СОЕДИНЕНИЯ И СПОСОБЫ ИНГИБИРОВАНИЯ ВЗАИМОДЕЙСТВИЯ БЕЛКОВ BCL С КОМПОНЕНТАМИ СВЯЗЫВАНИЯ

Настоящее изобретение относится к гетероциклическим соединениям формулы I ! ! где Y означает -(С=O)-, Х означает -N(R10)-, А означает -C(A1)(A2)-, В означает О, S, -(С=O)- или характеризуется формулой ! ! где D означает N или СR10 и где значения остальных заместителей раскрыты в формуле изобретения. Соединения формулы 1, а также композиции на его основе обладают способностью ингибировать белки семейства bcl-2, что обуславливает возможность применения таких соединений и композиций при лечении или модулировании нарушений, ассоциированных с гиперпролиферацией, таких как рак. 7 н. и 13 з.п. ф-лы.

СПОСОБ ПОЛУЧЕНИЯ N-ГИДРОКСИ-3-[4-[[[2-(2-МЕТИЛ-1Н-ИНДОЛ-3-ИЛ)ЭТИЛ]АМИНО]МЕТИЛ]ФЕНИЛ]-2Е-2-ПРОПЕНАМИДА И ИСХОДНЫХ МАТЕРИАЛОВ ДЛЯ НЕГО

Изобретение относится к способу получения N-гидрокси-3-[4-[[[2-(2-метил-1Н-индол-3-ил)этил]амино]метил]фенил]-2Е-2-пропенамида, включающего: (а) объединение при перемешивании гидроксида натрия и гидрохлорида метилового эфира (Е)-3-(4-{[2-(2-метил-1Н-индол-3-ил)этиламино]метил}фенил)акриловой кислоты в растворе с получением смеси при температуре ниже около -10°С; и затем (б) добавление гидроксиламина к полученной смеси с получением N-гидрокси-3-[4-[[[2-(2-метил-1Н-индол-3-ил)этил]амино]метил]фенил]-2Е-2-пропенамида, после чего при необходимости проведение (в) кристаллизации N-гидрокси-3-[4-[[[2-(2-метил-1Н-индол-3-ил)этил]амино]метил]фенил]-2Е-2-пропенамида и необязательно (г) выделение целевого продукта. Способ снижает образование побочных продуктов и позволяет получать целевой продукт с чистотой, достаточной для производства лекарственных препаратов. 15 з.п. ф-лы, 5 пр.

ПРОИЗВОДНЫЕ ПИРРОЛИДИНА

Изобретение относится к соединениям формулы (I), обладающим свойствами антагониста рецептора нейрокинина-3 (NK-3), лекарственному средству на их основе, их применению и способу лечения с их использованием. Соединения формулы (I) могут найти применение для лечения депрессии, боли, психоза, болезни Паркинсона, шизофрении, беспокойства и синдрома гиперактивности с дефицитом внимания (ADHD). В общей формуле (I) Rпредставляет собой водород, галоген, низший алкил; n представляет собой 1, 2, если n представляет 2; Rпредставляет собой водород или метил; R3 представляет собой (CH2)-C(O)NH, где r представляет собой 1 или 2, или представляет собой неароматическую гетероциклическую группу, где X представляет собой N или СН; Y представляет собой -C(R)(R)-; -N(R)-, -S(O)или О; Rпредставляет собой водород, ди-низший алкил или =O; о и m могут быть независимо друг от друга 0, 1 или 2; р представляет собой 0, 1 или 2. 6 н. и 16 з.п. ф-лы, 1 табл., 321 пр.

ПРОИЗВОДНЫЕ 3-АМИНОПИРРОЛИДИНА В КАЧЕСТВЕ МОДУЛЯТОРОВ РЕЦЕПТОРОВ ХЕМОКИНОВ

Изобретение относится к новым соединениям формулы I: !! его оптическим изомерам или смеси их оптических изомеров и фармацевтически приемлемым солям, где: ! его оптические изомеры или смесь его оптических изомеров и фармацевтически приемлемые соли, где: ! R1 независимо выбирают из группы, состоящей из арила, гетероарила, арилкарбоксамидо, гетероарилкарбоксамидо, арилокси, арилалкокси или ариламино, и где указанные группы арила, арилалкила или гетероарила могут быть замещены 0-3 заместителями R1a, где R1a независимо выбирают из группы, состоящей из галогена, алкила, алкенила, алкокси, алкоксиалкила, гидроксиалкила, моно-, ди- или тригалогеноалкила, моно-, ди- или тригалогеноалкокси, моно- или дизамещенного аминоалкила, аминокарбонила, моно- или дизамещенного аминоалкила, аминокарбонила, моно- или дизамещенного аминокарбонила, циклического аминокарбонила, алкилсульфонила, остатка этерифицированной карбоновой кислоты, арилкарбониламино, карбамата, R1b-арила или R1b-гетероарила, где ! R1b представляет ...

ИНГИБИТОРЫ ДПП-IV

Настоящее изобретение относится к новым соединениям общей формулы (I) или их фармацевтически приемлемым солям, где Z представляет собой фенил; где Z может быть замещен одним или более R8, где R8представляет собой галоген; R1, R4 представляют собой Н; R2, R5 представляют собой H; R3 представляет собой Н; Х выбран из группы, состоящей из S(O)2 и С(O); R6, R7 независимо выбраны из группы, состоящей из Н, (C(R29R30))m-X1-Z1 и (C(R31R32))n-X2-X3-Z2 и С1-4алкил, который несет замещение одним или более R29a, где R29a независимо выбран из группы, состоящей из R29b и Z1, при условии, что R6 и R7 выбирают таким образом, чтобы R6 и R7 не были одновременно независимо выбраны из группы, состоящей из Н, СН3, СН2СН3, СН2СН2СН3и СН(СН3)2; R29, R29b, R30, R31, R32 независимо выбраны из группы, состоящей из Н, C1-6алкила и N(R32a)-C1-6алкила, R32a представляет собой C1-6алкил; m равно 0, 1 или 2; n равно 2; X1 независимо выбран из группы, состоящей из ковалентной связи, -C1-6алкила и -C1-6алкил-N(R33)-; ...

ЗАМЕЩЕННЫЕ ПИРРОЛИДИНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ФАКТОРА XIA ДЛЯ ЛЕЧЕНИЯ ТРОМБОЭМБОЛИЧЕСКИХ ЗАБОЛЕВАНИЙ

Изобретение относится к соединениям общей формулы (I), их фармацевтически приемлемым солям, фармацевтическим композициям, содержащим указанные соединения. Соединения общей формулы (I) являются ингибиторами фактора XIa и пригодны для профилактики и/или лечения тромбоэмболических заболеваний. 5 н. и 17 з.п. ф-лы, 1 табл., 115 пр.

ПРОИЗВОДНЫЕ НАФТАЛИНА, ПРИГОДНЫЕ В КАЧЕСТВЕ ЛИГАНДОВ РЕЦЕПТОРОВ 3 ГИСТАМИНА

Изобретение относится к новым производным нафталина формулы I , а также к их фармацевтически приемлемым солям, которые могут найти применение для лечения и/или профилактики заболеваний, связанных с модулированием Н-3 рецепторов. В формуле I R1 выбран из водорода, низшего алкила, фенила, фенила-низшего алкила и низшего алкоксиалкила; R2 выбран из водорода, низшего алкила, С3-С7-циклоалкила, низшего алкоксиалкила или низшего алкилсульфанилалкила (все значения R1 и R2 приведены в формуле изобретения); или R1 и R2 вместе с атомом азота, к которому они присоединены, образуют 4-7-членное насыщенное или частично ненасыщенное гетероциклическое кольцо, которое может содержать еще один гетероатом, выбранный из атомов азота, кислорода и серы, где указанное гетероциклическое кольцо может быть незамещенным или замещенным 1-2 группами, либо оно может быть конденсировано с незамещенным фенильным кольцом; ! А выбран из ! или ! (значения R3-R7, R9, R10, X, m, n, t, p, q и s приведены в формуле изобретения ...

АЗАЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ ДЛЯ ПРИМЕНЕНИЯ ПРИ ЛЕЧЕНИИ ОПОСРЕДОВАННЫХ СЕРОТОНИНОМ ЗАБОЛЕВАНИЙ

Изобретение относится к новым соединениям формулы (I) ! ! где Z означает ! ! где R означает водород, С4-С6циклоалкильную группу, присоединенную либо через один из атомов углерода кольца, либо через присоединенную к кольцу низшую алкиленовую группу, или линейно-цепочечную или разветвленную низшую алкильную группу или низшую гидроксиалкильную группу, или низшую аминоалкильную группу, или фенил (низшую алкильную) группу, необязательно замещенную 1-2 заместителями, выбранными из низшего алкила, низшего алкокси, галогена и гидрокси, или гетероарил (низшую алкильную) группу, где гетероарил выбран из группы, состоящей из тиенила, замещенного низшей алкильной группой, имидазолила, и тиазолила, замещенного низшей алкильной группой; n означает 0 или 1; или ! Z означает группу ! ! где R означает низшую алкильную группу; X1 означает метилен или NH группу; и Х2 означает метилен; или Х1 означает метилен и Х2 означает метилен или связь; или X1 означает метилен и Х2 означает О, S или связь; Y1 означает ...

АГОНИСТЫ РЕЦЕПТОРА МЕЛАНОКОРТИНА-4

Изобретение относится к области органической химии, а именно к соединению формулы 1 или его фармацевтически приемлемой соли, где R1 представляет собой C2-C5 алкил. Также изобретение относится к фармацевтической композиции на основе соединения формулы 1, ее применению для получения лекарственного средства и к способу лечения или профилактики указанных заболеваний. Технический результат: превосходная агонистическая активность в отношении рецепторов меланокортина, проявляемая соединением формулы 1, что может быть использовано для предотвращения или лечения ожирения, диабета, воспалений и эректильной дисфункции. 10 н. и 9 з.п. ф-лы, 10 табл., 16 пр. Формула 1 ...

ПРОИЗВОДНЫЕ 2-ФЕНОКСИ И 2-ФЕНИЛСУЛЬФОНАМИДА С ССR3 АНТАГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ ДЛЯ ЛЕЧЕНИЯ АСТМЫ И ДРУГИХ ВОСПАЛИТЕЛЬНЫХ ИЛИ ИММУНОЛОГИЧЕСКИХ ЗАБОЛЕВАНИЙ

... 1. Производное бензолсульфонамида, имеющее формулу (I), его таутомерные и стереоизомерные формы и его соли где Х представляет О или S; R1 представляет водород, галоген, гидрокси, нитро, циано, С1-6алкоксикарбонил, амино, С1-6алкиламино, ди(С1-6алкил)амино, С1-6алканоил, фенил, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами, или С1-6алкокси, необязательно замещенный одним, двумя или тремя галогенами; R2 представляет водород, галоген, гидрокси, нитро, циано, С1-6алкоксикарбонил, С1-6алкиламино, ди(С1-6алкил)амино, С1-6 алканоил, фенил, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами, или С1-6алкокси, необязательно замещенный одним, двумя или тремя галогенами; R3 представляет водород, галоген, гидрокси, нитро, циано, амино, карбокси, тетразолил, С1-6алкокси, С1-6алкоксикарбонил, С1-6алканоил, С1-6 алканоиламино, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами или гидрокси; R4 представляет или где R40 представляет С1-6алкил, ...

БЕНЗИЛЭФИРАМИНЫ, ПОЛЕЗНЫЕ КАК АНТАГОНИСТЫ CCR-5

... 1. Соединение общей формулы I его энантиомеры, диастереомеры, соли и сольваты, в которой Х представляет собой связь или кислород; m представляет собой 0, 1, 2, 3 или 4; n представляет собой 0, 1 или 2; R1 представляет собой необязательный заместитель, независимо выбираемый в каждом случае из галогена, алкила, галоалкила, нитро или -NR5R6; R2 представляет собой a) водород; или b) алкил, циклоалкил, алкенил, арил или гетероарил, любой из которых может быть, необязательно, замещен группой Y; Y представляет собой a) арил или гетероарил, каждый из которых может быть, необязательно, замещен одним или несколькими Z1, Z2, Z3; b) циклоалкил или гетероцикло, каждый из которых может быть, необязательно, замещен одним или несколькими Z1, Z2, Z3; c) -COOR7; d) -NR8R9; e) CHR10(OR11); f) -C(=O)-NR8R9; g) -NR12-(C=O)-NR8 R9; h) -CN; i) -C(=N-OR13); j) алкокси; R3 и R4 независимо выбирают из a)водорода; b) алкила, циклоалкила, (циклоалкил)алкила, арила, (арил)алкила, гетероцикло, (гетероцикло)алкила, гетероарила ...

НОВОЕ ПРОИЗВОДНОЕ АРИЛАМИДИНА ИЛИ ЕГО СОЛЬ

... 1. Производное ариламидина или его соль, представленное следующей общей формулой: где Х представляет собой незамещенную или замещенную низшую алкиленовую или алкениленовую группу; G1 представляет собой атом кислорода, атом серы или иминогруппу; G2 представляет собой атом углерода или атом азота; Ra представляет собой, по меньшей мере, одну группу, выбранную из группы, состоящей из атома водорода, атома галогена и незамещенных или замещенных алкильной, циклоалкильной и алкоксигрупп; R1 представляет собой незащищенную или защищенную или незамещенную или замещенную амидиногруппу; и R2 представляет собой группу, представленную следующей формулой (1), (2) или (3): (1) где R3 представляет собой атом водорода, аминозащитную группу, незамещенную или замещенную циклоалкильную или алкенильную группу или группу, представленную следующей формулой: где W представляет собой незамещенную или замещенную низшую алкиленовую группу или прямую связь; Yc представляет собой незамещенную или замещенную С2-4 низшую ...

ПРОИЗВОДНЫЕ 1-ПРОПАНОЛА И 1-ПРОПИЛАМИНА И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ГЛЮКОКОРТИКОИДНЫХ ЛИГАНДОВ

... 1. Соединение формулы (IA) где R1 означает арил, гетероарил или С5-С15циклоалкил, каждый из которых необязательно и независимо содержит от одного до трех заместителей, причем каждый заместитель группы R1 независимо означает C1-С5алкил, С2 -С5алкенил, С2-С5алкинил, С3-С8циклоалкил, гетероциклил, арил, гетероарил, C1-C5алкокси, С2-С5 алкенилокси, С2-С5алкинилокси, арилокси, ацил, С1-С5алкоксикарбонил, С1-С5алканоилокси, С1-С5алканоил, ароил, аминокарбонил, алкиламинокарбонил, диалкиламинокарбонил, аминокарбонилокси, С1-С5алкиламинокарбонилокси, С1-С5диалкиламинокарбонилокси, С3-С5циклоалкиламинокарбонилокси, С1-С5алканоиламино, С1-С5алкоксикарбониламино, С1-С5алкилсульфониламино, аминосульфонил, С1-С5алкиламиносульфонил, С1-С5диалкиламиносульфонил, галоген, гидрокси, оксо, карбокси, циано, трифторметил, трифторметокси, нитро или амино, причем атом азота необязательно независимо моно- или дизамещен группой С1-С5алкил или арил; или уреидо, причем каждый атом азота необязательно независимо замещен ...

ПРОИЗВОДНЫЕ ПИПЕРАЗИНИЛ-3-АМИНОПИРРОЛИДИНА В КАЧЕСТВЕ АНТАГОНИСТА CCR2

... 1. Соединение, имеющее следующую формулу IФормула 1Формула 2Формула 3иФормула 4в которых:Rможет быть независимо выбран из групп, состоящих из атома водорода,C-Cалкила, фенила, бензила, бензоила, бензолсульфонила,C-Cалкилкарбонила,C-Cциклоалкила, формулы II, III и IV;R,RиRмогут быть независимо выбраны из групп, состоящих из атома водорода,C-Cалкила, фенила и бензила;все бензильные группы, включенные как частьR, могут иметь множество заместителей, независимо выбранных из групп, состоящих изC-Cалкила,C-Cгалогеналкила, атома галогена и циано;R,R,R,R,R,R,RиRмогут быть независимо выбраны из атома водорода иC-Cалкила;RиR,RиRмогут быть независимо выбраны как карбонильная группа;причем указанный галоген выбран из групп, состоящих из атома фтора, хлора и брома.2. Соединение по п.1, причем соединение выбрано из групп, состоящих изN-{[1-(2-(1-(фениламинокарбонил)пиперазин-4-ил)этил)пирролидин-(3R)-илкарбамоил]метил}-3-трифторметилбензамида,N-{[1-(2-(1-(п-толиламинокарбонил)пиперазин-4-ил)этил)пирролидин ...

3-ФЕНОКСИМЕТИЛПИРРОЛИДИНОВЫЕ СОЕДИНЕНИЯ

... 1. Соединение формулы I:где Rвыбран из -Cалкила, -Cциклоалкила, необязательно замещенного 1 или 2 атомами фтора, -Cалкенила и -Cалкинила;R-Rнезависимо выбраны из водорода, галогена, -Cалкила, -CF, -O-Cлкила, -CN, -C(O)-Cалкила, -S-Cалкила, -Cциклоалкила и -NO; или Rи Rвзяты вместе с образованием -CH=CH-CH=CH-; или Rи Rвзяты вместе с образованием -CH-CH=CH-CH-;при условии, что когда Rпредставляет этил, Rпредставляет фтор-, Rпредставляет хлор-, Rпредставляет водород, и Rпредставляет водород, то Rне представляет фтор или хлор;или его фармацевтически приемлемая соль.2. Соединение по п.1, где Rпредставляет -Cалкил, выбранный из этила, пропила, изопропила, бутила, изобутила и 3-пентила.3. Соединение по п.1, где Rпредставляет -Cциклоалкил, необязательно замещенный 1 или 2 атомами фтора, выбранный из циклопропила, циклопентила, циклогексила и 4,4-дифторциклогексила.4. Соединение по п.1, где Rпредставляет бут-3-енил.5. Соединение по п.1, где Rпредставляет проп-2-инил.6. Соединение по п.1, где Rпредставляет ...

2-АМИНОБЕНЗАМИДНОЕ ПРОИЗВОДНОЕ

... 1. Ингибитор активации VR1, который включает 2-аминобензамидное производное общей формулы (I) или его соль в качестве активного ингредиента ! ! где - бензольное кольцо или пиридиновое кольцо, ! R3 - одинаковые или отличные друг от друга и каждый представляет собой H, галоген, галоген-низший алкил, циано, нитро, низший алкил, -NR4R5, -низший алкилен-NR4R5, -низший алкилен-NR6-CO2-низший алкил, -O-низший алкил, -O-галоген-низший алкил, фенил или тиенил, ! m - 1, 2 или 3, ! R4 и R5 - одинаковые или отличные друг от друга и каждый представляет собой H или низший алкил, где R4 и R5 могут быть объединены со смежным атомом азота с образованием моноциклического азотсодержащего насыщенного гетерокольца, которое может быть замещено низшим алкилом или группой низший алкилен-OH, ! R6 - H или низший алкил, !- моноциклическое гетерокольцо, циклоалкен или бензольное кольцо, ! где кольцо, представленное как А, может быть замещено 1-4 группами, выбранными из групп -OH, -низший алкилен-OH, -низший алкилен-NR4R5 ...

N-ФЕНИЛ-ФЕНИЛАЦЕТАМИДНЫЕ НЕНУКЛЕОЗИДНЫЕ ИНГИБИТОРЫ ОБРАТНОЙ ТРАНСКРИПТАЗЫ

... 1. Соединение формулы I ! , ! где R1 обозначает галоген, C1-6алкил, С3-7циклоалкил, C1-6алкоксигруппу, нитрогруппу или аминогруппу; ! R2 обозначает водород или фтор; ! R3 обозначает фенил, замещенный от одного до трех заместителями, независимо выбранными из группы, включающей C1-6алкил, C1-6галоалкил, С3-8циклоалкил, галоген, цианогруппу или нитрогруппу; ! R4 обозначает водород, C1-6алкил или галоген; ! R5 обозначает водород, C1-6алкил, С3-7циклоалкил или галоген; ! R6 и R7 обозначают водород, C1-6алкил, SO2C1-6алкил или C1-3ацил; ! Х обозначает ОН, C1-6алкоксигруппу или NRaRb; ! один из Ra или Rb обозначает водород, C1-6алкил, С3-6циклоалкил или C1-6гидроксиалкил, а другой из Ra или Rb выбирают из группы, включающей ! (а) водород, ! (б) C1-6алкил, ! (в) C1-6гидроксиалкил, ! (г) C1-6карбоксиалкил, ! (д) (алкилен)rNRcRd, ! (е) SO2-С1-6алкил, и ! (ж) пиридинилметил, ! (з) гетероциклилалкил, где названный гетероциклил обозначает группу А1, А2, A3, А4 или А5: ! ! при этом названная гетероциклильная ...

