АМИНОПИРИМИДИНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ КИНАЗ

Изобретение относится к соединению формулы I или его таутомеру или их фармацевтически приемлемым солям, где R2 представляет собой С1-3-алкил или циклопропил; R9 представляет собой галоген, С1-3-алкил, -O-(C1-3-алкил), -S-(С1-3-алкил) или CF3 и р равно 1-2. Предлагаемые соединения являются ингибиторами Аврора-протеинкиназ. Они могут использоваться в способе ингибирования активности Аврора-протеинкиназы. Изобретение также предоставляет фармацевтически приемлемые композиции, включающие такие соединения; и способ лечения пролиферативного расстройства у пациента с применением указанного соединения. 4 н. и 7 з.п. ф-лы, 7 табл.

АНИЛИДЫ АМИНОКИСЛОТ В КАЧЕСТВЕ НИЗКОМОЛЕКУЛЯРНЫХ МОДУЛЯТОРОВ IL-17

Изобретение относится к соединению формулы (I) или его фармацевтически приемлемым солям, которые обладают ингибирующей активностью в отношении IL-17. В формуле (I) R1 выбирают из группы, состоящей из 5-членного гетероарила, который содержит от 2 до 3 гетероатомов, выбранных из N, O и S, 9- или 10-членного бициклического гетероарила, который содержит от 2 до 3 гетероатомов, выбранных из N, O и S, фенила, (C1-C6)алкокси, (C3-C7)циклоалкокси, (C1-C6)алкила, фенил-(C1-C4)алкила, (C3-C7)циклоалкила и -NRcRd, где указанный 5-членный гетероарил, 9- или 10-членный бициклический гетероарил, фенил, (C1-C6)алкокси, (C3-C7)циклоалкокси, (C1-C6)алкил, фенил-(C1-C4)алкил и (C3-C7)циклоалкил необязательно замещен одним или более заместителями, независимо выбранными из Ra; Ra представляет собой галоген, гидрокси, -NRcRd, (C1-C6)алкил, (C3-C7)циклоалкил, фенил, 5- или 6-членный гетероарил, который содержит от 1 до 3 гетероатомов, выбранных из N, O и S, или 4-6-членный гетероциклоалкил, который содержит ...

ИНГИБИТОРЫ НЕПРИЛИЗИНА

Изобретение относится к соединениям, характеризующимся формулой XII, где значения R, R, R, Rи X определены в формуле изобретения, или к их фармацевтически приемлемой соли. Соединение по изобретению обладает ингибирующей активностью в отношении неприлизина (NEP) и предназначено для получения лекарственного средства для лечения гипертензии, сердечной недостаточности или заболевания почек. 7 н. и 21 з.п. ф-лы, 11 пр.

ПРИМЕНЕНИЕ СИГМА ЛИГАНДОВ ПРИ БОЛИ, СВЯЗАННОЙ С ДИАБЕТОМ 2 ТИПА

Изобретение относится к применению сигма лиганда, представляющего собой 4-{2-[5-метил-1-(нафталин-2-ил)-1Н-пиразол-3-илокси]этил}морфолин или его фармацевтически приемлемую соль, для предотвращения и/или лечения боли, ассоциированной с диабетом 2 типа, и связанных с этим симптомов. 4 н. и 2 з.п. ф-лы, 9 ил., 4 пр.

ИНГИБИТОРЫ НЕПРИЛИЗИНА

Изобретение относится к соединению формулы I, где Rпредставляет собой -OR; Rпредставляет собой Н; X выбран из пиразола, триазола, бензотриазола, тетразола, оксазола, изоксазола, тиазола, пиридазина, пиримидина и пиридилтриазола; Rотсутствует или выбран из Н; галогена; -Салкилен-ОН; -Салкила; -Сциклоалкила; -Салкилен-О-Салкила; -C(O)R; -Салкилен-COOR; -С(О)NRR; -NHC(O)R; =O; фенила, необязательно замещенного одной или двумя группами, независимо выбранными из галогена, -ОСН, -NHC(O)CHи фенила; нафталенила; пиридинила; пиразинила; и R, когда он присутствует, соединен с атомом углерода; Rвыбран из Н; -ОН; -Cалкилен-COOR; -пиридинила; и фенила или бензила, необязательно замещенного одной или более группами, выбранными из галогена и -ОСН; и R, когда он присутствует, соединен с атомом углерода или атомом азота; а равен 0; или а равен 1; и Rвыбран из галогена и -CN; b равен 0; или b равен 1, и Rвыбран из Cl, F, -ОН, -СН, -ОСНи -CF; или b равен 2, и Rкаждый независимо выбран из галогена, -ОН, -СН ...

ФАРМАЦЕВТИЧЕСКИЕ КОМБИНАЦИИ ИНГИБИТОРА CDK4/6 И ИНГИБИТОРА В-Raf

Фармацевтическая комбинация, содержащая (а) ингибитор CDK4/6, (b) ингибитор B-Raf и необязательно (c) ингибитор MEK 1/2; их комбинированные композиции и фармацевтические композиции; применение такой комбинации в лечении пролиферативных заболеваний; способы лечения субъектов, страдающих от пролиферативных заболеваний, включая введение терапевтически эффективного количества такой комбинации. 5 н. и 5 з.п. ф-лы, 4 пр., 1 ил.

БЕНЗОПИРАНОВЫЕ И БЕНЗОКСЕПИНОВЫЕ ИНГИБИТОРЫ РI3K И ИХ ПРИМЕНЕНИЕ

Изобретение относится к соединению Формулы I, включая его стереоизомеры, геометрические изомеры, таутомеры или фармацевтически приемлемые соли:где Zпредставляет собой CR; Zпредставляет собой CR; Zпредставляет собой CRили N; Zпредставляет собой CRили N; где (i) Xпредставляет собой N и Хпредставляет собой S или (iv) Хпредставляет собой S и Хпредставляет собой CR; R, R, R, Rи Rнезависимо выбраны из Н, F, Cl, Br, I, -CN, -CHOR, -(C-Cалкилен)NRR, -(C-Cалкилен)NRC(=O)R, -COR, -C(=O)N(R)OR, -NRR, -C(=O)NRR, -C(=O)NR(C-Cалкилен)NRR, -C(=O)NR(C-Cалкилен)NRC(=O)OR, -C(=O)NR(C-Cалкилен)NRC(=O)R, -C(=O)NR(C-Cалкилен)R, -C(=O)NR(C-Cалкилен)R, -C(=NR)NRR, -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -NRC(=O)(C-Cалкилен)NRR, NR(C=O)C-Cалкилен)NR(C=O)R, -C≡CR, C-Cгетероарила, указанный гетероарил представляет собой ненасыщенный карбоциклический остаток, содержащий 5-6 кольцевых атомов, из которых 1-4 кольцевых атома представляют собой азот, и фенила, где гетероарил и фенил возможно имеют в качестве заместителей ...

ГЕТЕРОЦИКЛИЧЕСКИЕ МОДУЛЯТОРЫ СИНТЕЗА ЛИПИДОВ ДЛЯ ПРИМЕНЕНИЯ ПРОТИВ РАКА И ВИРУСНЫХ ИНФЕКЦИЙ

Изобретение относится к соединению, имеющему структуру I, или его фармацевтически приемлемой соли, которые ингибируют синтазу жирных кислот (FASN) и могут найти применение при лечении рака. В формуле I L-Ar представляет собой или ; Ar представляет собой ; R1 представляет собой -CN или -O-(C1-C4 алкил), необязательно замещенный одним или более галогенами; каждый R2 представляет собой водород; R3 представляет собой H или F; R21 представляет собой C1-C4 алкил; R22 представляет собой Н или С1-С2 алкил; R24 представляет собой -O-(C1-C4 алкил), -O-(C1-C4 алкил)-O-(C1-C4 алкил) или -O-(4-6-членный гетероцикл), причем R24 необязательно замещен одним или более гидроксилами или галогенами; и R25 представляет собой C1-C4 алкил. Изобретение относится также к фармацевтической композиции, содержащей указанные соединения, и способу лечения рака, характеризующегося нарушением регуляции пути синтазы жирных кислот. 3 н. и 23 з.п. ф-лы, 2 табл., 2 пр.

Быстрорастворимая фармацевтическая композиция

Группа изобретений относится к химико-фармацевтической промышленности и представляет собой способ получения лекарственного препарата, включающего введение жидкого препарата, содержащего фармацевтически активный ингредиент, леван и инулин в растворителе, в углубления блистерной упаковки, сублимирование растворителя из препарата путем лиофильной сушки с получением твердых единичных лекарственных форм и запечатывание углублений блистерной упаковки герметизирующей пленкой или фольгой, а также лекарственный продукт, полученный вышеуказанным способом, содержащий твердые единичные лекарственные формы в блистерной упаковке, где лекарственная форма содержит открытую матричную сетчатую структуру, несущую фармацевтически активный ингредиент и содержащую леван и инулин. Изобретения позволяют получать лекарственный препарат с высокой скоростью растворения в водной среде или слюне, при этом имея предел прочности на разрыв от 0,05 до 1,6 Н/мм, что позволяет легко извлекать его из упаковки. 2 н. и 18 з.п ...

ПРОИЗВОДНЫЕ ТИЕНО[2,3-C]ПИРАНОВ В КАЧЕСТВЕ CFTR МОДУЛЯТОРОВ

Изобретение относится к соединениям, выбранным из: N-(3-карбамоил-5,5,7,7-тетраметил-5,7-дигидро-4H-тиено[2,3-c]пиран-2-ил)-1H-пиразол-5-карбоксамида и 2-(2-гидроксибензамидо)-5,5,7,7-тетраметил-5,7-дигидро-4H-тиено[2,3-c]пиран-3-карбоксамида, предназначенных для лечения кистозного фиброза или хронического обструктивного заболевания легких (ХОЗЛ). 3 н. и 2 з.п. ф-лы, 21 табл.

НОВЫЕ ЗАМЕЩЕННЫЕ БИАРИЛОВЫЕ СОЕДИНЕНИЯ В КАЧЕСТВЕ ИНГИБИТОРОВ ИНДОЛАМИН-2,3-ДИОКСИГЕНАЗЫ (IDO)

Изобретение относится к соединению формулы (I) или его фармацевтически приемлемой соли, которые обладают ингибирующей активностью по отношению к индоламин-2,3-диоксигеназе (IDO). В указанной формуле n представляет собой 1; p представляет собой 1; в каждом случае A представляет собой -CH=; M представляет собой -O-; R1 представляет собой пиридинил; где пиридинил необязательно замещен 1-3 заместителями, независимо выбранными из: (a) галогена, (b) -C3-8-циклоалкила, необязательно замещенного -OH, (e) -O-C1-8-алкила, необязательно замещенного 1-5 атомами галогена, (f) -O-C3-8-циклоалкила, (g) -C1-8-алкила, необязательно замещенного 1-4 заместителями, независимо выбранными из галогена, -OH, -NH2, (i) -C(O)-Rf, где Rf выбран из -OH, -NH2 и -NH-C1-8-алкила; R2 представляет собой фенил; где фенил необязательно замещен 1-3 заместителями, независимо выбранными из: (a) галогена, (c) -CN, (d) -O-C1-8-алкила, необязательно замещенного 1-3 атомами галогена, и (e) -C1-8-алкила, необязательно замещенного ...

ИЗОИНДОЛИНОНОВЫЕ ИНГИБИТОРЫ ВЗАИМОДЕЙСТВИЯ MDM2-P53, ОБЛАДАЮЩИЕ ПРОТИВОРАКОВОЙ АКТИВНОСТЬЮ

Изобретение относится к соединению формулы (I) или его таутомеру или фармацевтически приемлемой соли, где R1 независимо выбран из галогена, нитрила, С1-4алкила, гидроксиС1-4алкила, С1-4алкокси, С2-4алкинила, -O0,1-(CRxRy)v-CO2H, -S(O)d-C1-6алкила и -S(O)d-гетероциклической группы, содержащей 6 членов кольца, содержащей два гетероатома, выбранных из N и О; R2 выбран из водорода, С1-4алкила, гидроксиС1-4алкила, и -(CRxRy)u-CO2H; s выбран из 0 и 1; R3 представляет собой водород или -(A)t-(CRxRy)q-X; t выбран из 0 и 1; q выбран из 0, 1 и 2; где когда R3 представляет собой -(A)t-(CRxRy)q-X, тогда (i) по меньшей мере один из s, t и q не равен 0 и (ii) когда t равен 0, тогда s равен 1 и q не равен 0; А представляет собой С3-6циклоалкильную группу или гетероциклическую группу, содержащую 4-5 членов кольца, где указанная гетероциклическая группа содержит один или два гетероатома, выбранных из N и О; X выбран из водорода, галогена, -CN, -OR9, -(CH2)v-CO2H, -NHSO2Rx, и -C(=O)NRxRy; R4 и R5 представляют ...

5-ЧЛЕННОЕ ГЕТЕРОЦИКЛИЧЕСКОЕ СОЕДИНЕНИЕ И ЕГО ПРИМЕНЕНИЕ ДЛЯ ЛЕКАРСТВЕННЫХ ЦЕЛЕЙ

... 1. 5-членное гетероциклическое соединение, представленное общей формулой (I) ! ! где Т представляет собой нитро, циано, трифторметил или атом галогена; ! кольцо J представляет собой кольцо арила или кольцо гетероарила; ! Q представляет собой карбокси, низший алкоксикарбонил, карбамоил, моно(ди)(низший алкил)карбамоил, сульфо, сульфамоил или 5-тетразолил; ! Х1 и Х2 независимо представляют собой CR2 или N, при условии, что оба из Х1 и Х2 одновременно не представляют собой N и, когда присутствуют два или более R2, эти R2 необязательно являются одинаковыми или отличными друг от друга; ! R2 представляет собой атом водорода или необязательно замещенный низший алкил; ! Y представляет собой атом водорода, гидрокси, амино, атом галогена, перфтор(низший алкил), необязательно замещенный низший алкил, необязательно замещенный низший алкокси, нитро, (низший алкил)карбониламино или (низший алкил)сульфониламино, при условии, что два или более Y необязательно присутствуют на кольце J, и эти Y необязательно ...

КОМБИНАЦИЯ

НОВЫЕ СОЕДИНЕНИЯ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АМИЛОИДОМ ИЛИ АМИЛОИД-ПОДОБНЫМИ БЕЛКАМИ

... 1. Соединения общей формулы (II) ! , ! в которой независимо представляет собой одинарную или двойную связь; ! p представляет собой 1, 2 или 3; ! каждый линкер К независимо представляет собой C1-3 алкилен, который необязательно замещен одной или несколькими С1-4 алкильными группами; ! каждое В независимо представляет собой 5- или 6-членное насыщенное или ненасыщенное гетероциклическое кольцо, где гетероциклическое кольцо В необязательно замещено одним или несколькими, предпочтительно, одним или двумя заместителями, выбранными из C1-4 алкильной, C1-4 алкокси, моно- и ди-C1-4 алкиламинной, С3-7 циклоалкиламинной и 5- или 6-членной насыщенной гетероциклильной группой, или два заместителя могут быть соединены, образуя насыщенное, ненасыщенное или ароматическое 5- или 7-членное кольцо, конденсированное с гетероциклическим кольцом В, и где гетероциклическое кольцо В может содержать в дополнение к фрагментам V и W один или более предпочтительно один или два гетероатома, выбранных из N, NR, S и ...

КОМБИНИРОВАННОЕ ЛЕЧЕНИЕ ОЖИРЕНИЯ С ПРИВЛЕЧЕНИЕМ ПРОИЗВОДНЫХ 4, 5-ДИГИДРО-1Н-ПИРАЗОЛА, ОБЛАДАЮЩИХ АНТАГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ ПО ОТНОШЕНИЮ К СВ1, И ИНГИБИТОРОВ ЛИПАЗЫ

... 1. Применение соединения, являющегося антагонистом рецептора CB1, предпочтительно производного 4,5-дигидро-1Н-пиразола, которое является активным и селективным антагонистом каннабиноидного рецептора CB1, или его пролекарства, таутомера или соли, в комбинации по меньшей мере с одним ингибирующим липазу соединением для приготовления лекарственных средств, предназначенных для лечения и/или профилактики ожирения, в частности, включая лечение и/или профилактику ожирения у пациентов юношеского возраста и/или вызванного лекарственными препаратами ожирения у пациентов юношеского возраста, а также у пациентов подросткового возраста. 2. Применение по п.1 соединения, являющегося антагонистом рецептора CB1, формулы (I), его пролекарства, его таутомера или его соли в комбинации по меньшей мере с одним ингибирующим липазу соединением при изготовлении лекарственного средства, предназначенного для лечения и/или профилактики ожирения у пациентов подросткового или юношеского возраста и/или для лечения и/ ...

НОВЫЙ ИНГИБИТОР ГЛУТАМИНИЛЦИКЛАЗ И ЕГО ПРИМЕНЕНИЕ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ ЛЕГКИХ И ДЫХАТЕЛЬНЫХ ПУТЕЙ

Группа изобретений относится к химико-фармацевтической промышленности и включает в себя фармацевтические композиции и их применение для модулирования активности глутаминилциклазы, для лечения расстройства, связанного с активностью глутаминилциклазы, а также для предупреждения и/или лечения расстройства, связанного с аберрантной активностью клеток иммунной системы, содержащие терапевтически эффективное количество соединения формулы:или его фармацевтически приемлемой соли, гидрата или сольвата и по меньшей мере одно фармацевтически приемлемое вспомогательное вещество. Группа изобретений позволяет получить эффективный модулятор глутаминилциклазы, характеризующийся высокой ингибирующей активностью и эффективностью в терапии заболеваний, связанных с аберрантной активностью клеток иммунной системы. 7 н. и 20 з.п. ф-лы, 1 ил., 10 табл., 2 пр.

АЛКИНИЛ-ЗАМЕЩЕННОЕ ГЕТЕРОЦИКЛИЧЕСКОЕ СОЕДИНЕНИЕ, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ЕГО ПРИМЕНЕНИЕ В МЕДИЦИНЕ

Изобретение относится к области органической химии, а именно к соединению формулы (II), или его изомеру, или его фармацевтически приемлемой соли:В формуле II: Rпредставляет собой Н или -NHR; Rпредставляет собой Н, C-алкил или 4-6-членный гетероциклил, где алкил и гетероциклил необязательно замещены галогеном, -OR, C-алкилом, Сциклоалкилом или 4-6-членным гетероциклилом; X отсутствует или представляет собой C-алкилен; Y отсутствует или представляет собой Сциклоалкилен или 4-6-членный гетероциклилен; Z представляет собой циано,связь а представляет собой двойную связь или тройную связь; в том случае, если указанная связь а представляет собой двойную связь, каждый R, Rи Rнезависимо представляют собой Н, галоген или C-алкил, где алкил необязательно замещен -ОСалкилом или -N(Cалкилом); в том случае, если указанная связь а представляет собой тройную связь, Rи Rотсутствуют и Rпредставляет собой Н или C-алкил; G, G, Gи G, каждый независимо, выбраны из группы, состоящей из Н, галогена, -ORи -C(O) ...

НОВОЕ ПИРРОЛОПИРИДИНОВОЕ СОЕДИНЕНИЕ, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ЕГО ПРИМЕНЕНИЕ

Изобретение относится к соединению химической формулы I, в которой Rпредставляют собой Cалкил и Rи Rкаждый независимо представляют собой водород. Изобретение также относится к применению соединения. Технический результат: получено новое соединение химической формулы I, которое эффективно при лечении или ингибировании вируса иммунодефицита человека (ВИЧ). 2 н. и 1 з.п. ф-лы, 6 табл., 9 пр.Химическая формула I ...

