СОЕДИНЕНИЯ И КОМПОЗИЦИИ В КАЧЕСТВЕ МОДУЛЯТОРОВ PPAR-РЕЦЕПТОРОВ, АКТИВИРУЕМЫХ ПРОЛИФЕРАТОРОМ ПЕРОКСИСОМ

Настоящее изобретение относится к соединению формулы I и его фармацевтически приемлемым солям. В формуле I ! ! R1 выбирают из C1-6алкила, С3-12циклоалкила, фенила, фуранила, тиенила, пиридила, где фенил, принадлежащий радикалу R1, необязательно замещен радикалом, который выбран из галогена, нитро, C1-6алкила, C1-6алкокси, замещенного галогеном C1-6алкила и -XC(O)YR5; где Х представляет собой С1-4алкилен, Y представляет собой О, и R5 представляет собой водород; R2 представляет собой -C(O)NR4XOR5, где Х представляет собой С1-4алкилен; R4 выбирают из водорода и C1-6алкила; R5 представляет собой фенил; где любой фенил, принадлежащий радикалу R2, необязательно замещен двумя радикалами, которые независимо выбирают из галогена, нитро и замещенного галогеном C1-6алкила; R3 представляет собой фенил, который необязательно замещен радикалами в количестве от 1 до 2, которые независимо выбирают из галогена, C1-6алкила, C1-6алкокси, -XOXC(O)OR5, -XC(O)OR5, где Х независимо выбирают из простой связи и ...

ИНГИБИТОРЫ НЕПРИЛИЗИНА

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

ПРОИЗВОДНЫЕ БЕНЗАМИДА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ

Изобретение относится к производным бензамида формулы I где R3 представляет собой (1-6С)алкил или галоген; Q - арил или гетероарил, который необязательно несет 1, 2, 3 или 4 заместителя, выбранных из гидрокси, галогена, циано, нитро, амино, карбокси, (1-6С)алкила, (2-6С)алкенила, (2-6С)алкинила, (1-6С)алкокси, (1-3С)алкилендиокси, (1-6С)алкиламино и т.д.; R2 - (1-6С)алкил, (2-6С)алкенил, (2-6С)алкинил, (1-6С)алкокси, (1-6С)алкиламино или ди-[(1-6С)алкил]амино; p = 0, 1 или 2; q = 0, 1, 2, 3 или 4; R4 - арил, арил-(1-6С)алкокси, арилокси, ариламино, циклоалкил или гетероарил и R4 необязательно несет 1, 2, 3 или 4 заместителя, выбранных из галогена, циано, (1-6С)алкила, (2-6С)алкенила, (2-6С)алкинила, (1-6С)алкокси, (1-6С)алкиламино и т.д., или его фармацевтически приемлемая соль, или расщепляемый in vivo сложный эфир. Предложены способы получения производных бензамида формулы (I). Также предложена фармацевтическая композиция, обладающая ингибирующей цитокины активностью, содержащая активный ...

МОДУЛЯТОРЫ СВЯЗАННЫХ С MAS РЕЦЕПТОРОВ G-БЕЛКА X4 И СВЯЗАННЫЕ С НИМИ ПРОДУКТЫ И СПОСОБЫ

Изобретение относится к соединению, имеющему одну из следующих структур, или его фармацевтически приемлемой соли: Соединение № Структура 1-55 1-78 5-1 4-10 1-65 4-11 1-58 1-56 9-1 1-82 1-85 1-29 1-101 2-3 1-103 1-112 4-7 11-1 Изобретение также относится к фармацевтической композиции и способу лечения MRGPR X4-зависимых состояний на основе указанного соединения. Технический результат: получено новое соединение и фармацевтическая композиция на его основе, которые могут найти применение в медицине для лечения MRGPR X4-опосредованных заболеваний. 4 н. и 35 з.п. ф-лы, 7 ил., 70 табл., 70 пр.

ИНГИБИТОРЫ НЕПРИЛИЗИНА

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

БЕНЗИЛАМИНОВЫЕ ПРОИЗВОДНЫЕ КАК ИНГИБИТОРЫ КАЛЛИКРЕИНА ПЛАЗМЫ

Настоящее изобретение относится к соединениям формулы (I), композициям, содержащим такие соединения; применению таких соединений в терапии для лечения или предотвращения заболеваний или состояний, при которых предполагается активность калликреина плазмы; и способам лечения пациентов с помощью таких соединений; где Rвыбирают из Н, алкила, -СОалкила, -СОарила, -СОгетероарила, -(СН)ОН, -(СН)COOR, -(СН)CONH, -SOалкила, -SОарила, -SO(СН)R, -СО(СН)R, -СОциклоалкила, -COCH=CHR, -СО(СН)NHCO(СН)kRи -CONRR; Rвыбирают из Н и алкила; Rвыбирают из алкила, -(СН)арила, -(СН)гетероарила, (СН)циклоалкила, -СН(циклоалкила)и -(СН)арил-O-(СН)-арила; Rи Rнезависимо выбирают из Н и алкила; Rвыбирают из Н и ОН; или Rи R, вместе с атомами, к которым они присоединены, могут связываться с образованием 5- или 6-членной азациклоалкильной структуры; Rвыбран из Н и галогена; Rвыбран из Н, алкила, галогена и CF; Rпредставляет собой арил или гетероарил; Rпредставляет собой Н или алкил; а, b, с, d, е, f, g, h, i, j, l ...

ПРОИЗВОДНЫЕ АМИДА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ

Изобретение относится к производным амида формулы I где R3 представляет собой (1-6С)алкил или галоген; m равно 0, 1, 2 или 3; R1 представляет собой гидрокси, галоген, трифторметил, нитро, амино, (1-6С)алкил, (2-6С)алкенил, (2-6С)алкинил, (1-6С)алкокси, (1-6С)алкиламино, ди-[(1-6С)алкил] амино, амино-(2-6С)алкиламино, (1-6С)алкиламино-(2-6С)алкиламино и т.д. или R1 представляет собой арил, арил-(1-6С)алкил, гетероарил, гетероарил-(1-6С)алкил, гетероарилокси, гетероарил-(1-6С)алкокси, гетероциклил, гетероциклил-(1-6С)алкил или гетероциклилокси, р равно 0, 1 или 2; R2 представляет собой гидрокси, галоген, трифторметил, (1-6С)алкил или (1-6С)алкокси; R4 представляет собой амино, (1-6С)алкиламино, ди-[(1-6С)алкил] амино, амино-(1-6С)алкил, (1-6С)алкиламино-(1-6С)алкил и т.д. или R4 представляет собой гетероарил, гетероарил-(1-6С)алкил, гетероарилокси, гетероарил-(1-6С)алкокси, гетероциклил и т.д., q равно 0, 1, 2, 3 или 4 и Q2 представляет собой гетероарил, гетероарилокси или гетероарил-(1-6С ...

НОВОЕ ПРОИЗВОДНОЕ АНТРАНИЛОВОЙ КИСЛОТЫ ИЛИ ЕГО СОЛЬ

Изобретение относится к новым производным антраниловой кислоты, обладающим ингибирующей активностью в отношении продуцирования металлопротеазы 13 матрикса формулы 1 ! , ! где R1 представляет собой атом водорода или карбоксизащитную группу, выбранную из C1-3алкила; R2 представляет собой фенил, С3-6циклоалкил, насыщенную или ненасыщенную 5-6-членную гетероциклическую группу, содержащую 1-3 гетероатома, выбранных из N, О, S, которая может быть конденсирована с фенилом, которые могут быть необязательно замещены C1-6алкилом, C1-6алкокси, ацетилом, ацетокси, галогеном, галогенС1-6алкилом, нитрогруппой, гидроксильной группой, CN, аминогруппой, фенилом, насыщенной или ненасыщенной 5-6-членной гетероциклической группой, содержащей 1-4 гетероатома, выбранных из N, О, S, которая может быть дизамещена C1-6алкилом; R3 представляет собой фенил, С3-6циклоалкил, С5циклоалкенил, насыщенную или ненасыщенную 5-6-членную гетероциклическую группу, содержащую 1-3 гетероатома, выбранных из N, О, S, которая может ...

ПРОИЗВОДНОЕ 4-БЕНЗОИЛИЗОКСАЗОЛА ИЛИ ЕГО ПРИЕМЛЕМАЯ ДЛЯ СЕЛЬСКОГО ХОЗЯЙСТВА СОЛЬ, ГЕРБИЦИДНАЯ КОМПОЗИЦИЯ И СПОСОБ БОРЬБЫ С СОРНЯКАМИ

Изобретение относится к новым производным 4-бензоилизоксазола формулы I, где R - водород или -CO2R4; R1 - C3-6-циклоалкил; R2 - галоген, н-алкил, возможно замещенный одним и более атомов галогена, или -OR5, -S(O)pR6; R3 - -S(O)qR7; X - -(CR9R10)t-; n = 0, 1 и 2; когда n больше 1, группы R2 могут быть одинаковыми или различными; R4, R5 и R6 -н-алкил; R7-н-алкил, возможно замещенный одним или большим числом атомов водорода, C3-C6-алкенил с прямой цепью или фенил; R9 и R10 - водород или C1-C6-алкил с прямой цепью; p и q = 0, 1 или 2; t - целое число от 1 до 4, когда t > 1, группы -CR9R10 могут быть одинаковыми или различными; или их приемлемые для сельского хозяйства соли. Соединения формулы I демонстрируют гербицидную активность против двудольных и однодольных сорняков при применении до и после появления всходов. 3 с. и 7 з.п. ф-лы. 9 табл.

ПРОИЗВОДНЫЕ 5-АРИЛИЗОКСАЗОЛА, СПОСОБЫ ИХ ПОЛУЧЕНИЯ, ГЕРБИЦИДНАЯ КОМПОЗИЦИЯ И СПОСОБ ПОДАВЛЕНИЯ СОРНЯКОВ В ЛОКУСЕ

Использование: в сельском хозяйстве в качестве гербицидов. Сущность: продукт-производные 5-арилизоксазола ф-лы 1 с определенными значениями радикалов. Получение соединений 1 ведут тремя способами. Гербицидная композиция, содержащая эффективное количество соединений ф-лы 1 и целевые добавки и способ подавления сорняков в локусе с использованием в качестве гербицида соединений ф-лы 1: 6 с. п. ф-лы, 5 з. п. ф-лы, 5 табл.

ЗАМЕЩЕННЫЕ БЕНЗОИЛЦИКЛОГЕКСЕНОНЫ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ГЕРБИЦИДНОГО СРЕДСТВА

... 1. Соединения формулы (I) в которой Q представляет собой О (кислород) или S (серу), R1 представляет собой водород, галоген или соответственно, при необходимости, замещенный алкил, алкилтио или арил, R2 представляет собой водород, галоген или, при необходимости, замещенный алкил, или вместе с R1 представляет собой O (кислород) или алкандиил (алкилен), R3 представляет собой водород, нитро, циано, карбокси, карбамоил, тиокарбамоил, галоген или соответственно, при необходимости, замещенный алкил, алкокси, алкилтио, алкилсульфинил, алкилсульфонил, алкиламино, диалкиламино, диалкиламино-карбонил или диалкиламиносульфонил, R4 представляет собой водород, нитро, циано, карбокси, карбамоил, тиокарбамоил, галоген или соответственно, при необходимости, замещенный алкил, алкокси, алкилтио, алкилсульфинил, алкилсульфонил, алкиламино, диалкиламино, диалкиламино-карбонил или диалкиламиносульфонил, R5 представляет собой водород или соответственно, при необходимости, замещенный алкил, алкокси, алкилтио, ...

НОВОЕ СУЛЬФОНАМИДНОЕ ПРОИЗВОДНОЕ МАЛОНОВОЙ КИСЛОТЫ И ЕГО ФАРМАЦЕВТИЧЕСКОЕ ПРИМЕНЕНИЕ

... 1. Производное сульфонилмалонамида, представленное следующей формулой (I) ! ! где R1 представляет собой необязательно замещенный C1-8 алкил, необязательно замещенный C2-6 алкенил, необязательно замещенный C2-6 алкинил, необязательно замещенный C3-10 циклоалкил, необязательно замещенный C3-10 циклоалкил C1-6 алкил, необязательно замещенный гетероцикл, необязательно замещенный арил, необязательно замещенный арил C1-6 алкил, необязательно замещенный арилокси C1-6 алкил, необязательно замещенный арил C2-6 алкенил, необязательно замещенный гетероарил, необязательно замещенный гетероарил C1-6 алкил, необязательно замещенный гетероарилокси C1-6 алкил или необязательно замещенный гетероарил C2-6 алкенил; ! один из R2 и R3 представляет собой атом водорода или атом галогена, а другой представляет собой атом галогена, необязательно замещенный C1-6 алкил, необязательно замещенный C1-6 алкокси, необязательно замещенный C2-6 алкенил, необязательно замещенный C2-6 алкинил, -(CH2)n-С(O)-NR5R6 (где n представляет ...

ФУНГИЦИДНЫЕ -ЦИКЛОАЛКИЛБЕНЗИЛАМИДНЫЕ ПРОИЗВОДНЫЕ

... 1. Соединение формулы (I): ! ! где A представляет собой карбо-связанную ненасыщенную 5-членную гетероциклильную группу, которая может быть замещена, в количестве вплоть до четырех, группами R; ! Z1 представляет собой незамещенный C3-C7-циклоалкил или C3-C7 циклоалкил, замещенный, в количестве вплоть до 10, атомами или группами, которые могут быть одинаковыми или отличными друг от друга и, которые могут быть выбраны из следующего перечня, включающего атомы галогена; циано; C1-C8-алкил; C1-C8-галогеноалкил, включающий вплоть до 9 атомов галогена, которые могут быть одинаковыми или отличными друг от друга; C1-C8-алкокси; C1-C8-галогеноалкокси, включающий вплоть до 9 атомов галогена, которые могут быть одинаковыми или отличными друг от друга; C1-C8-алкоксикарбонил; C1-C8-галогеноалкоксикарбонил, включающий вплоть до 9 атомов галогена, которые могут быть одинаковыми или отличными друг от друга; C1-C8-алкиламинокарбонил; ди-C1-C8-алкиламинокарбонил; ! Z2 и Z3, которые могут быть одинаковыми или ...

СПОСОБ ПОЛУЧЕНИЯ СОЛЕВОГО СОЕДИНЕНИЯ (4,5-ДИГИДРОИЗОКСАЗОЛ-3-ИЛ)ТИОКАРБОКСАМИДИНА

... 1. Способ получения солевого соединения (4,5-дигидроизоксазол-3-ил)тиокарбоксамидина формулы (2) где каждый из R1 и R2 независимо друг от друга представляет атом водорода, алкил или циклоалкил, каждый из R3 и R4 независимо друг от друга представляет атом водорода или алкил при условии, что R1 и R2 или R2 и R3 могут быть связаны друг с другом с образованием циклоалкила вместе с атомами углерода, к которым они присоединены, и X2 представляет галоген или анионный остаток, полученный из кислоты, включающий взаимодействие соединения 3-галоген-4,5-дигидроизоксазола формулы (1) где R1, R2, R3 и R4 имеют указанные выше значения и X1 представляет галоген, с тиомочевиной в присутствии кислоты. 2. Способ получения солевого соединения (4,5-дигидроизоксазол-3-ил)тиокарбоксамидина по п.1, где кислота является неорганической кислотой. 3. Способ получения солевого соединения (4,5-дигидроизоксазол-3-ил)тиокарбоксамидина по п.1, где кислота является хлороводородной кислотой, бромоводородной кислотой или ...

ПРОИЗВОДНЫЕ 6-АМИНО-5,6,7,8-ТЕТРАГИДРОНАФТАЛЕН-2-ИЛА ИЛИ 3-АМИНОХРОМАН-7-ИЛА В КАЧЕСТВЕ МОДУЛЯТОРОВ TAAR

ПРОИЗВОДНЫЕ 3-ГЕТЕРОАРОИЛАМИНОПРОПИОНОВОЙ КИСЛОТЫ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ

... 1. Соединение формулы I в любой из его стереоизомерных форм или в виде смеси стереоизомерных форм в любом отношении, или его физиологически приемлемая соль, или физиологически приемлемый сольват любого из них,в которой Нt выбран из группы, состоящей изG выбран из группы, состоящей из R-O-C(O)-, R-N(R)-С(O)-, NC- и тетразол-5-ила;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, CF, (С-C)-циклоалкил-CH-, Ar-CH-, Ar-O, (C-C)-алкил-O-, (C-C)-алкил-S(O)- и NC-; где s представляет собойцелое число, выбранное из группы, состоящей из 0, 1, 2 и 3;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, CF, (C-C)-алкил-O-, (C-C)-алкил-S(O)- и NC-;Rвыбран из группы, состоящей из водорода, (C-C)-алкила;Rвыбран из группы, состоящей из (C-C)-алкила, (С-C)-циклоалкил-CH- и Ar-CH-, где s представляет собой целое число, выбранное из группы чисел, состоящей из 0, 1, 2 и 3;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, (C-C)-алкил-O-, (C-C)-алкил-S(О)- и NC-;Rвыбран ...

ПРОИЗВОДНЫЕ N-АЦИЛ-N-ФЕНИЛПИПЕРАЗИНА, ИСПОЛЬЗУЕМЫЕ (КРОМЕ ТОГО) ДЛЯ ПРОФИЛАКТИКИ ИЛИ ЛЕЧЕНИЯ ДИАБЕТА

... 1. Соединение, представленное формулойгде кольцо A представляет собой бензольное кольцо, необязательно дополнительно замещенное;кольцо B представляет собой пиперазиновое кольцо, необязательно дополнительно замещенное; иR представляет собой заместитель,при условии, что трет-бутил 4-[2-трет-бутил-5-({[2-(1H-индазол-6-иламино)пиридин-3-ил]карбонил}амино)фенил]пиперазин-1-карбоксилат,или его соль.2. Соединение или его соль по п.1, где R представляет собой необязательно замещенную углеводородную группу, необязательно замещенную гетероциклическую группу, необязательно замещенную аминогруппу или ацильную группу.3. Соединение или его соль по п.1, где кольцо A представляет собой бензольное кольцо, необязательно замещенное 1-3 заместителями, выбранными из (a) атома галогена и (b) Cалкильной группы.4. Соединение или его соль по п.1, где кольцо A представляет собой бензольное кольцо.5. Соединение или его соль по п.1, где кольцо B представляет собой пиперазиновое кольцо.6. Соединение или его соль по ...

СОЕДИНЕНИЯ И СПОСОБЫ ДЛЯ ИНГИБИРОВАНИЯ ВЗАИМОДЕЙСТВИЯ Bcl БЕЛКОВ С КОМПОНЕНТАМИ ПО СВЯЗЫВАНИЮ

... 1. Соединение формулы 1 или его фармацевтически приемлемые соли, сольваты или гидраты, где Y означает -C(R9)2-, -C(O)-, -C(S)- или -C(=NR10)-, Х означает -N(R11)-, необязательно замещенный фенил или химическую связь, Х1 каждый независимо означает О, N(R10) или S, m равно 0, 1, 2, 3, 4, 5 или 6, n каждое независимо равно 0, 1, 2, 3, 4, 5 или 6, R1 означает алкил, аралкил или гетероаралкил формулы 1а или 1b, где R12 каждый независимо означает Н, алкил, арил, гетероарил или аралкил, где любые два R12 соединены ковалентной связью, Ar1 означает моноциклический или бициклический арил, содержащий от 6 до 14 атомов в цикле, или моноциклический или бициклический гетероарил, содержащий от 5 до 14 атомов в цикле, где один, два или три атома в цикле независимо являются S, О или N, W означает химическую связь или двухвалентный алкил, алкенил или алкинил, Z означает химическую связь, -(C(R12)2)n- или -X'(C(R12)2)n-, R13 и R14 независимо означают Н, алкил, арил, циклоалкил, гетероциклоалкил, аралкил, ...

ИНГИБИТОРЫ ГИСТОНДЕАЦЕТИЛАЗЫ

... 1. Соединение формулы (I) !! и его N-оксиды, гидраты, сольваты, фармацевтически приемлемые соли, пролекарства и комплексы указанного соединения, и рацемические и скалемические смеси, таутомеры, диастереомеры и энантиомеры, где ! выбирают из группы, включающей арил, гетероарил, циклоалкил и гетероциклил, где каждый арил, гетероарил, циклоалкил и гетероциклил является необязательно замещенным; ! W выбирают из группы, включающей N, -C= и -C(R1)-, причем если представляет собой циклоалкил или гетероциклил, тогда W представляет собой -C(R1)-; ! M выбирают из группы, включающей -C(O)N(R1)OR2, -C(O)NR1R2, -C(O)OH, -C(O)OR1, -C(O)C1-C3алкил-SR1, -NHC(O)C1-C3алкил-SR1, -NHC(O)C1-C3алкил-OR1, -C(O)CH2-S(ацетил), -C(O)-гетероарил, -C(O)-гетероциклил, -C(NOH)NR1R2, -C(O)C1-C3алкил-OR1, -C(O)C1-C3алкил-NR1R2, -C(O)CF3, -C(O)C(O)OR1, -C(O)C(O)NR1R2, -C(O)C1-C4алкил, -N(OH)C(O)H, -N(OR1)C(O)R2, -NR1SO2NR1R2, -SO2NR1OH, -N(OH)C(O)NR1R2, -NR1C(O)N(OH)R2, -OC(O)N(OH)R2, -C(NOH)NR1R2 и группу, хелатирующую ...

