АРИЛКАРБОНИЛЬНЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ТЕРАПЕВТИЧЕСКИХ СРЕДСТВ

Изобретение относится к соединениям общей формулы (Ib) и его фармацевтически приемлемым солям, которые являются активаторами глюкокиназы. В формуле (Ib) R24 выбран из группы, состоящей из галогена, -CF3, -OCF3, -OR2, С1-6-алкил-Z- и R6-W1-С1-6алкилен-Z-; L1 означает связь, -O-, -S-, -S(O)2-, -С(O)- или -N(R11)-; G1 означает C1-6-алкил, С3-10-циклоалкил или пиперидил, необязательно замещенные одним или несколькими заместителями, выбранными из С3-10-циклоалкила; L2 означает -N(R20)-; L3означает -С(O)-; R1 означает водород; G2 означает 32 з.п. ф-лы.

АНАЛОГИ CYP-ЭЙКОЗАНОИДОВ ДЛЯ ПРИМЕНЕНИЯ В ЛЕЧЕНИИ ИЛИ ПРЕДОТВРАЩЕНИИ НАРУШЕНИЯ, СВЯЗАННОГО С НЕОВАСКУЛЯРИЗАЦИЕЙ И/ИЛИ ВОСПАЛЕНИЕМ

Изобретение относится к применению соединения формулы (I) или его фармацевтически приемлемой соли, которые являются метаболически устойчивыми аналогами биологически активных липидных медиаторов, образующихся из полиненасыщенных жирных кислот омега-3 (ПНЖК n-3), для лечения, снижения риска развития или предотвращения нарушения, связанного с неоваскуляризацией и/или воспалением. Технический результат: лечение, снижение риска развития или предотвращение нарушения, связанного с неоваскуляризацией и/или воспалением. В общей формуле (I) P представляет собой группу, представленную общей формулой (II), E представляет собой группу, представленную общей формулой (III) или (IV), I представляет собой -(CH2)m-Y. Остальные значения переменных указаны в формуле изобретения. 14 з.п. ф-лы, 5 ил., 7 табл., 5 пр. P-E-I (I) -(CH2)n-O-(CH2)k-X (II), ...

МОЛЕКУЛЫ С ПЕСТИЦИДНОЙ ФУНКЦИЕЙ И ПРОМЕЖУТОЧНЫЕ СОЕДИНЕНИЯ, КОМПОЗИЦИИ И СПОСОБЫ, СВЯЗАННЫЕ С НИМИ

Изобретение относится к молекулам, имеющих пестицидную функцию в отношении вредителей типов членистоногие, моллюски и нематоды. Предложено соединение формулы (1), где R1и R5выбраны из H, F, Cl, Br и I; R2и R4выбраны из H, F, Cl, Br, I, CN, (C1-C4)алкила, (C1-C4)алкокси и (C1-C4)галогеналкила; R3выбран из H, F, Cl, Br, I, NO2и (C1-C4)галогеналкокси; R6и R15выбраны из H и (C1-C4)алкила; R7и R8выбраны из группы, состоящей из F, Cl, Br и I; R9, R10,R11, R12и R14представляют собой H; R13выбран из H, F, Cl, Br, I и (C1-C4)галогеналкила; R16выбран из группы, состоящей из (C3-C8)циклоалкила, азетидинила, изоксазолидинонила, морфолинила, оксазолидинонила, оксетанила, тетрагидрофуранила, тетрагидропиранила, тетрагидротиофенила, тетрагидротиофенил-оксида, тетрагидротиофенил-диоксида, который может быть необязательно замещен одним или более заместителями, выбранными из группы, состоящей из H, F, Cl, Br, I, CN, оксо, (C1-C4)алкила, (C1-C4)галогеналкила, C(=O)O(C1-C4)алкила, (C=O)NH(C1-C4)алкила, (C= ...

ПРОИЗВОДНЫЕ ТИАЗОЛА

Использование: в производстве фармакологических препаратов для терапии ревматизма, нефритов, тромбоцитопении. Сущность изобретения: продукт 2-пропиониламино-5-(4-нитрофенилтио)тиазол. Выход 78,7% т. пл. 227 229°С (разложение); 2-пропионилтио-5-(4-аминофенилтио)тиазол. Выход 96,3% т.пл. 185 187°С; 2-амино-5-(1-метил -1Н-тетразол-5-илтио)тиазол, выход 48,5% т.пл. 186 188°С (разложение). 5 з. п. ф-лы, 4 табл.

ХИНОНОВЫЕ ПРОИЗВОДНЫЕ И ИХ ФАРМАКОЛОГИЧЕСКИ ПРИЕМЛЕМЫЕ СОЛИ

Использование: в гетероциклической химии, в частности в способе получения производных хинона терапевтических агентов для лечения болезней печени. Сущность изобретения: продукт производные хинона ф-лы I: A-CH(двойная связь) CCR′-C(O)-R2 или их фармацевтически приемлемые соли, где A группа ф-лы II R3 и R4 равные или разные, метокси-или этоксигруппа: R5 метил или группа ф-лы III: где R3 R4 R5 - см. выше, X, Y равные или разные, гидроксил или группа: -(OCH2)n-OR6 при n=0 или 1; R6 низший алкил; R′ C9H19 пентил, бензил, циклогексилметил, фенил или одна из групп CH2-(CH2-CH2 -CH2) CN или -(CH2)2-S-CH3 2-метилентиенил: R2 группа OR8 при R8 водород или алкил. Выход 90% Реагент 1: кетон ф-лы CR′ при R2 группа OR8 и R8 низший алкил. Реагент 2: гидроокись натрия. 4 табл.

АМИНОПРОИЗВОДНЫЕ, СПОСОБ ИНГИБИРОВАНИЯ СИНТЕЗА ОКСИДА АЗОТА, СПОСОБ СЕЛЕКТИВНОГО ИНГИБИРОВАНИЯ СИНТЕЗА ОКСИДА АЗОТА, ПРОДУЦИРУЕМОГО ИНДУЦИРУЕМОЙ NO-СИНТАЗОЙ, СПОСОБ СНИЖЕНИЯ УРОВНЯ ОКСИДА АЗОТА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ

Изобретение относится к новым аминопроизводным формулы (I), где R1 - R4 - атомы водорода; X - алкилен с 1 - 6 атомами углерода; Y - низший алкил; B - NR5R11, где R5 - атом водорода, R11 выбран из 5 - 6-членного гетероциклического радикала, в котором один кольцевой член является углеродом и 1 - 4 члена - гетероатомами азота или серы, или их фармацевтически приемлемые соли, полезные как ингибиторы синтеза оксида азота. Предложены также способ ингибирования синтеза оксида азота, способ селективного ингибирования синтеза оксида азота, продуцируемого индуцируемой NO-синтазой, способ снижения уровня оксида азота и фармацевтическая композиция. 5 з.п. ф-лы, 1 табл.

АРИЛАНИЛИНОВЫЕ АГОНИСТЫ БЕТА2 АДРЕНЕРГИЧЕСКИХ РЕЦЕПТОРОВ

... 1. Соединение формулы (I) где каждый из R1-R5 независимо выбран из группы, включающей водород, алкил, алкенил, алкинил, арил, гетероарил, циклоалкил, гетероциклил и Ra; или R1 и R2, R2 и R3, R3 и R4 или R4 и R5 объединены вместе с образованием группы, выбранной из группы, включающей -С(Rd)=C(Rd)С(=O)NRd-, -CRdRd-CRdRd-C(=O)NRd-, -NRdC(=O)C(Rd)=C(Rd)-, -NRdC(=O)CRdRd-CRdRd-, -NRdC(=O)S-, -SC(=O)NRd-, -(CRdRd)p-, -S(CRdRd)q-, -(CRdRd)qS-, -S(CRdRd)rO-, -O(CRdRd)rS- и -NHC(Rj)=C(Rk)-; R6 представляет собой водород, алкил или алкокси; R7 представляет собой водород или алкил; R8 представляет собой водород или алкил; или R8 вместе с R9представляет собой -CH2- или -СН2СН2-; R9 независимо выбран из группы, включающей алкил, алкенил, алкинил, арил, гетероарил, циклоалкил, гетероциклил и Ra, или R9вместе с R8 представляет собой -CH2 - или -СН2СН2-; R10 представляет собой водород или алкил; R11, R12 и R13 независимо выбраны из группы, включающей водород, алкил, циклоалкил, алкенил, алкинил, арил, ...

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, ...

НОВЫЕ СОЕДИНЕНИЯ В КАЧЕСТВЕ ЛИГАНДОВ КАННАБИНОИДНЫХ РЕЦЕПТОРОВ И ИХ ПРИМЕНЕНИЕ

... 1. Соединение формулы (I) !! или его фармацевтически приемлемая соль, пролекарство, соль пролекарства или их комбинация, где ! R1 представляет собой алкоксиалкил, алкоксиалкоксиалкил, гидроксиалкил, A или A-алкилен; ! R2 представляет собой атом водорода, алкокси, алкоксиалкил, алкоксикарбонил, алкоксикарбонилалкил, алкил, алкил-S(O)2-, арил, арилалкил, арилалкенил, азидоалкил, циано, циклоалкил, галоген, галогеналкил, гетероарил, гетероцикл, -(CR21R22)m-OH, RaRbN-, RaRbN-алкил-, RcRdNC(О)- или R8-R7-; ! R3 представляет собой атом водорода, алкокси, алкоксиалкил, алкил, алкилкарбонил, алкил-S(О)2-, арил, арилалкил, арилалкенил, циано, циклоалкил, галоген, галогеналкил, гетероарил, гетероцикл, -(CR31R32)m-OH, RaRbN-, RaRbN-алкил- или R8-R7; или ! R2 и R3 вместе с атомами углерода, к которым они присоединены, образуют 4-, 5-, 6- или 7-членное моноциклическое кольцо, необязательно конденсированное с бензольным кольцом или моноциклическим гетероарилом, причем указанное моноциклическое кольцо ...

ПРОИЗВОДНОЕ ТИАЗОЛА

... 1. Производное тиазола, представленное следующей общей формулой (I), или его фармацевтически приемлемая соль ! ! A - циклоалкил или циклоалкенил, который может быть соответственно замещен, ! B - группа, выбранная из фенила, пиридила, хинолила, изохинолила, хиноксалинила, хиназолинила и циннолинила, которая может быть замещена 1 или 2 заместителями, ! R1 - -H, галоген или -R0, ! R4 - -H, -OH или галоген, ! или R1 и R4 вместе образуют связь, ! R2 и R3 одинаковые или отличаются друг от друга, и каждый является группой, выбранной из следующего (i) или (ii), ! (i) -CH(ORA)-RB, -CO-CO-NRCRD, -CO-CO-NRC-ORD, -CO-низший алкилен-ORE, -C(ORE)(ORF)-RB, -C(ORE)(ORF)-R0, -C(RG)(ORE)-CH(ORF)-RC, -C(RG)(ORE)-C(R0)(ORF)-RC, -CH(ORE)-CH(ORF)-RB, -C(RG)(ORE)-низший алкилен-ORF, -CH(CH2ORE)-CH2ORF, -C(RG)(CH2ORE)-CH2ORF, низший алкилен-C(RG)(ORE)-CH(ORF)-RC, низший алкилен-C(RG)(ORE)-C(R0)(ORF)-RC, низший алкилен-CH(CH2ORE)-CH2ORF и/или низший алкилен-C(RG)(CH2ORE)-CH2ORF, ! (ii) -H, галоген, -NO2, -CN, - ...

ПРОИЗВОДНОЕ ЦИКЛОПЕНТИЛАКРИЛАМИДА

... 1. Соединение, представленное общей формулой (1) или его фармацевтически приемлемая соль ! [химическая формула 1] ! ! (в которой R1 и R2 независимо представляют атом водорода, атом галогена, аминогруппу, гидроксильнуную группу, гидроксиаминогруппу, нитрогруппу, цианогруппу, сульфамоильную группу, C1-С6 алкильную группу, С1-С6 алкоксигруппу C1-С6 алкилсульфанильную группу, C1-С6 алкилсульфинильную группу, С1-С6 алкилсульфонильную группу или С1-С6алкокси-С1-С6 алкилсульфонильную группу, а А - замещенную или незамещенную гетероарильную группу). ! 2. Соединение по п.1 или его фармацевтически приемлемая соль, отличающееся тем, что R1 и R2 независимо представляют собой атом водорода, атом галогена или С1-С6 алкилсульфонильную группу. ! 3. Соединение по п.1 или его фармацевтически приемлемая соль, отличающееся тем, что R1 представляет собой атом водорода или атом галогена, a R2 представляет собой С1-С6 алкилсульфонильную группу. ! 4. Соединение по п.1 или его фармацевтически приемлемая соль, отличающееся ...

Аминогетероцикламиды в качестве пестицидов и антипаразитарных агентов

... 1. Соединения формулы где R1 обозначает водород, галоген, C1-С6алкил, C1-С6алкокси, C1 -С6галоалкил или незамещенный или замещенный 1-5 заместителями фенил, где заместители выбирают из группы, включающей C1-С6алкил, C1-С6галоалкил, C1-С6алкокси, арилокси, галоген, циано и нитро, причем, если количество заместителей превышает 1, то заместители могут быть одинаковыми или различными; R2 обозначает водород, C1-С6алкил, (C1-С6алкилен)фенил, пиридил, COOR6, CONR7R8, COR6, аллил или СН2 -О-R6; R3 обозначает незамещенный или замещенный гетероциклил, где заместители в каждом случае выбирают из группы, включающей незамещенный или замещенный фенил, где заместители выбирают из группы, включающей C1-С6алкил, C1-С6алкокси, галоген, циано и нитро, причем, если количество заместителей превышает 1, то заместители могут быть одинаковыми или различными; бензил, C1-С6алкил, C1-С6галоалкил, C1-С6 алкокси, арилокси, галоген, циано, гидроксил, амино и нитро, причем, если количество заместителей превышает 1, то ...

ПРОИЗВОДНЫЕ 3-ЦИКЛИЛ-2-(4-СУЛЬФАМОИЛФЕНИЛ)-N-ЦИКЛИЛПРОПИОНАМИДА, ПРИМЕНИМЫЕ ДЛЯ ЛЕЧЕНИЯ НАРУШЕННОЙ ПЕРЕНОСИМОСТИ ГЛЮКОЗЫ И ДИАБЕТА

... 1. Соединение формулы ! ! в которой ! Q совместно с атомами углерода и азота, к которым он присоединен, образует 5-6-членное моноциклическое гетероароматическое кольцо; или ! Q совместно с атомами углерода и азота, к которым он присоединен, образует 9-10-членный бициклический гетероцикл; ! R1 и R2 независимо друг от друга обозначают водород, галоген, цианогруппу, нитрогруппу, необязательно замещенный алкил, алкоксигруппу, алкилтиогруппу, алкилтионогруппу, сульфонил, свободную или этерифицированную карбоксигруппу, карбамоил, сульфамоил, необязательно замещенную аминогруппу, арил или гетероциклил; или ! R2 отсутствует; ! R3 обозначает С3-С6циклоалкил или С3-С6гетероциклил; ! R4 обозначает водород, галоген, цианогруппу, низш. алкил или низш. алкоксигруппу; ! R5 обозначает водород, необязательно замещенный алкил или циклоалкил; ! R6 обозначает -(CR7R8)m-W-R9, в котором ! R7 и R8 независимо друг от друга обозначают водород, необязательно замещенный алкил или циклоалкил; или ! R7 и R8 вместе ...

ИНГИБИТОРЫ ЦИСТЕИНОВОЙ ПРОТЕАЗЫ

... 1. Соединение формулы I:где Rозначает H иRозначает C-C-алкил, необязательно замещенный 1-3 заместителями, независимо выбираемыми из группы, включающей: галоген, гидрокси, циано, азидо, C-C-галогеналкил, C-C-алкокси, C-C-галогеналкокси, C-C-алкоксикарбонил, C-C-алкилкарбонил, амин, C-C-алкиламин, C-C-диалкиламин, C-C-алкилсульфонил, C-C-алкилсульфониламино, аминокарбонил, аминосульфонил, карбоциклил и Het; илиRозначает карбоциклил или Het; илиRи R, вместе с атомом азота, к которому присоединены, означают насыщенный циклический амин с 3-6 атомами в цикле;где карбоциклил, Het или циклический амин необязательно замещен 1-3 заместителями, независимо выбираемыми из группы, включающей галоген, гидрокси, циано, азидо, C-C-алкил, C-C-галогеналкил, C-C-алкокси, C-C-галогеналкокси, C-C-алкоксикарбонил, C-C-алкилкарбонил, амин, C-C-алкиламин, C-C-диалкиламин, C-C-алкилсульфонил, C-C-алкилсульфониламино, аминокарбонил, аминосульфонил, RxOOC-C-C-алкилен (где Rx означает H, C-C-алкил или C-C-галогеналкил ...

ТИАЗОЛЬНОЕ ПРОИЗВОДНОЕ И ЕГО ПРИМЕНЕНИЕ В КАЧЕСТВЕ ИНГИБИТОРА VAP-1

Изобретение относится к соединениям общей формулы (I), где Rпредставляет собой низший алкилкарбонил; X представляет собой двухвалентный остаток, полученный из тиазола; Z имеет формулу (II), где А представляет собой двухвалентный остаток, полученный из бензола, необязательно замещенного 1 или 2 атомами галогена, или двухвалентный остаток, полученный из тиофена, необязательно замещенного низшим алкилом; В представляет собой -(CH)-NR-СО-, где Rпредставляет собой водород, l равно целому числу от 1 до 6, -(СН)-O-CO- или -(CH)-S-CO- (где m равно целому числу от 0 до 6); D представляет собой -NR-, где Rпредставляет собой водород; E представляет собой амино; Y имеет формулу (III), где J представляет собой связь, низший алкилен, -(CH)-O-, -(СН)-CO- (где n равно целому числу от 0 до 6); L представляет собой связь, -О-, -NH-; M представляет собой связь, низший алкилен. Также изобретение относится к фармацевтической композиции, содержащей указанные соединения и обладающей ингибирующей активностью в ...

МОНОГИДРАТ МЕЗИЛАТА N-[5-(АМИНОСУЛЬФОНИЛ)-4-МЕТИЛ-1,3-ТИАЗОЛ-2-ИЛ]-N-МЕТИЛ-2-[4-(2-ПИРИДИНИЛ)ФЕНИЛ]АЦЕТАМИДА

... 1. Способ получения N-[5-(аминосульфонил)-4-метил-1,3-тиазол-2-ил]-N-метил-2-[4-(2-пиридинил)фенил]ацетамида в соответствии со следующими стадиями:Стадия А:Взаимодействие соединения А следующей общей формулы А*гдеRпредставляет собой уходящую группу иRпредставляет собой алкильный остаток, содержащий от 1 до 6 атомов углерода, или циклоалкильный остаток, содержащий от 3 до 6 атомов углерода,с производным бороновой кислоты, бороланом, боринаном или реагентом дибороновой кислоты при удалении R-H или R-B(OR)и образовании промежуточного производного бороновой кислоты соединения А,в котором промежуточное производное бороновой кислоты затем подвергают взаимодействию с пиридином соединения В следующей общей формулы В*гдеRпредставляет собой уходящую группупри основных условиях для непосредственного получения (4-пиридин-2-илфенил)уксусной кислоты, которую затем очищают.Стадия В:Взаимодействие (4-пиридин-2-илфенил)уксусной кислоты, полученной на стадии А, с 4-метил-2-(метиламино)-1,3-тиазол-5-сульфонамидомдля ...

МОДУЛЯТОРЫ ROR ГАММА(RORy)

Способ получения -формилированных соединений

SULFONAMIDDERIVATE ALS ASPARTYLPROTEASE-INHIBITOREN

Farbphotographisches Material, das einen Farbkuppler fuer Gelb enthaelt

GLUKOKINASE AKTIVATOREN

AMINOHETEROCYCLYLAMIDE ALS PESTIZIDE UND ANTIPARASITISCH WIRKSAME WIRKSTOFFE

DURCH KOHLENSTOFF SUBSTITUIERTE AMINOTHIAZOLE ALS INHIBITOREN VON ZYCLIN-ABHÄGIGEN KINASEN

SULFONAMID-DERIVATE ALS 5-HT6 RECEPTOR ANTAGONISTEN UND VERFAHREN ZU IHRER HERSTELLUNG

7-ACYLAMINO-3-VINYLCEPHALOSPORANIC ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM; THEIR STARTING COMPOUNDS AND THEIR PREPARATION

NEUES VERFAHREN ZUR HERSTELLUNG VON 2-(2-AMINOTHIAZOL-4-YL)-GLYOXYLSAEURE-DERIVATEN ODER EINES SALZES DERSELBEN SOWIE ZWISCHENPRODUKTE DERSELBEN UND VERFAHREN ZUR HERSTELLUNG DER ZWISCHENPRODUKTE

CEPHALOSPORIN DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Herstellung von gemischten Säureanhydriden und Amidverbindungen

MOLEKÜLMODELL FÜR VLA-4-INHIBITOREN

Perfluorpolyaetherfluide und diese enthaltende Zusammensetzungen

N-substituted-ª‰-hydroxy aralkylamines, processes for making them and therapeutic compositions containing them

The invention comprises N-substituted-b -hydroxyphenethylamines of the formula wherein Het represents a polyhetero-monocyclicaryl radical, other than a pyrimidine radical, having 5 or 6 ring atoms, 2 or 3 of which are hetero atoms consisting of 1 to 3 nitrogen atoms and not more than 1 oxygen or sulphur atom, said radical being attached to the amino nitrogen atom by a ring carbon or ring nitrogen atom, R represents a hydrogen -atom or a C1- 4 alkyl, benzyl or phenyl radical and R1\h represents a hydrogen atom or a methyl radical, the phenyl and heterocyclic rings optionally bearing substituents not adversely affecting the pharmacological properties of the compounds, e.g. halogen, C1- 4 alkyl, C1- 4 alkoxy, methylenedioxy, amino, nitro, trihalomethyl, mercapto, C1- 4 alkylthio, carboxy and acetamide substituents, and the acid addition salts and esters thereof. The compounds may be prepared by (a) heating to a temperature up to 200 DEG C. an appropriate b -hydroxyphenethylamine ...

