СОЕДИНЕНИЯ ДЛЯ ХРОМАТОГРАФИЧЕСКОГО ВЫДЕЛЕНИЯ РЕДКОЗЕМЕЛЬНЫХ ЭЛЕМЕНТОВ И s-, p-, d- МЕТАЛЛОВ, СПОСОБ ВЫДЕЛЕНИЯ И ИХ ПРИМЕНЕНИЕ

Настоящее изобретение относится к применению соединений общей формулы (I), где X выбран из группы, включающей H, C1-C6 алкил, галоген (F, Cl, Br или I); Y выбран из группы, включающей азот, N-оксид; Z1, Z2, Zm, где m обозначает 1 или 2, независимо, выбраны из группы, включающей -CH2-CH2- и -CH2-CH2-CH2-; A, Am, где m обозначает 1 или 2, независимо, выбраны из H, -CH2COOH, -CH2C(O)NH2, -CH2P(O)(OH)2 и ; n обозначает 1 или 2; R1, R2, R3, независимо, представляют собой H; и/или два соседних R1, R2, R3 вместе с двумя соседними атомами углерода ароматического цикла образуют шестичленное кольцо; при условии, что, когда n обозначает 2 и все Z1, Z2, Zm представляют собой -CH2-CH2-, тогда A не представляет собой -CH2COOH, для хроматографического выделения редкоземельных элементов и/или металлов s-, p- и d- блоков. Кроме того, изобретение относится к способу хроматографического выделения редкоземельных элементов и/или металлов s-, p- и d- блоков, к соединениям общей формулы (Ia). Технический результат ...

СПОСОБ ПОЛУЧЕНИЯ ИЗОБРАЖЕНИЯ КРОВОСНАБЖЕНИЯ МИОКАРДА

Изобретение относится к области медицины, а именно к контрастному агенту структурной формулы:где J представляет собой О; Y представляет собой углерод; K и L независимо выбраны из водорода и C-Салкила; М выбран из водорода, C-Салкилокси или C-Салкила, незамещенных или замещенныхF; Т и U вместе с атомами углерода, к которым они присоединены, образуют шестичленное ароматическое кольцо, которое незамещено или замещеноF; R, Rи Rнезависимо выбраны из водорода и фрагментаF; R, R, Rи Rявляются водородом; n=2; причем по меньшей мере одинF присутствует в структуре указанного контрастного агента и является фрагментом, обеспечивающим изображение. Изобретение также относится к применению указанного контрастного агента, композиции или диагностического набора на его основе для выявления, визуализации и/или мониторинга перфузии миокарда. Группа изобретений обеспечивает расширение арсенала диагностических маркеров для получения изображения кровоснабжения миокарда. 5 н. и 4 з.п. ф-лы, 55 пр.

СПОСОБ ПОЛУЧЕНИЯ ИНГИБИТОРОВ ATR КИНАЗЫ (ВАРИАНТЫ)

Изобретение относится к способу получения соединения формулы I-1, включающему стадии: a) взаимодействия соединения формулы 6a* с соединением формулы 27 при соответствующих условиях образования амидной связи, где соответствующие условия для образования амидной связи включают взаимодействие соединения формулы 6a* с соединением формулы 27 в апротонном растворителе при нагреве, с образованием соединения формулы 28; b) очистки соединения формулы 28 с использованием соответствующего хелатирующего агента для палладия, выбранного из пропан-1,2-диамина; этан-1,2-диамина; этан-1,2-диамина; пропан-1,3-диамина; тетраметилэтилендиамина; этиленгликоля; 1,3-бис(дифенилфосфанил)пропана; 1,4-бис(дифенилфосфанил)бутана и 1,2-бис(дифенилфосфанил)этан/Pr-1,2-диамина; c) взаимодействия соединения формулы 28 при соответствующих условиях снятия защиты, где соответствующие условия снятия защиты включают взаимодействие соединения формулы 28 с кислотой в присутствии растворителя, с образованием соединения формулы ...

СОЕДИНЕНИЯ ДЛЯ ВИЗУАЛИЗАЦИИ АГРЕГАТОВ БЕЛКА ТАУ

Изобретение относится к соединению формулы (II), где R1 представляет18F; R2 представляет Н. Также изобретение относится к промежуточному соединению формулы (II), значения радикалов которые указаны в формуле изобретения, применению немеченного соединения формулы (II) в качестве аналитического стандарта, а также к способу получения меченого соединения формулы (II), набору для получения радиофармацевтического препарата, способу сбора данных для диагностики расстройства, ассоциированного с агрегатами белка тау, для определения предрасположенности к расстройству, ассоциированному с агрегатами белка тау, для мониторинга остаточного проявления расстройства у пациента, страдающего расстройством, ассоциированным с агрегатами белка тау, и для прогнозирования реактивности пациента, страдающего расстройством, ассоциированным с агрегатами белка тау. Технический результат: получены гетероциклические соединения, которые можно использовать в селективном выявлении расстройств и аномалий, ассоциированных ...

КОНТРАСТНЫЕ АГЕНТЫ ДЛЯ ОТОБРАЖЕНИЯ ПЕРФУЗИИ МИОКАРДА

... 1. Способ получения изображения кровоснабжения миокарда, включающий введение пациенту контрастного агента, который содержит фрагмент, обеспечивающий изображение, и соединение, выбранное из дегелина, пиридабена, пиридимифена, тебуфенпирада, феназаквина, аналога дегелина, аналога пиридабена, аналога пиридимифена, аналога тебуфенпирада и аналога феназаквина, и сканирование пациента с применением диагностического изображения. 2. Способ по п.1, отличающийся тем, что фрагмент, обеспечивающий изображение, представляет собой радиоизотоп для ядерно-магнитной томографии, парамагнитные фрагменты для применения в MRI, эхогенную группу для ультразвукового исследования, флуоресцентную группу для применения при получении флуоресцентного изображения или светоактивную группу для применения при получении оптического изображения. 3. Контрастный агент, содержащий фрагмент, обеспечивающий изображение, и соединение, выбранное из дегелина, пиридабена, пиридимифена, тебуфенпирада, феназаквина, аналога дегелина ...

РАДИОАКТИВНО-МЕЧЕНЫЕ СОЕДИНЕНИЯ

СПОСОБЫ И РЕАКТИВЫ ДЛЯ ВВЕДЕНИЯ РАДИОАКТИВНОЙ МЕТКИ

ДЕЙТРИРОВАННЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ СРЕДСТВ ВИЗУАЛИЗАЦИИ

Способ получения флутеметамола

2-АМИНО-3-ФТОР-3-(ФТОРМЕТИЛ)-6-МЕТИЛ-6-ФЕНИЛ-3,4,5,6-ТЕТРАГИДРОПИРИДИНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ BACE1

СО-КРИСТАЛЛЫ И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ

ОРГАНИЧЕСКИЕ СОЕДИНЕНИЯ

СПОСОБ ТВЕРДОФАЗНОЙ ЭКСТРАКЦИИ

... 1. Способ получения радиофторированного соединения формулы I:,где:Rпредставляет собой водород, галоген или Cалкокси;Rи Rнезависимо представляют собой метил, этил или бензил, или вместе с азотом, к которому они присоединены, образуют пирролидинильное, пиперидинильное, азепанильное или морфолинильное кольцо;Yпредставляет собой CH, CH-СН, CH(CH)-CHили СН-СН-CH; иn равен 1, 2 или 3,включающий:(1) предоставление соединения-предшественника формулы Ia:,где R, Yи m являются такими, как определено для R, Yи n формулы I, и каждый из них является таким же, как R, Yи n в формуле I, соответственно, и LG представляет собой сульфонатную уходящую группу;(2) взаимодействие указанного соединения-предшественника формулы Ia с подходящим источником [F]-фторида;(3) очистку реакционной смеси, полученной на стадии (2), включающую:(a) предоставление одного или более картриджей для твердофазной экстракции (ТФЭ), где сорбент содержит частицы, имеющие диаметр от 10 до 120 мкм, и связанные углеводороды;(б) кондиционирование ...

ДЕЙТЕРИРОВАННЫЕ ТИАЗОЛИДИНОНОВЫЕ АНАЛОГИ В КАЧЕСТВЕ АГОНИСТОВ РЕЦЕПТОРА ФОЛЛИКУЛОСТИМУЛИРУЮЩЕГО ГОРМОНА

... 1. Дейтерированное тиазолидиноновое производное в соответствии с формулой (I)(I),где каждый Y независимо друг от друга выбирают из группы, состоящей из водорода (H), дейтерия (D);X выбирают из группы, состоящей из S, сульфоксида;R, Rнезависимо друг от друга выбирают из группы, состоящей из водорода (H), дейтерия (D), метила, CHD, CHD, CD, этила, CHDCH, CHDCHD, CHDCHD, CHDCD, CDCH, CDCHD, CDCHD, CDCD;при условии, что, по меньшей мере, один Y представляет собой дейтерий (D), или, по меньшей мере, один из R, Rсодержит, по меньшей мере, один дейтерий (D);необязательно, по меньшей мере, один атом углерода независимо друг от друга замененC;и его физиологически приемлемые соли, сольваты, таутомеры и стереоизомеры, включая их смеси во всех соотношениях.2. Дейтерированное тиазолидиноновое производное по п. 1, где,по меньшей мере, один атом углерода замененC;и его физиологически приемлемые соли, сольваты, таутомеры и стереоизомеры, включая их смеси во всех соотношениях.3. Дейтерированное тиазолидиноновое ...

Compound

1, 3, 4-THIADIAZOLE COMPOUNDS AND THEIR USE IN TREATING CANCER

Fused benzoxazepinones as ion modulators

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS

4-Aryl-N-phenyl-1,3,5,-triazin-2-amines containinga sulfoximine group

SUBSTITUTED DIHYDROISOQUINOLINONE COMPOUNDS

ETHER COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS

COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

NOVEL HETEROCYCLIC DERIVATIVES AND THEIR USE IN THE TREATMENT OF NEUROLOGICAL DISORDERS

4-aryl-N-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group

PHOSPHONATE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

1, 3, 4-THIADIAZOLE COMPOUNDS AND THEIR USE IN TREATING CANCER

Biaryl amide compounds as kinase inhibitors

ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

AMIDE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Novel heterocyclic derivatives and their use in the treatment of neurological disorders

Fused benzoxazepinones as ion modulators

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

AMIDE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Novel heterocyclic derivatives and their use in the treatment of neurological disorders

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Fused benzoxazepinones as ion modulators

SUBSTITUTED DIHYDROISOQUINOLINONE COMPOUNDS

1, 3, 4-THIADIAZOLE COMPOUNDS AND THEIR USE IN TREATING CANCER

COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

AMIDE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

PHOSPHONATE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

ETHER COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

4-Aryl-N-phenyl-1,3,5,-triazin-2-amines containinga sulfoximine group

Novel heterocyclic derivatives and their use in the treatment of neurological disorders

ETHER COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

PHOSPHONATE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Biaryl amide compounds as kinase inhibitors

SUBSTITUTED DIHYDROISOQUINOLINONE COMPOUNDS

4-Aryl-N-phenyl-1,3,5,-triazin-2-amines containinga sulfoximine group

AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS

RADIO-MARKED NEUROKININ-1 RECEPTOR ANTAGONIST

BIFUNCTIONAL CHELATIERMITTEL FOR ACTINIUM

RADIOACTIVE MEANS FOR IN VIVO PET BILDGEBUNG OF CCR5

CHELATIERUNGSMITTEL TO THE CONNECTION FROM METAL IONS TO PROTEINS.

ANTIKREBSBENZALDEHYDVERBINDUNGEN

HYDRAZINE WITH A N3S CONFIGURATION AS RADIONUKLEIDE CHELATOREN

RADIO PHARMACEUTICALS FOR THE DIAGNOSIS OF ALZHEIMER'S

Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosisof alzheimer's disease and (in vivo) imaging and prevention of amyloid depositi on

Radiolabeled macrocyclic EGFR inhibitor

The present invention relates to 18-Fluor radiolabeled macrocyclic quinazoline compounds, which are suitable as positron emission tomography (PET) tracers for imaging epidermal growth factor receptors (EGFR), and their use in ...

Tau PET imaging ligands

The present invention relates to novel, selective radiolabelled tau ligands which are useful for imaging and quantifying tau aggregates, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue or a subject, in vitro or in vivo, and to precursors of said compounds.

Pentylenetetrazole derivatives

Provided are compounds having formula I: (1) wherein RR 2, R3, R4, R, 5R6, R, R, R9 and R 1° are as disclosed herein, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions comprising the compounds and methods of their use, for instance in treating senility, senile confusion, psychoses, psychoneuroses when anxiety and nervous tension were present, cerebral arteriosclerosis, nausea, depression, fatigue, debilitation, mild behavioural disorders, irritability, emotional instability, antisocial attitudes, anxiety, vertigo or incontinence, or symptom thereof, or in improving cognitive function in individuals, for instance, in individuals with Down syndrome and other conditions, are also provided. 9 Rio -6 N R5 N--N (I) ...

Bicyclic compounds for diagnosis and therapy

The present invention relates to the compounds of formula (I) that can be employed in the diagnosis, monitoring of disease progression or monitoring of drug activity, of a group of disorders and abnormalities associated with alpha-synuclein (a-synuclein, A- synuciein, aSynuciein, A-syn, a-syn, aSyn) aggregates including, but not limited to, Lewy bodies and/or Lewy neurites, such as Parkinson's disease. The instant compounds are particularly useful in determining a predisposition to such a disorder, monitoring residual disorder, or predicting the responsiveness of a patient who is suffering from such a disorder to the treatment with a certain medicament. The present compounds can also be used to treat, alleviate or prevent a disorder or abnormality associated with alpha-synuclein aggregates.

Methods of manufacturing benzoquinoline compounds

METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS Abstract of the Disclosure The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediatesthereof. R4 R6 R16 R21 R7 R 18 R25 R 3 0 N R14 R27 R 26 R2F u R13 R1R1O Formula I ...

Complex comprising a PSMA-targeting compound linked to a lead or thorium radionuclide

The present invention relates to complexes comprising a prostate- specific membrane antigen (PSMA) targeting compound linked to a radionuclide, such as ...

Deuterated heterocyclic compounds and their use as imaging agents

DEUTERATED HETEROCYCLIC COMPOUNDS AND THEIR USE AS IMAGING AGENTS Abstract 11, "1 X14 (V) x~ X17'-"X1r The present invention relates to deuterated and optionally detectably labeled compounds of formula (I): R1 -A-R2 and formula (V) and salts thereof, wherein R, R2 , A, and X 10-X19 have any of the values defined in the specification. Also included are pharmaceutical compositions comprising such compounds and salts, and methods of using such compounds and salts as imaging agents, in particular in measuring the radioactive signal of the compound associated with amyloid deposits and/or tau protein aggregates.

New compounds

Fluoride processing method

The invention relates to methods for processing [ ...

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

Labeled molecular agents for imaging cystine/glutamate anti porter

Imaging agents are described that comprise labeled substrates capable of being introduced into cells via the cystine/glutamate antiporter. The substrates may be used for imaging or detecting oxidative stress in cells by introducing the labeled agents into cells via the cystine/glutamate antiporter and subsequent detection.

Deuterated ibrutinib

The present invention in one embodiment provides a compound of Formula (I); or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula (I) are as defined in the specification.

Cage amine ligands for metallo-radiopharmaceuticals

The present invention relates to compounds that are useful as metal ligands and which can be bound to a biological entity such as a molecular recognition moiety and methods of making these compounds. Once the compounds that are bound to a biological entity are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilising the radiolabelled compounds of the invention.

Contrast agent for imagining myocardial perfusion

The present disclosure is directed to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a compound linked to an imaging moiety, wherein said compound binds MC-1, and scanning the patient using diagnostic imaging. The invention also relates to kits comprising said compound or precursor compounds linked or not linked to an imaging moiety.

Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alphalpha responses

Compounds having the following formula I: or a stereoisomer or pharmaceutically-acceptable salt thereof, where R ...

2-amino-3,5-difluoro-3,6-dimethyl-6-phenyl-3,4,5,6-tetrahydropyridines as BACE1 inhibitors for treating Alzheimer's disease

The present invention is directed to compounds according to Formula (I) which compounds are inhibitors of the BACE1 enzyme. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders for 5 which the reduction of Aβ deposits is beneficial such as Alzheimer's disease.

Solid phase extraction method

The present invention provides a method to prepare an ...

Probes for imaging huntingtin protein

Provided are imaging agents comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and methods of their use. (I).

Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

Compounds of Formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.

Protein kinase inhibitors

The present invention concerns novel deuterated and non-deuterated cyclic chemical compounds and their corresponding salts thereof active on protein kinases in general, and in particular as inhibitors of protein kinases. Additionally, methods of treating mammals with protein kinase-mediated diseases or conditions by administering a therapeutically effective amount of the novel deuterated or non-deuterated cyclic chemical compounds and their corresponding salts thereof.

Diagnostic compositions for pet imaging, a method for manufacturing the diagnostic composition and its use in diagnostics

The present application relates to a diagnostic composition comprising: a. a compound of Formula I, b. ethanol, c. water, and d. a hydroxycarboxylic acid, a salt of a hydroxycarboxylic acid or a mixture thereof. The diagnostic composition can be used in the selective detection of disorders and abnormalities associated with Tau aggregates such as Alzheimer's disease (AD) and other tauopathies, for example, using Positron Emission Tomography (PET). The present invention also relates to a method of preparing the claimed diagnostic composition.

Bicyclic AZA compounds as muscarinic M1 receptor agonists

Abstract This invention relates to compounds that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the 5 therapeutic uses of the compounds. Compounds provided are of formula Ra where R1-R5 , X1, X2 and p are as defined herein.

Analogs of cocaine

CYCLOPROPYL MODULATORS OF P2Y12 RECEPTOR

The present invention relates to new cyclopropyl modulators of P2Y12 receptor activity, pharmaceutical compositions thereof, and methods of use thereof.

NEW COMPOUNDS SUITABLE AS PRECURSORS TO COMPOUNDS THAT ARE USEFUL FOR IMAGING AMYLOID DEPOSITS

The present invention relates to novel derivatives that are suitable as precursors to compounds that are useful for imaging amyloid deposits in living patients, their compositions, methods of use and processes to make such compounds. The compounds deriving from these precursors are useful in methods of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimer's disease by positron emission tomography (PET) as well as measuring clinical efficacy of Alzheimer's disease therapeutic agents. Furthermore, the present invention also discloses the precursor compounds in crystalline form.

SUBSTITUTED 4-PHENYL PYRIDINE COMPOUNDS AS NON-SYSTEMIC TGR5 AGONISTS

The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula: (I'), where R1, R2, R2', R3, R4, X1, X2, X3, X4, Q, and n are described herein.

DEUTERATED DOMPERIDONE COMPOSITIONS, METHODS, AND PREPARATION

Deuterated domperidone compositions, methods of synthesis, methods of use, and dosing formulations providing beneficial safety and other effects.

MAGL INHIBITORS

Provided herein are piperazine carbamates and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL. Furthermore, the subject compounds and compositions are useful for the treatment of pain.

METHOD FOR PRODUCING FLUTEMETAMOL

Provided is a method for producing flutemetamol including the steps of: reacting a precursor compound represented by a predetermined general formula with a radioactive fluoride to obtain a 18F labeling compound represented by a predetermined general formula;allowing a strong base to act on the reaction mixture of the above step containing the precursor compound and the 18F labeling compound;after the above step, purifying the 18F labeling compound using a reverse phase solid phase extraction cartridge;and removing a protective group to obtain [18F] flutemetamol.

