CN104379573A - Isoindolone derivatives - Google Patents
Isoindolone derivatives Download PDFInfo
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- CN104379573A CN104379573A CN201380032233.3A CN201380032233A CN104379573A CN 104379573 A CN104379573 A CN 104379573A CN 201380032233 A CN201380032233 A CN 201380032233A CN 104379573 A CN104379573 A CN 104379573A
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- alkyl
- isoindole
- tetrahydrochysene
- methyl
- aryl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention provides for compounds of formula (I) wherein A, Y, J, R1, R2, and R3 have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, diabetes, obesity, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).
Description
the cross reference of related application
This application claims the rights and interests of the PCT application PCT/CN2012/074411 of the U.S.'s non-provisional application submission on April 20th, 13/796,731 and 2012 submitted on March 12nd, 2013, its instruction is incorporated to herein as a reference separately.
Background technology
Bu Luomo structural domain (bromodomains) refers to that the protein structure guarded folds, and it is combined on the N-acetylated lysine residue that finds in some albumen.The BET family comprising Bu Luomo domain protein is made up of four members (BRD2, BRD3, BRD4 and BRDt).Each member of BET family adopts two Bu Luomo structural domains to identify the N-acetylated lysine residue that main but non-fully finds on the amino terminal tails of histone.These interactions are expressed with regulatory gene to the specific gene group position in chromatin by raising transcription factor.Such as, the BRD4 of bonding histone raises transcription factor P-TEFb to promotor, causes the expression (people such as Yang, Mol. Cell. Biol. 28:967-976 (2008)) of the gene subset related in cell cycle progression.The transcription regulaton factor of BRD2 and BRD3 also as GPG plays a role (people such as LeRoy, Mol. Cell 30:51-60 (2008)).The maintenance that BET family member confirms as recently for several cancer types is important (people such as Zuber, Nature 478:524-528 (2011); The people such as Mertz; Proc. Nat'l. Acad. Sci. 108:16669-16674 (2011); The people such as Delmore, Cell 146:1-14, (2011); The people such as Dawson, Nature 478: 529-533 (2011)).BET family member has also involved the NF-κ B path mediated acute inflammatory response (people such as Huang by classics, Mol. Cell. Biol. 29:1375-1387 (2009)), cause producing the relevant gene upregulation (people such as Nicodeme with cytokine, Nature 468:1119-1123, (2010)).In animal model, effective ways people such as (, J. Biol. Chem. 287:28840-28851 (2012)) Zhang of the inflammation mediated kidney diaseases for the treatment of have been proved to be by the induction of the BET Bu Luomo structural domain inhibitor T suppression cell factor.BRD2 function is relevant to following tendency: the inflammation overview of hyperlipemia or adipogenic improper adjustment, rising and the susceptibility (Denis, Discovery Medicine 10:489-499 (2010)) increased autoimmune disorder.Human immunodeficiency virus utilizes BRD4 to start viral RNA transcribing (people such as Jang, Mol. Cell, 19:523-534 (2005)) from the viral DNA of stable integration.T cell of hiding infect and the infection of latent monocyte model in confirmed that BET Bu Luomo structural domain inhibitor reactivates HIV and transcribes people such as (, J. Leukocyte Biol. doi:10.1189/jlb.0312165) Banerjee.BRDt has vital role in spermatogenesis, its block by BET Bu Luomo structural domain inhibitor (people such as Matzuk, Cell 150:673-684 (2012)).Therefore; seeking to suppress BET family Bu Luomo structural domain and the protein bound compound of its homology acetylated lysine for Therapeutic cancer, inflammatory diseases, kidney disease, the disease relating to metabolism or Fat Accumulation and some virus infectiones, and for being provided for the method for male contraception.Therefore, the medical requirement continued is existed to the new medicine of these indications of exploitation treatment.
summary of the invention
On the one hand, the present invention relates to formula (I) compound or its pharmacy acceptable salt,
Wherein A is C (R
8r
9); Y is C (R
6r
7); J is C (R
4r
5); R
1hydrogen or C
1-C
3alkyl; R
2hydrogen or C
1-C
3alkyl; R
3be heteroaryl, 9-12 unit bicyclic aryl, naphthalene-1-base, unsubstituted phenyl or X, wherein X is
,
Wherein said heteroaryl, 9-12 unit's bicyclic aryl or naphthalene-1-base can be replaced independently selected from following substituting group by 1-3: NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl) ,-NH-C (O)-C
1-C
3alkyl ,-NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein X replaces as described in (i) or (ii):
R
10, R
11, R
12, R
13and R
14in four be hydrogen, and R
10, R
11, R
12, R
13or R
14one of be selected from following groups:
R
10nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group--C
3-C
5cycloalkyl, C
1-C
3alkylidene group-C
7-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
11nR
16r
18, fluorine, iodine, bromine, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
12nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
2-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
13and R
14nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein R
10, R
11, R
12, R
13and R
14in 5-n be hydrogen, and R
10, R
11, R
12, R
13and R
14in n be selected from following groups:
NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein n is 2,3,4 or 5;
Wherein-O-aryl ,-S-aryl, C
1-C
3alkylene-aryl, C
1-C
3the described aryl of alkylenyl-O-aryl; Described Heterocyclylalkyl;-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3the described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl and-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3the described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl and-O-C
1-C
3alkylidene group-C
3-C
14any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace: halogen, C
1-C
3alkyl, C
1-C
3haloalkyl, CN and NR
16r
18; R
4and R
5be selected from hydrogen and C independently of one another
1-C
4alkyl; R
6and R
7be selected from hydrogen and C independently of one another
1-C
4alkyl; R
8and R
9be selected from hydrogen and C independently of one another
1-C
4alkyl; And R
16and R
18be selected from hydrogen and C independently of one another
1-C
3alkyl.In certain embodiments, R
4and R
5hydrogen; And R
8and R
9each hydrogen naturally.In certain embodiments, R
6and R
7hydrogen; R
4and R
5hydrogen; And R
8and R
9each hydrogen naturally.In certain embodiments, R
6and R
7hydrogen.In certain embodiments, R
2hydrogen.In certain embodiments, R
1c
1-C
3alkyl.In certain embodiments, R
1it is methyl.In certain embodiments, R
13nR
16r
18,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl or NH-C (O)-heteroaryl.In certain embodiments, R
13nR
16r
18,-NR
16-SO
2-C
1-C
3alkyl or-NH-SO
2-C
1-C
3haloalkyl.In certain embodiments, R
3heteroaryl, 9-12 unit bicyclic aryl, or naphthalene-1-base.In certain embodiments, R
3indyl, 1,3-benzodioxole base (benzodioxolyl) or benzimidazolyl-.In certain embodiments, R
3x.In certain embodiments, R
10, R
11, R
12, R
13And R
14In four be hydrogen, and R
10, R
11, R
12, R
13Or R
14One of be selected from following groups: R
10It is NR
16R
18, halogen, hydroxyl, C
1-C
3Alkyl, C
1-C
3Alkylene-aryl, C
1-C
3Alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3Alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3Alkyl ,-NR
16-SO
2-NR
18-C
1-C
3Haloalkyl ,-NR
16-SO
2-C
1-C
3Alkyl ,-NR
16-SO
2-C
1-C
3Haloalkyl, SO
2-NR
16R
18, SO
2-C
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-C (O)-O-C
1-C
3Alkyl ,-C (O)-OH ,-C (O)-NR
16R
18,-C (O)-NH (C
1-C
3Haloalkyl) ,-C (O)-NH (C
1-C
3Alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3Alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3Alkylidenyl-heterocyclic alkyl ,-O-C
3-C
5Cycloalkyl ,-O-C
3-C
5Cycloalkyl ,-O-C
3-C
5Cycloalkyl ,-O-C
3-C
5Cycloalkyl ,-O-C
3-C
5Cycloalkyl ,-O-C
1-C
3Alkylidene-C
3-C
5Cycloalkyl, C
1-C
3Alkylidene-C
7-C
14Cycloalkyl ,-O-C
1-C
3Alkylene-heteroaryl or heteroaryl; R
11It is NR
16R
18, fluorine, iodine, bromine, hydroxyl, C
1-C
3Alkyl ,-O-aryl, C
1-C
3Alkylene-aryl, C
1-C
3Alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3Alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3Alkyl ,-NR
16-SO
2-NR
18-C
1-C
3Haloalkyl ,-NR
16-SO
2-C
1-C
3Alkyl ,-NR
16-SO
2-C
1-C
3Haloalkyl, SO
2-NR
16R
18, SO
2-C
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-C (O)-O-C
1-C
3Alkyl ,-C (O)-OH ,-C (O)-NR
16R
18,-C (O)-NH (C
1-C
3Haloalkyl) ,-C (O)-NH (C
1-C
3Alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3Alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3Alkylidenyl-heterocyclic alkyl ,-O-C
1-C
3Alkylidene-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylene-heteroaryl or heteroaryl; R
12It is NR
16R
18, halogen, hydroxyl, C
1-C
3Alkyl, C
1-C
3Alkylene-aryl, C
1-C
3Alkylenyl-O-aryl ,-S-aryl ,-O-C
2-C
3Alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3Alkyl ,-NR
16-SO
2-NR
18-C
1-C
3Haloalkyl ,-NR
16-SO
2-C
1-C
3Alkyl ,-NR
16-SO
2-C
1-C
3Haloalkyl, SO
2-NR
16R
18, SO
2-C
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-C (O)-O-C
1-C
3Alkyl ,-C (O)-OH ,-C (O)-NR
16R
18,-C (O)-NH (C
1-C
3Haloalkyl) ,-C (O)-NH (C
1-C
3Alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3Alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3Alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylidene-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylene-heteroaryl or heteroaryl; R
13And R
14It is NR
16R
18, halogen, hydroxyl, C
1-C
3Alkyl ,-O-aryl, C
1-C
3Alkylene-aryl, C
1-C
3Alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3Alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3Alkyl ,-NR
16-SO
2-NR
18-C
1-C
3Haloalkyl ,-NR
16-SO
2-C
1-C
3Alkyl ,-NR
16-SO
2-C
1-C
3Haloalkyl, SO
2-NR
16R
18, SO
2-C
1-C
3Alkyl ,-O-C
1-C
3Alkyl ,-C (O)-O-C
1-C
3Alkyl ,-C (O)-OH ,-C (O)-NR
16R
18,-C (O)-NH (C
1-C
3Haloalkyl) ,-C (O)-NH (C
1-C
3Alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3Alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3Alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylidene-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylene-heteroaryl or heteroaryl; And wherein-O-aryl ,-S-aryl, C
1-C
3Alkylene-aryl, C
1-C
3The described aryl of alkylenyl-O-aryl; Described Heterocyclylalkyl;-C (O)-NH (C
1-C
3Alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3The described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl and-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3The described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14Cycloalkyl ,-O-C
1-C
3Alkylidene-C
3-C
5Cycloalkyl and-O-C
1-C
3Alkylidene-C
3-C
14Any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace: halogen, C
1-C
3Alkyl, C
1-C
3Haloalkyl, CN and NR
16R
18.In certain embodiments, R
10, R
11, R
12, R
13and R
14in 5-n be hydrogen, and R
10, R
11, R
12, R
13and R
14in n be selected from following groups: NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl; Wherein n is 2,3,4 or 5; Wherein-O-aryl ,-S-aryl, C
1-C
3alkylene-aryl, C
1-C
3the described aryl of alkylenyl-O-aryl; Described Heterocyclylalkyl;-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3the described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl and-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3the described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl and-O-C
1-C
3alkylidene group-C
3-C
14any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace: halogen, C
1-C
3alkyl, C
1-C
3haloalkyl, CN and NR
16r
18.In certain embodiments, n is 3.In certain embodiments, n is 2.In certain embodiments, R
13nR
16r
18,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl or NH-C (O)-heteroaryl.In certain embodiments, R
16be H and R
18c
1-C
3alkyl.In certain embodiments, R
18be H and R
16c
1-C
3alkyl.In certain embodiments, R
16be H and R
18h.In certain embodiments, R
16c
1-C
3alkyl and R
18c
1-C
3alkyl.In certain embodiments, R
13nR
16r
18, and R
16be hydrogen and R
18hydrogen.In certain embodiments, R
13-NR
16-SO
2-C
1-C
3alkyl and R
16hydrogen.In certain embodiments, R
13-NR
16-SO
2-C
1-C
3haloalkyl, and R
16hydrogen.In certain embodiments, R
13nR
16r
18,-NR
16-SO
2-C
1-C
3alkyl or-NH-SO
2-C
1-C
3haloalkyl.In certain embodiments, R
10it is O-aryl.In certain embodiments, R
10be O-phenyl or the O-phenyl replaced independently by the group of 1-3 independent selected from halo.In certain embodiments, R
10it is-O-2,4-difluorophenyl.In certain embodiments, R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it can by 1-3 independent selected from halo and C
1-C
3the group of alkyl replaces.In certain embodiments, R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it is by 1-3 independent selected from halo and C
1-C
3the group of alkyl replaces.In certain embodiments, R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it is replaced by the group of 1-3 independent selected from halo.In certain embodiments, n is 2 and R
11, R
12and R
14hydrogen.In certain embodiments, formula I is selected from:
3-methyl isophthalic acid-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(4-aminomethyl phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
4-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzsulfamide;
1-(2-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[4-(methyl sulphonyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzamide;
1-(1H-indoles-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(4-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3,4-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(4-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[3-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3,5-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(2-{ [3-(trifluoromethyl) phenoxy group] methyl } phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(phenoxymethyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-{ 2-[(2-methylphenoxy) methyl] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(furans-2-base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-hydroxy phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-3-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(cyclopentylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-4-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-{ 2-[2-(morpholine-4-base) oxyethyl group] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(pyridine-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(quinoline-8-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(1-thionaphthene-7-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(pyridin-3-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(1H-indazole-5-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(5-amino-2-Phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] ethanamide;
1-[5-amino-2-(phenylsulfartyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-(phenylsulfartyl) phenyl] Toluidrin;
1-[5-amino-2-(2,4 difluorobenzene oxygen base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethyl sulfonamide;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-2,2,2-trifluoro ethyl sulfonamides;
N'-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-N, N-dimethyl methyl diamide (sulfuric diamide);
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethanamide;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-1H-pyrroles-2-methane amide;
N-{4-[(4,4-difiuorocyclohexyl) oxygen base]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl } ethyl sulfonamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid methyl esters;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid;
N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(tetrahydrofuran (THF)-2-ylmethyl) benzamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(1,3-thiazoles-2-base) benzamide;
3,6,6-trimethylammonium-1-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2,5-3,5-dimethylphenyl)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3,6,6-trimethylammonium-1-[2-(morpholine-4-base) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(benzyloxy) phenyl]-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3,6,6-trimethylammonium-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin;
3,6-dimethyl-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(5-amino-2-Phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
3-methyl-6-(2-methyl-propyl)-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-{3-[3-methyl-6-(2-methyl-propyl)-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin;
3-methyl isophthalic acid-(2-Phenoxyphenyl)-6-(propane-2-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-{3-[3-methyl-4-oxo-6-(propane-2-base)-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin;
N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin; With
1-[2-(cyclo propyl methoxy)-5-(methyl sulphonyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4
h-isoindole-4-ketone.
In certain embodiments, formula I is selected from:
1-(1,3-benzodioxole-5-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(naphthalene-1-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(1H-benzoglyoxaline-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(1H-indoles-7-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzyl]-1H-isoindole-1,3 (2H)-diketone; With
1-(1,3-benzodioxole-5-base)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
On the other hand, the present invention relates to and comprise pharmaceutically acceptable vehicle and treatment formula (I) compound of significant quantity or the pharmaceutical composition of its pharmacy acceptable salt.
