JP2010535816A - Heteroaryl amide analogues - Google Patents

Abstract

ある実施形態では、ヘテロアリールアミド類似体は、ドーパミン受容体のアゴニストおよび／又はリガンドであり、とりわけＰ２Ｘ_７受容体調節に応答する症状、例えば、疼痛、炎症、神経障害若しくは神経変性障害、心血管障害、眼障害、又は免疫系障害を治療するために有用な可能性がある。Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogs of formula Ia and / or Ib.

In some embodiments, the heteroaryl amide analogs are agonists and / or a ligand of dopamine receptors, symptoms responsive to, inter alia P2X ₇ receptor regulation, for example, pain, inflammation, neurological disorders or neurodegenerative disorders, cardiovascular It may be useful for treating disorders, eye disorders, or immune system disorders.

Description

The present invention relates generally to heteroaryl amide analogs having useful pharmacological properties. The present invention further for the treatment of conditions associated with activation of P2X ₇ receptors, for identifying other agents that bind to P2X ₇ receptors, and detection and localization of P2X ₇ receptor ( The use of such compounds as probes for localization).

  Pain, or nociception, is mediated by the peripheral endings of a special group of sensory neurons called “nociceptors”. A variety of physical and chemical stimuli triggers the activation of such neurons in mammals, and stimuli that can be harmful are recognized. However, inappropriate or excessive activation of nociceptors can result in debilitating acute or chronic pain.

  Neuropathic pain, typically resulting from damage to the nervous system, is painful signal transmission in the absence of stimulation, pain due to normally innocuous stimuli (allodynia), and augmentation of pain due to stimuli that are usually painful (Including hyperalgesia). In most cases, neuropathic pain is thought to occur due to sensitization of the peripheral and central nervous system after initial damage of the peripheral nervous system (eg, due to direct damage or systemic disease). Neuropathic pain is typically burning, itching, unrelenting in strength, and sometimes more debilitating than the initial injury or disease process that induced it.

  Current treatments for neuropathic pain are generally not optimal. Opiates such as morphine are potent analgesics, but bodily epilepsy and withdrawal, as well as reduced bowel motility with respiratory depression, mood changes, and constipation, nausea, vomiting, and endocrine system Due to side effects such as changes in the autonomic nervous system, their usefulness is limited. In addition, neuropathic pain often does not respond or only partially responds to conventional opioid analgesic therapy or treatment with other drugs such as gabapentin. Treatment with ketamine, an N-methyl-D-aspartate antagonist, or clonidine, an α (2) -adrenergic agonist, can reduce acute or chronic pain, but can reduce opioid intake. These drugs are often poorly tolerated due to side effects.

  Another common symptom where current therapy is inadequate or problematic is inflammation. Transient inflammation is a beneficial mechanism that protects mammals from invading pathogens. However, uncontrolled inflammation causes tissue damage and pain and is the root cause of many diseases, including asthma, as well as other allergic diseases, infections, autoimmune diseases, degenerative diseases, and idiopathic diseases. Become. Current treatments often show low, slow or only temporary efficacy, undesirable side effects, and / or lack of selectivity. For immunosuppression or for the treatment of allergic disorders, autoimmune disorders, inflammatory disorders including fibrogenic disorders, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease or There is a continuing need for new drugs that overcome one or more of the shortcomings of drugs currently used for prevention.

P2X ₇ receptors are activated by ATP, microglia of the central nervous system and is the ligand-gated ion channels present in a variety of cell types, including cells involved in inflammation and immune system function, such as immune cells . In particular, P2X ₇ is involved in activation of lymphocytes and monocytes / macrophages, thereby releasing proinflammatory cytokines from these cells (e.g., TNF [alpha] and IL-l [beta]) is increased. Recent studies have shown that inflammation (eg, rheumatoid arthritis and other autoimmune diseases, osteoarthritis, uveitis, asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease) or interstitial fibrosis conditions in that inhibition of activation of P2X _7, it has been suggested that therapeutic effects appear. From these and other studies, P2X ₇ receptor antagonist, acute pain, chronic pain, and pain, including neuropathic pain, as well as osteoarthritis, rheumatoid arthritis, artherosclerosis, inflammatory bowel disease, Alzheimer's disease, It is suggested that it can be used for the treatment and prevention of various other conditions, including traumatic brain injury, asthma, chronic obstructive pulmonary disease, and visceral fibrosis (eg, interstitial fibrosis).

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Greene and Wuts, “Protective Groups in Organic Synthesis” (2nd Edition, John Wiley & Sons, 1991) Philip J. et al. Kocienski, “Protecting Groups”, 2nd ed. , John Wiley & Sons, Inc. , New York (2005) Richard C. Larock, “Comprehensive Organic Transformation,” (VCH Publisher, Inc. 1989). Martindale--The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott Williams & Wilkins, Philadelphia, PA (2005) sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York Wang et al. , J .; Org. Chem. 2006, 71, 4021-4023

P2X ₇ receptor antagonist is a small molecule, preferably in such therapy. The present invention fulfills this need and provides other related advantages.

｛式中：
Ｕは、ＣＲ_１Ａ又はＮであり；
Ｗは、−Ｃ（＝Ｏ）ＮＲ_４−、−ＮＲ_４Ｃ（＝Ｏ）−又は−ＮＲ_４−ＮＲ_４−Ｃ（＝Ｏ）−であり；
各Ｒ_４は、独立して、水素、Ｃ_１〜Ｃ_６アルキル、（Ｃ_３〜Ｃ_８シクロアルキル）Ｃ_０〜Ｃ_２アルキルであるか、又はＸの置換基と一緒に４員〜７員のヘテロシクロアルキルを形成し；
Ｘは、存在しないか、又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅから選択される１〜４個の置換基で任意に置換されたＣ_１〜Ｃ_６アルキレンであり；
Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅはそれぞれ独立して、ヒドロキシ、−ＣＯＯＨ、Ｃ_１〜Ｃ_８アルキル、（Ｃ_３〜Ｃ_８シクロアルキル）Ｃ_０〜Ｃ_４アルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_２〜Ｃ_８アルキルエーテル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノＣ_０〜Ｃ_４アルキル、（４員〜７員のヘテロシクロアルキル）Ｃ_０〜Ｃ_４アルキル、およびフェニルＣ_０〜Ｃ_２アルキルであるか；又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅのいずれか２つは、それらと結合している１個若しくは複数の炭素原子と一緒に、３員〜７員のシクロアルキル若しくは４員〜７員のヘテロシクロアルキルを形成するか；又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅのいずれか１つは、Ｒ_４およびそれらと結合している１個若しくは複数の原子と一緒に、４員〜７員のヘテロシクロアルキルを形成し；
Ｙは、Ｃ_１〜Ｃ_８アルキル、Ｃ_３〜Ｃ_１６シクロアルキル、４員〜１６員のヘテロシクロアルキル、６員〜１６員のアリール又は５員〜１６員のヘテロアリール［これらはそれぞれ、ヒドロキシ、ハロゲン、シアノ、アミノ、ニトロ、オキソ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、および（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノから独立して選択される１〜６個の置換基で任意に置換されている］であり；
Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４は、独立してＣＲ_１又はＮであり；
Ｒ_１Ａは、水素、ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、又は（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノであり；
各Ｒ_１は、独立して水素、ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、又は（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノであり；
Ｒ_Ａは、式−Ｌ−Ａ−Ｍの基であり、式中：
Ｌは、存在しないか、又は、（ｉ）炭素−炭素単結合を炭素−炭素二重若しくは三重結合で置換すること、若しくは（ｉｉ）オキソ、−ＣＯＯＨ、−ＳＯ_３Ｈ、−ＳＯ_２ＮＨ_２、−ＰＯ_３Ｈ_２、テトラゾール、若しくはオキサジアゾロンで置換することにより任意に修飾されているＣ_１〜Ｃ_６アルキレンであり；
Ａは、存在しないか、又は、ＣＯ、Ｏ、ＮＲ_６、Ｓ、ＳＯ、ＳＯ_２、ＣＯＮＲ_６、ＮＲ_６ＣＯ、（Ｃ_４〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_２アルキル、４員〜７員のヘテロシクロアルキル、若しくは、５員若しくは６員のヘテロアリール［式中、Ｒ_６は水素若しくはＣ_１〜Ｃ_６アルキルである］であり；そして
Ｍは：
（ｉ）ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、カルボキシアルキル、若しくはＣＯＯＨ；又は
（ｉｉ）Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６アルコキシ、（４員〜１０員の炭素環基（ｃａｒｂｏｃｙｃｌｅ））Ｃ_０〜Ｃ_４アルキル、（４員〜１０員の複素環基（ｈｅｔｅｒｏｃｙｃｌｅ））Ｃ_０〜Ｃ_４アルキル、Ｃ_１〜Ｃ_６アルカノイルオキシ、Ｃ_１〜Ｃ_６アルカノイルアミノ、Ｃ_１〜Ｃ_６アルキルスルホニル、Ｃ_１〜Ｃ_６アルキルスルホニルアミノ、Ｃ_１〜Ｃ_６アルキルスルホニルオキシ、モノ−若しくはジ−Ｃ_１〜Ｃ_６アルキルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、若しくは、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル［これらはそれぞれ、オキソ、アミノ、ハロゲン、ヒドロキシ、シアノ、アミノカルボニル、アミノスルホニル、−ＣＯＯＨ、アルコキシカルボニル、アルカノイルオキシ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルキルスルホニル、Ｃ_１〜Ｃ_６アルキルスルホニルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキルアミノ）カルボニル、および、４員〜７員の複素環基から独立して選択される１〜４個の置換基で任意に置換されている］；
である｝
のヘテロアリールアミド類似体を提供する。 The present invention provides compounds of formula Ia or Ib:

{In the formula:
U is CR _1A or N;
W is —C (═O) NR ₄ —, —NR ₄ C (═O) — or —NR ₄ —NR ₄ —C (═O) —;
Each R ₄ is independently hydrogen, C ₁ -C ₆ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₂ alkyl, or 4 to 7 members with X substituents. Forming a heterocycloalkyl of
X is absent or C ₁ -C ₆ alkylene optionally substituted with 1 to 4 substituents selected from R _B , R _C , R _D , and R _E ;
R _B , R _C , R _D , and R _E are each independently hydroxy, —COOH, C ₁ -C ₈ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C _{6 aminoalkyl,} C 2 -C ₈ alkyl ether, mono- - or di - _(C 1 -C ₆ alkyl) amino _C 0 -C ₄ alkyl, (4- to 7-membered _{heterocycloalkyl)} C 0 -C ₄ alkyl And phenyl C ₀ -C ₂ alkyl; or any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms attached thereto Forms a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or any one of R _B , R _C , R _D , and R _E is R ₄ and with them 1 united young Or together with a plurality of atoms form a 4- to 7-membered heterocycloalkyl;
Y is C ₁ -C ₈ alkyl, C ₃ -C ₁₆ cycloalkyl, 4 to 16 membered heterocycloalkyl, 6 to 16 membered aryl, or 5 to 16 membered heteroaryl [these are hydroxy , halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, _COOH, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl, C} 1 ~ C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C ₆ alkylsulfonyl , _(C 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _(C 1 -C ₆ alkyl) amino, ₁ -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, and _(C 1 -C ₆ alkyl) sulfonylamino Optionally substituted with 1 to 6 substituents independently selected from
Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently CR ₁ or N;
R _1A is hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkyl ether, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C It is ₆ alkyl) sulfonylamino;
Each R ₁ is independently hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or Di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or (C It is ₁ -C ₆ alkyl) sulfonylamino;
R _A is a group of formula -LAM, where:
L is absent, or (i) a carbon-carbon single bond is replaced with a carbon-carbon double or triple bond, or (ii) oxo, —COOH, —SO ₃ H, —SO ₂ NH ₂ , _-PO 3 _{H 2,} tetrazole, or be a _C 1 -C ₆ alkylene which is optionally modified by replacing oxadiazolone;
A is absent _{or, CO, O, NR 6,} S, SO, SO 2, CONR 6, NR 6 CO, (C 4 ~C 7 _cycloalkyl) C 0 -C ₂ alkyl, 4- to 7 A membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl; and M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, carboxyalkyl, or COOH; or _(ii) C 1 ~C _{6 haloalkyl,} C 1 -C ₆ alkoxy, (4-membered to 10-membered carbocyclic ring Group) C ₀ -C ₄ alkyl, (4- to 10-membered heterocycle) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanoylamino, C ₁ -C _{6 alkylsulfonyl,} C 1 -C _{6 alkylsulfonylamino,} C 1 -C ₆ alkylsulfonyloxy, mono - or di _-C 1 -C ₆ alkylamino, mono- - or di - _(C 1 -C ₆ alkyl ) Aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocal Each Boniru [these, oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, -COOH, alkoxycarbonyl, _alkanoyloxy, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkyl ether, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, mono- - or di - _(C 1 -C ₆ alkylamino) carbonyl, and, 1 to 4 substituents independently selected from 4- to 7-membered heterocyclic groups It is replaced with ';
Is}
The heteroaryl amide analogs are provided.

In certain embodiments, the heteroaryl amide analog of Formula Ia and / or Ib is no greater than 20 micromolar, no greater than 10 micromolar, no greater than 5 micromolar in an in vitro assay for P2X ₇ receptor antagonist activity. A P2X ₇ receptor antagonist having an IC ₅₀ value of micromolar or less, 500 nanomolar or less, or 100 nanomolar or less. In certain embodiments, such P2X ₇ receptor antagonist is a concentration equal to an IC ₅₀ in an in vitro assay of P2X ₇ receptor activity (eg, in the assay described in Example 7 herein), 10 times the concentration of IC _50, or 100 times the concentration of _{IC 50,} and / or a concentration of 2,500nM exhibit no detectable agonist activity.

  In certain embodiments, the heteroaryl amide analogs described herein are labeled with a detectable marker (eg, radiolabeled or fluorescently labeled).

  The invention further provides, in another aspect, a pharmaceutical composition comprising at least one heteroaryl amide analog described herein in combination with a physiologically acceptable carrier or excipient. To do.

In other embodiments, cells expressing P2X ₇ receptor (e.g., microglia, astrocytes, or peripheral macrophage or monocyte), the contacting at least one P2X ₇ receptor modulator as described herein including, regulate the activation or activity of a cell P2X ₇ receptor (e.g., reduce) a method. Such contact may be carried out in well or in vitro carried out by in vivo, in general, P2X ₇ receptor activity in in vitro (e.g., determined using the assay described in Example 7) It is performed using the P2X ₇ receptor modulator sufficient concentrations to cause detectably changed.

The present invention further treats a condition responsive to the patient's P2X ₇ receptor modulation comprising administering to the patient a therapeutically effective amount of at least one P2X ₇ receptor antagonist described herein. Provide a way to do it.

In another aspect, a pain (or, there is a risk) to the patient a therapeutically effective amount of at least one P2X ₇ receptor antagonists described herein, comprising administering the patient the pain Provide a method of treating.

In another aspect, a inflammation (or risk is) patient, a therapeutically effective amount of at least one P2X ₇ receptor antagonists described herein, comprising administering, inflammation of the patient Provide a method of treatment.

Patients with osteoarthritis, rheumatoid arthritis, arthrosclerosis, inflammatory bowel disease, Alzheimer's disease, traumatic brain injury, asthma, chronic obstructive pulmonary disease, ocular symptoms (eg glaucoma), cirrhosis, lupus, scleroderma Or a visceral fibrosis (eg, interstitial fibrosis), wherein the patient has (or is at risk of) one or more of the aforementioned symptoms, as described herein a therapeutically effective amount of at least one P2X ₇ receptor antagonist further provides a method comprising administering.

In yet another aspect, the invention inhibits at least one P2X ₇ an effective amount of a receptor antagonist in the treatment, comprising administering, death of a patient's retinal ganglion cells as described herein to a patient Provide a way to do it.

(A) A P2X ₇ receptor is contacted with and bound to a labeled compound that is a heteroarylamide analog described herein under conditions that allow the compound to bind to the P2X ₇ receptor. (B) detecting a signal corresponding to the amount of bound labeled compound in the absence of the test agent; (c) contacting the test agent with the bound labeled compound; ) Detecting a signal corresponding to the amount of labeled compound bound in the presence of the test agent; and (e) the signal detected in step (d) compared to the signal detected in step (b) comprising the step of detecting a reduction further provides a method for identifying an agent that binds to the P2X ₇ receptor.

In another aspect, the invention provides (a) contacting a sample with a compound described herein under conditions that allow the compound to modulate P2X ₇ receptor activity, and (b) P2X _7. comprising the step of detecting a signal indicative of the level of compounds that modulate receptor activity, provides a method for determining the presence or absence of P2X ₇ receptors in the sample.

The present invention also provides (a) a pharmaceutical composition as described herein in a container; and (b) (i) pain, osteoarthritis, rheumatoid arthritis, arthrosclerosis, inflammatory bowel disease, Alzheimer Disease, traumatic brain injury, asthma, chronic obstructive pulmonary disease, eye symptoms (eg glaucoma), cirrhosis, lupus, scleroderma, and / or visceral fibrosis (eg interstitial fibrosis) to treat one or more symptoms responsive to P2X ₇ receptor modulation, or (ii) to provide a retinal neuroprotection (e.g., to inhibit death of retinal ganglion cells) in order to use the composition Packaged pharmaceutical formulations are also provided, including instructions for use.

  In yet another aspect, the present invention provides a method for preparing the compounds disclosed herein, including intermediates.

  These and other aspects of the invention will become apparent upon reference to the following detailed description.

Terms As used herein, compounds are generally described using standard nomenclature. It should be understood that for compounds having asymmetric centers, all optical isomers and mixtures thereof are encompassed (unless otherwise stated). Furthermore, compounds having a carbon-carbon double bond can occur in the Z and E forms, and all isomeric forms of the compounds are included in the present invention unless otherwise stated. Where a compound exists in various tautomeric forms, the compounds described are not limited to any one particular tautomer, but are intended to encompass all tautomeric forms. Certain compounds are described herein using a general formula that includes variables (eg, R1, A, X). Unless otherwise specified, each symbol in such a formula is defined independently of any other symbol, and any symbol that appears more than once in a formula is defined independently of each other. The

  The phrase “heteroarylamide analog” as used herein refers to all compounds of Formula Ia or Formula Ib and other formulas described herein (any enantiomer, racemate). And various crystal forms and polymorphs), and pharmaceutically acceptable salts, solvates (eg, hydrates including salt hydrates) of such compounds ), Amides, and esters.

  “Pharmaceutically acceptable salts” of the compounds described herein are not excessively toxic or carcinogenic, preferably free of irritation, allergic reactions, or other problems or complications, and Acid or basic salt suitable for use in contact with tissue. Such salts include mineral and organic acid salts of basic groups such as amines, and alkali or organic salts of acidic groups such as carboxylic acids. Specific pharmaceutically acceptable anions used for salt formation include acetic acid, 2-acetoxybenzoic acid, ascorbic acid, benzoic acid, bicarbonate, bromide, calcium edetate, carbonic acid, chloride , Citric acid, dihydrochloric acid, diphosphoric acid, ditartaric acid, edetic acid, estrate (ethyl succinic acid), formic acid, fumaric acid, glutceptic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexyl resorcinic acid , Hydrabamine, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, iodide, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methyl bromide, methyl nitric acid, Methyl sulfuric acid, mucinic acid, napsic acid, nitric acid, pamoic acid, pantothenic acid, phenyl vinegar , Phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, sulfonic acids [besylic acid (benzenesulfonic acid), camsylic acid (camphorsulfonic acid), Edicylic acid (ethane-1,2-disulfonic acid), ethylic acid (ethanesulfonic acid), 2-hydroxyethylsulfonic acid, mesylic acid (methanesulfonic acid), triflic acid (trifluoromethanesulfonic acid), and tosylic acid (p -Toluenesulfonic acid)], tannic acid, tartaric acid, teocric acid, and triethiodide anions. Similarly, pharmaceutically acceptable cations used for salt formation include ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and aluminum, calcium, lithium, magnesium, potassium, sodium. , And metals such as zinc, but are not limited to these. Those skilled in the art will recognize other pharmaceutically acceptable salts of the compounds described herein. In general, a pharmaceutically acceptable acidic or basic salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts react the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile is preferred.

  Each compound described herein can be formulated as a solvate (eg, hydrate) or non-covalent complex, but this is not necessary. In addition, various crystal forms and polymorphs are within the scope of the present invention. Prodrugs of compounds of the described formula are also provided herein. A “prodrug” may not fully meet the structural requirements of the compounds described herein, but is converted in vivo after administration to a patient and described herein A compound that produces a compound of formula For example, a prodrug may be an acylated derivative of such a compound. As a prodrug, when administered to a mammalian subject, a hydroxy group, an amine group, or a sulfhydryl group is bonded to any group that cleaves to form a free hydroxy group, a free amino group, or a free sulfhydryl group, respectively. The compound which is doing is mentioned. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate and peptide derivatives of alcohol and amine functional groups in the compounds described herein. Prodrugs are generally prepared by modifying functional groups present in the compound such that the modifying moiety is cleaved in vivo to yield the parent compound.

  As used herein, the term “alkyl” refers to a straight or branched chain saturated aliphatic hydrocarbon. Examples of the alkyl group include groups having 1 to 8 carbon atoms (C1 to C8 alkyl), 1 to 6 carbon atoms (C1 to C6 alkyl), and 1 to 4 carbon atoms (C1 to C4 alkyl), such as methyl, ethyl, Examples include propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. "C0-Cn alkyl" refers to a single bond (C0) or an alkyl group having 1 to n carbon atoms; for example, "C0-C4 alkyl" refers to a single bond or a C1-C4 alkyl group. In some cases, substituents on alkyl groups are specifically indicated. For example, “C 1 -C 6 hydroxyalkyl” is a C 1 -C 6 alkyl group substituted with at least one —OH; “C 1 -C 6 aminoalkyl” is C 1 -C 6 alkyl substituted with at least one —NH 2. A C1-C6 cyanoalkyl is a C1-C6 alkyl group substituted with at least one -CN.

  “Alkenyl” refers to a straight or branched alkene group containing at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-C8 alkenyl groups, C2-C6 alkenyl groups, and C2-C4 alkenyl groups each having 2 to 8, 2 to 6, or 2 to 4 carbon atoms, such as ethenyl, allyl, or isopropenyl Etc. “C 2 -C 6 cyanoalkenyl” is a C 2 -C 6 alkenyl group substituted with at least one —CN.

  “Alkynyl” refers to a straight or branched alkyne group having one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Examples of the alkynyl group include C2-C8 alkynyl groups, C2-C6 alkynyl groups, and C2-C4 alkynyl groups each having 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

  “Alkylene” refers to a divalent alkyl group as defined above. C1-C2 alkylene is methylene or ethylene; C0-C4 alkylene is a single bond or an alkylene group having 1, 2, 3 or 4 carbon atoms; C0-C2 alkylene is a single bond, methylene or ethylene. “C1-C6 alkylene optionally modified by substituting a carbon-carbon single bond with a carbon-carbon double bond or triple bond” means a C1-C6 alkylene group as described above, or a divalent C2- C6 alkene or C2-C6 alkyne.

  “Cycloalkyl” means a group containing one or more saturated and / or partially saturated rings in which all ring members are carbon, eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, miltanyl , And partially saturated variations thereof, such as cyclohexenyl. Cycloalkyl groups do not include aromatic or heterocyclic rings. One particular cycloalkyl group is a C3-C7 cycloalkyl containing a single ring in which the cycloalkyl group has 3 to 7 ring members (all of which are carbon). “(C 3 -C 7 cycloalkyl) C 0 -C 4 alkyl” is a C 3 -C 7 cycloalkyl group bonded via a single bond or a C 1 -C 4 alkylene group.

“(C 4 -C 7 cycloalkyl) C 0 -C 4 alkylene” is a divalent (C 3 -C 7 cycloalkyl) C 0 -C 4 alkyl group attached to two specific moieties via two single bonds. In general, one single bond is placed in a cyclic moiety and the other, if present, is placed in an alkylene moiety; or in the absence of an alkylene group, both single bonds are on different ring members. For example, with respect to the RA group, when A is (C6 cycloalkyl) C2 alkylene and M is COOH, one RA moiety so formed is as follows:

“Alkoxy” as used herein means an alkyl group as defined above attached through an oxygen bridge. The alkoxy groups, respectively include _C 1 -C ₆ alkoxy and _C 1 -C ₄ alkoxy group is 1 to 6 or 1 to 4 carbon atoms. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3- Methylpentoxy is a typical alkoxy group.

The term “oxo” is used herein to refer to an oxygen substituent of a carbon atom that forms a carbonyl group (C═O). -CH 2 by oxo group that is a substituent of a nonaromatic carbon atom _- is -C (= O) - are converted to. An oxo group which is a substituent of an aromatic carbon atom may convert —CH— into —C (═O) —, thereby losing aromaticity.

The term “alkanoyl” refers to an acyl group (eg, — (C═O) -alkyl) in which the carbon atom is in a linear or branched alkyl configuration and attached through the carbon of the keto group. The alkanoyl group has the indicated number of carbons, and the carbon of the keto group is included in the counted carbon atoms. For example, a C ₂ alkanoyl group is — (C═O) CH ₃ . Examples of the alkanoyl group, for example, carbon atoms respectively 2～8,2～6, or 2 to 4 _C 2 -C _{8 alkanoyl,} C 2 -C ₆ alkanoyl group, and a _C 2 -C ₄ alkanoyl group mentioned It is done. “C ₁ alkanoyl” refers to — (C═O) H, which is encompassed by the term “C ₁ -C ₈ alkanoyl” (along with C ₂ -C ₈ alkanoyl).

