CN102485720B - Heat shock protein 90 inhibitor - Google Patents
Heat shock protein 90 inhibitor Download PDFInfo
- Publication number
- CN102485720B CN102485720B CN200910210364.1A CN200910210364A CN102485720B CN 102485720 B CN102485720 B CN 102485720B CN 200910210364 A CN200910210364 A CN 200910210364A CN 102485720 B CN102485720 B CN 102485720B
- Authority
- CN
- China
- Prior art keywords
- sup
- trannum
- sub
- certain embodiments
- sup trannum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a heat shock protein 90 inhibitor compound, such as a compound in formula I, a medicinal composition containing the compound, and their preparation method. The invention also provides a method for using them to treat proliferative diseases.
Description
Technical field
Provide the compound of inhibitor of heat shock protein 90 herein, the pharmaceutical composition that comprises this compounds and the method for preparing them.The method that they is used for the treatment of to proliferative disease is also provided.
Background technology
Heat shock protein 90 (Heat shock protein 90, HSP90) be the interior molecular chaperones of cell of high conservative, it regulates folding (the Welch and Feramiscom J.Biol.Chem.1982 of rear translation of client's albumen (client protein), 257,14949-14959).HSP90 brings into play its conpanion's function, to guarantee to participate in correct conformation, activation, thin inner cellular localization and proteolysis upset (the Maloney andWorkman of a series of albumen of Growth of Cells, differentiation and survival, Expert Opin.Biol.Ther.2002,2,3-24; And Whitesell andLindquist, Nature Reviews Cancer 2005,5,761-772).For the stable and function of many carinogenicity client's albumen, HSP90 is necessary, this client's albumen comprises ERBB2, BCR-ABL, AKT/PKB, C-RAF, CDK4, PLK-1, MET, mutant p53, HIF-1 α, steroid hormone receptor (oestrogenic hormon and male sex hormone) and Telomere terminal transferase hTERT (Maloney and Workman, Expert Opin.Biol.Ther.2002,2,3-24).
In tumour cell HSP90 express and activation conventionally by regulate.HSP90 in tumour cell demonstrates with overactivity state and exists, and has the atpase activity of rising, and a large amount of resting forms of finding in itself and normal cell compare extremely sensitive (the Richter et al. of HSP90 restraining effect, Nat.Struct.Mol.Biol.2007,14,90-94).This shows, HSP90 inhibitor can be used for selectivity target tumor cell.In addition, because some carinogenicity client albumen and the multiple symbolic characteristic of malignant tumour for example take off the signal transduction, cell cycle progress, apoptosis, immortalization, the blood vessel that regulate, occur, attack and shift relevant, the restraining effect of HSP90 is for providing concerning the blocking-up of the effective combination of tumour cell (the Hanahan and Weinberg that is desirable, Cell 2000,100,57-70; And Workman, Cancer Lett.2004,206,149-157).The restraining effect that has shown HSP90 causes that client's albumen degrades by ubiquitin-proteasome pathway, under the signal combination that exhausts when this causes multiple cancer protein and propagate by many carinogenicity signal pathways, regulate (Connell et al., Nature Cell Biology 2001,3,93-96; Demand et al., Current Biology 2001,11,1569-1577; Maloney and Workman, ExpertOpin.Biol.Ther.2002,2,3-24; And Workman, Cancer Lett.2004,206,149-157).
For example, small molecules HSP90 inhibitor 17-AAG (17-allyamino-17-demethoxygeldanamycin, 17-AAG), it is at the NH of HSP90
2-stub area is in conjunction with ATP-binding site, and suppress its atpase activity, demonstrated this small molecules HSP90 inhibitor and in cancerous cell line and people's tumour transplatation object model, effectively suppressed kinds cancer (Kelland et al., J.Natl.Cancer Inst.1999,91,1940-1949; Solit et al., Clin.Cancer Res.2002,8,986-993; Jones et al., Blood, 2003,103,1855-1861; Price et al., Cancer Res.2005,65,4929-4938; And Banerji et al., Clin.Cancer Res.2005,11,7023-7032).The inhibition of the basic atpase activity of HSP90 can cause multiple client's albumen to regulate by under ubiquitin-proteasome pathway, cause the cell cycle to stop and apoptosis (Schulte et al., Biochem.Biophys.Res.Commun.1997,239,655-659; And Hostein etal., Cancer Res.2001,61,4003-4009).Therefore, need to have and can be used for effectively treating for example HSP90 inhibitor of cancer of proliferative disease.
Summary of the invention
Summary of the invention