АЦИЛИРОВАННЫЕ ИНДАНИЛАМИНЫ И ИХ ИСПОЛЬЗОВАНИЕ В КАЧЕСТВЕ ФАРМАЦЕВТИЧЕСКИХ СРЕДСТВ

... 1. Ацилированный инданиламин общей формулы (I) в любой из его стереоизомерных форм или их смесей в любом соотношении или его фармацевтически приемлемая соль где R1 и R4, независимо выбраны из группы, состоящей из Н; незамещенных и, по меньшей мере, монозамещенных С1-С10-алкила, С2-С10-алкенила и С2-С10-алкинила, заместители которых выбраны из группы, состоящей из F, OH, С1-С8-алкокси, (С1-С8-алкил)меркапто, CN, COOR6, CONR7R8 и незамещенных и, по меньшей мере, монозамещенных фенила и гетероарила, заместители которых выбраны из группы, состоящей из галогенов, псевдогалогенов, С1-С3-алкила, С1-С3-алкокси и CF3; R9CO; CONR10R11; COOR12; CF3; галогенов; псевдогалогенов; NR13R14; OR15; S(O)mR16; SO2NR17R18 и NO2; R2 и R3 независимо выбраны из группы, состоящей из Н; галогенов; псевдогалогенов, незамещенного и, по меньшей мере, монозамещенного С1-С10-алкила, заместители которого выбраны из группы, состоящей из ОН, фенила и гетероарила; ОН; C1-C10-алкокси; фенокси; S(O)m R19; CF3; CN; NO2; (С1 ...

Способ получения пенициллинов или их солей или гидратированных форм

Способ получения аминоэфиров или их солей

5-TRICHLOROMETHYL ISOXAZOLE, PROCESS FOR ITS PREPARATION AND ITS USE

DIAMID-DERIVATE VON HETEROCYCLISCHEN DICARBONSÄUREN, INSEKTIZIDE FÜR ACKER- UND GARTENBAU UND EIN VERFAHREN ZU IHRER VERWENDUNG

BASISCHE ESTER UND VERFAHREN ZUR HERSTELLUNG DERSELBEN

SUBSTITUIERTE ISOXAL-DERIVATE ALS ÖSTROGENREZEPTORMODULATOREN

EIN ISOXAZOLDERIVAT, VERFAHREN ZU SEINER HERSTELLUNG, DIESE VERBINDUNG ENTHALTENDE MITTEL UND VERWENDUNG

Verfahren zur Herstellung von Isoxazol-3,4-dicarbonsäurederivaten

HYDRAZID UND ALKOXYAMID ANGIOGENESEINHIBITOREN

3-SUBSTITUIERTE 5-ARYL-4-ISOXAZOLCARBONITRILE MIT ANTIVIRALER WIRKUNG

Acylamino-substituierte Isoxazol- bzw. Isothiazolderivate, Verfahren zu deren Herstellung und ihre Verwendung

Process for the production of an isoxazole derivative

... 3 - Hydroxy - 5 - aminomethylisoxazole and its acid addition salts are prepared by reducing 3 - hydroxy - 5 - isoxazole carboxamide with diborane in an organic solvent, optionally followed by salt formation. Reference has been directed by the Comptroller to Specification 1,034,939.

DIPHENYL ETHER COMPOUNDS

NOVEL BEZ[e]INDENE AND PHENANTHRENE DERIVATIVES

... 1298219 Steroid precursors F HOFFMANNLA ROCHE & CO AG 20 Nov 1969 [22 Nov 1968] 28140/71 Divided out of 1298214 Heading C2C The invention comprises d, I and dl compounds of Formula I wherein m is 1 or 2; R1 is C 1-5 primary alkyl; R2 is lower alkyl; and Z4 is di- (lower alkoxy) -methylene, phenylenedioxymethylene, a methylene group substituted by a divalent -ORO-, -ORS-, -SRS- or -ORNH- group (where R is lower alkylene), or is a group of formula wherein R6 is H or lower aliphatic or alicyclic hydrocarbyl and R7 is H, lower alkyl, (lower alkoxy)-(lower alkyl), phenyl-(lower alkyl) or tetrahydropyran-2-yl. The term "lower" means having up to 8 carbon atoms. Compounds I are prepared from compounds II [wherein R2 and R3 are identical lower alkyl groups or one of R2 and R3 is H and the other is lower alkyl, and Z2 is as defined for Z4 above or is #- (lower acyloxy)- or -R6-methylene (where ...

Diphenyl ether compounds

Herbicidal compounds of the general formula I, in which A<1> represents a hydrogen or halogen atom or an alkyl or haloalkyl group, and each of A<2> and A<3> independently represents a hydrogen or halogen atom or an alkyl, haloalkyl, nitro or cyano group; X represents an oxygen atom, R represents a group of formula COZ where Z represents a hydroxy group or an optionally substituted alkyl, alkoxy, aryl or aryloxy group and Y represents a group of formula CR<1> where R<1> represents an optionally substituted aryl group or a group of formula COZ; or X represents an oxygen atom, R represents a hydrogen or halogen atom and Y represents a group of formula CH; or X represents a sulphur atom, Y represents a group of formula CR<1> and R<1> represents a group of formula COZ and R represents a hydrogen atom or an optionally substituted alkyl or aryl group, or a group of formula COZ; or X represents a sulphur atom, Y represents a nitrogen atom and R represents a group of formula COZ; and salts ...

ISOXAZOLOPYRIMIDINE DERIVATIVES AND THEIR USE AS HERBICIDES

... 1314801 Isoxazolopyrimidine derivatives FMC CORP 22 April 1971 [23 April 1970] 10760/71 Heading C2C Isoxazolopyrimidine derivatives of the formula wherein R and R1, which may be the same or different, are each C 1-4 aliphatic hydrocarbon, C 3-6 cycloaliphatic hydrocarbon, or trifluoromethyl radicals, or metallic or amine salts thereof, may be prepared by known methods. The compounds of Formula (I) may be obtained, for example, by reacting malononitrile with an appropriate trialkyl orthoalkanoate to give the corresponding 2 - cyano - 3 - alkoxy - 2 -alkenonitrile, reacting the latter with hydroxylamine to form a 5-amino-4-cyano-3-alkylisoxazole (II), and reacting this with an appropriate acylating agent. The compound (II) may be hydrolysed to give the corresponding amide (which may also be prepared by reacting cyanaocetamide with a chlorinated aldoxime) and reacting the amidewith an acylating agent to give the compound of Formula (I). The compounds of Formula (I) may also be obtained ...

Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones

A compound of the formula where R<6> is either wherein R' is (C1-C4)alkyl or phenyl; wherein W is hydrogen or halo, and n is 1 or 2; wherein Q is sulfur or oxygen; and V is hydrogen or (C1-C3)alkyl; or wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C1-C3)alkoxy; X<1> is hydrogen or methyl; and X<2> is hydrogen or halo. The compounds are intermediates for certain hypoglycemic compounds.

Compounds

INSECTICIDAL ISOXAZOLYLBENZAMIDE DERIVATIVES

Chemical compounds

AMINOALKYLBENZENE DERIVATIVES

Isoxazole Derivatives and Process for their production

... 1,154,026. C.N.S. - inhibiting compositions. J. R. GEIGY A.G. 3 June, 1966 [4 June, 1965], No. 24755/66. Heading A5B [Also in Division C2] Pharmaceutical compositions comprise alkyl esters of 3 - hydroxy - 5 - ( - amino - carboxymethyl) - isoxazole or acid-addition salts thereof e.g. hydrochlorides, and carriers. The isoxazole compounds are stated to have an inhibiting action on the central nervous system and to be suitable for the treatment of sleep disturbance and conditions of anxiety and agitation. Tablets and ampoules are described. Reference has been directed by the Comptroller to Specification 1,114,116.

Aryl-Sulphonyl-Semicarbazides

... 1,176,310. Sulphonyl-ureas. FARBENFABRIKEN BAYER A.G. 14 Nov., 1968 [25 Nov., 1967; 2 Jan., 1968; 2 Sept., 1968], No. 54121/68. Heading C2C. Novel compounds (I) (including alkali metal and alkaline earth metal salts thereof) in which R is H or alkyl, R1 and R11 signify hydrogen or halogen or alkyl, aryl, aralkyl or cycloalkyl which may be substituted by halogen, alkyl, alkoxy or CF 3 , or R1 and R11 may be joined together to constitute an alkylene chain, NR111R1111 is a saturated or unsaturated, monocyclic or polycyclic radical which contains one or more hetero atoms, e.g. N, O, S, SO or SO 2 , and which may be substituted by alkyl, alkoxy, hydroxy or oxo, X signifies an oxygen or sulphur atom or a nitrogen atom having attached thereto a hydrogen atom or an alkyl, aryl or aralkyl radical which may be substituted by halogen, alkyl, alkoxy or CF 3 , Y is a direct bond, or a straight chain or branched C 1-8 alkylene radical, and n is 0, ...

A PROCESS FOR THE MANUFACTURE OF 19-NORSTEROIDS

... 1298214 19-Norsteroid synthesis F HOFF. MANN-LA ROCHE & CO AG 20 Nov 1969 [22 Nov 1968] 56793/69 Headings C2C and C2U The invention comprises the preparation of d-, l- and dl-19-norsteroids of partial Formula (I) by three routes from d-, l- and dl-19-isoxazolyl-de-A-steroids of partial Formula (II) wherein R2 and R3 are identical C 1-8 alkyl groups or one of R2 and R3 is H and the other is C 1-8 alkyl, and R4 is H or a C 1-7 alkyl group having one CH 2 group less than R2 or R3. Route 1 comprises hydrogenation of (II) to yield a 4-azagon-2-ene of partial Formula (A) treatment of which with an anhydrous strong base yields a 4-azagona-2,5(10)-diene of partial Formula (D) hydrolysis of which yields a de-A-steroid of partial Formula (C) cyclization of which yields (I). The specific examples do not illustrate this route. Route 2 comprises hydrogenation of (II) to yield (A) as in route 1, treatment of (A) with an aqueous strong base ...

5-METHYLISO-OXAZOLE-4-CARBOXYLIC ACID ANILIDES HAVING PHARMACEUTICAL ACTIVITY

Novel 5-methyl-isoxazole-4-carboxylic acid anilides of the formula I wherein one, two or three of the radicals R1, R2 and R3 denote a carboxyl group and/or a hydroxyl group and the remaining radicals R1, R2 and R3, which may be identical or different, denote alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 and 3 carbon atoms or alkylthio having 1, 2 or 3 carbon atoms, which groups may each be completely or partially substituted by identical or different halogen atoms, or denote hydrogen, halogen, nitro, cyano or carbalkoxy having 1, 2 or 3 carbon atoms in the alkyl group, are prepared by reacting a 5-methyl-isoxazole-4-carboxylic acid derivative with an appropriately substituted aniline. The compounds of the formula I are pharmacologically active. They exhibit a powerful antiphlogistic, antipyretic and analgesic action. Their toxicity is low and their gastric toleration is good.

SALTS OF 5-METHYL-ISOXAZOLE-3-CARBOXYLIC ACID

... 1508090 Purine derivatives JOHANN A WULFING 2 Dec 1976 50209/76 Heading C2C Novel salts of Formula I in which each of R 1 and R 2 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, cyclohexyl or C 2-6 alkoxyalkyl, are prepared by reacting 5-methyl-isoxazole-3- carboxylic acid with the appropriate purine base. Hypolipidemic compositions comprise a compound I together with a pharmaceutically acceptable carrier.

NOVEL BEZ[e]INDENE AND PHENANTHRENE DERIVATIVES

... 1298218 Steroid precursors F HOFFMANNLA ROCHE & CO AG 20 Nov 1969 [22 Nov 1968] 28139/71 Divided out of 1298214 Heading C2C The invention comprises d, I and dl compounds of Formulµ Ia and Ib wherein m is 1 or 2; R1 is C 1-5 primary alkyl; R2 and R3 are identical lower alkyl groups or one of R2 and R3 is H and the other is lower alkyl; Z1 is carbonyl, (lower alkylenedioxy)- methylene, di - (lower alkoxy) - methylene, phenylenedioxy-methylene or a group of formula where R5 is H, lower alkyl, (lower alkoxy)- (lower alkyl), phenyl-(lower alkyl), tetrahydropyran-2-yl or lower acyl and R6 is H or lower aliphatic or alicyclic hydrocarbyl; and Z2 is di- (lower alkoxy) - methylene, phenylenedioxymethylene, a methylene group substituted by a divalent -ORO-, -ORS-, -SRS- or -ORNH- group (where R is lower alkylene), or is a group of Formula III defined above. The term " lower" means having up to 8 carbon atoms. Compounds ...

Derived acylés and their process from preparation.

Indanyl-and tetrahydronaphtyl-amino-thiourea compounds for combating animal pests

"4-benzoyl isoxazoles and their use as herbcides".

... 4-Benzoylisoxazole derivatives of formula (1) ...

Method for combatting nematodes and novel isoxazole compounds.

A method for killing or controlling nematode pests which comprises ...

Azabicyclic carbamoyloxy mutilin derivatives for antibacterial use.

Compounds of formula (3), and pharmaceutically acceptable salts and derivatives thereof: in which: R.1 is vinyl or ethyl; and R2 is a group R3, R4CH2~, or R5R6C=CH-; wherein each of R3 and R4 is an azabicyclic ring system or R5 and R^ together with the carbon atom to which they are attached form an azabicyclic ring system, are useful in the prevention and treatment of microbial infections.

"Benzoyl isoxazoles and their use as herbicides".

The invention relates to 4-benzoylisoxazole derivatives of formula (1): wherein: r represents the hydrogen atom or a group -c02r4; r1 represents alkyl, haloalkyl or optionally substituted cycloalkyl; r2 represents halogen, optionally halogenated alkyl, alkenyl or alkynyl, alkyl substituted by one or more groups -0r5; or a group selected from nitro, cyano, -c02r5, -s(0)pr6, -0(ch2)m0r5, -cor5, -nr61rr62,-n(r8)so2r7, -0r5, -0s02r7 and -(cr9r10)t-s(0)qr7; r3 represents -s(0)qr7; x represents -(cr9r10)t; n represents zero or an integer from one to four; r4 represents alkyl or haloalkyl r5 represents optionally halogenated alkyl, alkenyl or alkynyl; r6,r61 and r62, which may be the same or differenct, each represents alkyl, haloalkyl or optionally substituted phenyl; r7 represents optionally halogenated alkyl, alkenyl or alkynyl or optionally substituted phenyl or benzyl; r8 represents hydrogen or optionally halogenated alkyl, alkenyl or alkynyl; r9 and r10 which may be the same or different ...

"4-Benzoyl isoxazoles and their use as herbicides"

The invention relates to 4-benzoylisoxazole derivatives of formula (1): wherein r represents hydrogen or -co2r4; r1 represents alkyl, haloalkyl or optionally substituted cycloalkyl; r2 represents halogen, alkyl, haloalkyl, alkly substituted by one or more groups -0r5; or a group selected from nitro, cyano, -c02r5, -s(o)pr6, p0(ch2)m0r6=5, -c0r5, -0r5 and -n(r8)s02r7; r3 represents the oxygen atom; n represents zero or an integer from one to four; r4 represents alkyl or haloalkyl; r5 and r6, independently represents alkyl, haloalkyl or optionally substituted phenyl; r7 represents alkyl, haloalkyl, optionally substituted phenyl or -nr5r6; r8 represents hydrogen, optionally halogenated alkyl, alkenyl or alkynyl; cycloalkyl, optionally substituted phenyl, -s02r6 or -0r5; p represents zero, one or two; and m represents an integer from one to three; and their use as herbicides is described.

Heterocyclic and phenyl compounds.

A compound of formula (i)r-s(o)nch2ch2ch=cf2, or a salt thereof, wherein n is 0, 1 or 2; and r is a group of formulae (ii)to (xxi), wherein: the s ch2ch2ch=cf2 group is at least one of r1 (when attached to a carbon atom). R2, r3, r4, r5 or r6; r1 (when attached to a ca atom)r2, r3 r4, r5 and r6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted heteroaryloxyalky, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen, hydroxy, cyano, notro, -nr7r8, -nr7cor8, -nr7csr8, -nr7so2r8 ...

New herbicides

Carbamoyloxy derivatives of mutiline and their use as antibacterials.

Derivatives of mutiline of formula (1a)and pharmaceutically acceptable salts and derivatives thereof, in which r1 is ethyl or vinyl, y is a carbamoyloxy group, which the n-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections.

Novel compounds

New herbicides

Heterocyclic and phenyl compounds

Herbicides

Antipicornaviral compounds, their preparation and use.

Peptido and peptidomimetic compounds of formula (i)wherein the formula variable are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3c protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as rvp. Intermediates and synthetic methods for preparing such compounds are also provided.

HETEROCYCLIC COMPOUNDS

Novel compounds.

Compounds of formula (1a)and pharmaceutically acceptable salts and derivativews thereof in which y is a carbamoyloxy group, in which the n-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections.

Estrogen modulators

Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

N,N' -substituted-1,3-diamino -2-hydroxypropane derivatives.

Disclosed are compounds of the formula (0, wherein the variables RN, RC, R1, R25, R2, and R3 are as defined herein. These compounds have activity as inhibitors of betasec-retase and are therefore useful in treating a variety of discorders such as Alzheimer's Disease.

Substituted aryl thioureas and related compounds; inhibitors of viral replication

Indanyl-and tetrahydronaphtyl-amino-thiourea compounds for combating animal pests

Compounds as bradykinin B1 antagonists.

Process for the preparation of derived from hydrazine substituted.

New weedkillers.

Carbamoyloxy derivatives of mutiline and their useas antibacterials.

N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives.

Heterocyclic compounds.

Antipicornaviral compounds, their preparation and use.

"Isoxazole derivatives".

Substituted aryl thioureas and related compounds, inhibitors of viral replication.

Indanylamines acylées and their use as a medicinal product.

“New 4-benzoyl-isoxazole Derivatives, their process of production and weedkillers compositions the container”.

(4,4-Difluorobut-3-enylthio)-substituted heterocyclic or carbocyclic ring compounds having pesticidal activity

New isoxazolo-pyrimidins and their application like weedkillers.

Substituted aryl thioureas and related compounds; inhibitors of viral replication

Herbicides

Compounds as bradykinin B1 antagonists.

Heterocyclic and phenyl compounds

Indanyl-and tetrahydronaphtyl-amino-thiourea compounds for combating animal pests

HETEROCYCLIC COMPOUNDS

Substituted aryl thioureas and related compounds; inhibitors of viral replication

New herbicides

New herbicides

Carb moylo y der vativ s of utiline and their use as antibacterials

Novel compounds

Novel compounds

Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

Estrogen modulators

Antipicornaviral compounds their preparation and use

Compounds as bradykinin B1 antagonists.

BIARYLSULFONAMIDE AS MMP INHIBITORS

Compound inhibiting in vivo phosphorus transport and medicine containing the same

An objective of the present invention is to provide compounds that can effectively suppress the concentration of phosphorus in serum to effectively prevent or treat diseases induced by an increase in concentration of phosphate in serum. The compounds according to the present invention are compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof: wherein A represents an optionally substituted five- to nine-membered unsaturated carbocyclic moiety or a five- to nine-membered unsaturated heterocyclic moiety, and represents a single bond or a double bond, R 5 represents optionally substituted aryl or the like, Z represents —N═CHR 6 R 7 or the like, R 6 and R 7 represent H, optionally substituted alkyl, optionally substituted aryl or the like, R 101 and R 102 together form ═O, and R 103 and R 104 represent H, or R 101 and R 104 together from a bond, and R 102 and R 103 together form a bond.

Substituted Esters as Cannabinoid-1 Receptor Modulators

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the promotion of wakefulness.

Compounds as bradykinin b1 antagonists

Compounds of the formula I wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined as described in the specification, which are bradykinin B1 antagonists, and their use as medicaments.

New compounds, pharmaceutical compositions and uses thereof

The invention relates to new compounds of the formula I to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Compositions and methods useful for treating diseases

The present invention relates to a chemotherapeutic cancer treatment in which compounds of Formula Ia′, Ib′, Ic′, or II′ (referred to as a group as BH3Is) are administered to a mammal for the treatment of B-cell Lymphoma or other hematopoietic cancers, including diseases associated with MCL-1. In another aspect, the invention provides a method for treating particular types of hematopoietic cancers, such as B-cell lymphoma, using a combination of one or more compounds selected from the group consisting of compounds or Formula Ia, Ib, Ic, or II in combination with other therapies, for example, a class of therapeutics known as 26S proteosome inhibitors, such as, for example, Bortezomib. In another aspect the present invention relates to autoimmune treatment with pharmaceutical compositions comprising one or more compounds of Formula Ia′, Ib′, Ic′, or II′. In another aspect, this invention relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have unique in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease.

CARBOXYLATION CATALYSTS

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

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.

LIGANDS FOR ANTIBODY AND Fc-FUSION PROTEIN PURIFICATION BY AFFINITY CHROMATOGRAPHY

The present invention relates to the use for affinity purification of an antibody or an fragment of an antibody, of a ligand-substituted matrix comprising a support material and at least one ligand covalently bonded to the support material, the ligand being represented by formula (I) 2. The use of wherein Aris phenylene claim 1 , preferably methoxy-substituted phenylene.3. The use of wherein the C═O and the NH group are bonded to Arin meta position to each other.4. The use of wherein the 5- or 6-membered heterocyclic aromatic ring of Aris attached to the C═O group via a carbon ring atom which is adjacent to a ring heteroatom claim 1 , preferably a nitrogen or oxygen atom.5. The use of wherein the 5- or 6-membered heterocyclic aromatic ring of Arcontains two or more nitrogen atoms or one or more nitrogen atoms and an oxygen atom.6. The use of wherein the 5- or 6-membered heterocyclic aromatic ring of Aris N-methyl-substituted pyrazole claim 5 , pyridine claim 5 , isoxazole or oxadiazole.7. The use according to wherein the support material comprises a material selected from carbohydrates or crosslinked carbohydrates claim 1 , preferably agarose claim 1 , cellulose claim 1 , dextran claim 1 , starch claim 1 , alginate and carrageenan claim 1 , Sepharose claim 1 , Sephadex; synthetic polymers claim 1 , preferably polystyrene claim 1 , styrene-divinylbenzene copolymers claim 1 , polyacrylates claim 1 , PEG-Polycacrylate copolymers polymethacrylates claim 1 , polyvinyl alcohol claim 1 , polyamides and perfluorocarbons; inorganic materials claim 1 , preferably glass claim 1 , silica and metal oxides; and composite materials.8. The use according to wherein the protein is an antibody claim 1 , preferably an IgG type antibody claim 1 , or an Fc fusion protein.9. The use of wherein the purification is attained by binding of the ligand of the ligand-substituted matrix to an Fc fragment or domain of the antibody or the fusion protein.10. The use according to wherein the Fc ...