ТЕРАПЕВТИЧЕСКИЕ СОЕДИНЕНИЯ И КОМПОЗИЦИИ

БЕНЗОИЛАМИНОГЕТЕРОЦИКЛИЛЬНЫЕ СОЕДИНЕНИЯ, ПОЛЕЗНЫЕ В ЛЕЧЕНИИ ЗАБОЛЕВАНИЯ, ОПОСРЕДОВАННОГО ЧЕРЕЗ ГЛЮКОКИНАЗУ (GLK)

... 1. Соединение формулы (I): ! , ! где R1 выбран из С1-4алкила и С3-6циклоалкила; ! НЕТ-1 представляет собой 5- или 6-членное С-связанное гетероарильное кольцо, содержащее атом азота в положении 2 относительно амидного азота, к которому это кольцо присоединено, и возможно 1 или 2 дополнительных кольцевых гетероатома, независимо выбранных из О, N и S; где это кольцо возможно замещено по любому атому азота (при условии, что он при этом не является четвертичным) заместителем, выбранным из R7, и/или по 1 или 2 доступным атомам углерода заместителем, независимо выбранным из R6; ! кольцо А выбрано из фенила, НЕТ-2 и НЕТ-3; в случае, когда кольцо А является фенилом, оно замещено R2 и возможно дополнительно замещено группой, выбранной из R3; ! R2 выбран из -C(O)NR4R5, SOpR4 и -SO2NR4R5; ! R3 выбран из галогено, метила и трифторметила; ! R4 выбран из водорода, С1-4алкила [возможно замещенного 1 или 2 заместителями, независимо выбранными из НЕТ-5, -OR5, -SO2R5, С3-6циклоалкила (возможно замещенного ...

СПОСОБ ПРИМЕНЕНИЯ СОЕДИНЕНИЙ, ИНГИБИРУЮЩИХ КАЛИЕВЫЕ КАНАЛЫ

... 1. Способ лечения, профилактики или подавления ожирения, сахарного диабета, прежде всего, диабета тучных типа I, диабета тучных типа II, диабета у нетучных больных типа I, диабета у нетучных больных типа II, и/или связанные с диабетом заболевания, такие как, метаболизм глюкозы - прежде всего, резистентность к инсулину, гипергликемия и/или непереносимость глюкозы - метаболического синдрома, синдрома X, инсулиномы, семейной гиперинсулинемии, гипогликемии, облысения мужского типа, гиперреактивности мышцы-сжимателя, астмы, метаболизма глюкозы - прежде всего, резистентности к инсулину, гипергликемии и/или непереносимости глюкозы - осуществления нейропротекции, эпилепсии, аналгезии, осуществления кардиопротективного действия, стенокардии, кардиоплегии, аритмии, коронарного спазма, заболевания периферических сосудов, церебрального спазма сосудов, регуляции аппетита, нейродегенерации, боли - включая нейропатическую и хроническую боль - и импотенции, при введении эффективного количества по крайней ...

ГРИЗЕОФУЛЬВИНОВОЕ СОЕДИНЕНИЕ

ХИНАЗОЛИНОН, ХИНОЛОН И РОДСТВЕННЫЕ АНАЛОГИ В КАЧЕСТВЕ МОДУЛЯТОРОВ СИРТУТУИНА

... 1. Соединение, имеющее структуру, описываемую структурной формулой (II): ! ! или его соль, где ! каждый из Z1, Z2 и Z3 независимо выбирают из N и C(R9), где ! не более чем один из Z1, Z2 и Z3 является N; ! каждый R9 независимо выбирают из водорода, галогена, -C≡N, фторзамещенного C1-C2 алкила, -O-(C1-C2) фторзамещенного алкила, -S-(C1-C2) фторзамещенного алкила, C1-C4 алкила, -S-(C1-C4) алкила, C3-C7 циклоалкила, -(C1-C2) алкил-N(R13)(R13), -O-CH2CH(OH)CH2OH, -O-(C1-C3) алкил-N(R13)(R13) и -N(R13)(R13); и ! представляет вторую химическую связь между либо W2 и C(R12), либо W1 и C(R12); ! W1 выбирают из -O-, -NH- или -N=, и ! W2(R14) выбирают из -N(R14)- и -C(R14)=, выбирая так, что ! когда W1 является -O-, один из Z1, Z2 и Z3 является N; ! когда W1 является -O- или -NH-, W2(R14) является -C(R14)= и представляет вторую химическую связь между W2 и C(R12); и ! когда W1 является -N=, W2(R14) является -N(R14)- и представляет вторую химическую связь между W1 и C(R12); ! R11 выбирают из карбоцикла ...

БЕНЗОПИРАНОВЫЕ И БЕНОКСЕПИНОВЫЕ ИНГИБИТОРЫ РI3K И ИХ ПРИМЕНЕНИЕ

... 1. Соединение, выбранное из соединений формулы I: ! ! Z1 представляет собой CR1 или N; ! Z2 представляет собой CR2 или N; ! Z3 представляет собой CR3 или N; ! Z4 представляет собой CR4 или N; ! где (i) X1 представляет собой N и X2 представляет собой S, (ii) X1 представляет собой S и X2 представляет собой N, (iii) X1 представляет собой CR7 и X2 представляет собой S или (iv) X1 представляет собой S и X2 представляет собой CR7; ! R1, R2, R3, R4 и R7 независимо выбраны из Н, F, Cl, Br, I, -CN, -СF3, -CH2OR10, -CH2R10, -(C1-C12 алкилен)NR10R11, -(C1-C12 алкилен)NR12C(=O)R10, -(C1-C12 алкилен)C(=O)NR10, -(C1-C12 алкилен)OR10, -CO2R10, C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, C(=O)NR10R11, -С(=O)NR10(С1-С12 алкилен)NR10R11, -C(=O)NR10(C1-C12 алкилен)NR10C(=O)OR11, -C(=O)NR10(C1-C12 алкилен)R11, -C(=O)NR10(C1-C12 алкилен)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12C(=O)(C1-C12 алкилен)NR10R11, -NR12(C1-C12 алкилен)NR10R11, -NR12(C1-C12 алкилен)OR10, - ...

ИНГИБИРОВАНИЕ IL17 И IFN-ГАММА ДЛЯ ЛЕЧЕНИЯ АУТОИММУННОГО ВОСПАЛЕНИЯ

... 1. Соединение общей формулы (I)и его фармацевтически приемлемые соли или сольваты, гдеRозначает арил, гетероарил, циклоалкил, гетероциклил или алкил, который может быть замещен одним или несколькими заместителями R′;Ar означает арил, циклоалкил, гетероциклил или гетероарил, который может быть замещен одним или несколькими заместителями R′;Z означает арил, гетероарил, циклоалкил или гетероциклил, который может быть замещен одним или несколькими заместителями R′;Y означает H, галоген, галогеналкил, алкил или сложный алкиловый эфир, который может быть замещен одним или несколькими заместителями R′;R′ независимо означает H, -COR′′, -CONHR′′, -CR′′O, -SON(R′′), -SONHR′′, -NR′′-CO-галогеналкил, -NO, -NR′′-SO-галогеналкил, -NR′′-SO-алкил, -SO-алкил, -NR′′-CO-алкил, -CN, алкил, циклоалкил, аминоалкил, алкиламино, алкокси, -OH, -SH, алкилтио, гидроксиалкил, гидроксиалкиламино, галоген, галогеналкил, галогеналкокси, амино, гетероциклил, арил, галогенарил, галогенарилалкил, арилалкил или гетероарил ...

C0ЕДИНЕНИЕ ИНДОЛА

1-((3S,4R)-4-(3-ФТОРФЕНИЛ)-1-(2-МЕТОКСИЭТИЛ)ПИРРОЛИДИН-3-ИЛ)-3-(4-МЕТИЛ-3-(2-МЕТИЛПИРИМИДИН-5-ИЛ)-1-ФЕНИЛ-1Н-ПИРАЗОЛ-5-ИЛ)МОЧЕВИНА В КАЧЕСТВЕ ИНГИБИТОРА TRKA КИНАЗЫ

АМИДНОЕ ПРОИЗВОДНОЕ ПИРОЗОЛА

СНИЖЕНИЕ СИСТЕМНОГО УРОВНЯ РЕГУЛЯТОРНЫХ Т-КЛЕТОК ИЛИ ИХ АКТИВНОСТИ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ И ТРАМВ ЦНС

ФАРМАЦЕВТИЧЕСКОЕ СОЕДИНЕНИЕ

СОЛИ 4-[2-[[5-МЕТИЛ-1-(2-НАФТАЛИНИЛ)-1Н-ПИРАЗОЛ-3-ИЛ]ОКСИ]ЭТИЛ]МОРФОЛИНА

... 1. Соль 4-[2-[[5-метил-1-(2-нафталинил)-1H-пиразол-3-ил]окси]этил]морфолина, выбранная из этансульфоната, фумарата, гидрохлорида, малата, малеата, малоната и метансульфоната.2. Соль 4-[2-[[5-метил-1-(2-нафталинил)-1H-пиразол-3-ил]окси]этил]морфолина по п.1, где указанная соль представляет собой гидрохлоридную соль 4-[2-[[5-метил-1-(2-нафталинил)-1H-пиразол-3-ил]окси]этил]морфолина.3. Способ получения гидрохлоридной соли по п.2, включающий:a) смешивание 4-[2-[[5-метил-1-(2-нафталинил)-1H-пиразол-3-ил]окси]этил]морфолина и раствора, содержащего хлористоводородную кислоту, иb) выделение полученной гидрохлоридной соли.4. Фармацевтическая композиция, включающая гидрохлоридную соль по п.2.5. Гидрохлоридная соль по п.2 для использования в качестве лекарственного средства.6. Гидрохлоридная соль по п.2, предназначенная для лечения и/или профилактики заболевания или состояния, опосредованного рецептором сигма.7. Гидрохлоридная соль по п.2, предназначенная для лечения и/или профилактики заболевания ...

ИНГИБИТОРЫ ВАСЕ ДЛЯ ПРИМЕНЕНИЯ В ЛЕЧЕНИИ ДИАБЕТА

... 1. Соединение формулы I,,гдеRвыбран из группы, состоящей изi) арила иii) гетероарила,Rвыбран из группы, состоящей изi) H,ii) C-алкила иiii) -N(R,R);Rвыбран из группы, состоящей изi) H иii) C-алкила,Rвыбран из группы, состоящей изi) -CH-арила иii) -CH-гетероарила;или Rи Rвместе с азотом, к которому они присоединены, образуют пятичленный гетероциклил, возможно замещенный Z, или 3-аза-бицикло[3.2.1]октан-3-ил, возможно замещенный C-алкилом;Rвыбран из группы, состоящей изi) H иii) C-алкила;Rпредставляет собой -SO-C-алкил;n представляет собой 0, 1 или 2;m представляет собой 0, 1 или 2;А независимо выбран из группы, состоящей изi) ацетамидила,ii) ацетила,iii) амидо,iv) амино,v) C-алкокси,vi) C-алкила,vii) карбокси,viii) циано,ix) галогена,x) галоген-C-алкокси,xi) галоген-C-алкила,xii) гидрокси,xiii) -N(C-алкил, C-алкил) иxiv) -N(H, C-алкил),xv) -SO-C-алкила, представляет собой C-алкил;Z независимо выбран из группы, состоящей изi) арила, возможно замещенного 1 или 2 заместителями, независимо выбранными ...

ДВУЗАМЕЩЕННЫЕ МЕТАНОНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ 11 (ВЕТА)-HSD1

... 1. Соединение следующей формулы или его фармацевтически приемлемая соль, гидрат или сольват:при этом:либо -Jи -Jвзятые совместно, образуют -СНСН- или -СН-;либо -Jпредставляет собой -Н и -Jпредставляет собой -Н;-Q представляет собой Cгетероарил и имеет n заместителей -R;n независимо равен 0,1, 2 или 3;каждый -Rнезависимо представляет собой -R, -F, -Cl, -CF, -ОН, -OR, -OCF, -CN, -NH, -NHR, -NR , ацетидино, пирролидино, пиперидипо, пиперазино, морфолино или ацепино;при этом каждый -Rнезависимо представляет собой насыщенный алифатический Cалкил или насыщенный Сциклоалкил и возможно замещен одним или более заместителями, выбранными из -F, -ОН, -OR, -OCHF, -OCHF, и -OCF;при этом каждый -Rпредставляет собой насыщенный алифатический Салкил; ипри этом каждый ацетидино, пирролидино, пиперидино, пиперазино, морфолино и ацепино возможно замещен одним или более насыщенным алифатическим Салкилом;-Y независимо представляет собой -Y, -Y, -Y, -Y, -Y, -Yили -Y;-Yпредставляет собой -ОН;-Yнезависимо представляет ...

ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, СОДЕРЖАЩИЕ ПРОПЕНОНОВЫЕ ПРОИЗВОДНЫЕ

... 1. Антиретровирусная композиция, содержащая в качестве действующих веществ соединение, представленное формулой (I): А-С(=O)-СН=С(ОН)-В, где А обозначает необязательно замещенный гетероарил; В обозначает необязательно замещенный гетероарил или необязательно замещенный арил; при условии, что исключаются варианты, когда А и/или В обозначают необязательно замещенный индол-3-ил; его таутомер, пролекарство, фармацевтически приемлемую соль или сольват и одно или несколько антиретровирусных действующих веществ другого типа. 2. Антиретровирусная композиция по п.1, где антиретровирусное действующее вещество в сочетании с соединением, представленным формулой (I), его таутомером, пролекарством, фармацевтически приемлемой солью или сольватом обладает синергетическим действием. 3. Антиретровирусная композиция по п.1 или 2, где антиретровирусное действующее вещество не является ингибитором интегразы. 4. Антиретровирусная композиция по любому из пп.1-3, где антиретровирусное действующее вещество представляет ...

СОЕДИНЕНИЯ N-ПИРРОЛИДИНИЛМОЧЕВИНЫ, N'-ПИРАЗОЛИЛМОЧЕВИНЫ, ТИОМОЧЕВИНЫ, ГУАНИДИНА И ЦИАНОГУАНИДИНА КАК ИНГИБИТОРЫ КИНАЗЫ TRKA

НОВОЕ ПРОИЗВОДНОЕ БЕНЗОАЗЕПИНА И ЕГО МЕДИЦИНСКОЕ ПРИМЕНЕНИЕ

ИНГИБИТОР HDAC В КОМБИНАЦИИ С МОДУЛЯТОРОМ ИММУННОЙ КОНТРОЛЬНОЙ ТОЧКИ ДЛЯ ТЕРАПИИ РАКА

КОМБИНАЦИЯ, СОДЕРЖАЩАЯ ИНГИБИТОР BTK И ИНГИБИТОР AKT

ПРИМЕНЕНИЕ ПРОИЗВОДНЫХ 4,5-ДИГИДРО-1Н-ПИРАЗОЛОВ ВКАЧЕСТВЕ АНТАГОНИСТОВ СВ1

... 1. Применение соединения формулы (I), обладающего антагонистической активностью в отношении рецептора CB1, его пролекарств, таутомеров и солей при получении лекарственных средств, предназначенных для лечения и/или профилактики заболеваний, связанных с рецептором CB1, у пациентов подросткового возраста и/или для лечения и/или профилактики ожирения, вызванного приемом лекарственных препаратов, у пациентов подросткового и юношеского возраста: , где R и R1 являются одинаковыми или различными и означают фенил, тиенил или пиридил, причем указанные группы могут быть замещены 1, 2 или 3 одинаковыми или различными заместителями Y, которые выбирают из группы, включающей С1-С3алкил или алкокси, гидрокси, галоген, трифторметил, трифторметилтио, трифторметокси, нитро, амино, моно- или диалкил(С1-С2)амино, моно- или диалкил(С1-С2)амидо, C1-С3алкилсульфонил, диметилсульфамидо, С1-С3алкоксикарбонил, карбоксил, трифторметилсульфонил, циано, карбамоил, сульфамоил и ацетил, или R и/или R1 означают нафтил; ...

СОЕДИНЕНИЕ ГРИЗЕОФУЛЬВИНА И ЕГО ФАРМАЦЕВТИЧЕСКОЕ ПРИМЕНЕНИЕ

ПОТЕНЦИАТОРЫ РЕЦЕПТОРОВ AMPA

СОЕДИНЕНИЯ ПИРРОЛИДИНИЛМОЧЕВИНЫ И ПИРРОЛИДИНИЛТИОМОЧЕВИНЫ КАК ИНГИБИТОРЫ КИНАЗЫ TRKA

... 1. Соединение Формулы I:или его стереоизомеры, таутомеры или фармацевтически приемлемые соли, сольваты или пролекарства, где:фрагмент Y-B и фрагмент NH-C(=X)-NH находятся в транс-конфигурации;R, R, Rи Rнезависимо выбраны из Н и (1-3С)алкила;X представляет собой О, S или NH;Rпредставляет собой (1-3С алкокси)(1-6С)алкил, (трифторметокси)(1-6С)алкил, (1-3С сульфанил)(1-6С)алкил, монофтор(1-6С)алкил, дифтор(1-6С)алкил, трифтор(1-6С)алкил, тетрафтор(2-6С)алкил, пентафтор(2-6С)алкил, циано(1-6С)алкил, аминокарбонил(1-6С)алкил, гидрокси(1-6С)алкил, дигидрокси(2-6С)алкил, (1-6С)алкил, (1-3С алкиламино)(1-3С)алкил, (1-4С алкоксикарбонил)(1-6С)алкил, амино(1-6С)алкил, гидрокси(1-3С алкокси)(1-6С)алкил, ди(1-3С алкокси)(1-6С)алкил, (1-3С алкокси)трифтор(1-6С)алкил, гидрокситрифтор(1-6С)алкил, (1-4С алкоксикарбонил)(1-3С алкокси)(1-6С)алкил, гидроксикарбонил(1-3С алкокси)(1-6С)алкил, гетAr(СН)или Ar(СН);Rпредставляет собой Н, F или ОН;Y представляет собой связь, -O- или -ОСН-;В представляет собой Ar ...

Verwendung von substituierten -Lactonverbindungen als Arzneimittel

Die vorliegende Erfindung betrifft die Verwendung von substituierten gamma-Lactonverbindungen zur Herstellung von Arzneimitteln zur Behandlung von Migräne, septischem Schock, neurodegenerativer Krankheiten, wie Multipler Sklerose, Morbus Parkinson, Morbus Alzheimer oder Morbus Huntington, Entzündungen, Entzündungsschmerz, cerebraler Ischämie, Diabetes, Meningitis, Arteriosklerose, Krebserkrankungen, Pilzerkrankungen oder zur Wundheilung.

Novel compounds, methods for their manufacture, and uses thereof

Synthetic cannabinoid analogue compounds of formula (I), wherein X is a group as defined herein. Also provided is a pharmaceutical composition of compounds of formula (I). Also provided is a compound of formula (I), or pharmaceutical composition, for use in a method of treatment, or for use as a medicament; which may be for use in the treatment of, or for use as a medicament for treating, epilepsy, generalised seizure, tonic-clonic seizure. Also provided is a method of preparing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III), both defined herein. The method may use a palladium catalyst. Also provided is a method of preparing compounds of formula (I), comprising reacting a compound of formula (II) with bis(pinacolato)diboron (B2pin2), and reacting the product of that with a compound of formula (IV). The steps of the method may use a palladium catalyst. Also provided is an intermediate compound of formula (II), for use in the preparation ...

Matrix metallproteinase inhibitors

COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS

Heterocyclic compounds suitable for the treatment of dyslipidemia

INDANE AND INDOLINE DERIVATIVES AND THE USE THEREOF AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS

ETHER COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS

Matrix metalloproteinase inhibitors

Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same

Pyrazole compounds as CRTH2 antagonists

Method of using cyclooxygenase-2 inhibitors in the prevention of cardiovascular disorders.

The invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing cardiovascular disorders ...

Pyrazoline compounds as mineralocorticoid receptorantagonists

Medicinal compositions containing propenone derivatives.

A combination of an integrase inhibitor with an anti-retrovirus active substance and medicinal compositions containing the same as the active ingredients.

Pyrazole derivatives.

This invention relates to the use of pyrazole derivatives of the formula and pharmaceutically acceptable salts and solvates thereof, in the manufacture of a reverse transcriptase inhibitor or modulator, to certain novel such pyrazole derivatives and to processes for the preparation of and compositions containing such novel derivatives.

Dipeptidyl peptidase-IV inhibitors

Pyrazoline compounds as mineralocorticoid receptorantagonists

3(5)-Amino-pyrazole derivatives, process for their preparation and their preparation and their use as antitumor agents.

Compounds which are 3-amino pyrazole derivatives represented by formula (i)wherein r is c3-c6 cycloalkyl group optionally substituted by a straight or branched c1-c6 alkyl or arylalkyl group; r1 is a straight or branched c1-c6 alkyl, c2-c4 alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, arylalkyl, arylcarbonyl, aryloxyalkyl or arylalkenyl group, each of which may be optionally further substituted as indicated in the description; or a pharmaceutically acceptable salt thereof. The compounds are useful for the treatment of cancer, cell proliferative disorders, alzheimer's disease, viral infections, auto-immune diseases or neurodegenerative diseases.