DEUTERATED COMPOUNDS FOR TREATING CANCER AND RELATED DISEASES AND CONDITIONS, AND COMPOSITIONS AND METHODS THEREOF

The present invention directs to chemical compounds according to generic formula (I-B), wherein each of R1, R2, R3, Ra, R5 and R9 is independently selected from H and D. The compounds are useful for treating cancer or a related disease or disorder thereof. The present invention further directs to pharmaceutical composition and methods of preparation and use thereof. (see above formula) ...

COMPOUNDS FOR IMAGING TAU PROTEIN AGGREGATES

The present invention relates to novel compounds of the formula (II) that can be employed in the selective Tau detection of disorders and abnormalities associated with Tau aggregates such as Alzheimer's disease and other tauopathies using Positron Emission Tomography (PET) Imaging.

AROMATIC AMINE COMPOUND AND USE THEREOF IN PREPARATION OF AR AND BRD4 DUAL INHIBITORS AND REGULATORS

Provided are an aromatic amine compound and a use thereof in the preparation of AR and BRD4 dual inhibitors and regulators. Specifically provided is the compound shown in formula I, said compound having dual inhibitory effects on AR and BRD4. The compound is not only capable of inhibiting the proliferation of androgen receptor AR multi-expressed prostate cancer cell line LNCAP/AR, but also shows good inhibitory effects on prostate cancer lines VCaP and RRRV1 which are resistant to prostate cancer drugs (enzalutamide) on the market. The compound is itself a compound capable of simultaneously identifying AR and BRD4 dual targets and can be used as a dual AR/BRD4 inhibitor, and is also capable of being used for preparing proteolysis-targeting chimeras (PROTACs) for inducing the degradation of AR/BRD4 dual targets, and has good prospects for application in the preparation of drugs for the treatment of AR and BRD4-related diseases.

CREATINE PRODRUGS, COMPOSITIONS AND METHODS OF USE THEREOF

The present disclosure provides creatine prodrug analogs and their compositions useful for the treatment of creatine deficiencies.

Radiolabeled cgrp antagonists

The present invention is directed to radiolabeled CGRP receptor antagonists which are useful for the quantitative imaging of CGRP receptors in mammals.

Iodine radiolabelling method

The present invention provides a novel method of labelling biological targeting molecules (BTMs) of interest with radioiodine. Also provided are novel radioiodinated BTMs prepared using the method, as well as radiopharmaceutical compositions comprising such radioiodinated BTMs. The invention also provides radioiodinated intermediates useful in the method, as well as in vivo imaging methods using the radioiodinated BTMs.

Heterodimers of Glutamic Acid

Compounds of Formula (Ia) wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Z is H or C 1 -C 4 alkyl, R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 1 -C 12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.

Fluorinated fructose derivatives for pet imaging

The present invention is directed to fructose-based radiopharmaceuticals, pharmaceutical compositions comprising same, precursors and methods for preparing same, and methods of using same for diagnostic imaging of cancer cells and non-imaging tracer studies.

NITROIMIDAZOLE DERIVATIVES

The present invention provides novel compounds useful in the treatment and diagnosis of mycobacterial infections. Compounds of the present invention have enhanced biological properties as compared to the related known compounds. The present invention also provides a precursor compound useful in the synthesis of certain compounds of the invention, and a method to obtain these compounds using said precursor compound. Methods of treatment and diagnosis in which the compounds of the invention fmd use are also provided. 2. The compound as defined in wherein Ris methyl.3. The compound as defined in wherein X is —O—.4. (canceled)5. The compound as defined in wherein said radioactive halogen is a gamma-emitting radioactive halogen selected from I claim 1 , I and Br.6. (canceled)7. The compound as defined in wherein said radioactive halogen is a positron-emitting radioactive halogen selected from F claim 1 , F claim 1 , Br claim 1 , Br and I.810.-. (canceled)1519.-. (canceled)20. A pharmaceutical composition comprising the compound as defined in together with a biocompatible carrier in a form suitable for mammalian administration.21. An in vivo imaging method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(a) administration of the compound as defined in ;'}(b) allowing said compound to bind to the cell wall of any mycobacteria present in said subject;(c) detecting by an in vivo imaging procedure signals emitted by said radioactive halogen;(d) generating an image representative of the location and/or amount of said signals; and,(e) determining the distribution of mycobacteria in said subject wherein said distribution is directly correlated with said signals.22. (canceled)23Mycobacterium tuberculosis.. The in vivo imaging method as defined in wherein said mycobacterium is24Mycobacterium tuberculosis.. The in vivo imaging method as defined in which is carried out repeatedly during the course of a treatment regimen for said subject claim 23 , said regimen ...

CARBOXYLATION CATALYSTS

The use of a complex of the form Z—M—OR in the carboxylation of a substrate is described. The group Z is a two-electron donor ligand, M is a metal and OR is selected from the group consisting of OH, alkoxy and aryloxy. The substrate may be carboxylated at a C—H or N—H bond. The metal M may be copper, silver or gold. The two-electron donor ligand may be a phosphine, a carbene or a phosphite ligand. Also described are methods of manufacture of the complexes and methods for preparing isotopically labelled caboxylic acids and carboxylic acid derivatives. 134-. (canceled)25. A method of carboxylation of a substrate , the method comprising;{'sub': '2', 'contacting a complex of the form Z—M—OR ,wherein the group Z is a two-electron donor ligand, M is a metal, and OR is selected from the group consisting of OH, alkoxy and aryloxy; with a substrate and a source of CO.'}26. The method according to claim 25 , wherein the metal M is selected from the group consisting of copper claim 25 , silver and gold.27. The method according to claim 25 , wherein the carboxylation is carried out in the presence of a base.28. The method according to claim 27 , wherein the base is an alkali metal hydroxide or alkoxide.29. The method according to claim 25 , wherein the two-electron donor ligand Z is selected from the group consisting of phosphines claim 25 , carbenes claim 25 , or phosphites.30. The method according to claim 29 , wherein the two-electron donor ligand Z is a nitrogen containing heterocyclic carbene ligand.33. The method according to claim 26 , wherein the complex is selected from the group consisting of: [M(OH)(IMes)] claim 26 , [M(OH)(SIMes)] claim 26 , [M(OH)(IPr)] claim 26 , [M(OH)(ItBu)] claim 26 , and [M(OH)(SIPr)] claim 26 , where M is Au claim 26 , Ag or Cu.34. The method according to claim 25 , wherein the substrate is carboxylated at a C—H or N—H bond.35. The method according to claim 25 , wherein the substrate is a substituted or unsubstituted aromatic compound.36. The ...

SOLID-PHASE FLUORINATION OF BENZOTHIAZOLES

The invention provides a process for the production of an F-labelled tracer which comprises treatment of a solid support-bound precursor of formula (I) 18-. (canceled)10. A radiopharmaceutical kit for the preparation of an F-labelled tracer for use in PET , which comprises:{'claim-ref': {'@idref': 'CLM-00009', 'claim 9'}, '(i) a vessel containing a compound of formula (I), (Ia), or (Ib) as defined in ; and'}{'sup': 18', '−, '(ii) means for eluting the vessel with a source of F;'}{'sup': 18', '−, '(iii) an ion-exchange cartridge for removal of excess F.'}11. A cartridge for a radiopharmaceutical kit for the preparation of an F-labelled tracer for use in PET which comprises:{'claim-ref': {'@idref': 'CLM-00009', 'claim 9'}, '(i) a vessel containing a compound of formula (I), (Ia), or (Ib) as defined in ; and'}{'sup': 18', '−, '(ii) means for eluting the vessel with a source of F.'}12. A radiopharmaceutical kit for the preparation of an F-labelled tracer for use in PET , which comprises:{'claim-ref': {'@idref': 'CLM-00009', 'claim 9'}, '(i) a vessel containing a compound of formula (III) as defined in ; and'}{'sup': 18', '−, '(ii) means for eluting the vessel with a source of F.'}13. A cartridge for a radiopharmaceutical kit for the preparation of an F-labelled tracer according to for use in PET which comprises:{'claim-ref': {'@idref': 'CLM-00009', 'claim 9'}, '(i) a vessel containing a compound of formula (III) as defined in ; and'}{'sup': '18', '(ii) means for eluting the vessel with a source of F.'}14. A method for obtaining a diagnostic PET image which comprises the step of using a radiopharmaceutical kit according to or a cartridge for a radiopharmaceutical kit according to . The present invention relates to novel solid-phase processes for the production of radiolabelled tracers, in particular for the production of F-labelled benzothiazole compounds which may be suitable for use as Positron Emission Tomography (PET) radiotracers. The invention also comprises ...

Labeled Alginate Conjugates for Molecular Imaging Applications

Described are bifunctional NOTA-based derivatives capable of conjugating with alginate and with metal ions, as well as NOTA-alginate conjugates which can be labeled with stable or radioactive metal ions. Also described are conjugation methods of the bifunctional NOTA-based linker with alginate, and methods of using radiometal-labeled NOTA-alginate conjugates or other radio-labeled alginate conjugates as imaging reagents. 2. The compound of claim 1 , wherein the compound further comprises a stable or radioactive metal ion chelated by the 1 claim 1 ,4 claim 1 ,7-triazacyclononane-1 claim 1 ,4 claim 1 ,7-triacetic acid moiety.3. The compound of claim 2 , wherein the stable or radioactive metal ion comprises a gallium ion.4. The compound of claim 2 , wherein the radioactive metal ion comprises Cu claim 2 , Cu claim 2 , Cu claim 2 , Cu claim 2 , Cu claim 2 , or In.6. The alginate conjugate of claim 5 , wherein the conjugate further comprises a stable or radioactive metal ion chelated by the 1 claim 5 ,4 claim 5 ,7-triazacyclononane-1 claim 5 ,4 claim 5 ,7-triacetic acid moiety of the conjugate.7. The alginate conjugate of claim 6 , wherein the stable or radioactive metal ion comprises a gallium ion.8. The alginate conjugate of claim 6 , wherein the radioactive metal ion comprises Cu claim 6 , Cu claim 6 , Cu claim 6 , Cu claim 6 , Cu claim 6 , or In.9. A method of imaging in a mammal comprising:administering a radio-labeled alginate conjugate to a mammal; andimaging the temporal and spatial distribution of the radio-labeled alginate conjugate.11. The method of claim 10 , wherein the stable or radioactive metal ion comprises a gallium ion.12. The method of claim 10 , wherein the radioactive metal ion comprises Cu claim 10 , Cu claim 10 , Cu claim 10 , Cu claim 10 , Cu claim 10 , or In.13. The method of claim 9 , wherein the alginate is conjugated to an iodinated tyramine or tyramine derivative.14. The method of claim 9 , wherein the radio-labeled alginate conjugate is ...

RADIOLABELLED mGluR2 PET LIGANDS

The present invention relates to novel, selective, radiolabelled mGluR2 ligands which are useful for imaging and quantifying the metabotropic glutamate receptor mGluR2 in tissues, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue, cells or a host, in vitro or in vivo and to precursors of said compounds. 3. The compound according to wherein{'sup': '1', 'Ris selected from cyclopropylmethyl and 2,2,2-trifluoroethyl; and'}{'sup': '2', 'Ris selected from chloro and trifluoromethyl.'}4. The compound according to claim 1 , wherein Ris cyclopropylmethyl and Ris chloro.5. The compound according to claim 1 , wherein n is 0 or 2.7. A sterile solution comprising a compound of Formula (I) as defined in .8. (canceled)9. A method of imaging a tissue claim 1 , cells or a host claim 1 , comprising contacting with or administering to a tissue claim 1 , cells or a host claim 1 , a compound of Formula (I) as defined in claim 1 , and imaging the tissue claim 1 , cells or host with a positron-emission tomography imaging system.11. The compound according to claim 10 , wherein n is 0 or 2. The present invention relates to novel, selective, radiolabelled mGluR2 ligands which are useful for imaging and quantifying the metabotropic glutamate receptor mGluR2 in tissues, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue, cells or a host, in vitro or in vivo and to precursors of said compounds.Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development ...

Fluorinated 2-Amino-4-(Benzylamino)Phenylcarbamate Derivatives

The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.

Benzoquinoline inhibitors of vesicular monoamine transporter 2

The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.

Morphinan compounds

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1 receptor agonist that also has NMDA antagonist activity.

RADIOFLUORINATION METHOD

Provided by the present invention is a novel method for obtaining an F-labelled compound wherein said compound comprises an F-labelled pyridyl ring. The method of the invention is advantageous over the prior art methods as it provides these compounds in higher radiochemical yields than have been possible with previous methods. Also provided by the present invention is an F-labelled synthon useful in the method of the invention. 4) The method as defined in which further comprises the step:{'sup': 18', '18, '(ii) coupling the F-labelled synthon of Formula Y as defined herein with a cross-coupling partner in a transition metal-mediated coupling reaction to obtain an F-labelled product.'}5) The method as defined in wherein said transition metal is palladium.12) The method as defined in which is automated. The present invention relates to a method for radiosynthesis and more specifically a novel method for the synthesis of F-labelled compounds. The invention also relates to a novel synthon for use in the inventive method of synthesis.In order to expand the range of applications for positron emission tomography (PET) there is an interest in developing synthetic methods for new PET tracers, i.e. biologically useful compounds labelled with C, F or Br. Currently, the most widely-used of these radiotracers for PET imaging is F.Typically, the synthesis of a PET tracer including its purification should be completed within three half-lives of the radiotracer. F has a relatively short half-life of 109.7 minutes and as such methods for its incorporation into a PET tracer demands fast and high-yielding reactions that can be performed on a small scale and under mild conditions.Direct labelling is desirable as it introduces F at the last possible step. However, direct labelling tends only to be possible using [F]fluoride in a nucleophilic substitution reaction can require the presence of activating groups, proton-free conditions and typically high temperatures of above 100° C. The ...

RADIOLABELED PDE10A LIGANDS

Compounds of formula (I) are disclosed 2. The compound of claim 1 , wherein said compound comprises a radiolabel.3. The compound of claim 1 , wherein R comprises a radiolabel.4. The compound of claim 1 , wherein HetAr comprises a radiolabel.7. The compound of claim 6 , wherein R is C-Calkyl.8. The compound of claim 7 , selected from the group consisting of:{'sup': '11', '2-((4-(1-[C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine; and'}{'sup': '18', '2-((4-(1-(2-[F]-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine.'}10. The compound of claim 9 , wherein R is C-Calkyl.11. The compound of claim 10 , selected from the group consisting of:{'sup': '11', '2-((4-(1-[C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine; and'}{'sup': '18', '2-((4-(1-(2-[F]-fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine.'}13. The compound of claim 12 , wherein R is C-Calkyl.14. The compound of claim 13 , selected from the group consisting of:{'sup': '11', '6-((4-(1-[C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine; and'}{'sup': '18', '6-((4-(1-(2-[F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine.'}16. The compound of claim 15 , wherein R is C-Calkyl.17. The compound of claim 16 , selected from the group consisting of:{'sup': '18', '2-((4-(1-(2-[F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazoline.'}19. The compound of claim 18 , wherein R is C-Calkyl.20. The compound of claim 19 , selected from the group consisting of:{'sup': '11', '2-((4-(1-[C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine; and'}{'sup': '18', '2-((4-(1-(2-[F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine.'}22. The compound of claim 21 , wherein{'sup': '1', 'Zis CH;'}{'sup': '1', 'sub': 1', '6, 'Ris C-Calkyl; and'}{'sub': 1', '6, 'R is C-Calkyl.'}23. The ...

RADIOLABELED 5-HT6 LIGANDS

Compounds of formula (I) are disclosed 2. The compound of claim 1 , wherein said compound comprises a radiolabel.3. The compound of claim 1 , wherein R comprises a radiolabel.4. The compound of claim 1 , wherein R is hydrogen.5. The compound of claim 1 , wherein R is C-Calkyl.6. The compound of claim 5 , wherein R is CH.7. The compound of claim 5 , wherein R is CHCH.8. The compound of claim 5 , wherein R is CHCHCH.9. The compound of claim 5 , wherein R is CHCHF.10. The compound of claim 5 , wherein R is CHCHCHF.11. The compound of claim 5 , wherein R is C-Chydroxyalkyl.12. The compound of claim 5 , wherein R is —COtBu.13. The compound of claim 1 , selected from the group consisting of:8-(piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;8-(1-methylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;8-(1-ethylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;8-(1-propylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;8-(1-(2-fluoroethyl)piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;8-(1-(3-fluoropropyl)piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;2-(4-(3-(pyridin-2-ylsulfonyl)quinolin-8-yl)piperidin-1-yl)ethanol;3-(4-(3-(pyridin-2-ylsulfonyl)quinolin-8-yl)piperidin-1-yl)propan-1-ol;tert-butyl 4-(3-(pyridin-2-ylsulfonyl)quinolin-8-yl)piperidine-1-carboxylate;{'sup': '11', '8-(1-[C]methylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;'}{'sup': '11', '8-(1-[1-C]ethylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;'}{'sup': '11', '8-(1-[1-C]propylpiperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;'}{'sup': '18', '8-(1-(2-[F]fluoroethyl)piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline;'}{'sup': '18', '8-(1-(3-[F]fluoropropyl)piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline; and'}{'sup': '3', '8-(1-([H]methyl)piperidin-4-yl)-3-(pyridin-2-ylsulfonyl)quinoline.'}14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt claim 1 , ester claim 1 , amide ...

Pyridine Compounds as Sodium Channel Blockers

The invention relates to substituted pyridine compounds of Formula I: (I) or a pharmaceutically acceptable salt, prodrug, or solvate thereof wherein A, X, A, R, R, R, G, and z are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain. 2. (canceled)412-. (canceled)1419-. (canceled)23. (canceled)26. (canceled)2829-. (canceled)31. The compound of claim 20 , wherein G is G-7 and n is 2 claim 20 , or a pharmaceutically acceptable salt or solvate thereof.3236-. (canceled)40. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , and a pharmaceutically acceptable carrier.4244-. (canceled)45. The method of claim 41 , wherein a disorder responsive to the blockade of Na1.7 sodium channels is treated.47. (canceled)48. The method of claim 46 , wherein said method is for treating pain.49. The method of claim 46 , wherein said method is for preemptive or palliative treatment of pain.50. The method of claim 48 , wherein said pain is selected from the group consisting of chronic pain claim 48 , inflammatory pain claim 48 , neuropathic pain claim 48 , acute pain claim 48 , and surgical pain.5259-. (canceled)60. The compound of claim 1 , wherein the compound is H claim 1 , C claim 1 , or C radiolabeled claim 1 , or a pharmaceutically acceptable salt or solvate thereof.61. A method of screening a candidate compound for the ability to bind to a binding site on a protein using a radiolabeled compound of claim 60 , comprising a) introducing a fixed concentration of the radiolabeled compound to a soluble or membrane-associated protein or fragment thereof to form a mixture; b) titrating the mixture with a candidate compound; and c) determining the binding of the candidate compound to said binding site.62. A method of ...

Substituted triazolophthalazine derivatives

This invention relates to novel substituted triazolophthalazines and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering selective α5 receptor partial or full inverse agonists.