ПРОИЗВОДНЫЕ ФЕНИЛГУАНИДИНА

... 1. Соединение формулы (I)или его соль, или любая из его стереоизомерных форм, или их смесь, в которой:Rи R' независимо выбраны из группы, состоящей из H, (С-C)алкила, CF, F, Cl, Br, I, -CN, OH, NH, -OCHи NO; при условии, что, по меньшей мере, один из Rи R' отличается от H;A представляет собой радикал, выбранный из прямого или разветвленного (C-C)алкила или из одной из известных карбоциклических или гетероциклических кольцевых систем с 1-2 кольцами, в которых каждое из колец, образующих кольцевую системусодержит 5-7 членов, где каждый член независимо друг от друга выбирается из C, N, O, S, CH, CH, NH;представляет собой насыщенное, частично ненасыщенное или ароматическое кольцо;при этом A замещен одним или несколькими радикалами, выбранными из группы, состоящей из H, галогена, нитро, циано, прямого или разветвленного (C-C)алкила, галоген-(C-C)алкила, прямого или разветвленного (C-C)алкенила, -OR, -COR, -COOR, -OC(O)R, -C(O)NRR, -NRR, -RNHR, -SR, -SO-R, -SO-Rи -SONRR; гдекаждый Rнезависимо ...

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 ...

АЛКАЛОИДНЫЙ ЭФИР И КАРБАМАТНЫЕ ПРОИЗВОДНЫЕ И ИХ МЕДИЦИНСКИЕ КОМПОЗИЦИИ

... 1. Соединение общей формулы (I)где X может представлять собой O или S;X′ может представлять собой O или S;Y может представлять собой NH или отсутствовать;Rвыбран из группы, состоящей из арила, гетероарила, арил(C-C)алкила, гетероарил(C-C)алкила и группы формулы (a) или (b)где Rи Rявляются одинаковыми или различными и могут независимо представлять собой H или выбраны из группы, состоящей из (C-C)циклоалкила, арила, арил(C-C)алкила, гетероарила и гетероарил(C-C)алкила, которые могут быть необязательно замещены одним или более заместителями, выбранными из группы, состоящей из атомов галогена, OH, (C-C)галогеналкила, (C-C)алкокси, оксо (=O), -SH, -NO, -CN, -CONH, -COOH, (C-C)алкоксикарбонила, (C-C)алкилсульфанила, (C-C)алкилсульфинила, (C-C)алкилсульфонила и (C-C)алкила или, когда оба Rи Rнезависимо представляют собой арил или гетероарил, они могут быть соединены друг с другом через (CH)с r=0-2, образуя трициклическую кольцевую систему, где любая из метиленовых (CH)групп может быть необязательно ...

ФЕНИЛПИРРОЛИДИНОВЫЕ СОЕДИНЕНИЯ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И СПОСОБ ЛЕЧЕНИЯ ИЛИ ПРОФИЛАКТИКИ МЕЛАТОНИНЕРГИЧЕСКИХ ЗАБОЛЕВАНИЙ

... 1. Фенилпирролидиновые соединения, выбранные из группы, включающей ! (S)-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-2,2-диметил-пропионамид, ! (S)-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-изобутирамид, ! (S)-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-пропионамид, ! (S)-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-ацетамид, ! (S)-[1-(3-метокси-фенил)-пирролидин-3-ил]-циклопропанкарбоксамид, ! (S)-[1-(3-метокси-фенил)-пирролидин-3-ил]-бутирамид, ! (S)-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-3-метил-бутирамид, ! метил(S)-[1-(3-метокси-фенил)-пирролидин-3-ил]-карбамат, ! этил(S)-[1-(3-метокси-фенил)-пирролидин-3-ил]-карбамат, ! (S)-2,2,2-трифтор-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-ацетамид, ! (S)-2-фтор-N-[1-(3-метокси-фенил)-пирролидин-3-ил]-пропионамид, ! (S)-3-[1-(3-метокси-фенил)-пирролидин-3-ил]-1-этилмочевину ! и их фармацевтически приемлемые соли и гидраты. ! 2. Применение соединений по п.1 для изготовления лекарственного средства при лечении или профилактике мелатонинергических заболеваний.

АРИЛАМИНЫ ДЛЯ ЛЕЧЕНИЯ СОСТОЯНИЙ, АССОЦИИРОВАННЫХ С КИНАЗОЙ-3 ГЛИКОГЕНСИНТАЗЫ (GSK-3)

... 1. Соединение, имеющее формулу I где Z представляет собой СН или N; Y представляет собой CONR5, NR5CO, SO2NR5, NR5SO2, CH2NR5, NR5CH2, NR5CONR5, С1-6алкилен, CH2CO, СОСН2, СН=СН, ОСН2 или СН2O; Х представляет собой СН или N; Р представляет собой фенильное кольцо или 5- либо 6-членное гетероароматическое кольцо, содержащее один или более чем один гетероатом, выбранный из N, О или S, и указанное фенильное кольцо или 5- либо 6-членное гетероароматическое кольцо возможно может быть конденсированным с 5- либо 6-членным насыщенным, частично насыщенным или ненасыщенным кольцом, содержащим один или более чем один атом, выбранный из С, N, О или S; Q представляет собой фенил или 5- либо 6-членное гетероароматическое кольцо, содержащее один или более чем один гетероатом, выбранный из N, О или S, из которых по меньшей мере один атом выбран из азота; R представляет собой СНО, фторметокси, дифторметокси, трифторметокси, С0-6 алкил(SO2)NR1R2, ОС0-6алкил(SO2)NR1R2, OC1-6алкил(SO)NR1R2, С1-6 алкил(SO)NR1R2 ...

Способ получения гетероциклических бензамидов или их солей

... . 1. Способ получения гетероциклических бензамидов общей формулы или связаны между собой с образованием азимидогруппы$ если С - Се-циклоалкильная группа, Rf - метильная группа, А - простая связь и 1 О, по меньшей мере один из заместителей R, Rj, Rj, Re - Ci - Сг-алкилсульфонильная группа или алкилсульфинильная группа или два из этих заместителей связаны между собой с-образованием а3имидогруппы, если R4. - Cj - Сб-циклоапки/1ьная группа, Rir - метильная группа, А метиленовая группа, и 1 и амидная группа связана с положением 2 пирролидина; R., - атом галогена, сульфамоильная СО метилсульфамоильная, диметилсульфамоильная или С - Сг.-алкилсульфонильная группа только в случае, если R,. R не означают одновременно г 3 где R 4. - циклоалкильная группа С - С , циклогексенильная группа, норборнильнай или адамантильная группа, А - простая связь или метилен, п О или 1 -, Rj - метил или пропйнил Re - водород, галоген. R RI ч 3 C - Cj алкильная, метоксильная, амино-, сульфамоильная, метилсульфамоильная ...

Способ получения бензамидов

СПОСОБ ПОЛУЧЕНИЯ БЕНЗАМИДОВ общей формулы ClO- lH-6l -k 0(Нз В где R- циклопропил или циклопропилметил , водород или аминогруппа, R- сульфамоил или этилсульфомоил , отличающийся тем, что, соединение общей формулы Odlla 1 : где R и R имеют указанные значения , и хлор или карбэтрксиоксигруппа , взаимодействует с хлоргидратом 1,5дихлорпентиламина в присутствии растворителя с последуиядей обработкой полученного бензамида общей фор (Л мулы do -WH-dHz odHj - d R и R имеют указанные значегде ния, О амином общей формулы R NH2 : ;о 4;; 1 где R имеет указанные значения, при температуре от до температуры кипеНиз реакционной смеси.

Способ получения пирролидин или пиперидинпроизводных бензамидов или их солей

3-(3,4-DIOXYPHENYL)-PYRROLIDINE ALS INHIBITONEN DER TYP IV - PHOSPHODIESTERASE ZUR BEHANDLUNG VON ENTZÜNDUNGSKRANKHEITEN

VERFAHREN ZUR HERSTELLUNG VON 3-AMINOPYRROLIDINE.

1,2-Ethandiolderivate und ihre Salze, Verfahren zu ihrer Herstellung und sie enthaltende gehirnfunktionsverbessernde Mittel.

1,2-Ethandiolderivate und ihre Salze, Verfahren zu ihrer Herstellung und sie enthaltende gehirnfunktionsverbessernde Mittel

CYSTEIN PROTEASE INHIBITORE

SUBSTITUIERTE HETEROCYCLISCHE BENZAMIDE, VERFAHREN ZU IHRER HERSTELLUNG UND DIESE ENTHALTENDE ARZNEIMITTEL

Verfahren zur Herstellung von optisch aktiven 3-Aminopyrrolidin-2,5-dion-derivaten und optisch aktiven 3-Aminopyrrolidin-derivaten

1-(HETERO)ARYL-3-AMINOPYRROLIDINDERIVATE ZUR VERWENDUNG ALS ANTAGONISTEN DES MGLUR3-REZEPTORS

Substituted 3-Aminopyrrolidines

... 1,173,372. Substituted 3-aminopyrrolidines. A. H. ROBINS CO. Inc. 20 March, 1967 [22 March, 1966], No. 12973/67. Heading C2C. Novel pyrrolidines I (including salts thereof) wherein R represents a phenyl, alkylphenyl, alkoxyphenyl, halophenyl or trifluoromethylphenyl group, and R1 represents an alkyl group, wherein the alkyl and alkoxy groups have up to 8 carbon atoms are obtained: (a) by reacting an amine R1NH2 with a maleimide II (prepared by the interaction of an amide, R.NH.CO.CH: CH.CO 2 H, and acetic anhydride in the presence of sodium acetate, the amide itself is obtained by reacting maleic anhydride with an amine, RNH 2 ) and subsequently reducing the resulting aspartimide compound III so obtained with lithium aluminium hydride; or (b) by reacting an amine, R1NH 2 , with a I - -R-substituted- 3 -pyrrolidinol -aryl -sulphonate. 1 -Phenyl-3-pyrrolidinol, obtained by the interaction of 1,4-dichloro-2-butanol and aniline, is converted into its p-methylbenzene ...

Amide derivatives as selective serotonin re-uptake inhibitors

BENZOIC ACID DERIVATIVES

BENZOIC ACID DERIVATIVES

N - PHENYL-INDOLINE DERIVATIVES THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Proline derivatives and their use as dipeptidyl peptidase IV inhibitors

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B

Polar-substituted hydrocarbons

Proline derivatives and their use as dipeptidyl peptidase IV inhibitors

Cyclopentyl-substituted glutaramide derivatives asinhibitors of neutral endopeptidase.

Il-8 receptor antagonists

Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds.

The compounds of formula (I) exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.

IL-8 Receptor Antagonists.

This invention relates to novel compounds of formula (I), and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase.

There are described according to the invention compounds of formula (I) (relative stereochemistry indicated), wherein RI, R2, R3 and X are as defined in the specification, together with processes for preparing them, compositions containing them and their use as pharmaceuticals. Compounds of formula (I) are indicated inter alia for the treatment of chronic bronchitis.

Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl) phenylalkyl]-azaheterocyclylamide compounds.

The compounds of formula (I) exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula (I) , compositions containing compounds of formula (I) , and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.

Retroviral protease inhibitors.

The invention relates to certain retroviral protease inhibitors, ...

Sulfamoyl-phenyl-ureido benzamidine-derivatives asantimalarial agents.

Sulfamoyl-phenyl-ureido benzamidine-derivatives asantimalarial agents

1-Aryl-2-Hydroxy-3-Isoquinoline Carboxamide HIV Protease Inhibitors, Their Preparation and Use.

HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compouns, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts with HIV virus, which is known to cause AIDS.

Proline derivatives and their use as dipeptidyl peptidase IV inhibitors.

3-Cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

Azabicycloalkanes as CCR5 modulators.

Compounds of the formula (I) [Region a]- [Region b]- [Region y]- [Region e] which are useful as modulators of chemokine activity. The invention also provides pharmaceutical formulations and methods of treatment using these compounds.

Subs itute sulf nic a id n- (aminoiminomethyl)phenylalkyl¾-azaheterocycla-mide compounds

3,3- Biarylpiperine and 2,2-biarylmorpholine derivatives.

The present invention relates to compounds of formula (i), wherein z1, z2, x, q, r1, r2 and r3 are defined as in the specification, pharmaceutical compositions containing such compounds, the use of such compounds to treat neurological and gastrointestinal disorders.

Substituted (sulfinic acid sulfonic acid sulfonylamino or sulfinylamino)N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclyclylamide compounds

2-amino-5, 6-dichlorobenzimidazole derivatives having antiviral activity.

The present invention relates to benzimidazole derivatives of formula (i)wherein: r1 represents h, c1-4 alkyl, c3-5 cycloalkyl; r2 represents h, c1-4 alkyl; or r1 and r2 together form with the nitrogen a 4 or 5 membered heterocyclic ring; r3 represents br4 or r4 wherein b represents a bridging group -c(o)nh-, -c(o)nc1-4alkyl-, or -c(o)o- and r4 represents h, c1-alkyl, c2-6alkenyl or halo (preferably fluoro); and each n is an integer independently selected from 0, 1, or 2 (preerably 0 or 1); and geometric isomers or mixtures thereof; and physiologically functional derivatives thereof, and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention relates to their preparation and pharmaceutical formulaltions containing them.

Piperidines as CCR5 modulators.

Compounds of formula 1: [Regiona]- [regionß]- [region?]- [regiond]which are useful as modulators of chemokine activity. The invention also provides pharmaceutical formulations and methods of treatment using these compounds ...

Polar-substituted hydrocarbons

Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase.

The invention provides compounds of formula i wherein r1 is optionally substituted c1-6alkyl, optionally substituted c3-7cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; n is 0, 1 or 2; and y is -nr18s(o)ur19 or a group shown below.

Hiv protease inhibitors

Pyrr lopyr olone deriv tives as inhibitors of neutrophil elastase

N-pyrrolidin-3-YL-amide derivatives as serotonin and noradrenaline reuptake inhibitors.

3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

N-[(3S)-pyrrolidin-3YL]-benzamide derivatives as monoamine re-uptake inhibitors

Proline derivatives and their use as dipeptidyl peptidase IV inhibitors

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B

Il-8 receptor antagonists

Azabicycloalkanes as ccr5 modulators

Substituted (sulfinic acid sulfonic acid sulfonylamino or sulfinylamino) n-Ä(aminoiminomethyl) phenylalkylÜ-azaheterocyclylamide compounds

Azabicycloalkanes as CCR5 modulators.

3-cycloalkylaminopyrrolidine derivates as modulators of chemokine receptors.

Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase.

Inhibitors of histone deacetylase.

Manufactoring process of new heterocyclic benzamides.

Carbonylamino-derivatives as novel inhibitors of histone deacetylase.

Arylthio compounds as antibacterial and antiviral agents

New inhibitors of histone deacetylase.

Sulfonyl-derivatives as novel inhibitors of histone deacetylase.

Antibacterial agents.

Sulfonylamino-derivatives as novel inhibitors of histone deacetylase.

IL-8 receptor antagonist.

Method of preparation of derivatives benzamidic pyrrolidine and piperidin.

New substituted heterocyclic benzamides, their methods of preparation and their application like modifiers of the behavior.

Substituted N-arylheterocycles, method for production end use thereof as medicaments.

Substituted sulfonic acid N-[(aminoiminomethyl)phenylal-kyl]-azaheterocyclamide compounds

N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors.

Sulfamoyl-phenyl-ureido benzamidine-derivatives asantimalarial agents.

Azabicycloalkanes as ccr5 modulators

Substituted (sulfinic acid sulfonic acid sulfonylamino or sulfinylamino)N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclyclylamide compounds

3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B

Pyrr lopyr olone deriv tives as inhibitors of neutrophil elastase

Subs itute sulf nic a id n- (aminoiminomethyl)phenylalkyl¾-azaheterocycla-mide compounds

11-Beta-Hydroxysteroid Dehydrogenase Type 1 Active Compounds

The use of substituted amides for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, of the general formula I. Their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11βHSDI and may be useful in the treatment of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Tri-, tetra-substituted-3-aminopyrrolidine derivative

An intermediate for production of a quinolone synthetic antibacterial agent and a therapeutic agent for an infection which exhibit broad spectrum and strong antibacterial activity for both Gram positive and Gram negative bacteria.

C7-Fluoro Substituted Tetracycline Compounds

The present invention is directed to a compound represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

3-aminopyrrolidine derivatives as modulators of chemokine receptors

The present invention relates to 3-aminopyrrolidine derivatives of the formula I: (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y and X are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as a modulator of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

4-carboxybenzylamino derivatives as histone deacetylase inhibitors

The present invention relates to a novel class of 4-carboxybenzylamino derivatives. The 4-carboxybenzylamino compounds can be used to treat cancer. The 4-carboxybenzylamino compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the 4-carboxybenzylamino derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the 4-carboxybenzylamino derivatives in vivo.

BENZAMIDE DERIVATIVES AND THEIR USE AS HSP90 INHIBTORS

The invention provides a compound which is (a) a phenylamide derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof: wherein R, R, R, R, R, Rand Rare as defined herein. The compounds are useful in the treatment of diseases mediated by HSP90. 2. A compound as claimed in wherein Ris hydroxy.3. A compound as claimed in wherein R claim 1 , R claim 1 , Rand Rare the same or different and represent hydrogen or halogen atoms or hydroxy claim 1 , unsubstituted Calkyl or unsubstituted Calkoxy groups.4. A compound as claimed in wherein either:{'sup': 6', '7', '8', '9', '8', '9, 'sub': 3', '1-4', '1-4, '(i) Rrepresents —CH, Rrepresents —CRR-A wherein Rand Rare the same or different and represent a hydrogen or halogen atom or an unsubstituted Calkyl or Calkoxy group, and A represents a phenyl ring substituted with a group W; or'}{'sup': 6', '7, 'sub': 1-4', '1-4', '1-4', '1-4', '1-4', '1-2, '(ii) Rand R, together with the nitrogen atom to which they are bonded, form a pyrrolidinyl, piperidinyl or isoindolinyl group which is substituted with a group W and is optionally further substituted with 1 or 2 groups which are the same or different and are selected from halogen atoms and unsubstituted Calkyl, Calkoxy, hydroxyl, Chaloalkyl, Chaloalkoxy, Chydroxyalkyl, cyano, nitro, —SR′ and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted Calkyl.'}5. A compound as claimed in wherein Alkrepresents a bond claim 1 , an unsubstituted Calkylene group claim 1 , or an unsubstituted —(Calkylene)-NH—(Calkylene)- group.6. A compound as claimed in wherein either:{'sup': 12', '13, 'sub': 1-6', '3-7', '6-10', '1-4', '6-10', '1-4', '3-7, '(i) Rand Rare the same or different and represent hydrogen, Calkyl, Ccarbocyclyl, Caryl, —(Calkyl)-(Caryl), or —(Calkyl)-(Ccarbocyclyl); or'}{'sup': 12', '13, 'sub': '3-7', '(ii) Rand R, together with the carbon atom to which they are bonded, ...

ARYLALKYLAMINE COMPOUND AND PROCESS FOR PREPARING THE SAME

The present invention relates to an arylalkylamine compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, a process for preparing the same, and use of the above-mentioned compound as an activating compound (CaSR agonist) of a Ca sensing receptor, a pharmaceutical composition containing the above-mentioned compound as an effective ingredient, etc. 5. The method according to claim 1 , wherein the disease of which condition is expected to be improved by activation of CaSR and/or suppression of PTH production is hyperparathyroidism.6. The method according to claim 2 , wherein the disease of which condition is expected to be improved by activation of CaSR and/or suppression of PTH production is hyperparathyroidism.7. The method according to claim 3 , wherein the disease of which condition is expected to be improved by activation of CaSR and/or suppression of PTH production is hyperparathyroidism.8. The method according to claim 4 , wherein the disease of which condition is expected to be improved by activation of CaSR and/or suppression of PTH production is hyperparathyroidism. This application is a Divisional of pending U.S. application Ser. No. 11/597,966, filed on May 4, 2007, which is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP2005/009795 which has an International filing date of May 27, 2005, which designated the United States of America, and also claims priority to Japanese Application No. 2004-158467 filed May 28, 2004, all of which are hereby incorporated by reference as if fully set forth herein.The present invention relates to a novel arylalkylamine compound which has activating effect on Ca sensing receptor (CaSR) and useful as a medicament, and a process for preparing the same.Parathyroid hormone (PTH) is a hormone having a physiological function which induces hone absorption to increase calcium (Ca) in blood, and has a role of maintaining homeostasis of Ca in blood. When ...

Diaminocyclohexane compounds and uses thereof

The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are agonists, partial agonists and modulators of the NPY Y4 receptor and may be used for the treatment and prophylaxis of various diseases and conditions.