This article provides a compound of formula I: <img TranNum = "84" file = "G2009102103641D00031.GIF" he = "530" img-content = "drawing" img-format = "tif" inline = "no" orientation = "portrait" wi = "590" /> or a single enantiomer, a mixture of enantiomers or non-enantiomeric mixture of isomers; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R <sup TranNum = "85"> 1 </ sup> is hydrogen, C <sub TranNum = "86"> 1-6 </ sub>-alkyl, C <sub TranNum = "87"> 2-6 </ sub > alkenyl, C <sub TranNum = "88"> 2-6 </ sub> alkynyl, C <sub TranNum = "89"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "90 "> 6-14 </ sub> aryl, C <sub TranNum =" 91 "> 7-15 </ sub> aralkyl, heteroaryl or heterocyclic group; R <sup TranNum =" 92 "> 2 </ sup> is heteroaryl or heteroaryl -C <sub TranNum = "93"> 1-6 </ sub> alkyl; R <sup TranNum = "94"> 5 </ sup> is (i) hydrogen, halogen, cyano or nitro; (ii) C <sub TranNum = "95"> 1-6 </ sub>-alkyl, C <sub TranNum = "96"> 2-6 </ sub> alkenyl , C <sub TranNum = "97"> 2-6 </ sub> alkynyl, C <sub TranNum = "98"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "99"> 6 -14 </ sub> aryl, C <sub TranNum = "100"> 7-15 </ sub> aralkyl, heteroaryl or heterocyclic group; or (iii) -C (O) R <sup TranNum = "101"> 1a </ sup>, - C (O) OR <sup TranNum = "102"> 1a </ sup>, - C (O) NR <sup TranNum = "103"> 1b </ sup> R <sup TranNum = "104"> 1c </ sup>, - C (NR <sup TranNum = "105"> 1a </ sup>) NR <sup TranNum = "106"> 1b </ sup> R <sup TranNum = "107"> 1c </ sup>, - OR <sup TranNum = "108"> 1a </ sup>, - OC (O) R <sup TranNum = "109"> 1a </ sup>, - OC (O) OR <sup TranNum = "110"> 1a </ sup>, - OC (O) NR <sup TranNum = "111"> 1b </ sup> R <sup TranNum = "112"> 1c </ sup >, - OC (= NR <sup TranNum = "113"> 1a </ sup>) NR <sup TranNum = "114"> 1b </ sup> R <sup TranNum = "115"> 1c </ sup>, -OS (O) R <sup TranNum = "116"> 1a </ sup>, - OS (O) <sub TranNum = "117"> 2 </ sub> R <sup TranNum = "118"> 1a </ sup>, - OS (O) NR <sup TranNum = "119"> 1b </ sup> R <sup TranNum = "120"> 1c </ sup>, - OS (O) <sub TranNum = "121"> 2 </ sub> NR <sup TranNum = "122"> 1b </ sup> R <sup TranNum = "123"> 1c </ sup>, - NR <sup TranNum = "124"> 1b </ sup> R <sup TranNum = "125"> 1c </ sup>, - NR <sup TranNum = "126"> 1a </ sup> C (O) R <sup TranNum = "127"> 1d </ sup>, - NR <sup TranNum = "128"> 1a </ sup> C (O) OR <sup TranNum = "129"> 1d </ sup>, - NR <sup TranNum = "130"> 1a </ sup> C (O ) NR <sup TranNum = "131"> 1b </ sup> R <sup TranNum = "132"> 1c </ sup>, - NR <sup TranNum = "133"> 1a </ sup> C (= NR <sup TranNum = "134"> 1d </ sup>) NR <sup TranNum = "135"> 1b </ sup> R <sup TranNum = "136"> 1c </ sup>, - NR <sup TranNum = "137 "> 1a </ sup> S (O) R <sup TranNum =" 138 "> 1d </ sup>, - NR <sup TranNum =" 139 "> 1a </ sup> S (O) <sub TranNum =" 140 "> 2 </ sub> R <sup TranNum =" 141 "> 1d </ sup>, - NR <sup TranNum =" 142 "> 1a </ sup> S (O) NR <sup TranNum =" 143 "> 1b </ sup> R <sup TranNum = "144"> 1c </ sup>, - NR <sup TranNum = "145"> 1a </ sup> S (O) <sub TranNum = "146"> 2 </ sub> NR <sup TranNum = "147"> 1b </ sup> R <sup TranNum = "148"> 1c </ sup>, - SR <sup TranNum = "149"> 1a </ sup>, - S (O) R <sup TranNum = "150"> 1a </ sup>, - S (O) <sub TranNum = "151"> 2 </ sub> R <sup TranNum = "152"> 1a </ sup> , -S (O) NR <sup TranNum = "153"> 1b </ sup> R <sup TranNum = "154"> 1c </ sup> or -S (O) <sub TranNum = "155"> 2 </ sub> NR <sup TranNum = "156"> 1b </ sup> R <sup TranNum = "157"> 1c </ sup>; and each R <sup TranNum = "158"> 1a </ sup>, R <sup TranNum = "159"> 1b </ sup>, R <sup TranNum = "160"> 1c </ sup> and R <sup TranNum = "161"> 1d </ sup> is independently hydrogen, C <sub TranNum = "162"> 1-6 </ sub>-alkyl, C <sub TranNum = "163"> 2-6 </ sub> alkenyl, C <sub TranNum = "164"> 2-6 </ sub> alkynyl, C <sub TranNum = "165"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "166"> 6-14 </ sub> aryl, C <sub TranNum = "167 "> 7-15 </ sub> aralkyl, heteroaryl or heterocyclic group; or R <sup TranNum =" 168 "> 1b </ sup> and R <sup TranNum =" 169 "> 1c </ sup> N atom to which they are attached form a heteroaryl or heterocyclyl group; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, aryl, and heteroaryl group - alkyl is optionally substituted with one or more groups Q, each Q is independently selected from (a) cyano, halo, and nitro; (b) C <sub TranNum = "170"> 1-6 </ sub> alkyl, C <sub TranNum = "171"> 2-6 </ sub> alkenyl, C <sub TranNum = "172"> 2-6 </ sub> alkynyl, C <sub TranNum = "173 "> 3-7 </ sub> cycloalkyl, C <sub TranNum =" 174 "> 6-14 </ sub> aryl, C <sub TranNum =" 175 "> 7-15 </ sub> aryl alkyl groups, heteroaryl and heterocyclyl, each optionally substituted with one or more (in one embodiment, 2, 3 or 4) substituents Q <sup TranNum = "176"> a </ sup > replace; and (c) -C (O) R <sup TranNum = "177"> a </ sup>, - C (O) OR <sup TranNum = "178"> a </ sup>, - C (O) NR <sup TranNum = "179"> b </ sup> R <sup TranNum = "180"> c </ sup>, - C (NR <sup TranNum = "181"> a </ sup>) NR <sup TranNum = "182"> b </ sup> R <sup TranNum = "183"> c </ sup>, - OR <sup TranNum = "184"> a </ sup>, - OC (O) R <sup TranNum = "185"> a </ sup>, - OC (O) OR <sup TranNum = "186"> a </ sup>, - OC (O) NR <sup TranNum = "187"> b </ sup> R <sup TranNum = "188"> c </ sup>, - OC (= NR <sup TranNum = "189"> a </ sup>) NR <sup TranNum = "190"> b </ sup > R <sup TranNum = "191"> c </ sup>, - OS (O) R <sup TranNum = "192"> a </ sup>, - OS (O) <sub TranNum = "193"> 2 </ sub> R <sup TranNum = "194"> a </ sup>, - OS (O) NR <sup TranNum = "195"> b </ sup> R <sup TranNum = "196"> c </ sup>, - OS (O) <sub TranNum = "197"> 2 </ sub> NR <sup TranNum = "198"> b </ sup> R <sup TranNum = "199"> c </ sup>, -NR <sup TranNum = "200"> b </ sup> R <sup TranNum = "201"> c </ sup>, - NR <sup TranNum = "202"> a </ sup> C (O) R <sup TranNum = "203"> d </ sup>, - NR <sup TranNum = "204"> a </ sup> C (O) OR <sup TranNum = "205"> d </ sup>, - NR <sup TranNum = "206"> a </ sup> C (O) NR <sup TranNum = "207"> b </ sup> R <sup TranNum = "208"> c </ sup>, - NR <sup TranNum = "209"> a </ sup> C (= NR <sup TranNum = "210"> d </ sup>) NR <sup TranNum = "211"> b </ sup> R <sup TranNum = "212 "> c </ sup>, - NR <sup TranNum =" 213 "> a </ sup> S (O) R <sup TranNum =" 214 "> d </ sup>, - NR <sup TranNum =" 215 "> a </ sup> S (O) <sub TranNum =" 216 "> 2 </ sub> R <sup TranNum =" 217 "> d </ sup>, - NR <sup TranNum =" 218 "> a </ sup> S (O) NR <sup TranNum = "219"> b </ sup> R <sup TranNum = "220"> c </ sup>, - NR <sup TranNum = "221"> a </ sup> S (O) <sub TranNum = "222"> 2 </ sub> NR <sup TranNum = "223"> b </ sup> R <sup TranNum = "224"> c </ sup>, - SR <sup TranNum = "225"> a </ sup>, - S (O) R <sup TranNum = "226"> a </ sup>, - S (O) <sub TranNum = "227"> 2 </ sub> R <sup TranNum = "228"> a </ sup>, - S (O) NR <sup TranNum = "229"> b </ sup> R <sup TranNum = "230"> c </ sup> and -S (O) <sub TranNum = "231"> 2 </ sub> NR <sup TranNum = "232"> b </ sup> R <sup TranNum = "233"> c </ sup>, where each R <sup TranNum = "234"> a </ sup>, R <sup TranNum = "235"> b </ sup>, R <sup TranNum = "236"> c </ sup> and R <sup TranNum = "237"> d </ sup> independently is (i) hydrogen; (ii) C <sub TranNum = "238"> 1-6 </ sub>-alkyl, C <sub TranNum = "239"> 2- 6 </ sub> alkenyl, C <sub TranNum = "240"> 2-6 </ sub> alkynyl, C <sub TranNum = "241"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "242"> 6-14 </ sub>-aryl, C <sub TranNum = "243"> 7-15 </ sub> arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or a plurality of (in one embodiment, 2, 3 or 4) substituents Q <sup TranNum = "244"> a </ sup>-substituted; or (iii) R <sup TranNum = "245"> b </ sup>, and R <sup TranNum = "246"> c </ sup> N atom to which they are attached form a heterocyclic group, optionally substituted with one or more (in one embodiment, 1,2 , 3 or 4) substituents Q <sup TranNum = "247"> a </ sup> replace; wherein each Q <sup TranNum = "248"> a </ sup> is independently selected from (a) a cyano group, halogen and nitro; (b) C <sub TranNum = "249"> 1-6 </ sub>-alkyl, C <sub TranNum = "250"> 2-6 </ sub> alkenyl, C <sub TranNum = "251"> 2-6 </ sub> alkynyl, C <sub TranNum = "252"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "253"> 6-14 </ sub > aryl, C <sub TranNum = "254"> 7-15 </ sub> arylalkyl, heteroaryl, and heterocyclyl; and (c) -C (O) R <sup TranNum = "255"> e </ sup>, - C (O) OR <sup TranNum = "256"> e </ sup>, - C (O) NR <sup TranNum = "257"> f </ sup> R <sup TranNum = "258"> g </ sup>, - C (NR <sup TranNum = "259"> e </ sup>) NR <sup TranNum = "260"> f </ sup> R <sup TranNum = "261" > g </ sup>, - OR <sup TranNum = "262"> e </ sup>, - OC (O) R <sup TranNum = "263"> e </ sup>, - OC (O) OR <sup TranNum = "264"> e </ sup>, - OC (O) NR <sup TranNum = "265"> f </ sup> R <sup TranNum = "266"> g </ sup>, - OC (= NR <sup TranNum = "267"> e </ sup>) NR <sup TranNum = "268"> f </ sup> R <sup TranNum = "269"> g </ sup>, - OS (O) R <sup TranNum = "270"> e </ sup>, - OS (O) <sub TranNum = "271"> 2 </ sub> R <sup TranNum = "272"> e </ sup>, - OS (O) NR <sup TranNum = "273"> f </ sup> R <sup TranNum = "274"> g </ sup>, - OS (O) <sub TranNum = "275"> 2 </ sub> NR <sup TranNum = "276"> f </ sup> R <sup TranNum = "277"> g </ sup>, - NR <sup TranNum = "278"> f </ sup> R <sup TranNum = "279 "> g </ sup>, - NR <sup TranNum =" 280 "> e </ sup> C (O) R <sup TranNum =" 281 "> h </ sup>, - NR <sup TranNum =" 282 "> e </ sup> C (O) OR <sup TranNum =" 283 "> f </ sup>, - NR <sup TranNum =" 284 "> e </ sup> C (O) NR <sup TranNum = "285"> f </ sup> R <sup TranNum = "286"> g </ sup>, - NR <sup TranNum = "287"> e </ sup> C (= NR <sup TranNum = "288 "> h </ sup>) NR <sup TranNum =" 289 "> f </ sup> R <sup TranNum =" 290 "> g </ sup>, - NR <sup TranNum =" 291 "> e </ sup> S (O) R <sup TranNum = "292"> h </ sup>, - NR <sup TranNum = "293"> e </ sup> S (O) <sub TranNum = "294"> 2 </ sub> R <sup TranNum = "295"> h </ sup>, - NR <sup TranNum = "296"> e </ sup> S (O) NR <sup TranNum = "297"> f </ sup > R <sup TranNum = "298"> g </ sup>, - NR <sup TranNum = "299"> e </ sup> S (O) <sub TranNum = "300"> 2 </ sub> NR <sup TranNum = "301"> f </ sup> R <sup TranNum = "302"> g </ sup>, - SR <sup TranNum = "303"> e </ sup>, - S (O) R <sup TranNum = "304"> e </ sup>, - S (O) <sub TranNum = "305"> 2 </ sub> R <sup TranNum = "306"> e </ sup>, - S (O ) NR <sup TranNum = "307"> f </ sup> R <sup TranNum = "308"> g </ sup> and -S (O) <sub TranNum = "309"> 2 </ sub> NR <sup TranNum = "310"> f </ sup> R <sup TranNum = "311"> g </ sup>; wherein each R <sup TranNum = "312"> e </ sup>, R <sup TranNum = "313 "> f </ sup>, R <sup TranNum =" 314 "> g </ sup> and R <sup TranNum =" 315 "> h </ sup> independently is (i) hydrogen; (ii) C <sub TranNum = "316"> 1-6 </ sub>-alkyl, C <sub TranNum = "317"> 2-6 </ sub> alkenyl, C <sub TranNum = "318"> 2-6 </ sub> alkynyl, C <sub TranNum = "319"> 3-7 </ sub> cycloalkyl, C <sub TranNum = "320"> 6-14 </ sub> aryl, C <sub TranNum = "321"> 7-15 </ sub> aralkyl, heteroaryl or heterocyclic group; or (iii) R <sup TranNum = "322"> f </ sup> and R <sup TranNum = "323" > g </ sup> N atom to which they are attached form a heterocyclic group.
In another embodiment, the compound of formula I has the structure of formula II:
or single enantiomer, the mixture of enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate; R wherein
1, R
2, R
5definition as described in formula I above.
