルまたはＣ_１−６ハロアルコキシで置換され；および
Ｒ^ｅ、Ｒ^ｅ１およびＲ^ｅ２は、独立して、Ｈ、ＣＮおよびＮＯ_２から選択される。）
で表わされる化合物、またはその医薬的に許容しうる塩を提供する。

(Where
A is absent, or O or NR ⁸ ;
D is absent or C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, O, S, NR ⁹ , CO, COO, CONR ⁹ , SO, SO ₂ , SONR ⁹ or NR ⁹ CONR ¹⁰ ;
Y is C _1-10 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ^c C (O) OR ^a , C (= NR ^e ) NR ^c R ^d , NR ^c C (= NR ^e ) NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S ( O) ₂ R ^b , Substituted with 1, 2, 3, 4 or 5 substituents independently selected from NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d ;
Z is H, C _1-10 alkyl, NR′R ″, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, respectively Depending on halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O ) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^{c1 R d1, NR c1 C (} O) OR a1, C (= NR e1) NR c1 R d1, NR c1 C (= NR e1) NR c1 R d1, ^{(O) R b1, S (} O) NR c1 R d1, S (O) 2 R b1, NR c1 S (O) 2 R b1 , and _S ^{(O) 2 NR} c1 1 independently selected from ^{R d1} Substituted with 2, 3, 4 or 5 substituents;
R ¹ is H or C _1-6 alkyl;
R ² and R ³ are independently H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C (O) NR ^c2 R ^d2 , NR ^c2 C (O) OR ^a2 , C (= NR ^e2 ) NR ^c2 R ^d2 , NR ^c2 C (= NR ^e2 ) NR ^c2 R ^d2 , S (O ) R ^b2 , S (O) NR ^c2 R ^d2 , S (O) ₂ R ^b2 , NR ^c2 S (O) ₂ R ^b2 and S (O) ₂ NR ^c2 R ^d2 ;
R ⁴ , R ⁵ and R ⁶ are independently selected from H, halo and C _1-4 alkyl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from H and C _1-4 alkyl;
Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN , NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^{c R d, NR c C (} O) R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR ^{e) NR c R d, S} (O) R b, S (O) NR c R d, S (O) 2 R b, NR c S (O) 2 R b , and _{^{S (O) 2 NR c R}} d Substituted with 1, 2, 3, 4 or 5 substituents independently selected from
R ′ and R ″ are independently H, C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^{b1, OC (O) NR c1} R d1, NR c1 R d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, C (= NR e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ Substituted with 1, 2 or 3 substituents independently selected from R ^b1 and S (O) ₂ NR ^c1 R ^d1 ;
R ^a , R ^a1 and R ^a2 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Selected from alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl , Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} halo Substituted by alkyl or _{C 1-6} haloalkoxy;
R ^b , R ^b1 and R ^b2 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Selected from alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl , Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} halo Substituted by alkyl or _{C 1-6} haloalkoxy;
R ^c and R ^d are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloalkyl Or substituted with C _1-6 haloalkoxy;
Alternatively, R ^c and R ^d together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each of which is optionally Substituted with 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;
R ^c1 and R ^d1 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloal Substituted with a kill or C _1-6 haloalkoxy;
Alternatively, R ^c1 and R ^d1 , together with the N atom to which they are attached, form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each optionally Substituted with 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;
R ^c2 and R ^d2 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloal Substituted with a kill or C _1-6 haloalkoxy;
Alternatively, R ^c2 and R ^d2 , together with the N atom to which they are attached, form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each optionally , 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy; and R ^e , R ^e1 And R ^e2 are independently selected from H, CN and NO ₂ . )
Or a pharmaceutically acceptable salt thereof.

  In some embodiments, A is absent.

  In some embodiments, A is O.

In some embodiments, A is NR ⁸ .

  In some embodiments, A is NH.

In some embodiments, Y is C _1-10 alkyl, aryl, or heteroaryl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl. , C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC ( ^{O) NR c R d, NR} c R d, NR c C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R ^{d, NR c C (= NR} e) NR c R d, S (O) R b, S (O) NR c R d, S (O) 2 R b, NR c S (O) 2 R b , and S _(O) 2 ^NR c left at 1, 2, 3, 4 or 5 substituents independently selected from ^{R d} It is.

In some embodiments, Y is C _1-10 alkyl or aryl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1. -6 ^{haloalkyl, CN, NO 2, OR a}} , SR a, C (O) R b, C (O) NR c R d, C (O) OR a, OC (O) R b, OC (O) NR ^{c R d, NR c R d} , NR c C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR ^{c C (= NR e) NR} c R d, S (O) R b, S (O) NR c R d, S (O) 2 R b, NR c S (O) 2 R b , and S (O) Substituted with 1, 2, 3, 4 or 5 substituents independently selected from ₂ NR ^c R ^d .

In some embodiments, Y is optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C ^{(O) R b, NR c} C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, Independently selected from S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d Aryl substituted with 1, 2, 3, 4 or 5 substituents.

In some embodiments, Y is optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C ^{(O) R b, NR c} C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, Independently selected from S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d It is phenyl substituted with 1, 2 or 3 substituents.

  In some embodiments, Y is phenyl optionally substituted with Cy.

  In some embodiments, Y is phenyl optionally substituted with Cy, wherein Cy is phenyl in the meta or para position.

In some embodiments, Y is optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C ^{(O) R b, NR c} C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, Independently selected from S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d C _1-10 alkyl substituted with 1, 2, 3, 4 or 5 substituents.

In some embodiments, Y is C _1-10 alkyl.

  In some embodiments, Y is isobutyl.

In some embodiments, Y is optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C ^{(O) R b, NR c} C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, Independently selected from S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d It is phenyl substituted with 1, 2, 3, 4 or 5 substituents.

In some embodiments, Y is optionally substituted with 1, 2 or 3 substituents independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl and OR ^a. Is phenyl.

In some embodiments, D is absent or C _1-4 alkylene or COO.

  In some embodiments, D is not present.

In some embodiments, D is C _1-4 alkylene.

  In some embodiments, D is COO.

In some embodiments, Z is H, C _1-10 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6. Alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC ( O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C ( = NR ^e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S ( O) Substituted with 1, 2, 3, 4 or 5 substituents independently selected from ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 .

In some embodiments, Z is H, C _1-10 alkyl, or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O ^{) NR c1 R d1, NR c1} R d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, C (= NR e1) NR c1 R d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S ( _O) 2 ^NR c1 ^{R d} It is substituted with 1, 2, 3, 4 or 5 substituents selected independently from.

In some embodiments, Z is H, C _1-10 alkyl or heterocycloalkyl.

  In some embodiments, Z is H.

In some embodiments, Z is optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1. , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O ) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C (= NR ^e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S ( 1, independently selected from O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 , Substituted with 2, 3, 4 or 5 substituents C _1-10 alkyl.

In some embodiments, Z is optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1. , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O ) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C (= NR ^e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S ( 1, independently selected from O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 , Substituted with 2, 3, 4 or 5 substituents Heterocycloalkyl.

In some embodiments, Z is pyrrolidinyl, piperidinyl, piperazinyl or morpholino, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6. Haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^{d1, NR c1 R d1, NR} c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, C (= NR e1) NR c1 R d1, NR c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c It is substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d1.

In some embodiments, -DZ is H, C (O) O- (C _1-10 alkyl), COOH, or heterocycloalkyl- (C _1-10 ) alkyl.

In some embodiments, R ¹ is H or methyl.

In some embodiments, R ¹ is methyl.

In some embodiments, R ² and R ³ are independently selected from H and halo.

In some embodiments, R ² is H.

In some embodiments, R ³ is H or halo.

In some embodiments, R ³ is H.

In some embodiments, R ³ is halo.

In some embodiments, R ³ is Br.

In some embodiments, R ⁴ , R ^5, and R ⁶ are each H.

In some embodiments, R ⁷ is H.

  In some embodiments, the compound has Formula II:

で表わされる。

It is represented by

  In some embodiments, the compound has Formula IIIa, IIIb, or IIIc:

で表わされる。

It is represented by

At various places in the present specification, substituents of compounds of the invention have been described in groups or in ranges. It is specifically contemplated that the present invention includes all independent sub-combinations of such group and range components. For example, the term “C _1-6 alkyl” specifically discloses methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl independently.

  It is further contemplated that the compounds of the present invention are stable. As used herein, “stable” refers to a compound that is sufficiently robust to withstand isolation from a reaction mixture to a useful degree of accuracy, and preferably to form an effective therapeutic agent.

  Further, it is understood that certain features of the invention that are described in the content of alternative embodiments for clarity may also be provided as a combination in a single embodiment. On the contrary, the various features of the invention described in the content of a single embodiment for short can be provided separately or in appropriate subcombinations.

  The term “alkyl” as used herein is meant to refer to a straight or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), pentyl (eg, n-pentyl, Isopentyl, neopentyl) and the like. The alkyl group contains 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, 1 to about 3 carbon atoms. sell.

  The term “alkylene” as used herein refers to a linking alkyl group.

  “Alkenyl” as used herein refers to an alkyl group having one or more double carbon-carbon bonds. Examples of alkenyl groups include ethenyl, propenyl and the like.

  As used herein, “alkenylene” refers to a linking alkenyl group.

  “Alkynyl” as used herein refers to an alkyl group that contains one or more triple carbon-carbon bonds. Examples of alkynyl groups include ethynyl, propynyl and the like.

  As used herein, “alkynylene” refers to a linking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF ₂ , CCl ₃ , CHCl ₂ , C ₂ Cl _{5 and the} like.

  As used herein, “aryl” refers to a monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) aromatic hydrocarbon such as phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl. And indenyl. In some embodiments, the aryl group has 6 to about 20 carbon atoms.

  “Cycloalkyl” as used herein refers to a non-aromatic carbocycle containing a cyclized alkyl or alkenyl group. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) systems, including spirocycles. In some embodiments, the cycloalkyl group can have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. it can. Furthermore, the cycloalkyl group can have 0, 1, 2, or 3 double bonds. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (ie, having a common bond), eg, benzo derivatives such as pentane, pentene, hexane, etc. . A cycloalkyl group having one or more fused aromatic rings can be attached via either an aromatic or non-aromatic moiety. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized and have, for example, an oxo or sulfide substituent. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclopeptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl and the like.

  As used herein, a “heteroaryl” group refers to an aromatic heterocycle having a ring component of at least one heteroatom such as sulfur, oxygen or nitrogen. Heteroaryl groups include monocyclic and polycyclic (eg, having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in the heteroaryl group can be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl , Triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like, but are not limited thereto. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and in further embodiments about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group contains 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

  As used herein, “heterocycloalkyl” refers to a non-aromatic heterocycle in which one or more ring-forming atoms is a heteroatom such as an O, N or S atom. Heterocycloalkyl groups can include mono- or polycyclic (eg, having 2, 3 or 4 fused rings) ring systems and spiro rings. Examples of “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, Examples include pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl and the like. Ring-forming carbon atoms and ring-forming heteroatoms can also be substituted with one or two oxo or sulfide groups. The definition of heterocycloalkyl also includes one or more aromatic rings fused to a non-aromatic heterocycle (ie, having a shared bond), for example, heterophthalyl, naphthalimidyl and benzo of heterocycles such as indolene and isoindolene. Also included are moieties having derivatives. A heterocycloalkyl group having one or more fused aromatic rings can be attached via an aromatic or non-aromatic moiety. In some embodiments, the heterocycloalkyl group has 1 to about 20 carbon atoms, and in yet embodiments, about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group contains 1 to about 4, 1 to about 3, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.

  “Halo” or “halogen” as used herein includes fluoro, chloro, bromo and iodo.

  “Alkoxy” as used herein refers to an —O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy and the like.

  As used herein, “haloalkoxy” refers to an —O-haloalkyl group.

  As used herein, “arylalkyl” refers to alkyl substituted with aryl, and “cycloalkylalkyl” refers to alkyl substituted with cycloalkyl. An example of an arylalkyl group is benzyl.

  As used herein, “heteroarylalkyl” refers to alkyl substituted with heteroaryl, and “heterocycloalkylalkyl” refers to alkyl substituted with heterocycloalkyl.

“Amino” as used herein refers to NH ₂ .

  As used herein, the term “compound”, unless stated otherwise, refers to all stereoisomers, eg, enantiomers and diastereomers, all geometric isomers, any tautomeric form, any isotopic form. , Any hydrated form, and any solvated form.

  The compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active forms, mixtures thereof or racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins, C═N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. . Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

  Isotopic forms include compounds containing various isotopes of member atoms. Isotopes refer to atoms having the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium. Accordingly, deuterated and tritiated forms of the compounds described herein are also included, as are other isotopic forms.

  Tautomeric forms occur as a result of the simultaneous transfer of protons when a single bond switches to an adjacent double bond. Tautomeric forms include proton tautomers that are isomeric protonated states with the same empirical formula and total charge. Examples of proton tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and protons occupy more than one position of the heterocyclic ring system Cyclic forms that can be made, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole Can be mentioned. Tautomeric forms can be sterically locked into one form by equilibrium or by appropriate substitution.

  A solvated or hydrated form of a compound refers to a solid formulation of the compound containing water or solvent molecules. Water or solvent molecules can often be present in stoichiometric ratio with the compound and may form part of the crystal lattice when the compound is in crystalline form.

  “Substituted” as used herein indicates that at least one hydrogen atom in a moiety is replaced by a non-hydrogen substituent or group. Where a moiety herein is “substituted” it may be carried out to the full balance of substitutions, for example, unless otherwise stated, methyl may be substituted by 1, 2 or 3 substituents, methylene Can be substituted by 1 or 2 substituents, phenyl can be substituted by 1, 2, 3, 4 or 5 substituents, naphthyl can be substituted by 1, 2, 3, 4, It can be substituted by 5, 6 or 7 substituents. Similarly, “substituted with one or more substituents” refers to substitution with a number of substituents from one substituent until the total number is physically acceptable. Furthermore, when a part is substituted with a plurality of substituents, the substituents may be the same or different.

  In some embodiments, the compounds of the invention or salts thereof are isolated. “Isolated” means that the compound is at least partially or substantially separated from the environment in which it was formed or discovered. Partial separation can include, for example, a composition rich in the compounds of the invention. Substantial separation can include a composition comprising at least about 90% by weight or more of a compound of the present invention or a salt thereof. Methods for isolating compounds and their salts are conventional in the art and include, for example, chromatographic methods, distillation, crystallization and the like.

  The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, a “pharmaceutically acceptable salt” is a derivative of a disclosed compound in which the parent compound is modified by converting any acid or base moiety present to its salt form. Refers to derivatives. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present invention include the parent compound formed, for example, conventional non-toxic salts or quaternary ammonium salts of non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or mixtures thereof. In general, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. , 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

  As used herein, the phrase “pharmaceutically acceptable” refers to a compound, substance, composition and / or dosage form which, within normal medical judgment, is excessively toxic, irritating, Appropriate for use in contact with human or animal tissue, commensurate with a reasonable benefit / risk ratio, without causing allergic reactions or other problems or complications.

  The present invention also provides prodrugs of the compounds described herein. As used herein, “prodrug” refers to any covalently bonded unit that releases an active parent drug when administered to a mammalian subject. Prodrugs can be produced by modifying functional groups present in the compound, which modification is made to cleave the parent compound during routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl or carboxyl group is attached to any group that is cleaved to form a free hydroxyl, amino, sulfhydryl or carboxyl group, respectively, when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Prodrug production and use are described in T.W. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", the A.S. C. S. Symposium Series, Volume 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, which are hereby incorporated by reference in their entirety.

Synthesis The compounds of the present invention can be prepared by various methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described herein below, along with synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art.

  The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It is understood that if there are typical or preferred conditions (ie reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions can be used unless otherwise stated. It will be. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

The process described herein can be monitored according to any suitable method known in the art. For example, product formation may be accomplished by spectroscopic means such as nuclear magnetic resonance spectroscopy (eg, ¹ H or ¹³ C), infrared spectroscopy, absorptiometry (eg, UV-visible) or mass spectrometry, or fast It can be monitored by chromatography such as liquid chromatography (HPLC) or thin layer chromatography.

  The manufacture of the compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Protecting group chemistry can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, Volume 2, Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.

  The reactions of the processes described herein can be carried out in a suitable solvent that can be easily selected by one skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction takes place, i.e. the temperature that can range from the freezing point temperature of the solvent to the boiling point temperature of the solvent. sell. Certain reactions can be performed in a single solvent or a mixture of solvents. Depending on the particular reaction step, an appropriate solvent can be selected for the particular reaction step.

  Resolution of a racemic mixture of compounds can be accomplished by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a “chiral resolving acid,” which is an optically active, salt-forming organic acid. Resolving agents suitable for fractional recrystallization are optically such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acid forms D and L. It is an active acid. Resolution of the racemic mixture can be accomplished by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

  The compounds of the present invention can be synthesized by those skilled in the art according to conventional methods and as shown in the following schemes.

Scheme 1 shows a general route to the compounds of the present invention. For example, amine 1-1 can be represented by the formula: YA-CO-L, wherein Y and A are as defined herein, and L is a leaving group such as halo, etc. To obtain an amine derivative 1-2. The N-atom of the amide group in 1-2 is then reacted with an alkylating reagent (eg, reaction with R ⁷ -L where R ⁷ is an alkyl group and L is a leaving group) Alkylation can be carried out by a conventional method to give compound 1-3.In more detail, amine compound 1-1 is combined with isocyanate 1-4, orthochloroformate 1-5, or acyl chloride 1-6. To the corresponding urea, carbamate and amine products 1-7, 1-8 and 1-9, respectively.

スキーム２は、本発明の化合物の製造（スキーム１を参照）において有用なアミン中間体２−２の製造を示す。たとえば、ニトロ化合物２−１は、加熱しながら酢酸／エタノール中、鉄粉などの還元剤の存在下で、対応するアミン２−２に変換することができる。

Scheme 2 illustrates the preparation of amine intermediate 2-2 useful in the preparation of compounds of the invention (see Scheme 1). For example, the nitro compound 2-1 can be converted to the corresponding amine 2-2 in the presence of a reducing agent such as iron powder in acetic acid / ethanol with heating.

スキーム３は、前記スキーム２で示した有用な合成前駆体である５−（５−ニトロベンゾフラン−７−イル）−１Ｈ−ピラゾール３−３への合成経路を示す。たとえば、７−ブロモ−５−ニトロベンゾフラン３−１は、スズキカップリング条件下で、ピラゾリルボロン酸３−２と反応し、目的生成物を得ることができる。

Scheme 3 shows a synthetic route to 5- (5-nitrobenzofuran-7-yl) -1H-pyrazole 3-3, which is a useful synthetic precursor shown in Scheme 2 above. For example, 7-bromo-5-nitrobenzofuran 3-1 can react with pyrazolylboronic acid 3-2 under Suzuki coupling conditions to give the desired product.

スキーム４は、ピラゾール置換ベンゾフランへの例示的合成経路を示す。たとえば、カルボン酸４−１は、場合によっては触媒量の酸または塩基の存在下、アルコールＲＯＨ（式中、Ｒは、たとえば、アルキル、シクロアルキルなどである）との反応によりエステル化することができる。得られたエステル４−２を、スキーム１および２の経路によって生成物４−３に変換することができ、あるいはＤＩＢＡＬ−Ｈなどの適切な還元剤で還元し、ヒドロキシメチル化合物４−４を得ることができる。エステル４−３を同様の方法により還元剤で処理し、対応するヒドロキシメチル生成物４−５を製造することもできる。

Scheme 4 shows an exemplary synthetic route to pyrazole substituted benzofurans. For example, the carboxylic acid 4-1 may be esterified by reaction with an alcohol ROH (where R is, for example, alkyl, cycloalkyl, etc.), optionally in the presence of a catalytic amount of an acid or base. it can. The resulting ester 4-2 can be converted to the product 4-3 by the route of Schemes 1 and 2, or reduced with a suitable reducing agent such as DIBAL-H to give the hydroxymethyl compound 4-4. be able to. Ester 4-3 can be treated with a reducing agent in a similar manner to produce the corresponding hydroxymethyl product 4-5.