Novel hydroxamates as therapeutic agents

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

Stem cell differentiating agents and uses therefor

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

BIPHENYL AND PHENYL-PYRIDINE AMIDES AS P2X3 AND P2X2/3 ANTAGONISTS

Compounds of the formula I: 2. The compound of claim 1 , wherein R claim 1 , Rand Rare hydrogen.3. The compound of claim 2 , wherein Ris phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2-position with halo.4. The compound of claim 2 , wherein Ris 4-methyl-phenyl.5. The compound of claim 2 , wherein Ris pyridin 2-yl substituted with methyl or halo at the 5-position.6. The compound of claim 2 , wherein Ris 5-methyl-pyridin-2-yl.8. The compound of claim 7 , wherein Ris hydrogen.9. The compound of claim 7 , wherein Ris methyl.10. The compound of claim 7 , wherein Ris: Calkyl; Calkyloxy-Calkyl; hydroxy-Calkyl; Calkylsulfanyl-Calkyl; Calkylsulfonyl-Calkyl; amino-Calkyl; N—Calkyl-amino-Calkyl; N claim 7 ,N-di-Calkyl-amino-Calkyl; Ccycloalkyl; optionally substituted phenyl; heteroaryl claim 7 , or heterocyclyl-Calkyl.11. The compound of claim 7 , wherein Ris: Calkyloxy-Calkyl; hydroxy-Calkyl; heteroaryl claim 7 , or heterocyclyl-Calkyl.12. The compound of claim 7 , wherein Ris methoxymethyl.13. The compound of claim 7 , wherein Ris hydroxymethyl.14. The compound of claim 7 , wherein Ris heteroaryl selected from pyridinyl claim 7 , pyrimidinyl claim 7 , or pyrazinyl claim 7 , each of which may be optionally substituted once or twice with methyl.15. The compound of claim 7 , wherein Ris hydroxymethyl claim 7 , methoxymethyl claim 7 , pyrazin-2-yl or 5-methyl-pyrazin-2-yl.16. The compound of claim 7 , wherein Ris Calkyl claim 7 , Ccycloalkyl or Ccycloalkyl-Calkyl.17. The compound of claim 7 , wherein Ris isopropyl claim 7 , isobutyl or tert butyl.18. The compound of claim 1 , wherein said compound is selected from:4-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;5-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;Furan-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;Thiophene-2- ...

ISOXAZOLE TREATMENTS FOR DIABETES

The present invention relates to compounds and methods for inducing synthesis and secretion of insulin from pancreatic beta cells. The methods may take place in vitro, ex vivo such as in isolates from adult mammalian tissue, or in vivo. Compounds and methods described herein may find use in the treatment of diabetes. 2. The method of claim 1 , wherein Ris a substituent of formula (A).3. The method of claim 2 , wherein G is S.4. The method of claim 3 , wherein R claim 3 , Ror Ris hydrogen.5. The method of claim 4 , wherein R claim 4 , Rand Rare each hydrogen.6. The method according to claim 1 , wherein Ris hydrogen.7. The method according to claim 1 , wherein Ris —NRR.8. The method of claim 7 , wherein Ror Ris cyclopropyl claim 7 , cyclobutyl claim 7 , cyclopentyl or cyclohexyl.9. The method of claim 8 , wherein Ror Ris cyclopropyl.11. The method of claim 10 , wherein G is S.12. The method of claim 11 , wherein R claim 11 , Ror Ris hydrogen.13. The method of claim 12 , wherein R claim 12 , Rand Rare each hydrogen.14. The method according to claim 1 , wherein Ris hydrogen.15. The method according to claim 1 , wherein Ris cyclopropyl or an aliphaticalcohol or an aliphaticpolyol.17. The method according to claim 1 , wherein said cell is located in an animal subject.18. The method according to claim 1 , wherein said cell is contacted ex vivo.2036-. (canceled)3852-. (canceled)5470-. (canceled)72. (canceled) This application claims benefit of priority to U.S. Provisional Application Ser. Nos. 61/563,419, filed Nov. 23, 2011, and 61/566,056, filed Dec. 2, 2011, the entire contents of both applications being incorporated by reference herein.The invention was made with government support under NIH P60 DK079626, R37 DK34128 and R01 DK55310 awarded by the National Institutes of Health. The government has certain rights in the invention.1. Field of the InventionThe present invention relates generally to the fields of cell biology, developmental biology and medicine. More ...

Sulfonyl compounds which modulate the cb2 receptor

Compounds of formula (I) and formula (II) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.

ACYLSULFONAMIDES AND PROCESSES FOR PRODUCING THE SAME

The present disclosure relates to acylsulfonamides and processes for their preparation. The processes involve a target-guided synthesis approach, whereby a thioacid and a sulfonyl azide are reacted in the presence of a biological target protein, a Bcl-2 family protein, to form the acylsulfonamide. 2. The compound of wherein the Bcl-2 family protein is Mcl-1.3. A composition comprising a Bcl-2 claim 1 , Bcl-XL claim 1 , and/or Bcl-w inhibitor; and an Mcl-1 and/or A1/Bfl-1 inhibitor claim 1 , wherein at least one inhibitor is the compound of .4. A method of treating or preventing cancer claim 1 , the method comprising administering the compound of .5. A compound comprising a first fragment selected from SZ1 to SZ31 and a second fragment selected from TA1 to TA15.6. The compound of having the formula selected from SZ31TA2 claim 5 , SZ15TA2 claim 5 , and SZ17TA2.7. A method of screening for an inhibitor claim 5 , as described herein.8. The method of comprising contacting a fragment library with a Bcl-2 family protein.9. The method of wherein the Bcl-2 family protein is selected from one or more of Bcl-2 claim 8 , Bcl-XL claim 8 , Bcl-w claim 8 , Mcl-1 claim 8 , and A1/Bfl-1.10. The method of wherein the Bcl-2 family protein is Mcl-1.11. The compound of claim 1 , wherein Zis aryl claim 1 , substituted aryl claim 1 , or heteroaryl.13. The compound of claim 1 , wherein Z claim 1 , Z claim 1 , Z claim 1 , Z claim 1 , and Zare independently hydrogen claim 1 , hydrocarbyl claim 1 , substituted hydrocarbyl claim 1 , amino claim 1 , alkoxy claim 1 , nitro claim 1 , or trihalomethoxy.15. The compound of claim 1 , wherein Zis substituted or unsubstituted furyl claim 1 , thienyl claim 1 , pyridyl claim 1 , oxazolyl claim 1 , isoxazolyl claim 1 , imidazolyl claim 1 , pyridyl claim 1 , pyrimidyl claim 1 , purinyl claim 1 , triazolyl claim 1 , or thiazolyl.16. The compound of claim 1 , wherein Zis substituted or unsubstituted morpholino claim 1 , pyran claim 1 , tetrahydropyran claim ...

CRYSTALLINE FORMS OF (R)-3-[N-(3'-CHLOROBIPHENYL-4-YLMETHYL)-N'-(3-HYDROXYISOXAZOLE-5-CARBONYL)HYDRAZINO]-2-HYDROXYPROPIONIC ACID ISOPROPYL ESTER

The invention provides crystalline forms of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′—(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester. This invention also provides pharmaceutical compositions comprising the crystalline compound, processes and intermediates for preparing the crystalline compound, and methods of using the crystalline compound to treat diseases. 1. A crystalline (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′—(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester , selected from:a neutral monohydrate Form 1 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.26±0.20, 14.68±0.20, 15.64±0.20, 16.36±0.20, 18.52±0.20, 20.40±0.20, 21.08±0.20, 21.48±0.20, 21.68±0.20, 23.18±0.20, 24.50±0.20, 24.80±0.20, 25.34±0.20, and 26.56±0.20;a neutral Form 2 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.48±0.20, 8.02±0.20, 9.38±0.20, 12.24±0.20, 14.86±0.20, 18.72±0.20, 20.94±0.20, 21.34±0.20, 22.32±0.20, and 24.68±0.20;a neutral solvated Form 2′ characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.26±0.20, 8.05±0.20, 12.20±0.20, 14.48±0.20, 15.84±0.20, 16.22±0.20, 18.78±0.20, 20.60±0.20, 21.29±0.20, 21.74±0.20, 23.10±0.20, 24.16±0.20, and 24.44±0.20;a neutral anhydrous Form 3 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.12±0.20, 8.86±0.20, 11.92±0.20, 13.68±0.20, 16.10±0.20, 18.12±0.20, 18.46±0.20, 19.06±0.20, 19.48±0.20, 20.60±0.20, 21.28±0.20, 24.46±0.20, 25.94±0.20, and 26.40±0.20;a neutral anhydrous Form 4 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.70±0.20, 13.00±0.20, 16.00±0.20, 16.94±0.20, 17.36±0.20, 18.72±0.20, 19.00±0.20, 19.78±0.20, 20.24±0.20, 21.70±0.20, 23.68±0.20, and 27.94±0.20;a tromethamine salt characterized by a powder x-ray diffraction pattern ...

Therapeutic Compounds for Protozoal and Microbial Infections and Cancer

The compounds of the invention exhibit antiprotozoal, antimicrobial, and anticancer properties that are useful for the treatment or prevention of infections or cancer in a patient (e.g., a human). For example, the compounds and methods described herein can be used for the treatment or prevention of protozoal infections such as leishmaniasis, malaria, and infections, bacterial infections such as and , and cancers such as breast, colon, lung, or prostate cancer. The invention further provides methods of synthesizing such compounds as well as kits useful for administering the compounds. 2. The compound of claim 1 , wherein said compound is selected from the group consisting of (3S claim 1 ,8R)-8-hydroxyheptadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8R)-8-hydroxyheptadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8S)-8-hydroxyheptadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8R)-8-hydroxyhexadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8S)-8-hydroxyhexadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8R)-8-hydroxyhexadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8S)-8-hydroxyhexadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8R)-8-hydroxypentadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8S)-8-hydroxypentadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8R)-8-hydroxypentadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8S)-8-hydroxypentadeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8R)-8-hydroxytetradeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8S)-8-hydroxytetradeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8R)-8-hydroxytetradeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8S)-8-hydroxytetradeca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8R)-8-hydroxytrideca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3S claim 1 ,8S)-8-hydroxytrideca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 ,8R)-8-hydroxytrideca-1-en-4 claim 1 ,6-diyn-3-yl acetate; (3R claim 1 , ...

FUNGICIDAL N-(2-PHENOXYETHYL)CARBOXAMIDE DERIVATIVES AND THEIR AZA, THIA AND SILA ANALOGUES

The present invention relates to fungicide N-(2-phenoxyethyl)carboxamide derivatives of formula (I), their aza, thia and sila analogues, their process of preparation, their use as fungicides, particularly in the form of fungicidal compositions and methods for the control of phytopathogenic fungi of plants using these compounds or their compositions. Formula (1) wherein A, T, W, X, n and Zto Zrepresent various substituents. 3. A compound according to wherein A is selected in the list consisting of A; A; Aand A.4. A compound according to wherein A represents Aand wherein Rrepresents a C-C-alkyl claim 3 , C-C-halogenoalkyl comprising up to 9 halogen atoms that can be the same or different; or C-C-alkoxy; Rrepresents a hydrogen atom or a halogen atom; Rrepresents a C-C-alkyl.5. A compound according to wherein W represents O or S.6. A compound according to wherein n represents 0 claim 1 , 1 or 2.7. A compound according to wherein X independently represents a halogen atom; C-C-alkyl; C-C-halogenoalkyl comprising up to 9 halogen atoms that can be the same or different; tri(C-C-alkyl)silyl; C-Calkoxy or C-C-halogenoalkoxy comprising up to 9 halogen atoms that can be the same or different or wherein two consecutive substituents X together with the phenyl ring form a substituted or non substituted 1 claim 1 ,3-benzodioxolyl; 1 claim 1 ,2 claim 1 ,3 claim 1 ,4-tetrahydro-quinoxalinyl; 3 claim 1 ,4-dihydro-2H-1 claim 1 ,4-benzoxazinyl; 1 claim 1 ,4-benzodioxanyl; indanyl; 2 claim 1 ,3-dihydrobenzofuranyl; or indolinyl.8. A compound according to wherein Zand Zindependently represent a C-C-alkyl.9. A compound according to wherein Zand Zindependently represent a hydrogen atom or a C-C-alkyl.10. A compound according to wherein Zand Zindependently represent a hydrogen atom or a C-C-alkyl.11. A compound according to wherein Zrepresents a C-Ccycloalkyl substituted by up to 10 groups or atoms that can be the same or different and that can be selected in the list consisting of halogen ...

NITRIC OXIDE DONOR NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 2. The compound of claim 1 , where Ris —Calkyl substituted with 1 or 2 —ONOgroups.3. The compound of claim 2 , where Ris —(CH)(ONO).6. The compound of claim 1 , where Ris —OH and Ris H.7. The compound of claim 1 , where Ris —CHOH and Ris —CH.8. The compound of claim 1 , where X is selected from —COOR claim 1 , pyrazole claim 1 , imidazole claim 1 , triazole claim 1 , benzotriazole claim 1 , furan claim 1 , pyrrole claim 1 , tetrazole claim 1 , pyrazine claim 1 , thiophene claim 1 , oxazole claim 1 , isoxazole claim 1 , thiazole claim 1 , isothiazole claim 1 , oxadiazole claim 1 , thiadiazole claim 1 , pyridazine claim 1 , pyridine claim 1 , pyrimidine claim 1 , pyran claim 1 , benzimidazole claim 1 , benzoxazole claim 1 , benzothiazole claim 1 , pyridylimidazole claim 1 , and pyridyltriazole.10. The compound of claim 8 , where X is —COOR claim 8 , and Ris H.12. The compound of claim 1 , where Ris absent or is selected from H claim 1 , —Calkylene-OH claim 1 , —Calkylene-O—Calkyl claim 1 , —C(O)—Calkyl claim 1 , ═O claim 1 , and phenyl substituted with one halo.13. The compound of claim 1 , where Ris selected from H claim 1 , —OH claim 1 , —Calkyl claim 1 , pyridinyl claim 1 , and phenyl optionally substituted with one halo.14. The compound of claim 1 , where b is 0 or b is 1 and Ris 3′-chloro.15. The compound of claim 1 , where c is 0 claim 1 , or c is 1 and Ris 3′-chloro claim 1 , or c is 0 and Ris 2′-fluoro claim 1 , 5′-chloro or 2′ claim 1 ,5′-dichloro.18. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.19. The pharmaceutical composition of claim 18 , further comprising a therapeutic agent selected from adenosine receptor antagonists claim 18 , α-adrenergic receptor antagonists claim 18 , β-adrenergic receptor antagonists claim 18 , β-adrenergic receptor agonists claim 18 , dual-acting β-adrenergic receptor antagonist/α-receptor antagonists claim ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula X: 7. The compound of claim 6 , where Ris H and Ris —CHCH.21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of .22. The pharmaceutical composition of claim 21 , further comprising a therapeutic agent selected from adenosine receptor antagonists claim 21 , α-adrenergic receptor antagonists claim 21 , β-adrenergic receptor antagonists claim 21 , β-adrenergic receptor agonists claim 21 , dual-acting β-adrenergic receptor antagonist/α-receptor antagonists claim 21 , advanced glycation end product breakers claim 21 , aldosterone antagonists claim 21 , aldosterone synthase inhibitors claim 21 , aminopeptidase N inhibitors claim 21 , androgens claim 21 , angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzyme/neprilysin inhibitors claim 21 , angiotensin-converting enzyme 2 activators and stimulators claim 21 , angiotensin-II vaccines claim 21 , anticoagulants claim 21 , anti-diabetic agents claim 21 , antidiarrheal agents claim 21 , anti-glaucoma agents claim 21 , anti-lipid agents claim 21 , antinociceptive agents claim 21 , anti-thrombotic agents claim 21 , ATreceptor antagonists and dual-acting ATreceptor antagonist/neprilysin inhibitors and multifunctional angiotensin receptor blockers claim 21 , bradykinin receptor antagonists claim 21 , calcium channel blockers claim 21 , chymase inhibitors claim 21 , digoxin claim 21 , diuretics claim 21 , dopamine agonists claim 21 , endothelin converting enzyme inhibitors claim 21 , endothelin receptor antagonists claim 21 , HMG-CoA reductase inhibitors claim 21 , estrogens claim 21 , estrogen receptor agonists and/or antagonists claim 21 , monoamine reuptake inhibitors claim 21 , muscle relaxants claim 21 , natriuretic peptides and their analogs claim 21 , natriuretic peptide clearance receptor antagonists claim 21 , neprilysin inhibitors claim 21 , nitric oxide donors claim 21 , non ...

NEPRILYSIN INHIBITORS

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

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 1. (canceled)2. The process of claim 18 , where X is selected from pyrazole claim 18 , imidazole claim 18 , triazole claim 18 , benzotriazole claim 18 , furan claim 18 , pyrrole claim 18 , tetrazole claim 18 , pyrazine claim 18 , thiophene claim 18 , oxazole claim 18 , isoxazole claim 18 , thiazole claim 18 , isothiazole claim 18 , oxadiazole claim 18 , thiadiazole claim 18 , pyridazine claim 18 , pyridine claim 18 , pyrimidine claim 18 , pyran claim 18 , benzimidazole claim 18 , benzoxazole claim 18 , benzothiazole claim 18 , pyridylimidazole claim 18 , and pyridyltriazole.3. The process of claim 2 , where X is selected from pyrazole claim 2 , triazole claim 2 , benzotriazole claim 2 , tetrazole claim 2 , oxazole claim 2 , isoxazole claim 2 , thiazole claim 2 , pyridazine claim 2 , pyrimidine claim 2 , and pyridyltriazole.4. The process of claim 18 , where Ris selected from —ORand —NRR claim 18 , where Ris H claim 18 , Ris H or —OH claim 18 , and Ris H.7. The process of claim 18 , where Ris H.8. The process of claim 18 , where Ris absent or is selected from H; halo; —Calkylene-OH; —NH; —Calkyl; —CF; —Ccycloalkyl; —Calkylene-O—Calkyl; —C(O)R; —Calkylene-COOR; —C(O)NRR; —NHC(O)R; ═O; —NO; —C(CH)═N(OH); phenyl optionally substituted with one or two groups independently selected from halo claim 18 , —OH claim 18 , —CF claim 18 , —OCH claim 18 , —NHC(O)CH claim 18 , and phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl optionally substituted with methyl; thiophenyl optionally substituted with methyl or halo; furanyl; and —CH-morpholinyl; and Ris H.10. The process of claim 18 , where Ris absent or is selected from H; halo; —Calkylene-OH; —Calkyl; —Ccycloalkyl; —Calkylene-O—Calkyl; —C(O)R; —Calkylene-COOR; —C(O)NRR; —NHC(O)R; —NHC(O)R; ═O; phenyl optionally substituted with one or two groups independently selected from halo claim 18 , —OH claim 18 , and —OCH; pyridinyl; and pyrazinyl; Ris —Calkyl; ...

NOVEL GLP-1 RECEPTOR STABILIZERS AND MODULATORS

Compounds that bind the glucagon-like peptide 1 receptor (GLP-1) receptor are provided including compounds which are modulators of the GLP-1 receptors and compounds which are capable of inducing a stabilizing effect on the receptor for use in structural analyses of the GLP-1 receptor. Methods of synthesis, methods of therapeutic and/or prophylactic use, and methods of use in stabilizing GLP-1 receptor in vitro for crystallization of the GLP-1 receptor of such compounds are provided. 2. The compound of wherein the compound has the structure of Formula I-R or a pharmaceutically acceptable salt claim 1 , ester claim 1 , prodrug claim 1 , homolog claim 1 , hydrate or solvate thereof.3. The compound of wherein the compound has the structure of Formula I-S or a pharmaceutically acceptable salt claim 1 , ester claim 1 , prodrug claim 1 , homolog claim 1 , hydrate or solvate thereof.4. The compound of wherein the compound is substantially enantiomerically pure.5. The compound of wherein Wis -L-(CRR)-L-R.6. The compound of wherein Wis -L-(CRR)—R.7. The compound of wherein one of Lis —O—.8. The compound of wherein one of Lis —C(O)O—.9. The compound of wherein one of Lis —S(O)—.10. The compound of wherein one of Lis —S—.11. The compound of wherein one of Lis —N(R).12. The compound of wherein one of Lis —N(R)—C(O)—N(R)—.13. The compound of wherein one of Lis —N(R)—C(O)—.14. The compound of wherein one of Lis —S(O)—N(R)—.15. The compound of wherein Ris H.16. The compound of wherein one of Lis —O—.17. The compound of wherein both Rand Rare H.18. The compound of wherein one of Rand Ris methyl.19. The compound wherein one of Rand Ris methoxy.20. The compound of wherein in at least one instance Rand Rtaken together with the carbon to which they are attached form a cycloalkyl.21. The compound of wherein Ris alkyl substituted with Rand Ris phenyl.22. The compound of wherein Wis —NHC(O)—(CH)-L-R.23. The compound of wherein Ris H or alkyl.24. The compound of wherein Ris cycloalkyl claim ...