Detailed Description Of The Invention
At general formula provided herein, comprise the radicals R in formula I and II
1, R
2and R
5herein, do further definition.All combinations of the embodiment for this type of group provided herein are all in the application scope of disclosure.
In certain embodiments, R
1hydrogen.In certain embodiments, R
1c
1-6alkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1methyl, ethyl or propyl group.In certain embodiments, R
1methyl, ethyl or sec.-propyl.In certain embodiments, R
1c
2-6thiazolinyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1c
2-6alkynyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1c
3-7cycloalkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1c
6-14aryl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1c
7-15aralkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
1be heteroaryl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
1be heterocyclic radical, optionally by one or more substituting group Q, replaced.
In certain embodiments, R
2be heteroaryl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
2heteroaryl-C
1-6alkyl, wherein this alkyl and heteroaryl are independent and optionally by one or more substituting group Q, replaced separately.In certain embodiments, R
2the heteroaryl-C of 6-unit
1-6alkyl, wherein this alkyl and heteroaryl are independent and optionally by one or more substituting group Q, replaced separately.In certain embodiments, R
2be 6-unit heteroaryl-methyl, wherein this heteroaryl is optionally replaced by one or more substituting group Q.In certain embodiments, R
2be pyridylmethyl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
2pyridine-2-base-methyl, pyridin-3-yl-methyl or pyridin-4-yl-methyl.
In certain embodiments, R
2bicyclic heteroaryl-C that 5,6-condenses
1-6alkyl, wherein this alkyl and heteroaryl are independent and optionally by one or more substituting group Q, replaced separately.In certain embodiments, R
2be bicyclic heteroaryl-methyl that 5,6-condenses, wherein this heteroaryl is optionally replaced by one or more substituting group Q.In certain embodiments, R
2pyrazolo [1,5-a] pyrimidin-3-yl) methyl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
2chlorine pyrazolo [1,5-a] pyrimidyl) methyl.In certain embodiments, R
26-chlorine pyrazolo [1,5-a] pyrimidin-3-yl) methyl.
In certain embodiments, R
2bicyclic heteroaryl-C that 6,6-condenses
1-6alkyl, wherein this alkyl and heteroaryl are independent and optionally by one or more substituting group Q, replaced separately.In certain embodiments, R
2be bicyclic heteroaryl-methyl that 6,6-condenses, wherein this heteroaryl is optionally replaced by one or more substituting group Q.In certain embodiments, R
2be quinolyl-methyl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
2be quinoline-6-base-methyl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
2it is the fluoro-quinoline-6-of 7-base-methyl.
In certain embodiments, R
5hydrogen.In certain embodiments, R
5it is halogen.In certain embodiments, R
5fluorine, chlorine, bromine or iodine.In certain embodiments, R
5chlorine.In certain embodiments, R
5cyano group.In certain embodiments, R
5it is nitro.In certain embodiments, R
5c
1-6alkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5methyl, methyl fluoride, difluoromethyl or trifluoromethyl.In certain embodiments, R
5c
2-6thiazolinyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5c
2-6alkynyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5c
3-7cycloalkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5be cyclopropyl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
5c
6-14aryl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5c
7-15aralkyl, is optionally replaced by one or more substituting group Q.In certain embodiments, R
5be heteroaryl, optionally by one or more substituting group Q, replaced.In certain embodiments, R
5be heterocyclic radical, optionally by one or more substituting group Q, replaced.
In certain embodiments, R
5-C (O) R
1a, R wherein
1aas defined herein.In certain embodiments, R
5-C (O) OR
1a, R wherein
1aas defined herein.In certain embodiments, R
5-C (O) NR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5be-C (NR
1a) NR
1br
1c, R wherein
1a, R
1band R
1cseparately as defined herein.In certain embodiments, R
5be-OR
1a, R wherein
1aas defined herein.In certain embodiments, R
5c
1-6alkoxyl group, is optionally replaced by one or more substituting groups as defined herein.In certain embodiments, R
5methoxyl group, oxyethyl group or propoxy-.In certain embodiments, R
5-OC (O) R
1a, R wherein
1aas defined herein.In certain embodiments, R
5-OC (O) OR
1a, R wherein
1aas defined herein.In certain embodiments, R
5-OC (O) NR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5be-OC (=NR
1a) NR
1br
1c, R wherein
1a, R
1band R
1cseparately as defined herein.In certain embodiments, R
5-OS (O) R
1a, R wherein
1aas defined herein.In certain embodiments, R
5-OS (O)
2r
1a, R wherein
1aas defined herein.In certain embodiments, R
5-OS (O) NR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5-OS (O)
2nR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5be-NR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5be-NR
1ac (O) R
1d, R wherein
1aand R
1dseparately as defined herein.In certain embodiments, R
5be-NR
1ac (O) OR
1d, R wherein
1aand R
1dseparately as defined herein.In certain embodiments, R
5be-NR
1ac (O) NR
1br
1c, R wherein
1a, R
1band R
1cseparately as defined herein.In certain embodiments, R
5be-NR
1ac (=NR
1d) NR
1br
1c, R wherein
1a, R
1b, R
1cand R
1dseparately as defined herein.In certain embodiments, R
5be-NR
1as (O) R
1d, R wherein
1aand R
1dseparately as defined herein.In certain embodiments, R
5be-NR
1as (O)
2r
1d, R wherein
1aand R
1dseparately as defined herein.In certain embodiments, R
5be-NR
1as (O) NR
1br
1c, R wherein
1a, R
1band R
1cseparately as defined herein.In certain embodiments, R
5be-NR
1as (O)
2nR
1br
1c, R wherein
1a, R
1band R
1cseparately as defined herein.In certain embodiments, R
5be-SR
1a, R wherein
1aas defined herein.In certain embodiments, R
5-S (O) R
1a, R wherein
1aas defined herein.In certain embodiments, R
5-S (O)
2r
1a, R wherein
1aas defined herein.In certain embodiments, R
5-S (O) NR
1br
1c, R wherein
1band R
1cseparately as defined herein.In certain embodiments, R
5-S (O)
2nR
1br
1c, R wherein
1band R
1cseparately as defined herein.
In certain embodiments, compound provided herein is not 1-(5-chloro-2,4-dihydroxy-benzene formyl radical)-N '-methyl-N '-(6-picoline-3-ylmethyl)-D-prolineamide.
In one embodiment, in general formula provided herein, R
1hydrogen or C
1-6alkyl, is optionally replaced by one or more substituting group Q; R
2heteroaryl or heteroaryl-C
1-6alkyl, is optionally replaced by one or more substituting group Q separately; And R
5halogen, C
1-6alkyl or C
3-7cycloalkyl, wherein alkyl and cycloalkyl are optionally replaced by one or more substituting group Q separately.
