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    3,4-diarylpyrazoles and their use in the therapy of cancer
    1.
    发明授权
    3,4-diarylpyrazoles and their use in the therapy of cancer 失效
    3,4-二芳基吡唑及其在癌症治疗中的应用

    公开(公告)号：US07247734B2

    公开(公告)日：2007-07-24

    申请号：US10499030

    申请日：2002-12-19

    申请人： Martin James Drysdale ,  Brian William Dymock ,  Xavier Barril-Alonso ,  Paul Workman ,  Laurence Harris Pearl ,  Chrisostomos Prodromou ,  Edward McDonald

    发明人： Martin James Drysdale ,  Brian William Dymock ,  Xavier Barril-Alonso ,  Paul Workman ,  Laurence Harris Pearl ,  Chrisostomos Prodromou ,  Edward McDonald

    IPC分类号： C07D231/10

    CPC分类号： C07D231/12 ,  A61K31/415 ,  C07D231/14 ,  C07D231/16 ,  C07D401/04 ,  C07D401/10 ,  C07D403/04 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/04 ,  C07D417/04

    摘要： The present invention pertains to the use of certain 3,4-diarylpyazoles of formula (I), both in vitro and in vivo, to inhibit heat shock protein 90 (HSP90), and in the treatment of conditions mediated by HSP90, including, for example, cancer; wherein: Ar3 is independently: a C5-20aryl group, and is optionally substituted; Ar4 is independently: a C5-20aryl group, and is optionally substituted; R5 is independently: hydrogen; halo; hydroxyl; ether; formyl; acyl; carboxy; ester; acyloxy; oxycarbonyloxy; amido; acylamido; aminocarbonyloxy; tetrazolyl; amino; nitro; cyano; azido; sulfhydryl; thioether; sulfonamide; C1-7alkyl; C3-20heterocycyl; or C5-20aryl; R N is independently: —H; C1-7alkyl; C3-20heterocycyl; or, C5-20aryl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, such compounds for medical use, such compounds use in the treatment of conditions mediated by HSP90, including, for example, cancer, and use of such compounds in the preparation of medicaments for such treatments.

    摘要翻译： 本发明涉及式（I）的某些3,4-二芳基吡唑（体外和体内）用于抑制热休克蛋白90（HSP90）的用途，以及用于治疗HSP90介导的病症，包括 例如癌症; 其中：Ar 3独立地是C 5-20-20芳基，并且是任选被取代的; Ar 4独立地是C 5-20-20芳基，并且是任选被取代的; R 5独立地为氢; 光环; 羟; 醚; 甲酰基 酰基; 羧基; 酯; 酰氧基 氧羰氧基 氨基酸 酰氨基; 氨基羰基氧基; 四唑基; 氨基; 硝基 氰基; 叠氮 巯基 硫醚 磺酰胺 C 1-7烷基; C 3-20杂环基; 或C 5-20-20芳基; R N 独立地为：-H; C 1-7烷基; C 3-20杂环基; 或C 5-20-20芳基; 和其药学上可接受的盐，溶剂合物，酰胺，酯，醚，化学保护形式及其前药。 本发明还涉及这样的化合物，包含这种化合物的药物组合物，用于医疗用途的这种化合物，这种化合物用于治疗由HSP90介导的病症，包括例如癌症，以及这些化合物在制备药物中的用途 用于治疗。

    Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors
    2.
    发明授权
    Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors 有权
    取代噻吩并[2,3-d]嘧啶作为HSP90抑制剂

    公开(公告)号：US08642594B2

    公开(公告)日：2014-02-04

    申请号：US12690983

    申请日：2010-01-21

    申请人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    发明人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    IPC分类号： A61K31/519 ,  A61K31/5377 ,  A61K31/497 ,  A61P25/28 ,  C07D487/04 ,  C07D295/04 ,  C07D295/104

    CPC分类号： C07D495/04 ,  A61K31/519

    摘要： Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, cancer: wherein R2 is a group of formula —(Ar1)m-(Alk1)P-(Z)r-(Alk2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