スキーム５は、さらにピラゾール置換されたベンゾフランへの例示的な合成経路を示す。たとえば、ヒドロキシメチル化合物５−１を、先ずＯＨ脱離基の活性化、次いでアミン（たとえば、置換または非置換アミン、アルキルアミン、ジアルキルアミン、環状アミン、ピロリジン、ピペリジン、ピペラジン、モルホリン、アゼピンなど）と処理することにより、ヘテロシクロアルキルメチル化合物５−２に変換することができる。そのような変換は、スキーム４のニトロ化合物４−４およびその対応アミンなどの、本発明の化合物になる種々のベンゾフラン前駆体にも影響を与えうる。

Scheme 5 shows an exemplary synthetic route to further pyrazole substituted benzofurans. For example, hydroxymethyl compound 5-1 is first activated with an OH leaving group and then with an amine (eg, substituted or unsubstituted amine, alkylamine, dialkylamine, cyclic amine, pyrrolidine, piperidine, piperazine, morpholine, azepine, etc.) Can be converted to the heterocycloalkylmethyl compound 5-2. Such transformations can also affect various benzofuran precursors that become compounds of the present invention, such as the nitro compound 4-4 in Scheme 4 and its corresponding amine.

スキーム６は、４−ブロモピラゾール化合物６−２を製造する例示的な方法を示す。たとえば、ピラゾール化合物６−１を、ＮＢＳなどの臭素化剤で処理し、所望の生成物を得ることができる。同様に、他の４−ハロピラゾール化合物を、適切なハロゲン化剤を使用し、類似の方法で製造することができる。

Scheme 6 illustrates an exemplary method for preparing 4-bromopyrazole compound 6-2. For example, pyrazole compound 6-1 can be treated with a brominating agent such as NBS to obtain the desired product. Similarly, other 4-halopyrazole compounds can be prepared in an analogous manner using appropriate halogenating agents.

使用方法
本発明の化合物は、５−ＨＴ_２Ａ受容体の活性を調節することができる。用語「調節する」は、受容体の活性を増加または減少する能力を言う。したがって、本発明の化合物は、５−ＨＴ_２Ａ受容体を調節する方法であって、該受容体に、本明細書に記載される、１種以上の化合物、その塩、またはその組成物を接触させる方法において使用することができる。いくつかの実施形態では、本発明の化合物は、５−ＨＴ_２Ａ受容体の拮抗薬（すなわち阻害剤）、作動薬または逆作動薬として作用しうる。

Methods of Use The compounds of the present invention can modulate the activity of 5-HT _2A receptors. The term “modulate” refers to the ability to increase or decrease the activity of a receptor. Accordingly, a compound of the invention is a method of modulating a 5-HT _2A receptor, wherein the receptor is contacted with one or more compounds, salts thereof, or compositions thereof described herein. Can be used in the process. In some embodiments, the compounds of the invention can act as antagonists (ie, inhibitors), agonists or inverse agonists of the 5-HT _2A receptor.

The compounds disclosed herein may be useful in the treatment of various diseases and disorders and in the improvement of symptoms thereof. These conditions include conditions associated with platelet aggregation, asthma, excitement, schizophrenia, sleep disorders, diabetes-related conditions, glaucoma, progressive multifocal leukoencephalopathy (PML), hypertension, pain and the like. However, it is not limited to these.
Antiplatelet therapy (conditions related to platelet aggregation)
Antiplatelet agents (antiplatelets) are prescribed in various states. For example, in coronary artery disease they are used to help prevent myocardial infarction or stroke in patients at risk of developing occlusive blood clotting (eg, coronary artery thrombosis).

  In a myocardial infarction (heart attack), the myocardium does not receive enough oxygen-rich blood as a result of blockage in the coronary vessels. If given during or immediately after an attack (preferably within 30 minutes), antiplatelets can reduce damage to the heart.

  A transient cerebral ischemic attack (“TIA” or “mild stroke”) is a short-term interruption of the flow of oxygen to the brain, usually due to occluded blood clotting, due to decreased blood flow through the arteries. Antiplatelet agents have been found to be effective in preventing TIA.

  Angina is a temporary and often recurrent chest pain, distress or discomfort caused by inadequate oxygen-rich blood flow (ischemia) to some parts of the heart. In patients with angina, antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.

  Stroke is a phenomenon in which the brain does not receive sufficiently oxygen-rich blood, usually due to blockage of cerebral blood vessels due to blood clotting. In high-risk patients, it has been discovered that taking antiplatelets regularly prevents the formation of blood clots that cause the first or second stroke.

  Angiogenesis is a catheter-based technique used to open arteries occluded by blood clotting. With or without stenting immediately following this procedure to keep the arteries open, antiplatelets can reduce the risk of additional blood clotting forming after the procedure.

  Coronary artery bypass surgery is a surgical procedure in which an artery or vein is taken from another part of the body, transplanted into an occluded coronary artery, bypassing the blood around the occlusion and passing through a newly attached blood vessel. After surgery, antiplatelets can reduce the risk of secondary blood clotting.

  Atrial fibrillation is the most common type of persistent irregular heart rhythm (arrhythmia). Each year about 2 million Americans are affected by atrial fibrillation. In atrial fibrillation, the atrium (the chamber above the heart) emits an electrical signal that causes the atrium to vibrate rather than normally contract. The result is an unusually fast and strong irregular heartbeat. When antiplatelets are given after the appearance of atrial fibrillation, the antiplatelets can reduce the risk of blood clotting (thrombosis) that forms in the heart and moves to the brain.

The 5-HT _2A receptor is expressed on vascular smooth muscle and 5-HT secreted by activated platelets causes vasoconstriction and activation of additional platelets during blood clotting. There is evidence that 5-HT _2A inverse agonists inhibit platelet aggregation and therefore become a potential treatment for antiplatelet therapy (Satimura, K, et al., Clin Cardiol 2002 Jan. 25 (1): 28. -32; and Wilson, HC, et al., Thromb Haemost, Sep. 2, 1991; 66 (3): 355-60).

5-HT _2A inverse agonists are, for example, intermittent claudication or peripheral arterial disease, and cardiovascular complications (see Br. Med. J. 298: 424-430, 1989), arterial thrombosis (Pawlak, D. et al. Et al., Thrombosis Research 90: 259-270, 1998), atherosclerosis (see Hayashi, T. et al., Atherosclerosis 168: 23-31, 2003), vasoconstriction caused by serotonin (Fujiwara, T. and Chiba, S. Journal of Cardiovascular Pharmacology 26: 503-510, 1995), arterial restenosis after angioplasty or stent placement (Fujita, M. et al., Am Heart J. 145: e16 200 Can be used to treat a reference). It can be used alone or in combination with thrombolysis therapy, such as tPA (Yamashita, T. et al., Haemostasis 30: 321-332, 2000), which provides cardioprotection after MI or post-ischemic myocardial dysfunction ( Muto, T. et al., Mol. Cell. Biochem. 272: 119-132, 2005), or protection from ischemic injury during percutaneous coronary intervention (Horibe, E. Circulation Research 68: 68-72, 2004). Complications resulting from them are also included.

5-HT _2A inverse antagonists can increase the patient's circulating adiponectin, which is related to signs associated with adiponectin, such as myocardial ischemia-reperfusion injury and atherosclerosis Suggests that it is also useful in protecting patients (see Nomura, Shosaku, et al., Blood Coagulation and Fibrinolysis 2005, 16, 423-428).

The 5-HT _2A inverse agonist disclosed herein may provide a beneficial improvement in the microcirculation to patients in need of antiplatelet therapy by antagonizing the vasoconstrictive products of aggregated platelets. However, these are examples and are not limited to those shown here. Accordingly, in some embodiments, the invention provides a method of reducing platelet aggregation in a patient in need of reduced platelet aggregation, wherein the patient is a compound of the invention that is a 5-HT _2A inverse agonist. A method comprising administering a composition comprising: In further embodiments, the present invention treats coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation or any of the symptoms described above in a patient in need of treatment. A method comprising administering to the patient a composition comprising a 5-HT _2A inverse agonist of the present invention.

In a further embodiment, the present invention provides a method for reducing the risk of thrombus formation in a patient undergoing angioplasty or coronary artery bypass graft surgery or suffering from atrial fibrillation, wherein the patient is at risk of such risk. A method comprising administering a composition comprising a 5-HT _2A inverse agonist disclosed herein, if present.

Asthma 5-HT (5-hydroxytryptamine) is associated with the pathophysiology of acute asthma (Cazzola, M. and Matera, MG, TIPS, 2000, 21, 13; and De Bie, JJ. Et al., British J. Pharm., 1998, 124, 857-864). The compounds of the invention disclosed herein are useful for the treatment of asthma and the symptoms thereof. Accordingly, in some embodiments, the present invention is a method of treating asthma in a patient in need of treatment comprising a compound comprising a compound of the invention that is a 5-HT _2A inverse agonist. Is provided. In a further embodiment, a method of treating a symptom of asthma in a patient in need of such treatment, comprising administering to said patient, a composition comprising a 5-HT _2A inverse agonist disclosed herein A method is provided.

Excitement Excitement is a well-recognized behavioral sign with many symptoms including hostility, extreme exaggeration, poor shock control, tension and lack of emphasis (Cohen-Mansfield J, and Billig, N.) (1986), Aggregated Behaviors in the Elderly, I. A Conceptual Review, J Am Geriatr Soc 34 (10): 711-721).

  Excitement usually occurs in older people, often involving dementia caused by diseases affecting the blood vessels such as Alzheimer's disease, Lewy bodies, Parkinson's disease and Huntington's disease, which are degenerative disorders of the nervous system, and diseases that affect blood vessels Dementia also includes multiple stroke dementia caused by multiple strokes in the brain. Alzheimer's disease accounts for approximately 50-70% of all dementias (Koss E, et al. (1997), Assessing patterns of Agitation in Alzheimer's disease and the sentiate association with the strength of the disease. Dis Assoc Disod11 (suppl2): see S45-S50).

  Approximately 5% of people over the age of 65 and up to 20% of people over the age of 80 are affected by dementia, and nearly half of these patients exhibit behavioral disorders such as excitement, epilepsy and violent explosions.

  Excitement behavior can also appear in older people without cognitive impairment and in older people with mental disorders as well as dementia.

Excitement is often treated with antipsychotics such as haloperidol in nursing homes and other assistive care settings. Agents, there is a new evidence that has the effect of reducing the excited in a patient, including Alzheimer's dementia (Katz, I.R. Et al, J Clin Psychiatry 2 1999 acting _{5-HT 2A} receptors in the brain , 60 (2): 107-115; and Street, JS et al., Arch Gen Psychiatry October 2000, 57 (10): 968-976).

The compounds of the invention disclosed herein may be useful for treating agitation and symptoms thereof. Accordingly, in some embodiments, the present invention provides a method for treating excitement in a patient in need of treating excitement comprising the compound of the invention being a 5-HT _2A inverse agonist. A method comprising administering a composition comprising: In some embodiments, the excitement depends on a mental disorder other than dementia. In some embodiments, the present invention provides a method of treating excitement or a symptom thereof in a patient suffering from dementia, the composition comprising a 5-HT _2A inverse agonist disclosed herein. A method comprising administering is provided. In some embodiments of such methods, dementia is a degenerative disorder of the nervous system, such as (but not limited to) Alzheimer's disease, Lewy bodies, Parkinson's disease and Huntington's disease, or stroke and multiple stroke dementia. Not) due to (but not limited to) dementia caused by a disease that affects the blood vessels. In some embodiments, a method of treating excitement or a symptom of an elderly patient who is in need of treatment of agitation or a symptom thereof and has no cognitive dysfunction, comprising: A method comprising administering a composition comprising a 5-HT _2A inverse agonist disclosed in.

Additional therapy for haloperidol in the treatment of schizophrenia and other disorders Schizophrenia is an unexplained psychotic disorder that first appears in adulthood and has many features, psychotic symptoms, pathologic progression, and stages in social behavior It is characterized by physical development and degradation and expertise in areas below the highest level achieved so far. Characteristic psychotic symptoms can be thought disorder (multiple, fragmented, inconsistent, non-credible or simple, paranoid content or thoughts) and mental disorders (lack of solidarity, Imaginary leap, confusion leading to incomprehension), as well as perceptual disabilities (hall hallucinations), emotional disabilities (superficial or inadequate emotions), disabilities of self-awareness, disabilities of will and desire, interpersonal disabilities and A final psychosomatic disorder (eg, catatonia). This disorder is also accompanied by other symptoms (see American Statistical and Diagnostic Handbook).

Haloperidol (Haldol) is a potent dopamine D ₂ receptor antagonist. It is widely prescribed for acute schizophrenic symptoms and is very effective for positive symptoms of schizophrenia. However, Haldol has no effect on the negative symptoms of schizophrenia and may actually induce negative symptoms as well as cognitive impairment. In accordance with some methods of the present invention, the addition of a 5-HT _2A inverse agonist at the same time as Haldol reduces or eliminates the inducing effect of negative symptoms and prolongs the recurrence of the patient's next schizophrenia occurrence while positive symptoms There may be an advantage in inducing the ability to use Haldol at lower dosages without losing the effect on.

Haloperidol is a variety of behavioral disorders, drug-induced psychosis, excitable psychosis, Gilles de la Tourette syndrome, mania, psychosis (organic and NOS), mental disorders, psychosis, schizophrenia (acute, chronic and NOS) Used for the treatment of. It is also used in the treatment of childhood autism, Huntington's chorea, nausea and vomiting with chemotherapy and chemotherapy antibodies. Administration of the compounds of the present invention, which are 5-HT _2A inverse agonists, with haloperidol also provides benefits for these indications.

In some embodiments, the invention relates to behavioral disorders, drug-induced psychosis, excitatory psychosis, Gilles de la Tourette syndrome, mania, psychosis (organic and NOS), mental disorders, psychosis, schizophrenia ( acute, a method of treating chronic and NOS), which method comprises administering a 5-HT _2A inverse agonist disclosed dopamine D ₂ receptor antagonist and herein to the patient.

In some embodiments, the invention relates to behavioral disorders, drug-induced psychosis, excitatory psychosis, Gilles de la Tourette syndrome, mania, psychosis (organic and NOS), mental disorders, psychosis, schizophrenia ( Acute, Chronic and NOS) are provided comprising administering to the patient a haloperidol and a 5-HT _2A inverse agonist disclosed herein.

In some embodiments, the present invention provides a method of treating childhood autism, Huntington's chorea, or nausea and vomiting with chemotherapy or chemotherapeutic antibodies, wherein the patient is a dopamine D ₂ receptor antagonist. And a 5-HT _2A inverse agonist disclosed herein.

In some embodiments, the invention provides a method of treating childhood autism, Huntington's chorea, or nausea and vomiting with chemotherapy or chemotherapy antibodies, wherein the patient is treated with haloperidol. A method comprising administering a disclosed 5-HT _2A inverse agonist.

In a further embodiment, the present invention is a method of treating schizophrenia in a patient in need of treatment, comprising the step of administering a dopamine D ₂ receptor antagonist to the 5-HT _2A disclosed herein. A method is provided that includes administering an inverse agonist. As the dopamine D ₂ receptor antagonist, haloperidol is preferable.

Administration of the dopamine D ₂ receptor antagonist can occur simultaneously with the administration of the 5-HT _2A inverse agonist, or they can be administered at different times. One skilled in the art can readily determine an appropriate dosing regimen that is most effective in reducing or eliminating the deleterious haloperidol effect. In some embodiments, the haloperidol and 5-HT _2A inverse agonist are administered as a single dosage form, and in other embodiments they are administered in separate dosage forms.

Furthermore, the present invention is a method for alleviating the negative symptoms of schizophrenia induced by administration of haloperidol to a patient suffering from schizophrenia, wherein the patient is administered a 5-HT _2A inverse agonist A method comprising:

Sleep Disorders National Sleep Foundation's 2002 Sleep America's America Poll shows that more than half of the adults surveyed (58%) experienced one or more symptoms of insomnia at least several nights within the past year It has been reported. In addition, about 3 out of 10 people (35%) say they experience insomnia-like symptoms every day or almost every day.

  The normal sleep cycle and sleep architecture can be hampered by various organic causes and environmental influences. According to the Sleep Disorder International Classification, there are over 80 recognized sleep disorders. Among these, the compounds of the present invention include, for example, the following sleep disorders (ICSD-Sleep disorder international classification: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, American Sleep Disorders associated with sleep disorder 19) It is effective for any one or more of sleep disorders associated with psychiatric disorders and pharmaceutical / mental disorders.

A. Sleep disorders a. Endogenous sleep disorders:
Psychophysiological insomnia, misperception of sleep status, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome and Unspecified intrinsic sleep disorder.
b. Exogenous sleep disorder:
Improper sleep hygiene, environmental sleep disorder, insomnia at height, adaptive sleep disorder, sleep deprivation syndrome, poor disciplined sleep disorder, sleep-related disorders, night feeding (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant Dependent sleep disorder, alcohol-dependent sleep disorder, toxic-induced sleep disorder and unspecified exogenous sleep disorder.
c. Circadian rhythm sleep disorder:
Time zone change (jet time difference) syndrome, shift work sleep disorder, irregular sleep / wake pattern, sleep phase regression syndrome, sleep phase advance syndrome, non-24 hour sleep awake disorder, and unspecified circadian rhythm sleep disorder.

B. Sleep-related complications a. Arousal disorder:
Confusional arousal, sleepwalking and night wonders.
b. Sleep-wake transition disorder:
Rhythmic movement disorders, sleep attraction, sleeping, and nighttime lower limb stiffness.
C. Internal medicine / psychiatric sleep disorders a. Mental disorders related:
Psychiatric, mood disorders, anxiety disorders, panic disorders and alcoholism.
b. Neuropathy related:
Brain degenerative disease, dementia, Parkinsonism, fatal familial insomnia, sleep-related epilepsy, sleep epileptic seizures and sleep-related headache.
c. Other medical disorders related:
Somnolence, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastro-esophageal reflux, peptic ulcer disease, connective tissue inflammation syndrome, osteoarthritis, rheumatoid arthritis, fibromyopathy and postoperative.

  Lack of sleep results in excess of excessive daytime sleepiness. High stress levels, anxiety, depression and medical illness have been reported for chronic insomnia (National Institutes of Health, National Heart, Lung, and Blood Institute, Insomnia Facts Sheet, October 1995). Preliminary evidence shows that sleep disorders that cause severe sleep deprivation are immunocompetent susceptibility, hypertension, arrhythmias, circulatory system complications such as stroke and myocardial infarction, vascular glucose tolerance, increased obesity and metabolism Suggest that it may be related to the syndrome. The compounds of the present invention are useful in preventing or alleviating these complications by improving sleep quality.

  The most common class of drugs for most sleep disorders are benzodiazepines, but the adverse action profiles of benzodiazepines include daytime sedation, reduced motor coordination, and cognitive impairment. In addition, the National Institutes of Health consensus conference on sleeping pills and insomnia in 1984 concerns that drug abuse, addiction, withdrawal, and insomnia rebound may occur. Guidelines were developed to stop using hypnotic sedatives for more than 4-6 weeks. Accordingly, it is desirable that pharmacological agents for the treatment of insomnia have agents that are more effective and / or have fewer side effects than currently used agents. In addition, benzodiazepines are used to induce sleep but have little or no effect on sleep maintenance, sleep enhancement or slow wave sleep. Thus, sleep maintenance disorders are not currently treated well.