N,N-SUBSTITUTED 3-AMINOPYRROLIDINE COMPOUNDS USEFUL AS MONOAMINES REUPTAKE INHIBITORS

The present invention provides a pyrrolidine compound of General Formula (1) 2. A pyrrolidine compound of General Formula (1) or a salt thereof according to claim 1 , wherein{'sup': '101', 'Ris'}(1) a phenyl group,(3) a benzothienyl group,(4) an indolyl group,(5) a 2,3-dihydro-1H-indenyl group,(6) a naphthyl group,(7) a benzofuryl group,(8) a quinolyl group,(12) a benzothiazolyl group,(18) a 2,4-dihydro-1,3-benzodioxinyl group,(19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group,(23) an indolinyl group,(28) an isoquinolyl group,(29) a 2,3-dihydro-1,4-benzoxadinyl group,(30) a quinoxalinyl group,(31) a quinazolinyl group,(32) a 1,2,3,4-tetrahydroquinolyl group,(40) a 1,3-benzodioxolyl group,(41) a 2,3-dihydro-1,4-benzodioxinyl group,(42) a 3,4-dihydro-1,5-benzodioxepinyl group,(44) a 1,2-dihydroquinolyl group,(45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group,(47) a benzoisothiazolyl group,(48) an indazolyl group or(49) a benzoimidazolyl group,{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'and each of which may have on the aromatic or heterocyclic ring one to three substituents selected from the groups (1-1) to (1-37) as defined in .'}3. A pyrrolidine compound of General Formula (1) or a salt thereof according to claim 2 , wherein{'sup': '101', 'Ris'}(1) a phenyl group or(3) a benzothienyl group,and each of which may have on the aromatic or heterocyclic ring one to three substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms.4. A pyrrolidine compound of General Formula (1) or a salt thereof according to claim 3 , wherein{'sup': '102', 'Ris'}(1) a phenyl group,(2) a pyridyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group(14) a thienyl group,(48) an indazolyl group,(59) a hydroxy-substituted lower alkyl group or(60) a lower alkoxy lower alkyl group,{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'and each of the ...

SMALL MOLECULE INHIBITORS OF EBOLA AND LASSA FEVER VIRUSES AND METHODS OF USE

The present invention relates to compositions and methods for the treatment of infection by enveloped viruses, such as Ebola and Lassa fever viruses. 1. (canceled)3. (canceled)5. (canceled)9. The method of claim 7 , wherein the viral infection is an Ebola infection.10. The method of claim 7 , wherein the viral infection is a Lassa fever infection. This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/379,138, filed Sep. 1, 2010, the contents of which are hereby incorporated by reference.This invention was made with government support under AI057159 awarded by the National Institutes of Health. The government has certain rights in the invention.Ebolaviruses (EboV) are enveloped negative-sense RNA viruses that cause sporadic outbreaks of rapidly fatal zoonotic infection. EboV is transmitted by close contact and virus levels increase by 75-fold/day for several days after initial infection. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines, including interferon-α and TNF-α in response to infection. The endothelial cell dysfunction associated with “cytokine storm” results in capillary leak, hypovolemic shock, disseminated intravascular coagulation and inadequate perfusion of major organs. In many outbreaks, the mortality rate from EboV infection exceeds 75% in 14 days. Current therapy is supportive; there is no effective anti-EboV vaccine or therapy. The unpredictable onset, ease of transmission, rapidity of progression, high mortality, and bio-terrorism potential have created a high level of public concern about EboV. Therefore, development of anti-EboV drugs is a high priority.Recent studies have identified promising drug targets. Previously, it was found that stepwise proteolytic cleavage of EboV envelope glycoprotein GP by the lysosomal cysteine proteases cathepsin L (Cat L) and cathepsin B (Cat B) is required for infection; and therefore, inhibitors of Cat L and Cat B are ...

CARBAMATE AND UREA INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1

This invention relates to novel compounds of the Formula (I) 2. (canceled)3. (canceled)7. The compound of claim 4 , wherein{'sub': 7', '12', '9', '12', '1', '3', '1', '3', '1', '3', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2, 'sup': 4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4, 'Cy is (C-C)bicycloalkyl or (C-C)tricycloalkyl which is optionally substituted with 1-3 groups independently selected from halogen, cyano, (C-C)alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, OR, N(R), COR, CHCOR; CON(R), CHCON(R), SON(R), SOR, NRCOR, NRCOR, NRSOR, NRCON(R)and OC(═O)N(R);'}{'sup': 1', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4, 'sub': 1', '8', '3', '8', '3', '8', '1', '3', '1', '3', '1', '3', '1', '3', '1', '3', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '1', '8', '3', '8', '3', '8', '1', '3', '1', '3, 'Ris (C-C)alkyl, (C-C)cycloalkyl, (C-C)cycloalkyl(C-C)alkyl or aryl, aryl(C-C)alkyl, each optionally substituted by 1-4 groups independently selected from halogen, cyano, (C-C)alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, OR, N(R), COR, CHCOR; CON(R), CHCON(R), SON(R), SOR, NRCOR, NRCOR, NRSOR, NRCON(R)and OC(═O)N(R), wherein the (C-C)alkyl, (C-C)cycloalkyl, (C-C)cycloalkyl(C-C)alkyl and the alkyl portion of aryl(C-C)alkyl are further optionally substituted with oxo;'}{'sup': 2', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4', '4, 'sub': 1', '8', '2', '8', '1', '3', '1', '3', '1', '3', '1', '3', '1', '3', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '1', '8', '2', '8', '1', '3', '1', '3, 'Ris (a) hydrogen; or (b) (C-C)alkyl, (C-C)alkenyl, aryl, aryl(C-C)alkyl, heteroaryl or heteroaryl(C-C)alkyl, each optionally substituted by 1-4 groups independently selected from halogen, cyano, (C-C)alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, OR, N(R), COR, CHCOR; CON(R), CHCON(R), SON(R), SOR, NRCOR, NRCOR, NRSOR, NRCON( ...

AMINOHYDROXYLATION OF ALKENES

The invention relates to a process for the aminohydroxylation of alkenes using N-oxycarbamate reagents, e.g. N-acyloxycarbamate, N-alkyloxycarbonyloxycarbamate and N-aralkoxycarbonyloxycarbamate reagents. The invention particularly relates to an intermolecular aminohydroxylation reaction that can be carried out in the absence of added base. The invention also relates to novel N-oxycarbamate reagents that are stable crystalline materials. The process of the invention is useful in the synthesis of compounds having a vicinal amino alcohol moiety, such as biologically active compounds.

MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein. 224-. (canceled)26. The compound of claim 25 , wherein R claim 25 , R claim 25 , Rand R are methyl.27. The compound of claim 26 , wherein R claim 26 , R claim 26 , R claim 26 , R claim 26 , Rand R′ are hydrogen.28. The compound of claim 26 , wherein Lis selected from —OCH— claim 26 , —CHO— claim 26 , —OC(O)— claim 26 , —N(R′)C(O)— claim 26 , —C(O)N(R′)— claim 26 , and optionally substituted ethenylene.2930.-. (canceled)31. The compound of claim 28 , wherein Lis —NH—C(O)— claim 28 , —OCH— claim 28 , —CHO— claim 28 , —OC(O)— claim 28 , and —CH═CH—.32. The compound of claim 25 , wherein Ring B is optionally substituted phenyl or optionally substituted pyridinyl.3336.-. (canceled)37. The compound of claim 32 , wherein Lis selected from —CHO— claim 32 , —O— claim 32 , and —CH(CH)O.38. The compound of claim 25 , wherein Ring C is optionally substituted phenyl.3940.-. (canceled)41. The compound of claim 25 , wherein Ring C is optionally substituted pyridinyl claim 25 , pyrimidinyl or pyrazinyl.43. (canceled)44. The compound of claim 25 , wherein Ring C is selected from the group consisting of cyclopropyl claim 25 , cyclobutyl claim 25 , cyclopentyl claim 25 , cyclohexyl and cycloheptyl.45. (canceled)46. The compound of claim 25 , wherein Ring C is selected from pyrrolidinyl claim 25 , furanyl claim 25 , pyrazolidinyl claim 25 , imidazolidinyl claim 25 , thiazolidinyl claim 25 , piperidinyl claim 25 , piperazinyl and morpholinyl.47. (canceled)48. The compound of claim 25 , wherein Ring C is optionally substituted indolyl claim 25 , quinolinyl claim 25 , isoquinolinyl or naphthyl.49. (canceled)50. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.5156-. (canceled) The present application claims priority to U.S. Provisional Application No. 61/415,713, filed Nov. 19, 2011, the entire contents of which are hereby incorporated herein ...

ASYMMETRIC SYNTHESIS METHOD, RELATED RAW MATERIAL AND PREPARATION METHOD OF (S,S)-2,8-DIAZABICYCLO[4,3,0]NONANE

The present invention relates to an asymmetric synthesis method of a chiral intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane (I) of moxifloxacin, wherein an imide or enamine compound is obtained by dehydration reaction of the pyrrolidine-3-ketone as shown in formula (II) and chiral amine(R)-1-phenylethylamine, followed by the reduction of the imide or enamine compound to obtain a compound of formula (III) or (IV) having the chiral structure of formula (I), and then a compound of formula (I) is obtained by intramolecular cyclization, and removal of the chiral auxiliary group and amino-protecting group. The present invention also relates to pyrrolidine-3-ketone as shown in formula (II) and a preparation method therefor, 2. The method according to claim 1 , characterized in that claim 1 , the reduction method is catalytic hydrogenation.3. The method according to claim 2 , characterized in that claim 2 , the catalyst in the catalytic hydrogenation is Raney nickel.4. The method according to claim 2 , characterized in that claim 2 , the catalyst in the catalytic hydrogenation is a palladium catalyst.5. The method according to claim 4 , characterized in that claim 4 , the palladium catalyst is palladium on carbon.6. The method according to claim 1 , characterized in that claim 1 , the dehydration reaction adopts a method of solvent refluxing water separation claim 1 , and the solvent is selected from the group consisting of methylbenzene claim 1 , benzene and n-hexane claim 1 , the solvent forming an azeotrope with water. The present invention relates to the technical field of preparation for a medicine intermediate, and in particular relates to the technical field of preparation for a chiral intermediate of quinolone antibacterial moxifloxacin, specifically an asymmetric synthesis method of a chiral intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane of quinolone antibacterial moxifloxacin, and simultaneously, the present invention further relates to a raw material ...

ARYLALKYLAMINE COMPOUND AND PROCESS FOR PREPARING THE SAME

An arylalkylamine compound is represented by the following formula [I-e] or a pharmaceutically acceptable salt thereof. 2. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein X is —CO— or —(CH)—CO—.37-. (canceled)8. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein Ar is a group which may be optionally substituted by group(s) selected from lower alkyl and lower alkoxy.9. (canceled)10. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein the ring portion of the group represented by Ris the following (i) claim 1 , (ii) or (iii):(i) phenyl;(ii) monocyclic heterocyclic group, hetero ring of which comprises one saturated or unsaturated 5 to 7-membered ring, and contains 1 to 4 hetero atom(s) selected from nitrogen atom, oxygen atom and sulfur atom; or(iii) bicyclic heterocyclic group, hetero ring of which comprises two saturated or unsaturated 5 to 7-membered rings being fused, and contain 1 to 6 hetero atom(s) selected from nitrogen atom, oxygen atom and sulfur atom.11. The compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein the ring portion of the group represented by Ris the following (i) claim 1 , (ii) or (iii):(i) phenyl;(ii) monocyclic heterocyclic group selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxolanyl, thiolanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isooxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyradinyl, pyridazinyl, pyranyl, perhydroazepinyl, perhydrothiazepinyl, partially or completely saturated group thereof, and a group in which the hetero atom(s) (N or S) thereof is/are oxidized; or(iii) bicyclic heterocyclic group selected from indolinyl, isoindolinyl, indolyl, indazolyl, isoindolyl, benzimidazolyl, benzotriazolyl, ...

INTRACELLULAR KINASE INHIBITORS

Intracellular kinase inhibitors and their therapeutic uses for patients with T cell malignancies, B cell malignancies, autoimmune disorders, and transplanted organs. 2. The protein kinase inhibitor of claim 1 , which is a compound of formula (X).3. The protein kinase inhibitor of claim 1 , which is a compound of formula (XII).4. The protein kinase inhibitor of claim 1 , which is a compound of formula (XIII).5. The protein kinase inhibitor of claim 1 , which is a compound of formula (XIV).6. The protein kinase inhibitor of claim 1 , which is a compound of formula (XV).7. The protein kinase inhibitor of claim 1 , which is a compound of formula (XVI).8. The protein kinase inhibitor of claim 1 , which is a compound of formula (XVII).9. The protein kinase inhibitor of claim 1 , which is a compound of formula (XVIII).10. The protein kinase inhibitor of claim 1 , which is a compound of formula (XIX).11. A composition claim 1 , comprising:(a) a pharmaceutically acceptable vehicle; and{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(b) the protein kinase inhibitor of .'}12. An adduct formed between (a) the protein kinase inhibitor of ; and (b) a DKC triad kinase domain.13. The adduct of claim 12 , wherein the DKC triad kinase comprises ITK.14. A complex claim 1 , comprising the protein kinase inhibitor of which is bound to a DKC triad kinase.15. The complex of claim 14 , wherein the DKC triad kinase comprises ITK.16. A method of inhibiting kinase activity claim 1 , comprising contacting a DKC triad kinase with the protein kinase inhibitor of or a pharmaceutically acceptable salt thereof claim 1 , whereby kinase activity of the DKC triad kinase is inhibited.17. The method of claim 16 , wherein the DKC triad kinase comprises ITK.18. The method of claim 16 , wherein the contacting occurs in a cell-free system.19. The method of claim 16 , wherein the contacting occurs in a cell.20. The method of claim 19 , wherein the cell is in vitro.21. The method of claim 19 , wherein the ...

METHODS OF LOWERING PROPROTEIN CONVERSATE SUBTILISIN/KEXIN TYPE 9 (PCSK9)

The invention relates to new methods of modulating cholesterol by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) with fatty acid derivatives; and new methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid derivative. The present invention is also directed to fatty acid bioative derivatives and their use in the treatment of metabolic diseases. 1. A method for treating a metabolic disease comprising inhibiting the production of or lowering serum levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) by administering to a patient in need thereof an effective amount of a fatty acid bioactive derivative.2. The method of claim 1 , wherein the metabolic disease is selected from hypertriglyceridemia claim 1 , severe hypertriglyceridemia claim 1 , hypercholesterolemia claim 1 , familial hypercholesterolemia claim 1 , elevated cholesterol caused by a genetic condition claim 1 , fatty liver disease claim 1 , nonalcoholic fatty liver disease (NFLD) claim 1 , nonalcoholic steatohepatitis (NASH) claim 1 , dyslipidemia claim 1 , mixed dyslipidemia claim 1 , Type I hyperlipoproteinemia (which can include 3 subtypes: Type Ia claim 1 , also called Buerger-Gruetz syndrome or familial hyperchylomicronemia; Type Ib claim 1 , also called familial apoprotein CII deficiency claim 1 , and Type Ic) claim 1 , Type V hyperlipoproteinemia claim 1 , atherosclerosis claim 1 , coronary heart disease claim 1 , Type 2 diabetes claim 1 , diabetic nephropathy claim 1 , diabetic neuropathy claim 1 , diabetic retinopathy claim 1 , metabolic syndrome claim 1 , or cardiovascular disease.3. The method of claim 2 , wherein the method further comprises administering another therapeutic agent selected from the group consisting of atorvastatin claim 2 , cerivastatin claim 2 , fluvastatin claim 2 , lovastatin claim 2 , pitavastatin claim 2 , pravastatin claim 2 , rosuvastatin claim 2 , simvastatin claim 2 , ...

C7-FLUORO SUBSTITUTED TETRACYCLINE COMPOUNDS

The present invention is directed to a compound represented by Structural Formula (A): 4. The compound of claim 3 , wherein Ris hydrogen or a (C-C)alkyl.5. The compound of claim 3 , wherein Ris selected from (C-C)alkyl claim 3 , (C-C)cycloalkyl(C-C)alkyl claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , phenyl claim 3 , phenyl(C-C)alkyl claim 3 , (C-C)cycloalkyl and halo(C-C)alkyl claim 3 , wherein each alkyl claim 3 , alkoxy and cycloalkyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl and halo; and each phenyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl claim 3 , halo claim 3 , (C-C)alkoxy claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , —CN claim 3 , halo(C-C)alkyl claim 3 , and halo(C-C)alkoxy.6. The compound of any one of claim 3 , wherein Ris selected from hydrogen claim 3 , methyl and ethyl.7. The compound of claim 6 , wherein Ris selected from the group consisting of cyclopropyl claim 6 , cyclobutyl claim 6 , cyclopentyl claim 6 , cyclopropylmethyl claim 6 , cyclobutylmethyl claim 6 , phenyl claim 6 , benzyl claim 6 , —(CH)—O—CH claim 6 , —(CH)—OCH claim 6 , —C(CH) claim 6 , —CH(CH) claim 6 , —CHC(CH) claim 6 , —CHCH(CH) claim 6 , —CH—CF claim 6 , —(CH)—CHF claim 6 , and —(CH)CH; n is 0 claim 6 , 1 claim 6 , 2 claim 6 , 3 claim 6 , 4 claim 6 , 5 or 6; and wherein the phenyl or benzyl group represented by Ris optionally substituted with one or two substituents independently selected from the group consisting of (C-C)alkyl claim 6 , halogen claim 6 , (C-C)alkoxy claim 6 , (C-C)alkoxy(C-C)alkyl claim 6 , —CN claim 6 , halo(C-C)alkyl claim 6 , and halo(C-C)alkoxy.8. The compound of claim 7 , wherein Ris selected from cyclopropyl claim 7 , cyclopropylmethyl claim 7 , cyclobutyl claim 7 , cyclopentyl claim 7 , cyclohexyl claim 7 , —(CH)—O—CH claim 7 , —C(CH) ...

(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula I as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. 6. The compound of claim 2 , wherein D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N claim 2 , O and S claim 2 ,wherein D is linked to the remainder of the compound of Formula I through a ring C atom,wherein one or more ring C atoms in ring D are optionally oxidized to form CO groups,{'sub': '2', 'wherein one or more S atoms in ring D, if present, are optionally oxidized to form independently SO groups or SOgroups, and'}{'sup': '3', 'wherein ring D is optionally substituted with one or more R.'}7. The compound of claim 2 , wherein D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O and S claim 2 ,wherein D is linked to the remainder of the compound of Formula I through a ring C atom,wherein one or more ring C atoms in ring D are optionally oxidized to form CO groups,{'sub': '2', 'wherein one or more S atoms in ring D, if present, are optionally oxidized to form independently SO groups or SOgroups, and'}{'sup': '3', 'wherein ring D is optionally substituted with one or more R.'}8. The compound of claim 2 , wherein D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N claim 2 , O and S claim 2 ,wherein D is linked to the remainder of the compound of Formula I through a ring C atom,wherein one or more ring C atoms in ring D are optionally oxidized to form CO groups,{'sub': '2', 'wherein one S atom in ring D, if present, is optionally oxidized to form an SO group or an SOgroup, and'}{'sup': '3', 'wherein ring D is optionally substituted with one or more R.'}9. The compound of claim 2 , ...

INHIBITORS OF TRKA KINASE

The present invention is directed to the compounds of Formula I which are inhibitors of tropomyosin-related kinase A (TrkA): Formula (I) or steroisomers, tautomers or a pharmaceutically acceptable salts, metabolites, isotopes, solvates or prodrugs thereof, wherein, Ra, Rb, Rc, Rd, R1, R2, L and Het-Ar are as defined herein. These compounds can be used for the preventive and/or therapeutic treatment of diseases or disorders associated with abnormal activities of nerve growth factor (NGF) receptor TrkA such as Pain, inflammation or an inflammatory diseases, Cancer, atherosclerosis, restenosis, thrombosis, Neurodegenerative diseases, Erectile Dysfunction (ED), Skin disorders, Autoimmune disease like Multiple sclerosis, Sjögren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis, Infectious diseases, diseases related to an imbalance of the regulation of bone remodeling, endometriosis, pelvic pain syndrome and diseases resulting from abnormal tissue remodelling and fibrotic disorders; or a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination. 118-. (canceled)20. The compound according to claim 19 , wherein L is selected from urea or optionally substituted urea.23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I in or a pharmaceutically acceptable salt thereof.24. The pharmaceutical composition of claim 23 , wherein the composition is used for treating or preventing a disorder or disease caused by abnormal or deregulated TrkA activity.25. The pharmaceutical composition of claim 24 , wherein said disease or disorder is selected from the group consisting of Pain claim 24 , inflammation or inflammatory diseases claim 24 , Cancer claim 24 , atherosclerosis claim 24 , restenosis claim 24 , thrombosis claim 24 , Neurodegenerative diseases claim 24 , Erectile Dysfunction (ED) claim 24 , Skin disorders claim 24 , Autoimmune disease claim 24 , Sjogren's syndrome claim 24 , ...

HISTONE DEACETYLASE INHIBITORS

Provided herein are compounds and methods for inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3). 2. The compound of claim 1 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom or a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom; Z is O claim 1 , NR claim 1 , S claim 1 , or SO; Ris Calkyl claim 1 , Chydroxyalkyl claim 1 , or Calkylene-Ccycloalkyl; Ris H claim 1 , F claim 1 , Cl claim 1 , or CH; Ris H claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , C(O)Calkyl claim 1 , or C(O)Calkylene-Ccycloalkyl; and Ris H or Calkyl.3. The compound of or claim 1 , wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom.4. The compound of or claim 1 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom.5. The compound of any one of to claim 1 , wherein Z is O or NR.6. The compound of any one of to claim 1 , wherein Ris Calkyl claim 1 , Chydroxyalkyl claim 1 , C(O)Calkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 1 , S claim 1 , N claim 1 , and N(Calkyl).7. The compound of any one of to claim 1 , wherein Ris H claim 1 , Calkyl claim 1 , Chydroxyalkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 1 , S claim 1 , N claim 1 , and N(Calkyl).8. The compound of claim 7 , wherein Ris Calkyl claim 7 , Chydroxyalkyl claim 7 , Calkylene-Ccycloalkyl claim 7 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 7 , S claim 7 , N claim 7 , and N(Calkyl).9. The compound of claim 7 , wherein Ris Calkyl claim 7 , Chydroxyalkyl claim 7 , or Calkylene-Ccycloalkyl.10. The compound of claim 7 , wherein Ris H.11. The compound of claim 7 , wherein Ris a Calkyl.12. The compound of claim 7 , wherein Ris methyl claim 7 , ...