“Alkyl ether” refers to a linear or branched ether substituent (ie, an alkyl group substituted with an alkoxy group). Examples of the alkyl ether group include C _{2 to} C ₈ alkyl ether groups, C _{2 to} C ₆ alkyl ether groups, and C _{2 to} C ₄ alkyl ether groups each having ₂ to ₈ , ₂ to ₆ , or 2 to 4 carbon atoms. Is mentioned. C ₂ alkyl ether substituent _is -CH 2 -O-CH _3.

The term “alkoxycarbonyl” refers to an alkoxy group attached through a keto (— (C═O) —) linking group (ie, a group having the general structural formula —C (═O) —O-alkyl). Alkoxycarbonyl Examples of the carbonyl _{group, C 1 ~C 8, C 1} ~C 6 carbon atoms in the alkyl moiety of the group are each 1～8,1～6, or 1 to 4, and _C 1 -C ₄ alkoxycarbonyl group (Ie, the carbon of the keto linking group is not included in the indicated number of carbon atoms). “C ₁ alkoxycarbonyl” refers to —C (═O) —O—CH ₃ ; C ₃ alkoxycarbonyl refers to —C (═O) —O— (CH ₂ ) ₂ CH ₃ or —C (═O ) -O- (CH) indicating the _{(CH 3) 2.}

“Alkanoyloxy” as used herein refers to an alkanoyl group attached through an oxygen linking group (ie, a group having the general structure —O—C (═O) -alkyl). As the alkanoyloxy group, C _{1 to} C ₈ , C _{1 to} C ₆ , and C _{1 to} C ₄ alkanoyloxy groups in which the carbon number of the alkyl portion of the group is ₁ to ₈ , ₁ to ₆ , or 1 to 4, respectively. Is mentioned. For example, “C ₁ alkanoyloxy” refers to —O—C (═O) —CH ₃ .

Similarly, “alkanoylamino” as used herein refers to an alkanoyl group attached through a nitrogen linking group (ie, a group having the general structure —N (R) —C (═O) -alkyl). Wherein R is hydrogen or C ₁ -C ₆ alkyl. The alkanoyl amino _{group, C 1 ~C 8, C 1} ~C 6 carbon atoms in the alkyl moiety of the alkanoyl group are each 1～8,1～6, or 1 to 4, and _C 1 -C ₄ alkanoylamino Groups.

“Alkylsulfonyl” refers to a radical of the formula — (SO ₂ ) -alkyl where the sulfur atom is the point of attachment. The alkylsulfonyl group, each having 1 to 6 carbon atoms, or 1 to 4 _C 1 -C ₆ alkylsulfonyl group is, and include _C 1 -C ₄ alkylsulfonyl group. Methylsulfonyl is one representative alkylsulfonyl group. “C ₁ -C ₄ haloalkylsulfonyl” is an alkylsulfonyl group having 1 to 4 carbon atoms and substituted with at least one halogen (eg, trifluoromethylsulfonyl).

“Alkylsulfonylamino” refers to a radical of the formula —N (R) — (SO ₂ ) -alkyl, where R is hydrogen or C ₁ -C ₆ alkyl and the nitrogen atom is the point of attachment. The alkylsulfonylamino group, each having 1 to 6 carbon atoms, or 1 to 4 _C 1 -C ₆ alkylsulfonylamino group a, and include _C 1 -C ₄ alkylsulfonylamino group. Methylsulfonylamino is a representative alkylsulfonylamino group. “C ₁ -C ₆ haloalkylsulfonylamino” is an alkylsulfonylamino group having 1 to 6 carbon atoms and substituted with at least one halogen (eg, trifluoromethylsulfonylamino).

“Aminosulfonyl” refers to a radical of the formula — (SO ₂ ) —NH ₂ where the sulfur atom is the point of attachment. The term “mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl” refers to a group satisfying the formula — (SO ₂ ) —NR ₂ , wherein the sulfur atom is the point of attachment and one R Is C ₁ -C ₆ alkyl and the other R is hydrogen or C ₁ -C ₆ alkyl independently selected.

“Alkylaminoalkyl” refers to an alkylamino group attached through an alkylene group (ie, a group having the general structural formula-alkylene-NH-alkyl or -alkylene-N (alkyl) (alkyl)), wherein Each alkyl is independently selected from alkyl, cycloalkyl and (cycloalkyl) alkyl groups. Examples of the alkylaminoalkyl group include mono- and di- (C ₁ -C ₈ alkyl) amino C ₁ -C ₈ alkyl, mono- and di- (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl, and the like. And mono- and di- (C ₁ -C ₆ alkyl) amino C ₁ -C ₄ alkyl. "Mono - or di - _(C 1 -C ₆ alkyl) amino _C 0 -C ₆ alkyl" mono linked via a single bond or a _C 1 -C ₆ alkylene group - or di - _(C 1 -C ₆ Alkyl) amino group. The following are representative alkylaminoalkyl groups:

The definition of “alkyl” as used in the terms “alkylamino” and “alkylaminoalkyl” refers to cycloalkyl and (cycloalkyl) alkyl groups (eg, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₆ alkyl It will be clear that this differs from the definition of “alkyl” used for all other alkyl-containing groups.

The term “aminocarbonyl” refers to an amide group (ie, — (C═O) NH ₂ ). “Mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl” refers to a group of formula — (C═O) —N (R) ₂ , where carbonyl is the point of attachment, and one R is C ₁ -C ₆ alkyl, the other R is hydrogen or independently selected C ₁ -C ₆ alkyl.

“Mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl C ₀ -C ₄ alkyl” is one in which one or both of the hydrogen atoms are substituted with C ₁ -C ₆ alkyl and bonded via a single bond An aminocarbonyl group (ie, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl) or an aminocarbonyl group attached via a C ₁ -C ₄ alkylene group (ie, — (C ₀ -C ₄ alkyl) - _{(C = O) N (C} 1 ~C 6 _{alkyl) 2).} When both hydrogen atoms are thus substituted, the C ₁ -C ₆ alkyl group may be the same or different.

The term “aminosulfonyl” refers to a sulfonamide group (ie, — (SO ₂ ) NH ₂ ). “Mono- or di- (C ₁ -C ₈ alkyl) aminosulfonyl” refers to a group of formula — (SO ₂ ) —N (R) ₂ , where the sulfur atom is the point of attachment and one R is _C 1 -C ₈ alkyl, the other R is a _C 1 -C ₈ alkyl is selected from hydrogen or independently.

“Mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl C ₀ -C ₄ alkyl” means that one or both of the hydrogen atoms are substituted with C ₁ -C ₆ alkyl and are bonded via a single bond. An aminosulfonyl group (ie, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl) or an aminosulfonyl group attached via a C ₁ -C ₄ alkylene group (ie, — (C ₁ -C _{4 alkyl)} - _{(SO 2) N (C 1} ~C 6 _{alkyl) 2).} When both hydrogen atoms are thus substituted, the C ₁ -C ₆ alkyl group may be the same or different.

  The term “halogen” refers to fluorine, chlorine, bromine or iodine.

A “haloalkyl” is an alkyl group substituted with one or more independently selected halogens (eg, a “C ₁ -C ₆ haloalkyl” group has ₁ to ₆ carbon atoms). Examples of haloalkyl groups include mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; , Di-, tri-, tetra- or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. The term “haloalkoxy” refers to a haloalkyl group as defined above attached through an oxygen linking group.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH ₂ is bonded through the carbon atom.

A “carbocycle” or “carbocyclic group” is at least one ring formed by a carbon-carbon bond (referred to herein as a carbocyclic ring). Including, but not containing a heterocycle. Unless stated otherwise, each ring of the carbocyclic group may independently be saturated, partially saturated, or aromatic, and optionally substituted as indicated. Yes. A carbocyclic group generally has 1 to 3 fused, pendant or spiro rings, and optionally further includes one or more alkylene linking groups; It has a ring or two fused rings. Typically, each ring has 3 to 8 ring members (ie, C _{3 to} C ₈ ); in certain embodiments, C _{5 to} C ₇ rings are described. The carbocyclic group including a fused ring, pendant ring or spiro ring typically has 9 to 16 ring members. Certain exemplary carbocyclic groups are the aforementioned cycloalkyl (eg, cyclohexyl, cycloheptyl, or adamantly). Other carbocyclic groups are aryl (ie, contain at least one aromatic carbocyclic ring and have or do not have one or more additional aromatic and / or cycloalkyl rings). Examples of such aryl carbocyclic groups include phenyl, naphthyl (eg, 1-naphthyl and 2-naphthyl), fluorenyl, indanyl and 1,2,3,4-tetrahydronaphthyl. The term “haloaryl” refers to an aryl group substituted with at least one halogen.

Certain carbocyclic groups described herein may be C ₆ -C ₁₀ aryl C ₀ -C ₈ alkyl groups (ie, 6- to 10-membered carbocyclic groups containing at least one aromatic ring). A single bond or a group bonded via a C _{1 to} C ₈ alkylene group). A phenyl group bonded through a single bond or a C ₁ -C ₂ alkylene group is referred to as phenyl C ₀ -C ₂ alkyl (eg, benzyl, 1-phenyl-ethyl and 2-phenyl-ethyl).

A “heterocyclic group” or “heterocyclic group” has 1 to 3 fused, pendant, or spiro rings, at least one of which is a heterocycle (ie, One or more ring atoms are heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon). Other rings, when present, may be heterocyclic or carbocyclic. Typically, a heterocycle contains 1, 2, 3 or 4 heteroatoms; in certain embodiments, each heterocycle has 1 or 2 heteroatoms per ring. Each heterocycle is generally 3 to 8 ring members (in certain embodiments, rings with 4 to 7 or 5 to 7 ring members are described) and includes fused, pendant, or spiro rings. The heterocyclic group typically has 9 to 14 ring members. Certain heterocyclic groups include sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO _2. Unless stated otherwise, heterocyclic groups are generally 4- to 7-membered heterocyclo, containing 1, 2, 3 or 4 ring atoms independently selected from C, O, N and S. A heterocycloalkyl group such as alkyl (ie, each ring is saturated or partially saturated); or a 5- to 10-membered heteroaryl (monocyclic or bicyclic). Or a heteroaryl group such as 6-membered heteroaryl (eg, pyridyl or pyrimidyl) (ie, at least one ring in the group is aromatic). The N-bonded heterocyclic group is bonded via a constituent nitrogen atom.

  As used herein, “aralkyl” refers to a moiety composed of an alkyl group having an aryl substituent, the aralkyl moiety having from about 7 to about 50 carbon atoms (and a range of carbon atoms therein). And all combinations and subcombinations of specific carbon numbers therein, aryl and alkyl are as defined above, with about 7 to about 11 carbon atoms being preferred. Examples include, but are not limited to, benzyl, diphenylmethyl, triphenylmethyl, α- or β-phenylethyl, and diphenylethyl, for example.

  As used herein, “heteroaralkyl” refers to a ring system composed of heteroaryl-substituted alkyl groups, where heteroaryl and alkyl are as defined above, and a heteroaralkyl group having from about 7 to 7 carbon atoms. About 50 (and having all the combinations and subcombinations of carbon number ranges and specific carbon numbers therein). Examples include, for example, 2- (1H-pyrrol-3-yl) ethyl, 3-pyridylmethyl, 5- (2H-tetrazolyl) methyl, and 3- (pyrimidin-2-yl) -2-methylcyclopentanyl However, it is not limited to these.

“Heterocyclic group C ₀ -C ₄ alkyl” is a heterocyclic group bonded via a single bond or a C ₁ -C ₄ alkylene group. “(4- to 7-membered heterocycloalkyl) C ₁ -C ₄ alkyl” is a 4- to 7-membered heterocycloalkyl ring bonded via a C ₁ -C ₄ alkylene group.

“(4- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkylene” is a divalent (4- to 7-membered heterocyclo) linked to two specific moieties via two single bonds. Alkyl) a C ₀ -C ₄ alkyl group. Generally, one such single bond is located in the ring moiety and the other, if present, is located in the alkylene moiety; or in the absence of an alkylene group, both such single bonds are in different rings. Located on the staff. For example, with respect to _{R A} group, A is (piperidinyl) _{C 2} alkylene, when M is COOH, 1 single _{R A} portion formed in this manner are as follows:

  “Substituent”, as used herein, refers to a molecular moiety that is covalently bonded to an atom in a molecule of interest. For example, the ring substituent may be a moiety such as a halogen, an alkyl group, a haloalkyl group, or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Aromatic group substituents are generally covalently bonded to a ring carbon atom. The term “substitution” refers to substitutions that do not exceed the valence of a specified atom and are chemically stable (ie, compounds that can be isolated, characterized, and tested for biological activity). Thus, it refers to replacing a hydrogen atom in a molecular structure with a substituent.

  An “optionally substituted” group is unsubstituted or is other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions. Substituted by one or more suitable groups, which may be the same or different. Optional substitution is also indicated by the phrase “substituted with 0 to X substituents,” where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with 0-2, 0-3, or 0-4 independently selected substituents (ie, unsubstituted or described). Substituted with up to the maximum number of substituents). Other optionally substituted groups are substituted with at least one substituent (e.g., substituted with 1-2, 1-3, or 1-4 independently selected substituents). .

The term "P2X ₇ receptor", any of the P2X7 receptor, its preferably a mammalian receptor such as P2X7 receptors of human or rat disclosed in Patent Document 1, and, seen in other species Refers to a homologue.

Also referred to as "modulators" as used herein, "P2X ₇ receptor modulator" activity (e.g., signal transduction) mediated by activation and / or P2X ₇ receptor P2X ₇ receptor to increase or decrease the A compound. The P2X ₇ receptor modulators specifically described herein are compounds of formula I and pharmaceutically acceptable salts, hydrates and esters thereof. The modulator may be a P2X ₇ receptor agonist or antagonist.

A modulator is considered an “antagonist” if the modulator detectably inhibits signaling mediated by the P2X ₇ receptor (eg, using the exemplary assay described in Example 7); The antagonist inhibits activation of the P2X ₇ receptor and has an IC ₅₀ value of less than 20 micromolar, preferably less than 10 micromolar, more preferably less than 5 micromolar, more preferably 1 micromolar in the assay described in Example 7. Less than a mole, even more preferably less than 500 nanomolar, most preferably less than 100 nanomolar. The P2X ₇ receptor antagonists include neutral antagonists and inverse agonists.

P2X "inverse agonist" of ₇ receptor is a compound that reduces the activity of P2X ₇ receptor below its basal activity level in the absence of other ligands. Inverse agonists of the P2X ₇ receptor, also inhibit binding of a ligand to the active and / or P2X ₇ receptor ligands in P2X ₇ receptors. Basal activity of P2X ₇ receptors, as well as reduction of the P2X ₇ receptor activity due to the presence of the P2X ₇ receptor antagonists can be determined from a calcium mobilization assay (e.g., Example 7 Assay).

"Neutral antagonist" of P2X ₇ receptor is a compound that inhibits the activity of ligand at P2X ₇ receptors are compounds which do not significantly change the basal activity of P2X ₇ receptor (i.e., is carried out in the absence of ligand in calcium mobilization assay as described in example 7, P2X ₇ receptor loss of activity of 10% or less, preferably 5% or less, further preferably 2% or less, and most preferably no decrease in detectable activity) . Neutral antagonists of P2X ₇ receptor can inhibit the binding of P2X ₇ receptor ligands.

As used herein, "P2X ₇ receptor agonist", P2X ₇ receptor activity enhances the basal activity level of the P2X ₇ receptor (i.e., activation of P2X ₇ receptors and / or signaling such as it is of improving the activity mediated by P2X ₇ receptor) compound. P2X ₇ receptor agonist activity can be detected using the exemplary assay described in Example 7. The P2X ₇ receptor agonists, ATP and 2 '(3') - O- (4- benzoyl - benzoyl), and adenosine 5'-triphosphate (BzATP) is.

A “therapeutically effective amount” (or dose) is an amount that, when administered to a patient, produces a discernible effect on the patient (eg, detectably alleviates at least one symptom being treated). Such relief can be detected using any suitable criteria including relief of one or more symptoms such as pain. Effective amount or dose treatment will generally alter the signal transduction mediated by P2X ₇ receptor (performed using the assay described in Example 7) of sufficient bodily fluids (blood, plasma, serum, CSF, Resulting in a concentration of the compound in the cerebrospinal fluid, lymph fluid, cellular interstitial fluid, tears or urine, etc. A recognizable effect on the patient may appear after administration of a single dose, or may appear after repeated administration of a therapeutically effective dose according to a predetermined treatment regimen, depending on the indication to which the compound is administered. It will be clear that it can be.

  “Statistically significant”, as used herein, is a significance of p <0.1 when the results are measured using a standard parameter test of statistical significance, such as the Student T test. Means that the level is different from the control.

A “patient” is any individual treated with a compound described herein. Patients include humans and other animals such as companion animals (eg, dogs and cats) and livestock. Patients may even signs of symptoms that respond to modulation P2X ₇ receptors are one or more, or may be without such signs (i.e., in patients thought to be at risk of such signs appear in , Treatment may be prophylactic).

｛式中：
Ｕは、ＣＲ_１Ａ又はＮであり；
Ｗは、−Ｃ（＝Ｏ）ＮＲ_４−、−ＮＲ_４Ｃ（＝Ｏ）−又は−ＮＲ_４−ＮＲ_４−Ｃ（＝Ｏ）−であり；
各Ｒ_４は、独立して、水素、Ｃ_１〜Ｃ_６アルキル、（Ｃ_３〜Ｃ_８シクロアルキル）Ｃ_０〜Ｃ_２アルキルであるか、又はＸの置換基と一緒に４員〜７員のヘテロシクロアルキルを形成し；
Ｘは、存在しないか、又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅから選択される１〜４個の置換基で任意に置換されたＣ_１〜Ｃ_６アルキレンであり；
Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅはそれぞれ独立して、ヒドロキシ、−ＣＯＯＨ、Ｃ_１〜Ｃ_８アルキル、（Ｃ_３〜Ｃ_８シクロアルキル）Ｃ_０〜Ｃ_４アルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_２〜Ｃ_８アルキルエーテル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノＣ_０〜Ｃ_４アルキル、（４員〜７員のヘテロシクロアルキル）Ｃ_０〜Ｃ_４アルキル、およびフェニルＣ_０〜Ｃ_２アルキルであるか；又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅのいずれか２つは、それらを結合している１個若しくは複数の炭素原子と一緒に、３員〜７員のシクロアルキル若しくは４員〜７員のヘテロシクロアルキルを形成するか；又は、Ｒ_Ｂ、Ｒ_Ｃ、Ｒ_Ｄ、およびＲ_Ｅのいずれか１つは、Ｒ_４およびそれらを結合している１個若しくは複数の原子と一緒に、４員〜７員のヘテロシクロアルキルを形成し；
Ｙは、Ｃ_１〜Ｃ_８アルキル、Ｃ_３〜Ｃ_１６シクロアルキル、４員〜１６員のヘテロシクロアルキル、６員〜１６員のアリール又は５員〜１６員のヘテロアリール［これらはそれぞれ、ヒドロキシ、ハロゲン、シアノ、アミノ、ニトロ、オキソ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、および（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノから独立して選択される１〜６個の置換基で任意に置換されている］であり；
Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４は、独立してＣＲ_１又はＮであり；
Ｒ_１Ａは、水素、ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、又は（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノであり；
各Ｒ_１は、独立して水素、ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、ＣＯＯＨ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６アミノアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイル、Ｃ_１〜Ｃ_６アルキルスルホニル、（Ｃ_３〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_４アルキル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、又は（Ｃ_１〜Ｃ_６アルキル）スルホニルアミノであり；
Ｒ_Ａは、式−Ｌ−Ａ−Ｍの基であり、式中：
Ｌは、存在しないか、又は、（ｉ）炭素−炭素単結合を炭素−炭素二重若しくは三重結合で置換することにより、若しくは（ｉｉ）オキソ、−ＣＯＯＨ、−ＳＯ_３Ｈ、−ＳＯ_２ＮＨ_２、−ＰＯ_３Ｈ_２、テトラゾール、若しくはオキサジアゾロンで置換することにより任意に修飾されているＣ_１〜Ｃ_６アルキレンであり；
Ａは、存在しないか、又は、ＣＯ、Ｏ、ＮＲ_６、Ｓ、ＳＯ、ＳＯ_２、ＣＯＮＲ_６、ＮＲ_６ＣＯ、（Ｃ_４〜Ｃ_７シクロアルキル）Ｃ_０〜Ｃ_２アルキル、４員〜７員のヘテロシクロアルキル、若しくは、５員若しくは６員のヘテロアリール［式中、Ｒ_６は水素若しくはＣ_１〜Ｃ_６アルキルである］であり；
Ｍは：
（ｉ）ヒドロキシ、ハロゲン、シアノ、アミノ、アミノカルボニル、アミノスルホニル、カルボキシアルキル、若しくはＣＯＯＨ；又は
（ｉｉ）Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６アルコキシ、（４員〜１０員の炭素環基）Ｃ_０〜Ｃ_４アルキル、（４員〜１０員の複素環基）Ｃ_０〜Ｃ_４アルキル、Ｃ_１〜Ｃ_６アルカノイルオキシ、Ｃ_１〜Ｃ_６アルカノイルアミノ、Ｃ_１〜Ｃ_６アルキルスルホニル、Ｃ_１〜Ｃ_６アルキルスルホニルアミノ、Ｃ_１〜Ｃ_６アルキルスルホニルオキシ、モノ−若しくはジ−Ｃ_１〜Ｃ_６アルキルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、若しくは、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノカルボニル［これらはそれぞれ、オキソ、アミノ、ハロゲン、ヒドロキシ、シアノ、アミノカルボニル、アミノスルホニル、−ＣＯＯＨ、アルコキシカルボニル、アルカノイルオキシ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキルエーテル、Ｃ_１〜Ｃ_６アルカノイルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノ、Ｃ_１〜Ｃ_６アルキルスルホニル、Ｃ_１〜Ｃ_６アルキルスルホニルアミノ、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキル）アミノスルホニル、モノ−若しくはジ−（Ｃ_１〜Ｃ_６アルキルアミノ）カルボニル、および、４員〜７員の複素環基から独立して選択される１〜４個の置換基で任意に置換されている］；
である｝
のヘテロアリールアミド類似体を提供する。 Heteroarylamide analogs As noted above, the present invention provides heteroarylamide analogs. In certain embodiments, the present invention provides compounds of formula Ia and / or Ib:

{In the formula:
U is CR _1A or N;
W is —C (═O) NR ₄ —, —NR ₄ C (═O) — or —NR ₄ —NR ₄ —C (═O) —;
Each R ₄ is independently hydrogen, C ₁ -C ₆ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₂ alkyl, or 4 to 7 members with X substituents. Forming a heterocycloalkyl of
X is absent or C ₁ -C ₆ alkylene optionally substituted with 1 to 4 substituents selected from R _B , R _C , R _D , and R _E ;
R _B , R _C , R _D , and R _E are each independently hydroxy, —COOH, C ₁ -C ₈ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C _{6 aminoalkyl,} C 2 -C ₈ alkyl ether, mono- - or di - _(C 1 -C ₆ alkyl) amino _C 0 -C ₄ alkyl, (4- to 7-membered _{heterocycloalkyl)} C 0 -C ₄ alkyl And phenyl C ₀ -C ₂ alkyl; or any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms to which they are attached. Forms a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or any one of R _B , R _C , R _D , and R _E defines R ₄ and them 1 united young Or together with a plurality of atoms form a 4- to 7-membered heterocycloalkyl;
Y is C ₁ -C ₈ alkyl, C ₃ -C ₁₆ cycloalkyl, 4 to 16 membered heterocycloalkyl, 6 to 16 membered aryl, or 5 to 16 membered heteroaryl [these are hydroxy , halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, _COOH, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl, C} 1 ~ C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C ₆ alkylsulfonyl , _(C 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _(C 1 -C ₆ alkyl) amino, ₁ -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, and _(C 1 -C ₆ alkyl) sulfonylamino Optionally substituted with 1 to 6 substituents independently selected from
Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently CR ₁ or N;
R _1A is hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkyl ether, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C It is ₆ alkyl) sulfonylamino;
Each R ₁ is independently hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or Di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or (C It is ₁ -C ₆ alkyl) sulfonylamino;
R _A is a group of formula -LAM, where:
L is absent, or (i) by replacing a carbon-carbon single bond with a carbon-carbon double or triple bond, or (ii) oxo, —COOH, —SO ₃ H, —SO ₂ NH ₂ , C ₁ -C ₆ alkylene optionally modified by substitution with —PO ₃ H ₂ , tetrazole, or oxadiazolone;
A is absent _{or, CO, O, NR 6,} S, SO, SO 2, CONR 6, NR 6 CO, (C 4 ~C 7 _cycloalkyl) C 0 -C ₂ alkyl, 4- to 7 A membered heterocycloalkyl, or 5- or 6-membered heteroaryl, wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl;
M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, carboxyalkyl, or COOH; or _(ii) C 1 ~C _{6 haloalkyl,} C 1 -C ₆ alkoxy, (4-membered to 10-membered carbocyclic ring _group) C 0 -C ₄ alkyl, (4- to 10-membered heterocyclic _group) C 0 -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C ₆ alkylsulfonyl C ₁ -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono- or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or Mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are oxo, amino, halogen, respectively , Hydroxy, cyano, aminocarbonyl, aminosulfonyl, -COOH, alkoxycarbonyl, _alkanoyloxy, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ alkoxy, C ₁ -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C Independent from ₆ alkylsulfonylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 4- to 7-membered heterocyclic groups Optionally substituted with 1-4 substituents selected as above];
Is}
The heteroaryl amide analogs are provided.