Clinical trials for drugs with a mechanism of action similar to the compounds of the present invention have demonstrated significant improvements in objective and subjective sleep parameters of normal healthy volunteers and patients with sleep and mood disorders ( Sharpley AL, et al., Slow Wave Sleep in Humans: Role of 5-HT _2A and 5HT _2C Receptors. Neuropharmacology, 1994, 33 (3/4): 467-Ac; Continuity and Sleep Architecture in Depressed Patents: A Pilot Study. Soc of Biol Psych 2000, Vol. 48: 75-78; and Landolt HP, et al., Serotonin-2Receptors and Human Sleep: Effect of Selective Antagonist on EEG Power Spectra.Neuropsychopharmacology, 1999, Vol. 21 (3): 455-66).

  Some sleep disorders may be discovered at the same time as other conditions, and therefore these conditions may also be treated by the compounds of formula I. For example, but not limited to, a patient suffering from a mood disorder, typically a patient suffering from a sleep disorder that can be treated by a compound of formula I. As in the present invention, one pharmacological agent for treating two or more existing or possible conditions is more cost effective and results in a better dose rate, There are fewer side effects than taking two or more drugs.

  In some embodiments, the present invention provides therapeutic agents used in the treatment of sleep disorders. In a further embodiment, the present invention provides one pharmaceutical formulation that may be useful for treating two or more conditions, one of which is a sleep disorder. In yet other embodiments, the compounds of the invention described herein can be used alone or in combination with a mild sleep-inducing drug (ie, antihistamine).

Sleep composition:
Sleep consists of two physiological states: slow eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep consists of four stages, each of which is characterized by a slowly gradual brain wave pattern with a more gradual pattern than a deep sleep. Thus, NREM sleep stages 3 and 4, called delta sleep, are the deepest and most recovered type of sleep. Many patients with sleep disorders cannot successfully reach stage 3 and 4 recoverable sleep. During the clinical period, the patient's sleep pattern is said to be disrupted, and the patient spends a long time going back and forth between stages 1 and 2 (semi-wake state) and awake state, and only a little for deep sleep Means spending only that time. As used herein, the term “disrupted sleep configuration” means that an individual, such as a sleep disorder patient, can easily perform NREM sleep stages 1 and 2 (the individual is restricted by external stimuli that are limited by the individual). Spend less time on sleep that can be awakened). As a result, the individual repeats many times of light sleep that are interrupted by frequent wake-ups throughout the entire sleep time. Many sleep disorders are characterized by a disrupted sleep organization. For example, many elderly patients who are dissatisfied with sleep have difficulty obtaining deep restorative sleep (NREM stages 3 and 4) for a long time, instead much of their sleep time is NREM sleep stage 1 And 2 are spent.

  In contrast to the disrupted sleep configuration used herein, the term “sleep enhancement” refers to NREM sleep time, especially the number of stages 3 and 4 and the length of the sleep time, while the waking time It means a state in which the number and length decrease. In effect, the composition of sleep disorder patients is unified during the night with increased sleep time and less awake sleep states, with more time spent on slow wave sleep (stages 3 and 4). Thus, the sleep vibration of stages 1 and 2 is reduced. The compounds of the present invention are effective in enhanced sleep patterns, and patients who had previously had disrupted sleep can now achieve longer and more consistent time of recoverable delta wave sleep.

  If sleep moves from stage 1 to a later stage, heart rate and blood pressure decrease, metabolic rate and sugar consumption increase, and muscles relax. In a normal sleep configuration, NREM sleep accounts for about 75% of total sleep time, of which stage 1 accounts for 5-10% of total sleep time, stage 2 is about 45-50%, and stage 3 is about 12% Stage 4 accounts for 13-15%. Approximately 90 minutes after the start of sleep, NREM sleep transitions to the first REM sleep episode that night. REM accounts for approximately 25% of total sleep time. In contrast to NREM sleep, REM sleep is characterized by a pattern similar to the physiological pattern found in high pulse, breathing and blood pressure, and other active wakefulness stages. Thus, REM sleep is also known as “paradoxical sleep”. Onset of sleep occurs during NREM sleep and takes 10-20 minutes in healthy young adults. The four stages of NREM sleep, together with the REM phase, form one complete sleep cycle, usually repeated four or five times during sleep. Sleep circulation is regular and punctual, and REM time occurs approximately every 90 minutes during the night. However, the initial REM time tends to be the shortest and often lasts less than 10 minutes, while the slower REM time can last up to 40 minutes. As you age, sleep duration changes and sleep composition changes that impair sleep quality increase the time between bedtime and sleep initiation and reduce the total number of hours of sleep at night. NREM (especially stages 3 and 4) and REM sleep are reduced. However, stage 1 of the shallowest sleep NREM sleep increases with age.

As used herein, the term “delta power” refers to an indication of the duration of EEG activity within the range of 0.5-3.5 Hz during NREM sleep, which is deeper and more refreshing of sleep. It is considered an indicator. Delta power is assumed to be an indicator of a theoretical process called Process S, and is considered inversely proportional to the amount of sleep and individual experiments during a given sleep time. Sleep is controlled by a constant mechanism, so the less sleep, the greater the willingness to sleep. Process S is thought to build up from the beginning to the end of the awakening time and discharge most efficiently during delta power sleep. Delta power is a measure of the size of process S before sleep time. The longer you are in wakefulness, the greater your willingness to process S or sleep, and therefore the greater the delta power during NREM sleep. However, individuals with sleep disorders are difficult to reach and sustain delta-wave sleep, and therefore the increase in process S is large and the ability to discharge this increase during sleep is also limited. Preclinical and clinically tested 5-HT _2A agonists mimic the effects of sleep deprivation on delta power, and subjects with sleep disorders treated with 5-HT _2A inverse agonists or antagonists are more profound Suggests that you can reach sleep, making it more exhilarating. These same effects have not been observed with currently marketed drug treatments. Furthermore, currently marketed sleep medications have side effects such as sequelae or addiction associated with GABA receptors. 5-HT _2A inverse agonists do not normally target GABA receptors and therefore typically do not have to worry about these side effects.

Subjective and objective determination of sleep disorders:
There are a number of ways to measure whether the onset, persistence or quality of sleep (eg, non-restorable or restorative sleep) has been inhibited or improved. One method is the patient's subjective determination, for example, when they get up, they feel lethargy or feel tired. Other methods include observing the patient by others while sleeping, such as how long it takes for the patient to fall asleep, how many times the patient wakes up during the night, and how restless the patient is during sleep And so on. Another method is to objectively measure the stage of sleep using a polysomnograph.

  The polysomnograph monitors multiple electrophysiological parameters during sleep and generally includes EEG activity, electrochromic activity and electromyographic activity and other measurements. These results, together with observation, not only sleep latency (time required to fall asleep), but also sleep persistence (overall balance of sleep and wakefulness), and sleep that can be an adaptive disease of sleep quality Enhancement (delta wave or percentage of sleep time spent on restorative sleep) can be measured.

  There are five different sleep stages that can be measured by polysomnographs: four stages of rapid eye movement (REM) sleep and slow eye movement (NREM) sleep (stages 1, 2, 3, and 4). Stage 1 of NREM sleep is the transition from wakefulness to sleep, accounting for about 5% of sleep time in healthy adults. NREM sleep stage 2 is characterized by specific EEG waveforms (sleep spindle and K complex) and occupies about 50% of sleep time. NREM sleep stages 3 and 4 (collectively also known as slow wave sleep or delta wave sleep) are the deepest levels of sleep and occupy about 10-20% of sleep time. REM sleep, which produces many vivid dreams, accounts for about 20-25% of total sleep.

  These sleep stages have a characteristic temporal organization throughout the night. NREM stages 3 and 4 tend to occur during the first 1/3 to 1/2 of the night and increase persistence in response to sleep deprivation. REM sleep occurs periodically during the night. Alternating with NREM sleep occurs about every 80-100 minutes. REM sleep time increases in duration towards the morning. Human sleep also changes characteristically over the lifetime. After relatively stable sleep, including large amounts of slow wave sleep in childhood and adolescence, sleep persistence and depth worsen during adulthood. This exacerbation reflects arousal and increased stage 1 sleep, and decreased stage 3 and 4 sleep.

In addition, the compounds of the present invention may be useful in the treatment of sleep disorders characterized by excessive daytime sleepiness such as narcolepsy. Inverse agonists at the serotonin 5-HT _2A receptor improve nighttime sleep quality, which can reduce excessive daytime sleepiness.

Accordingly, another aspect of the present invention relates to the therapeutic use of compounds of the present invention for the treatment of sleep disorders. The compounds of the present invention are potent inverse agonists at the serotonin 5-HT _2A receptor and do not act on REM sleep, with the following: decreased sleep onset latency (indication of sleep onset), number of nighttime arousals Can be effective in treating sleep disorders by facilitating one or more of a decrease in delta-wave sleep and an increase in sleep time (an indicator of improved sleep quality and enhanced sleep). Furthermore, the compounds of the present invention may be effective as monotherapy or in combination with sleep-inducing agents including, but not limited to, antihistamines.

Diabetes-related conditions Hyperglycemia is a major cause of pathogenesis of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR). Increased plasma serotonin levels in patients have also been suggested to play a role in disease pathology progression (Pietraszek, MH, et al., Thrombosis Res. 1992, 66 (6), 765-74; and Andrzejewska) -Buczko J, et al., Klin Oczna. 1996; 98 (2), 101-4). Serotonin is thought to play a role in increasing vasospasm and platelet aggregation. Improvement of microvascular blood flow can benefit diabetic complications.

Naunyn Schmiedebergs Arch Pharmacol. In a recent study by Cameron and Cotter, June 2003; 367 (6): 607-14, the 5-HT _2A antagonist test agent AT-1015 and other non-specific 5-containing ritanserin and sarpogrelate An HT _2A antagonist was used. These studies have found that all three drugs can provide significant correction (82.6-99.7%) to 19.8% loss of sciatic motor transmission in diabetic rats. Similarly, the 44.7% and 14.9% reductions were completely reversed in sciatic intimal blood flow and sensory transmission rates.

  In another patient study, sarpogrelate was determined to prevent the onset or progression of diabetic nephropathy (Takahashi, T., et al., Diabetes Res Clin Pract. November 2002; 58 (2): 123-9 ). In a 24-month treatment experiment, sarpogrelate significantly reduced urinary albumin excretion levels.

Glaucoma By topical intraocular administration of 5-HT2 receptor antagonists, monkeys (Chang et al., J. Ocul Pharmacol 1: 137-147 (1985)) and humans (Mastropasqua et al., Acta Ophthalmol Scan Suppl 224: 24-25 (1997) ) Suggests the utility of similar compounds such as 5-HT _2A inverse agonists in the treatment of ocular hypertension associated with glaucoma. The 5-HT2 receptor antagonists ketanserin (Mastropasqua, supra) and sarpogrelate (Takenaka et al., Investig Ophthalmol Vis Sci36: S734 (1995)) have been shown to significantly reduce IOP in glaucoma patients.

Progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) is a lethal demyelinating disease caused by opportunistic viral infection of oligodendrocytes in immunocompromised patients. The causative agent is JC virus, an ubiquitous papovavirus that infects many pre-adult populations and establishes a potential infection in the kidney. In immunocompromised hosts, the virus can reactivate oligodendrocytes and become productively infected. This previously uncommon condition, reported in humans with basal lymphoproliferative disorders until 1984, is now more common because it occurs in 4% of AIDS patients. Patients usually present with unrelenting local neuropathy, such as hemiplegia or visual field loss, or pathological changes in mental status. In brain MRI, there are one or more white matter lesions, a high signal in the T2-weighted image and a low signal in the T1-weighted image. There is no mass effect and contrast enhancement is rare. Diagnosis can be confirmed by brain biopsy, in situ hybridization methods or viral demonstration by immunocytochemistry. Polymerase chain reaction amplification of JC viral sequences from CSF can confirm the diagnosis without the need for biopsy (eg, Antinori et al., Neurology (1997) 48: 687-694; Berger and Major, Seminars). in Neurology (1999) 19: 193-200; and Portegies, et al., Eur. J. Neurol. (2004) 11: 297-304). There is currently no effective treatment. The survival time after diagnosis of AIDS patients is about 3-5 months.

JC virus enters cells by receptor-mediated clathrin-dependent endocytosis. Binding of JC virus to human glial cells (eg, oligodendrocytes) induces intracellular signals important for entry and infection by receptor-mediated clathrin-dependent mechanisms (Querbes et al., J Virology (2004)). 78: 250-256). Recently, 5-HT _2A has been shown to be a receptor on human glial cells that mediates infectious entry of JC virus by clathrin-dependent endocytosis (Elphick et al., Science (2004) 306: 1380-1383). 5-HT _2A antagonists, including ketanserin and ritanserin, inhibited JC virus infection of human glial cells. Ketanserin and ritanserin have inverse agonist activity at 5-HT _2A .

5-HT _2A antagonists, including inverse agonists, are contemplated to be useful in the treatment of PML (Elphick et al., Science (2004) 306: 1380-1383). Preventive treatment of HIV-infected patients with 5-HT _2A antagonists envisions the spread of JC virus to the central nervous system and prevention of PML. Aggressive therapeutic treatment of PML patients is envisioned to reduce the spread of the virus within the central nervous system and prevent further demyelination from occurring.

In some embodiments, a method of treating progressive multifocal leukoencephalopathy in a patient in need of treatment comprising a composition comprising a 5-HT _2A inverse agonist disclosed herein. A method comprising administering an article is provided.

Hypertension Serotonin has been observed to play an important role in the regulation of vascular tone, vasoconstriction and pulmonary hypertension (Deuchar, G. et al., Pulm. Pharmacol. Ther. 18 (1): 23-31. 2005; and Marcos, E. et al., Circ. Res. 94 (9): 1263-70 2004). Ketanserin, a 5-HT _2A inverse agonist, protects against cerebral ischemia during circulatory shock, intracerebral hypertension, and sunstroke (Chang, C. et al., Shock24 (4): 336-340 2005); It has been demonstrated to stabilize blood pressure in spontaneously hypertensive rats (see Miao, C. Clin. Exp. Pharmacol. Physiol. 30 (3): 189-193). Mianserin, a 5-HT _2A inverse agonist, has been shown to prevent DOCA-salt-induced hypertension in rats (Silva, A. Eur, J. Pharmacol. 518 (2-3): 152-7 2005. reference).

Pain 5-HT _2A inverse agonists are also effective in treating pain. Sarpogrelate has been observed to have significant analgesic effects on both heat pain in rats following intraperitoneal administration and inflammatory pain in rats after intrathecal or intraperitoneal administration (Nishiyama, T. et al. Eur. J. Pharmacol. 516: 18-22 2005). In humans, this same 5-HT _2A inverse agonist has been shown to be an effective treatment for low back pain, leg pain and numbness associated with sciatica caused by lumbar disc herniation (Kanayama, M. et al. Et al., J. Neurosurg: Spine 2: 441-446 2005).

One aspect of the present invention is a method of modulating the activity of a 5-HT _2A serotonin receptor, wherein the receptor is a compound according to any embodiment described herein, a pharmaceutically acceptable salt thereof. Or by contacting with a pharmaceutical composition.

  One aspect of the present invention is a method for treating platelet aggregation in a patient, wherein a patient in need of such treatment is treated with a therapeutically effective amount of a compound according to any embodiment described herein, its pharmaceutically acceptable A method comprising administering a pharmaceutically acceptable salt or pharmaceutical composition.

  One aspect of the present invention is a method of treating an indication disease selected from coronary artery disease, myocardial infarction, transient cerebral ischemic attack, angina pectoris, stroke and atrial fibrillation in a patient, the treatment requiring Comprising administering to a patient a therapeutically effective amount of a compound according to any embodiment described herein, a pharmaceutically acceptable salt or pharmaceutical composition thereof.

  One aspect of the present invention is a therapeutic method for reducing the risk of thrombus formation in a patient undergoing angioplasty or coronary artery bypass graft surgery, as described herein in a therapeutically effective amount for a patient in need thereof. A method comprising administering a compound according to any embodiment, a pharmaceutically acceptable salt or pharmaceutical composition thereof.

  One aspect of the present invention is a therapeutic method for reducing the risk of thrombus formation in a patient suffering from atrial fibrillation according to any embodiment described herein in a therapeutically effective amount for the patient in need thereof. It includes a method comprising administering a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition.

  One aspect of the present invention is a method of treating asthma in a patient, wherein a patient in need of such treatment is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein, its pharmaceutically acceptable. A method comprising administering a pharmaceutically acceptable salt or pharmaceutical composition.

  One aspect of the present invention is a method for treating a symptom of asthma in a patient, wherein the patient in need thereof is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein, its pharmaceutically A method comprising administering an acceptable salt or pharmaceutical composition.

  One aspect of the present invention is a method of treating patient excitement or a symptom thereof, wherein a patient in need thereof is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein, its pharmaceutical A method comprising administering an acceptable salt or pharmaceutical composition. In some embodiments, the patient is an elderly person without cognitive impairment.

  One aspect of the present invention is a method of treating excitement or a symptom thereof in a patient suffering from dementia, wherein the patient in need of said treatment is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein, A method comprising administering a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the dementia is due to a degenerative disease of the nervous system. In some embodiments, the dementia is Alzheimer's disease, Lewy bodies, Parkinson's disease or Huntington's disease. In some embodiments, the dementia is due to a disease that affects a blood vessel. In some embodiments, the dementia is due to stroke or multiple infarct dementia.

One aspect of the invention includes behavioral disorders, drug-induced psychosis, excitatory psychosis, Gilles de la Tourette syndrome, gonorrhea, organic or NOS psychosis, mental disorders, psychosis, acute schizophrenia, chronic schizophrenia and A method for treating a patient suffering from at least one indication disease selected from NOS schizophrenia, wherein an individual in need of the treatment is treated with a therapeutically effective amount of a dopamine D ₂ receptor antagonist, Including administering a compound according to any of the embodiments described herein, a pharmaceutically acceptable salt thereof or a pharmaceutical composition. In some embodiments, the dopamine D ₂ receptor antagonist is haloperidol.

One aspect of the present invention is a method of treating a patient with childhood autism, Huntington's disease, or nausea and vomiting caused by chemotherapy or chemotherapy antibodies, wherein an individual in need of such treatment is treated. It includes an effective amount of a dopamine D ₂ receptor antagonist, compounds according to any of the embodiments described herein, the method comprising administering a pharmaceutically acceptable salt or a pharmaceutical composition. In some embodiments, the dopamine D ₂ receptor antagonist is haloperidol.

One aspect of the present invention is a method of treating schizophrenia in a patient, wherein the patient in need of such treatment is treated with a therapeutically effective amount of a dopamine D ₂ receptor antagonist, and any of the herein described Including a method comprising administering a compound according to an embodiment, a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the dopamine D ₂ receptor antagonist is haloperidol.

  One aspect of the present invention is a therapeutic method for alleviating the negative symptoms of schizophrenia induced by administering haloperidol to a patient suffering from schizophrenia, wherein the patient in need of such treatment has a therapeutically effective amount. A method comprising administering a compound according to any embodiment described herein, a pharmaceutically acceptable salt thereof or a pharmaceutical composition. In some embodiments, haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments, the haloperidol and the compound, pharmaceutically acceptable salt or pharmaceutical composition thereof are administered in a single dosage form.

  One aspect of the present invention is a method of treating a sleep disorder in a patient, wherein the patient in need thereof is treated with a therapeutically effective amount of a compound according to any embodiment described herein, its pharmaceutically acceptable A method comprising administering a pharmaceutically acceptable salt or pharmaceutical composition.

  In some embodiments, the sleep disorder is a dyssomnia. In some embodiments, the sleep dysfunction is psychophysiological insomnia, sleep state misidentification, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome , Periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, insomnia at height, adaptive sleep disorder, sleep deprivation syndrome, poor sleep sleep disorder, sleep related disorders, night feeding or Drinking syndrome, sleep-drug-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxic-induced sleep disorder, time zone change (jet time difference) syndrome, shift work sleep disorder, irregular sleep / wake pattern, Selected from the group consisting of sleep phase regression syndrome, sleep phase advance syndrome and non-24 hour sleep-wake disorder.