KAPPA OPIOID AGONISTS AND USES THEREOF

Provided are compounds of Formula I: 2. The compound of claim 1 , wherein Ris a phenyl substituted with 1 claim 1 , 2 claim 1 , or 3 halogen atoms.3. The compound of claim 1 , wherein Ris methyl.4. The compound of claim 1 , wherein Ris phenyl substituted with —X-POLY.5. The compound of claim 1 , wherein Rand Rare taken together to form an optionally substituted pyrrolidinyl.6. The compound of claim 1 , wherein X is:{'sub': 2', '2', '2', '2', '2', '2', '2', '2, 'a covalent bond; —C(O)NH—; —C(O)NHCH—; —C(O)NHCHCH—; —OC(O)NH—; —C(O)NH—; —O—; —NHC(O)—; —NHC(O)CH—; —NHC(O)CHO—; —NHC(O)CHCH—; —NH—; or —NHS(O)—.'}7. The compound of claim 1 , wherein POLY is a poly(alkylene oxide) oligomer.8. The compound claim 1 , wherein POLY is a poly(ethylene oxide) oligomer.9. The compound of claim 1 , wherein POLY is end-capped with a hydroxyl group claim 1 , a lower alkoxy group claim 1 , or a trifluoromethoxy group.15. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable excipient.16. A method of treating pain or inflammation comprising administering a compound of to a patient in need thereof. This application a Continuation of U.S. application Ser. No. 14/900,039, filed 18 Dec. 2015, which is a 35 U.S.C. §371 application of International Application No. PCT/US2014/044535, filed 27 Jun. 2014, designating the United States, which claims the benefit of priority under 35 U.S.C. §119(e) to both U.S. Provisional Patent Application Ser. No. 61/929,685, filed 21 Jan. 2014, and U.S. Provisional Patent Application Ser. No. 61/841,042, filed 28 Jun. 2013, the disclosures of which are incorporated herein by reference in their entireties.The present disclosure relates to novel compounds and to their use as agonists of the kappa opioid receptor. The disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions containing such compounds. The compounds described herein relate to and/or have application(s) in ( ...

HETEROCYCLIC COMPOUND AND USE THEREOF

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. 2. The compound or salt according to claim 1 , whereinRing B is a ring [{'sub': '6-14', '(a) an optionally substituted Caryl group,'}, {'sub': '6-14', '(b) an optionally substituted Caryloxy group,'}, {'sub': '7-16', '(c) an optionally substituted Caralkyl group,'}, {'sub': '3-10', '(d) an optionally substituted Ccycloalkyl group,'}, {'sub': '3-10', '(e) an optionally substituted Ccycloalkenyl group,'}, {'sub': '3-10', '(f) an optionally substituted Ccycloalkoxy group,'}, '(g) an optionally substituted 5- to 14-membered aromatic heterocyclic group, or', '(h) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, and, 'further substituted by'}optionally having additional substituent(s).3. The compound or salt according to claim 1 , wherein{'sup': '1', 'Ris'}{'sub': '1-6', 'claim-text': (a) a halogen atom,', '(b) a cyano group,', '(c) a hydroxy group, and', {'sub': '1-6', '(d) a Calkoxy group,'}], '(1) a Calkyl group optionally substituted by 1 to 3 substituents selected from'}{'sub': '2-6', '(2) a Calkenyl group,'}{'sub': '3-10', '(3) a Ccycloalkyl group optionally substituted by 1 to 3 halogen atoms,'}{'sub': '1-6', '(4) a mono- or di-Calkylamino group, or'}(5) a 3- to 14-membered non-aromatic heterocyclic group;{'sup': '2', 'Ris a hydrogen atom;'}{'sup': '3', 'Ris'}(1) a hydrogen atom,{'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '1-6', '(b) a Calkoxy group,'}, {'sub': '3-10', 'claim-text': (i) a halogen atom, and', {'sub': '1-6', '(ii) a Calkyl group, and'}], '(c) a Ccycloalkyl group optionally substituted by 1 to 3 substituents selected from'}, '(d) a 3- to 14-membered non-aromatic heterocyclic group,, '(2) a Calkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from'}{'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '3-10', '(b) a Ccycloalkyl group,'}, '(c) a hydroxy group, and', {'sub': '1- ...

Small Molecule Inhibitors of Ebola and Lassa Fever Viruses and Methods of Use

The present invention relates to compositions and methods for the treatment of infection by enveloped viruses, such as Ebola and Lassa fever viruses. 5. The method of claim 3 , wherein the viral infection is an Ebola infection.6. The method of claim 3 , wherein the viral infection is a Lassa fever infection. This application is a divisional application of U.S. patent application Ser. No. 13/818,790, which is the National Stage application of PCT/US11/050164, filed Sep. 1, 2011, which claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/379,138, filed Sep. 1, 2010, the contents of all of which are hereby incorporated by reference.This invention was made with government support under AI057159 awarded by the National Institutes of Health. The government has certain rights in the invention.Ebolaviruses (EboV) are enveloped negative-sense RNA viruses that cause sporadic outbreaks of rapidly fatal zoonotic infection. EboV is transmitted by close contact and virus levels increase by 75-fold/day for several days after initial infection. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines, including interferon-α and TNF-α in response to infection. The endothelial cell dysfunction associated with “cytokine storm” results in capillary leak, hypovolemic shock, disseminated intravascular coagulation and inadequate perfusion of major organs. In many outbreaks, the mortality rate from EboV infection exceeds 75% in 14 days. Current therapy is supportive; there is no effective anti-EboV vaccine or therapy. The unpredictable onset, ease of transmission, rapidity of progression, high mortality, and bio-terrorism potential have created a high level of public concern about EboV. Therefore, development of anti-EboV drugs is a high priority.Recent studies have identified promising drug targets. Previously, it was found that stepwise proteolytic cleavage of EboV envelope glycoprotein GP by the lysosomal cysteine ...

(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula I as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. 2176-. (canceled)178. (canceled)179. The method of claim 177 , wherein said cancer is chosen from breast cancer claim 177 , lung cancer claim 177 , prostate cancer claim 177 , colorectal cancer claim 177 , brain cancer claim 177 , skin cancer claim 177 , blood cancer claim 177 , leukemia claim 177 , lymphoma and myeloma.180183-. (canceled)184. The method of claim 177 , wherein said neurological disease is selected from depression claim 177 , Alzheimer's disease claim 177 , Huntington disease claim 177 , Parkinson's disease claim 177 , Amyotrophic Lateral Sclerosis claim 177 , Dementia with Lewy Bodies claim 177 , and Frontotemporal Dementia.185196-. (canceled)197. The method of claim 177 , wherein said subject is a human.199. (canceled)202203-. (canceled)206. The compound of claim 200 , wherein D is a 3- to 7-membered monocycle saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N claim 200 , O and S claim 200 ,wherein D is linked to the remainder of the compound of Formula I through a ring C atom,wherein one or more ring C atoms in ring D are optionally oxidized to form CO groups,{'sub': '2', 'wherein one or more S atoms in ring D, if present, are optionally oxidized to form independently SO groups or SOgroups, and'}{'sup': '3', 'wherein ring D is optionally substituted with one or more R.'}207. (canceled)208. The compound of claim 200 , wherein D is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N claim 200 , O and S claim 200 ,wherein D is linked to the remainder of the compound of Formula I through a ring C atom,wherein one or more ring C atoms in ring D are optionally oxidized to form CO ...

SULFAMOYL-ARYLAMIDES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Inhibitors of HBV replication of Formula (I) 2. The compound according to claim 1 , wherein Rrepresents a 3-7 membered saturated ring claim 1 , containing one or more heteroatoms each independently selected from the group consisting of O claim 1 , S and N claim 1 , such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen claim 1 , halo claim 1 , C-Calkyloxy claim 1 , C(═O)—C-Calkyl claim 1 , C-Calkyl claim 1 , OH claim 1 , CN claim 1 , CFH claim 1 , CFH and CF;{'sub': 1', '2', '1', '4', '1', '3', '1', '4', '2', '2', '3, 'Or RRtogether with the Nitrogen to which they are attached form a 5-7 membered saturated ring, optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, CCalkyloxy, oxo, C(═O)—C-Calkyl, C-Calkyl, OH, CN, CFH, CFH and CF.'}3. The compound according to wherein Rrepresents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms claim 1 , such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen claim 1 , halo claim 1 , CCalkyloxy claim 1 , C(═O)—C-Calkyl claim 1 , C-Calkyl claim 1 , OH claim 1 , CN claim 1 , CFH claim 1 , CFH and CF.4. The compound according to claim 1 , wherein B represents phenyl or thiophene claim 1 , optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen claim 1 , halogen claim 1 , C-Calkyl claim 1 , CN claim 1 , CFH claim 1 , CFH and CF.5. The compound according to claim 1 , wherein Rrepresents C-Calkyl-Ror a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently ...

INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF

Disclosed are compounds, for example, compounds of formula I, 137-. (canceled)39. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein Ris a substituted or unsubstituted group selected from phosphonooxy claim 38 , phosphonoalkyloxy claim 38 , alkylcarbonyloxyalkyloxy claim 38 , aminocarbonyloxyalkyloxy claim 38 , arylcarbonyloxy claim 38 , arylalkylcarbonyloxy claim 38 , aryloxycarbonyloxy claim 38 , heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.40. The compound claim 39 , (Z)- or (E)-isomer thereof claim 39 , or a pharmaceutically acceptable salt thereof claim 39 , of claim 39 , wherein Ris a substituted or unsubstituted group selected from phosphonooxy claim 39 , phosphonoalkyloxy claim 39 , arylcarbonyloxy claim 39 , arylalkylcarbonyloxy claim 39 , aryloxycarbonyloxy claim 39 , heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.41. The compound claim 40 , (Z)- or (E)-isomer thereof claim 40 , or a pharmaceutically acceptable salt thereof claim 40 , of claim 40 , wherein Ris a substituted or unsubstituted group selected from phosphonooxy claim 40 , phosphonoalkyloxy claim 40 , arylcarbonyloxy claim 40 , arylalkylcarbonyloxy and aryloxycarbonyloxy.42. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein R′ is furanylalkyl optionally substituted with one or more of halo claim 38 , alkyl claim 38 , haloalkyl or alkoxy.43. The compound claim 42 , (Z)- or (E)-isomer thereof claim 42 , or a pharmaceutically acceptable salt thereof claim 42 , of claim 42 , wherein the furanylalkyl.44. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein R claim 38 , R claim 38 , Rand Rare independently selected from hydrogen claim 38 , halogen claim 38 , alkoxy claim 38 , alkyl claim 38 , and haloalkyl.45. The ...

Opsin-Binding Ligands, Compositions and Methods of Use

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

BICYCLOHEPTANE PYRROLIDINE OREXIN RECEPTOR AGONISTS

The present invention is directed to bicyclo[4.1.0]heptane pyrrolidine compounds which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved. 4. The compound of or a pharmaceutically acceptable salt thereof wherein Ris selected from:{'sub': 1-6', '3-6', '1-6', '1-6, '(1) —Calkyl, where the alkyl is unsubstituted or substituted with one to three substituents independently selected from hydroxyl, halo, —Ccycloalkyl, —O—Calkyl, —O(C═O)—Calkyl, and'}{'sub': '3-6', 'sup': '4', '(2) —Ccycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R.'}5. The compound of or a pharmaceutically acceptable salt thereof wherein Rand Rare selected from:(1) hydrogen,{'sub': '1-6', '(2) —Calkyl, where the alkyl is unsubstituted or substituted with one to three fluoro,'}{'sub': '1-6', '(3) phenyl, which is unsubstituted or substituted with one to three fluoro, —CN, or —Calkyl, where the alkyl is unsubstituted or substituted with one to three fluoro, and'}{'sub': 3-6', '1-6', '1-6, '(4) heteroaryl, where the heteroaryl is selected from: pyridyl, pyrimidinyl, benzothiazolyl, thiazolyl and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents selected from halo, —Ccycloalkyl, —O—Calkyl, CN, or —Calkyl, where the alkyl is unsubstituted or substituted with one to three fluoro;'}{'sup': 2a', '2b, 'Provided that at least one of Rand Ris hydrogen.'}6. The compound of or a pharmaceutically acceptable salt thereof wherein Rand Rare selected from:(1) ...

HETEROCYCLIC COMPOUND AND USE THEREOF

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. 2. The compound or salt according to claim 1 , wherein Ring B is a ring [{'sub': '6-14', '(a) an optionally substituted Caryl group,'}, {'sub': '6-14', '(b) an optionally substituted Caryloxy group,'}, {'sub': '7-6', '(c) an optionally substituted Caralkyl group,'}, {'sub': '3-10', '(d) an optionally substituted Ccycloalkyl group,'}, {'sub': '3-10', '(e) an optionally substituted Ccycloalkenyl group,'}, {'sub': '3-10', '(f) an optionally substituted Ccycloalkoxy group,'}, '(g) an optionally substituted 5- to 14-membered aromatic heterocyclic group, or', '(h) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, and, 'further substituted by'}optionally having additional substituent(s).3. The compound or salt according to claim 1 , wherein{'sup': '1', 'Ris'}{'sub': '1-6', 'claim-text': (a) a halogen atom,', '(b) a cyano group,', '(c) a hydroxy group, and', {'sub': '1-6', '(d) a Calkoxy group,'}], '(1) a Calkyl group optionally substituted by 1 to 3 substituents selected from'}{'sub': '2-6', '(2) a Calkenyl group,'}{'sub': '3-10', '(3) a Ccycloalkyl group optionally substituted by 1 to 3 halogen atoms,'}{'sub': '1-6', '(4) a mono- or di-Calkylamino group, or'}(5) a 3- to 14-membered non-aromatic heterocyclic group;{'sup': '2', 'Ris a hydrogen atom;'}{'sup': '3', 'Ris'}(1) a hydrogen atom,{'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '1-6', '(b) a Calkoxy group,'}, {'sub': '3-10', 'claim-text': (i) a halogen atom, and', {'sub': '1-6', '(ii) a Calkyl group, and'}], '(c) a Ccycloalkyl group optionally substituted by 1 to 3 substituents selected from'}, '(d) a 3- to 14-membered non-aromatic heterocyclic group,, '(2) a Calkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from'}{'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '3-10', '(b) a Ccycloalkyl group,'}, '(c) a hydroxy group, and', {'sub': '1- ...

TETRACYCLINE COMPOUNDS

The present invention is directed to a compound represented by Structural Formula (I): 125-. (canceled)27. The compound of claim 26 , wherein:{'sup': 2', '3, 'sub': 1', '3', '1', '3', '1', '3, 'Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine, piperidine, piperazine or morpholine, wherein the ring is optionally substituted with one or more substituents independently selected from fluoro, —OH, —C-Calkyl and —C-Calkylene-O—C-Calkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.'}28. The compound of claim 27 , wherein:{'sup': 2', '3, 'Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine and piperidine.'}29. The compound of claim 28 , wherein X is chloro.30. The compound of claim 29 , wherein:{'sup': 2', '3, 'Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine and piperidine, wherein the ring is fused to phenyl.'}32. The compound of claim 26 , wherein:{'sub': 3', '10', '1', '3', '1', '3', '1', '3, 'the (4-7 membered) monocyclic heterocylic ring, or a (6-13 membered) bicyclic heterocylic ring, wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic heterocyclic ring is substituted with at least one substituent independently selected from C-Ccarbocyclyl, (4-13 membered) heterocyclyl, and is optionally substituted with one or more substituents independently selected from fluoro, —OH, —C-Calkyl and —C-Calkylene-O—C-Calkyl.'}33. The compound of claim 32 , wherein:{'sup': 2', '3, 'the Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine, piperidine, piperazine or morpholine.'}34. The compound of claim 33 , wherein:{'sub': 3', '10, 'the C-Ccarbocyclyl is a phenyl.'}35. The compound of claim 34 , wherein Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from ...

METHOD OF TREATING OR PREVENTING RAS-MEDIATED DISEASES

Disclosed are compounds, for example, a compound of formula I, wherein R, R, R-R, n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition for example, cancer, mediated by the ras gene. 2. The compound or salt for use according to claim 1 , wherein Ris selected from fluorine and methoxy.3. The compound or salt for use according to claim 1 , wherein Ris selected from hydrogen claim 1 , hydroxyl claim 1 , halogen claim 1 , alkyl claim 1 , amino claim 1 , and dialkylamino.4. The compound or salt for use according to claim 3 , wherein Ris selected from hydroxy and amino.5. The compound or salt for use according to claim 1 , wherein the heterocycle of the heterocyclyl and heterocycloalkyl is selected from pyridinyl claim 1 , piperidinyl claim 1 , piperazinyl claim 1 , and pyrrolidinyl.6. The compound or salt for use according to claim 1 , wherein R′ is phenyl or arylalkyl claim 1 , optionally substituted on the phenyl or the aryl of the arylalkyl by one or more halogen atoms.7. The compound or salt for use according to claim 1 , wherein said selectivity index is at least ten.8. The compound or salt for use according to claim 7 , wherein said selectivity index is at least one hundred.9. The compound or salt for use according to claim 1 , wherein said compound is selected from:(Z)-N-(2-(dimethylamino)ethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (003),(Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(pyridin-3-yl)acetamide (004),(Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide (009),(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide (010),(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide (011),(Z)-N-benzyl-2-(5- ...

SUBSTITUTED PYRROLIDINE CARBOXAMIDE COMPOUNDS

The present disclosure provides pyrrolidine carboxamide compounds having Formula I and the pharmaceutically acceptable salts and solvates thereof, wherein A, B, X, Y, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer. 4. The compound of claim 3 , or a pharmaceutically acceptable salt or hydrate thereof claim 3 , wherein Ris Calkyl.5. The compound of claim 4 , or a pharmaceutically acceptable salt or hydrate thereof claim 4 , wherein Ris methyl.6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein X is selected from the group consisting of —S(═O)— and —C(═O)—; or X is absent.7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof claim 6 , wherein X is —S(═O)—.8. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof claim 6 , wherein X is —C(═O)—.9. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein X is absent.10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Z is selected from the group consisting of optionally substituted Calkyl claim 1 , hydroxyalkyl claim 1 , (amino)alkyl claim 1 , (alkylamino)alkyl claim 1 , (dialkylamino)alkyl claim 1 , (cycloalkylamino)alkyl claim 1 , (heterocyclo)alkyl claim 1 , optionally substituted Caryl claim 1 , optionally substituted 4- to 14-membered heterocyclo claim 1 , optionally substituted 5- to 14-membered heteroaryl claim 1 , optionally substituted Ccycloalkyl claim 1 , aralkyl claim 1 , and heteroaralkyl.11. (canceled)12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Y is —CH—.13. The compound of claim 1 , or a ...

INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF

Disclosed are compounds, for example, compounds of formula I, 137-. (canceled)39. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein Ris selected from hydroxyl claim 38 , hydroxyalkyl claim 38 , amino claim 38 , aminoalkyl claim 38 , mercapto and carboxyl.40. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from the group consisting of diazinyl claim 38 , oxazinyl claim 38 , thiazinyl claim 38 , dioxinyl claim 38 , dithiinyl claim 38 , thiophenyl claim 38 , imidazolidinyl claim 38 , pyrazolidinyl claim 38 , oxazolidinyl claim 38 , isoxazolidinyl claim 38 , dioxolanyl claim 38 , dithiolanyl claim 38 , imidazolyl claim 38 , pyrazolyl claim 38 , oxazolyl claim 38 , isoxazolyl claim 38 , thiazolyl claim 38 , isothiazolyl claim 38 , furazanyl claim 38 , and oxadiazolyl.41. The compound claim 38 , (Z)- or (E)-isomer thereof claim 38 , or a pharmaceutically acceptable salt thereof claim 38 , of claim 38 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from diazinyl claim 38 , thiophenyl claim 38 , oxazolyl claim 38 , isoxazolyl claim 38 , thiazolyl claim 38 , isothiazolyl claim 38 , dioxolanyl claim 38 , pyrazolyl and imidazolyl claim 38 , wherein the heterocyclyl is optionally substituted with one or more of halo claim 38 , alkyl claim 38 , haloalkyl claim 38 , hydroxyl claim 38 , alkoxy claim 38 , amino claim 38 , alkylamino claim 38 , dialkylamino claim 38 , mercapto claim 38 , alkylmercapto claim 38 , and carboxamido.42. The compound claim 41 , (Z)- or (E)-isomer thereof claim 41 , or a pharmaceutically acceptable salt thereof claim 41 , of claim 41 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from oxazolyl claim 41 , ...