Pyrazole analogs

Matrix metallproteinase inhibitors

Novel macrocyclic inhibitors of hepatitis c virus replication

Pyrazole compounds as CRTH2 antagonists

Glucagon receptor modulator

PHOSPHONATE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

CARBOXAMIDE DERIVATIVES

Indole and indazole compounds that activate AMPK

Substituted 2-aza-bicyclo[2.2.1] heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C

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

AMIDE COMPOUNDS FOR TREATMENT OF COMPLEMENT MEDIATED DISORDERS

New indanyloxydihydrobenzofuranylacetic acid derivatives and their use as GPR40 receptor agonists

Heterocyclic compounds suitable for the treatment of dyslipidemia

Pyrazole compounds as CRTH2 antagonists.

Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same.

Heteroaryls amide derivatives and their use as glucokinase activators.

Pyrazole compounds as CRTH2 antagonists

Glucagon receptor modulator

Novel compounds for the treatment of dyslipidemia and related diseases

Method of using cyclooxygenase-2 inhibitors in theprevention of cardiovascular disorders

3(5)-Amino-pyrazole derivatives, process for theirpreparation and their use as antitumor agents.

Pyrazole compounds as CRTH2 antagonists.

Novel compounds for the treatment of dyslipidemia and related diseases

3(5)-Amino-pyrazole derivatives process for their preparation and their use as antitumor agents

Medicinal compositions containing propenone derivatives

Substituted 2-aza-bicyclo[2.2.1] heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C

Matrix metallproteinase inhibitors

CARBOXAMIDE DERIVATIVES

Pyrazole derivatives

Novel compounds for the treatment of dyslipidemia and related diseases

Heterocyclic compounds suitable for the treatment of dyslipidemia

Pyrazole derivatives

New indanyloxydihydrobenzofuranylacetic acid derivatives and their use as GPR40 receptor agonists

Pyrazole compounds as crth2 antagonists

The present invention relates to pyrazole compounds of formula (I) and pharmaceutically acceptable salts thereof having CRTH2-activity, wherein W, L 1 , L 2 , X, L 3 , Y, R 1 and R 2 are as defined in the specification and claims, to their use as medicaments and to pharmaceutical formulations, containing said compounds or containing a combination of said compounds with one or more active substances.

Nitrogen-containing aromatic heterocyclyl compound

The present invention provides a compound having excellent regulating action on blood lipid level that is represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein, in one embodiment, A represents a 5-membered nitrogen-containing aromatic heterocyclyl group; R 1 represents COOH; each R 2 represents an alkyl; each R 3 represents an optionally substituted phenyl, an optionally substituted phenylalkyl; m represents 0, 1, 2, or 3; n represents 0 or 1; each of R 4 , R 5 , R 6 , and R 7 represents H, an alkyl; and B represents an optionally substituted naphthyl, an optionally substituted aromatic heterocyclyl, or a group represented by the following formula (II) wherein each of B 1 and B 2 represents an optionally substituted phenyl or an optionally substituted aromatic heterocyclyl.

Integrin-linked kinase inhibitors

A number of compounds and use of the compounds in a method for treating or preventing cancer in a subject by administering to the subject a pharmaceutical composition including a compound of formula I or a pharmaceutically acceptable salt thereof are described. The compounds can also be used to inhibit integrin-linked kinase in a cell, which has an effect on the Akt signaling pathway.

Inhibition of p38 kinase activity using substituted heterocyclic ureas

This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases, other than cancer and proteolytic enzyme mediated diseases, other than cancer, and pharmaceutical compositions for use in such therapy.

Combination

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof, and combinations thereof with other anti-cancer agents, for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3.

Heterocyclyl pyrazolopyrimidine analogues as jak inhibitors

The invention relates to compounds of formula (I) wherein X 1 to X 5 , Y, Z 1 to Z 3 , and R have the meaning as cited in the description and the claims. Said compounds are useful as JAK inhibitors for the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders, and immunologically-mediated diseases. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.

Pyrazole derivatives as protein kinase modulators

The invention provides compounds of the formula (I) having protein kinase B inhibiting activity: Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

Therapeutic agent and preventative agent for alzheimer's disease

A therapeutic agent or prophylactic agent for Alzheimer's disease has an effect to inhibit or delay the progress of Alzheimer's disease and exhibits a long-lasting therapeutic effect on Alzheimer's disease even when used for a long period of time. The therapeutic agent or prophylactic agent for Alzheimer's disease includes as an effective ingredient a cyclohexane derivative exemplified by the formula below, or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Combination

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, or a pharmaceutically acceptable hydrate and/or salt thereof, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

THROMBOPOIETIN MIMETICS

Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative. 150-. (canceled)52. The method of wherein Q is —COOH claim 51 , which is the compound 3′-{N′-[1-(3 claim 51 ,4-Dimethylphenyl)-3-methyl-5-oxo-1 claim 51 ,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof.53. The method of wherein Q is tetrazol-5-yl claim 51 , which is the compound 3-{N′-[1-(3 claim 51 ,4-dimethylphenyl)-3-methyl-5-oxo-1 claim 51 ,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl or a pharmaceutically acceptable salt thereof.54. The method of wherein the compound is administered orally.55. The method of wherein the compound is administered parenterally.56. The method of further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor claim 51 , cytokine claim 51 , chemokine and an interleukin or cytokine receptor agonist or antagonist.57. The method of wherein the agent is selected from the group consisting of: G-CSF claim 56 , GM-CSF claim 56 , TPO claim 56 , M-CSF claim 56 , EPO claim 56 , Gro-beta claim 56 , IL-11 claim 56 , SCF claim 56 , FLT3 ligand claim 56 , LIF claim 56 , IL-3 claim 56 , IL-6 claim 56 , IL-1 claim 56 , NESP claim 56 , SD-01 claim 56 , IL-8 and IL-5.59. The method of wherein Q is —COOH claim 58 , which is the compound 3′-{N′-[1-(3 claim 58 ,4-Dimethylphenyl)-3-methyl-5-oxo-1 claim 58 ,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof.60. The method of wherein Q is tetrazol-5-yl claim 58 , which is the compound 3-{N′-[1-( ...

IRE-1alpha INHIBITORS

Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts there-of. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response or with regulated IRE1-dependent decay (RIDD) and can be used as single agents or in combination therapies. 114-. (canceled)16. A product comprising a compound of , wherein the product is selected from the group consisting of (a) a pharmaceutical composition comprising the compound of and a pharmaceutically acceptable vehicle; and (b) a complex comprising IRE-1α and the compound of .17. A method of inhibiting IRE-1α activity claim 15 , comprising contacting IRE-1α with a compound of or a prodrug or pharmaceutically acceptable salt thereof.18. The method of wherein the IRE-1α activity is selected from the group consisting of cleavage of RNA claim 17 , cleavage of mRNA claim 17 , RNA splicing claim 17 , and mRNA splicing.19. The method of wherein the IRE-1α activity is cleavage of mRNA and wherein the mRNA is selected from the group consisting of Blos1 mRNA claim 18 , DGAT2 mRNA claim 18 , CD59 mRNA claim 18 , and IRE-1α mRNA.20. The method of claim 18 , wherein the IRE-1α activity is inhibited to treat a disorder associated with the unfolded protein response claim 18 , comprising administering to a patient in need thereof the compound of or the prodrug or pharmaceutically acceptable salt thereof.21. The method of further comprising administering a therapeutic agent that induces or up-regulates IRE-1α expression.2202. The method of claim further comprising administering a therapeutic agent which is less effective when IRE-1α is expressed.23. The method of claim 20 , further comprising administering to the patient a proteasome inhibitor.24. The method of claim 20 , wherein the IRE-1α activity is inhibited to treat a disorder associated with a target of regulated IRE 1-dependent decay (RIDD) claim 20 , comprising administering to a patient in need ...

BENZOPYRAN AND BENZOXEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Benzopyran and benzoxepin compounds of Formulas I and II, and including stereoisomers, geometric isomers, tautomer solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formulas I and II for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. 2. The method of wherein Xis N and Xis S.3. The method of wherein Xis S and Xis CR.6. The method of wherein the compound of formula I is selected from:N2-(2-chlorophenyl)-N2,N8,N8-trimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide;7-acetamido-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N2-(2-chlorophenyl)-N8-(3-(diethylamino)propyl)-N2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide;N-(2-chlorophenyl)-7-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-chlorophenyl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-chloro-4-fluorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2,4-dichlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;2-(4-isopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamide;1-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-3-methylurea;methyl 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-ylcarbamate;7-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide;N-(4-(3-amino-5-methyl-1H-pyrazole-1-carbonyl)-2-chlorophenyl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d] ...

3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-methanones as inhibitors of 11 (beta)-hsd1

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, 3,3-disubstituted-(6-aza-bicyclo[3.1.1]hept-6-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, and 4,4-disubstituted piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds of the following formula that, inter alia, inhibit 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11β-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11β-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.

Methods for Treating Degenerative Diseases/Injuries

Invented is a method of treating degenerative diseases/injuries, in a mammal, including a human, in need thereof which comprises the administration of a therapeutically effective amount of a non-peptide TPO receptor agonist to such mammal. 1. An in vitro or ex vivo method of enhancing the differentiation of blood components in human fetal cord blood into functional cells which method comprises the addition of an effective amount of a non-peptide TPO receptor agonist selected from:3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid,or a pharmaceutically acceptable salt thereof, and3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl,or a pharmaceutically acceptable salt thereof;to a culture medium containing human fetal cord blood;followed by optional isolation of the functional cells.2. The method of wherein progenitor cells are enhanced.3. A method of transfusing human fetal cord blood which method comprises the addition of an effective amount of a non-peptide TPO receptor agonist selected from:3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid,or a pharmaceutically acceptable salt thereof, and3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl,or a pharmaceutically acceptable salt thereof;to a patient receiving human fetal cord blood. This application is a Continuation of U.S. application Ser. No. 12/496,867 which was filed on Jul. 2, 2009, which is a Continuation-in-Part of U.S. application Ser. No. 12/474,560, filed on May 29, 2009, which is a Continuation-in-Part of U.S. application Ser. No. 10/554,811, filed on Nov. 10, 2006, which is a 371 of International Application No. PCT/US2004/013468 filed Apr. 29, 2004, which claims the benefit of U.S. Provisional Application Nos. 60/556,390 ...

USE OF HISTONE ACETYLTRANSFERASE INHIBITORS AS NOVEL ANTI-CANCER THERAPIES

The present invention provides methods for treating cancer comprising inhibiting the activity of p300/CBP histone acetyltransferase (HAT). Also provided are p300/CBP HAT inhibitors for treating a subject having cancer. In addition, the present invention includes biomarkers for p300/CBP HAT inhibition, which are used to i) monitor the effectiveness of cancer therapy, and ii) identify anti-cancer agents for use in combination therapy. 2. The method of claim 1 , wherein the p300/CBP HAT inhibitor is a p300-selective inhibitor.35.-. (canceled)6. The method of claim 1 , wherein the method further comprises administering radiation therapy or at least one additional anti-cancer agent.7. The method of claim 6 , wherein the anti-cancer agent is a DNA damaging chemotherapeutic agent.8. The method of claim 7 , wherein the DNA damaging chemotherapeutic agent is cisplatin or temozolamide.9. The method of claim 1 , wherein the cancer is leukemia claim 1 , brain cancer claim 1 , lung cancer claim 1 , central nervous system (CNS) cancer claim 1 , melanoma claim 1 , renal cancer claim 1 , prostate cancer claim 1 , colon cancer claim 1 , ovarian cancer claim 1 , or breast cancer.1011.-. (canceled)1316.-. (canceled)1716. The method of claim claim 1 , wherein the method further comprises exposing the cell to radiation therapy or contacting the cell with at least one additional anti-cancer agent.18. The method of claim 17 , wherein the anti-cancer agent is a DNA damaging chemotherapeutic agent.19. The method of claim 18 , wherein the DNA damaging chemotherapeutic agent is cisplatin or temozolamide.20. The method of claim 19 , wherein the neoplastic cell is from a leukemia claim 19 , brain cancer claim 19 , lung cancer claim 19 , CNS cancer claim 19 , melanoma claim 19 , renal cancer claim 19 , prostate cancer claim 19 , colon cancer claim 19 , ovarian cancer claim 19 , or breast cancer.21. (canceled)22. The method of claim 17 , wherein the method is carried out in vitro or in vivo.2427 ...

Stem cell differentiating agents and uses therefor

The present invention relates to screens for compounds that can induce stem cell differentiation. In addition, isoxazoles and sulfonyl hydrazones are identified as general classes of compounds that can induce differentiation of stem cells into cells of neuronal and cardiac fate, respectively.

3-(Fluorovinyl)pyrazoles and their use

The present application relates to novel 3-(fluorovinyl)pyrazole derivatives, to processes for their preparation, to their use for treatment and/or prevention of diseases and to their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be carried out as monotherapy or also in combination with other medicaments or further therapeutic measures. 6. (canceled)7. (canceled)8. (canceled)9. (canceled)10. (canceled)11. A pharmaceutical composition comprising a compound as defined in in combination with one or more inert claim 1 , non-toxic claim 1 , pharmaceutically suitable auxiliary substances.12. A pharmaceutical composition comprising a compound as defined in in combination with one or more other active compounds.13. (canceled)14. (canceled)15. A method for the treatment and/or prevention of a cancer disease or tumour disease comprising administering to a human or animal in need thereof an effective amount of at least one compound as defined in .16. A method for the treatment and/or prevention of ischaemic cardiovascular diseases claim 1 , cardiac insufficiency claim 1 , cardiac infarction claim 1 , arrhythmia claim 1 , stroke claim 1 , pulmonary hypertension claim 1 , fibrotic diseases of the kidney and lung claim 1 , psoriasis claim 1 , diabetic retinopathy claim 1 , macular degeneration claim 1 , rheumatic arthritis claim 1 , or Chugwash polycythaemia comprising administering to a human or animal in need thereof an effective amount of at least one compound as defined in . The present application relates to novel 3-(fluorovinyl)pyrazole derivatives, to processes for their preparation, to their use for treatment and/or prevention of diseases and to their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular ...

Autotaxin inhibitors and uses thereof

Described herein are compounds that are inhibitors of autotaxin. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such inhibitors, alone and in combination with other compounds, for treating autotaxin-dependent or autotaxin-mediated conditions or diseases.

SUBSTITUTED N- [1-CYANO-2- (PHENYL) ETHYL] -2-AZABICYCLO [2.2.1] HEPTANE-3-CARBOXAMIDE INHIBITORS OF CATHEPSIN C

Disclosed are N-1-cyano-2-(phenyl)ethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamides of formula I 2. The compound according to whereinn is 0, 1, 2, 3 or 4;{'sup': '1', 'sub': '2', 'is Ris Me-, F—, HO—, MeO—, HN;'}{'sup': '2', 'sub': 1-6', '2-6', '3-6', '3-6, 'claim-text': [{'sub': '5-7', 'sup': '2.1', 'a monocyclic C-heterocyclyl-, wherein one or two carbon atoms are replaced by heteroatoms selected from —O— or —N— and the ring is fully or partially saturated, optionally substituted independently from each other with one, two, three or four R;'}, {'sub': '8-10', 'sup': '2.1', 'a bicyclic C-heterocyclyl-, wherein one, two, three or four carbon atoms are replaced by heteroatoms selected from —S—, —O— or —N— and the ring is fully or partially saturated, optionally substituted independently from each other with one, two, three or four R;'}, {'sub': '5-10', 'sup': '2.1', 'a C-heteroaryl-, wherein one, two or three carbon atoms are replaced by heteroatoms selected from —O— or —N— and the ring is aromatic, optionally substituted independently from each other with one, two, three or four R;'}, {'sup': '2.1', 'aryl-, optionally substituted independently from each other with one, two, three or four R;'}, {'sup': '2.1', 'aryl-(O)C—HN—, optionally substituted independently from each other with one, two, three or four R;'}], 'Ris selected from the group consisting of halogen, C-alkyl-, C-alkenyl-, C-cycloalkyl-, C-cycloalkenyl- or a ring system selected from the group consisting of'}{'sup': '2.1', 'sub': 1-4', '3-6', '1-4', '1-4', '2', '1-4', '2', '1-4', '2', '1-4', '3-6', '1-4', '1-4', '1-4', '2', '2', '1-4', '2', '1-4', '2', '1-4, 'Ris halogen, C-alkyl-, C-cycloalkyl-, O═, C-alkyl-(O)C—, C-alkyl-(O)S—, C-alkyl-(O)SO—, (C-alkyl)N(O)C—, C-alkyl-HN(O)C—, C-cycloalkyl-(O)C—, phenyl-C-alkyl-, MeO—C-alkyl-, NC—, (C-alkyl)N(O)S—, C-alkyl-HN(O)S—, (C-alkyl)(HO)C— or phenyl-, optionally substituted with C-alkyl-O—;'}or a salt thereof.3. The compounds according to whereinn is 0, 1, 2 or 3 ...

Dihydropyrazoles

Novel dihydropyrazole derivatives of formula (I) 2. The compound according to claim 1 , wherein R claim 1 , L denote Ar.3. The compound according to claim 1 , wherein{'sup': 1', '2', '3', '4, 'X, X, X, Xdenote a single bond, and'}m denotes 0.4. The compound according to claim 1 , wherein{'sup': 1', '1', '2, 'Ardenotes an aromatic, monocyclic carbocycle having 5-8 C atoms, which is mono-, di- or trisubstituted by at least one substituent selected from the group of Rand R.'}5. The compound according to claim 1 , wherein{'sup': '1', 'Hetdenotes an unsaturated or aromatic monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms, which is substituted by at least one substituent selected from the group of Hal, A and OA.'}9. A pharmaceutical composition comprising at least one compound according to and/or a physiologically acceptable salt thereof.10. The pharmaceutical composition according to claim 9 , comprising pharmaceutically tolerable adjuvants for oral administration.11. The pharmaceutical composition according to claim 9 , comprising at least a second active pharmaceutical ingredient.13. The method according to claim 12 , wherein an effective amount of at least one compound and/or a physiologically acceptable salt thereof is administered to a mammal in need of treating fertility disorders. This application claims the benefit of U.S. Provisional application Ser. No. 61/503,694 filed on Jul. 1, 2011, which is hereby incorporated by reference.The present invention relates to compounds of formula (I)wherein L, R, R, R, R, R, R, X, X, X, X, Y, m and n have the meaning according to the claims, and/or physiologically acceptable salts thereof. The compounds of formulas (I) can be used as positive allosteric modulators of the follicle stimulating hormone receptor (FSHR). Objects of the invention are also pharmaceutical compositions comprising the compounds of formula (I), and the use of the compounds of formula (I) for the treatment of fertility disorders. ...

Pyrazole Compounds

Aryl substituted pyrazole derivatives are provided, as well as processes for their preparation. The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention, alone or in combination with additional antiviral agents, in a therapeutically effective amount. 157-. (canceled)72. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to .73. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to .74. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to .75. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a combination of the compound according to claim 58 , or a therapeutically acceptable salt or hydrate thereof claim 58 , and at least one additional agent selected from an interferon claim 58 , ribavirin claim 58 , an HCV protease inhibitor claim 58 , an HCV polymerase inhibitor claim 58 , an HCV IRES inhibitor claim 58 , an HCV Helicase claim 58 , an HCV ATPase inhibitor claim 58 , an NS5A phosphorylation inhibitor claim 58 , and an HCV NS2 inhibitor.76. A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound of according to in a pharmaceutically acceptable carrier.77. The pharmaceutical composition of claim 76 , further comprising a second antiviral agent claim 76 , wherein the second anti-viral agent is selected from the group consisting of an interferon claim 76 , ribavirin claim 76 , an HCV protease inhibitor claim 76 , an HCV polymerase inhibitor claim 76 , an HCV IRES inhibitor claim 76 , an HCV Helicase claim 76 , an HCV ATPase inhibitor claim 76 , an NS5A phosphorylation inhibitor claim 76 , and an HCV NS2 inhibitor. Strategies in ...