ROUTE TO 4-HYDROXY-1,2-BENZOTHIAZINE-3-CARBOXYAMIDES

... 1414887 1,2-Benzothiazine-3-carboxamido- 1,1-dioxides and intermediates therefor PFIZER Inc 1 Oct 1973 [23 April 1973] 45863/73 Heading C2C The invention comprises novel compounds (II) where R 1 is phenyl optionally monosubstituted by F, Cl, Me or MeO, 2-thiazolyl, 4,5-dimethyl-2- thiazolyl, 2-pyridyl, 6-methyl-2-pyridyl or 5- methyl-3-isoxazolyl, R 2 is C 1 to C 3 alkyl, X is H, Me, MeO, F, Cl or Br and R 3 is C 1 to C 3 alkyl; they are made by reacting compounds (III) with compounds or formula R 2 NHCH 2 CONHR 1 (obtained by treating benzyloxy compounds of formula PhCH 2 O.CONR 2 CH 2 CONHR 1 with HBr, the benzyloxy compounds themselves being obtained by reacting PhCH 2 OCONR 2 CH 2 CO 2 H with R 1 NH 2 in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline). The invention also comprises a process for preparing antiinflammatory compounds (I) by treating (II) with an alkali or alkaline earth metal hydride in inert solvent at 50‹-150‹ C.

PROCESS FOR FORMYLATING ORGANIC BASIC NITROGEN COMPOUNDS

... 1434320 Formylation of organic nitrogen compounds DEUTSCHE GOLD-UND SILBER-SCHEIDEANSTALT 25 April 1974 [14 July 1973] 18136/74 Heading C2C A process for the formylation of an organic basic nitrogen compound comprises formylating the nitrogen compound in the form of a salt, in the presence of acetic anhydride, with an alkali metal formate or ammonium formate in an organic solvent which is substantially immiscible with water. The nitrogen compound and formate are preferably used in stoichiometric amounts, with from 1 to 4 mols. of anhydride per mole of nitrogen compound, at a temperature of from 20‹ to 60‹ C. using an aliphatic, halogenated aliphatic or aromatic hydrocarbon, ether or mixture thereof as the solvent.

HETEROCYCLIC COMPOUNDS

L-Tert.-Leucine-2-pyridylamide

The invention relates to L- tert -leucine-2-pyridylamide which is a useful intermediate for the preparation of matrix metalloproteinase inhibitor compounds.

STABILIZED FLUID PERFLUOROPOLYETHERS

... 1351321 Mono- and di-arylamide perfluoropolyethers MONTECATINE EDISON SpA 25 June 1971 [27 June 1970] 29859/71 Heading C2C [Also in Divisions C3 and C5] Mono- and di-arylamide perfluoropolyether compounds having the general formula where A is a perfluoro-C 1-3 -alkyl radical, or a radical of formula -CF(Z)-CO-N(R)Ar; -C 3 F 6 - and -C 2 F 4 - are perfluoroalkylene groups derived respectively from the opening of the double bond of hexafluoropropylene and of tetrafluoroethylene; p, q, r are each 0, 1-100, p+q+r being 3-200; Z is F or CF 3 ; Ar is an unsubstituted aryl or anthraquinoyl group or an aryl group substituted in 1-3 positions of the nucleus by alkyl, aryl, aralkyl, nitro or halogen groups; R is H, alkyl, alkylaryl or an aryl group optionally bound to Ar either directly or through a heteroatom are prepared by reacting an aromatic amine Ar(R)NH with a derivative of a perfluoropolyether mono- or dicarboxylic acid having the formula where B is a perfluoro C 1-3 alkylene radical or a ...

CEPHALOSPORIN DERIVATIVES

PHOTOGRAPHIC DYE IMAGES AND COLOUR COUPLERS THEREOF

Organic compounds

Sulphonamides

The invention comprises thiazole-2-sulphonamides of the general formula and alkali-metal salts thereof, wherein R is a C1-C3 alkyl group, e.g. CH3 or C3H7, and Y is a chlorine atom or a phenyl group, and their preparation by reacting a thiazole-2-mercaptan with chlorine and treating the resulting 4-substituted - 5 - acylamine-thiazole-2-sulphonyl chloride with ammonia. If Y is to be a chlorine atom, as for example in 5-acetamido-4 - chlorothiazole - 2-sulphonamide, the starting material may be 5-acetamido-2-mercaptothiazole which on reaction with chlorine undergoes substitution of chlorine in the 4-position and oxidation to sulphonyl chloride. Pharmaceutical preparations in the form of tablets or injectable p solutions having diuretic activity are prepared comprising the above sulphonamides.

Herbicidal compositions and methods of application thereof

... 5 - Halo - 2 - alkanoamido - thiazoles of the formula wherein Y is a C1-C6 alkanoyl group, are prepared by acylating 2-aminothiazole with an acid halide or anhydride of a lower alkanoic acid and halogenating the 2-alkanoamido-thiazole thus obtained. The following 5-halo-2-alkanoamido-thiazoles have been prepared by this method and have been found to have herbicidal activity (see Division A5/A6): 2-formamido - 5 - chlorothiazole, N - (5 - chloro-2 - thiazolyl) - propionamide, N - (5 - bromo-2 - thiazolyl) - propionamide, N - (5 - chloro-2 - thiazolyl) - butyramide and N - (5 - bromo-2-thiazolyl)-butyramide.ALSO:A herbicidal composition comprises a compound of the general formula: wherein Y is a hydrogen atom or a C1-C6 alkanoyl group and a carrier. The compositions may be in the form of solutions, emulsions, suspensions, dispersible powders, emulsifiable concentrates, granules or dusts. Non-ionic emulsifiers are specified as adjuvants which may ...

2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents

INTERMEDIATES IN THE PREPARATION OF SUBSTITUTED CEPHAM CARBOXYLIC ACID DERIVATIVES AND THE PREPARATION THEREOF

4-ACYL AMINO-2-HALO-THIAZOLES FOR USE IN ANTI-ULCER COMPOSITIONS

Improvements in or relating to colour couplers for colour photography

... o-, m- and p-Nitrobenzenesulphofluorides, p - chloro - m - nitrobenzenesulphofluoride, p - dimethylamino - m - nitrobenzenesulphofluoride, p - acetaminobenzenesulphofluoride, 2 - methoxy 5 - acetaminobenzenesulphofluoride, and 3 - acetamino - 4 - methoxybenzensulphofluoride, are prepared by reacting the corresponding sulphochlorides with potassium fluoride. Reduction of the nitro compounds and of p-methyl-m-nitrobenzenesulphofluoride in ethyl alcohol with hydrogen in presence of Raney nickel yields the corresponding amino compounds. m - Nitro - p - aminobenzenesulphofluoride is prepared by boiling with a methanol solution of HCl m - nitro - p - acetylaminobenzenesulphofluoride, itself prepared by nitrating p-acetylaminobenzenesulphofluoride. p - Methoxy - m - aminobenzenesulphofluoride, 2 - methoxy - 5 - aminobenzenesulphofluoride, and 2 : 5 - dimethoxy - 3 - aminobenzenesulphofluoride are similarly prepared from the corresponding acetylamino compounds. p - Myristoylamino - m - aminobenzenesulphofluoride ...

SYN ISOMER 3,7 DISUBSTITUTED 3 CEPHEM 4 CARBOXYLIC ACID COMPOUNDS AND PROCESSES FOR THE PREPARATION THEREOF

Halogenated benzamide derivatives

Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors

Broadspectrum heterocylclic substituted phenyl containing sulfonamide HIV protease inhibitors.

The present invention concerns the compounds having the formula (I), N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein Haryl is an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and which may optionally be substituted on (i) one or more carbon atoms by C1-6alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC1-6alkyl, carboxyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from R5 and -A-R6; and on (ii) a nitrogen atom if present by hydroxy or -A-R6. It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits ...

Halogenated benzamide derivatives

Arylmethyl-carbonylamino-thiazole derivatives and their use as antitumor agents.

... 2-amino-1,3-thiazole derivatives represented by formula (i) or (ii): where R, R1, R2 and R3 are as defined herein, or pharmaceutically acceptable salts thereof, are useful in, for example, the treatment of cancer, cell proliferative disorders, alzheimer's disease, viral infections, auto-immune diseases or neurodegenertive diseases.

Metal cyanide comprising aqueous solutions for thecyanide process for extracting gold and silver

Reverse hydroxamate derivatives as metalloprotease inhibitors.

A family of compounds having general structural formula (i)wherein w is a reverse hydroxamic acid group (a); r5 is hydrogen or lower alkyl; r6 is (b); where z1 is heteroarylen; preferably: r1 is methyl, ethyl, isopropyl, n-propyl or 3,3,3-trifluoro-n-propyl; r2 is isobutyl or sec-butyl; r3 is hydrogen; r4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl or 2-(2-pyridylcarbonylamino)-1-ethyl; r5 is hydrogen; and r6 is 2-thiazolyl or 2-pyridyl. Such compounds show potent inhibition of mmp's, cell-free tnf convertase enzyme and tnf release from cells, and in some cases inhibit tnf convertase and tnf release from cells in preference to matrix metalloprotease.

Arylmethyl-carbonyla minothiazole derivates and their use as antitumor agents

Haloalkyl heteroaryl benzamide compounds

Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors

Metal cyanide comprising aqueous solutions for thecyanide process for extracting gold anf silver

2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof

N-(3-amino-2-hydroxy-propyl) substituted alkylamide compounds.

Disclosed are compounds of the formula (I): useful in treating Alzheimer' s disease and other similar diseases. These compounds include inhibitors of the betasecretase enzyme that are useful in the treatment of Alzeheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical composition and methods of treatment to reduce A beta peptide formation.

Thiazole compounds for the treatment of neurodegenerative disorders

Halogenated benzamide derivatives

CYCLOALKYL-LINKED DIHETEROCYCLE DERIVATIVES

Haloalkyl heteroaryl benzamide compounds.

Metal cyanide comprising aqueous solutions for thecyanide process for extracting gold anf silver

2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof

Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

New derivatives of the carboxylic acid 4-hydroxy 3-quinoline substituted into 2, their preparation like drug, compositions containing them and new intermediaries obtained.

Use of derived from the malonic acid to improve the output of the cultures.

N-(3-amino-2-hydroxy-propyl)substituted alkylamidecompounds.

Arylmethyl-carbonylamino-thiazole derivatives and their use as antitumor agents.

Thiazole compounds for the treatment of neurodegenerative disorders.

Il-8 receptor antagonists

Method of preparation of new derivatives of the benzamido-2 nitro-5 thiazole.

Use of derived from the malonic acid to delay the growth of the plants.

Derived from 2-acylamino-4-phénylthiazole, their preparation and their application into therapeutic.

Derived thiazolyl with weedkiller use, their preparation and the compositions which contain them.

Thiazole compounds for the treatment of neurodegenerative disorders

Arylmethyl-carbonyla minothiazole derivates and their use as antitumor agents

N-(3-amino-2-hydroxy-propyl) substituted alkylamide compounds.

Arylmethyl-carbonyla minothiazole derivates and their use as antitumor agents

Metal cyanide comprising aqueous solutions for thecyanide process for extracting gold anf silver

Haloalkyl heteroaryl benzamide compounds.

N-(3-amino-2-hydroxy-propyl) substituted alkylamide compounds.

CYCLOALKYL-LINKED DIHETEROCYCLE DERIVATIVES

Halogenated benzamide derivatives

Haloalkyl heteroaryl benzamide compounds.

Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors

CYCLOALKYL-LINKED DIHETEROCYCLE DERIVATIVES

GLUKOKINASE AFFECTING CONNECTIONS

GLUKOKINASE AFFECTING CONNECTIONS

MODEL OF MOLECULES FOR VLA-4-INHIBITOREN

THIAZOL IMIDAZOLUND OXAZOLVERBINDUNGEN AND TREATMENT OF WITH PROTEIN AGING CONNECTED ILLNESSES

PROCEDURES FOR the PRODUCTION OF NEW ONES, IN 2-STELLUNG SUBSTITUTED DERIVATIVES of the 4-HYDROXY-3 CHINOLIN CARBONIC ACID

PROCEDURE FOR the PRODUCTION OF TAUTOMEREN 2 (2AMINOTHIAZOL-4-YL) - GLYOXYLSAEURE DERIVATIVES OR SALTS OR LOESUNGSMITTEL ADDUCTS THE SAME

2-CARBAMID-4-PHENYLTHIAZOL-DERIVATE, THEIR PRODUCTION AND THERAPEUTIC USE

ARYL ANILINE PRAY-PRAYING A2 ADRENERGIC RECEPTOR AGONISTE

VERFAHREN ZUR HERSTELLUNG VON NEUEN CEPHEMVERBINDUNGEN

MODULATORS OF THE GLUCOCORTICOIDREZEPTOR, AP-1UND/ODER NF-KB-ACTIVITY AND THEIR USE

Modulators of atp-binding cassette transporters

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

METHOD OF TREATING DIABETES, METABOLIC SYNDROME AND OBESITY USING PHENYLACETAMIDE DERIVATIVE

Phenylacetamide compounds of the formula 1. (canceled)2. The method of claim 18 , wherein n is 0.3. The method of claim 2 , wherein Ris methyl claim 2 , trifluoromethyl claim 2 , or cyclopropyl.4. The method of claim 3 , wherein Ris cyclopropyl.6. The method of claim 5 , wherein Ring A is pyrazolyl claim 5 , thiazolyl claim 5 , thiadiazolyl claim 5 , pyridyl or pyrazinyl claim 5 , each of which may be substituted with up to five moieties independently selected from the group consisting of halogen claim 5 , cyano claim 5 , lower alkyl which may be substituted with —OR claim 5 , —OR claim 5 , —O-lower alkylene —OR claim 5 , and —C(O)R.7. The method of claim 6 , wherein [Chem. 21] is a single bond.8. The method of claim 6 , wherein [Chem. 22] is a double bond.9. The method of claim 18 , wherein the compound is selected from the group consisting of:(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-fluoro-1,3-thiazol-2-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,(2R)—N-(4-acetyl-1,3-thiazol-2-yl)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyridin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)—N-(5-chloropyrazin-2-yl)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methoxypyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-hydroxycyclopentyl]-N-(5 ...

INHIBITORS OF CALCIUM-ACTIVATED CHLORIDE CHANNELS

Provided herein are methods for identifying compounds that are inhibitors of a calcium-activated chloride channel. Aminothiophene and aminothiazole compounds, and compositions comprising these compounds, described herein that inhibit efflux of chloride through a calcium-activated chloride channel are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased chloride and fluid secretion, for example, secretory diarrhea. 425-. (canceled)27. The composition of wherein at least one of Rand Ris not hydrogen.29112.-. (canceled)113. An isolated epithelial cell comprising (i) a calcium-activated chloride channel and (ii) a recombinant cytoplasmic indicator protein that binds halide.114. The epithelial cell of wherein the epithelial cell is an intestinal epithelial cell or a pulmonary epithelial cell.115. The epithelial cell of wherein the intestinal epithelial cell is an HT-29 cell.116. The epithelial cell of wherein the cytoplasmic indicator protein is a yellow fluorescent protein (YFP) mutant.117. The epithelial cell of claim 116 , wherein the YFP mutant is YFP-H148Q/I152L.118. The epithelial cell of wherein the calcium-activated chloride channel is TMEM16A.119. The epithelial cell of wherein TMEM16A is human TMEM16A.120. The epithelial cell of wherein the recombinant cytoplasmic indicator protein is introduced into the cell by a recombinant expression vector that is a viral vector.121. The method of wherein the viral vector is a retroviral vector.122. The method of wherein the retroviral vector is a lentiviral vector.123. A method of identifying an agent that is an inhibitor of a calcium-activated chloride channel comprising:{'claim-ref': {'@idref': 'CLM-00113', 'claim 113'}, '(a) contacting the isolated epithelial cell of and a candidate agent in a test sample to permit interaction between the candidate agent and the cell;'}{'sup': '2', '(b) adding to the test sample (i) at least one ...

Guanidine compound

[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that the compound or a salt thereof of the present invention exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. In addition, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound or a salt thereof of the present invention, and an excipient.

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.

Modulators of ATP-Binding Cassette Transporters

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1230-. (canceled)232. The method according to claim 231 , wherein Xis CH claim 231 , CF claim 231 , or O.233. The method according to claim 231 , wherein Xis CH.234. The method according to claim 231 , wherein Ais selected from phenyl claim 231 , triazinyl claim 231 , pyrazinyl claim 231 , pyrimidinyl claim 231 , pyridazinyl claim 231 , pyridyl claim 231 , thiadiazolyl claim 231 , triazolyl claim 231 , oxadiazolyl claim 231 , isothiazolyl claim 231 , pyrazolyl claim 231 , imidazolyl claim 231 , thiazolyl claim 231 , oxazolyl claim 231 , pyrrolyl claim 231 , thienyl claim 231 , furanyl claim 231 , indolizinyl claim 231 , indolyl claim 231 , isoindolyl claim 231 , benzofuranyl claim 231 , benzo[b]thienyl claim 231 , 1H-indazolyl claim 231 , benzimidazolyl claim 231 , benzthiazolyl claim 231 , purinyl claim 231 , quinolinyl claim 231 , isoquinolinyl claim 231 , cinnolinyl claim 231 , phthazinyl claim 231 , quinazolinyl claim 231 , quinoxalinyl claim 231 , 1 claim 231 ,8-naphthyridinyl claim 231 , pteridinyl claim 231 , carbazolyl claim 231 , acridinyl claim 231 , phenazinyl claim 231 , phenothiazinyl claim 231 , phenoxazinyl claim 231 , indenyl claim 231 , naphthyl claim 231 , azulinyl claim 231 , or anthracenyl.235. The method according to claim 231 , wherein each Bis independently selected from optionally substituted C6-C10 aryl.236. The method according to claim 231 , wherein each Bis independently an optionally substituted phenyl or naphthyl.237. The method according to claim 231 , wherein each Bis an unsubstituted phenyl.238. The method according to claim 231 , wherein each Bis independently selected from optionally substituted C5-C12 heteroaryl.239. ...

Compounds with (1E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof

The present invention includes compounds, pharmaceuticals and cosmetics having at least one (substituted phenyl)-propenal moiety. The compounds and compositions of the present invention are useful in the treatment or prevention of medical conditions including androgen associated conditions, androgen associated inflammation, a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia; Kennedy's disease (spinal and bulbar muscular atrophy, or SBMA), polyglutamine-mediated motor neuron degeneration; cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular (liver) cancer, and pancreatic cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof. 2. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is an androgen receptor associated medical condition that is induced claim 1 , caused or mediated by a normal or abnormal androgen receptor.3. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is inflammation.4. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is acne.5. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is alopecia.6. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is hirsutism.7. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is a wound.8. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated ...