METHOD FOR RAPID PREPARATION OF SUITABLEFLUORIDE FOR NUCLEOPHILICFLUORINATION

The invention generally relates to the preparation of F-labeled radiopharmaceuticals. In particular, this invention relates to the advanced processes for an efficient eiution of [F]fluoride trapped in a cartridge filled with quaternary ammonium polymer which comprises inert non-basic and non-nucleophilic counter anions. The said methods and polymer cartridges allow the rapid preparation of suitable [F]fluoride solution, which is also less basic to reduce the formation of byproducts, finally to increase radiochemical yield and purity of F-radiopharmaceuticals. 2. quaternary ammonium polymer according to claim 1 , wherein NRis selected from the group consisting of trimethylamine claim 1 , triethylamine claim 1 , tri-n-propylamine claim 1 , tri-n-butylamine claim 1 , N-methylimidazole claim 1 , and pyridine.3. A quaternary ammonium polymer according to claim 1 , wherein the X is selected from the group consisting of methanesulfonate (OMs) claim 1 , trifluoromethanesulfonate (OTf) claim 1 , para-toluenesulfonate (OTs) claim 1 , para-nitrobenzenesulfonate (ONs) claim 1 , tetrafluoroborate (BF) claim 1 , hexafluorophosphate (PF) claim 1 , hexafluoroantimonate (SbF) claim 1 , and N claim 1 ,N-bis(trifluoromethanesulfonyl)amide (N(Tf)).6. A polymer cartridge 6 containing neutral ammonium polystyrene of for solid-phase anion extraction.7. A method for separation of [F]fluoride from aqueous solution claim 6 , wherein [F]fluoride dissolved in aqueous solution is passed through the polymer cartridge of .8. A method for the preparation of an eluting solution for eluting [18F] from a cartridge according to claim 6 , wherein the eluting solution is prepared by composing three ingredients (Ingredient A claim 6 , Ingredient B claim 6 , and Ingredient C) claim 6 , and dissolving in an alcohol solvent.9. A method according to claim 8 , wherein Ingredient A is K222 that is used as a phase transfer catalyst of [F]fluorination in a range from 10 to 20 mg.10. A method according to claim 8 ...

Isotopically enriched arylsulfonamide ccr3 antagonists

Provided herein are isotopically enriched arylsulfonamides, for example, of Formula I, that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disease, disorder, or condition.

Deuterated cftr potentiators

This invention relates to compounds of Formula I: and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a CFTR potentiator.

Half-Curcuminoids as Amyloid-Beta PET Imaging Agents

Provided herein are curcumin analogues that are able to interact with amyloid beta (Aβ) and to attenuate the copper-induced crosslinking of Aβ. Also provided herein are methods of using the compounds as imaging agents of amyloid beta and for the treatment of diseases associated with amyloid beta. Methods of preparing unlabeled and radiolabeled compounds useful for interacting with amyloid beta and pharmaceutical compositions are also provided. 2. The method of claim 1 , wherein the imaging technique is selected from the group consisting of fluorescence imaging claim 1 , positron emission tomography imaging claim 1 , magnetic resonance imaging claim 1 , single-photon emission computed tomography claim 1 , positron emission tomography with computed tomography imaging claim 1 , and positron emission tomography with magnetic resonance imaging.3. The method of claim 1 , wherein the imaging technique is selected from the group consisting of fluorescence imaging claim 1 , position emission tomography imaging claim 1 , and single-photon emission computed tomography.5. The method of claim 1 , wherein:{'sup': 4', '5, 'X is BRR;'}{'sup': 1', '1A, 'sub': '6-10', 'Ris selected from the group consisting of Caryl and 5-10 membered heteroaryl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected Rgroups;'}{'sup': 1A', 'N1', 'N2', '6, 'sub': 1-6', '1-6', '1-6', '1-6', '6-10', '1-6', '1-6', '6-10, 'each Ris independently selected from the group consisting of halo, Calkyl, Chaloalkyl, Calkoxy, Chaloalkoxy, NRR, and Caryl, wherein the Calkyl, Calkoxy, and Caryl are each optionally substituted by 1, 2, 3, or 4 independently selected Rgroups;'}{'sup': 2', '2A, 'sub': 1-6', '3-6, 'Ris selected from the group consisting of Calkyl, Ccycloalkyl, and phenyl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected Rgroups;'}{'sup': '3', 'Ris H;'}{'sup': 4', '5, 'Rand Rare each halo; and'}m is 1.6. The method of claim 5 , wherein:{'sup ...

5-DEUTERO-2,4-THIAZOLIDINEDIONE DERIVATIVES AND COMPOSITIONS COMPRISING AND METHODS OF USING THE SAME

The invention provides 5-deuterium-enriched 2,4-thiazolidinediones (e.g., 5-[4-[2-(5-ethyl-2-pyridyl)-2-oxoethoxy]benzyl]-5-deutero-thiazolidine-2,4-dione), deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same. 12-. (canceled)858-. (canceled)59. The compound of claim 5 , wherein Ris D.60. The compound of claim 6 , wherein Ris D.61. The deuterium-enriched compound of claim 59 , or a stereoisomer or pharmaceutically acceptable salt form thereof claim 59 , wherein Ris ethyl; and Z is H or D claim 59 , provided that the abundance of deuterium in Z is at least 50%.62. The deuterium-enriched compound of claim 59 , wherein the abundance of deuterium in Z is at least 80%.63. The deuterium-enriched compound of claim 59 , wherein the abundance of deuterium in Z is at least 95%.64. The deuterium-enriched compound of claim 60 , or a pharmaceutically acceptable salt form thereof claim 60 , wherein Ris ethyl; and wherein the compound has an enantiomeric excess claim 60 , with respect to the C—Z carbon claim 60 , of at least 80% claim 60 , and Z is H or D claim 60 , provided that the abundance of deuterium in Z is at least 50%.65. The deuterium-enriched compound of claim 64 , wherein the abundance of deuterium in Z is at least 80%.66. The deuterium-enriched compound of claim 64 , wherein the abundance of deuterium in Z is at least 95%.67. The deuterium-enriched compound of claim 64 , wherein the compound has an enantiomeric excess claim 64 , with respect to the C—Z carbon claim 64 , of at least 90%.68. The deuterium-enriched compound of claim 64 , wherein the compound has an enantiomeric excess claim 64 , with respect to the C—Z carbon claim 64 , of at least 95%.69. The deuterium-enriched compound of claim 7 , wherein the compound has an enantiomeric excess claim 7 , with respect to the C(RR) carbon claim 7 , of at least 80%.70. The deuterium-enriched compound of claim 7 , wherein the ...

Methods and compositions for radiohalogen protein labeling

Methods and compositions are provided for labeling proteins with radiohalogen-label reagents. Radiohalogen-labeled proteins may be used for imaging studies, as therapeutics and in diagnostic tests. The [ 125 I] HIP-DOTA label reagent 6 is prepared by an efficient and convenient process.

INDAZOLES AND USE THEREOF

In one aspect, the present disclosure provides indazoles of Formula I: (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R, R, R, R, Z, Z, Z, and G are defined as set forth in the specification. Further, the present disclosure also provides compounds of Formulae II and IA, and the pharmaceutically acceptable salts and solvates thereof. The present disclosure is also directed to the use of compounds of Formulae I, II, and IA, and the pharmaceutically acceptable salts and solvates thereof, to treat a disorder responsive to the blockade of sodium channels. In one embodiment, compounds of the present disclosure are especially useful for treating pain. 2. The compound of claim 1 , wherein G is dihydroxyalkyl claim 1 , or a pharmaceutically acceptable salt or solvate thereof.4. (canceled)6. The compound of claim 5 , wherein:{'sup': '2', 'Zis selected from the group consisting of N and CH;'}{'sup': '3', 'Ris selected from the group consisting of hydrogen and alkyl; and'}{'sup': '4', 'Ris selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl,'}or a pharmaceutically acceptable salt or solvate thereof.7. The compound of claim 1 , wherein Ris hydrogen claim 1 , and Zis N claim 1 , or a pharmaceutically acceptable salt or solvate thereof.89-. (canceled)10. The compound of claim 1 , wherein G is —(CHR)—C═O)E claim 1 , E is —NRR claim 1 , and Rand Rare hydrogen claim 1 , or a pharmaceutically acceptable salt or solvate thereof.11. The compound of claim 1 , wherein Ris selected from the group consisting of hydrogen claim 1 , hydroxyalkyl claim 1 , and —X—R claim 1 , or a pharmaceutically acceptable salt or solvate thereof.12. The compound of claim 11 , wherein Ris hydrogen claim 11 , or a pharmaceutically acceptable salt or solvate thereof.13. (canceled)15. The compound of claim 11 , wherein Ris —X—R claim 11 , wherein X is —O— or —NH— claim 11 , or a pharmaceutically acceptable salt or solvate thereof.1619-. (canceled)21. The ...

2',6'-DIOXO-3'-DEUTERO-PIPERDIN-3-YL-ISOINDOLINE COMPOUNDS

The present application describes 2-(2′,6′-dioxo-3′-deutero-piperidin-3′-yl)isoindoles, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treating using the same. 13-. (canceled)524-. (canceled)25. The deuterium-enriched compound of claim 4 , wherein X is C═O.26. The deuterium-enriched compound of claim 4 , wherein Ris aryl.27. The deuterium-enriched compound of claim 25 , wherein Ris aryl.28. The deuterium-enriched compound of claim 26 , wherein said aryl is phenyl.29. The deuterium-enriched compound of claim 27 , wherein said aryl is phenyl.30. The deuterium-enriched compound of claim 27 , wherein Ris (CH).31. The deuterium-enriched compound of claim 29 , wherein Ris (CH).32. The deuterium-enriched compound of claim 27 , wherein Ris (C-C)heterocycloalkyl.33. The deuterium-enriched compound of claim 30 , wherein Ris (C-C)heterocycloalkyl.34. The deuterium-enriched compound of claim 31 , wherein Ris (C-C)heterocycloalkyl.35. The deuterium-enriched compound of claim 33 , wherein (C-C)heterocycloalkyl is morpholinyl.36. The deuterium-enriched compound of claim 34 , wherein (C-C)heterocycloalkyl is morpholinyl.37. The deuterium-enriched compound of claim 33 , wherein the abundance of deuterium in Z is at least 90%.38. The deuterium-enriched compound of claim 34 , wherein the abundance of deuterium in Z is at least 90%.39. The deuterium-enriched compound of claim 36 , wherein the abundance of deuterium in Z is at least 90%.40. The deuterium-enriched compound of claim 33 , wherein R-Rare H claim 33 , and Ris H.41. The deuterium-enriched compound of claim 34 , wherein R-Rare H claim 34 , and Ris H.42. The deuterium-enriched compound of claim 36 , wherein R-Rare H claim 36 , and Ris H.43. The deuterium-enriched compound of claim 39 , wherein R-Rare H claim 39 , and Ris H.441. A pharmaceutical composition comprising a deuterium-enriched compound of claim and one or more excipients.45. A pharmaceutical ...

CYCLOPROPYL MODULATORS OF P2Y12 RECEPTOR

The present invention relates to new cyclopropyl modulators of P2Y12 receptor activity, pharmaceutical compositions thereof, and methods of use thereof. 2. The compound or salt thereof of wherein each position represented as D has deuterium enrichment of no less than about 50%.3. The compound or salt thereof of wherein each position represented as D has deuterium enrichment of no less than about 90%.4. The compound or salt thereof of wherein each position represented as D has deuterium enrichment of no less than about 98%.5. A method of treating a P2Y12 receptor-mediated disorder comprising administering to a patient in need thereof claim 1 , a therapeutically effective amount of a compound or salt thereof as recited in .6. The method of claim 5 , wherein said disorder is arterial thrombosis or coronary artery disease.7. The method of claim 5 , further comprising administering an additional therapeutic agent.8. The method of wherein said additional therapeutic agent is an alpha adrenergic receptor antagonist claim 7 , a beta adrenergic receptor antagonist claim 7 , an angiotensin II receptor antagonist claim 7 , an angiotensin-converting enzyme inhibitor claim 7 , an anti-arrhythmic claim 7 , an antithrombotic claim 7 , an antiplatelet agent claim 7 , a calcium channel blocker claim 7 , a fibrate claim 7 , or a HMG-CoA reductase inhibitor.9. The method of wherein said alpha adrenergic receptor antagonist is abanoquil claim 8 , adimolol claim 8 , ajmalicine claim 8 , alfuzosin claim 8 , amosulalol claim 8 , arotinolol claim 8 , atiprosin claim 8 , benoxathian claim 8 , buflomedil claim 8 , bunazosin claim 8 , carvedilol claim 8 , CI-926 claim 8 , corynanthine claim 8 , dapiprazole claim 8 , DL-017 claim 8 , domesticine claim 8 , doxazosin claim 8 , eugenodilol claim 8 , fenspiride claim 8 , GYKI-12 claim 8 ,743 claim 8 , GYKI-16 claim 8 ,084 claim 8 , indoramin claim 8 , ketanserin claim 8 , L-765 claim 8 ,314 claim 8 , labetalol claim 8 , mephendioxan claim 8 , ...

Compositions for binding sphingosine-1-phosphate receptor 1 (s1p1), imaging of s1p1, and methods of use thereof

Among the various aspects of the present disclosure is the provision of a compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof. Provided are imaging agents for imaging S1P1 and S1P1 associated diseases, disorders, and conditions. Also provided are therapeutic compositions and methods for the treatment of S1P1 associated diseases, disorders, and conditions.

AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS

The invention provides certain azetidinyloxyphenylpyrrolidine compounds, particularly compounds of formula I, and pharmaceutical compositions thereof. The invention further provides methods of using a compound of formula I to treat overactive bladder. 4. The compound or salt of wherein Ris Cl.6. The compound which is (2S)-3-[(3S claim 3 ,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-chloropyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1 claim 3 ,2-diol.8. A pharmaceutical composition comprising a compound of or claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , and a pharmaceutically acceptable carrier claim 3 , diluent or excipient.9. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound of or claim 3 , or a pharmaceutically acceptable salt thereof.10. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound of or claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , in combination with an effective amount of tadalafil.11. (canceled)12. (canceled)13. (canceled) The invention provides certain azetidinyloxyphenylpyrrolidine compounds, pharmaceutical compositions thereof, methods of using the same, and processes for preparing the same.Overactive bladder (OAB) is a symptomatically defined medical condition referring to the symptoms of urinary frequency and urgency, with or without urge incontinence. OAB is a condition that adversely affects the quality of life and social functioning of approximately 17 percent of the adult population. In spite of progress made for OAB treatment, many patients suffer with OAB for years without resolution. The first-line treatment for OAB are antimuscarinic drugs which have a good initial response, but experience diminishing patient compliance over the long term due to adverse effects and decreasing efficacy. There remains a ...

Creatine prodrugs, compositions and methods of use thereof

The present disclosure provides creatine prodrug analogs and their compositions useful for the treatment of creatine deficiencies.

COMPOUNDS, COMPOSITIONS, AND METHODS

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof. 131.-. (canceled)33. The method of claim 32 , wherein Rand Rare methyl.34. The method of claim 32 , wherein at least one of Rand Ris hydrogen.35. The method of claim 34 , wherein both Rand Rare hydrogen.36. The method of claim 32 , wherein Ris optionally substituted cyclopropyl or optionally substituted cyclobutyl.37. The method of claim 36 , wherein Ris cyclopropyl independently substituted with one or more halo claim 36 , hydroxy claim 36 , cyano claim 36 , or heteroaryl.38. The method of claim 36 , wherein Ris cyclopropyl claim 36 , cyclobutyl claim 36 , hydroxycylobut-3-yl claim 36 , cyanocylobut-3-yl claim 36 , triazol-2yl-cyclobut-3-yl claim 36 , triazol-1-yl-cyclobut-3-yl claim 36 , or fluorocyclobut-3-yl.39. The method of claim 32 , wherein Ris CD claim 32 , ethyl claim 32 , prop-2-yl claim 32 , or methyl optionally substituted with halo.40. The method of claim 32 , wherein Ris halo claim 32 , cyano claim 32 , or Calkyl optionally substituted with one or more halo.41. The method of claim 40 , wherein Ris bromo.42. The method of claim 40 , wherein Ris —CF.43. The method of claim 32 , wherein Ris optionally substituted cycloalkyl claim 32 , optionally substituted Calkoxy claim 32 , or —N(R)(R).44. The method of claim 43 , wherein Ris optionally substituted Calkyl.45. The method of claim 43 , wherein Ris H and Ris ethyl.46. The method of claim 32 , wherein Ris cyclopropyl claim 32 , methoxy claim 32 , 1 claim 32 ,1-difluoroeth-2-ylamino claim 32 , cyclopropylamino claim 32 , —NH(CH) claim 32 , or —NH(CHCH).47. The method of claim 32 , wherein Ris hydrogen.48. The method of claim 32 , wherein Ris cycloalkyl independently substituted with one or more hydroxy claim 32 , cyano claim 32 , or heteroaryl; Ris halo or Chaloalkyl; Ris —N(R)(R) ...

HETEROCYCLIC COMPOUNDS AS IMAGING PROBES OF TAU PATHOLOGY

Pyridazinone compounds of Formula I: (I) wherein: R′ is alkyl or Ar, optionally substituted with at least one alkyl, halogen, hydroxyl, alkoxy, haloalkoxy, acid, ester, amino, nitro, amide, or alkoxyhalo; 2 R is independently alkyi, alkynyl, ester, amino, amide, acid, aryl, heteroaryl, aminoalkyl, —C(=0)alkyl, —C(=0)aryl, —C(=0)heteroaryl, —C(=0)heterocycloalkyl, —C(=0)heterocycloalkylAr, —C(=0)(CH)halo, —C(═O)(CH)nheterocyclyl, or —SĈAr, optionally substituted with at least one alkyi, alkylhalo, halogen, nitro, aryl, heteroaryl, or heteroaryl(CH)nhalo; Rand Rare independently hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl; Ar is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl group; n is an integer from 0-10; or a radiolabeled derivative thereof. The compounds are useful as imaging probes of Tau pathology in Alzheimer's disease are described. Compositions and methods of making such compounds are also described. 3. (canceled)10. (canceled)12. (canceled)13. (canceled)14. (canceled)15. (canceled)16. (canceled)17. A composition comprising a compound according to and a pharmaceutically acceptable carrier or excipient.18. (canceled)19. A method of imaging using a compound according to or a pharmaceutical composition thereof.20. A method of detecting tau aggregates in vitro and/or in vivo using a compound according to or a pharmaceutical composition thereof.21. (canceled)22. (canceled)23. (canceled) The present invention relates to radiolabeled pyridazinone compounds, compositions thereof, methods of making such compounds and their use as imaging probes of Tau pathology especially as it relates to Alzheimer's Disease. Compounds of the present invention may be used for Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging.Alzheimer's disease (AD) is the most common cause of dementia in the elderly. It is definitively diagnosed and staged on the basis of post-mortem neuropathology. The pathological hallmark of AD is a ...

RADIOLABELLED AND NONRADIOLABELLED PEGYLATED COMPOUNDS AND USES THEREOF

The disclosure provides compounds for detecting neurodegeneration and/or identifying and monitoring the progression of inflammation in neurodegenerative diseases. The disclosure further provides compounds that inhibit the activity of monoamine oxidases, and uses thereof. 2. The compound of claim 1 , wherein R-Ris selected from —ORand H claim 1 , and one of R-Ris —OR.3. The compound of claim 2 , wherein R claim 2 , Rand Rare H claim 2 , and Ris —OR.4. The compound of claim 1 , wherein R-Ris selected from —OR claim 1 , a radiohalogen claim 1 , and H claim 1 , and wherein one of R-Ris —ORand one of R-Ris I or I.5. The compound of claim 1 , wherein Rand Rare H claim 1 , Ris —OR claim 1 , and Ris a radiohalogen.6. The compound of claim 5 , wherein Ris I or I.7. The compound of claim 1 , wherein R-Ris selected from At and H claim 1 , and one of R-Ris a radiohalogen.8. The compound of claim 7 , wherein R claim 7 , R claim 7 , and Rare H claim 7 , and Ris a radiohalogen.9. The compound of claim 8 , wherein Ris I claim 8 , I or At.10. The compound of claim 1 , wherein R-Ris selected from —ORand H claim 1 , and one of R-Ris —OR.11. The compound of claim 1 , wherein X is a radiohalogen selected from I claim 1 , At claim 1 , I claim 1 , I claim 1 , and Br.12. The compound of claim 11 , wherein X is F.14. A method of imaging neurodegeneration in a postmortem brain specimen claim 11 , comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'contacting a postmortem brain specimen from a subject who has a neurodegenerative disorder or is suspected of having a neurodegenerative disorder with a compound of ,'}detecting and/or quantitating binding of the compound to brain tissue comprising neurodegeneration using an imaging technique that detects radioactivity emitted by the compound.15. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier claim 1 , diluent claim 1 , and/or excipient claim 1 , wherein the compound comprises a ...