  In some embodiments, the sleep disorder is a parasomnia. In some embodiments, the sleep-related comorbidity is selected from the group consisting of confusional awakening, sleepwalking and night wonders, rhythmic movement disorders, sleep seizures, bedriddens, and night leg distortion. In some embodiments, the sleep disorder is characterized by excessive daytime sleepiness, such as narcolepsy.

  In some embodiments, the sleep disorder is associated with a medical or mental disorder. In some embodiments, the medical or mental disorder is psychosis, mood disorder, anxiety disorder, panic disorder, alcoholism, brain degenerative disease, dementia, Parkinsonism, lethal familial insomnia, sleep-related Epilepsy, epileptic seizures during sleep, sleep-related headache, lethargy, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastric / esophageal reflux, peptic ulcer disease, connective tissue syndrome, bone Selected from the group consisting of arthritis, rheumatoid arthritis, fibromyopathy and postoperative sleep disorder.

  One aspect of the present invention is a method of treating a diabetes-related disorder in a patient, wherein the patient in need thereof is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein, pharmaceutically A method comprising administering an acceptable salt or pharmaceutical composition.

  In some embodiments, the diabetes-related disorder is diabetic peripheral neuropathy.

  In some embodiments, the diabetes-related disorder is diabetic nephropathy.

  In some embodiments, the diabetes-related disorder is diabetic retinopathy.

  One aspect of the invention includes a method of treating glaucoma or other diseases of the eye with abnormal intraocular pressure.

  One aspect of the present invention is a method of treating progressive multifocal leukoencephalopathy in a patient, wherein the patient in need of such treatment is treated with a therapeutically effective amount of a compound according to any of the embodiments described herein. , Including administering a pharmaceutically acceptable salt or pharmaceutical composition thereof.

  In some embodiments, the individual in need of treatment has a lymphoproliferative disorder. In some embodiments, the lymphoproliferative disorder is leukemia or lymphoma. In some embodiments, the leukemia or lymphoma is chronic lymphocytic leukemia, Hodgkin's disease, or the like.

  In some embodiments, the patient in need of treatment has a myeloproliferative disorder.

  In some embodiments, the patient in need of treatment has carcinoma.

  In some embodiments, the patient in need of treatment has a granulomatous or inflammatory disease. In some embodiments, the granulomatous or inflammatory disease is tuberculosis or sarcoidosis.

  In some embodiments, the patient in need of the treatment is immunocompromised. In some embodiments, the immunocompromised patient has impaired cellular immunity. In some embodiments, inhibited cellular immunity comprises inhibited T-cell immunity.

In some embodiments, the patient in need of treatment is infected with HIV. In some embodiments, the number of CD4 + cells in a patient infected with HIV is ≦ 200 / mm ³ . In some embodiments, the patient infected with HIV has AIDS. In some embodiments, a patient infected with HIV has AIDS associated disease (ARC). In certain embodiments, the ARC has 2 consecutive CD4 + cell counts of 200 / mm ³ and has the following signs or symptoms: oral hairy leukoplakia, recurrent oral candidiasis, at least 2.5 kg or body weight within the last 6 months 10% reduction, multi-cured herpes zoster, more than 14 consecutive days in 30 days or more than 15 days, body temperature above 38.5 ° C, or more than 3 times per day for at least 30 days There is at least two defined diarrhea with liquid stool (see, for example, Yamada et al., Clin. Diagnostic. Virol. (1993) 1: 245-256).

  In some embodiments, the patient in need of treatment is receiving immunosuppressive therapy. In some embodiments, immunosuppressive therapy comprises administering an immunosuppressive agent (eg, Mueller, Ann Thorac Surg (2004) 77: 354-362; and Krieger and Emre, Pediatr Transplantation (2004) 8: 594-599). In some embodiments, the immunosuppressive therapy is a corticosteroid (eg, prednisone, etc.), a calcineurin inhibitor (eg, cyclosporine, tacrolimus, etc.), an antiproliferative agent (eg, azathioprine, mycophenolate mofetil, sirolimus, everolimus). Etc.), T-cell depleting agents (eg, OKT® 3 monoclonal antibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-1H (anti-CD52) mAb, anti-CD4 mAb, anti-CD4 -T cell receptor mAb, etc.), anti-IL-2 receptor (CD25) mAb (eg, basiliximab, daclizumab etc.), costimulatory inhibitors (eg, CTLA4-Ig, anti-CD154 (CD40 ligand) mAb etc. ), Deoxyspec Guarin and its analogs (eg, 15-DSG, LF-08-0299, LF14-0195, etc.), leflunomide and its analogs (eg, leflunomide, FK778, FK779, etc.), FTY720, anti-alpha-4-integrin monoclonal Administering an immunosuppressive agent selected from the group consisting of an antibody and an anti-CD45RB monoclonal antibody. In some embodiments, the immunosuppressive agent and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments, the immunosuppressive agent and the compound or pharmaceutical composition are administered in a single dosage form.

  In some embodiments, the patient in need of treatment is receiving immunosuppressive therapy after organ transplantation. In some embodiments, the organ is a liver, kidney, lung, heart, etc. (see, eg, Singh et al., Transplantation (2000) 69: 467-472).

  In some embodiments, the patient in need of treatment is undergoing treatment for rheumatic disease. In some embodiments, the rheumatic disease is systemic lupus erythematosus and the like.

  In some embodiments, the compound or pharmaceutical composition inhibits JC virus infection of human glial cells.

  One aspect of the invention includes a method of making a composition comprising combining a compound according to any embodiment described herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment of a 5-HT _2A related disorder. is there.

One aspect of the present invention is the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of a 5-HT _2A related disorder.

  The term “cell” as used herein is meant to refer to a cell in vitro, ex vivo or in vivo. In some embodiments, the ex vivo cells may be part of a tissue sample cut from an organism such as a mammal. In some embodiments, the in vitro cell may be a cell in a cell culture. In some embodiments, the in vivo cell is a living cell in an organism such as a mammal.

The term “contacting” as used herein refers to bringing together the indicated moiety in an in vitro or in vivo system. For example, to "contact" with a compound of the present invention the 5-HT _2A receptor, to a compound of the invention is administered to an individual or patient, such as a human having a 5-HT _2A receptor, and for example, the Introducing a compound of the invention into a sample containing a cellular preparation or purified preparation containing the 5-HT _2A receptor.

  The term “individual” or “patient” as used herein and interchangeably refers to a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, cow, sheep, horse. Or any animal, including primates, most preferably humans.

  As used herein, the phrase “in need of treatment” or “in need of” refers to a caregiver (eg, in the case of a human, a doctor, nurse, clinical nurse, or other non-human mammal). In the case of an animal comprising, it refers to the judgment made by the veterinarian) that the individual or animal needs or will need the benefit of treatment. This determination can vary in the realm of caregiver experience, including knowledge that an individual or animal is or will become ill as a result of a disease, condition or disorder that is treatable by a compound of the present invention. Made based on factors. Thus, the compounds of the present invention can be used in prevention or prevention methods, or the compounds of the present invention can be used to alleviate, inhibit or ameliorate a disease, condition or disorder.

As used herein, the phrase “therapeutically effective amount” refers to a biological or drug response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual or human. The amount of active compound or pharmaceutical formulation refers to one or more of the following.
(1) Prevention of disease; for example, prevention of a disease, condition or disorder in an individual who may be susceptible to a disease, condition or disorder but has not yet experienced or exhibited the disease state or symptom of the disease thing;
(2) inhibition of the disease; for example, inhibiting the disease, condition or disorder in an individual experiencing or showing the pathology or symptom of the disease, condition or disorder; and (3) recovery of the disease; Recovering a disease, condition or disorder so as to reduce the severity of the disease in an individual experiencing or exhibiting the pathology or general symptom of the condition or disorder (ie, pathology and / or symptom symptom) To reverse).

The term “agonist” is meant to refer to a moiety that interacts with and activates a receptor, such as the 5-HT _2A receptor, and induces the physiological or pharmacological response properties of that receptor. For example, certain moieties, when bound to a receptor, activate an intracellular response or enhance GTP binding to the membrane.

  The term “antagonist” binds competitively to a receptor at the same site as an agonist (eg, an endogenous ligand), but without activating the intracellular response induced by the active form of the receptor. Is meant to refer to a moiety that can inhibit an intracellular response by an agonist or partial agonist. Antagonists do not reduce baseline intracellular responses in the absence of agonists or partial agonists.

The term “inverse agonist” binds the endogenous form of the receptor or binds to a constitutively activated form of the receptor and is observed in the absence of an agonist or partial agonist. Refers to the moiety that inhibits the baseline intracellular response induced by the active form of the receptor below normal normal levels of or reduces GTP binding to the membrane. The baseline intracellular response is preferably inhibited by at least 30% in the presence of the inverse agonist compared to the baseline response in the absence of the inverse agonist, more preferably by at least 50%, most preferably Preferably it is at least 75%.
Combination Therapy The compounds of the present invention can be administered as a single active pharmaceutical formulation (ie, monotherapy) to treat any one or more of the diseases / conditions / disorders described herein, It can also be used in combination (ie, combination therapy). Accordingly, the present invention is a method of treating a 5-HT _2A serotonin receptor related disorder or disease, wherein a patient in need of such treatment is treated with a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Also included are methods comprising administering a possible salt in combination with one or more of the additional pharmaceutical formulations described herein.

  Suitable pharmaceutical formulations that can be used in combination with the compounds of the present invention include antiplatelets, antithrombotic or anticoagulants, antiarrhythmic agents, cholesteryl ester transfer protein (CETP) inhibitors, niacin or niacin analogs, adenosine or Examples include adenosine analogues, nitroglycerin or nitrates, and thrombus formation agents. Other pharmaceutical formulations, including those described below, are well known to those of skill in the art or can be readily obtained in light of the present disclosure.

  The compounds of the present invention may include other antiplatelets, antithrombotic or anticoagulants such as thrombin inhibitors, aspirin, clopidogrel (Plavix®), ticlovidin or CS-747 {ie acetate 5- [2- Cyclopropyl-1- (2-fluorophenyl) -2-oxoethyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ester and its active metabolite R-99224, ( Inhibition of platelet aggregation such as Z) -2- [1- [2-cyclopropyl-1 (S)-(2-fluorophenyl) -2-oxoethyl] -4 (R) -sulfanylpiperidin-3-ylidene] acetic acid} Agents, abciximab (ReoPro®), eptifibatide (Integrilin®), Fiban (Aggrastat®), warfarin, low molecular weight heparin (eg LOVENOX), GPIIb / GPIIIa blocker, XR-330 (ie (3Z, 6Z) -3-benzylidene-6- (4-methoxybenzylidene) -1-methylpiperazine-2,5-dione) and T-686 (ie, 3 (E) -benzylidene-4 (E)-(3,4,5-trimethoxybenzylidene) pyrrolidine-2,5-dione) Inhibitors of α-2-antiplasmin such as PAI-1 inhibitors such as anti-α-2-antiplasmin antibodies and thromboxane receptor antagonists (eg, ifetroban), prostacyclin mimetics, dipyridamole (Persantine ( )) Or phosphodiesterases such as cilostazol PDE) inhibitors, PDE inhibitors in combination with thromboxane receptor antagonists / thromboxane A synthetase inhibitors (eg picotamide), serotonin-2-receptor antagonists (eg ketanserin), fibrinogen receptor antagonists, HMG-CoA reductase inhibitors, for example, antihyperlipidemic drugs such as pravastatin, sumvastatin, atorvastatin, fluvastatin, selvastatin, AZ4522 and itavastatin (Nissan / Kowa); microsomal triglyceride transport protein inhibitor (Eg, those disclosed in US Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), angiotensin converting enzyme inhibitors (eg, captop Anti-hypertensive drugs such as le, lisinopril or fosinopril); angiotensin-II receptor antagonists (eg irbesartan, losartan or valsartan); and / or ACE / NEP inhibitors (eg omabatrilat and gemopatrilat); It can be used in combination with blockers (eg, propranolol, nadolol and carvedilol), PDE inhibitors in combination with aspirin, ifetroban, ketanserin or clopidogrel (Plavix®).

  The compounds of the invention can also be used in combination with antiarrhythmic agents, for example for atrial fibrillation, such as amiodarone or dofetilide.

  The compounds of the present invention include cholesteryl ester transfer protein (CETP) inhibitors for dyslipidemia and atherosclerosis, niacin or niacin analogs for dyslipidemia and atherosclerosis, adenosine or adenosine analogs for vasodilation It can also be used in combination with nitroglycerin or nitrates for body and vasodilation.

  The compounds of the present invention include tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activate, renoteplase, urokinase, prourokinase, anisylated streptokinase plasminogen activator complex (ASPAC) It can also be used in combination with a thrombus formation promoter such as an animal salivary gland plasminogen activator. The compounds of the present invention include β-adrenergic drugs such as albuterol, terbutaline, formoterol, salmeterol, biolterol, pyrbuterol or fenoterol; anticholinergics such as ipratropium bromide; It may be used in combination with anti-inflammatory corticosteroids; and anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast and pranlukast.

  Suitable pharmaceutical formulations that can be used in combination with the compounds of the present invention include antiretroviral agents (see, eg, Turpin, Expert Rev AntiInfect Ther (2003) 1: 97-128). In some embodiments of the invention, a method of treating progressive multifocal leukoencephalopathy described herein, wherein an individual in need of such treatment is treated with a therapeutically effective amount or dose. The compounds of the present invention can be combined with nucleoside reverse transcriptase inhibitors (eg, Retrovir®, Epivir®, Combivir®, Hivid®). , Videx (R), Trizvir (R), Zerit (R), Ziagen (R), Vired (R), Emtricitabine, DAPD, etc.), non-nucleoside inversion Coenzyme inhibitors (eg, Viramune (registered) Trademark), Rescriptor (registered trademark), Sustiva (registered trademark), GW687, DPC083, TMC125, emivirin, couplerabilin, BMS561390, UC-781 and other oxathiin carboxyanilides, SJ-3366, alkenyldiaryl Methane (ADAM), telchiband, calanolide A, HBY097, lopiride, HEPT family derivatives, TIBO derivatives, etc.), protease inhibitors (e.g. Fortovase (registered trademark), Invirase (registered trademark), Novir ( (Registered trademark), Crixivan (registered trademark), Viracep (registered trademark), aphenerase (Ageber) se) <(R)>, Kaletra <(R)>, atazanavir, tipranavir, DMP450, etc.), inhibitors of HIV-cell interactions (e.g., monoclonal antibodies to soluble CD4, toxin-binding CD4, CD4 or gp120, PRO542, dextrin sulfate, Rersoben, FP-23199, Cyanovirin-N, Zintevir (T30177, AR177), L-ticolinic acid and derivatives), co-receptor inhibitor ligands (eg, R5, X4, Modified ligand (R5), modified ligand (X4), etc.), co-receptor inhibitor X4 (eg, T22, T134, ALX40-4C, AMD3100, bicyclam derivatives, etc.), co-receptor inhibitor R5 (eg, TAK- 779, SCH-C (SCH-351125), SCH-D (SCH-350634), NSC651016, ONO Pharmaceutical Merck, etc., fusion inhibitors (eg, Fuzeon® (T-20, DP178, Enfuvirtide) ) Trimers, T-1249, TMC125, etc.), integrase inhibitors (eg, 5CITEP, L731,988, L708,906, L-870,812, S-1360, etc.), NCp7 nucleocapsid Zn finger inhibitors (eg, NOBA, DIBA, dithiane, PD-161374, pyridineioalkanoyl thioester (PATES), azodicarbonamide (ADA), cyclic 2,2 dithiobisbenzamide, etc.) Ribonum reaase H inhibitors (eg, BBHN, CPHM PD-26388, etc.), Tat inhibitors (eg, dominant negative mutants, Ro24-7429, Ro5-3335, etc.), Rev inhibitors (eg, dominant negative mutants, leptomycin, etc.) B, PKF050-638, etc.), transcriptional inhibitors (eg, Temacrazine, K-12 and K-37, EM2487, etc.), inhibitors of HIV assembly / maturation (eg, CAP-1 and CAP-2) And the like, and administration in combination with at least one pharmaceutical formulation selected from the group consisting of a pharmaceutical formulation for a cellular anti-HIV target (eg, LB6-B275 and HRM1275, a Cdk9 inhibitor, etc.) It is done.

  In certain embodiments, the compounds of the invention can be used in combination with highly active antiretroviral therapy (HAART). When an antiretroviral agent is used in combination with 3 or 4 drugs, this treatment is called HAART (see, eg, Portegies, et al., Eur. J. Neurol. (2004) 11: 297-304).

  According to the present invention, a combination of a compound of the present invention and a pharmaceutical formulation mixes each active ingredient together or separately with a pharmaceutically acceptable carrier, excipient, binder, diluent, etc. The mixture (s) is administered orally or parenterally as the pharmaceutical composition (s). When administered as a combination therapy with other active compounds, one or more compounds of the invention, or pharmaceutically acceptable salts thereof, are formulated as separate pharmaceutical compositions that are given at the same time or different times, respectively. be able to. Alternatively, in some embodiments, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutical formulations (s). A single pharmaceutical composition.

Pharmaceutical Formulations and Dosage Forms When used as pharmaceuticals, the compound of the present invention or a pharmaceutically acceptable salt thereof comprises at least one compound of the present invention or a pharmaceutically acceptable salt thereof and at least one compound of the present invention. It can be administered in the form of a pharmaceutical composition that is a mixture with a pharmaceutically acceptable carrier. These compositions can be manufactured in a manner well known in the pharmaceutical art and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the location to be treated. Administration is topically (eg, to the mucosa, including ophthalmic and intranasal, intravaginal, and rectal delivery), pulmonary (eg, nebulizer inhalation or gas infusion, intratracheal, intranasal) (Percutaneously and transdermally), ocular, orally or parenterally. Delivery methods to the eye include topical administration (eye drops), subconjunctival, periorbital or intravitreal injection, or introduction with a balloon catheter or ophthalmic insert placed surgically in the conjunctival sac. it can. Parenteral administration includes intravenous, arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, or intracerebral administration, eg, intrathecal or intracerebral administration. Parenteral administration can be in the form of a single bolus or may be performed, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, liquid drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

  In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or within the carrier, for example, in the form of a capsule, sachet, paper or other container Enclosed. When an excipient is used as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, carrier or vehicle for the active ingredient. Thus, the composition can be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), eg up to 10% by weight It may be in the form of ointments containing the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

  In preparing a formulation, the active compound can be milled to the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to obtain a substantially uniform distribution in the formulation, for example about 40 mesh.

  Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water , Syrup and methylcellulose. The formulation further includes lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and fragrances. it can. The compositions of the present invention can be formulated to release the active ingredient quickly, sustainedly or delayed after administration to a patient using techniques known in the art.

  The compositions can be formulated in unit dosage form, with each dose containing from 5 to about 100 mg, more usually from about 10 to about 30 mg of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit together with suitable pharmaceutical excipients to produce the desired therapeutic effect. Contains a calculated predetermined amount of active substance.

  The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, the amount of compound actually administered will usually depend on the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. It will be understood that it will be determined by the doctor according to the relevant circumstances, including the beginning.

  In the manufacture of solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention. When these pre-formulation compositions are said to be homogeneous, the active ingredient is typically such that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Specifically, it is evenly distributed throughout the composition. This solid preformulation is then subdivided into unit dosage forms of the type previously described containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

  The tablets or pills of the invention can be coated or formulated to provide a dosage form with the benefit of sustained action. For example, a tablet or pill can contain internal and external dosage components, with the latter component being in a form that encloses the previous component. The two components are not disintegrated in the stomach and can be separated by an enteric layer that acts to pass the internal components directly into the duodenum or delay release. A variety of materials can be used as such enteric layers or films, such as a number of polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol and cellulose acetate. Is mentioned.