Process for the Production of 2-Amino-5-Fluorothiazole

A process for the production of fluorinated compound represented by the formula (I): 115-. (canceled)17. The method according to claim 16 , wherein each of Rand Ris a hydrogen atom.18. The method according to claim 16 , wherein Ris a hydrogen atom and Ris an optionally substituted carbonyl group which forms a carbamate with the adjacent nitrogen.19. The method according to claim 16 , wherein Ris a hydrogen atom and Ris an optionally substituted carbonyl group which forms an amide with the adjacent nitrogen.20. The method according to claim 16 , wherein each of Rand Ris an optionally substituted carbonyl group which forms an amide with the adjacent nitrogen.21. The method according to claim 20 , wherein Rand Rare taken together to form isoindoline 1 claim 20 ,3-dione.22. The method according to claim 16 , wherein Rand Rare the same or different and each is selected from the group consisting of a hydrogen atom claim 16 , an optionally substituted Calkoxy-carbonyl claim 16 , an optionally substituted Calkyl-carbonyl claim 16 , an optionally substituted sulfonyl claim 16 , and an optionally substituted phosphoryl.23. The method according to claim 22 , wherein Ris a hydrogen atom and Ris not a hydrogen atom.24. The method according to claim 16 , wherein Rand Rare the same or different and each is selected from the group consisting of a hydrogen atom claim 16 , tert-butoxycarbonyl claim 16 , benzyloxycarbonyl claim 16 , methylcarbonyl claim 16 , diphenoxyphosphoryl claim 16 , and 4-methylphenylsulfonyl.25. The method according to claim 24 , wherein Ris a hydrogen atom and Ris not a hydrogen atom.26. The method according to claim 16 , wherein Ris a hydrogen atom and Ris Calkyl-carbonyl which is substituted by optionally substituted phenyl.27. The method according to claim 16 , wherein the fluorine donor is 1-Chloromethyl-4-fluoro-1 claim 16 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).28. The method according to claim 16 , wherein the fluorine donor is 1-fluoro-4 ...

THIAZOLE AND THIADIAZOLE COMPOUNDS FOR INFLAMMATION AND IMMUNE-RELATED USES

The invention relates to compounds of structural formula (I): 1137-. (canceled)141. The compound of claim 140 , wherein Y′ is an optionally substituted phenyl or an optionally substituted pyridinyl.142. The compound of claim 141 , wherein Y′ is substituted with one to two substituents.143. The compound of claim 142 , wherein the one to two substituents are each independently a lower alkyl or a halo.144. The compound of claim 143 , wherein Y′ is 2 claim 143 ,6-difluorophenyl.145. The compound of claim 140 , wherein L′ is —NRCH— claim 140 , —CHNR— claim 140 , —C(O)— claim 140 , —NR—C(O)— claim 140 , —C(O)—NR— claim 140 , —OC(O)— claim 140 , —C(O)O— claim 140 , —C(S)— claim 140 , —NR—C(S)— claim 140 , or —C(S)—NR—.146. The compound of claim 145 , wherein L′ is —NH—C(O)—.147. The compound of claim 140 , wherein L′ is —NRS(O)— claim 140 , —S(O)NR— claim 140 , —NRS(O)NR— claim 140 , —NRC(O)CH— claim 140 , —NRC(O)CH═CH— claim 140 , —NRC(O)NR— claim 140 , —NRC(NR)NR— claim 140 , —NRC(S)NR— claim 140 , —NRCHNR— claim 140 , —NRN═CR— claim 140 , —C(NR)— claim 140 , —CR═NNR—; —CH═CH— or148. The compound of claim 140 , wherein Zis lower alkyl.149. The compound of claim 140 , wherein Zis —H.150. The compound of claim 140 , whereinY′ is a phenyl substituted with one to two substituents or a pyridinyl substituted with one to two substituents, wherein the one to two substituents are each independently a lower alkyl or a halo;L′ is —NR—C(O)—;{'sub': '1', 'Zis lower alkyl or —H; and'}{'sub': 5', '6', '3, 'Zand Zare each independently chloro, bromo, fluoro, cyano, trifluoromethyl, —C(O)CH, 2-methyl-2H-tetrazolyl, methoxy, nitro, dimethylamino, thiazol-2-yl, oxazol-2-yl, or methyl.'}153. The compound of claim 138 , wherein the compound is selected from the group consisting of:N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[4-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[5-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[5-(2-Chloro-5- ...

COMPOUNDS AND METHODS FOR INHIBITING PHOSPHATE TRANSPORT

Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): 2. A compound of wherein Y is halogen.3. A compound of wherein Y is chloro.4. A compound of wherein Y is alkylamino.5. A compound of wherein Y is diethylamino.6. A compound of wherein Y is alkoxy.7. A compound of wherein Y is heterocyclyl.9. A compound of wherein Y is —O(cycloalkyl).10. A compound of wherein X is —ZR claim 1 , and wherein Z is aryl or heteroaryl and Ris a non-hydrogen substituent11. A compound of wherein Z is aryl.12. A compound of wherein Z is phenyl.14. A compound of wherein Z is heteroaryl.15. A compound of wherein Z is pyridinyl.17. A compound of wherein Ris:{'sub': 2', '0-2', '1-6', '6', '3, '(a) —CHS(O)(optionally substituted Calkyl)C(═O)NRR,'}{'sub': 2', '0-2', '1-6', '6', '3, '(b) —CHS(O)O(optionally substituted Calkyl)NRR,'}{'sub': 2', '0-2', '1-6', '4, '(c) —C(HS(O)(optionally substituted Calkyl)C(═O)OR,'}{'sub': 2', '0-2', '1-6', '4, '(d) —CHS(O)(optionally substituted Calkyl)OR,'}{'sub': 2', '2', '1-6', '5, '(e) —CHS(O)O(optionally substituted Calkyl)R,'}{'sub': 2', '0-2', '5, '(f) —CHS(O)R,'}{'sub': 2', '0-2', '6', '3, '(g) —CHS(O)NRR,'}{'sub': 2', '0-2', '2', '2', 'x', '4, '(h) —CHS(O)(CHCHO)R,'}{'sub': 2', '6', '2', '2', 'x', '4, '(i) —CHNR(CHCHO)R,'}{'sub': 6', '1-6', '6', '3, '(j) —C(═)NR(optionally substituted Calkyl)C(═O)NRR,'}{'sub': 6', '1-6', '6', '3, '(k) —C(═O)NR(optionally substituted Calkyl)NRR,'}{'sub': 6', '1-6', '4, '(l) —C(═O)NR(optionally substituted Calkyl)C(═O)OR,'}{'sub': 6', '1-6', '4, '(m) —C(═O)NR(optionally substituted Calkyl)OR,'}{'sub': 6', '1-6', '5, '(n) —C(═O)NR(optionally substituted Calkyl)R, or'}{'sub': 6', '2', '2', 'x', '4, '(o) —C(═O)NR(CHCHO)R;'}wherein{'sub': 3', '1-6, 'Ris hydrogen, hydroxyl, alkoxy, optionally substituted Calkyl, optionally substituted aryl, optionally substituted ...

Compounds with (1E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof

The present invention includes compounds, pharmaceuticals and cosmetics having at least one (substituted phenyl)-propenal moiety. The compounds and compositions of the present invention are useful in the treatment or prevention of medical conditions including androgen associated conditions, androgen associated inflammation, a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia; Kennedy's disease (spinal and bulbar muscular atrophy, or SBMA), polyglutamine-mediated motor neuron degeneration; cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular (liver) cancer, and pancreatic cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof. 2. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is an androgen receptor associated medical condition that is induced claim 1 , caused or mediated by a normal or abnormal androgen receptor.3. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is inflammation.4. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is acne.5. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is alopecia.6. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is hirsutism.7. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated medical condition is a wound.8. The pharmaceutical composition according to claim 1 , wherein said androgen receptor associated ...

Small molecule inhibitors of necroptosis

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

Positive Allosteric Modulators of the Alpha 7 Nicotinic Acetylcholine Receptor and uses Thereof

The present invention relates to compounds useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also inflammatory diseases.

METHOD FOR PRODUCING AMINOTHIAZOLE DERIVATIVE AND PRODUCTION INTERMEDIATE

Provided is a method for selectively demethylating a 2-methoxy group. Specifically provided is a production method of a compound represented by formula (7) below through the following reactions. 1. (canceled)3. The compound according to claim 2 , wherein Ris a hydrogen atom; Rand Rare each a methoxy group; and Ris a hydrogen atom. This application is a divisional of U.S. application Ser. No. 11/573,409 filed Jul. 10, 2013 and which is a National Stage of PCT/JP05/15259.The present invention relates to a method for selectively demethylating a methoxy group present at the ortho position (2-position) of an aromatic carboxylic acid, and a method for producing an aminothiazole derivative via the demethylation method.It is known that compounds in which 2-hydroxybenzoic acids are amide-bonded to 2-aminothiazoles have an excellent gastroprokinetic effect and are useful as prophylactic and therapeutic agents for epigastric indefinite complaints, nausea, vomiting, heartburn, anorexia, abdominal bloating, gastro-oesophageal reflux, and the like (patent documents 1 to 3). Among these compounds, the compound represented by formula (7a) below:particularly, has a high safety as well as an excellent gastroprokinetic effect and is useful as a prophylactic and therapeutic agent for the above-described various gastroprokinetic disorders.As a method for producing these 2-hydroxybenzoic acid amide derivatives, patent document 1 adopts a method which involves reacting a 2-methoxybenzoic acid amide derivative with a demethylating reagent such as pyridine hydrochloride to make a 2-hydroxybenzoic acid derivative. However, the demethylation reaction has been problematic to adopt industrially because the reaction produces many side reactions, making it difficult to selectively demethylate only a methoxy group selectively at the 2-position of the amide derivative.On the other hand, patent documents 2 and 3 describe that the reaction of 2-methoxybenzoic acid amide derivatives with amines such ...

Modulators of ATP-binding cassette transporters

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Guanidine compound

[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that the compound or a salt thereof of the present invention exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. In addition, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound or a salt thereof of the present invention, and an excipient.

Inhibitors of N-Linked Glycosylation and Methods Using Same

The present invention includes novel compounds and methods for preventing or treating diseases associated with N-linked glycosylation in a subject in need thereof. The methods comprise administering to the subject an effective amount of at least one compound of the invention. 45-. (canceled)711-. (canceled)13. The composition of claim 12 , further comprising at least one additional therapeutic compound that treats or prevents cancer.15. (canceled)16. The method of claim 14 , wherein the cell is a receptor tyrosine kinase-dependent cancer cell.17. The method of claim 16 , wherein the cancer is selected from the group consisting of non-small cell lung cancer claim 16 , small cell lung cancer claim 16 , head and neck squamous cell carcinoma claim 16 , breast cancer claim 16 , gastric cancer claim 16 , cervical cancer claim 16 , colon cancer claim 16 , and glioma.18. (canceled)19. The method of claim 14 , wherein the cell is in vivo in a mammal and wherein the agent is administered to the mammal.20. (canceled)22. (canceled)23. The method of claim 21 , wherein the cancer is receptor tyrosine kinase-dependent.24. The method of claim 23 , wherein the agent blocks or inhibits cell surface expression of the receptor tyrosine kinase in a cell from the cancer.25. (canceled)26. The method of claim 21 , further comprising administering to the subject at least one additional therapeutic compound that treats or prevents cancer.27. The method of claim 26 , wherein the agent and the at least one additional therapeutic compound are co-administered to the subject.28. The method of claim 27 , wherein the agent and the at least one additional therapeutic compound are coformulated.29. (canceled)30. The method of claim 21 , wherein the cancer is selected from the group consisting of squamous cell cancer claim 21 , small cell lung cancer claim 21 , non-small cell lung cancer claim 21 , vulval cancer claim 21 , thyroid cancer claim 21 , adenocarcinoma of the lung and squamous carcinoma of ...

SUBSTITUTED AMINOTHIAZOLES AS INHIBITORS OF NUCLEASES

Compounds represented by the structural formula (1) R1, R2, R3, R4, R5, R6 are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases. 2: The compound according to claim 1 , wherein Ris selected from C-Caryl and heteroaryl having 5 to 12 ring atoms claim 1 , wherein the aryl or heteroaryl is substituted with one to three OH groups claim 1 , preferably with two OH groups claim 1 , and the aryl or heteroaryl may optionally be further substituted by one or more substituents claim 1 , independently selected from the group consisting of F claim 1 , Cl claim 1 , Br claim 1 , C-Calkyl claim 1 , O(C-Calkyl) claim 1 , phenyl claim 1 , O-phenyl claim 1 , NH claim 1 , N(C-Calkyl) claim 1 , NO claim 1 , NHCO(C-Calkyl) claim 1 , CF claim 1 , OCF claim 1 , CN claim 1 , S(O)C-C-alkyl claim 1 , SONH(C-C-alkyl) claim 1 , SON(C-C-alkyl); in particular selected from F claim 1 , Cl claim 1 , Br claim 1 , C-Calkyl claim 1 , O(C-Calkyl) claim 1 , CF claim 1 , OCF; provided that Ris not 4-hydroxy-3-methoxyphenyl when Ris 4-ethylphenyl and R claim 1 , R claim 1 , R claim 1 , Rare H.3: The compound according to claim 1 , wherein Ris selected from C-Caryl and heteroaryl having 5 to 12 ring atoms claim 1 , wherein the aryl or heteroaryl is substituted with two OH groups or one OH group and one group selected from CN claim 1 , Cl claim 1 , Br claim 1 , F claim 1 , and the aryl or heteroaryl may optionally be further substituted by one or more substituents claim 1 , independently selected from the group consisting of F claim 1 , Cl claim 1 , Br claim 1 , C-Calkyl claim 1 , O(C-Calkyl) claim 1 , phenyl claim 1 , O-phenyl claim 1 , NH claim 1 , N(C-Calkyl) claim 1 , NO claim 1 , NHCO(C-Calkyl) claim 1 , CF claim 1 , OCF claim 1 , CN claim 1 , S(O)C-C-alkyl claim 1 , SONH(C-C-alkyl) claim 1 , SON(C-C-alkyl); in particular selected from F claim 1 , Cl ...

Enzyme and receptor modulation

Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid, leads to accumulation of the carboxylic acid hydrolysis product in the cell and enables improved or more prolonged enzyme or receptor modulation relative to the unconjugated modulator.

INHIBITORS OF EGFR AND METHODS OF USE THEREOF

The disclosure relates to a compound having Formula (I′): 119.-. (canceled)21. The compound of claim 20 , wherein m is 0.23. The compound of claim 20 , wherein one Ris phenyl or heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N claim 20 , O claim 20 , and S claim 20 , wherein the phenyl and heteroaryl are each optionally substituted with one or more R.25. The compound of claim 20 , wherein Ris phenyl optionally substituted with two or more R.27. A method of inhibiting epidermal growth factor receptor (EGFR) or treating or preventing a disease claim 20 , comprising administering to a subject in need thereof an effective amount of a compound of .29. The compound of claim 28 , wherein m is 0.31. The compound of claim 28 , wherein one Ris phenyl or heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N claim 28 , O claim 28 , and S claim 28 , wherein the phenyl and heteroaryl are each optionally substituted with one or more R.33. The compound of claim 28 , wherein Ris phenyl optionally substituted with two or more R.34. A method of inhibiting epidermal growth factor receptor (EGFR) or treating or preventing a disease claim 28 , comprising administering to a subject in need thereof an effective amount of a compound of . This application is a division of U.S. application Ser. No. 15/580,088, filed on Dec. 6, 2017, which is a U.S. National Phase application, filed under 35 U.S.C. § 371, of International Application No. PCT/US2016/040421, filed on Jun. 30, 2016, which claims the benefit of, and priority to, U.S. provisional application No. 62/186,563, filed on Jun. 30, 2015, and 62/259,895, filed on Nov. 25, 2015, the entire contents of each of which are incorporated herein by reference in their entireties.The work described herein was supported by the National Institutes of Health, NIH Grant No. P01 CA154303. The U.S. Government has certain rights to the claimed invention.The epidermal growth ...

SUBSTITUTED AMIDE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN

The present invention relates to substituted amide derivatives having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. 116-. (canceled)19. The compound according to claim 18 , wherein W is nitrogen.21. The compound according to claim 17 , whereinX is a bond, C═O, —C(O)O— or —O—.22. The compound according to claim 21 , wherein X is a bond or —O—.23. The compound according to claim 17 , wherein{'sub': 1', '1-6', '2-6', '2-6, 'Ris selected from the group consisting of substituted or unsubstituted Calkyl, substituted or unsubstituted Calkenyl, substituted or unsubstituted Calkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted monocyclic heterocyclyl.'}24. The compound according to claim 23 , wherein Ris substituted or unsubstituted ethyl claim 23 , substituted or unsubstituted isobutyl claim 23 , substituted or unsubstituted phenyl claim 23 , substituted or unsubstituted pyridine and substituted or unsubstituted thiazole.25. The compound according to claim 17 , wherein{'sub': Z', '1-6', '2-6', '2-6, 'Ris selected from the group consisting of substituted or unsubstituted Calkyl, substituted or unsubstituted Calkenyl, substituted or unsubstituted Calkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl.'}26. The compound according to claim 25 , wherein Ris selected from the group consisting of substituted or unsubstituted methyl claim 25 , substituted or unsubstituted ethyl claim 25 , substituted or unsubstituted isopropyl claim 25 , substituted or unsubstituted isobutyl claim 25 , —CF claim 25 , —CHCF claim 25 , substituted or unsubstituted phenyl claim 25 , substituted or unsubstituted pyridine claim 25 , substituted or ...

Oxazole containing compounds as activators of ido1 and ahr

Provided herein are methods and compositions related to a method of stimulating the immune system in a subject in need thereof by administering an agent that increases the level or activity of indoleamine 2,3-dioxygenase (IDO1) and/or aryl hydrocarbon receptor (Ahr).

Aminothiazole compounds as c-kit inhibitors

The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other serine-threonine kinase mediated diseases, having the Formula:wherein A, L, R1, R2, R3, and n are described herein.

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: 14-. (canceled)5. The compound of claim 24 , where Ris selected from —ORand —NRR claim 24 , Ris H claim 24 , Ris H or —OH claim 24 , and Ris H.8. The compound of claim 24 , where Ris —NRR claim 24 , where Ris H and Ris H.9. The compound of claim 24 , where Ris H.1015-. (canceled)16. The compound of claim 24 , where a is 0; or a is 1 and Ris 3-chloro.17. The compound of claim 24 , where b is 0; orb is 1 and Ris 3′-chloro claim 24 , 3′-methyl claim 24 , or 2′-methoxy; or b is 2 and Ris 2′-fluoro-5′-chloro claim 24 , 2′ claim 24 ,5′-dichloro claim 24 , 2′-methyl-5′-chloro claim 24 , or 3′-chloro-5′-hydroxy.18. The compound of claim 24 , where the methylene linker on the biphenyl is substituted with 2 methyl groups.20. The compound of claim 24 , where{'sup': 1', '7, 'Ris —OR;'}{'sup': '2', 'Ris H;'}X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole;{'sup': 3', '20', '21', '22', '23', '24, 'sub': 0-5', '1-6', '3', '3-7', '0-2', '1-6', '0-1', '3', '3, 'Ris selected from H; halo; —Calkylene-OH; —Calkyl; —CF; —Ccycloalkyl; —Calkylene-O—Calkyl; —C(O)R; —Calkylene-COOR; —C(O)NRR; —NHC(O)R; ═O; —C(CH)═N(OH); phenyl optionally substituted with one or two groups independently selected from halo, —OH, and —OCH; pyridinyl; pyrazinyl; and thiophenyl substituted with methyl or halo;'}{'sup': 4', '35', '3', '4, 'sub': 1-6', '1-2', '2', '2', '2', '1-3, 'Ris selected from H; —OH; —Calkyl; —Calkylene-COOR; —CHCH(OH)CHOH; pyridinyl; and phenyl optionally substituted with one halo group; or Rand Rare taken together to form -phenylene-O—(CH)—;'}{'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;'}{'sup': '20', 'sub': '1-6', 'Ris —Calkyl;'}{'sup': '21', 'Ris H;'}{'sup': 22', '23', '22', ' ...

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

The present invention relates to modulator of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1226-. (canceled)228230-. (canceled)231. The pharmaceutical composition according to claim 227 , wherein Xis CH claim 227 , CF claim 227 , or O.232. The pharmaceutical composition according to claim 227 , wherein Xis CH.233. The pharmaceutical composition according to claim 227 , wherein Ais selected from phenyl claim 227 , triazinyl claim 227 , pyrazinyl claim 227 , pyrimidinyl claim 227 , pyridazinyl claim 227 , pyridyl claim 227 , thiadiazolyl claim 227 , triazolyl claim 227 , oxadiazolyl claim 227 , isothiazolyl claim 227 , pyrazolyl claim 227 , imidazolyl claim 227 , thiazolyl claim 227 , oxazolyl claim 227 , pyrrolyl claim 227 , thienyl claim 227 , furanyl claim 227 , indolizinyl claim 227 , indolyl claim 227 , isoindolyl claim 227 , benzofuranyl claim 227 , benzo[b]thienyl claim 227 , 1H-indazolyl claim 227 , benzimidazolyl claim 227 , benzthiazolyl claim 227 , purinyl claim 227 , quinolinyl claim 227 , isoquinolinyl claim 227 , cinnolinyl claim 227 , phthazinyl claim 227 , quinazolinyl claim 227 , quinoxalinyl claim 227 , 1 claim 227 ,8-naphthyridinyl claim 227 , pteridinyl claim 227 , carbazolyl claim 227 , acridinyl claim 227 , phenazinyl claim 227 , phenothiazinyl claim 227 , phenoxazinyl claim 227 , indenyl claim 227 , naphthyl claim 227 , azulinyl claim 227 , or anthracenyl.234. The pharmaceutical composition according to claim 227 , wherein each Bis independently selected from optionally substituted C6-C10 aryl.235. The pharmaceutical composition according to claim 227 , wherein each Bis independently an optionally substituted phenyl or naphthyl.236. The pharmaceutical composition according to claim 227 , wherein each Bis an unsubstituted ...