PHENYL-ISOXAZOL DERIVATIVES AND PREPARATION PROCESS THEREOF

Disclosed are a phenyl-isoxazol derivative compound, which is useful as a treatment material for virus infection, especially, infection of an influenza virus, or its pharmaceutically acceptable derivative, a preparation method thereof, and an illness treatment pharmaceutical composition including the compound as an active ingredient. 2. The compound of or its pharmaceutically acceptable salt claim 1 , hydrate claim 1 , solvate claim 1 , prodrug claim 1 , or composite claim 1 , wherein when Ris the radical of Formula 2:{'sub': 1', '2', '3', '4', '5', '6', '7, 'two from among R, Rand Rare hydrogen, the remaining one is lower alkyl optionally substituted with halogen, lower alkoxy optionally substituted with halogen, or halogen, Ris methyl or amine, and from among R, Rand R, one or two each independently is hydrogen, lower alkyl optionally substituted with halogen, hydroxy, lower alkoxy, or halogen; or'}{'sub': 1', '2', '3', '4', '5', '6', '7, 'two from among R, Rand Rare hydrogen, the remaining one is trifluoromethyl, fluoro, or trifluoromethoxy, Ris methyl or amine, and from among R, Rand R, one or two each independently is hydrogen, methoxy, chlorine, fluoro, trifluoromethyl or hydroxy; or'}{'sub': 1', '4', '2', '3', '5', '7', '6, 'Ris halogen, preferably chlorine, Ris methyl or amine, R, R, R, and Reach is hydrogen, and Ris alkoxy.'}3. The compound of or its pharmaceutically acceptable salt claim 1 , hydrate claim 1 , solvate claim 1 , prodrug claim 1 , or composite claim 1 , wherein when Ris the radical of Formula 2:{'sub': 1', '2', '3', '4', '5', '6', '7, 'Ris trifluoromethyl or trifluoromethoxy, Rand Rare hydrogen, Ris methyl or amine, and from among R, Rand R, one or two each independently is hydrogen, hydroxy, methoxy, or chlorine; or'}{'sub': 1', '4', '2', '3', '5', '7', '6, 'Ris chlorine, Ris methyl, R, R, Rand Reach is hydrogen, and Ris methoxy; or'}{'sub': 2', '1', '3', '4', '5', '6', '7, 'Ris fluoro, trifluoromethyl, or trifluoromethoxy, Rand Reach is ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 6. The compound of claim 5 , where Ris selected from —CH claim 5 , —OCH claim 5 , and Cand Ris H; or Ris selected from H claim 5 , —CH claim 5 , Cl claim 5 , and F claim 5 , and Ris Cl; or Ris H and Ris selected from —CHand —CN; Ris selected from H claim 5 , —Calkyl claim 5 , and —(CH)ORwhere Ris H or —CH; and Ris H.10. The compound of claim 9 , where Ris F claim 9 , Ris Cl claim 9 , Ris H claim 9 , Ris —OCHor —OCHCH claim 9 , and Ris H.14. The compound of claim 13 , where Ris F claim 13 , Ris Cl claim 13 , Ris H claim 13 , and Ris H.17. The compound of claim 16 , where Rand Rare H; Ris selected from —Calkyl claim 16 , —(CH)OR claim 16 , and —(CH)NRR; Ris selected from —OH claim 16 , —OCH claim 16 , —OCHCH claim 16 , and —Calkyl; and Ris H.18. The compound of claim 17 , where Rand Rare H claim 17 , Ris —CH claim 17 , Ris —OH or —OCH claim 17 , and Ris H.20. The compound of claim 19 , where Ris H claim 19 , Ris Cl claim 19 , Ris H claim 19 , —CH claim 19 , —CHCHor —(CH)OH claim 19 , Ris —OH or —OCH claim 19 , and Ris H; or Ris F claim 19 , Ris Cl claim 19 , Ris H or —Calkyl claim 19 , Ris —OH claim 19 , —OCHor —Calkyl claim 19 , and Ris H.22. The compound of claim 21 , where Ris H or F; Ris Cl; Ris H or —Callyl; Ris —OCH claim 21 , —OCHCH claim 21 , or —Calkyl; R claim 21 , if present claim 21 , is H; and Ris H.24. The compound of claim 23 , where Ris F claim 23 , Ris Cl claim 23 , Ris H or —Calkyl claim 23 , R claim 23 , if present claim 23 , is H claim 23 , and Ris H.27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of .28. The pharmaceutical composition of claim 27 , further comprising a therapeutic agent selected from adenosine receptor antagonists claim 27 , α-adrenergic receptor antagonists claim 27 , β-adrenergic receptor antagonists claim 27 , β-adrenergic receptor agonists claim 27 , dual-acting β-adrenergic receptor antagonist/α-receptor ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 14-. (canceled)5. The compound of claim 22 , where Ris selected from —ORand —NRR claim 22 , Ris H claim 22 , Ris H or —OH claim 22 , and Ris H.8. The compound of claim 22 , where Ris —NRR claim 22 , where Ris H and Ris H.9. The compound of claim 22 , where Ris H.1015-. (canceled)16. The compound of claim 22 , where a is 0; or a is 1 and Ris 3-chloro.17. The compound of claim 22 , where b is 0; or b is 1 and Ris 3′-chloro claim 22 , 3′-methyl claim 22 , or 2′-methoxy; or b is 2 and Ris 2′-fluoro-5′-chloro claim 22 , 2′ claim 22 ,5′-dichloro claim 22 , 2′-methyl-5′-chloro claim 22 , or 3′-chloro-5′-hydroxy.18. The compound of claim 22 , where the methylene linker on the biphenyl is substituted with 2 methyl groups.20. The compound of claim 22 , where{'sup': 1', '7, 'Ris —OR;'}{'sup': '2', 'Ris H;'}{'sup': '5', 'a is 0; or a is 1 and Ris 3-chloro;'}{'sup': 6', '6, 'b is 0; or b is 1 and Ris 3′-chloro, 3′-methyl, or 2′-methoxy; or b is 2 and Ris 2′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy;'}andthe methylene linker on the biphenyl is optionally substituted with 2 methyl groups.21. (canceled)2328-. (canceled) This application claims the benefit of U.S. Provisional Application No. 61/423,180, filed on Dec. 15, 2010; the entire disclosure of which is incorporated herein by reference.1. Field of the InventionThe 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.2. State of the ArtNeprilysin (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, ...

SYNTHESIS OF TETRACYCLINES AND INTERMEDIATES THERETO

The tetracycline class of antibiotics has played a major role in the treatment of infectious diseases for the past 50 years. However, the increased use of the tetracyclines in human and veterinary medicine has led to resistance among many organisms previously susceptible to tetracycline antibiotics. The recent development of a modular synthesis of tetracycline analogs through a chiral enone intermediate has allowed for the efficient synthesis of novel tetracycline analogs never prepared before. The present invention provides more efficient routes for preparing the enone intermediate and allows for substituents at positions 4a, 5, 5a, and 12a of the tetracycline ring system. 2. The compound of claim 1 , wherein Ris hydrogen claim 1 , halogen claim 1 , —OR claim 1 , or Calkyl.3. The compound of claim 1 , wherein Ris hydrogen claim 1 , halogen claim 1 , —OR claim 1 , or Calkyl.4. The compound of claim 1 , wherein Ris —N(R)or —OR.5. The compound of claim 1 , wherein Ris —OR.6. The compound of claim 1 , wherein Ris Calkyl.7. The compound of claim 1 , wherein Ris —N(R).8. The compound of claim 1 , wherein Ris substituted or unsubstituted alkyl claim 1 , —OR claim 1 , or halogen.9. The compound of claim 1 , wherein Ris hydrogen or substituted or unsubstituted alkyl.10. The compound of claim 1 , wherein Ris —ORor —N(R). The present application is a continuation of and claims priority under 35 U.S.C. §120 to U.S. Application, U.S. Ser. No. 13/266,788, filed Jan. 11, 2012, which is a national stage filing under 35 U.S.C. §371 of international PCT application, PCT/US2010/001284, filed Apr. 30, 2010, which claims priority under 35 U.S.C. §119(e) to U.S. provisional patent applications, U.S. Ser. No. 61/174,185, filed Apr. 30, 2009, and U.S. Ser. No. 61/322,613, filed Apr. 9, 2010, each of which is incorporated herein by reference.This invention was made with U.S. Government support under grant R01 AI048825 and predoctoral fellowship GM007598-30 awarded by the National ...

AMIDE DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND USE THEREOF AS INSECTICIDE

An object of the present invention is to provide a compound represented by Formula (1): 114-. (canceled) The present invention relates to a compound represented by Formula (1):wherein A, A, Aand Aeach represent a carbon atom, a nitrogen atom or an oxidized nitrogen atom;Rand Reach represent a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C1-C4 alkylcarbonyl group;Gand Geach represent an oxygen atom or a sulfur atom;X, which may be identical or different, represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a trifluoromethyl group;n is an integer of 0 to 4; andQand Qeach represent an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heterocyclic group,an insecticide comprising the compound as the active ingredient, and a process for preparation thereof and use thereof.International Publication WO 2000/55120 and U.S. Pat. No. 6,548,514 describe a compound similar to the compound of the present invention for the use as medicament, but they do not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.International Publication WO 2000/7980 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.US Patent Laid-Open No. 2002-032238 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.The object of the present invention is to provide a pesticide having a high insecticidal efficacy. Another object of the present invention is to provide a compound represented by Formula (1), a process for ...

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) ...

CRYSTALLINE(2S,4R)-5-(5'-CHLORO-2'-FLUORO-[1,1'-BIPHENY]-4-YL)-2-(ETHOXYMETHYL)-4-(3-HYDROXYISOXAZOLE-5-CARBOXAMIDO)-2-METHYLPENTANOIC ACID AND USES THEREOF

In one aspect, the invention relates to a crystalline form of the structure: 116-. (canceled)17. A method for treating hypertension , heart failure , or renal disease , the method comprising administering (2S ,4R)-5-(5′-chloro-2′-fluoro-[1 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I) or crystalline free acid form of (2S ,4R)-5-(5′-chloro-2′-fluoro-[1 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3 -hydroxyi soxazole-5-carboxamido)-2-methylpentanoic acid (Compound to a patient once-daily.18. The method according to claim 17 , wherein hypertension is primary hypertension claim 17 , pulmonary arterial hypertension claim 17 , chronic thromboembolic pulmonary hypertension claim 17 , or hypertension with renal artery stenosis.19. The method according to claim 17 , wherein renal disease is diabetic nephropathy claim 17 , chronic kidney disease claim 17 , proteinuria claim 17 , acute kidney injury claim 17 , nephrotic syndrome claim 17 , focal segmental glomerulosclerosis or polycystic kidney disease.20. A method of treating hypertension claim 17 , heart failure claim 17 , or renal disease in a renally-impaired patient claim 17 , the method comprising administering a therapeutically effective amount of (2S claim 17 ,4R)-5-(5′-chloro-2′-fluoro-[1 claim 17 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid Compound or crystalline free acid form of (2S claim 17 , 4R)-5-(5′-chloro-2′-fluoro-[1 claim 17 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I′) to the patient once-daily.21. The method according to claim 20 , wherein the renally-impaired patient has chronic kidney disease with an estimated glomerular filtration rate (eGFR) between 60 mL/min/1.73 mand 15 mL/min/1.73 m.22. A method of increasing atrial natriuretic peptide (ANP) or cyclic guanosine monophosphate (cGMP) levels in a human for at least 24 hours ...

A CRYSTAL OF A CASPASE INHIBITOR

Disclosed herein a crystal structure of a caspase inhibitor, and more specifically a crystal structure of an (S)-3-((S)-2-(5-(2-chlorophenyl)isoxazole-3-formylamide)proponamide)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)valeric acid, a preparation method therefor, a crystal polymer, a pharmaceutical composition and uses thereof. The compound A of formula (I) disclosed herein exhibits high crystal structure stability, low hygroscopicity, and advantageously shows physical properties, safety and metabolic stability while having relatively high pharmaceutical value. 232-. (canceled)33. The crystal according to claim 1 , wherein the crystal is crystal IV of the compound of formula I-A claim 1 , and wherein the X-ray powder diffraction spectrum represented by 2θ values has diffraction peaks at about 5.6° claim 1 , 11.2° claim 1 , 12.9° claim 1 , 15.1° claim 1 , 15.6° claim 1 , 16.7° claim 1 , 22.7° claim 1 , and 25.6°.34. The crystal according to claim 33 , wherein the X-ray powder diffraction spectrum represented by 2θ values has diffraction peaks at about 5.6° claim 33 , 7.6° claim 33 , 8.6° claim 33 , 9.1° claim 33 , 11.2° claim 33 , 12.0° claim 33 , 12.9° claim 33 , 14.0° claim 33 , 15.1° claim 33 , 15.6° claim 33 , 16.4° claim 33 , 16.7° claim 33 , 19.3° claim 33 , 22.7° claim 33 , 23.5° claim 33 , 25.1° claim 33 , 25.6° claim 33 , 27.2° claim 33 , 27.8° claim 33 , 29.1° claim 33 , 30.7° claim 33 , 31.5° claim 33 , 33.7° claim 33 , 34.7° claim 33 , 36.6° claim 33 , 37.0° claim 33 , and 38.2°.35. The crystal according to claim 1 , wherein the crystal is crystal IV of the compound of formula I-A claim 1 , and wherein in a differential scanning calorimetry (DSC) measurement pattern claim 1 , an onset of absorption peak is at about 167° C.36. The crystal according to claim 1 , wherein the crystal is crystal I of the compound of formula I-A claim 1 , and wherein the X-ray powder diffraction spectrum represented by 2θ values has diffraction peaks at about 9.6° claim 1 , 14.0° ...

Compounds, compositions, and methods for increasing cftr activity

The present disclosure is directed to disclosed compounds that increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.

Neprilysin inhibitors

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

NEPRILYSIN INHIBITORS

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

COMPOUNDS, COMPOSITIONS AND METHODS

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors. 2. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , tautomer claim 1 , stereoisomer or mixture of stereoisomers thereof claim 1 , and a pharmaceutically acceptable excipient.4. A pharmaceutical composition comprising the compound of claim 3 , and a pharmaceutically acceptable excipient.6. A pharmaceutical composition comprising the compound of claim 5 , and a pharmaceutically acceptable excipient. This application is a continuation of U.S. application Ser. No. 15/424,216, filed Feb. 3, 2017, which application claims priority under 35 U.S.C. 119(e) of U.S. Provisional Application Nos. 62/292,202, filed Feb. 5, 2016, 62/341,019, filed May 24, 2016, 62/363,775, filed Jul. 18, 2016, 62/385,217, filed Sep. 8, 2016, and 62/417,219, filed Nov. 3, 2016. The entire contents of these applications are incorporated by reference into this application.The present disclosure relates generally to inhibitors of kinase, therapeutic methods of use, and manufacture thereof.Although inflammation can be a protective mechanism in response to harmful stimuli such as invasion of pathogens and tissue damages, chronic inflammation is an important underlying factor in many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, the activation of cell death pathways, such as necrosis and apoptosis which are useful in eliminating infected or damaged cells, is also an important underlying mechanism for human diseases, including acute and chronic neurodegenerative diseases.Receptor-interacting protein kinase 1 is a key regulator of inflammation, apoptosis and necroptosis. Receptor-interacting protein kinase 1 has an important role in modulating inflammatory responses mediated by nuclear-factor kappa-light chain enhancer of activated B cells (NF-κB). More ...

BIOMARKER

The invention is directed, in part, to selective cancer treatment regimes based on assaying for the presence or absence of a mutation in a nucleic acid that encodes MLL1 or for the presence of reduced levels of MLL1. 1. A method of selectively treating a subject having cancer , including selectively administering a therapeutically effective amount of (5-(2 ,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide , or a pharmaceutically acceptable salt thereof , to the subject on the basis of the subject having reduced levels of MLL12. A method according to further comprising:a) assaying a biological sample from the subject for the level of MLL1; andb) selectively administering a therapeutically effective amount of (5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide or a pharmaceutically acceptable salt thereof, to the subject on the basis that the sample has reduced levels of MLL1.3. (canceled)4. A method according to further comprising:a) assaying a biological sample from the subject for the levels of MLL1;b) thereafter selecting the subject for treatment with (5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (AUY922), or a pharmaceutically acceptable salt thereof, on the basis that the subject has reduced levels of MLL1; andc) thereafter administering (5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide or a pharmaceutically acceptable salt thereof to the subject on the basis that the subject has reduced levels of MLL1.57-. (canceled)8. A method of genotyping an individual including detecting a genetic variant that results in an amino acid variant at position 859 of the encoded catalytic p110α subunit of PI3K claim 2 , wherein a lack of variant at position 859 indicates that (5-(2 claim 2 ,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4- ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 128-. (canceled)29. (2R ,4R)-5-Biphenyl-4-yl-4-{[5-(3-carbamoylpyrrolidine-1-carbonyl)-2H-pyrazole-3-carbonyl]-amino}-2-hydroxy-pentanoic acid or a pharmaceutically acceptable salt thereof.30. (2R ,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(4-hydroxypiperidine-1-carbonyl)-2H-pyrazole-3-carbonyl]-amino}-pentanoic acid or a pharmaceutically acceptable salt thereof.31. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.32. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.33. The pharmaceutical composition of claim 31 , further comprising an ATreceptor antagonist.34. The pharmaceutical composition of claim 32 , further comprising an ATreceptor antagonist.35. The pharmaceutical composition of claim 33 , wherein the ATreceptor antagonist is selected from abitesartan claim 33 , azilsartan claim 33 , azilsartan medoxomil claim 33 , benzyllosartan claim 33 , candesartan claim 33 , candesartan cilexetil claim 33 , elisartan claim 33 , embusartan claim 33 , enoltasosartan claim 33 , eprosartan claim 33 , EXP3174 claim 33 , fonsartan claim 33 , forasartan claim 33 , glycyllosartan claim 33 , irbesartan claim 33 , isoteoline claim 33 , losartan claim 33 , milfasartan claim 33 , olmesartan claim 33 , olmesartan medoxomil claim 33 , opomisartan claim 33 , pratosartan claim 33 , ripisartan claim 33 , saprisartan claim 33 , saralasin claim 33 , sarmesin claim 33 , TAK-591 claim 33 , tasosartan claim 33 , telmisartan claim 33 , valsartan claim 33 , and zolasartan.36. The pharmaceutical composition of claim 34 , wherein the ATreceptor antagonist is selected from abitesartan claim 34 , azilsartan claim 34 , azilsartan medoxomil claim 34 , benzyllosartan claim 34 , candesartan claim 34 , candesartan cilexetil claim 34 , elisartan claim 34 , embusartan claim 34 , enoltasosartan claim 34 , eprosartan claim 34 , EXP3174 claim 34 , ...

RADIOLABELING AGENTS, METHODS OF MAKING, AND METHODS OF USE THEREOF

Described herein are labeling agents, specifically [C]fluoroform, [C]difluoromethane, [C]fluoromethyl iodide, [C]fluoromethyl bromide, [C]fluoromethyl chloride, [C]fluoromethyl trifluoromethansulfonate, [C]difluoromethyl iodide, [C]difluoromethyl bromide, [C]difluoromethyl chloride, [C]difluoromethyl trifluoromethansulfonate, [C]trifluoromethyl iodide, [C]trifluoromethyl bromide, [C]trifluoromethyl chloride, [C]trifluoromethyl trifluoromethansulfonate, []fluoroform, [F]difluoromethane, [F]difluoromethyl bromide or [F]trifluoromethyl bromide. Also included are methods of labeling precursors to provide labeled fluoroalkanes and imaging methods. 1. A gas phase solvent-free method for producing an C- or F-labeled fluoroalkane , the method comprising{'sup': 11', '18', '18', '11', '11, 'sub': 11', '11', '3, 'contacting [C]methane, [F]fluoromethane, [F]fluoromethyl bromide, [C]methyl iodide, [C]methyl bromide, [C]methyl chloride, or [C]methyl trffluoromethansuifonate, with CoFat a temperature of 50 to 450° C., and'}{'sup': 11', '18, 'isolating the C- or F-labeled fluoroalkane that is produced.'}2. The method of claim 1 , wherein{'sup': 11', '11, 'the precursor is [C]methane and the labeled fluoroalkane is [C]fluoroform,'}{'sup': 18', '18, 'the precursor is [F]fluoromethane and the labeled fluoroalkane is [F]fluoroform,'}{'sup': 18', '18, 'the precursor is [F]fluoromethane and the labeled fluoroalkane is [F]difluoromethane,'}{'sup': 18', '18, 'the precursor is [F]fluoromethyl bromide and the labeled fluoroalkane is [F]difluoromethyl bromide,'}{'sup': 18', '18, 'the precursor is [F]fluoromethyl bromide and the labeled fluoroalkane is [F]trifluoromethyl bromide,'}{'sup': 11', '11, 'the precursor is [C]methyl iodide and the labeled fluoroalkane is [C]fluoromethyl iodide,'}{'sup': 11', '11, 'the precursor is [C]methyl bromide and the labeled fluoroalkane is [C]fluoromethyl bromide,'}{'sup': 11', '11, 'the precursor is [C]methyl chloride and the labeled fluoroalkane is [C] ...