  Liquid forms in which the compounds and compositions of the invention can be incorporated for oral or injection administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil Or edible oils such as peanut oil, and emulsions flavored with elixirs and similar pharmaceutical vehicles.

  Compositions for inhalation or insufflation include solutions or suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal aspiration route to obtain a local or systemic effect. The composition of the present invention can be atomized using an inert gas. The nebulized solution may be drawn directly from the nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

  The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prevention or treatment, the condition of the patient, the method of administration, and the like. For therapeutic use, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially alleviate the symptoms of the disease and its complications. The effective dose depends on the judgment of the attending physician depending on such factors as the disease to be treated and the severity of the disease, the age, weight and approximate condition of the patient.

  The composition administered to the patient may take the form of the pharmaceutical composition described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions may be packaged in the use form or lyophilized, the lyophilized product being combined with an aqueous carrier prior to administration. The pH of the compound product is usually 3-11, more preferably 5-9, most preferably 7-8. It will be understood that pharmaceutical salts are formulated by using the preceding excipients, carriers or stabilizers.

  The therapeutic dosage of the compounds of the present invention can vary, for example, according to the particular application being treated, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the invention in the pharmaceutical composition may vary depending on a number of factors such as dosage, chemical characteristics (eg, hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in the form of an aqueous physiological buffer solution containing 0.1 to about 10% / v compound for parenteral administration. Some typical dose ranges are from about 1 μg / kg to about 1 g / kg / body weight / day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg / body weight / day. Dosage depends on variables such as the type and extent of the disease state progression of the disease or disorder, the overall health status of the particular patient, the biological relative effects of the selected compound, the excipient form, and its route of administration. The possibility of responding is high. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

  The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, such as antiviral agents, vaccines, antibodies, immune enhancing agents, immunosuppressive agents, anti-inflammatory agents. Any pharmaceutical formulation such as

Labeled compounds and assay methods Other aspects of the invention are for localizing and quantifying receptors in tissue samples, including humans, and for identifying receptor ligands by inhibiting the binding of labeled compounds. It relates to the fluorescent dyes, spin labels, heavy metals or radiolabeled compounds of the invention which are useful in assays as well as in vitro and in vivo imaging. Accordingly, the present invention includes receptor assays that contain such labeled compounds.

The invention further relates to isotopically labeled compounds of the invention. An “isotopically” or “radiolabeled” compound has one or more atoms that have an atomic mass or mass number that is different from the atomic mass or mass number normally found in nature (ie, natural) A compound of the invention that is substituted or substituted by an atom. Suitable radionuclides that may be introduced into the compounds of the invention include ² H (also described as D next to double hydrogen), ³ H (also described as T for tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I can be mentioned, but is not limited thereto. The radionuclide introduced into the present radiolabeled compound depends on the specific use of the radiolabeled compound. For example, for in vitro IDO enzyme labeling and competition assays, compounds that incorporate ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, ³⁵ S are generally most useful. For radiographic applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most useful.

It is understood that a “radiolabel” or “labeled compound” is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br.

  Synthetic methods of incorporating radioactive isotopes into organic compounds apply to the compounds of the present invention and are well known in the art.

  The radiolabeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. In general terms, a newly synthesized or identified compound (ie, a test compound) can be evaluated as the ability to reduce binding of a radiolabeled compound of the invention to the receptor. Thus, the ability of a test compound to compete with a radiolabeled compound for binding to an IDO enzyme is directly correlated to binding affinity.

Kits The present invention also includes, for example, a pharmaceutical kit useful in the treatment of a 5-HT _2A related disease or disorder as referred to herein, the kit comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. It includes one or more containers containing a pharmaceutical composition that includes an acceptable salt. Such kits may further include, if desired, one or more various conventional such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., which will be readily apparent to those skilled in the art. Pharmaceutical kit components from Instructions indicating the amount of ingredients to be administered, guidelines for administration and / or guidelines for mixing the ingredients can also be included in the kit, either as an insert or as a label.

  The invention is explained in more detail by means of specific examples. The following examples are given for illustrative purposes and do not limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to achieve essentially the same results.

Exemplary compounds of the present invention are listed in Table 1. These compounds could be found as inverse agonists of 5-HT _2A receptors according to one or more assays herein.

表１に挙げた化合物を、以下に記載する方法に従って製造した。この前後で記載する化合物は、ＣＳ Ｃｈｅｍ Ｄｒａｗ Ｕｌｔｒａ Ｖｅｒｓｉｏｎ７．０．１またはＡｕｔｏＮｏｍ２０００に従って命名されている。ある場合には慣用名を使用し、これらの慣用名は当業者に認識されていることが理解されよう。

The compounds listed in Table 1 were prepared according to the method described below. The compounds described before and after this are named according to CS Chem Draw Ultra Version 7.0.1 or AutoNom2000. It will be understood that in some cases, common names are used, and that these common names are recognized by those skilled in the art.

Chemistry: Proton Nuclear Magnetic Resonance ( ¹ H NMR) spectra can be obtained using a 4-nucleus auto switchable probe and a Varian Mercury Vx-400 with a z-gradient, or a QNP (Quad Nucleus Probe). )) Or BBI (Broad Band Inverse) and a Bruker Avance-400 or 500 MHz with z-gradient. Chemical shifts are expressed as parts per million by the residual solvent signal used as a reference. Abbreviations used in NMR are as follows. s = 1 singlet, d = 2 doublet, dd = 2 doublet, dt = triplet doublet, t = triplet, q = quadruple, m = multiplet, br = Wide. The microwave irradiation method was performed using Emrys Synthesizer (Personal Chemistry). Thin layer chromatography (TLC) was performed on silica gel 60F ₂₅₄ (Merck), preparative thin layer chromatography (preparative TLC) was performed on 1 mm Whatman of PK6F silica gel 60A, and column chromatography was performed on Kieselgel 60, 0. Performed on a silica gel column using 0.063-0.200 mm (Merck). Evaporation was performed in vacuo using a Buchi rotary evaporator. Celite 545 (registered trademark) was used during palladium filtration.

  LCMS specifications: 1) PC: HPLC-pump: LC-10AD VP, Shimadzu; HPLC system controller: SCL-10A VP, Shimadzu; UV-detector: SPD-10A VP, Shimadzu; Automatic sampler: CTC HTS Mass spectrometer: API150EX with turbo ion spray source, AB / MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pump: LC-8A VP, Shimadzu; HPLC system controller: SCL -10A VP, Shimadzu.

  UV-detector: SPD-10A VP, Shimadzu; Autosampler: 215 Liquid Handler, Gilson; Mass Spectrometer: API 150EX with turbo ion spray source, AB / MDS Sciex Software: Masschrom 1.5.2.

Example 1.1: Preparation of 1-methyl-5- (5-nitrobenzofuran-7-yl) -1H-pyrazole (intermediate) 7-Bromo-5-nitrobenzofuran (1.747 g, 7.22 mmol), 1-methyl -1H- pyrazol-5-ylboronic acid (1.788g, 14.2mmol) and _{Cs 2 CO 3 (7.86g, 24.1mmol} ) in dimethoxyethane; in (DME 125 mL) suspension, under argon , Pd (PPh ₃ ) ₄ (372 mg, 0.322 mmol) was added. The reaction mixture was heated to 85 ° C. overnight, cooled to room temperature, then diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over MgSO ₄ and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give the compound as a solid (708 mg, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.61 (d, J = 2.27 Hz, 1H), 8.28 (d, J = 2.27 Hz, 1H), 7.86 (d, J = 2) .23 Hz, 1H), 7.64 (d, J = 1.94 Hz, 1H), 7.04 (d, J = 2.23 Hz, 1H), 6.60 (d, J = 1.95 Hz, 1H) , 3.94 (s, 3H).

Example 1.2: Preparation of 4-bromo-1-methyl-5- (5-nitrobenzofuran-7-yl) -1H-pyrazole (intermediate) 1-methyl-5- (5-nitrobenzofuran-7- Yl) -1H-pyrazole (680 mg, 2.80 mmol) in THF (25 mL) was added N-bromosuccinimide (NBS; 540 mg, 3.03 mmol) and stirred for 1 hour. The resulting material was purified by silica gel chromatography to give the title compound as a solid (761 mg, 84%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.67 (d, J = 2.27 Hz, 1H), 8.31 (d, J = 2.26 Hz, 1H), 7.85 (d, J = 2) 24 Hz, 1H), 7.64 (s, 1H), 7.06 (d, J = 2.25 Hz, 1H), 3.83 (s, 3H).

  Example 1.3: Preparation of 7- (4-Bromo-1-methyl-1H-pyrazol-5-yl) benzofuran-5-amine (intermediate)

４−ブロモ−１−メチル−５−（５−ニトロベンゾフラン−７−イル）−１Ｈ−ピラゾール（７４０ｍｇ、２．３０ｍｍｏｌ）のエタノール（３０ｍＬ）および酢酸（３０ｍＬ）溶液に、鉄粉末（１．５ｇ、２７ｍｍｏｌ）を加えた。反応混合物を６時間で７５℃に加熱し、室温に冷却し、ろ過し、真空濃縮した。得られた物質をＨＰＬＣで精製し、標題化合物（３４９ｍｇ、５２％）を得た。ＬＣＭＳ ｍ／ｚ（％）＝２９２（Ｍ＋Ｈ ^７９Ｂｒ，９８），２９４（Ｍ＋Ｈ ^８１Ｂｒ，１００）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：７．８３（ｄ，Ｊ＝２．１３Ｈｚ，１Ｈ），７．６９（ｓ，１Ｈ），６．９０（ｄ，Ｊ＝２．２０Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝２．１７Ｈｚ，１Ｈ），６．６２（ｄ，Ｊ＝２．１８Ｈｚ，１Ｈ），５．０８（ｂｓ，２Ｈ），３．６９（ｓ，３Ｈ）。

To a solution of 4-bromo-1-methyl-5- (5-nitrobenzofuran-7-yl) -1H-pyrazole (740 mg, 2.30 mmol) in ethanol (30 mL) and acetic acid (30 mL) was added iron powder (1.5 g 27 mmol) was added. The reaction mixture was heated to 75 ° C. for 6 hours, cooled to room temperature, filtered and concentrated in vacuo. The resulting material was purified by HPLC to give the title compound (349 mg, 52%). LCMS m / z (%) = 292 (M + H ⁷⁹ Br, 98), 294 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.83 (d, J = 2.13 Hz, 1H), 7.69 (s, 1H), 6.90 (d, J = 2.20 Hz, 1H) ), 6.82 (d, J = 2.17 Hz, 1H), 6.62 (d, J = 2.18 Hz, 1H), 5.08 (bs, 2H), 3.69 (s, 3H).

Example 1.4: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-chloro-phenyl) -urea (compound 12 7- (4-Bromo-1-methyl-1H-pyrazol-5-yl) benzofuran-5-amine (24.2 mg, 0.083 mmol) in CH ₂ Cl ₂ (2 mL) was added 4-chlorophenyl. Isocyanate (15 mg, 0.098 mmol) was added and stirred overnight. The resulting white solid was collected by filtration to give the title compound (15.7 mg, 43%). LCMS m / z (%) = 445 (M + H ⁷⁹ Br, 72), 447 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.90 (bs, 1H), 8.89 (bs, 1H), 8.03 (d, J = 2 Hz, 1H), 7.95 (d, J = 2 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2 Hz, 1H), 3.73 (s, 3H).

Example 1.5: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (2,4-difluoro-phenyl) -urea ( Preparation of Compound 6) The title compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 447 (M + H ⁷⁹ Br, 100), 449 (M + H ⁸¹ Br, 87). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.20 (bs, 1H), 8.54 (bs, 1H), 8.12-8.04 (m, 1H), 8.03 (d, J = 2.16 Hz, 1H), 7.95 (d, J = 2.14 Hz, 1H), 7.75 (s, 1H), 7.39 (d, J = 2.11 Hz, 1H), 7. 36-7.28 (m, 1H), 7.09-7.02 (m, 2H), 3.73 (s, 3H).

Example 1.6: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-methoxy-phenyl) -urea (compound 21 The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 441 (M + H ⁷⁹ Br, 100), 443 (M + H ⁸¹ Br, 87). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (bs, 1H), 8.53 (bs, 1H), 8.02 (d, J = 2.15 Hz, 1H), 7.95 ( d, J = 2.10 Hz, 1H), 7.75 (s, 1H), 7.42-7.34 (m, 3H), 7.04 (d, J = 2.19 Hz, 1H), 6. 87 (d, J = 9.04 Hz, 2H), 3.73 (s, 3H), 3.72 (s, 3H).

Example 1.7: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-fluoro-phenyl) -urea (compound 18 The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 429 (M + H ⁷⁹ Br, 96), 431 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.85 (bs, 1H), 8.76 (bs, 1H), 8.02 (d, J = 2.16 Hz, 1H), 7.95 ( d, J = 2.11 Hz, 1H), 7.75 (s, 1H), 7.51-7.44 (m, 2H), 7.39 (d, J = 2.10 Hz, 1H), 7. 17-7.09 (m, 2H), 7.05 (d, J = 2.18 Hz, 1H), 3.73 (s, 3H).

Example 1.8: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (3-chloro-phenyl) -urea (compound 13 The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 445 (M + H ⁷⁹ Br, 70), 447 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.96 (bs, 1H), 8.95 (bs, 1H), 8.03 (d, J = 2.16 Hz, 1H), 7.96 ( d, J = 2.13 Hz, 1 H), 7.75 (s, 1 H), 7.75-7.71 (m, 1 H), 7.40 (d, J = 2.11 Hz, 1 H), 7. 34-7.27 (m, 2H), 7.06 (d, J = 2.16 Hz, 1H), 7.04-6.99 (m, 1H), 3.73 (s, 3H).

Example 1.9: Preparation of [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -carbamic acid 4-methoxy-phenyl ester (Compound 7) 7- To a solution of (4-bromo-1-methyl-1H-pyrazol-5-yl) benzofuran-5-amine (21.2 mg, 0.073 mmol) and pyridine (30 μL) in CH ₂ Cl ₂ (2 ml) was added 4-methoxy. Phenyl chloroformate (13 μL, 0.087 mmol) was added and stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography to give the title compound as a white solid (24.1 mg, 75%). LCMS m / z (%) = 442 (M + H ⁷⁹ Br, 81), 444 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ: 7.93 (bs, 1H), 7.71 (d, J = 2.18 Hz, 1H), 7.57 (s, 1H), 7.35 ( d, J = 2.19 Hz, 1H), 7.17 (bs, 1H), 7.12 (d, J = 9.06 Hz, 2H), 6.92 (d, J = 9.07 Hz, 2H), 6.89 (d, J = 2.21 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H).

Example 1.10: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (3-methoxy-phenyl) -urea (compound 3 The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 441 (M + H ⁷⁹ Br, 100), 443 (M + H ⁸¹ Br, 91). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 (bs, 1H), 8.74 (bs, 1H), 8.02 (d, J = 2.16 Hz, 1H), 7.97 ( d, J = 2.14 Hz, 1H), 7.75 (s, 1H), 7.38 (d, J = 2.11 Hz, 1H), 7.23-7.15 (m, 2H), 7. 06 (d, J = 2.17 Hz, 1H), 6.97-6.92 (m, 1H), 6.58-6.53 (m, 1H), 3.73 (s, 6H).

Example 1.11: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-trifluoromethyl-phenyl) -urea ( Preparation of Compound 1) The title compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 479 (M + H ⁷⁹ Br, 94), 481 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.19 (bs, 1H), 9.02 (bs, 1H), 8.04 (d, J = 2.14 Hz, 1H), 7.98 ( d, J = 2.12 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.90 Hz, 2H), 7.64 (d, J = 8.97 Hz, 2H), 7.42 (d, J = 2.11 Hz, 1H), 7.07 (d, J = 2.15 Hz, 1H), 3.74 (s, 3H).

Example 1.12: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-isopropyl-phenyl) -urea (compound 14 The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 453 (M + H ⁷⁹ Br, 100), 455 (M + H ⁸¹ Br, 95). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.82 (bs, 1H), 8.63 (bs, 1H), 8.02 (d, J = 2.15 Hz, 1H), 7.96 ( d, J = 2.09 Hz, 1H), 7.75 (s, 1H), 7.40-7.35 (m, 3H), 7.15 (d, J = 8.52 Hz, 2H), 7. 05 (d, J = 2.18 Hz, 1H), 3.73 (s, 3H), 2.83 (Sevent, J = 6.91 Hz, 1H), 1.18 (d, J = 6.90 Hz, 6H).

Example 1.13: Preparation of 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3-p-tolyl-urea (Compound 8) The compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 425 (M + H ⁷⁹ Br, 100), 427 (M + H ⁸¹ Br, 91). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.80 (bs, 1H), 8.60 (bs, 1H), 8.02 (d, J = 2.15 Hz, 1H), 7.95 (D, J = 2.11 Hz, 1H), 7.74 (s, 1H), 7.38 (d, J = 2.11 Hz, 1H), 7.34 (d, J = 8.42 Hz, 2H) 7.08 (d, J = 8.28 Hz, 2H), 7.05 (d, J = 2.19 Hz, 1H), 3.73 (s, 3H), 2.24 (s, 3H).

Example 1.14: Preparation of ethyl 7-bromo-5-nitrobenzofuran-2-carboxylate (intermediate) 7-Bromo-5-nitrobenzofuran-2-carboxylic acid (3.38 g, 11.8 mmol) in ethanol A 1.25 M HCl solution in (150 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a solid (3.413 g, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59 (d, J = 2.16 Hz, 1H), 8.55 (d, J = 2.15 Hz, 1H), 7.70 (s, 1H) 4.49 (q, J = 7.12 Hz, 2H), 1.45 (t, J = 7.15 Hz, 3H).

  Example 1.15: Preparation of ethyl 7- (1-methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-carboxylate (intermediate)

標題化合物を、実施例１．１に記載の方法と同様の方法で製造し、固体を得た。ＬＣＭＳ ｍ／ｚ（％）＝３１６（Ｍ＋Ｈ，１００）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：８．６９（ｄ，Ｊ＝２．２７ Ｈｚ，１Ｈ），８．４１（ｄ，Ｊ＝２．２６Ｈｚ，１Ｈ），７．７２（ｓ，１Ｈ），７．６８（ｄ，Ｊ＝２．００Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝２．０１Ｈｚ，１Ｈ），４．４６（ｑ，Ｊ＝７．１３Ｈｚ，２Ｈ），４．００（ｓ，３Ｈ），１．４３（ｔ，Ｊ＝７．１４Ｈｚ，３Ｈ）。

The title compound was prepared in a similar manner as described in Example 1.1 to give a solid. LCMS m / z (%) = 316 (M + H, 100). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.69 (d, J = 2.27 Hz, 1H), 8.41 (d, J = 2.26 Hz, 1H), 7.72 (s, 1H) 7.68 (d, J = 2.00 Hz, 1H), 6.67 (d, J = 2.01 Hz, 1H), 4.46 (q, J = 7.13 Hz, 2H), 4.00 ( s, 3H), 1.43 (t, J = 7.14 Hz, 3H).

Example 1.16: Preparation of ethyl 7- (4-bromo-1-methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-carboxylate (intermediate) The title compound was prepared according to Example 1. A white solid was obtained by the same method as described in 2. LCMS m / z (%) = 394 (M + H ⁷⁹ Br, 95), 396 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.75 (d, J = 2.27 Hz, 1H), 8.46 (d, J = 2.27 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 4.46 (q, J = 7.13 Hz, 2H), 3.87 (s, 3H), 1.43 (t, J = 7.12 Hz, 3H).