Benzamide Compounds and Related Methods of Use

Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease. 3. The compound of wherein each of Eand Eis CH.4. The compound of wherein n is 0.5. The compound of wherein o is 1-2.6. The compound of wherein Ris selected from benzyl and mono- and disubstituted benzyl moieties.7. The compound of selected from compounds B wherein m is 1-2.8. The compound of wherein Ris selected from phenyl and mono- and disubstituted phenyl moieties.9. The compound of wherein Eis CH claim 8 , and Eis selected from CH and N.10. The compound of wherein n is 0. This application is a continuation of and claims priority benefit of application Ser. No. 14/139,763 filed Dec. 23, 2013 which claimed priority from application Ser. No. 61/745,056 filed Dec. 21, 2012—each of which is incorporated herein by reference in its entirety.This invention was made with government support under grant number 5 U01 NS066912 awarded by the National Institutes of Health. The government has certain rights in the invention.Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss. There currently is no treatment for delaying the onset of the disease or for slowing the progression of HD. Management of HD is focused on symptom reduction, and the only drug approved by the FDA is tetrabenazine, which is indicated to suppress involuntary movements (chorea) but does not slow the disease progression. The disease is caused by an elongated CAG trinucleotide repeat expansion located within exon 1 of the IT-15 gene encoding huntingtin, a 350-kDa protein of unknown function. The CAG repeat is translated into a polyglutamine (polyQ) stretch. In HD patients, huntingtin is expressed with 38-180 glutamine residues, whereas in healthy individuals the protein is synthesized with 8-37 ...

COMPOUNDS AND METHODS FOR INDUCING CHONDROGENESIS

The present invention provides compounds and compositions for the amelioration of arthritis and joint injuries by inducing mesenchymal stem cells into chondrocytes. 2. The method of claim 1 , wherein{'sup': 1', '2', '2, '(a) Lis a bond, Lis —C(O)NH—, ring B is phenyl, Ris —CN or phenyl, and subscript m is 1, or'}{'sup': 1', '2', '1, 'sub': '2', '(b) Ris —C(O)OH, subscript n is 1, ring A is phenyl, Lis —C(O)NH—, and Lis a bond or —CH—, or'}{'sup': 1', '2', '2, 'sub': '2', '(c) each of ring A and ring B is phenyl, Ris —C(O)OH or combined with L, subscript n is 1, and at least one Ris selected from the group consisting of H, —CN and —COH.'}5. The method of claim 4 , wherein each Ris independently selected from the group consisting of —C(O)R claim 4 , —C(O)OR claim 4 , Calkyl-C(O)OR claim 4 , —NRC(O)OR claim 4 , —NRC(O)NRR claim 4 , —SOOR claim 4 , —SONRR claim 4 , —NRSOR claim 4 , and —CN.6. The method of claim 4 , wherein each Ris independently selected from the group consisting of —CH—C(O)OH claim 4 , —C(O)Me claim 4 , —NHC(O)NH claim 4 , —NHC(O)OMe claim 4 , —NHSOMe claim 4 , —SONH claim 4 , —SONHMe claim 4 , —SOH claim 4 , —C(O)OH claim 4 , and —CN.7. The method of claim 4 , whereinring A is phenyl; andsubscript n is 1.8. The method of claim 4 , whereinring A is selected from the group consisting of biphenyl and pyridyl, orsubscript n is 2.11. The method of claim 10 , wherein each Ris independently selected from the group consisting of H claim 10 , —CHNHCONH claim 10 , —CHNHCOOMe claim 10 , —CHNHMe claim 10 , —CHOPh claim 10 , 2-CN claim 10 , 4-CN claim 10 , —C(O)OH claim 10 , —CONHOH claim 10 , —OCF2H claim 10 , —POH claim 10 , —SOH claim 10 , phenyl claim 10 , pyridyl claim 10 , imidazole and tetrazole.13. The method of claim 12 , wherein{'sup': '2', 'sub': 2', '2', '2', '2', '2', '2', '2', '2, 'each Ris independently selected from the group consisting of H, Me, —Cl, —CHOH, —CHCHOH, —CHNH, —C(O)Me, —C(O)OH, —C(O)NH, —CN, morpoholine, 3,4-difluorophenyl and —SONH; ...

FUNGICIDAL 3-[(1,3-THIAZOL-4-YLMETHOXYIMINO)(PHENYL)METHYL]-2-SUBSTITUTED-1,2,4-OXADIAZOL-5(2H)-ONE DERIVATIVES

The present invention relates to 3-[(1,3-thiazol-4-ylmethoxyimino)(phenyl)methyl]-2-substituted-1,2,4-oxadiazol-5(2H)-one derivatives of formula (I), their process of preparation, their use as fungicide active agents, particularly in the form of fungicide compositions, and methods for the control of phytopathogenic fungi, notably of plants, using these compounds or compositions. 2. A compound according to wherein Xrepresents substituted or non-substituted C-C-alkyl claim 1 , substituted or non-substituted C-C-cycloalkyl or a substituted or non-substituted C-C-alkenyl.3. A compound according to wherein Xrepresents a methyl group claim 1 , an ethyl group claim 1 , a n-propyl group claim 1 , an isopropyl group or a cyclopropyl group.4. A compound according to wherein Zrepresents a hydrogen atom claim 1 , a halogen atom claim 1 , a nitro group claim 1 , an amino group claim 1 , an hydroxyamino group claim 1 , substituted or non-substituted C-C-alkoxyamino group claim 1 , substituted or non-substituted C-C-alkylamino claim 1 , substituted or non-substituted C-C-cycloalkylamino claim 1 , substituted or non-substituted C-C-cycloalkenylamino claim 1 , substituted or non-substituted C-C-fused bicycloalkylamino claim 1 , substituted or non-substituted C-C-fused bicycloalkenylamino claim 1 , substituted or non-substituted di-C-C-alkylamino claim 1 , substituted or non-substituted phenylamino claim 1 , substituted or non-substituted heterocyclylamino claim 1 , or a group of formula QC(═U)NR—.5. A compound according to wherein Zrepresents a hydrogen atom claim 1 , a halogen atom claim 1 , a nitro group claim 1 , an amino group claim 1 , substituted or non-substituted C-C-alkylamino claim 1 , substituted or non-substituted C-C-cycloalkylamino claim 1 , or a group of formula QC(═U)NR—.6. A compound according to wherein U represents an oxygen atom.7. A compound according to wherein Rrepresents a hydrogen atom claim 1 , a hydroxy group claim 1 , substituted or non-substituted C-C- ...

Glycosidase Inhibitors

Compounds of formula (I) 2. The medicament according to claim 1 , wherein{'sup': '1', 'Xdenotes S.'}3. The medicament according to claim 1 , wherein{'sup': '2', 'Xdenotes CY; and/or'}W denotes N or CH.4. The medicament according to claim 1 , whereinW denotes N;{'sup': '2', 'sub': '2', 'Rdenotes COY, COAlk, CONYor COOY; and/or'}{'sub': '2', 'L denotes CY.'}5. The medicament according to claim 1 , whereinm, p denote independently from one another 1 or 2, and/orn, q denote independently from one another 0 or 1.11. A pharmaceutical composition comprising as active ingredient the medicament according to together with pharmaceutically tolerable adjuvants and/or excipients claim 1 , optionally in combination with one or more further active ingredients.12. A medicament according to for use in a prophylactic or therapeutic treatment and/or monitoring of a condition selected from the group of neurodegenerative diseases claim 1 , diabetes claim 1 , cancer and stress.13. The medicament for use according to claim 12 , wherein the condition is selected from the group of Alzheimer's disease claim 12 , Amyotrophic lateral sclerosis (ALS) claim 12 , Amyotrophic lateral sclerosis with cognitive impairment (ALSci) claim 12 , Argyrophilic grain dementia claim 12 , Bluit disease claim 12 , Corticobasal degeneration (CBP) claim 12 , Dementia pugilistica claim 12 , Diffuse neurofibrillary tangles with calcification claim 12 , Down's syndrome claim 12 , Familial British dementia claim 12 , Familial Danish dementia claim 12 , Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) claim 12 , Gerstmann-Straussler-Scheinker disease claim 12 , Guadeloupean parkinsonism claim 12 , Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1) claim 12 , Multiple system atrophy claim 12 , Myotonic dystrophy claim 12 , Niemann-Pick disease (type C) claim 12 , Pallido-ponto-nigral degeneration claim 12 , Parkinsonism-dementia complex of Guam claim 12 , Pick's ...

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 , ...

COMPOSITIONS AND METHODS OF MODULATING 15-PGDH ACTIVITY

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors and 15-PGDH activators described herein. 181-. (canceled)82: A method of treating oral and/or gastrointestinal diseases associated with inflammation and/or ulcers in a subject in need thereof , the method comprising:administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.83: The method of claim 82 , wherein the ulcer comprises at least one of a mucosal or submucosal ulcer.84: The method of claim 82 , wherein the gastrointestinal disease comprises at least one of oral ulcers or gastrointestinal ulcers.85: The method of claim 82 , wherein the gastrointestinal disease comprises at least one of colitis claim 82 , gastritis claim 82 , or cryptitis.86: The method of claim 82 , wherein the gastrointestinal disease comprises ulcerative colitis.87: The method of claim 82 , wherein the gastrointestinal disease comprises inflammatory bowel disease.88: The method of wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject89: The method of claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal ulcer formation.90: The method of claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal inflammation.92: A method of treating oral and/or gastrointestinal inflammation and/or ulcers in a subject in need thereof claim 82 , the method comprising:administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.93: The method of claim 92 , wherein the subject has at least one of oral ulcers or gastrointestinal ulcers ...

COMPOUNDS AND METHODS FOR INDUCING BROWNING OF WHITE ADIPOSE TISSUE

The present invention provides a compound for inducing browning of white adipose tissue in vitro and in vivo of formula I, the preparation method thereof, as well as a composition comprising the same. Further, the present invention also relates to the use of the compound and the method to treat metabolic disorders, such as obesity and diabetes. 115-. (canceled)19. The compound or physiologically acceptable salt or hydrate or solvate thereof of claim 16 , wherein the compound is selected from the following compounds:1. 4-(3,4-dimethoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;2. 4-(3,4-dimethoxyphenyl)-N-(4-methylpyridin-2-yl)thiazol-2-amine;3. 4-(3-methoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;4. 4-phenyl-N-(pyridin-2-yl)thiazol-2-amine;5. 5. 3-(2-(pyridin-2-ylamino)thiazol-4-yl)benzonitrile;6. 6. 4-(3,4-dimethoxyphenyl)-N-(isoquinolin-3-yl)thiazol-2-amine;7. 6. 4-(1H-indol-3-yl)-N-(pyridin-2-yl)thiazol-2-amine;8. 4-(4-methoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;9. N-(pyridin-2-yl)-4-(pyridin-3-yl)thiazol-2-amine;10. 4-(3,4-dimethoxyphenyl)-N-(6-methylpyridin-2-yl)thiazol-2-amine;11. 4-(3,4-dimethoxyphenyl)-N-(5-methylpyridin-2-yl)thiazol-2-amine;12. 4-(3,4-dimethoxyphenyl)-N-(3-methylpyridin-2-yl)thiazol-2-amine;13. N-(4-chloropyridin-2-yl)-4-(3,4-dimethoxyphenyl)thiazol-2-amine;14. N-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)-6-methylbenzo[d]thiazol-2-amine;15. 4-(2,4-dimethoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;16. 4-(4-(dimethylamino)phenyl)-N-(pyridin-2-yl)thiazol-2-amine;17. N-(pyridin-2-yl)-4-(3,4,5-trimethoxyphenyl)thiazol-2-amine;18. 4-(3,5-dimethoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;19. 4-(3,4-dimethoxyphenyl)-5-methyl-N-(pyridin-2-yl)thiazol-2-amine;20. 4-(3,4-dimethoxyphenyl)-N-phenylthiazol-2-amine;21. N-(pyridin-2-yl)-4-p-tolylthiazol-2-amine;22. 4-fluorophenyl)-N-(pyridin-2-yl)thiazol-2-amine;23. N-(pyridin-2-yl)-4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine;24. 4-(2-methoxyphenyl)-N-(pyridin-2-yl)thiazol-2-amine;25. 4-(4-bromo-2-methoxyphenyl)- ...

INHIBITORS OF CYCLIN-DEPENDENT KINASES

The present invention provides novel compounds of Formulae (I′), (I), (II′), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject. 2. (canceled)412-. (canceled)13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring B is cyclohexyl.1517-. (canceled)18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring C is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl.1930-. (canceled)31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring A is optionally substituted monocyclic heteroaryl.32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring A is optionally substituted 5-membered heteroaryl or optionally substituted 6-membered heteroaryl.33. (canceled)3539-. (canceled)40. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring A is optionally substituted phenyl.4148-. (canceled)49. ...

COMPOSITIONS AND METHODS OF TREATMENT WITH PRODRUGS OF TIZOXANIDE, AN ANALOGUE OR SALT THEREOF

Prodrugs of tizoxanide, an analogue or salt thereof are disclosed. The prodrugs have an ester moiety comprising an amino acid moiety, and increase the bioavailability of the tizoxanide, an analogue or salt thereof. Compositions and methods of treating an intracellular protozoan infection, a viral infection or a cancer are also disclosed. 142.-. (canceled)44. A pharmaceutically acceptable salt of the compound of .45. The salt of claim 44 , which is a hydrochloric salt.46. A pharmaceutical composition comprising the compound of or its pharmaceutically acceptable salt.47. The pharmaceutical composition of claim 46 , wherein the composition is an injectable formulation.48. The pharmaceutical composition of claim 46 , wherein the composition is an intravenous formulation.491. The pharmaceutical composition of claim 47 , comprising an aqueous solution of the compound of claim or its pharmaceutically acceptable salt.50. The pharmaceutical composition of in a dosage form suitable for injection.51. The pharmaceutical composition of claim 50 , wherein the dosage form is suitable for intravenous administration.52. The pharmaceutical composition of claim 46 , wherein the composition is an oral formulation.53. A pharmaceutical formulation comprising an aqueous solution of the compound of or its pharmaceutically acceptable salt. This application claims the benefit of U.S. Provisional Application Ser. No. 62/078,384, filed Nov. 11, 2014, which is incorporated by reference herein.Nitazoxanide (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide) is a compound having the following structure:Tizoxanide is the active circulating metabolite of nitazoxanide.The preparation and uses of nitazoxanide arc disclosed, for example, in U.S. Pat. No. 3,950,351 to Rossignol.Pharmaceutical compositions containing nitazoxanide and its metabolite, tizoxanide, were originally developed and marketed for treating intestinal parasitic infections. However, nitazoxanide, tizoxanide and various analogues ...

Cycloalkyl-Linked Diheterocycle Derivatives

The present invention relates to compounds of formula (I) 2. A pharmaceutical formulation comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and at least one pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient. This application is a continuation application of U.S. application Ser. No. 15/826,027, filed Nov. 29, 2017, which is a continuation of U.S. application Ser. No. 15/306,979, filed Oct. 26, 2016, which is a § 371 filing of PCT/IB2015/052833 filed Apr. 17, 2015, which claims the benefit of priority to U.S. Provisional Application No. 61/986,876 filed Apr. 30, 2014; the entire contents of which are incorporated herein by reference.The present invention relates to novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.Tumor cells require nutrients to generate ATP and macromolecules to sustain survival and proliferation. (Ward P. S., et al., “Metabolic Reprogramming: a Cancer Hallmark even Warburg did not Anticipate”, 21(3) (2012), pp. 297-308.) Glucose and glutamine are two major sources of nutrients that tumor cells depend on. Tumor cells prefer to use glycolysis pathways, even under aerobic conditions, to metabolize glucose to produce lactic acid and ATP, the so-called Warburg's effect. In addition to glucose, many tumor cells are addicted to glutamine (“Gln”) for survival (DeBerardinis R. J., et al., “Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer”, 29(3) (2010), pp. 313-24; Shanware N. P., et al., “Glutamine: Pleiotropic Roles in Tumor Growth and Stress Resistance”, (). 89(3) (2011), pp. 229-36.). This amino acid can be metabolized to generate intermediates of tricarboxylic acid ...

COMPOUNDS AND METHODS FOR INDUCING CHONDROGENESIS

Described herein are compounds and compositions for the amelioration of arthritis or joint injuries by inducing mesenchymal stem cells into chondrocytes. 96. The method of any one of , , , or wherein:{'sup': 2', '4', '7', '8', '4', '7', '8', '9', '10', '4', '7', '8', '9', '10', '4', '7', '8', '4', '7', '8', '4', '11, 'Ris halo, C(O)R, alkyl, optionally substituted alkoxy, haloalkyl, (CRR)OR, (CRR)(CRR)OR, X(CRR)(CRR)OR, X(CRR)C(O)OR, or X(CRR)C(O)NRR; and'}{'sup': 3', '4', '4', '11, 'sub': '2', 'each Ris independently selected from CN, halo, C(O)R, COH, C(O)NRR, alkyl, or optionally substituted alkoxy;'}{'sup': 3', '3', '2, 'or Rtogether with an adjacent Ror with Rform a ring.'}10. The method of wherein:{'sup': 2', '7', '8', '4', '7', '8', '9', '10', '4', '7', '8', '9', '10', '4', '7', '8', '4', '7', '8', '4', '11, 'sub': 3', '3', '3', '3', '3', '2, 'Ris F, Cl, C(O)CH, CH, CF, OCH, OEt, OPr, OCF, OCHF, (CRR)OR, (CRR)(CRR)OR, X(CRR)(CRR)OR, X(CRR)C(O)OR, or X(CRR)C(O)NRR; and'}{'sup': '3', 'sub': 3', '2', '2', '3', '3', '3, 'each Ris independently selected from CN, F, Cl, C(O)CH, COH, C(O)NH, CH, OCF, or OCH;'}{'sup': 3', '3', '2, 'or Rtogether with an adjacent Ror with Rform a ring.'}11. The method of wherein Ris F claim 10 , Cl claim 10 , C(O)CH claim 10 , CH claim 10 , CF claim 10 , OCH claim 10 , OEt claim 10 , OPr claim 10 , OCF claim 10 , OCHF claim 10 , CHOCH claim 10 , CHOH claim 10 , CHCHOH claim 10 , CHOHCHOH claim 10 , CHCHCHOH claim 10 , CHCHOHCHOH claim 10 , OCHC(O)OH claim 10 , or OCHC(O)NH.12. The method of wherein each Ris independently selected from CN claim 11 , F claim 11 , Cl claim 11 , C(O)CH claim 11 , or COH.13. The method of wherein Ris F claim 12 , Cl claim 12 , C(O)CH claim 12 , CH claim 12 , CF claim 12 , OCH claim 12 , OEt claim 12 , OPr claim 12 , OCF claim 12 , or CHCHCHOH.147. The method of any one of claim 12 , claim 12 , claim 12 , or wherein:{'sup': 2', '7', '8', '9', '10', '4', '7', '8', '9', '10', '4', '7', '8', '9', '10', '4', '11 ...

NRF2 SMALL MOLECULE INHIBITORS FOR CANCER THERAPY

Small molecule inhibitors of Nrf2 and methods of their use are provided for treating or preventing a disease, disorder or condition associated with an Nrf2-regulated pathway. The compound can be administered as a single agent or can be administered to enhance the efficacy of a chemotherapeutic drug and/or radiation therapy. 21. A method for treating or preventing a disease , disorder or condition associated with an Nrf2-regulated pathway , the method comprising administering at least one compound of formula (1) , formula (2) , or formula (3);or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, prodrug, or solvate thereof;to a subject in an amount effective to decrease Nrf2 expression, thereby treating or preventing the disease, disorder, or condition.22. The method of claim 21 , wherein the disease claim 21 , disorder or condition is associated with a disregulated Nrf2 activity.23. The method of claim 21 , wherein administering the at least one compound occurs in combination with another compound that affects an Nrf2-regulated gene to improve the efficacy of the another compound.24. The method of claim 23 , wherein the Nrf2-regulated gene is a gene that encodes for an efflux transporter or a metabolic protein.25. The method of claim 21 , wherein the at least one compound is administered before claim 21 , during claim 21 , or after administration of a chemotherapeutic drug and/or radiation therapy to the subject.26. The method of claim 25 , wherein administering the at least one compound enhances the efficacy of the chemotherapeutic drug and/or the radiation therapy.27. The method of claim 25 , wherein the chemotherapeutic drug is selected from the group consisting of a topoisomerase inhibitor claim 25 , alkylating agent claim 25 , antimetabolite claim 25 , anthracycline claim 25 , and plant alkoid.28. The method of claim 27 , wherein the chemotherapeutic drug is selected from the group consisting of etoposide claim 27 , cisplatin claim 27 , ...