（式中、Ｒ_ｘはＨ又はＣ（＝Ｏ）−Ｏ−アルキルである）
以外であり；
（ｄ）Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４の１つがＮであり、Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４の他のものがそれぞれＣＨであり、Ｒ_ＡおよびＹがそれぞれ独立してアルキル、アリールアラルキル又はヘテロアリールであり、Ｗが−Ｃ（＝Ｏ）Ｎ（Ｈ）−であり、ＵがＣＲ_１Ａであるとき、Ｒ_１ＡはＯＨ以外であり；
（ｅ）Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４がそれぞれＣＨであり、Ｒ_Ａが非置換フェニルであり、Ｗが−Ｃ（＝Ｏ）Ｎ（Ｈ）−であり、Ｘが非置換アルキレン又は１つのヒドロキシルで置換されたアルキレンであり、Ｙがジアルキルアミノ、非置換へテロシクロアルキル、又は１つのアルキルで置換されたへテロシクロアルキルであり、ＵがＣＲ_１Ａであるとき、Ｒ_１Ａはハロゲン以外であり；および
（ｆ）Ｚ_１、Ｚ_２、Ｚ_３およびＺ_４がそれぞれＣＲ_１であり、Ｒ_１の少なくとも２つがＨであり、残りのＲ_１がそれぞれ独立してＨ、ハロゲン、ニトロ、ヒドロキシ、又はアルコキシであり、Ｒ_Ａがシクロアルキル又は置換若しくは非置換フェニルであり、Ｗが−Ｃ（＝Ｏ）Ｎ（Ｈ）−であり、Ｘが非置換アルキレンであり、Ｙが１つのＣＯＯＨでそれぞれ任意に置換されたアルキル若しくはシクロアルキル、ジアルキルアミノ、非置換へテロアリール、非置換へテロシクロアルキル、又はニトリル若しくはアミノで置換されたヘテロシクロアルキルであり、ＵがＣＲ_１Ａであるとき、Ｒ_１Ａはアルキル以外である；
ように、式Ｉａおよび／又はＩｂの化合物又は塩若しくは水和物を提供する。 In certain embodiments,
(A) when U is N, W is —C (═O) NH—, and L and A are absent, M is thienyl or an unsubstituted or halogen-substituted 4- to 10-membered carbocyclic group. Other than;
(B) when U is N, W is —NHC (═O) —, and A is absent, M is other than thienyl or an unsubstituted or halogen-substituted 4- to 10-membered carbocyclic group ;
(C) When U is CH, W—X—Y is

Wherein R _x is H or C (═O) —O-alkyl.
Other than;
(D) _one of Z ₁ , Z ₂ , Z ₃ and Z ₄ is N, the other of Z ₁ , Z ₂ , Z ₃ and Z ₄ is CH, and R _A and Y are each independently R _1A is other than OH when W is -C (= O) N (H) _-and U is CR _1A ;
(E) Z ₁ , Z ₂ , Z ₃ and Z ₄ are each CH, R _A is unsubstituted phenyl, W is —C (═O) N (H) —, and X is unsubstituted alkylene Or R _1A is alkylene substituted with one hydroxyl, Y is dialkylamino, unsubstituted heterocycloalkyl, or heterocycloalkyl substituted with one alkyl, and U is CR _1A And (f) Z ₁ , Z ₂ , Z ₃ and Z ₄ are each CR ₁ , at least two of R ₁ are H, and the remaining R ₁ are each independently H, halogen, nitro, hydroxy, or alkoxy, R _a is cycloalkyl or substituted or unsubstituted phenyl, W is -C (= O) N (H ) - and is, X is an unsubstituted alkylene, Y is 1 COOH optionally substituted alkyl or cycloalkyl respectively, dialkylamino, unsubstituted heteroaryl, unsubstituted heterocycloalkyl, or heterocycloalkyl substituted with nitrile or amino, when U is CR _1A , R _1A is other than alkyl;
Thus, a compound or salt or hydrate of formula Ia and / or Ib is provided.

In certain embodiments, such compounds are used in vitro or in vivo as modulators of P2X ₇ receptors that can be used in a variety of situations, including the treatment of conditions that respond to P2X ₇ receptor modulation, such as pain. obtain. Such modulators are also, P2X ₇ as a probe for receptor detection and localization (localization), and P2X ₇ also useful as standards for signaling assays mediated by receptors.

In certain embodiments, such compounds exhibit no detectable agonist activity in vitro assay of P2X ₇ receptor agonism.

In certain other specific embodiments, such compounds can exhibit IC ₅₀ values of 20 micromolar or less in a P2X ₇ receptor antagonism assay.

  In some embodiments, a compound of the present invention or a salt or hydrate thereof is a compound of formula Ia.

  In other embodiments, the compound of the invention or salt or hydrate thereof is a compound of formula Ib.

  In certain embodiments of the invention, the compound of formula Ia and / or Ib is provided as a salt or hydrate thereof.

は、示されているように、少なくとも１つの窒素原子を含み、Ｕ、Ｖ、Ｚ_１、Ｚ_２、Ｚ_３および／又はＺ_４の１つ以上に追加の窒素原子を任意に含む。ある特定の実施形態では、ＵはＣＲ_１Ａであり；他の実施形態では、ＵはＣＨである。他の実施形態では、Ｚ_１、Ｚ_２およびＺ_３はそれぞれＣＲ_１である。 In formula Ia and / or Ib, heteroaryl nucleus:

Includes at least one nitrogen atom, as indicated, and optionally additional nitrogen atoms in one or more of U, V, Z ₁ , Z ₂ , Z ₃ and / or Z ₄ . In certain embodiments, U is CR _1A ; in other embodiments, U is CH. In other embodiments, Z ₁ , Z _2, and Z ₃ are each CR ₁ .

  In some other embodiments of the compounds of formula Ia and / or Ib, X is substituted.

In other embodiments of compounds of Formula Ia and / or Ib, R _B , R _C , R _D and R _E are each independently —COOH, C ₁ -C ₈ alkyl, (C ₃ -C ₈ cyclo Alkyl) C ₀ -C ₄ alkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₈ alkyl ether, mono- or di- (C ₁ -C ₆ alkyl) amino C ₀ -C ₄ alkyl, (4 membered- 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, and phenyl C ₀ -C ₂ alkyl; or any two of R _B , R _C , R _D and R _E bind them Together with the one or more carbon atoms, form a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or R _B , R _C , R _D , and R _E Any one of R ₄ and with one or more atoms are bonded to them, form a heterocycloalkyl of 4 to 7-membered.

In certain other embodiments of compounds of formula Ia and / or Ib, R _B , R _C , R _D and R _E are each independently C ₁ -C ₄ alkyl, (C ₃ -C ₈ cyclo Alkyl) C ₀ -C ₂ alkyl, or phenyl C ₀ -C ₂ alkyl.

In other embodiments of the compounds of Formula Ia and / or Ib, any two of R _B , R _C , R _D, and R _E are three-membered, together with one or more atoms connecting them Forms a -7 membered cycloalkyl or a 4-7 membered heterocycloalkyl.

In certain embodiments of compounds of formula Ia and / or Ib, any one of R _B , R _C , R _D , and R _E is R ₄ and the one or more carbon atoms that bind them. Together with 4 to 7 membered heterocycloalkyl.

In some embodiments of compounds of Formula Ia and / or Ib, U is CR _1A (eg, CH).

  In other embodiments of compounds of Formula Ia and / or Ib, U is N.

In certain embodiments of compounds of Formula Ia and / or Ib, Y is C ₁ -C ₈ alkyl, C ₃ -C ₁₆ cycloalkyl, 6 to 16 membered aryl, or 5 to 16 membered. Heteroaryl, each of which is optionally substituted, preferably C ₁ -C ₈ alkyl, 6 to 16 membered aryl, or 5 to 16 membered heteroaryl, each of which is optionally Has been replaced).

  In other embodiments of the compounds of formula Ia and / or Ib, Y is optionally substituted with 1 to 3 substituents. In other embodiments, Y is optionally substituted with 1 or 2 substituents.

In still other embodiments of compounds of Formula Ia and / or Ib, Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently CH. In another aspect, Z ₄ is N. In other embodiments, at least one of Z ₁ , Z ₂ , Z _3, and Z ₄ is CR ₁ . In certain other specific embodiments, Z ₁ or Z ₄ is CR ₁ ; or Z ₁ is CR ₁ .

In certain embodiments of formula Ia and / or Ib, R ₁ is hydrogen, halogen, cyano, aminocarbonyl, or C ₁ -C ₆ haloalkyl. In certain embodiments where R ₁ is halogen, the halogen is fluoro, chloro, or bromo; the halogen is fluoro. In certain other specific embodiments, R ₁ is C ₁ -C ₃ haloalkyl; in yet other embodiments, R ₁ is C ₁ haloalkyl; in yet other embodiments, the C ₁ haloalkyl is trifluoromethyl. . Alternatively, each R ₁ is H.

In certain other embodiments of formula Ia and / or Ib, preferably formula Ia, R _1A is hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halo _alkoxy, C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C _{6 alkylsulfonyl, (C} 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _(C 1 ~ C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- Or di- (C ₁ -C ₆ alkyl) aminosulfonyl or (C ₁ -C ₆ alkyl) sulfonylamino; preferably hydrogen, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C _1- C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C _{6 alkylsulfonyl, (C} 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl Aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C ₆ alkyl) be a sulfonylamino; more preferably hydrogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH , _C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C _{6 alkylsulfonyl, (C} 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _{(C 1} -C ₆ alkyl) _amino, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) Iminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C ₆ alkyl) sulfonylamino.

In some embodiments of compounds of Formula Ia and / or Ib, W is —NR ₄ C (═O) — or —NR ₄ —NR ₄ —C (═O) —. In another aspect, W is —C (═O) NR ₄ —.

In other embodiments, R ₄ is H.

In certain embodiments of compounds of Formula Ia and / or Ib, M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or COOH; or _(ii) C 1 ~C _{6 haloalkyl,} C 1 -C ₆ alkoxy, (4 to 10 membered _{aryl) C} 0 ~ C ₄ alkyl, (4- to 10-membered heterocyclic _group) C 0 -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono- or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are oxo, amino, halogen, hydroxy, cyano, respectively , Aminocarbonyl, aminosulfonyl, _-COOH, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy, C} 2 ~ C ₆ alkyl ether, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfonylamino, mono- or di- _{1 to} 4 independently selected from (C ₁ -C ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 4- to 7-membered heterocyclic groups Optionally substituted with substituents];
It is.

In certain other embodiments of the compounds of formula Ia and / or Ib, M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or COOH; or _(ii) C 1 ~C _{6 haloalkyl,} C 1 -C ₆ alkoxy, (4 to 10 membered _{aryl) C} 0 ~ C ₄ alkyl, (4- to 10-membered _{heterocycloalkyl)} C 0 -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono- or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are oxo, amino, halogen, hydro, respectively Alkoxy, cyano, aminocarbonyl, aminosulfonyl, _-COOH, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C ₆ haloalkoxy, C ₂ -C ₆ alkyl _ether, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - Or di- (C ₁ -C ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 1 to 4 independently selected from 4- to 7-membered heterocyclic groups Optionally substituted with 4 substituents];
It is.

In still other embodiments of compounds of Formula Ia and / or Ib, M is aryl C ₁ -C ₄ alkyl or heteroaryl C ₁ -C ₄ alkyl. In some such compounds, M is substituted; in others, M is not substituted.

In still other embodiments of the compounds of formula Ia and / or Ib, M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or COOH; or (ii) C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (4 to 10 membered heterocycloalkyl) C ₀ -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C _{6 alkylsulfonyl,} C 1 -C _{6 alkylsulfonylamino,} C 1 -C ₆ alkylsulfonyloxy, mono - Or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are oxo, respectively , Amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl _, -COOH, C 1 ~C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl ether, C ₁ -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - or di - _(C 1 -C ₆ Optionally substituted with 1 to 4 substituents independently selected from alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 4- to 7-membered heterocyclic groups Is]
It is.

In certain embodiments of compounds of Formula Ia and / or Ib, M is optionally substituted with 1 or 2 substituents. In certain embodiments, these substituents are independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy.

In some embodiments of compounds of Formula Ia and / or Ib, R _A is other than halophenyl, other than haloaryl, other than cycloalkyl, and / or other than thienyl.

In certain embodiments of compounds of formula Ia and / or Ib, when R _A is optionally substituted heteroaryl, said heteroaryl is at least one oxygen or nitrogen ring atom, preferably at least one It has a nitrogen ring atom, more preferably at least 2 nitrogen ring atoms.

In certain other embodiments of the compounds of formula Ia and / or Ib, R _A is other than a carbocycle.

In still other embodiments of the compounds of formula Ia and / or Ib, W—X—Y is optionally substituted —C (═O) N (H) R _v . Alternatively, in some embodiments, W—X—Y is other than unsubstituted —C (═O) N (H) heteroaralkyl; or W—X—Y is unsubstituted —C (═O). Is other than N (H) heterocycle; or W—X—Y is other than unsubstituted —C (═O) N (H) alkoxyalkyl; or W—X—Y is unsubstituted —C. (= O) Other than N (H) aralkyl.

In some embodiments of compounds of Formula Ia and / or Ib, R _v is aryl C ₁ -C ₄ alkyl or heteroaryl C ₁ -C ₄ alkyl. In some embodiments, R _y is substituted; in other embodiments, it is not substituted. Alternatively, in some embodiments, R _v is other than aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl, alkyl, alkenyl, or alkynyl.

  In certain embodiments of compounds of formula Ia and / or Ib, W is C (═O) N (H) —.

  In another embodiment of the compounds of formula Ia and / or Ib, M is an optionally substituted heteroaryl; preferably said heteroaryl contains at least one nitrogen ring atom, more preferably said hetero Aryl contains at least 2 nitrogen ring atoms. In certain embodiments, M is an optionally substituted pyrimidinyl, preferably an optionally substituted pyrimidin-2-yl.

In some embodiments of compounds of Formula Ia and / or Ib, X is C ₁ -C ₂ alkylene, optionally substituted, preferably substituted with C ₁ -C ₄ alkyl. In other _{embodiments, X} is any of _{R B, R C, R D} , and _R is substituted with at least two substituents selected from _{E, R B, R C,} R D, and _{R E} The two together with one or more carbon atoms connecting them form a 3 to 7 membered cycloalkyl. Alternatively, in some embodiments, X is substituted with at least two substituents selected from R _B , R _C , R _D , and R _E , and R _B , R _C , R _D , and Any two of R _E together with one or more carbon atoms connecting them form a 3 to 7 membered cycloalkyl, preferably a 5 to 6 membered cycloalkyl.

  In certain embodiments of compounds of Formula Ia and / or Ib, Y is an optionally substituted carbocyclic or heterocyclic group, preferably adamantyl, phenyl, pyridyl, or morpholinyl, each of which is optionally Has been replaced.

  In certain other embodiments of compounds of formula Ia and / or Ib, the compound is a compound described in Table A herein, or a salt or hydrate thereof.

  Exemplary heteroarylamide analogs described herein include, but are not limited to, those specifically described in Examples 1-6 and the accompanying Table A. It will be apparent that the specific compounds described herein are exemplary only and are not intended to limit the scope of the invention. Furthermore, as noted above, all of the compounds of the present invention may exist as the free acid or free base, or as a pharmaceutically acceptable salt. Furthermore, other forms such as hydrates and prodrugs of such compounds are also explicitly contemplated by the present invention.

In certain aspects of the invention, the heteroarylamide analogs described herein have P2X ₇ receptor activity determined using an assay such as the assay described in Example 7 herein. Change (adjust) detectably. Other assays that can be used for this purpose include assays that measure IL-1β release; assays that measure uptake of membrane-impermeable fluorescent dyes such as YO-PRO1; assays that measure uptake of lucifer yellow; ethidium bromide assays for measuring the uptake; and include assays using calcium imaging to detect P2X ₇ activity, all these assays are well known in the art. Described herein, certain modulators, at micromolar concentrations, at nanomolar concentrations, or nanomolar concentrations below modulating detectably a P2X ₇ receptor activity.

As described above, in certain embodiments, the compounds P2X ₇ receptor antagonist is preferred. The standard in vitro P2X ₇ receptor mediated calcium mobilization assay described in Example 7 can be used to determine IC ₅₀ values for such compounds. Briefly, cells expressing P2X ₇ receptors, the compounds and intracellular calcium concentration indicator of interest (e.g., Fluo-3, Fluo-4 or Fura-2 (Invitrogen, Carlsbad, CA) membrane permeability, such as Calcium-sensitive dyes, each of which generates a fluorescent signal when bound to Ca ⁺⁺ , are contacted. Such contacting is preferably performed by performing one or more incubations of the cells in a buffer or medium containing either or both of the compound and the indicator in solution. Contact is maintained for a period of time sufficient for the dye to enter the cells (eg, 1-2 hours). After removal of excess dye the cells are washed or filtered, P2X ₇ receptor agonist (e.g., equal concentrations on _{EC 50} s concentration, e.g., ATP or 2 '(3') - O- (4- benzoyl - benzoyl ) Adenosine 5′-triphosphate) and the fluorescence reaction is measured. The cells contacted with the agonist, when contacting a compound P2X ₇ receptor antagonist, the fluorescence response is generally compared to contact with the agonist in the absence of test compound the cells, at least 20%, preferably at least It is reduced by 50%, more preferably at least 80%. In certain embodiments, the P2X ₇ receptor antagonists described herein do not exhibit detectable agonist activity at compound concentrations equal to the IC ₅₀ in an in vitro assay of P2X ₇ receptor agonistic action. Certain such antagonists exhibit no detectable agonist activity at 100-fold higher concentration of compound from the _{IC 50} in an in vitro assay of P2X ₇ receptor agonism.

P2X ₇ receptor modulating activity may likewise or alternatively, may be evaluated using an in vivo pain relief assay as described in Example 8. Modulators described herein preferably have such a functional assay (functional assay) by the P2X ₇ statistics receptor activity biologically significant specific effect.

  In certain embodiments, preferred modulators are non-sedating. In other words, a sedation of a dose that is twice the minimum dose sufficient to cause analgesia in an animal model for measuring pain relief (such as the model described in Example 8 herein). In an animal model assay (using the method described by Fitzgerald et al. (1988) Toxicology 49 (2-3): 433-9), which is transient (ie, half the time that pain relief lasts) Sedation (which persists below) occurs, or preferably no statistically significant sedation occurs. Preferably, a statistically significant sedation does not occur at a dose 5 times the minimum dose sufficient to provide analgesia. More preferably, the modulators described herein are administered at an intravenous dose of less than 25 mg / kg (preferably less than 10 mg / kg) or less than 140 mg / kg (preferably less than 50 mg / kg, more preferably 30 mg / kg. Oral doses (<kg) do not cause sedation.

Optionally, certain pharmaceutical properties of the compounds described herein, such as but not limited to oral bioavailability (preferred compounds are less than 140 mg / kg, preferably less than 50 mg / kg, more Preferably a therapeutically effective compound concentration can be achieved with an oral dose of preferably less than 30 mg / kg, even more preferably less than 10 mg / kg, even more preferably less than 1 mg / kg, most preferably less than 0.1 mg / kg. Oral bioavailability), toxicity (preferred compounds are non-toxic when a therapeutically effective amount is administered to a subject), side effects (preferred compounds are administered a therapeutically effective amount of a compound to the subject) The resulting side effects are equivalent to placebo), serum protein binding and in vitro and in vi o Half-life (preferred compounds are in vivo half-lives that allow administration 4 times a day, preferably 3 times a day, more preferably 2 times a day, most preferably once a day. May be evaluated). Furthermore, a total oral daily dose as described above, the extent effective to treat pain or neurodegenerative by adjusting the P2X ₇ receptor activity of the CNS such that modulation of P2X ₇ receptor activity of the CNS resulting For modulators used to treat disease, differential penetration of the blood brain barrier may be desirable, but peripheral nerve mediated pain or certain inflammatory diseases (e.g., it may be preferable brain levels low modulator used in the treatment of rheumatoid arthritis) (i.e., in such doses, P2X ₇ receptor activity significantly in sufficient brain to modulate (e.g., CSF) Compound level not obtained). Usual assays well known in the art may be used to assess these properties and identify compounds that are superior for a particular application. For example, assays used to predict bioavailability include transport in human intestinal cell monolayers, including Caco-2 cell monolayers. The permeability of the compound to the blood-brain barrier in humans may be predicted from the level of compound in the brain in experimental animals administered the compound (eg, by intravenous injection). Serum protein binding may be predicted from albumin binding assays. The half-life of a compound is inversely proportional to the frequency of compound administration. The in vitro half-life of the compound may be predicted, for example, from the microsomal half-life assay described in Example 7 of US Pat.

  As mentioned above, preferred compounds described herein are non-toxic. In general, the term “non-toxic” shall be understood in a relative sense and approved or established by the United States Food and Drug Administration (“FDA”) for administration to mammals (preferably humans). It is intended to refer to any substance that meets established standards and can be approved by the FDA for administration to a mammal (preferably a human). Furthermore, highly preferred non-toxic compounds generally meet one or more of the following criteria: (1) dose does not substantially inhibit cellular ATP production; (2) dose does not significantly extend cardiac QT interval (3) the dose does not cause substantial liver enlargement; or (4) the dose does not cause substantial release of liver enzymes.

  As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria described in Example 8 of Patent Document 2. In other words, cells treated with 100 μM of such compounds as described in the aforementioned patent document show ATP levels that are at least 50% of the ATP levels detected in untreated cells. In a further highly preferred embodiment, such cells exhibit an ATP level of at least 80% of the ATP level detected in untreated cells.

A compound that does not significantly extend the cardiac QT interval is the cardiac QT interval (measured by electrocardiogram) in guinea pigs, minipigs, or dogs when administered at a dose that results in a serum concentration equal to the EC ₅₀ or IC ₅₀ of the compound. This compound does not cause a statistically significant extension of In certain preferred embodiments, at doses of 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 40, or 50 mg / kg (parenteral or oral administration) There is no statistically significant extension of the QT interval.

Daily treatment of experimental rodents (eg, mice or rats) for 5-10 days at a dose that yields a serum concentration equal to the compound's EC ₅₀ or IC ₅₀ results in a corresponding increase in liver to body weight ratio. On the other hand, if less than 100%, the compound does not cause substantial liver enlargement. In a further highly preferred embodiment, such doses do not cause 75% or more than 50% liver enlargement relative to the corresponding control. When using a mammal other than a rodent (eg, a dog), such a dose will result in greater than 50%, preferably greater than 25%, more preferably greater than 10% liver pairs relative to the corresponding untreated control. There should be no increase in weight ratio. Preferred doses for such assays include 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 40, or 50 mg / kg (parenteral or oral administration).

Similarly, serum levels of ALT, LDH, or AST in laboratory animals (eg, rodents) by administration of twice the minimum dose to obtain a serum concentration equal to the EC ₅₀ or IC ₅₀ of the compound at the P2X ₇ receptor If it does not increase more than 100% relative to the corresponding mock-treated control, the compound does not promote substantial release of liver enzymes. In a further highly preferred embodiment, at such doses, such serum levels do not rise above 75% or above 50% relative to the corresponding control. Alternatively, in an in vitro hepatocyte assay, the corresponding sham treatment at a concentration equal to the EC ₅₀ or IC ₅₀ of the compound (in culture medium or other such solution that is contacted with hepatocytes in vitro and incubated together) If there is no detectable release of any such liver enzyme into the medium above the baseline level found in the control cell medium, the compound does not promote substantial release of the liver enzyme. In a further highly preferred embodiment, when such a compound concentration is 5 times, preferably 10 times the EC ₅₀ or IC ₅₀ of the compound, any such liver enzyme is detectable in the medium above the baseline level. There is no significant release.

In other embodiments, certain preferred compounds, P2X ₇ microsomal at a concentration equal on _{EC 50} s or _{IC 50} of the compound in the receptor cytochrome P450 enzyme activities (CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity , CYP2E1 activity, or CYP3A4 activity).

Certain preferred compounds are not chromosomally inducible (eg, mouse erythroid progenitor cell micronucleus test, Ames micronucleus test, or spiral micronucleus test at a concentration equal to the EC ₅₀ or IC ₅₀ of the compound) (When determined using, for example, spiral micronucleus assay). In other embodiments, certain preferred compounds do not induce sister chromatid exchange (eg, in Chinese hamster ovary cells) at such concentrations.

As described in more detail below, the modulators described herein may be isotopically or radiolabeled for detection purposes. For example, a compound may have one or more atoms replaced with atoms of the same element having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be present in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine ( ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl). Further, substitution with a heavy isotope such as deuterium (ie, ² H) may result from a relatively high metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. It can provide therapeutic benefits and may therefore be preferred in some circumstances.

The compounds may be radiolabeled by performing their synthesis using precursors containing at least one atom that is a radioisotope. Each radioisotope is preferably carbon (eg, ¹⁴ C), hydrogen (eg, ³ H), sulfur (eg, ³⁵ S), or iodine (eg, ¹²⁵ I). Tritium-labeled compounds can also be used as a substrate, platinum-catalyzed exchange in tritium-labeled acetic acid, acid-catalyzed exchange in tritium-labeled trifluoroacetic acid, or heterogeneous with tritium gas. It may be prepared using a catalyst by exchange with a system catalyst. Furthermore, certain precursors may be suitably exchanged with tritium gas and tritium-halogen, the unsaturated bond may be reduced with tritium gas, or may be reduced using sodium triborate. Preparation of the radiolabeled compound may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.