  Example 1.17: Preparation of ethyl 5-amino-7- (4-bromo-1-methyl-1H-pyrazol-5-yl) benzofuran-2-carboxylate (intermediate)

標題化合物を、実施例１．３に記載の方法と同様の方法で製造し、黄色固体を得た。ＬＣＭＳ ｍ／ｚ（％）＝３６４（Ｍ＋Ｈ ^７９Ｂｒ，１００），３６６（Ｍ＋Ｈ ^８１Ｂｒ，９８）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：７．７４（ｓ，１Ｈ），７．６４（ｓ，１Ｈ），６．９７（ｄ，Ｊ＝２．２５Ｈｚ，１Ｈ），６．８４（ｄ，Ｊ＝２．２６Ｈｚ，１Ｈ），５．３３（ｂｓ，２Ｈ），４．３２（ｑ，Ｊ＝７．１０Ｈｚ，２Ｈ），３．７１（ｓ，３Ｈ），１．３０（ｔ，Ｊ＝７．１０Ｈｚ，３Ｈ）。

The title compound was prepared in a similar manner as described in Example 1.3 to give a yellow solid. LCMS m / z (%) = 364 (M + H ⁷⁹ Br, 100), 366 (M + H ⁸¹ Br, 98). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.74 (s, 1H), 7.64 (s, 1H), 6.97 (d, J = 2.25 Hz, 1H), 6.84 ( d, J = 2.26 Hz, 1H), 5.33 (bs, 2H), 4.32 (q, J = 7.10 Hz, 2H), 3.71 (s, 3H), 1.30 (t, J = 7.10 Hz, 3H).

Example 1.18: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-chloro-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester Preparation of (Compound 22) The title compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 517 (M + H ⁷⁹ Br, 100), 519 (M + H ⁸¹ Br, 82). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.05 (bs, 1H), 8.94 (bs, 1H), 8.14 (d, J = 2.15 Hz, 1H), 7.86 ( s, 1H), 7.79 (s, 1H), 7.57 (d, J = 2.14 Hz, 1H), 7.51 (d, J = 8.92 Hz, 2H), 7.34 (d, J = 8.90 Hz, 2H), 4.35 (q, J = 7.10 Hz, 2H), 3.76 (s, 3H), 1.32 (t, J = 7.11 Hz, 3H).

Example 1.19: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (2,4-difluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid Preparation of ethyl ester (Compound 19) The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 519 (M + H ⁷⁹ Br, 89), 521 (M + H ⁸¹ Br, 100). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 9.32 (bs, 1H), 8.57 (bs, 1H), 8.14 (d, J = 1.95 Hz, 1H), 8.10 − 8.04 (m, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.55 (d, J = 2.27 Hz, 1H), 7.36-7.30 ( m, 1H), 7.09-7.03 (m, 1H), 4.35 (q, J = 6.96 Hz, 2H), 3.76 (s, 3H), 1.32 (t, J = 7.04 Hz, 3H).

Example 1.20: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (2,4-difluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid Preparation of (Compound 15) 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (2,4-difluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid To a solution of the ethyl ester (23.8 mg, 0.0458 mmol) in methanol (1 mL) and THF (5 mL) was added 1M LiOH in water (1 mL). After 1 hour, the organic solvent was removed in vacuo and the remaining aqueous mixture was acidified by the addition of 1M HCl. The resulting white solid was collected by filtration to give the title compound (17.8 mg, 79%). LCMS m / z (%) = 491 (M + H ⁷⁹ Br, 100), 493 (M + H ⁸¹ Br, 86). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 13.70 (bs, 1H), 9.32 (bs, 1H), 8.58 (bs, 1H), 8.12 (d, J = 2. 14 Hz, 1 H), 8.11-8.04 (m, 1 H), 7.79 (s, 1 H), 7.77 (s, 1 H), 7.54 (d, J = 2.13 Hz, 1 H) 7.38-7.29 (m, 1H), 7.10-7.03 (m, 1H), 3.76 (s, 3H).

Example 1.21: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-methoxy-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester Preparation of (Compound 9) The title compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 513 (M + H ⁷⁹ Br, 92), 515 (M + H ⁸¹ Br, 100).

Example 1.22: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-methoxy-phenyl) -ureido] -benzofuran-2-carboxylic acid (compound 4) Preparation The title compound was prepared in a similar manner as described in Example 1.20 to give a white solid. ^{LCMS m / z (%) =} 485 (M + H 79 Br, 100), 487 (M + H 81 Br, 95).

Example 1.23: Preparation of 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5-isobutoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester (Compound 2) A white solid was obtained by the same method as that described in Example 1.9. LCMS m / z (%) = 464 (M + H ⁷⁹ Br, 78), 466 (M + H ⁸¹ Br, 100).

Example 1.24: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-fluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester Preparation of (Compound 16) The title compound was prepared in the same manner as described in Example 1.4 to give a white solid. LCMS m / z (%) = 501 (M + H ⁷⁹ Br, 92), 503 (M + H ⁸¹ Br, 100).

Example 1.25: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-trifluoromethyl-phenyl) -ureido] -benzofuran-2-carboxylic acid Preparation of ethyl ester (Compound 10) The title compound was prepared in a manner similar to that described in Example 1.4 to give a white solid. LCMS m / z (%) = 551 (M + H ⁷⁹ Br, 100), 553 (M + H ⁸¹ Br, 89).

Example 1.26: 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-fluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid (compound 23) Preparation The title compound was prepared in a similar manner as described in Example 1.20 to give a white solid. LCMS m / z (%) = 473 (M + H ⁷⁹ Br, 88), 475 (M + H ⁸¹ Br, 100).

Example 1.27: Preparation of 7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5-isobutoxycarbonylamino-benzofuran-2-carboxylic acid (Compound 20) Prepared in a manner similar to that described in Example 1.20 to give a white solid. LCMS m / z (%) = 436 (M + H ⁷⁹ Br, 100), 438 (M + H ⁸¹ Br, 93).

  Example 1.28: Preparation of (7- (1-Methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-yl) methanol (intermediate)

エチル７−（１−メチル−１Ｈ−ピラゾール−５−イル）−５−ニトロベンゾフラン−２−カルボキシレート（８０４ｍｇ、２．５５ｍｍｏｌ）のＣＨ_２Ｃｌ_２（３０ｍＬ）およびＴＨＦ（２０ｍＬ）溶液に、ＴＨＦ（３０ｍＬ、３０ｍｍｏｌ）中の１ＭのＤＩＢＡＬ−Ｈを加え、３時間攪拌した。反応系を、メタノール（１ｍＬ）および酒石酸ナトリウムカリウム水溶液（１５０ｍＬ）の添加によりクエンチした。２時間攪拌した後、混合物を水（１００ｍＬ）で希釈し、ＣＨ_２Ｃｌ_２（３×２５０ｍＬ）で抽出した。合わせた有機層を（ＭｇＳＯ_４）で乾燥し、真空濃縮した。得られた物質をＨＰＬＣで精製し、標題化合物を黄色固体（２８２ｍｇ、４０％）として得た。ＬＣＭＳ ｍ／ｚ（％）＝２７４（Ｍ＋Ｈ，１００）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：８．６９（ｄ，Ｊ＝２．３４Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝２．３４Ｈｚ，１Ｈ），７．６２（ｄ，Ｊ＝１．９２Ｈｚ，１Ｈ），７．１０（ｓ，１Ｈ），６．６８（ｄ，Ｊ＝１．９２Ｈｚ，１Ｈ），５．６７（ｔ，Ｊ＝６．００Ｈｚ，１Ｈ），４．６４（ｄ，Ｊ＝５．８９Ｈｚ，２Ｈ），３．８５（ｓ，３Ｈ）。

To a solution of ethyl 7- (1-methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-carboxylate (804 mg, 2.55 mmol) in CH ₂ Cl ₂ (30 mL) and THF (20 mL) was added THF. 1M DIBAL-H in (30 mL, 30 mmol) was added and stirred for 3 hours. The reaction was quenched by the addition of methanol (1 mL) and aqueous potassium sodium tartrate (150 mL). After stirring for 2 hours, the mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3 × 250 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo. The resulting material was purified by HPLC to give the title compound as a yellow solid (282 mg, 40%). LCMS m / z (%) = 274 (M + H, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.69 (d, J = 2.34 Hz, 1H), 8.21 (d, J = 2.34 Hz, 1H), 7.62 (d, J = 1.92 Hz, 1H), 7.10 (s, 1H), 6.68 (d, J = 1.92 Hz, 1H), 5.67 (t, J = 6.00 Hz, 1H), 4.64. (D, J = 5.89 Hz, 2H), 3.85 (s, 3H).

  Example 1.29: Preparation of (5-amino-7- (1-methyl-1H-pyrazol-5-yl) benzofuran-2-yl) methanol (intermediate)

（７−（１−メチル−１Ｈ−ピラゾール−５−イル）−５−ニトロベンゾフラン−２−イル）メタノール（２１７ｍｇ、０．７９４ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に、５％Ｐｄ／Ｃ（５６．３ｍｇ）を加えた。反応混合物を水素下で３日間攪拌し、次いでセライト（１００ｍＬのメタノールで洗浄）でろ過した。混合物を真空濃縮し、ＨＰＬＣで精製し、標題化合物を黄褐色の固体（４５ｍｇ、３４％）として得た。ＬＣＭＳ ｍ／ｚ（％）＝２４４（Ｍ＋Ｈ，１００）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：７．５１（ｄ，Ｊ＝１．８５Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝２．２０Ｈｚ，１Ｈ），６．６１−６．５８（ｍ，２Ｈ），６．４２（ｄ，Ｊ＝１．８５Ｈｚ，１Ｈ），５．３８（ｔ，Ｊ＝５．９４Ｈｚ，１Ｈ），４．９７（ｂｓ，２Ｈ），４．４７（ｄ，Ｊ＝５．９０Ｈｚ，２Ｈ），３．７７（ｓ，３Ｈ）。

To a solution of (7- (1-methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-yl) methanol (217 mg, 0.794 mmol) in methanol (20 mL) was added 5% Pd / C (56. 3 mg) was added. The reaction mixture was stirred under hydrogen for 3 days and then filtered through celite (washed with 100 mL methanol). The mixture was concentrated in vacuo and purified by HPLC to give the title compound as a tan solid (45 mg, 34%). LCMS m / z (%) = 244 (M + H, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.51 (d, J = 1.85 Hz, 1H), 6.77 (d, J = 2.20 Hz, 1H), 6.61-6.58 (M, 2H), 6.42 (d, J = 1.85 Hz, 1H), 5.38 (t, J = 5.94 Hz, 1H), 4.97 (bs, 2H), 4.47 (d , J = 5.90 Hz, 2H), 3.77 (s, 3H).

  Example 1.30: N- (2- (hydroxymethyl) -7- (1-methyl-1H-pyrazol-5-yl) benzofuran-5-yl) -3- (trifluoromethyl) benzamide (Compound 24) Manufacturing of

（５−アミノ−７−（１−メチル−１Ｈ−ピラゾール−５−イル）ベンゾフラン−２−イル）メタノール（４４ｍｇ、０．１８１ｍｍｏｌ）およびトリエチルアミン（７０μＬ）のＣＨ_２Ｃｌ_２（５ｍＬ）溶液に、３−（トリフルオロメチル）塩化ベンゾイル（２７μＬ、０．１７９ｍｍｏｌ）を加え、２時間攪拌した。反応混合物を真空濃縮し、得られた残渣をＨＰＬＣで精製し、標題化合物を白色固体（４９．８ｍｇ、６６％）として得た。ＬＣＭＳ ｍ／ｚ（％）＝４１６（Ｍ＋Ｈ，１００）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：１０．６０（ｂｓ，１Ｈ），８．３５−８．２７（ｍ，２Ｈ），８．１８（ｄ，Ｊ＝２．００Ｈｚ，１Ｈ），８．０２−７．９６（ｍ，１Ｈ），７．８５−７．７７（ｍ，１Ｈ），７．６９（ｄ，Ｊ＝２．０５Ｈｚ，１Ｈ），７．５８（ｄ，Ｊ＝１．８７Ｈｚ，１Ｈ），６．９１（ｓ，１Ｈ），６．５５（ｄ，Ｊ＝１．８９Ｈｚ，１Ｈ），４．５８（ｂｓ，２Ｈ），３．８４（ｓ，３Ｈ）。

To a solution of (5-amino-7- (1-methyl-1H-pyrazol-5-yl) benzofuran-2-yl) methanol (44 mg, 0.181 mmol) and triethylamine (70 μL) in CH ₂ Cl ₂ (5 mL), 3- (Trifluoromethyl) benzoyl chloride (27 μL, 0.179 mmol) was added and stirred for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by HPLC to give the title compound as a white solid (49.8 mg, 66%). LCMS m / z (%) = 416 (M + H, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 10.60 (bs, 1H), 8.35-8.27 (m, 2H), 8.18 (d, J = 2.00 Hz, 1H), 8.02-7.96 (m, 1H), 7.85-7.77 (m, 1H), 7.69 (d, J = 2.05 Hz, 1H), 7.58 (d, J = 1) .87 Hz, 1H), 6.91 (s, 1H), 6.55 (d, J = 1.89 Hz, 1H), 4.58 (bs, 2H), 3.84 (s, 3H).

Example 1.31: N- [7- (2-methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3-trifluoromethyl-benzamide (Compound 17 ) N- (2- (hydroxymethyl) -7- (1-methyl-1H-pyrazol-5-yl) benzofuran-5-yl) -3- (trifluoromethyl) benzamide (49 mg, 0.118 mmol) Methanesulfonyl chloride (15 μL, 0.194 mmol) was added to a CH ₂ Cl ₂ (5 mL) solution of triethylamine (30 μL) and stirred overnight. Pyrrolidine (50 μL, 0.609 mmol) was added and stirring was continued overnight. The reaction mixture was concentrated in vacuo and the resulting residue was purified by HPLC to give the title compound as a white solid (15.8 mg, 29%). LCMS m / z (%) = 469 (M + H, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 10.60 (bs, 1H), 8.34-8.27 (m, 2H), 8.16 (d, J = 2.00 Hz, 1H), 7.99 (d, J = 7.86 Hz, 1H), 7.81 (t, J = 7.78 Hz, 1H), 7.68 (d, J = 2.00 Hz, 1H), 7.59 (d , J = 1.87 Hz, 1H), 6.91 (s, 1H), 6.55 (d, J = 1.87 Hz, 1H), 3.84 (s, 3H), 3.77 (bs, 2H) ), 2.61-2.50 (m, 4H), 1.76-1.65 (m, 4H).

  Example 1.32: Preparation of 4-bromo-1-methyl-5- (5-nitro-2- (pyrrolidin-1-ylmethyl) benzofuran-7-yl) -1H-pyrazole (intermediate)

（７−（１−メチル−１Ｈ−ピラゾール−５−イル）−５−ニトロベンゾフラン−２−イル）メタノール（２７５ｍｇ、１．０１ｍｍｏｌ）およびトリフェニルホスフィン（２７４．５ｍｇ、１．０５ｍｍｏｌ）のジメチルアセトアミド（ＤＭＡ；３０ｍＬ）溶液に、ＮＢＳ（１９７．１ｍｇ、１．１１ｍｍｏｌ）を加えた。２時間後、ＬＣ／ＭＳ分析は、反応が完了していないことを示したので、追加のトリフェニルホスフィン（２５４ｍｇ、０．９７ｍｍｏｌ）、次いでＮＢＳ（２８２ｍｇ、１．５８ｍｍｏｌ）を加えた。２時間後、さらにＮＢＳ（３０５ｍｇ、１．７１ｍｍｏｌ）を加えた。１時間後、ピロリジン（０．５００ｍＬ、６．０９ｍｍｏｌ）を加え、反応混合物を１４５℃に２０分加熱した。反応混合物をＨＰＬＣで精製し、標題化合物を褐色の固体（２８２ｍｇ、６９％）として得た。ＬＣＭＳ ｍ／ｚ（％）＝４０５（Ｍ＋Ｈ ^７９Ｂｒ，１００），４０７（Ｍ＋Ｈ ^８１Ｂｒ，９２）．^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：８．７４（ｄ，Ｊ＝２．３３Ｈｚ，１Ｈ），８．２５（ｄ，Ｊ＝２．３６Ｈｚ，１Ｈ），７．８１（ｓ，１Ｈ），７．１３（ｓ，１Ｈ），３．８３（ｓ，２Ｈ），３．７７（ｓ，３Ｈ），２．５８−２．４５（ｍ（ＤＭＳＯと重なっている），４Ｈ），１．７１−１．６４（ｍ，４Ｈ）。

Dimethylacetamide of (7- (1-methyl-1H-pyrazol-5-yl) -5-nitrobenzofuran-2-yl) methanol (275 mg, 1.01 mmol) and triphenylphosphine (274.5 mg, 1.05 mmol) To the (DMA; 30 mL) solution, NBS (197.1 mg, 1.11 mmol) was added. After 2 hours, LC / MS analysis indicated that the reaction was not complete, so additional triphenylphosphine (254 mg, 0.97 mmol) was added followed by NBS (282 mg, 1.58 mmol). After 2 hours, more NBS (305 mg, 1.71 mmol) was added. After 1 hour, pyrrolidine (0.500 mL, 6.09 mmol) was added and the reaction mixture was heated to 145 ° C. for 20 minutes. The reaction mixture was purified by HPLC to give the title compound as a brown solid (282 mg, 69%). LCMS m / z (%) = 405 (M + H ⁷⁹ Br, 100), 407 (M + H ⁸¹ Br, 92). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (d, J = 2.33 Hz, 1H), 8.25 (d, J = 2.36 Hz, 1H), 7.81 (s, 1H ), 7.13 (s, 1H), 3.83 (s, 2H), 3.77 (s, 3H), 2.58-2.45 (m (overlapping with DMSO), 4H), 1 .71-1.64 (m, 4H).

Example 1.33: Preparation of 4-bromo-1-methyl-5- (5-amino-2- (pyrrolidin-1-ylmethyl) benzofuran-7-yl) -1H-pyrazole (intermediate) 4-Bromo- 1-methyl-5- (5-nitro-2- (pyrrolidin-1-ylmethyl) benzofuran-7-yl) -1H-pyrazole (200 mg, 0.494 mmol), saturated aqueous NH ₄ Cl (0.5 mL) and THF To a stirred mixture of (10 mL) at 0 ° C., zinc dust (280 mg, 4.28 mmol) was added. After warming to room temperature overnight, the reaction mixture was filtered through celite and purified by HPLC to give the title compound as a yellow wax (90.5 mg, 49%). LCMS m / z (%) = 375 (M + H ⁷⁹ Br, 100), 377 (M + H ⁸¹ Br, 71). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.69 (s, 1H), 6.82 (d, J = 2.21 Hz, 1H), 6.62 (s, 1H), 6.55 ( d, J = 2.20 Hz, 1H), 5.04 (bs, 2H), 3.69 (s, 3H), 3.66 (s, 2H), 2.52-2.45 (m (with DMSO) 4H), 1.71-1.65 (m, 4H).

Example 1.34: 1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3- (4-chloro Preparation of -phenyl) -urea (compound 11) 4-Bromo-1-methyl-5- (5-amino-2- (pyrrolidin-1-ylmethyl) benzofuran-7-yl) -1H-pyrazole (39 mg, 0. 104 mmol) in CH ₂ Cl ₂ (5 mL) was added 4-chlorophenyl isocyanate (20 mg, 0.130 mmol) and stirred overnight. The reaction mixture was purified by HPLC to give the title compound as a white solid (49.4 mg, 90%). LCMS m / z (%) = 528 (M + H ⁷⁹ Br, 66), 530 (M + H ⁸¹ Br, 100). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.86 (bs, 1H), 8.85 (bs, 1H), 7.87 (d, J = 2.06 Hz, 1H), 7.74 ( s, 1H), 7.50 (d, J = 8.88 Hz, 2H), 7.35-7.31 (m, 3H), 6.84 (s, 1H), 3.75-3.72 ( m, 5H), 2.53-2.49 (m (overlapping with DMSO), 4H), 1.72-1.67 (m, 4H).