ALKYLAMIDOTHIAZOLES, COSMETIC OR DERMATOLOGICAL PREPARATIONS CONTAINING SAID ALKYLAMIDOTHIAZOLES, AND USE THEREOF TO COMBAT OR PREVENT UNDESIRED PIGMENTATION OF THE SKIN

Alkylamidothiazoles of general formula (I), wherein R 1=—C1-C24 alkyl (linear and branched), —C1-C24 alkenyl (linear and branched), —C1-C8 cycloalkyl, —C1-C8 cycloalkyl-alkylhydroxy, —C1-C24 alkylhydroxy (linear and branched), —C1-C24 alkylamine (linear and branched), —C1-C24 alkylaryl (linear and branched), —C1-C24 alkylaryl-alkyl-hydroxy (linear and branched), —C1-C24 alkyl-heteroaryl (linear and branched), —C1-C24-alkyl-O—C1-C24-alkyl (linear and branched), —C1-C24 alkyl morpholino, —C1-C24 alkyl piperidino, —C1-C24 alkyl piperazino, —C1-C24 alkyl-piperazino-N-alkyl, as well as cosmetic or dermatological preparations having an effective content of one or more alkylamidothiazoles, as well as the use thereof for the cosmetic or dermatological treatment and/or prophylaxis of undesired skin pigmentation. 111.-. (canceled)13. The alkylamidothiazole of claim 12 , wherein X is selected from substituted phenyl groups.19. The alkylamidothiazole of claim 12 , wherein the alkylamidothiazole is present as a halide claim 12 , carbonate claim 12 , ascorbate claim 12 , sulfate claim 12 , acetate or phosphate.20. A cosmetic or dermatological composition claim 12 , wherein the composition comprises at least one alkylamidothiazole of and a cosmetic or dermatological carrier.21. The preparation of claim 20 , wherein the preparation comprises from 0.000001% to 10% by weight of the at least one alkylamidothiazole claim 20 , based on a total weight of the preparation.22. The preparation of claim 21 , wherein the preparation comprises from 0.0001% to 3% by weight of the at least one alkylamidothiazole.23. The preparation of claim 21 , wherein the preparation comprises from 0.001% to 1% by weight of the at least one alkylamidothiazole.27. A method for the cosmetic or dermatological treatment of undesired skin pigmentation in a subject in need thereof claim 20 , wherein the method comprises applying to skin affected by the undesired skin pigmentation the preparation of in an amount which ...

2,2'-tandem dithiazole compound, preparation method therefor, and use thereof

The present invention relates to a thiazole-based compound, a preparation method therefor, and a use thereof. More specifically, the present invention relates to a 2,2′-bis-thiazole-based compound, a preparation method therefor, and a use of 2,2′-bis-thiazole-based compound a histone deacetylase inhibitor in the preparation of an antitumor medicament, a medicament for treating autoimmune diseases, a medicament for treating type II diabetes mellitus and complication thereof, or a medicament for treating neurodegenerative diseases.

P14-Kinase Inhibitors with Anti-Cancer Activity

Methods of treating a subject for cancer using a PI4-kinase inhibitor are provided. Also provided are methods of inhibiting PI4-kinase in a cancer cell to reduce cellular proliferation. The PI4-kinase inhibitor can be a compound that is a 5-aryl or heteroaryl-thiazole, e.g., as described herein. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or substituted 2-amino-5-pyridylthiazole compound. The subject compounds may be formulated or provided to a subject in combination with one or more additional anti-cancer agents. Use of PI4-kinase inhibitors in methods of reducing cellular proliferation and methods of treatment is provided in a variety of cancer cells and cancer subjects.

PI-kinase Inhibitors with Broad Spectrum Anti-Infective Activity

Compounds and methods are provided for the treatment of pathogen infections. In some embodiments, the anti-infective compounds have broad spectrum activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of inhibiting a PI4-kinase and methods of inhibiting viral infection. In some embodiments, the compound is a PI4-kinase inhibiting compound that is a 5-aryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribivarin, and the like. 6. The compound of claim 1 , wherein Ris lower alkoxy.7. The compound of claim 1 , wherein Ris lower alkyl.10. The compound of claim 1 , wherein the compound is described by a structure of Table 1.11. An anti-infective pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.12. A method of inhibiting a PI4-kinase claim 1 , the method comprising contacting a sample comprising the PI4-kinase with the compound of .13. The method of claim 12 , wherein the PI4-kinase is a PI4-III kinase.14. The method of claim 13 , wherein the PI4-III kinase is a PI4KIIIα- or PI4KIIIβ-kinase.15. A method of treating a subject for an infective disease condition claim 1 , the method comprising administering to the subject an effective amount of the compound of .16. The method of claim 15 , wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.17P. falciparumfrancisella tularensisP. aeruginosa. The method of wherein the infective disease condition results from infection with a pathogen selected from the group consisting of HCV claim 16 , rhinovirus (e.g. claim 16 , B or C). claim 16 , ebola virus claim 16 , claim 16 , hantavirus claim 16 , vaccinia claim 16 ...

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.

Benzamide Compounds and Related Methods of Use

Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease. 3. The compound of wherein Ris selected from phenyl claim 2 , 2- claim 2 , 3- claim 2 , and 5-pyridinyl claim 2 , 2-pyrimidinyl claim 2 , 3-pyridazinyl claim 2 , 2-thiazolyl claim 2 , methylene-2-thiazolyl claim 2 , 2-oxadiazolyl claim 2 , 5-isoxazolyl claim 2 , 2-nicotintate and 2-nicotinamide moieties; and Ris selected from phenyl and 2-pyridinyl moieties.4. The compound of wherein a least one of Rand Ris substituted claim 3 , said substituents independently selected from halo claim 3 , cyano claim 3 , C-Calkyl claim 3 , substituted alkyl claim 3 , alkoxy claim 3 , methylsulfinyl claim 3 , hydroxy claim 3 , methylsulfonyl claim 3 , amino claim 3 , alkylamino claim 3 , dialkylamino claim 3 , aceto claim 3 , acetamido claim 3 , nitro claim 3 , aminoalkyl claim 3 , methylthio and 1-hydroxyethyl substituents and combinations thereof.6. The compound of wherein Y is alkyl-substituted methylene and Z is O claim 5 , said alkylene moiety providing a chiral center.7. The compound of wherein said methylene substituent is methyl claim 6 , said compound selected from the (R) and (S) enantiomers.9. The compound of wherein Z is selected from amino claim 8 , alkylamino claim 8 , thio claim 8 , sulfinyl and sulfonyl moieties. This application is a continuation of and claims priority to and the benefit of application Ser. No. 14/139,763 filed on Dec. 23, 2013 and issued as U.S. Pat. No. 9,371,277 on Jun. 21, 2016, which claimed priority to and the benefit of application Ser. No. 61/745,056 filed Dec. 21, 2012—each of which is incorporated herein by reference in its entirety.This invention was made with government support under grant number NS066912 awarded by the National Institutes of Health. The government has certain rights in the invention.Huntington's disease (HD) is an autosomal dominant inherited ...

Cycloalkyl-Linked Diheterocycle Derivatives

The present invention relates to compounds of formula (I) 2. The compound or salt of claim 1 , wherein A and D are independently thiadiazolyl claim 1 , pyridazinyl optionally substituted by one or two Rgroups claim 1 , and 1 claim 1 ,2 claim 1 ,4-triazinyl optionally substituted by R.4. The compound or salt of any of - claim 1 , wherein y is 0.6. The compound or salt of or claim 1 , wherein x is 1.10. The compound or salt of any of - claim 1 , wherein{'sup': 1', '10a', '2', '10b', '15, 'sub': 1', '4', '3', '6', '3', '6, 'Ris —C(O)Rand Ris hydrogen, C-Calkyl, C-Ccycloalkyl, —C(O)R, or 5-6 membered heteroaryl, wherein the C-Ccycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two Rgroups; or'}{'sup': 2', '10b', '1', '10b', '15, 'sub': 1', '4', '3', '6', '3', '6, 'Ris —C(O)Rand Ris hydrogen, C-Calkyl, C-Ccycloalkyl, —C(O)R, or 5-6 membered heteroaryl, wherein the C-Ccycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two Rgroups; or'}{'sup': 1', '10a', '2', '10b, 'Ris —C(O)Rand Ris —C(O)R.'}11. The compound or salt of claim 10 , wherein Ris —C(O)Rand Ris —C(O)R.12. The compound or salt of claim 11 , wherein Ris —[C(R)(R)]—(C-Ccycloalkyl) claim 11 , —[C(R)(R)]-(4-6 membered heterocycloalkyl) claim 11 , —[C(R)(R)]—(C-Caryl) claim 11 , or —[C(R)(R)]-(5-10 membered heteroaryl) and Ris —[C(R)(R)]—(C-Ccycloalkyl) claim 11 , —[C(R)(R)]-(4-6 membered heterocycloalkyl) claim 11 , —[C(R)(R)]—(C-Caryl) claim 11 , or —[C(R)(R)]-(5-10 membered heteroaryl) claim 11 , wherein the C-Ccycloalkyl claim 11 , the 4-6 membered heterocycloalkyl claim 11 , the C-Caryl claim 11 , and the 5-10 membered heteroaryl in Rand Rare each independently optionally substituted by one claim 11 , two or three halogen claim 11 , cyano claim 11 , C-Calkyl claim 11 , hydroxy claim 11 , C-Calkoxy claim 11 , —(CH)—N(R)(R) claim 11 , —(CH)—C(O)N(R)(R) claim 11 , —C(O)OR claim 11 , —N(R)C(O)R claim 11 , —S(O)R claim 11 , or —S(O) ...

Substituted propanamides as inhibitors of nucleases

Compounds represented by the structural formula (1) where R1, R2, R3, R4, R5, R6 are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases.

THIAZOLE AND THIADIAZOLE COMPOUNDS FOR INFLAMMATION AND IMMUNE-RELATED USES

The invention relates to compounds of structural formula (I): 1137-. (canceled)141. The compound of claim 140 , wherein Y′ is an optionally substituted phenyl or an optionally substituted pyridinyl.142. The compound of claim 141 , wherein Y′ is substituted with one to two substituents.143. The compound of claim 142 , wherein the one to two substituents are each independently a lower alkyl or a halo.144. The compound of claim 143 , wherein Y′ is 2 claim 143 ,6-difluorophenyl.145. The compound of claim 140 , wherein L′ is —NRCH— claim 140 , —CHNR— claim 140 , —C(O)— claim 140 , —NR—C(O)— claim 140 , —C(O)—NR— claim 140 , —OC(O)— claim 140 , —C(O)O— claim 140 , —C(S)— claim 140 , —NR—C(S)— claim 140 , or —C(S)—NR—.146. The compound of claim 145 , wherein L′ is —NH—C(O)—.147. The compound of claim 140 , wherein L′ is —NRS(O)— claim 140 , —S(O)NR— claim 140 , —NRS(O)NR— claim 140 , —NRC(O)CH— claim 140 , —NRC(O)CH═CH— claim 140 , —NRC(O)NR— claim 140 , —NRC(NR)NR— claim 140 , —NRC(S)NR— claim 140 , —NRCHNR— claim 140 , —NRN═CR— claim 140 , —C(NR)— claim 140 , —CR═NNR—; —CH═CH— or —C≡C—.148. The compound of claim 140 , wherein Zis lower alkyl.149. The compound of claim 140 , wherein Zis —H.150. The compound of claim 140 , whereinY′ is a phenyl substituted with one to two substituents or a pyridinyl substituted with one to two substituents, wherein the one to two substituents are each independently a lower alkyl or a halo;L′ is —NR—C(O)—;{'sub': '1', 'Zis lower alkyl or —H; and'}{'sub': 5', '6', '3, 'Zand Zare each independently chloro, bromo, fluoro, cyano, trifluoromethyl, —C(O)CH, 2-methyl-2H-tetrazolyl, methoxy, nitro, dimethylamino, thiazol-2-yl, oxazol-2-yl, or methyl.'}153. The compound of claim 138 , wherein the compound is selected from the group consisting of:N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[4-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[5-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;N-[5-(2- ...

SMALL MOLECULE FATTY ACID SYNTHASE INHIBITORS

Provided herein are small molecule Fatty Acid Synthase Inhibitors, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds. 1. Use of an inhibitor of the thioesterase enzymatic domain of Fatty Acid Synthase in the treatment or prevention of a disease or condition in a mammal that would benefit from the inhibition or reduction of Fatty Acid Synthase activity.3. The use of claim 1 , wherein the disease or condition is cancer or a viral infection.4. The use of claim 1 , wherein the disease or condition is cancer.5. The use of claim 4 , wherein the cancer is selected from prostate claim 4 , ovarian claim 4 , breast claim 4 , liver claim 4 , endometrial claim 4 , colon claim 4 , stomach claim 4 , thyroid claim 4 , colorectal claim 4 , bladder claim 4 , lung claim 4 , thyroid claim 4 , oral claim 4 , tongue claim 4 , esophageal claim 4 , pancreatic claim 4 , or melanoma.6. The use of claim 3 , wherein the disease or condition is a viral infection.7. The use of claim 6 , wherein the viral infection is selected from hepatitis C (HCV) claim 6 , hepatitis B (HBV) claim 6 , Dengue virus (DENY) claim 6 , West Nile virus (WNV) claim 6 , Epstein-Barr virus (EBV) claim 6 , or yellow fever.9. The use of claim 8 , wherein:{'sup': '1', 'sub': 1', '8, 'Ris substituted or unsubstituted C-Calkyl.'}10. The use of claim 9 , wherein:{'sup': '1', 'Ris selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, 1-ethyl-propyl, n-pentyl, n-hexyl, and n-heptyl.'}11. The use of claim 8 , wherein:{'sup': '1', 'Ris substituted or unsubstituted aryl.'}12. The use of claim 11 , wherein:{'sup': '1', 'sub': 1', '6', '1', '6', '1', '6', '1', '6, 'Ris phenyl optionally substituted with halogen, —CN, —OH, C-Calkyl, C-Chaloalkyl, C-Calkoxy, or C-Chaloalkoxy.'}13. The use of claim 8 , wherein:{'sup': '1', 'sub': 3', '8, 'Ris substituted or unsubstituted C-Ccycloalkyl.'}14. The use of any one of - ...

AROMATIC 5-MEMBERED HETEROCYCLIC DERIVATIVE HAVING TRPV4-INHIBITING ACTIVITY

The present invention is related to a compound represented by formula (I) 13. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.14. A method of inhibiting a TRPV4 receptor in a subject claim 13 , comprising administering an effective amount of the pharmaceutical composition according to to the subject.15. A method for treating pain in a subject claim 1 , which comprises administering an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , to the subject.1617-. (canceled) The present invention relates to a compound that has a TRPV4 inhibitory activity and is useful in the treatment and/or prevention of a TRPV4 receptor-mediated disorder, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing thereof.TRPV4 is one of a cation channel of the TRP (Transient Receptor Potential) superfamily. It was discovered as an osmotic-sensitivity receptor activated by hypotonic stimulus. Then, it was shown that TRPV4 had a temperature-sensitive property, that is, TRPV4 was activated at the body temperature rage, and TRPV4 is activated by heat and low pH. It is reported that the gene and protein of TRPV4 is expressed in brain, spinal code, peripheral nerve fiber, skin, kidney, trachea, cochlea and bone, etc. Moreover, it is also reported that TRPV4 is activated by the compounds, such as arachidonic acid, arachidonate metabolite, endocannabinoids, and phorbol ester. The increase of activation of the C-fiber by hypotonic stimulation under the inflammatory environment induced by inflammatory mediators, is known, and it is also reported that TRPV4 relates to this activation. Furthermore, it is also reported that TRPV4 is activated by fluid pressure and mechanical stimuli, and TRPV4 relates to hyperalgesia caused by mechanical stimuli. In addition, it is also reported that TRPV4 ...

GUANIDINE COMPOUNDS AND USE THEREOF

The present invention relates to guanidine compounds for inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and use thereof. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating a OXPHOS-related disease, particularly cancer, by inhibiting mitochondrial oxidative phosphorylation and reprogramming cellular metabolism. 120-. (canceled)23. The compound of claim 22 , wherein each of R claim 22 , Rand Ris hydrogen in chemical formula 2.25. The compound of claim 24 , wherein each of R claim 24 , Rand Ris hydrogen in chemical formula 3.27. The compound of claim 25 , wherein each of R claim 25 , Rand Ris hydrogen in chemical formula 4.29. The compound of claim 28 , wherein each of R claim 28 , Rand Ris hydrogen in chemical formula 5.30. The compound of claim 21 , wherein each of Rand Ris hydrogen in chemical formula 6.31. A compound selected from the group consisting of the following compounds claim 21 , and pharmaceutically acceptable salts claim 21 , pharmaceutically acceptable solvates claim 21 , prodrug forms of claim 21 , and derivatives of claim 21 , such compounds:N-1-(3,4-dichloro)phenethylbiguanide,N-1-(2,5-dichloro)phenethylbiguanide,N-1-(2-chloro)phenethylbiguanide,N-1-(2,4-dichloro)phenethylbiguanide,N-1-(3-fluoro)phenethylbiguanide,N-1-(4-trifluoromethoxy)phenethylbiguanide,N-1-(4-trifluoromethyl)phenethylbiguanide,N-1-(3-methoxy)phenethylbiguanide,N-1-(2-fluoro)phenethylbiguanide,N-1-(4-methyl)phenethylbiguanide,N-1-(4-methanesulphoneamine)phenethylbiguanide,N-1-(4-(N,N-dimethyl)phenethylbiguanide,N-1-(4-phenoxy)phenethylbiguanide,N-1-(4-isopropyl)phenethylbiguanide,N-1-(3,4-dimethyl)phenethylbiguanide,N-1-(2,4-dimethyl)phenethylbiguanide,N-1-(4-fluoro-2-methyl)phenethylbiguanide,N-1-(2,4-dimethyl)benzylbiguanide,N-1-(4-fluoro-3-methoxy)phenethylbiguanide,N-1-(3,4-difluoro)phenethylbiguanide,N-1-(2-morpholinoethyl)biguanide,N-1-(2-methyl)phenethylbiguanide,N-1-(3-bromo-4-fluoro)benzylbiguanide,N-1 ...

HETEROARYL COMPOUNDS WITH CYCLIC BRIDGING UNIT

This invention relates to certain heteroaryl compounds for use as medicaments, more specifically as medicaments for treating animals. The medicament can be used for the treatment of helminth infections and the treatment of parasitosis caused by helminth infections. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to animals in need of the treatments. This invention also relates to pharmaceutical compositions and kits comprising the compounds. 120-. (canceled)22. A compound according to claim 21 , wherein{'sup': '1', 'sub': 'S', 'Ris hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkoxyalkyl, alkylthioalkyl, alkylcarbonyl, alkylsulfonyl, SF, alkoxycarbonyl, wherein each of the carbon-containing radicals optionally is substituted by one or more halogen atoms,'}{'sup': '13', 'Ris hydrogen, alkyl, alkylthio, dialkylamino, wherein each of the carbon-containing radicals optionally is substituted by one or more halogen atoms,'}{'sup': 1', '2', '4', '5, 'Yand Ymay form a ring system or Yand Ymay form a ring system,'}{'sup': '15', 'Ris missing.'}2326-. (canceled)28. A method according to claim 27 , wherein Ris hydrogen claim 27 , halogen claim 27 , alkyl or alkoxy and R claim 27 , R claim 27 , Rand Rare hydrogen.29. A method according to claim 27 , wherein{'sup': '1', 'sub': '5', 'Ris hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, alkenyl, alkylcarbonyl, alkoxycarbonyl, alkinyl, alkylthioalkyl, SF, thiophenyl, imidazolyl, phenyl, furanyl,'}{'sup': '2', 'Ris hydrogen, halogen or alkyl,'}{'sup': '3', 'Ris hydrogen, halogen or alkyl,'}{'sup': 4', '5', '6', '7, 'R, R, Rand Ris hydrogen,'}{'sup': '10', 'Ris hydrogen,'}{'sup': '11', 'Ris hydrogen, and'}in formula II:{'sup': '12', 'Ris hydrogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitrilo, amino, nitro, alkylsulfonyl, alkylsulfoxyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ...

Compounds for Increasing Lipid Synthesis and Storage

This invention relates to methods for increasing lipid accumulation and lipid production in cells. Methods of producing biofuel from cells and preparing nutraceuticals comprising lipids produced according to a method provided herein are also provided.