METHODS OF USE OF SMALL MOLECULE MODULATORS OF HEPATOCYTE GROWTH FACTOR (SCATTER FACTOR) ACTIVITY

The present invention provides methods for treating a disease or condition by administering to a subject at a frequency of more than 24 hours between doses, compositions and formulations of compounds having formula (I), and pharmaceutically acceptable derivatives thereof, wherein p, R1, R2 and B are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of injuries, conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role. 2. The method of wherein the frequency is every other day.3. The method of wherein the frequency is three times per week.4. The method of wherein the frequency is twice per week.5. The method of wherein the composition is administered Monday claim 1 , Wednesday claim 1 , and Friday of each week.6. The method of wherein the composition is administered Monday and Friday of each week.7. The method of wherein the composition is administered twice per week at greater than 72 hour intervals.8. The method of wherein the composition is administered once per week.9. The method of wherein the composition is administered orally.10. The method of wherein the composition is administered parenterally.11. The method of wherein the parenteral administration is intravenously claim 10 , rectally claim 10 , intracisternally claim 10 , intravaginally claim 10 , intraperitoneally claim 10 , subcutaneously claim 10 , intraarterially claim 10 , intradermally claim 10 , intraocularly claim 10 , topically claim 10 , nasally or pulmonarily.12. The method of wherein each R is independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R; —NRR; —S(O)Rwhere n=0-2; Calkoxy optionally substituted with one or more substituents independently selected from halogen and Calkyl; an optionally substituted fused ...

INHIBITORS OF LONG AND VERY LONG CHAIN FATTY ACID METABOLISM AS BROAD SPECTRUM ANTI-VIRALS

The present invention provides methods and compounds for treating viral infections using modulators of host cell enzymes relating to long chain fatty acid and lipid droplet metabolism. It includes a method of treating viral infections using triacsin C and its relatives, analogues and derivatives as well as other inhibitors of long chain fatty acid metabolism and lipid droplet metabolism. 181-. (canceled)82. A method of treating or preventing viral infection in a mammal , comprising administering to a mammalian subject in need thereof a therapeutically effective amount of an agent that inhibits a long chain fatty acid synthesis enzyme.83. The method of claim 82 , wherein the enzyme is an elongase.84. The method of claim 82 , wherein the enzyme is selected from the group consisting of:i) acyl-CoA synthetase long-chain family member 1 (ACSL1)ii) elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 2 (ELOVL2),iii) elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 3 (ELOVL3),iv) elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 6 (ELOVL6), andv) solute carrier family 27 (fatty acid transporter), member 3 (SLC27A3).85. The method of claim 82 , wherein the agent is an inhibitory polynucleotide.86. The method of claim 82 , wherein the agent is a small molecule.96. The method of claim 82 , wherein the virus is an enveloped virus.97. The method of claim 82 , wherein the virus is human cytomegalovirus (HCMV) claim 82 , hepatitis C virus (HCV) claim 82 , herpes simplex virus (HSV) claim 82 , hepatitis B virus (HBV) claim 82 , Human immunodeficiency virus (HIV) claim 82 , or influenza virus.981. The method of claim claim 82 , wherein the virus is HCMV claim 82 , which further comprises administering a therapeutically effective amount of an agent that inhibits HCMV-encoded DNA polymerase.991. The method of claim claim 82 , wherein the virus is HSV claim 82 , which further comprises administering a ...

PDE10 INHIBITORS AND RELATED COMPOSITIONS AND METHODS

Compounds that inhibit PDE10 are disclosed that have utility in the treatment of a variety of conditions, including (but not limited to) psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders. Pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs of the compounds are also provided. Also disclosed are compositions containing a compound in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for inhibiting PDE10 in a warm-blooded animal in need of the same. 11. A pharmaceutical composition of wherein Ris hydrogen.12. A pharmaceutical composition of wherein Ris Calkyl.13. A pharmaceutical composition of wherein Ris methyl.14. A pharmaceutical composition of wherein Ris Calkyl.15. A pharmaceutical composition of wherein Ris methyl.16. A pharmaceutical composition of wherein Ris ethyl.17. A pharmaceutical composition of wherein Ris substituted or unsubstituted phenyl.18. A pharmaceutical composition of wherein Ris substituted phenyl.19. A pharmaceutical composition of wherein Ris 4-bromo-3 claim 18 ,5-dimethoxyphenyl.20. A pharmaceutical composition of wherein Ris 4-chloro-3 claim 18 ,5-dimethoxyphenyl.21. A pharmaceutical composition of wherein Ris 3 claim 18 ,4 claim 18 ,5-trimethoxyphenyl.22. A pharmaceutical composition of wherein Ris substituted or unsubstituted aryl.23. A pharmaceutical composition of wherein Ris substituted or unsubstituted phenyl.24. A pharmaceutical composition of wherein Ris substituted phenyl.25. A pharmaceutical composition of wherein Ris phenyl substituted with Calkoxy.26. A pharmaceutical composition of wherein Ris phenyl substituted with substituted or unsubstituted ...

METHOD AND COMPOSITION FOR TREATING ALZHEIMER'S DISEASE AND DEMENTIAS OF VASCULAR ORIGIN

A composition and method of treating Alzheimer's disease or a dementia of vascular origin are disclosed. The composition and method utilize an endothelin antagonist as the active agent to treat Alzheimer's disease or a dementia of vascular origin in mammals, including humans. 1. A method of treating Alzheimer's disease comprising administering to a mammal in need thereof a therapeutically effective amount of a specific endothelin-A antagonist.2. The method of wherein the specific endothelin-A antagonist is selected from the group consisting of BMS-182874 claim 1 , BQ123 TBC2576 claim 1 , TBC3214 claim 1 , PD180988 claim 1 , RPR118031A claim 1 , SB247083 claim 1 , and mixtures thereof.3. The method of wherein the endothelin antagonist comprises BQ123.4. The method of further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of Alzheimer's disease.5. The method of wherein the second therapeutic agent comprises a cholinesterase inhibitor.6. The method of wherein the cholinesterase inhibitor is selected from the group consisting of tacrine claim 5 , metrifonate claim 5 , bethanacol claim 5 , physostigmine claim 5 , donepezil claim 5 , rivastigmine claim 5 , galantamine claim 5 , and mixtures thereof.7. The method of wherein the second therapeutic agent comprises a statin.8. The method of wherein the statin is selected from the group consisting of atorvastatin claim 7 , fluvastatin claim 7 , lovastatin claim 7 , pravastatin claim 7 , and mixtures thereof.9. The method of wherein the second therapeutic agent is selected from the group consisting of a nonsteroidal antiinflammatory drug claim 4 , memantine claim 4 , CX516 claim 4 , AN-1792 claim 4 , COSNIShunt claim 4 , and mixtures thereof.10. The method of wherein the endothelin antagonist and second therapeutic agent are administered simultaneously.11. The method of wherein the endothelin antagonist and second therapeutic agent are administered from a single ...

Hydroxamate-based inhibitors of deacetylases

The present teachings relate to compounds of Formula (I): and pharmaceutically acceptable salts, hydrates, esters, and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , ring A, and Z are as defined herein. The present teachings also provide methods of preparing compounds of Formula (I) and methods of use compounds of Formula (I) in treating pathologic conditions or disorders mediated wholly or in part by deacetylases.

COMBINATION

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof. 2. A combination according to where the compounds of Structure (I) and Structure (II) are in the form of a monohydrochloride salt.3. A combination kit comprising a combination according to together with a pharmaceutically acceptable carrier or carriers.4. A combination according to where the amount of the compound of Structure (I) is an amount selected from 50 mg to 1 claim 1 ,200 mg claim 1 , and that amount is administered once per day in one or more tablets claim 1 , and the amount of the compound of Structure (II) is an amount selected from 5 mg to 500 mg claim 1 , and that amount is administered once per day.5. (canceled)6. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2 claim 1 ,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , to such human claim 1 ,wherein the combination is administered within a specified period, andwherein the combination is administered for a duration of time.7. A method according to wherein the amount of 5-[[4-[(2 claim 6 ,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl] ...

NEURONAL CIRCUIT-DEPENDENT NEUROPROTECTION BY INTERACTION BETWEEN NICOTINIC RECEPTORS

A method of inhibiting excitotoxicity by indirectly activating α4β2 nicotinic acetylcholine receptors (nAChRs) which indirectly activate synaptic AMPA and NMDA receptors is disclosed. Inhibitors of α7 nACHRs, such as macrocyclic diterpenoids, more specifically cembranoids or methyllycaconitine (MLA), indirectly activate α4β2 nAChRs and can be used to treat neurodegenerative diseases, including, but not limited to, Alzheimer's Disease, Parkinson Disease, AIDS related dementia and the delayed effects of stroke. They can also be used to treat diseases associated with neuronal impairment, including, but not limited to glaucoma caused by optical nerve damage, delayed effects of epilepsy; and multiple sclerosis. 1. A method of treating or preventing neuronal damage in a subject comprising: administering to the subject at least one macrocyclic diterpenoid , or a biologically active fragment , analog , or derivative thereof.2. The method of wherein at least one macrocyclic diterpenoid is administered in an amount sufficient to achieve a concentration between about 200 nM to about 20 μM.3. The method of wherein the subject has suffered claim 1 , suffers from claim 1 , or is at risk for at least one neurodegenerative disease selected from the group consisting of:(a) Alzheimer's Disease;(b) Parkinson's Disease;(c) Frontotemporal Dementia;(d) Amyotrophic Lateral Sclerosis (ALS);(e) Motor Neuron Disease;(f) delayed effects of stroke;(g) delayed effects of traumatic brain injury; and(h) AIDS-related dementia.4. The method of wherein the subject has suffered claim 1 , suffers from claim 1 , or is at risk for developing a disease associated with neuronal impairment selected from the group consisting of:(a) glaucoma caused by optical nerve damage;(b) delayed effects of epilepsy; and(c) multiple sclerosis.5. The method of wherein the macrocyclic diterpenoid is administered during prenatal or postnatal treatment.6. The method of wherein the macrocyclic diterpenoid is selected from the ...

NEW INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS

The present invention relates to compounds of general formula I, 3. A compound according to claim 2 , wherein{'sup': '1', 'Ris selected from the group consisting of a phenyl ring, a 5-membered heteroaromatic ring which contains 2 or 3 heteroatoms independently of each other selected from ═N—, —NH—, —O— and —S—, and a 6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms;'}{'sup': N', '3, 'wherein in said 5-membered heteroaromatic ring the H-atom in one or more NH groups is replaced with Ror R, and'}{'sup': 3', '4, 'wherein each of said phenyl ring, tetrazolyl ring, and heteroaromatic rings is substituted with one group Rand optionally additionally substituted with 1 or 2 substituents independently selected from R;'}{'sup': N', '3', '4, 'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'wherein R, Rand Rare defined as in ,'}or a salt thereof.6. A compound according to to claim 2 , wherein{'sup': '3', 'sub': 1-4', '1-4', '3-6, 'Ris selected from the group consisting of C-alkyl, C-alkyl-O—, and C-cycloalkyl-O—,'}{'sup': '5', 'wherein each alkyl and cycloalkyl group and each alkyl and cycloalkyl sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from Rand optionally substituted with 1 to 3 F atoms;'}or from{'sub': 3', '2', '3, 'C-alkyl-S(═O)— substituted with 1 HO— or HC—O— group; and'}{'sub': 2', '3', '2', '2', '1-3', '1-4', '3-6', '1-4', '2', '2, 'sup': N', 'N', 'N', 'N', 'N, 'heterocyclyl-C(═O)—, HN—C(═O)—, HO—(HC)O—CH—NH—C(═O)—, C-alkyl-NR—C(═O)—, C-alkyl-C(═O)NR—, C-cycloalkyl-C(═O)NR—, heterocyclyl-O(═O)NR—, C-alkyl-S(═O)NR—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, heterocyclyl-S(═O)—, heterocyclyl, phenyl, and heteroaryl,'}{'sup': '5', 'wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from Rand optionally substituted with 1 or more F atoms; and'}{'sup': '6', 'wherein each phenyl and heteroaryl ...

Indole and indazole compounds that activate ampk

The present invention relates to indole and indazole compounds of Formula (I) that activate 5′ adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.

3,5-diaminopyrazole kinase inhibitors

Provided herein are 3,5-diaminopyrazoles, for example, compounds of Formula IA, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RC kinase-mediated disorder, disease, or condition.

HETEROCYCLIC COMPOUNDS SUITABLE FOR THE TREATMENT OF DYSLIPIDEMIA

The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. 2. The compounds as claimed in wherein ‘A’ is selected from optionally substituted aryl or heterocyclyl groups.3. The compounds as claimed in wherein when ‘A’ represents aryl group the aryl groups is selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups.4. The compound as claimed in wherein the aryl group is an optionally substituted phenyl group.5. The compound as claimed in wherein when ‘A’ represents heterocyclyl group claim 1 , the heterocyclyl group is selected from single or fused mono claim 1 , bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O claim 1 , N or S.65. The compound as claimed in wherein the heterocyclyl group is selected from pyridyl claim 1 , thienyl claim 1 , furyl claim 1 , pyrrolyl claim 1 , oxazolyl claim 1 , thiazolyl claim 1 , isothiazolyl claim 1 , imidazolyl claim 1 , isoxazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , triazolyl claim 1 , tetrazolyl claim 1 , benzofuranyl claim 1 , benzothienyl claim 1 , indolinyl claim 1 , indolyl claim 1 , azaindolyl claim 1 , azaindolinyl claim 1 , pyrazolopyrimidinyl claim 1 , azaquinazolinyl claim 1 , pyridofuranyl claim 1 , pyridothienyl claim 1 , thienopyrimidyl claim 1 , quinolinyl claim 1 , pyrimidinyl claim 1 , pyrazolyl claim 1 , quinazolinyl claim 1 , pyridazinyl claim 1 , triazinyl claim 1 , benzimidazolyl claim 1 , benzotriazolyl claim 1 , phthalazynil claim 1 , naphthylidinyl claim 1 , purinyl claim 1 , carbazolyl claim 1 , phenothiazinyl claim 1 , phenoxazinyl claim 1 , benzoxazolyl claim 1 , benzothiazolyl claim 1 , thiazepinyl claim 1 , oxazolidinyl claim 1 , thiazolidinyl claim 1 , ...

COMBINATION

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering a proteasome inhibiting compound, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, and optional additional antineoplastic agents, to a human in need thereof. 3. A combination kit comprising a combination according to together with a pharmaceutically acceptable carrier or carriers.4. A combination according to where the amount of the compound of Structure (II) is an amount selected from 5 mg to 500 mg claim 1 , and that amount is administered once per day.59-. (canceled)10. A method treating a cancer selected from: brain (gliomas) claim 1 , glioblastomas claim 1 , Bannayan-Zonana syndrome claim 1 , Cowden disease claim 1 , Lhermitte-Duclos disease claim 1 , breast claim 1 , inflammatory breast cancer claim 1 , Wilm's tumor claim 1 , Ewing's sarcoma claim 1 , Rhabdomyosarcoma claim 1 , ependymoma claim 1 , medulloblastoma claim 1 , colon claim 1 , head and neck claim 1 , kidney claim 1 , lung claim 1 , liver claim 1 , melanoma claim 1 , ovarian claim 1 , pancreatic claim 1 , prostate claim 1 , sarcoma claim 1 , osteosarcoma claim 1 , giant cell tumor of bone claim 1 , thyroid claim 1 ,Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, ...

SEROTONIN REUPTAKE INHIBITORS

In one aspect, the invention relates to compounds of formula I: 1. (canceled)2. The method of claim 20 , where Y is —CH—.3. The method of claim 20 , where Ris selected from —Calkyl optionally substituted with 1 to 5 fluoro atoms claim 20 , —O—Calkyl optionally substituted with 1 to 5 fluoro atoms claim 20 , and —NO.4. The method of claim 3 , where Ris —Calkyl optionally substituted with 1 to 5 fluoro atoms.5. The method of claim 4 , where Ris —CF.6. The method of claim 20 , where Ris selected from hydrogen and —CN.7. The method of claim 20 , where Ris hydrogen.8. The method of claim 20 , where n is 1.9. The method of claim 20 , where Q is —NRSOR.10. The method of claim 9 , where Ris selected from hydrogen claim 9 , —CH claim 9 , and —C(O)CH.11. The method of claim 9 , where Ris selected from —CH; —CHCH; —CH(CH); cyclopropyl; —NH; —NH(CH); —N(CH); —CHSO—CH; pyrazole; pyrazole substituted with —CH; triazole; morpholine; benzoxadiazole; and phenyl optionally substituted with R; where Ris selected from —CN claim 9 , —COOH claim 9 , —NO claim 9 , —OCH claim 9 , —C(O)NHCH claim 9 , —NHC(O)CH claim 9 , —SO—CH claim 9 , —SO—NH claim 9 , —SO—NHCH claim 9 , oxazole claim 9 , pyrimidine claim 9 , tetrazole claim 9 , pyrazole claim 9 , and pyrazole substituted with two methyl groups.12. The method of claim 20 , where Q is —SONRR.13. The method of claim 12 , where Ris selected from hydrogen and —CH.14. The method of claim 12 , where Ris selected from hydrogen claim 12 , —CH claim 12 , and benzyl.1519-. (canceled)21. The method of claim 20 , where the disease is pulmonary arterial hypertension. This application claims the benefit of U.S. Provisional Application No. 61/419,346, filed on Dec. 3, 2010; the entire disclosure of which is incorporated herein by reference.1. Field of the InventionThe present invention relates to and 2-phenoxy-2-pyrrolidin-3-yl-ethylsulfonamide and 2-phenoxy-2-pyrrolidin-3-ylethanesulfonic acid amide compounds having activity as serotonin (5-HT) reuptake ...

Isoindolinone derivatives

The present invention relates to compounds of the formula I, as well as pharmaceutically-acceptable salts thereof, pharmaceutical compositions containing said compounds and methods of using said compounds in the treatment or prophylaxis of diseases and disorders. The compounds and compositions disclosed herein are glucokinase activators useful for the treatment or prophylaxis of metabolic diseases and disorders, for example diabetes mellitus, including type II diabetes mellitus.

MATRIX METALLOPROTEINASE INHIBITORS

The present invention relates to β-hydroxy and amino-substituted carboxylic acids, which act as matrix metalloproteinase inhibitors, particularly diastereomerically pure β-hydroxy carboxylic acids, corresponding processes for their synthesis, and pharmaceutical compositions containing the compounds of the present invention. Compounds of the present invention are useful in the treatment of various inflammatory, autoimmune, and allergic diseases, such as methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, wound healing disorders, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, neointimal proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases, tumor metastasis, and other inflammatory disorders characterized by the over-expression and over-activation of a matrix metalloproteinase. 2. A compound which is selected from:(2S,3R)-5-(3,3′-difluoro-4′-methoxybiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic acid (Compound No. 47);(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic acid (Compound No. 50);(2S,3R)-5-(4′-chloro-3-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic acid (Compound No. 56);(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-β-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxypentanoic acid (Compound No. 58);(2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic acid (Compound No. 153);(2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic acid (Compound No. 154);(2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3- ...

3,5-DIAMINOPYRAZOLE KINASE INHIBITORS

Provided herein are 3,5-diaminopyrazoles, for example, compounds of Formula IA, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RC kinase-mediated disorder, disease, or condition. 4. The compound of claim 1 , wherein Ris Ccycloalkyl claim 1 , Caryl claim 1 , or heteroaryl claim 1 , each of which is optionally substituted with one claim 1 , two claim 1 , three claim 1 , four claim 1 , or five substituents Q.5. The compound of claim 4 , wherein Ris Ccycloalkyl claim 4 , optionally substituted with one or more substituents Q.6. The compound of claim 5 , wherein Ris cyclopropyl claim 5 , cyclobutyl claim 5 , cyclopentyl claim 5 , cyclohexyl claim 5 , or cycloheptyl claim 5 , each of which is optionally substituted with one or more substituents Q.7. The compound of claim 6 , wherein Ris cyclopropyl or cyclohexyl claim 6 , each of which is optionally substituted with one or more substituents Q.8. The compound of claim 4 , wherein Ris heteroaryl claim 4 , optionally substituted with one or more substituents Q.9. The compound of claim 8 , wherein Ris 5- or 6-membered heteroaryl claim 8 , each of which is optionally substituted with one or more substituents Q.10. The compound of claim 9 , wherein Ris pyridinyl claim 9 , optionally substituted with one or more substituents Q.11. The compound of claim 4 , wherein Ris Ccycloalkyl claim 4 , Caryl claim 4 , or heteroaryl claim 4 , each of which is optionally substituted with one claim 4 , two claim 4 , three claim 4 , four claim 4 , or five substituents Q claim 4 , wherein each substituent Q is independently selected from cyano claim 4 , nitro claim 4 , halo claim 4 , Calkyl claim 4 , and Calkoxy claim 4 , where the alkyl and alkoxy are each optionally substituted with one or more substituents Q.12. The compound of claim 11 , wherein each substituent Q is ...

NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF METABOLIC AND INFLAMMATORY DISEASES

Compounds are disclosed that have a formula represented by the following: 3. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Y is Me claim 1 , Et claim 1 , Pr claim 1 , iPr claim 1 , or —CH-Ph.5. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Ris —(CH)—COOH claim 1 , —(CH)—COOH claim 1 , —(CH)—SONH claim 1 , or —(CH)—SONHMe.6. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Cyis phenyl claim 1 , or naphthalene.7. A compound or pharmaceutically acceptable salt thereof claim 1 , according to claim 1 , wherein Cyis thiophenyl claim 1 , benzothiophenyl claim 1 , benzofuranyl claim 1 , benzoisoxazolyl claim 1 , benzoxazolyl or indolyl.8. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 1 or 2.9. A compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein each Rgroup is independently selected from F claim 8 , Cl claim 8 , Br claim 8 , Me claim 8 , CF claim 8 , and OMe.10. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 0.11. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Lis a single bond.12. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Lis —CH—.13. A compound according to claim 1 , wherein the compound is 4-[[(R)-1-(Benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid; or a pharmaceutically acceptable salt claim 1 , or a solvate claim 1 , or a solvate of the pharmaceutically acceptable salt.14. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof claim 1 , according to claim 1 , and a pharmaceutically acceptable carrier.15. The pharmaceutical composition according to comprising a further therapeutic agent.16. (canceled)17. A method for the treatment of inflammatory conditions claim 1 ...

Carbazole-Containing Sulfonamides as Cryptochrome Modulators

The subject matter herein is directed to carbazole-containing sulfonamide derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R, R, R, R, R, R, R, A, B, C, D, E, F, G, H, a, and b are accordingly described. Also provided are pharmaceutical compositions comprising the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, obesity, metabolic syndrome, Cushing's syndrome, and glaucoma. 2. The compound according to claim 1 , wherein each of A claim 1 , B claim 1 , C claim 1 , D claim 1 , E claim 1 , F claim 1 , G claim 1 , and H are C; each of Rand Ris independently selected from H or halo; Ris H or (C-C)alkyl claim 1 , Rand Rare H; Ris —CF claim 1 , —CHF claim 1 , —CHF claim 1 , (C-C)alkyl claim 1 , (C-C)alkenyl claim 1 , (C-C)alkynyl claim 1 , —(CRR)(3-10)-membered cycloalkyl claim 1 , —(CRR)(C-C)aryl claim 1 , —(CRR)(4-10)-membered heterocyclyl claim 1 , —(CRR)O(CRR)(C-C)aryl claim 1 , —(CRR)O(CRR)(4-10)-membered heterocyclyl claim 1 , —(CRR)S(O)(CRR)(C-C)aryl claim 1 , and —(CRR)S(O)(CRR)(4-10)-membered heterocyclyl; Ris —CF claim 1 , —CHF claim 1 , —CHF claim 1 , (C-C)alkyl claim 1 , (C-C)alkenyl claim 1 , (C-C)alkynyl claim 1 , —(CRR)(3-10)-membered cycloalkyl claim 1 , —(CRR)(C-C)aryl claim 1 , —(CRR)(4-10)-membered heterocyclyl claim 1 , —(CRR)O(CRR)(C-C)aryl claim 1 , —(CRR)O(CRR)(4-10)-membered heterocyclyl claim 1 , —(CRR)S(O)(CRR)(C-C)aryl claim 1 , and —(CRR)S(O)(CRR)(4-10)-membered heterocyclyl.3. The compound according to claim 1 , wherein each of A claim 1 , B claim 1 , C claim 1 , D claim 1 , E claim 1 , F claim 1 , G claim 1 , and H are C; each of Rand Ris independently selected from H or halo; Ris H or (C-C)alkyl claim 1 , Rand Rare H; Rand Rare linked to each other as a 4-12 membered mono- or bicyclic ring.4. The compound according to claim 1 , wherein each of A claim 1 , B claim 1 , C claim 1 , D claim 1 , E claim 1 , F claim 1 , G claim 1 , and H are C; ...

COMPOSITIONS AND METHODS FOR TREATING FOXP3+ TREG RELATED DISEASES

Methods for treating or preventing a Foxp3+ T regulatory cell (Treg) related disease in a subject in need thereof comprise administering to the subject an effective amount of a pharmaceutical composition comprising an inhibitor of a histone/protein acetyltransferase (HAT). Methods for identifying an agent useful for treating or preventing a Foxp3+ T regulatory cell (Treg) related disease comprise (a) contacting a candidate agent with a test sample comprising Foxp3+ T regulatory cells (Tregs), and (b) comparing a function of the Foxp3+ Tregs in the test sample with that in a control sample, wherein inhibition of the function of the Foxp3+ Tregs in the test sample when compared with the control sample indicates that the candidate agent is an agent useful for treating or preventing a Foxp3+ Treg related disease. 1. A method for treating or preventing a Foxp3+ T regulatory cell (Treg) related disease in a subject in need thereof , comprising administering to the subject an effective amount of a pharmaceutical composition comprising an inhibitor of a histone/protein acetyltransferase (HAT).2. The method of claim 1 , wherein Foxp3+ Tregs are not depleted in the subject.3. The method of claim 1 , wherein the HAT inhibitor inhibits a function of Foxp3+ Tregs.4. The method of claim 3 , wherein the Foxp3+ Tregs are obtained from the subject.5. The method of claim 1 , wherein the HAT inhibitor does not inhibit a function of effector T cells.6. The method of claim 5 , wherein the function of the effector T cells is selected from the group consisting of T cell activation claim 5 , T cell proliferation claim 5 , and cytokine production.7. The method of claim 5 , wherein the effector T cells are obtained from the subject.8. The method of claim 1 , wherein the HAT is obtained from the subject.9. The method of claim 1 , wherein the HAT is selected from the group consisting of GCN5 claim 1 , p300/CBP-associated factor (PCAF) claim 1 , Myst1 claim 1 , Myst2 claim 1 , Myst3 claim 1 , ...

Compounds useful as modulators of trpm8

The present invention includes compounds useful as modulators of TRPM8, such as compounds of Formula (I) and the subgenus and species thereof; personal products containing those compounds; and the use of those compounds and the personal products, particularly the use of increasing or inducing chemesthetic sensations, such as cooling or cold sensations.

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula XII: 3. The compound of claim 2 , where Ris H and Ris selected from H and —CHCH.5. The compound of claim 4 , where Ris H and Ris selected from H and —CHCH.13. The compound of claim 12 , where Ris H and Ris selected from H claim 12 , —CHOC(O)CH claim 12 , —CHOC(O)OCHCH claim 12 , —CHOC(O)OCH(CH) claim 12 , and —C(O)CH[CH(CH)]—NHC(O)OCH.15. The compound of claim 14 , where R is —CH claim 14 , Ris H claim 14 , and Ris selected from —CHOC(O)CH claim 14 , —CHOC(O)OCH(CH) claim 14 , —CHOC(O)OCHCH claim 14 , and —CHOC(O)CH[CH(CH)]—NHC(O)OCH.19. The compound of claim 18 , where Ris H and Ris selected from —CHOC(O)OCHCHand —CHOC(O)CH[CH(CH)]—NHC(O)OCH.21. The compound of claim 20 , where Ris H claim 20 , Ris —CHOP(O)(OH)or —CHOC(O)CH[CH(CH)]NH claim 20 , and Ris —CHCH; or Ris —C(O)CH[CH(CH)]NH claim 20 , Ris H claim 20 , and Ris —CHCH.23. The compound of claim 22 , where R claim 22 , R claim 22 , and Rare H; or Rand Rare H claim 22 , and Ris —CHOC(O)OCHCH.25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of .26. The pharmaceutical composition of claim 25 , further comprising a therapeutic agent selected from adenosine receptor antagonists claim 25 , α-adrenergic receptor antagonists claim 25 , β-adrenergic receptor antagonists claim 25 , β-adrenergic receptor agonists claim 25 , dual-acting β-adrenergic receptor antagonist/α-receptor antagonists claim 25 , advanced glycation end product breakers claim 25 , aldosterone antagonists claim 25 , aldosterone synthase inhibitors claim 25 , aminopeptidase N inhibitors claim 25 , androgens claim 25 , angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzyme/neprilysin inhibitors claim 25 , angiotensin-converting enzyme 2 activators and stimulators claim 25 , angiotensin-II vaccines claim 25 , anticoagulants claim 25 , anti-diabetic agents claim 25 , antidiarrheal agents claim 25 , anti- ...

SMALL MOLECULE INHIBITORS OF AGBL2

Small molecule inhibitors of AGBL2 are provided, as well as methods of using the inhibitors to treat or prevent cancer and neurologic disorders. 2. The compound of claim 1 , wherein Rand Rcombine to form a substituted or unsubstituted heterocycloalkyl.6. The compound of claim 5 , wherein Rand Rcombine to form a substituted or unsubstituted cycloalkyl.1110. A composition comprising a compound of any of - and a pharmaceutically acceptable carrier.13. The method of claim 12 , wherein Rand Rcombine to form a substituted or unsubstituted heterocycloalkyl.17. The method of claim 16 , wherein Rand Rcombine to form a substituted or unsubstituted cycloalkyl.2322. The method of any of - claims 1 , further comprising administering a second therapeutic agent to the subject.24. The method of claim 23 , wherein the second therapeutic agent is a chemotherapeutic agent.26. The method of claim 25 , wherein Rand Rcombine to form a substituted or unsubstituted heterocycloalkyl.30. The method of claim 29 , wherein Rand Rcombine to form a substituted or unsubstituted cycloalkyl.3635. The method of any of - claims 25 , further comprising administering a second therapeutic agent to the subject.37. The method of claim 36 , wherein the second therapeutic agent is an anti-depressant or an anxiolytic. This application claims priority to U.S. Provisional Application No. 61/443,069, filed Feb. 15, 2011, which is incorporated herein by reference in its entirety.The removal of the C-terminal tyrosine of α-tubulin to form detyrosinated α-tubulin is involved in several aspects of microtubule function, including kinesin interactions, spindle dynamics, mitosis, and neuronal specification. Microtubules containing large amounts of detyrosinated α-tubulin are more stable and resistant to depolymerization by destabilizing agents. Further, detyrosinated α-tubulin has been shown to be elevated in aggressive breast and prostate cancers.Provided herein are small molecule inhibitors of ATP/GTP binding protein ...

ARYLSULFONYL PYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS

This invention concerns arylsulfonyl pyrazoline carboxamidine derivatives as antagonists of 5-ht6 receptors, to methods for the preparation of these compounds and to novel intermediates useful for their synthesis. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in parkinson's disease, huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, irritable bowel syndrome, obesity and type-2 diabetes. The compounds have the general formula (1) wherein the symbols have the meanings given in the description. 119-. (canceled)27. The method of claim 22 , wherein the compound is an optically active enantiomer.28. The method of claim 22 , further comprising at least one additional therapeutic agent. This invention relates to the fields of pharmaceutical and organic chemistry, and provides arylsulfonyl pyrazoline carboxamidine derivatives, intermediates, formulations and methods.Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, mediated through a number of receptor families termed 5-HT, 5-HT, 5-HT, 5-HT, 5-HT, 5-HTand 5-HT. Although the functions of the latter three are less well understood than those of the others, it is generally accepted that compounds which selectively interfere with 5-HT-mediated signal transduction are ...

COMPOSITIONS AND METHODS FOR INHIBITING CYTOCHROME P450

Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters to improve the pharmacokinetics, enhance the bioavailability, and enhance the therapeutic effect of drugs that undergo in vivo degradation by cytochrome P450 enzymes. 125-. (canceled)28. The compound according to wherein X is selected from the group consisting of alkyl claim 27 , alkenyl claim 27 , alkynyl claim 27 , alkoxyalkyl claim 27 , cycloalkyl claim 27 , cycloalkylalkyl claim 27 , heterocycloalkyl claim 27 , heteroaryl claim 27 , heterocycloalkylalkyl claim 27 , aryl claim 27 , aralkyl claim 27 , and heteroaralkyl; wherein X optionally is substituted with one or more substituents selected from the group consisting of C-Calkenyl claim 27 , C-Calkynyl claim 27 , C-Ccycloalkyl claim 27 , C-Ccycloalkenyl claim 27 , heterocyclo; halo claim 27 , OR claim 27 , ROH claim 27 , R-halo claim 27 , NO claim 27 , CN claim 27 , COR claim 27 , CON(R) claim 27 , C(S)R claim 27 , C(S)N(R) claim 27 , SON(R) claim 27 , SR claim 27 , SOR claim 27 , N(R) claim 27 , N(R)COR claim 27 , NRS(O)R claim 27 , NRC[═N(R)]N(R) claim 27 , N(R)N(R)COR claim 27 , NRPON(R) claim 27 , NRPOOR claim 27 , oxo claim 27 , ═N—OR claim 27 , ═N—N(R) claim 27 , ═NR claim 27 , ═NNRC(O)N(R) claim 27 , ═NNRCOR claim 27 , ═NNRS(O)N(R) claim 27 , and ═NNRS(O)(R).29. The compound according to or wherein X is selected from the group consisting of alkyl claim 27 , cycloalkyl claim 27 , aryl claim 27 , aralkyl claim 27 , heteroaryl claim 27 , and heteroaralkyl.30. The compound according to wherein X optionally is substituted with one or more substituents selected from the group consisting of halo claim 27 , OR claim 27 , ROH claim 27 , R-halo claim 27 , CN claim 27 , COR claim 27 , CON(R) claim 27 , SON(R) claim 27 , SR claim 27 , SOR claim 27 , N(R) claim 27 , ...

Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

CRYSTALLINE N--5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride

An improved AKT inhibiting compound, crystalline N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride. 1. N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride in crystalline form.2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier or diluent.3. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 , which process comprises bringing the compound of into association with a pharmaceutically acceptable carrier.4. A method of treating or lessening the severity of cancer in a mammal in need thereof claim 1 , which comprises administering to such mammal a therapeutically effective amount of a compound of .5. The method of wherein the mammal is a human.6. The method according to wherein said cancer is selected from: Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,', "malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,", 'neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer., "brain (gliomas), glioblastomas, Bannayan-Zonana ...

PYRAZINE-CONTAINING COMPOUND

Compositions and methods related to the amelioration of pancreatitis through the pharmaceutical manipulation of calcium signaling are disclosed. Such compositions and methods may be used to ameliorate symptoms of acute or chronic pancreatitis or to reduce the chance or severity of pancreatitis in an individual at risk of the condition. In other embodiments, disclosed herein are compositions and methods related to the amelioration of viral diseases through the pharmaceutical manipulation of calcium signaling. In further embodiments, disclosed herein are compositions and methods related to the amelioration of Th17-induced diseases through the pharmaceutical manipulation of calcium signaling. 1. A method for trealing renal failure in a subject , comprising administering to the subject a therapeutically effective amount of a compound having a chemical name of N-[5-(6-chloro-2 ,2-difluorobenzo [d]1 ,3-dioxolen-5-yl)pyrazin-2-yl](2-fluoro-6-methylphenyl)carboxamide or a pharmaceutically acceptable sale thereof.2. The method of claim 1 , wherein the renal failure is severe chronic renal failure.3. The method of claim 1 , wherein the renal failure is associated with an flammatory response in the subject.4. The method of claim 3 , wherein the inflammatory response is a chronic inflammatory disease.5. The method of claim 4 , wherein the chronic inflammatory disease is T helper 17 cell (Th17) induced.6. The method of claim 5 , wherein the Th17 induced chronic inflammatory disease is an autoimmune disorder claim 5 ,7. The method of claim 3 , wherein the inflammatory response is associated with a group of inflammatory mediators consisting of TNF-α and IL-1.8. The method of claim 6 , further comprising inhibiting Th17 differentiation.9. The method of claim 1 , wherein the compound is administered to achieve a plasma level concentration that is about 1 μM.10. The method of claim 1 , wherein the compound is administered to achieve a plasma level concentration that is from about 1 μ ...

Neuronal circuit-dependent neuroprotection by interaction between nicotinic receptors

A method of inhibiting excitotoxicity by indirectly activating α4β2 nicotinic acetylcholine receptors (nAChRs) which indirectly activate synaptic AMPA and NMDA receptors is disclosed Inhibitors of α7 nACHRs, such as macrocyclic diterpenoids, more specifically cembranoids or methyllycaconitine (MLA), indirectly activate α4β2 nAChRs and can be used to treat neurodegenerative diseases, including, but not limited to, Alzheimer's Disease, Parkinson Disease, AIDS related dementia and the delayed effects of stroke. They can also be used to treat diseases associated with neuronal impairment, including, but not limited to glaucoma caused by optical nerve damage, delayed effects of epilepsy; and multiple sclerosis.

USE OF ITK INHIBITORS FOR THE TREATMENT OF CANCER

This invention relates generally to the use of ITK (IL-2 inducible T-cell kinase) inhibitors for the treatment of patients who have melanoma or other solid tumors. Applicants demonstrate that ITK lentiviral small hairpin RNA knockdowns and a small molecule inhibitor can each decrease the proliferation and migration of melanoma cell lines and a small molecule inhibitor can be used to inhibit the growth of melanomas in vivo. 1. A method of inhibiting the growth of a solid tumor in a subject which comprises administering an effective amount of a selective interleukin-2 inducible T-cell kinase (ITK) inhibitor to the subject.2. The method of claim 1 , wherein the solid tumor is a breast claim 1 , a gastric claim 1 , a head and neck claim 1 , a kidney claim 1 , a liver claim 1 , a lung claim 1 , a melanoma claim 1 , a non-small cell lung cancer (NSCLC) claim 1 , a pancreatic claim 1 , or a uterine tumor.3. The method of claim 2 , wherein the melanoma tumor is a primary melanoma tumor.4. The method of claim 2 , wherein the melanoma tumor is a melanoma metastasis tumor.5. The method of claim 2 , wherein the breast tumor is an estrogen receptor negative (ER(−)) or a progesterone receptor negative (PR(−)) breast tumor.6. The method of claim 1 , wherein the selective interleukin-2 inducible T-cell kinase (ITK) inhibitor is a 2-amino-5-(thioaryl)thiazole claim 1 , a 2-amino-5-[(thiomethyl)aryl]thiazole claim 1 , a 4-arylpyrazolyl indole claim 1 , a 5-arylpyrazolyl indole claim 1 , a benzimidazole claim 1 , an imidazo quinoxalin claim 1 , or a pyrazolopyrimidine.18. A method of inhibiting melanoma cell motility in a subject which comprises administering an effective amount of a selective interleukin-2 inducible T-cell kinase (ITK) inhibitor to the subject.19. (canceled)20. (canceled)21. The method of claim 18 , wherein the selective interleukin-2 inducible T-cell kinase (ITK) inhibitor is a 2-amino-5-(thioaryl)thiazole claim 18 , a 2-amino-5-[(thiomethyl)aryl]thiazole claim 18 , ...

METHODS FOR TREATING DEGENERATIVE DISEASES/INJURIES

Invented is a method of treating degenerative diseases/injuries, in a mammal, including a human, in need thereof which comprises the administration of a therapeutically effective amount of a non-peptide TPO receptor agonist to such mammal. 1. An in vitro or ex vivo method of enhancing the differentation of blood components in human fetal cord blood into functional cells which method comprises the addition of an effective amount of a non-peptide TPO receptor agonist selected from:3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid,or a pharmaceutically acceptable salt thereof, and3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl,or a pharmaceutically acceptable salt thereof;to a culture medium containing human fetal cord blood;followed by optional isolation of the functional cells.2. The method of wherein progenitor cells are enhanced.3. A method of transfusing human fetal cord blood which method comprises the addition of an effective amount of a non-peptide TPO receptor agonist selected from:3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid,or a pharmaceutically acceptable salt thereof, and3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-tetrazol-5-ylbiphenyl,or a pharmaceutically acceptable salt thereof;to a patient receiving human fetal cord blood. This invention relates to non-peptide tbrombopoietin (TPO) receptor agonists and their use in the treatment of degenerative diseases/injuries.Thrombopoietin (TPO) has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 389:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. ...