MODULATORS OF MAS-RELATED G-PROTEIN RECEPTOR X4 AND RELATED PRODUCTS AND METHODS

Methods are provided for modulating MRGPR X4 generally, or for treating a MRGPR X4 dependent condition more specifically, by contacting the MRGPR X4 or administering to a subject in need thereof, respectively, an effective amount of a compound having the structure of Formula (I). 3. The method of claim 2 , wherein the MRGPR X4 dependent condition is a condition that is caused by the activation of MRGPR X4 by a bile acid or analog thereof.4. The method of wherein the MRGPR X4 dependent condition is an itch associated condition claim 2 , a pain associated condition claim 2 , or an autoimmune disorder.5rubra. The method of wherein the itch associated condition is chronic itch claim 4 , cholestatic pruritus claim 4 , contact dermatitis claim 4 , allergic blepharitis claim 4 , anemia claim 4 , atopic dermatitis claim 4 , bullous pemphigoid claim 4 , candidiasis claim 4 , chicken pox claim 4 , cholestasis claim 4 , end-stage renal failure claim 4 , hemodialysis claim 4 , contact dermatitis claim 4 , dermatitis herpetiformis claim 4 , diabetes claim 4 , drug allergy claim 4 , dry skin claim 4 , dyshidrotic dermatitis claim 4 , ectopic eczema claim 4 , eczema claim 4 , erythrasma claim 4 , folliculitis claim 4 , fungal skin infection claim 4 , hemorrhoids claim 4 , herpes claim 4 , HIV infection claim 4 , Hodgkin's disease claim 4 , hyperthyroidism claim 4 , iron deficiency anemia claim 4 , kidney disease claim 4 , leukemia claim 4 , liver disease claim 4 , lymphoma claim 4 , malignancy claim 4 , multiple myeloma claim 4 , neurodermatitis claim 4 , onchocerciasis claim 4 , Paget's disease claim 4 , pediculosis claim 4 , polycythemia vera claim 4 , pruritus ani claim 4 , pseudorabies claim 4 , psoriasis claim 4 , rectal prolapse claim 4 , scabies claim 4 , schistosomiasis claim 4 , scleroderma claim 4 , severe stress claim 4 , stasia dermatitis claim 4 , swimmer's itch claim 4 , thyroid disease claim 4 , tinea cruris claim 4 , uremic pruritus claim 4 , or urticaria.6. The ...

ALPHA-CINNAMIDE COMPOUNDS AND COMPOSITIONS AS HDAC8 INHIBITORS

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors. 116-. (canceled)17. A method of treating cancer , neurological disease , inflammatory disease , autoimmune disease , infection , metabolic disease , hematological disease , or cardiovascular disease in a subject in need thereof , comprising administering to the subject an effective amount of a compound selected from:(E)-3-(2-((1H-benzo[d]imidazol-2-yl)amino)phenyl)-N-hydroxyacrylamide (I-1);(E)-N-hydroxy-3-(2-(((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)phenyl)acrylamide (I-2);(E)-N-hydroxy-3-(2-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)amino)phenyl)acrylamide (I-3);(E)-N-hydroxy-3-(2-(((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)phenyl)acrylamide (I-4);(E)-N-hydroxy-3-(2-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)acrylamide (I-5);(E)-1-hydroxy-N-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)cyclobutane-1-carboxamide (I-6);(E)-N-hydroxy-3-(2-((3-(trifluoromethyl)phenyl)sulfonamido)phenyl)acrylamide (I-7);(E)-3-(2-(4-aminopiperidin-1-yl)phenyl)-N-hydroxyacrylamide (I-8);(E)-N-hydroxy-3-(2-(4-(2-(4-methoxyphenyl)acetamido)piperidin-1-yl)phenyl)acrylamide (I-9);(E)-3-(2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)phenyl)-N-hydroxyacrylamide (I-10);(E)-N-(1-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)piperidin-4-yl)-1,8-naphthyridine-2-carboxamide (I-11);(E)-N-(1-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)piperidin-4-yl)-1-methylazetidine-3-carboxamide (I-12);(E)-3-(2-(4-(2-(4-chlorophenyl)acetamido)piperidin-1-yl)phenyl)-N-hydroxyacrylamide (I-13);(E)-N-(1-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)piperidin-4-yl)-3-methylbenzamide (I-14);(E)-5-(4-chlorophenyl)-N-(1-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)piperidin-4-yl)-2-methylfuran-3-carboxamide (I-15);(E)-N-(1-(2-(3-( ...

SULFONYLUREAS AND RELATED COMPOUNDS AND USE OF SAME

The present invention provides for certain sulfonyl ureas and related compounds which have advantageous properties and show useful activity in the inhibition of activation of the NLRP3 inflammasome. Such compounds are useful in the treatment of a wide range of disorders in which the inflammation process, or more specifically the NLRP3 inflammasome, have been implicated as being a key factor. 2. The compound of wherein Ris selected from the group consisting of Cor Ccycloalkyl claim 1 , 5-membered or 6-membered heteroaryl claim 1 , bicyclic heteroaryl wherein at least one ring is heteroaryl claim 1 , phenyl claim 1 , biphenyl claim 1 , phenylheterocyclyl claim 1 , 5-membered or 6-membered heterocyclyl claim 1 , and heterocyclylcycloalkyl claim 1 , all of which may be optionally substituted.3. The compound of or wherein Ris selected from the group consisting of pyrazole claim 1 , furan claim 1 , tetrahydrofuran claim 1 , tetrahydropyran claim 1 , pyran claim 1 , pyrrolidine claim 1 , pyrrole claim 1 , triazole claim 1 , tetrazole claim 1 , imidazole claim 1 , pyridine claim 1 , morpholine claim 1 , piperazine claim 1 , piperidine claim 1 , substituted phenyl claim 1 , phenylheteroaryl claim 1 , phenylheterocyclyl claim 1 , biphenyl claim 1 , quinoline claim 1 , isoquinoline claim 1 , naphthyl claim 1 , pyrazine and pyrimidine claim 1 , all of which may be optionally substituted as appropriate.4. The compound of any one of the preceding claims wherein Ris 5-membered heterocyclyl or heteroaryl claim 1 , each of which may be optionally substituted claim 1 , comprising at least one ring heteroatom selected from N claim 1 , O and S.5. The compound of wherein Ris 5-membered nitrogen heterocyclyl or 5-membered nitrogen heteroaryl claim 4 , each of which may be optionally substituted.6. The compound of or wherein Ris 5-membered heterocyclyl or 5-membered heteroaryl claim 4 , each of which may be optionally substituted claim 4 , comprising at least two ring nitrogen atoms.7. ...

AMINOCARBAMOYL COMPOUNDS FOR THE TREATMENT OF VIRAL INFECTIONS

The present invention relates to compounds of formula (I),

Small molecule mediated transcriptional induction of e-cadherin

In one aspect, the invention relates to N-acetamidoalkyl-5-arylisoxazole-3-carboxamide analogs, derivatives thereof, and related compounds, which are useful as mediators of transcriptional induction of E-cadherin; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with E-cadherin activity using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

ISOXAZOLE ANALOGS AS MEDIATORS OF TRANSCRIPTIONAL INDUCTION OF E-CADHERIN

In one aspect, the invention relates to N-((arylamino)alkyl)-5-arylisoxazole-3-carboxamide analogs, derivatives thereof, and related compounds, which are useful as mediators of transcriptional induction of E-cadherin; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with E-cadherin activity using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention. 2. The compound of claim 1 , wherein Ris (CHR)Ar.3. The compound of claim 1 , wherein Ris (CH)Ar.4. The compound of claim 1 , wherein Ris CHAr.5. The compound of claim 1 , wherein Ris Ar.6. The compound of claim 1 , wherein Aris aryl claim 1 , and Aris substituted with 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3 groups independently selected from halogen claim 1 , —OH claim 1 , —CN claim 1 , —N claim 1 , —NH claim 1 , C1-C4 alkyl claim 1 , C1-C4 alkoxy claim 1 , C1-C4 monohaloalkyl claim 1 , C1-C4 polyhaloalkyl claim 1 , C1-C4 alkylamino claim 1 , and C1-C4 dialkylamino.7. The compound of claim 1 , wherein Aris phenyl claim 1 , and Aris substituted with 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3 groups independently selected from halogen claim 1 , —OH claim 1 , —CN claim 1 , —N claim 1 , —NH claim 1 , C1-C4 alkyl claim 1 , C1-C4 alkoxy claim 1 , C1-C4 monohaloalkyl claim 1 , C1-C4 polyhaloalkyl claim 1 , C1-C4 alkylamino claim 1 , and C1-C4 dialkylamino.8. The compound of claim 1 , wherein Ris hydrogen and Aris not substituted or unsubstituted pyridinyl.9. The compound of claim 1 , wherein Ris hydrogen and Aris not substituted or unsubstituted pyridinyl claim 1 , phenyl claim 1 , or benzo[d]isothiazole.17. The method of claim 16 , wherein the disorder associated with E-cadherin activity is a disorder of uncontrolled cellular proliferation.18. The method of claim 17 , wherein the disorder of uncontrolled ...

Compounds for use in screening methods for spinal muscular atrophy

Disclosed herein are compositions and methods for treatment of spinal muscular atrophy (SMA). In certain embodiments, compounds are provided that increase full-length survival of motor neuron (SMN) protein production by an SMN2 gene.

5-CARBAMOYL-ADAMANTAN-2-YL AMIDE DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AND PREPARATION PROCESS THEREOF

Provided are a novel derivative of 5-carbamoyl adamantan-2-yl amide or a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof for inhibiting the activity of 11β-hydroxystreroid dehydrogenase type 1 (11b-HSD1) or for preventing and/or treating various diseases mediated by 11β-hydroxystreroid dehydrogenase type 1. 123-. (canceled)25. The compound of claim 24 , wherein Ris linear or branched C-Calkyl claim 24 , —O—R claim 24 , phenyl substituted with one to three substituents independently selected from Rwhich is selected from the group consisting of —H claim 24 , halo claim 24 , linear or branched C-Calkyl claim 24 , trifluoromethyl claim 24 , nitro and —O—R.33. The compound of claim 24 , which is selected from the group consisting of:N-(5-carbamoyl-2-adamantyl)-5-phenylfuran-2-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(4-chlorophenyl)furan-2-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(4-nitrophenyl)furan-2-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(4-methylphenyl)furan-2-carboxamide,5-t-butyl-N-(5-carbamoyl-2-adamantyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(3-methylphenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(2-methoxyphenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(2-methylphenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(3-methoxyphenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(furan-3-yl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(thiophen-3-yl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(3-fluorophenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(4-chlorophenyl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-5-(2-methyl-1,3-thiazol-4-yl)-1,2-oxazole-3-carboxamide,N-(5-carbamoyl-2-adamantyl)-6-methylpyridine-2-carboxamide,N-(5-carbamoyl-2-adamantyl)pyridine-2-carboxamide,N-(5-carbamoyl-2-adamantyl)-1-methylpyrrole-2-carboxamide,N-(5-carbamoyl-2-adamantyl)quinoline-2-carboxamide,N-(5-carbamoyl-2-adamantyl) ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 129-. (canceled)31: A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.32: The pharmaceutical composition of claim 31 , further comprising an ATreceptor antagonist.33: A method for therapeutically treating hypertension claim 30 , heart failure claim 30 , or renal disease claim 30 , comprising administering to a patient a therapeutically effective amount of the compound of . This application claims the benefit of U.S. Provisional Application No. 61/443,828, filed on Feb. 17, 2011; 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 enzyme (ACE) are also known, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopeptidase inhibitors, this ...

T1r hetero-oligomeric taste receptors, cell lines that express said receptors, and taste compounds

The invention relates to compounds that specifically bind a T1R1/T1R3 or T1R2/T1R3 receptor or fragments or sub-units thereof. The present invention also relates to the use of hetero-oligomeric and chimeric taste receptors comprising T1R1/T1R3 and T1R2/T1R3 in assays to identify compounds that respectively respond to umami taste stimuli and sweet taste stimuli. Further, the invention relates to the constitutive of cell lines that stably or transiently co-express a combination of T1R1 and T1R3; or T1R2 and T1R3; under constitutive or inducible conditions. The use of these cells lines in cell-based assays to identify umami and sweet taste modulatory compounds is also provided, particularly high throughput screening assays that detect receptor activity by use of fluorometric imaging.

ALPHA-CINNAMIDE COMPOUNDS AND COMPOSITIONS AS HDAC8 INHIBITORS

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors. 139-. (canceled)41. The method of claim 40 , wherein Rand Rare combined to form a heterocycle claim 40 , wherein said heterocycle is optionally substituted with one or more R.42. The method of claim 41 , wherein Ris at least one of hydrogen claim 41 , C-Calkyl claim 41 , oxo claim 41 , or C-Ccycloalkyl.43. The method of claim 41 , wherein Ris at least one of hydrogen claim 41 , oxo claim 41 , C-Ccycloalkyl claim 41 , or two Rwhen attached to the same carbon atom can form a C-Cspirocycle or a 3- to 12-membered spiroheterocycle.44. The method of claim 40 , wherein Ris aryl claim 40 , optionally substituted with one or more R.45. The method of claim 44 , wherein Ris —OR.46. The method of claim 40 , wherein the compound is (E)-N-(2-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)-2-phenoxybenzamide claim 40 , or a pharmaceutically acceptable salt thereof.47. The method according to claim 40 , wherein the disease or disorder associated with HDAC8 inhibition is cancer claim 40 , neurological disease claim 40 , inflammatory disease claim 40 , autoimmune disease claim 40 , infection claim 40 , metabolic disease claim 40 , hematological disease claim 40 , or cardiovascular disease.48. The method according to claim 47 , wherein the cancer is colon cancer claim 47 , lung cancer claim 47 , neuroblastoma claim 47 , ovarian cancer claim 47 , hepatocellular carcinoma claim 47 , gastric cancer claim 47 , prostate cancer claim 47 , pancreatic cancer claim 47 , renal cancer claim 47 , cervical cancer claim 47 , ovarian cancer claim 47 , head and neck cancer claim 47 , lymphoma claim 47 , colorectal cancer claim 47 , non-small cell lung carcinoma claim 47 , breast cancer claim 47 , bladder cancer claim 47 , acute myeloid leukemia claim 47 , acute lymphoblastic ...

Small Molecule Agonists and Antagonists of NR2F6 Activity in Animals

The present technology is directed to modulators of nuclear receptor activity, specifically to the modulation of NR2F6 activity and NR2F6 utilizing compounds, and the immune modulation and modulation of cancer stem cell activity through administration of compounds described herein to animals. 2. A solid form of a compound of .3. A pharmaceutical composition comprising the solid form of a compound of claim 1 , with a pharmaceutically acceptable carrier or excipient.4. A method of increasing activity of a cell in an animal claim 1 , comprising contacting a composition of with the cell.5. A method of reducing the size of a tumor in an animal claim 1 , comprising administering a compound of to the tumor.6. The method of claim 5 , comprising the steps of:(a) extracting an amount of an animal's cellular material;(b) isolating immune cells from the cellular material;{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(c) activating the NR2F6 target in the isolated immune cells by binding them with a compound of ; and'}(d) re-administering the isolated immune cells to the animal's body.7. The method of claim 6 , wherein the animal's cellular material is blood.8. The method of claim 6 , wherein the re-administering step comprises injection of the immune cells into the animal's body.9. The pharmaceutical composition of claim 3 , in an oral dosage form.10. A method of treating or reducing the effect of a reaction claim 1 , disease or disorder claim 1 , the method comprising activating the NR2F6 target in immune cells by contacting them with a compound of .11. The method of claim 10 , wherein the reaction claim 10 , disease or disorder comprises an autoimmune response.12. A method of treating a disorder comprising administering to a subject an effective amount of a compound of or a composition thereof.13. The method of claim 12 , wherein the subject is an animal.14. The method of claim 10 , wherein the disorder is cancer. The present technology relates to agonists and ...

CRYSTALLINE (2S,4R)-5-(5'-CHLORO-2'-FLUORO-[1,1'-BIPHENYL]-4-YL)-2-(ETHOXYMETHYL)-4-(3-HYDROXYISOXAZOLE-5-CARBOXAMIDO)-2-METHYLPENTANOIC ACID AND USES THEREOF

In one aspect, the invention relates to a crystalline form of the structure: 136-. (canceled)38. The composition of claim 37 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising peaks at 6.51±0.2 and 15.07±0.2 degrees 2θ.39. The composition of claim 37 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising peaks at 11.62±0.2 claim 37 , 13.05±0.2 claim 37 , and 23.28±0.2 degrees 2θ.40. The composition of claim 38 , wherein the powder x-ray diffraction pattern further comprises at least one peak selected from 11.62±0.2 claim 38 , 13.05±0.2 claim 38 , and 23.28±0.2 degrees 2θ.41. The composition of claim 38 , wherein the powder x-ray diffraction pattern further comprises peaks at 11.62±0.2 claim 38 , 13.05±0.2 claim 38 , and 23.28±0.2 degrees 2θ.42. The composition of claim 38 , wherein the powder x-ray diffraction pattern further comprises at least one peak selected from 15.72±0.2 claim 38 , 17.12±0.2 claim 38 , 18.77±0.2 claim 38 , 19.63±0.2 claim 38 , 20.79±0.2 claim 38 , and 24.48±0.2 degrees 2θ.43. The composition of claim 38 , wherein the powder x-ray diffraction pattern further comprises peaks at 15.72±0.2 claim 38 , 17.12±0.2 claim 38 , 18.77±0.2 claim 38 , 19.63±0.2 claim 38 , 20.79±0.2 claim 38 , and 24.48±0.2 degrees 2θ.44. The composition of claim 41 , wherein the powder x-ray diffraction pattern further comprises peaks at 15.72±0.2 claim 41 , 17.12±0.2 claim 41 , 18.77±0.2 claim 41 , 19.63±0.2 claim 41 , 20.79±0.2 claim 41 , and 24.48±0.2 degrees 2θ.45. The composition of claim 37 , wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endotherm in the range of about 214 to 218° C.46. The composition of claim 41 , wherein the crystalline form is further characterized by a differential scanning calorimetry thermogram comprising an endotherm in the range of about 214 to 218° C.47. The composition of claim 44 , wherein ...

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.

DIPEPTIDOMIMETICS AS INHIBITORS OF HUMAN IMMUNOPROTEASOMES

The compounds of the present invention are represented by the following compounds having Formula I: 17.-. (canceled)15. The method of claim 8 , wherein an autoimmune disorder is treated claim 8 , said autoimmune disorder being selected from the group consisting of arthritis claim 8 , colitis claim 8 , multiple sclerosis claim 8 , lupus claim 8 , systemic sclerosis claim 8 , and sjögren syndrome.16. The method of claim 8 , wherein immunosuppression is provided for transplanted organs or tissues claim 8 , said immunosuppression being used to prevent transplant rejection and graft-verse-host disease.17. The method of claim 8 , wherein an inflammatory disorder is treated claim 8 , said inflammatory disorder being Crohn's disease and ulcerative colitis.18. The method of claim 8 , wherein cancer is treated claim 8 , said cancer being selected from the group consisting of neoplastic disorders claim 8 , hematologic malignancies claim 8 , and lymphocytic malignancies.1926.-. (canceled)34. The method of claim 27 , wherein an autoimmune disorder is treated claim 27 , said autoimmune disorder being selected from the group consisting of arthritis claim 27 , colitis claim 27 , multiple sclerosis claim 27 , and lupus.35. The method of claim 27 , wherein immunosuppression is provided for transplanted organs or tissues claim 27 , said immunosuppression being used to prevent transplant rejection and graft-verse-host disease.36. The method of claim 27 , wherein an inflammatory disorder is treated claim 27 , said inflammatory disorder being Crohn's disease.37. The method of claim 27 , wherein cancer is treated claim 27 , said cancer being selected from the group consisting of neoplastic disorders claim 27 , hematologic malignancies claim 27 , and lymphocytic malignancies.38. (canceled) This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62/038,636, filed Aug. 18, 2014, which is hereby incorporated by reference in its entirety.This invention was made with ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 129-. (canceled)30. A compound selected from:(a) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid ethyl ester;(b) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid;(c) (2S,4R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid(d) (R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(2H-[1,2,4]triazole-3-carbonyl)-amino]-pentanoic acid(e) (R)-5-Biphenyl-4-yl-4-[(5-chloro-2H-[1,2,4]triazole-3-carbonyl)-amino]-2-hydroxy-2-methyl-pentanoic acid(f) (R)-5-Biphenyl-4-yl-4-[(7-fluoro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-2-methyl-pentanoic acid(g) (R)-5-Biphenyl-4-yl-4-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-2-methyl-pentanoic acid(h) (2S,4R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(1H-[1,2,3]triazolo[4,5-b]pyridine-6-carbonyl)-amino]-pentanoic acid(i) (R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester(j) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(2-hydroxy-pyrimidine-5-carbonyl)-amino]-2-methyl-pentanoic acid; and(k) 5-((1R,3R)-1-Biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid;or a pharmaceutically acceptable salt thereof.31. (R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid or a pharmaceutically acceptable salt thereof.32. (2S ,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(2-hydroxy-pyrimidine-5-carbonyl)-amino]-2-methyl-pentanoic acid or a pharmaceutically acceptable salt thereof.33. 5-((1R ,3S)-1-Biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-butylcarbamoyl)-2H-pyrazole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.34. (R)-5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxy-2H-pyrazole-3-carbonyl)-amino]-2-methyl-pentanoic acid or a pharmaceutically acceptable salt thereof.35. A pharmaceutical composition comprising the ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 128-. (canceled)30. The method of claim 29 , wherein the disease is selected from hypertension claim 29 , heart failure claim 29 , and renal disease.31. The method of claim 29 , further comprising administering a therapeutic agent selected from an ATreceptor antagonist claim 29 , an angiotensin-converting enzyme inhibitor claim 29 , a phosphodiesterase inhibitor claim 29 , a renin inhibitor claim 29 , and a diuretic claim 29 , or a combination thereof.32. The method of claim 29 , further comprising administering an ATreceptor antagonist claim 29 , wherein the ATreceptor antagonist is selected from abitesartan claim 29 , azilsartan claim 29 , azilsartan medoxomil claim 29 , benzyllosartan claim 29 , candesartan claim 29 , candesartan cilexetil claim 29 , elisartan claim 29 , embusartan claim 29 , enoltasosartan claim 29 , eprosartan claim 29 , EXP3174 claim 29 , fonsartan claim 29 , forasartan claim 29 , glycyllosartan claim 29 , irbesartan claim 29 , isoteoline claim 29 , losartan claim 29 , milfasartan claim 29 , olmesartan claim 29 , olmesartan medoxomil claim 29 , opomisartan claim 29 , pratosartan claim 29 , ripisartan claim 29 , saprisartan claim 29 , saralasin claim 29 , sarmesin claim 29 , TAK-591 claim 29 , tasosartan claim 29 , telmisartan claim 29 , valsartan claim 29 , and zolasartan.33. The method of claim 29 , wherein Ris —OR; and Ris selected from H and —Calkyl.34. The method of claim 29 , wherein Ris H.35. The method of claim 29 , wherein X is selected from oxazole and isoxazole.36. The method of claim 29 , wherein Ris selected from H claim 29 , —Calkylene-OH claim 29 , —Calkyl claim 29 , and —Calkylene-O—Calkyl; and Ris H.37. The method of claim 29 , wherein a is 0; b is 0 claim 29 , 1 or 2; and each Ris independently selected from halo.38. The method of claim 29 , wherein Ris —OR; Ris selected from H and —Calkyl; Ris H; X is selected from oxazole and isoxazole; Ris selected from H ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 130-. (canceled)31. A compound selected from:(a) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(b) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;(c) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(d) (2S,4R)-5-biphenyl-4-yl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-hydroxymethyl-2-methylpentanoic acid;(e) (2S,4R)-5-biphenyl-4-yl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;(f) (2S,4R)-5-biphenyl-4-yl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;(g) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(h) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-ethylisoxazole-5-carbonyl)amino]-2-hydroxymethyl-2-methylpentanoic acid;(i) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-isobutylisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(j) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-4-[(3-propylisoxazole-5-carbonyl)amino]pentanoic acid;(k) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;(l) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-(2-hydroxyethoxymethyl)-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(m)(2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(n) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(o) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-ethylisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;(p) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3- ...