Preparation of Heteroarylamide Analogs Heteroarylamide analogs can generally be prepared using standard synthetic methods. The starting material was Sigma-Aldrich Corp. (St. Louis, MO) or may be synthesized from commercially available precursors using established procedures. By way of example, synthetic routes similar to those shown in any of the following schemes may be used with synthetic methods known in the field of synthetic organic chemistry. In some cases, protecting groups may be required during preparation. Such a protecting group can be removed by methods well known to those skilled in the art, such as those described in Non-Patent Document 1 or Non-Patent Document 2. In some cases, further organic conversion may be performed using methods well known to those skilled in the art, such as those described in Non-Patent Document 3. Each symbol in the following scheme refers to any group consistent with the description of the compounds described herein. Typical reaction conditions used in the following schemes are described in the examples.

Certain abbreviations used in the following schemes and elsewhere in this specification include the following:
BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate δ chemical shift DCM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide Et ethyl EtOAc ethyl acetate EtOH ethanol h time
¹ H NMR proton nuclear magnetic resonance Hz hertz iPr isopropyl MeOH methanol min min Ms methanesulfonyl (M + 1) mass +1
Ph ₃ P triphenylphosphine POCl ₃ phosphorus oxychloride PTLC preparative thin layer chromatography rt room temperature TEA triethylamine TFA trifluoroacetic acid (CF ₃ CO) ₂ O trifluoroacetic anhydride

スキーム６は、式Ｘのある特定の中間体ＮＨ_２−ＣＨ_２−ＣＨＲ_５−Ｙ［式中、Ｒ_５は置換フェニル又はヘテロアリールであり、Ｙ＝Ｎ−Ｒ_５ｂＲ_５ｂ（Ｒ_５ｂは独立して水素、Ｃ_１〜Ｃ_６アルキル、若しくはＣ_３〜Ｃ_７シクロアルキルであるか；又は両方のＲ_５ｂは一緒に複素環基を形成する）である］の一般的な調製方法を説明する。アセトニトリルなどの溶媒中のＴＭＳＣＮを用いた、又は、ｐＨ３〜４（塩酸で調整）のＭｅＯＨ−水若しくは水などの溶媒中のＮａＣＮ若しくはＫＣＮを用いたアリールカルボキシアルデヒドとアミンのストレッカー（Ｓｔｒｅｃｋｅｒ）縮合によりアミノニトリルを得、これを、ＴＨＦなどの溶媒中のＬＡＨによって又は、メタノール中７Ｎのアンモニアなどの溶媒中でラネーニッケル（Ｒａｎｅｙ Ｎｉｃｋｅｌ）を触媒として用いた水素化により還元し、アミン中間体ＮＨ_２−ＣＨ_２−ＣＨＲ_５−Ｙを得る。

スキーム７は、式Ｘのある特定の中間体ＮＨ_２−ＣＨ_２−ＣＨＲ_５−Ｙ又はＮＨ_２−ＣＨ_２−ＣＲ_５Ｒ_５−Ｙ（式中、Ｙは置換フェニル又はヘテロアリールである）の一般的な調製方法を説明する。ＴＨＦ−ＤＭＳＯなどの溶媒中の水素化ナトリウムなどの塩基を用いて、出発アセトニトリルを１当量のＸ−Ｒ_５（Ｘ＝Ｂｒ又はＩ）でアルキル化し、中間体Ｙ−Ｘ（Ｒ_５）−ＣＮを得る。ＴＨＦ−ＤＭＳＯなどの溶媒中の水素化ナトリウムなどの塩基を用いて、出発アセトニトリルを２当量のＸ−Ｒ_５（Ｘ＝Ｂｒ若しくはＩ）又は１当量のジブロモ若しくはジヨード（Ｒ_５とＲ_５が一緒に環を形成するとき）でアルキル化し、中間体Ｙ−Ｘ（Ｒ_５）（Ｒ_５）−ＣＮを得る。どちらかの生成物を、ＴＨＦなどの溶媒中のＬＡＨにより、又は、メタノール中７Ｎのアンモニアなどの溶媒中でラネーニッケル（Ｒａｎｅｙ Ｎｉｃｋｅｌ）を触媒として用いた水素化により還元し、ＮＨ_２−ＣＨ_２−ＣＨＲ_５−Ｙ又はＮＨ_２−ＣＨ_２−ＣＲ_５Ｒ_５−Ｙを得る。

スキーム８は、式Ｘのある特定の中間体ＮＨ_２−ＣＨ_２−ＣＲ_５Ｒ_５−Ｙ［式中、Ｒ_５は、独立して、水素、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_７シクロアルキル若しくはフェニルであるか；又は両方のＲ_５は一緒にＣ_３〜Ｃ_８シクロアルキル若しくは複素環基を形成し、Ｙ＝Ｎ−Ｒ_５ｂＲ_５ｂ（式中、Ｒ_５ｂは、ハロゲン、ヒドロキシル、Ｃ_１〜Ｃ_４アルキル、Ｃ_１〜Ｃ_４アルコキシ、若しくはＣＯ_２Ｈで任意に置換されたＣ_１〜Ｃ_６アルキルであるか、又は両方のＲ_５ｂは一緒に５員〜７員の複素環を形成する）である］の一般的な調製方法を説明する。ＺｎＩ_２などの触媒と共にメタノールなどの溶媒中のＴＭＳＣＮを用いた、又は、ｐＨ３〜４（塩酸で調整）のＭｅＯＨ−水若しくは水などの溶媒中のＮａＣＮ若しくはＫＣＮを用いたケトンとアミンのストレッカー（Ｓｔｒｅｃｋｅｒ）縮合によりアミノニトリルを得る。アミノニトリルを、ＴＨＦなどの溶媒中のＬＡＨにより、又は、メタノール中７Ｎのアンモニアなどの溶媒中でラネーニッケル（Ｒａｎｅｙ Ｎｉｃｋｅｌ）を触媒として用いた水素化により還元し、ＮＨ_２−ＣＨ_２−ＣＲ_５Ｒ_５−Ｙを得る。 Schemes 1-8 describe certain embodiments of the invention and are intended to be exemplary only and not limiting. For example, each reaction described in the scheme may be performed in combination with some or all of the other reactions described therein, even if performed in combination with any of the other reactions described therein. It will be clear that In addition, various changes in reaction conditions will be apparent, including the use of different solvents and acids / bases, and changes in reaction time and temperature. All processes disclosed in connection with the present invention are contemplated to be performed on any scale, including milligrams, grams, multigrams, kilograms, multikilograms, or industrial scales. The starting material for each step and each reaction product may be the indicated compound, or a salt (eg, a pharmaceutically acceptable salt) or a solvate (eg, a hydrate) thereof. It will be further clear that it is good. Unless otherwise stated, each symbol in the following scheme is as defined above.

Scheme 6 shows certain intermediates NH ₂ —CH ₂ —CHR ₅ —Y wherein R ₅ is a substituted phenyl or heteroaryl and Y═N—R _5b R _5b (R _5b is independently Is hydrogen, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl; or both R _5b together form a heterocyclic group) . Strecker condensation of arylcarboxaldehyde and amine using TMSCN in a solvent such as acetonitrile or MeOH-water or pH 3-4 (adjusted with hydrochloric acid) using NaCN or KCN in a solvent such as water To give an aminonitrile, which is reduced by LAH in a solvent such as THF or by hydrogenation using Raney Nickel as a catalyst in a solvent such as 7N ammonia in methanol to give the amine intermediate NH _2. get a -CH ₂ -CHR ₅ -Y.

Scheme 7 illustrates the preparation of certain intermediates NH ₂ —CH ₂ —CHR ₅ —Y or NH ₂ —CH ₂ —CR ₅ R ₅ —Y where Y is a substituted phenyl or heteroaryl. A general preparation method will be described. The starting acetonitrile was alkylated with 1 equivalent of X—R ₅ (X═Br or I) using a base such as sodium hydride in a solvent such as THF-DMSO, and the intermediate Y—X (R ₅ ) —CN. Get. Using a base such as sodium hydride in a solvent such as THF-DMSO, start acetonitrile with 2 equivalents of X—R ₅ (X═Br or I) or 1 equivalent of dibromo or diiodo (R ₅ and R ₅ together the alkylated when) to form a ring, the intermediate _{Y-X (R 5) (} R 5) get -CN. Either product is reduced by LAH in a solvent such as THF or by hydrogenation using Raney Nickel as a catalyst in a solvent such as 7N ammonia in methanol and NH ₂ —CH ₂ —. CHR obtain ₅ -Y or _{NH 2 -CH 2 -CR 5 R 5} -Y.

Scheme 8 illustrates certain intermediates NH ₂ —CH ₂ —CR ₅ R ₅ —Y [wherein R ₅ is independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C _7. Cycloalkyl or phenyl; or both R ₅ together form a C ₃ -C ₈ cycloalkyl or heterocyclic group, and Y = N—R _5b R _5b , where R _5b is halogen, hydroxyl C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₆ alkyl optionally substituted with CO ₂ H, or both R _5b together are 5- to 7-membered A general method for preparing a ring is described. ZnI with TMSCN in a solvent such as methanol with a catalyst such as _2, or, pH 3-4 (adjusted with hydrochloric acid) in MeOH- water or such as water in the solvent NaCN or Strecker ketone with an amine using KCN Aminonitrile is obtained by (Strecker) condensation. Aminonitrile is reduced by LAH in a solvent such as THF or by hydrogenation using Raney Nickel as a catalyst in a solvent such as 7N ammonia in methanol, NH ₂ —CH ₂ —CR ₅ R _5- Y is obtained.

Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising at least one physiologically acceptable carrier or excipient with one or more compounds described herein. The pharmaceutical composition may be, for example, water, buffer (eg, sodium bicarbonate, neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, hydrocarbon (eg, glucose, 1 of mannose, sucrose, starch, mannitol, or dextran, protein, adjuvants, polypeptides or amino acids (such as glycine), antioxidants, chelating agents such as EDTA or glutathione, and / or preservatives It may include more than one. In addition, other active ingredients may be included (but need not be) in the pharmaceutical compositions described herein.

  The pharmaceutical composition may be formulated for any suitable method of administration including, for example, topical administration, oral administration, nasal administration, rectal administration, or parenteral administration. The term parenteral, as used herein, is subcutaneous, intradermal, intravascular (eg, intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, and any Including similar injection or infusion methods. In certain embodiments, compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In yet other embodiments, the pharmaceutical composition may be formulated as a lyophilized formulation. For certain symptoms (eg for the treatment of skin conditions such as burns or itching), topical formulations may be preferred. To treat urinary incontinence and overactive bladder, formulations that are administered directly to the bladder (intravesical administration) may be preferred.

  Compositions intended for oral use may further comprise one or more ingredients such as sweeteners, flavoring agents, coloring agents, and / or preservatives to provide a appealing and delicious formulation. Good. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (eg, calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate), granulating and disintegrating agents (eg, corn starch or alginic acid), binding Agents (eg, starch, gelatin or gum arabic) and lubricants (eg, magnesium stearate, stearic acid or talc). Tablets may be formed using standard methods including dry granulation, direct compression, and wet granulation. The tablets may be uncoated or they may be coated by known methods.

  Formulations for oral use are as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (eg calcium carbonate, calcium phosphate or kaolin) or the active ingredient is water or an oil medium (eg peanut oil, liquid Soft gelatin capsules mixed with paraffin or olive oil).

  Aqueous suspensions contain the active substances in a suspension (eg, sodium carboxymethyl cellulose, methyl cellulose, hydropropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum); and a dispersing or wetting agent [eg, natural Phospholipids (such as lecithin), condensation products of alkylene oxides and fatty acids (such as polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (such as heptadecaethyleneoxycetanol), fatty acids and Condensation products of partial esters derived from hexitol and ethylene oxide (such as polyoxyethylene sorbitol monooleate), or partial esters derived from fatty acids and anhydrous hexitol and ethylene oxide Condensation products of de contained in mixture with suitable excipients, such as (polyethylene sorbitan monooleate etc.). Aqueous suspensions may also contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and / or One or more sweetening agents such as sucrose or saccharin may be included.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (eg, arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and / or flavoring agents may be added to provide a palatable oral preparation. Such a suspension may be preserved by adding an antioxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents include those already mentioned above. There may also be additional excipients such as sweetening, flavoring, and coloring agents.

  The pharmaceutical composition may also be formulated as an oil-in-water emulsion. The oily phase may be a vegetable oil (eg olive oil or peanut oil), a mineral oil (eg liquid paraffin) or a mixture of these. Suitable emulsifiers include natural gums (eg, gum arabic or tragacanth), natural phospholipids (eg, soy lecithin, and esters or partial esters derived from fatty acids and hexitol), acid anhydrides (eg, sorbitan) Monooleate) and condensation products of partial esters derived from fatty acids and hexitol and ethylene oxide (eg, polyoxyethylene sorbitan monooleate). The emulsion may also contain one or more sweetening and / or flavoring agents.

  Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

  Formulations for topical administration typically include a topical vehicle that is combined with the active agent with or without additional optional ingredients. Suitable topical vehicles and additional components are well known in the art and it will be apparent that the choice of vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohol (eg, ethanol or isopropyl alcohol) or glycerine; glycols (eg, butylene glycol, isoprene glycol or propylene glycol); aliphatic alcohols (eg, lanolin); water and organic solvents And mixtures of alcohols and organic solvents such as glycerol; fatty acids, acylglycerols (including oils such as mineral oil and natural or synthetic fats), lipid-based substances such as phosphoglycerides, sphingolipids and waxes; collagen and gelatin Protein-based materials such as: silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. The composition is further applied to a formulation such as a stabilizer, suspending agent, emulsifier, viscosity modifier, gelling agent, preservative, antioxidant, skin penetration enhancer, moisturizer and sustained release material. One or more ingredients may be included that are configured to improve the stability or effectiveness of the. Examples of such components are described in Non-Patent Document 4 and Non-Patent Document 5. The formulation may comprise microcapsules such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

  Topical formulations may be prepared in any of a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous solutions, and emulsions. The physical appearance and viscosity of such pharmaceutically acceptable forms may be governed by the presence and amount of emulsifiers and viscosity modifiers present in the formulation. Solid agents are generally hard and cannot be poured, and are generally formulated as bars or sticks, or in particulate form; the solid agent may be opaque or transparent and may be a solvent, emulsifier, Moisturizers, emollients, perfumes, pigments / colorants, preservatives, and other active ingredients that increase or improve the effectiveness of the final product can optionally be included. Creams and lotions are often similar to each other, the main difference being their viscosity; both lotions and creams are opaque, translucent, or transparent. May contain emulsifiers, solvents and viscosity modifiers, as well as humectants, emollients, perfumes, pigments / colorants, preservatives and other active ingredients that increase or improve the effectiveness of the final product. There are many cases. Gels can be prepared to have a viscosity ranging from a thick or high viscosity to a thin or low viscosity. These formulations, as well as lotion and cream formulations, are solvents, emulsifiers, humectants, emollients, fragrances, pigments / colorants, preservatives and other active ingredients that increase or improve the effectiveness of the final product It may contain. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, humectants, emollients, fragrances, pigments / colorants, preservatives and other active ingredients that increase or improve the effectiveness of the final product.

  Suitable emulsifiers used in topical formulations include ionic emulsifiers, cetearyl alcohol, polyoxyethylene oleyl ether, stearic acid PEG-40, cetealess-12, cetealess-20, cetealess-30, cetealess alcohol, stearin Non-ionic emulsifiers such as, but not limited to, acid PEG-100 and glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. . The gel composition may be formed by the addition of a gelling agent such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammonium glycyrrhizinate. . Suitable surfactants include, but are not limited to, nonionic surfactants, amphoteric surfactants, ionic surfactants, and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropylphosphatidyl PG-dimonium chloride, and ammonium laureth sulfate It may be used in topical formulations. Suitable preservatives include antimicrobial agents (such as methylparaben, propylparaben, sorbic acid, benzoic acid and formaldehyde), as well as physical stabilizers and antioxidants (vitamin E, sodium ascorbate / ascorbic acid, and gallic acid Propyl) and the like, but is not limited thereto. Suitable humectants include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable fragrances and colorants include FD & C Red No. 40 and FD & C Yellow No. 5, but is not limited thereto. Other suitable additional ingredients that may be included in the topical formulation include abrasives, absorbents, anti-caking agents, antifoaming agents, antistatic agents, astringents (eg, witch hazel, alcohol, And herb extracts such as chamomile extract), binders / excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusting agents, and protective agents. For example, but not limited to.

  An example of a topical vehicle suitable for gel formulation is hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol / water (90.9%); propylene glycol (5.1%); and Polysorbate 80 (1.9%). Examples of suitable topical vehicles for formulation as foams are: cetyl alcohol (1.1%); stearyl alcohol (0.5%); Quaterium 52 (1.0%); propylene glycol (2.0%) Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percentages are percentages by weight.

  Typical delivery methods for topical compositions include application using a finger; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spray (including mist, aerosol or foam spray) Dropper administration; spraying; dipping; and washing.

  The pharmaceutical compositions may be prepared as sterile aqueous or oily suspension injections. The compounds described herein can be suspended or dissolved in the vehicle, depending on the vehicle and concentration used. Such compositions may be formulated according to known methods using suitable dispersing, wetting agents and / or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be used are water, 1,3-butanediol, Ringer's solution and physiological saline. In addition, sterile, fixed oils may be used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable compositions, and adjuvants such as local anesthetics, preservatives and / or buffering agents can be dissolved in the vehicle.

  The pharmaceutical composition may also be formulated as a suppository (eg, for rectal administration). Such a composition may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature, thus melting in the rectum and releasing the drug. it can. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

  Inhalable compositions are typically solutions, suspensions, or emulsions that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (eg, dichlorodifluoromethane or trichlorofluoromethane). Can be provided.

  The pharmaceutical composition may be formulated to be released at a predetermined rate. For example, immediate release may be achieved by sublingual administration (ie administration by mouth such that the active ingredient is rapidly absorbed by the sublingual blood vessels rather than the gastrointestinal tract). Controlled release formulations (ie, formulations such as capsules, tablets or coated tablets that slow and / or delay the release of the active ingredient after administration) are for example by oral, rectal or subcutaneous implantation or at the target site It may be administered by implanting. In general, controlled release formulations include matrices and / or coatings that delay disintegration and absorption in the gastrointestinal tract (or implantation site), thereby providing a delayed action or a sustained action over a relatively long period of time. One type of controlled release formulation is a sustained release formulation in which at least one active ingredient is continuously released at a constant rate over a period of time. Preferably, the therapeutic agent is such that the blood (eg, plasma) concentration is maintained within the therapeutic range but below the toxic level for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours. Released at a rate. Such formulations are generally prepared using well-known methods and may be administered, for example, by buccal, rectal, or subcutaneous implantation, or by implantation at a desired target site. The carriers used in such formulations may be biocompatible and biodegradable; preferably the formulation releases the modulator at a relatively constant level. The amount of modulator contained in the sustained release formulation depends, for example, on the implantation site, rate, and expected release duration, and the nature of the condition being treated or prevented.

  Controlled release may be achieved by combining the active ingredient with a matrix material that itself changes the rate of release and / or by using a controlled release coating. (A) changing the thickness or composition of the coating, (b) changing the amount or method of addition of the plasticizer in the coating, (c) including additional components such as a release modifier, (d) the matrix. The release rate can be varied using methods well known in the art, including varying the composition, particle size, or particle shape, and (e) providing one or more passages through the coating. The amount of modulator contained in the sustained release formulation depends, for example, on the method of administration (eg, implantation site), the rate of release and the expected duration, and the nature of the condition being treated or prevented.

  A matrix material that may or may not perform its own controlled release function is generally any material that supports the active ingredient. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The active ingredient may be combined with a matrix material before forming a dosage form (eg, tablet). Alternatively or additionally, the active ingredient may be coated on the surface of particles, granules, spheres, microspheres, beads or pellets containing matrix material. Such coating may be accomplished by conventional means such as spraying the active ingredient dissolved in water or other suitable solvent. Optionally, additional components are added prior to coating (eg, to help bind the active ingredients to the matrix material or to color the solution). The matrix may then be coated with a barrier agent prior to applying the controlled release coating. The multilayer coated matrix unit may be encapsulated to form the final dosage form, if desired.

  In certain embodiments, controlled release is achieved through the use of a controlled release coating (ie, a coating that allows the active ingredient to be released at a controlled rate in an aqueous medium). The controlled release coating must be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert, and non-sticky. Coatings that regulate modulator release include pH-independent coatings, pH-dependent coatings (which can be used to release modulators into the stomach), enteric coatings (formulations that pass through the stomach and enter the small intestine). , Where the coating dissolves and allows the contents to be absorbed by the body). It will be apparent that multilayer coatings may be used (for example to allow a portion of the dose to be released in the stomach and a portion to be released further along the gastrointestinal tract). For example, a portion of the active ingredient is coated on the enteric coating so that it is released in the stomach, and the remainder of the active ingredient in the matrix core is protected with the enteric coating, further down the gastrointestinal tract. It may be released. Examples of the pH-dependent coating include shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylate copolymer and zein.

  In certain embodiments, the coating is preferably a hydrophobic material used in an amount effective to slow the hydration of the gelling agent after administration. Suitable hydrophobic materials include alkyl celluloses (eg ethyl cellulose or carboxymethyl cellulose), cellulose ethers, cellulose esters, acrylic polymers (eg poly (acrylic acid), poly (methacrylic acid), co-polymerization of acrylic acid and methacrylic acid. Copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, poly (methyl methacrylate), polyacrylamide, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer, poly (anhydrous) Methacrylic acid) and glycidyl methacrylate copolymers), and mixtures thereof. Representative aqueous dispersions of ethyl cellulose include, for example, AQUACOAT® (FMC Corp., Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), which are Both can be applied to the substrate according to the manufacturer's instructions. Exemplary acrylic polymers include, for example, various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which can be used alone, depending on the desired release profile, according to the manufacturer's instructions. They may be used or used in combination.

  One or more plasticizers may be added to improve the physical properties of the coating comprising the aqueous dispersion of hydrophobic material. Suitable plasticizers for alkyl cellulose include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin. Suitable plasticizers for acrylic polymers include, for example, citrate esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, and triacetin.

  Controlled release coatings are generally applied using conventional methods such as spraying in the form of an aqueous dispersion. If desired, the coating may include pores or channels to facilitate the release of the active ingredient. The pores and channels may be generated by well known methods including adding organic or inorganic materials that dissolve, extract or leach from the coating in the environment of use. Certain such pore-forming materials include hydrophilic polymers such as hydroxyalkylcellulose (eg, hydroxypropylmethylcellulose), cellulose ethers, synthetic water-soluble polymers (eg, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and polyethylene oxide), Water-soluble polydextrose, saccharides and polysaccharides, and alkali metal salts. Alternatively or additionally, the controlled release coating can be formed by one or more methods that can be formed by methods such as those described in US Pat. An orifice may be included. Controlled release may also be achieved by using conventional techniques and using transdermal patches (see, for example, US Pat.

  Other examples of controlled release formulations and components thereof are, for example, Patent Document 10, Patent Document 11, Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, Patent Literature 19, Patent Literature 20, Patent Literature 21, Patent Literature 22, Patent Literature 23, Patent Literature 24, Patent Literature 25, Patent Literature 26, Patent Literature 27, Patent Literature 28, Patent Literature 29, Patent Literature 30, Patent Literature 31, Patent Literature 32, Patent Literature 33, Patent Literature 34, Patent Literature 35, Patent Literature 36, Patent Literature 37, Patent Literature 39, Patent Literature 39, Patent Literature 40, Patent Literature 41, Patent Literature 42, Patent Literature 43 and See US Pat. No. 6,057,096, each of which is hereby incorporated by reference with respect to the teaching of the preparation of controlled release dosage forms.

  In addition to or in conjunction with the above modes of administration, the compounds described herein may be conveniently added to food or drinking water (eg, companion animals (such as dogs and cats) and livestock) For administration to non-human animals). Animal feed and drinking water compositions may be formulated so that the animal receives an appropriate amount of the composition along with the diet. It may also be advantageous to provide the composition as a premix that is added to the feed or drinking water.

  The compound is generally administered in a therapeutically effective amount. A preferred systemic dose is 50 mg or less per kilogram of body weight per day (eg, in the range of about 0.001 mg to about 50 mg per kilogram of body weight per day), and oral doses are generally about 5 to 20 times greater than intravenous doses. High (eg, in the range of 0.01 to 40 mg per kilogram of body weight per day).

  The amount of active ingredient that can be combined with a carrier material to produce a dosage unit will vary depending, for example, upon the patient being treated, the particular mode of administration, and any other co-administered drugs. Dosage units generally contain about 10 μg to about 500 mg of the active ingredient. Optimal dosages can be established using routine testing and procedures well known in the art.

The pharmaceutical compositions may, symptoms that respond to modulation P2X ₇ receptor (e.g., pain, inflammation, other conditions described in neurodegeneration or described herein) may be packaged for treating. The packaged pharmaceutical composition generally comprises (i) a container containing a pharmaceutical composition comprising at least one modulator described herein, and (ii) the contained composition is the patient's P2X ₇ receptor Includes instructions (eg, a label or package insert) indicating that it can be used to treat a condition responsive to modulation.