    摘要翻译： 式（1）化合物是体外或体内HSP90活性的抑制剂，尤其用于治疗癌症：其中R2是式 - （Ar1）m-（Alk1）P-（Z） r-（Alk2）SQ其中Ar1是任选取代的芳基或杂芳基，Alk'和Alk 2是任选取代的二价C 1 -C 3亚烷基或C 2 -C 3亚烯基，m，p，r和s独立地为0或1， Z是-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO 2 - ， - C（= O） （= S）NRA，-SO2NRA-，-NRAC（= O） - ，-NRASO2-或-NRA-，其中RA是氢或C1-C6烷基，Q是氢或任选取代的碳环或杂环基; R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基。

    Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors
    3.
    发明授权
    Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors 有权
    取代噻吩并[2,3-d]嘧啶作为HSP90抑制剂

    公开(公告)号：US07820658B2

    公开(公告)日：2010-10-26

    申请号：US10569287

    申请日：2004-08-26

    申请人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    发明人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    IPC分类号： C07D487/04 ,  A61K31/519 ,  C07D295/04 ,  C07D295/104 ,  A61K31/5377 ,  A61K31/497 ,  A61P25/28

    CPC分类号： C07D495/04 ,  A61K31/519

    摘要： Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, Cancer: wherein R2 is a group of formula —(Ar1)m-(Alk1)P-(Z)r-(Alk 2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)_, —NRASO2- or —NRA—wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

    摘要翻译： 式（1）的化合物是体外或体内的HSP90活性的抑制剂，并且用于治疗尤其是癌症：其中R2是式 - （Ar1）m-（Alk1）P-（Z） r-（Alk 2）SQ其中Ar1是任选取代的芳基或杂芳基，Alk'和Alk 2是任选取代的二价C 1 -C 3亚烷基或C 2 -C 3亚烯基，m，p，r和s独立地为0或1 ，Z为-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO 2 - ， - C（= O） 其中RA是氢或C 1 -C 6烷基，Q是氢或任选取代的碳环或杂环基; C（= O）NR A - ， - SO 2 NRA-，-NRAC（= O） R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基。

    Pyridothiophene Compounds
    4.
    发明申请
    Pyridothiophene Compounds 审中-公开
    吡啶并噻吩化合物

    公开(公告)号：US20110034457A1

    公开(公告)日：2011-02-10

    申请号：US12909014

    申请日：2010-10-21

    申请人： Martin James Drysdale ,  Brian William Dymock ,  Xavier Barril-Alonso

    发明人： Martin James Drysdale ,  Brian William Dymock ,  Xavier Barril-Alonso

    IPC分类号： A61K31/4365 ,  C07D471/04 ,  A61K31/496 ,  A61K31/5377 ,  A61P35/00 ,  A61P37/06 ,  A61P29/00

    CPC分类号： A61K31/4365

    摘要： The use of compounds of formula (I) in therapy, particularly for the treatment of a disorder mediated by excessive or inappropriate HSP90 activity formula (I), wherein R2 is a group of formula (IA): —(Ar1)m-(Alk1)p-(Z)r-(Alk2)S-Q  (IA) Ar1, Alk1, Z, Alk2 and Q being as defined in the specification; m, p, r and s are independently 0 or 1; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group; or a salt, N-oxide, hydrate, or solvate thereof.

    摘要翻译： 式（I）化合物在治疗中的用途，特别是用于治疗由过量或不适当的HSP90活性式（I）介导的病症，其中R2是式（IA）的基团： - （Ar1）m-（Alk1 ）p（Z）r-（Alk2）SQ（IA）Ar1，Alk1，Z，Alk2和Q如说明书中所定义; m，p，r和s独立地为0或1; R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基团; 或其盐，N-氧化物，水合物或溶剂合物。

    Pyrimidothiophene Compounds
    5.
    发明申请
    Pyrimidothiophene Compounds 有权
    嘧啶并噻吩化合物

    公开(公告)号：US20100120767A1

    公开(公告)日：2010-05-13

    申请号：US12690983

    申请日：2010-01-21

    申请人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    发明人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

    IPC分类号： A61K31/5377 ,  A61K31/519 ,  A61P29/00 ,  A61P19/02 ,  A61P11/06 ,  C07D495/04

    CPC分类号： C07D495/04 ,  A61K31/519

    摘要： Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, cancer: wherein R2 is a group of formula —(Ar1)m-(Alk1)P-(Z)r-(Alk2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, -S02-, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, -S02NRA—, —NRAC(═O)—, —NRAS02- or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