On the other hand, the present invention relates to the method for the cancer for the treatment of target, comprise formula (I) compound to subject in need or its pharmacy acceptable salt.In certain embodiments, described cancer is selected from: acoustic tumor, acute leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia (monocarpotic cellularity, myeloblastic, gland cancer, angiosarcoma, astrocytoma, myelo-monocytic and promyelocytic leukemic cell), acute t chronic myeloid leukemia, rodent cancer, cholangiocarcinoma, bladder cancer, the cancer of the brain, mammary cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocyte) leukemia, chronic granulocytic leukemia (chronic myelogenous leukemia), colorectal carcinoma, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dispersivity large B cell lymphatic cancer, paraplasm (dysproliferative) change (heteroplasia and change life), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, the esophageal carcinoma, estrogen receptor positive mammary cancer, idiopathic thrombocythemia, Ewing sarcoma, fibrosarcoma, follicular lymphoma, sexual cell carcinoma of testis, glioma, glioblastoma, glioma sarcomatosum, heavy chain disease, hemangioblastoma, liver neoplasm, hepatocellular carcinoma, Hormone-refractory prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma (lymphagioendotheliosarcoma), lymphangiosarcoma, lymphocytoblast leukemia, lymphoma (Huo Qi metal type and non-Hodgkin′s type), bladder, mammary gland, colon, lung, ovary, pancreas, prostate gland, the malignant tumour in skin and uterus and excessively proliferative disease, the lymphoid malignancy in T cell or B cell source, leukemia, lymphoma, medullary carcinoma, myeloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, marrow-derived leukocythemia, myelomatosis, myxosarcoma, neuroblastoma, NUT center line cancer (NUT midline carcinoma, NMC), nonsmall-cell lung cancer, mesoglioma, oral carcinoma, osteogenic sarcoma, ovarian cancer, carcinoma of the pancreas, papillary carcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, the rectum cancer, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, sebaceous carcinoma, spermocytoma, skin carcinoma, small cell lung cancer, noumenal tumour (cancer and sarcoma), small cell lung cancer, cancer of the stomach, squamous cell carcinoma, synovioma, syringocarcinoma, thyroid carcinoma, macroglobulinemia Waldenstron, tumor of testis, uterus carcinoma and wilms' tumor.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
On the other hand, the present invention relates to the disease for the treatment of target or the method for illness, comprise formula (I) compound to subject in need or its pharmacy acceptable salt, wherein said disease or illness are selected from: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcets disease, bullous dermatosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, systemic lupus erythematosus, multiple sclerosis, myocarditis, myositis, ephritis, organ-graft refection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriatic, psoriasis arthropathica, rheumatoid arthritis, scleritis, sclerosing cholangitis, septicemia, systemic lupus erythematous, high iS-One arteritis, toxic shock, thyroiditis, type i diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wei Genashi granulomatosis.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
On the other hand, the present invention relates to the method for the AIDS for the treatment of target, comprise formula (I) compound to subject in need or its pharmacy acceptable salt.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
On the other hand, the present invention relates to the method for the obesity for the treatment of target, comprise formula (I) compound to subject in need or its pharmacy acceptable salt.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
On the other hand, the present invention relates to the method for the type ii diabetes for the treatment of target, comprise formula (I) compound to subject in need or its pharmacy acceptable salt.In certain embodiments, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
On the other hand, the present invention relates to the method for the disease for the treatment of target, comprise formula (I) compound to subject in need or its pharmacy acceptable salt, the disease during wherein said disease is selected from one of following group:
Cancer;
Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcets disease, bullous dermatosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, systemic lupus erythematosus, multiple sclerosis, myocarditis, myositis, ephritis, organ-graft refection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriatic, psoriasis arthropathica, rheumatoid arthritis, scleritis, sclerosing cholangitis, septicemia, systemic lupus erythematous, high iS-One arteritis, toxic shock, thyroiditis, type i diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wei Genashi granulomatosis,
Diabetic nephropathy, hypertensive nephropathy, HIV associated nephropathy, glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, FSGS, membranous glomerulonephritis, minimal change, multicystic kidney disease and tubulointerstitial nephritis;
The kidney disease that kidney disease, pneumonia that the kidney disease that the kidney disease that kidney disease, percutaneous coronary intervention (pci) that the kidney disease that ischemia-reperfusion brings out, heart and major surgery are brought out bring out, radiopaque contrast medium bring out, septicemia are brought out are brought out and the kidney disease that drug toxicity is brought out;
AIDS；
Obesity;
Type ii diabetes; With
Obesity, hyperlipemia, hypercholesterolemia, Alzheimer, metabolism syndrome, fatty degeneration of liver, type ii diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy.
detailed Description Of The Invention
definition
It should be noted that singulative " ", " one " and " being somebody's turn to do " comprise plural, unless the context clearly determines otherwise as what use in the claim of this specification sheets and intention.Therefore, such as, mention that " a kind of compound " comprises individualized compound and one or more identical or different compounds, mention that " optionally pharmaceutically acceptable carrier " refers to single optional pharmaceutically acceptable carrier and one or more pharmaceutically acceptable carriers etc.
When using in specification sheets and appended claim, unless made contrary regulation, otherwise following term has pointed implication:
Term as used herein " alkyl " refers to saturated, straight or branched hydrocarbon chain radical.In some cases, the carbon atom number in alkyl is by prefix " C
x-C
y" represent, wherein x is carbon atom number minimum in substituting group, and y is carbon atom number maximum in substituting group.Therefore, such as " C
1-C
6alkyl " refer to the alkyl substituent comprising 1 to 6 carbon atom, and " C
1-C
3alkyl " refer to the alkyl substituent comprising 1 to 3 carbon atom.The representative example of alkyl comprises, but be not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-methyl-propyl, 1-ethyl propyl, 1,2,2-thmethylpropyl, 3-methylhexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl groups, n-heptyl, n-octyl, n-nonyl and positive decyl.
Term " alkylidene group (alkylene or alkylenyl) " refers to derived from such as 1 to 10 carbon atom or 1 to 6 carbon atom (C
1-C
6alkylidene group) or 1 to 4 carbon atom or 1 to 3 carbon atom (C
1-C
3alkylidene group) the divalent group of saturated hydrocarbon chain of straight or branched.The example of alkylidene group includes but not limited to-CH
2-,-CH
2cH
2-,-CH
2cH
2cH
2-,-CH
2cH
2cH
2cH
2-and-CH
2cH (CH
3) CH
2-.
Term " C
3-C
14cycloalkyl " (independent or combine with other one or more term) refer to saturated cyclic hydrocarbon radical substituting group containing 3-14 carboatomic ring atom.Term cycloalkyl comprises monocyclic cycloalkyl, bicyclic cycloalkyl, bridge ring alkyl and spiro cycloalkyl group.The example of monocyclic cycloalkyl comprises, but be not limited to, cyclopropyl (cyclopropane base), cyclobutyl (tetramethylene base), cyclopentyl (pentamethylene base), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexyl), cyclohexenyl, suberyl, ring octyl group etc.Except as otherwise noted, term " C
3-C
8monocyclic cycloalkyl " refer to monocyclic cycloalkyl containing 3-8 carbon.
In volution cycloalkyl, atom is that two different rings have.The example of volution cycloalkyl comprises spiral shell [2.2] pentyl, spiral shell [2.4] heptane base and spiral shell [2.5] octyl.Except as otherwise noted, term " C
5-C
8volution cycloalkyl " refer to volution cycloalkyl containing 5-8 carbon.
In the cycloalkyl of bridge joint, ring shares at least two common non-conterminous atoms.The example of the cycloalkyl of bridge joint comprises dicyclo [2.2.1] heptane base and adamantyl.Except as otherwise noted, term " C
7-C
10the cycloalkyl of bridge joint " refer to the cycloalkyl of the bridge joint containing 5-10 carbon.
Bicyclic cycloalkyl is thick and arrives monocycle C
5-C
7c on cycloalkyl ring
5-C
7monocyclic cycloalkyl.The limiting examples of bicyclic cycloalkyl comprises decahydro naphthyl, octahydro-1H-indenyl, octahydro pentalene and decahydro Azulene.Bicyclic cycloalkyl can contain one or two alkylidene bridge, and each carbon atom being, two, three or four by length forms, and the carbon atom that two of each bridging T-Ring system non-adjacent.The limiting examples of dicyclo bridge joint group comprises dicyclo [3.1.1] heptane base, dicyclo [2.2.1] heptane base, dicyclo [2.2.2] octyl, dicyclo [3.2.2] nonyl, dicyclo [3.3.1] nonyl and dicyclo [4.2.1] nonyl, three ring [3.3.1.0
3,7] nonyl (octahydro-2,5-first bridge pentadienyl (methanopentalenyl) or noradamantyl) and three ring [3.3.1.1
3,7] decyl (adamantyl).
Term " cycloalkenyl group " (independent or combine with other one or more term) refers to the naphthenic substituent of the fractional saturation containing 3-14 carboatomic ring atom.Cycloalkenyl group can be monocycle carbocyclic ring, and it comprises 3-8 carboatomic ring atom (that is, C usually
3-C
8cycloalkenyl group), and be more typically 4-6 carboatomic ring atom (i.e. C
4-C
6cycloalkenyl group).The example of monocyclic cycloalkenyl comprises cyclopentenyl and cyclohexenyl.Cycloalkenyl group can be dicyclo alternatively.The example of bicyclic cycloalkenyl base comprise bridge joint with volution cycloalkyl.
" Heterocyclylalkyl " refers to containing carbon atom and 1-3 the heteroatomic 3-15 unit's non-aromatic monocyclic independently selected from O, N or S or dicyclo cyclic group as the term is employed herein.Heterocyclylalkyl nuclear nitrogen and sulfur heteroatom can be optionally oxidized (such as 1,1-titanium dioxide tetrahydro-thienyl, 1,2-titanium dioxide-1,2-thiazolidyl, 1,1-titanium dioxide thio-morpholinyls), and nitrogen-atoms is optionally quaternized.Unless otherwise directed, aforementioned Heterocyclylalkyl can be C-connect or N-connect, if this situation be possible and its cause produce stable structure.Such as, piperidyl can be piperidin-1-yl (N-connection) or piperidin-4-yl (C-connection).The example of Heterocyclylalkyl comprises the bicyclic heterocycloalkyl of 3-8 unit monocyclic heterocycloalkyl, 8-12 unit's bicyclic heterocycloalkyl and 7-15 unit bridge joint.
Phrase " 3-8 unit monocyclic heterocycloalkyl " refers to have carbon atom and 1-3 the heteroatomic non-aromatic cyclic group independently selected from S, N or O, wherein when existence two O atoms or an O atom and a S atomic time, described two O atoms or an O atom and S atom not bonding each other respectively.The illustrative example of 3-8 unit monocyclic heterocycloalkyl comprises ethylenimine-1-base, 1-oxa--tetramethylene-2-base, tetrahydrofuran (THF)-3-base, morpholine-4-base, 2-thia hexamethylene (thiacyclohex)-1-base, 2-oxo-2-thia hexamethylene-1-base, 2,2-dioxo-2-thia hexamethylene-1-bases and 4-thyl-piperazin-2-base.
" 3 yuan of monocyclic heterocycloalkyl " be there are 2 carbon atoms and 1 be selected from 1O; 1S; With heteroatomic 3 yuan of monocyclic cycloalkyl rings of 1N.The illustrative example of 3 yuan of monocyclic heterocycloalkyl comprises Oxyranyle, ethylenimine base and thiirane base.
" 4 yuan of monocyclic heterocycloalkyl " be there are 3 carbon atoms and 1 be selected from 1O; 1S; With heteroatomic 4 yuan of monocyclic cycloalkyl rings of 1N.The illustrative example of 4 yuan of monocyclic heterocycloalkyl comprises oxetanylmethoxy, azelidinyl and thietanyl.
" 5 yuan of monocyclic heterocycloalkyl " has 1-4 carbon atom and 1-3 to be selected from 1O; 1S; 1N; 2N; 3N; 1S and 1N; 1S and 2N; 1O and 1N; And heteroatomic 5 yuan of monocyclic cycloalkyl rings of 1O and 2N.The illustrative example of 5 yuan of monocyclic heterocycloalkyl comprises tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, imidazolidyl, oxazolidinyl, imidazolinyl, isoxazole alkyl, pyrrolidyl, 2-pyrrolinyl and 3-pyrrolinyl.
" 6 yuan of monocyclic heterocycloalkyl " has 3-5 carbon atom and 1-3 to be selected from 1O; 2O; 3O; 1S; 2S; 3S; 1N; 2N; 3N; 1S, 1O and 1N; 1S and 1N; 1S and 2N; 1S and 1O; 1S and 2O; 1O and 1N; And heteroatomic 6 yuan of monocyclic cycloalkyl rings of 1O and 2N.The illustrative example of 6 yuan of monocyclic heterocycloalkyl comprises THP trtrahydropyranyl, dihydro pyranyl, alkyl dioxin, 1,3-dioxolyl, 1,4-dithiane base, hexahydropyrimidine, morpholinyl, piperazinyl, piperidyl, 2H-pyranyl, 4H-pyranyl, pyrazolidyl, pyrazolinyl, 1,2,3,6-tetrahydro pyridyl, tetrahydro thiapyran base, thio-morpholinyl, thioxane base (thioxanyl) and trithian base.
" 7 yuan of monocyclic heterocycloalkyl " has 5 or 6 carbon atoms and 1-3 to be selected from 1O; 2O; 1S; 2S; 1N; 2N; 1S, 1O and 1N; 1S and 1N; 1S and 2N; 1S and 1O; 1S and 2O; 1O and 1N; And heteroatomic 7 yuan of monocyclic cycloalkyl rings of 1O and 2N.The illustrative example of 7 yuan of monocyclic heterocycloalkyl comprises azepan base, 2,3,4,5-tetrahydrochysene-1H-nitrogen heterocyclic heptantriene base, oxepane alkyl (oxepanyl), 2,3,4,5-tetrahydrochysene-1H-oxepin base, thia suberane base (thiepanyl) and 2,3,45-tetrahydrochysene-1H-thia cycloheptatriene base.
" 8 yuan of monocyclic heterocycloalkyl " has 5-7 carbon atom and 1-3 to be selected from 1O; 2O; 3O; 1S; 2S; 3S; 1N; 2N; 3N; 1S, 1O and 1N; 1S and 1N; 1S and 2N; 1S and 1O; 1S and 2O; 1O and 1N; And heteroatomic 8 yuan of monocyclic cycloalkyl rings of 1O and 2N.The illustrative example of 8 yuan of monocyclic heterocycloalkyl comprises Azacyclooctane base (azocanyl), thia cyclooctane base (thiocanyl), oxocane base (oxocanyl), 3,4,5,6-tetrahydrochysene-2H-oxa-cyclooctatetraenyl (oxocinyl) etc.
Dicyclo 8-12 unit Heterocyclylalkyl be condense with phenyl monocycle 5-7 unit Heterocyclylalkyl, or with monocycle C
5-C
7cycloalkylfused monocycle 5-7 unit Heterocyclylalkyl, or the monocycle 5-7 unit Heterocyclylalkyl condensed with monocycle 5-7 unit Heterocyclylalkyl.The representative example of bicyclic heterocycloalkyl includes but not limited to, benzopyranyl, benzo thiapyran base, 2,3-dihydro benzo furyls, 2,3-dihydrobenzo thienyls, 2,3-dihydro-1H-indyl, 3,4-dihydro-isoquinoline-2 (1H)-Ji, 2,3,4,6-tetrahydrochysene-1H-pyrido [1,2-a] pyrazine-2-base, six hydrogen pyrans also [3,4-b] [Isosorbide-5-Nitrae] oxazine-1 (5H)-Ji.
Monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can containing one or two alkylidene bridge or alkenylene bridge or its mixtures, are eachly made up of no more than 4 carbon atoms, and the atom that two of each shack system non-adjacent.The example of the Heterocyclylalkyl of such bridge joint comprises, but be not limited to, azabicyclo [2.2.1] heptyl (comprising 2-azabicyclo [2.2.1]-2-in heptan base), the pungent-8-base of 8-azabicyclo [3.2.1], octahydro-2,5-epoxy pentalene (epoxypentalene), six hydrogen-2H-2,5-first bridge cyclopenta [b] furans, six hydrogen-1H-1,4-first bridge cyclopenta [c] furans, azepine-diamantane (1-aza-tricycle [3.3.1.1
3,7] decane) and oxa--diamantane (2-oxatricyclo [3.3.1.1
3,7] decane).The term bicyclic heterocycloalkyl of bridge joint " 6-9 unit " refers to saturated or undersaturated cyclic group, and its to be 5,6 or 7 yuan of monocyclic heterocycloalkyl be fused on 3,4 or 5 yuan of monocyclic heterocycloalkyl, or 5,6 or 7 yuan of monocyclic heterocycloalkyl are fused to C
5-C
7-cycloalkyl produces, wherein condenses connection and there is 1-3 annular atoms (intervening ring atoms) between two parties.The term bicyclic heterocycloalkyl of bridge joint " 6-9 unit " comprises saturated with undersaturated " bicyclic heterocycloalkyl of 6-9 unit bridge joint "." bicyclic heterocycloalkyl of 6-9 unit bridge joint " can as above be substituted for described in alkyl." bicyclic heterocycloalkyl of 6-9 unit bridge joint " comprises 3-azabicyclo [4.2.1] nonyl and 7-azabicyclo [2.2.1] heptane base.
Spiroheterocyclic alkyl is 7-15 unit Heterocyclylalkyl, and two substituting groups in the identical carbon atoms of wherein monocycle 5-7 unit heterocycloalkyl ring are formed together with described carbon atom and are selected from the second following member ring systems: monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocycloalkyl or bicyclic heterocycloalkyl.The example of spiroheterocyclic alkyl comprises, but be not limited to, pungent-6-the base of 6-azaspiro [2.5], 1'H, 4H-spiral shell [1,3-benzo dioxa glutinous rehmannia-2,4'-piperidines]-1'-base, 1'H, 3H-spiral shell [2-cumarone-1,4'-piperidines]-1'-base and Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5]-8-in last of the ten Heavenly stems base.Monocycle, dicyclo and spiroheterocyclic alkyl can be unsubstituted or replace.Monocycle, being connected on parent molecular moiety by any carbon atom of containing in described member ring systems or any nitrogen-atoms with spiro heterocyclic radical of dicyclo.Heterocyclylalkyl nuclear nitrogen and sulfur heteroatom can be optionally oxidized (such as 1,1-titanium dioxide tetrahydro-thienyl, 1,2-titanium dioxide-1,2-thiazolidyl, 1,1-titanium dioxide thio-morpholinyls), and nitrogen-atoms is optionally quaternized.
Aryl is aromatic hydrocarbons group.Typical aryl comprises phenyl and naphthyl.In addition, term " aryl " comprises 9-12 unit bicyclic aryl.Term " 9-12 unit bicyclic aryl " is the bicyclic radicals formed by phenyl ring being fused to following groups: (1) C
5-C
8monocyclic cycloalkyl (such as, indanyl; 1,2,3,4-tetralyl; 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl etc.); Or (2) 5-7 unit Heterocyclylalkyl, it can be replaced by one or two oxo group (such as, indolinyl, 1,3-benzodioxole base, 1,3-dioxo iso-dihydro-indole-group, iso-dihydro-indole-group etc.); Wherein condensing connection is on the adjacent carbons on phenyl ring.
The first heteroaryl of monocycle 5 or 6 yuan of heteroaryls and dicyclo 8-12 contained in term as used herein " heteroaryl ".
" 5 yuan of heteroaryls " has 1-4 carbon atom and 1-4 to be selected from 1O; 1S; 1N; 2N; 3N; 4N; 1S and 1N; 1S and 2N; 1O and 1N; And heteroatomic 5 yuan of mono-cyclic aromatic cyclic groups of 1O and 2N.The illustrative example of 5 yuan of heteroaryls comprises, but be not limited to, furyl, 2-furyl, 3-furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrryl, 2-or 3-pyrryl, thienyl, 2-thienyl, 3-thienyl, tetrazyl, thiazolyl, thiadiazolyl group and triazolyl.
" 6 yuan of heteroaryls " has 3-5 carbon atom and 1-3 to be selected from 1N; Heteroatomic 6 yuan of mono-cyclic aromatic cyclic groups of 2N and 3N.The illustrative example of 6 yuan of heteroaryls includes, but not limited to pyridyl, 2-, 3-or 4-pyridyl, pyrimidyl, 2-, 4-or 5-pyrimidyl, pyrazinyl, pyridazinyl, 3-or 4-pyridazinyl, 2-pyrazinyl and triazinyl.
" 8-to 12-unit bicyclic heteroaryl " condenses by 5 or 6 yuan of heteroaryls and following groups the ring structure formed: (1) independent 5 yuan of heteroaryls selected; (2) the independent 6 yuan of heteroaryls (such as, naphthyridinyl, pteridyl, phthalazinyl, purine radicals etc.) selected; (3) C
5-C
8monocyclic cycloalkyl; (4) 5-7 unit Heterocyclylalkyl; Or (5) phenyl ring (such as, benzimidazolyl-, benzofuryl, benzofuraxan base, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolines base, indyl or 2,3-, 4-, 5-, 6-or 7-indyl, quinazolyl, quinoxalinyl, pseudoindoyl and isoquinolyl), wherein this condenses that to connect be at adjacent annular atoms place.Condense that connect can nitrogen (such as, indolizine) in 5 or 6 yuan of heteroaryls or carbon atom place.
Term " hydrogen " (independent or combine with other one or more term) refers to hydrogen base, and can be expressed as-H.
Term " hydroxyl " (independent or combine with other one or more term) refers to-OH.
Term " carboxyl " (independent or combine with other one or more term) refers to-C (O)-OH.
Term " amino " (independent or combine with other one or more term) refers to-NH
2.
Term " halogen " or " halo " (independent or combine with other one or more term) refer to fluorine-based (can be expressed as-F), chloro (can be expressed as-Cl), bromo (can be expressed as-Br) or iodo (can be expressed as-I).Prefix " halo " represents that the substituting group that this prefix connects is replaced by one or more independent halogen group selected.Such as, haloalkyl refers to the alkyl substituent that wherein at least one hydrogen base is substituted by halogen group.The example of haloalkyl comprises chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl.Should be clear, if substituting group is replaced by more than one halogen group, these halogen groups can identical or different (unless otherwise indicated).The example of haloalkyl comprises C
1-C
3haloalkyl, it is the haloalkyl comprising 1-3 carbon atom.
If group is described as " (quilt) replaces ", then non-hydrogen group instead of any hydrogen base replacing atom of this group.Therefore, such as, the heteroaryl of replacement is that wherein at least one non-hydrogen group instead of the heteroaryl of this heterocycle ring hydrogen base.It should be known that if group occurs in more than one replacement, then each non-hydrogen group can identical or different (unless otherwise indicated).
If group is described as " optional replace ", then this group can (1) unsubstituted or (2) be substituted.If group is described to optionally be replaced by the non-hydrogen group of given number at the most, then this group can be that (1) is not substituted; Or (2) are by the non-hydrogen group of this given number at the most, or the maximum number of the position of substitution can be replaced by this group at the most, see which is less.Therefore, such as, if group is described as optionally by the heteroaryl that maximum 3 non-hydrogen groups replace, then can the position of substitution be less than 3 any heteroaryl can optionally by can replacing by the as many non-hydrogen group of the position of substitution of only having with this heteroaryl at most.For example, tetrazyl (it only have can the position of substitution) can optionally be replaced by a maximum non-hydrogen group.Again such as, can optionally be replaced by maximum 2 non-hydrogen groups if amino nitrogen is described as, then primary amino nitrogen can optionally be replaced by maximum 2 non-hydrogen groups, and secondary amino nitrogen can optionally be replaced by maximum only 1 non-hydrogen group.
Term " treatment (treat, treating, treatment) " refers to be alleviated or eliminates a disease and/or the method for its simultaneous phenomenon.
Term " prevention (prevent, preventing, prevention) " refers to the method preventing disease and/or the outbreak of its simultaneous phenomenon or prevention object from falling ill.When using in this article, " prevention " also comprises the outbreak that delays disease and/or its simultaneous phenomenon and reduces the risk that object falls ill.
Phrase " treatment significant quantity " refer to when separately or combine with another kind of medicament or treatment use in special object or subject population time, one or more symptoms being enough to the patient's condition or the illness preventing from being to a certain extent treated produce or alleviate the compound of described symptom or the amount of its pharmacy acceptable salt.Such as, in people or other Mammals, for specific disease and the object that is treated, treatment significant quantity can be determined by experiment in laboratory or clinical setting, can be maybe the amount required by the guide of the foreign agencies of food and drug administration or equivalence.
Term " object " is defined as in this article and refers to animal, and such as Mammals, includes but not limited to: primates (such as the mankind), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.In preferred embodiments, described to liking people.
compound
Geometrical isomer may reside in the compounds of this invention.Compound of the present invention can contain carbon-to-carbon double bond or the carbon-nitrogen double bond of E or Z configuration, wherein as by Cahn-Ingold-Prelog priority rule determined, term " E " represents the offside of high-order substituting group in carbon-to-carbon or carbon-nitrogen double bond, and term " Z " represents the homonymy of high-order substituting group in carbon-to-carbon or carbon-nitrogen double bond.Compound of the present invention can also exist with the form of mixtures of " E " and " Z " isomer.Substituting group around cycloalkyl or Heterocyclylalkyl also can be appointed as cis or transconfiguration.
Compound of the present invention can contain the carbon atom of the Asymmetrical substitute of R or S configuration, wherein term " R " and " S " are as IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13-10 defined.There is the carbon atom of Asymmetrical substitute and the compound with R and the S configuration of equivalent is racemic at those carbon atom places.The atom with excessive a kind of configuration (relative to another kind of configuration) is appointed as the configuration existed with more, preferably excessive about 85%-90%, more preferably excessive about 95%-99%, and is still more preferably excessively greater than about 99%.Therefore, the present invention includes racemic mixture, relatively with absolute stereo isomer and mixture that is relative and absolute stereo isomer.
Formula (I) compound can comprise the atom of one or more asymmetric replacements.Formula I can also exist as single steric isomer (comprising enantiomer and diastereomer) and composition thereof.The single steric isomer of formula I can be from the commercially available Material synthesis preparation obtained containing asymmetric or chiral centre, or by preparing racemic mixture, use method known to persons of ordinary skill in the art to split each steric isomer to prepare subsequently.The example split is that such as, enantiomeric mixture is connected with chiral auxiliary(reagent) by (I), by the non-enantiomer mixture of recrystallization or chromatography resulting separation, and release optical purity product subsequently; Or (ii) is separated the mixture of enantiomer or diastereomer on chirality chromatography column.
The compound of formula I also can comprise various geometrical isomers owing to obtaining around the substituent distribution of carbon-to-carbon double bond, carbon-nitrogen double bond, cycloalkyl or Heterocyclylalkyl and composition thereof.Substituting group around carbon-to-carbon double bond or carbon-nitrogen double bond is designated as to be Z or E and to be designated as around the substituting group of cycloalkyl or Heterocyclylalkyl to be cis or transconfiguration.
Should be understood that in the present invention, compound disclosed herein can demonstrate tautomerism and all tautomers are included in scope of the present invention.
Therefore, the one in tautomerism, rotamerism or stereoisomeric forms in any ratio that the structural formula figure in this specification sheets can only express possibility.But should be appreciated that and the present invention includes any tautomerism, rotamerism or stereoisomeric forms in any ratio, and their mixture, and be not only confined to any one tautomerism, rotamerism or stereoisomeric forms in any ratio used in structural formula figure.
the compound of isotopic enrichment or mark
Compound of the present invention can exist with form that is isotope-labeled or enrichment, comprises to have to be different from the nucleidic mass of natural modal nucleidic mass or total mass number or one or more atoms of total mass number.Isotropic substance can be radioactivity or inactive isotropic substance.The isotropic substance of atom as hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and iodine includes but not limited to
2h,
3h,
13c,
14c,
15n,
18o,
32p,
35s,
18f,
36cl and
125i.Comprise other isotopic compound of these and/or other atom within the scope of the present invention.
In another embodiment, the compound of isotropic substance-mark comprise deuterium (
2h), tritium (
3h) or
14c isotropic substance.Prepared by the general method that isotope-labeled compound of the present invention is known by those of ordinary skill in the art.This type of isotope-labeled compound by performing method disclosed in embodiment disclosed herein and scheme, can be prepared by replacing cold reagent with the isotope-labeled reagent be easy to get easily.In some cases, compound can by isotope-labeled agent treated to exchange normal atom and its isotropic substance, such as, hydrogen for deuterium by deuteric acid (deuteric acid) such as D
2sO
4/ D
2o be used for exchange.Except above-mentioned, methods involving and intermediate are disclosed in, the people such as such as Lizondo, J,
drugs Fut, 21 (11), 1116 (1996); Brickner, SJ
deng people, J Med Chem, 39 (3), 673 (1996); The people such as Mallesham, B,
org Lett, 5 (7), 963 (2003); PCT open WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Patent number 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; With U.S. Patent Application Publication No. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416 and 20090082471, described method is incorporated to herein as a reference.
In combination measures, isotope-labeled compound of the present invention can be used as the effect that standard determines BET Bu Luomo structural domain inhibitor.Containing isotopic compound in drug research with the mechanism of action and pathways metabolism by evaluating nonisotopically labelled parent compound study compound internal metabolism home to return to (people such as Blake,
j. Pharm. Sci.64,3,367-391 (1975)).Such metabolism research is very important in the design of safe and effective medicine; because be applied to patient active compound in vivo or because the metabolite produced from parent compound is proved to be the poisonous or carcinogenic (people such as Foster; Advances in Drug Research Vol.14; pp.2-36; Academic press; London, 1985; The people such as Kato, J.
labelled Comp. Radiopharmaceut., 36 (10): 927-932 (1995); The people such as Kushner,
can. J. Physiol. Pharmacol., 77,79-88 (1999).
In addition, containing the isotopic medicine of non-radioactive, as being called the deuterate medicine of " heavy medicine ", may be used for the treatment disease relevant to BET Bu Luomo domain activity and the patient's condition.The natural abundance that the isotopic amount existed in compound is increased to higher than it is called as enrichment.The example of the amount of enrichment comprises about 0.5,1,2,3,4,5,6,7,8,9,10,12,16,21,25,29,33,37,42,46,50,54,58,63,67,71,75,79,84,88,92,96 to about 100 % by mole.The normal atom of at the most about 15% is replaced Mammals with heavy isotope; comprise in rodent and dog and realized and maintained several days periods to several weeks; and observe MIN untoward reaction (Czajka D M and Finkel A J, Ann. N. Y. Acad. Sci. 1960 84:770; Thomson J F, Ann. New York Acad. Sci 1960 84:736; The people such as Czakja D M, Am. J. Physiol. 1961 201:357).Be found not cause the toxicity (people such as Blagojevic N with the human body fluid of the acute replacement of deuterium up to 15%-23%; " Dosimetry & Treatment Planning for Neutron Capture Therapy "; Zamenhof R; Solares G and Harling O edits. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23:251 (1997)).
The cold labeling of medicine can change its physico-chemical property, such as pKa and lipid solubility.If isotropic substance replaces the region that have impact on and participate in ligand-receptor interaction, then these impacts and change can affect the pharmacodynamics reaction of drug molecule.Although some physical propertiess of stable isotopic labeling molecule be different from unlabelled those, but chemistry and biology character is identical, except an important exception: because the quality of heavy isotope increases, anyly relate to heavy isotope and another monatomic key can be stronger than the identical key between light isotope and this atom.Therefore, isotropic substance mixes metabolism or Enzymatic transformation position described reaction of slowing down, and may change the pharmacokinetic profile relative to heterotope compound or effect.
scheme
Compound of the present invention (such as, formula I) is prepared by the synthetic method applying synthetic method known in the art and summarize in scheme described below.Compound as herein described, comprises the compound of general formula (I) and specific embodiment, passable, such as, is prepared by the reaction scheme shown in scheme 1-5.The variables A used in following scheme, Y, J, R
1, R
2, R
3, R
10, R
11, R
12, R
13and R
14there is the implication as described in summary of the invention and detailed Description Of The Invention part, except as otherwise noted.