OXINDOLE DERIVATIVES CARRYING A PIPERIDYL-SUBSTITUTED AZETIDINYL SUBSTITUENT AND USE THEREOF FOR TREATING VASOPRESSINE-RELATED DISEASES

The present invention relates to novel substituted oxindole derivatives of formula (I) wherein the variables are as defined in the claims and description; to pharmaceutical compositions comprising them, and to their use for treatment of vasopressin-related disorders. 2. The compound of claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom.3. The compound of claim 1 , wherein Xis C—Rand R claim 1 , Rand R claim 1 , independently of each other claim 1 , are selected from the group consisting of hydrogen claim 1 , halogen claim 1 , C-C-alkyl claim 1 , fluorinated C-C-alkyl claim 1 , C-C-alkoxy and fluorinated C-C-alkoxy.4. The compound of claim 3 , wherein R claim 3 , Rand R claim 3 , independently of each other claim 3 , are selected from the group consisting of hydrogen claim 3 , fluorine and methoxy.5. The compound of claim 4 , wherein Ris selected from hydrogen claim 4 , fluorine and methoxy.6. The compound of claim 4 , wherein Ris selected from the group consisting of hydrogen claim 4 , fluorine and methoxy.7. The compound of claim 4 , wherein Ris hydrogen or fluorine.8. The compound of claim 1 , wherein Xis N and Rand R claim 1 , independently of each other claim 1 , are selected from the group consisting of hydrogen claim 1 , halogen claim 1 , C-C-alkyl claim 1 , fluorinated C-C-alkyl claim 1 , C-C-alkoxy and fluorinated C-C-alkoxy.9. The compound of claim 8 , wherein Ris selected from the group consisting of hydrogen claim 8 , fluorine and methoxy.10. The compound of claim 8 , wherein Ris selected from the group consisting of hydrogen claim 8 , fluorine and methoxy.11. The compound of claim 1 , wherein Ris selected from the group consisting of methoxy and ethoxy.12. The compound of claim 1 , wherein Ris hydrogen or methoxy.13. The compound of claim 1 , wherein Ris selected from the group consisting of cyano claim 1 , fluorine and chlorine.14. The compound of claim 1 , wherein Ris hydrogen or fluorine.15. The compound of claim 1 , ...

PYRIDINES AND PYRIMIDINES AND USE THEREOF

The present disclosure provides pyridines and pyrimidines of Formula I and pharmaceutically acceptable salts and solvates thereof: wherein A, G, W, W, W, and Rare defined as set forth in the specification. The present disclosure also provides uses of the compounds of Formula I and pharmaceutically acceptable salts and solvates thereof. In certain embodiments, Compounds of the present disclosure are useful for treating pain. In another embodiment, Compounds of the present disclosure are useful for treating a disorder responsive to blockade of sodium channels, or alleviating symptoms of the disorder. 36-. (canceled)910-. (canceled)11. The compound of claim 1 , wherein Ris selected from the group consisting of alkyl claim 1 , optionally substituted cycloalkyl claim 1 , optionally substituted heterocyclo claim 1 , optionally substituted aryl claim 1 , optionally substituted heteroaryl claim 1 , and —SOR claim 1 , or a pharmaceutically acceptable salt or solvate thereof.12. The compound of claim 11 , wherein Ris optionally substituted phenyl or (C-C)alkyl claim 11 , or a pharmaceutically acceptable salt or solvate thereof.13. (canceled)1517-. (canceled)18. The compound of claim 1 , wherein Wis N claim 1 , Wis CH claim 1 , and Wis CH claim 1 , or a pharmaceutically acceptable salt or solvate thereof.19. The compound of claim 1 , wherein Wis N claim 1 , Wis N claim 1 , and Wis CH claim 1 , or a pharmaceutically acceptable salt or solvate thereof.20. (canceled)22. The compound of claim 1 , wherein G is —C(═O)E claim 1 , or a pharmaceutically acceptable salt or solvate thereof.23. (canceled)2530-. (canceled)31. The compound of claim 1 , wherein Ris selected from the group consisting of hydrogen claim 1 , hydroxyalkyl claim 1 , and —X—R claim 1 , or a pharmaceutically acceptable salt or solvate thereof.32. (canceled)3438-. (canceled)40. The compound of selected from the group consisting of:6-(1-(4-(Trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)picolinamide ...

Cot modulators and methods of use thereof

The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

IN VIVO IMAGING OF MATRIX METALLOPROTEINASES IN LUNG DISEASE

The present invention provides a method of imaging a subject's lung which comprises contacting the subject's lung with a matrix metalloproteinase inhibitor labeled with a radioisotope under conditions such that the inhibitor binds to matrix metalloproteinase in the lung, and then imaging the radiolabeled inhibitor bound to matrix metalloproteinase in the subject's lung. 1. A method of imaging a subject's lung which comprises contacting the subject's lung with a matrix metalloproteinase inhibitor labeled with a radioisotope under conditions such that the inhibitor binds to matrix metalloproteinase in the lung , and then imaging the radiolabeled inhibitor bound to matrix metalloproteinase in the subject's lung so as to image the subject's lung.2. The method of claim 1 , wherein the matrix metalloproteinase inhibitor is Ro 32-3555 or a modified form of CGS27023A.3. The method of claim 2 , wherein the radioisotope is I-123.4. The method of claim 3 , wherein the matrix metalloproteinase inhibitor is Ro 32-3555.5. The method of claim 3 , wherein the matrix metalloproteinase inhibitor is a modified form of CGS27023A.8. The method of claim 1 , wherein the subject is claim 1 , or is suspected of being claim 1 , afflicted with a destructive lung disease.9. (canceled)10. The method of claim 8 , wherein the destructive lung disease is chronic obstructive pulmonary disease (COPD) claim 8 , lymphangioleiomyomatosis (LAM) claim 8 , idiopathic pulmonary fibrosis (IPF) claim 8 , or acute lung injury (ALI).11. The method of claim 8 , wherein the destructive lung disease is emphysema.12. The method of claim 1 , wherein the imaging is single-photon emission computed tomography (SPECT) imaging.13. The method of claim 1 , wherein the contacting comprises administering to the subject an imageable amount of the matrix metalloproteinase inhibitor labeled with a radioisotope.14. (canceled)15. The method of claim 1 , wherein the imaging is effected with a computer tomography (CT) scanner.167 ...

LABELED INHIBITORS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA), THEIR USE AS IMAGING AGENTS AND PHARMACEUTICAL AGENTS FOR THE TREATMENT OF PROSTATE CANCER

The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of prostate cancer. Thus, the present invention concerns compounds that are represented by the general Formulae (Ia) or (Ib). 114-. (canceled)16. The compound of claim 15 , wherein Chelator is a radical of:1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA);N,N″-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″-diacetic acid (HBED-CC);1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA);2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA);2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA);1,4,7-triazacyclononane phosphinic acid (TRAP);1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO);3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA);N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO);diethylenetriaminepentaacetic acid (DTPA);trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA);1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A);p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA);1-(p-isothiocyanatobenzyI)-3-methyl-DTPA (1B3M);2-(p-isothiocyanatobenzyI)-4-methyl-DTPA (1M3B); or1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).18. A radiolabeled compound of .19. A radiolabeled compound of .20. A metal complex comprising a radionuclide and a compound of .21. The metal complex of claim 20 , wherein the radionuclide is selected from Zr claim 20 , Sc claim 20 , In claim 20 , Y claim 20 , Ga claim 20 , Lu claim 20 , Tc claim 20 , Cu claim 20 , Cu claim 20 , Gd claim 20 , Gd claim 20 , Gd claim 20 , Bi claim 20 , or Ac.22. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable ...

COMPOSITIONS AND METHODS FOR INHIBITION OF THE JAK PATHWAY

Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful. Also disclosed are methods of making the compounds. 1. A pharmaceutical composition , comprising:a means for inhibiting a Janus kinase (JAK); anda pharmaceutically acceptable excipient.2. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient is a liquid carrier.3. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient is a solid carrier.4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for oral administration claim 1 , parenteral administration claim 1 , inhalation spray nasal administration claim 1 , vaginal administration claim 1 , rectal administration claim 1 , sublingual administration claim 1 , urethral administration claim 1 , or topical administration.5. The pharmaceutical composition of claim 4 , wherein parenteral administration is selected from intramuscular claim 4 , intraperitoneal claim 4 , intravenous claim 4 , ICV claim 4 , intracisternal injection or infusion claim 4 , subcutaneous injection claim 4 , or implant administration.6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a gel claim 1 , ointment claim 1 , cream claim 1 , aerosol claim 1 , a semi-solid claim 1 , a solid claim 1 , a powder claim 1 , a tablet claim 1 , a suppository claim 1 , a pill claim 1 , a soft elastic capsule claim 1 , a jelly claim 1 , a hard gelatin capsule claim 1 , a solution claim 1 , a suspension claim 1 , or a combination thereof.7. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient is selected from binding agents claim 1 , fillers claim 1 , lubricants claim 1 , disintegrants claim 1 , ...

Process for Making Biologically Active Compounds and Intermediates Thereof

A process of manufacturing biologically active compounds, their analogs, pharmaceutically acceptable salts, solvates, polymorphs, isotopic variants, and intermediates thereof. Notably, the compounds of the formula IA, 1B, 1C. 1D. 1E, 1F and IG for which novel processes have been disclosed, selectively act on the cannabinoid receptors, and with high affinity. The processes for the preparation of the compounds enable the syntheses of cannabinoid modulators on a large-scale that are eco-friendly and economically viable. Additionally, the processes disclosed enable the synthesis of cannabinoid modulators with high purity and in high yield for their use in making drug substance and drug products. 8. The process of claim 1 , wherein X1 is —SO2- claim 1 , —O— or —CH2-.9. The process of claim 7 , wherein X1 is —SO2- claim 7 , —O— or —CH2-. The present invention relates to a chemical process for the preparation of compounds of one of Formulae I, IA, IB, IC, ID, IE, 1F. and 1G. and IV, IVA, IVB, IVC, V and VI and intermediates thereof.More specifically, the invention relates to a chemical process for the preparation of 5-[4-(4-cyano-1-butyn-1-yl)phenyl]-1-(2,4-dichlorophenyl)-N-(1,1-dioxido-4-thiomorpholinyl)-4-methyl-1H-pyrazole-3-carboxamide and 5-(4-(4-cyanobut-1-yn-1-yl)phenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-morpholino-1H-pyrazole-3-carboxamide and their analogs, solvates, polymorphs and isotopic variations thereof.Compounds of this class with unique pharmacological properties and therapeutic value have been disclosed in WO200674445, WO2008154015 and WO2010104488.Disclosed herein are processes for the preparation of compounds comprising, reacting a compound of Formula II with a compound of Formula III to provide a compound of Formula VII, second by reacting a compound of Formula VII with an alkyne in the presence of a palladium reagent and copper (I) iodide, in a basic medium and in an aprotic solvent to obtain a product of Formula I, third by hydrolysis of a compound ...

Deuterium-Substituted 7-Substituted-2-(Benzylamino)-6-Ozopurine Compounds and Uses Thereof

The invention relates to compounds of formula (I): The compounds are useful as antibacterial agents, especially again -associated diseases. 2. The compound of claim 1 , wherein at least one of Y claim 1 , Y claim 1 , Y claim 1 , and Yis deuterium.4. The compound of claim 2 , wherein the level of deuterium incorporation at each of Y claim 2 , Y claim 2 , Y claim 2 , and Ydesignated as deuterium is at least 52.5% claim 2 , at least 75% claim 2 , at least 82.5% claim 2 , at least 90% claim 2 , at least 95% claim 2 , at least 97% claim 2 , at least 98% claim 2 , or at least 99%.5. The compound of claim 1 , wherein at least one of least one of Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Yand Yis deuterium.7. The compound of claim 5 , wherein the level of deuterium incorporation at each of Y Y claim 5 , Y claim 5 , Y claim 5 , Y claim 5 , Yand Ydesignated as deuterium is at least 52.5% claim 5 , at least 75% claim 5 , at least 82.5% claim 5 , at least 90% claim 5 , at least 95% claim 5 , at least 97% claim 5 , at least 98% claim 5 , or at least 99%.8. The compound of claim 1 , wherein at least one of Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Y claim 1 , Yand Yis deuterium.10. The compound of claim 8 , wherein the level of deuterium incorporation at each of Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Y claim 8 , Yand Ydesignated as deuterium is at least 52.5% claim 8 , at least 75% claim 8 , at least 82.5% claim 8 , at least 90% claim 8 , at least 95% claim 8 , at least 97% claim 8 , at least 98% claim 8 , or at least 99%.12. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.13Clostridium difficileClostridium difficile. A method of inhibiting ...

CONTRAST AGENTS FOR MYOCARDIAL PERFUSION IMAGING

The present disclosure is directed, in part, to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a contrast agent which comprises a compound that binds MC-1, and an imaging moiety, and scanning the patient using diagnostic imaging. 125-. (canceled)27. A composition , comprising:{'claim-ref': {'@idref': 'CLM-00026', 'claim 26'}, 'the compound of and a solvent.'}29. A composition comprising:{'claim-ref': {'@idref': 'CLM-00028', 'claim 28'}, 'the compound of and a solvent.'}31. The precursor compound of claim 30 , wherein the precursor compound is provided in a solution.32. The precursor compound of claim 30 , wherein the precursor compound is provided as a solid preparation.33. The precursor compound of claim 32 , wherein the solid preparation is a lyophilized solid. The present application claims the benefit of priority under 35 U.S.C. §119(e) from the provisional application 60/544,861 filed Feb. 13, 2004, the contents of which are herein incorporated by reference.The present disclosure relates to novel compounds comprising imaging moieties, and their use for diagnosing certain disorders in a patient.Mitochondria are membrane-enclosed organelles distributed through the cytosol of most eukaryotic cells. Mitochondria are especially concentrated in myocardium tissue.Complex 1 (“MC-1”) is a membrane-bound protein complex of 46 dissimilar subunits. This enzyme complex is one of three energy-transducing complexes that constitute the respiratory chain in mammalian mitochondria. This NADH-ubiquinone oxidoreductase is the point of entry for the majority of electrons that traverse the respiratory chain, eventually resulting in the reduction of oxygen to water (1992, 25, 253-324).Known inhibitors of MC-1 include deguelin, piericidin A, ubicidin-3, rolliniastatin-1, rolliniastatin-2 (bullatacin), capsaicin, pyridaben, fenpyroximate, amytal, MPP+, quinolines, and quinolones (1998, 1364, 222-235).The present disclosure is based, in ...

Novel organic compounds for organic light-emitting diode and organic light-emitting diode including the same

The present invention relates to a compound for organic light-emitting diodes that can operate organic light-emitting diodes at a low driving voltage and an organic light-emitting diode comprising the same and, more particularly, to a compound for use as a fluorescent host in organic light-emitting diodes, which can bring about excellent diode properties by operating organic light-emitting diodes at a low driving voltage, and an organic light-emitting diode comprising the same. 3. The organic luminescent compound as set forth in claim 1 , wherein at least one of the substituents R1 to R5 in Chemical Formula A contains a deuterium.4. The organic luminescent compound as set forth in claim 4 , wherein R1 is a deuterium and k is 5.5. The organic luminescent compound as set forth in claim 3 , wherein R2 and/or R3 is a deuterium claim 3 , and l is 2 or greater claim 3 , or m is 2 or greater.6. The organic luminescent compound as set forth in claim 3 , wherein R4 and/or R5 is a deuterium claim 3 , and n is 2 or greater or o is 2 or greater.8. An organic light-emitting diode comprising:a first electrode;a second electrode facing the first electrode; and{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'an organic layer interposed therebetween, wherein the organic layer contains at least one organic luminescent compound of any one of .'}9. The organic light-emitting diode as set forth in claim 8 , wherein the organic layer comprises at least one of a hole injecting layer claim 8 , a hole transport layer claim 8 , a functional layer capable of both hole injection and hole transport claim 8 , a light-emitting layer claim 8 , an electron transport layer claim 8 , and an electron injecting layer.10. The organic light-emitting diode as set forth in claim 9 , wherein the organic layer interposed between the first electrode and the second electrode is a light-emitting layer composed of a host and a dopant claim 9 , the organic luminescent compound serving as the host.11. The ...

DEUTERATED ORGANIC COMPOUND, MIXTURE AND COMPOSITION CONTAINING SAID COMPOUND, AND ORGANIC ELECTRONIC DEVICE

The present disclosure discloses a deuterated organic compound and a formulation and an organic electronic device containing the same, wherein the deuterated organic compound has the following structural formula: 113-. (canceled)15. The organic compound according to claim 14 , wherein (S1-T1)≦0.25 eV.16. The organic compound according to claim 14 , wherein at least one H atom in at least one electron donor group D is substituted by deuterium.17. The organic compound according to claim 14 , wherein at least one H atom in at least one electron acceptor group A is substituted by deuterium.18. The organic compound according to claim 14 , wherein at least one H atom in Ar is substituted by deuterium.22. The organic compound according to claim 14 , wherein more than 20% of the H atoms are substituted by deuterium.24. A mixture comprising at least one organic compound according to and further an organic functional material selected from a hole-injection or hole-transport material claim 14 , a hole-blocking material claim 14 , an electron-injection or electron-transport material claim 14 , an electron-blocking material claim 14 , an organic host material claim 14 , a singlet emitter claim 14 , and a triplet emitter.26. The formulation according to claim 25 , wherein the organic solvent selecting from methanol claim 25 , ethanol claim 25 , 2-methoxyethanol claim 25 , dichloromethane claim 25 , trichloromethane claim 25 , chlorobenzene claim 25 , o-dichlorobenzene claim 25 , tetrahydrofuran claim 25 , anisole claim 25 , morpholine claim 25 , toluene claim 25 , o-xylene claim 25 , m-xylene claim 25 , p-xylene claim 25 , 1 claim 25 ,4-dioxahexane claim 25 , acetone claim 25 , methyl ethyl ketone claim 25 , 1 claim 25 ,2-dichloroethane claim 25 , 3-phenoxytoluene claim 25 , 1 claim 25 ,1 claim 25 ,1-trichloroethane claim 25 , 1 claim 25 ,1 claim 25 ,2 claim 25 ,2-tetrachloroethane claim 25 , ethyl acetate claim 25 , butyl acetate claim 25 , dimethylformamide claim 25 , ...