Methods of Use The P2X ₇ receptor modulators described herein can be used to alter P2X ₇ receptor activity and / or activation both in vitro and in vivo in a variety of situations. In certain aspects, a P2X ₇ receptor antagonist can be used to inhibit binding of a ligand agonist to the P2X ₇ receptor in vitro or in vivo. In general, such methods, an aqueous solution, in the presence of ligand, and other ligand under suitable conditions to bind P2X ₇ receptors, the P2X ₇ receptor, as described herein 1 One containing more P2X ₇ contacting the receptor modulators. Modulators are generally present in a concentration sufficient to alter the signal transduction mediated (using the assays described in Example 7) by P2X ₇ receptor. P2X ₇ receptors, the solution or suspension (e.g., in isolated membranes (isolated membrane) or cell sample (cell preparation)), or present in the cell that that has been or isolated cultures Can do. In certain embodiments, P2X ₇ receptor expressed by cells present in the patient, the aqueous solution is a body fluid. Preferably, one or more in an amount such that the modulator is present in at least one bodily fluid of the animal at a therapeutically effective concentration of 20 micromolar or less, 10 micromolar or less, 5 micromolar or less, or 1 micromolar or less Are administered to animals. For example, such compounds may be administered at a therapeutically effective dose of less than 20 mg / kg body weight, preferably less than 5 mg / kg, and in some cases less than 1 mg / kg.

Also described herein are methods of modulating, preferably reducing, the activation and / or activity of cellular P2X ₇ receptors, such as signaling activity (eg, calcium conductance). Such modulation involves contacting the P2X ₇ receptor (in vitro or in vivo) with one or more modulators described herein in conditions suitable to bind the modulator to the P2X ₇ receptor. Can be achieved. Modulators are generally present in a concentration sufficient to alter the signal transduction mediated by P2X ₇ receptor described herein. The receptor may be present in solution or suspension, in a cultured or isolated cell specimen, or in a patient's cells. For example, the animal may be contacted with an in vivo cell. Modulation of signaling activity can be assessed by detecting effects on calcium ion conductance (also referred to as calcium mobilization or calcium influx). Modulation of signaling activity can alternatively be assessed by detecting changes in symptoms (eg, pain or inflammation) in patients treated with one or more modulators described herein.

The P2X ₇ receptor modulators described herein are preferably administered orally or topically to a patient (eg, a human) and are present in at least one body fluid of the animal, at which time P2X ₇ receptor signaling activity To adjust.

The present invention further provides a method of treating a condition responsive to modulation P2X ₇ receptor. In the context of the present invention, the term “treatment” includes both disease modifying treatment and symptomatic treatment, both of which are prophylactic (ie prevent symptoms before onset of symptoms). May be delayed, delayed or reduced in severity), or therapeutic (ie, after the onset of symptoms, to reduce the severity of symptoms and / or the duration of symptoms). When symptoms are characterized by inappropriate P2X ₇ receptor activity regardless of the amount of P2X ₇ agonist present locally, and / or when symptoms or signs thereof are reduced as a result of modulation of P2X ₇ receptor activity Symptom "responds to P2X ₇ receptor modulation". Such symptoms include, for example, pain, inflammation, cardiovascular disorders, eye disorders, neurodegenerative disorders, and respiratory disorders (cough, asthma, chronic obstructive pulmonary disease, chronic bronchitis, cystic fibrosis, and Allergic rhinitis such as seasonal or perennial rhinitis, and rhinitis including non-allergic rhinitis), fibrosis, and other symptoms described in more detail below. Such symptoms can be diagnosed and monitored using criteria established in the art. Patients include humans, domestic companion animals and livestock, and the dosage is as described above.

  The treatment regime may vary depending on the compound used and the particular condition that can be treated; however, a frequency of administration of 4 times daily or less is preferred for the treatment of most disorders. In general, a twice daily dosing regimen is more preferred, with once a day administration being particularly preferred. For the treatment of acute pain, a single dose that quickly reaches an effective concentration is desirable. However, the specific dose level and treatment plan for any particular patient will depend on the activity, age, weight, overall health, sex, diet, time of administration, route of administration, and the particular compound used. It will be appreciated that it depends on a variety of factors including excretion rate, drug combination, and the severity of the particular disease being treated. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. In general, the patient's therapeutic effect may be monitored using medical or veterinary criteria suitable for the condition being treated or prevented.

  Pain that can be treated using the modulators described herein includes, for example, acute pain, chronic pain, inflammatory pain, and neuropathic pain. Specific pain indications that can be treated as described herein include pain associated with osteoarthritis or rheumatoid arthritis; various neuropathic pain syndromes (postherpetic neuralgia, trigeminal neuralgia, reflexes) Sensitive dystrophy, diabetic neuropathy, Guillain-Barre syndrome, fibromyalgia, oral neuropathic pain, phantom limb pain, post-mastectomy pain, peripheral neuropathy, myofascial pain syndrome, MS-related neuropathy, HIV or AIDS-related neuropathy and chemotherapy-induced and other iatrogenic neuropathies); visceral pain (gastroesophageal reflux disease (GERD), irritable bowel syndrome, inflammatory bowel disease, pancreatitis, intestinal gas, Gynecological disorders (eg, menstrual pain, dysmenorrhea, pain associated with cystitis, labor labor, chronic pelvic pain, chronic prostatitis, endometriosis, heart pain, and abdominal pain) and those associated with urological disorders Na ); Dental pain (eg, toothache, denture pain, nerve root pain, pain resulting from periodontal disease, and pain due to dental surgery including surgical and postoperative pain); headache (eg, headache with peripheral nerve activity, Sinusitis headache, cluster headache (ie, migrainous neuralgia), tension headache, migraine, temporomandibular joint pain, and maxillary sinus pain); stump pain; sensory abnormal femoral neuralgia; Pain associated with nerve and root injuries, such as peripheral neuropathy (eg, nerve strangulation and brachial plexus detachment, amputation, peripheral neuropathy including bilateral peripheral nerve injury, trigeminal pain tics, atypical facial pain, Nerve root injury and arachnoiditis), causalgia, neuritis (eg, sciatic neuritis, peripheral neuritis, polyneuritis, optic neuritis, post-fever neuritis, migratory neuritis, segmental neuritis, and Gombo nerve flame( neuronitis, neuralgia (eg, those described above, cervical neuralgia, cranial neuralgia, knee neuralgia, glossopharyngeal neuralgia, idiopathic neuralgia, intercostal neuralgia, breast neuralgia, jaws) Pain associated with joint neuralgia, Morton neuralgia, rhinocephalic neuralgia, occipital neuralgia, erythema, thruder neuralgia, splenopalatine neuralgia, supraorbital neuralgia, and Vidian neuralgia); surgery related pain; musculoskeletal pain; Include, but are not limited to, nervous system pain (eg, pain due to brainstem injury, sciatica, and ankylosing spondylitis); and spinal pain, including spinal cord injury related pain.

  Other pain conditions that can be treated as described herein include Charcot's pain, ear pain, muscle pain, eye pain, orofacial pain (eg, toothache), carpal tunnel syndrome, Acute and chronic back pain (eg, back pain), gout, scar pain, colic, dyspepsia, angina, nerve root pain, "non-painful" neuropathy, complex local pain syndrome, primary pain pain) and ectopic pain, such as pain associated with carcinomas often referred to as cancer-associated pain (eg, in patients with osteosarcoma), venom exposure (eg, snake bites, spiders) Pain (and inflammation) associated with bites or insect stings, and pain associated with trauma (eg, postoperative pain, perineal incision pain, pain due to cuts, musculoskeletal pain, bruises and Folding, and burn pain, especially include primary hyperalgesia) associated with it. Other pain symptoms that can be treated as described herein include autoimmune diseases or immune deficiency disorders, hot flashes, burns, sunburn pain, and fever, cold or external chemistry. Pain that occurs as a result of exposure to a stimulus.

  Symptoms associated with inflammation and / or immune system disorders that can be treated using the modulators described herein include arthritis (osteoarthritis, rheumatoid arthritis, psoriatic arthropathy, Reiter syndrome, gout, traumatic) Arthritis, rubella arthritis, rheumatoid spondylitis, gouty arthritis, and juvenile arthritis); cystic fibrosis; uveitis; systemic lupus erythematosus (and associated glomerulonephritis); spondyloarthropathy; Scleritis; allergic symptoms (including allergic reactions, allergic rhinitis, allergic contact hypersensitivity, allergic dermatitis, eczema and contact dermatitis), reperfusion injury (eg heart and kidney reperfusion injury), respiratory tract System disorders (airway hyperresponsiveness, cough, asthma (eg, bronchial, allergy, intrinsic, extrinsic, exercise-induced, drug-induced (eg, aspirin To prevent or reduce the severity of both acute early asthma attacks and late late reactions following such asthma attacks, including NSAID-induced) and dust-induced asthma), reactive airway disease, qi Tumor, acute (adult) dyspnea syndrome (ARDS), bronchitis (eg infectious and eosinophilic bronchitis), bronchiectasis, chronic obstructive pulmonary disorder (COPD), chronic inflammatory lung disease, silicosis , Pulmonary sarcoid, farmer's lung, including irritable pneumonia and pulmonary fibrosis), viral infection, fungal infection, bacterial infection, Crohn's disease, glomerulonephritis, HIV infection and AIDS, irritable bowel syndrome, inflammatory Bowel disease, dermatomyositis, multiple sclerosis, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolysis and thrombocytopenia, good path Syndrome (and associated glomerulonephritis and pulmonary hemorrhage), tissue graft rejection, hyperacute rejection of transplanted organs, allograft rejection, organ transplant toxicity, neutropenia, sepsis, septic shock, endotoxin Shock, conjunctivitis shock, toxic shock syndrome, Alzheimer's disease, inflammation associated with severe burns, lung injury, systemic inflammatory response syndrome (SIRS), neonatal-onset multiple organ inflammatory disease (NOMID), Hashimoto's disease, Graves' disease , Addison's disease, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE syndrome, antiphospholipid antibody syndrome, leprosy, Sezary syndrome, paraneoplastic syndrome, Mackle-Wells syndrome, lichen planus, family Cold autoinflammatory syndrome (FCAS), colitis, ruptured abdominal aortic aneurysm, and multiple organ dysfunction syndrome (MODS) Not determined. Also, pathological sequelae (including diabetic retinopathy) associated with insulin-dependent diabetes, lupus nephropathy, Hayman nephritis, membranous nephritis, and other forms of glomerulonephritis, macular degeneration, contact hypersensitivity reactions, and Occurs during extracorporeal circulation of blood, such as, for example, post-external dialysis syndrome (eg, during hemodialysis or in cardiopulmonary, used, for example, during vascular surgery such as coronary artery bypass grafting or heart valve replacement) Such as from contact with blood and artificial surfaces, or with contact with other artificial blood vessels or container surfaces (eg, assistive heart, artificial heart, transfusion tubes, blood storage bags, plasmapheresis, and plateletpheresis, etc.) The inflammation that occurs is also mentioned.

Still other conditions that can be treated using the modulators described herein include the following:
Cardiovascular diseases such as cardiovascular disease, stroke, cerebral ischemia, myocardial infarction, atherosclerosis, ischemic heart disease, ischemia reperfusion injury, aortic aneurysm, and congestive heart failure;
Eye disorders such as glaucoma;
But not limited to: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Creutzfeldt-Jakob disease, Lewy body dementia, traumatic brain injury, spinal cord injury, neurotrauma, cerebral amyloid angiopathy, And progressive central nervous system disorders including encephalitis; epilepsy and seizure disorders; multiple sclerosis and other demyelinating syndromes; cerebral arteriosclerosis; vasculitis; temporal arteritis; myasthenia gravis; neurosarcoidosis; Neuropathies such as neurodegenerative symptoms associated with central and peripheral nervous system complications of malignant, infectious, or autoimmune processes (eg, neurodegeneration); using the modulators described herein to promote nerve regeneration May be;
Central neuropsychiatric disorders such as depression, manic depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders, and cognitive disorders; and cirrhosis, interstitial fibrosis, prostate, bladder, and intestines Dysfunction (eg, urinary incontinence, urinary tract, rectal hypersensitivity, fecal incontinence and benign prostatic hypertrophy); itch / pruritus; obesity; lipid disorder; cancer; hypertension; renal disorder; abnormal wound healing; diabetes; meningitis; varicose veins; muscle degeneration; vicious fluid; restenosis; thrombosis; cerebral malaria; bone and joint disorders (eg, osteoporosis, bone resorption disease, artificial joint implants) Looseness and other previously mentioned); epidermolysis bullosa; ocular angiogenesis; corneal damage; corneal scarring; and other disorders such as tissue ulceration.

  The modulators described herein may also be used for neuroprotection of the optic nerve (eg, to inhibit death of a patient's retinal ganglion cells).

In another aspect, a combination therapy for the treatment of a modulator as described herein, symptoms that respond to modulation P2X ₇ receptor (symptoms e.g., pain and / or inflammatory component (inflammatory components) it is involved) May be used for Such symptoms include, for example, autoimmune disorders and pathological autoimmune reactions known to have an inflammatory component, such as, but not limited to, arthritis (especially rheumatoid arthritis), psoriasis, Crohn's disease, Lupus erythematosus, irritable bowel syndrome, tissue graft rejection, and hyperacute rejection of transplanted organs. Other such symptoms include trauma (eg, head or spinal cord injury), cardiovascular and cerebrovascular diseases, and certain infections.

  In such combination therapy, the modulator is administered to the patient along with a second therapeutic agent (eg, an analgesic and / or anti-inflammatory agent). The modulator and the second therapeutic agent may be present in the same pharmaceutical composition, or may be administered separately in either order. Anti-inflammatory agents include, for example, non-steroidal anti-inflammatory drugs (NDAIDs), non-specific and cyclooxygenase-2 (COX-2) -specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, leflunomide, cyclosporin A, IM gold, minocycline, azathioprine, tumor necrosis factor (TNF) receptor antagonist, soluble TNFα receptor (etanercept), anti-TNFα antibody (eg, infliximab and adalimumab), anti-C5 antibody, interleukin-1 (IL-1) receptor Body antagonists (eg, anakinra or IL-1 trap), IL-18 binding proteins, CTLA4-Ig (eg, abatacept), anti-human IL-6 receptor monoclonal antibodies (eg, tocilizumab), L FA-3-Ig fusion protein (eg, alefacept), LFA-1 antagonist, anti-VLA4 monoclonal antibody (monoantibody) (eg, natalizumab), anti-CD11a monoclonal antibody, anti-CD20 monoclonal antibody (eg, rituximab), anti-IL-12 Monoclonal antibodies, anti-IL-15 monoclonal antibodies, CDP484, CDP870, chemokine receptor antagonists, selective iNOS inhibitors, p38 kinase inhibitors, integrin antagonists, angiogenesis inhibitors, and TMI-1 dual inhibitors. Other anti-inflammatory agents include meloxicam, rofecoxib, celecoxib, etoroxixib, parecoxib, valdecoxib, and chilicoxib.

  NSAIDs include ibuprofen, flurbiprofen, naproxen or naproxen sodium, diclofenac, diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone , Sulfasalazine, tolmetin sodium, and hydroxychloroquine, but are not limited to these. One type of NSAIDs consists of compounds that inhibit the cyclooxygenase (COX) enzyme; such compounds include celecoxib and rofecoxib. NSAIDs further include salicylates such as acetylsalicylic acid or aspirin, sodium salicylate, choline magnesium salicylate, and salsalate, and corticosteroids such as cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. It is done.

Suitable dosages P2X ₇ receptor modulator such combination therapy are generally as described above. The dosage and method of administration of the anti-inflammatory agent can be found, for example, in the manufacturer's instructions for Physician's Desk Reference. In certain embodiments, co-administration of a modulator and an anti-inflammatory agent results in a decrease in the dose of anti-inflammatory agent necessary to produce a therapeutic effect (ie, a minimal therapeutically effective amount). Thus, preferably, the dose of anti-inflammatory agent in the combination or combination therapy method is less than the maximum dose recommended by the manufacturer for administration of the anti-inflammatory agent when the modulator is not administered in combination. More preferably, this dose is less than 3/4 of the maximum dose, even more preferably less than 1/2, very preferably less than 1/4, and most preferably the dose is administered without co-administration of the modulator. Less than 10% of the maximum dose recommended by the manufacturer for administration of anti-inflammatory agents. It will be apparent that the dosage of the combined modulator component necessary to achieve the desired effect can also be reduced by co-administration of anti-inflammatory agents.

  In certain preferred embodiments, the combined administration of a modulator and an anti-inflammatory agent includes placing one or more modulators and one or more anti-inflammatory agents in the same package, in separate containers within the package, or one This is accomplished by packaging in the same container as a mixture of the above modulator and one or more anti-inflammatory agents. Preferred mixtures are formulated for oral administration (eg, as a pill, capsule or tablet). In certain embodiments, the packaging includes a label having an indication that one or more modulators and one or more anti-inflammatory agents can be taken together for the treatment of inflammatory pain symptoms.

  In other aspects, the modulators described herein may be used in combination with one or more additional analgesics. Certain such agents are also anti-inflammatory agents and have been described above. Other such agents are analgesics, including anesthetics that typically act as one or more opioid receptor subtypes (eg, μ, κ and / or δ), preferably as agonists or partial agonists. is there. Such agents include opiates, opiates and opioids, and pharmaceutically acceptable salts and hydrates thereof. Specific examples of anesthetic analgesics include, in a preferred embodiment, alfentanil, alphaprozine, anilellidine, vegitramide, buprenorphine, butorphanol, codeine, diacetyldihydromorphine, diacetylmorphine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, Heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphan, levorphanol, meperidine, metazocine, methadone, metorphan, methopone, morphine, nalbuphine, opium extract, opiate extract, opium powder, granular opium, raw Opium, opiate tincture, oxycodone, oxymorphone, opiate benzoin tincture, pentazocine, pethidine, phenazosin, pimidine, propoxyphene, race Turpan, racemorphan, sulfentanyl, thebaine, as well as the pharmaceutically acceptable salts and hydrates of the foregoing agents.

  Other examples of anesthetic analgesics include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprozin, alphaacetylmethadol, alphameprozin, alphamethadol, benzethidine, benzylmorphine, betacetylmethadol, beta Meprozin, betamethadol, betaprozin, clonitazene, codeine methyl bromide, codeine-N-oxide, cyprenorphine, desomorphine, dextromoramide, dianpromide, diethylthianbutene, dihydromorphine, dimenoxador, dimefeptanol, dimethyl Dimethylthiamubutene, dioxafetil butyrate, dipipanone, drotevanol, etano , Ethylmethylthianbutene, etonithazen, etorphine, ethoxeridine, fretidine, hydromorphinol, hydroxypetidin, ketobemidone, levomoramide, levofenacil morphane, methyl desorbin, methyl dihydromorphine, morpheridine, morphine, methyl bromide ), Morphine methyl sulfonate, morphine-N-oxide, myrophine, naloxone, naltyhexone, nicocodeine, nicomorphine, norasimethadol, norlevorphanol, normethadone, normorphinone a) , Phenadoxone, phenampromide, phenomorphan, pheno Lysine, piritramide, pholcodine, Puroheputajin (proheptazoine), Puroperijin, Puropiran, racemoramide, thebacon, trimeperidine, and these pharmaceutically acceptable salts and hydrates thereof.

  Other specific representative analgesics include, for example, acetaminophen (paracetamol); aspirin and other aforementioned NSAIDs; NR2B antagonists; bradykinin antagonists; antimigraine agents; anticonvulsants such as oxcarbazepine and carbamazepine Drugs; antidepressants (TCAs, SSRIs, SNRIs, substance P antagonists, etc.); spinal anesthesia; pentazocine / naloxone; meperidine; levorphanol; buprenorphine; hydromorphone; fentanyl; sufentanil; oxycodone; oxycodone / acetaminophen, nalbuphine and And oxymorphone. Still other analgesics include CB2-receptor agonists such as AM1241, capsaicin receptor antagonists, and compounds that bind to the α2δ subunit of voltage-gated calcium channels such as gabapentin and pregabalin.

Representative anti-migraine agents used in combination with the modulators described herein include CGRP antagonists, capsaicin receptor antagonists, ergotamine, and sumatriptan, naratriptan, zolmitriptan ( Zolmatriptan) and include 5-HT ₁ agonists such as rizatriptan.

In yet other aspects, the modulators described herein are one or more β (2) -adrenergic receptor agonists or leukotriene receptor antagonists (eg, for the treatment of pulmonary disorders such as asthma, such as A drug that inhibits the cysteinyl leukotriene CysLT ₁ receptor) may be used in combination. CysLT ₁ antagonists include montelukast, zafirlukast, and pranlukast.

For the treatment of retinal neuroprotection and eye disorders, eye, of the P2X ₇ receptor modulators, for example, agents that inhibit ATP release, the drug and / or retinal ganglion cells to increase the conversion of ATP to adenosine It may be administered in combination with one or more agents that inhibit Ca ⁺² influx. Such agents include, for example, adenosine A ₃ receptor agonist, adenosine A ₁ receptor agonist, ectonucleotidase agonists include Ca ⁺² chelator and NMDA receptor antagonists.

Suitable dosages P2X ₇ receptor modulator within such combination therapy are generally as described above. Other pain relief medication dosages and methods of administration can be found, for example, in the manufacturer's instructions for Physician's Desk Reference. In certain embodiments, administering a modulator in combination with one or more additional analgesics reduces the dose of each therapeutic agent required to produce a therapeutic effect (eg, for one or both agents). (The dose may be less than 3/4, less than 1/2, less than 1/4, or less than 10% of the maximum dose mentioned above or recommended by the manufacturer.)

For use in combination therapy, the aforementioned pharmaceutical composition may further comprise one or more additional agents as described above. In certain such compositions, the additional drug is an analgesic. Also described herein is a packaged pharmaceutical formulation comprising one or more modulators and one or more additional agents (eg, analgesics) in the same package. Such packaged pharmaceutical formulations generally comprise (i) a container containing a pharmaceutical composition comprising at least one modulator as described herein; (ii) at least one additional agent (analgesic agent) as described above. and / or anti-inflammatory agents, etc.) pharmaceutical compositions comprising a container for housing; treating or preventing a condition responsive (including symptoms of pain and / or inflammation is prominent) in and (iii) P2X ₇ receptors of the patient adjusting Instructions for use (eg, labels or package inserts) indicating that the compositions can be used simultaneously, separately or sequentially.

In another aspect, the present invention provides various non-pharmaceutical uses in vitro and in vivo of the modulator compounds described herein. For example, labeled such compounds, P2X ₇ receptor may be used as probes for the detection and localization (cell sample, or tissue sections, in a sample, such as the sample or fraction). In addition, the modulators described herein containing suitable reactive groups (such as arylcarbonyl groups, nitro groups or azide groups) may be used for studying receptor binding sites by photoaffinity labeling. Furthermore, the modulators described herein may be used as a positive control in receptor activity assays or as a radiotracer (eg, in receptor mapping methods). For example, the modulator compound can be labeled using any of a variety of well-known methods (eg, radiolabeled with a radionuclide such as tritium as described herein) and P2X ₇ in cultured cells or tissue samples. It may be used as a probe for receptor autoradiography (receptor mapping) of the receptor, which may be performed as described by Kuhar in Non-Patent Document 6; Which is incorporated herein by reference. How such receptors mapping method also positron emission tomography (PET) imaging or single photon emission computed tomography, such as (SPECT), can be used to characterize the P2X ₇ receptor in the living body including.

  The following examples are given for illustrative purposes and are not intended to be limiting. Unless otherwise noted, all reagents and solvents are of standard commercial grade and are used without further purification. Conventional modification methods may be used to vary the starting materials and use additional steps to produce other compounds described herein.

  The mass spectrometry data described herein is electrospray MS obtained in positive ion mode. Unless otherwise stated, such data is obtained from a Waters 600 pump (Waters Corp.), a Waters 996 photodiode array detector (Waters Corp.), and a Gilson 215 autosampler (Gilson, Inc .; Middleton, WI). ) With Micromass Time-of-Flight LCT (Waters Corp .; Milford, Mass.). MassLynx (TM) (Waters Corp.) version 4.0 software with OpenLynx Global Server (TM), OpenLynx (TM), and AutoLynx (TM) processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 350 ° C. and 120 ° C. each; mass range = 181-750, scan time 0. 22 seconds and interscan delay 0.05 seconds.

  In the data marked with “§”, the mass spectrometry data were obtained from a Waters 600 pump (Waters Corp.), a Waters 996 photodiode array detector (Waters Corp.), and a Gilson 215 autosampler (Gilson, Inc .; Middleton). , WI) with a Waters ZMD II Mass Spectrometer (Waters Corp.). MassLynx ™ (Waters Corp.) version 4.0 software with OpenLynx Global Server ™, OpenLynx ™, and AutoLynx ™ processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and ion source temperature = 250 ° C. and 100 ° C. each; mass range = 100-800, scan time 0.5 sec and inter Scan delay 0.1 seconds.

  In both methods, a 1 microliter sample volume is injected into a 50 × 4.6 mm Chromolith SpeedROD RP-18e column (Merck KGaA, Darmstadt, Germany) and a two-phase linear concentration gradient (2- Elute using phase linear gradient). Samples are detected using total absorbance counts over the 220-340 nm UV range. The elution conditions are: mobile phase A—95% water, MeOH (with 0.05% TFA) 5%; mobile phase B—5% water, MeOH (with 0.025% TFA) 95%. Use the following gradient: 0-0.5 min, B10-100%, hold at B100% until 1.2 min, return to B10% at 1.21 min. The cycle from injection to injection is 2.15 minutes.

When displayed, the LC retention time (R _T ) is stated in minutes.