BENZOANNULENE DERIVATIVES AS ANTIVIRAL AGENTS

The present disclosure is concerned with benzoannulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika, using these compounds. 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 m is 0.3. The compound of claim 1 , wherein n is 0 and Ris not hydrogen.4. The compound of claim 1 , wherein each of m and n is 0.5. The compound of claim 4 , wherein Ris not hydrogen.6. The compound of claim 1 , wherein Ris selected from —OH and C1-C4 alkoxy.7. The compound of claim 1 , wherein Ris C2-C5 heteroaryl substituted with 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3 groups independently selected from halogen claim 1 , —CN claim 1 , —NH claim 1 , —OH claim 1 , C1-C4 alkyl claim 1 , C1-C4 haloalkyl claim 1 , C1-C4 cyanoalkyl claim 1 , C1-C4 hydroxyalkyl claim 1 , C1-C4 alkoxy claim 1 , C1-C4 alkylamino claim 1 , (C1-C4)(C1-C4) dialkylamino claim 1 , (C1-C4 alkyl)Ar claim 1 , and Ar.8. The compound of claim 7 , wherein Ris selected from pyrazolyl claim 7 , thiazolyl claim 7 , and pyridinyl.12. The compound of claim 1 , wherein each of Rand Rare covalently bonded together and claim 1 , together with the intermediate atoms claim 1 , comprise a 3- to 6-membered heterocycloalkyl substituted with 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3 groups independently selected from halogen claim 1 , —CN claim 1 , —NH claim 1 , —OH claim 1 , C1-C4 alkyl claim 1 , C1-C4 haloalkyl claim 1 , C1-C4 cyanoalkyl claim 1 , C1-C4 hydroxyalkyl claim 1 , C1-C4 alkoxy claim 1 , C1-C4 alkylamino claim 1 , and (C1-C4)(C1-C4) dialkylamino.18. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of and a pharmaceutically acceptable carrier.19. A method for the treatment of a viral infection ...

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 ...

RIBONUCLEOTIDE REDUCTASE INHIBITORS AND METHODS OF USE

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases. 4. The compound of claim 3 , whereinR is unsubstituted aryl,{'sub': 1', '2', '3', '4', '5', '6', '7, 'R, R, R, R, R, R, and Rare independently hydrogen, unsubstituted aryl, or unsubstituted alkyl.'}5. The compound of claim 3 , wherein Rand Rare optionally joined together to form an acetal protecting group and Rand Rare optionally joined together to form an acetal protecting group.6. The compound of claim 5 , wherein said acetal is a diphenyl methylene acetal.8. The compound of claim 7 , wherein R claim 7 , R claim 7 , Rand Rare independently substituted or unsubstituted alkyl claim 7 , substituted or unsubstituted heteroalkyl claim 7 , substituted or unsubstituted aryl or a substituted silyl.9. The compound of claim 7 , wherein R claim 7 , R claim 7 , Rand Rare independently an activated ethylene protecting group claim 7 , a benzyl ether protecting group claim 7 , a silicon-based carbonate protecting group claim 7 , or a cyclic acetal protecting group.11. A composition comprising the compound of and toluene claim 3 , dimethylformamide or dichloromethane.12. A composition comprising the compound of claim) and a hydroxyl deprotecting agent.13. The composition of claim 12 , wherein said alocohol deprotecting agent is boron tribromide claim 12 , an aryl methyl ether claim 12 , tetrabutylammonium fluoride claim 12 , hydrogen/Pd/C claim 12 , Zn/acid or ammonia.15. The method of claim 14 , wherein said deprotecting agent is boron tribromide claim 14 , an aryl methyl ether claim 14 , tetrabutylammonium fluoride claim 14 , hydrogen/Pd/C claim 14 , Zn/acid or ...

Compositions and methods of targeting mutant k-ras

Compounds and compositions are presented that inhibit K-ras, and especially mutant K-ras. Certain compounds preferentially or even selectively inhibit specific forms of mutant K-Ras, and particularly the G12D mutant form.

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 ...

INHIBITORS OF EGFR AND METHODS OF USE THEREOF

The disclosure relates to a compound having Formula (I′): 2. The compound of claim 1 , wherein m is 0.4. The compound of any one of the preceeding claims claim 1 , wherein one Ris phenyl or heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N claim 1 , O claim 1 , and S claim 1 , wherein the phenyl and heteroaryl are each optionally substituted with one or more R.5. The compound of any one of the preceeding claims claim 1 , wherein Ris halogen claim 1 , O(CH)—OH claim 1 , or optionally substituted (CH)-heterocyclyl which comprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N claim 1 , O claim 1 , and S.6. The compound of any one of the preceeding claims claim 1 , wherein Ris piperazinyl or piperazinyl substituted with one or more substituents independently selected from (C-C) alkyl claim 1 , S(O)NH claim 1 , (CH)OH claim 1 , and C(O)(CH)OH.8. The compound of any one of the preceeding claims claim 1 , wherein Ris phenyl substituted with two or more R.9. The compound of any one of the preceeding claims claim 1 , wherein at least one Ris halogen or at least one Ris halogen and at least one Ris OH.10. The compound of any one of the preceeding claims claim 1 , wherein n is 0.11. The compound of any one of the preceeding claims claim 1 , wherein n is 1.13. A pharmaceutical composition comprising a compound of any one of to claim 1 , and a pharmaceutically acceptable carrier.14. A method of inhibiting a kinase claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of any one of to .15. A method of inhibiting epidermal growth factor receptor (EGFR) claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of any one of to .16. A method of treating or preventing a disease claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of any one of to .17. The method of claim 16 , wherein the disease is ...

Glycosidase Inhibitors

Compounds of formula (I) 115-. (canceled)17. The compound according to claim 16 , wherein{'sup': '2', 'Xdenotes CY.'}18. The compound according to claim 16 , whereinm denotes 1 or 2.20. A pharmaceutical composition comprising as active ingredient an effective amount of a compound according to and/or a physiologically acceptable salt thereof claim 16 , wherein the active ingredient is provided together with pharmaceutically tolerable adjuvants and/or excipients in the pharmaceutical composition claim 16 , optionally in combination with one or more further active ingredients.21. A method for treating conditions selected from the group consisting of a neurodegenerative disease claim 16 , diabetes claim 16 , cancer and stress claim 16 , wherein a compound according to and/or a physiologically acceptable salt thereof is administered to a mammal in need thereof.22. The method according to claim 21 , wherein the condition is a neurodegenerative disease.23. The method according to claim 21 , wherein the condition is selected from the group of Alzheimer's disease claim 21 , Amyotrophic lateral sclerosis (ALS) claim 21 , Amyotrophic lateral sclerosis with cognitive impairment (ALSci) claim 21 , Argyrophilic grain dementia claim 21 , Bluit disease claim 21 , Corticobasal degeneration (CBP) claim 21 , Dementia pugilistica claim 21 , Diffuse neurofibrillary tangles with calcification claim 21 , Down's syndrome claim 21 , Familial British dementia claim 21 , Familial Danish dementia claim 21 , Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) claim 21 , Gerstmann-Straussler-Scheinker disease claim 21 , Guadeloupean parkinsonism claim 21 , Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1) claim 21 , Multiple system atrophy claim 21 , Myotonic dystrophy claim 21 , Niemann-Pick disease (type C) claim 21 , Pallido-ponto-nigral degeneration claim 21 , Parkinsonism-dementia complex of Guam claim 21 , Pick's disease (PiD) claim ...

TREATING VIRAL INFECTIONS HAVING VIRAL RNAs TRANSLATED BY A NON-IRES MEDIATED MECHANISM

Provided herein are methods for preventing or treating a viral infection in a subject, wherein the viral infection is mediated by a virus comprising one or more viral RNA molecules translated by a ribosomal shunting mechanism or a non-IRES mediated mechanism. The methods comprise administering to a subject an agent that reduces ribosomal protein (Rps25) expression or function. Also provided are methods of inhibiting or promoting ribosomal shunting-mediated translation or non-IRES mediated translation. Also provided are methods of screening for an agent that inhibits or promotes ribosomal shunting-mediated translation or non-IRES mediated translation. 1. A method of treating or preventing a viral infection in a subject , the method comprising:(a) identifying a subject with or at risk of developing a viral infection, wherein the viral infection is mediated by a virus comprising one or more viral RNAs that are translated by a ribosomal shunting mechanism or a non-IRES mediated mechanism;(b) administering to the subject a therapeutically effective amount of an agent that reduces ribosomal protein S25 (Rps25) expression or function in the subject in comparison to a control.210-. (canceled)12. The method of claim 11 , wherein Rand Rare combined to form a substituted or unsubstituted aryl claim 11 , substituted or unsubstituted heteroaryl claim 11 , substituted or unsubstituted cycloalkyl claim 11 , substituted or unsubstituted cycloalkenyl claim 11 , substituted or unsubstituted cycloalkynyl claim 11 , substituted or unsubstituted heterocycloalkyl claim 11 , substituted or unsubstituted heterocycloalkenyl claim 11 , or substituted or unsubstituted heterocycloalkynyl.13. The method of claim 11 , wherein Rand Rare combined to form a substituted or unsubstituted aryl claim 11 , substituted or unsubstituted heteroaryl claim 11 , substituted or unsubstituted cycloalkyl claim 11 , substituted or unsubstituted cycloalkenyl claim 11 , substituted or unsubstituted cycloalkynyl ...

Cyclopentylacrylamide derivative

A compound having a hypoglycemic effect is provided. The compound and a pharmaceutically acceptable salt thereof are useful for the treatment or prevention of diabetes, obesity, and the like. The compound is represented by the general formula (1): (wherein R 1 and R 2 are each independently a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a hydroxyamino group, a nitro group, a cyano group, a sulfamoyl group, a C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group, a C 1 to C 6 alkylsulfanyl group, a C 1 to C 6 alkylsulfinyl group, a C 1 to C 6 alkylsulfonyl group, or a C 1 to C 6 alkoxy-C 1 to C 6 alkylsulfonyl group, and A is a substituted or unsubstituted heteroaryl group).

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.

NOVEL EFFECTIVE ANTIVIRAL COMPOUNDS AND METHODS USING SAME

The present invention includes compounds that are useful in preventing or treating viral infections caused by an enveloped RNA virus, such as viral infections caused by a Filovirus, arenavirus, rhabdovirus, paramyxovirus, orthomyxovirus and/or retrovirus. The present invention further includes compositions comprising such compounds, and methods of treating a viral infection in a subject using such compounds. 1. A method of treating or preventing a viral infection in a subject in need thereof , the method comprising administering to subject an effective amount of at least one inhibitor of a channel selected from the group consisting of calcium-release activated calcium (CRAC) channel and transient receptor potential mucolipin I (TRPML1) channel , whereby the viral infection is treated or prevented in the subject.2. The method of claim 1 , wherein administration of the inhibitor blocks claim 1 , inhibits or interferes with viral spread or viral trafficking within the subject or to another subject.3. The method of claim 1 , wherein administration of the inhibitor blocks claim 1 , inhibits or interferes with viral budding within the subject.4. The method of claim 1 , wherein administration of the inhibitor blocks claim 1 , inhibits or interferes with virus dissemination within the subject or to another subject.5. The method of claim 1 , wherein administration of the inhibitor blocks claim 1 , inhibits or interferes with viral disease progression in the subject or viral disease transmission within the subject or to another subject.6. The method of claim 1 , wherein the virus is selected from the group consisting of a filovirus claim 1 , arenavirus claim 1 , rhabdovirus claim 1 , paramyxovirus claim 1 , retrovirus claim 1 , orthomyxovirus claim 1 , and any combinations thereof.7. The method of claim 6 , wherein the virus is selected from the group consisting of Influenza A claim 6 , Influenza B claim 6 , Influenza C claim 6 , Junin claim 6 , Ebola claim 6 , Marburg claim ...

Ribonucleotide reductase inhibitors and methods of use

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases.

ENZYME AND RECEPTOR MODULATION

Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid, leads to accumulation of the carboxylic acid hydrolysis product in the cell and enables improved or more prolonged enzyme or receptor modulation relative to the unconjugated modulator. 2. A covalent conjugate according to wherein the position of conjugation is remote when the conjugate has a potency in a cellular activity assay at least as high as that of the unconjugated binding compound in the same assay claim 17 , which assay is a cell proliferation inhibition assay carried out in U937 cancer cells.3. A covalent conjugate according to wherein:{'sub': 1', '9', '9, 'Ris an ester group of formula —(C═O)ORwherein Ris{'sub': 7', '8', '7', '1', '3', 'a', '1', '3', '2', '3', 'a', '1', '3', '8', '1', '3', '7', '8', '3', '7, 'sup': 1', '1', '1, '(i) RRCH— wherein Ris optionally substituted (C-C)alkyl-(Z)—(C-C)alkyl- or (C-C)alkenyl-(Z)—(C-C)alkyl- wherein a is 0 or 1 and Zis —O—, —S—, or —NH—, and Ris hydrogen or (C-C)alkyl- or Rand Rtaken together with the carbon to which they are attached form an optionally substituted C-Ccycloalkyl ring or an optionally substituted heterocyclic ring of 5- or 6-ring atoms; or'}(ii) optionally substituted phenyl or monocyclic heterocyclic ring having 5 or 6 ring atoms.4. A covalent conjugate according to wherein:{'sub': 1', '9', '9, 'Ris an ester group of formula —(C═O)OR, wherein Ris methyl, ethyl, n- or iso-propyl, n- or sec-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl.'}5. A covalent conjugate according to wherein:{'sub': 2', 'a', 'b', 'c, 'Ris a group —CRRRin which{'sub': a', 'b', 'c', '1', '6', '2', '6', '2', '6', '1', '6', '3', '8, 'each of R, Rand Ris independently hydrogen, (C-C)alkyl, ...

Ribonucleotide reductase inhibitors and methods of use

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases.

2-hydroxyarylamide derivative or pharmaceutically acceptable salt thereof, preparation method thereof, and pharmaceutical composition for preventing or treating cancer containing same as active ingredient

The present invention relates to a 2-hydroxyarylamide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. The 2-hydroxyarylamide derivative prepared by the present invention is excellent in the inhibition of the activity of TMPRSS4 serine protease and the suppression of the infiltration of TMPRSS4-expressed cancer cells, and thus can be useful as a composition for preventing or treating cancer by inhibiting TMPRSS4 over-expressed in cancer cells, particularly, colorectal cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, or stomach cancer cells.

SMALL MOLECULE INHIBITORS OF NECROPTOSIS

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role. 113-. (canceled)1539-. (canceled)4168-. (canceled)7092-. (canceled)100. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 14 , or any pharmaceutically acceptable salt or solvate thereof claim 14 , or any stereoisomer thereof.101. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 40 , or any pharmaceutically acceptable salt or solvate thereof claim 40 , or any stereoisomer thereof.102. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 69 , or any pharmaceutically acceptable salt or solvate thereof claim 69 , or any stereoisomer thereof.103. A method of treating a condition in a subject claim 14 , said method comprising the step of administering the compound of claim 14 , or any pharmaceutically acceptable salt or solvate thereof claim 14 , or any stereoisomer thereof claim 14 , to said subject in a dosage sufficient to decrease necroptosis.104. A method of treating a condition in a subject claim 40 , said method comprising the step of administering the compound of claim 40 , or any pharmaceutically acceptable salt or solvate thereof claim 40 , or any stereoisomer thereof claim 40 , to said subject in a dosage sufficient to decrease necroptosis.105. A method of treating a condition in a ...

COMPOSITIONS AND METHODS OF MODULATING 15-PGDH ACTIVITY

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors and 15-PGDH activators described herein. 181-. (canceled)82: A method of treating oral and/or gastrointestinal diseases associated with inflammation and/or ulcers in a subject in need thereof , the method comprising:administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.83: The method of claim 82 , wherein the ulcer comprises at least one of a mucosal or submucosal ulcer.84: The method of claim 82 , wherein the gastrointestinal disease comprises at least one of oral ulcers or gastrointestinal ulcers.85: The method of claim 82 , wherein the gastrointestinal disease comprises at least one of colitis claim 82 , gastritis claim 82 , or cryptitis.86: The method of claim 82 , wherein the gastrointestinal disease comprises ulcerative colitis.87: The method of claim 82 , wherein the gastrointestinal disease comprises inflammatory bowel disease.88: The method of wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject89: The method of claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointestinal ulcer formation.90: The method of claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointestinal inflammation.92: A method of treating oral and/or gastrointestinal inflammation and/or ulcers in a subject in need thereof claim 82 , the method comprising:administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.93: The method of claim 92 , wherein the subject has at least one of oral ulcers or gastrointestinal ulcers ...

Cycloalkyl-Linked Diheterocycle Derivatives

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A, L, D, R 1 -R 15 , w, x, y, and z are defined herein. The novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

Benzamide Compounds and Related Methods of Use

Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease. 1. (canceled)5. The compound of wherein Y is selected from oxy claim 4 , alkylene claim 4 , alkyl-substituted alkylene claim 4 , amino and substituted amino moieties.6. The compound of wherein Ris a substituted benzyl moiety claim 5 , said substituents selected from 1-3 halo and cyano substituents and combinations thereof.7. The compound of wherein Y is a substituted amino moiety and Ris selected from phenyl claim 5 , substituted phenyl claim 5 , benzyl claim 5 , substituted benzyl claim 5 , heteroaryl claim 5 , substituted heteroaryl claim 5 , heteroarylalkyl and substituted heteroarylalkyl moieties.8. The compound of wherein said amino substituent is selected from alkyl and cycloalkyl moieties.9. The compound of wherein said amino substituent is selected from methyl claim 8 , ethyl claim 8 , isopropyl and cyclopropyl moieties.10. The compound of wherein said amino substituent is a divalent alkylene moiety claim 9 , where a said Rand said alkylene moiety together provide a cycloheteroalkyl moiety.11. The compound of wherein said amino substituent is a divalent alkylene moiety claim 7 , where a said Rsubstituent and said alkylene moiety together provide a cycloheteroalkyl moiety.13. The compound of wherein Ris selected from phenyl claim 12 , 2- claim 12 , 3- claim 12 , and 5-pyridinyl claim 12 , 2-pyrimidinyl claim 12 , 3-pyridazinyl claim 12 , 2-thiazolyl claim 12 , methylene-2-thiazolyl claim 12 , 2-oxadiazolyl claim 12 , 5-isoxazolyl claim 12 , 2-nicotintate and 2-nicotinamide moieties; and Ris selected from phenyl and 2-pyridinyl moieties.14. The compound of wherein a least one of Rand Ris substituted claim 13 , said substituents independently selected from halo claim 13 , cyano claim 13 , C-Calkyl claim 13 , substituted alkyl claim 13 , alkoxy claim 13 , methylsulfinyl claim 13 , hydroxy claim ...

RIBONUCLEOTIDE REDUCTASE INHIBITORS AND METHODS OF USE

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases. 115.-. (canceled)17. The compound of claim 16 , whereinR is substituted aryl.18. The compound of claim 16 , wherein{'sub': 1', '2', '3', '7', '2', '3', '2, 'R, R, R, and Rare independently hydrogen, —OH, —NH, —SH, —CN, —CF, —NO, oxo, or halogen.'}19. The compound of claim 16 , wherein{'sub': 1', '2', '3', '7, 'R, R, R, and Rare independently hydrogen.'}20. The compound of claim 16 , wherein{'sub': 1', '2', '3', '7', '17', '17', '17', '17', '17', '17, 'R, R, R, and Rare independently R-substituted or unsubstituted alkyl, R-substituted or unsubstituted heteroalkyl, R-substituted or unsubstituted cycloalkyl, R-substituted or unsubstituted heterocycloalkyl, R-substituted or unsubstituted aryl, or R-substituted or unsubstituted heteroaryl.'}21. The compound of claim 16 , wherein{'sub': 1', '2', '3', '7', '17', '17, 'R, R, R, and Rare independently R-substituted or unsubstituted alkyl, R-substituted or unsubstituted heteroalkyl.'}23. The method of claim 22 , whereinR is substituted aryl.24. The method of claim 22 , wherein{'sub': 1', '2', '3', '4', '5', '6', '7', '2', '3', '2, 'R, R, R, R, R, Rand Rare independently hydrogen, —OH, —NH, —SH, —CN, —CF, —NO, oxo, or halogen.'}25. The method of claim 22 , wherein{'sub': 1', '2', '3', '4', '5', '6', '7, 'R, R, R, R, R, Rand Rare hydrogen.'}26. The method of claim 22 , wherein{'sub': 1', '2', '3', '4', '5', '6', '7', '17', '17', '17', '17', '17', '17, 'R, R, R, R, R, Rand Rare independently R-substituted or unsubstituted alkyl, R-substituted or unsubstituted heteroalkyl, R-substituted or unsubstituted ...

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) ( ...