The abbreviation used in the description of scheme and specific embodiment has following implication: DME is 1,2-glycol dimethyl ether, DMF is dimethyl formamide, and DMSO is dimethyl sulfoxide (DMSO), and EDAC is 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride; EtOH is ethanol; EtOAc is ethyl acetate; HATU is O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate, PdCl
2(PPh
3)
2for two (triphenylphosphine) palladium chloride (II); Pd
2(dba)
3it is three (dibenzalacetone) two palladium (0); THF is tetrahydrofuran (THF), and TFA is trifluoroacetic acid, and HPLC is high performance liquid chromatography.
The compound of general formula (I) can use as in scheme 1 the general method summarized prepare.The halogenide (wherein X is Cl, Br or I) of formula (2) can use the general method for these reactions to prepare from the halogenating reaction of formula (1) compound, such as, by at solvent such as, but be not limited to, with N-bromosuccinimide in tetrahydrofuran (THF), acetonitrile or acetone, at the temperature of about-78 DEG C to 25 DEG C, process (1) to provide formula (2) compound, wherein X is Br.(2) conversion to general formula (I) compound can by (2) and formula R
3b (OH)
2boric acid or derivatives thereof (as pinacol ester) react under Suzuki coupling condition and realize (N. Miyama and A. Suzuki, Chem. Rev. 1995,95:2457-2483, J. Organomet. Chem. 1999,576:147-148).Usually, linked reaction can under the existence of palladium catalyst and alkali, and optionally under the existence of part, and in suitable solvent at elevated temperatures (about 80 DEG C to about 150 DEG C) carry out.Reaction can be promoted by microwave radiation.The example of palladium catalyst comprises, but be not limited to, tetrakis triphenylphosphine palladium (0), three (dibenzalacetone) two palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride (II).The example of operable suitable alkali includes, but not limited to carbonate or the phosphoric acid salt of sodium, potassium and caesium; And cesium fluoride.The example of suitable part includes, but not limited to 1, and 3,5,7-tetramethyl--6-phenyl-2,4,8-trioxa-6-phosphinylidyne diamantane, 2-dicyclohexyl phosphino--2', 4', 6'-tri isopropyl biphenyl (X-phos) or two (diphenylphosphine) ferrocene of 1,1'-.The nonrestrictive example of suitable solvent comprises methyl alcohol, ethanol, glycol dimethyl ether, DMF, dimethyl sulfoxide (DMSO), diox, tetrahydropyrans and water, or its mixture.
Or formula (I) compound can by isoindolinone (1) and formula R
3the halogenide (wherein X is Br or I) of X at palladium (II) catalyzer as under allyl palladium chloride (II) dimeric existence, reaction in solvent is such as, but not limited to N,N-DIMETHYLACETAMIDE or DMF at the temperature of about 80 DEG C to about 150 DEG C is synthesized.
Scheme 1
Formula (1) compound (wherein R
2hydrogen, and R
1c
1-C
3alkyl) those route of synthesis such as, but not limited to describing in scheme 2 can be used to prepare.
Formula (3) compound (wherein R
1c
1-C
3alkyl) and 2-amidomalonic acid ester derivative (4) (wherein R
2hydrogen) under sodium acetate exists, provide the intermediate of formula (3) at solvent such as, but not limited to the reaction in acetic acid.Can react at elevated temperatures, such as, but not limited to about 80 DEG C to about 120 DEG C.(5) decarboxylic reaction of Ester hydrolysis gained carboxylic acid subsequently obtains the compound of formula (1).Such as, Ester hydrolysis can alkali such as, but not limited to, realize under the existence of the oxyhydroxide of lithium, potassium or sodium.This reaction, generally at solvent, such as, but not limited in, tetrahydrofuran (THF) or water, is carried out to the temperature of about 80 DEG C in about room temperature.Gained carboxylic acid, in alcoholic solvent (such as, ethanol), under the existence of acid such as, but not limited to hydrochloric acid or sulfuric acid, heats, provides formula (1) compound, wherein R at about 50 DEG C to about 100 DEG C
1c
1-C
3alkyl and R
2hydrogen.
Scheme 2
Can preparation formula (I) compound as shown in Scheme 3, wherein R
3that there is ortho-substituent OR
101phenyl, wherein R
101c
1-C
3alkyl, aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylidenyl-heterocyclic alkyl, C
1-C
3alkylene-cycloalkyl or C
1-C
3alkylene-heteroaryl.
Formula (7) compound can use Suzuki coupling condition to be prepared by (2a) and the reaction of the boric acid or derivatives thereof (as pinacol ester) of formula (6) as described in scheme 1.By the phenol formula R of the formula (7) of gained
101the suitable halogenide of X as under the existence of the carbonate of caesium, potassium and sodium at alkali, in solvent such as dimethyl formamide or dimethyl sulfoxide (DMSO), processes, provides the compound of formula (10) at the about room temperature temperature to about 100 DEG C.Alternately, phenol (7) and formula R
101the alcohol of OH is under the existence of triphenylphosphine, and under the existence of diisopropyl azodiformate or diethyl azodiformate, at solvent as in tetrahydrofuran (THF) Huo diox, react at the about room temperature temperature to about 100 DEG C, the compound of formula (10) is provided.
Alternately, the compound of formula (10) can by the reaction conditions coupling (2a) described in (a) operational version 1 and (8); (b) formula R is used
101the fluorine atom of the alcohol displaced type (9) of OH obtains.The displacement of fluorine atom can solvent such as, but not limited to, in dimethyl sulfoxide (DMSO), dimethyl formamide, diox or tetrahydrofuran (THF), at alkali such as but be not limited to, under the carbonate of caesium, potassium and sodium or the existence of sodium hydride, realize at the temperature of about 40 DEG C to about 120 DEG C.
Scheme 3
Formula (I) compound (wherein R
10oR
101(wherein R
101as hereinbefore defined) and R
13nO
2) can further derivatize described by scheme 4.
The aniline that the nitro-compound of formula (11) is reduced to formula (12) can use iron powder under the existence of ammonium chloride, solvent such as, but not limited to, in tetrahydrofuran (THF), ethanol or water or their mixture, and realize at the temperature of about 80 DEG C to about 120 DEG C.Alternately, the available tin chloride of this reduction, in hydrochloric acid, carries out at the temperature of about 80 DEG C to about 120 DEG C.(11) conversion to (12) also under the existence of catalyzer such as platinum oxide or palladium/charcoal, in solvent such as ethanol or methyl alcohol, and can be carried out under hydrogen pressure.Aniline (12) uses formula R
102sO
2sULPHURYL CHLORIDE (the wherein R of Cl
102alkyl or haloalkyl) at alkali, under the existence of such as triethylamine or diisopropylethylamine, at solvent as in methylene dichloride or tetrahydrofuran (THF), process at the temperature of about 0 DEG C to about 40 DEG C, sulfonamides (13) is provided.
Aniline (12) uses formula R
103carboxylic acid (the wherein R of COOH
103c
1-C
3alkyl) at coupling agent if HATU or EDAC and alkali are as under the existence of diisopropyl ethyl amine or triethylamine, and at solvent as in tetrahydrofuran (THF), diox or dimethyl formamide, process at the temperature of about 0 DEG C to about 40 DEG C, the acid amides of formula (14) is provided.
Scheme 4
Can as shown in scheme 5 preparation formula (I) compound, wherein R
10oR
101and R
13c (O) N (R
104) (R
105), wherein R
101as above-mentioned definition, R
104be hydrogen and R
105hydrogen, C
1-C
3alkyl ,-C
1-C
3alkylidenyl-heterocyclic alkyl or heteroaryl.
(15) hydrolysis of ester moiety provides the acid of formula (16).Hydrolysing step can at alkali, such as, under the existence of the oxyhydroxide of lithium, sodium or potassium, at solvent, such as, but not limited to, in tetrahydrofuran (THF), water, methyl alcohol Huo diox or their combination, and carry out to the temperature of 60 DEG C at about 25 DEG C.Utilize the acid amides linked reaction condition discussed in scheme 4, the acid of formula (16) can use formula NHR
104r
105amine process, to provide the acid amides of formula (17).
Scheme 5
Be appreciated that the synthetic schemes of explaining in synthetic example part and specific embodiment are illustrative, and be not considered as being limited in scope of the present invention defined in the appended claims.All replacements of synthetic method and specific embodiment, amendment and equivalent include within the scope of claim.
Can change according to the substituting group existed in adopted concrete reactant and reactant used for the reaction conditions of the best of each single step and reaction times.Concrete grammar is provided in synthetic example part.Reaction can process in a conventional manner, such as by from residue except desolventizing and use be used for be further purified from the method for reaction mixture purifying compounds, described method such as but not limited to, precipitation, crystallization, distillation, extraction, grinding and chromatography.
Normal experiment, comprises the proper handling of reaction conditions, reagent and synthetic route order, the protection of any chemical functional group that cannot be compatible with reaction conditions, and the protection of going at suitable point in the reaction sequence of the method all comprises within the scope of the invention.The method of suitable protecting group and the protection of this type of suitable protecting group of use and deprotection different substituents can be used; the example can see T. Greene and P. Wuts; Protecting Groups in Organic Synthesis (third edition); John Wiley & Sons; NY (1999), it is incorporated to herein as a reference with its entirety.The synthesis of compound of the present invention can by with the synthetic schemes above described in and those the similar methods described in specific embodiment come.
Parent material, if can not be commercially available, by being selected from following method to prepare: standard organic chemical technology, the technology similar with the synthesis of known structurally similar compounds or with such scheme or the similar technology of the method described in synthetic example part.
When needing the optically active form of compound, usually it can use the starting raw material (such as being prepared by the reactions steps that asymmetric introducing is suitable) of optically-active to obtain by carrying out one of method as herein described, or is obtained by the stereoisomer mixture using standard method (as chromatographic separation, crystallization or enzyme split) to split compound or intermediate.
Similarly, when needing the pure geometrical isomer of compound, it can, by carrying out one of aforesaid method, use pure geometrical isomer as starting raw material, or is prepared by the mixture using standard method to split the geometrical isomer of compound or intermediate as chromatographic separation.
Formula I can use as a pharmaceutically acceptable salt form.Term " pharmacy acceptable salt " refers to such salt, they are within the scope of rational medical judgment, be applicable to there is no excessive toxicity, pungency, transformation reactions etc. with the contact tissue of the mankind and lower etc. animal, and match with rational interests/Hazard ratio.
Pharmacy acceptable salt has been described in the people such as S. M. Berge, J. Pharmaceutical Sciences, 1977,66:1-19.
The compound of formula (I) can comprise alkalescence or acidic functionality or both, and when needed, pharmacy acceptable salt can be converted to by using suitable acid or alkali.This salt can in the final abstraction and purification process situ preparation of compound of the present invention.
The example of acid salt comprises, but be not limited to: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isothionate), lactic acid salt, malate, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, Basic nitrogen-containing groups can be quaternized with such reagent: elementary alkyl halide, such as but not limited to, the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide, such as but not limited to, the muriate of decyl, lauryl, myristyl and stearyl, bromide and iodide; Arylalkyl halide is as the bromide etc. of benzyl and styroyl.Obtain water or oil soluble or dispersible product thus.The example that can be used for the acid forming pharmaceutically acceptable acid salt comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid is as acetic acid, fumaric acid, toxilic acid, 4-toluene sulfonic acide, succsinic acid and citric acid.
Base addition salt can in the final abstraction and purification process of compound of the present invention, by make containing carboxylic acid part and suitable alkali (such as, but be not limited to, the oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate) or react to carry out original position and prepare with ammonia or organic primary, secondary or tertiary amine.Pharmacy acceptable salt comprises, but be not limited to, based on the positively charged ion of basic metal or alkaline-earth metal, such as but not limited to lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., with nontoxic season ammonia and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine etc.Other example that can be used for the organic amine forming base addition salt comprises quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Term used herein " pharmaceutically acceptable prodrug " or " prodrug " refer to those prodrugs of the compounds of this invention, they are within the scope of rational medical judgment, be applicable to there is no excessive toxicity, pungency, transformation reactions etc. with the contact tissue of the mankind and lower etc. animal, match with rational interests/Hazard ratio, and the desired use for them is effective.
The present invention considers the compound of the formula (I) formed by synthesis mode or the compound by the formula (I) of bio-transformation prodrug formation in body.
Compound as herein described with non-solvation and solvation form, can comprise hydrated form, and the form of such as semihydrate exists.Usually, with pharmaceutically acceptable solvent, the solvation form that wherein such as water and ethanol are formed is equal to the non-solvation form for object of the present invention.
pharmaceutical composition
The present invention also provides pharmaceutical composition, and it comprises formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, thinner or vehicle for the treatment of significant quantity.Phrase " pharmaceutical composition " refers to the composition being applicable to use with medical science or veterinary purpose.
Comprise separately or the pharmaceutical composition of formula (I) compound combine with the second active agents can oral, rectum, parenteral, in brain pond, intravaginal, intraperitoneal, locally (as passed through pulvis, ointment or drops), through cheek or as oral cavity or nose spray application in object.Term as used herein " parenteral " refers to administering mode, and it comprises interior, the subcutaneous and intra-articular injection of intravenously, intramuscular, intraperitoneal, breastbone and infusion.
Term used herein " pharmaceutically acceptable carrier " refers to the formulation auxiliary agents of nontoxic inert solid, semisolid or liquid filling agent, thinner, encapsulating material or any type.Some examples that can be used as the material of pharmaceutically acceptable carrier are sugar, such as, but are not limited to, lactose, dextrose plus saccharose; Starch, such as, but is not limited to, W-Gum and yam starch; Cellulose and its derivates such as, but is not limited to, Xylo-Mucine, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle such as, but is not limited to, theobroma oil and suppository wax; Oil such as, but is not limited to, peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols; As propylene glycol; Ester class such as, but is not limited to, ethyl oleate and Laurate ethyl; Agar; Buffer reagent such as, but is not limited to, magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffer soln, and other nontoxic biocompatible lubricant, such as, but be not limited to, Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, seasonings and perfume compound, according to the judgement of makers-up, sanitas and antioxidant also can be present in composition.
Pharmaceutical composition for parenteral injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion, and reconstructs the sterilized powder of aseptic injectable solution or dispersion before facing use.Suitable water-based and non-aqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), vegetables oil (as sweet oil), injectable organic ester (as ethyl oleate) and suitable mixture thereof.Suitable mobility can be kept, such as, by using coating material as Yelkin TTS, by maintaining required particle diameter when dispersion liquid and by using tensio-active agent.
These compositions can also comprise adjuvant, as sanitas, wetting agent, emulsifying agent and dispersion agent.Prevent the effect of microorganism can such as, by comprising various antiseptic-germicide and anti-mycotic agent ensures, p-Hydroxybenzoate, butylene-chlorohydrin, phenol, Sorbic Acid etc.Also desirably isotonic agent can be comprised, such as sugar, sodium-chlor etc.The prolongation of injectable medicament forms absorbs can by comprising the reagent postponing to absorb, and such as aluminum monostearate and gelatin realize.
In some cases, in order to the effect of prolong drug, expect to delay medicine from absorption that is subcutaneous or intramuscularly.This can realize by using the crystallization of poorly water-soluble or the liquid suspension of amorphous substance.So the uptake rate of this medicine depends on its dissolution rate, this may depend on crystallographic dimension and crystal formation again.Or the delay of the medicament forms of parenteral administration absorbs by dissolving in oily vehicle or suspended drug and realizes.
Injectable depot forms is prepared by the microencapsule matrices by forming medicine in biodegradable polymkeric substance is as polylactide-polyglycolide.Depend on the ratio of medicine and polymkeric substance and the character of concrete polymkeric substance used, can the speed of Drug controlled release.The example of other Biodegradable polymeric comprises poly-(ortho ester) and poly-(acid anhydrides).Bank injectable formulation also can be prepared by pharmaceutical pack being embedded in the liposome compatible with bodily tissue or micro emulsion.