ジオキサン５０ｍＬ中のメチル１Ｈ−インドール−３−カルボキシレート（３．５ｇ、０．０２ｍｏｌ）と２−クロロピリミジン（２．２８ｇ、０．０２ｍｏｌ）の混合物にカリウムｔ−ブトキシド（２．５２ｇ、０．０２２ｍｏｌ）を添加する。反応混合物を１１０℃に加熱し、２０時間攪拌する。減圧下でジオキサンを留去し、残留物を水（１００ｍＬ）で希釈する。固体をろ過し、シリカゲルカラムクロマトグラフィー（１５％ＥｔＯＡｃ／ＤＣＭ）で精製し、標記化合物を白色固体として得る。 Example 1
N- (adamantan-1-ylmethyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide Step 1. Methyl 1- (pyrimidin-2-yl) -1H-indole-3-carboxylate

To a mixture of methyl 1H-indole-3-carboxylate (3.5 g, 0.02 mol) and 2-chloropyrimidine (2.28 g, 0.02 mol) in 50 mL of dioxane was added potassium t-butoxide (2.52 g,. 022 mol) is added. The reaction mixture is heated to 110 ° C. and stirred for 20 hours. Dioxane is distilled off under reduced pressure and the residue is diluted with water (100 mL). The solid is filtered and purified by silica gel column chromatography (15% EtOAc / DCM) to give the title compound as a white solid.

ＥｔＯＨ５０ｍＬ中のメチル１−（ピリミジン−２−イル）−１Ｈ−インドール−３−カルボキシレート（１．４ｇ、０．００５５ｍｏｌ）の混合物に１．０ＮのＮａＯＨ水溶液（１０ｍＬ）を添加し、７０℃で４時間加熱する。反応混合物を減圧下で濃縮し、水（５０ｍＬ）で希釈し、濃ＨＣｌでｐＨ２．０の酸性にする。分離した白色固体をろ過し、水（２×２５ｍＬ）で洗浄し、乾燥させて標記化合物を得る。 Step 2.1- (Pyrimidin-2-yl) -1H-indole-3-carboxylic acid

To a mixture of methyl 1- (pyrimidin-2-yl) -1H-indole-3-carboxylate (1.4 g, 0.0055 mol) in 50 mL EtOH was added 1.0 N aqueous NaOH (10 mL) at 70 ° C. Heat for 4 hours. The reaction mixture is concentrated under reduced pressure, diluted with water (50 mL) and acidified to pH 2.0 with concentrated HCl. The separated white solid is filtered, washed with water (2 × 25 mL) and dried to give the title compound.

ＤＭＦ２．０ｍＬ中の１−（ピリミジン−２−イル）−１Ｈ−インドール−３−カルボン酸（７２ｍｇ、０．３ｍｍｏｌ）の混合物に、ジイソプロピルエチルアミン（０．２ｍＬ）、１−アダマンタンメチルアミン（４９．５ｍｇ、０．３ｍｍｏｌ）、およびＢＯＰ（１５０ｍｇ）を順次添加する。得られる混合物を室温で２０時間攪拌する。水（３ｍＬ）を添加し、固体をろ過し、シリカゲルカラムクロマトグラフィー（２５％ＥｔＯＡｃ／ヘキサン）で精製し、標記化合物を白色固体として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ８．８１（１Ｈ，ｄ），８．７１（３Ｈ，ｄｄ）８．１３（１Ｈ，ｄ），７．３３（２Ｈ，ｍ），７．１１（１Ｈ，ｄ），６．１３（１Ｈ，ｓ），３．２１（２Ｈ，ｄ），１．６１（１２Ｈ，ｍ）。質量分析（３８７．２４，Ｍ＋Ｈ）。 Step 3. N- (adamantan-1-ylmethyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide

To a mixture of 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (72 mg, 0.3 mmol) in 2.0 mL of DMF was added diisopropylethylamine (0.2 mL), 1-adamantanemethylamine (49. 5 mg, 0.3 mmol) and BOP (150 mg) are added sequentially. The resulting mixture is stirred at room temperature for 20 hours. Water (3 mL) is added and the solid is filtered and purified by silica gel column chromatography (25% EtOAc / hexanes) to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (1H, d), 8.71 (3H, dd) 8.13 (1H, d), 7.33 (2H, m), 7.11 ( 1H, d), 6.13 (1H, s), 3.21 (2H, d), 1.61 (12H, m). Mass spectrometry (387.24, M + H).

ＤＭＦ５０ｍＬを仕込んだ丸底フラスコを０℃に冷却し、オキシ塩化リン（８．１ｍＬ、８８ｍｍｏｌ）を滴下する。約５分間攪拌した後、ＤＭＦ５０ｍＬ中の４−ブロモインドール（５．０ｍＬ、４０ｍｍｏｌ）の溶液を滴下する。氷浴を取り除き、反応混合物を室温で１時間攪拌する。反応は非常に濃厚な懸濁液になる。混合物を再び０℃に冷却し、水８０ｍＬ中のＫＯＨ２２ｇと共に注意深く急冷する。得られる混合物をＥｔＯＡｃ（２００ｍＬ）と飽和ＮａＨＣＯ_３（１００ｍＬ）の間で分配する。ＥｔＯＡｃ層を飽和食塩水（ｂｒｉｎｅ）（１００ｍＬ）と水（１００ｍＬ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、減圧下で蒸発させて褐色固体を得、エーテル中で粉砕し、標記化合物をオフホワイトの固体として得る。 Example 2
N-[(1-Pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide Step 1.4-Bromo-1H-indole- 3-carbaldehyde

A round bottom flask charged with 50 mL of DMF is cooled to 0 ° C. and phosphorus oxychloride (8.1 mL, 88 mmol) is added dropwise. After stirring for about 5 minutes, a solution of 4-bromoindole (5.0 mL, 40 mmol) in 50 mL DMF is added dropwise. The ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The reaction becomes a very thick suspension. The mixture is again cooled to 0 ° C. and carefully quenched with 22 g of KOH in 80 mL of water. The resulting mixture is partitioned between EtOAc (200 mL) and saturated NaHCO ₃ (100 mL). The EtOAc layer was washed with brine (100 mL) and water (100 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give a brown solid, triturated in ether, The title compound is obtained as an off-white solid.

ＤＭＦ６５ｍＬ中の４−ブロモ−１Ｈ−インドール−３−カルバルデヒド（３．１ｇ、１３．８ｍｍｏｌ）の溶液に、２−（フルオロスルホニル）ジフルオロ酢酸メチル（３．５ｍＬ、２７．６ｍｍｏｌ）およびヨウ化銅（Ｉ）（５．３ｇ、２７．６ｍｍｏｌ）を添加する。反応を８５℃に１８時間加熱する。室温に冷却した後、混合物をＥｔＯＡｃで希釈し、セライトでろ過する。セライトをＥｔＯＡｃで十分洗浄する。ろ液を水（３回）および飽和食塩水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、蒸発させて、褐色油状物を得る。シリカゲルカラムクロマトグラフィー（１０％ＥｔＯＡｃ／ヘキサン〜４０％ＥｔＯＡｃ／ヘキサンの勾配）で精製し、標記化合物を褐色固体として得る。 Step 2.4- (Trifluoromethyl) -1H-indole-3-carbaldehyde

To a solution of 4-bromo-1H-indole-3-carbaldehyde (3.1 g, 13.8 mmol) in 65 mL DMF was added methyl 2- (fluorosulfonyl) difluoroacetate (3.5 mL, 27.6 mmol) and copper iodide. (I) (5.3 g, 27.6 mmol) is added. The reaction is heated to 85 ° C. for 18 hours. After cooling to room temperature, the mixture is diluted with EtOAc and filtered through celite. Celite is washed thoroughly with EtOAc. The filtrate is washed with water (3 times) and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give a brown oil. Purify by silica gel column chromatography (gradient from 10% EtOAc / hexanes to 40% EtOAc / hexanes) to give the title compound as a brown solid.

ジオキサン２０ｍＬ中の４−（トリフルオロメチル）−１Ｈ−インドール−３−カルバルデヒド（１．３ｇ、６．１０ｍｍｏｌ）と２−クロロピリミジン（６９９ｍｇ、６．１０ｍｍｏｌ）の混合物にカリウムｔ−ブトキシド（７５３ｍｇ、６．７１ｍｍｏｌ）を添加する。反応混合物を１００℃に加熱し、１５時間攪拌する。ジオキサンを減圧下で留去し、残留物をＥｔＯＡｃと水（各３０ｍＬ）の間で分配する。水相を更に２回ＥｔＯＡｃ（各２０ｍＬ）で抽出し、合わせたＥｔＯＡｃ抽出物を乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、減圧下で蒸発させ、褐色固体を得る。シリカゲルカラムクロマトグラフィー（２％ＥｔＯＡｃ／ＤＣＭ）で精製し、標記化合物を淡褐色固体として得る。 Step 3. 1-Pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carbaldehyde

To a mixture of 4- (trifluoromethyl) -1H-indole-3-carbaldehyde (1.3 g, 6.10 mmol) and 2-chloropyrimidine (699 mg, 6.10 mmol) in 20 mL of dioxane was added potassium t-butoxide (753 mg). 6.71 mmol). The reaction mixture is heated to 100 ° C. and stirred for 15 hours. Dioxane is distilled off under reduced pressure and the residue is partitioned between EtOAc and water (30 mL each). The aqueous phase is extracted twice more with EtOAc (20 mL each) and the combined EtOAc extracts are dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give a brown solid. Purify by silica gel column chromatography (2% EtOAc / DCM) to obtain the title compound as a light brown solid.

ジオキサン１５ｍＬおよび水５ｍＬ中の１−ピリミジン−２−イル−４−（トリフルオロメチル）−１Ｈ−インドール−３−カルバルデヒド（４５０ｍｇ、１．５５ｍｍｏｌ）の溶液に、亜塩素酸ナトリウム（１８３ｍｇ、２．０２ｍｍｏｌ）およびスルファミン酸（８５８ｍｇ、８．８４ｍｍｏｌ）を添加する。室温で１０分間攪拌した後、飽和ＮａＨＣＯ_３水溶液と共に反応を注意深く急冷し、減圧下で濃縮する。残留物を１０％ＭｅＯＨ／ＤＣＭに溶解させ、１０％ＨＣｌと水で洗浄する。合わせた水相を１０％ＭｅＯＨ／ＤＣＭで（４回）逆抽出し、合わせた有機抽出層を乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、減圧下で蒸発させ、黄白色固体を得る。エーテル中で粉砕し、標記化合物を白色固体として得る。 Step 4. 1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxylic acid

To a solution of 1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carbaldehyde (450 mg, 1.55 mmol) in 15 mL dioxane and 5 mL water was added sodium chlorite (183 mg, 2 0.02 mmol) and sulfamic acid (858 mg, 8.84 mmol) are added. After stirring for 10 minutes at room temperature, the reaction is carefully quenched with saturated aqueous NaHCO ₃ and concentrated under reduced pressure. Dissolve the residue in 10% MeOH / DCM and wash with 10% HCl and water. The combined aqueous phases are back extracted with 10% MeOH / DCM (4 times) and the combined organic extracts are dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give a pale yellow solid. Trituration in ether gives the title compound as a white solid.

ＴＨＦ（４５０ｍＬ）およびＤＭＳＯ（４５０ｍＬ）中のピリジン−３−イル−アセトニトリル（１４．６５ｇ）と１，５−ジブロモ−ペンタン（２８．５２ｇ）の混合物にＮａＨ（鉱油中６０％、１０．４２ｇ）を幾つかの部分に分けて０℃で１時間にわたって添加する。混合物を室温に加温し、終夜攪拌する。反応混合物を水に注ぎ込み、ＥｔＯＡｃで２回抽出する。抽出物を濃縮し、残留物をシリカゲルクロマトグラフィーで精製し、１−ピリジン−３−イル−シクロヘキサンカルボニトリルを得る。 Step 5. (1-Pyridin-3-yl-cyclohexyl) -methylamine

NaH (60% in mineral oil, 10.42 g) to a mixture of pyridin-3-yl-acetonitrile (14.65 g) and 1,5-dibromo-pentane (28.52 g) in THF (450 mL) and DMSO (450 mL). Is added in several portions at 0 ° C. over 1 hour. The mixture is warmed to room temperature and stirred overnight. The reaction mixture is poured into water and extracted twice with EtOAc. The extract is concentrated and the residue is purified by silica gel chromatography to give 1-pyridin-3-yl-cyclohexanecarbonitrile.

To a solution of NH ₃ solution the product in 140mL of MeOH in 7.0 N (18.5 g), is added carefully slurry of Raney nickel (16g). The mixture is hydrogenated at 50 psi overnight. The mixture is filtered through celite and concentrated under reduced pressure to give the title compound.

ＤＭＦ１．０ｍＬ中の１−（（１−メチル−１Ｈ−イミダゾール−２−イル）メチル）−１Ｈ−インドール−２−カルボン酸（２１ｍｇ、０．０５ｍｍｏｌ）の混合物に、ジイソプロピルエチルアミン（０．０２ｍＬ、０．１０ｍｍｏｌ）、１−（１−ピリジン−３−イルシクロヘキシル）メタンアミン（９．５ｍｇ、０．０５ｍｍｏｌ）、およびＢＯＰ（２７ｍｇ、０．０６ｍｍｏｌ）を順次添加する。得られる混合物を室温で２０時間攪拌する。水（３ｍＬ）を添加し、混合物をＥｔＯＡｃ（５ｍＬ）で抽出する。ＥｔＯＡｃ層を乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、減圧下で蒸発させる。残留物を分取クロマトグラフィー（４％ＭｅＯＨ／ＤＣＭ）で精製し、標記化合物を淡褐色固体として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ９．１０（１Ｈ，ｄ，Ｊ８．４），８．９５（２Ｈ，ｄ，Ｊ４．８），８．６２（１Ｈ，ｄ，Ｊ２），８．４０（２Ｈ，ｍ），８．１６（１Ｈ，ｔ，Ｊ６），７．８３（１Ｈ，ｄ，Ｊ８），７．６３（１Ｈ，ｄ，Ｊ７．６），７．５１（２Ｈ，ｍ），７．３６（１Ｈ，ｍ），３．３９（２Ｈ，ｄ，Ｊ６．４），２．２０（２Ｈ，ｄ，Ｊ１３．６），１．７０（ｔ，２Ｈ，Ｊ１１．２），１．５８（ｍ，２Ｈ），１．３５（ｍ，４Ｈ）。質量分析（４８０．２４，Ｍ＋Ｈ）。 Step 6. N-[(1-Pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide

To a mixture of 1-((1-methyl-1H-imidazol-2-yl) methyl) -1H-indole-2-carboxylic acid (21 mg, 0.05 mmol) in 1.0 mL DMF was added diisopropylethylamine (0.02 mL, 0.10 mmol), 1- (1-pyridin-3-ylcyclohexyl) methanamine (9.5 mg, 0.05 mmol), and BOP (27 mg, 0.06 mmol) are added sequentially. The resulting mixture is stirred at room temperature for 20 hours. Water (3 mL) is added and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography (4% MeOH / DCM) to give the title compound as a light brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (1H, d, J8.4), 8.95 (2H, d, J4.8), 8.62 (1H, d, J2), 8. 40 (2H, m), 8.16 (1H, t, J6), 7.83 (1H, d, J8), 7.63 (1H, d, J7.6), 7.51 (2H, m) , 7.36 (1H, m), 3.39 (2H, d, J6.4), 2.20 (2H, d, J13.6), 1.70 (t, 2H, J11.2), 1 .58 (m, 2H), 1.35 (m, 4H). Mass spectrometry (480.24, M + H).

４−クロロインドール（２５．０ｇ、１６５ｍｍｏｌ）とＤＭＦ（１７０ｍＬ）の溶液に、無水トリフルオロ酢酸（２７．５ｍＬ、２００ｍｍｏｌ）をＮ_２下で３０分にわたって添加する。反応容器を密封する。２０時間後、溶液を水（７００ｍＬ）に注ぎ込み、ＥｔＯＡｃ（３００ｍＬ）で抽出する。有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過し、濃縮する。フラッシュシリカゲルカラムクロマトグラフィー（４：１のヘキサン／ＥｔＯＡｃ〜１：１のヘキサン／ＥｔＯＡｃ）で精製し、標記化合物を赤褐色固体として得る。 Example 3
4-Chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide Step 1.1- (4-Chloro-1H-indole-3 -Yl) -2,2,2-trifluoroethanone

To a solution of 4-chloroindole (25.0 g, 165 mmol) and DMF (170 mL) is added trifluoroacetic anhydride (27.5 mL, 200 mmol) under N ₂ over 30 minutes. Seal the reaction vessel. After 20 hours, the solution is poured into water (700 mL) and extracted with EtOAc (300 mL). The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash silica gel column chromatography (4: 1 hexane / EtOAc to 1: 1 hexane / EtOAc) affords the title compound as a reddish brown solid.

１−（４−クロロ−１Ｈ−インドール−３−イル）−２，２，２−トリフルオロエタノン（１０．１ｇ、４０．８ｍｍｏｌ）、２−クロロピリミジン（９．３ｇ、８１ｍｍｏｌ）、炭酸セシウム（２６．６ｇ、８１．６ｍｍｏｌ）、および１，４−ジオキサン（８０ｍＬ）の混合物をＮ_２下で１００℃に３時間加温する。室温に冷却した後、水（２００ｍＬ）を添加する。ろ過により沈殿物を捕集し、標記化合物を黄褐色の粉末として得る。 Step 2.1- (4-Chloro-1-pyrimidin-2-yl-1H-indol-3-yl) -2,2,2-trifluoroethanone

1- (4-Chloro-1H-indol-3-yl) -2,2,2-trifluoroethanone (10.1 g, 40.8 mmol), 2-chloropyrimidine (9.3 g, 81 mmol), cesium carbonate ( A mixture of 26.6 g, 81.6 mmol) and 1,4-dioxane (80 mL) is warmed to 100 ° C. under N ₂ for 3 h. After cooling to room temperature, water (200 mL) is added. The precipitate is collected by filtration to give the title compound as a tan powder.

空気下で１−（４−クロロ−１−ピリミジン−２−イル−１Ｈ−インドール−３−イル）−２，２，２−トリフルオロエタノン（８．３３ｇ、２５．６ｍｍｏｌ）、１０ＭのＮａＯＨ水溶液（６０ｍＬ）、水（２０ｍＬ）およびエタノール（２０ｍＬ）の混合物を６５℃に２０時間加温する。室温に冷却した後、揮発性物質を減圧下で留去する。水性混合物を０℃に冷却した後、５ＭのＨＣｌ水溶液（１１０ｍＬ）で酸性にする。混合物をろ過する。ろ液をＨ_２Ｏ（５０ｍＬ）で、その後Ｅｔ_２Ｏ（１００ｍＬ）で洗浄し、標記化合物を黄褐色の粉末として得る。 Step 3. 4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid

1- (4-Chloro-1-pyrimidin-2-yl-1H-indol-3-yl) -2,2,2-trifluoroethanone (8.33 g, 25.6 mmol) in air, 10M NaOH aqueous solution (60 mL), a mixture of water (20 mL) and ethanol (20 mL) is warmed to 65 ° C. for 20 hours. After cooling to room temperature, the volatile material is distilled off under reduced pressure. The aqueous mixture is cooled to 0 ° C. and then acidified with 5M aqueous HCl (110 mL). Filter the mixture. The filtrate is washed with H ₂ O (50 mL) followed by Et ₂ O (100 mL) to give the title compound as a tan powder.

Ｎ_２下で４−クロロ−１−ピリミジン−２−イル−１Ｈ−インドール−３−カルボン酸（２７ｍｇ、９８ｍｍｏｌ）、（１−ピリジン−３−イルシクロヘキシル）メチルアミン（２１ｍｇ、１１０ｍｍｏｌ）、ｉＰｒ_２ＮＥｔ（５０μＬ、２９０ｍｍｏｌ）、およびＤＭＦ（０．５ｍＬ）のスラリーにＢＯＰ（５８ｍｇ、１３０ｍｍｏｌ）を添加する。反応容器を密封し、溶液を６４時間攪拌する。溶液を５０％飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）に注ぎ込んだ後、ＥｔＯＡｃ（２×１０ｍＬ）で抽出する。合わせた有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過し、濃縮する。ＰＴＬＣ（９５：５ＤＣＭ／ＭｅＯＨ）で精製し、標記化合物を白色粉末として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ８．６１−８．７７（ｍ，４Ｈ），８．５５（ｓ，１Ｈ），８．４１（ｓ，１Ｈ），７．７５（ｄ，１Ｈ），７．０８−７．３１（ｍ，４Ｈ），６．１４（ｓ，１Ｈ），３．６８（ｄ，２Ｈ），２．１１−２．２２（ｍ，２Ｈ），１．２８−１．８６（ｍ，８Ｈ）。ＬＣ−ＭＳｍ／ｚ（Ｍ＋Ｈ^＋）：４４６．１８。 Step 4. 4-Chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide

Under N ₂ 4-chloro-1-pyrimidin-2-yl -1H- indole-3-carboxylic acid (27mg, 98mmol), (1- pyridin-3-yl-cyclohexyl) methylamine (21mg, 110mmol), iPr ₂ To a slurry of NEt (50 μL, 290 mmol), and DMF (0.5 mL) is added BOP (58 mg, 130 mmol). The reaction vessel is sealed and the solution is stirred for 64 hours. The solution is poured into 50% saturated aqueous NaHCO ₃ (10 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. Purify with PTLC (95: 5 DCM / MeOH) to give the title compound as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61-8.77 (m, 4H), 8.55 (s, 1H), 8.41 (s, 1H), 7.75 (d, 1H), 7 .08-7.31 (m, 4H), 6.14 (s, 1H), 3.68 (d, 2H), 2.11-2.22 (m, 2H), 1.28-1.86 (M, 8H). LC-MS m / z (M + H ^< + ^> ): 446.18.

ＤＭＦ（２０ｍＬ）中のエチル１Ｈ−インドール−２−カルボキシレート（１．１３ｇ、０．００５９ｍｏｌ）の混合物に６０％ＮａＨ（５２７ｍｇ、０．０１３２ｍｏｌ）を室温で添加し、１０分間攪拌する。次いで、混合物に２−クロロメチル−１−メチルイミダゾール塩酸塩を添加し、２０時間攪拌する。混合物を氷水（１００ｍＬ）で希釈し、白色固体をろ過して標記化合物を得る。 Example 4
N1-((1-Methyl-1H-imidazol-2-yl) methyl) -N-((1- (pyridin-3-yl) cyclohexyl) methyl) -1H-indole-2-carboxamide Step 1. Ethyl 1-((1-methyl-1H-imidazol-2-yl) methyl) -1H-indole-2-carboxylate

To a mixture of ethyl 1H-indole-2-carboxylate (1.13 g, 0.0059 mol) in DMF (20 mL) is added 60% NaH (527 mg, 0.0132 mol) at room temperature and stirred for 10 minutes. Then, 2-chloromethyl-1-methylimidazole hydrochloride is added to the mixture and stirred for 20 hours. Dilute the mixture with ice water (100 mL) and filter the white solid to give the title compound.

ＥｔＯＨ２５ｍＬ中のエチル１−（（１−メチル−１Ｈ−イミダゾール−２−イル）メチル）−１Ｈ−インドール−２−カルボキシレート（１．５ｇ、０．００５３ｍｏｌ）の混合物に１．０ＮのＮａＯＨ水溶液（１０ｍＬ）を添加し、２５℃で１６時間攪拌する。反応混合物を減圧下で濃縮し、水（５０ｍＬ）で希釈し、濃ＨＣｌでｐＨ２．０の酸性にする。分離した白色固体をろ過し、水（２×２５ｍＬ）で洗浄し、乾燥させて標記化合物を得る。 Step 2.1-((1-Methyl-1H-imidazol-2-yl) methyl) -1H-indole-2-carboxylic acid

To a mixture of ethyl 1-((1-methyl-1H-imidazol-2-yl) methyl) -1H-indole-2-carboxylate (1.5 g, 0.0053 mol) in 25 mL of EtOH was added 1.0 N aqueous NaOH ( 10 mL) and stir at 25 ° C. for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with water (50 mL) and acidified to pH 2.0 with concentrated HCl. The separated white solid is filtered, washed with water (2 × 25 mL) and dried to give the title compound.

ＤＭＦ２．０ｍＬ中の１−（（１−メチル−１Ｈ−イミダゾール−２−イル）メチル）−１Ｈ−インドール−２−カルボン酸（５１ｍｇ、０．２ｍｍｏｌ）の混合物に、ジイソプロピルエチルアミン（０．２ｍＬ）、１−（１−ピリジン−３−イルシクロヘキシル）メタンアミン（３８ｍｇ、０．２５ｍｍｏｌ）、およびＢＯＰ試薬（１００ｍｇ、０．２２ｍｍｏｌ）を順次添加する。得られる混合物を室温で２０時間攪拌する。水（３ｍＬ）を添加し、混合物をＥｔＯＡｃ（５ｍＬ）で抽出する。ＥｔＯＡｃ層を乾燥させ（Ｎａ_２ＳＯ_４）、ろ過し、減圧下で蒸発させる。残留物をシリカゲルカラムクロマトグラフィー（４％ＭｅＯＨ／ＤＣＭ）で精製し、標記化合物を白色固体として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ８．５６（１Ｈ，ｓ），８．３４（２Ｈ，ｍ），７．７０（１Ｈ，ｄ），７．５８（１Ｈ，ｄ），７．５３（１Ｈ，ｄ），７．２５（１Ｈ，ｍ），７．１７（１Ｈ，ｔ），７．００（３Ｈ，ｍ），６．６７（１Ｈ，ｓ），５．７１（２Ｈ，ｓ），３．４６（３Ｈ，ｓ），３．３２（２Ｈ，ｄ），２．１４（ｄ，２Ｈ），１．１４−１．６３（８Ｈ，ｍ）。質量分析（４２８．２８，Ｍ＋Ｈ）。 Step 3. N1-((1-methyl-1H-imidazol-2-yl) methyl) -N-((1- (pyridin-3-yl) cyclohexyl) methyl) -1H-indole-2-carboxamide

To a mixture of 1-((1-methyl-1H-imidazol-2-yl) methyl) -1H-indole-2-carboxylic acid (51 mg, 0.2 mmol) in 2.0 mL DMF was added diisopropylethylamine (0.2 mL). , 1- (1-Pyridin-3-ylcyclohexyl) methanamine (38 mg, 0.25 mmol) and BOP reagent (100 mg, 0.22 mmol) are added sequentially. The resulting mixture is stirred at room temperature for 20 hours. Water (3 mL) is added and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (4% MeOH / DCM) to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (1H, s), 8.34 (2H, m), 7.70 (1H, d), 7.58 (1H, d), 7.53 (1H, d), 7.25 (1H, m), 7.17 (1H, t), 7.00 (3H, m), 6.67 (1H, s), 5.71 (2H, s) 3.46 (3H, s), 3.32 (2H, d), 2.14 (d, 2H), 1.14 to 1.63 (8H, m). Mass spectrometry (428.28, M + H).