TrKA Kinase Inhibitors, Compositions and Methods Thereof

The present invention is directed to substituted five membered heteroaryl benzamide compounds of formula (I) (Formula (I)) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA. 2. The compound according to wherein B is selected from the group consisting of optionally substituted pyrazolyl claim 1 , imidazolyl claim 1 , thiazolyl claim 1 , triazolyl claim 1 , oxazolyl claim 1 , isoxazolyl claim 1 , isothiadiazolyl claim 1 , thiadiazolyl claim 1 , tetrahydrocyclopentapyrazolyl claim 1 , dihydropyrroloimidazolyl claim 1 , oxo-tetrahydropyrazolopyridinyl claim 1 , oxodihydropyrazolyl.3. The compound according to wherein B is optionally substituted pyrazolyl.4. The compound according to wherein B is optionally substituted imidazolyl.5. The compound according to wherein one of Rand Ris hydrogen and the other is (CHR)Cheterocycle claim 1 , said heterocycle optionally substituted with 1 to 3 groups of R.6. The compound according to wherein the optionally substituted heterocycle of Rand Ris a five or six membered ring containing at least one of which is nitrogen.7. The compound according to wherein the heterocycle is selected from the group consisting of oxodiazolyl claim 6 , pyrazolyl claim 6 , pyridyl claim 6 , thiazolyl claim 6 , thiadiazolyl claim 6 , oxazolyl claim 6 , pyrimidinyl claim 6 , and oxodihydropyridinyl claim 6 , said groups optionally substituted.8. The compound according to wherein the heterocycle is optionally substituted pyrazolyl.10. The compound according to wherein one of Rand Ris selected from hydrogen claim 9 , Calkyl claim 9 , and Caryl and the other is selected from Calkyl claim 9 , C(O)N(R) claim 9 , (CH)NH(CH)OR ...

FTO Inhibitors

The invention provides compounds that inhibit FTO (fat mass and obesity), including pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof, particularly obesity, with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition. 4. The composition of wherein:R1 and R2 are independently H or Me;R3 is H, OH or NHR, wherein R is H or C1-C4 alkyl; andR4 is optionally substituted, heterocyclic C3-C18 hydrocarbyl comprising an n-membered ring wherein n=3-18, including 1 to n−1 heteroatoms independently selected from N, O, S and P.5. The composition of wherein the heterocyclic C3-C18 hydrocarbyl is:a 3 membered ring that is an optionally substituted aziridine, oxirane or oxaziridine;a 4 membered ring that is an optionally substituted azetidine, oxetane or oxazetidine;a 5 membered ring that is an optionally substituted pyrrole, 1,2-diazole (pyrazole), 1,3 diazole (imidazole), thiazole, isothiazole, oxazole, isoxazole, furan, dioxole or thiophene;a 6 membered ring that is an optionally substituted pyridine, diazine, triazine, oxazine, thiazine, dioxine, oxathiine or dithiine;a 9 membered ring that is an optionally substituted indole, benzothiazole, benzooxazole, benzofuran, benzodioxole, benzothiophene or benzodithiole; ora 10 membered ring that is an optionally substituted quinoline, quinoxaline, quinazoline, chromene, benzodioxine, thiochromene or benzodithiine.6. The composition of wherein the heterocyclic C3-C18 hydrocarbyl is:a 4 membered ring that is an optionally substituted azetidine, oxetane or oxazetidine.7. The composition of wherein the heterocyclic C3-C18 hydrocarbyl is:a 5 membered ring that is an optionally substituted pyrrole, 1,2-diazole (pyrazole), 1,3 diazole (imidazole), thiazole, isothiazole, oxazole, isoxazole, furan, dioxole or thiophene.8. ...

RIBONUCLEOTIDE REDUCTASE INHIBITORS AND METHODS OF USE

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases. 4. The compound of claim 3 , whereinR is unsubstituted aryl,{'sub': 1', '2', '3', '4', '5', '6', '7, 'R, R, R, R, R, R, and Rare independently hydrogen, unsubstituted aryl, or unsubstituted alkyl.'}5. The compound of claim 3 , wherein Rand Rare optionally joined together to form an acetal protecting group and Rand Rare optionally joined together to form an acetal protecting group.6. The compound of claim 5 , wherein said acetal is a diphenyl methylene acetal.8. The compound of claim 7 , wherein R claim 7 , R claim 7 , Rand Rare independently substituted or unsubstituted alkyl claim 7 , substituted or unsubstituted heteroalkyl claim 7 , substituted or unsubstituted aryl or a substituted silyl.9. The compound of claim 7 , wherein R claim 7 , R claim 7 , Rand Rare independently an activated ethylene protecting group claim 7 , a benzyl ether protecting group claim 7 , a silicon-based carbonate protecting group claim 7 , or a cyclic acetal protecting group.11. A composition comprising the compound of and toluene claim 3 , dimethylformamide or dichloromethane.12. A composition comprising the compound of and a hydroxyl deprotecting agent.13. The composition of claim 12 , wherein said hydroxyl deprotecting agent is boron tribromide claim 12 , an aryl methyl ether claim 12 , tetrabutylammonium fluoride claim 12 , hydrogen/Pd/C claim 12 , Zn/acid or ammonia.15. The method of claim 14 , wherein said hydroxyl deprotecting agent is boron tribromide claim 14 , an aryl methyl ether claim 14 , tetrabutylammonium fluoride claim 14 , hydrogen/Pd/C claim 14 , Zn/acid ...

SMALL MOLECULE INHIBITORS OF PROTEIN TYROSINE PHOSPHATASES AND USED THEREOF

Small molecule compounds derived from α-sulfophenylacetic amide (SPAA) are provided as novel sulfonic acid based pTyr mimetics. These compounds effectively inhibit a variety of protein tyrosine phosphatases (PTPs), such as mPTPA, mPTPB, LMWPTP, and Laforin. Use of these compounds as pharmaceutical agents for treating diseases associated with abnormal protein tyrosine phosphatase activity is also provided. 2. The compound of claim 1 , wherein Ris phenyl or benzo[d]thiazol-2-yl claim 1 , optionally substituted with one or more substituent selected from the group consisting of C-Calkyl claim 1 , C-Calkoxy claim 1 , C-Calkoxy carbonyl claim 1 , amino claim 1 , aryl claim 1 , benzyloxy (—OBn) claim 1 , —CF claim 1 , carboxy claim 1 , halogen claim 1 , 1-imidazolyl claim 1 , 4-morpholinyl claim 1 , and nitro.5. A method of inhibiting a protein tyrosine phosphatase (PTP) selected from the group consisting of mPTPA claim 1 , mPTPB claim 1 , low molecular weight PTP (LMWPTP) claim 1 , and Laforin in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .6. A method of treating tuberculosis in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .7. A method of treating a cancer in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .8. The method of wherein the cancer is selected from the group consisting of breast cancer claim 7 , colon cancer claim 7 , bladder cancer claim 7 , and kidney cancer.9. A method of treating Lafora disease in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .10. A method of treating type 2 diabetes in a subject in need thereof claim 1 , the method comprising administering to the subject a ...

PROTEIN TYROSINE PHOSPHATASES OR SHP2 INHIBITORS AND USES THEREOF

Small molecule compounds derived from α-sulfophenylacetic amide (SPAA) are provided as novel sulfonic acid based pTyr mimetics. These compounds effectively inhibit a variety of protein tyrosine phosphatases (PTPs), such as mPTPA, mPTPB, LMWPTP, and Laforin. Use of these compounds as pharmaceutical agents for treating diseases associated with abnormal protein tyrosine phosphatase activity is also provided. 4. A method of inhibiting Src homogloy 2 typrosine phosophatase (SHP2) in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .5. A method of treating a cancer in a subject in need thereof claim 1 , the method comprising administering to the subject a therapeutically effective amount of the compound of .6. The method of wherein the cancer is selected from the group consisting of breast cancer claim 5 , lung cancer claim 5 , colon cancer claim 5 , prostate cancer claim 5 , neuroblastoma claim 5 , glioblastoma claim 5 , melanoma claim 5 , hepatocellular carcinoma claim 5 , and leukemia.7. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.8. A method of inhibiting Src homogloy 2 typrosine phosophatase (SHP2) in a subject in need thereof claim 2 , the method comprising administering to the subject a therapeutically effective amount of the compound of .9. A method of treating a cancer in a subject in need thereof claim 2 , the method comprising administering to the subject a therapeutically effective amount of the compound of .10. The method of wherein the cancer is selected from the group consisting of breast cancer claim 9 , lung cancer claim 9 , colon cancer claim 9 , prostate cancer claim 9 , neuroblastoma claim 9 , glioblastoma claim 9 , melanoma claim 9 , hepatocellular carcinoma claim 9 , and leukemia.11. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.12. A method of inhibiting Src ...

Pi-kinase inhibitors with anti-infective activity

Compounds and methods are provided for the treatment of pathogen infections. In some embodiments, the anti-infective compounds have broad spectrum activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of inhibiting a PI4-kinase and methods of inhibiting viral infection. In some embodiments, the compound is a PI4-kinase inhibiting compound that is a 5-aryl-thiazole or a 5-hetereoaryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribivarin, and the like.

INHIBITORS OF CYCLIN-DEPENDENT KINASES

The present invention provides novel compounds of Formulae (I′), (I), (II′), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject. 2. (canceled)4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein the Ring B is optionally substituted monocyclic heterocyclyl.5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein the Ring B is optionally substituted piperidinyl.711-. (canceled)12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring B is optionally substituted monocyclic carbocyclyl.13. (canceled)1517-. (canceled)18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring C is optionally substituted.bicyclic aryl or heteroaryl.1920-. (canceled)2230-. (canceled)31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ring A is optionally substituted monocyclic heteroaryl.3239-. (canceled)40. The compound of claim 1 , or a ...

Methods for Modulating Bacterial Virulence and Related Compounds

The present invention relates to compounds and methods for the treatment of bacterial infections. The compounds and methods involve the disruption of the QseC signaling pathway which modulates the virulence of some bacteria. This methodology for treatment of bacterial infections reduces evolutionary pressure to develop resistance because the bacteria are not killed in the process. 2. The method according to claim 1 , wherein Ris hydrogen.3. The method according to claim 1 , wherein Ris methyl.4. The method according to claim 1 , wherein Ris hydrogen.5. The method according to claim 1 , wherein Ris methyl.6. The method according to claim 1 , wherein Ris hydrogen.7. The method according to claim 1 , wherein Ris methyl.8. The method according to claim 1 , wherein Rare halo.9. The method of claim 8 , wherein Ris fluoro.10. The method according to claim 1 , wherein Ris nitro.11. The method according to claim 1 , wherein Ris substituted aryl and Ris hydrogen.12. The method according to claim 1 , wherein the aryl group on Ris substituted with a methyl group in the 4-position.13. The method according to claim 1 , wherein Ris cyano and Ris hydrogen.14. The method according to claim 1 , wherein Ris hydrogen and Ris cyano.15. The method according to claim 1 , wherein Ris —C(O)OCHCHand Ris hydrogen.16. The method according to claim 1 , wherein Ris aryl or substituted aryl.17. The method according to claim 1 , wherein Ris substituted aryl.19. The method according to claim 1 , wherein Ris a substituted aryl where X claim 1 , X claim 1 , and Xare halo.20. The method according to claim 1 , wherein Ris a substituted aryl where X claim 1 , X claim 1 , and Xare —F.21. The method according to claim 1 , wherein Ris a substituted aryl where X claim 1 , X claim 1 , and Xare —Cl.22. The method according to claim 1 , wherein Ris a substituted aryl where Xand X claim 1 , are —OMe and Xis hydrogen.23. The method according to claim 1 , wherein Ris a substituted aryl where Xand X claim 1 , are ...

PI-KINASE INHIBITORS WITH ANTI-INFECTIVE ACTIVITY

Compounds and methods are provided for the treatment of pathogen infections. In some embodiments, the anti-infective compounds have broad spectrum activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of inhibiting a PI4-kinase and methods of inhibiting viral infection. In some embodiments, the compound is a PI4-kinase inhibiting compound that is a 5-aryl-thiazole or a 5-hetereoaryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribivarin, and the like. 46.-. (canceled)10. (canceled)12. (canceled)1518.-. (canceled)2126.-. (canceled)29. (canceled)31. The compound of claim 30 , wherein Ris methyl claim 30 , isopropyl claim 30 , cyclohexyl claim 30 , substituted cyclohexyl claim 30 , phenyl claim 30 , substituted phenyl claim 30 , benzyl claim 30 , substituted benzyl or —CH-4-tetrahydropyran.3233.-. (canceled)34. A method of inhibiting a PI4-kinase claim 1 , the method comprising contacting a sample comprising the PI4-kinase with the compound of .35. The method of claim 34 , wherein the PI4-kinase is a PI4-III kinase.36. (canceled)37. A method of treating a subject for an infective disease condition claim 1 , the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.38. The method of claim 37 , wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.39. The method of claim 37 , wherein the infective disease condition results from infection with a virus selected from the Picornaviridae claim 37 , Flaviviridae claim 37 , Caliciviridae claim 37 , Filoviridae claim 37 , ...

T-BOX RIBOSWITCH-BINDING ANTI-BACTERIAL COMPOUNDS

The present disclosure identifies compounds that bind to a t-RNA-dependent riboswitch of aaRS gene expression unique to Gram-positive bacteria. The compounds have anti-bacterial activity. 5. A compound of claim of claim 4 , wherein said compound has bacteriostatic or bactericidal activity against Gram-positive bacteria.6. A compound of for use in the treatment of Gram-positive bacterial infection.7. A composition of for use in the treatment of Gram-positive bacterial infection.8. A compound of for use in killing or inhibiting the growth of Gram-positive bacteria.9. A composition of for use in killing or inhibiting the growth of Gram-positive bacteria.10. A method for inhibiting the growth of Gram-positive bacteria comprising contacting said bacteria with a compound of .11. A method for the treatment of a Gram-positive bacterial infection in an individual comprising administering a compound of .12Staphylococcus aureusBacillus subtilis.. The method of claim 10 , wherein the Gram-positive bacteria is or13. A composition of claim 2 , further comprising an additional antibacterial agent.14. A method for inhibiting the growth of Gram-positive bacteria comprising contacting said bacteria with a compound of .15. A method for the treatment of a Gram-positive bacterial infection in an individual comprising administering a compound of .16Staphylococcus aureusBacillus subtilis.. The method of claim 11 , wherein the Gram-positive bacteria is or17. A composition of claim 1 , further comprising an additional antibacterial agent. This application claims priority to U.S. Provisional application Ser. No. 61/857,492 filed Jul. 23, 2014, the contents of which are incorporated by reference into the present application.The present invention generally relates to antibacterial agents. More particularly, the present invention relates to compounds with bactericidal/bacteriostatic activity against Gram-positive organisms.As is the case with many Gram-positive pathogens including bacilli and ...

Inhibitors of heat shock factors and uses thereof

The present disclosure relates to a class of mammalian heat shock factor (HSF) inhibitors, to pharmaceutical compositions comprising these inhibitors as well as to methods for using the inhibitors. The inhibitors inhibit stress-induced expression from heat shock gene promoters. Furthermore, the inhibitors are cytotoxic to a variety of human cancer cells types. 2. (canceled)6. The HSF inhibitor of claim 1 , wherein the inhibitor is (E)-3-(5 claim 1 ,6-dihydro-4H-[1 claim 1 ,3]oxazin-2-yl)-N-methyl-N-(5-(pyridin-3-yl-thiazol-2-yl)acrylamide or a salt thereof.7. (canceled)8. (canceled)9. (canceled)12. (canceled)13. (canceled)14. The HSF inhibitor for use in treatment of claim 11 , wherein the HSF inhibitor is (E)-3-(5 claim 11 ,6-dihydro-4H-[1 claim 11 ,3]oxazin-2-yl)-N-methyl-N-(5-(pyridin-3-yl-thiazol-2-yl)acrylamide.15. (canceled)16. (canceled)17. The HSF inhibitor for use in the treatment or prophylaxis in a mammalian claim 11 , including human claim 11 , subject of a disease or condition that is mediated or enhanced by an activity of the HSF of claim 11 , wherein the disease is a hyperproliferative disease.18. The HSF inhibitor for use in the treatment or prophylaxis in a mammalian claim 17 , including human claim 17 , subject of a disease or condition that is mediated or enhanced by an activity of the HSF of claim 17 , wherein the hyperproliferative disease is a cervical cancer claim 17 , a breast cancer claim 17 , a lung cancer claim 17 , a prostate cancer claim 17 , an ovarian cancer claim 17 , a neuroblastoma claim 17 , a peripheral nerve sheath cancer claim 17 , a leukemia claim 17 , a myeloma claim 17 , a liver cancer or an osteosarcoma.19. (canceled) The present disclosure relates to heat shock factor inhibitors and uses thereof in the treatment of diseases and other conditions that depend on or are enhanced by heat shock factor activity.Heat shock genes were discovered more than 50 years ago as genes whose activity is increased in cells exposed to elevated ...

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.

COMPOUNDS AND METHODS FOR INDUCING CHONDROGENESIS

Described herein are compounds and compositions for the amelioration of arthritis or joint injuries by inducing mesenchymal stem cells into chondrocytes. 1119.-. (canceled)121. The method of claim 120 , wherein B is NHC(O)R.122. The method of claim 120 , wherein each Rand Ris independently optionally substituted alkyl.123. The method of claim 120 , wherein Rand Rtogether with the N to which they are attached make a ring.124. The method of claim 120 , wherein Ris optionally substituted phenyl.125. The method of claim 120 , wherein the phenyl of Ris monosubstituted or disubstituted.126. The method of claim 125 , wherein substitution on the phenyl of Ris independently selected from F claim 125 , Cl claim 125 , COH claim 125 , CN claim 125 , OCH claim 125 , C(O)CH claim 125 , CF claim 125 , CH claim 125 , CHOH claim 125 , CHCHOH claim 125 , and CHCHCHOH.129. The method of claim 128 , wherein X is O or NH and A is CH—CRR—C(O)R.130. The method of claim 128 , X is NRand A is C(O) or CH.131. The method of claim 128 , wherein Ris phenyl and the phenyl of Ris monosubstituted or disubstituted.132. The method of claim 131 , wherein substitution on the phenyl is independently selected from F claim 131 , Cl claim 131 , COH claim 131 , CN claim 131 , OCH claim 131 , C(O)CH claim 131 , CF claim 131 , CH claim 131 , CHOH claim 131 , CHCHOH claim 131 , and CHCHCHOH.133. The method of claim 128 , wherein n is 0 or 1.134. The method of claim 133 , wherein Ris independently selected from Cl claim 133 , F claim 133 , CHOH claim 133 , CHNH claim 133 , OCH claim 133 , OCF claim 133 , OCHF claim 133 , CN claim 133 , NO claim 133 , COH claim 133 , and COCH.137. A pharmaceutical composition comprising a compound of claim 136 , or a pharmaceutically acceptable salt claim 136 , solvate claim 136 , polymorph claim 136 , prodrug claim 136 , ester claim 136 , metabolite claim 136 , N-oxide claim 136 , stereoisomer claim 136 , or isomer thereof claim 136 , and a pharmaceutically acceptable ...

FTO Inhibitors

The invention provides compounds that inhibit FTO (fat mass and obesity), including pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof, particularly obesity, with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition. 2. The pharmaceutical composition of claim 1 , wherein the heterocyclic C3-C18 hydrocarbyl comprises:a 3 membered ring that is an optionally substituted: aziridine, oxirane, oxaziridine;a 4 membered ring that is an optionally substituted: azetidine, oxetane, oxazetidine;a 5 membered ring that is an optionally substituted: pyrrole, 1, 2-diazole (pyrazole), 1, 3 diazole (imidazole), thiazole, isothiazole, oxazole, isoxazole, furan, dioxole, thiophene;a 6 membered ring that is an optionally substituted: pyridine, diazine, triazine, oxazine, thiazine, dioxine, oxathiine, dithiine;a 9 membered ring that is an optionally substituted: indole, benzothiazole, benzooxazole, benzofuran, benzodioxole, benzothiophene, benzodithiole; ora 10 membered ring that is an optionally substituted: quinoline, quinoxaline, quinazoline, chromene, benzodioxine, thiochromene, benzodithiine.4. The pharmaceutical composition of claim 1 , copackaged or coformulated with a second claim 1 , different medicament for inhibiting weight gain claim 1 , promoting weight loss claim 1 , reducing serum LDL claim 1 , cholesterol claim 1 , LDL-c claim 1 , or triglycerides claim 1 , or treating obesity or an obesity related disease or Alzheimer's disease.5. A method comprising administering to a person in need thereof a composition of to inhibit weight gain claim 1 , promote weight loss claim 1 , reduce serum LDL claim 1 , cholesterol claim 1 , LDL-c claim 1 , or triglycerides claim 1 , or treat obesity or an obesity related disease or Alzheimer's disease.6. The method of ...