SMALL MOLECULES AND METHODS OF REDUCING INJURIES CAUSED BY RADIATION OR CHEMICALS

A series of small molecule, radioprotective agents based on a compound of the general formula (I): 2. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to .3. A method of protecting healthy living tissues/organs of a subject from radiation-induced injuries which method comprises administration of the composition according to to the subject.4. The method according to wherein the radiation-induced injuries are induced by total-body irradiation or localized radiotherapy.5. The method according to wherein the radiation-induced injuries are induced by localized radiotherapy applied to a cancer patient for treatment of cancer.6. The method according to wherein said total-body irradiation is applied to a cancer patient for therapeutic purpose or applied to a subject exposed to non-medical radiation resulting from terrorism claim 4 , nuclear war or accidental exposure.7. A method of protecting healthy living tissues or organs from chemical-induced injuries which method comprises administration of the composition according to .8. The method according to wherein the chemical-induced injuries are induced by chemotherapy.9. The method according to wherein the chemical-induced injuries are induced by accidental chemical exposure. The application is based on U.S. provisional application Ser. No. 62/903,032, filed Sep. 20, 2019 to which priority is claimed under 35 U.S.C. § 120 and of which the entire specification is hereby expressly incorporated by reference.The present invention relates generally to a series of new compounds and methods of reducing injuries caused by radiation or chemicals.There are generally two types of total-body irradiation (TBI). One type of TBI is used in conjunction with bone marrow transplantation as a medical treatment for cancer patients. In such cases, TBI is often used together with high dose chemotherapy to kill leukemia, lymphoma, and/or myeloma cells in bone marrow. In this type of medical ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula X: 124-. (canceled)25. A compound of:(a) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[1-(3-chlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl]hydrazino}-2-hydroxypropionic acid;(b) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[1-(3-chlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl]hydrazino}-2-hydroxypropionic acid ethyl ester;(c) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[1-(3-chlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl]hydrazino}-2-hydroxypropionic acid isobutyl ester;(d) (S)-2-amino-3-methylbutyric Acid (R)-3-{N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[1-(3-chlorophenyl)-5-hydroxy-1H-[1,2,4]triazole-3-carbonyl]hydrazino}-2-hydroxypropionyloxymethyl ester;(e) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[1-(3-chlorophenyl)-5-hydroxy-1H-[1,2,4]triazole-3-carbonyl]hydrazino}-2-hydroxypropionic acid acetoxymethyl ester;(f) (S)-2-amino-3-methylbutyric Acid 5-[N′4(R)-2-Carboxy-2-hydroxyethyl)-N′-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazinocarbonyl]-2-(3-chlorophenyl)-2H-[1,2,4]triazol-3-yloxymethyl ester; or(g) (R)-3-[N′-[5-acetoxymethoxy-1-(3-chlorophenyl)-1H-[1,2,4]triazole-3-carbonyl]-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid.26. A compound of:(a) (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(2-hydroxythiazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid; or(b) (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(2-hydroxythiazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid ethyl ester.27. A compound of:(a) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid;(b) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid isobutyl ester;(c) (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5- ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 122-. (canceled)23: A compound of:(a) (2R,3R)-4-(2-Chloro-phenyl)-3-{[3-(2-chloro-phenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-butyric acid;(b) (2R,3R)-4-(2-Chloro-phenyl)-3-{[3-(3-chloro-phenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-butyric acid;(c) (2R,3R)-4-(2-Chloro-phenyl)-3-{[3-(4-chloro-phenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-butyric acid;(d) (2R,3R)-4-(2-Chloro-phenyl)-3-{[5-(2-chloro-phenyl)-isoxazole-3-carbonyl]-amino}-2-hydroxy-butyric acid;(e) (2R,3R)-3-{[2-(4-Chloro-2-fluoro-benzyl)-3-oxo-2,3-dihydro-isoxazole-5-carbonyl]-amino}-4-(2-chloro-phenyl)-2-hydroxy-butyric acid;(f) (2R,3R)-4-(2-Chloro-phenyl)-3-{[2-(2,3-difluoro-4-methoxy-benzyl)-3-oxo-2,3-dihydro-isoxazole-5-carbonyl]-amino}-2-hydroxy-butyric acid; 'a pharmaceutically acceptable salt thereof.', '(g) (2R,3R)-4-(2-Chloro-phenyl)-2-hydroxy-3-[(2-phenyl-oxazole-5-carbonyl)-amino]-butyric acid; or'}24: A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.25: The pharmaceutical composition of claim 24 , further comprising an ATreceptor antagonist.26: A method for treating hypertension claim 23 , heart failure claim 23 , or renal disease claim 23 , comprising administering to a patient a therapeutically effective amount of the compound of . This application claims the benefit of U.S. Provisional Application No. 61/491,749, filed on May 31, 2011; the entire disclosure of which is incorporated herein by reference.Field of the InventionThe 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.State of the ArtNeprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial ...

SMALL MOLECULES FOR DISRUPTING THE SUPER ELONGATION COMPLEX AND INHIBITING TRANSCRIPTION ELONGATION FOR CANCER THERAPY

Disclosed are compounds which may be utilized to inhibit transcription by RNA Polymerase II (Pol II), and in particular to disrupt the Super Elongation Complex (SEC). The compounds may be utilized in pharmaceutical compositions and methods for treating diseases and disorders associated with the biological activity of SEC, and in particular, diseases and disorders that are associated with high levels of expression of genes whose expression is SEC-dependent and that promote, support, or otherwise are required for the disease or disorder such as cancers. 2. The compound of claim 1 , wherein n is 0 or 1.3. The compound of claim 1 , wherein Y is unsubstituted or substituted phenyl.4. The compound of claim 1 , wherein X is unsubstituted or substituted phenyl.5. The compound of claim 1 , wherein X is selected from the group consisting of unsubstituted or substituted pyridinyl claim 1 , unsubstituted or substituted pyrimidinyl claim 1 , unsubstituted or substituted pyrazinyl claim 1 , unsubstituted or substituted thiazol claim 1 , unsubstituted or substituted tetrazolyl claim 1 , and unsubstituted or substituted oxadiazolyl.9. The pharmaceutical composition of claim 8 , wherein n is 0 or 1.10. The pharmaceutical composition of claim 8 , wherein Y is unsubstituted or substituted phenyl.11. The pharmaceutical composition of claim 8 , wherein X is unsubstituted or substituted phenyl.12. The pharmaceutical composition of claim 8 , wherein X is selected from the group consisting of unsubstituted or substituted pyridinyl claim 8 , unsubstituted or substituted pyrimidinyl claim 8 , unsubstituted or substituted pyrazinyl claim 8 , unsubstituted or substituted thiazol claim 8 , unsubstituted or substituted tetrazolyl claim 8 , and unsubstituted or substituted oxadiazolyl.16. A method for treating a disease or disorder associated with Super Elongation Complex (SEC) activity in a subject in need thereof claim 1 , the method comprising administering to the subject an effective amount ...

Alpha 7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof

The present application is related to compounds represented by Formula I, which are novel positive allosteric modulators of al nAChRs. The application also discloses the treatment of disorders that are responsive to enhancement of acetylcholine action on al nAChRs in a mammal by administering an effective amount of a compound of Formula I. 8. The compound of wherein:{'sup': 9', '12, 'Rand Rare hydrogen; and pharmaceutically acceptable salts and prodrugs thereof.'}9. The compound of wherein:{'sup': 17', '13, 'Xis CR;'}{'sup': 18', '14, 'Xis CR;'}{'sup': 19', '15, 'Xis CR;'}and pharmaceutically acceptable salts and prodrugs thereof.10. The compound of wherein:{'sup': 17', '13, 'Xis CR;'}{'sup': 18', '14, 'Xis CR;'}{'sup': '19', 'Xis N;'}and pharmaceutically acceptable salts and prodrugs thereof.11. The compound of wherein:{'sup': '17', 'Xis N;'}{'sup': 18', '14, 'Xis CR;'}{'sup': 19', '15, 'Xis CR;'}and pharmaceutically acceptable salts and prodrugs thereof.12. The compound of wherein:{'sup': 17', '13, 'Xis CR;'}{'sup': '18', 'Xis N;'}{'sup': 19', '15, 'Xis CR;'}and pharmaceutically acceptable salts and prodrugs thereof.14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof claim 1 , and a pharmaceutically acceptable carrier or diluent.15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from:[2-(benzylamino)pyridin-3-yl](5-chloro-2,3-dihydro-1H-indol-1-yl)methanone (compound 1);(5-chloro-2,3-dihydro-1H-indol-1-yl)[2-(phenylamino)pyridin-3-yl]methanone (compound 2);(5-chloro-2,3-dihydro-1H-indol-1-yl)[2-[(pyridin-2-ylmethyl)amino]pyridin-3-yl]-methanone (compound 3);(5-chloro-2,3-dihydro-1H-indol-1-yl)[2-[(2-phenylethyl)amino]pyridin-3-yl]methanone (compound 4);(5-chloro-2,3-dihydro-1H-indol-1-yl)[2-[(pyridin-3-ylmethyl)amino]pyridin-3-yl]-methanone (compound 5);(5-chloro-2,3-dihydro-1H-indol-1-yl)[2-[[2-(pyridin-2-yl)ethyl]amino]-pyridin-3-yl]- ...

Compounds, compositions and methods

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.

Il-17a modulators and uses thereof

The disclosure herein provides compounds and pharmaceutical compositions for the modulation of IL-17A useful for the treatment of inflammatory conditions, such as psoriasis.

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 122-. (canceled)23: A compound of:(a) (2R,3R)-3-{[3-(6-bromo-pyridin-3-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carbonyl]-amino}-2-hydroxy-4-phenyl-butyric acid;(b) (2R,3R)-2-hydroxy-3-[(7-methyl-2-propyl-3-pyridin-3-ylmethyl-3H-benzoimidazole-5-carbonyl)-amino]-4-phenyl-butyric acid;(c) (2R,3R)-2-hydroxy-3-[(7-methyl-2-propyl-3-pyridin-3-ylmethyl-3H-benzoimidazole-5-carbonyl)-amino]-4-phenyl-butyric acid ethyl ester;(d) (2R,3R)-3-[(3-carboxymethyl-7-methyl-2-propyl-3H-benzoimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid;(e) (2R,3R)-2-hydroxy-3-{[3-(2-methoxy-benzyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carbonyl]-amino}-4-phenyl-butyric acid;(f) (2R,3R)-2-hydroxy-3-{[3-(4-methoxy-benzyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carbonyl]-amino}-4-phenyl-butyric acid;(g) (2R,3R)-3-[(3-carbamoylmethyl-7-methyl-2-propyl-3H-benzoimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid;(h) (2R,3R)-3-[(7-chloro-2-ethyl-3H-benzoimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid;(i) (2R,3R)-3-[(7-chloro-2-ethyl-1H-benzoimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid ethyl ester;(j) (2R,3R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid;(k) (2R,3R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid ethyl ester;(l) (2R,3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid;(m) (2R,3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid ethyl ester;(n) (2R,3R)-2-hydroxy-3-[(7-methyl-3H-benzotriazole-5-carbonyl)-amino]-4-phenyl-butyric acid; 'a pharmaceutically acceptable salt thereof.', '(o) (2R,3R)-3-[(7-fluoro-1H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butyric acid; or'}24: A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.25: The pharmaceutical composition of claim 24 , further comprising an ...

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( ...

Screening methods for spinal muscular atrophy

Disclosed herein are compositions and methods for treatment of spinal muscular atrophy (SMA). In certain embodiments, compounds are provided that increase full-length survival of motor neuron (SMN) protein production by an SMN2 gene.

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula X: 29-. (canceled)1215-. (canceled)1824-. (canceled) This application claims the benefit of U.S. Provisional Application No. 61/657,220, filed on Jun. 8, 2012 and U.S. Provisional Application No. 61/774,148, filed on Mar. 7, 2013; the entire disclosures of which are incorporated herein by reference.1. Field of the InventionThe present invention relates to novel compounds which are metabolized in vivo to compounds having activity as neprilysin inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds, processes and intermediates for preparing these compounds and methods of using these compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.2. State of the ArtCommonly-assigned U.S. Patent Publication No. 2012/0157386, filed on Dec. 14, 2011 to Smith et al., describes novel compounds that have activity as neprilysin inhibitors, the disclosure of which is incorporated herein by reference. In particular, compounds of the genus:are described. Depending upon the variables, compounds within this genus can be referred to as being in the active form or as being a prodrug, which is metabolized in vivo to generate the active form of the compound.In spite of these compounds however, there remains a need for compounds and prodrugs within this genus that have different metabolic and cleavage properties. For example, there remains a need for active compounds and/or prodrug compounds having improved oral absorption and for prodrug compounds that undergo rapid cleavage to form the active compound. This invention is directed to that need.One aspect of the invention relates to a compound of the formula X:where:(i) Ris F; Ris Cl; X isandwhen X is:Ris H and Ris selected from —CHCH, —CHCH(CH), —CHCF, —(CH)CF, —CHCFCH, —CHCFCF, —C(CH)(CF), —CH(CHCH)CF, —CH(CH)CFCF, —(CH)OH, —CHCH(NH)COOCH, —(CH)OCH, —CHROC(O)—Calkyl, —CHROC(O)O— ...

COMPOUNDS, COMPOSITIONS AND METHODS

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors. 220-. (canceled)27. The compound of claim 1 , wherein Ris methyl.28. The compound of claim 1 , wherein L is absent claim 1 , —O— or —C(R)—.29. The compound of claim 28 , wherein L is —C(R)— and two Rtogether with the carbon atom to which they are attached claim 28 , form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.30. The compound of claim 1 , wherein L is —C(R)— and two Rtogether with the carbon atom to which they are attached form a cycloalkyl ring.31. The compound of claim 1 , wherein Ris optionally substituted pyridyl claim 1 , phenyl or 2 claim 1 ,3-dihydro-1H-indenyl.32. The compound of claim 1 , wherein Ris optionally substituted phenyl.33. The compound of claim 1 , wherein Ris pyridyl claim 1 , phenyl or 2 claim 1 ,3-dihydro-1H-indenyl claim 1 , each independently optionally substituted with one or two substituents selected from cyano claim 1 , halo claim 1 , optionally substituted C-Calkyl and C-Calkoxy.34. The compound of claim 1 , wherein q is 0.35. The compound of claim 1 , wherein ring A is phenyl claim 1 , benzo[d]thiazolyl claim 1 , isoxazolyl claim 1 , oxazolyl claim 1 , pyrazolyl claim 1 , triazolyl claim 1 , 5 claim 1 ,6-dihydro-4H-pyrrolo[1 claim 1 ,2-b]pyrazolyl claim 1 , pyrrolyl claim 1 , thiazolyl claim 1 , imidazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , cyclobutyl claim 1 , cyclopropyl claim 1 , or azetidinyl.36. The compound of claim 1 , wherein ring A is triazolyl.37. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.40. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.42. A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof and a pharmaceutically ...

HDAC Inhibitors and Therapeutic Methods Using the Same

Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed 135.-. (canceled)38. The method of claim 36 , wherein the HDAC is HDAC6.39. The method of claim 36 , further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.40. The method of claim 36 , wherein the disease or condition is cancer.41. The method of claim 40 , wherein the cancer is selected from a cancer disclosed in paragraphs [0137] and [0139] through [0146].42. The method of wherein the second therapeutic agent is a chemotherapeutic agent selected from an anticancer agent disclosed in paragraphs [0168] through [0172] and paragraphs [0176] through [0179].43. The method of claim 36 , wherein the disease or condition is a neurological disease claim 36 , a neurodegenerative disorder claim 36 , peripheral neuropathy claim 36 , a traumatic brain injury claim 36 , stroke claim 36 , an inflammation claim 36 , an autoimmune disease claim 36 , a parasitic infection claim 36 , autism claim 36 , or an autism spectrum disorder.44. The method of claim 43 , wherein the disease or condition is a neurological disease claim 43 , a neurodegenerative disorder claim 43 , peripheral neuropathy claim 43 , or a traumatic brain injury claim 43 , and is selected from a disease or condition disclosed in paragraphs [0186] through [0191] herein.45. The method of claim 43 , wherein the disease or condition is an autoimmune disease or inflammation claim 43 , and is selected from a condition disclosed in paragraphs [0208] and [0209].46. The method of claim 43 , wherein the disease or ...

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula I: where R 1 -R 6 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 these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

Isoxazole Hydroxamic Acids As Histone Deacetylase 6 Inhibitors

The present disclosure provides compounds represented by Formula (I): and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof wherein X and n are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat diseases and conditions, e.g., cancer, wherein inhibition of HDAC provides a benefit. 210-. (canceled)12. The compound of claim 11 , or a pharmaceutically acceptable salt claim 11 , solvate claim 11 , or prodrug thereof claim 11 , wherein R claim 11 , R claim 11 , R claim 11 , Rand Rare each independently selected from the group consisting of hydrogen claim 11 , halogen claim 11 , hydroxy claim 11 , nitro claim 11 , cyano claim 11 , —NRR claim 11 , —C(═O)NRR claim 11 , —C(═O)R claim 11 , Calkyl claim 11 , Calkoxy claim 11 , and Chaloalkyl.13. The compound of claim 12 , or a pharmaceutically acceptable salt claim 12 , solvate claim 12 , or prodrug thereof claim 12 , wherein R claim 12 , R claim 12 , R claim 12 , R claim 12 , and Rare each independently selected from the group consisting of hydrogen claim 12 , halogen claim 12 , cyano claim 12 , Calkyl claim 12 , and Calkoxy.1421-. (canceled)22. The compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , or prodrug thereof claim 1 , selected from the group consisting of:5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide;5-(2-(3,4-dichlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;5-(2-([1,1′-biphenyl]-3-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;5-(4-(5,6-dichloro-1H-indol-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;5-(4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;5-(3-(3,4-dichlorophenoxy)propyl)-N-hydroxyisoxazole-3-carboxamide;5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepin ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula XII: 128-. (canceled)30. The compound or salt of claim 29 , wherein the compound is a compound of Formula (1).31. The compound or salt of claim 29 , wherein the compound is a compound of Formula (2).32. The compound or salt of claim 29 , wherein the compound is a compound of Formula (3).33. The compound or salt of claim 29 , wherein the compound is a compound of Formula (4).36. The method of claim 35 , further comprising contacting the compound of Formula (2) with sodium hydride prior to the contacting of (ii).37. The method of claim 35 , further comprising purifying the compound of Formula (3).39. The method of claim 38 , further comprising contacting the compound of Formula (3) with sodium hexamethyldisilazide prior to the contacting of (iii).40. The method of claim 38 , further comprising purifying the compound of Formula (4).43. The method of claim 42 , further comprising contacting the compound of Formula (3) with sodium hexamethyldisilazide prior to the contacting of (iii).44. The method of claim 42 , further comprising purifying the compound of Formula (4).47. The method of claim 46 , further comprising contacting the compound of Formula (2) with sodium hydride prior to the contacting of (ii).48. The method of claim 46 , further comprising purifying the compound of Formula (3). This application claims the benefit of U.S. Provisional Application No. 61/657,229, filed on Jun. 8, 2012 and U.S. Provisional Application No. 61/773,969, filed on Mar. 7, 2013; the entire disclosures of which are incorporated herein by reference.The present invention relates to novel compounds which are metabolized in vivo to compounds having activity as neprilysin inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds, processes and intermediates for preparing these compounds and methods of using these compounds to treat diseases such as hypertension, heart failure, ...

METHANETHIONE COMPOUNDS HAVING ANTIVIRAL ACTIVITY

A compound of formula (I) is useful as an antiviral agent, in particular for the treatment of influenza. A method for preparing the compound of formula (I) and a composition including the compound of formula (I) are described. 127-. (canceled)29. The compound according to claim 28 , wherein each Ris independently selected from C1-C6 alkyl; OH; halogen; and RRN;{'sup': '2', 'Ris selected from H and C1-C6 alkyl;'}{'sup': '3', 'each Ris independently selected from C1-C6 alkyl;'}{'sup': '4', 'sub': '2', 'each Ris independently selected from NO; halogen; and C1-C6 alkyl;'}{'sup': 5', '6, 'each Rand Ris independently selected from H and C1-C6 alkyl;'}wherein any alkyl is optionally substituted with one or several halogen atoms;or a pharmaceutically acceptable salt thereof.30. The compound according to claim 28 , wherein any C1-C6 alkyl moiety is selected from C1-C3 alkyl;or a pharmaceutically acceptable salt thereof.31. The compound according to claim 30 , wherein any C1-C6 alkyl moiety is methyl;or a pharmaceutically acceptable salt thereof.32. The compound according to claim 28 , wherein n is 0 claim 28 , or a pharmaceutically acceptable salt thereof.33. The compound according to claim 28 , wherein m is 0 claim 28 , or a pharmaceutically acceptable salt thereof.34. The compound according to claim 28 , wherein U is C claim 28 , or a pharmaceutically acceptable salt thereof.35. The compound according to claim 28 , wherein Y is N claim 28 , or a pharmaceutically acceptable salt thereof.36. The compound according to claim 28 , wherein Y is NH claim 28 , or a pharmaceutically acceptable salt thereof.37. The compound according to claim 28 , wherein Y is O claim 28 , or a pharmaceutically acceptable salt thereof.38. The compound according to claim 28 , wherein X is N claim 28 , or a pharmaceutically acceptable salt thereof.39. The compound according to claim 28 , wherein X is NH claim 28 , or a pharmaceutically acceptable salt thereof.40. The compound according to claim 28 , ...