    摘要翻译： 式（1）化合物是体外或体内HSP90活性的抑制剂，尤其用于治疗癌症：其中R2是式 - （Ar1）m-（Alk1）P-（Z） r-（Alk2）SQ其中Ar1是任选取代的芳基或杂芳基，Alk'和Alk 2是任选取代的二价C 1 -C 3亚烷基或C 2 -C 3亚烯基，m，p，r和s独立地为0或1， Z是-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO2-，-C（= O）O-，-C（= O）NRA，-C 其中RA是氢或C 1 -C 6烷基，Q是氢或任选取代的碳环或杂环基;（≡S）NRA-，-SO 2 NR-，-NRAC（= O） - ， - NRASO 2 - 或-NRA- R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基。

    Substituted 5-membered ring compounds and their use
    7.
    发明授权
    Substituted 5-membered ring compounds and their use 失效
    取代的5元环化合物及其用途

    公开(公告)号：US07728016B2

    公开(公告)日：2010-06-01

    申请号：US10561969

    申请日：2004-06-24

    申请人： Kwai Ming Cheung ,  Brian William Dymock ,  Edward McDonald ,  Martin James Drysdale

    发明人： Kwai Ming Cheung ,  Brian William Dymock ,  Edward McDonald ,  Martin James Drysdale

    IPC分类号： A61K31/4192 ,  C07D249/06

    CPC分类号： A61K31/4196 ,  A61K31/4192 ,  A61K31/427 ,  A61K31/433

    摘要： Compound of a compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity: wherein ring A is an aromatic or non-aromatic carbocyclic or heterocyclic ring having 5 ring atoms, for example 1,2,3-triazolyl or a 1,2,4-triazolyl or a tetrazolyl ring; and R1 R2 R3 are as defined in the specification are inhibitors of HSP90 and therefore of use in the treatment of, for example, cancers, viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor, or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapie/CJD, Huntingdon's and Alzheimer's disease.

    摘要翻译： 式（I）化合物或其盐，N-氧化物，水合物或溶剂化物的化合物在制备抑制HSP90活性的组合物中的用途：其中环A是具有5个或更多个碳原子的芳族或非芳族碳环或杂环 环原子，例如1,2,3-三唑基或1,2,4-三唑基或四唑基环; 和R1 R2 R3如本说明书中所定义的是HSP90的抑制剂，因此用于治疗例如癌症，病毒性疾病，炎性疾病如类风湿性关节炎，哮喘，多发性硬化，I型糖尿病，狼疮，牛皮癣 和炎症性肠病; 囊性纤维化血管生成相关疾病如糖尿病性视网膜病变，血管瘤和子宫内膜异位症; 或用于保护正常细胞免受化疗诱导的毒性; 或未能进行细胞凋亡的疾病是潜在的因素，或由于心脏和脑中Hsp70的升高而保护缺氧缺血性损伤; 瘙痒病/ CJD，亨廷顿氏症和阿尔茨海默病。

    Pyrazole compounds
    8.
    发明授权
    Pyrazole compounds 失效
    吡唑化合物

    公开(公告)号：US07612201B2

    公开(公告)日：2009-11-03

    申请号：US10536899

    申请日：2003-12-18

    申请人： Mandy Christine Beswick ,  Martin James Drysdale ,  Brian William Dymock ,  Edward McDonald

    发明人： Mandy Christine Beswick ,  Martin James Drysdale ,  Brian William Dymock ,  Edward McDonald

    IPC分类号： C07D231/38 ,  C07D401/04 ,  C07D403/04 ,  C07D405/12 ,  C07D409/12 ,  C07D417/12

    CPC分类号： C07D231/38 ,  A61K31/415 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D403/12 ,  C07D405/10 ,  C07D405/12 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12