In another embodiment, in general formula provided herein, R
1hydrogen or C
1-6alkyl, is optionally replaced by one or more substituting group Q; R
2the heteroaryl-C of 6-unit
1-6alkyl, 5, the bicyclic heteroaryl that the bicyclic heteroaryl that 6-condenses or 6,6-condense, is optionally replaced by one or more substituting group Q separately; And R
5halogen, C
1-6alkyl or C
3-7cycloalkyl, wherein alkyl and cycloalkyl are optionally replaced by one or more substituting group Q separately.
In another embodiment again, in general formula provided herein, R
1hydrogen, methyl, ethyl or propyl group; R
2pyridylmethyl, chlorine pyrazolo [1,5-a] pyrimidyl) methyl or quinolyl methyl; And R
5chlorine, methyl or cyclopropyl.
In another embodiment again, in general formula provided herein, R
1hydrogen, methyl, ethyl or sec.-propyl; R
2pyridylmethyl, 6-chlorine pyrazolo [1,5-a] pyrimidin-3-yl) methyl or quinolyl methyl; And R
5chlorine, methyl or cyclopropyl.
In one embodiment, compound provided herein is selected from:
and pharmacologically acceptable salts, solvate and hydrate.In one embodiment, also provide following formula: compound herein
and pharmacologically acceptable salts, solvate and hydrate.Pharmaceutical composition
Pharmaceutical composition provided herein comprises the compound as activeconstituents provided herein, and for example formula I compound, comprises the mixture of enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate; And the acceptable medium of pharmacy, carrier, thinner or vehicle or its mixture.
Suitable vehicle is well known to a person skilled in the art, and the limiting examples of suitable vehicle is provided herein.No matter whether specific vehicle is suitable for being incorporated in pharmaceutical composition or formulation, it depends on and well known to a person skilled in the art many factors, the method that includes, but are not limited to use.For example, oral dosage form for example tablet can contain the vehicle that is not suitable for parenteral dosage form type.The suitability of concrete vehicle also depends on the concrete activeconstituents in this formulation.For example, the decomposition of some activeconstituentss may be because of some vehicle lactose or be accelerated when contacting with water for example.The activeconstituents that contains primary amine and secondary amine is responsive especially to this kind of accelerate decomposition.Therefore, pharmaceutical composition provided herein or formulation, if any, contain a little lactose other is single-or two-sugar.As used herein, term " lactose free " expression, if any, the amount that lactose exists is not enough to increase the degradation rate of activeconstituents substantially.In one embodiment, lactose free composition comprises activeconstituents provided herein, tackiness agent/weighting agent and lubricant.In another embodiment, lactose free formulation comprises activeconstituents, Microcrystalline Cellulose, pregelatinized Starch and Magnesium Stearate.
Compound provided herein can be used separately, or uses with one or more other compound combinations provided herein.This pharmaceutical composition comprises compound provided herein, and for example formula I compound, comprises the mixture of enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate, this pharmaceutical composition can be mixed with the different dosage form that is applicable to oral, parenteral and topical application.This pharmaceutical composition can also be mixed with modified release formulation, comprise delay-, extend-, extend-, continue-, pulse-, control-, accelerate-, fast-, directed-, follow procedure-discharge and Entogastric lingering formulation.These formulations can according to the preparation of ordinary method well known by persons skilled in the art and technology (referring to, Remington:Science and Practiceof Pharmacy, 21st ed.; Lippincott Williams & Wilkins:Philadelphia, PA, 2005; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker, Inc.:New York, NY, 2008).
In one embodiment, this pharmaceutical composition is to provide for Orally administered formulation, and this formulation comprises compound provided herein, and for example formula I compound, comprises the mixture of enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate; And the acceptable vehicle of one or more pharmacy or carrier.
In another embodiment, this pharmaceutical composition is that the formulation of using for parenteral provides, and this formulation comprises compound provided herein, and for example formula I compound, comprises the mixture of enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate; And the acceptable vehicle of one or more pharmacy or carrier.
In another embodiment again, this pharmaceutical composition is that the formulation for topical application provides, and this formulation comprises compound provided herein, and for example formula I compound, comprises the mixture of enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate; And the acceptable vehicle of one or more pharmacy or carrier.
Pharmaceutical composition provided herein can provide with single dose form or multiple doses form.As used herein, single dose form refers to the physically discrete unit that is applicable to being applied to humans and animals experimenter, and packing separately, and this is known in the art.The activeconstituents of therapeutic action that is enough to produce needs that each unitary dose contains predetermined amount, and the pharmaceutical carrier or the vehicle that need.The example of single dose form comprises ampulla, syringe agent and the Tablet and Capsula agent of packing respectively.For example, 100mg unitary dose contains the activeconstituents of the 100mg that has an appointment in the tablet of packing or capsule.Single dose form can or repeatedly be used with its part.Multiple doses form is a plurality of identical single dose form being packaged in single container, with separated single dose form, uses.The example of multiple doses form comprises the bottle of vial, tablet or capsule, or the bottle of pint or gallon.
Pharmaceutical composition provided herein can applied once, or repeatedly uses with certain interval.Should be understood that accurate dosage and treatment can change with patient's to be treated age, body weight and situation the time length, and can with known testing scheme or in body or in vitro tests or diagnostic data extrapolate and empirically determine.Should also be understood that for any specific individuality, concrete dosage should and be used or instruct the people's that formula uses professional judgement according to this individual demand and adjust in time.Using method
In one embodiment, the method for the treatment of or prevention experimenter proliferative disease is provided herein, the method comprises the compound provided herein to this experimenter's administering therapeutic significant quantity, for example formula I compound, comprises the mixture of single enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate.
In another embodiment, treatment, prevention are provided herein or have improved the method for one or more symptoms of experimenter's proliferative disease, the method comprises the compound provided herein to this experimenter's administering therapeutic significant quantity, for example formula I compound, comprises the mixture of single enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate.
In another embodiment again, treatment, prevention are provided herein or have improved the method for one or more symptoms of obstacle, disease or the state of an illness of experimenter HSP90-mediation, the method comprises the compound provided herein to this experimenter's administering therapeutic significant quantity, for example formula I compound, comprises the mixture of single enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate.In one embodiment, obstacle, disease or the state of an illness of this HSP90-mediation are proliferative diseases.
In certain embodiments, this experimenter is Mammals.In certain embodiments, this experimenter is people.
In one embodiment, this proliferative disease is tumour.In another embodiment, this proliferative disease is noumenal tumour.In another embodiment, this proliferative disease is cancer.In certain embodiments, this proliferative disease is resistance cancer.In certain embodiments, this proliferative disease is metastatic cancer.