Ｎ_２下、−１０℃で、ｉＰｒ_２ＮＥｔ（４２０μＬ、２．４ｍｍｏｌ）およびアセトン（７．０ｍＬ）中の４−クロロ−１−ピリミジン−２−イル−１Ｈ−インドール−３−カルボン酸（６２９ｍｇ、２．３０ｍｍｏｌ）のスラリーに、クロロギ酸エチル（２３０μＬ、２．４ｍｍｏｌ）を５分間にわたって滴下する。１時間後、水（４ｍＬ）中のアジ化ナトリウム（４５０ｍｇ、６．９ｍｍｏｌ）を一度に添加し、混合物を空気下で１５時間攪拌する。揮発性物質を減圧下で留去する。得られる水性混合物を水（１０ｍＬ）で希釈した後、ろ過する。固体を捕集し、減圧下で乾燥させ、標記化合物を黄褐色の粉末として得る。 Example 5
2-adamantan-1-yl-N- (4-chloro-1-pyrimidin-2-yl-1H-indol-3-yl) -acetamide step 1.4-chloro-1-pyrimidin-2-yl-1H- Indole-3-carbonyl azide

4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (629 mg) in iPr ₂ NEt (420 μL, 2.4 mmol) and acetone (7.0 mL) at −10 ° C. under N _2. 2.30 ml) of slurry is added dropwise ethyl chloroformate (230 μL, 2.4 mmol) over 5 minutes. After 1 hour, sodium azide (450 mg, 6.9 mmol) in water (4 mL) is added in one portion and the mixture is stirred under air for 15 hours. Volatiles are distilled off under reduced pressure. The resulting aqueous mixture is diluted with water (10 mL) and then filtered. Collect the solid and dry under reduced pressure to give the title compound as a tan powder.

空気下でトルエン（５ｍＬ）中の４−クロロ−１−ピリミジン−２−イル−１Ｈ−インドール−３−カルボニルアジド（４４２ｍｇ、１．４８ｍｍｏｌ）のスラリーを１００℃に１時間加温する。濃ＨＣｌ（１ｍＬ）を滴下する。混合物を１１０℃に２時間加温する。揮発性物質を減圧下で留去する。ＴＥＡ（１ｍＬ）および水（１０ｍＬ）を添加する。混合物をＣＨ_２Ｃｌ_２（４×３０ｍＬ）で抽出し、合わせた有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過し、濃縮する。フラッシュカラムクロマトグラフィー（５：１のヘキサン：ＥｔＯＡｃ〜３：１のヘキサン：ＥｔＯＡｃ）で精製し、標記化合物を黄褐色固体として得る。ＬＣ−ＭＳｍ／ｚ（Ｍ＋Ｈ^＋）：２４４．９９。 Step 2. 4-Chloro-1-pyrimidin-2-yl-1H-indol-3-ylamine

A slurry of 4-chloro-1-pyrimidin-2-yl-1H-indole-3-carbonylazide (442 mg, 1.48 mmol) in toluene (5 mL) is warmed to 100 ° C. under air for 1 hour. Concentrated HCl (1 mL) is added dropwise. The mixture is warmed to 110 ° C. for 2 hours. Volatiles are distilled off under reduced pressure. Add TEA (1 mL) and water (10 mL). The mixture is extracted with CH ₂ Cl ₂ (4 × 30 mL) and the combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. Purify by flash column chromatography (5: 1 hexane: EtOAc to 3: 1 hexane: EtOAc) to give the title compound as a tan solid. LC-MS m / z (M + H ^< + ^> ): 244.99.

Ｎ_２下で、４−クロロ−１−ピリミジン−２−イル−１Ｈ−インドール−３−イルアミン（５０ｍｇ、２００μｍｏｌ）、１−アダマンタン酢酸（５２ｍｇ、２７０μｍｏｌ）、ｉＰｒ_２ＮＥｔ（７０μＬ、４００μｍｏｌ）、およびＤＭＦ（１．０ｍＬ）のスラリーにＢＯＰ（１３５ｍｇ、３０５μｍｏｌ）を添加する。反応容器を密封し、溶液を４．５日間攪拌する。水（５ｍＬ）を添加し、粗生成物をろ過により捕集する。固体をＥｔＯＡｃ（４０ｍＬ）に溶解させた後、水と飽和食塩水（ｂｒｉｎｅ）の１：１溶液（２０ｍＬ）で洗浄する。有機層をＮａ_２ＳＯ_４で乾燥させ、ろ過し、濃縮する。分取薄層クロマトグラフィー（ｐｒｅｐａｒａｔｉｖｅ ｌａｙｅｒ ｃｈｒｏｍａｔｏｇｒａｐｈｙ）（７．５：１のヘキサン：ＥｔＯＡｃ）で精製し、標記化合物を象牙色の粉末として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：９．１０（ｓ，１Ｈ），８．８１（ｄ，１Ｈ），８．６７（ｄ，２Ｈ），８．６４（ｂｓ，１Ｈ），７．２４（ｔ，１Ｈ），７．１７（ｄ，１Ｈ），７．０４（ｔ，１Ｈ），２．２０（ｓ，２Ｈ），１．９４−２．０３（ｍ，３Ｈ），１．５８−１．８１（ｍ，１２Ｈ）。ＬＣ−ＭＳｍ／ｚ（Ｍ＋Ｈ^＋）：４２１．１１。 Step 3. 2-adamantan-1-yl-N- (4-chloro-1-pyrimidin-2-yl-1H-indol-3-yl) -acetamide

Under N ₂ , 4-chloro-1-pyrimidin-2-yl-1H-indol-3-ylamine (50 mg, 200 μmol), 1-adamantaneacetic acid (52 mg, 270 μmol), iPr ₂ NEt (70 μL, 400 μmol), and BOP (135 mg, 305 μmol) is added to a slurry of DMF (1.0 mL). The reaction vessel is sealed and the solution is stirred for 4.5 days. Water (5 mL) is added and the crude product is collected by filtration. The solid is dissolved in EtOAc (40 mL) then washed with a 1: 1 solution of water and brine (20 mL). The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. Purification by preparative layer chromatography (7.5: 1 hexane: EtOAc) affords the title compound as an ivory powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.10 (s, 1H), 8.81 (d, 1H), 8.67 (d, 2H), 8.64 (bs, 1H), 7.24 (T, 1H), 7.17 (d, 1H), 7.04 (t, 1H), 2.20 (s, 2H), 1.94-2.03 (m, 3H), 1.58- 1.81 (m, 12H). LC-MS m / z (M + H ^< + ^> ): 421.11.

３３％の酢酸水溶液１０ｍＬ中の４−クロロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．２ｇ、７．６ｍｍｏｌ、本質的に非特許文献７に記載されているように調製される）およびヘキサメチレンテトラミン（１．６ｇ、１１．４ｍｍｏｌ）の混合物を加熱還流し、１４時間攪拌する。透明な溶液を室温に冷却し、水で希釈する。混合物は濁り、溶液から固体が沈殿し始める。混合物を氷浴中で冷却し、３０分間攪拌する。次いで、沈殿した固体を減圧濾過により捕集し、減圧下で乾燥させ、標記化合物を淡褐色固体として得る。質量分析（１８０．９２，Ｍ＋Ｈ）。 Example 6
4-Chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide Step 1.4-Chloro- 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde

4-Chloro-1H-pyrrolo [2,3-b] pyridine (1.2 g, 7.6 mmol, prepared essentially as described in Non-Patent Document 7) in 10 mL of 33% aqueous acetic acid And a mixture of hexamethylenetetramine (1.6 g, 11.4 mmol) is heated to reflux and stirred for 14 hours. Cool the clear solution to room temperature and dilute with water. The mixture becomes cloudy and solids begin to precipitate from the solution. The mixture is cooled in an ice bath and stirred for 30 minutes. The precipitated solid is then collected by vacuum filtration and dried under reduced pressure to give the title compound as a light brown solid. Mass spectrometry (180.92, M + H).

ジオキサン５〜１０ｍｌ中の４−クロロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルバルデヒド（２２０ｍｇ、１．２２ｍｍｏｌ）、２−クロロピリミジン（２１０ｍｇ、１．８３ｍｍｏｌ）および炭酸セシウム（４７６ｍｇ、１．４６ｍｍｏｌ）の混合物を１００℃に加熱する。１５時間攪拌した後、反応混合物を冷却し、減圧下でジオキサンを留去する。残留物を水中でスラリー化し、ろ過する。捕集した固体をより多くの水で洗浄し、減圧下で乾燥させ、標記化合物を淡褐色固体として得る。質量分析（２５８．９５，Ｍ＋Ｈ）。 Step 2. 4-Chloro-1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde

4-Chloro-1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (220 mg, 1.22 mmol), 2-chloropyrimidine (210 mg, 1.83 mmol) and cesium carbonate (476 mg) in 5-10 ml of dioxane. , 1.46 mmol) is heated to 100 ° C. After stirring for 15 hours, the reaction mixture is cooled and dioxane is distilled off under reduced pressure. Slurry the residue in water and filter. The collected solid is washed with more water and dried under reduced pressure to give the title compound as a light brown solid. Mass spectrometry (258.95, M + H).

ジオキサン３ｍｌおよび水１ｍｌ中の４−クロロ−１−ピリミジン−２−イル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルバルデヒド（８８ｍｇ、０．３４ｍｍｏｌ）の混合物に、亜塩素酸ナトリウム（４０ｍｇ、０．４４ｍｍｏｌ）およびスルファミン酸（１８８ｍｇ、１．９４ｍｍｏｌ）を添加する。室温で２０分間攪拌した後、減圧下で溶媒を留去する。残留物を１０％ＭｅＯＨ／ＣＨ_２Ｃｌ_２に溶解させ、得られる混合物をろ過する。ろ液を濃縮し、標記化合物を褐色固体として得る。質量分析（２７４．９５，Ｍ＋Ｈ）。 Step 3. 4-Chloro-1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid

To a mixture of 4-chloro-1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (88 mg, 0.34 mmol) in 3 ml dioxane and 1 ml water was added sodium chlorite. (40 mg, 0.44 mmol) and sulfamic acid (188 mg, 1.94 mmol) are added. After stirring for 20 minutes at room temperature, the solvent is distilled off under reduced pressure. The residue is dissolved in 10% MeOH / CH ₂ Cl ₂ and the resulting mixture is filtered. Concentrate the filtrate to give the title compound as a brown solid. Mass spectrometry (274.95, M + H).

ＤＭＦ１．０ｍｌ中の４−クロロ−１−ピリミジン−２−イル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルボン酸（４５ｍｇ、０．１６ｍｍｏｌ）の混合物に、ジイソプロピルエチルアミン（０．０６ｍｌ、０．３２ｍｍｏｌ）、１−（１−ピリジン−３−イルシクロヘキシル）メタンアミン（３０ｍｇ、０．１６ｍｍｏｌ）およびＢＯＰ（８４ｍｇ、０．１９ｍｍｏｌ）を順次添加する。得られる混合物を室温で２０時間攪拌する。水（３ｍｌ）を添加し、沈殿した固体を減圧ろ過により捕集し、減圧下で乾燥させ、標記化合物を褐色固体として得る。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ８．９７（２Ｈ，ｄ，Ｊ４．８），８．６１（１Ｈ，ｓ），８．３５（３Ｈ，ｍ），８．２３（１Ｈ，ｓ），７．７９（１Ｈ，ｄ，Ｊ６．８），７．５４（１Ｈ，ｔ，Ｊ４．４），７．３９（１Ｈ，ｄ，Ｊ５．２），７．３２（１Ｈ，ｂｓ），３．４１（２Ｈ，ｄ，Ｊ５．６），２．１７（２Ｈ，ｍ），１．２−１．８（８Ｈ，ｍ）。質量分析（４４７．１５，Ｍ＋Ｈ）。 Step 4. 4-Chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide

To a mixture of 4-chloro-1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid (45 mg, 0.16 mmol) in 1.0 ml DMF was added diisopropylethylamine (0.06 ml). , 0.32 mmol), 1- (1-pyridin-3-ylcyclohexyl) methanamine (30 mg, 0.16 mmol) and BOP (84 mg, 0.19 mmol) are added sequentially. The resulting mixture is stirred at room temperature for 20 hours. Water (3 ml) is added and the precipitated solid is collected by vacuum filtration and dried under reduced pressure to give the title compound as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (2H, d, J4.8), 8.61 (1H, s), 8.35 (3H, m), 8.23 (1H, s) , 7.79 (1H, d, J6.8), 7.54 (1H, t, J4.4), 7.39 (1H, d, J5.2), 7.32 (1H, bs), 3 .41 (2H, d, J5.6), 2.17 (2H, m), 1.2-1.8 (8H, m). Mass spectrometry (447.15, M + H).

Other heteroaryl amide analogs prepared using the general methods disclosed herein are listed in Table A. In the column of Table A labeled “IC ₅₀ ”, “*” indicates that the IC ₅₀ determined as described in Example 7A is 2 micromolar or less (ie, 80 μM 2 ′ (3 ′) The concentration of such compounds required to reduce the fluorescence response of cells exposed to -O- (4-benzoyl-benzoyl) adenosine 5'-triphosphate by 50% is less than 2 micromolar) Indicates.

The mass spectrometry data is listed as (M + 1) in the column of Table I with the heading “M + H”. The LC retention time (in minutes) is listed in the column with the _RT heading.

Example 7
P2X7 Calcium Mobilization Assay This example describes an exemplary calcium mobilization assay used to evaluate agonist and antagonist activity of test compounds.

A. High-throughput assay of P2X7 receptor SH-SY5Y cells, ATCC number CRL-2266, (American Type Culture Collection, Manassas, Va.), 10% FBS, and 10 mM HEPES (Invitrogen Corp., Carlsbad, CA). Incubate at 37 ° C. in DMEM / High medium under 5% CO ₂ . One day prior to the experiment, cells were plated at a density of 100,000 cells / well in 96-well black / clear TC plates (Corning® Costar®, Sigma-Aldrich Co., St. Louis, Mo.). Plating. At the beginning of the experiment, the medium was removed and the cells were assayed (5 mM KCl, 9.6 mM NaH ₂ PO ₄ .H ₂ O, 25 mM HEPES, 280 mM sucrose, 5 mM glucose, and 0.5 mM glucose). Incubate with 50 μL of 2.3 μM Fluo-4 AM dye (Invitrogen Corp.) in CaCl ₂ ; pH adjusted to 7.4 with NaOH for 1 hour at 37 ° C. After incubating with the dye for 1 hour, the wells are washed once with 50 μL of assay solution and then incubated with 100 μL of assay solution containing the test compound for 1 hour at room temperature. The final concentration of test compound is generally in the range of 1-2500 nM; in positive control cells, no test compound is added. After 1 hour incubation, the plates are transferred to the FLIPR ^TETRA instrument (Molecular Devices, Sunnyvale, CA) for calcium mobilization analysis.

To determine the activity of the antagonist, the final agonist concentration is 80μM so that (approximately _{EC 50),} P2X ₇ agonist in the assay solution (2 '(3') - O- (4- benzoyl - benzoyl) adenosine 5' Transfer 50 μL of triphosphate (BzATP; Sigma-Aldrich) to the plate using FLIPR. For negative control cells, 50 μL of assay solution without agonist is added at this stage. The peak fluorescence signal is then measured over 2 minutes.

The data is analyzed as follows. First, the mean maximum relative fluorescence unit (RFU) response from negative control wells (no agonist) is subtracted from the maximum response detected for each of the other experimental wells. Next, the mean maximum RFU response is calculated for positive control wells (agonist wells). The inhibition rate for each compound tested is then calculated using the following formula:
Inhibition rate = 100-100 × (peak signal of test cell / peak signal of control cell)

The% inhibition data is plotted as a function of test compound concentration and the data is best fit to the formula using, for example, KALEIDAGRAPH software (Synergy Software, Reading, PA) to determine the IC _{50 of the} test compound:
y = m ₁ ^* (1 / (1+ (m ₂ / m ₀ ) ^m3 ))
Where y is the inhibition rate, m ₀ is the concentration of the agonist, m ₁ is the maximum RFU, m ₂ is the IC _{50 of the} test compound (the response observed in the presence of the agonist and without the antagonist). M ₃ is the Hill coefficient, corresponding to the concentration required to reduce by 50% in comparison. Alternatively, the IC _{50 of the} test compound is determined using linear regression, where x is ln (test compound concentration) and y is ln (inhibition rate / (100-inhibition rate)). Data with an inhibition rate higher than 90% or lower than 15% is rejected and not used for regression. The IC ₅₀ calculated in this way is e ^{(−intercept / slope)} . The antagonists of the P2X ₇ receptor, IC ₅₀ is calculated, preferably less than 20 micromolar, more preferably less than 10 micromolar, even more preferably less than 5 micromolar, and most preferably less than 1 micromolar.

Similar assays are performed in the absence of other agonists to determine the agonist activity of the test compound. In such assays, the ability of the test compound to act as an agonist of P2X ₇ receptors is determined by measuring the fluorescence response elicited by the test compound as a function of the concentration of the compound. P2X ₇ receptor antagonists that exhibit no detectable agonist activity does not induce detectable fluorescence response at a concentration of 2,500 nM.

B. P2X electrophysiological assay SH-SY5Y cells ₇ receptor, 10% FBS, and 10mM of HEPES (Invitrogen Corp., Carlsbad, CA ) in DMEM / High medium supplemented with, 37 ° C. in 5% CO ₂ under On a cover glass (BD Biosciences, San Jose, CA) coated with 12 mm circular Poly-D-Lysine (PDL) in a 35 mm dish at a density of 130K cells / dish one day before the experiment. Divide into Whole cell potential fixed recording is performed with an Axopatch-200B amplifier (Axon Instruments, Foster City, CA). The recording electrode is pulled from a borosilicate pipette (World Precision Instruments, Sarasota, FL) on a horizontal puller (Sutter Instrument Model P-87) and has a resistance in the range of 2-3 MΩ when filled with internal liquid. All potential protocols are generated using pClamp8 (Axon Instruments) software. Data is digitized at 1 kHz or 5 kHz and recorded on a PC for further analysis. Data are analyzed using Clampfit (Axon Instruments), Excel (Microsoft, Redmond, WA), and Origin software (MicroCal, LLC; Northampton, Mass.). All cell recordings are performed at room temperature. The internal solution contains 100 mM KF, 40 mM KCl, 5 mM NaCl, 10 mM EGTA and 10 mM HEPES (adjusted to pH = 7.4 with KOH). External solution (adjusted to pH = 7.4 with NaOH), the NaCl in 70 mM, CaCl _2, 5 mM of KCl, 0.3 mM, 20 mM of HEPES, 10 mM glucose, and containing sucrose 134 mm. Unless otherwise noted, all chemicals are from Sigma.

P2X ₇ receptors are agonists of P2X ₇ of 200 [mu] M, it is activated by BzATP. Record the activated inward current in the presence and absence of test compound at a holding potential of −80 mV. The following equation is then used to calculate the percent inhibition for each compound tested:
% Inhibition = 100-100 × (current amplitude in compound / current amplitude in control).

To electrophysiologically determine the IC ₅₀ of a test compound for the P2X ₇ receptor, the compounds are tested at several concentrations and their inhibition on the P2X ₇ current is calculated as described above. Use Origin software (Microcal, MA) and best fit this dose-response curve using the following formula:
Inhibition rate = 100 / (1+ (IC ₅₀ / C) ^N )
Where C is the concentration of the antagonist, N is the Hill coefficient, and IC ₅₀ represents the compound's IC ₅₀ value for the P2X ₇ receptor.

Example 8
Carrageenan-induced mechanical hyperalgesia (Paw Pressure) assay for measuring pain relief This example describes an exemplary method for assessing the degree of pain relief provided by a test compound.

  Adult male Sprague Dawley rats (200-300 g; obtained from Harlan Sprague Dawley, Inc., Indianapolis, Ind.) Have free access to food and water in a 12 hour light / dark cycle To accommodate. For the assay, all animals are acclimated once, two baselines are measured and one test is performed, but each procedure is performed on a separate day. Prior to each day's procedure, animals are allowed to acclimate for at least 1 hour in the test room before the start of the procedure. For habituation, each animal is lightly restrained and each hind limb is continuously extended in front of the animal as required for testing. This procedure is performed alternately on both hind limbs and is repeated three times for each hind limb. Each day, then, a first baseline measurement, a second baseline measurement, and a test of the animal are performed. For each baseline measurement, animals are restrained as at habituation time and limb testing is performed using a limb pressure test device (Digital Randall Selitto, IITC Inc., Woodhill Hills, Calif.). Baseline measurements and tests are performed in groups of 10 animals, with one test performed on the left and right hind limbs of each animal, followed by the next consecutive animal test. This procedure is repeated three times for a total of three measurements on each hind limb. If at any given hind limb, any individual reading is very different from the other two (difference is greater than about 100 g), the hind limb is tested again for the fourth time and the average of the three most consistent scores is used. . On the day of testing, 3 hours prior to testing, all animal intraplants are injected with 0.1 mL of 0.5% to 1.5% carrageenan (dissolved in saline). The test compound or vehicle can be administered at various times prior to the test by various routes, but in any particular assay, each treatment group animal to which the test compound is administered (each such group has a different dose of test). The route and time point are the same for animals in the treatment group to which the vehicle control is administered). If the compound is administered orally, the animals are fasted the night before the test. For the baseline, each hind limb is tested three times and the results are recorded and analyzed.

  The hypersensitivity value for each treatment group is calculated as the average gram-force score (left foot only or LFO score) on the left foot of the study day. Statistical significance between treatment groups is determined by performing an ANOVA on the LFO score followed by a least significant difference (LSD) post-test. If p <0.05, a statistically significant difference is considered.

  As described above when administered as a single bolus immediately before the test or for several days: once or twice or three times daily (0.01-50 mg / kg, oral, parenteral or topical) prior to the test A compound is said to alleviate pain in this model if the value of hyperalgesia sought for is statistically significantly reduced by the compound compared to the vehicle control.

  Those skilled in the art will appreciate that many changes and modifications can be made to the preferred embodiments of the present invention, and that such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalent modifications as fall within the true spirit and scope of this invention.