3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula I: (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

COMPOUNDS USEFUL AS IMMUNOMODULATORS

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases. 2. A compound of wherein Ris hydrogen.3. A compound of wherein Rand Rare selected from —CHand halo.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein:{'sup': 2', '3', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', '1', '3', '3', '6', '2', 'm', '2', '2, 'one of Rand Ris hydrogen and the other is selected from —O(CH)Ph, —(CH)OPh, —O(CH)NRR, —S(O)NH(CH)NRR, —S(O)NH(CH)COH, —O(CH)pyridinyl, —(CH)NH(CH)NRR, —C(O)NH(CH)NRR, —NHC(O)(CH)NRR, —NHC(O)NH(CH)NRR; and —NHC(O)NH(CH)COH; wherein each piperidinyl group is optionally substituted with a C-Calkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C-Calkoxy, C-Calkyl, C-Calkylcarbonyl, amino, carboxy, (C-Ccycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, —CHO, —C(O)NRR, —(CH)NRR, —OCHphenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCHpyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; and'}{'sup': 6', '7', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', ...

C7-fluoro substituted tetracycline compounds

The present invention is directed to a compound represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

PIPERIDINYL-3-(ARYLOXY)PROPANAMIDES AND PROPANOATES

Disclosed are compounds of Formula 1, 2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Xis CR claim 1 , Xis CR claim 1 , Xis CR claim 1 , and Xis CR.3. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R claim 2 , R claim 2 , R claim 2 , and Rare each independently selected from(a) hydrogen, halo, and cyano; and{'sub': 1-4', '3-6', '1-4, '(b) Calkyl, Ccycloalkyl, and Calkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.'}46-. (canceled)7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Xis N claim 1 , Xis CR claim 1 , Xis CR claim 1 , and Xis CR.8. The compound or pharmaceutically acceptable salt according to claim 7 , wherein R claim 7 , R claim 7 , and Rare each independently selected from(a) hydrogen, halo, and cyano; and{'sub': 1-4', '3-6', '1-4, '(b) Calkyl, Ccycloalkyl, and Calkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.'}9.10.11.12. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Ris selected from(a) hydrogen, halo, hydroxy, and cyano; and{'sub': 1-4', '3-6', '1-4, '(b) Calkyl, Ccycloalkyl, and Calkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo.'}1314-. (canceled)15. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Rand Rare each independently selected from fluoro and methyl or together with the carbon atom to which they are attached form a cyclopropan-1 claim 1 ,1-diyl or a cyclobutan-1 claim 1 ,1-diyl.16. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of Rand Ris methyl.17. The compound or pharmaceutically acceptable salt according to claim 1 , wherein L is NR.18. (canceled)19. The compound or pharmaceutically acceptable salt according ...

IRE-1alpha INHIBITORS

The invention provides compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response and can be used as single agents or in combination therapies. 19-. (canceled)11. The compound of claim 10 , wherein Het is thienyl optionally substituted with alkyl.12. A pharmaceutical composition claim 10 , comprising the compound of claim 10 , and a pharmaceutically acceptable vehicle.13. A method of treating a disease associated with the unfolded protein response claim 10 , comprising administering to a patient in need thereof an effective amount of the compound of .15. A pharmaceutical composition claim 14 , comprising the compound of claim 14 , and a pharmaceutically acceptable vehicle.16. A method of treating a disease associated with the unfolded protein response claim 15 , comprising administering to a patient in need thereof an effective amount of the compound of . This application claims the benefit of and incorporates by reference Ser. No. 61/257,696 filed Nov. 3, 2009.The invention relates to IRE-1α inhibitors and their therapeutic uses.Protein folding stress in the endoplasmic reticulum of a cell initiates a signal transduction cascade termed the unfolded protein response or UPR. A key enzyme, inositol requiring enzyme 1 (IRE-1α), relieves protein folding stress by enhancing molecular chaperone activity and therefore protects cells from stress induced apoptosis. Inhibitors of IRE-1 α are useful for treating at least B cell autoimmune diseases, certain cancers, and some viral infections.The invention provides IRE-1α inhibitor compounds and prodrugs and pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions and methods of using the IRE-1α inhibitor compounds, prodrugs, and pharmaceutically acceptable salts thereof therapeutically to treat disorders associated with the ...

N-BENZYL-N-ARYLSULFONAMIDE DERIVATIVE AND PREPARATION AND USE THEREOF

The invention provides an N-benzyl-N-arylsulfonamide derivative, which is an N-benzyl-N-arylsulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. The N-benzyl-N-arylsulfonamide derivative is obtained by condensing a substituted nitrobenzene with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B), reducing the nitro group to an amino group, and subjecting the amino group to reductive amination, sulfonamidation; or by subjecting a substituted nitrobenzene to nitro reduction, reductive amination and sulfonamidation, and condensing the resultant intermediate with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B). It has been experimentally demonstrated that the N-benzyl-N-arylsulfonamide derivative of the invention can specifically bind to Kv1.3 potassium channel and inhibit or decrease its activity, and is useful in the treatment of autoimmune diseases caused by abnormal activation of the Kv1.3 potassium channel in human or animals. The invention further provides a medicament or a pharmaceutical composition comprising the N-benzyl-N-arylsulfonamide derivative. 4. The N-benzyl-N-arylsulfonamide derivative according to claim 1 , characterized in that the N-benzyl-N-arylsulfonamide derivative is selected from the group consisting of the following compounds:ethyl 4-(2-cyano-4-((4-fluoro-N-propylphenyl)sulfonamido)phenyl) piperazin-1-formate,ethyl 4-(2-cyano-4-(N-(4-fluorobenzyl)propanesulfonamido)phenyl) piperazin-1-formate,ethyl 4-(2-cyano-4-(N-isobutylphenylsulfonamido)phenyl)piperazin-1-formate,N-(3-cyano-4-(4-hydroxypiperidin-1-yl)phenyl)-N-(4-fluorobenzyl) propane-1-sulfonamide,4-(2-cyano-4-(N-(4-fluorobenzyl)propyl)phenyl)-N,N-dimethyl piperazin-1-formamide,ethyl 4-(4-(N-benzylpropanesulfonamido)2-cyanophenyl)piperazin-1-formate,ethyl 4-(2-cyano-4-(N-(3-fluorobenzyl)propanesulfonamido)phenyl) piperazin-1-formate,ethyl 4-(4-(4-(N-(4-chlorobenzyl)propanesulfonamido)2- ...

CARBAMATE COMPOUNDS AND METHODS OF MAKING AND USING SAME

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition. 28.-. (canceled)9. The compound of claim 1 , wherein:{'sup': '3', 'sub': 2', '2, 'Lis selected from the group consisting of a bond, —CH—, —C(O)—, and —S(O)—.'}10. The compound of claim 9 , wherein Lis —CH—.11. The compound of claim 10 , wherein Ris selected from the group consisting of indazole claim 10 , isoxazole claim 10 , pyridine claim 10 , and pyrazole claim 10 , and Ris optionally substituted by one claim 10 , two claim 10 , or three substituents selected from the group consisting of halogen claim 10 , phenyl (optionally substituted by one claim 10 , two claim 10 , or three substituents selected from the group consisting of: halogen claim 10 , methyl claim 10 , ethyl claim 10 , propyl claim 10 , t-butyl claim 10 , CFor Calkoxy) claim 10 , Calkyl (optionally substituted by one claim 10 , two or three halogens claim 10 , or hydroxyl) claim 10 , Calkoxy (optionally substituted by one claim 10 , two or three halogens) claim 10 , and heteroaryl (optionally substituted by one or two substituents each selected from Calkyl and halogen).14. The compound of claim 13 , wherein{'sup': i', 'j', 'c', 'c, 'sub': 3', '2-6, 'Rand Rare independently selected from the group consisting of: H, halogen, CH, Calkyl (optionally substituted by one, two or three moieties independently selected from R), and phenyl (optionally substituted by one or two moieties independently selected from R);'}{'sup': 'c', 'sub': 1-6', '1-6, 'Ris selected from the group consisting of halogen, Calkyl (optionally ...

3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula I: (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

TETRACYCLINE COMPOUNDS

The present invention is directed to a compound represented by Structural Formula (I): 3. The compound of claim 1 , wherein:{'sup': 1a', '2', '3, 'Y is selected from fluoro, methyl, and —CH(R)—N(R)(R);'}{'sup': '1a', 'Ris selected from hydrogen and methyl;'}{'sup': '2', 'sub': 1', '3', '2, 'Ris selected from hydrogen, C-Cstraight chained alkyl and —CH-cyclopropyl;'}{'sup': 3', '3', '2', '3, 'sub': 1', '8', '2', '2', '1', '6', '1', '3', '3', '10', '2', '2', '3', '10', '1', '3', '1', '3', '1', '2, 'Ris selected from hydrogen, C-Calkyl, —CH—CHF, —C-Calkylene-O—C-Calkyl, C-Ccycloalkyl, —(CH)-phenyl and C-Ccycloalkyl-substituted C-Calkyl, wherein each cycloalkyl in the group represented by Ris optionally substituted with —C-Calkyl or optionally benzofused and when Ris hydrogen or —C-Calkyl, Ris additionally selected from benzyl; or'}{'sup': 2', '3, 'sub': 1', '3', '1', '3', '1', '3, 'Rand Rtaken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine and piperidine, wherein the ring is optionally substituted with one or more substituents independently selected from fluoro —C-Calkyl and —C-Calkylene-O—C-Calkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.'}4. The compound of claim 1 , wherein at least one of X and Z is other than hydrogen.5. The compound of claim 4 , wherein both X and Z are other than hydrogen.6. The compound of claim 4 , wherein one of X and Z is hydrogen.7. The compound of claim 6 , wherein:{'sub': 3', '2, 'X is selected from hydrogen, fluoro, chloro, —CN, and —N(CH); and'}{'sub': 2', '2', '2', '3', '3, 'Z is hydrogen, NHor —CH—NH—CH—C(CH).'}9. The compound of claim 8 , wherein X is fluoro claim 8 , chloro or —N(CH).16. The compound of claim 1 , wherein:{'sup': '3', 'Y is —NHR, and'}{'sup': 3', '3, 'sub': 1', '8', '1', '3', '1', '3', '1', '3, 'Ris pyridyl, C-Calkyl, —C(O)—C-Calkylene-piperidine, —C(O)—C-Calkylene-pyrrolidine, wherein each piperidine or pyrrolidine in the group ...

(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. 1140-. (canceled)141. A compound chosen from N-(4′-((trans)-2-((4-aminocyclohexyl)amino) cyclopropyl)-[1 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide , an optically active stereoisomer thereof , and a salt or solvate thereof.142. The compound of claim 141 , wherein the compound is an optically active stereoisomer.143. The compound of claim 141 , wherein the compound is N-(4′-((trans)-2-((4-aminocyclohexyl)amino) cyclopropyl)-[1 claim 141 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide or a pharmaceutically acceptable salt or solvate thereof.144. The compound of claim 141 , wherein the compound is a hydrochloride salt of N-(4′-((trans)-2-((4-aminocyclohexyl)amino) cyclopropyl)-[1 claim 141 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide.145. A pharmaceutical composition comprising a compound chosen from N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 claim 141 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide claim 141 , an optically active stereoisomer thereof claim 141 , and a pharmaceutically acceptable salt or solvate thereof claim 141 , and a pharmaceutically acceptable carrier.146. The pharmaceutical composition of claim 145 , wherein the compound is an optically active stereoisomer.147. The pharmaceutical composition of claim 145 , wherein the compound is N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 claim 145 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide or a pharmaceutically acceptable salt or solvate thereof.148. The pharmaceutical composition of claim 145 , wherein the compound is a hydrochloride salt of N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 claim 145 ,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide.149. A method of treating cancer ...

LYSINE DEMETHYLASE INHIBITORS FOR MYELOPROLIFERATIVE OR LYMPHOPROLIFERATIVE DISEASES OR DISORDERS

The present invention relates to methods and compositions for the treatment or prevention of diseases and disorder associated with myeloproliferative and lymphoproliferative disorders. In particular, the invention relates to an LSD1 inhibitor for use in treating or preventing diseases and disorder associated with myeloproliferative and lymphoproliferative disorders. 12-. (canceled)3. A method of treating or preventing a hematological cancer comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.4. (canceled)5. The method of claim 3 , wherein said hematological cancer is a hematological cancer caused by or related to myeloproliferation.6. The method of claim 3 , wherein said hematological cancer is acute myelogenous leukemia (AML) claim 3 , chronic myelogenous leukemia (CML) claim 3 , chronic neutrophilic leukemia claim 3 , or chronic eosinophilic leukemia.7. The method of claim 3 , wherein said hematological cancer is a hematological cancer caused by or related to lymphoproliferation.8. The method of claim 3 , wherein said hematological cancer is follicular lymphoma claim 3 , chronic lymphocytic leukemia (CLL) claim 3 , acute lymphoblastic leukemia (ALL) claim 3 , hairy cell leukemia claim 3 , lymphoma claim 3 , multiple myeloma claim 3 , or Waldenstrom's macroglobulinemia.9. The method of claim 3 , wherein said hematological cancer is a lymphoma chosen from precursor B-lymphoblastic leukemia/lymphoma claim 3 , B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma claim 3 , B-cell prolymphocytic leukemia claim 3 , lymphoplasmacytic lymphoma claim 3 , splenic marginal zone B-cell lymphoma (+/− villous lymphocytes) claim 3 , hairy cell leukemia claim 3 , plasma cell myeloma/plasmacytoma claim 3 , extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type claim 3 , nodal marginal zone lymphoma (+/− monocytoid B-cells) claim 3 , follicle center lymphoma claim 3 , follicular claim 3 , mantle cell ...

EBNA1 INHIBITORS AND THEIR METHOD OF USE

Pharmaceutical compositions of the invention comprise EBNA1 inhibitors useful for the treatment of diseases caused by EBNA1 activity such as cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by lytic Epstein-Barr Virus (EBV) infection. 4. The method of claim 1 , wherein the compound is at least one selected from the group consisting of:3-{2-[3-(methylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid;3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoic acid;3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[2-( ...

1-CYANO-PYRROLIDINE COMPOUNDS AS USP30 INHIBITORS

The present invention relates to novel compounds and method for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (II) or a pharmaceutically acceptable salt thereof, wherein R, R, R, R, R, R, R, R, R, Z, Y and m are as defined herein. 2. The compound according to claim 1 , wherein Ris unsubstituted or substituted with one or more of -Q-(R) claim 1 , wherein:p is 0 or 1;{'sup': 1', '14', '14', '15', '14', '14', '14', '14', '14', '15', '14', '14', '15', '14', '15', '16', '14', '15', '16', '14', '15', '14', '14', '15', '14', '15', '14', '14', '15, 'sub': 0', '3', '0', '3', '0', '3', '0', '3', '0', '3', '2', '0', '3', '0', '3', 'q', '0', '3', '2', '0', '3', '2', '1', '6', '1', '6', '1', '6', '0', '3', '2', '0', '3', '0', '3', '0', '3', '2', '0', '3', '0', '3', '2', '0', '3', '2', '0', '3', '2', '0', '3', '0', '3', '2', '2', '1', '6', '2', '6', '1', '6, 'Qrepresents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, —C-Calkylene-NR—, —C-Calkylene-NRR, —C-Calkylene-CONR—, —C-Calkylene-NRCO—, —C-Calkylene-NRSO—, an oxygen atom, —C-Calkylene-CO—, —C-Calkylene-S(O)—, —C-Calkylene-SONR, —C-Calkylene-SONRR, —C-Calkoxy, C-Chaloalkoxy, C-Chydroxyalkyl, —C-Calkylene-SOR, —C-Calkylene-NRCOR, —C-Calkylene-NRCONRR, —C-Calkylene-NRSONRR, —C-Calkylene-CONRR, —C-Calkylene-COR, —C-Calkylene-NRCOR, —C-Calkylene-SONRR, —C-Calkylene-C(O)Rand —C-Calkylene-NRSOR, NO, or an optionally substituted C-Calkylene, —C-Calkenylene or —C-Calkyl group;'}q is 0, 1 or 2;{'sup': 14', '15', '16, 'sub': 1', '6', '1', '6, 'R, Rand Reach independently represent a hydrogen atom or an optionally substituted C-Calkyl, or an optionally substituted C-Calkylene group;'}{'sup': 13', '1', '13, 'when ...

Inhibitors Of Histone Deacetylase

This invention comprises the novel compounds of formula (I) wherein n, R 1 , R 2 , R 3 , R 4 , Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

METHOD OF PREPARING (+)-1,4-DIHYDRO-7-[(3S,4S)-3-METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID

Methods of preparing (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid are disclosed. Also provided are pharmaceutical compositions comprising (+)-1,4-dihydro-7-[(3S,45)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, and methods of treatment using such compositions. 141-. (canceled)4344-. (canceled) This application claims priority to U.S. Provisional Application Ser. No. 61/141,856, filed Dec. 31, 2008, entitled “METHOD OF PREPARING VORELOXIN.” The disclosure of the above referenced application is incorporated by reference herein in its entirety.Provided herein are methods for preparing (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, methods for preparing intermediates useful in the preparation of the compound, compositions comprising the compound, methods of use of such compositions for treatment of cancer and methods of using the intermediates in preparing (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.The compound (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, having the structure:is also known as SNS-595 or AG-7352. The United States Adopted Names Council (USANC) has assigned the name “Voreloxin” to this compound.SNS-595 is known for its anti-tumor activity (see, Tsuzuki et al., 47:2097-2106, 2004 and Tomita et al., 45:5564-5575, 2002). Treatment of various cancers with SNS-595 has been proposed in the literature, and has shown preclinical activity against various cancer cell lines and xenografts. Various dosing regimens for the use of this compound have been reported. For example, see U.S. Patent Application Pub. Nos. 2005-0203120 A1; 2005-0215583 A1 and 2006-0025437 A1, all of which are ...

PYRROLIDINE OREXIN RECEPTOR AGONISTS

The present invention is directed to pyrrolidine compounds which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved. 2. The compound of or a pharmaceutically acceptable salt thereof wherein X is —O—.3. The compound of or a pharmaceutically acceptable salt thereof wherein X is —NH—.4. The compound of or a pharmaceutically acceptable salt thereof wherein Ris selected from:(1) methyl,(2) ethyl,{'sub': '2', '(3) —CHOH,'}{'sub': 2', '3, '(4) —CHCF,'}{'sub': 2', '2, '(5) —CHCHF,'}{'sub': 3', '2, '(6) —CH(CH),'}{'sub': 2', '2', '2, '(7) —CHCHCHF,'}(8) cyclopropyl,{'sub': '2', '(9) —CH-cyclopropyl,'}{'sub': '2', '(10) —CH-cyclobutyl, and'}{'sub': 2', '3, '(11) —CHO(C═O)CH.'}5. The compound of any of - or a pharmaceutically acceptable salt thereof wherein Ris selected from:(1) hydrogen,{'sub': 2', '3', '2, '(2) —CH(CH),'}{'sub': '3', '(3) —CF,'}{'sub': 2', '2, '(4) —CHCHF,'}{'sub': 2', '3, '(5) —CHCF, and'}{'sub': 3', '2', '3, '(6) phenyl, which is unsubstituted or substituted with —CFor —CHCF.'}6. The compound of any of - or a pharmaceutically acceptable salt thereof wherein Ris selected from:{'sub': '1-6', '(1) —Calkyl, where the alkyl is unsubstituted or substituted with one to three fluoro,'}{'sub': '3-6', '(2) —Ccycloalkyl,'}{'sub': '2', '(3) —NH,'}{'sub': '1-6', '(4) —NH(Calkyl),'}{'sub': 1-6', '1-6, '(5) —N(Calkyl)(Calkyl), and'}(6) -phenyl.7. The compound of or a pharmaceutically acceptable salt thereof wherein Ris selected from:(1) methyl,{'sub': '3', '(2) —CF,'}{'sub': '2', '(3) —CHF,'}(4) ethyl,(5) cyclopropyl,{'sub': 3', ' ...

Substituted Pyrrolidines and Methods of Use

The invention discloses compounds of Formula (I) wherein R 1 , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , and R 5 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 comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

PHARMACEUTICAL COMPOUNDS

This invention relates to compounds that are agonists of the muscarinic Mreceptor or Mand Mreceptors and which are useful in the treatment of muscarinic Mor M/Mreceptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula 2. A compound according to wherein Qis an optionally substituted five or six membered aromatic carbocyclic or heterocyclic group selected from optionally substituted phenyl; optionally substituted pyridyl; optionally substituted imidazolyl; andoptionally substituted thienyl.3. (canceled)4. A compound according to wherein the five or six membered aromatic carbocyclic or heterocyclic group Qis unsubstituted or is substituted with one or more substituents Qselected from halogen; cyano; hydroxy; amino; and a Cnon-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one claim 1 , two or three claim 1 , but not all claim 1 , carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O claim 1 , N and S and oxidized forms thereof.5. A compound according to wherein Qis selected from hydrogen; fluorine; cyano; hydroxy; amino; methyl claim 1 , ethyl and methoxy.6. (canceled)8. A compound according to wherein Ris H claim 7 , COOR claim 7 , CONRR claim 7 , SORor an optionally substituted Calkyl group.9. (canceled)10. A compound according to wherein Rand Rare independently selected from hydrogen; fluorine; chlorine; cyano; hydroxy; amino; and any Calkyl or Calkoxy group which is optionally substituted with one to six fluorine atoms.11. (canceled)12. (canceled)13. (canceled)14. A compound according to wherein Z is C.15. A compound according to wherein p is 0; or p is 1 and Ris selected from fluorine and methyl.16. (canceled)17. A compound according to wherein V is a bond and Qis nitrogen.18. A compound according to wherein V is NH or NH—CH.19. (canceled)20. (canceled ...