Injectable preparation can carry out sterilizing, and such as filtered by bacteria retaining filter or disinfectant by adding aseptic solid composite form, it can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
Capsule, tablet, pill, pulvis and granule is comprised for Orally administered solid dosage.In certain embodiments, solid dosage can contain the formula I of 1% to 95% (w/w).In certain embodiments, formula I can be present in solid dosage with the scope of 5% to 70% (w/w).In such solid dosage, active compound can mix with following: at least one inertia, pharmaceutically acceptable vehicle or carrier, as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or a) weighting agent or extender as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting Agent for Printing Inks, such as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate and sodium carbonate; E) retarding agent is dissolved as paraffin; F) absorption enhancer is as quaternary ammonium compound; G) wetting agent is as hexadecanol and glyceryl monostearate; H) absorption agent, such as kaolin and wilkinite and i) lubricant are as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and their mixture.When capsule, tablet and pill, this formulation can also comprise buffer reagent.
This pharmaceutical composition can be unit dosage.In this form, preparation is subdivided into the unitary dose containing appropriate activeconstituents.This unit dosage can be that the preparation of packaging, packaging containing discrete magnitude preparation are as the tablet of packaging, capsule and the powder in bottle or ampoule.In addition, unit dosage itself can be capsule, tablet, cachet or lozenge, or it can be these packaged form any of proper amt.According to the effect of specific purposes and active ingredient, the amount of the activeconstituents in unit dose formulations can at 0.1mg to 1000mg, 1mg to 100mg, or 1% to 95% of unitary dose (w/w) change or adjustment.Said composition is passable, if needed, also containing other compatible therapeutical agent.
Be administered to the effect of dosage by used specific compound of object and the patient's condition of this object, and the body weight of object to be treated or surface-area are determined.The existence of any adverse side effect used in special object by adjoint specific compound, nature and extent are also determined by the size of dosage.When determining the significant quantity of compound will used in the treatment of illness to be treated or prevention, doctor can assess the circulating plasma level of such as this compound, the toxicity of compound, and/or the factor of the progress of disease etc.In the ordinary course of things, the dose,equivalent of compound is about 1 micro-g/kg to 100 mgs/kg for general object.
In order to administration, the compound of formula I can be used by the speed determined by following factor, and described factor can include but not limited to, the LD of described compound
50, the pharmacokinetic profile of this compound, taboo medicine, and the side effect of this compound under different concns, and the body weight of subject and holistic health.Use and can have been come by single or fractionated dose.
The compound used in pharmaceutical methods of the present invention can be used with the predose being about 0.001mg/kg to about 100mg/kg every day.In certain embodiments, every day, dosage range was about 0.1mg/kg to about 10mg/kg.But dosage also can according to the demand of object, the severity of the patient's condition that is treated, and the compound adopted and changing.The suitable dosage of particular case is determined within the skill of doctor.Treatment can from the less dosage of optimal dose being less than compound.After this, dosage increases, until reach best effect in this case with little increment.If needed, for simplicity, total dosage every day can be divided and use in batches in one day.
The solids composition of similar type can also as using carrier as the weighting agent use in the gelatine capsule of the soft hard filling of lactose or toffee and high molecular weight polyethylene glycol etc.
The solid dosage of tablet, drageeing, capsule, pill and granule can prepare other dressing having and know in dressing and shell such as enteric coating and field of pharmaceutical preparations.They optionally can contain opalizer, can be also compositions, make they only or preferential certain part at enteron aisle in optionally with delayed mode release of active ingredients.The example of spendable embedding composition comprises polymeric material and wax.
If suitable, active compound also can be the micro-encapsulated form of above-mentioned carrier with one or more.
Pharmaceutically acceptable emulsion, solution, suspensoid, syrup and elixir is comprised for Orally administered liquid dosage form.Except active ingredient beyond the region of objective existence, liquid dosage form can contain the normally used inert diluent in this area, such as, water or other solvent, solubilizing agent and emulsifying agent are as the fatty acid ester of ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitan and their mixture.
Besides inert diluents, oral compositions also can comprise adjuvant, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, seasonings and perfume compound.
Suspension also can contain suspension agent except active ingredient beyond the region of objective existence, such as, and ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar, tragacanth gum and their mixture.
Composition for rectum or vaginal application is preferably suppository, it is prepared by mixing compound of the present invention and suitable non-irritating carriers or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax, and described suppository is at room temperature solid but is liquid under body temperature and therefore melts and release of active compounds in rectum or vaginal canal.
Formula I can also be used with the form of liposome.Liposome usually can derived from phosphatide or other lipid matter.Liposome is formed by disperseing list in an aqueous medium or multilayer hydrated liquid crystals.Any nontoxic, physiology can accept can use with metabolizable lipid that can form liposome.Except formula (I) compound, the present composition of liposomal form also can contain stablizer, sanitas, vehicle etc.The example of lipid includes, but not limited to phosphatide that is natural and that synthesize and phosphatidylcholine (Yelkin TTS), uses separately or together.
Form the method for liposome to have been described in, see such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (l976), p.33 and below.
The formulation of the topical application of compound as herein described comprises pulvis, sprays, ointment and inhalation.This active compound can aseptically mix with pharmaceutically acceptable carrier and any required sanitas, buffer reagent or the propellent that may need.Ophthalmic preparation, ophthalmic ointment, pulvis and solution are also contained within the scope of the present invention.
Using method
The compound of formula I, or its pharmacy acceptable salt, and the compound of contained I or the pharmaceutical composition of its pharmacy acceptable salt, can be applied to and suffer from the illness of Bu Luomo domain mediates or the object of the patient's condition.Term administering " instigate the method for compound and object contact.Namely in intravenously, intramuscular, intracutaneous, subcutaneous, duodenum therefore, the compound of formula I can by injection, and, parenteral or intraperitoneal use.Further, compound described herein can by sucking, such as intranasal administration.In addition, formula I can through skin, locally, via implantation, through skin, local using via implantation.In certain embodiments, formula I can oral delivery.Described compound can also per rectum, through cheek, intravaginal, through eye, per anum or send by being blown into.The illness of Bu Luomo domain mediates and the patient's condition can use that formula I is preventative, short-term and long-term treatment, depend on the character of this illness or the patient's condition.Usually, the host in these methods each or to as if people, he although other Mammals also can benefits from using of formula I.
The feature of " illness of Bu Luomo domain mediates or the patient's condition " is that one or more Bu Luomo structural domain (such as BRD4) participates in the beginning of one or more symptoms of illness or the patient's condition or disease marker, performance, seriousness or progress.Therefore, formula I may be used for Therapeutic cancer, includes but not limited to: acoustic tumor, acute leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia (monocarpotic cellularity, myeloblastic, gland cancer, angiosarcoma, astrocytoma, myelo-monocytic and promyelocytic leukemic cell), acute t chronic myeloid leukemia, rodent cancer, cholangiocarcinoma, bladder cancer, the cancer of the brain, mammary cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocyte) leukemia, chronic granulocytic leukemia (chronic myelogenous leukemia), colorectal carcinoma, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dispersivity large B cell lymphatic cancer, paraplasm (dysproliferative) change (heteroplasia and change life), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, the esophageal carcinoma, estrogen receptor positive mammary cancer, idiopathic thrombocythemia, Ewing sarcoma, fibrosarcoma, follicular lymphoma, sexual cell carcinoma of testis, glioma, glioblastoma, glioma sarcomatosum, heavy chain disease, hemangioblastoma, liver neoplasm, hepatocellular carcinoma, Hormone-refractory prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma (lymphagioendotheliosarcoma), lymphangiosarcoma, lymphocytoblast leukemia, lymphoma (Huo Qi metal type and non-Hodgkin′s type), bladder, mammary gland, colon, lung, ovary, pancreas, prostate gland, the malignant tumour in skin and uterus and excessively proliferative disease, the lymphoid malignancy in T cell or B cell source, leukemia, lymphoma, medullary carcinoma, myeloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, marrow-derived leukocythemia, myelomatosis, myxosarcoma, neuroblastoma, NUT center line cancer (NUT midline carcinoma, NMC), nonsmall-cell lung cancer, mesoglioma, oral carcinoma, osteogenic sarcoma, ovarian cancer, carcinoma of the pancreas, papillary carcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, the rectum cancer, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, sebaceous carcinoma, spermocytoma, skin carcinoma, small cell lung cancer, noumenal tumour (cancer and sarcoma), small cell lung cancer, cancer of the stomach, squamous cell carcinoma, synovioma, syringocarcinoma, thyroid carcinoma, macroglobulinemia Waldenstron, tumor of testis, uterus carcinoma and wilms' tumor.
In addition, formula I may be used for treating inflammatory diseases, the inflammatory patient's condition, and autoimmune disorder, include but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcets disease, bullous dermatosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, systemic lupus erythematosus, multiple sclerosis, myocarditis, myositis, ephritis, organ-graft refection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriatic, psoriasis arthropathica, rheumatoid arthritis, scleritis, sclerosing cholangitis, septicemia, systemic lupus erythematous, high iS-One arteritis, toxic shock, thyroiditis, type i diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wei Genashi granulomatosis.
Formula I or its pharmacy acceptable salt may be used for treating AIDS.In addition, formula I or its pharmacy acceptable salt may be used for treatment of obesity.Formula I or its pharmacy acceptable salt may be used for treating type ii diabetes.
Formula I or its pharmacy acceptable salt can be used for treating and are selected from following disease or the patient's condition: obesity, hyperlipemia, hypercholesterolemia, Alzheimer, metabolism syndrome, fatty degeneration of liver, type ii diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy.
By compound or its pharmacy acceptable salt of the formula (I) of administering therapeutic significant quantity, formula I or its pharmacy acceptable salt can be used to be provided for the contraception in male subjects.
By the compound of the formula (I) of administering therapeutic significant quantity, formula I or its pharmacy acceptable salt can be used to treat chronic renal disease or the patient's condition, and wherein said disease or the patient's condition are selected from: diabetic nephropathy, hypertensive nephropathy, HIV associated nephropathy, glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, FSGS, membranous glomerulonephritis, minimal change, multicystic kidney disease and tubulointerstitial nephritis.
What formula I or its pharmacy acceptable salt can be used for treatment target is selected from following acute kidney diseases or the patient's condition: the kidney disease that kidney disease, pneumonia that the kidney disease that the kidney disease that kidney disease, percutaneous coronary intervention (pci) that the kidney disease that ischemia-reperfusion brings out, heart and major surgery are brought out bring out, radiopaque contrast medium bring out, septicemia are brought out are brought out and the kidney disease that drug toxicity is brought out.
Formula I can be applied to object jointly.Term " is jointly used " and is referred to using of two or more different agents or treatment (such as, radiation treatment), its by combined administration in same medicine composition or in the pharmaceutical composition separated in object.Therefore, use while jointly using the single pharmaceutical composition relating to and comprise two or more medicaments, or two or more different compositions are identical or different time using same object.
Compound of the present invention can be used with Therapeutic cancer together with one or more medicaments for the treatment of significant quantity, and the example of wherein said medicament comprises: such as radiation agent, alkylating reagent, angiogenesis inhibitor, antibody, metabolic antagonist, antimitotic drug, antiproliferative pharmaceutical, antiviral drug, aurora kinase inhibitors, apoptosis promoters (such as, Bcl-xL, Bcl-w and Bfl-1) inhibitor, the activator of death receptor4, Bcr-Abl kinase inhibitor, BiTE (dual specific T cell bridging body) antibody, antibody drug conjugate, biological response conditioning agent, cyclin-dependent kinase inhibitor, cell cycle inhibitor, COX-2 inhibitors, DVD (two variable domain antibody), leukosis virus oncogene homologue (ErbB2) acceptor inhibitor, growth factor receptor inhibitors, heat shock protein(HSP) (HSP)-90 inhibitor, histone deacetylase (HDAC) inhibitor, hormonotherapy medicine, immune drug, the inhibitor of inhibitor of apoptosis protein (IAPs), embed antibody, kinase inhibitor, kinesin inhibitor, Jak2 inhibitor, Mammals rapamycin target inhibitor, microRNA, inhibition of mitogen-activated extracellular signal-regulated kinase inhibitor, multivalent binding proteins, nonsteroidal anti-inflammatory agent (NSAIDs), poly ADP (adenosine diphosphate (ADP)) ribose polymerase (PARP) inhibitor, platinum-based chemotherapy medicine, polo sample kinases (Plk) inhibitor, phosphoinositide-3-kinases (Bu Luomo structural domain) inhibitor, proteasome inhibitor, purine analogue, pyrimidine analogue, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloid, inhibition tiny RNA (small inbibitory ribonucleic acid) (siRNAs), topoisomerase enzyme inhibitor, ubiquitin ligase inhibitor etc., and one or more the combination in these medicaments.
BiTE antibody is bi-specific antibody, and it, by simultaneously in conjunction with T-cell and cancer cells, is guided the former and attack the latter.So T cell target of attack cancer cells.The example of BiTE antibody comprises A De wood monoclonal antibody (Micromet MT201), blinatumomab (Micromet MT103) etc.Without being limited by theory, T cell causes one of mechanism of targeted cancerous cells apoptosis to be exocytosis by CG component (comprising perforin and granzyme B).In this respect, Bcl-2 has demonstrated the apoptosis weakening and brought out by perforin and granzyme B.These data show, the suppression of Bcl-2 can strengthen cytotoxic effect (V. R. Sutton, D. L. Vaux and J. A. Trapani, the J. of Immunology 1997 that T cell causes when target cancer cell, 158 (12), 5783).
SiRNAs is the molecule of the Nucleotide with endogenous RNA base or chemical modification.Described modification does not eliminate cytoactive, but gives the cell usefulness of stability and/or the increase improved.The example of chemical modification comprise thiophosphate group, 2'-deoxynucleotide, containing 2'-OCH
3ribonucleotide, 2'-F-ribonucleotide, 2'-methoxyethyl ribonucleoside acid, their combination etc.SiRNA can have different length (such as, 10-200bps) and structure (such as, hair clip, list/double-strand, projection, otch/crack, mispairing), and processed to provide active gene reticent in cell.Double-strand siRNA (dsRNA) can have the Nucleotide of similar number on every bar chain (flush end) or asymmetric end (overhang).The overhang of 1-2 Nucleotide can be present on sense strand and/or antisense strand, and is present in 5'-and/or the 3'-end of designated strands.
Multivalent binding proteins is the associated proteins containing two or more antigen bound site.Multivalent binding proteins is had three or more antigen bound site by artificial reconstructed one-tenth and the antibody of normally non-natural existence.Term " multi-specific binding protein " means that associated proteins can be correlated with or incoherent target in conjunction with two or more.Two variable domain (DVD) associated proteins is the tetravalence or the multivalent binding proteins that contain two or more antigen bound site.This DVD can be (that is, can in conjunction with two or more antigen) of monospecific (that is, can in conjunction with a kind of antigen) or polyspecific.DVD associated proteins containing two heavy chain DVD polypeptide and two light chain DVD polypeptide is referred to as DVD Ig.Every half of DVD Ig all contains a heavy chain DVD polypeptide, a light chain DVD polypeptide and two antigen bound site.Each bound site contains a heavy chain variable domain and a light-chain variable domain, and each antigen bound site has total 6 CDR to participate in antigen combination.Polyspecific DVD comprises in conjunction with DLL4 and VEGF, or C-met and EFGR, or the DVD associated proteins of ErbB3 and EGFR.
Alkylating reagent comprises altretamine, AMD-473, AP-5280, A Paqi quinone (apaziquone), bendamustine, brostallicin, busulfan, carboquone, carmustine (BCUN), Chlorambucil, CLORETAZINE
?(La Luomositing (laromustine), VNP 40101M), endoxan, Dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), Mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, mustargen oxynitride, ranomustine, Temozolomide, thio-tepa, TREANDA
?(bendamustine), Treosulfan, rofosfamide etc.
Angiogenesis inhibitor comprises endothelium-specific receptor Tyrosylprotein kinase (Tie-2) inhibitor, EGF-R ELISA (EGFR) inhibitor, insulin-like growth factor-2 acceptor (IGFR-2) inhibitor, MMP-2 (MMP-2) inhibitor, Matrix Metalloproteinase-9 (MMP-9) inhibitor, platelet derived growth factor receptor (PDGFR) inhibitor, thrombospondin analogue, vascular endothelial growth factor receptor Tyrosylprotein kinase (VEGFR) inhibitor etc.