COMBINATION TREATING PROSTATE CANCER, PHARMACEUTICAL COMPOSITION AND TREATMENT METHOD

Disclosed are a combination treating prostate cancer, a pharmaceutical composition and a treatment method. The combination includes one of a benzoheterocyclic compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a crystalline form thereof, a co-crystal thereof, a stereoisomer thereof, an isotope compound thereof, a metabolite thereof and a prodrug thereof, and an androgen receptor pathway modulator. The combination, the pharmaceutical composition thereof and the treatment method inhibit prostate cancer in a more effective manner. 4. The combination for the treatment of prostate cancer according to claim 1 , wherein claim 1 , the androgen receptor pathway modulator is one of the following compounds: AR1-1 claim 1 , AR1-2 claim 1 , AR2-1 claim 1 , AR2-2 claim 1 , AR2-3 claim 1 , AR2-4 claim 1 , AR2-5 claim 1 , AR3-1 claim 1 , AR3-2 claim 1 , AR3-3 claim 1 , AR3-4.5. The combination for the treatment of prostate cancer according to claim 3 , wherein claim 3 , the combination of benzoheterocyclic compound of formula(I) and the androgen receptor pathway modulator is one of the following compositions:the combination of “B001 or F001 or K001 or D108” and AR1-1, the combination of “B001 or F001 or K001 or D108” and AR1-2, the combination of “B001 or F001 or K001 or D108” and AR1-3, the combination of “B001 or F001 or K001 or D108” and AR1-4, the combination of “B001 or F001 or K001 or D108” and AR2-1, the combination of “B001 or F001 or K001 or D108” and AR2-2, the combination of “B001 or F001 or K001 or D108” and AR2-3, the combination of “B001 or F001 or K001 or D108” and AR2-4, the combination of “B001 or F001 or K001 or D108” and AR2-5, the combination of “B001 or F001 or K001 or D108” and AR2-6, the combination of “B001 or F001 or K001 or D108” and AR2-7, the combination of “B001 or F001 or K001 or D108” and AR2-8, the combination of “B001 or F001 or K001 or D108” and AR2-9, the combination of “B001 or F001 or K001 or D108” ...

COMPOSITIONS AND METHODS RELATING TO HEAT SHOCK TRANSCRIPTION FACTOR ACTIVATING COMPOUNDS AND TARGETS THEREOF

The present invention relates to HSF activating compounds, methods for their discovery, and their research and therapeutic uses, as well as pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, mixtures (including both R and S enantiomeric forms and racemic mixtures thereof), and pharmaceutical Formulations thereof. In particular, the present invention provides compounds capable of facilitating HSF1 homotrimerization, and methods of using such compounds as therapeutic agents to treat a number of conditions associated with irregular HSF1 activity. 3. The method of claim 2 , whereinA) wherein the compound of Formula II is selected from following group consisting of:1) N-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-2-(thiophen-2-yl)acetamide,2) 2-(Benzyloxy)-N-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)acetamide,3) 2-(Benzyloxy)-N-(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)acetamide,4) N-(1,3-Bis(4-chlorophenyl)-1H-pyrazol-5-yl)-4-butylbenzamide,5) 2-Methoxy-N-(3-(4-methoxyphenyl)-1-p-tolyl-1H-pyrazol-5-yl)benzamide,6) 4-Butyl-N-(3-phenyl-1-o-tolyl-1H-pyrazol-5-yl)benzamide,7) 4-Butyl-N-(1-butyl-3-(4-chlorophenyl)-1H-pyrazol-5-yl)benzamide,8) N-(3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-2-(3-methoxyphenyl)acetamide,9) 2-(Benzyloxy)-N-(3-(4-methoxyphenyl)-1-o-tolyl-1H-pyrazol-5-yl)acetamide,10) 4-Butyl-N-(4-butylbenzoyl)-N-(3-phenyl-1-o-tolyl-1H-pyrazol-5-yl)benzamide,11) 4-Butyl-N-(3-(thiophen-2-yl)-1-o-tolyl-1H-pyrazol-5-yl)benzenesulfonamide,12) N-(1,3-Diphenyl-1H-pyrazol-5-yl)-4-ethylbenzenesulfonamide,13) 4-Ethyl-N-(3-(4-methoxyphenyl)-1-p-tolyl-1H-pyrazol-5-yl)benzenesulfonamide,14) 4-Ethyl-N-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide,15) N-(1-(2-Fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)-4-methoxybenzenesulfonamide,16) N-(3-tert-Buyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-4-ethylbenzenesulfonamide,17) 4-Ethyl-N-(4-ethylphenylsulfonyl)-N-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide,18) ...

COMPOUNDS USEFUL AS KINASE INHIBITORS

This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases. 2. The method of claim 1 , wherein the cancer is selected from the group consisting of: lymphoma claim 1 , leukemia claim 1 , multiple myeloma claim 1 , a B-cell malignancy and bone cancer.3. The method of claim 2 , wherein the cancer is selected from: multiple myeloma claim 2 , diffuse large B cell lymphoma (DLBCL) claim 2 , follicular lymphoma claim 2 , mantle cell lymphoma claim 2 , marginal zone lymphoma claim 2 , Burkitt lymphoma claim 2 , Waldenstrom's macroglobulinemia claim 2 , chronic lymphocytic leukemia claim 2 , B-cell prolymphocyte leukemia claim 2 , and hairy cell leukemia.4. The method of claim 1 , wherein the cancer has one or more BTK inhibitor resistance mutations.5. The method of claim 4 , wherein the one or more BTK inhibitor resistance mutations is selected from the group consisting of C481S claim 4 , C481Y claim 4 , C481R claim 4 , and C481F.15. The method of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.17. The method of claim 16 , wherein the cancer is selected from the group consisting of: lymphoma claim 16 , leukemia claim 16 , multiple myeloma claim 16 , a B-cell malignancy and bone cancer.18. The method of claim 17 , wherein the cancer is selected from: multiple myeloma claim 17 , diffuse large B cell lymphoma (DLBCL) claim 17 , follicular lymphoma claim 17 , mantle cell lymphoma claim 17 , marginal zone lymphoma claim 17 , Burkitt lymphoma claim 17 , Waldenstrom's macroglobulinemia claim 17 , chronic lymphocytic leukemia claim 17 , B-cell prolymphocyte leukemia claim 17 , and hairy cell ...

INHIBITORS OF HEMOPOIETIC CELL KINASE (P-59-HCK) AND THEIR USE IN THE TREATMENT OF INFLUENZA INFECTION

The present invention relates inter alia to the treatment or prevention of influenza virus infection (including subtypes influenza A virus, influenza B virus, avian strain H5N1, A/H1N1, H3N2 and/or pandemic influenza) using compounds which inhibit the activity of p59-HCK and to a method of screening for a candidate drug substance intended to prevent or treat influenza virus infection in a subject, said method comprising identifying a test substance capable of inhibiting p59-HCK activity. 117-. (canceled)19. The method of claim 18 , wherein the influenza infection is secondary to at least one of the following conditions:I. pregnancyII. chemotherapy;III. complications arising from infection by influenza virus (A, B and C strains); orIV. chronic disease.20. The method of claim 18 , wherein the compound is administered in combination with one or more anti-viral drugs.21. The method of claim 20 , wherein the anti-viral drug is selected from the group consisting of zanamrivir claim 20 , oseltamivir claim 20 , laninamivir claim 20 , peramivir claim 20 , ribavirin and exogenous interferons.22. A compound capable of inhibiting hemopoietic cell kinase (p59-HCK) activity wherein the compound is not N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-lyloxy)pyridin-2-yl)-2-methoxyacetamide or a pharmaceutically acceptable salt or solvate thereof.23. The compound of claim 22 , wherein the compound is a molecule that suppresses the expression of p59-HCK.24. The compound of claim 23 , wherein the molecule is an RNAi molecule or microRNA (miRNA) molecule.25. A method of screening for a candidate drug substance intended to prevent or treat influenza virus infection (A claim 23 , B and C strains) in a subject which comprises identifying a test substance capable of inhibiting p59-HCK activity by measuring the effects of said test substance on p59-HCK activity.26. A method of screening according to comprising:a. contacting p59-HICK with a test substance in the ...

REDUCING SYSTEMIC REGULATORY T CELL LEVELS OR ACTIVITY FOR TREATMENT OF DISEASE AND INJURY OF THE CNS

A pharmaceutical composition comprising an active agent that causes reduction of the level of systemic immunosuppression in an individual for use in treating a disease, disorder, condition or injury of the CNS that does not include the autoimmune neuroinflammatory disease, relapsing-remitting multiple sclerosis (RRMS), is provided. The pharmaceutical composition is for administration by a dosage regimen comprising at least two courses of therapy, each course of therapy comprising in sequence a treatment session followed by an interval session. 1. A method for treating a disease , disorder , condition or injury of the Central Nervous System (CNS) that does not include the autoimmune neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS) , said method comprising administering to an individual in need thereof an active agent that causes reduction of the level of systemic immunosuppression , wherein said active agent is administered by a dosage regime comprising at least two courses of therapy , each course of therapy comprising in sequence a treatment session followed by an interval session.2. The method according to claim 1 , wherein said active agent causes reduction of the level of systemic immunosuppression by release of a restraint imposed on the immune system by one or more immune checkpoints.3. The method according to claim 2 , wherein said reduction of the level of systemic immunosuppression is associated with an increase in systemic presence or activity of IFNγ-producing leukocytes.4. The method according to claim 2 , wherein said active agent causes reduction of the level of systemic immunosuppression and thereby an increase in the systemic presence or activity of effector T cells.5. The method according to claim 2 , wherein said active agent causes release from immunosuppression by blockade of said one or more immune checkpoints.6. The method according to claim 5 , wherein said one or more checkpoints is selected from the group consisting of ...

PYRAZOLE DERIVATIVES AS INHIBITORS OF STAT3

Compositions that modulate the activity of signal transducer and activator of transcription-3 (STAT3) activity as well as their methods of use, such as treatment and imaging are provided. Compositions contain small molecules such as substituted pyrazoles and are useful in treatment of diseases related to the activity of STAT3 including, for example, cancer and other diseases. 141-. (canceled)43. The compound of claim 42 , wherein:{'sup': '2', 'Ris H;'}{'sup': '3', 'sub': 6-12', '1-6', '1-6, 'Ris Caryl, optionally substituted with 1, 2, or 3 substituents selected from Calkyl, Chaloalkyl, halo, and CN;'}{'sup': 4', 'c2', 'd2, 'Ris NRR;'}{'sup': 'c2', 'sub': 1-6', '2-6', '2-6, 'Rand R are independently selected from H, Calkyl, Calkenyl and Calkynyl;'}{'sup': 5', 'c1', 'd1', 'c1', 'b1', 'c1', 'c1', 'd1, 'sub': 6-12', '2', 'n', '2', 'm, 'Ris Caryl, optionally substituted with 1 or 2 substituents selected from NRR, NRC(O)R, and NRC(O)(CH)O(CH)C(O)NRR;'}{'sup': c1', 'd1, 'sub': 1-6', '2-6', '2-6', '1-6', '2-6', '2-6', '1-6, 'Rand Rare independently selected from H, Calkyl, Calkenyl, Calkynyl, cycloalkyl, wherein each Calkyl, Calkenyl, Calkynyl, or cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from OH, Calkoxy, CN, amino, alkylamino, dialkylamino, and halo; and'}{'sup': 'b1', 'sub': 1-6', '1-6', '1-6, 'Ris selected from Calkyl, cycloalkyl, aryl, and heteroaryl, wherein each Calkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from OH, Calkoxy, CN, amino, alkylamino, dialkylamino, and halo.'}44. The compound of claim 42 , wherein:{'sup': '2', 'Ris H;'}{'sup': '3', 'sub': '6-12', 'Ris Caryl, optionally substituted with 1, 2, or 3 halo;'}{'sup': '4', 'sub': '2', 'Ris NH;'}{'sup': 5', 'c1', 'd1', 'c1', 'b1', 'c1', 'c1', 'd1, 'sub': 6-12', '2', 'n', '2', 'm, 'Ris Caryl, optionally substituted with 1 or 2 substituents selected from NRR, NRC(O)R, and NRC(O)(CH)O(CH)C(O)NRR;'}{'sup': ...

SMALL MOLECULE INHIBITORS OF LACTATE DEHYDROGENASE AND METHODS OF USE THEREOF

Provided is a compound of formula (I) 2. The compound or salt of claim 1 , wherein Ris hydrogen claim 1 , substituted or unsubstituted C-Calkyl claim 1 , substituted or unsubstituted C-Calkenyl claim 1 , substituted or unsubstituted C-Calkynyl claim 1 , substituted or unsubstituted C-Ccycloalkyl claim 1 , substituted or unsubstituted C-Ccycloalkylalkyl claim 1 , substituted or unsubstituted aryl claim 1 , substituted or unsubstituted arylalkyl claim 1 , hydroxyl claim 1 , hydroxyalkyl claim 1 , halo claim 1 , C-Chaloalkyl claim 1 , —CN claim 1 , cyanoalkyl claim 1 , —NRR claim 1 , or substituted or unsubstituted heteroarylalkyl.3. The compound or salt of claim 2 , wherein Ris substituted or unsubstituted C-Calkyl claim 2 , substituted or unsubstituted cyclopropyl claim 2 , substituted or unsubstituted —(C-Calkyl)-cyclopropyl claim 2 , substituted or unsubstituted —CH═CH claim 2 , substituted or unsubstituted —C≡C-cyclopropyl claim 2 , substituted or unsubstituted phenyl claim 2 , substituted or unsubstituted benzyl claim 2 , —OH claim 2 , —CHOH claim 2 , —CF claim 2 , —CFCF claim 2 , —Cl claim 2 , —F claim 2 , —I claim 2 , —CN claim 2 , —CHCN claim 2 , —NH claim 2 , or —CH-tetrazolyl.4. The compound or salt of claim 1 , wherein Ris —COH or —CO(C-Calkyl) claim 1 , wherein the C-Calkyl is substituted or unsubstituted.5. The compound or salt of claim 1 , wherein Rand Rare the same or different and each is H or C-Calkyl.6. The compound or salt of claim 1 , wherein each Ris independently halo claim 1 , C-Chaloalkyl claim 1 , C-Chaloalkoxy claim 1 , substituted or unsubstituted C-Calkyl claim 1 , substituted or unsubstituted C-Calkenyl claim 1 , substituted or unsubstituted C-Calkynyl claim 1 , substituted or unsubstituted —(CH)aryl claim 1 , substituted or unsubstituted —(CH)heteroaryl claim 1 , or substituted or unsubstituted —(CH)heterocycloalkyl.7. The compound or salt of claim 1 , wherein m is 0 claim 1 , 1 claim 1 , or 2.8. The compound or salt of claim 1 , wherein ...

Derivatives of Xanthone Compounds

The present invention relates to xanthone analogs. Such compounds may be used in the treatment of bacterial infections. 136.-. (canceled)40. The compound of claim 39 , wherein each occurrence of Rin Formula (IIa-2) is independently optionally substituted alkyl.41. The compound of claim 40 , wherein Rindependently for each occurrence is —N(H)(C═NH)NH.42. The compound of claim 37 , wherein Ris hydrogen claim 37 , and Ris alkyl.46. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 37 , or a pharmaceutically acceptable salt thereof claim 37 , and a pharmaceutically acceptable excipient.47. The pharmaceutical composition of claim 46 , further comprising one or more additional therapeutic agents.48. A method for treating a microbial infection in a patient in need thereof claim 37 , the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 37 , or a pharmaceutically acceptable salt thereof.49. The method of claim 48 , wherein the microbial infection is a Gram negative bacterial infection or a Gram positive bacterial infection.50StreptococcusStaphylococcusBacillusCarynebacteriumClostridiumListeriaEnterococcus. The method of claim 49 , wherein the Gram positive bacteria is selected from the group consisting of spp. claim 49 , spp. claim 49 , spp. claim 49 , spp. claim 49 , spp. claim 49 , spp. claim 49 , and spp.51Staphylococcus aureus.. The method of claim 50 , wherein the Gram positive bacteria is52Staphylococcus aureusStaphylococcus aureus.. The method of claim 51 , wherein the is Methicillin resistant53. The method of claim 48 , the method further comprising administering one or more additional therapeutic agents.55. The compound of claim 54 , wherein Ris hydrogen claim 54 , and Ris alkyl.60. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 54 , or a pharmaceutically acceptable salt thereof claim ...

TRICYCLIC SPIRO COMPOUND

A medicinal agent for the prevention and/or treatment of diseases caused by EPreceptor activation. A compound having antagonistic activity against the EPreceptor is contained as an active ingredient in the medicinal agent. The compound represented by the following general formula (I) as defined in the specification, a salt, an N-oxide, or a solvate thereof, or a prodrug of these is useful as a medicinal component having antagonistic activity against the EPreceptor for the prevention and/or treatment of diseases caused by EPreceptor activation. 3. The compound according to claim 1 , wherein at least one Ris —CONHR.4. The compound according to claim 1 , wherein Lis —NHCO— claim 1 , or —CONH—.6. The compound according to claim 1 , which is any one of the following:(1) 4-[4-cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(2) 4-{4-cyano-2-[({(2′R,4S)-6-[(cyclopropylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(3) 4-{4-cyano-2-[({(2′R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(4) 4-{4-cyano-2-[({(2′R,4S)-6-[(2-methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(5) 4-[4-cyano-2-({[(2′R,4S)-6-{[(2S)-1-methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(6) 4-{4-cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(7) 4-[4-cyano-2-({[(2′R,4S)-6-(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene-4, 1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(8) 4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(9) 4-[4-cyano-2-({[(2′R,4S)-6-(cyclopentylcarbamoyl)-2,3- ...

PKM2 MODULATORS AND METHODS FOR THEIR USE

Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): 190-. (canceled)92. A method of treating cancer in a mammal in need thereof claim 91 , the method comprising providing a therapeutically effective amount of the pharmaceutical formulation of to the subject. The present invention is generally directed to novel PKM2 modulators and use of the same for treatment of various cancers.Proliferation of cancer cells requires the accumulation of sufficient biosynthetic building blocks (i.e., biomass) to replicate each nucleic acid, protein and lipid in the cell. As a tumor grows, the need for nutrients and oxygen can exceed the capacity of poorly vascularized blood vessels. Faced with such challenges, cancer cells must be able to adjust metabolic pathways.Glucose provides cancer cells with building blocks in the form of glycolytic pathway intermediates (Mazurek S., 43(7):969-80 (2010); Vander Heiden M. G., Cantley L. C., Thompson C. B., 324(5930):1029-33 (2009)). The main enzyme regulating flux through the glycolitic pathway in cancer cells, and thus the level of available intermediates, is the M2 splice form of pyruvate kinase (PKM2), which controls the rate-limiting final step in glycolysis. PKM2 is allosterically regulated by fructose-1,6-bisphosphate (FBP), an upstream glycolytic intermediate that binds to and converts PKM2 from a less active dimeric form with low affinity for its substrate, phosphoenolpyruvate (PEP), to an active tetrameric form with high PEP affinity (Ashizawa K., Willingham M. C., Liang C. M., Cheng S. Y., 266(25):16842-46 (1991); Mazurek S., Boschek C. B., Hugo F., Eigenbrodt E., 15(4):300-08 (2005)). When glucose is abundant, FBP levels increase and PKM2 is activated, leading to high glycolytic flux. When glucose is limiting, FBP levels decrease and PKM2 is inactivated, allowing upstream glycolytic intermediates to accumulate and be diverted into biosynthetic pathways (Mazurek S., Michel A., ...