Substituted Acyloxyamidines as HCV NS3/4A Inhibitors

Disclosed herein is a compound of Formula I 3. The compound claim 1 , according to claim 1 , in which A is{'sub': 1', '7, '1) C-Calkyl,'}{'sub': 3', '7, '2) C-Calkyl,'}{'sub': 1', '7', 'n, '3) C-Calkyl-(aryl),'}{'sup': 3', '4, '4) (R)(R)C,'}{'sup': 5', '6', '7, '5) (R)(R)(R)C,'}6) aryl,7) heteroaryl,8) heterocyclyl, or9) biphenyl,{'sup': 10', '10, 'wherein the aryl is substituted with one or more Rsubstituents and the biphenyl is optionally substituted with one or more Rsubstituents;'}{'sup': '20', 'wherein the heteroaryl is substituted with one or more Rsubstituents; and'}{'sub': 1', '7', '1', '7, 'sup': '10', 'wherein the heterocyclyl is optionally substituted with C-Calkyl, aryl C-Calkyl, the aryl moiety being optionally substituted with one or more Rsubstituents.'}4. The compound claim 1 , according to claim 1 , in which G is1) aryl,{'sub': 1', '7, '2) C-Calkyl-aryl,'}3) heteroaryl, or{'sub': 1', '7, '4) C-Calkyl-heteroaryl,'}{'sup': '40', 'wherein the aryl and the heteroaryl are substituted with one or more Rsubstituents.'}5. The compound claim 1 , according to claim 1 , in which Rand Rare each independently1) H,{'sub': 1', '7, '2) C-Calkyl,'}{'sub': 3', '7, '3) C-Ccycloalkyl,'}4) aryl,5) heteroaryl, or{'sub': '2', '6) CH-heteroaryl,'}{'sup': 11', '20, 'wherein the aryl is optionally substituted with one or more Rsubstituents, and wherein the heteroaryl is optionally substituted with one or more Rsubstituents; or'}{'sup': 1', '2, 'when Ris H, Ris covalently bonded to G to form a 3 to 7-membered heterocycle containing one or more heteroatoms selected from N, S or O.'}6. The compound claim 1 , according to claim 1 , in which claim 1 , R claim 1 , Rwhen covalently bonded together form C-Ccycloalkyl or a heterocycle containing N or O heteroatoms optionally substituted with one or more Rsubstituents.7. The compound claim 1 , according to claim 1 , in which RRand Rare each independently{'sub': 1', '7, '1) C-Calkyl,'}{'sub': 3', '7, '2) C-Ccycloalkyl, or'}{'sup': 'X', ...

BENZYLAMINE DERIVATIVES AS INHIBITORS OF PLASMA KALLIKREIN

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein Rto Rare as defined herein. 2. A compound of claim 1 , wherein Ris phenyl or naphthyl claim 1 , wherein phenyl may be optionally substituted with up to 3 substituents independently selected from alkyl claim 1 , alkoxy claim 1 , OH claim 1 , halo claim 1 , CN claim 1 , COOR claim 1 , CFand NRR.3. A compound of claim 1 , wherein Ris phenyl claim 1 , 1-naphthalene claim 1 , 2 claim 1 ,4-dichlorophenyl claim 1 , 3 claim 1 ,4-dichlorophenyl claim 1 , 3 claim 1 ,4-difluorophenyl claim 1 , 4-chlorophenyl claim 1 , 4-trifluoromethylphenyl claim 1 , or 4-ethoxyphenyl.4. A compound of claim 1 , wherein Ris H claim 1 , —COaryl claim 1 , —COalkyl claim 1 , —CHCOOH claim 1 , —SOPh claim 1 , or —SOCH.5. A compound of claim 1 , wherein Ris —COalkyl or —COaryl.7. A compound of claim 1 , wherein Rand Rare independently H or CH.8. A compound of claim 1 , wherein the stereochemical configuration about chiral centre *1 is R.9. A compound of claim 1 , wherein the stereochemical configuration about chiral centre *2 is S.10. A compound of claim 1 , wherein a is 2 and b claim 1 , c claim 1 , d claim 1 , e claim 1 , f claim 1 , g claim 1 , h claim 1 , j claim 1 , l and m are each 1.11. A compound as claimed in claim 1 , the compound being:(S)—N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide;N—[(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide;{(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid;(S)—N-(4-Aminomethyl-3-fluoro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide ...

Substituted Cyclohexylamine Compounds

The present disclosure provides substituted cyclohexylamine compounds having Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein R, R, R, R, R, R, R, and Rare 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 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein R claim 1 , R claim 1 , R claim 1 , and Rare hydrogen.5. The compound of claim 1 , or a pharmaceutical acceptable salt or solvate thereof claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , and benzyl.6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , and benzyl.7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —C(═O)R.8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —S(═O)R.11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris Calkyl.12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris hydrogen.13. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris selected from the group consisting of —CHCHOH claim 1 , —CHCHNH claim 1 , —CHCHCHOH claim 1 , and —CHCHCHNH.1416-. (canceled)17. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris ethyl.18. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris cyclopropyl.19. (canceled)20. A pharmaceutical composition comprising the compound ...

AMIDE DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND USE THEREOF AS INSECTICIDE

An object of the present invention is to provide a compound represented by Formula (1): 114-. (canceled) The present invention relates to a compound represented by Formula (1):wherein A, A, Aand Aeach represent a carbon atom, a nitrogen atom or an oxidized nitrogen atom;Rand Reach represent a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C1-C4 alkylcarbonyl group;Gand Geach represent an oxygen atom or a sulfur atom;X, which may be identical or different, represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a trifluoromethyl group;n is an integer of 0 to 4; andQand Qeach represent an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heterocyclic group,an insecticide comprising the compound as the active ingredient, and a process for preparation thereof and use thereof.International Publication WO 2000/55120 and U.S. Pat. No. 6,548,514 describe a compound similar to the compound of the present invention for the use as medicament, but they do not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.International Publication WO 2000/7980 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.US Patent Laid-Open No. 2002-032238 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.The object of the present invention is to provide a pesticide having a high insecticidal efficacy. Another object of the present invention is to provide a compound represented by Formula (1), a process for ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula I: 122-. (canceled)2427-. (canceled) This application claims the benefit of U.S. Provisional Application No. 61/933,406 filed on Jan. 30, 2014 and U.S. Provisional Application No. 62/016,742 filed on Jun. 25, 2014; the entire disclosures of which are incorporated herein by reference.Field of the InventionThe present invention relates to novel compounds having neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising these compounds, processes and intermediates for preparing these compounds and methods of using these compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.State of the ArtNeprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Znmetallopeptidase 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 enzyme (ACE) are also known, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopeptidase inhibitors, this latter class of compounds is described in Robl et al. (1999) 9(12): 1665-1677.In spite of these compounds however, there remains a need for NEP inhibitors that have improved potency, different metabolic and cleavage properties, and/or having improved oral absorption. This ...

6-AMINO-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL OR 3-AMINOCHROMAN-7-YL DERIVATIVES

The present invention relates to compounds TAAR receptor antagonists of formula I wherein X, R, L, Ar and Rare as described herein, compositions containing compounds of formula I, methods of manufacture of compounds of formula I and methods of treating psychiatric disorders with compounds of formula I. 2. The compound according to wherein L is —C(O)NH—.3. The compound according to claim 2 , said compound selected from the group consisting of:N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)isonicotinamide;N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-bromo-5-cyclopropyl-1H-pyrazole-3-carboxamide;N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-methyl-2-(trifluoromethyl)-pyrimidine-4-carboxamide;(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-methyl-2-(trifluoromethyl)-pyrimidine-4-carboxamide;N-(3-aminochroman-7-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;N-(3-aminochroman-7-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;(R)—N-(3-aminochroman-7-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;(S)—N-(3-aminochroman-7-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;(R)—N-(3-aminochroman-7-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;(S)—N-(3-aminochroman-7-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-chlorobenzamide;(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-chlorobenzamide;(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-methylisonicotinamide;(S)-2-acetamido-N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)isonicotinamide;(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-ethoxyisonicotinamide;(S ...

GLYCOLATE OXIDASE INHIBITORS AND USE THEREOF

The present invention provides pyrazoles, isoxazoles, isothiazoles, thiadiazoles, and pyridazines according to Formula I as described herein, and pharmaceutically acceptable salts thereof. Pharmaceutical compositions and methods for treating primary hyperoxaluria, type I (PH) and kidney stones are also described. 3. (canceled)57-. (canceled)8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein W is —NR—.913-. (canceled)14. The compound of claim 8 , or a pharmaceutically acceptable salt thereof claim 8 , wherein:subscript n is 1;{'sup': 1', '1a, 'sub': '6-10', 'Ris selected from the group consisting of heteroaryl and -L-(Caryl), wherein aryl is substituted with R;'}{'sup': '1a', 'Ris selected from the group consisting of halo, cyano, and -M-heterocyclyl, heterocyclyl is optionally substituted with one or more amine protecting groups,'}{'sub': '1-6', 'L is selected from the group consisting of a bond, —O—, and Calkylene, and'}M is 2- to 6-membered heteroalkylene.1517-. (canceled)18. The compound of claim 8 , or a pharmaceutically acceptable salt thereof claim 8 , wherein:subscript n is 1{'sup': '1', 'Ris halo;'}{'sup': 3', '3a, 'sub': '7-16', 'Ris Carylalkyl substituted with R; and'}{'sup': '3a', 'Ris halo.'}1920-. (canceled)21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein each Y is independently selected from the group consisting of —O— and —CHR—.22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , Ris independently selected from the group consisting of halo claim 1 , cyano claim 1 , -M-(8- to 12-membered heterocyclyl) claim 1 , -M-(5- to 6-membered heteroaryl) claim 1 , -M-(Ccycloalkyl) claim 1 , and -M-(Caryl) claim 1 , wherein heterocyclyl claim 1 , heteroaryl claim 1 , cycloalkyl claim 1 , and aryl are optionally substituted with R.23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein L claim 1 , M claim 1 , ...

PROTEASOME INHIBITORS AND USES THEREOF

The compounds of the present invention are represented by the following compounds having Formula (I): 153.-. (canceled) This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 62/242,139 filed Oct. 15, 2015, which is hereby incorporated by reference in its entirety.The present invention relates to proteasome inhibitors and uses thereof.Proteasomes are highly conserved self-compartmentalizing proteases found in three kingdoms of life. A proteasome is a large, ATP-dependent, multi-subunit, barrel-shaped N-terminal nucleophile hydrolase present in the cytosol and nucleus of eukaryotic cells and is responsible for the degradation of the majority of cellular proteins (Baumeister et al., “The Proteasome: Paradigm of a Self-Compartmentalizing Protease,” 92(3):367-380 (1998); Goldberg A L., “Functions of the Proteasome:from Protein Degradation and Immune Surveillance to Cancer Therapy,” 35(Pt 1):12-17 (2007)). Through regulated degradation, a proteasome regulates protein homeostasis, the cell cycle, signal transduction, protein trafficking, immune responses, etc, which are important cellular functions. Degradation product oligopeptides are reservoirs of antigenic peptides for MHC class I antigen presentation.Proteasome inhibition interrupts many cellular pathways, particularly, the NF-kB activation pathway, the induction of unfolded protein response, and ER stress, while strongly inducing apoptosis. For this reason, highly specific proteasome inhibitors have been approved for the treatment of hematological cancer. Proteasome inhibitors can also markedly limit the overall supply of peptides for MHC class I molecules and thus block antigen presentation (Rock et al., “Protein Degradation and the Generation of MHC Class I-Presented Peptides,” 80:1-70 (2002)). As a result, proteasome inhibitors reduce immune response via multiple routes.: (), the most deadly of the human malarias, accounts for nearly 0.5 million deaths a year, primarily in ...

MODULATORS OF THE RELAXIN RECEPTOR 1

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R, and Rare as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1. 120-. (canceled)21. A method for therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1 claim 104 , the method comprising administering to a mammal in need thereof an effective amount of a compound or salt of .2239-. (canceled)40. The method of claim 21 , whereinthe facet of mammalian health is cardiovascular disease.41. The method of claim 40 , wherein the cardiovascular disease is selected from myocardial ischemia-reperfusion injury claim 40 , cardiac fibrosis claim 40 , acute congestive heart failure claim 40 , cerebrovascular disease and stroke claim 40 , post-infarction heart claim 40 , cardiac anaphylaxis claim 40 , cerebral ischemia (stroke) claim 40 , intestinal ischemia-reperfusion injury claim 40 , systemic and pulmonary hypertension claim 40 , vascular inflammation claim 40 , hypertension claim 40 , high blood pressure; left ventricular hypertrophy (LVH); vasodilation; renal hypertension; diuresis; nephritis; natriuresis; scleroderma renal crisis; angina pectoris (stable and unstable); myocardial infarction; heart attack; coronary artery disease; coronary heart disease; cardiac arrhythmias; atrial fibrillation; portal hypertension; raised intraocular pressure; vascular restenosis; chronic hypertension; valvular disease; myocardial ischemia; acute pulmonary edema; acute coronary syndrome; hypertensive retinopathy; hypertensive pregnancy sickness; Raynaud's phenomenon; erectile dysfunction claim 40 , glaucoma claim 40 , ...

13-OXIDIZED INGENOL DERIVATIVE AND USE THEREOF

The present invention relates to a derivative of 13-oxidized ingenol, use thereof in the prevention and/or treatment of a disease associated with proliferation or tumor in a subject, or a cosmetic indication, and use thereof in the prevention and/or treatment of a disease responsive to neutrophil oxidative burst, a disease responsive to a release of IL-8 by keratinocyte, or a disease responsive to induction of necrosis. 2. The compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , prodrug claim 1 , metabolite or crystal form thereof claim 1 , wherein Ris selected from the group consisting of hydrogen and M-C(O)— claim 1 , wherein M is selected from the group consisting of linear alkyl and C-Clinear alkenyl.3. The compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , prodrug claim 1 , metabolite or crystal form thereof claim 1 , wherein claim 1 , Ris selected from the group consisting of hydrogen and Q-C(O)— claim 1 , wherein Q is selected from the group consisting of C-Clinear alkyl claim 1 , C-Cbranched alkyl claim 1 , C-Clinear alkenyl claim 1 , C-Cbranched alkenyl claim 1 , 5-6 membered cycloalkyl claim 1 , phenyl claim 1 , 5-6 membered nitrogen-containing aliphatic heterocyclic group claim 1 , 5-6 membered heteroaryl claim 1 , 8-10 membered partially saturated nitrogen-containing fused heterocyclic group claim 1 , and NR′R″ claim 1 , wherein claim 1 , R′ is methyl group claim 1 , R″ is phenyl group optionally substituted with halogen(s); and in the 5-6 membered heteroaryl group claim 1 , the heteroatom is selected from the group consisting of nitrogen and oxygen;{'sub': 1', '5', '4', '5', '3', '5', '3', '5, 'optionally, the C-Clinear alkyl group, C-Cbranched alkyl group, C-Clinear alkenyl group or C-Cbranched alkenyl group is independently substituted with one or more phenyl groups, wherein the phenyl group is optionally substituted with methyl group(s);'}{'sub': 2', '3', '2, 'optionally, the 5-6 ...

SULFONAMIDE DERIVATIVE HAVING PGD2 RECEPTOR ANTAGONISTIC ACTIVITY

The present invention provides an sulfonamide derivative having DP receptor antagonistic activity and a pharmaceutical composition comprising the said compound as an active ingredient, and further a therapeutic agent for treating allergic diseases. 140-. (canceled)42. The compound according to claim 41 ,{'sup': '2C', 'wherein Ris heteroaryl optionally substituted with a substituent group selected from the group consisting of alkyl, alkenyl and alkynyl,'}or a pharmaceutically acceptable salt thereof. This invention relates to a sulfonamide derivative having DP receptor antagonistic activity and a medicinal use thereof.Prostaglandin D2(PGD2) is a metabolic product of arachidonic acid through PGG2 and PGH2, and known to have various potent physiological activities. For example, in non-patent literature 1 it is described that PGD2 is involved in sleeping and secretion of hormones in central nervous system, and in inhibiting activity of platelet aggregation, contraction of bronchial smooth muscle, vasodilation and constriction of a blood vessel etc. in peripheral system. Moreover, PGD2 is considered to be involved in forming pathological condition of an allergic disease such as bronchial asthma since it is a major metabolic product of arachidonic acid produced from a mast cell, and has a potent bronchoconstricting effect, causing an increase of vascular permeability and migration of inflammatory cell such as eosinophils.A DP receptor (also called DP1 receptor) or CRTH2 receptor (also called DP2 receptor) is known as a receptor of PGD2. A phenylacetic acid derivative having a DP receptor antagonistic activity is disclosed in Patent literature 1, a sulfonamide derivative having a CRTH2 receptor antagonistic activity is disclosed in Patent literature 2 and a phenoxyacetic acid derivative having a CRTH2 receptor antagonistic activity is disclosed in Patent literatures 3-6.Also, sulfonamide derivatives having an activity other than the PGD2 receptor antagonistic activity are ...

LIGANDS FOR ANTIBODY AND Fc-FUSION PROTEIN PURIFICATION BY AFFINITY CHROMATOGRAPHY

The present invention relates to the use for affinity purification of an antibody or a fragment of an antibody, of a ligand-substituted matrix comprising a support material and at least one ligand covalently bonded to the support material. 115-. (canceled)17. The use of claim 16 , wherein Aris phenylene claim 16 , preferably methoxy-substituted phenylene.18. The use of claim 16 , wherein the C═O and the NH group are bonded to Arin meta position to each other.19. The use of claim 16 , wherein the 5- or 6-membered heterocyclic aromatic ring of Aris attached to the C═O group via a carbon ring atom which is adjacent to a ring heteroatom claim 16 , preferably a nitrogen or oxygen atom.20. The use of claim 16 , wherein the 5- or 6-membered heterocyclic aromatic ring of Arcontains two or more nitrogen atoms or one or more nitrogen atoms and an oxygen atom.21. The use of claim 20 , wherein the 5- or 6-membered heterocyclic aromatic ring of Aris N-methyl-substituted pyrazole claim 20 , pyridine claim 20 , isoxazole or oxadiazole.22. The use according to claim 16 , wherein the support material comprises a material selected from carbohydrates or crosslinked carbohydrates claim 16 , preferably agarose claim 16 , cellulose claim 16 , dextran claim 16 , starch claim 16 , alginate and carrageenan claim 16 , Sepharose claim 16 , Sephadex; synthetic polymers claim 16 , preferably polystyrene claim 16 , styrene-divinylbenzene copolymers claim 16 , polyacrylates claim 16 , PEG-Polyacrylate copolymers polymethacrylates claim 16 , polyvinyl alcohol claim 16 , polyamides and perfluorocarbons; inorganic materials claim 16 , preferably glass claim 16 , silica and metal oxides; and composite materials.23. The use according to claim 16 , wherein the protein is an antibody claim 16 , preferably an IgG type antibody claim 16 , or an Fc fusion protein.24. The use of claim 23 , wherein the purification is attained by binding of the ligand of the ligand-substituted matrix to an Fc fragment or ...

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 128.-. (canceled)29. A method of treating a disease mediated , at least in part by , neprilysin in a subject in need thereof , comprising administering to the subject an effective amount of a compound selected from:(a) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid ethyl ester;(b) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid;(c) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;(d) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-methoxyisoxazole-5-carbonyl)amino]-pentanoic acid;(e) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(4-chlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(f) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(2-methoxy-benzoylamino)-isoxazole-5-carbonyl]-amino}-pentanoic acid;(g) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2-chlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(h) (2R,4R)-5-Biphenyl-4-yl-4-[(3-cyclohexyl-isoxazole-5-carbonyl)-amino]-2-hydroxy-pentanoic acid;(i) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(3-fluorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(j) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2-fluorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(k) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(1-methyl-1H-pyrazol-4-yl)-isoxazole-5-carbonyl]-amino}-pentanoic acid;(l) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2,5-dichlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(m) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(3,4-dichlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;(n) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(2-methoxy-phenyl)-isoxazole-5-carbonyl]-amino}-pentanoic acid;(o) 5-((1R,3R)-1-Biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl)-isoxazole-3-carboxylic acid;(p) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(2-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;(q) ( ...

ISOXAZOLE CARBOXAMIDE COMPOUNDS

The present disclosure provides substituted isoxazole carboxamide compounds having Formula (1) and the pharmaceutically acceptable salts and solvates thereof, wherein R, R, A, X, 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. 2. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is Calkylenyl.4. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is optionally substituted Carylenyl.7. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is optionally substituted Ccycloalkylenyl.9. (canceled)10. (canceled)11. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is —C(H)RR.1214-. (canceled)16. (canceled)18. The compound of claim 17 , or a pharmaceutically acceptable salt or hydrate thereof claim 17 , wherein:{'sup': 7', '7, 'sub': '2', 'X is selected from the group consisting of —C(═O)N(R)— and —S(═O)N(R)—;'}{'sub': 1-6', '6-14', '3-12, 'Z is optionally substituted Calkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted Caryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted Ccycloalkyl, aralkyl, and (heteroaryl)alkyl; and'}{'sup': '12', 'Ris hydrogen.'}19. (canceled)2124-. (canceled)25. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris selected from the group consisting of Calkyl and Ccycloalkyl.26. The compound of claim 25 , or a pharmaceutically acceptable salt or solvate thereof claim ...