Metabolic antagonist comprises ALIMTA
?(pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA
?(capecitabine), carmofur, LEUSTAT
?(CldAdo), Clofarex, cytosine arabinoside, cytosine arabinoside octadecyl phosphoric acid salt, cytosine arabinoside (cytosine arabinoside), Decitabine, Deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-β-D-RIBOSE base imidazoles-4-methane amide), enocitabine, ethynylcytidine, fludarabine, 5 FU 5 fluorouracil separately or combine with folinic acid, GEMZAR
?(gemcitabine), hydroxyurea, ALKERAN
?(melphalan), purinethol, 6-MPR, methotrexate, Mycophenolic Acid, Nelzarabine, Nolatrexed, octadecyl phosphoric acid salt, the pyrrole bent rope of profit (pelitrexol), pentostatin, Raltitrexed, ribavirin, triapine, trimetrexate, S-1, tiazofurine, Tegafur, TS-1, vidarabine, UFT etc.
Antiviral drug comprises ritonavir, Oxychloroquine etc.
Aurora kinase inhibitors comprises ABT-348, AZD-1152, MLN-8054, VX-680, BTAK-specificity kinase inhibitor, aurora kinase B specificity kinase inhibitor and pan-aurora kinase inhibitors etc.
Bcl-2 protein inhibitor comprises AT-101 ((-) gossypol), GENASENSE
?(G3139 or Ao Limeisheng (oblimersen) (Bcl-2 target antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chlorine (1, 1'-biphenyl)-2-base) methyl) piperazine-1-base) benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfartyl) methyl) propyl group) is amino)-3-nitrobenzene sulfonamide) (ABT-737), N-(4-(4-((2-(4-chloro-phenyl-)-5, 5-dimethyl-1-hexamethylene-1-alkene-1-base) methyl) piperazine-1-base) benzoyl)-4-(((1R)-3-(morpholine-4-base)-1-((phenylsulfartyl) methyl) propyl group) is amino)-3-((trifluoromethyl) alkylsulfonyl) benzsulfamide (ABT-263), GX-070 (obatoclax), ABT-199 etc.
Bcr-Abl kinase inhibitor comprises DASATINIB
?(BMS-354825), GLEEVEC
?(imatinib) etc.
CDK inhibitor comprise AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,
Flavones pyrrole many (flavopyridol), GPC-286199, MCS-5A, PD0332991, PHA-690509, plug profit Seeley (seliciclib) (CYC-202, R-roscovitine), ZK-304709 etc.
Cox 2 inhibitor comprises ABT-963, ARCOXIA
?(Etoricoxib), BEXTRA
?(valdecoxib), BMS347070, CELEBREX
?(celecoxib), COX-189 (Prexige), CT-3, DERAMAXX
?(deracoxib), JTE-522,4-methyl-2-(3,4-3,5-dimethylphenyl)-1-(4-sulfamoyl phenyl-1H-pyrroles), MK-663 (Etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX
?(rofecoxib) etc.
EGFR inhibitor comprises EGFR antibody, ABX-EGF, anti-EGFR immunoliposome, EGF vaccine, EMD-7200, ERBITUX
?(Cetuximab), HR3, IgA antibody, IRESSA
?(Gefitinib), TARCEVA
?(Tarceva or OSI-774), TP-38, EGFR fusion rotein, TYKERB
?(lapatinibditosylate) etc.
ErbB2 acceptor inhibitor comprises CP-724-714, CI-1033 (Ka Na is for Buddhist nun), HERCEPTIN
?(Herceptin), TYKERB
?(lapatinibditosylate), OMNITARG
?(2C4, handkerchief trastuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER2/neu bi-specific antibody, B7.her2IgG3, ASHER2 trifunctional bi-specific antibody, mAB AR-209, mAB 2B-1 etc.
Histone deacetylase inhibitor comprises depsipeptides, LAQ-824, MS-275, trapoxin, Vorinostat (SAHA), TSA, valproic acid etc.
HSP-90 inhibitor comprises 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024,17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB
?(people's recombinant antibodies of HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 etc.
The inhibitor of apoptosis protein inhibitor comprises HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 etc.
Antibody drug conjugate comprises anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 etc.
The activator of death receptor4 comprises TRAIL, the antibody of target TRAIL or death receptor (such as DR4 and DR5) or other reagent, but such as that wooden monoclonal antibody (conatumumab) of Apomab, ETR2-ST01, GDC0145, (carrying out husky wooden monoclonal antibody (lexatumumab)), HGS-1029, LBY-135, PRO-1762 and Herceptin.
The inhibitor of kinesin comprises Eg5 inhibitor, such as AZD4877, ARRY-520; CENPE inhibitor such as GSK923295A etc.
JAK-2 inhibitor comprises CEP-701 (lesaurtinib), XL019 and INCB018424 etc.
Mek inhibitor comprises ARRY-142886, ARRY-438162, PD-325901, PD-98059 etc.
MTOR inhibitors comprises AP-23573, CCI-779, everolimus, RAD-001, rapamycin, CCI-779, competitive TORC1/TORC2 inhibitor (comprising PI-103, PP242, PP30, Torin 1) of ATP-etc.
Nonsteroidal anti-inflammatory agent comprises AMIGESIC
?(salsalate), DOLOBID
?(diflunisal), MOTRIN
?(Ibuprofen BP/EP), ORUDIS
?(Ketoprofen), RELAFEN
?(nabumetone), FELDENE
?(piroxicam), Ibuprofen cream, ALEVE
?(Naproxen Base) and NAPROSYN
?(Naproxen Base), VOLTAREN
?(diclofenac), INDOCIN
?(indomethacin), CLINORIL
?(sulindac), TOLECTIN
?(tolmetin), LODINE
?(R-ETODOLAC), TORADOL
?(ketorolac), DAYPRO
?(Taisho)) etc.
PDGFR inhibitor comprises C-451, CP-673, CP-868596 etc.
Platinum-based chemotherapy medicine comprises cis-platinum, ELOXATIN
?(oxaliplatin), eptaplatin, lobaplatin, S 254, PARAPLATIN
?(carboplatin), Satraplatin, JM473 etc.
Polo sample kinase inhibitor comprises BI-2536 etc.
PI-3 kinase (PI3K) inhibitor comprises wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 etc.
Thrombospondin analogue comprises ABT-510, ABT-567, ABT-898, TSP-1 etc.
VEGFR inhibitor comprises AVASTIN
?(Avastin), ABT-869, AEE-788, ANGIOZYME
tM(ribozyme (Ribozyme Pharmaceuticals (the Boulder of inhibiting angiogenesis, and Chiron (Emeryville CO.), CA)), Ah former times for Buddhist nun (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (Pei Jiatani), NEXAVAR
?(Xarelto, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT
?(Sutent, SU-11248), VEGF trap, ZACTIMA
tM(ZD6474, ZD-6474), GA101, method difficult to understand wood monoclonal antibody (ofatumumab), ABT-806 (mAb-806), ErbB3 specific antibody, BSG2 specific antibody, DLL4 specific antibody and C-met specific antibody etc.
Microbiotic comprises embedding microbiotic aclarubicin, dactinomycin, amrubicin, anthracycline (annamycin), Zorubicin, BLENOXANE
?(bleomycin), daunorubicin, CAELYX
?or MYOCET
?(Mycocet), elsamitrucin, epirubicin, glarbuicin, ZAVEDOS
?(idarubicin), ametycin, Nemorubicin, neocarzinostatin, peplomycin, pirarubicin, butterfly mycin (rebeccamycin), stimalamer, streptozocin, VALSTAR
?(valrubicin), zinostatin etc.
Topoisomerase enzyme inhibitor comprises aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, Bei Teka make (becatecarin), Belotecan, BN-80915, CAMPTOSAR
?(U 101440E), camptothecine, CARDIOXANE
?(ADR-529), Diflomotecan, Ai Te click woods (edotecarin), ELLENCE
?or PHARMORUBICIN
?(epirubicin), she asks pool glycosides, Yi Sha for health, 10-hydroxycamptothecine, gefitinib, lurtotecan, mitoxantrone, Orathecin, pirarubicin, pixantrone (pixantrone), rubitecan, sobuzoxane, SN-38, his fluorine pool glycosides (tafluposide), Hycamtin etc.
Antibody comprises AVASTIN
?(Avastin), CD40-specific antibody, chTNT-1/B, promise monoclonal antibody, ERBITUX
?(Cetuximab), HUMAX-CD4
?(pricking wooden monoclonal antibody (zanolimumab)), IGF1R-specific antibody, lintuzumab, PANOREX
?(Edrecolomab), RENCAREX
?(WXG250), RITUXAN
?(Rituximab), for former times wood monoclonal antibody (ticilimumab), Herceptin, CD20 antibody type I and II type etc.
ARIMIDEX drawn together by hormonotherapy cartridge bag
?(Anastrozole), AROMASIN
?(Exemestane), arzoxifene, CASODEX
?(bicalutamide), CETROTIDE
?(cetrorelix), Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, deslorelin, DESOPAN
?(Win-24540), dexamethasone, DROGENIL
?(flutamide), EVISTA
?(raloxifene), AFEMA
tM(fadrozole), FARESTON
?(toremifene), FASLODEX
?(fulvestrant), FEMARA
?(letrozole), formestane, glucocorticosteroid, HECTOROL
?(doxercalciferol), RENAGEL
?(2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate), Lasofoxifene, acetic acid leuproside, MEGACE
?(megestrol), MIFEPREX
?(mifepristone), NILANDRON
tM(Nilutamide), NOLVADEX
?(TAMOXIFEN CITRATE), PLENAXIS
tM(abarelix), prednisone, PROPECIA
?(finasteride), rilostane, SUPREFACT
?(buserelin), TRELSTAR
?(luteinising hormone-releasing hormo (LHRH)), VANTAS
?(histrelin implant), VETORYL
?(Win-24540 or modrastane), ZOLADEX
?(fosrelin, goserelin) etc.
Deltoids and retinoids comprises seocalcitol (EB1089, CB1093), Lexacalcitol (KH1060), fenretinide, PANRETIN
?(9-cis-retinoic acid (aliretinoin)), ATRAGEN
?(vitamin A acid liposome), TARGRETIN
?(bexarotene), LGD-1550 etc.
PARP inhibitor comprises ABT-888 (veliparib), Aura handkerchief profit, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 etc.
Plant alkaloid includes, but is not limited to vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine etc.
Proteasome inhibitor comprises VELCADE
?(Velcade), MG132, NPI-0052, PR-171 etc.
The example of immune drug comprises Interferon, rabbit and other immunostimulant.Interferon, rabbit comprises interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a, ACTIMMUNE
?(gamma interferon 1-b) or interferon-gamma-n1, its composition etc.Other medicament comprises ALFAFERONE
?(IFN-α), BAM-002 (oxidized glutathione), BEROMUN
?(tasonermin), BEXXAR
?(tositumomab), CAMPATH
?(A Lun pearl monoclonal antibody), CTLA4 (cytotoxic lymphocite antigen 4), decarbazine (decarbazine), denileukin, epratuzumab, GRANOCYTE
?(lenograstim), lentinan, white corpuscle interferon-alpha, miaow quinoline be moral, MDX-010 (anti-CTLA-4), Melacine, mitumomab, Sch-39300, MYLOTARG not
tM(lucky trastuzumab ozogamicin), NEUPOGEN
?(filgrastim), OncoVAC-CL, OVAREX
?(Ao Gefu monoclonal antibody (oregovomab)), pemtumomab (Y-muHMFG1), PROVENGE
?(western general Ruse (sipuleucel)-T), Sargramostim, sizofiran, teceleukin, THERACYS
?(bacille Calmette-Guerin vaccine), ubenimex, VIRULIZIN
?(immunotherapy medicine, Lorus Pharmaceuticals), Z-100 (material-specific (SSM) of Maruyama), WF-10 (tetrachloro ten oxide compound (TCDO)), PROLEUKIN
?(rIL-2), ZADAXIN
?(Thymosin-Alpha1), ZENAPAX
?(daclizumab), ZEVALIN
?(90Y-ibritumomab tiuxetan) etc.
Biological response conditioning agent regulates the organic defense mechanism or biological response (such as histiocytic survival, growth or differentiation) of living with the reagent guiding them to have anti-tumor activity, comprises polystictin, lentinan, Schizophyllan, Picibanil PF-3512676 (CpG-8954), ubenimex etc.
Pyrimidine analogue comprises cytosine arabinoside (araC or Arabinoside C), cytarabin, doxifluridine, FLUDARA
?(fludarabine), 5-FU (5 FU 5 fluorouracil), floxuridine, GEMZAR
?(gemcitabine), TOMUDEX
?(Raltitrexed), TROXATYL
tM(Triacetyluridine troxacitabine) etc.
Purine analogue comprises LANVIS
?(Tioguanine) and PURI-NETHOL
?(purinethol).
Antimitotic drug comprises Ba Tabulin (batabulin), epothilone d (KOS-862), N-(2-((4-hydroxy phenyl) is amino) pyridin-3-yl)-4-methoxybenzenesulphoismide, ipsapirone (BMS247550), taxol, TAXOTERE
?(docetaxel), PNU100940 (109881), appropriate of handkerchief are grand, XRP-9881 (La Luotasai (larotaxel)), Vinflunine, ZK-EPO (esperamicin of synthesis) etc.
Ubiquitin ligase inhibitor comprises MDM2 inhibitor, and such as nutlins, NEDD8 inhibitor is as MLN4924 etc.
The compounds of this invention also can be used as the radiosensitizer strengthening radiotherapy effect and uses.The example of radiotherapy comprises external beam radiation treatment, teletherapy, brachytherapy and the radiotherapy of closed source and unsealed source radiotherapy etc.