ORGANIC COMPOUNDS

The invention relates to particular deuterated substituted heterocycle fused gamma-carbolines, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HTreceptor, the serotonin transporter (SERT), pathways involving the dopamine Dand Dreceptor signaling system, and/or the μ-opioid receptor. 2. A compound according to claim 1 , wherein Z is O.3. A compound according to claim 1 , wherein Z is —C(O).4. A compound according to claim 1 , wherein Ris methyl.5. A compound according to claim 1 , wherein Ris H and Ris D.6. A compound according to claim 1 , wherein Ris D and Ris D.7. A compound according to claim 1 , wherein Ris H and Ris H.8. A compound according to claim 1 , wherein any one claim 1 , or any two claim 1 , or any three of Rto Ris D.9. A compound according to claim 1 , wherein any one claim 1 , or any two claim 1 , any three claim 1 , any four claim 1 , any five or any six of Rto Ris D.10. A compound according to claim 1 , wherein all four of Rto Ris D.11. A compound according to claim 1 , wherein all six of Rto Ris D.12. A compound according to claim 1 , in the form of a salt claim 1 , e.g. claim 1 , in the form of a pharmaceutically acceptable salt.13. A compound according to claim 1 , having greater than 50% incorporation of deuterium at one or more of the indicated positions of the structure (i.e. claim 1 , greater than 50 atom % D) claim 1 , e.g. claim 1 , greater than 60% claim 1 , or greater than 70% claim 1 , or greater than 80% claim 1 , or greater than 90% or greater than 95% claim 1 , or greater than 96% claim 1 , or greater than 97% claim 1 , or greater than 98% claim 1 , or greater than 99%.14. A pharmaceutical composition comprising a compound according to claim 1 , in free or pharmaceutically acceptable salt form claim 1 , in admixture with a pharmaceutically acceptable diluent or carrier.15. The ...

PYRIDONE DERIVATIVES HAVING TETRAHYDROPYRANYLMETHYL GROUPS

The present disclosure provides novel compounds or salts thereof, or crystals of the compounds or the salts, which inhibit Axl and are useful in the treatment of a disease caused by hyperfunction of Axl, the treatment of a disease associated with hyperfunction of Axl, and/or the treatment of a disease involving hyperfunction of Axl. 2. The method of claim 1 , wherein the compound of formula (I) is administered to patient having lung cancer or non-small cell lung cancer.4. The method of claim 3 , wherein the cancer is lung cancer or non-small cell lung cancer.7. The method of claim 6 , wherein the compound of formula (I) is administered to patient having lung cancer or non-small cell lung cancer.9. The combination of claim 8 , wherein the compound of formula (I) claim 8 , or the pharmaceutically acceptable salt thereof claim 8 , and the tyrosine kinase inhibitor are separately contained in different formulations.10. The combination of claim 8 , wherein the compound of formula (I) claim 8 , or the pharmaceutically acceptable salt thereof claim 8 , and the tyrosine kinase inhibitor are contained in a single formulation.13. A methanesulfonate claim 11 , phosphate claim 11 , naphthalene-1 claim 11 ,5-disulfonate claim 11 , or sulfate of the compound of .15. The method of claim 14 , wherein the compound of formula (I) claim 14 , or the pharmaceutically acceptable salt thereof claim 14 , and the tyrosine kinase inhibitor are administered at the same time.16. The method of claim 14 , wherein the compound of formula (I) claim 14 , or the pharmaceutically acceptable salt thereof claim 14 , and the tyrosine kinase inhibitor are administered at different times.17. The method of claim 14 , wherein the cancer is lung cancer or non-small cell lung cancer. This application is a continuation of U.S. patent application Ser. No. 15/036,981, filed May 16, 2016, entitled “PYRIDONE DERIVATIVES HAVING TETRAHYDROPYRANYLMETHYL GROUPS,” which is a national stage application under 35 U.S.C. § ...

Compound for organic optoelectronic device organic light emitting diode including the same and display including the organic light emitting diode

A compound for an organic optoelectronic device is represented by the following Chemical Formula 1. wherein R 1 , R 2 , R 3 , R 4 , Ar 1 , Ar 2 , Ar 3 , L 1 , L 2 , L 3 , n 1 , n 2 , and n 3 are further defined in the specification.

DEUTERATED IBRUTINIB

The present invention in one embodiment provides a compound of Formula I: 2. The compound of claim 1 , wherein Y claim 1 , Y claim 1 , and Yare each hydrogen.3. The compound of claim 1 , wherein Y claim 1 , Y claim 1 , and Yare each deuterium.413.-. (canceled)14. The compound of claim 1 , wherein each Yis hydrogen and each Yis hydrogen.15. The compound of claim 1 , wherein each Yis deuterium and each Yis deuterium.17. (canceled)18. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.19. A method of inhibiting BTK in a cell claim 1 , comprising contacting the cell with a compound of .20. A method of treating a disease selected from the group consisting of chronic lymphocytic leukemia claim 1 , mantle cell lymphoma claim 1 , and multiple myeloma claim 1 , comprising administering to a subject in need of such treatment a compound of .21. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.22. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%. This application is a continuation of U.S. application Ser. No. 14/418,831, which is the U.S. National Stage of International Application No. PCT/US2013/052721, which designated the United States and was filed on Jul. 30, 2013, published in English, which claims the benefit of U.S. Provisional Application No. 61/677,307, filed on Jul. 30, 2012. The entire teachings of the above applications are incorporated herein by reference.Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME ...

DEUTERATED ANALOGS OF PRIDOPIDINE USEFUL AS DOPAMINERGIC STABILIZERS

The present invention provides novel deuterated analogs of Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine. Pridopidine is a drug substance currently in clinical development for the treatment of Huntington's disease. 2. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': 1', '2, 'R-Rrepresent deuterium (D); and'}{'sup': 3', '23, 'all of R-Rrepresent hydrogen (H).'}3. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': 1', '7, 'at least one of R-Rrepresents deuterium (D); and'}{'sup': 1', '23, 'the remaining of R-Rrepresent hydrogen (H).'}4. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': 1', '7, 'all of R-Rrepresent deuterium (D); and'}{'sup': 8', '23, 'all of R-Rrepresent hydrogen (H).'}5. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': 8', '9', '10', '11, 'R, R, Rand Rrepresent deuterium (D); and'}{'sup': 1', '7', '12', '23, 'all of R-Rand R-Rrepresent hydrogen (H).'}6. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': '12', 'Rrepresents deuterium (D); and'}{'sup': 1', '11', '13', '23, 'all of R-Rand R-Rrepresent hydrogen (H).'}7. The deuterated analog according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': 17', '20, 'R-Rrepresent deuterium (D); and'}{'sup': 1', '16', '21', '23, 'all of R-Rand R-Rrepresent hydrogen (H).'}8. A pharmaceutical composition claim 1 , comprising a therapeutically effective amount of a deuterated analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine according to any one of - claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , together with at least one pharmaceutically acceptable carrier claim 1 , excipient or diluent.9. The deuterated ...

DEUTERATED ANALOGS OF ETIFOXINE, THEIR DERIVATIVES AND USES THEREOF

This invention relates to deuterated analogs of etifoxine of Formula 1, solvates, prodrugs, and pharmaceutically acceptable salts thereof, as well as to methods for their preparation and use, and to pharmaceutical compositions. Briefly, this invention is generally directed to deuterated analogs of etifoxine as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. 2. The compound of wherein the compound is: 6-chloro-N-(ethyl-d)-4-methyl-4-phenyl-4H-3 claim 1 ,1-benzoxazin-2-amine claim 1 , 6-chloro-N-(ethyl-d)-4-methyl-4-(phenyl-d)-4H-3 claim 1 ,1-benzoxazin-2-amine claim 1 , 6-chloro-N-(ethyl-d5)-4-(methyl-d3)-4-(phenyl-d5)-4H-3 claim 1 ,1-benzoxazin-2-amine or 6-chloro-N-(ethyl-1 claim 1 ,1-d2)-4-methyl-4-phenyl-4H-3 claim 1 ,1-benzoxazin-2-amine or a pharmaceutically acceptable salt claim 1 , solvate or prodrug thereof.3. The compound of claim 1 , wherein said compound is an enantiomerically pure S-etifoxine analog claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate or prodrug thereof.4. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.5. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.6. A method of modulating the GABAreceptor complex in a subject in need thereof comprising administering to said subject an effective amount of the compound of .7. A method of increasing endogenous neurosteroid and/or neuroactive steroid levels in a subject in need thereof comprising administering to said subject an effective amount of the compound of .8. The compound of claim 1 , wherein a deuterium is present at an abundance that is at least 3340 times greater than the natural abundance of deuterium.9. The compound of claim 1 , wherein said compound is an enantiomerically pure R-etifoxine analog claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate or prodrug thereof. This application is ...

DEUTERIUM-SUBSTITUTED OXADIAZOLES

Described are deuterated modulators of S1P1 receptors, pharmaceutical compositions thereof, and methods of use thereof. 156-. (canceled)58. The compound as recited in claim 57 , wherein Ris deuterium.59. The compound as recited in claim 57 , wherein R-Rare deuterium.60. The compound as recited in claim 57 , wherein R-Rare deuterium.61. The compound as recited in claim 57 , wherein Ris deuterium.62. The compound as recited in claim 57 , wherein Rand Rare deuterium.63. The compound as recited in claim 57 , wherein R-Rare deuterium.64. The compound as recited in claim 57 , wherein R-Rare deuterium.65. The compound as recited in claim 57 , wherein R-Rare deuterium.66. The compound as recited in claim 57 , wherein Rand R-Rare deuterium.67. The compound as recited in claim 57 , wherein R-Rand R-Rare deuterium.68. The compound as recited in wherein at least one of R-Rindependently has deuterium enrichment of no less than about 10%.73. The compound as recited in claim 72 , wherein each position represented as D has deuterium enrichment of no less than about 10%.74. The compound as recited in claim 73 , wherein each position represented as D has deuterium enrichment of no less than about 10%.75. A pharmaceutical composition comprising a compound as recited in together with a pharmaceutically acceptable carrier.76. A method of treatment or prevention of a S1P1 receptor-mediated disorder comprising the administration claim 57 , to a patient in need thereof claim 57 , of a therapeutically effective amount of a compound as recited in . This application claims the benefit of U.S. Provisional Application No. 62/143,489, filed on Apr. 6, 2015, the disclosure of which is hereby incorporated by reference in its entirety.Disclosed herein are new oxadiazole compounds and compositions and their application as pharmaceuticals for the treatment or prevention of disorders. Methods of modulation of sphingosine-1-phosphate subtype 1 receptor (S1P1 receptor) activity in a subject are also ...

2-(2,4,5-SUBSTITUTED ANILINE) PYRIMIDINE DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE THEREOF

Disclosed are a 2-(2,4,5-substituted aniline) pyrimidine derivative, a pharmaceutical composition and a use thereof. The pharmaceutical composition comprises a therapeutically effective amount of the 2-(2,4,5-substituted aniline) pyrimidine derivative, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also disclosed is a use of the 2-(2,4,5-substituted aniline) pyrimidine derivative, a solvate, or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating cancers. The compounds of the present invention have a relatively high solubility in water and a relatively high permeability, and/or a relatively low binding ability to plasma proteins, and at the same time have a relatively low toxicity characteristic and a relatively high anti-tumor activity. 2. The 2-(2 claim 1 ,4 claim 1 ,5-substituted aniline)pyrimidine derivative represented by formula I claim 1 , or the solvate claim 1 , or the pharmaceutically acceptable salt thereof according to claim 1 , wherein claim 1 , the methyl substituted by 1 to 3 of deuterium atom(s) is a tri-deuterated methyl.3. The 2-(2 claim 1 ,4 claim 1 ,5-substituted aniline)pyrimidine derivative represented by formula I claim 1 , or the solvate claim 1 , or the pharmaceutically acceptable salt thereof according to claim 1 , which is selected from the group consisting of{'sub': '3', 'N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-(D-methyl)indol-3-yl)pyrimidin-2-yl]amino}phenyl)-2-acrylamide;'}{'sub': '3', 'N-(2-{2-dimethylaminoethyl-methylamino}-4-(D-methoxy)-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-2-acrylamide;'}{'sub': '3', 'N-(2-{2-dimethylaminoethyl-(D-methyl)amino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-2-acrylamide;'}{'sub': '3', 'N-(2-{2-di(D-methyl)aminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-2-acrylamide;'}{'sub': '3', 'N-(2-{2-[methyl(D-methyl)amino]ethyl- ...

Deuterated tic10

This invention relates to novel imidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions alone or in combination with other therapeutics in the treatment of diseases and conditions that are beneficially treated by administering an inducer of the gene encoding tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) superfamily member 10.

STABILISED RADIOLABELLING REACTION

The present invention provides a method for the synthesis of an injectable composition comprising a [F]-labelled pyridaben derivative that is advantageous over prior methods. In particular, the method of the present invention comprises a method of radiosynthesis that permits a more facile purification using solid phase extraction (SPE). 1. A method comprising reacting a precursor compound with F-fluoride in the presence of (2 ,2 ,6 ,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) to obtain an F-labelled compound wherein: {'br': None, 'BTM-LINKER-LG \u2003\u2003(I)'}, 'said precursor compound is of Formula Iwherein:BTM is an analogue of pyridaben;LINKER is an alkylene or an alkoxyalkylene; and,LG is a sulfonate-containing leaving group; and{'sup': '18', 'claim-text': {'br': None, 'sup': '18', 'BTM-LINKER-F \u2003\u2003(II)'}, 'said F-labelled compound is of Formula IIwherein BTM and LINKER are as defined for Formula I.3. The method as defined in wherein Ris Calkyl.4. The method as defined in wherein Ris methyl claim 2 , ethyl claim 2 , propyl claim 2 , n-butyl claim 2 , s-butyl claim 2 , or t-butyl.5. The method as defined in wherein Ris halo.6. The method as defined in wherein Ris chloro.7. The method as defined in wherein W is heteroalkylene.8. The method as defined in wherein W is alkoxyalkylene.11. The method as defined in wherein LG is selected from mesylate claim 1 , tosylate claim 1 , triflate claim 1 , nosylate claim 1 , or 1 claim 1 ,2-cyclic sulfate.12. The method as defined in wherein LG is tosylate.13. The method as defined in wherein said precursor compound is dissolved in acetonitrile.14. The method as defined in wherein said TEMPO is present in a molar ratio to the precursor compound of between 0.01:1 and 5:1.15. The method as defined in wherein the starting radioactivity is at least 100 GBq.16. The method as defined in wherein the starting radioactivity is between 100-1000 GBq.17. The method as defined in wherein the starting radioactivity is between 100-750 ...

USE OF FLUORINATED DERIVATIVES OF 4-AMINOPYRIDINE IN THERAPEUTICS AND MEDICAL IMAGING

The present disclosure provides novel compounds, including compounds that bind to potassium channels, methods for their manufacture, and methods for their use, including their use to diagnose and/or assess traumatic brain injury and use to treat dymeylinating diseases, and/or in vivo imaging of the central neverous system, and to diagnose and/or assess the progression of MS or other diseases. 3. The method of claim 2 , wherein a dose is from about 0.005 to 50 mCi.4. The method of claim 2 , further comprising quantifying an amount of the compound in the subject.5. The method of claim 2 , wherein the demyelinating disease is multiple sclerosis claim 2 , spinal cord compression claim 2 , ischemia claim 2 , acute disseminated encephalomyelitis claim 2 , optic neuromyelitis claim 2 , leukodystrophy claim 2 , progressive multifocal leukoencephalopathy claim 2 , metabolic disorders claim 2 , toxic exposure claim 2 , congenital demyelinating disease claim 2 , peripheral neuropathy claim 2 , encephalomyelitis claim 2 , central pontine myelolysis claim 2 , Anti-MAG Disease claim 2 , Guillain-Barre syndrome claim 2 , chronic inflammatory demyelinating polyneuropathy claim 2 , or multifocal motor neuropathy (MMN).6. The method of claim 2 , wherein the radiodiagnostic method is Positron Emission Tomography (PET) claim 2 , PET-Time-Activity Curve (TAC) claim 2 , PET-Magnetic Resonance Imaging (MRI) claim 2 , or PET/CT.7. The method of claim 2 , wherein a demyelinated region in the subject is detected by detecting the compound.8. The method of claim 2 , wherein the compound binds to potassium channels located at a demyelinated region in an axon in the subject.10. The method of claim 9 , wherein the subject is at risk for traumatic brain injury or a concussion.11. The method of claim 9 , wherein the imaging is affected by a radiodiagnostic method.12. The method of claim 11 , wherein the radiodiagnostic method is Positron Emission Tomography (PET) claim 11 , PET-Time-Activity Curve ...

USE OF FLUORINATED DERIVATIVES OF 4-AMINOPYRIDINE IN THERAPEUTICS AND MEDICAL IMAGING

The present disclosure provides novel compounds, including compounds that bind to potassium channels, methods for their manufacture, and methods for their use, including their use to diagnose and/or assess traumatic brain injury and use to treat dymeylinating diseases, and/or in vivo imaging of the central neverous system, and to diagnose and/or assess the progression of MS or other diseases. 115-. (canceled)17. The compound of claim 16 , wherein at least one hydrogen atom is a deuterium isotope.18. The compound of claim 16 , wherein the compound is [F]3-fluoro-4-aminopyridine.19. The compound of claim 16 , wherein the compound 3-[F]fluoromethyl-4-aminopyridine.20. The compound of claim 16 , wherein the compound 3-[F]fluoroethyl-4-aminopyridine.21. The compound of claim 16 , wherein the compound 3-[F]trifluoromethyl-4-aminopyridine.22. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier. This application is is a continuation of U.S. patent application Ser. No. 16/584,071 filed Sep. 26, 2019, which is a continuation of U.S. patent application Ser. No. 15/452,179 filed Mar. 7, 2017, which is a continuation of U.S. patent application Ser. No. 14/329,597 filed Jul. 11, 2014, which is a continuation-in-part of U.S. patent application Ser. No. 13/897,035 filed May 17, 2013 and PCT Application PCT/US2013/041638 filed May 17, 2013, both of which claim priority to U.S. Provisional Patent Application Ser. No. 61/648,214 filed May 17, 2012. U.S. patent application Ser. No. 14/329,597 also claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/845,878 filed Jul. 12, 2013. The entire contents of each of the above-referenced disclosures are specifically incorporated herein by reference without disclaimer.The present invention relates generally to the fields of biology, chemistry and medicine. More particularly, it concerns derivatives of potassium channel inhibitors, including derivatives of 4-aminopyridine, ...

PET Imaging Agents

Preparation of novel 2-benzyl-5-methyl-2H-tetrazole derivatives of the formula (I) for use as PET imaging agents. The present invention relates to novel compounds of formula (I) their preparation and use as PET imaging agents for imaging techniques and diagnostics in the field of diseases and disorders mediated by or related to the enzyme autotaxin.

METHODS AND REAGENTS FOR RADIOLABELING

The present invention provides methods for radiolabeling compounds useful as Hsp90 inhibitors. The present invention also provides intermediates useful in such methods, and compositions of radiolabeled compounds. The present invention provides, among other things novel methods for the synthesis of radiolabeled compounds. In certain embodiments, the present invention provides compounds of formula I. 190-. (canceled)93. The method of claim 92 , wherein Z claim 92 , Z claim 92 , and Zare —N—.94. The method of claim 93 , wherein Yis —CR—.95. The method of claim 94 , wherein Yis —CR—.96. The method of claim 95 , wherein each of Ris hydrogen.97. The method of claim 96 , wherein X is —CH— or —S—.98. The method of claim 97 , wherein X is —CH—.99. The method of claim 97 , wherein X is —S—.100. The method of claim 97 , wherein Ris hydrogen.101. The method of claim 97 , wherein Ris halogen.102. The method of claim 101 , wherein Ris fluoro.103. The method of claim 96 , wherein -L-Rcomprises a methylene that is replaced with —NH— to form a secondary amine.104. The method of claim 97 , wherein L is a Caliphatic group claim 97 , wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.105. The method of claim 104 , wherein L is a Caliphatic group claim 104 , wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.108. The method of claim 96 , wherein two Rgroups are taken together with their intervening atoms to form Ring A claim 96 , wherein Ring A is a 5- to 6-membered partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen claim 96 , nitrogen claim 96 , or sulfur claim 96 , 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen claim 96 , nitrogen claim 96 , or sulfur claim 96 , or 6-membered aryl.109. The method of claim 108 , wherein Ring A is a 5-membered partially unsaturated monocyclic heterocyclyl having 2 heteroatoms selected from oxygen.110. The method ...

AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHA RESPONSES

Compounds having the following formula I: 2. A compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein Ris —C(O)R; or Calkyl claim 1 , Ccycloalkyl claim 1 , phenyl claim 1 , pyrazolyl claim 1 , thiazolyl claim 1 , pyridyl claim 1 , pyrimidinyl claim 1 , pyridazinyl claim 1 , pyrazinyl claim 1 , quinolinyl or pyrrolopyridinyl claim 1 , each group substituted by 0-4 groups selected from R.3. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein both Rand Rare hydrogen.5. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein Ris pyrazolyl claim 1 , thiazolyl claim 1 , pyridyl claim 1 , pyrimidinyl claim 1 , pyridazinyl claim 1 , pyrazinyl or quinolinyl claim 1 , each group substituted with 0-3 R.6. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein Ris —C(O)R; or Calkyl claim 1 , Ccycloalkyl or phenyl substituted with 0-3 R.8. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein Ris phenyl claim 1 , cyclopentyl claim 1 , cyclohexyl claim 1 , triazolyl claim 1 , oxadiazolyl claim 1 , pyrimidinyl claim 1 , tetrazolyl claim 1 , pyrazolyl claim 1 , thiazolyl claim 1 , furanyl claim 1 , or pyranyl claim 1 , each group substituted with 0-4 R. (Especially phenyl substituted with 0-4 R).9. A compound according to claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof claim 1 , wherein:{'sup': 3a', 'b', '11', '11', 'b', 'c', 'b', 'c', 'b', 'a', 'a, 'sub': 2', '3', '2', '11', '11', 'p', 'p', '1-6, 'Rat each occurrence independently is hydrogen, Ph, CN, NH, OCF, OR, halo, cycloalkyl, C(O)NRR, S(O)NRR, C(O)R, SOR, NRSOR, NRC(O)R, haloalkyl, CN, 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O substituted with 0-3 Rand Calkyl substituted ...

OPIOID RECEPTOR MODULATING OXABICYCLO[2.2.2]OCTANE MORPHINANS

The application is directed to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R, R, Y, Z, and G are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I), and pharmaceutically acceptable salts and solvates thereof, to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain. 4. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein Ris hydrogen , hydroxy , halo , cyano , carboxy , or aminocarbonyl; or alkyl , alkenyl , alkynyl , alkoxy , alkenyloxy , or alkynyloxy , any of which is optionally substituted with 1 , 2 , or 3 substituents , each independently selected from the group consisting of hydroxy , halo , haloalkyl , amino , alkylamino , dialkylamino , carboxy , alkoxy , alkoxycarbonyl , aryl , heteroaryl , heterocyclo , cycloalkyl , and cycloalkenyl , wherein said aryl , heteroaryl , heterocyclo , cycloalkyl , and cycloalkenyl are optionally substituted with 1 , 2 , or 3 independently selected Rgroups.5. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof claim 4 , wherein Ris hydroxy or unsubstituted Calkoxy claim 4 , preferably unsubstituted Calkoxy claim 4 , further preferably methoxy.6. The compound of any one of - claim 4 , or a pharmaceutically acceptable salt or solvate thereof claim 4 , wherein Ris —O-PG.7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof claim 6 , wherein PG is selected from the group consisting of alkyl claim 6 , arylalkyl claim 6 , heterocyclo claim 6 , (heterocyclo)alkyl claim 6 , acyl claim 6 , silyl claim 6 , and carbonate claim 6 , any of which is optionally substituted.8. The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof claim 7 , wherein PG is selected from ...

CONDENSED 5-OXAZOLIDINONE DERIVATIVE

Provided are condensed 5-oxazolidinone derivatives and pharmaceutically permissible salts thereof, which have excellent anticoagulant effects, are well absorbed orally, and are useful as therapeutic drugs for thrombosis, etc. Compounds represented by formula (1) and pharmaceutically permissible salts thereof. [In the formula, L represents a C-Calkylene group that may be substituted; Rand Reach independently represent a hydrogen atom or C-Calkyl group, etc. that may be substituted; Xrepresents N or CR; Rand Reach independently represent a hydrogen atom, halogen atom, or C-Calkyl group; Rrepresents a C-Ccycloalkyl group, etc. that may be substituted; and Rrepresents a hydrogen atom, etc.] 3. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein L is a Calkylene group which may be optionally substituted by 1 to 3 fluorine atoms.7. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein Rand Rare each independently a hydrogen atom or a Calkyl group which may be optionally substituted by 1 to 3 identical or different halogen atoms.8. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein Rand Rform claim 1 , together with the carbon atom bonded thereto claim 1 , a 4- to 7-membered cycloalkane ring or a 4- to 7-membered saturated heterocyclic ring wherein the 4- to 7-membered cycloalkane ring and the 4- to 7-membered saturated heterocyclic ring may be each optionally substituted by 1 to 4 identical or different groups selected from the group consisting of a halogen atom and Calkyl.9. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein L is a Calkylene group substituted by 1 to 3 fluorine atoms.14. The compound according to or a pharmaceutically acceptable salt thereof claim 10 , wherein Rand Rare each independently a hydrogen atom or a Calkyl group which may be optionally substituted by 1 to 3 identical or different halogen atoms. ...

SUBSTITUTED N-ARYL PYRIDINONES

Disclosed herein are substituted N-Aryl pyridinone fibrotic inhibitors and/or collagen infiltration modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof. 2. The compound as recited in claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rindependently has deuterium enrichment of no less than about 98%.3. The compound as recited in claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rindependently has deuterium enrichment of no less than about 90%.4. The compound as recited in claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rindependently has deuterium enrichment of no less than about 50%.5. The compound as recited in claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rindependently has deuterium enrichment of no less than about 10%.7. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 98%.8. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 90%.9. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 50%.10. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 10%.12. A pharmaceutical composition as recited in claim 11 , further comprising one or more release-controlling excipients.13. The pharmaceutical composition as recited in claim 11 , further comprising one or more non-release controlling excipients ...

ARYL SUBSTITUTED INDOLES AND THE USE THEREOF

The invention relates to aryl and heteroaryl substituted compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein G, R, and Z-Zare defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain. 160-. (canceled)62. (canceled)6474-. (canceled)75. A pharmaceutical composition claim 61 , comprising the compound of claim 61 , or a pharmaceutically acceptable salt claim 61 , prodrug or solvate thereof claim 61 , and a pharmaceutically acceptable carrier.7679-. (canceled)80. A method for treating pain in a mammal claim 61 , comprising administering an effective amount of a compound as claimed in or a pharmaceutically acceptable salt claim 61 , prodrug or solvate thereof claim 61 , to a mammal in need of such treatment.81. (canceled)82. The method of claim 80 , wherein the method is for preemptive or palliative treatment of pain.83. The method of claim 80 , wherein said pain is selected from the group consisting of chronic pain claim 80 , inflammatory pain claim 80 , neuropathic pain claim 80 , postsurgical pain claim 80 , acute pain claim 80 , and surgical pain.84. A method of modulating sodium channels in a mammal claim 61 , comprising administering to the mammal at least one compound as claimed in or a pharmaceutically acceptable salt claim 61 , prodrug or solvate thereof claim 61 , wherein Na1.7 sodium channel is modulated.85. (canceled)86. A compound as claimed in claim 61 , wherein the compound is H claim 61 , C claim 61 , or C radiolabeled claim 61 , or a pharmaceutically acceptable salt claim 61 , prodrug or solvate thereof.8791-. (canceled)92. A pharmaceutical composition claim 63 , comprising the compound of claim 63 , or a pharmaceutically acceptable salt claim 63 , prodrug or solvate thereof claim 63 , and a pharmaceutically ...

ISOTOPOLOGUES OF 2-(TERT-BUTYLAMINO)-4-((1R,3R,4R)-3-HYDROXY-4-METHYLCYCLOHEXYLAMINO)-PYRIMIDINE-5-CARBOXAMIDE

Provided herein are isotopologues of Compound A, which are enriched with isotopes such as, for example, deuterium. Pharmaceutical compositions comprising the isotope-enriched compounds, and methods of using such compounds are also provided. Embodiments provided herein encompass isotopologues of Compound A and pharmaceutically acceptable salts, stereoisomers, tautomers, solid forms, polymorphs, hydrates, clathrates, and solvates thereof. 3. The compound of claim 1 , wherein the isotopologues are deuterium-enriched.5. The compound of claim 4 , wherein one of Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , and Yis isotopically enriched with deuterium claim 4 , and the others are non-enriched hydrogens.6. The compound of claim 4 , wherein two of Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , Y claim 4 , and Yare isotopically enriched with deuterium claim 4 , and the others are non-enriched hydrogens.8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.9. A method of treating claim 1 , managing or preventing a disease or disorder comprising administering to a patient a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein the disease or disorder is cancer claim 1 , cardiovascular disease claim 1 , inflammatory disease claim 1 , autoimmune disease or a metabolic disorder. This application claims the benefit of U.S. Provisional Application No. 62/109,096, filed Jan. 29, 2015, the entire content of which is incorporated herein by reference.Provided herein are isotopologues ...

NOVEL COMPOUNDS FOR THE TREATMENT OF HEPATITIS C

The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV. 3. A compound of where Ris deuterated alkyl or deuterated alkoxy.4. A compound of where Ris cyano.5. A compound of where Aris phenyl or pyridinyl substituted with 1 CON(R)(R) and also with 0-3 substituents selected from cyano claim 1 , halo claim 1 , deuterated alkyl claim 1 , and deuterated alkoxy.6. A compound of where Aris phenyl or pyridinyl substituted with 1 CON(R)(R) and with 1 deuterated alkoxy substituent.7. A compound of where Aris pyrimidinyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , or imidazopyridinyl.11. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.12. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of to a patient. This application claims priority to Provisional Patent Application U.S. Ser. No. 62/119,550 filed Feb. 23, 2015, hereby incorporated by reference in its entirety.The disclosure generally relates to the novel compounds of formula I, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV. The disclosure also relates to compositions and methods of using these compounds.Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. 2001, 345, 41-52).HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive ...

CARBOXYLIC ACID COMPOUND, METHOD FOR PREPARATION THEREOF, AND USE THEREOF

The present invention relates to the technical field of medicine, and specifically relates to the carboxylic acid compound represented by the chemical formula I or chemical formula II, and a pharmaceutically acceptable salt, a prodrug, and a solvate thereof, and a method for preparation thereof, as well as a pharmaceutical composition containing the described substances, and a use thereof. 116-. (canceled)27. A pharmaceutical composition comprising the carboxylic acid compound according to claim 17 , or a pharmaceutically acceptable salt thereof claim 17 , and a pharmaceutically acceptable carrier. The invention relates to pharmaceutical technical field, specifically, to carboxylic acid compounds and pharmaceutically acceptable salts, prodrugs, and solvates thereof and preparation methods thereof, and to pharmaceutical compositions comprising the same and uses thereof.Uric acid is the final metabolite of diet and purine in human body. In vivo environment (pH 7.4, 37 degrees), uric acid is present in blood mainly in the form of sodium salt of uric acid, the serum uric acid value of normal people is generally lower than 6 mg/dL. When uric acid in serum exceeds 7 mg/dL (Shi, et al., Nature 2003, 425: 516-523), sodium salt of uric acid will crystallize out and precipitate on joints and other parts of the body, and result in disorders such as gout, urinary stones, kidney stones, etc. Patients with gout are often accompanied with other complications, including hypertension, diabetes, hyperlipidemia, dyslipidemia, atherosclerosis, obesity, metabolic disease, nephropathy, cardiovascular disease, and respiratory disease, etc. (Rock, Et al., Nature Reviews Rheumatology 2013, 9: 13-23). In 2002, Japanese scientists Endou group reported that anion transport channel protein URAT1 is a major protein responsible for reabsorption of uric acid in kidney, they also found that the blood uric acid in people with URAT1 gene mutation (causing the synthesis of such protein being ...

9h-pyrrolo-dipyridine derivatives

The invention relates to 9H-pyrrolo-dipyridine derivatives of formula I, processes for preparing them, pharmaceutical compositions containing them and their use as radiopharmaceuticals in particular as imaging agents for the detection of Tau aggregates.

N-SUBSTITUTED 8-[(2,6-DIFLUOROBENZYL)OXY]-2,6-DIMETHYLIMIDAZO[1,2-A]PYRAZIN-3-CARBOXAMIDE DERIVATIVES AS STIMULATORS OF SOLUBLE GUANYLATE CYCLASE (SGC) FOR THE TREATMENT OF CARDIOVASCULAR DISEASES

The present application relates to novel substituted imidazo[1,2-a]pyrazine carboxamides, to processes for their preparation, to their use, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders. 9. (canceled)10. (canceled)11. A medicament comprising the compound as defined in in combination with one or more inert claim 1 , nontoxic claim 1 , pharmaceutically suitable excipients.12. A medicament comprising the compound as defined in in combination with a further active compound selected from the group consisting of organic nitrates claim 1 , NO donors claim 1 , cGMP-PDE inhibitors claim 1 , antithrombotic agents claim 1 , hypotensive agents and lipid metabolism modifiers.13. (canceled)14. A method for the treatment and/or prophylaxis of heart failure claim 1 , angina pectoris claim 1 , hypertension claim 1 , pulmonary hypertension claim 1 , ischaemias claim 1 , vascular disorders claim 1 , renal insufficiency claim 1 , thromboembolic disorders claim 1 , arteriosclerosis claim 1 , dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of at least one compound of to a human or animal in need thereof.15. A method for the treatment and/or prophylaxis of heart failure claim 2 , angina pectoris claim 2 , hypertension claim 2 , pulmonary hypertension claim 2 , ischaemias claim 2 , vascular disorders claim 2 , renal insufficiency claim 2 , thromboembolic disorders claim 2 , arteriosclerosis claim 2 , dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of the compound of to a human or animal in need thereof.16. A method for the treatment and/or prophylaxis of heart failure claim 3 , angina pectoris claim 3 , hypertension claim 3 , pulmonary hypertension claim 3 , ...

Ether compounds for treatment of complement mediated disorders

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R 12 or R 13 on the A group is an ether (R 32 ) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

Compounds for Treatment of Complement Mediated Disorders

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. 7. The pharmaceutical composition of claim 6 , wherein Xis CRand Xis CR.8. The pharmaceutical composition of claim 7 , wherein Ris C-Calkyl.9. The pharmaceutical composition of claim 8 , wherein Ris hydrogen.10. The pharmaceutical composition of claim 8 , wherein C-Calkyl is methyl.11. The pharmaceutical composition of claim 10 , wherein Ris hydrogen.12. The pharmaceutical composition of claim 7 , wherein Rand Rare both hydrogen.17. The pharmaceutical composition of claim 1 , wherein the composition is suitable for delivery to a human.18. The pharmaceutical composition of claim 1 , wherein the composition is suitable for systemic delivery.19. The pharmaceutical composition of claim 1 , wherein the composition is suitable for topical delivery.20. The pharmaceutical composition of claim 1 , wherein the composition is suitable for ocular delivery.21. The pharmaceutical composition of claim 1 , wherein the composition is suitable for intravitreal delivery. This application is a continuation of U.S. application Ser. No. 14/631,828, filed Feb. 25, 2015, which claims the benefit of provisional U.S. Application No. 61/944,189 filed Feb. 25, 2014, provisional U.S. Application No. 62/022,916 filed Jul. 10, 2014, and provisional U.S. Application 62/046,783 filed Sep. 5, 2014. The entirety of each of ...

DEUTERATED CFTR POTENTIATORS

This invention relates to compounds of Formula I: 119.-. (canceled)21. The compound of claim 20 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.22. The compound of claim 20 , wherein the isotopic enrichment coefficient for each designated deuterium is at least 3500 claim 20 , wherein the isotopic enrichment coefficient refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.24. The salt of claim 23 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.25. The salt of claim 23 , wherein the isotopic enrichment coefficient for each designated deuterium is at least 3500 claim 23 , wherein the isotopic enrichment coefficient refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. This application is a continuation-in-part of International Application No. PCT/US12/38297, filed May 17, 2012, which claims the benefit of U.S. Provisional Application Ser. No. 61/487,497, filed May 18, 2011. This application also claims the benefit of U.S. Provisional Application Ser. No. 61/727,941, filed Nov. 19, 2012; U.S. Provisional Application Ser. No. 61/780,681, filed Mar. 13, 2013; and U.S. Provisional Application Ser. No. 61/860,602, filed Jul. 31, 2013. The contents of these applications are incorporated herein by reference in their entirety.Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of ...

MORPHINAN COMPOUNDS

This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σreceptor agonist that also has NMDA antagonist activity. 127-. (canceled)29. The pharmaceutically acceptable salt of claim 28 , wherein the salt is selected from chloride claim 28 , bromide claim 28 , and phosphate.30. The pharmaceutically acceptable salt of claim 28 , wherein the salt is phosphate.31. The pharmaceutically acceptable salt of claim 28 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.32. The pharmaceutically acceptable salt of claim 28 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.33. The pharmaceutically acceptable salt of claim 28 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.34. A pharmaceutical composition comprising the pharmaceutically acceptable salt of and a pharmaceutically acceptable carrier.35. The pharmaceutical composition of claim 34 , further comprising a second therapeutic agent selected from quinidine claim 34 , quinidine sulfate claim 34 , oxycodone claim 34 , and gabapentin.36. The pharmaceutical composition of claim 34 , wherein the amount of the pharmaceutically acceptable salt of the compound is in the range from 4 mg to 350 mg.37. The pharmaceutical composition of claim 34 , wherein the amount of the pharmaceutically acceptable salt of the compound is in the range from 10 mg to 90 mg.38. A method of treating a subject suffering from a disease or condition selected from emotional lability; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; brain injuries; disturbances of consciousness disorders; cardiovascular diseases; glaucoma; tardive dyskinesia; cancer; rheumatoid ...

METHOD FOR SYNTHESIZING IODO- OR ASTATOARENES USING DIARYLIODONIUM SALTS

The present invention concerns a method of synthesizing a iodo- or astatoarene comprising the reaction of a diaryliodonium compound with a iodide or astatide salt, respectively. The invention also relates to said iodo- or astatoarene and diaryliodonium compound as such. The invention also concerns a method of synthesizing a iodo- or astatolabelled biomolecule and/or vector using said iodo- or astatoarene. 4. The method according to claim 1 , wherein the iodo- or astatoarene is of formula (I):{'br': None, 'Ar—X \u2003\u2003(I)'}wherein:X is I or At; and{'sub': 1', '2, 'Ar is Aror Ar.'}5. The method according to claim 1 , wherein the iodine or astatide salt is of formula (III):{'br': None, 'sup': +', '−, 'AX\u2003\u2003(III)'}wherein:{'claim-ref': {'@idref': 'CLM-00004', 'claim 4'}, 'X is as defined in ; and'}A is a monovalent cation selected among Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium.6. The method according to claim 1 , wherein X is radioactive.7. The method according to claim 6 , wherein X is At.8. The method according to claim 6 , wherein X is I.9. The method according to claim 1 , wherein the reaction is carried out in a solvent selected from the group consisting of: acetonitrile claim 1 , an alcohol such as methanol claim 1 , dimethylformamide claim 1 , water claim 1 , and mixtures thereof.10. The method according to claim 1 , further comprising an astatide or iodide salt, and the diaryliodonium salt of formula (II) are insoluble, and', 'said iodo- or astatoarene is soluble., 'a purification step wherein a iodo- or astatoarene is extracted by a solvent in which11. The method of synthesizing an astatoarene according to claim 1 , previously comprising a step of reduction of astatine.12. A method of synthesizing a iodo- or astatolabeled biomolecule and/or vector comprising the steps of:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(i) synthesizing a iodo- or astatoarene according to the method of ;'}(ii) reacting said iodo- or astatoarene ...