NOVEL COMPOUNDS FOR CONTROLLING ARTHROPODS

The present invention relates to novel halogen-substituted compounds, to processes for their preparation and to their use for controlling animal pests, in particular arthropods and especially insects and arachnids. 2. Compound according to claim 1 ,whereinQ is O;{'sup': '2', 'Lis C═O;'}{'sup': '3', 'sub': 2', 'n', '2', 'm', '1', '4', '3', '5, 'claim-text': 'n and m are independently 0, 1 or 2;', 'Lis a group (CH)—(CH═CH)—CH), which is optionally substituted with up to 2 groups independently selected from C-Calkyl, C-Ccycloalkyl and halogen, wherein'}And/or a salt thereof.3. Compound according to claim 1 ,whereinQ is O;{'sup': '2', 'Lis C═O;'}{'sup': '3', 'sub': 2', 'n', '2', 'm, 'Lis a group (CH)—(CH═CH)—CH), wherein n and m are 0'}And/or a salt thereof.4. Compound according to claim 1 ,whereinQ is O{'sup': '2', 'Lis C═O'}{'sup': '3', 'sub': 1', '4', '1', '4', '3', '6', '1', '4, 'Lis linear C-Calkanediyl, which is optionally substituted with one or more groups independently selected from C-Calkyl, C-Ccycloalkyl and halogen, wherein two C-C-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and'}And/or a salt thereof.5. Compound according to claim 1 ,whereinQ is O;{'sup': '2', 'Lis absent;'}{'sup': '3', 'sub': 1', '4', '1', '4', '3', '6', '1', '4, 'Lis linear C-Calkanediyl, which is optionally substituted with one or more groups independently selected from C-Calkyl, C-Ccycloalkyl and halogen, wherein two C-C-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and'}And/or a salt thereof.6. Compound according to claim 1 ,wherein{'sup': 1', '2, 'L, Land Q are absent;'}And/or a salt thereof.7. Compound according to claim 1 ,wherein one or more of the following conditions applyQ is O;and/or{'sup': '1', 'sub': 2', '4', '1', '4', '1', '4, 'Lis linear C-Calkanediyl, which is optionally substituted with one or more C-Calkyl groups, wherein two C-C-alkyl substituents may form a ring together with ...

Novel compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis.

The present invention discloses compounds according to Formula I: wherein R 1 , R 2 , R 3 , L, and the subscript m are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions, and methods of treatment using the same, for the treatment of cystic fibrosis by administering a compound of the invention.

Protein Kinase Inhibitors and Uses Thereof

The invention is compounds of formula (I), and salts thereof, compositions thereof, and methods of use therefor. In particular, disclosed herein are certain compounds that can be useful for inhibiting protein kinase, including Bruton's tyrosine kinase (Btk), and for treating disorders mediated thereby. 2. The compound of claim 1 , wherein:{'sup': '2', 'X—Y—Z is C—N—N and Ris absent; and'}{'sup': 1', '4, 'Ris 3-8 membered, N-containing ring, N-substituted with R.'}3. The compound of claim 1 , wherein:{'sup': '2', 'X—Y—Z is N—C—C and Ris present,'}{'sup': 1', '4, 'Ris 3-8 membered, N-containing ring, N-substituted with R; and'}{'sup': '2', 'Ris H or lower alkyl.'}4. The compound of claim 1 , wherein:{'sup': '2', 'X—Y—Z is N—C—C and Ris present; and'}{'sup': 1', '2', '4, 'Rand R, together with the atoms to which they are attached, form a 4-8 membered ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings unsubstituted or substituted with at least one substituent L-R.'}5. The compound of claim 1 , wherein:{'sup': '2', 'X—Y—Z is N—C—C and Ris present; and'}{'sup': 1', '2', '4', '4, 'Rand R, together with the atoms to which they are attached, form a 4-8 membered ring that is (a) phenyl substituted with a single -L-R, or (b) dihydropyrrole or tetrahydropyridine, N-substituted with a single -L-Rwherein L is bond.'}6. The compound of wherein:{'sup': 1', '4, 'Ris piperidine or azaspiro[3.3]heptane, N-substituted with R.'}7. The compound of claim 1 , wherein:{'sup': 1', '4, 'Ris piperidine or azaspiro[3.3]heptane, N-substituted with R; and'}{'sup': '4', 'sub': '2', 'Ris COR′ or SOR′, and R′ is substituted or unsubstituted alkenyl.'}8. The compound of claim 1 , wherein:{'sup': 3', '5', '5, 'Ris —OR, Ris phenyl, and n is 1.'}9. The compound of claim 1 , wherein:{'sup': '2', 'X—Y—Z is C—N—N and Ris absent;'}{'sup': 1', '4, 'Ris piperidine, N-substituted with R;'}{'sup': 3', '5, 'Ris —OR;'}n is 1;{'sup': '4', 'Ris COR′, and R′ is ethenyl; ...

Neuronal circuit-dependent neuroprotection by interaction between nicotinic receptors

A method of inhibiting excitotoxicity by indirectly activating α4β2 nicotinic acetylcholine receptors (nAChRs) which indirectly activate synaptic AMPA and NMDA receptors is disclosed. Inhibitors of α7 nACHRs, such as macrocyclic diterpenoids, more specifically cembranoids or methyllycaconitine (MLA), indirectly activate α4β2 nAChRs and can be used to treat neurodegenerative diseases, including, but not limited to, Alzheimer's Disease, Parkinson Disease, AIDS related dementia and the delayed effects of stroke. They can also be used to treat diseases associated with neuronal impairment, including, but not limited to glaucoma caused by optical nerve damage, delayed effects of epilepsy; and multiple sclerosis.

Compounds, compositions, and methods for preventing metasasis of cancer cells

Disclosed are methods for preventing metastasis of cancer cells. The disclosed compounds can be used to prevent the spread of tumor or other types of cancer cells.

A CARBOXAMIDE DERIVATIVE AND ITS DIASTEREOMERS IN STABLE CRYSTALLINE FORM

The present disclosure relates to solid crystalline forms of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) and the diastereomers thereof, and to methods for preparing such crystalline forms. Compound (I) and the diastereomers thereof are potent androgen receptor (AR) modulators useful as a medicament. 1. Crystalline form I of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl) propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having an X-ray powder diffraction pattern comprising characteristic peaks at about 8.5 , 10.4 , 16.6 , 16.9 , and 24.3 degrees 2-theta.2. (canceled)3. Crystalline form I′ of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (Ia) having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.3 , 15.7 , 17.0 , 24.1 and 25.1 degrees 2-theta.4. (canceled)5. Crystalline form I″ of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (Ib) having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.2 , 10.9 , 15.1 , 15.8 and 22.1 degrees 2-theta.6. (canceled)7. A process for preparing crystalline form I , I′ or I″ of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl) propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) , N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (Ia) or N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (Ib) , respectively , comprisinga) mixing N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl) propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I), N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (Ia) or N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl) ...

NANOPARTICLE COMPOSITIONS

Provided herein are nanoparticle compositions comprising modulators of the Bcl-2 family proteins, and pharmaceutically acceptable carriers. 1. A composition comprising nanoparticles , wherein the nanoparticles comprise a modulator of a Bcl-2 family protein; and a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier comprises albumin.2. The composition of claim 1 , wherein the modulator of the Bcl-2 family protein is a modulator of Bcl-2 claim 1 , Bcl-xL claim 1 , Bcl-w claim 1 , Bcl-b claim 1 , A1 claim 1 , and/or Mcl-1.3. The composition of claim 1 , wherein the modulator of the Bcl-2 family protein is a modulator of Bcl-2 claim 1 , Bcl-xL claim 1 , Bcl-w claim 1 , and/or Mcl-1.4. The composition of claim 1 , wherein the modulator of the Bcl-2 family protein is a modulator of Bcl-2 claim 1 , Bcl-xL claim 1 , and/or Mcl-1.5. The composition of any one of - claim 1 , wherein the nanoparticles have an average diameter of about 1000 nm or less for at least about 15 minutes after nanoparticle formation.6. The composition of any one of - claim 1 , wherein the nanoparticles have an average diameter of about 10 nm or greater for at least about 15 minutes after nanoparticle formation.7. The composition of any one of - claim 1 , the nanoparticles have an average diameter of from about 10 nm to about 1000 nm for at least about 15 minutes after nanoparticle formation.8. The composition of any one of - claim 1 , wherein the nanoparticles have an average diameter of about 1000 nm or less for at least about 2 hours after nanoparticle formation.9. The composition of any one of - claim 1 , wherein the nanoparticles have an average diameter of about 10 nm or greater for at least about 2 hours nanoparticle formation.10. The composition of any one of - claim 1 , the nanoparticles have an average diameter of from about 10 nm to about 1000 nm for at least about 2 hours after nanoparticle formation.11. The composition of any one of - claim 1 , wherein the ...

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula: where R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

CANCER TREATMENT METHOD

Invented is a method of treating cancer or a pre-cancerous syndrome in a mammal, including a human, in need thereof which comprises the administration of an effective amount of a non-peptide thrombopoietin (TPO) receptor agonist to such mammal, suitably a human. 2. The method according to wherein the mammal is a human.3. The method according to wherein the compound is administered orally.4. The method according to wherein the compound is administered parenterally.6. The method according to wherein the compound is:3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid bis-(monoethanolamine). This invention relates to a method of treating cancer and pre-cancerous syndromes in a mammal, including a human, in need thereof which comprises the administration of an effective amount of a combination of at least one non-peptide thrombopoietin (TPO) receptor agonist or TPO cell cycle activator and at least one chemotherapeutic agent to such mammal. Suitably, the method relates to methods of treating cancers and pre-cancerous syndromes by administration of 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid and pharmaceutically acceptable salts, thereof, suitably the bis-(monoethanolamine) salt, (hereinafter the bis-(monoethanolamine) salt is Compound A and the corresponding salt free compound is Compound B) and at least one chemotherapeutic agent.Thrombopoietin (TPO) has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, TPO is ...

METHODS AND PHARMACEUTICAL COMPOSITIONS FOR MODULATING AUTOPHAGY IN A SUBJECT IN NEED THEREOF

The present invention provides novel methods for the modulation of autophagy and the treatment of autophagy-re lated diseases, including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis. 120-. (canceled)21. A method of treating cancer in a subject in need thereof , comprising administering to the subject at least one acetyl CoA (AcCoA) depleting agent and at least one chemotherapeutic agent , wherein the AcCoA depleting agent is an inhibitor of ATP-citrate lyase (ACLY).22. The method according to claim 21 , wherein the inhibitor of ACLY is selected from the group consisting of hydroxycitrate claim 21 , (R claim 21 ,S)—S-(3 claim 21 ,4-dicarboxy-3-hydroxy-3-methyl-butyl)-CoA claim 21 , S-carboxymethyl-CoA claim 21 , (3R claim 21 ,5S)-rel-5-[6-(2 claim 21 ,4-Dichlorophenyl)hexyl]tetrahydro-3-hydroxy-2-oxo-3-furanacetic acid and 3 claim 21 ,5-Dichloro-2-hydroxy-N-(4-methoxy[1 claim 21 ,1′-biphenyl]-3-yl)-benzenesulfonamide.23. The method according to claim 21 , wherein the chemotherapeutic agent is selected from the group consisting of danurobicin claim 21 , doxorubidin claim 21 , epirubicin claim 21 , idarubicin claim 21 , mitoxantrone claim 21 , paclitaxel and docetaxel.24. The method according to claim 21 , wherein the cancer is selected from the group consisting of cancer cells from the bladder claim 21 , blood claim 21 , bone claim 21 , bone marrow claim 21 , brain claim 21 , breast claim 21 , colon claim 21 , esophagus claim 21 , gastrointestine claim 21 , gum claim 21 , head claim 21 , kidney claim 21 , liver claim 21 , lung claim 21 , nasopharynx claim 21 , neck claim 21 , ovary claim 21 , prostate claim 21 , skin claim 21 , stomach claim 21 , testis claim 21 , tongue claim 21 , or uterus.25coli. The method according to claim 21 , wherein the cancer is selected from the group consisting of malignant; carcinoma; carcinoma claim 21 , undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; ...

THERAPEUTIC COMPOUNDS AND USES THEREOF

Provided herein are compounds of formula I: 23-. (canceled)4. The compound of claim 1 , wherein X is —CH— claim 1 , —CHCH— or —CHCHCH—.79-. (canceled)11. The compound of claim 1 , wherein X is or —N(R)C(R)—.1214-. (canceled)15. The compound of claim 1 , wherein Ris hydrogen claim 1 , halo claim 1 , heteroaryl claim 1 , —OR claim 1 , CN claim 1 , —C(O)—N(R)or —C(O)—OR claim 1 , wherein any heteroaryl of Ris optionally substituted with one or more Rgroups.1618-. (canceled)2022-. (canceled)2425-. (canceled)27. (canceled)2933-. (canceled)36. (canceled)40. (canceled)42. (canceled)43. A method of treating cancer in an animal comprising administering to the animal in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as described in .44. A method of treating an LSD1-mediated disorder in an animal comprising administering to the animal in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as described in .4549-. (canceled)50. A method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as described in .51. (canceled)52. A method of delaying or preventing development of cancer resistance to a cytotoxic agent in an animal claim 1 , comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described in .53. A method of extending the duration of response to a cancer therapy in an animal claim 1 , comprising administering to the animal undergoing the cancer therapy a compound of formula I or a pharmaceutically acceptable salt thereof claim 1 , as described in claim 1 , wherein the duration of response to the cancer therapy when the compound of formula I is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula I or ...

METHODS AND COMPOSITIONS OF SMALL MOLECULE MODULATORS OF HEPATOCYTE GROWTH FACTOR (SCATTER FACTOR) ACTIVITY

The present invention provides compositions and formulations of compounds having formula (I) and pharmaceutically acceptable derivatives thereof, wherein p, R, Rand B are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of injuries, conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role. In addition, methods are provided for treating such diseases or diseases starting at a time after the onset of the injury, condition or disease. 2. The composition of wherein the polyethylene glycol 300 is present at about 50% (v/v).3. The composition of wherein the polysorbate 80 is present at about 10% (v/v).4. The composition of wherein the buffer is phosphate-buffered saline.5. The composition of wherein the pH is about 7.4.6. The composition of wherein the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter.7. The composition of wherein the polyethylene glycol 300 is present at about 50% (v/v) claim 1 , the polysorbate 80 is present at about 10% (v/v) claim 1 , the buffer is phosphate-buffered saline claim 1 , pH 7.4 claim 1 , and the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter.8. The composition of wherein each R is independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R; —NRR; —S(O)Rwhere n=0-2; Calkoxy optionally substituted with one or more substituents independently selected from halogen and Calkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N claim 1 , O claim 1 , and S; and Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , or Ccycloalkyl claim 1 , each independently optionally substituted with one ...

Reducing Systemic Regulatory T Cell Levels or Activity for Treatment of Disease and Injury of the CNS

The present specification discloses a pharmaceutical composition comprising an active agent that causes reduction of the level of systemic immunosuppression in an individual for use in treating a disease, disorder, condition or injury of the CNS. The pharmaceutical composition is administered by a dosage regimen comprising at least one course of therapy, each course of therapy comprising in sequence a treatment session followed by an interval session of non-treatment.

Methods and compositions for modulating ire1, src, and abl activity

Disclosed herein are, inter alia, compositions for modulating Ire1, Src, or Abl, methods for identifying modulating activity in test compounds, and methods for treating diseases caused by the activity or inactivity of Ire1, Src, or Abl.

Compounds and Compositions for the Treatment of Cancer

The present disclosure provides compounds, pharmaceutical compositions, and methods for the treatment of cancer and fibrosis. The disclosed pharmaceutical compositions may include one or more pyrazolyl-containing compounds, or a derivative thereof.

MCT4 INHIBITORS FOR TREATING DISEASE

Provided herein is a method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof. The method comprises the step of administering to the subject a compound of structural Formula I 2. The method as recited in claim 1 , wherein{'sup': 1', '2, 'Aand Aare C; and'}{'sup': '3', 'Ais N.'}4. The method as recited in claim 3 , wherein Z is chosen from phenyl and pyridinyl claim 3 , either of which may be optionally substituted with one to three Rgroups each independently chosen from alkenyl claim 3 , alkoxy claim 3 , alkyl claim 3 , alkylamino claim 3 , aryl claim 3 , halo claim 3 , heteroaryl claim 3 , and haloalkyl.5. The method as recited in claim 4 , wherein Y is chosen from aryl and heteroaryl claim 4 , any of which may be optionally substituted with one to three Rgroups each independently chosen from alkenyl claim 4 , alkoxy claim 4 , cycloalkoxy claim 4 , cycloalkylmethoxy claim 4 , haloalkoxy claim 4 , alkyl claim 4 , aryl claim 4 , halo claim 4 , heteroaryl claim 4 , and haloalkyl.7. The method as recited in claim 6 , wherein Z is chosen from phenyl and pyridinyl claim 6 , either of which may be optionally substituted with one to three Rgroups each independently chosen from alkenyl claim 6 , alkoxy claim 6 , alkyl claim 6 , alkylamino claim 6 , aryl claim 6 , halo claim 6 , heteroaryl claim 6 , and haloalkyl.8. The method as recited in claim 7 , wherein Y is chosen from phenyl claim 7 , thienyl claim 7 , and thiazolyl claim 7 , any of which may be optionally substituted with one to three Rgroups each independently chosen from alkoxy claim 7 , cycloalkoxy claim 7 , cycloalkylmethoxy claim 7 , haloalkoxy claim 7 , alkyl claim 7 , halo claim 7 , and haloalkyl.9. The method as recited in claim 8 , wherein Rand Rare chosen from the following combinations:{'sup': 4', '5, 'Rand Rare each methyl;'}{'sup': 4', '5, 'Rand Rare each ethyl; and'}{'sup': 4', '5, 'Ris methyl and Ris ethyl.'}11. The method as recited in claim 10 , wherein:{' ...

Calpain modulators and therapeutic uses thereof

Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.

NITROGEN-CONTAINING HETEROCYCLIC COMPOUND

The present invention provides a compound having a cholinergic muscarinic Ml receptor positive allosteric modulator activity and useful as an agent for the prophylaxis or treatment of Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, dementia with Lewy bodies, and the like. 14. 2-[(3S ,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4 ,5-dimethyl-2 ,3-dihydro-1H-isoindol-1-one , or a salt thereof.15. 4-Fluoro-2-[(3S ,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2 ,3-dihydro-1H-isoindol-1-one , or a salt thereof.16. 2-((1S ,2S)-2-Hydroxycyclohexyl)-4 ,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-one , or a salt thereof.17. A medicament comprising the compound according to or a salt thereof.18. The medicament according to claim 17 , which is a cholinergic muscarinic M1 receptor positive allosteric modulator.19. The medicament according to claim 17 , which is an agent for the prophylaxis or treatment of Alzheimer's disease claim 17 , schizophrenia claim 17 , pain claim 17 , sleep disorder claim 17 , Parkinson's disease dementia or dementia with Lewy bodies.20. The compound according to or a salt thereof for use in the prophylaxis or treatment of Alzheimer's disease claim 1 , schizophrenia claim 1 , pain claim 1 , sleep disorder claim 1 , Parkinson's disease dementia or dementia with Lewy bodies.21. A method of cholinergic muscarinic M1 receptor positive allosteric modulation in a mammal claim 1 , which comprises administering an effective amount of the compound according to or a salt thereof to the mammal.22. A method for the prophylaxis or treatment of Alzheimer's disease claim 1 , schizophrenia claim 1 , pain claim 1 , sleep disorder claim 1 , Parkinson's disease dementia or dementia with Lewy bodies in a mammal claim 1 , which comprises administering an effective amount of the compound according to or a salt thereof to the mammal.23. Use of the compound according to or a ...

1-ARYL-3-AMINOALKOXY PYRAZOLES AS SIGMA LIGANDS ENHANCING ANALGESIC EFFECT OF OPIOIDS AND ATTENUATING THE DEPENDENCY THEREOF

The invention relates to the use of a group of sigma receptor ligands of formula (I) 2. The combination of wherein Ris selected from H claim 1 , —COR claim 1 , and substituted or unsubstituted alkyl.3. The combination of wherein Ris H or alkyl.4. The combination of wherein Rand Rare situated in the meta and para positions of the phenyl group.5. The combination of wherein Rand Rare independently selected from halogen claim 1 , or substituted or unsubstituted alkyl.6. The combination of where Rand Rtogether form a fused naphthyl ring system.7. The combination of wherein n is selected from 2 claim 1 , 3 claim 1 , and 4.8. The combination of wherein Rand Rtogether form a morpholine-4-yl group.9. The combination of wherein compound of formula I is selected from the group consisting of:4-{2-(1-(3,4-dichlorophenyl)-5-methyl-1H pyrazol-3-yloxy)ethyl}morpholine;2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]-N,N-diethylethanamine;1-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperidine,1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine;1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-4-methylpiperazine;Ethyl 4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazine carboxylate;1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone;4-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine;1-(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazole;1-(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-1H-pyrazole;1-[2-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidine;1-{2-[1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}-1H-imidazole;4-{2-[1-(3,4- ...

New somatostatin receptor subtype 4 (sstr4) agonists

3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid amide derivatives which are agonists of somatostatin receptor subtype 4 (SSTR4), useful for preventing or treating medical disorders related to SSTR4.