SUBSTITUTED PYRAZOLES AS HEAT SHOCK TRANSCRIPTION FACTOR ACTIVATORS

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

Substituted Hydrophobic Benzene Sulfonamide Thiazole Compounds for Use in Treating Cancer

The present invention relates to compound of general formula (I) Ris selected from H, aryl and alkyl, Ris selected from H, alkyl, aryl and CO—R; Ris selected from H, halogen, alkyl, alkenyl, alkynyl, aryl, NHR, NRR, ORand SR; Ris selected from (C-C) alkyl, (C-C) alkenyl, (C-C) alkynyl and (C-C) aryl, Rrepresents H, R, aryl, OH, OR, O-aryl, SH, SR, S-aryl, CN, NO, CF, COOR, SONRR, CONRR, NH, NHR, NH-aryl, NRR, NHCORor aminoacyl; Ris alkyl optionally substituted with halogen, OH, SH, NH, O-alkyl, S-alkyl, NH-alkyl or NH-di(alkyl); Rand Ridentical or different are H or alkyl optionally substituted with halogen, OH, SH, NH, O-alkyl, S-alkyl, NH-alkyl or NH-di (alkyl), their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof. The compounds are useful for the treatment of cancers. 2. The compound according to claim 1 , wherein Ris H.3. The compound according to claim 1 , wherein Ris selected from H claim 1 , methyl or COCH.4. The compound according to claim 1 , wherein Ris H.5. The compound according to claim 1 , wherein Ris{'sub': 6', '12, '(C-C) alkyl,'}{'sub': 6', '10, '(C-C) aryl,'}{'sub': 9', '9', '1', '12, 'CH═CHR, wherein Ris (C-C) alkyl, or'}{'sub': 10', '10', '1', '8', '1', '8', '3', '5', '3', '8, 'C≡CR, wherein Ris selected from H, C-Calkyl, hydroxy (C-C) alkyl, cyclo (C-C) alkyl and hydroxyl-cyclo (C-Calkyl).'}6. The compound according to claim 1 , wherein Ris in the meta or para position with respect to the sulfonyl group.7. The compound according to claim 1 , wherein the compound is selected from the group consisting of:N-(4-(3-(4-(oct-1-ynyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamideN-(4-(3-(3-(oct-1-ynyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamideN-(4-(3-(3-(3-hydroxyprop-1-ynyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamideN-(4-(3-(3-((trimethylsilyl)ethynyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamideN-(4-(3-(3-ethynylphenylsulfonamnido)phenyl)thiazol-2-yl)acetamideN-(3-(2-aminothiazol-4-yl) ...

MODULATORS OF MYOCYTE LIPID ACCUMULATION AND INSULIN RESISTANCE AND METHODS OF USE THEREOF

Formulations and methods for reducing blood glucose and/or increasing insulin signaling in a subject have been developed. The formulations include SBI-477 and compounds based on SBI-477 i.e., SBI-477 analogs (collectively, SBI-477 compounds) and/or Mondo family inhibitors, in an effective amount to inhibit intracellular lipid accumulation and/or increase cellular glucose uptake when compared to levels in a control subject not administered the composition. Also disclosed are methods of reducing intracellular lipid accumulation and/or increase glucose uptake in a subject in need thereof. The method includes administering to the subject an effective amount of SBI-477 compounds and/or Mondo family inhibitor to reducing intracellular lipid accumulation and/or increase glucose uptake in the subject. Also disclosed are method for treating one or more Myc-driven cancers, including neuroblastoma, lung squamous cell carcinoma/lung adenocarcinoma, liver hepatocellular carcinoma, colon adenocarcinoma, acute myeloid leukemia, and breast invasive carcinoma. 1. A pharmaceutical composition comprising {'br': None, 'sub': 1', '2', '2', 'n, 'A-L-B-L-D-(R′),\u2003\u2003 Formula I'}, '(i) a compound represented by the general Formula Iwherein{'sub': 3', '30', '3', '30, 'A is substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C-Ccycloalkyl, unsubstituted C-Ccycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, substituted alkylthio, or unsubstituted alkylthio;'}{'sub': '1', 'Lis —C(O)NR′—, —NR′C(O)—, —C(O)O—, —OC(O)—, —O—, a bond, substituted alkyl, unsubstituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted ...

NOVEL SULFONYLAMINOBENZAMIDE COMPOUNDS AS ANTHELMINTICS

The present invention relates to a new compound of formula (I) wherein the variables have the meaning as indicated in the claims; or an enantiomer or salt thereof. The compounds of formula (I) are useful in the control of parasites, in particular endoparasites, in and on vertebrates. 3. A compound according to claim 2 , wherein Y′ is phenyl which is substituted by 2 or 3 same or different radicals selected from halogen or CF; and A′ is C-C-alkyl; CF;{'sub': 1', '2', '1', '2', '1', '2, 'pyrrolidinyl, piperazinyl, morpholinyl or dioxaborolanyl, which is each unsubstituted or substituted by methyl; pyrryl, pyrazolyl, triazolyl, thienyl, thiazinyl, thiazolyl, pyridyl or pyrimidinyl, which is each unsubstituted or substituted by halogen, cyano, C-C-alkyl, C-C-alkoxy, C-C-haloalkyl, acetyl, propionyl, phenyl or morpholin-4-yl-methyl; or indolyl, benzopyrazolyl or benzothiazolyl, which is each unsubstituted or substituted by methyl; and n is 1.'}5. A compound according to claim 4 , wherein A is phenyl which is unsubstituted or mono-substituted by chlorine claim 4 , fluorine or CF claim 4 , Y is phenyl which is substituted by 2 or 3 same or different radicals selected from halogen or CF claim 4 , and T is C-C-alkyl claim 4 , which is unsubstituted or substituted by halogen claim 4 , cyclopropyl claim 4 , cyclohexyl claim 4 , trimethylsilyl claim 4 , carboxy or C-C-alkoxycarbonyl; cyclopropyl or cyclohexyl; the radical of (+)- or (−)-camphor; phenyl which is unsubstituted or substituted by fluorine claim 4 , chlorine claim 4 , methyl claim 4 , methoxy claim 4 , CFor nitro; or pyridyl claim 4 , thienyl or pyrimidinyl; piperidinyl claim 4 , piperazinyl claim 4 , tetrahydropyranyl claim 4 , morpholinyl claim 4 , thiomorpholinyl or thiomorpholin-4-yl-1 claim 4 ,1-dioxide claim 4 , which is each unsubstituted or substituted by methyl or benzyloxycarbonyl.8. A composition for the control of parasites claim 1 , which contains as an active ingredient at least one compound of formula ...

NOVEL ANTIVIRAL AGENTS AGAINST HBV INFECTION

The present invention is directed toward novel compounds and novel methods of use of said compounds of the formula (I), useful as nucleocapsid assembly inhibitors for the treatment of viruses, especially but not exclusively, including pregenomic RNA encapsidation inhibitors of HBV for the treatment of Hepatitis B virus (HBV) infection and related conditions. 161-. (canceled)63. The compound of claim 62 , wherein a substituted group is substituted with at least one selected from the group consisting of Calkyl claim 62 , Chaloalkyl claim 62 , Calkenyl claim 62 , Calkynyl claim 62 , Ccycloalkyl claim 62 , —F claim 62 , —Cl claim 62 , —Br claim 62 , —I claim 62 , —CN claim 62 , —NO claim 62 , —OR claim 62 , —SR claim 62 , —N(R) claim 62 , —NRC(O)R claim 62 , —SOR claim 62 , —SOOR claim 62 , —SON(R) claim 62 , —C(O)R claim 62 , —C(O)OR claim 62 , —C(O)N(R) claim 62 , aryl claim 62 , heterocyclyl claim 62 , or heteroaryl claim 62 , wherein each occurrence of Ris independently selected from the group consisting of hydrogen claim 62 , Calkyl claim 62 , Chaloalkyl claim 62 , Calkenyl claim 62 , Calkynyl claim 62 , and Ccycloalkyl claim 62 , or two Runits taken together with the atom(s) to which they are bound form optionally substituted 3- to 7-membered carbocyclyl or optionally substituted 3- to 7-membered heterocyclyl.64. The compound of claim 62 , wherein the heteroaryl is selected from the group consisting of diazolyl claim 62 , imidazolyl claim 62 , imidazolyl claim 62 , triazinyl claim 62 , thiazolyl claim 62 , isothiazolyl claim 62 , oxazolyl claim 62 , isoxazolinyl claim 62 , furanyl claim 62 , thiophenyl claim 62 , pyrimidinyl claim 62 , pyridinyl claim 62 , tetrazolyl claim 62 , benzofuranyl claim 62 , benzothiophenyl claim 62 , benzoxazolyl claim 62 , benzthiazolyl claim 62 , benztriazolyl claim 62 , cinnolinyl claim 62 , naphthyridinyl claim 62 , phenanthridinyl claim 62 , 7H-purinyl claim 62 , 9H-purinyl claim 62 , 6-amino-9H-purinyl claim 62 , 5H-pyrrolo[3 ...

ENZYME AND RECEPTOR MODULATION

Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid, leads to accumulation of the carboxylic acid hydrolysis product in the cell and enables improved or more prolonged enzyme or receptor modulation relative to the unconjugated modulator. 2. The covalent conjugate according to wherein the position of conjugation is remote when the conjugate has a potency in an enzyme assay at least as high as that of the unconjugated binding compound in the same assay claim 1 , which assay measures the ability of the covalent conjugate or the unconjugated binding compound to inhibit p38 MAP kinase α activity.3. The covalent conjugate according to wherein the conjugate has a potency in a human whole blood assay at least as high as that of the unconjugated binding compound in the same assay claim 1 , which assay measures the ability of the covalent conjugate or the unconjugated binding compound to inhibit TNF-α production.4. The covalent conjugate according to wherein the conjugate has a potency in a human whole blood assay at least as high as that of the unconjugated binding compound in the same assay claim 2 , which assay measures the ability of the covalent conjugate or the unconjugated binding compound to inhibit TNF-α production. This application is a continuation of U.S. patent application Ser. No. 15/650,031 filed on Jul. 14, 2017, which is a continuation of U.S. patent application Ser. No. 14/508,248 filed on Oct. 7, 2014, which is a continuation of U.S. patent application Ser. No. 11/918,138 filed on Oct. 10, 2007, which is a national phase application under 35 U.S.C. § 371 that claims priority to PCT Application No. PCT/GB2006/001635 filed on May 4, 2006, which claims the benefit of U.S. Patent Provisional Application No. 60/680,542 filed May 13, 2005, and claims the ...

2-ACYLAMINOTHIAZOLES FOR THE TREATMENT OF CANCER

The present invention relates to inhibitors of the oncogenic protein kinase ALK of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) are useful in the preparation of a medicament, in particular for the treatment of cancer. 2. The compounds of wherein{'sub': 2', '1', '3, 'Ris hydrogen or linear or branched C-Calkyl; and'}{'sub': 3', '4, 'Ris —C≡C—R.'}3. The compounds of wherein{'sub': 2', '4, '—Ris —C≡C—R; and'}{'sub': 3', '1', '3, 'Ris hydrogen or linear or branched C-Calkyl.'}9. The compounds of selected from the list of4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-(phenylethynyl)phenyl)thiazol-2-yl)benzamide;4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-(p-tolylethynyl)phenyl)thiazol-2-yl)benzamide;N-(4-(3-((4-methoxyphenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(4-methyl-3-(phenylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamideN-(4-(4-methyl-3-(p-tolylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(3-((4-methoxyphenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(4-methyl-3-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide:N-(4-(3-((2-methoxyphenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(3((4-fluorophenyl)ethynyl)-4-methylphenyl)thiazol-2-yl)-4-(4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(3-methyl-4-(p-tolylethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(3-methyl-4-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;4-((4-methylpiperazin-1-yl)methyl)-N-(4-(3-((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)benzamide;N-(4-(3,4-bis((2-(trifluoromethyl)phenyl)ethynyl)phenyl)thiazol-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;N-(4-(4-methyl-3-((triisopropylsilyl)ethynyl)phenyl)thiazol-2-yl)-4-((4- ...

ANTI-MIGRATION AND ANTI-INVASION THIAZOLE ANALOGS FOR TREATMENT OF CELLULAR PROLIFERATIVE DISEASE

Thiazole analog compounds and their pharmaceutically acceptable salts are disclosed, including pharmaceutical compositions comprising the thiazole analog compounds, either alone or in combination with at least one additional therapeutic agent, and/or with a pharmaceutically acceptable carrier. Methods of using the thiazole analog compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular proliferative diseases, such as cancer, are also disclosed. 2. The compound of claim 1 , wherein{'sup': '1', 'Rphenyl, methoxyphenyl at any position 2-6, dimethoxyphenyl at any two positions 2-6, trimethoxyphenyl at any three positions 2-6;'}{'sup': '5', 'Ris —C(═O)—; and'}{'sup': '7', 'Ris phenyl, xylyl, or trimethoxyphenyl at any three positions 2-6,'}or a salt thereof.3. The compound of claim 1 , wherein{'sup': '1', 'Ris phenyl;'}{'sup': '2', 'Ris hydrogen, methyl, or is absent;'}{'sup': '4', 'Ris hydrogen or methyl;'}{'sup': '5', 'Ris —C(═O)—; and'}{'sup': '6', 'Ris phenyl, xylyl, cyclopropyl, chlorophenyl, bromophenyl, or'}bis(trifluoromethyl)phenyl,or a salt thereof.4. The compound of selected from the group consisting of: 2-Amino-4-phenylthiazole claim 1 , 2-Amino-4-(2 claim 1 ,4-dimethylphenyl)thiazole claim 1 , N-(4-Phenylthiazol-2-yl)thiophene-2-carboxamide claim 1 , N-(4-Phenylthiazol-2-yl)furan-2-carboxamide claim 1 , 4-Chloro-N-(4-phenylthiazol-2-yl)benzamide claim 1 , 4-Bromo-N-(4-phenylthiazol-2-yl)benzamide claim 1 , 3 claim 1 , 4 claim 1 , 5-Trimethoxy-N-(4-phenylthiazol-2-yl)benzamide claim 1 , N-(4-(2 claim 1 ,4-Dimethylphenyl)thiazol-2-yl)thiophene-2-carboxamide claim 1 , 3 claim 1 , 4-Dimethoxy-N-(4-phenylthiazol-2-yl)benzamide claim 1 , N-(4-Phenylthiazol-2-yl)nicotinamide claim 1 , N-(4-Phenylthiazol-2-yl)isonicotinamide claim 1 , N-(4-Phenylthiazol-2-yl)benzamide claim 1 , N-(4-Phenylthiazol-2-yl)cyclopentanecarboxamide claim 1 , N-(4-Phenylthiazol-2-yl)cyclohexanecarboxamide claim 1 , ...

New benzene sulfonamide thiazole compounds

The present invention relates to compound of general formula (1) wherein R 1 represents C 6 -C 10 aryl comprising one or two fused rings, wherein from 2 to 5 carbon atoms may be replaced with a heteroatom selected from O, S and NR 6 , and eventually substituted with from 5 to 11 substituents selected from R 6 , halo, CN, NO 2 , CF 3 , OCF 3 , COOR 6 , OCOR 6 , SO 2 NR 6 R 7 , CONR 6 R 7 , NR 6 R 7 , NR 6 COR 7 , (CH 2 ) p —NR 6 R 7 , (CH 2 ) p —OR 6 and (CH 2 ) p SR 6 , as well as, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof. The compounds are useful for the treatment of cancers.

Inhibitors of calcium-activated chloride channels

Provided herein are methods for identifying compounds that are inhibitors of a calcium-activated chloride channel. Aminothiophene and aminothiazole compounds, and compositions comprising these compounds, described herein that inhibit efflux of chloride through a calcium-activated chloride channel are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased chloride and fluid secretion, for example, secretory diarrhea.

Cycloalkyl-Linked Diheterocycle Derivatives

The present invention relates to compounds of formula (I) 2. A pharmaceutical formulation comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and at least one pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient. This application is a continuation application of U.S. application Ser. No. 16/157,618, filed Oct. 11, 2018, which is a continuation application of U.S. application Ser. No. 15/826,027, filed Nov. 29, 2017, now U.S. patent Ser. No. 10/125,130, issued on Nov. 13, 2018, which is a continuation of U.S. application Ser. No. 15/306,979, filed Oct. 26, 2016, which is a § 371 filing of PCT/IB2015/052833 filed Apr. 17, 2015, which claims the benefit of priority to U.S. Provisional Application No. 61/986,876 filed Apr. 30, 2014; the entire contents of which are incorporated herein by reference.The present invention relates to novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.Tumor cells require nutrients to generate ATP and macromolecules to sustain survival and proliferation. (Ward P. S., et al., “Metabolic Reprogramming: a Cancer Hallmark even Warburg did not Anticipate”, 21(3) (2012), pp. 297-308.) Glucose and glutamine are two major sources of nutrients that tumor cells depend on. Tumor cells prefer to use glycolysis pathways, even under aerobic conditions, to metabolize glucose to produce lactic acid and ATP, the so-called Warburg's effect. In addition to glucose, many tumor cells are addicted to glutamine (“Gln”) for survival (DeBerardinis R. J., et al., “Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer”, 29(3) (2010), pp. 313-24; Shanware N. P., et al., “Glutamine: ...

SMALL MOLECULE ACTIVATORS OF CALCIUM-ACTIVATED CHLORIDE CHANNELS AND METHODS OF USE

Provided herein are small molecule activators of calcium-activated chloride channels. These small molecules may be used for treatment of diseases and disorders that are treatable by activating calcium-activated chloride channels, such as cystic fibrosis, disorders related to salivary gland dysfunction (for example, Sjogren's syndrome and dysfunction following radiation injury), dry eye syndrome, and intestinal hypomotility. 3. (canceled)4. The pharmaceutical composition of claim 1 , wherein at least one of R claim 1 , Ror Ris methoxy.5. (canceled)6. The pharmaceutical composition of claim 1 , wherein Ris benzyl claim 1 , tetrahydrofuran-2-yl-methyl claim 1 , furan-2-yl-methyl claim 1 , 2-methoxyethyl claim 1 , tetrahydropyran-2-yl-methyl claim 1 , pyrid-4-yl-methyl or pyrid-2-yl-methyl.78.-. (canceled)9. The pharmaceutical composition of claim 1 , wherein at least one of Ror Ris hydrogen.10. (canceled)11. The pharmaceutical composition of claim 1 , wherein at least one of Ror Ris methoxy claim 1 , chloro claim 1 , or fluoro.1218.-. (canceled)2227.-. (canceled)30. The method of claim 29 , wherein the calcium-activated chloride ion channel is TMEM16A.31. The method of claim 29 , wherein the disease or condition is salivary gland dysfunction claim 29 , cystic fibrosis claim 29 , dry eye syndrome claim 29 , dry mouth claim 29 , intestinal hypomotility claim 29 , Sjoren's syndrome claim 29 , or a salivary gland dysfunction caused by radiation injury.3233.-. (canceled)35. The method of claim 34 , wherein the calcium-activated chloride ion channel is TMEM16A.36. The method of claim 34 , wherein the disease or condition is salivary gland dysfunction claim 34 , cystic fibrosis claim 34 , dry eye syndrome claim 34 , dry mouth claim 34 , intestinal hypomotility claim 34 , Sjogren's syndrome claim 34 , or salivary gland dysfunction caused by radiation injury.3738.-. (canceled)41. (canceled)42. The compound if claim 39 , wherein at least one of R claim 39 , Ror Ris methoxy.43. ( ...

COMPOSITIONS AND METHODS OF TREATMENT WITH PRODRUGS OF TIZOXANIDE, AN ANALOGUE OR SALT THEREOF

Prodrugs of tizoxanide, an analogue or salt thereof are disclosed. The prodrugs have an ester moiety comprising an amino acid moiety, and increase the bioavailability of the tizoxanide, an analogue or salt thereof. Compositions and methods of treating an intracellular protozoan infection, a viral infection or a cancer are also disclosed. 142.-. (canceled)44. A pharmaceutically acceptable salt of the compound of .45. The salt of claim 44 , which is a hydrochloric salt.46. A pharmaceutical composition comprising the compound of or its pharmaceutically acceptable salt.47. The pharmaceutical composition of claim 46 , wherein the composition is an injectable formulation.48. The pharmaceutical composition of claim 46 , wherein the composition is an intravenous formulation.49. The pharmaceutical composition of claim 47 , comprising an aqueous solution of the compound or its pharmaceutically acceptable salt.50. The pharmaceutical composition of in a dosage form suitable for injection.51. The pharmaceutical composition of claim 50 , wherein the dosage form is suitable for intravenous administration.52. The pharmaceutical composition of claim 46 , wherein the composition is an oral formulation.53. A pharmaceutical formulation comprising an aqueous solution of the compound of or its pharmaceutically acceptable salt. This application claims the benefit of U.S. Provisional Application Ser. No. 62/078,384, filed Nov. 11, 2014, which is incorporated by reference herein.Nitazoxanide (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide) is a compound having the following structure:Tizoxanide is the active circulating metabolite of nitazoxanide.The preparation and uses of nitazoxanide are disclosed, for example, in U.S. Pat. No. 3,950,351 to Rossignol.Pharmaceutical compositions containing nitazoxanide and its metabolite, tizoxanide, were originally developed and marketed for treating intestinal parasitic infections. However, nitazoxanide, tizoxanide and various analogues thereof have ...