COMPOUNDS USEFUL AS IMMUNOMODULATORS

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases. 3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein m is 1 and Ris halo.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein A is —CHO—.6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris —(CH)Ar claim 5 , wherein n is 1 and Ar is pyridinyl optionally substituted with one or two groups independently selected from C-Calkyl claim 5 , C-Calkylsulfonyl claim 5 , amido claim 5 , cyano claim 5 , and halo.7. A compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Y and Rare independently selected from —CHand halo.17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.18. A method of enhancing claim 1 , stimulating claim 1 , modulating and/or increasing the immune response in a subject in need thereof claim 1 , said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.19. The method of further comprising administering an additional agent prior to claim 1 , after claim 1 , or simultaneously with the compound of claim 1 , or the pharmaceutically acceptable salt thereof.20. The method of wherein the additional agent is an antimicrobial agent claim 17 , an antiviral agent claim 17 , a cytotoxic agent claim 17 , a gene expression modulatory agent claim 17 , and/or an immune response modifier.21. A method of inhibiting growth ...

C7-FLUORO SUBSTITUTED TETRACYCLINE COMPOUNDS

The present invention is directed to a compound represented by Structural Formula (A): 4. The compound of claim 3 , wherein Ris hydrogen or a (C-C)alkyl.5. The compound of claim 3 , wherein Ris selected from (C-C)alkyl claim 3 , (C-C)cycloalkyl(C-C)alkyl claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , phenyl claim 3 , phenyl(C-C)alkyl claim 3 , (C-C)cycloalkyl and halo(C-C)alkyl claim 3 , wherein each alkyl claim 3 , alkoxy and cycloalkyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl and halo; and each phenyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl claim 3 , halo claim 3 , (C-C)alkoxy claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , —CN claim 3 , halo(C-C)alkyl claim 3 , and halo(C-C)alkoxy.6. The compound of claim 3 , wherein Ris selected from hydrogen claim 3 , methyl and ethyl.7. The compound of claim 6 , wherein Ris selected from the group consisting of cyclopropyl claim 6 , cyclobutyl claim 6 , cyclopentyl claim 6 , cyclopropylmethyl claim 6 , cyclobutylmethyl claim 6 , phenyl claim 6 , benzyl claim 6 , —(CH)—O—CH claim 6 , —(CH)—OCH claim 6 , —C(CH) claim 6 , —CH(CH) claim 6 , —CHC(CH) claim 6 , —CHCH(CH) claim 6 , —CH—CF claim 6 , —(CH)—CHF claim 6 , and —(CH)CH; n is 0 claim 6 , 1 claim 6 , 2 claim 6 , 3 claim 6 , 4 claim 6 , 5 or 6; and wherein the phenyl or benzyl group represented by Ris optionally substituted with one or two substituents independently selected from the group consisting of (C-C)alkyl claim 6 , halogen claim 6 , (C-C)alkoxy claim 6 , (C-C)alkoxy(C-C)alkyl claim 6 , —CN claim 6 , halo(C-C)alkyl claim 6 , and halo(C-C)alkoxy.8. The compound of claim 7 , wherein Ris selected from cyclopropyl claim 7 , cyclopropylmethyl claim 7 , cyclobutyl claim 7 , cyclopentyl claim 7 , cyclohexyl claim 7 , —(CH)—O—CH claim 7 , —C(CH) claim 7 , —CH( ...

Fluorinated Bridged Spiro[2.4]Heptane Derivatives as ALX Receptor Agonists

The present invention relates to fluorinated bridged spiro[2.4]heptane derivatives of formula (I), 2. The compound according to claim 1 , wherein n represents 1; or a salt thereof.3. The compound according to claim 1 , wherein n represents 2; or a salt thereof.4. The compound according to claim 1 , wherein Rrepresents hydrogen; or a salt thereof.5. The compound according to claim 1 , wherein Rrepresents fluoro; or a salt thereof.6. The compound according to claim 1 , wherein Rrepresents hydrogen and the two stereogenic centers at the heterocyclyl group claim 1 , which is attached to the amide nitrogen-atom claim 1 , are relative to each other in trans-configuration; or a salt thereof.7. The compound according to claim 1 , wherein said compound is:(1S,2R,3R,4R)—N2-(4-bromo-2-fluorobenzyl)-N3-((3S,4S)-3-fluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide;(1S,2R,3R,4R)—N2-(4-bromo-2-fluorobenzyl)-N3-((3R,4R)-3-fluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide;(1S,2R,3R,4R)—N2-(4-bromo-2-fluorobenzyl)-N3-(cis-3-fluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide;(1S,2R,3R,4R)—N2-(4-bromo-2-fluorobenzyl)-N3-(3,3-difluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide;(1S,2R,3R,4R)—N2-(4-Bromo-2-fluorobenzyl)-N3-(cis-4-fluoropyrrolidin-3-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide; or(1S,2R,3R,4R)—N2-(4-Bromo-2-fluorobenzyl)-N3-(trans-4-fluoropyrrolidin-3-yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide;or a salt thereof.8. The compound according to claim 1 , wherein the compound is: (1S claim 1 ,2R claim 1 ,3R claim 1 ,4R)—N2-(4-bromo-2-fluorobenzyl)-N3-((3S claim 1 ,4S)-3-fluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7 claim 1 ,1′-cyclopropane]-2 claim 1 ,3-dicarboxamide; or a salt thereof.9. The compound according to claim 1 , wherein the compound is: (1S claim 1 ,2R claim 1 ,3R claim 1 ,4R ...

(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and theft use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. 6. The compound of any of to for use as a medicament.9. A pharmaceutical composition comprising the compound of any of to and a pharmaceutically acceptable carrier.16. The compound of any of to or the compound for use as a medicament according to any of to or the pharmaceutical composition of any of to , wherein D is a cycloalkyl group having from 4 to 7 C atoms , wherein said cycloalkyl group has one or two substituents Rand is further optionally substituted with one or more R.17. The compound of any of to or the compound for use as a medicament according to any of to or the pharmaceutical composition of any of to , wherein D is a cycloalkyl group having from 4 to 7 C atoms , wherein said cycloalkyl group has one substituent Rand is further optionally substituted with one or more R.18. The compound of any of to or the compound for use as a medicament according to any of to or the pharmaceutical composition of any of to , wherein D is a cycloalkyl group having from 4 to 7 C atoms , wherein said cycloalkyl group has one substituent R.19181818. The compound of any of to or to or the compound for use as a medicament according to any of to or to or the pharmaceutical composition of any of to or to , wherein the cycloalkyl group having from 4 to 7 C atoms which forms part of D is a cyclohexyl group.222121. The compound of any of to or to or the compound for use as a medicament according to any of to or to or the pharmaceutical composition of any of to , wherein each Ris independently selected from —NRR , —NHOH , —NRCOR , —NRSOR , —NRCOOR , —NRCONRR , —NRSONRR , —CONRR , oxo , —Calkylene-NRR , —Calkylene-NHOH , —Calkyene-NRCOR , —Calkylene-NRSOR , —Calkylene-NRCOOR , —Calkylene- ...

BACTERIAL EFFLUX PUMP INHIBITORS

Disclosed herein are compounds of formula I: and salts thereof. Also disclosed are compositions comprising compounds of formula I and methods using compounds of formula I. 2. The compound or salt of claim 1 , wherein A is —C(═O)N(R)—R claim 1 , —(C-C)alkyl-C(═O)N(R)R claim 1 , —(C-C)alkyl-O —R claim 1 , or —O—R.3. The compound or salt of claim 1 , wherein A is —C(═O)N(R)—R.4. The compound or salt of claim 1 , wherein A is —(C-C)alkyl-C(═O)N(R)R.5. The compound or salt of any one of - claim 1 , wherein Ris hydrogen.6. The compound or salt of claim 1 , wherein A is —O—R.7. The compound or salt of any one of - claim 1 , wherein Ris hydrogen claim 1 , halo claim 1 , (C-C)alkyl claim 1 , (C-C)haloalkyl claim 1 , (C-C)alkoxy claim 1 , or (C-C)haloalkoxy.8. The compound or salt of any one of - claim 1 , wherein Ris hydrogen.9. The compound or salt of any one of - claim 1 , wherein Ris aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo claim 1 , —NO claim 1 , —CN claim 1 , (C-C)alkyl claim 1 , (C-C)haloalkyl claim 1 , (C-C)alkoxy and (C-C)haloalkoxy.10. The compound or salt of any one of - claim 1 , wherein Ris phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from halo claim 1 , —NO claim 1 , —CN claim 1 , (C-C)alkyl claim 1 , (C-C)haloalkyl claim 1 , (C-C)alkoxy and (C-C)haloalkoxy.11. The compound or salt of any one of - claim 1 , wherein Ris 4-fluorophenyl or 4-trifluoromethyphenyl.12. The compound or salt of any one of - claim 1 , wherein Ris hydrogen claim 1 , halo claim 1 , (C-C)alkyl claim 1 , (C-C)haloalkyl claim 1 , (C-C)alkoxy claim 1 , (C-C)haloalkoxy.13. The compound or salt of any one of - claim 1 , wherein Ris hydrogen.14. The compound or salt of any one of - claim 1 , wherein Ris aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo claim 1 , —NO claim ...

Inhibitors of Influenza Viral Entry

Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for acute treatment of influenza infections to control this virus and prevent epidemic/pandemic situations from developing. Described herein are fast-acting, orally active acylated amino-substituted heterocyclyl compounds effective to control this virus. In one aspect, described herein is a method of treating an influenza infection in a subject comprising administering to the subject the compounds described herein.

COMPOSITIONS AND METHODS FOR TREATING CANCER

K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer. 174-. (canceled)76. (canceled)77. The compound or pharmaceutically acceptable salt of claim 75 , wherein Lis or unsubstituted heterocycloalkylene.78. The compound or pharmaceutically acceptable salt of claim 75 , wherein Lis monocyclic 4 claim 75 , 5 claim 75 , or 6-membered heterocycloalkylene.79. The compound or pharmaceutically acceptable salt of claim 75 , wherein Lis unsubstituted piperazino or unsubstituted piperidino.80. The compound or pharmaceutically acceptable salt of claim 75 , wherein Lis bicyclic fused heterocycloalkylene.81. (canceled)82. The compound or pharmaceutically acceptable salt of claim 75 , wherein E is an unsubstituted vinyl sulfone moiety claim 75 , a substituted or unsubstituted vinyl sulfonamide moiety claim 75 , or a substituted or unsubstituted acrylamide moiety.84. A method of treating pancreatic cancer claim 75 , colorectal cancer claim 75 , or lung cancer in a subject in need thereof claim 75 , the method comprising:a. determining the presence or absence of a K-Ras mutation in a malignant or neoplastic cell isolated from the subject; and{'claim-ref': {'@idref': 'CLM-00075', 'claim 75'}, 'b. if a K-Ras mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of .'}85114-. (canceled)117. The compound or pharmaceutically acceptable salt of claim 75 , wherein E is an unsubstituted vinyl sulfone moiety claim 75 , substituted or unsubstituted vinyl sulfonamide moiety claim 75 , substituted or unsubstituted peroxide moiety claim 75 , substituted or unsubstituted fluoro(C-C)alkylketone moiety claim 75 , substituted or unsubstituted chloro(C-C)alkylketone moiety claim 75 , substituted or unsubstituted acrylamide moiety claim 75 , substituted or unsubstituted disulfide moiety claim 75 , ...

EFFLUX-PUMP INHIBITORS AND THERAPEUTIC USES THEREOF

The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC is —N(R8)(R9)ASC-1 ASC-1 is Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom and wherein one CH2 moiety in ring A is optionally replaced by CH(R21) and wherein one carbon atom in ring A that is not adjacent to the nitrogen atom is optionally replaced by O, and wherein ring A is connected to X via a carbon atom; X represents a bond, —CH2- or —C(═O)—; AR1, AR2 represent independently phenyl or a 5- to 6-membered heteroaryl ring containing one to three heteroatoms selected from O, S and N, wherein AR1 is connected to LI via a carbon atom, and wherein AR2 is connected to L1 and L2 via a carbon atom; R1, R2, R3 represent independently hydrogen, halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —C1-C6alkylene-N(R12)R13, —N(R12)R13, —C(O)OR111, —C(O)N(R12)R13, —S(O)OR11 or phenyl; R4 represents hydroxyl, hydrogen, halogen, nitro, cyano, amino, C1-C6alkyl optionally substituted by 1 to 5 R14, C2-C6alkenyl optionally substituted by 1 to 5 R14, C2-C6alkynyl optionally substituted by 1 to 5 R14, C1-C6alkoxy optionally substituted by 1 to 5 R14, C2-C6alkenyloxy optionally substituted by 1 to 5 R14, C2-C6alkynyloxy optionally substituted by 1 to 5 R14, —C(O)OR15, —CHO, —C(O)N(R16)R17, —C1-C6alkylene-N(R9)(R16)R17, —O-Cycle-P or —O-Cycle-Q; R5, R6, R7 represent independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy; R8 represents hydrogen, methyl or ASC-1; R9 is methyl or absent, and wherein when R9 is present the respective nitrogen atom carries a positive charge; R10 represents hydrogen or methyl; R111 represents independently at each occurrence hydrogen or C1-C6alkyl; R12, R13 represent independently at each occurrence hydrogen or C1-C6alkyl; R14 represents independently at each ...

SULFAMOYL-ARYLAMIDES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Inhibitors of HBV replication of Formula (I) 113-. (canceled)15. The compound of claim 14 , wherein Ris hydrogen.16. The compound of claim 14 , wherein Ris a 4-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O claim 14 , S and N claim 14 , said 4-7 membered saturated ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen claim 14 , halogen claim 14 , C-Calkyloxy claim 14 , C-Calkyloxycarbonyl claim 14 , C(═O)—C-Calkyl claim 14 , C-Calkyl claim 14 , OH claim 14 , CN claim 14 , CFH claim 14 , CFH and CF.17. The compound of claim 14 , wherein Ris C-Ccycloalkyl.18. The compound of claim 14 , wherein B is imidazolyl or thiazolyl claim 14 , each optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen claim 14 , halogen claim 14 , C-Calkyl claim 14 , CN claim 14 , CFH claim 14 , CFH and CF.19. A compound of claim 14 , wherein at least one Ris fluoro claim 14 , and one other Ris selected from the group consisting of C-Calkyl claim 14 , C-Calkenyl claim 14 , CHFand cyclopropyl.20. A compound of claim 14 , wherein one Ris fluoro and one other Ris selected from methyl or CHF claim 14 , and wherein the location of said fluoro is on the para position related to the nitrogen(*) claim 14 , and the location of said methyl or CHFis on the meta position related to the nitrogen(*).21. The compound of claim 14 , wherein each Ris hydrogen.23. A pharmaceutical composition comprising at least one compound of and a pharmaceutically acceptable carrier.24. A product containing (a) at least one compound of claim 14 , and (b) an HBV inhibitor claim 14 , as a combined preparation for simultaneous claim 14 , separate or sequential use in the treatment of HBV infection.25. A method of preventing or treating an HBV infection in a subject in need thereof claim 14 , comprising administering ...

PHENYL AMINO PIPERIDINE mTORC INHIBITORS AND USES THEREOF

The present invention provides compounds, compositions thereof, and methods of using the same. 2. The compound according to claim 1 , wherein Ais N.3. The compound according to claim 2 , wherein Ais N(Ring A).4. The compound according to claim 2 , wherein m is 1 and n is 1.5. The compound according to claim 2 , wherein Ais C(R′).6. The compound according to claim 2 , wherein Ais CH.7. The compound according to claim 2 , wherein p is 1 and q is independently 0 claim 2 , 1 claim 2 , or 2.8. The compound according to claim 2 , wherein each of Rand Ris independently R claim 2 , or: two Rgroups are optionally taken together to form ═O; two Rgroups are optionally taken together to form ═O; two Rgroups are optionally taken together to form a covalent bond or a bivalent Calkylene chain; or two Rgroups are optionally taken together to form a covalent bond or a bivalent Calkylene chain.10. The compound according to claim 8 , wherein Ris hydrogen or methyl.11. The compound according to claim 2 , wherein claim 2 , each of Ris independently R claim 2 , halogen claim 2 , —OR claim 2 , or —CN.13. The compound according to claim 2 , wherein Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms.15. The compound according to claim 2 , wherein Lis a covalent bond or a Cbivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —C(O)— claim 2 , —C(S)— claim 2 , —C(R)— claim 2 , —CH(R)— claim 2 , —C(F)— claim 2 , —N(R)— claim 2 , or —S(O)—.16. (canceled)18. The compound according to claim 1 , wherein the compound is selected from those depicted in Table 1.19. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable adjuvant claim 1 , carrier claim 1 , or vehicle.20. A method for treating a mTORC-mediated disorder in a patient in need ...

SUBSTITUTED PYRROLIDINES AS FACTOR XIA INHIBITORS FOR THE TREATMENT THROMBOEMBOLIC DISEASES

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases. 6. The compound according to claim 4 , wherein Cyc E represents imidazolyl.7. The compound according to claim 1 , wherein Cyc A represents C3-C6 cycloalkyl claim 1 , C6-C10 aryl or 5- to 6-membered heterocycloalkyl.8. The compound according to claim 7 , wherein Cyc A represents cyclohexyl claim 7 , phenyl claim 7 , piperidinyl or piperazinyl.9. The compound according to claim 1 , wherein Cyc B represents C6-C10 aryl or 5- to 6-membered heteroaryl.10. The compound according to claim 9 , wherein Cyc B represents phenyl or pyridyl.11. The compound according to claim 1 , wherein Cyc C represents pyrrolidinyl claim 1 , piperidinyl claim 1 , piperazinyl or morpholinyl.14. (canceled)15. A pharmaceutical composition which comprises the compound according to claim 1 , a salt thereof claim 1 , an N-oxide thereof claim 1 , a solvate thereof claim 1 , or a prodrug thereof.16. The pharmaceutical composition according to claim 15 , which is a factor XIa inhibitor.17. The pharmaceutical composition according to claim 16 , which is an agent for the treatment or prevention of a thromboembolic disease.18. (canceled)19. The method according to claim 21 , wherein the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolic disorders claim 21 , venous cardiovascular thromboembolic disorders claim 21 , arterial cerebrovascular thromboembolic disorders claim 21 , venous cerebrovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.20. The method according to claim 19 , wherein the thromboembolic disease is selected from disseminated ...

INTERMEDIATE COMPOUNDS OF TAMIFLU, METHODS OF PREPARATION AND USES THEREOF

Chiral amino compounds, methods of preparation and uses thereof. Tamiflu can be obtained from the said compounds. Multi-substituted chiral tetrahydropyrrolyl amine which can be used as intermediate compounds of medicament can also be produced by the said compounds. 2. The chiral amino compound according to claim 1 , wherein Ris alkyl having 1˜4 carbon atoms claim 1 , alkoxy having 1˜4 carbon atoms claim 1 , alkyl having 1˜4 carbon and substituted by R claim 1 , phenyl claim 1 , phenyl monosubstituted claim 1 , disubstituted or trisubstituted by electron-withdrawing group or electron-donating group.3. The chiral amino compound according to claim 2 , wherein the electron-withdrawing group is halogen claim 2 , cyano or nitro claim 2 , the electron-donating group is alkyl having 1˜4 carbon atoms claim 2 , alkoxy having 1˜4 carbon atoms claim 2 , amino or hydroxyl.4. The chiral amino compound according to claim 1 , wherein alkoxy having 1˜10 carbon atoms in Ris 3-pentyloxy:{'sub': '1', 'alkenyl having 2˜6 carbon atoms in Ris isobutenyl.'}5. (canceled)8. (canceled)9. (canceled)11. The preparation method according to claim 10 , whereinin step (1), the reduction reaction includes the following steps: carrying out reduction reaction of nitro group of compound II to prepare compound I in the presence of zinc powder and trimethylchlorosilane, acetic acid or hydrochloric acid, and solvent; wherein, the solvent is ethanol and/or methanol; the amount of zinc powder is 10˜30 times mole of compound II; the amount of trimethylchlorosilane is 10˜20 times mole of compound II; the volume mass ratio of acetic acid or hydrochloric acid to compound II is 10˜40 ml/g; the reaction is stopped until the reactant is consumed complete as monitored; the reaction temperature is 40˜80° C.;{'sub': 5', '5, 'in step (2), the reaction of removing RSH includes the following steps: removing RSH from compound I in the presence of the alkali, ammonia gas, and solvent; wherein, the solvent is ethanol and/ ...