Claims (67)

Formula Ia or Ib:

[Where:
U is CR _1A or N;
W is —C (═O) NR ₄ —, —NR ₄ C (═O) — or —NR ₄ —NR ₄ —C (═O) —;
Each R ₄ is independently hydrogen, C ₁ -C ₆ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₂ alkyl, or 4 to 7 members with X substituents. Forming a heterocycloalkyl of
X is absent or C ₁ -C ₆ alkylene optionally substituted with 1 to 4 substituents selected from R _B , R _C , R _D , and R _E ;
R _B , R _C , R _D , and R _E are each independently hydroxy, —COOH, C ₁ -C ₈ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C _{6 aminoalkyl,} C 2 -C ₈ alkyl ether, mono- - or di - _(C 1 -C ₆ alkyl) amino _C 0 -C ₄ alkyl, (4- to 7-membered _{heterocycloalkyl)} C 0 -C ₄ alkyl And phenyl C ₀ -C ₂ alkyl; or any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms attached thereto Forms a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or any one of R _B , R _C , R _D , and R _E is R ₄ and with them 1 united young Or together with a plurality of atoms form a 4- to 7-membered heterocycloalkyl;
Y is C ₁ -C ₈ alkyl, C ₃ -C ₁₆ cycloalkyl, 4 to 16 membered heterocycloalkyl, 6 to 16 membered aryl, or 5 to 16 membered heteroaryl, each of which is , hydroxy, halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, _COOH, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, C ₁ -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C _{6 alkylsulfonyl, (C} 3 -C _{7 cycloalkyl)} C 0 -C ₄ alkyl, mono- - or di - _(C 1 -C ₆ alkyl) A _Roh, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, and _(C 1 -C ₆ alkyl ) Optionally substituted with 1 to 6 substituents independently selected from sulfonylamino;
Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently CR ₁ or N;
R _1A is hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkyl ether, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C It is ₆ alkyl) sulfonylamino;
Each R ₁ is independently hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C ₆ alkanoyl, C ₁ -C ₆ alkylsulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or Di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or (C It is ₁ -C ₆ alkyl) sulfonylamino;
R _A is a group of formula -LAM, where:
L is absent, or (i) by replacing a carbon-carbon single bond with a carbon-carbon double or triple bond, or (ii) oxo, —COOH, —SO ₃ H, —SO ₂ NH ₂ , C ₁ -C ₆ alkylene optionally modified by substitution with —PO ₃ H ₂ , tetrazole, or oxadiazolone;
A is absent _{or, CO, O, NR 6,} S, SO, SO 2, CONR 6, NR 6 CO, (C 4 ~C 7 _cycloalkyl) C 0 -C ₂ alkyl, 4- to 7 Membered heterocycloalkyl, or 5- or 6-membered heteroaryl; wherein R ₆ is hydrogen or C ₁ -C ₆ alkyl;
M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, carboxyalkyl, or —COOH; or (ii) C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (4 to 10 membered carbon Cyclic group) C ₀ -C ₄ alkyl, (4- to 10-membered heterocyclic group) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanoylamino, C ₁ -C ₆ alkyl _sulfonyl, C 1 -C _{6 alkylsulfonylamino,} C 1 -C ₆ alkylsulfonyloxy, mono - or di _-C 1 -C ₆ alkylamino, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or Mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl (which are oxo, amino, halogen, respectively) Emissions, hydroxy, cyano, aminocarbonyl, aminosulfonyl, -COOH, alkoxycarbonyl, _alkanoyloxy, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkyl ether, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkylsulfonyl, C _1- From C ₆ alkylsulfonylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 4- to 7-membered heterocyclic groups Optionally substituted with 1-4 independently selected substituents);
Is]
Or a salt or hydrate thereof,
However, for compounds of formula Ia,
(A) when U is N, W is —C (═O) NH—, and L and A are absent, M is thienyl or an unsubstituted or halogen-substituted 4- to 10-membered carbocyclic group. Other than;
(B) when U is N, W is —NHC (═O) —, and A is absent, M is other than thienyl or an unsubstituted or halogen-substituted 4- to 10-membered carbocyclic group ;
(C) When U is CH, W—X—Y is

Wherein R _x is H or C (═O) —O-alkyl.
Other than;
(D) _one of Z ₁ , Z ₂ , Z ₃ and Z ₄ is N, the other of Z ₁ , Z ₂ , Z ₃ and Z ₄ is CH, respectively, and R _A and Y are each Independently R _1A is other than OH when it is alkyl, arylaralkyl or heteroaryl, W is —C (═O) N (H) — and U is CR _1A ;
(E) Z ₁ , Z ₂ , Z ₃ and Z ₄ are each CH, R _A is unsubstituted phenyl, W is —C (═O) N (H) —, and X is unsubstituted alkylene Or R _1A is alkylene substituted with one hydroxyl, Y is dialkylamino, unsubstituted heterocycloalkyl, or heterocycloalkyl substituted with one alkyl, and U is CR _1A It is other than halogen; and _(f) a Z _1, Z 2, _{Z 3} and _{Z 4} are each CR _1, at least two of _{R 1} is H, and the remaining _{R 1} are each independently H, halogen, nitro, hydroxy, or alkoxy, R _a is cycloalkyl or substituted or unsubstituted phenyl, W is -C (= O) N (H ) - and is, X is an unsubstituted alkylene, There one alkyl or cycloalkyl are each optionally substituted with COOH, dialkylamino, unsubstituted heteroaryl, heterocycloalkyl unsubstituted or heterocycloalkyl substituted with nitrile or amino, U is CR _{1A Where} R _1A is other than alkyl,
A compound of formula Ia or Ib or a salt or hydrate thereof.   The compound according to claim 1, wherein U is CH or N, or a salt or hydrate thereof.   3. A compound according to claim 2 having the formula Ia or a salt or hydrate thereof. R _1A is hydrogen, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C _{6 hydroxyalkyl,} C 1 -C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C ₆ alkyl Sulfonyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C _1- C ₆ alkyl) aminocarbonyl, mono- - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, or _(C 1 -C ₆ alkyl) The compound according to claim 3, which is sulfonylamino, or a salt or hydrate thereof. R _1A is hydrogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C _1- C _{6 aminoalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl _ether, C 1 -C _{6 alkanoyl,} C 1 -C _{6 alkylsulfonyl, (C} 3 _{~C 7} cycloalkyl Alkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkanoylamino, mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl, mono- Or di- (C ₁ -C ₆ alkyl) aminosulfonyl or (C ₁ -C ₆ alkyl) sulfonylamino. Or a salt or hydrate thereof. R _B , R _C , R _D , and R _E are each independently —COOH, C ₁ -C ₈ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C ₆ amino _alkyl, C 2 -C ₈ alkyl ether, mono- - or di - _(C 1 -C ₆ alkyl) amino _C 0 -C ₄ alkyl, (4- to 7-membered _{heterocycloalkyl)} C 0 -C ₄ alkyl, and Phenyl C ₀ -C ₂ alkyl; or three members together with one or more carbon atoms to which any two of R _B , R _C , R _D , and R _E are attached. Forms a 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or any one of R _B , R _C , R _D , and R _E is bound to R ₄ and them One or more 6. The compound according to any one of claims 1 to 5, or a salt or hydrate thereof, which forms a 4- to 7-membered heterocycloalkyl together with an atom. R _B , R _C , R _D , and R _E are each independently C ₁ -C ₄ alkyl, (C ₃ -C ₈ cycloalkyl) C ₀ -C ₂ alkyl, or phenyl C ₀ -C ₂ alkyl Or any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms attached to them, 3 to 7 membered cycloalkyl or 4 Form a 7 to 7 membered heterocycloalkyl; or any one of R _B , R _C , R _D , and R _E together with R ₄ and one or more atoms connecting them Or a salt or hydrate thereof according to any one of claims 1 to 6, which forms a 4- to 7-membered heterocycloalkyl.   The compound of any one of Claims 1-7 whose U is CH, or its salt or hydrate.   The compound of any one of Claims 1-7 whose U is N, or its salt or hydrate.   The compound according to any one of claims 1 to 9, or a salt or hydrate thereof, wherein X is substituted. Y _is, C 1 -C _{8 alkyl,} C 3 _{-C 16} cycloalkyl, an aryl or a 5-membered to 16-membered heteroaryl 6-membered to 16-membered, which are each optionally substituted, claim The compound of any one of 1-10, its salt, or a hydrate. Y is, C ₁ -C ₈ alkyl, an aryl or a 5-membered to 16-membered heteroaryl 6-membered to 16-membered, which are each optionally substituted, compound or a salt thereof according to claim 11 Or hydrate.   The compound according to any one of claims 1 to 12, or a salt or hydrate thereof, wherein Y is optionally substituted with 1 to 3 substituents. The compound according to any one of claims 1 to 13, wherein Z ₁ , Z ₂ , Z ₃ and Z ₄ are CH, or a salt or hydrate thereof. W _{is, -NR 4 C (= O)} - or _{-NR 4 -NR 4 -C (= O} ) - in which the compound or salt or hydrate thereof according to any one of claims 1 to 14 . M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or —COOH; or (ii) C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (4 to 10 membered aryl) C ₀ -C ₄ alkyl, (4- to 10-membered heterocyclic _group) C 0 -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C _{6 alkylsulfonyl, C} 1 ~ C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono- or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di - _(C 1 ~C ₆ alkyl) respectively aminocarbonyl [these, oxo, amino, halogen, hydroxy, shea Bruno, aminocarbonyl, aminosulfonyl, _-COOH, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C ₆ haloalkoxy, _{C 2} -C ₆ alkyl _ether, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - or di - _(C 1 -C ₆ alkyl) aminosulfonyl, mono- - or di - _(C 1 -C ₆ alkylamino) carbonyl, and, from 1 to 4 substituents independently selected from heterocyclic group having 4 to 7-membered Optionally substituted with a substituent of
The compound according to any one of claims 1 to 15, or a salt or hydrate thereof. M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or COOH; or _(ii) C 1 ~C _{6 haloalkyl,} C 1 -C ₆ alkoxy, (4 to 10 membered _{aryl) C} 0 ~ C ₄ alkyl, (4- to 10-membered _{heterocycloalkyl)} C 0 -C _{4 alkyl,} C 1 -C _{6 alkanoyloxy,} C 1 -C _{6 alkanoylamino,} C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono- or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are oxo, amino, halogen, hydro, respectively Alkoxy, cyano, aminocarbonyl, aminosulfonyl, _-COOH, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C ₆ haloalkoxy, C ₂ -C ₆ alkyl _ether, C 1 -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - Or di- (C ₁ -C ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 1 to 4 independently selected from 4- to 7-membered heterocyclic groups Optionally substituted with 4 substituents];
The compound according to claim 16 or a salt or hydrate thereof. M is:
(I) hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, or —COOH; or (ii) C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, (4 to 10 membered heterocycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanoylamino, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyloxy, mono -Or di-C ₁ -C ₆ alkylamino, mono- or di- (C ₁ -C ₆ alkyl) aminosulfonyl, or mono- or di- (C ₁ -C ₆ alkyl) aminocarbonyl [these are each Oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonate Le, _-COOH, C 1 -C _{6 alkyl,} C 1 -C _{6 hydroxyalkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkyl ether, C ₁ -C ₆ alkanoylamino, mono- - or di - _(C 1 -C ₆ alkyl) _amino, C 1 -C _{6 alkylsulfonyl,} C 1 -C ₆ alkylsulfonylamino, mono - or di - _(C 1 -C Optionally with 1 to 4 substituents independently selected from ₆ alkyl) aminosulfonyl, mono- or di- (C ₁ -C ₆ alkylamino) carbonyl, and 4- to 7-membered heterocyclic groups Has been replaced];
The compound according to claim 17, or a salt or hydrate thereof. The compound or a salt or hydrate thereof according to any one of claims 1 to 18, wherein R _A is other than halophenyl. 20. The compound according to claim 19, or a salt or hydrate thereof, wherein R _A is other than haloaryl. The compound according to any one of claims 1 to 18, or a salt or hydrate thereof, wherein R _A is other than cycloalkyl. The compound according to any one of claims 1 to 18, or a salt or hydrate thereof, wherein R _A is other than thienyl. 23. _A compound according to any one of claims 1 to 22, or a salt or hydration thereof, wherein when _RA is an optionally substituted heteroaryl, said heteroaryl has at least one oxygen or nitrogen ring atom. object. 24. The compound according to claim 23, or a salt or hydrate thereof, wherein R _A is other than optionally substituted heteroaryl. 24. The compound according to claim 23, or a salt or hydrate thereof, wherein when R _A is an optionally substituted heteroaryl, the heteroaryl contains at least one nitrogen ring atom. 26. A compound according to claim 25 or a salt or hydrate thereof, wherein when R _A is an optionally substituted heteroaryl, said heteroaryl contains at least 2 nitrogen ring atoms. 27. The compound according to any one of claims 1 to 26, or a salt or hydrate thereof, wherein R _A is other than a carbocycle.   28. The compound according to any one of claims 1 to 27, or a salt or hydrate thereof, wherein U is CH and W—X—Y is other than unsubstituted —C (═O) N (H) aralkyl. .   29. The compound according to any one of claims 1 to 28, or a salt or water thereof, wherein U is CH and W—X—Y is other than unsubstituted —C (═O) N (H) heteroaralkyl. Japanese products.   30. The compound according to any one of claims 1 to 29, or a salt or hydration thereof, wherein U is CH and W—X—Y is other than an unsubstituted —C (═O) N (H) heterocyclic ring. object.   31. The compound according to any one of claims 1 to 30, or a salt or hydration thereof, wherein U is CH and W—X—Y is other than unsubstituted —C (═O) N (H) alkoxyalkyl. object. U is CH and W—X—Y is unsubstituted —C (═O) N (H) R _V , where R _V is aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl, alkyl, alkenyl, or The compound or a salt or hydrate thereof according to any one of claims 1 to 31, which is other than alkynyl. —C (═O) N (H) R _V , wherein U is CH and W—X—Y is optionally substituted, where R _V is aryl C ₁ -C ₄ alkyl or heteroaryl C ₁ -C ₄ alkyl and is), the compound or salt or hydrate thereof according to any one of claims 1 to 32.   The compound according to any one of claims 1 to 14, or a salt or hydrate thereof, wherein W is -C (= O) N (H)-.   35. The compound according to claim 34, or a salt or hydrate thereof, wherein M is an optionally substituted heteroaryl.   36. The compound according to claim 35, or a salt or hydrate thereof, wherein the heteroaryl contains at least one nitrogen ring atom.   37. The compound of claim 36, or a salt or hydrate thereof, wherein the heteroaryl contains at least 2 nitrogen ring atoms.   38. The compound according to claim 37, or a salt or hydrate thereof, wherein M is an optionally substituted pyrimidinyl.   39. The compound according to claim 38, or a salt or hydrate thereof, wherein M is optionally substituted pyrimidin-2-yl. X is a C ₁ -C ₂ alkylene optionally substituted, compound or salt or hydrate thereof according to any one of claims 34 to 39. X _is, C 1 -C a _C 1 -C ₂ alkylene optionally substituted with _alkyl, compound or salt or hydrate thereof according to claim 40. X is substituted with at least two substituents selected from R _B , R _C , R _D , and R _E ;
41. Any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms attached to them form a 3- to 7-membered cycloalkyl. Or a salt or hydrate thereof. X is substituted with at least two substituents selected from R _B , R _C , R _D , and R _E ;
43. Any two of R _B , R _C , R _D , and R _E together with one or more carbon atoms attached to them form a 5- to 6-membered cycloalkyl. Or a salt or hydrate thereof.   40. The compound according to any one of claims 34 to 39, or a salt or hydrate thereof, wherein Y is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group.   45. The compound according to claim 44, or a salt or hydrate thereof, wherein Y is adamantyl, phenyl, pyridyl, or morpholinyl, each optionally substituted. The compound is:
N- (adamantan-1-ylmethyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- {4-methyl-2- [4- (trifluoromethyl) phenyl] pentyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) pentyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-[(1-Pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
1-pyrimidin-2-yl-N-({1- [4- (trifluoromethyl) phenyl] cyclohexyl} methyl) -1H-indole-3-carboxamide;
N-{[1- (4-chlorophenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-methoxyphenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-[(1-morpholin-4-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
2- {3-[(adamantan-1-ylmethyl) carbamoyl] -1H-indol-1-yl} benzoic acid;
N- [4-methyl-2- (4-methylphenyl) pentyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- (4-methyl-2-pyridin-3-ylpentyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- (4-methyl-2-phenylpentyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (6-methylpyridin-3-yl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-fluorophenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
2- {3-[(adamantan-1-ylmethyl) carbamoyl] -1H-indol-1-yl} pentanoic acid;
1- (5-fluoropyrimidin-2-yl) -N-[(1-pyridin-3-ylcyclohexyl) methyl] -1H-indole-3-carboxamide;
1- (3-ethylpyrazin-2-yl) -N-[(1-pyridin-3-ylcyclohexyl) methyl] -1H-indole-3-carboxamide;
4-chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-methoxyphenyl) cyclopentyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-methylphenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-Chloro-3-fluorophenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
Methyl 2- (3-{[(1-pyridin-3-ylcyclohexyl) methyl] carbamoyl} -1H-indol-1-yl) nicotinate;
N-[(1-Pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
4-bromo-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-cyano-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-methoxyphenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
N-{[1- (4-fluorophenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
N-{[1- (6-methylpyridin-3-yl) cyclohexyl] methyl} -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
7-chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N- (4-methyl-2-pyridin-3-ylpentyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -4-methylpentyl] -4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N- [4-methyl-2- (4-methylphenyl) pentyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N- {4-methyl-2- [4- (trifluoromethyl) phenyl] pentyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-chloro-3-fluorophenyl) cyclohexyl] methyl} -4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N-{[1- (4-methylphenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N-{[1- (4-methoxyphenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N-{[1- (4-fluorophenyl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-chlorophenyl) cyclohexyl] methyl} -4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
1-pyrimidin-2-yl-1H-indole-3,4-dicarboxylic acid 4-amide 3-[(1-pyridin-3-yl-cyclohexylmethyl) -amide];
1-[(1-methyl-1H-imidazol-2-yl) methyl] -N-[(1-pyridin-3-ylcyclohexyl) methyl] -1H-indole-2-carboxamide;
4-methyl-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-methyl-N- (4-methyl-2-pyridin-3-ylpentyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-methoxyphenyl) cyclohexyl] methyl} -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -4-methylpentyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N-{[1- (4-chlorophenyl) cyclohexyl] methyl} -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-4- (trifluoromethyl) -1H-indole-3-carboxamide;
N- (adamantan-1-ylmethyl) -4-chloro-1- [2- (dimethylamino) ethyl] -1H-indole-3-carboxamide;
N- (adamantan-1-ylmethyl) -4-chloro-1- [3- (dimethylamino) propyl] -1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -4-methylpentyl] -1- [3- (dimethylamino) propyl] -1H-indole-3-carboxamide;
4-chloro-1- [3- (dimethylamino) propyl] -N- (4-methyl-2-pyridin-3-ylpentyl) -1H-indole-3-carboxamide;
4-chloro-1- [2- (dimethylamino) ethyl] -N- (4-methyl-2-pyridin-3-ylpentyl) -1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -4-methylpentyl] -1- [2- (dimethylamino) ethyl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-fluoro-N- [2- (6-methoxypyridin-3-yl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (6-methoxypyridin-3-yl) -2-piperidin-1-ylethyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- (adamantan-1-ylmethyl) -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -2-piperazine] -1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- (2-morpholin-4-yl-2-phenylethyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- {2-piperidin-1-yl-2- [4- (trifluoromethyl) phenyl] ethyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chloro-3-fluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (6-methoxypyridin-3-yl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (3,4-difluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
3-chloro-1-[(1-methyl-1H-imidazol-2-yl) methyl] -N- (4-methyl-2-pyridin-3-ylpentyl) -1H-indole-2-carboxamide;
4-chloro-N-[(1-pyridin-3-ylcyclohexyl) methyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
4-chloro-N- (4-methyl-2-pyridin-3-ylpentyl) -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
2-adamantan-1-yl-N- (4-chloro-1-pyrimidin-2-yl-1H-indol-3-yl) acetamide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (adamantan-1-ylmethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-adamantan-1-yl-ethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid ((R) -6,6-dimethylbicyclo [3.1.1] hept-2-ylmethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-p-toluyl-pentyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2- (4-chloro-phenyl) -4-methyl-pentyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1- (4-chloro-phenyl) -cyclohexylmethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1- (4-trifluoromethyl-phenyl) -chlorohexylmethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [4- (4-chloro-phenyl) -tetrahydro-pyran-4-ylmethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1- (4-methoxy-phenyl) -cyclohexylmethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [4-methyl-2- (4-trifluoromethyl-phenyl) -pentyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2- (4-chloro-phenyl) -pentyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-pyridin-3-yl-pentyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1- (4-chloro-phenyl) -cyclobutylmethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-adamantan-1-yl-2-hydroxy-ethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-methyl-butyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-phenyl-pentyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-phenyl-pentyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-cyclopentyl-2-phenyl-propyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-cyclohexyl-2-phenyl-ethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2,3-diphenyl-propyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-phenyl-butyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-phenyl-butyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2- (4-bromo-phenyl) -ethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid adamantane-2-ylamide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid cycloheptylmethyl-amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2- (2-bromo-phenyl) -ethyl] -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid ((1S, 2R) -2-hydroxy-cyclohexylmethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclopentylmethyl) -amide;
4-chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-hydroxy-tetrahydro-thiopyran-4-ylmethyl) -amide;
N- [2- (4-fluorophenyl) -2-piperidin-1-ylethyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (3,4-difluorophenyl) -2-piperidin-1-ylethyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-methyl-N- (2-morpholin-4-yl-2-phenylethyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
3-Chloro-N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1-[(1-methyl-1H-imidazol-2-yl) methyl] -1H-indole-2-carboxamide ;
N-{[4- (4-chlorophenyl) tetrahydro-2H-pyran-4-yl] methyl} -4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;
3-chloro-N-{[4- (4-chlorophenyl) tetrahydro-2H-pyran-4-yl] methyl} -1-[(1-methyl-1H-imidazol-2-yl) methyl] -1H-indole -2-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -4-methyl-1-pyrazin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -4-methyl-1-pyrazin-2-yl-1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1- (3-cyanopyridin-2-yl) -4-methyl-1H-indole-3-carboxamide;
1- (3-cyanopyridin-2-yl) -4-methyl-N- (2-morpholin-4-yl-2-phenylethyl) -1H-indole-3-carboxamide;
N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -1- (3-cyanopyridin-2-yl) -4-methyl-1H-indole-3-carboxamide;
4-methyl-N- (4-methyl-2-morpholin-4-ylpentyl) -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- {2-piperidin-1-yl-2- [6- (trifluoromethyl) pyridin-3-yl] ethyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-fluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N-[(1-hydroxycycloheptyl) methyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (3,4-difluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (2,4-difluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -2-morpholin-4-ylethyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
4-chloro-N- [2- (4-chlorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
4-chloro-N-{[4- (4-chlorophenyl) tetrahydro-2H-pyran-4-yl] methyl} -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3- Carboxamide;
4-chloro-N-[(1-hydroxycycloheptyl) methyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
4-chloro-N-[(1-hydroxycyclohexyl) methyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide;
4-Chloro-N- [2- (3,4-difluorophenyl) -2-piperidin-1-ylethyl] -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide ;
4-chloro-N- (2-morpholin-4-yl-2-phenylethyl) -1-pyrimidin-2-yl-1H-pyrrolo [2,3-b] pyridine-3-carboxamide; or 4-chloro- N-{[1- (4-methylpiperazin-1-yl) cyclohexyl] methyl} -1-pyrimidin-2-yl-1H-indole-3-carboxamide;
The compound according to claim 1, or a salt or hydrate thereof. It said compound exhibit no detectable agonist activity in vitro assay of P2X ₇ receptor agonism compound or salt or hydrate thereof according to any one of claims 1-46. Wherein the compound is in the assay of P2X ₇ receptor antagonism, 20 can exhibit submicromolar IC ₅₀ values, the compound or salt or hydrate thereof according to any one of claims 1-47.   49. A pharmaceutical composition comprising at least one compound according to any one of claims 1-48 or a salt or hydrate thereof in combination with a physiologically acceptable carrier or excipient.   50. The pharmaceutical composition of claim 49, wherein the composition is formulated as an injection, aerosol, cream, oral fluid, tablet, gel, pill, capsule, syrup, or transdermal patch. A method of modulating the activity of P2X ₇ receptors in vitro, the P2X ₇ receptor, at least one compound or salt or hydrate thereof according to any one of claims 1 to 48, P2X _7. A method comprising contacting in conditions and amounts sufficient to detectably change receptor activity. A method of modulating the activity of P2X ₇ receptors of the patient, the cells expressing P2X ₇ receptor, at least one compound or salt or hydrate thereof according to any one of claims 1 to 48 a method comprising contacting in an amount sufficient to detectably alter the P2X ₇ receptor activity in in vitro, thereby altering the activity of the P2X ₇ receptor in the patient.   53. The method of claim 52, wherein the patient is a human. A method of treating a condition responsive to P2X ₇ receptor modulation in a patient, at least one compound or a therapeutically effective amount of a salt or hydrate thereof according to any one of claims 1 to 48, Administering to a patient, thereby alleviating the patient's symptoms.   55. The method of claim 54, wherein the symptom is pain.   56. The method of claim 55, wherein the pain is neuropathic pain.   Pain associated with arthritis, neuropathic pain syndrome, visceral pain, dental pain, headache, stump pain, sensory abnormal femoral neuralgia, mouth cauterization syndrome, pain associated with nerve and root injury, causalgia, nerve Inflammation, neuronitis, neuralgia, surgery-related pain, musculoskeletal pain, central nervous system pain, spinal pain, Charcot's pains, ear pain, muscle pain, eye pain, oral and facial pain, carpal tunnel syndrome, acute And chronic back pain, gout, scar pain, colic, dyspepsia, angina, nerve root pain, complex local pain syndrome, cancer pain, pain associated with venom exposure, pain associated with trauma, autoimmune disease or immunodeficiency 56. The method of claim 55, wherein the pain is as a result of disability pain, hot flashes, burns, sunburn, or exposure to heat, cold or external chemical stimuli.   55. The method of claim 54, wherein the symptom is inflammation, neuropathy or neurodegenerative disorder, cardiovascular disorder, eye disorder, or immune system disorder.   Said symptoms include osteoarthritis, rheumatoid arthritis, arthrosclerosis, glaucoma, irritable bowel syndrome, inflammatory bowel disease, cirrhosis, lupus, scleroderma, Alzheimer's disease, traumatic brain injury, asthma, chronic obstructive lung 55. The method of claim 54, wherein the method is disease or interstitial fibrosis.   49. A therapeutically effective amount of at least one compound according to any one of claims 1-48 or a salt or hydrate thereof is administered to the patient, thereby inhibiting the death of the patient's retinal ganglion cells. A method of inhibiting death of a retinal ganglion cell in a patient, comprising:   61. The method of any one of claims 54-60, wherein the patient is a human.   49. The compound according to any one of claims 1 to 48, or a salt or hydrate thereof, wherein the compound is radiolabeled. The following steps:
(A) the sample, contacting at conditions which a compound or salt or hydrate thereof according to any one of claims 1 to 48, allow adjustment of the P2X ₇ receptor activity by the compound; (B) detecting a signal indicating the level of the compound or a salt or hydrate thereof that modulates P2X ₇ receptor activity, and then determining the presence or absence of the P2X ₇ receptor in the sample;
Method of determining the presence or absence of P2X ₇ receptor in a sample comprising. Less than:
(A) a pharmaceutical composition according to claim 49 or 50 in a container, and (b) instructions for using said composition for the treatment of pain,
A packaged pharmaceutical formulation comprising: Less than:
(A) a pharmaceutical composition according to claim 49 or 50 in a container, and (b) using said composition for the treatment of inflammation, neuropathy or neurodegenerative disorder, cardiovascular disorder, ocular disorder or immune system disorder Instructions for use,
A packaged pharmaceutical formulation comprising: P2X ₇ for the manufacture of a medicament for the treatment of conditions responsive to receptor regulation, use of a compound or salt or hydrate thereof according to any one of claims 1 to 48.   67. Use according to claim 66, wherein the symptom is pain, inflammation, neuropathy or neurodegenerative disorder, cardiovascular disorder, eye disorder, or immune system disorder.