Example 1.35: N- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3-trifluoromethyl- Preparation of benzamide (Compound 5) 4-Bromo-1-methyl-5- (5-amino-2- (pyrrolidin-1-ylmethyl) benzofuran-7-yl) -1H-pyrazole (39.4 mg, 0.105 mmol) To a solution of triethylamine (50 μL) in CH ₂ Cl ₂ (5 mL) was added 3- (trifluoromethyl) benzoyl chloride (18 μL, 0.122 mmol) and stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue was purified by HPLC to give the title compound as a white solid (30.1 mg, 52%). LCMS m / z (%) = 547 (M + H ⁷⁹ Br, 100), 549 (M + H ⁸¹ Br, 85). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 10.64 (bs, 1H), 8.35-8.22 (m, 3H), 7.99 (d, J = 7.77 Hz, 1H), 7.81 (t, J = 7.81 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 6.95 (bs, 1H), 3.83-3.72 ( m, 5H), 2.61-2.49 (m (overlapping with DMSO), 4H), 1.77-1.67 (m, 4H).

Example A
Receptor expression A. pCMV
A person skilled in the art can obtain various expression vectors, and the vector used is preferably pCMV. This vector was found in the American Type Culture Collection (ATCC) on October 13, 1998 (10801 University Blvd., Manassas, VA 20110-2209 USA) under the provisions of the Budapest Treaty of International Approval of Deposit of Microorganisms for the purpose of patent proceedings. Deposited. The DNA was tested by ATCC and confirmed to be viable. The ATCC has assigned the following deposit number: pCMV: ATCC # 203351.
B. Transfection procedure HEK293 cells were transfected for the IP accumulation assay (below). For the DOI binding assay (below), COS7 cells were transfected. Several protocols well known in the art can be used to transfect cells. The following protocol is representative of the transfection procedure used here for COS7 or 293 cells.

On the first day, COS-7 cells were usually placed in 24-well plates at 1 × 10 5 cells / well or 2 × 10 5 cells / well, respectively. On day 2, the cells were transfected by first mixing 0.25 ug of cDNA with 50 μl of serum free DMEM / well and then 2 μL of lipofectamine in 50 μL of serum free DMEM / well. The solution (“transfection medium”) was mixed gently and incubated at room temperature for 15-30 minutes. The cells were washed with 0.5 mL PBS, then 400 μL of serum free medium was mixed with the transfection medium and added to the cells. Cells were then incubated for 3-4 hours at 37 ° C./5% CO ₂ . The transfection medium was then removed and replaced with 1 mL / well of standard growth medium.

For 293 cells, on day 1, 13 × 10 6 293 cells / 150 mm plates were plated out. On the second day, 2 mL of serum Optimeml (Invitrogen) was added per plate, followed by 60 μL Lipofectamine and 16 μg cDNA. It should be noted that Lipofectamine needs to be added to Optimeml and mixed well before the addition of cDNA. While the complex was formed between Lipofectamine and cDNA, the medium was carefully aspirated and the cells were gently rinsed with 5 mL Optimeml medium and then carefully aspirated. Thereafter, 12 mL of Optimeml was added to each plate, 2 mL of transfection solution was added, and then incubated at 37 ° C. in a 5% CO ₂ incubator for 5 hours. The plate was then carefully aspirated and 25 mL of complete medium was added to each plate and the cells were then incubated until use.

Example B
Inositol phosphate (IP) accumulation assay The 5-HT _2A receptor IP accumulation assay can be used to test the ability of the compounds of the present invention to activate 5-HT _2A receptor clones. That is, as described in Example A, HEK293 cells were transiently transfected with a pCMV expression vector containing the human 5-HT _2A receptor (see US Pat. No. 6,541 for receptor sequence). 209, SEQ ID NO: 24). The IP accumulation assay can be performed as described below.

B. Constitutively active 5-HT _2A receptor IP accumulation assay was used to test the ability of the compounds of the invention to inhibit constitutively active 5-HT _2A receptor clones. That is, as described in Example A, 293 cells were transfected to one activity with a pCMV expression vector containing a constitutively active human 5-HT _2A receptor (see US Pat. No. 6,541,209, SEQ ID NO: 30). The constitutively active human 5-HT _2A receptor is human 5 as described in Part A except that the intracellular loop 3 (IC3) and cytoplasmic ends are replaced by the corresponding human INI5-HT _2C cDNA. -Contained the HT _2A receptor. The IP accumulation assay was performed as described below. Certain compounds of the present invention had activity values ranging from about 10 μM to about 0.8 nM in this assay.

C. IP Accumulation Assay Protocol One day after transfection, the medium is removed and the cells are washed with 5 mL PBS and then carefully aspirated. The cells are then trypsinized with 2 mL of 0.05% trypsin for 20-30 seconds, then 10 mL of warm medium is added, gently titrated to separate the cells, and an additional 13 mL of warm medium is slowly added. The cells are then counted and 55,000 cells are added to a 96-well sterile poly-D-lysine treated plate. Cells are incubated for 6 hours at 37 ° C. in a 5% CO ₂ incubator. The medium is then carefully aspirated, 100 μL of warm inositol-free medium and 0.5 μCi 3 H-inositol are added to each well, and the plate is incubated for 18-20 hours at 37 ° C. in a 5% CO ₂ incubator.

  The next day, the medium is carefully aspirated and then 0.1 mL of assay medium containing inositol-free / serum-free medium, 10 μM pargyline, 10 mM lithium chloride and the indicated concentration of test compound is added. The plate is then incubated at 37 ° C. for 3 hours and then the wells are carefully aspirated. 200 μL of ice-cold 0.1 M formic acid is then added to each well. The plate can be frozen at this point at −80 ° C. until further processing. The frozen plate is thawed for 1 hour, and the contents of the well (about 220 μL) are placed on 400 μL of washed ion exchange resin (AG1-X8) contained in the multi-screen filtration plate and incubated for 10 minutes. And vacuum filtration. The resin is then washed 9 times with 200 μL of water and then tritiated inositol phosphates (IP, IP2 and IP3) are eluted in the collection plate by adding 200 μL of 1M ammonium formate and incubated for an additional 10 minutes. . The eluate is then transferred to a 20 mL scintillation vial, 8 mL SuperMix or Hi-Safe scintillation cocktail is added, and the vial is counted for 0.5-1 min on a Wallac 1414 scintillation counter.

Example C
Binding Assay A radioligand binding assay was used to test the ability of the compounds of the invention to bind to 5-HT _2A receptor clonal membrane preparations. That is, as described in Example A, COS cells were transiently transfected with a pCMV expression vector containing the human 5-HT _2A receptor (for receptor sequence, see US Pat. No. 6,541,541). 209, SEQ ID NO: 24).
A. Production of crude membrane preparations for radioligand binding assays Recombinant human 5-HT _2A receptor transfected COS7 cells were cultured, harvested, and ice-cold phosphate buffer for 48 hours post-transfection. Washed with saline, pH 7.4 (PBS), then centrifuged at 48,000 xg for 20 minutes at 4 ° C. The cell pellet is then resuspended in wash buffer containing 20 mM HEPES, pH 7.4 and 0.1 mM EDTA, homogenized on ice using a Brinkman Polytron, 20 minutes at 4 ° C., 48,000 × Centrifuge again at g. The resulting pellet was then resuspended in 20 mM HEPES, pH 7.4, homogenized on ice and centrifuged (48,000 × g, 4 ° C., 20 minutes). Crude membrane pellets were stored at −80 ° C. until used for radioligand binding assays.
B. [ ¹²⁵ I] DOI Radioligand Binding Assay A radioligand binding assay for the human 5-HT _2A receptor was performed using a 5-HT ₂ agonist [ ¹²⁵ I] DOI as the radioligand. To define non-specific binding, 10 μM DOI was used for all assays. Competition binding experiments used 0.5 nM [ ¹²⁵ I] DOI and compounds were assayed in the range of 0.01 nM to 10 μM. The assay uses 96-well Perkin Elmer GF / C filter plates in assay buffer (50 mM Tris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl ₂ and 10 μM pargyline), using a total volume. Performed at 200 μL. The assay incubation was performed at room temperature for 60 minutes and the reaction mixture was terminated by rapid filtration under vacuum with Whatman GF / C glass fiber filters pre-soaked in 0.5% PEI using a Brandell cell harvester. The filter was then washed several times with ice-cold wash buffer (50 mM Tris-HCl, pH 7.4). The plate was then dried at room temperature and counted with a Wallac MicroBeta scintillation counter. Certain other inventive compounds had activation values in this assay ranging from about 10 μM to about 0.2 nM.

Example D
In Vitro Human Platelet Aggregation Assay The ability of the compounds of the present invention to aggregate human platelets can be tested. The agglutination assay is performed using a Chrono-Log optical aggregometer model 410. Human blood (approximately 100 mL) is collected from a human donor in a glass vacutainer (light blue top) containing 3.8% sodium citrate at room temperature. A platelet rich plasma (PRP) aqueous layer was isolated by centrifugation at 100 g for 15 minutes at room temperature. After removal of the aqueous PRP layer, platelet-poor plasma (PPP) is prepared by high speed centrifugation at 2400 g for 20 minutes. Platelets are counted and the concentration is diluted with PPP and set to 250,000 cells / μL. Aggregation assays are performed according to manufacturer's specifications. That is, a suspension of 450 μL of PRP is stirred (1200 rpm) in a glass cuvette to establish a baseline, then 1 μM ADP, then saline or 1 μM 5HT and the desired compound (at the desired concentration) And record the agglutination response. The concentration of ADP used is about 10-20% of the maximum aggregation. The 5-HT concentration corresponds to the concentration that produces the greatest enhancement. The inhibition rate of aggregation is calculated from the maximum decrease in optical density of the sample containing control and inhibitor.

Example E
Efficacy of Compounds of the Invention in Attenuating DOI-Induced Locomotor Suppression in Rats In this example, compounds of the invention are used to determine whether these compounds may attenuate rat DOI-induced locomotor inhibition. Can be tested in a new environment for inverse agonist activity. DOI is a potent 5-HT _{2A / 2C} receptor agonist and crosses the blood-brain barrier. The standard protocol used is briefly described below.
animal:
Male Sprague-Dawley rats weighing between 200-300 g are used for all tests. Rats are housed in a cage for 3-4 days. These rats have never undergone experimental testing and drug treatment. Prior to testing, the rats are handled for 1 to 3 days to adapt to the experimental procedure. Prior to testing, rats are fasted overnight.
Compound:
(R) -DOI HCl (C ₁₁ H ₁₆ INO ₂ .HCl) is available from Sigma-Aldrich and is dissolved in 0.9% saline. The compounds of the present invention are synthesized by Arena Pharmaceutical and dissolved in 100% PEG400. DOI is injected subcutaneously in a volume of 1 mL / kg, while the compound of the invention is administered orally in a volume of 2 mL / kg.

procedure:
“Motor Monitor” (Hamilton-Kinder, Poway, Calif.) Is used for all activity measurements. This device uses an infrared photo beam to record the rise.

  The locomotor test is performed during the lighting cycle (0630-1830) between 9:00 am and 4:00 pm The animals are allowed to acclimate for 30 minutes before the test begins.

  To determine the effect of a compound of the present invention on inhibiting DOI-induced activity, animals are first injected with their vehicle or a compound of the present invention (50 μmol / kg) in their home cage. Sixty minutes later, saline or DOI (0.3 mg / kg salt) is injected. Ten minutes after DOI administration, the animals are placed in an activity measuring apparatus and the rising activity is measured for 10 minutes.

Statistics and results:
Results (overall rise over 10 minutes) are analyzed by t-test. Let P <0.05 be significant.

Example F
In vitro binding of 5-HT _2A receptor Animals:
Animals (Sprague-Dawley rats) are sacrificed, brains are quickly dissected and frozen in isopentane maintained at -42 ° C. A horizontal section is prepared with a cryostat and kept at -20 ° C.

LSD replacement protocol:
Lysergic acid diethylamide (LSD) is a potent 5-HT _2A receptor and dopamine D2 receptor ligand. An indication of compound selectivity for either or both of these receptors is associated with displacement of radiolabeled bound LSD from pretreated brain sections. For these experiments, radiolabeled ¹²⁵ I-LSD (NEN Life Sciences, Boston, Mass., Catalog number: NEX-199) can be utilized and spiperone (RBI, Natick, Mass. Catalog number s). -128), 5-HT _2A receptor and dopamine D2 receptor antagonists can also be utilized. The buffer consists of 50 nanomolar TRIS-HCl, pH 7.4.

The brain section can be divided into (a) buffer and 1 nanomolar ¹²⁵ I-LSD, (b) buffer and 1 nanomolar ¹²⁵ I-LSD and 1 micromolar spiperone; or buffer and 1 nanomolar ¹²⁵ I-LSD and Incubate for 30 minutes at room temperature in 1 micromolar compound of interest. The sections are then washed in buffer at 4 ° C. for 2 × 10 minutes and then in distilled H ₂ O for 20 seconds. The sections are then air dried.

  After drying, the sections are contacted with X-ray film (Kodak Hyperfilm) and exposed for 4 days.

Example G
Serotonin 5-HT ₂ receptor occupancy experiments in monkeys In this example, the occupancy of 5-HT _2A receptors of compounds of the present invention can be measured. Experiments can be performed on rhesus monkeys using PET and 18F-altanserin.
Radioligand:
The PET radioligand used in the occupancy experiments is ¹⁸ F-altanserin. Radiosynthesis of ¹⁸ F-altanserin is achieved with high specificity activity and is suitable for radiolabeled 5-HT _2A receptor in vivo (Stalley et al., Nucl. Med. Biol., 28: 271-279 ( 2001) and the reference examples cited in the literature). Quality is controlled (chemical and radiochemical purity, specific activity, stability, etc.) and proper binding of radioligand is confirmed in rat brain sections prior to use in PET experiments.

Drug dosage and prescription:
Briefly, the radiopharmaceutical is dissolved in sterile 0.9% saline to a pH of about 6-7. On the same day as the PET experiment, the compound of the invention is dissolved in 60% PEG 400-40% sterile saline.

Serotonin 5-HT _2A occupancy experiments in humans have been reported for M100,907 (Grunder et al., Neurosychopharmacology, 17: 175-185 (1997), and Talvik-Lofti et al., Psychopharmacology, 148: 400-403 (2000). )). High occupancy of 5-HT _2A receptors has been reported for various oral doses (dose tested in the range of 6-20 mg). For example,> 90% occupancy is reported for a 20 mg dose (Talvik-Lofti et al., Supra), which translates to approximately 0.28 mg / kg. Therefore, it can be expected that an intravenous dose of 0.1-0.2 mg / kg M100,907 will likely give high receptor occupancy. A 0.5 mg / kg dose of the compound of the invention can be used for these experiments.

PET experiment:
The monkey is anesthetized using ketamine (10 mg / kg) and kept using 0.7-1.25% isoflurane. Typically, monkeys have two intravenous lines, one for each arm. One intravenous line is used to administer the radioligand and the other line is used to run blood samples for pharmacokinetic data of radioligand and non-radioactive drugs. Generally, a blood sample is taken quickly when the radioligand is administered (and then gradually reduced by the end of the scan). A volume of approximately 1 mL of blood is drawn at every point interval, allowed to settle, and the plasma activity is counted for radioactivity in the blood.

  An initial control experiment is performed to determine a baseline of receptor density. Separate PET scans in monkeys for at least 2 weeks. Unlabeled compounds of the invention are dissolved in 80% PEG400: 40% sterile saline and administered intravenously.

PET data analysis:
PET data is analyzed using the distributed volume region (DVR) method with the cerebellum as the reference region. This method has been applied to the analysis of 18F-altanserin PET data in non-human primates and human experiments (Smith et al., Synapse, 30: 380-392 (1998)).

Example H
Effect of Compounds of the Invention and Zolpidem on Delta Power in Rats In this example, the effects of compounds of the invention on sleep and wakefulness can be compared to the reference drug zolpidem. The drug is administered during the intermediate and light hours (inactive time).

Briefly, the effects of the compounds of the present invention on sleep parameters were tested and zolpidem (5.0 mg / kg, Sigma, St. Louis, MO) and vehicle control (80% Tween 80, Sigma, St. Louis, MO). Compare with A repeated measures design is used in which each rat receives 7 separate doses via oral tubes. The first and seventh doses are vehicle and the second through sixth doses give the test compound and zolpidem in a balanced order. All drugs have been administered, but since the rats are connected to the recording device, 60% CO ₂ /40% O ₂ gas is used during the oral tube treatment to obtain light sedation. After treatment, the rat recovers completely within 60 seconds. Allow at least 3 days between doses. In order to test the effect of the compounds on sleep enhancement, dosing is carried out during the middle time of normal activity of the rat (6 hours after the light is on). Dosing is typically performed between 13:15 and 13:45 using a 24-hour display. All dosing solutions are made fresh on the day of dosing. After each dose, animals are recorded continuously until the next daylight disappears (approximately 30 hours).

Animal records and surgery:
Animals are housed in a temperature-controlled recording room under a 12/12 light-dark cycle (lights on at 7:00 am), with food and water ad libitum. Room temperature (24 + 2 ° C.), humidity (50 + 20% relative humidity) and lighting conditions are continuously monitored by a computer. The drug is administered by oral tube as described above, with a minimum of 3 days between dosing. Animals are examined daily according to NIH guidelines.

  Eight male Wistar rats (300 + 25 g; Charles River, Wilmington, Mass.) Are implanted with long-term recording grafts for continuous electroencephalograph (EEG) and electromyography (EMG) recording. Under isoflurane anesthesia (1-4%), the hair at the top of the skull was shaved and the skin was disinfected with betadine and alcohol. A dorsal midline incision is made, the temporal muscle is retracted, the skull is paralyzed and thoroughly cleaned with 2% hydrogen peroxide solution. Stainless steel (# 000) is implanted into the skull and used as an epidural electrode. EEG electrodes are placed on both sides from pregma to +2.0 mmAP and 2.0 mmML, and -6.0 mmAP and 3.0 mmML. To record the EMG, a multi-strand twisted stainless steel wire electrode is sutured to both sides of the neck muscle. EMG and EEG electrodes are soldered to a head plug connector attached to the skull with dental acrylic. The incision is closed with suture (silk 4-0) and antibiotics are administered topically. A long-lasting analgesic (buprenorphine) is injected intramuscularly once after surgery to relieve pain. After surgery, each animal is placed in a clean cage and observed until it recovers. Animals are given a minimum postoperative recovery period of 1 week prior to the experiment.

  For sleep recording, animals are connected via a cable and balance commutator to a Neurodata model 15 data collector (Grass-Telefactor, West Warwick, RI). Animals are acclimated at least 48 hours prior to the start of the experiment and connected to a device that records continuously throughout the experiment, except that broken cables are replaced. Amplified EEG and EMG signals are digitized and stored on a computer using SleepSign software (Kissei Comtec, Irvine CA).

Data analysis:
EEG and EMG data are recorded visually for wakefulness (W), REMS, NREMS in a 10 second epoch. The recorded data is analyzed and expressed as elapsed time in each state every 30 minutes. The length of sleep sleep for each state and its number are calculated in time increments. A “one period” consists of at least two consecutive sections of a state. The EEG delta power (0.5-3.5 Hz) in NREMS is also analyzed in the time unit range. EEG spectra in NREMS are obtained off-line using a fast Fourier transform algorithm in all sections without artifacts. Delta power is normalized to average delta power with NREMS between 23:00 and 10:00, when delta power is usually the lowest.

  Data are analyzed using repeated measures ANOVA. Analyze the light and dark phase data separately. Both the treatment effect within each rat and the time due to the treatment effect within each rat are analyzed. Since two comparisons are made, a minimum value of P <0.025 is needed for post hoc analysis of the data. If ANOVA yields statistical significance, a t-test is performed to compare all compounds to vehicle and test compounds to zolpidem.

Example I
Efficacy of Compounds of the Invention for Inhibiting JC Virus Infection of Human Glial Cells Basically, as briefly described herein, the compounds of the invention are derived from the in vitro model Elphick et al. (Science (2004) 306: 1380-1383). Can be used to show inhibition of JC virus infection of human glial cells.