In addition, formula (1) compound can with other chemotherapeutics coupling, described chemotherapeutics such as ABRAXANE
tM(ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN
?(Ad5CMV-p53 vaccine), ALTOCOR
?or MEVACOR
?(lovastatin), AMPLIGEN
?(polyI:polyC12U, the RNA of synthesis), APTOSYN
?(exisulind), AREDIA
?(pamidronic acid), Arglabine (arglabin), L-ASP, Atamestane (1-methyl-3,17-diketone-androstane-Isosorbide-5-Nitrae-diene), AVAGE
?(Tazarotene (tazarotne)), AVE-8062 (Combretastatin derivatives (combreastatin derivative)), BEC2 (mitumomab), cachectin or cachexin (tumour necrosis factor), canvaxin (vaccine), CEAVAC
?(cancer vaccine), CELEUK
?(celmoleukin), CEPLENE
?(Peremin), CERVARIX
?(Human-papilloma Vaccine), CHOP
?(C:CYTOXAN
?(endoxan); H:ADRIAMYCIN
?(hydroxyl Dx); O: vincristine(VCR) (ONCOVIN
?); P: prednisone), CYPAT
tM(cyproterone acetate), Combretastatin A-4 4P, DAB (389) EGF (catalysis of diphtheria toxin and transposition structural domain are fused to human epidermal growth factor via His-Ala joint) or TransMID107R
tM(diphtheria toxin), Dacarbazine, gengshengmeisu, DMXAA (DMXAA), eniluracil, EVIZON
tM(lactic acid squalamine), DIMERICINE
?(T4N5 liposome lotion), discodermolide (discodermolide), DX-8951f (Exatecan mesylate), enzastaurin, EP0906 (epothilone B), GARDASIL
?(quadrivalent human papillomavirus (6,11,16,18 type) recombiant vaccine), GASTRIMMUNE
?, GENASENSE
?, GMK (ganglioside conjugate vaccines), GVAX
?(prostate cancer vaccine), halofuginone, histrelin (histerelin), hydroxyurea, Ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (the pungent interleukin of shellfish (cintredekin besudotox)), IL-13-Pseudomonas exotoxin, interferon-' alpha ', interferon-γ, JUNOVAN
tMor MEPACT
tM(rice lumbering peptide (mifamurtide)), SCH-66336 (lonafanib), 5,10-CH2-THFA, miltefosine (HEXADECYL PHOSPHOCHOLINE), NEOVASTAT
?(AE-941), NEUTREXIN
?(trimetrexate glucuronate), NIPENT
?(pentostatin), ONCONASE
?(a kind of rnase), ONCOPHAGE
?(Melacine therapy), ONCOVAX
?(IL-2 vaccine), ORATHECIN (rubitecan), OSIDEM
?(cell drug based on antibody), OVAREX
?mAb (mouse monoclonal antibody), taxol (paclitaxel), PANDIMEX (comprising the ginsenoside aglycon of 20 (S) protopanoxadiol (aPPD) and 20 (S) Protopanaxatriol (aPPT)), Victibix (panitumumab), PANVAG
?-VF (trial period cancer vaccine), pegaspargase, PEG interferon A, benzene Tuo Dier, the third kappa callosity, Rui Masita (rebimastat), REMOVAB
?(blocking appropriate rope monoclonal antibody), REVLIMID
?(Revlimid), RSR13 (Efaproxiral), SOMATULINE
?lA (Lanreotide), SORIATANE
?(Etretin), star shaped spore native (streptomyces staurospore (Streptomyces staurospores)), Ta Bosita (PTl00), TARGRETIN
?(bexarotene), TAXOPREXIN
?(DHA-taxol), TELCYTA
?(canfosfamide, TLK286), temilifene, TEMODAR
?(Temozolomide), Tesmilifene, thalidomide, THERATOPE
?(STn-KLH), thymitaq (amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio) the quinazoline dihydrochlorides of 2-), TNFERADE (adenovirus carrier: the DNA vector containing TNF-α gene), TRACLEER
?or ZAVESCA
?(bosentan), vitamin A acid (Retin-A), Tetrrine, TRISENOX
?(white arsenic), VIRULIZIN
?, ukrain (alcaloid-derivatives from pilewort plant), vitaxin (anti alpha V β 3 antibody), XCYTRIN
?(motexafin gadolinium), XINLAY
tM(atrasentan), XYOTAX (PPX), YONDELIS
?(ET-743), ZD-6126, ZINECARD
?(dexrazoxane), ZOMETA
?(Zoledronic acid), zorubicin etc.
Compound of the present invention also can be used to treat inflammatory diseases or the patient's condition with one or more medicaments for the treatment of significant quantity jointly, or autoimmune disorder, and the example of wherein said medicament comprises, as methotrexate, Ismipur, azathioprine, sulfasalazine, mesalazine, Olsalazine, chloroquine/Oxychloroquine, Trolovol, Sodium Aurothiomalate (intramuscular and oral), azathioprine, colchicine, reflunomide is (oral, suck and local injection), beta-2-adrenoceptor agonist (salbutamol, terbutaline, Salmeterol (salmeteral)), xanthine (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium bromide and oxitropine, S-Neoral, FK506, rapamycin, mycophenlate mofetil, Leflunomide, NSAID is Ibuprofen BP/EP such as, reflunomide is as Ultracortene-H, phosphodiesterase inhibitor, adenosine agonists, antithrombotic agent, complement inhibitor, adrenergic agent, by medicament (the such as NIK that pro-inflammatory cytokine transmits as TNF α or IL-1 undesired signal, IKK, p38 or map kinase inhibitor), IL-1 β converting enzyme inhibitor, T cell signal transmission inhibitor such as kinase inhibitor, inhibitors of metalloproteinase, sulfasalazine, Ismipur, angiotensin converting enzyme inhibitor, soluble cytokine receptor and derivative (such as solubility p55 or p75 TNF acceptor and derivative p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R), anti-inflammatory cytokines is (as IL-4, IL-10, IL-11, IL-13 and TGF β), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, Naproxen Base, valdecoxib, sulfasalazine, methyl meticortelone, meloxicam, acetic acid methyl meticortelone, Sodium Aurothiomalate, Asprin, Triamcinolone Acetonide, Propoxyphene naphthalenesulfonate/Paracetamol, folic acid, nabumetone, diclofenac, piroxicam, R-ETODOLAC, Diclofenac Sodium, Taisho), oxycodone hydrochloride, Synkonin/Paracetamol, Diclofenac Sodium/Misoprosrol, fentanyl, Kineret, tramadol hydrochloride, salsalate, sulindac, cyanocobalamin/FA/ pyridoxol, Paracetamol, alendronate sodium, prednisolone, morphine sulfate, Xylotox, indomethacin, Glucosamine Sulphate/chrondroitin, Warner), Sulphadiazine Sodium, oxycodone hydrochloride/paracetamol, Olopatadine hydrochloride Misoprostol, naproxen sodium, omeprazole, endoxan, Rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonist (such as FTY720), PKC family's group inhibitor (as Lu Baisita or AEB-071) and Mesopram.In certain embodiments, combination comprises methotrexate or leflunomide, and when moderate or severe rheumatoid arthritis, comprises S-Neoral and anti-TNF antibodies as above.
The limiting examples of the inflammatory bowel disease therapeutical agent jointly can used with the compound of formula of the present invention (I) comprises as follows: budesonide (budenoside); Urogastron; Reflunomide; S-Neoral, sulfasalazine; Aminosalicylate; Ismipur; Azathioprine; Metronidazole (metronidazole); Lipoxygenase inhibitor; Mesalazine; Olsalazine; Balsalazine (balsalazide); Antioxidant; Thromboxane inhibitors; IL-1 receptor antagonist; Anti-IL-1 β monoclonal antibody; Anti-IL-6 monoclonal antibody; Somatomedin; Elastatinal; Pyridinylimidazoles compound; For antibody or the antagonist of other human cell factor or somatomedin (such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF and PDGF); Cell surface molecule such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or its part; Methotrexate; S-Neoral; FK506; Rapamycin; Mycophenolate mofetile; Leflunomide; NSAID, such as Ibuprofen BP/EP; Reflunomide, such as prednisolone; Phosphodiesterase inhibitor; Adenosine agonists; Antithrombotic agent; Complement inhibitor; Adrenergic agent; By the medicament (such as NIK, IKK or map kinase inhibitor) that pro-inflammatory cytokine is transduceed as TNF α or IL-1 undesired signal; IL-1 'beta ' converting emzyme inhibitor; TNF α converting enzyme inhibitor; T-Signaling Inhibitors On Specific, such as kinase inhibitor; Inhibitors of metalloproteinase; Sulfasalazine; Azathioprine; Ismipur; Angiotensin-convertion enzyme inhibitor; Soluble cytokine receptor and its derivative (such as solubility p55 or p75 TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10, IL-11, IL-13 and TGF β).Can comprise following with the preferred embodiment of the therapeutical agent for Crohn disease of the compound combination of formula (I): TNF antagonist (such as anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP571, TNFR-Ig construct, (p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept
tM)) inhibitor and PDE4 inhibitor.Formula (I) compound can with following combination: reflunomide, such as budesonide and dexamethasone; Sulfasalazine, 5-aminosalicylic acid; Olsalazine; And disturb the synthesis of pro-inflammatory cytokine such as IL-1 or the reagent of effect, such as IL-1 'beta ' converting emzyme inhibitor and IL-1ra; T cell signal transduction inhibitor such as tyrosine kinase inhibitor; Ismipur; IL-11; 5-ASA; Prednisone; Azathioprine; Purinethol; Infliximab; Methyl meticortelone sodium succinate; Diphenoxylate/Tropintran; Loperamide hydrochloride; Methotrexate; Omeprazole; Folic acid; Ciprofloxacin/glucose-water; Dihydrocodeinone bitartrate/Paracetamol; Tetracycline hydrochloride; Fluocinonide; Metronidazole; Thiomersalate/boric acid; QUESTRAN/sucrose; Ciprofloxacin HCl; Hyoscyamine sulfate; Pethidine hydrochloride; Midazolam hydrochloride; OXYCODONE HYDROCHLORIDE/Paracetamol; Promethazine hydrochloride; Sodium phosphate; Sulfamethoxazole/trimethoprim; Celecoxib; Polycarbophil; Propoxyphene napsylate; Hydrocortisone; Vitamin complex; Balsalazide disodium; Codeine phosphate/Paracetamol; Colesevelam hydrocholoride; Cyanocobalamin; Folic acid; Levofloxacin; Methyl meticortelone; Natalizumab and interferon-γ.
The limiting examples of the therapeutical agent for multiple sclerosis jointly can used with formula (I) compound comprises following: reflunomide; Ultracortene-H; Methyl meticortelone; Azathioprine; Endoxan; Ciclosporin; Methotrexate; 4-aminopyridine; Tizanidine; Interferon-beta 1a (Avonex
?; Biogen), interferon-beta 1b (Betaseron
?; Chiron/Berlex), Alferon N) (Interferon Sciences/Fujimoto), interferon-' alpha ' (Alfa Wassermann/J & J), interferon beta 1A-IF (Serono/Inhale Therapeutics), glycol interferon alpha 2b (Enzon/Schering-Plough), copolymer 1 (Cop-1; Copaxone
?; Teva Pharmaceutical Industries, Inc); Hyperbaric oxygen; Intravenous immunoglobuin; CldAdo; The antibody of other people cytokine or somatomedin and acceptor (such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF and PDGF) thereof or antagonist.Formula (I) compound can with the antibody of cell surface molecule (such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90) or their ligand combination.Formula (I) compound can also combine with following agents: as methotrexate, S-Neoral, FK506, rapamycin, mycophenlate mofetil, Leflunomide, S1P1 agonist, NSAIDs is Ibuprofen BP/EP such as, reflunomide is Ultracortene-H such as, phosphodiesterase inhibitor, adenosine agonists, antithrombotic agent, complement inhibitor, adrenergic agent, by medicament (the such as NIK that pro-inflammatory cytokine transmits as TNF α or IL-1 undesired signal, IKK, p38 or map kinase inhibitor), IL-1 β converting enzyme inhibitor, tace inhibitor, T-cell signal transmits inhibitor as kinase inhibitor, inhibitors of metalloproteinase, sulfasalazine, azathioprine, Ismipur, angiotensin converting enzyme inhibitor, soluble cytokine receptor and derivative thereof are (such as, solubility p55 or p75 TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (as IL-4, IL-10, IL-13 and TGF β).
The compound of formula (I) also can be used with following agents jointly: as Ah coming organizes monoclonal antibody, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, Fampridine, Glatiramer acetate, natalizumab, Xin Nabidao (sinnabidol), α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor anagonists, BBR-2778, the ancient woods (calagualine) of OK a karaoke club, CPI-1189, LEM (mitoxantrone of liposome encapsulation), THC.CBD (cannabinoid agonists), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap1258 (RDP-1258), sTNF-R1, Talampanel, Teriflunomide, TGF-β 2, tiplimotide (tiplimotide), VLA-4 antagonist (such as TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon-gamma antagonist and IL-4 agonist.
The nonrestrictive example of the treating ankylosing spondylitis agent jointly can used with the compound of formula (I) comprises following: Ibuprofen BP/EP, diclofenac, Misoprostol, Naproxen Base, meloxicam, INDOMETHACIN, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, Minocycline HCl, Ultracortene-H and anti-TNF antibody, D2E7 (HUMIRA
?), CA2 (infliximab), CDP571, TNFR-Ig construct, (p75TNFRIgG (ENBREL
?) and p55TNFRIgG (Lenercept
?).
The nonrestrictive example of the treating asthma agent jointly can used with the compound of formula (I) comprises following: salbutamol, Salmeterol/fluticasone, Menglusitena, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, Levalbuterol hydrochloride, salbutamol sulfate/Rinovagos, prednisolone phosphate sodium, Triamcinolone Acetonide, beclomethasone dipropionate, ipratropium bromide, Azythromycin, pirbuterol acetate, prednisolone, Theophylline Anhydrous, methyl meticortelone sodium succinate, clarithromycin, Zafirlukast, Formoterol Fumarate, influenza virus vaccine, Utimox, flunisolide, transformation reactions injection, Sodium Cromoglicate, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, sucker supplementary unit, Guaifenesin, dexamethasone sodium phosphate, Moxifloxacin hydrochloride, Vibramycin hydrochloride, Guaifenesin/d-methorphan, p-racephedrine/cod/ Toldrin, Gatifloxacin, cetrizine hcl, furoic acid momisone, salmeterol xinafoate, benzonatate, Cephalexin Monohydrate Micro/Compacted, PE/ hydrocodone/Toldrin, cetrizine hcl/pseudoephedrine, synephrine/cod/ promethazine, morphine monomethyl ether/promethazine, Prozef, dexamethasone, Guaifenesin/pseudoephedrine, chlorphenamine/hydrocodone, sodium nedocromil, bricalin, suprarenin, methyl meticortelone, anti-il-13 antibody, and orciprenaline sulfate.
The nonrestrictive example of the COPD therapeutical agent jointly can used with the compound of formula (I) comprises following: salbutamol sulfate/Rinovagos, ipratropium bromide, Salmeterol/fluticasone, salbutamol, salmeterol xinafoate, fluticasone propionate, prednisone, Theophylline Anhydrous, methyl meticortelone sodium succinate, Menglusitena, budesonide, Formoterol Fumarate, Triamcinolone Acetonide, levofloxacin, Guaifenesin, Azythromycin, beclomethasone dipropionate, Levalbuterol hydrochloride, flunisolide, ceftriaxone sodium, Utimox, Gatifloxacin, Zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorphenamine/hydrocodone, orciprenaline sulfate, methylprednisolone, furoic acid momisone, p-racephedrine/cod/ Toldrin, pirbuterol acetate, p-racephedrine/Loratadine, bricalin, tiotropium bromide, (R, R)-formoterol, TgAAT, cilomilast and roflumilast.
The nonrestrictive example of the curing psoriasis agent jointly can used with the compound of formula (I) comprises following: calcipotriol, clobetasol propionate, Triamcinolone Acetonide, halobetasol propionate, Tazarotene, methotrexate, fluocinonide (fluocinonide), the betamethasone dipropionate of amplification, fluocinolone acetonide (fluocinolone acetonide), A Quting, tar shampoo, Valisone, Mometasone Furoate, KETOKONAZOL, Pramoxine/fluocinolone acetonide, valerate cortisone, flurrenolone, urea, Betamethasone Valerate, clobetasol propionate/emoll, fluticasone propionate, Azythromycin, hydrocortisone, moisten formula (moisturizing formula), folic acid, (11BETA,16ALPHA)-16,17-[methylethylidenebis(oxy), pimecrolimus, coal tar, acetic acid diflorasone, folic acid etanercept, lactic acid, Methoxsalen, hc/ bismuth subgallate/znox/resor, acetic acid methyl meticortelone, prednisone, opalizer, halcinonide, Whitfield's ointment, Dithranol, clocortolone pivalate, coal extract, coal tar/Whitfield's ointment, coal tar/Whitfield's ointment/sulphur, desoximetasone, diazepam, softener, fluocinonide/softener, mineral oil/Viscotrol C/na lact, mineral oil/peanut oil, oil/Isopropyl myristate, psoralene, Whitfield's ointment, soap/tribromsalan, Thiomersalate/boric acid, celecoxib, infliximab, ciclosporin, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and excellent spy gram monoclonal antibody.
The nonrestrictive example of the psoriasis arthropathica therapeutical agent jointly can used with the compound of formula (I) comprises following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, Naproxen Base, leflunomide, acetic acid methyl meticortelone, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, the Sch-11460 of amplification, infliximab, methotrexate, folic acid, Triamcinolone Acetonide, diclofenac, dimethyl sulfoxide (DMSO), piroxicam, diclofenac sodium, Ketoprofen, meloxicam, methyl meticortelone, nabumetone, tolmetin sodium, calcipotriol, ciclosporin, Diclofenac Sodium/Misoprosrol, fluocinonide, Glucosamine Sulphate, disodium aurothiomalate, Hycodan/Paracetamol, Ibuprofen BP/EP, risedronate sodium, Sulphadiazine Sodium, Tioguanine, Valdecoxib, Ah method's Saite, D2E7 (adalimumab) and efalizumab.