KAPPA OPIOID AGONISTS AND USES THEREOF

Provided are compounds of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds of Formula I described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry. 2. The compound of claim 1 , wherein Ris an optionally substituted phenyl.3. The compound of any one of the proceeding claims claim 1 , wherein Ris selected from phenyl claim 1 , phenyl substituted with 1 to 3 halogens claim 1 , and phenyl substituted with X-POLY.4. The compound of any one of the proceeding claims claim 1 , wherein Ris optionally substituted amino.5. The compound of any one of the proceeding claims claim 1 , wherein Ris amino substituted with an optionally substituted aryl.6. The compound of any one of the proceeding claims claim 1 , wherein Ris amino substituted with an optionally substituted phenyl.7. The compound of any one of the proceeding claims claim 1 , wherein Ris amino substituted with a phenyl group.8. The compound of any one of the proceeding claims claim 1 , wherein Ris hydrogen.9. The compound of any one of the proceeding claims claim 1 , wherein Ris X-POLY.10. The compound of any one of the proceeding claims claim 1 , wherein Ris an optionally substituted aryl.11. The compound of any one of the proceeding claims claim 1 , wherein Ris an optionally substituted phenyl.12. The compound of any one of the proceeding claims claim 1 , wherein Ris phenyl.13. The compound of any one of the proceeding claims claim 1 , wherein Ris hydrogen.14. The compound of any one of the proceeding claims claim 1 , wherein Ris an optionally substituted lower alkyl.15. The compound of any one of the proceeding claims claim 1 , wherein Ris methyl.16. The compound of any one of the proceeding claims claim 1 , wherein Ris selected from an optionally substituted phenyl.17. The compound of any one of the proceeding claims claim 1 , wherein Ris selected from phenyl and phenyl ...

Carbamate compounds and of making and using same

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.

PHENYL DERIVATIVES AS CANNABINOID RECEPTOR 2 AGONISTS

The invention relates to a compound of formula (I) 2. The compound according to claim 1 , wherein Ris cyclopropyl.3. The compound according to claim 1 , wherein Ris cyclopropylmethoxy claim 1 , alkoxy claim 1 , haloalkoxy or halopyrrolidinyl.4. The compound according to claim 1 , wherein Ris cyclopropylmethoxy claim 1 , propyloxy claim 1 , fluoroethoxy claim 1 , trifluoroethoxy or difluoropyrrolidinyl.5. The compound according to claim 1 , wherein Rand Rare independently selected from the group consisting of hydrogen claim 1 , alkyl claim 1 , cycloalkyl and cycloalkylalkyl.6. The compound according to claim 1 , wherein Rand Rare independently selected from the group consisting of hydrogen claim 1 , methyl claim 1 , butyl claim 1 , cyclopropyl and cyclopropylmethyl.7. The compound according to claim 1 , wherein Ris aminocarbonyl claim 1 , 5-methyl-1 claim 1 ,2 claim 1 ,4-oxadiazol-3-yl claim 1 , hydroxyalkyl or alkylaminocarbonyl.8. The compound according to claim 1 , wherein Ris aminocarbonyl claim 1 , 5-methyl-1 claim 1 ,2 claim 1 ,4-oxadiazol-3-yl claim 1 , hydroxymethyl or methylaminocarbonyl.9. The compound according to claim 1 , wherein Ris (aminocarbonyl)(difluoro)pyrrolidinyl.10. The compound according to claim 1 , wherein Ris 3-tert-butyl-1 claim 1 ,2 claim 1 ,4-oxadiazol-5-yl claim 1 , 5-tert-butyl-1 claim 1 ,2 claim 1 ,4-oxadiazol-3-yl or 5-methyl-1 claim 1 ,2 claim 1 ,4-oxadiazol-3-yl.11. The compound according to claim 1 , wherein the compound is selected from the group consisting of:(R)-N-(1-amino-4-methyl-1-oxopentan-2-yl)-3-(cyclopropylmethoxy)-4-methylbenzamide;3-(cyclopropylmethoxy)-4-methyl-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]benzamide;4-cyclopropyl-3-(cyclopropylmethoxy)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]benzamide;N2-[4-cyclopropyl-3-(cyclopropylmethoxy)benzoyl]-L-leucinamide;4-cyclopropyl-3-(cyclopropylmethoxy)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide;4-cyclopropyl-3-(cyclopropylmethoxy)-N-[2-(1,3-thiazol-2-yl)propan-2 ...

Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection

The compounds of the invention as shown by general structure I, as shown below, are effective in treating filovirus infections.X is selected from the group consisting of O and H;R1 is selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, andR2 is selected from (C1 to C10) alkyl, (C1 to C10) alkenyl, (C1 to C10) alkynyl, (C3 to C10) cycloalkyl, and (C5 to C10) cycloalkenyl, andNR3aR3b is defined in the specification.These compounds are effective in treating filovirii infections including Ebolavirus and Marburg virus.

HETEROCYCLIC COMPOUNDS AND METHODS OF THEIR USE

The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT) receptor. More particularly the invention relates to pyrrolidine and azetidine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with ATreceptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration. 2. A compound according to wherein X is absent and Y is —CHRCH— or X is —CH— and Y is —CHR—.3. A compound according to wherein X is absent and Y is —CHRCHRCH— claim 1 , —CHCHRCHR— or —CHCHCHR— or X is —CHR— and Y is —CHRCHR— claim 1 , —CHCHR— claim 1 , —CHR═CH— or —CH═CHR— or X is —CHCHR— and Y is —CHR—.4. A compound according to wherein Ris —C(═O)CH(aryl)(aryl) claim 1 , —C(═O)CH(aryl)(cycloalkyl) claim 1 , —C(═O)CH(cycloalkyl)(cycloalkyl) claim 1 , —C(═O)N(aryl)(aryl) claim 1 , —C(═O)N(aryl)(cycloalkyl) or —C(═O)N(cycloalkyl)(cycloalkyl).5. A compound according to wherein Ris —C(═O)CH(phenyl)(phenyl) claim 4 , —C(═O)CH(phenyl)(cyclohexyl) claim 4 , —C(═O)CH(cyclohexyl)(cyclohexyl) claim 4 , —C(═O)N(phenyl)(phenyl) claim 4 , —C(═O)N(phenyl)(cyclohexyl) or —C(═O)N(cyclohexyl)(cyclohexyl) wherein each phenyl or cyclohexyl is optionally substituted with one or more substituents selected from —Calkyl claim 4 , —OCalkyl and halo.6. A compound according to wherein Ris cycloalkyl claim 1 , cycloalkenyl claim 1 , aryl claim 1 , heterocyclyl claim 1 , heteroaryl claim 1 , -heterocyclylaryl claim 1 , -heterocyclylCalkylenearyl claim 1 , —Calkylenecycloalkyl claim 1 , —Calkylenecycloalkenyl claim 1 , —Calkylenearyl claim 1 , —Calkyleneheterocyclyl claim 1 , —Calkyleneheteroaryl claim 1 , —Calkenylenecycloalkyl claim 1 , —Calkenylenecycloalkenyl ...

Novel biphenyl compound or salt thereof

The present invention provides a compound represented by Formula (I) or a salt thereof; an LSD1 inhibitor that contains the compound or a salt thereof as an active ingredient; a pharmaceutical composition that contains the compound or a salt thereof; and an antitumor agent that contains the compound or a salt thereof as an active ingredient.

Acly inhibitors and uses thereof

The present invention provides compounds useful as inhibitors of ATP citrate lyase (ACLY), compositions thereof, and methods of using the same.

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula: where R 1 -R 5 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.

Carbamate compounds and methods of making and using same

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from post-traumatic stress disorder comprising administering a disclosed compound or composition.

METHOD OF TREATING OR PREVENTING RAS-MEDIATED DISEASES

Disclosed are compounds, for example, a compound of formula I, 133-. (canceled)35. The method of claim 34 , wherein Y and Y′ together is oxygen.36. The method of claim 35 , wherein R claim 35 , R claim 35 , and Rare hydrogen and Ris selected from hydroxyl claim 35 , halogen claim 35 , alkyl claim 35 , trifluoromethyl claim 35 , alkoxy claim 35 , and alkylmercapto.37. The method of claim 36 , wherein Ris selected from halogen and alkoxy.38. The method of claim 37 , wherein Ris selected from fluorine and methoxy.39. The method of claim 34 , wherein Ris hydrogen and Ris independently selected from alkyl claim 34 , trifluoromethyl claim 34 , and alkoxy.40. The method of claim 39 , wherein Ris alkyl.41. The method of claim 34 , wherein Ris selected from hydroxy claim 34 , formyloxy claim 34 , alkylcarbonyloxy claim 34 , hydroxyalkyl claim 34 , aldehydo claim 34 , amino claim 34 , alkylamino claim 34 , aminoalkyl claim 34 , alkylaminoalkyl claim 34 , dialkylamino claim 34 , alkylsulfonyl claim 34 , alkylsulfinyl claim 34 , alkylsulfinyloxy claim 34 , alkylsulfonyloxy claim 34 , carbamate claim 34 , carbamido claim 34 , alkoxycarbonyl claim 34 , alkylaminocarbonyl claim 34 , aminocarbonyl claim 34 , and sulfonamido.42. The method of claim 41 , wherein Ris selected from hydroxy and methylsulfonyloxy.43. The method of claim 34 , wherein the heterocycle of the heterocyclyl and heterocycloalkyl is selected from furanyl claim 34 , pyrrolyl claim 34 , N-methyl pyrrolyl claim 34 , pyridyl claim 34 , diazolyl claim 34 , pyrrolidinyl claim 34 , and N-methyl pyrrolidinyl.44. The method of claim 34 , wherein Ris aryl or arylalkyl claim 34 , optionally substituted on the aryl by one or more halogen atoms.45. The method of claim 34 , wherein the activated Ras is encoded in the tumor cell by a Ras-activating mutation in a ras gene.46. The method of claim 34 , wherein said selectivity index is at least ten.47. The method of claim 46 , wherein said selectivity index is at least one ...

INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF

Disclosed are compounds, for example, compounds of formula I, 2. (canceled)3. The compound claim 1 , salt claim 1 , prodrug of claim 1 , wherein E is a phenyl ring claim 1 , substituted with one or more substituents selected from hydroxyl claim 1 , halogen claim 1 , alkyl claim 1 , haloalkyl claim 1 , cyano claim 1 , cyanoalkyl claim 1 , nitro claim 1 , oxo claim 1 , alkoxy claim 1 , formyloxy claim 1 , amino claim 1 , alkylamino claim 1 , dialkylamino claim 1 , aminoalkyl claim 1 , alkylaminoalkyl claim 1 , hydroxyalkyl claim 1 , aldehydo claim 1 , mercapto claim 1 , alkylmercapto claim 1 , azido claim 1 , and substituted or unsubstituted groups selected from alkylsulfinyloxy claim 1 , alkylsulfonyloxy claim 1 , alkylcarbonyloxy claim 1 , carbamate claim 1 , carbamido claim 1 , alkoxycarbonyl claim 1 , alkylaminocarbonyl claim 1 , aminocarbonyl claim 1 , sulfonamido claim 1 , and alkylenedioxy spanning two substituent positions.45-. (canceled)8. The compound claim 7 , prodrug claim 7 , or salt of claim 7 , wherein X is NR′R″ where R′ is selected from trifluoromethyl claim 7 , alkenyl claim 7 , alkynyl claim 7 , hydroxyalkyl claim 7 , alkylaminoalkyl claim 7 , dialkylaminoalkyl claim 7 , heterocyclyl claim 7 , and heterocyclylalkyl claim 7 , where the heterocycle is selected from pyrrolyl claim 7 , thiophenyl claim 7 , and imidazolyl claim 7 , and the cyclic structure of heterocyclyl and heterocyclylalkyl is optionally substituted with one or more of halo claim 7 , alkyl claim 7 , trifluoromethyl claim 7 , hydroxyl claim 7 , alkoxy claim 7 , amino claim 7 , alkylamino claim 7 , dialkylamino claim 7 , mercapto claim 7 , alkylmercapto claim 7 , and carboxamido; R″ is selected from hydrogen claim 7 , cyanoalkyl claim 7 , and dialkylaminoalkyl claim 7 , or R′ and R″ together form a 5- claim 7 , 6- or 7-membered claim 7 , saturated or unsaturated claim 7 , heterocyclic ring containing at least one nitrogen claim 7 , and optionally oxygen claim 7 , and the heterocyclic ...

CHEMICAL COMPOUNDS AS ANTIBIOTICS

The invention relates to a compound which is an indane derivative according to Formula (I), or a pharmaceutically acceptable salt thereof, [FORMULA (I)] wherein R, R, R, n, R, p, q, L, X and m are as defined herein. The compounds are useful in the treatment of antibacterial infection either as stand alone antibiotics, or in combination with further antibiotics. The compounds can also be used in vitro, for example in cleaning compositions. 131.-. (canceled)33. A compound according to wherein:{'sup': 1', '1a, 'Ris selected from H and R;'}{'sup': '2', 'sub': 1', '2, 'Ris selected from H and unsubstituted Cto Calkyl; and'}{'sup': '4', 'Ris H.'}34. A compound according to claim 32 , wherein n is an integer from 0 to 2 and each Rgroup is independently selected from halogen; —OH; and —NH.35. A compound according to wherein Ris H claim 32 , Ris H claim 32 , n is 0 claim 32 , and Ris H.36. A compound according to wherein q is 0.40. A compound according to wherein {circle around (A)} is a 5- to 10-membered heteroaryl group or a 4- to 10-membered heterocyclic group.41. A compound according to wherein {circle around (A)} is selected from pyrazole claim 32 , benzene claim 32 , benzothiazole claim 32 , benzofuran claim 32 , benzimidazole claim 32 , benzothiophene claim 32 , benzoxazole claim 32 , indole claim 32 , isoquinoline claim 32 , 2 claim 32 ,3-dihydrobenzofuran claim 32 , 2 claim 32 ,3-dihydrobenzo[b][1 claim 32 ,4]dioxine claim 32 , and 4 claim 32 ,5 claim 32 ,6 claim 32 ,7-tetrahydrothiazolo[5 claim 32 ,4-c]pyridine.42. A compound according to wherein each X is independently selected from:{'sup': 10', '11', '+', '10', '11', '12', '10', '11', '2', '13, '(i) a 4- to 7-membered nitrogen-containing heterocyclic group which is unsubstituted or is substituted by one or two substituents independently selected from —NRR; —NRRR; —NRC(NR)NR;'}{'sup': 10', '+', '11', '12', '13', '14', '10', '11', '12', '11', '12', '10', '11', '+', '10', '11', '12', '10', '11', '12', '13', '10', ...

N,n-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors

The present invention provides a pyrrolidine compound of General Formula (1) or a salt thereof, wherein R 101 and R 102 are each independently a phenyl group or a pyridyl group, the phenyl group or the pyridyl group may have one or more substituents selected from halogen atoms and lower alkyl groups optionally substituted with one or more halogen atoms, etc. The pyrrolidine compound or a salt thereof of the present invention is usable to produce a pharmaceutical preparation having a wider therapeutic spectrum and being capable of exhibiting sufficient therapeutic effects after short-term administration.

IRE-1alpha INHIBITORS

The invention provides compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response and can be used as single agents or in combination therapies. 2. (canceled)4. (canceled)5. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'the compound or pharmaceutically acceptable salt of ; and'}a pharmaceutically acceptable vehicle.6. A method of inhibiting IRE-1α claim 1 , comprising contacting IRE-1α with the compound or pharmaceutically acceptable salt of claim 1 , thereby inhibiting IRE-1α.7. A method of treating a disease associated with the unfolded protein response claim 1 , comprising administering to a patient in need thereof an effective amount of the compound or pharmaceutically acceptable salt of .8. (canceled)9. (canceled)10. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00003', 'claim 3'}, 'the compound or pharmaceutically acceptable salt of ; and'}a pharmaceutically acceptable vehicle.11. A method of inhibiting IRE-1a claim 3 , comprising contacting IRE-1α with the compound or pharmaceutically acceptable salt of claim 3 , thereby inhibiting IRE-1α.12. A method of treating a disease associated with the unfolded protein response claim 3 , comprising administering to a patient in need thereof an effective amount of the compound or pharmaceutically acceptable salt of .14. The compound of claim 1 , whereinR3 and R8 are hydrogen; andR4 is alkoxy.15. The compound of claim 1 , whereinR4 and R8 are hydrogen; andR3 is alkoxy.16. The compound of claim 1 , whereinR3 and R4 are alkoxy; andR8 is hydrogen.21. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00017', 'claim 17'}, 'the compound or pharmaceutically acceptable salt of ; and'}a pharmaceutically acceptable vehicle.22. A method of inhibiting IRE-1α claim 17 , comprising ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula:

(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and theft use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.

Heterocyclic compound and use thereof

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the specification, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

EFFLUX-PUMP INHIBITORS AND THERAPEUTIC USES THEREOF

The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC is —N(R8)(R9)ASC-1 ASC-1 is Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom and wherein one CH2 moiety in ring A is optionally replaced by CH(R21) and wherein one carbon atom in ring A that is not adjacent to the nitrogen atom is optionally replaced by O, and wherein ring A is connected to X via a carbon atom; X represents a bond, —CH2- or —C(═O)—; AR1, AR2 represent independently phenyl or a 5- to 6-membered heteroaryl ring containing one to three heteroatoms selected from O, S and N, wherein AR1 is connected to L1 via a carbon atom, and wherein AR2 is connected to L1 and L2 via a carbon atom; R1, R2, R3 represent independently hydrogen, halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —C1-C6alkylene-N(R12)R13, —N(R12)R13, —C(O)OR111, —C(O)N(R12)R13, —S(O)OR11 or phenyl; R4 represents hydroxyl, hydrogen, halogen, nitro, cyano, amino, C1-C6alkyl optionally substituted by 1 to 5 R14, C2-C6alkenyl optionally substituted by 1 to 5 R14, C2-C6alkynyl optionally substituted by 1 to 5 R14, C1-C6alkoxy optionally substituted by 1 to 5 R14, C2-C6alkenyloxy optionally substituted by 1 to 5 R14, C2-C6alkynyloxy optionally substituted by 1 to 5 R14, —C(O)OR15, —CHO, —C(O)N(R16)R17, —C1-C6alkylene-N(R9)(R16)R17, —O-Cycle-P or —O-Cycle-Q; R5, R6, R7 represent independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy; R8 represents hydrogen, methyl or ASC-1; R9 is methyl or absent, and wherein when R9 is present the respective nitrogen atom carries a positive charge; R10 represents hydrogen or methyl; R11 represents independently at each occurrence hydrogen or C1-C6alkyl; R12, R13 represent independently at each occurrence hydrogen or C1-C6alkyl; R14 represents independently at each ...

SULFONAMIDE-SUBSTITUTED CYANOPYRROLIDINES WITH ACTIVITY AS DUB INHIBITORS

The present invention relates to a class of sulfonamide-substituted cyanopyrrolidines of Formula (Ia) and (Ib) with activity as inhibitors of deubiquitilating enzymes, in particular, ubiquitin C-terminal hydrolase L1 (UCHL1) and ubiquitin C-terminal hydrolase 30 or ubiquitin specific peptidase 30 (USP30), having utility in a variety of therapeutic areas including cancer and conditions involving mitochondrial dysfunction: (Formulae (Ia), (Ib)). 2. The compound according claim 1 , wherein m is 0 claim 1 , 1 or 2.3. The compound according to claim 1 , wherein{'sup': '1', 'each Ris independently selected from fluoro, cyano, methyl, methoxy, and methoxymethyl;'}{'sup': 2', '3, 'Rand Rare selected from hydrogen and methyl;'}{'sup': 1', '2', '1', '2, 'or where Rand NRare situated on adjacent ring atoms, Rtogether with Rmay form a morpholine, piperidine, or pyrrolidine ring.'}4. The compound compound according to claim 1 , wherein{'sup': '1', 'Lis selected from a covalent bond, methylene, and ethylene.'}5. The compound according to claim 1 , wherein{'sup': '2', 'sub': '2', 'Lis selected from a covalent bond, an oxygen atom, methylene, OCH, and NHC(O).'}6. The compound according to claim 1 , whereingroup ‘A’ is selected from indanyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, tetralinyl, benzothiazolyl, imidazolyl, isoxazolyl, piperidinyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, 1,2,4-triazolyl, and quinolinyl;{'sup': 1', '3, 'or A-L-N—Rmay form a ring selected from azetidinyl, isoindolinyl, piperazinyl, piperidinyl, tetrahydroisoquinolinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.'}7. The compound according to claim 1 , whereingroup ‘B’ is selected from phenyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, 1,2-thiazolidinyl, and thiazolyl.8. The compound according to claim 1 ,{'sub': 1', '6', '1', '6', '3', '3', '1', '6, 'each carbocyclic and heterocyclic ring may be optionally substituted with 1 to 2 substituents ...

EBNA1 INHIBITORS AND THEIR METHOD OF USE

Pharmaceutical compositions of the invention comprise EBNA1 inhibitors useful for the treatment of diseases caused by EBNA1 activity such as cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by lytic Epstein-Barr Virus (EBV) infection. 122-. (canceled)25. The compound of claim 23 , wherein the compound is selected from the group consisting of:3-{2-[3-(methylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid;3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoic acid;3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[2-( ...

1-cyano-pyrrolidine compounds as usp30 inhibitors

The present invention relates to novel compounds and method for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , Z, Y and m are as defined herein.