Cells and the JC virus human glial cell line SVG (or an appropriate subclone thereof, eg, SVG-A) is used for this experiment. SVG is a human glial cell line established by transforming human fetal glial cells with an origin defective SV40 mutant (Major et al., Proc. Natl. Acad. Sci. USA (1985) 82: 1257. -1261). SVG cells are cultured in Eagle's minimal essential medium (Mediatech, Herndon, Va.) Supplemented with 10% heat-inactivated fetal bovine serum and kept in a humidified 37 ° C. 5% CO 2 incubator.

  The Mad-1 / SVEΔ strain of JC virus (Vacante et al., Virology (1989) 170: 353-361) is used for these experiments. While the host range of JC viruses is typically limited to growth in human fetal glial cells, the host range of Mad-1 / SVEΔ extends to human kidney and monkey cell types. Mad-1 / SVEΔ grows in HEK cells. Viral titer is measured by hemagglutination of human type O red blood cells.

Inhibition assay for JC virus infection SVG cells growing on coverslips are preincubated for 45 minutes at 37 ° C. with or without the compound diluted in medium containing 2% FCS. For purposes of illustration and not limitation, compounds of the present invention may be present at a concentration of about 1 nM to about 100 μM, a concentration of about 10 nM to about 100 μM, a concentration of about 1 nM to about 10 μM, or a concentration of about 10 nM to about 10 μM. use.

  JC virus (Mad-1 / SVEΔ) is then added at a MOI of 1.0 and the cells are incubated at 37 ° C. for 1 hour in the presence of the compound of the invention continuously. The cells are then washed 3 times with PBS, which is fed with a growth medium containing a compound of the invention. 72 hours after infection, V antigen positive cells are recorded by indirect immunofluorescence (see below). Controls include the addition of the compounds of the invention 24 and 48 hours after infection. The percentage of infected cells in the intact culture is taken as 100%.

Indirect immunofluorescence For indirect immunofluorescence analysis of V antigen expression, SVG cells growing on coverslips are fixed in ice-cold acetone. To detect V antigen expression, the cells are incubated for 30 minutes at 37 ° C. with a 1:10 dilution of the hybridoma from PAB597. The PAB597 hybridoma produces a monoclonal antibody against the SV40 capsid protein VP1, which has been shown to cross-react with JC virus VP1. The cells are then washed and incubated with goat anti-mouse Alexa Fluor 488 secondary antibody for an additional 30 minutes. After the last wash, the cells are counterstained with 0.05% Evans blue, placed on a glass slide using 90% glycerol in PBS and visualized on a Nikon E800 epifluorescence scope. Images are taken using a Hamamatsu digital camera and analyzed using software.

Example J
In Vitro Canine Platelet Aggregation Assay Approximately 50 mL of blood is taken from 3 male beagles. The protocol for analyzing the effect of compounds on platelet aggregation was the protocol used for human platelets (except the one described above), except that 5 μM ADP and 2 μM 5-HT were used to activate the amplification of platelet aggregation. (See Example D).

Example K
Ex vivo canine whole blood aggregation One hour after PO administration of test compound, whole blood is collected from male beagle dogs with a 5 mL vacutainer containing exogenous heparin (5 U / mL) and added to the vacutainer. Aggregation experiments are evaluated using a whole blood aggregometer (Chronolog). That is, whole blood (400 μL) is added to physiological saline (600 μL) with constant stirring, and activated with 5 μg of collagen (Chronolog). A serotonin response is obtained by adding 5-HT (Sigma) to a final concentration of 2.5 μM. Results: The anti-platelet aggregation activity of selected compounds is tested after single rapid oral dosing. The dose that results in maximal inhibition of 5-HT amplified platelet aggregation is identified and used for comparison.

Example L
In vivo thrombus, bleeding, aggregation, PK assay in rats Thrombus formation and bleeding time:
This model simultaneously measures thrombus formation, bleeding time, platelet aggregation and drug exposure in a single live dosed rat. Test compounds are administered to male rats (body weight 250-350 g) by PO injection at various concentrations depending on the compound titer range of 1 mpk to 100 mpk. Approximately 30 minutes after PO, the animals are anesthetized using Nembutal. Once the animal is fully anesthetized, the animal's right femoral artery is isolated in two different sections, approximately 4-6 mm in length, with certified surgery. One location is for the probe installation and the other is the location for placing the Ferric Chloride patch. The artery is then stabilized and recovered from the surgery. During stabilization, animals are intubated and placed in a ventilator (Harvard Apparatus) with a volume of 2.5 cubic cm at 75 strokes / min. After intubation and stabilization, an arterial microprobe (Transonic Systems) is placed in the distal isolated femoral artery. Once the probe is in place, the flow is monitored using a Powerlab recorder (AD Instruments) and the rate of pulsatile flow is monitored. A small piece of filter paper soaked in 30% ferric chloride is placed at the arterial location for 10 minutes upstream of the probe. Five minutes after replacement of the ferric chloride patch, the last 3 mm of the rat's tail is removed. The tail is placed in a glass vial filled with saline at 37 ° C. and the time until bleeding stops is recorded. After removing the ferric chloride patch, the flow is recorded until the artery is occluded and the occlusion time is recorded.

Whole blood aggregation and PK:
After measurement of bleeding and occlusion time, 5 mL of blood is obtained by cardiac puncture in heparin (5 U / mL) for ex vivo aggregation analysis. An additional 500 μL of blood is collected in a separate vacutainer for PK analysis (plasma drug concentration). Ex vivo aggregation experiments were evaluated using a whole blood aggregometer (Chronolog), whole blood (400 μL) was added to physiological saline (600 μL) with constant agitation, and activated with 2.55 μg of collagen (Chronolog) Turn into. A serotonin response is obtained by adding 5-HT (Sigma) to a final concentration of 2.5 μM. Results: The effect of thrombus formation, bleeding, and platelet activity in a single model is evaluated for test compounds or reference compounds that are at an acceptable level of binding to the rat 5-HT _2A receptor. This allows the most accurate demonstration of the separation of the effect on bleeding and the effect on platelet-mediated thrombus formation on the test compound.

  Those skilled in the art will recognize that various modifications, additions, substitutions and variations to the illustrative embodiments described herein can be made without departing from the spirit of the invention and therefore within the scope of the invention. Will understand that can be done. All references cited above, including printed publications, provisional applications and ordinary patent applications, are hereby incorporated by reference in their entirety.

Claims (77)

Compounds of formula I:

(Where
A is absent, or O or NR ⁸ ;
D is absent or C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, O, S, NR ⁹ , CO, COO, CONR ⁹ , SO, SO ₂ , SONR ⁹ or NR ⁹ CONR ¹⁰ ;
Y is C _1-10 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^b , NR ^c C (O) NR ^c R ^d , NR ^c C (O) OR ^a , C (= NR ^e ) NR ^c R ^d , NR ^c C (= NR ^e ) NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S (O ) ₂ R ^b , N Substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d ;
Z is H, C _1-10 alkyl, NR′R ″, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, respectively Depending on halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O ) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^{c1 R d1, NR c1 C (} O) OR a1, C (= NR e1) NR c1 R d1, NR c1 C (= NR e1) NR c1 R d1, ^{(O) R b1, S (} O) NR c1 R d1, S (O) 2 R b1, NR c1 S (O) 2 R b1 , and _S ^{(O) 2 NR} c1 1 independently selected from ^{R d1} Substituted with 2, 3, 4 or 5 substituents;
R ¹ is H or C _1-6 alkyl;
R ² and R ³ are independently H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C (O) NR ^c2 R ^d2 , NR ^c2 C (O) OR ^a2 , C (= NR ^e2 ) NR ^c2 R ^d2 , NR ^c2 C (= NR ^e2 ) NR ^c2 R ^d2 , S (O ) R ^b2 , S (O) NR ^c2 R ^d2 , S (O) ₂ R ^b2 , NR ^c2 S (O) ₂ R ^b2 and S (O) ₂ NR ^c2 R ^d2 ;
R ⁴ , R ⁵ and R ⁶ are independently selected from H, halo and C _1-4 alkyl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from H and C _1-4 alkyl;
Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN , NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^{c R d, NR c C (} O) R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR ^{e) NR c R d, S} (O) R b, S (O) NR c R d, S (O) 2 R b, NR c S (O) 2 R b , and _{^{S (O) 2 NR c R}} d Substituted with 1, 2, 3, 4 or 5 substituents independently selected from
R ′ and R ″ are independently H, C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^{b1, OC (O) NR c1} R d1, NR c1 R d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, C (= NR e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ Substituted with 1, 2 or 3 substituents independently selected from R ^b1 and S (O) ₂ NR ^c1 R ^d1 ;
R ^a , R ^a1 and R ^a2 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Selected from alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl , Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} halo Substituted by alkyl or _{C 1-6} haloalkoxy;
R ^b , R ^b1 and R ^b2 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Selected from alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl , Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are optionally 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} halo Substituted by alkyl or _{C 1-6} haloalkoxy;
R ^c and R ^d are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloalkyl Or substituted with C _1-6 haloalkoxy;
Alternatively, R ^c and R ^d together with the N atom to which they are attached form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each of which is optionally Substituted with 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;
R ^c1 and R ^d1 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloal Substituted with a kill or C _1-6 haloalkoxy;
Alternatively, R ^c1 and R ^d1 , together with the N atom to which they are attached, form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each optionally Substituted with 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy;
R ^c2 and R ^d2 are independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl Selected from alkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl , Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl may optionally be 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloal Substituted with a kill or C _1-6 haloalkoxy;
Alternatively, R ^c2 and R ^d2 , together with the N atom to which they are attached, form a 4-membered, 5-membered, 6-membered or 7-membered heterocycloalkyl group or heteroaryl group, each optionally , 1, 2 or 3 OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or C _1-6 haloalkoxy; and R ^e , R ^e1 And R ^e2 are independently selected from H, CN and NO ₂ )
And compounds selected from pharmaceutically acceptable salts, solvates and hydrates thereof.   2. A compound according to claim 1 wherein A is absent.   The compound according to claim 1, wherein A is O. A is NR ^8, A compound according to claim 1.   2. A compound according to claim 1 wherein A is NH. Y is C _1-10 alkyl, aryl or heteroaryl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , ^{NR c R d, NR c C} (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR ^e ) NR ^c R ^d , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R independent of ^d is substituted with 1, 2, 3, 4 or 5 substituents selected, claim 1 A compound according to any one of. Y is C _1-10 alkyl or aryl, each optionally Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^{d, NR c C (O)} R b, NR c C (O) NR c R d, NR c C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) independently of ^{NR c R d, S (O} ) R b, S (O) NR c R d, S (O) 2 R b, NR c S (O) 2 R b , and _{^{S (O) 2 NR c R}} d 6. Substituted with 1, 2, 3, 4 or 5 substituents selected as described above. The compounds described. Y is Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C ^{(O) NR c R d,} C (O) OR a, OC (O) R b, OC (O) NR c R d, NR c R d, NR c C (O) R b, NR c C (O ^{) NR c R d, NR c} C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, S (O) R b, S (O) _{^{NR c R d, S (O}} ) 2 R b, NR c S (O) 2 R b , and _{^{S (O) 2 NR c R}} d from independently 1, 2, 3, 4 or 5 which is selected _6. A compound according to any one of claims 1 to 5, which is C1-10 alkyl optionally substituted with a substituent. _6. A compound according to any one of claims 1 to 5, wherein Y is _C1-10 alkyl.   The compound according to any one of claims 1 to 5, wherein Y is isobutyl. Y is Cy, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C ^{(O) NR c R d,} C (O) OR a, OC (O) R b, OC (O) NR c R d, NR c R d, NR c C (O) R b, NR c C (O ^{) NR c R d, NR c} C (O) OR a, C (= NR e) NR c R d, NR c C (= NR e) NR c R d, S (O) R b, S (O) _{^{NR c R d, S (O}} ) 2 R b, NR c S (O) 2 R b , and _{^{S (O) 2 NR c R}} d from independently 1, 2, 3, 4 or 5 which is selected 6. A compound according to any one of claims 1 to 5, which is phenyl optionally substituted with a substituent. 2. Y is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl and OR ^a. The compound as described in any one of -5. 13. A compound according to any one of claims 1 to 12, wherein D is absent or is _C1-4 alkylene or COO.   13. A compound according to any one of claims 1 to 12, wherein D is absent. The compound according to any one of claims 1 to 12, wherein D is _C1-4 alkylene.   13. A compound according to any one of claims 1 to 12, wherein D is COO. Z is H, C _1-10 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC ( ^{O) NR c1 R d1, NR} c1 R d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, C (= NR e1) NR c1 R ^d1 , NR ^c1 C (= NR ^e1 ) NR ^c1 R ^d1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 is substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d1, a compound according to any one of claims 1 to 16. Z is H, C _1-10 alkyl or heterocycloalkyl, each optionally halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN , NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , C (= NR ^e1 ) NR ^c1 R ^d1 , NR ^c1 C (= NR ^{e1) NR c1 R d1, S} (O) R b1, S (O) NR c1 R d1, S (O) 2 R b1, NR c1 S (O) 2 R b1 , and _{^{S (O) 2 NR c1 R}} d1 Selected independently from , 2, 3, 4 or 5 are substituted with a substituent A compound according to any one of claims 1 to 16. 17. A compound according to any one of claims 1 to 16, wherein Z is H, _C1-10 alkyl or heterocycloalkyl. 20. The method according to claim 1, wherein —DZ is H, C (O) O— (C _1-10 alkyl), COOH or heterocycloalkyl- (C _1-10 ) alkyl. Compound. R ¹ is H or methyl, A compound according to any one of claims 1 to 20. R ¹ is methyl, A compound according to any one of claims 1 to 20. R ² and R ³ are independently selected from H and halo, A compound according to any one of claims 1 to 22. R ² is H, A compound according to any one of claims 1 to 23. R ³ is H or halo, A compound according to any one of claims 1 to 23. R ³ is H, A compound according to any one of claims 1 to 23. R ³ is halo, A compound according to any one of claims 1 to 23. R ³ is Br, compound according to any one of claims 1 to 23. R ^{4, R 5} and ^{R 6} are each is H, A compound according to any one of claims 1 to 28. R ⁷ is H, A compound according to any of claims 1 to 29. Formula II:

The compound of claim 1 having Formula IIIa, IIIb or IIIc:

The compound of claim 1 having The following compounds:
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-trifluoromethyl-phenyl) -urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5-isobutoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (3-methoxy-phenyl) -urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-methoxy-phenyl) -ureido] -benzofuran-2-carboxylic acid;
N- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3-trifluoromethyl-benzamide;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (2,4-difluoro-phenyl) -urea [7- (4-bromo -2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -carbamic acid 4-methoxy-phenyl ester;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3-p-tolyl-urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-methoxy-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-trifluoromethyl-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3- (4-chloro-phenyl) -urea;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-chloro-phenyl) -urea;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (3-chloro-phenyl) -urea;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-isopropyl-phenyl) -urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (2,4-difluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-fluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester;
N- [7- (2-Methyl-2H-pyrazol-3-yl) -2-pyrrolidin-1-ylmethyl-benzofuran-5-yl] -3-trifluoromethyl-benzamide;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-fluoro-phenyl) -urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (2,4-difluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5-isobutoxycarbonylamino-benzofuran-2-carboxylic acid;
1- [7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -benzofuran-5-yl] -3- (4-methoxy-phenyl) -urea;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-chloro-phenyl) -ureido] -benzofuran-2-carboxylic acid ethyl ester;
7- (4-Bromo-2-methyl-2H-pyrazol-3-yl) -5- [3- (4-fluoro-phenyl) -ureido] -benzofuran-2-carboxylic acid; and N- (2- ( Hydroxymethyl) -7- (1-methyl-1H-pyrazol-5-yl) benzofuran-5-yl) -3- (trifluoromethyl) benzamide;
And a pharmaceutically acceptable salt, solvate or hydrate thereof.   34. A composition comprising a compound according to any one of claims 1-33 and at least one pharmaceutically acceptable carrier. A method of treating a 5-HT _2A-related disorder in a patient, the method comprising administering to a patient in need of such treatment, by administering a compound according to any one of claims 1 to 33 in a therapeutically effective amount of . The 5-HT _2A related disorder, coronary artery disease, myocardial infarction, transient ischemic attack, angina, selected from stroke, and atrial fibrillation, the method according to claim 35.   34. A method of treating a condition associated with platelet aggregation in a patient comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-33.   34. A method of reducing the risk of thrombus formation in a patient's angioplasty or coronary artery bypass graft surgery, wherein a therapeutically effective amount of the compound of any one of claims 1-33 is applied to a patient in need of the treatment. A method comprising administering.   A method for reducing the risk of thrombus formation in a patient suffering from atrial fibrillation, comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1 to 33. Including methods.   34. A method of treating a sleep disorder in a patient comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-33.   41. The method of claim 40, wherein the sleep disorder is a sleep disorder.   41. The method of claim 40, wherein the sleep disorder is insomnia.   41. The method of claim 40, wherein the sleep disorder is sleep-related comorbidity.   34. A method of treating a diabetes-related disorder in a patient, comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-33.   A method of treating progressive multifocal leukoencephalopathy in a patient comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 33 to a patient in need thereof. Including methods.   34. A method of treating hypertension in a patient comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-33.   34. A method of treating pain in a patient comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1-33. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of 5-HT _2A related disorder. The 5-HT _2A related disorder, coronary artery disease, myocardial infarction, transient ischemic attack, angina, selected from stroke, and atrial fibrillation, Use according to claim 48.   34. Use of a compound according to any one of claims 1-33 in the manufacture of a medicament for use in the treatment of conditions associated with platelet aggregation.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in reducing the risk of thrombus formation in a patient undergoing angioplasty or coronary artery bypass graft surgery.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in reducing the risk of thrombus formation in a patient.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in reducing the risk of thrombus formation in a patient suffering from atrial fibrillation.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of sleep disorders.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of sleep disorders.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of insomnia.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of parasomnia.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of diabetes related disorders.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of progressive multifocal leukoencephalopathy.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of hypertension.   34. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for use in the treatment of pain.   34. A compound according to any one of claims 1 to 33 for use in a method of treating a human or animal by therapy. A compound according to any one of claims 1 to 33 for use in a method of treating a 5-HT _2A associated disorder in a human or animal by therapy. The method of claim 63 wherein the 5-HT _2A related disorder, coronary artery disease, myocardial infarction, transient ischemic attack, angina, selected from stroke, and atrial fibrillation.   34. A compound according to any one of claims 1 to 33 for use in a method of treating a condition associated with platelet aggregation.   34. A compound according to any one of claims 1 to 33 for use in a method of reducing the risk of thrombus formation in a patient undergoing angioplasty or coronary artery bypass surgery.   34. A compound according to any one of claims 1 to 33 for use in a method of reducing the risk of thrombus formation in a patient.   34. A compound according to any one of claims 1-33 for use in a method of reducing the risk of thrombus formation in a patient suffering from atrial fibrillation.   34. A compound according to any one of claims 1 to 33 for use in a method of treating human or animal sleep disorders by therapy.   34. A compound according to any one of claims 1 to 33 for use in a method of treating dyssomnia.   34. A compound according to any one of claims 1 to 33 for use in a method of treating insomnia.   34. A compound according to any one of claims 1 to 33 for use in a method of treating parasomnia.   34. A compound according to any one of claims 1 to 33 for use in a method of treating a diabetes-related disorder in a human or animal by therapy.   34. A compound according to any one of claims 1 to 33 for use in a method of treating progressive multifocal leukoencephalopathy in humans or animals by therapy.   34. A compound according to any one of claims 1 to 33 for use in a method of treating hypertension.   34. A compound according to any one of claims 1 to 33 for use in a method of treating pain.   34. A method for producing a composition comprising mixing a compound according to any one of claims 1-33 and at least one pharmaceutically acceptable carrier.