RADIOLABELED ERLOTINIB ANALOGS AND USES THEREOF

Radiolabeled compounds which are erlotinib analogs that feature a radioactive halogen and processes of preparing same are disclosed. Uses of these radiolabeled compounds in radioimaging, for identifying and monitoring a level, distribution and/or mutational status of deregulated EGFR, and/or in radiotherapy, are also disclosed. 147-. (canceled)49. The radiolabeled compound of claim 48 , wherein at least one of Yand Yis said Q.50. The radiolabeled compound of claim 49 , wherein Q is a saturated or unsaturated hydrocarbon chain of 2 to 20 carbon atoms claim 49 , optionally interrupted by one or more heteroatoms claim 49 , substituted by or terminating with said radioactive halogen claim 49 , and optionally substituted by one or more additional substituents.51. The radiolabeled compound of claim 49 , wherein Q is an alkylene chain or is or comprises an alkylene glycol or a derivative thereof claim 49 , each being substituted by or terminating with said radioactive halogen.52. The radiolabeled compound of claim 49 , wherein Q is represented by (CR′R″)nX claim 49 ,wherein R′ and R″ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, hydroxyl, halogen, trihaloalkyl, trihaloalkoxy, amine, cyano, nitro, carbonyl, thiocarbonyl, carboxylate, thioacarboxylate, amide, thioamide, carbamate, thiocarbamate, alkaryl, aralkyl, sulfinyl, sylfonyl, sulfonate, and sulfonamide;n is an integer of from 1 to 20; andX is said radioactive halogen.53. The radiolabeled compound of claim 52 , wherein each of R′ and R″ is hydrogen.54. The radiolabeled compound of claim 52 , wherein n is 2.55. The radiolabeled compound of claim 48 , wherein at least one of Yand Yis said radioactive halogen.56. The radiolabeled compound of claim 48 , wherein each of R-Ris hydrogen; and/or{'sub': 5', '12, 'each of R-Ris hydrogen; and/or'}{'sub': 17', '21, 'each of R-Ris hydrogen; and/or'}{'sub': 13', '16, 'each of R-Ris ...

ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein Ror Ron the A group is an aryl, heteroaryl or heterocycle (R) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. 2. The process of claim 1 , wherein Rand R are independently chosen from hydrogen claim 1 , halogen claim 1 , and C-Calkyl.3. The process of claim 1 , wherein Ris hydrogen.5. The process of claim 1 , wherein Ris hydrogen.6. The process of claim 1 , wherein B is —(C-Calkyl)(aryl) or —(C-Calkyl)(heteroaryl); each of which B is unsubstituted or substituted with one or more substituents independently chosen from Rand R claim 1 , and 0 or 1 substituents chosen from Rand R.7. The process of claim 1 , wherein B is —(C-Calkyl)(heteroaryl) which is unsubstituted or substituted with one or more substituents independently chosen from Rand R.8. The process of claim 1 , wherein Ris selected from halogen and C-Calkyl.14. The process of claim 13 , wherein Rand R are independently chosen from hydrogen claim 13 , halogen claim 13 , and C-Calkyl.15. The process of claim 14 , wherein Ris C-Calkanoyl.16. The process of claim 15 , wherein B is —(C-Calkyl)(heteroaryl); each of which B is unsubstituted or substituted with one or more substituents independently chosen from Rand R.17. The process of claim 16 , wherein Ris hydrogen.18. The process of claim 17 , wherein Ris selected from halogen and C-Calkyl. This application is a continuation of U.S ...

SOLID PHASE EXTRACTION

The present invention provides a method for the synthesis of an injectable composition comprising a [F]-labelled pyridaben derivative that is amenable to automation. In particular, the method of the present invention comprises a method of purification carried out by means of solid phase extraction (SPE) alone. 1. A method comprising: [{'br': None, 'BTM-LINKER-LG\u2003\u2003(I)'}, 'wherein:', 'BTM is a biological targeting moiety;', 'LINKER is an alkylene or an alkoxyalkylene; and,', 'LG is a sulfonate-containing leaving group, '(a) reacting in acetonitrile a precursor compound of Formula I{'sup': 18', '18, 'claim-text': {'br': None, 'sup': '18', 'BTM-LINKER-F\u2003\u2003(II)'}, 'with F-fluoride to obtain a crude reaction mixture comprising an F-labelled compound of Formula IIwherein BTM and LINKER are as defined for Formula I;(b) diluting the crude reaction mixture obtained in step (a) to obtain a diluted crude reaction mixture; (i) transferring said diluted crude reaction mixture to an SPE cartridge;', '(ii) optionally passing water through said SPE cartridge;', '(iii) passing a wash solution comprising an organic solvent through said SPE cartridge;', '(iv) optionally passing water through said SPE cartridge to remove said organic solvent; and,', '(v) passing an elution solution comprising ethanol through said SPE cartridge to elute said compound of Formula I from said SPE cartridge;, '(c) purifying the diluted crude reaction mixture obtained in step (b) by means of one or more solid phase extraction (SPE) cartridges to obtain a purified compound of Formula II where said purifying comprises the sequential steps ofwherein step (b) includes adding a hydrolyzing reagent to said crude reaction mixture and/or said water of step (ii) and/or step (iv) comprises a hydrolyzing reagent.2. The method as defined in wherein said BTM is a small molecule.3. The method as defined in wherein said small molecule is an analogue of pyridaben.5. The method as defined in wherein Ris ...

8-HYDROXYQUINOLINE DERIVATIVES AS DIAGNOSTIC AND THERAPEUTIC AGENTS

The present application provides compounds useful in methods of treating neurological disorders such as Alzheimer's disease, and cancer such as prostate cancer. Also provided herein are radiolabeled compounds useful for imaging techniques, and techniques for diagnosis and monitoring of treatment of neurological disorders and cancer. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography or single-photon emission computed tomography. Methods for preparing radiolabeled compounds and methods for preparing unlabeled compounds are also provided. 1195-. (canceled)198. The compound of claim 196 , wherein:Hal is selected from the group consisting of: Cl, F, and I;{'sup': 'N', 'X is selected from the group consisting of O and NR;'}{'sup': '1', 'sub': 1-6', '1-3, 'Lis —Calkylene-, wherein said alkylene group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, Calkoxy, and amino;'}{'sup': '2', 'sub': 1-6', '1-3, 'Lis —Calkylene-, wherein said alkylene group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, Calkoxy, and amino;'}{'sup': 'N', 'sub': '1-6', 'Ris selected from the group consisting of H and Calkyl;'}{'sup': 'A', 'group A is 5 or 6 membered heteroaryl, which is optionally substituted by 1, 2, or 3 independently selected Rgroups;'}alternatively, group A is H;{'sup': N', '1', '2', 'N, 'sub': 1-6', '1-6', '1-6, 'with the proviso that when X is NR, Lis —Calkylene-, Lis —Calkylene-, and Ris Calkyl, group A is not H; and'}{'sup': 'A', 'sub': 2', '1-6', '2-6', '2-6', '1-6', '1-6', '1-6', '1-3', '1-3', '1-6', '1-6, 'each Ris independently selected from the group consisting of OH, NO, CN, halo, Calkyl, Calkenyl, Calkynyl, Chaloalkyl, Calkoxy, Chaloalkoxy, cyano-Calkyl, HO—Calkyl, amino, Calkylamino, and di(Calkyl)amino.'}208. A pharmaceutical composition comprising a compound of claim 196 , or a pharmaceutically acceptable salt ...

NOVEL TETRAHYDROISOQUINOLINE COMPOUNDS FOR USE IN THE DIAGNOSIS AND TREATMENT OF NEURODEGENERATIVE DISEASES

The invention relates to a new class of compounds with high affinity and selectivity towards P-glycoprotein. The invention also relates to the utilization of such compounds in the in vivo diagnosis of neurodegenerative diseases and as medicaments for use in the prevention and treatment of neurodegenerative disease involving P-glycoprotein. 2. A compound according to claim 1 , wherein Ris H.3. A compound according to claim 1 , wherein X is oxygen; Ris H claim 1 , and Ris H claim 1 , F claim 1 , Br claim 1 , OCHor OH.4. A compound according to claim 1 , wherein X is sulfur; Ris H; and Ris H claim 1 , R claim 1 , Br claim 1 , OCHor OH.6. A compound according to claim 1 , wherein the compound is isotopically radio labeled.7. The compound according to claim 6 , wherein the compound is labeled with an isotope selected from the group consisting of H claim 6 , C claim 6 , C claim 6 , N claim 6 , O claim 6 , F F claim 6 , Br claim 6 , Br claim 6 , Br claim 6 , I claim 6 , I claim 6 , I claim 6 , and I.810-. (canceled)11. A diagnostic imaging composition comprising as imaging agent a compound according to the and a carrier.12. The diagnostic imaging composition according to for use in vivo diagnosis of a neurodegenerative disease involving P-glycoprotein.13. The diagnostic imaging composition according to wherein the neurodegenerative disease is the Alzheimer's or Parkinson's disease.14. The diagnostic imaging composition according to in the form of an injectable solution wherein the imaging agent is from 4 mg/ml to 7.5 mg/ml.1517-. (canceled)18. A pharmaceutical composition comprising a compound according to and a pharmacologically acceptable excipient and/or diluent.19. A pharmaceutical kit formed by a first element containing a compound according to and a second element containing radionuclide suitable for imaging.21. The method according to claim 20 , further comprising the step of reacting with a radioisotope.22. A method for treatment of a neurodegenerative disease that ...

Allenamide as an orthogonal handle for selective modification of cysteine in peptides and proteins

There is provided a compound of formula I, having the structure: wherein R 1 to R 5 have the meanings given in the description.

METHODS AND REAGENTS FOR RADIOLABELING

The present invention provides methods for radiolabeling compounds useful as Hsp90 inhibitors. The present invention also provides intermediates useful in such methods, and compositions of radiolabeled compounds. The present invention provides, among other things, novel methods for the synthesis of radiolabeled compounds. In certain embodiments, the present invention provides compounds of formula I. 4. The compound of any one of the preceding claims , wherein Yis —CR—.5. The compound of any one of - , wherein Yis —N—.6. The compound of any one of the preceding claims , wherein Yis —CR—.7. The compound of any one of - , wherein Yis —N—.8. The compound of any one of the preceding claims , wherein Ris hydrogen.9. The compound of any one of the preceding claims , wherein Zis —CH—.10. The compound of any one of - , wherein Zis —N—.11. The compound of any one of the preceding claims , wherein Zis —CH—.12. The compound of any one of - , wherein Zis —N—.13. The compound of any one of the preceding claims , wherein Zis —CH—.14. The compound of any one of - , wherein Zis —N—.16. The compound of any one of the preceding claims , wherein L is a straight or branched , Caliphatic group wherein one or more carbons are independently replaced by —NR— , wherein R is other than a -Boc protecting group.17. The compound of any one of the preceding claims , wherein X is —CH— or —S—.18. The compound of any one of the preceding claims , wherein X is —CH—.19. The compound of any one of - , wherein X is —S—.20. The compound of any one of the preceding claims , wherein Ris hydrogen.21. The compound of any one of - , wherein Ris halogen.22. The compound of claim 21 , wherein Ris fluro.23. The compound of any one of - claim 21 , wherein -L-Rcomprises a methylene that is replaced with —NH— to form a secondary amine.24. The compound of any one of the preceding claims claim 21 , wherein L is a straight or branched claim 21 , Caliphatic group wherein a methylene of the aliphatic group is replaced ...

RADIOLABELED COMPOUNDS

The present invention relates to radiolabeled compounds of formula I 2. The radiolabeled compound of claim 1 , wherein{'sup': '1', 'sub': '1-7', 'Ris Calkyl,'}{'sup': '2', 'sub': '1-7', 'Ris Cfluoroalkyl,'}{'sup': '3', 'Ris methyl,'}{'sup': 4', '2', '18', '3', '3', '11, 'Ris hydrogen, wherein either Ris labeled with F or H, or Ris labeled with C.'}3. The radiolabeled compound of claim 1 , wherein{'sup': 1', '2, 'Rand Rtogether with the nitrogen atom to which they are attached, form a heterocycloalkyl, preferably morpholinyl,'}{'sup': '3', 'Ris methyl,'}{'sup': 4', '4', '18, 'sub': '1-7', 'Ris Cfluoroalkyoxy, wherein Ris labeled with F.'}4. The radiolabeled compound of claim 1 , wherein{'sup': 1', '2, 'Rand Rtogether with the nitrogen atom to which they are attached, form a heterocycloalkyl, preferably morpholinyl,'}{'sup': '3', 'Ris methyl,'}{'sup': 4', '4', '3', '11, 'sub': '1-7', 'Ris Calkyoxy, wherein Ris either labeled with H or C.'}69.-. (canceled)10. A method for positron emission tomography (PET) imaging of PDE10A in tissue of a subject claim 1 , the method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a) administering an effective amount of a compound of to the subject,'}b) allowing the compound to penetrate into the tissue of the subject; andc) collecting a PET image of the CNS or brain tissue of the subject.11. A method for the detection of PDE10A functionality in a tissue of a subject claim 1 , the method comprising{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a) administering an effective amount of a compound of to the subject,'}b) allowing the compound to penetrate into the tissue of the subject; andc) collecting a PET image of the CNS or brain tissue of the subject.12. (canceled)13. A pharmaceutical composition comprising a compound as claimed in and a pharmaceutically acceptable excipient.14. (canceled) The present invention relates to radiolabeled compounds of formula IwhereinRand Rare independently selected from Calkyl, ...

ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising formula I, or a pharmaceutically acceptable salt or composition thereof wherein Ror Ron the A group is an aryl, heteroaryl or heterocycle (R) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. 12. The pharmaceutical composition of claim 1 , wherein B is —(C-Calkyl)(aryl) or —(C-Calkyl)(heteroaryl) each of which B is unsubstituted or substituted with one or more substituents independently chosen from Rand R claim 1 , and 0 or 1 substituents chosen from Rand R.13. The pharmaceutical composition of claim 12 , wherein B is —(CH)(aryl) substituted with two substituents independently chosen from Rand R.14. The pharmaceutical composition of claim 13 , wherein Ris halogen.15. The pharmaceutical composition of claim 14 , wherein there are two Rsubstituents and one is chlorine and the other is fluorine.18. The pharmaceutical composition of claim 12 , wherein B is aryl or heteroaryl each of which B is unsubstituted or substituted with one or more substituents independently chosen from Rand R.19. The pharmaceutical composition of claim 18 , wherein B is aryl.20. The pharmaceutical composition of claim 18 , wherein B is heteroaryl.21. The pharmaceutical composition of claim 20 , wherein heteroaryl is 2-pyridine.22. The pharmaceutical composition of claim 21 , wherein 2-pyridine is substituted with one substituent independent chosen from R.23. The pharmaceutical composition of claim 22 , wherein Ris halogen.31. The ...

AZA-PYRIDONE COMPOUNDS AND USES THEREOF

Disclosed herein are aza-pyridone compounds, pharmaceutical compositions that include one or more aza-pyridone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with an aza-pyridone compounds. Examples of an orthomyxovirus viral infection include an influenza infection. 184-. (canceled) Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled ALIOS078, created Apr. 28, 2016, which is 4 kb bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are aza-pyridone compounds, pharmaceutical compositions that include one or more aza-pyridone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating an orthomyxovirus viral infection with one or more aza-pyridone compounds.The viruses of the Orthomyxoviridae family are negative-sense, single-stranded RNA viruses. The Orthomyxoviridae family contains several genera including Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. Influenzaviruses can cause respiratory viral infections, including upper and lower respiratory tract viral infections. Respiratory viral infections are a leading cause of death of millions of people each year. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the ...

Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

DEUTERATED TRIAZOLOPYRIDAZINE AS A KINASE MODULATOR

The invention is directed to a triazolopyridazine compound of formula (I): This continuation application claims priority to U.S. patent application Ser. No. 15/531,780 filed May 31, 2017, which is a 371 National Stage Entry of PCT/EP2015/078525 filed Dec. 3, 2015, which claims priority to European Patent Application No. 14196585.5 filed Dec. 5, 2014 and European Patent Application No. 14196387.6 filed Dec. 4, 2014, which are incorporated by reference herein in their entirety.The invention relates to a novel compound that functions as a protein tyrosine kinase modulator. More particularly, the invention relates to a novel compound that functions as an inhibitor of c-Met.The present invention relates to a triazolopyridazine as an inhibitor of tyrosine kinases, including c-Met. Triazolopyridazines have been reported with useful therapeutic properties including in WO2007/075567.Protein kinases are enzymatic components of the signal transduction pathways that catalyze the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and/or threonine residues of proteins. Thus, compounds that inhibit protein kinase functions are valuable tools for assessing the physiological consequences of protein kinase activation. The overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been a topic of extensive study and has been demonstrated to play a significant role in the development of many diseases, including diabetes, angiogenesis, psoriasis, restenosis, ocular diseases, schizophrenia, rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer. The cardiotonic benefit of kinase inhibition has also been studied. In sum, inhibitors of protein kinases have particular utility in the treatment of human and animal disease.The hepatocyte growth factor (HGF) (also known as scatter factor (SF)) receptor, c-Met, is a receptor tyrosine kinase that regulates cell proliferation, morphogenesis, and motility. The c- ...

Compounds for treatment of complement mediated disorders

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE

The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention. 1121-. (canceled)123. The process of claim 122 , wherein suitable conditions for forming the amide bond comprise reacting the compound of formula 30 with the compound of formula 25 in the presence of an amide coupling partner claim 122 , an aprotic solvent claim 122 , and a base.124. The compound of claim 123 , wherein the aprotic solvent is independently selected from NMP claim 123 , DMF claim 123 , or tetrahydrofuran.125. The process of claim 124 , wherein the aprotic solvent is tetrahydrofuran.126. The process of claim 123 , wherein the base is an aliphatic amine.127. The process of claim 126 , wherein the base is DIPEA.128. The process of claim 123 , wherein the amide coupling partner is independently selected from CDI claim 123 , TBTU claim 123 , or TCTU.129. The process of claim 128 , wherein the amide coupling partner is TCTU.130. The process of claim 128 , wherein the amide coupling partner is CDI.131. The process of claim 122 , wherein suitable deprotection conditions comprise reacting the compound of formula 28 with an acid in the presence of a solvent.132. The process of claim 131 , wherein the acid is HCl.133. The process of claim 131 , wherein the solvent is 1 claim 131 ,4-dioxane.134. The process of claim 122 , wherein the suitable conditions for forming the amide bond comprise reacting the compound of formula 6a* with the compound of formula 27 in an aprotic solvent under heat.135. The process of claim 134 , wherein the aprotic solvent is independently selected from NMP claim ...