In certain embodiments, the cancer of available method treatment provided by the invention comprises, but be not limited to bladder cancer, breast cancer, cervical cancer, colorectal carcinoma (for example colorectal carcinoma), the esophageal carcinoma, head and neck cancer, liver cancer, lung cancer (for example small cell lung cancer and non--small cell lung cancer), melanoma, myelomatosis, neuroblastoma, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, sarcoma (for example osteosarcoma), skin carcinoma (for example squamous cell carcinoma), cancer of the stomach, carcinoma of testis, thyroid carcinoma and uterus carcinoma.
In one embodiment, cytostatic method is provided herein, the method comprises makes this cell and compound provided herein, and for example formula I compound, comprises its single enantiomer, the mixture of enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate contact.
In certain embodiments, this cell is mammalian cell.In certain embodiments, this cell is people's cell.In certain embodiments, this cell is tumour cell.In certain embodiments, this cell is mammalian tumor cell.In certain embodiments, this cell is human tumor cells.In certain embodiments, this cell is cancer cells.In certain embodiments, this cell is mammalian cancer cells.In certain embodiments, this cell is human cancer cell.
In certain embodiments, can include but not limited to the cancer cells of method treatment provided herein the cell of bladder cancer, breast cancer, cervical cancer, colorectal carcinoma (for example colorectal carcinoma), the esophageal carcinoma, head and neck cancer, liver cancer, lung cancer (for example small cell lung cancer and non--small cell lung cancer), melanoma, myelomatosis, neuroblastoma, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, sarcoma (for example osteosarcoma), skin carcinoma (for example squamous cell carcinoma), cancer of the stomach, carcinoma of testis, thyroid carcinoma and uterus carcinoma.
In one embodiment, this cell is the cell of bladder cancer, squamous cell carcinoma, head and neck cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, gynecological cancer, carcinoma of the pancreas, the rectum cancer, breast cancer, prostate cancer, the carcinoma of vulva, skin carcinoma, the cancer of the brain, genitourinary tract cancer, lymphsystem cancer, cancer of the stomach, laryngocarcinoma or lung cancer.
In certain embodiments, this cancer cells is metastatic carcinoma cell, includes but not limited to the cell of bladder cancer, breast cancer, cervical cancer, colorectal carcinoma (for example colorectal carcinoma), the esophageal carcinoma, head and neck cancer, liver cancer, lung cancer (for example small cell lung cancer and non--small cell lung cancer), melanoma, myelomatosis, neuroblastoma, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, sarcoma (for example osteosarcoma), skin carcinoma (for example squamous cell carcinoma), cancer of the stomach, carcinoma of testis, thyroid carcinoma and uterus carcinoma.
The restraining effect of Growth of Cells can be measured, its mode be by, for example, the cell count contacting with interested compound is counted, cell identical with other side but that do not contact with this compound compares, or measures the size of the tumour that comprises this cell.The size of cell count and cell can easily be used any method known in the art to evaluate that (for example, trypanblue exclusion method (trypan blue exclusion) and cell counting, measure and to be incorporated in the nascent DNA in cell
3h-Thymine deoxyriboside).
In one embodiment, the method that suppresses HSP90 enzymic activity is provided herein, the method comprises makes HSP90 enzyme and compound formula I compound provided herein, comprises the mixture of single enantiomer, enantiomer or the mixture of diastereomer; Or its pharmacologically acceptable salts, solvate or hydrate contact.
Disclosure case will further be understood by following non-limiting example.
Embodiment
Embodiment
For following all embodiment, can use standard operation well known by persons skilled in the art and purification process.Unless otherwise, all temperature with ℃ (degree Celsius) represent.To respond be all at room temperature to carry out, unless otherwise.The synthetic method wish of describing in scheme 4 to 18 is anticipated by illustrate available chemical action with specific embodiment, and does not represent the scope of disclosure case.Embodiment 1
2,4-bis-(methoxymethoxy) methyl benzoate is used general procedure to prepare as follows: at N
2under atmosphere, chloromethyl methyl ether (26mL, 342mmol) and DIEA (84ml_, 480mmol) are added in the reaction soln of 2,4-methyl dihydroxy benzoate (13.4g, 80mmol) in the DMF of 40mL.Gained mixture is at room temperature stirred 12 hours.Make reaction mixture at EtOAc (3x 500mL) and water (200mL), saturated NaHCO
3between solution (2x 200mL) and salt solution (200mL), distribute.Make organic layer be dried (Na
2sO
4), filter, then by vacuum concentration, obtain oily resistates.This resistates, by silica gel chromatography (gradient eluent 0 → 30%EtOAc/ hexane) purifying, is obtained to the midbody product 2 of needs, 4-bis-(methoxymethoxy) methyl benzoate (19.20g, 93% productive rate).
1h NMR (400MHz, chloroform-D) δ ppm 3.47 (s, 3H) 3.51 (s, 3H) 3.85 (s, 3H) 5.18 (s, 2H), 5.23 (s, 2H) 6.70 (dd, J=8.84,2.27Hz, 1H) 6.83 (d, J=2.27Hz, 1H) 7.80 (d, J=8.84Hz, 1H).Then be prepared as follows 5-chloro-2,4-bis-(methoxymethoxy) methyl benzoate.The preparation of the 0.7M calcium hypochlorite solution in 10%HOAc: under stirring in ice bath, Losantin (9.743g, 44.29mmol) is dissolved in the 10%HOAc of 64mL.Calcium hypochlorite solution is dropped in 2,4-bis-(methoxymethoxy) methyl benzoate (as preparation above) (9.45g, 36.9mmol) reaction soln in 50.0mL acetone.Gained mixture is at room temperature stirred 12 hours.Make reaction mixture at EtOAc (3x 500mL) and saturated NaHCO
3between solution (200mL), distribute.Make organic layer be dried (Na
2sO
4), filter, then pass through vacuum concentration.Resistates is obtained to the product 5-that needs by silica gel chromatography purifying (gradient eluent 0 → 30%EtOAc/ hexane) chloro-2,4-bis-(methoxymethoxy) methyl benzoate (6.6g, 62% productive rate).