Dye composition comprising a cationic o-alkyl-substituted meta-phenylenediamine derivative

The invention relates to a meta-phenylenediamine compound of formula (I) below, the addition salts thereof with an acid and the solvates thereof: in which: R represents a hydrogen or halogen atom; a C 1 -C 4 alkyl radical; a carboxyl radical or a (C 1 -C 4 ) alkoxycarbonyl radical, R 1 represents a linear C 1 -C 10 alkyl radical substituted with a cationic radical, said alkyl radical being optionally interrupted with one or more oxygen atoms and/or with one or more NR 6 groups, said cationic radical being optionally substituted with one or more radicals chosen from C 1 -C 4 alkoxy or C 1 -C 4 (hydroxy)alkyl; R 6 represents a hydrogen atom or a linear or branched C 1 -C 4 alkyl radical; An − represents an anion or a mixture of anions which are organic or inorganic and cosmetically acceptable.

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 131- (canceled)33. (2S ,4R)-5-(3′-chlorobiphenyl-4-yl)-4-formylamino-2-hydroxymethyl-2-methyl-pentanoic acid or a pharmaceutically-acceptable salt thereof.34. A pharmaceutical composition comprising the compound of or and a pharmaceutically acceptable carrier.35. The pharmaceutical composition of claim 34 , further comprising an ATreceptor antagonist.36. A method for treating hypertension claim 34 , heart failure claim 34 , or renal disease claim 34 , comprising administering to a patient a therapeutically effective amount of the compound of or . This application claims the benefit of U.S. Provisional Application No. 61/772,721, filed on Mar. 5, 2013; the entire disclosure of which is incorporated herein by reference.The present invention relates to novel compounds having neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriuresis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.NEP inhibitors, such as thiorphan, candoxatril, and candoxatrilat, have been studied as potential therapeutics. Compounds that inhibit both NEP and angiotensin-I converting ...

INHIBITORS OF BACTERIAL DNA GYRASE WITH EFFICACY AGAINST GRAM-NEGATIVE BACTERIA

The present invention provides N-benzyl-3-sulfonamidopyrrolidines and related compounds, as well as pharmaceutical compositions and sanitizing compositions containing the same. The compounds and compositions are useful as antibiotic agents. Methods for making and using the compounds and compositions are also described. 3. The compound of claim 2 , wherein A is selected from the group consisting of phenyl claim 2 , substituted phenyl claim 2 , thiophenyl claim 2 , and pyrazolyl.4. The compound of claim 4 , wherein A is selected from the group consisting of phenyl claim 4 , 4-chlorophenyl claim 4 , 3-chlorophenyl claim 4 , thiophen-2-yl claim 4 , and 1H-pyrazol-1-yl.5. The compound of claim 1 , wherein A is selected from the group consisting of —OCaryl claim 1 , —OCheteroaryl claim 1 , —OCcycloalkyl claim 1 , and —OCheterocycloalkyl.6. The compound of claim 5 , wherein A is selected from the group consisting of cyclopropyloxy claim 5 , cyclobutyloxy claim 5 , and cyclopentyloxy.7. The compound of claim 1 , wherein each R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris independently selected from the group consisting of hydrogen claim 1 , Calkyl claim 1 , Calkoxy claim 1 , cyano claim 1 , haloCalkyl claim 1 , halogen claim 1 , haloCalkoxy.8. The compound of claim 7 , wherein each R claim 7 , R claim 7 , R claim 7 , R claim 7 , and Ris independently selected from the group consisting of hydrogen claim 7 , chloro claim 7 , trifluoromethyl claim 7 , and trifluoromethoxy.9. The compound of claim 1 , wherein both Rand Rare hydrogen.12. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.13. A composition comprising a compound of and an antibiotic.14. The composition of claim 13 , wherein the antibiotic is selected from the group consisting of a gyrase inhibitor claim 13 , a macrolide antibiotic claim 13 , and a β-lactam.15. (canceled)16. The composition of claim 14 , wherein the antibiotic is a macrolide antibiotic and is ...

PRMT5 INHIBITORS AND USES THEREOF

Described herein are compounds of Formula (I)-(XIII), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described. 48. The compound of or , wherein one Ris —CHor —CH.49. The compound of or , wherein both instances of Rare hydrogen.50. The compound of or , wherein one instance of Ris —COH.56. The compound of any of - , wherein Q is O.57. The compound of any of - , wherein Ris —NH.58. The compound of any of - , wherein Z is N.59. The compound of claim 16 , wherein n is 0.60. The compound of claim 16 , wherein Ris hydrogen.61. The compound of claim 16 , wherein Ris —CHCHNHC(═O)R; and Ris unsubstituted phenyl.64. The compound of any of - claim 16 , wherein Ris —NMe.65. The compound of any of - claim 16 , wherein Ris hydrogen claim 16 , -Me claim 16 , —F claim 16 , or —NH.67. The compound of claim 23 , wherein M is a bond; and Ris —OR.68. The compound of claim 23 , wherein M is NH; and Ris a halogen.69. The compound of any of - claim 23 , wherein Ris —NMe.70. The compound of any of - claim 23 , wherein Ris unsubstituted phenyl.71. The compound of any of - claim 23 , wherein Ris unsubstituted Calkyl.72. The compound of any of - claim 23 , wherein Lis a bond.73. The compound of any of - claim 23 , wherein Lis NH.78. A compound selected from the group consisting of the compounds listed in Table 1A-Table 1O claim 23 , and pharmaceutically acceptable salts thereof.79. A pharmaceutical composition comprising a compound of any one of - claim 23 , or a pharmaceutically acceptable salt thereof claim 23 , and a pharmaceutically acceptable excipient.80. A kit or packaged pharmaceutical comprising a compound of any one of - and instructions for use thereof.81. A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of any one of - or a pharmaceutically ...

N,n-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors

The present invention provides a pyrrolidine compound of General Formula (1) or a salt thereof, wherein R 101 and R 102 are each independently a phenyl group or a pyridyl group, the phenyl group or the pyridyl group may have one or more substituents selected from halogen atoms and lower alkyl groups optionally substituted with one or more halogen atoms, etc. The pyrrolidine compound or a salt thereof of the present invention is usable to produce a pharmaceutical preparation having a wider therapeutic spectrum and being capable of exhibiting sufficient therapeutic effects after short-term administration.

LIQUID CRYSTAL COMPOSITION CONTAINING NITROGEN-CONTAINING CYCLIC COMPOUND AND LIQUID CRYSTAL DISPLAY DEVICE

The disclosure shows a liquid crystal composition that contains a compound having an effect of preventing photolysis of the liquid crystal composition and having high solubility in the liquid crystal composition, and that satisfies at least one of characteristics such as high maximum temperature, low minimum temperature, small viscosity, suitable optical anisotropy, large positive or negative dielectric anisotropy, large specific resistance, high stability to ultraviolet light or heat, and a suitable elastic constant, etc. and so on. 6. The liquid crystal composition according to , wherein in formulae (Q-1) and (Q-2) of , Ris hydrogen , —O. , —OH , alkyl having 1 to 10 carbons , or alkoxy having 1 to 10 carbons.15. The compound according to , wherein in formulae (Q-1) and (Q-2) of , Ris hydrogen , —O. , —OH , alkyl having 1 to 10 carbons , or alkoxy having 1 to 10 carbons.17. A liquid crystal composition claim 11 , containing at least one compound according to .18. A liquid crystal display device claim 1 , containing at least one liquid crystal composition according to . This application claims the priority benefit of Japan application serial no. 2015-005929, filed on Jan. 15, 2015. The entirety of the above-mentioned patent application is hereby incorporated by reference herein and made a part of this specification.The invention relates to a liquid crystal composition that contains a nitrogen-containing cyclic compound, and a liquid crystal display device. More specifically, the invention relates to a liquid crystal composition that contains a compound having an azolidine ring or azepane ring, and a liquid crystal display device. The invention also relates to a compound having an azepane ring.For liquid crystal display devices, a classification based on an operating mode of liquid crystal molecules includes phase change (PC), twisted nematic (TN), super twisted nematic (STN), electrically controlled birefringence (ECB), optically compensated bend (OCB), in-plane ...

COMPOSITIONS AND METHODS FOR TREATING CANCER

K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer. 1. A method of treating cancer in a patient in need of thereof , the method comprising administering to the patient a therapeutically effective amount of a compound; wherein the compound is capable of covalently binding to cysteine residue 12 of a Ras protein and contacting a residue of a Ras protein Switch 2 binding pocket.2. The method of claim 1 , wherein the residue of the Switch 2 binding pocket is V7 claim 1 , V9 claim 1 , G10 claim 1 , P34 claim 1 , T58 claim 1 , G60 claim 1 , Q61 claim 1 , E62 claim 1 , E63 claim 1 , R68 claim 1 , Y71 claim 1 , M72 claim 1 , Y96 claim 1 , Q99 claim 1 , or 1100.4. The method of claim 3 , wherein:{'sup': 1', '3, 'Ris R-substituted or unsubstituted heteroaryl;'}{'sup': 3', '10', '7', '8', '7', '8', '7', '8', '7', '8', '9', '9', '7', '8', '10', '7', '10', '7', '9', '7', '9', '7', '9', 'c, 'sub': 3', '2', 'n', 'v', '2', '2', 'm', '2', '3', '2, 'Ris independently hydrogen, oxo, halogen, —CX, —CN, —SOCl, —SOR, —SONRR, —NHNH, —ONRR, —NHC═(O)NHNH, —NHC═(O)NRR, —N(O), —NRR, —C(O)R, —C(O)—OR, —C(O)NRR, —OR, —NRSOR, —NRC═(O)R, —NRC(O)—OR, —NROR, —OCX, —OCHX, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;'}{'sup': 7', '8', '9', '10, 'sub': 3', '2', '2', '2', '2', '3', '4', '2', '2', '2', '2', '2', '2', '2', '3', '2, 'R, R, R, and Rare independently hydrogen, halogen, —CF, —CN, —OH, —NH, —COOH, —CONH, —NO, —SH, —SOCl, —SOH, —SOH, —SONH, —NHNH, —ONH, —NHC═(O)NHNH, —NHC═(O) NH, —NHSOH, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF, —OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ...

GLYCOSIDASE INHIBITORS AND USES THEREOF

The invention provides compounds for inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc. 2. (canceled)3. The compound of wherein the compound is selected from the following group:N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)acetamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4S,5S)-4-fluoro-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-fluoro-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5R)-5-(fluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5R)-5-(difluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3R,5R)-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-methyl-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4S)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropanoyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-1-(3-(6-fluoropyridin-3-yl)propyl)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(4,4,4-trifluorobutyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-(5-(trifluoromethoxy)benzo[d]thiazol-2-yl)propyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-((Z)-5,5,5-trifluoropent-3-en-1-yl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(pent-4-yn-1-yl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-1-butyryl-4-hydroxy-5-(hydroxymethyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S)-1-(3-(6-fluoropyridin-3-yl)propanoyl)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-3-yl)propionamide;N-((3S,4R,5S ...

Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders

The present invention relates to methods and compositions for the treatment or prevention of diseases and disorder associated with myeloproliferative and lymphoproliferative disorders. In particular, the invention relates to an LSD1 inhibitor for use in treating or preventing diseases and disorder associated with myeloproliferative and lymphoproliferative disorders.

OXALIC ACID MONOAMIDE LIGAND, AND USES THEREOF IN COUPLING REACTION OF COPPER-CATALYZED ARYL HALOGEN SUBSTITUTE

The present invention provides oxalic amide ligands and uses thereof in copper-catalyzed coupling reaction of aryl halides. Specifically, the present invention provides a use of a compound represented by formula I, wherein definitions of each group are described in the specification. The compound represented by formula I can be used as a ligand in copper-catalyzed coupling reaction of aryl halides for the formation of C—N, C—O and C—S bonds. 3. The use of claim 1 , characterized in that R is selected from the group consisting of substituted or unsubstituted phenyl claim 1 , substituted or unsubstituted naphthyl claim 1 , substituted or unsubstituted benzyl claim 1 , C1-C4alkyl claim 1 , pyridyl claim 1 , and adamantyl;{'sub': 'a', 'Ris selected from (a) or (b)(a) OR′; wherein R′ is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl; or{'sub': '2', '(b) N(R″); wherein each R″ is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, and substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S; the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure.'}5. The method of wherein claim 4 , in the reaction claim 4 , the molar ratio of the ligand to the reactant of aryl halide is 1-50:100 claim 4 , and preferably 5-20:100; and/orthe molar ratio of the ligand to the copper catalyst is 1-5: 1, and preferably 1-2:1.7. The method of wherein the reaction temperature is 50-180° C. claim 4 , and preferably 100-130° C. The present invention relates to the field of organic synthesis. Specifically, the present invention ...

CARBAMATE COMPOUNDS AND METHODS OF MAKING AND USING SAME

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition. 2. The compound of claim 1 , wherein T is CX.3. The compound of claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , iso-propyl claim 1 , tert-butyl claim 1 , benzyl and phenyl.4. The compound of anyone of - claim 1 , wherein at least four occurrences of X is halogen.5. The compound of any one of - claim 1 , wherein six occurrences of X is halogen.7. The compound of any one of - claim 1 , wherein Rand Rtaken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring B having an additional nitrogen.9. The compound of claim 8 , wherein:{'sup': '3', 'sub': 1', '2', 'w', '1', '2', 'w', '1', '2', '1-6, 'Lis selected from the group consisting of a bond, C-Calkylene, —C(O)—, —CH—C(O)—NH, —S(O)—, and C-Calkylene-S(O)—, wherein w is 0, 1, or 2, and wherein C-Calkylene is optionally substituted by a substituent selected from the group consisting of: phenyl, biphenyl, phenyloxyphenyl (each optionally substituted by halogen, Calkyl (optionally substituted by one, two or three halogens, or hydroxyl)), mono or bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, S, or N and mono or bicyclic heterocycle having 1, 2 or 3 heteroatoms independently selected from O, S, or N; and'}{'sup': 7', '7', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a, 'sub': 3', '1-6', '1-6', '2', 'w', '1-6', '1-6', '1-6, 'Ris selected from the group consisting of phenyl, biphenyl, phenyloxyphenyl, and mono or bicyclic ...

INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF

Disclosed are compounds, for example, compounds of formula (I), (Formula (I) wherein R, R, R-R, n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition, for example, cancer. 117-. (canceled)19. The compound or salt of claim 18 , wherein Ris a substituted or unsubstituted group selected from phosphonooxy claim 18 , phosphonooxyalkyloxy claim 18 , alkyloxy claim 18 , formyloxy claim 18 , alkylcarbonyloxy claim 18 , alkylcarbonyloxyalkyloxy claim 18 , aminocarbonyloxyalkyloxy claim 18 , alkylsulfinyloxy claim 18 , alkylsulfonyloxy claim 18 , carbamate claim 18 , carbamido claim 18 , arylcarbonyloxy claim 18 , arylalkylcarbonyloxy claim 18 , aryloxycarbonyloxy claim 18 , heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.20. The compound or salt of claim 19 , wherein Ris a substituted or unsubstituted group selected from from aminocarbonyloxyalkyloxy claim 19 , dimethylaminocarbonyloxy claim 19 , dimethylaminocarbonyloxyalkyloxy claim 19 , piperidinylcarbonyloxy claim 19 , piperidinylcarbonyloxyalkyloxy claim 19 , dipiperidinylcarbonyloxy claim 19 , and dipiperidinylcarbonyloxyalkyloxy.21. The compound or salt of claim 18 , wherein R is selected from heterocyclyl and heterocyclylalkyl claim 18 , wherein the cyclic structure of heterocyclyl and heterocyclylalkyl is selected from furanyl claim 18 , pyrrolyl claim 18 , thiophenyl claim 18 , and imidazolyl claim 18 , and said cyclic structure is optionally substituted with one or more of halo claim 18 , alkyl claim 18 , haloalkyl claim 18 , hydroxy claim 18 , alkoxy claim 18 , amino claim 18 , alkylamino claim 18 , dialkylamino claim 18 , mercapto claim 18 , alkylmercapto claim 18 , and carboxamido.22. The compound or salt of claim 21 , wherein R′ is selected from heterocyclyl and heterocyclylalkyl claim 21 , wherein the cyclic structure of heterocyclyl and heterocyclylalkyl is selected from furanyl and pyrrolyl ...

SUBSTITUTED CYCLOHEXANES AS MUSCARINIC M1 RECEPTOR AND/OR M4 RECEPTOR AGONISTS

This invention relates to compounds that are agonists of the muscarinic Mreceptor or Mand Mreceptors and which are useful in the treatment of muscarinic Mor M/Mreceptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula 2. The compound according to wherein Ris H claim 1 , methyl claim 1 , CHCONH claim 1 , COEt or SOMe.3. The compound according to wherein Ris H.4. The compound according to wherein Rand Rare independently selected from H claim 1 , methyl claim 1 , fluoro claim 1 , OMe claim 1 , chloro and cyano.5. The compound according to wherein Ris oxo.6. The compound according to wherein Z is C.7. The compound according to wherein p is 0; or p is 1 and Ris selected from fluorine and methyl.8. The compound according to wherein V is a bond and Qis nitrogen.9. The compound according to wherein W is optionally substituted 1-oxa-2 claim 1 ,4-diazole.10. The compound according to wherein W is -QC(O)YCHR claim 1 , wherein Qis a bond claim 1 , NH or NMe claim 1 , Y is O and Ris selected from H claim 1 , methyl and ethyl.12. The compound according to which is selected from the group consisting of:ethyl [(3S)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3R)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(7′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(6′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(5′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(4′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamateethyl [(3S)-1-(5′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane ...

HETEROCYCLIC COMPOUND AND USE THEREOF

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. 2. The compound or salt according to claim 1 , whereinRing B is a ring [{'sub': '6-14', '(a) an optionally substituted Caryl group,'}, {'sub': '6-14', '(b) an optionally substituted Caryloxy group,'}, {'sub': '7-16', '(c) an optionally substituted Caralkyl group,'}, {'sub': '3-10', '(d) an optionally substituted Ccycloalkyl group,'}, {'sub': '3-10', '(e) an optionally substituted Ccycloalkenyl group,'}, {'sub': '3-10', '(f) an optionally substituted Ccycloalkoxy group,'}, '(g) an optionally substituted 5- to 14-membered aromatic heterocyclic group, or', '(h) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, and, 'further substituted by'}optionally having additional substituent(s).3. The compound or salt according to claim 1 , wherein{'sup': '1', 'claim-text': [{'sub': '1-6', 'claim-text': (a) a halogen atom,', '(b) a cyano group,', '(c) a hydroxy group, and', {'sub': '1-6', '(d) a Calkoxy group,'}], '(1) a Calkyl group optionally substituted by 1 to 3 substituents selected from'}, {'sub': '2-6', '(2) a Calkenyl group,'}, {'sub': '3-10', '(3) a Ccycloalkyl group optionally substituted by 1 to 3 halogen atoms,'}, {'sub': '1-6', '(4) a mono- or di-Calkylamino group, or'}, '(5) a 3- to 14-membered non-aromatic heterocyclic group;, 'Ris'}{'sup': '2', 'Ris a hydrogen atom;'}{'sup': '3', 'claim-text': (1) a hydrogen atom,', {'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '1-6', '(b) a Calkoxy group,'}, {'sub': '3-10', 'claim-text': (i) a halogen atom, and', {'sub': '1-6', '(ii) a Calkyl group, and'}], '(c) a Ccycloalkyl group optionally substituted by 1 to 3 substituents selected from'}, '(d) a 3- to 14-membered non-aromatic heterocyclic group,, '(2) a Calkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from'}, {'sub': '1-6', 'claim-text': (a) a halogen atom,', {'sub': '3-10', '(b) a Ccycloalkyl group,'}, ...

PHENYL AMINO PIPERIDINE mTORC INHIBITORS AND USES THEREOF

The present invention provides compounds, compositions thereof, and methods of using the same. 119.-. (canceled)22. The method according to or , wherein Ais N.23. The method according to claim 22 , wherein m is 1 and n is 1.24. The method according to claim 22 , wherein Ais C(R′).25. The method according to claim 22 , wherein Ais CH.26. The method according to claim 22 , wherein p is 1 and q is independently 0 claim 22 , 1 claim 22 , or 2.27. The method according to claim 22 , wherein each of Rand Ris independently R claim 22 , or: two Rgroups are optionally taken together to form ═O; two Rgroups are optionally taken together to form ═O; two Rgroups are optionally taken together to form a covalent bond or a bivalent Calkylene chain; or two Rgroups are optionally taken together to form a covalent bond or a bivalent Calkylene chain.29. The method according to claim 27 , wherein Ris hydrogen or methyl.30. The method according to claim 22 , wherein claim 22 , each of Ris independently R claim 22 , halogen claim 22 , —OR claim 22 , or —CN.32. The method according to claim 22 , wherein Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms.34. The method according to claim 22 , wherein Lis a covalent bond or a Cbivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —C(O)— claim 22 , —C(S)— claim 22 , —C(R)— claim 22 , —CH(R)— claim 22 , —C(F)— claim 22 , —N(R)— claim 22 , or —S(O)—.37. The method of claim 20 , wherein the mTORC-mediated cellular proliferative disorder is a fibrotic disease selected from idiopathic pulmonary fibrosis (IPF) claim 20 , kidney fibrosis claim 20 , scleroderma claim 20 , hypertrophic scarring claim 20 , keloid disease claim 20 , and cardiac fibrosis. The present invention relates to compounds and methods useful for modulating mTORC1 activity. The invention also provides pharmaceutically ...