AMINO ACID TRANSPORT INHIBITORS AND THE USES THEREOF

These compounds are glutamine transporter inhibitors, e.g., alanine, serine, cysteine-preferring transporter 2 (ASCT2) inhibitors. Glutamine transporter inhibitors are useful to treat a variety of diseases, disorders, or conditions including cancer. 4. The compound of claim 1 , wherein Ris optionally substituted heteroaryl claim 1 , or a pharmaceutically acceptable salt or solvate thereof.5. The compound of claim 1 , wherein Ris optionally substituted aryl claim 1 , or a pharmaceutically acceptable salt or solvate thereof.7. The compound of claim 6 , wherein R claim 6 , R claim 6 , R claim 6 , R claim 6 , R claim 6 , and Rare each hydrogen claim 6 , or a pharmaceutically acceptable salt or solvate thereof.8. The compound of claim 1 , wherein Q is Q-1 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.10. The compound of claim 1 , wherein Q is Q-2 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.12. The compound of claim 1 , wherein Q is Q-3 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.14. The compound of claim 1 , wherein Q is Q-4 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.16. The compound of claim 1 , wherein Q is Q-5 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.18. The compound of claim 1 , wherein R is hydrogen claim 1 , or a pharmaceutically acceptable salt or solvate thereof.19. The compound of selected from the group consisting of:5-([1,1′-biphenyl]-4-yl)-1H-indole-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)benzofuran-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)benzo[b]thiophene-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazole-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)benzo[d]oxazole-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)benzo[d]thiazole-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)furo[3,2-b]pyridine-2-carboxylic acid;5-([1,1′-biphenyl]-4-yl)thieno[3,2-b]pyridine-2-carboxylic ...

CRYSTALLINE (2S,4R)-5-(5'-CHLORO-2'-FLUORO-[1,1'-BIPHENYL]-4-YL)-2-(ETHOXYMETHYL)-4-(3-HYDROXYISOXAZOLE-5-CARBOXAMIDO)-2-METHYLPENTANOIC ACID AND USES THEREOF

In one aspect, the invention relates to a crystalline form of the structure: 124-. (canceled)25. A process for preparing (2S ,4R)-5-(5′-chloro-2′-fluoro-[1 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I) , the process comprising:(a) coupling benzyl (2S,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride with 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid in a solvent in approximately a 1:1 molar ratio to give benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate; and(b) deprotecting benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate to form (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I).26. The process of claim 25 , wherein (a) further comprises a peptide coupling agent and a base in approximately a 1:3:1:1 molar ratio of coupling agent to base to benzyl (2S claim 25 ,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1 claim 25 ,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride to 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid.27. The process of claim 26 , wherein the coupling agent is 2-(6-chloro-1H-benzo[d][1 claim 26 ,2 claim 26 ,3]triazol-1-yl)-1 claim 26 ,1 claim 26 ,3 claim 26 ,3-tetramethyluronium hexafluorophosphate(V) and the base is N claim 26 ,N-diisopropylethylamine.28. The process of claim 25 , wherein (b) is performed with a palladium catalyst and hydrogen gas.2936-. (canceled)37. The process of claim 25 , wherein (a) further comprises a peptide coupling agent.38. The process of claim 37 , wherein the peptide coupling agent is selected from O-(benzotriazol-1-yl)-N claim 37 ,N claim 37 ,N′ claim 37 ,N′-tetramethyluronium hexafluorophosphate claim 37 , O-( ...

Compounds and methods

The present invention relates to novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.

Isoxazole Carboxamide Compounds

The present disclosure provides substituted isoxazole carboxamide compounds having Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R, R, A, X, 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. 2. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is Calkylenyl.4. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is optionally substituted Carylenyl.7. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is optionally substituted Ccycloalkylenyl.9. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is optionally substituted 4- to 14-membered heterocyclenyl.11. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof claim 1 , wherein A is —C(H)RR.12. The compound of claim 11 , wherein Ris selected from the group consisting of Calkyl and optionally substituted Ccycloalkyl; and Ris optionally substituted Caryl.13. The compound of claim 11 , or a pharmaceutically acceptable salt or hydrate thereof claim 11 , wherein Ris optionally substituted 4- to 14-membered heterocyclo.14. The compound of claim 13 , or a pharmaceutically acceptable salt or hydrate thereof claim 13 , wherein Ris Calkyl claim 13 , hydroxyalkyl claim 13 , alkoxyalkyl claim 13 , alkoxycarbonyl claim 13 , optionally substituted Caryl claim 13 , and aralkyl.16. The compound of claim 13 , or a pharmaceutically acceptable salt or hydrate thereof claim 13 , wherein Ris selected from the group consisting of hydrogen and methyl.18. The compound of claim 17 , or a pharmaceutically acceptable salt or hydrate ...

Neprilysin inhibitors

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

NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula I: 2. The compound of claim 1 , where Ris H claim 1 , —CHCH claim 1 , —CH(CH) claim 1 , —(CH)CH claim 1 , or —(CH)CH.7. The compound of claim 1 , where Ris H or Cl.8. The compound of claim 1 , where Ris H or F.9. The compound of claim 1 , where Ris H or Cl.10. The compound of claim 1 , where Ris H claim 1 , Ris F claim 1 , and Ris Cl; or Rand Rare H and Ris Br or Cl; or R claim 1 , R claim 1 , and Rare H; or Ris Cl claim 1 , Ris F claim 1 , and Ris Cl; or Ris H claim 1 , Ris F claim 1 , and Ris H.11. The compound of claim 10 , where Ris H claim 10 , Ris F claim 10 , and Ris Cl; or Rand Rare H and Ris Cl; or R claim 10 , R claim 10 , and Rare H; or Ris Cl claim 10 , Ris F claim 10 , and Ris Cl; or Ris H claim 10 , Ris F claim 10 , and Ris H.12. The compound of claim 1 , where Ris 3H-oxazol-2-one claim 1 , 4H-[1 claim 1 ,2 claim 1 ,4]oxadiazol-5-one claim 1 , [1 claim 1 ,2 claim 1 ,3 claim 1 ,5]oxatriazole claim 1 , [1 claim 1 ,2 claim 1 ,4]triazolo[1 claim 1 ,5-α]pyridine claim 1 , [1 claim 1 ,2 claim 1 ,3]triazole claim 1 , [1 claim 1 ,2 claim 1 ,4]triazole claim 1 , pyrazole claim 1 , imidazole claim 1 , oxazole claim 1 , isoxazole claim 1 , isothiazole claim 1 , pyridine claim 1 , oxadiazole claim 1 , or pyrimidine.13. The compound of claim 12 , where Ris 3H-oxazol-2-one claim 12 , 4H-[1 claim 12 ,2 claim 12 ,4]oxadiazol-5-one claim 12 , [1 claim 12 ,2 claim 12 ,4]triazolo[1 claim 12 ,5-α]pyridine claim 12 , [1 claim 12 ,2 claim 12 ,3]triazole claim 12 , [1 claim 12 ,2 claim 12 ,4]triazole claim 12 , pyrazole claim 12 , oxazole claim 12 , isoxazole claim 12 , isothiazole claim 12 , pyridine claim 12 , or pyrimidine.14. The compound of claim 1 , where the nitrogen atoms in the heterocycle are unsubstituted.15. The compound of claim 1 , where Ris —OH claim 1 , —(CH)OH claim 1 , —OCH claim 1 , —OCHCH claim 1 , —CH claim 1 , —CHF claim 1 , or —CF.16. The compound of claim 1 , where Ris phenyl.17. The ...

COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY

The present disclosure is directed to disclosed compounds that increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. 135.-. (canceled)37. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier or excipient.38. The pharmaceutical composition of claim 37 , wherein the composition further comprises at least one additional CFTR modulator.39. The pharmaceutical composition of claim 37 , wherein the composition further comprises at least two additional CFTR modulators.40. A method of enhancing cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof comprising administering to said subject an effective amount of a compound of .41. The method of claim 40 , wherein the activity of a mutant CFTR is enhanced.42. The method of claim 41 , wherein the mutant CFTR is selected from the group consisting ΔF508 claim 41 , S549N claim 41 , G542X claim 41 , G551D claim 41 , R117H claim 41 , N1303K claim 41 , W1282X claim 41 , R553X claim 41 , 621+1G>T claim 41 , 1717-1G>A claim 41 , 3849+10kbC>T claim 41 , 2789+5G>A claim 41 , 3120+1G>A claim 41 , I507del claim 41 , R1162X claim 41 , 1898+1G>A claim 41 , 3659delC claim 41 , G85E claim 41 , D1152H claim 41 , R560T claim 41 , R347P claim 41 , 2184insA claim 41 , A455E claim 41 , R334W claim 41 , Q493X claim 41 , and 2184delA CFTR.43. The method of claim 42 , wherein ΔF508 CFTR activity is enhanced.44. The method of claim 40 , wherein the subject is suffering from a disease associated with decreased CFTR activity.45. The method of claim 44 , wherein the disease is selected from the group consisting of cystic fibrosis claim 44 , congenital bilateral absence of vas deferens (CBAVD) claim 44 , acute claim 44 , recurrent claim 44 , or chronic pancreatitis claim 44 , disseminated bronchiectasis claim 44 , asthma claim 44 , allergic pulmonary aspergillosis claim 44 , chronic obstructive ...

AMIDE DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND USE THEREOF AS INSECTICIDE

A compound represented by Formula (1): 114-. (canceled) The present invention relates to a compound represented by Formula (1):wherein A, A, Aand Aeach represent a carbon atom, a nitrogen atom or an oxidized nitrogen atom;Rand Reach represent a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C1-C4 alkylcarbonyl group;Gand Geach represent an oxygen atom or a sulfur atom;X, which may be identical or different, represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a trifluoromethyl group;n is an integer of 0 to 4; andQand Qeach represent an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heterocyclic group,an insecticide comprising the compound as the active ingredient, and a process for preparation thereof and use thereof.International Publication WO 2000/55120 and U.S. Pat. No. 6,548,514 describe a compound similar to the compound of the present invention for the use as medicament, but they do not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.International Publication WO 2000/7980 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.US Patent Laid-Open No. 2002-032238 describes a compound similar to the compound of the present invention for the use as medicament, but it does not describe on the insecticidal activity of the compound. The compound clearly does not fall within the scope of claims of the present invention.The object of the present invention is to provide a pesticide having a high insecticidal efficacy. Another object of the present invention is to provide a compound represented by Formula (1), a process for preparation of the compound, an insecticide ...

Ingenol-3-acylates iii and ingenol-3-carbamates

The invention relates to compounds of general formula I wherein R is heteroaryl optionally substituted by R7; or R is heterocycloalkyl or heterocycloalkenyl, optionally substituted by R8; or R is X wherein X is —NR11R12; and pharmaceutically acceptable salts, hydrates, or solvates thereof, for use—alone or in combination with one or more other pharmaceutically active compounds—in therapy, for preventing, treating or ameliorating diseases or conditions responsive to stimulation of neutrophil oxidative burst, responsive to stimulation of keratinocyte IL-8 release or responsive to induction of necrosis.

PROCESS FOR THE PREPARATION OF ISOCARBOXAZID

This invention relates to a novel chemical process for the synthesis of N′-benzyl-5-methylisoxazole-3-carbohydrazide (Isocarboxazid) which comprises reacting 5-methyl-3-isoxazole carboxylic acid ester with benzylhydrazine or a salt thereof in an aprotic organic solvent and in the presence of an organic base. 2. The process according to claim 1 , further comprisingb) isolating the material as Isocaboxazid (I) and optionallyc) re-crystallizing the isolated Isocaboxazid (I) obtained in step (b).3. The process according to claim 1 , wherein R in formula (II) is methyl.4. The process according to claim 1 , wherein the aprotic solvent is toluene claim 1 , heptane claim 1 , cyclohexane claim 1 , isopropyl acetate or a mixture thereof.5. The process according to claim 1 , wherein the organic base is triethylamine.6. The process according to claim 1 , wherein the reaction is performed at a temperature below 50°.7. The process according to claim 6 , wherein the temperature is in the range of 25° C. to 50° C.8. The process according to claim 1 , wherein the compound (III) is benzylhydrazine dihydrochloride.9. The process according to claim 2 , wherein the re-crystallization is performed by dissolving the product obtained in step (b) in a solvent selected from acetone claim 2 , methanol claim 2 , acetic acid and DMSO claim 2 , or a mixture thereof at a temperature between 20 and 40° C. claim 2 , followed by the addition of an anti-solvent selected from water claim 2 , toluene claim 2 , alkanes claim 2 , and cycloalkanes claim 2 , or a mixture thereof claim 2 , or a mixture of water and isopropanol.10. The process according to claim 1 , wherein the amount of said aprotic solvent is in the range of 8 to 15 Volumes.11. The process according to claim 1 , wherein the ratio between said organic base and benzylhydrazine (III) is in the range of 1.9 to 2.2 mol/mol.12. The process according to claim 5 , wherein the ratio between triethylamine and benzylhydrazine (III) is in the range of ...

NOVEL COMPOUNDS AND USES

The present invention relates to compounds of formula (I): wherein Q is O or S; Ris a cyclic group substituted with at least one group X, wherein Rmay optionally be further substituted; X is any group comprising a carbonyl group; and Ris a cyclic group substituted at the α-position, wherein Rmay optionally be further substituted. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the dual action of NLRPinhibition and the stimulation of insulin secretion. 2. The compound or pharmaceutically acceptable salt claim 1 , solvate or prodrug of claim 1 , wherein Ris an aryl or a heteroaryl group claim 1 , wherein the aryl or the heteroaryl group is substituted at the α-position claim 1 , and wherein Rmay optionally be further substituted.3. The compound or pharmaceutically acceptable salt claim 2 , solvate or prodrug of claim 2 , wherein Ris an aryl or a heteroaryl group claim 2 , wherein the aryl or the heteroaryl group is substituted at the α and α′ positions claim 2 , and wherein Rmay optionally be further substituted or wherein Ris a fused aryl or a fused heteroaryl group claim 2 , wherein a first cycloalkyl claim 2 , cycloalkenyl claim 2 , non-aromatic heterocyclic claim 2 , aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α claim 2 ,β positions and a second cycloalkyl claim 2 , cycloalkenyl claim 2 , non-aromatic heterocyclic claim 2 , aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′ claim 2 ,β′ positions claim 2 , wherein Rmay optionally be further substituted.4. (canceled)5. The compound or pharmaceutically acceptable salt claim 1 , solvate or prodrug of claim 1 , wherein Ris a cyclic group substituted at the α and α′ positions claim 1 , wherein Rmay optionally be further substituted.6. The compound ...

SOLID FORMS OF INGENOL 3-(3,5-DIETHYLISOXAZOLE-4-CARBOXYLATE) AND METHOD FOR PREPARING THE SAME

Disclosed are solid forms of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from an amorphous form or a crystalline anhydrous form. Also disclosed are solid solvates of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from an acetone solvate, a dimethylcarbonate solvate, an isopropyl ether solvate, an acetonitrile solvate, a toluene solvate, a mesitylene solvate, a nitromethane solvate, a dichloromethane/heptane solvate and an ethyl acetate solvate, for use as intermediates. 1. Solid forms of ingenol 3-(3 ,5-diethylisoxazole-4-carboxylate) selected from an amorphous form or a crystalline anhydrous form.2. The amorphous solid form of characterized by a XRPD pattern showing absence of diffraction peaks claim 1 , a FTIR spectrum having peaks at about 2940-1708-1597-1444-1380-1288-1188-1105-1033-959-880-803-678±4 cmand by a Glass Transition (Tg) approximately between 60° C. and 110° C. with a maximum at about 76° C.3. The crystalline anhydrous form of characterized by a XRPD pattern showing peaks at about 6.0-9.4-11.9-13.2-13.8-15.3-19.1-20.1-24.0-28.1±0.2 degrees two theta claim 1 , a FTIR pattern with peaks at about 3582-3416-2979-2940-1709-1594-1442-1380-1288-1103-1030-959-881-794-686±4 cmand by a TG/DTA thermogram showing an endothermic signal with maximum at about 100.5° C. and a melting peak with maximum at about 134.4° C.4. Solid solvates of ingenol 3-(3 claim 1 ,5-diethylisoxazole-4-carboxylate) selected from an acetone solvate claim 1 , a dimethylcarbonate solvate claim 1 , an isopropyl ether solvate claim 1 , an acetonitrile solvate claim 1 , a toluene solvate claim 1 , a mesitylene solvate claim 1 , a nitromethane solvate claim 1 , a dichloromethane/heptane solvate and an ethyl acetate solvate claim 1 , for use as intermediates.5. The acetone solvate of characterized by a XRPD pattern showing peaks at about 5.7-8.5-11.4-12.1-13.1-15.4-19.1-20.6-21.6-24.0±0.2 degrees two theta claim 4 , by a FTIR pattern with peaks at about 3579-3478-3364-2940- ...

Isoxazole Treatments for Diabetes

The present invention relates to compounds and methods for inducing synthesis and secretion of insulin from pancreatic beta cells. The methods may take place in vitro, ex vivo such as in isolates from adult mammalian tissue, or in vivo. Compounds and methods described herein may find use in the treatment of diabetes. 118-. (canceled)20. The method of claim 19 , wherein Ris a substituent of formula (A).21. The method of claim 20 , wherein G is S.22. The method of claim 21 , wherein R claim 21 , Ror Ris hydrogen.23. The method of claim 22 , wherein R claim 22 , Rand Rare each hydrogen.2410. The method according to claim claim 22 , wherein Ris hydrogen.25. The method according to claim 19 , wherein Ris —NRR.26. The method claim 25 , wherein Ror Ris cyclopropyl claim 25 , cyclobutyl claim 25 , cyclopentyl or cyclohexyl.27. The method of claim 26 , wherein Ror Ris cyclopropyl.29. The method of claim 28 , wherein G is S.30. The method of claim 29 , wherein R claim 29 , Ror Ris hydrogen.31. The method of claim 30 , wherein R claim 30 , Rand Rare each hydrogen.32. The method according to claim 19 , wherein Ris hydrogen.33. The method according to claim 19 , wherein Ris cyclopropyl or an aliphaticalcohol or an aliphaticpolyol.35. The method according to claim 19 , wherein said cell is located in an animal subject.36. The method according to claim 19 , wherein said cell is contacted ex vivo.38. The method of claim 37 , wherein Ris a substituent of formula (A).39. The method of claim 38 , wherein G is S.40. The method of claim 39 , wherein R claim 39 , Ror Ris hydrogen.41. The method of claim 40 , wherein R claim 40 , Rand Rare each hydrogen.42. The method according to claim 37 , wherein Ris hydrogen.43. The method according to claim 37 , wherein Ris —NRR.44. The method claim 43 , wherein Ror Ris cyclopropyl claim 43 , cyclobutyl claim 43 , cyclopentyl or cyclohexyl.45. The method of claim 44 , wherein Ror Ris cyclopropyl.47. The method of claim 46 , wherein G is S.48. The ...

TRYPANOSOMES INHIBITORS

The invention relates to a compound of formula (I) 2. The compound according to claim 1 , wherein A is —C(O)—.3. The compound according to wherein Ris R.4. The compound according to claim 1 , wherein Ris (D) or (E).5. The compound according to wherein Ris hydrogen claim 1 , methyl or difluoroethyl.6. The compound according to wherein Ris methyl claim 1 , tert.-butyl claim 1 , trifluoromethyl claim 1 , cyclopropyl claim 1 , phenyl claim 1 , chlorophenyl claim 1 , fluorophenyl or methoxyphenyl.7. The compound according to wherein Ris fluorophenyl.8. The compound according to claim 1 , wherein Ris chlorophenyl.9. The compound according to wherein Ris methyl.10. The compound according to claim 1 , wherein Ris alkyl claim 1 , phenyl claim 1 , halophenyl claim 1 , pyridinyl or halopyridinyl.11. The compound according to claim 1 , wherein Ris methyl claim 1 , propyl claim 1 , tert.-butyl claim 1 , phenyl claim 1 , fluorophenyl claim 1 , chlorophenyl claim 1 , pyridinyl or fluoropyridinyl.12. The compound according to wherein:A is —C(O)—;{'sup': '2', 'Ris (D) or (E);'}{'sup': '4', 'Ris hydrogen, methyl or difluoroethyl;'}{'sup': '5', 'Ris methyl, tert.-butyl, trifluoromethyl, cyclopropyl, phenyl, chlorophenyl, fluorophenyl or methoxyphenyl;'}{'sup': '6', 'Ris fluorophenyl{'sup': '7', 'Ris chlorophenyl;'}{'sup': '8', 'Ris methyl{'sup': '9', 'Ris alkyl, methyl, propyl, tert.-butyl, phenyl, fluorophenyl, chlorophenyl, pyridinyl or fluoropyridinyl; or'}a pharmaceutically acceptable salt or ester thereof.13. The compound according to wherein Ris chlorophenyl or fluorophenyl.14. The compound according to wherein Ris phenyl or bromophenyl.15. The compound according to claim 1 , wherein Ris halogen claim 1 , haloalkoxy or alkoxyalkoxy.16. The compound according to wherein:{'sup': '11', 'Ris chlorophenyl or fluorophenyl;'}{'sup': '12', 'Ris phenyl or bromophenyl;'}{'sup': '13', 'Ris halogen, haloalkoxy or alkoxyalkoxy; or,'}a pharmaceutically acceptable salt or ester thereof.17. The ...