1h NMR (400MHz, chloroform-D) δ ppm (400MHz, chloroform-D) 3.51 (s, 6H) 3.86 (s, 3H), 5.22 (s, 2H) 5.27 (s, 2H) 7.03 (s, 1H) 7.88 (s, 1H).5-is chloro-2,4-bis-(methoxymethoxy) phenylformic acid: then the LiOH aqueous solution (40mL, 2.0M) is added to 5-chloro-2, (5.8g, 20mmol_ is at THF: H for 4-bis-(methoxymethoxy) methyl benzoate
2o (4: 1, in the reaction soln in 80mL).Gained mixture is at room temperature stirred 12 hours.Reaction mixture, by vacuum concentration, is removed to most of solvent, then use ether (200mL) extraction.Use 2.0N HCl solution that water layer is neutralized to pH 6.5, then extract CH
2cl
2(5x 100mL).By the dry (Na of the organic layer merging
2sO
4), then by vacuum concentration, obtaining the final product of the needs of 5.2g, 5-is chloro-2, and 4-bis-(methoxymethoxy) phenylformic acid, is white solid (92% productive rate).
1H?NMR(400MHz，DMSO-D6)δppm
1H?NMR(400MHz，DMSO-D6)δppm?3.52-3.56(d，J＝8.34Hz，6H)5.29(s，2H)5.39(s，2H)7.10(s，1H)，8.17(s，1H)。
5-cyclopropyl-2,4-bis-(methoxymethoxy) methyl benzoate: add 5-chloro-2 under nitrogen in flame-dried flask, 4-bis-(methoxymethoxy) methyl benzoate (3.625g, 12.5mmol) and cyclopropylboronic acid (0.86g, 10.0mmol), then be added in sodium iodide (186mg, 1.25mmol), K in dry toluene (250mL)
2cO
3(2.76g, 20.0mmol), 18-are preced with-6 (2.64g, 10.0mmol), Pd (OAc)
245.00mg (0.2mmol, 2mol%) and glyoxalidine (dihydroimidazolium) hydrochloride part 85mg (0.2mmol, 2mol%).Gained suspension is stirred 12 hours at 80 ℃.Make this reaction mixture concentrated, then add methylene dichloride (10mL).Then by this dichloromethane solution NaHCO
3the aqueous solution, salt brine solution washing 3 times, then use anhydrous magnesium sulfate drying.By rotary evaporation concentrated solvent, then this thick material is used to ethyl acetate/hexane (5-30%) purifying by silica gel chromatography.Obtain 1.57 grams of white solids (53% productive rate).
1h NMR (400MHz, chloroform-D) δ ppm1.22-1.24 (m, 4H), 1.52 (m, 1H), 3.51 (s, 6H) 3.86 (s, 3H), 5.22 (s, 2H) 5.27 (s, 2H) 7.03 (s, 1H) 7.88 (s, 1H).5-cyclopropyl-2,4-bis-(methoxymethoxy) phenylformic acid: then the LiOH aqueous solution (10mL, 2.0M) is added to 5-cyclopropyl-2,4-bis-(methoxymethoxy) methyl benzoate (1.5g, 5.0mmol) is at THF: H
2o (4: 1, in the reaction soln in 20mL).Gained mixture is at room temperature stirred 12 hours.Reaction mixture, by vacuum concentration, is removed to most of solvent, then use ether (100mL) extraction.Use 2.0N HCl solution that water layer is neutralized to pH 6.5, then extract CH
2cl
2(5x 100mL).By the dry (Na of the organic layer merging
2sO
4), then by vacuum concentration, obtain the final product of the needs of 1.27g, 5-cyclopropyl-2,4-bis-(methoxymethoxy) phenylformic acid, is white solid (90% productive rate).
1H?NMR(400MHz，DMSO-D6)δppm?1.21-1.24(m，4H)，1.51(m，1H)，3.52-3.56(d，J＝8.34Hz，6H)5.29(s，2H)5.39(s，2H)7.10(s，1H)，8.17(s，1H)。
s-2-(sec.-propyl (pyridin-3-yl methyl) formamyl) tetramethyleneimine-1-manthanoate: under argon atmospher by N-sec.-propyl-N-(3-pyridylmethyl) amine (1.95g; 13.0mmol) add in Boc-L-Pro-OH (3.655g, 17.0mmol), DIEA (500.0mmol) and the solution of HATU (110mmol) in the DMF of 150.0mL.Reaction is at room temperature stirred 12 hours, then add saturated NaHCO
3with quencher, react.By using EtOAc extractive reaction thing.Merge EtOAc layer, use Na
2sO
4dry.Concentrated organic moiety, then purify with EtOAc/ hexane by silica gel chromatography, product 3.88g (86% productive rate) obtained.
1H?NMR(400MHz，DMSO-D6)δppm：1.08(m，6H)，1.30(m，3H)，1.41-1.44(m，6H)，1.84-1.86(m，2H)，1.92-2.35(m，2H)，2.62-2.84(m，2H)，3.48-3.61(m，2H)，4.59-4.67(m，2H)，7.67-7.71(m，1H)，7.99(s，1H)，8.48-8.52(m，2H)。S-N-sec.-propyl-N-(pyridin-3-yl methyl) tetramethyleneimine-2-methane amide: hydrogenchloride (4.0M, in dioxane for 8ml, 32mmol) is added in the solution of above compound (660mg, 1.9mmol) in DCM 5.0mL.Reaction is at room temperature stirred 12 hours.This mixture is concentrated, obtain gluey product, it is not purified for next step.
(S)-1-(5-cyclopropyl-2; 4-bis-(methoxymethoxy) benzoyl)-N-sec.-propyl-N-(pyridine-2-ylmethyl) tetramethyleneimine-2-methane amide: under argon atmospher by S-N-sec.-propyl-N-(pyridin-3-yl methyl) tetramethyleneimine-2-methane amide (321mg; 1.3mmol) add to 5-cyclopropyl-2; in 4-bis-(methoxymethoxy) phenylformic acid (423mg, 1.5mmol), DIEA (5.0mmol) and the solution of HATU (1.1mmol) in the DMF of 10.0mL.Reaction is at room temperature stirred 12 hours, then add saturated NaHCO
3with quencher, react.By using EtOAc extractive reaction thing three times.Merge EtOAc layer, use Na
2sO
4dry.Concentrated organic moiety, then by silica gel chromatography EtOAc/ hexane (20% to 50%) purifying, obtain Huang-white solid product 479mg (72% productive rate).(S)-1-(5-cyclopropyl-2; 4-dihydroxy-benzene formyl radical)-N-sec.-propyl-N-(pyridine-2-ylmethyl) tetramethyleneimine-2-methane amide: by hydrogenchloride (2ml; 8mmol; 4.0M; in dioxane) add in the solution of above compound (185mg, 0.36mmol) in DCM 5.0mL.Reaction is at room temperature stirred 12 hours.By the saturated NaHCO of this mixture
3(aqueous solution) neutralization, then uses EtOAc (3x20mL) extraction.Merge organic moiety, more concentrated with purifying in silica gel chromatography at EtOAc/ hexane (20% to 60%), obtain 127mg (82% productive rate);
1hNMR (400MHz, DMSO-D6) δ ppm 0.53 (m, 2H), 0.78 (m, 2H), 1.18 (m, 6H), 1.84-1.86 (m, 2H), 1.92-2.35 (m, 3H), 2.63-2.84 (m, 2H), 3.49-3.60 (m, 2H), 4.33-4.75 (m, 2H), 6.40 (s, 1H), 6.72 (s, 1H), 7.67-7.71 (m, 1H), 8.02 (m, 1H), 8.48-8.52 (m, 2H).With reference to above working method, those skilled in the art can easily synthesize following compound in conjunction with existing knowledge.