    摘要： Compounds of formula (IA) or (IB) or a salt, N-oxide, hydrate or solvate thereof are inhibitors of HSP90, and are of value in the treatment of diseases responsive to HSP90 inhibition such as cancers. In the formulae, Ar is an aryl, aryl(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl, heteroarylaryl(C1-C6 alkyl), or heteroarylaryl(C1-C6 alkyl) group, any of which being optionally substituted in the aryl or heteroaryl part thereof; R1, is hydrogen or optionally substituted C1-C6 alkyl; R2 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide or carboxyl ester group; and ring A is a non aromatic carbocyclic or heterocyclic ring wherein (i) a ring carbon is optionally substituted, and/or (ii) a ring nitrogen is optionally substituted by a group of formula -(Alk1)p (Cyc)n-(Alk3)m-(Z)r (Alk2)s Q where Alk1, Alk2 and Alk3 are optionally substituted C1-C3 alkyl, Cyc is an optionally substituted carbocyclic or heterocyclic radical; m, n, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —S02-, —C(═O)O—, —OC(═O)—, —NW—, —C(═O)NRA-, —NRAC(═O)—, —SO2NRA—, or —NRASO2— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical.

    摘要翻译： 式（IA）或（IB）化合物或其盐，N-氧化物，水合物或溶剂合物是HSP90的抑制剂，并且在治疗对HSP90抑制作用的疾病如癌症的治疗中具有价值。 在式中，Ar是芳基，（C 1 -C 6烷基），芳基（C 1 -C 6烷基），杂芳基，杂芳基芳基（C 1 -C 6烷基）或杂芳基芳基（C 1 -C 6烷基） 在其芳基或杂芳基部分取代; R1是氢或任选取代的C 1 -C 6烷基; R 2是氢，任选取代的环烷基，环烯基，C 1 -C 6烷基，C 1 -C 6烯基或C 1 -C 6炔基; 或羧基，羧酰胺或羧基酯基团; 环A是非芳族碳环或杂环，其中（i）环碳任选被取代，和/或（ii）环氮任选地被式 - （Alk1）p（Cyc）n-（ Alk3）m-（Z）r（Alk2）sQ其中Alk1，Alk2和Alk3是任选取代的C 1 -C 3烷基，Cyc是任选取代的碳环或杂环基; m，n，p，r和s独立地为0或1，Z为-O - ， - S - ， - （CO） - ， - SO2-，-C - ，-NW-， - C（ - O）NRA - ， - NRAC（-O） - ， - SO2NRA-或-NRASO2-，其中RA是氢或C1-C6烷基，Q是氢或任选取代的碳环 或杂环基。

    Isoxazole compounds as inhibitors of heat shock proteins
    9.
    发明授权
    Isoxazole compounds as inhibitors of heat shock proteins 有权
    异恶唑化合物作为热休克蛋白的抑制剂

    公开(公告)号：US07705027B2

    公开(公告)日：2010-04-27

    申请号：US10544443

    申请日：2004-02-09

    申请人： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

    发明人： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

    IPC分类号： C07D261/06 ,  A01N43/80

    CPC分类号： A61K31/541 ,  A61K31/42 ,  A61K31/422 ,  A61K31/427 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4709 ,  A61K31/496 ,  A61K31/5377 ,  C07D261/08 ,  C07D261/10 ,  C07D413/04 ,  C07D413/10 ,  C07D417/04 ,  C07D495/04

    摘要： Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

    摘要翻译： 式（A）或（B）的异恶唑是HSP90活性的抑制剂，可用于治疗例如癌症：（A），（B）其中R1是式（IA）的基团：-Ar1-（Alk1 ）对 - （Z）r-（Alk 2）sQ，其中在任何相容的组合中，Ar 1是任选取代的芳基或杂芳基，Alk1和Alk2是任选取代的C 1 -C 6亚烷基或C 2 -C 6亚烯基，p，r和 s是独立的0或1，Z是-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO 2 - ， - C（= O） 其中RA为氢或C 1 -C 6烷基，Q为氢或任选地为（C 1 -C 6）烷基， 取代的碳环或杂环基; R2是（i）上述式（IA）的基团或（ii）甲酰胺基团; 或（iii）非芳族碳环或杂环，其中环碳任选被取代，和/或环氮任选被式 - （Alk1）对（Z）r-（Alk2）sQ基团取代，其中Q ，Alk1，Alk2，Z，p，r和s如上文关于组（IA）所定义; 并且R 3是氢，任选取代的环烷基，环烯基，C 1 -C 6烷基，C 1 -C 6烯基或C 1 -C 6炔基; 或羧基，羧酰胺或羧基酯基团。