Opsin-Binding Ligands, Compositions and Methods of Use

Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described. 3. The compound of claim 2 , wherein Rand Rare each independently hydrogen or methyl.4. The compound of claim 2 , wherein Rand Rare each independently hydrogen or lower alkyl.6. The compound of claim 5 , wherein a and b are each 1 claim 5 , X is hydrogen claim 5 , Y is C—C(O)NRRor N—C(O)NRRwherein R claim 5 , Rand Rare all hydrogen.7. The compound of claim 1 , wherein X is H claim 1 , lower alkyl or —C≡CR.8. The compound of claim 1 , wherein Y is O or N—C(O)—NRR.920-. (canceled)21. A method of reducing or inhibiting mislocalization of an opsin protein claim 1 , comprising contacting an opsin protein with a compound of .22. The method of claim 21 , wherein said opsin protein is pressent in a rod cell or a cone cell.23. (canceled)24. The method of claim 22 , wherein said cell is present in a mammalian eye.25. A method of inhibiting the formation or accumulation of a visual cycle product claim 1 , comprising contacting an opsin protein with a compound of .26. The method of claim 25 , wherein said visual cycle product is lipofuscin or N-retinylidene-N-retinylethanolamine (A2E).27. A method of treating or preventing an ophthalmic condition in a subject at risk thereof claim 1 , comprising administering to the subject an effective amount of a compound of .28. The method of claim 27 , wherein said ophthalmic condition is an ocular protein mislocalization disorder.29. The method of claim 27 , wherein said ophthalmic condition is selected from the group consisting of wet or dry age related macular degeneration (ARMD) claim 27 , retinitis pigmentosa ...

TRIAZOLE AGONISTS OF THE APJ RECEPTOR

Compounds of Formula I and Formula II, pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: 1. A compound or a pharmaceutically acceptable salt thereof , wherein the compound is(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;(2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;(1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;(1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide;(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide;(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;(2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-2-propanesulfonamide;(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;(1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrazinyl)-2- ...

10-SUBSTITUTED MORPHINAN HYDANTOINS

The application is directed to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R-R, Y, Z are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I) and the maceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain. 2. (canceled)4. (canceled)6. (canceled)911-. (canceled)13. (canceled)16. (canceled)17. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein Ris hydroxy , or unsubstituted Calkoxy.1822-. (canceled)23. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris alkyl claim 1 , alkenyl claim 1 , alkynyl claim 1 , cycloalkyl claim 1 , cycloalkenyl claim 1 , heterocyclo claim 1 , aryl claim 1 , heteroaryl claim 1 , (cycloalkyl)alkyl claim 1 , (cycloalkenyl)alkyl claim 1 , (heterocyclo)alkyl claim 1 , arylalkyl claim 1 , heteroarylalkyl claim 1 , alkylcarbonyl claim 1 , alkoxycarbonyl claim 1 , (arylalkoxy)carbonyl claim 1 , or (heteroarylalkoxy)carbonyl claim 1 , any of which is optionally substituted with 1 claim 1 , 2 claim 1 , or 3 substituents claim 1 , each independently selected from the group consisting of hydroxy claim 1 , alkyl claim 1 , halo claim 1 , haloalkyl claim 1 , amino claim 1 , alkylamino claim 1 , dialkylamino claim 1 , carboxy claim 1 , alkoxy claim 1 , alkoxycarbonyl claim 1 , aryl claim 1 , heteroaryl claim 1 , heterocyclo claim 1 , cycloalkyl claim 1 , and cycloalkenyl claim 1 , wherein said aryl claim 1 , heteroaryl claim 1 , heterocyclo claim 1 , cycloalkyl claim 1 , and cycloalkenyl are optionally substituted with 1 claim 1 , 2 claim 1 , or 3 independently selected Rgroups.2425-. (canceled)26. The compound of claim 23 , or a pharmaceutically acceptable salt or ...

ORGANIC COMPOUNDS

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms. 3. The compound according to claim 1 , wherein Ris H.4. The compound according to claim 1 , wherein Ris Calkyl.5. The compound according to claim 1 , wherein Ris Calkyl optionally substituted with D.6. The compound according to claim 1 , wherein Ris CH.7. The compound according to wherein Ris CD.8. The compound according to claim 1 , wherein Ris a pharmaceutically acceptable and physiologically labile moiety.9. The compound according to claim 1 , wherein Ris —C(O)—R claim 1 , and wherein Ris Calkyl.10. The compound according to claim 1 , wherein Ris —C(O)—R claim 1 , and wherein Ris Calkyl.11. The compound according to claim 1 , wherein Ris —C(O)—R claim 1 , and wherein Ris Calkyl.12. The compound according to claim 1 , wherein Ris —C(O)—R claim 1 , and wherein Ris methyl claim 1 , ethyl or propyl.13. The compound according to claim 1 , wherein Ris —C(O)—R claim 1 , and wherein Ris methyl.14. The compound according to claim 1 , wherein X is N(H) claim 1 , N(R) or O.15. The compound according to claim 1 , wherein X is O.16. The compound according to claim 1 , wherein X is N(H).17. The compound according to claim 1 , wherein X is N(R) claim 1 , and wherein Ris Calkyl.18. The compound according to claim 1 , wherein X is N(R) claim 1 , and wherein Ris CH.19. The compound according to claim 1 , wherein X is N(R) claim 1 , and wherein Ris CD.20. The compound according to claim 1 , wherein Ris D.21. The compound according to claim 1 , wherein Ris D.22. The compound according to claim 1 , wherein Rand Rare D.23. The compound ...

Morphinan Compounds

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1 receptor agonist that also has NMDA antagonist activity.

TAU PET IMAGING LIGANDS

The present invention relates to novel, selective radiolabelled tau ligands which are useful for imaging and quantifying tau aggregates, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue or a subject, in vitro or in vivo, and to precursors of said compounds. 4. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof claim 1 , and a pharmaceutically acceptable carrier or diluent.5. The pharmaceutical composition according to claim 4 , wherein such composition is a sterile solution.6. A compound of for use in binding and imaging tau aggregates.7. A compound of claim 1 , for use in diagnostic imaging of tau aggregates in the brain of a subject.8. A compound of claim 1 , for use in binding and imaging tau aggregates in a patient suffering from claim 1 , or suspected to be suffering from claim 1 , a tauopathy.9. Use of a compound of claim 1 , for binding and imaging tau aggregates. The present invention relates to novel, selective radiolabelled tau ligands which are useful for imaging and quantifying tau aggregates, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue or a subject, in vitro or in vivo, and to precursors of said compounds.Alzheimer's Disease (AD) is a neurodegenerative disease associated with aging. AD patients suffer from cognition deficits and memory loss as well as behavioural problems such as anxiety. Over 90% of those afflicted with AD have a sporadic form of the disorder while less than 10% of the cases are familial or hereditary. In the United States, about one in ten people at age 65 have AD while at age ...

SYNTHESIS OF THE RADIOLABELED PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITORDCFPYL

Methods, and related compositions, for the improved synthesis of [F]DCFPyL are disclosed. Also provided are methods, and related compositions, for the use of [F]DCFPyL so produced. 1. A method of synthesizing 2-(3-{1-carboxy-5-[(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([F]DCFPyL) , the method comprising:(i) radiofluorinating a DCFPyL precursor comprising ester moiety protecting groups to form a radiofluorinated DCPFPyL precursor;{'sup': '18', '(ii) deprotecting the ester moiety protecting groups of the radiofluorinated DCPFPyL precursor of step (i) with phosphoric acid to form [F]DCFPyL in a reaction mixture; and'}{'sup': 18', '18, '(iii) purifying the [F]DCFPyL from the reaction mixture of step (ii) to provide [F]DCFPyL.'}2. The method of claim 1 , wherein the protecting groups are selected from the group consisting of benzyl claim 1 , p-methoxybenzyl claim 1 , tertiary butyl claim 1 , methoxymethyl claim 1 , methoxyethoxymethyl claim 1 , methylthiomethyl claim 1 , tetrahydropyranyl claim 1 , tetrahydrofuranyl claim 1 , benzyloxymethyl claim 1 , trimethylsilyl claim 1 , triethylsilyl claim 1 , t-butyldimethylsilyl (TBDMS) claim 1 , and triphenylmethyl.3. The method of claim 1 , wherein step (i) and step (ii) are performed in one reactor.4. The method of claim 1 , wherein the synthesizing is automated by use of a radiofluorination module (RFM) comprising a heating block claim 1 , two syringe pumps claim 1 , a multi-port cap claim 1 , and valved reagent addition vials.5. The method of claim 4 , wherein the RFM further comprises a thermal heating cavity.6. The method of claim 1 , wherein the synthesizing is automated by use of an automated radiochemistry synthesizer.7. The method of claim 4 , wherein components of the RFM or the automated radiochemistry synthesizer are free of fluorine.8. The method of claim 1 , wherein the DCFPyL precursor is 5-(((S)-6-(tert-butoxy)-5-(3-((S)-1 claim 1 ,5-di-tert-butoxy-1 claim 1 ,5-dioxopentan-2-yl) ...

SUBSTITUTED DIHYDROISOQUINOLINONE COMPOUNDS

This invention relates to compounds of general formula (I) 2. The compound or salt of claim 1 , wherein Ris H.3. The compound or salt of claim 1 , wherein Ris Cl claim 1 , F claim 1 , Br or CH.4. The compound or salt of of claim 1 , wherein X is CH claim 1 , OCHor OCHFand Z is CH.5. The compound or salt of claim 1 , wherein Ris C-Calkoxy optionally substituted by one or more R.6. The compound or salt of claim 5 , wherein said C-Calkoxy is OCH.7. The compound or salt of claim 1 , wherein Ris C-Calkyl optionally substituted by one or more R.8. The compound or salt of claim 1 , wherein L is a bond and Ris 3-12 membered heterocyclyl optionally substituted by one or more R.9. The compound or salt of claim 8 , wherein said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl claim 8 , tetrahydrofuranyl and tetrahydropyranyl claim 8 , each optionally substituted by one or more R.11. The compound or salt of claim 10 , wherein Ris 3-12 membered heterocyclyl selected from the group consisting of oxetanyl claim 10 , tetrahydrofuranyl and tetrahydropyranyl claim 10 , each optionally substituted by one or more R.12. A compound of that is 5 claim 10 ,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1 claim 10 ,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3 claim 10 ,4-dihydroisoquinolin-1(2H)-one.14. The compound or salt of claim 13 , wherein Rand Rare taken together to form a 3-12 membered heterocyclyl selected from the group consisting of azetidinyl claim 13 , pyrrolidinyl claim 13 , piperidinyl and homopiperidinyl claim 13 , each optionally substituted by one or more R.15. The compound or salt of claim 14 , wherein Ris CHO claim 14 , C(O)Ror SORand each Ris independently C-Calkyl optionally substituted by one or more R.16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier or excipient.17. A pharmaceutical composition comprising the ...

MACROCYCLE AND COMPOSITION COMPRISING THEREOF

A macrocycle represented by formula (I) and a pharmaceutical composition comprising the macrocycle, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvent compound, stereoisomer, prodrug, or isotopic variant of the macrocycle. The macrocycle and the composition thereof inhibit a protein kinase. 111-. (canceled)13. The compound claim 12 , or a crystal form claim 12 , a pharmaceutically acceptable salt claim 12 , a prodrug claim 12 , a stereoisomer claim 12 , a hydrate claim 12 , or a solvate thereof according to claim 12 , wherein R claim 12 , R claim 12 , and Rare isotopes.14. The compound claim 12 , or a crystal form claim 12 , a pharmaceutically acceptable salt claim 12 , a prodrug claim 12 , a stereoisomer claim 12 , a hydrate claim 12 , or a solvate thereof according to claim 12 , wherein R claim 12 , R claim 12 , and Rare isotopes.15. The compound claim 13 , or a crystal form claim 13 , a pharmaceutically acceptable salt claim 13 , a prodrug claim 13 , a stereoisomer claim 13 , a hydrate claim 13 , or a solvate thereof according to claim 13 , wherein R claim 13 , R claim 13 , and Rare isotopes.16. The compound claim 12 , or a crystal form claim 12 , a pharmaceutically acceptable salt claim 12 , a prodrug claim 12 , a stereoisomer claim 12 , a hydrate claim 12 , or a solvate thereof according to claim 12 , wherein R claim 12 , R claim 12 , R claim 12 , and Rare isotopes.17. The compound claim 13 , or a crystal form claim 13 , a pharmaceutically acceptable salt claim 13 , a prodrug claim 13 , a stereoisomer claim 13 , a hydrate claim 13 , or a solvate thereof according to claim 13 , wherein R claim 13 , R claim 13 , R claim 13 , and Rare isotopes.18. The compound claim 14 , or a crystal form claim 14 , a pharmaceutically acceptable salt claim 14 , a prodrug claim 14 , a stereoisomer claim 14 , a hydrate claim 14 , or a solvate thereof according to claim 14 , wherein R claim 14 , R claim 14 , R claim 14 , and Rare isotopes.19. The compound ...

Quinazolinone derivative, preparation method therefore, pharmaceutical composition, and applications

Disclosed are a quinazolinone derivative, a preparation method therefor, a pharmaceutical composition, and applications. Provided are a compound represented by formula I, a pharmaceutically acceptable salt, a solvate, a crystal form, a eutectic crystal, a stereoisomer, an isotope compound, a metabolite, or a prodrug thereof. Generation or activity of a cell factor can be regulated, and accordingly, cancers and inflammatory diseases can be effectively treated.

GAMMA-CARBOLINE COMPOUNDS FOR THE DETECTION OF TAU AGGREGATES

The present invention relates to novel compounds of the formula (II) and formula (III) 3. (canceled)6. (canceled)7. The compound according to claim 1 , wherein Ris F and Ris H claim 1 , Ris F and Ris H claim 1 , or Ris LG and Ris H or PG.8. (canceled)9. (canceled)10. The compound according to claim 1 , wherein LG is nitro claim 1 , halogen or trimethyl ammonium.11. The compound according to claim 1 , wherein PG is tert-butyloxycarbonyl (BOC) claim 1 , triphenylmethyl (Trityl) or dimethoxytrityl (DMT).12. The compound according to claim 1 , wherein the compound is detectably labeled claim 1 , preferably wherein the detectable label is F.13. (canceled)14. A diagnostic composition comprising a compound as defined in and optionally a pharmaceutically acceptable carrier claim 12 , diluent claim 12 , adjuvant or excipient.15. (canceled)16. A method of imaging Tau aggregates claim 12 , particularly a method of imaging Tau aggregates by positron emission tomography claim 12 , wherein a diagnostically effective amount of a compound as defined in is administered to a patient.17. A method of diagnosing a disorder associated with Tau aggregates or tauopathy claim 12 , particularly wherein the diagnosis is conducted by positron emission tomography wherein a diagnostically effective amount of a compound as defined in is administered to a patient.18. (canceled)19. (canceled)20. The method according to claim 17 , wherein the disorder is selected from Alzheimer's disease (AD) claim 17 , familial AD claim 17 , Creutzfeldt-Jacob disease claim 17 , dementia pugilistica claim 17 , Down's Syndrome claim 17 , Gerstmann-Sträussler-Scheinker disease claim 17 , inclusion-body myositis claim 17 , prion protein cerebral amyloid angiopathy claim 17 , traumatic brain injury claim 17 , amyotrophic lateral sclerosis claim 17 , Parkinsonism-dementia complex of Guam claim 17 , non-Guamanian motor neuron disease with neurofibrillary tangles claim 17 , argyrophilic grain disease claim 17 , ...

9h-pyrrolo-dipyridine derivatives

The invention relates to 9H-pyrrolo-dipyridine derivatives of formula I, processes for preparing them, pharmaceutical compositions containing them and their use as radiopharmaceuticals in particular as imaging agents for the detection of Tau aggregates.

DIAGNOSTIC COMPOSITIONS FOR PET IMAGING, A METHOD FOR MANUFACTURING THE DIAGNOSTIC COMPOSITION AND ITS USE IN DIAGNOSTICS

The present application relates to a diagnostic composition comprising: 2. A diagnostic composition according to claim 1 , wherein F in Formula I is F or F claim 1 , preferably F or a mixture of F and F.45.-. (canceled)6. A diagnostic composition according to claim 1 , wherein the hydroxycarboxylic acid claim 1 , the salt of the hydroxycarboxylic acid or the mixture thereof are selected from the group consisting of ascorbic acid and salts of ascorbic acid claim 1 , hydroxybenzoic acids and salts of hydroxybenzoic acids claim 1 , hydroxybenzoic acid derivatives and salts of hydroxybenzoic acid derivatives claim 1 , citric acid and salts of citric acid and a mixture thereof claim 1 , preferably wherein the hydroxybenzoic acid derivative is selected from the group consisting of hydroxybenzoic acid claim 1 , dihydroxybenzoic acid and trihydroxybenzoic acid claim 1 , more preferably wherein the dihydroxybenzoic acid is gentisic acid.79.-. (canceled)10. A diagnostic composition according to comprising about 2.5 to about 500 μmol/mL of the hydroxycarboxylic acid claim 1 , the salt of the hydroxycarboxylic acid or the mixture thereof claim 1 , preferably about 10 to about 300 μmol/mL of the hydroxycarboxylic acid claim 1 , the salt of the hydroxycarboxylic acid or the mixture thereof claim 1 , more preferably about 25 to about 300 μmol/mL of the hydroxycarboxylic acid claim 1 , the salt of the hydroxycarboxylic acid or the mixture thereof.1113.-. (canceled)14. A diagnostic composition according to further comprising one or more of an inorganic acid claim 1 , an organic acid claim 1 , a base claim 1 , or a salt claim 1 , wherein the organic acid claim 1 , the salt or the mixture thereof is/are different from the hydroxycarboxylic acid claim 1 , the salt of the hydroxycarboxylic acid or the mixture thereof claim 1 , preferably wherein the inorganic acid claim 1 , the organic acid claim 1 , the base claim 1 , the salt or the mixture thereof is/are selected from the group ...

IMAGING TUMOR GLYCOLYSIS BY NON-INVASIVE MEASUREMENT OF PYRUVATE KINASE M2

The present disclosure provides a positron emission tomography (PET)-detectable 1-((2-fluoro-6-[F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([F]DASA-23) probe that can selectively bind to the pyruvate kinase variant M2 (PKM2) found in cancer cells, such as of human glioma. Given the importance of PKM2 in the regulation of tumor metabolism, there is an on-going need to non-invasively measure its expression through the development of PKM2-specific radiopharmaceuticals. Precursors useful for the synthesis of the radiolabeled [F]DASA-23-PKM2-specific probe and related compounds, and their methods of synthesis, are provided. Since the half-life of the F isotope is approximately 110 min, it is advantageous for a practitioner to attach the radionuclide to the precursor shortly before administration. Therefore, a precursor compound suitable for receiving the radionuclide and capable of specifically binding to the PKM2 variant can be provided. 2. The pyruvate kinase M2 activator precursor of claim 1 , wherein Ris an alkoxyphenyl or an aminophenyl.3. The pyruvate kinase M2 activator precursor of claim 1 , wherein Ris 4-methoxyphenyl claim 1 , 4-ethoxyphenyl claim 1 , 4-propoxyphenyl claim 1 , or 4-aminophenyl.5. The pyruvate kinase M2 activator precursor of claim 4 , wherein Ris 4-methoxyphenyl.7. The Positron Emission Tomography (PET)-detectable probe of claim 6 , wherein Ris an alkoxyphenyl or an aminophenyl.8. The Positron Emission Tomography (PET)-detectable probe of claim 7 , wherein Ris 4-methoxyphenyl claim 7 , 4-ethoxyphenyl claim 7 , 4-propoxyphenyl claim 7 , or 4-aminophenyl.12. The pharmaceutically acceptable probe composition of claim 10 , further comprising a pharmaceutically acceptable carrier.14. The method of claim 13 , wherein step (d) comprises reacting the TFA salt of 1-((4-methoxyphenyl)sulfonyl)piperazine (9) product of step (c) with 2-fluoro-6-nitrobenzenesulfonyl chloride to generate 1-((2-fluoro-6-nitrophenyl)sulfonyl)-4-((4- ...