biological activity Hsp90 cell analysis is used Akt luminex analytical method to evaluate tiring of the anti-HSP-90 based on cell, the upset of this assay HSP-90 client albumin A kt.NCI-H1299 cell is processed 24 hours by the serial dilutions of HSP-90 compound.Then by Akt/PKBBeadmate, use luminex 100 systems, analysis of cells lysate, the loss of expressing to measure Akt, determines cell IC thus
50.Find that the compounds of this invention 1,3,4,5,11,12,13,15,16 suppresses NCI-H1299 clones and has and be less than 1.0 micromolar IC
50value.Anti-proliferative activity: the anti-proliferative activity of the compounds of this invention be the clone of some amount for example in CCL188 HCT116 cytostatic ability measure.The restraining effect of Growth of Cells is to use Alamar Blue assay.The method is to take the ability that survivaling cell makes resazurin (resazurin) be reduced into its fluorescence-causing substance resorufin (resorufin) to be basis.For each hyperplasia, analyze, make the auxiliary plate of cell to 96 orifice plates, then make it to recover 16 hours, then add inhibitor compound and reach other 6 hours, then at 535nM ex/590nM em place, measure fluorescence-causing substance.In the situation that non-hyperplasia is analyzed, make cell keep merging and reach 96 hours, then add inhibitor compound and reach other 72 hours.As previously mentioned by the quantity of Alamar Blue assay survivaling cell.Find that the compounds of this invention 1,2,3,4,5,6,7,8,9,10,11,13,15,16 suppresses HCT clones and has and be less than 1.0 micromolar IC
50value.Compound 12 and 14 suppresses HCT clones to be had and is less than 5.0 micromolar IC
50value.＊＊＊＊＊
To those skilled in the art, provide above-described embodiment, with full disclosure and description, how to implement and use the embodiment of being advocated, rather than for limiting scope disclosed herein.Apparent modification will be within the scope of the appended claims to those skilled in the art.All publications, patent and the patent application of this specification sheets citation is incorporated to herein by reference, as these publications, patent and patent application, shows especially and individually to be separately incorporated to by reference herein.
Claims (2)
1. following compound, it is selected from:
With
And pharmacologically acceptable salts, solvate and hydrate.
2. a pharmaceutical composition, the compound that it comprises claim 1, and the acceptable vehicle of pharmacy or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910210364.1A CN102485720B (en) | 2009-10-30 | 2009-10-30 | Heat shock protein 90 inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910210364.1A CN102485720B (en) | 2009-10-30 | 2009-10-30 | Heat shock protein 90 inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102485720A CN102485720A (en) | 2012-06-06 |
| CN102485720B true CN102485720B (en) | 2014-08-20 |
Family
ID=46151295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910210364.1A Expired - Fee Related CN102485720B (en) | 2009-10-30 | 2009-10-30 | Heat shock protein 90 inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102485720B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3215186A4 (en) * | 2014-11-04 | 2018-10-24 | University of Southern California | COMPOSITIONS AND METHODS FOR TREATING HIF-1alpha OVER-EXPRESSING CANCERS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008053319A1 (en) * | 2006-10-30 | 2008-05-08 | Pfizer Products Inc. | Amide resorcinol compounds |
-
2009
- 2009-10-30 CN CN200910210364.1A patent/CN102485720B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008053319A1 (en) * | 2006-10-30 | 2008-05-08 | Pfizer Products Inc. | Amide resorcinol compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102485720A (en) | 2012-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11345707B2 (en) | Atropisomerism for increased kinase inhibitor selectivity | |
| US20200190126A1 (en) | Inhibitors of Cyclin-Dependent Kinase 7 (CDK7) | |
| JP6869947B2 (en) | Use of substituted quinazoline compound and its G12C mutant KRAS, HRAS and / or NRAS protein as an inhibitor | |
| KR101920456B1 (en) | Novel imidazopyridine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient | |
| US20220127281A1 (en) | Heteroaryl compounds that inhibit g12c mutant ras proteins | |
| TWI399379B (en) | Kinase inhibitor | |
| WO2017172979A1 (en) | Substituted quinazoline compounds and methods of use | |
| AU2022206702B2 (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compounds | |
| CN105237515A (en) | Pentadeuteropyridine compounds, and preparation method, pharmaceutical compositions and uses thereof | |
| AU2014228374A1 (en) | CDC7 inhibitors | |
| CN109843858A (en) | Certain chemical entities, composition and method | |
| CN113395963B (en) | Non-ATP/catalytic site p38 mitogen-activated protein kinase inhibitors | |
| MX2011006724A (en) | PREPARATION METHOD OF DIHYDROINDENE AMIDE COMPOUNDSï¼THEIR PHARMACEUTICAL COMPOSITIONS CONTAING COMPOUNDS THEREOF AND USE AS PROTEIN KINASES INHIBITOR. | |
| JP7013453B2 (en) | Non-catalytic substrate-selective p38α-specific MAPK inhibitor with endothelial stabilizing and anti-inflammatory activity, and how to use it | |
| EP3641776B1 (en) | Atropisomerism for enhanced kinase inhibitor selectivity | |
| TW202136252A (en) | Compounds and uses thereof | |
| CN106604731B (en) | Anticancer compounds targeting RAL GTPase and methods of using the same | |
| Brooke et al. | Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2, 6-bisphosphatase 3 (PFKFB3) | |
| CN105492445B (en) | Compound (variant) and its application for treating tumor disease | |
| TW202200581A (en) | Sik-3 inhibitors and uses thereof | |
| CN103648500A (en) | Methods and use of bifunctional enzyme-building clamp-shaped molecules | |
| CN102485720B (en) | Heat shock protein 90 inhibitor | |
| CN112533581A (en) | PRC1 inhibitors and methods of treatment therewith | |
| CN110845476B (en) | High-selectivity CSF1R inhibitor, preparation method and pharmaceutical application thereof | |
| KR20210151849A (en) | Quinoline derivatives and their use for the treatment of cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140820 Termination date: 20151030 |
|
| EXPY | Termination of patent right or utility model |