6-HYDROXY-8-OXATRICYCLO[3.2.1.02,4]OCTANE-2-CARBOXAMIDE DERIVATIVES FOR INDUCING CHONDROGENESIS FOR TREATING JOINT DAMAGE

The present invention provides 6-hydroxy-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide derivatives of Formula (1) wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds. The compounds are used for inducing chondrogenesis, in methods of treating or preventing joint damage, resulting from joint injury or arthritis, and for inducing hyaline cartilage production. The present description discloses the preparation of exemplary compounds as well as pharmacological data thereof (examples 1 to 82; tables 1 and 2). An exemplary compound is e.g. rac-(1R,2R,4S,5R,6S)-4-(2-fluoropyridin-4-yl)-6-hydroxy-N-(4-(trifluoromethyl)pyridin-2-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide (example 1). 6. The compound according to or an enantiomer claim 1 , an enantiomeric mixture thereof or a pharmaceutically acceptable salt thereof;{'sup': '3', 'wherein R, if present, is fluoro, chloro, methyl, methoxy, ethoxy, trifluomethyl, cyano, cyclopropyl or morpholinyl.'}7. The compound according to or an enantiomer claim 1 , an enantiomeric mixture thereof or a pharmaceutically acceptable salt thereof; wherein Ris hydrogen and n is 0.8. The compound according to or an enantiomer claim 1 , an enantiomeric mixture thereof or a pharmaceutically acceptable salt thereof; wherein Ris phenyl claim 1 , pyrazolyl claim 1 , pyridyl or pyrimidinyl; each of which is substituted by 1-2 substituents independently selected from halo claim 1 , Calkyl claim 1 , Chaloalkyl or Calkoxy.10. The compound according to or an enantiomer claim 1 , an enantiomeric mixture thereof or a pharmaceutically acceptable salt thereof; wherein Ris hydrogen.11. The compound according to claim 1 , wherein said compound is selected from;rac-(1R,2R,4S,5R,6S)-4-(2-fluoropyridin-4-yl)-6-hydroxy-N-(4-(trifluoromethyl)pyridin-2-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide;rac-(1R,2R,4S,5R,6S)—N-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(2-fluoropyridin- ...

PREPARATION AND USE OF 7A-HETEROCYCLE SUBSTITUTED- 6,6-DIFLUORO BICYCLIC HIMBACINE DERIVATIVES AS PAR-1 RECEPTOR ANTAGONISTS

The present invention relates to bicyclic himbacine derivatives of the formula 4. A pharmaceutical composition comprising an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.5. The pharmaceutical composition as defined in claim 4 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.6. The pharmaceutical composition as defined in claim 5 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel claim 5 , wherein clopidogrel is a free base or pharmaceutically acceptable salt.7. A pharmaceutical composition comprising an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.8. The pharmaceutical composition as defined in claim 7 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.9. The pharmaceutical composition as defined in claim 8 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel claim 8 , wherein clopidogrel is a free base or pharmaceutically acceptable salt.11. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof. The present invention relates to 7a-heterocycle substituted 6,6-difluro bicyclic himbacine derivatives, which are useful as protease activated receptor-1 (PAR-1) antagonists and might be expected to be cannabinoid (CB) receptor inhibitors. PAR-1 receptors are also known in the art as thrombin receptor antagonists (TRA). The inventive compounds have utility in treating disease states such as acute coronary syndrome (ACS) (unstable angina, non-ST-segment elevation [NSTE] myocardial infarction [MI], and ST segment-elevation myocardial infarction [STEMI]), secondary prevention of myocardial infarction or ...

FURO [3, 2-B] PYRR0L-3-0NES AS CATHESPIN S INHIBITORS

A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,

Methods and compositions for modulating tau levels

Methods and agents for reducing a level of an acetylated Tau polypeptide in a cell are provided. Methods for treating a tauopathy in an individual are also provided. Also provided is a method for diagnosing a cognitive impairment disorder in an individual. Methods for identifying an agent suitable for treating a tauopathy are also provided.

CNS-ACCESSIBLE PHARMACOLOGICAL CHAPERONES FOR TREATMENT OF ACID BETA-GLUCOSIDASE-RELATED DISEASE STATES

Disclosed herein are β-glucosidase (GCase) chaperones and methods of using GCase chaperones in an individual in need thereof. GBA1 mutations lead to GCase deficiency and substrate accumulation, causing Gaucher disease. Currently, no FDA or EMA-approved therapeutic for neuronopathic Gaucher disease is available. Improved GCase activity in brain cells using a chaperone may reduce substrate accumulation and associated pathology. Disclosed herein are novel non-inhibitory chaperone compounds of GCase that have properties of a central nervous system drug. Those compounds effectively restored mutant GCase activity by stabilizing protein and enhancing lysosomal localization and may be useful for chaperone therapy to treat neuronopathic Gaucher disease and likely to Parkinson's disease. 8. The method of claim 1 , wherein said chaperone is the R enantiomer.9. The method of claim 1 , wherein said administration is oral administration.10. The method of claim 1 , wherein said chaperone is administered in an amount sufficient to functionally recover mutant GCase by one or more of improving protein folding claim 1 , stability claim 1 , and trafficking to lysosome.11. The method of claim 1 , wherein said disorder is selected from Parkinson's disease or Gaucher disease.12. The method of claim 1 , wherein said chaperone is used in combination with substrate reduction therapy (SRT) claim 1 , wherein said SRT comprises administering a glucosylceramide synthase inhibitor in an amount sufficient for to degrade glucosylceramide.13. The method of claim 1 , wherein said administration is for the treatment of Parkinson's disease in an individual in need thereof.14. The method of claim 1 , wherein said administration is for the treatment of Gaucher disease in an individual in need thereof.15. A method of improving enzyme replacement therapy claim 1 , comprising administering a composition according to any preceding claim in combination with GCase replacement therapy claim 1 , wherein said ...

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula: where R 1 -R 6 , a, b, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

Fap-activated therapeutic agents, and uses related thereto

Disclosed are prodrugs of cytotoxic anthracyclines (such as doxorubicin) and other therapeutic agents that are selectively cleaved and activated by fibroblast activating protein (FAP). The prodrugs are useful for targeted delivery of cytotoxic and other agents to FAP-expressing tissues, including cancer (e.g., solid tumors). Also provided are pharmaceutical compounds comprising the prodrugs, as well as methods of using the prodrugs to treat a disorder characterized by FAP upregulation, e.g., cancer, fibrosis, and inflammation.

SMALL MOLECULE IRE1-ALPHA INHIBITORS

Described herein are IRE1α inhibitors, compositions containing such inhibitors, and methods of treatment that include administration of such compounds. Exemplary compounds are provided throughout the application. 2. The compound of claim 1 , wherein the A ring is heteroaromatic.3. The compound of claim 2 , wherein the A ring is a fusion of two rings.4. The compound of claim 2 , wherein the A ring is indazole claim 2 , imadazopyridine claim 2 , imadazopyrazine claim 2 , imadazopyridazine claim 2 , pyrrolopyridine claim 2 , hexahydrothienopyrimidine claim 2 , imidazole claim 2 , pyrazole claim 2 , pyrazine claim 2 , pyridine claim 2 , pyrimidine claim 2 , phenylpyrimidinamine claim 2 , quinolinyl claim 2 , isoquinolinyl claim 2 , tetrahydroquinolinyl claim 2 , and quinazolinyl.5. The compound of claim 1 , wherein the B ring is a single claim 1 , non-fused ring.6. The compound of claim 5 , wherein the B ring is pyrazolyl claim 5 , imidazolyl claim 5 , or triazolyl.7. The compound of claim 1 , wherein the B ring is a fusion of two rings.8. The compound of claim 1 , wherein the C ring is phenyl.10. The compound of claim 1 , wherein the Rsubstituents on the A ring are selected from the group consisting of amino and optionally substituted C-Calkyl.11. The compound of claim 10 , wherein the Rsubstituents on the A ring are selected from the group consisting of —NHand CH.12. The compound of claim 1 , wherein x=0 claim 1 , 1 or 2.13. The compound of claim 1 , wherein the R; substituent on the C ring is CF.15. The compound of claim 1 , wherein v is 1.16. The compound of claim 1 , wherein Ris selected from the group consisting of H claim 1 , optionally substituted C-Calkyl claim 1 , (optionally substituted C-Calkylene)-OH claim 1 , hydroxy claim 1 , optionally substituted aryl claim 1 , and optionally substituted benzyl.17. The compound of claim 16 , wherein Ris selected from H and optionally substituted C-Calkyl.18. A composition comprising a carrier and a compound of .19. The ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula XII: 128-. (canceled)30. The compound of claim 29 , wherein Ris H.31. The compound of claim 29 , wherein Ris selected from H claim 29 , —CHCHand —CHCH(CH).32. The compound of claim 31 , wherein Ris —CHCH.33. The compound of claim 30 , wherein Ris —CHCH.34. The compound of claim 29 , wherein P is selected from H claim 29 , t-butoxycarbonyl claim 29 , trityl claim 29 , benzyloxycarbonyl claim 29 , 9-fluorenylmethoxycarbonyl claim 29 , formyl claim 29 , trimethylsilyl and t-butyldimethylsilyl.35. The compound of claim 34 , wherein P is H.36. The compound of claim 33 , wherein P is H.37. The compound of claim 29 , wherein Ris H.38. The compound of claim 29 , wherein Ris F.39. The compound of claim 36 , wherein Ris F.40. The compound of claim 29 , wherein the compound is (2R claim 29 ,4R)-4-amino-5-(5′-chloro-2′-fluoro-biphenyl-4-yl)-2-hydroxypentanoic acid or a pharmaceutically acceptable salt thereof.41. The compound of claim 29 , wherein the compound is (2R claim 29 ,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof.42. The compound of claim 29 , wherein the compound is (2R claim 29 ,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo-[1 claim 29 ,3]dioxol-4-ylmethyl ester or a pharmaceutically acceptable salt thereof.43. The compound of claim 29 , wherein the compound is (2R claim 29 ,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 2 claim 29 ,2 claim 29 ,3 claim 29 ,3 claim 29 ,3-pentafluoropropyl ester or a pharmaceutically acceptable salt thereof.44. The compound of claim 29 , wherein the compound is (2R claim 29 ,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester or a pharmaceutically acceptable salt thereof.45. A method of performing a coupling reaction claim 29 , comprising contacting the compound of with a ...

Novel compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis

The present invention discloses compounds according to Formula I: wherein R 1 is as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment cystic fibrosis by administering a compound of the invention.

FIXED DOSE COMBINATION FOR PAIN RELIEF WITHOUT EDEMA

Compositions and methods for individualized therapy of pain using a non-steroidal anti-inflammatory drug (NSAID) and an anti-hypertensive without inducing intolerable edema. Said methods comprise basing NSAID/anti-hypertensive dose on each patient's pharmacokinetic response to said NSAID. 1. A composition for treating pain without inducing edema comprising a NSAID and an anti-hypertensive in a fixed-dose combination and , optionally , further comprising one or more pharmaceutically acceptable carriers.2. The composition of claim 1 , wherein the NSAID is aspirin claim 1 , diclofenac claim 1 , diflusnisal claim 1 , etodolac claim 1 , fenoprofen claim 1 , flubiprofen claim 1 , ibuprofen claim 1 , indomethacin claim 1 , ketoprofen claim 1 , ketorolac claim 1 , meclofenamate claim 1 , nabumetone claim 1 , naproxen claim 1 , oxaprozin claim 1 , phenylbutazone claim 1 , piroxicam claim 1 , salicylate claim 1 , sulindac claim 1 , tolmetin claim 1 , celecoxib claim 1 , rofecoxib claim 1 , etoricoxib claim 1 , lumiracoxib claim 1 , parecoxib claim 1 , polmacoxib claim 1 , valdecoxib claim 1 , chlorthalidone claim 1 , or a combination thereof.3. The composition of claim 2 , wherein the NSAID is celecoxib claim 2 , etoricoxib claim 2 , lumiracoxib claim 2 , parecoxib claim 2 , polmacoxib claim 2 , valdecoxib claim 2 , chlorthalidone claim 2 , or a combination thereof.4. The composition of claim 3 , wherein the NSAID is celecoxib.5. The composition of claim 1 , wherein the anti-hypertensive is azilsartan claim 1 , candesartan claim 1 , eprosartan claim 1 , irbesartan claim 1 , losartan claim 1 , olmesartan claim 1 , telmisartan claim 1 , valsartan claim 1 , benazepril claim 1 , captopril claim 1 , enalapril claim 1 , fosinopril claim 1 , lisinopril claim 1 , moexipril claim 1 , perindopril claim 1 , quinapril claim 1 , ramipril claim 1 , trandolapril claim 1 , or a combination thereof.6. The composition of claim 5 , wherein the anti-hypertensive is olmesartan.7. The composition ...

PYRAZOLE DERIVATIVES AND THEIR USES THEREOF

The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein U, R1, R2, R3 and Q are as defined herein. The disclosure also provides a method for treating or preventing a method for the prevention, treatment and/or alleviation of one or more autoimmune or alloimmune disease, pharmaceutical compositions and combination comprising a therapeutically effective amount of a compound, as defined herein. 2. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R2 is H.3. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R1 is H or alkyl.4. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R1 is C1-3 alkyl.5. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R3 is C6-10-aryl claim 1 , —C1-2alkyl-C6-10aryl claim 1 , 5-6 membered heterocycle claim 1 , —C1-2alkyl-5-6 membered heterocycle claim 1 , C5-6-cycloalkyl claim 1 , —C1-2alkyl-C5-6cycloalkyl or C1-6 substituted alkyl.6. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R3 is phenyl claim 1 , CH-phenyl; cyclopentyl; cyclohexyl claim 1 , CH-cyclopentyl; CH-cyclohexyl; CH—COOH or CHCHNH.7. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein U is an alkylene residue of 1-5 members.8. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein U is an alkylene residue of 2-5 members claim 1 , wherein one carbon atom is replaced by O or NR10.9. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein U is CH—CH claim 1 , CH; CH—O claim 1 , O—CH; or CH—NH—CH.10. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein when Q is comprising R4 claim 1 , said R4 is hydroxyl.11. A compound according to having the formula of compound #14 claim 1 , 15 claim 1 , 18 claim 1 , 20 claim 1 , 24 claim 1 , 28 claim 1 , 32 claim 1 , 37 claim 1 , 41 ...

Combination

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering a proteasome inhibiting compound, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl)}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, and optional additional antineoplastic agents, to a human in need thereof. 3. A combination kit comprising a combination according to together with a pharmaceutically acceptable carrier or carriers.4. A combination according to where the amount of the compound of Structure (II) is an amount selected from 5 mg to 500 mg claim 1 , and that amount is administered once per day.5. A method treating a cancer selected from: brain (gliomas) claim 1 , glioblastomas claim 1 , Bannayan-Zohana syndrome claim 1 , Cowden disease claim 1 , Lhermitte-Duclos disease claim 1 , breast claim 1 , inflammatory breast cancer claim 1 , Wilm's tumor claim 1 , Ewing's sarcoma claim 1 , Rhabdomyosarcoma claim 1 , ependymoma claim 1 , medulloblastoma claim 1 , colon claim 1 , head and neck claim 1 , kidney claim 1 , lung claim 1 , liver claim 1 , melanoma claim 1 , ovarian claim 1 , pancreatic claim 1 , prostate claim 1 , sarcoma claim 1 , osteosarcoma claim 1 , giant cell tumor of bone claim 1 , thyroid claim 1 ,Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia. Acute lymphoblastic T cell leukemia, Plasmacytoma, immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocyte leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular ...

Combination comprising a btk inhibitor and an akt inhibitor

A novel combination comprising a BTK inhibitor, for example: 1-[(3R)-3-[ 4 -amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]pipiperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt thereof, and an AKT inhibiting compound, for example: N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, and optional additional antineoplastic agents; pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which BTK inhibition and/or AKT inhibition is beneficial, e.g., cancer.

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 131-. (canceled)32: A compound selected from:(a) (2R,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(b) (2S,4S)-5-(2′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(c) (2S,4S)-5-(3′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(d) (2S,4S)-5-(3′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid ethyl ester;(e) (2S,4S)-5-(3′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 2-methoxy-ethyl ester;(f) (2S,4S)-5-(3′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 2-(2-methoxy-ethoxy)-ethyl ester;(g) (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(1-hydroxy-1H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(h) (2S,4S)-5-(2′-Fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(1-hydroxy-1H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(i) (2S,4S)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxymethyl-4-[(1H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(j) (2S,4S)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxymethyl-4-[(1-hydroxy-1H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(k) (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(1H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid;(l) (S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(2H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid;(m) (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(5-methyl-2H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid;(n) (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(5-hydroxy-2H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid;(o) (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(5-hydroxy-2H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid ethyl ester;(p) (2S,4S)-4-[(5-Chloro-2H-[1,2,4]triazole-3-carbonyl)-amino]-5-(2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-pentanoic acid;(q) (2S,4S)-5-Biphenyl-4- ...

Dye-stabilized nanoparticles and methods of their manufacture and therapeutic use

Described herein are nanoparticles which are largely made of (e.g., 90 wt. %) hydrophobic drugs and are stabilized by water soluble dyes. The nanoparticles can range in size from 30 nm to 150 nm and have highly negative surface charge (e.g., −55 mV). These nanoparticles are highly soluble in water, stable for days in PBS buffer and can be easily lyophilzed and reconstituted in water. Using quantitative self-assembly prediction calculations, topochemical molecular descriptors were identified and validated as highly predictive indicators of nano-assembly, nanoparticle size, and drug loading. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. The nanoparticles exhibited remarkable anti-tumor efficacy in vitro and in vivo in models of hepatocellular carcinoma.

COMPOSITIONS AND METHODS OF TREATMENT FOR NEUROLOGICAL DISORDERS COMPRISING DEPRESSION

This invention, in at least some embodiments, relates to an inventive molecule, compositions comprising same, and methods of use thereof for treatment of a neurological disorder. 114.-. (canceled)15. The method of claim 26 , wherein said subtype includes one or more of disruptive mood dysregulation disorder (in children up to the age of 18) claim 26 , major depressive disorder (including major depressive episode) claim 26 , persistent depressive disorder (dysthymia) claim 26 , premenstrual dysphoric disorder claim 26 , substance/medication-induced depressive disorder claim 26 , depressive disorder due to another medical condition claim 26 , other specified depressive disorder claim 26 , unspecified depressive disorder; depression with another feature claim 26 , including but not limited to anxious distress; mixed features; melancholic features; atypical features (depression that includes the ability to temporarily be cheered by happy events claim 26 , increased appetite claim 26 , excessive need for sleep claim 26 , sensitivity to rejection claim 26 , and a heavy feeling in the arms or legs); psychotic features; catatonia; seasonal pattern depression (also referred to as seasonal affective disorder); or treatment-resistant depression (TRD).16. The method of claim 26 , further comprising delaying disease onset in individuals at risk for disease development according to one or more predictive markers.17. The method of claim 26 , further comprising administering a drug selected from the group consisting of tricyclic antidepressant compounds (TCAs) claim 26 , selective serotonin re-uptake inhibitors (SSRIs) claim 26 , monoamine oxidase inhibitors (MAOIs) claim 26 , serotonin-norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants.18. The method of claim 17 , wherein said:a. TCA is selected from the group consisting of imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline;b. SSR1 is selected from the group ...

JAK1 PATHWAY INHIBITORS FOR THE TREATMENT OF CYTOKINE-RELATED DISORDERS

This disclosure relates to JAK1 pathway inhibitors and the use thereof in treating cytokine-related diseases or disorders such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and CAR-T-cell-related encephalopathy syndrome (CRES). 1. A method for treating cytokine release syndrome in a subject , said method comprising administering to the subject one or more pharmaceutical compositions each comprising a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile , or a pharmaceutically acceptable salt thereof , and one or more pharmaceutically acceptable carriers.29-. (canceled)10. The method of claim 1 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2 claim 1 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.1114-. (canceled)15. The method of claim 1 , further comprising administering tocilizumab to said subject.16. The method of claim 1 , further comprising administering a corticosteroid to said subject.17. The method of claim 1 , further comprising administering prednisone to said subject.18. The method of claim 1 , further comprising administering tocilizumab and a corticosteroid to said subject.19. The method of claim 15 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2 claim 15 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.20. The method of claim 16 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2 claim 16 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.21. The method of claim 17 , wherein the JAK1 selective pathway inhibitor ...