The preferred example of SLE (lupus) therapeutical agent jointly can used with the compound of formula (I) comprises following: NSAIDS, such as, and diclofenac, Naproxen Base, Ibuprofen BP/EP, piroxicam, indomethacin; COX2 inhibitor, such as celecoxib, rofecoxib, Valdecoxib; Antimalarial drug, such as Oxychloroquine; Steroid, such as prednisone, Ultracortene-H, budesonide, dexamethasone; Cytotoxin, such as azathioprine, endoxan, mycophenolate mofetile, methotrexate; PDE4 inhibitor or purine synthetic inhibitor, such as Cellcept.The compound of formula (I) can also with following pharmaceutical agent combinations: such as sulfasalazine, 5-aminosalicylic acid, Olsalazine, according to lily magnolia
?with interference pro-inflammatory cytokine if the medicament such as Caspase inhibitors of the synthesis of IL-1, generation or effect is as IL-1 β converting enzyme inhibitor and IL-1ra.Formula (I) compound can also with T cell signal transduction inhibitor, such as tyrosine kinase inhibitor; Such as, or the molecule of targeting T-cells activating molecules, CTLA-4-IgG or anti-B7 family antibody, anti-PD-1 family antibody uses together.The compound of formula (I) can with IL-11 or anti-cytokine antibodies, such as, fonotolizumab (antibody of anti-IFNg), or anti-receptor receptor antibody, the such as Antibody Combination of anti-IL-6 receptor antibody and B cell surface molecular.The compound of formula (I) also can with LJP394 (abetimus), exhaust or the reagent of deactivation B cell, such as, Rituximab (anti-CD20 antibodies), lymphostat-B (anti-BlyS antibody), TNF antagonist such as, anti-TNF antibody, D2E7 (adalimumab), CA2 (infliximab), CDP571, TNFR-Ig construct, (p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept
tM) use together.
Compound of the present invention also can be used with the prevention at AIDS for the treatment of significant quantity or one or more medicaments used in treating jointly, and the example of wherein said medicament comprises hiv reverse transcriptase inhibitor, hiv protease inhibitor, immunomodulator and other retroviral drugs.The example of reverse transcriptase inhibitors includes but not limited to, Abacavir, Adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine, nevirapine, stavudine zalcitabine and zidovudine.The example of proteinase inhibitor includes, but not limited to amprenavir, Indinavir, rltonavir, viracept see nelfinaivr, ritonavir and Saquinavir.
The compound of formula (I) also can use treatment for type i diabetes with Regular Insulin jointly.
Compound of the present invention also can be used with the prevention at AIDS for the treatment of significant quantity or one or more medicaments used in treating jointly, and the example of wherein said medicament comprises hiv reverse transcriptase inhibitor, hiv protease inhibitor, immunomodulator and other retroviral drugs.The example of reverse transcriptase inhibitors includes but not limited to, Abacavir, Adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tynofovir, zalcitabine and zidovudine.The example of proteinase inhibitor includes, but not limited to amprenavir, Reyataz R, DRV, Indinavir, fosamprenavir, rltonavir, viracept see nelfinaivr, ritonavir, Saquinavir and tipranavir.The example of other retroviral drugs includes, but not limited to dust for drawing Wei, enfuirtide, MVC and Merck.
Compound of the present invention also can be used with one or more medicaments used in the treatment of obesity for the treatment of significant quantity jointly, and the example of wherein said medicament comprises xenical see orlistat.
Compound of the present invention also can be used with one or more medicaments used in the treatment of type ii diabetes for the treatment of significant quantity jointly, the example of wherein said medicament comprises alpha-glucosidase inhibitor, Regular Insulin, N1,N1-Dimethylbiguanide, sulfonylurea (such as, carbutamide, tsiklamid, P-607, Glyburide, glibornuride, gliclazide, glimepiride, Glipizide, gliquidone, glisoxepide, glyclopyramide, tolbutamide and tolazamide), non-sulfonylurea (such as, nateglinide and repaglinide) and thiazolidinedione is (such as, pioglitazone).
The compounds of this invention can use to prevent or treat type ii diabetes jointly with one or more medicaments for the treatment of significant quantity, fatty degeneration of liver, insulin resistant, Metabolic syndrome seek peace associated conditions, and the example of wherein said medicament includes but not limited to Regular Insulin and modified with the insulin type of action time in improved body; The medicament stimulated insulin secretion, such as tsiklamid, P-607, Glyburide, glimepiride, Glipizide, gliclazide, glyclopyramide, gliquidone, repaglinide, nateglinide (nataglinide), tolazamide and tolbutamide; For the medicament of glucagon-like peptide agonist, such as Exenatide (exanatide), Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (liraglutide) and Ta Silutai (taspoglutide); Suppress the medicament of dipeptidyl-peptidase IV, such as vildagliptin, sitagliptin, BMS-477118, BI 1356, allogliptin and septagliptin; The medicament be combined with Peroxisome proliferator-activators γ, such as rosiglitazone and pioglitazone; Reduce the medicament of insulin resistant, such as N1,N1-Dimethylbiguanide; Reduce the medicament of glucose absorption in small intestine, such as acarbose, miglitol and voglibose.
Compound of the present invention can be used to prevent or treat acute renal dysfunction and chronic renal disease with one or more medicaments for the treatment of significant quantity jointly, the example of wherein said medicament comprises, but be not limited to, Dopamine HCL, diuretic(s) be Furosemide, bumetanide, thiazine etc. such as, N.F,USP MANNITOL, calglucon, sodium bicarbonate, salbutamol, Zemplar, doxercalciferol and cinacalcet.
The following examples may be used for illustrative object, should not be considered to limit the scope of the invention.
Embodiment
embodiment 1. 3-methyl isophthalic acid-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 1a. 1-bromo-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one (Clezy, the P.S. in tetrahydrofuran (THF) (8mL) is enclosed in the 50mL round-bottomed flask with stirring rod; Fookes, C.J.R.; Mirza, A.H.
aust. J. Chem.1977,
30, 1337-47.) and (0.502 gram, 3.36 mmol) be cooled to-78 DEG C under a nitrogen.Add the N-bromine succinimide (0.608 gram, 3.42 mmol) of recrystallization, and mixture is stirred 30 minutes.Reaction mixture is poured into the separating funnel containing sodium sulfite aqueous solution and extract and enter 100mL ether.Organic layer is also dry on anhydrous sodium sulfate with sodium bicarbonate aqueous solution washing.Roughage to be adsorbed on silica gel and at 40 grams of silica gel prepackage column chromatographies, with 10-100% ethyl acetate/hexane wash-out, to provide title compound.
embodiment 1b. 3-methyl isophthalic acid-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.to being equipped with in the 5mL microwave reaction container of stirring rod the embodiment 1a (0.0556 gram added in ethanol (1.2mL)/DME (1.2mL), 0.244mmol), phenyl-boron dihydroxide (0.030 gram, 0.244mmol), 2M aqueous sodium carbonate (1.5mL, 3.00mmol) and two (triphenylphosphine) palladium chloride (II) (0.171 gram, 0.244mmol) sealing.In Biotage Initiator 2 single mold microwave reactor, mixture is heated to 120 DEG C, continues 30 minutes, be then cooled to envrionment temperature.Mixture shakes together with 50mL water with 50mL ethyl acetate in separating funnel.By organism through anhydrous sodium sulfate drying.To filter and after removing desolventizing, resistates is by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
embodiment 2. 3-methyl isophthalic acid-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 2 is prepared for the method for the preparation of embodiment 1b, with 2-phenoxyphenyl boronic acid substituted-phenyl boric acid, to provide title compound according to being similar to.
embodiment 3. 1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 3 is prepared for the method for the preparation of embodiment 1b, with 2-aminophenyl boronic acid substituted-phenyl boric acid, to provide title compound according to being similar to.
embodiment 4. 3-methyl isophthalic acid-(4-aminomethyl phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.stirring rod, embodiment 1a (20mg is loaded in the bottle of 4mL, solution 0.088mmol) in ethanol (1mL), p-tolyl boric acid (16mg, 1.2eq, 0.105mmol) solution, 1M Cs in ethanol (1mL)
2cO
3the aqueous solution (180 μ L, 2.0eq, 0.18mmol), and Silia
catdPP-Pd resin (Silicycle, Inc.) (32mg, 0.10 equivalent, 0.27mmol/g carrying capacity).By bottle capping and be placed in the parallel microwave synthesizer of Anton Paar Synthos 3000 120 DEG C continue 30 minutes.After completing, roughage filters, dry also by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
embodiment 5. 4-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzsulfamide.preparing embodiment 5 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) benzsulfamide.
embodiment 6. 1-(2-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 6 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 2-methoxyphenyl-boronic acid.
embodiment 7. 3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 7 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 3,4,5-trimethoxyphenylboronic acid.
embodiment 8. 3-methyl isophthalic acid-[4-(methyl sulphonyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 8 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 4-(methylsulfonyl) phenyl-boron dihydroxide.
embodiment 9. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzamide.preparing embodiment 9 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 3-Carbamoylphenyl boric acid.
embodiment 10. 1-(1H-indoles-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 10 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 1H-indoles-4-ylboronic acid.
embodiment 11. 1-(4-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 11 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 4-methoxyphenyl-boronic acid.
embodiment 12. 1-(3,4-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 12 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 3,4-dimethylphenylboronic acid.
embodiment 13. 1-(4-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 13 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 4-chlorophenylboronic acid.
embodiment 14. 1-[3-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 14 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 2-(3-(benzyloxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane.
embodiment 15. 1-(2-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 15 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 2-chlorophenylboronic acid.
embodiment 16. 1-(1,3-benzodioxole-5-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 16 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with benzo [d] [1,3] dioxole-5-ylboronic acid.
embodiment 17. 1-(3,5-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 17 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 3,5-dimethylphenylboronic acid.
embodiment 18. 1-[2-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 18 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 2-benzyloxyphenylboronic acid.
embodiment 19. 3-methyl isophthalic acid-(naphthalene-1-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 19 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 1-naphthalenylboronic acid.
embodiment 20. 1-(3-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 20 according to being similar to for the method for the preparation of embodiment 4, replacing p-tolyl boric acid, to provide title compound with 3-methoxyphenyl-boronic acid.
embodiment 21. 1-(1H-benzoglyoxaline-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 21 is prepared for the method for the preparation of embodiment 1b, with 1H-benzo [d] imidazol-4 yl boric acid substituted-phenyl boric acid, to provide title compound according to being similar to.
embodiment 22. 1-(1H-indoles-7-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 22 is prepared for the method for the preparation of embodiment 1b, with 1H-indoles-7-ylboronic acid substituted-phenyl boric acid, to provide title compound according to being similar to.
embodiment 23. 3-methyl isophthalic acid-(2-{ [3-(trifluoromethyl) phenoxy group] methyl } phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.to being equipped with in the 10mL microwave reaction container of stirring rod the embodiment 1a (80mg be enclosed in DME (1.5mL)/EtOH (1.5mL), 0.351mmol), 4,4,5,5-tetramethyl--2-({ [(3-trifluoromethyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane (141mg, 0.456mmol), Na
2cO
3(2M, 1.754mL, 3.51mmol) and Pd (Ph
3p)
2cl
2(14.77mg, 0.021mmol) also seals.Mixture heats 30 minutes in Biotage microwave at 120 DEG C.Reaction mixture diluted ethyl acetate, with water (3x25mL) washing, through Na
2sO
4drying, filters through sintered glass funnel and concentrates to provide yellow solid.Sample in solution is transferred on 18 × 150mm plate.Plate with 50% ethyl acetate/heptane wash-out to obtain title compound.
embodiment 24. 3-methyl isophthalic acid-[2-(phenoxymethyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 24 is prepared for the method for the preparation of embodiment 23 according to being similar to, with 4,4,5,5-tetramethyl--2-(2-(phenoxymethyl) phenyl)-1,3,2-dioxaborolan alkane replaces 4,4,5,5-tetramethyl--2-({ [(3-trifluoromethyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane, to provide title compound.
embodiment 25. 3-methyl isophthalic acid-{ 2-[(2-methylphenoxy) methyl] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 25 is prepared for the method for the preparation of embodiment 23 according to being similar to, with 4,4,5,5-tetramethyl--2-({ [(2-methyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane replaces 4,4,5,5-tetramethyl--2-({ [(3-trifluoromethyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane, to provide title compound.
embodiment 26. 2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzyl]-1H-isoindole-1,3 (2H)-diketone.embodiment 26 is prepared for the method for the preparation of embodiment 23, with 2-(2-(4,4 according to being similar to, 5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) benzyl) isoindoline-1,3-diketone replaces 4,4,5,5-tetramethyl--2-({ [(3-trifluoromethyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane, to provide title compound.
embodiment 27. 1-[2-(furans-2-base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 27 is prepared for the method for the preparation of embodiment 23, with 2-(2-(furans-2-base) phenyl)-4,4 according to being similar to, 5,5-tetramethyl--1,3,2-dioxaborolan alkane replaces 4,4,5,5-tetramethyl--2-({ [(3-trifluoromethyl) phenoxy group] methyl } phenyl)-1,3,2-dioxaborolan alkane, to provide title compound.
embodiment 28. 1-(2-hydroxy phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 28 is prepared for the method for the preparation of embodiment 1b, with 2-hydroxyphenyl boronic acid substituted-phenyl boric acid according to being similar to.Title compound (39mg, 32%) is obtained by flash chromatography (silica gel, 2-4% ethanol/methylene) purifying.
embodiment 29.3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-3-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.From embodiment 28 (48.3mg, product 0.20mmol), (tetrahydrofuran (THF)-3-base) methyl alcohol (0.020mL, 0.210mmol) and triphenylphosphine (55.1mg, 0.210mmol) to be incorporated in tetrahydrofuran (THF) (0.1mL) and supersound process until dissolution of solid.Add diisopropyl azodiformate (0.041mL, 0.210mmol), and supersound process continues 2 hours.Reaction mixture distributes between ethyl acetate and water.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues to obtain title compound (13mg, 20%).
embodiment 30. 1-[2-(cyclopentylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.from embodiment 28 (48.3mg, product 0.20mmol), (brooethyl) pentamethylene (39.1mg, 0.240mmol) with salt of wormwood (33.2mg, 0.240mmol) be incorporated in dimethyl formamide (1mL), and 50 DEG C of heating 16 hours.Reaction mixture distributes between ethyl acetate and water.Organic layer is concentrated, and resistates is by reversed-phase HPLC (C18, the 50-95% acetonitrile in 10mM ammonium acetate/water) purifying, to obtain title compound (31mg, 48%).
Embodiment 31.
3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 31 according to being similar to for the method for the preparation of embodiment 30, replacing (brooethyl) pentamethylene, to provide title compound (24mg, 37%) with 2-(brooethyl) tetrahydrofuran (THF).
embodiment 32. 3-methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-4-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 32 according to being similar to for the method for the preparation of embodiment 30, replacing (brooethyl) pentamethylene, to provide title compound (41mg, 60%) with 4-(brooethyl) tetrahydrochysene-2H-pyrans.
embodiment 33. 3-methyl isophthalic acid-{ 2-[2-(morpholine-4-base) oxyethyl group] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 33 according to being similar to for the method for the preparation of embodiment 30, replacing (brooethyl) pentamethylene, to provide title compound (46mg, 65%) with 4-(2-bromotrifluoromethane) morpholine.
embodiment 34. 3-methyl isophthalic acid-[2-(pyridine-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 34 is prepared for the method for the preparation of embodiment 30 according to being similar to, (brooethyl) pentamethylene is replaced with 2-(brooethyl) pyridine hydrobromide salt, and at room temperature but not react at 50 DEG C, to provide title compound (52mg, 78%).
embodiment 35. 3-methyl isophthalic acid-[2-(quinoline-8-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 35 is prepared for the method for the preparation of embodiment 30 according to being similar to, (brooethyl) pentamethylene is replaced with 8-(brooethyl) quinoline, and at room temperature but not react at 50 DEG C, to provide title compound (48mg, 63%).
embodiment 36. 1-[2-(1-thionaphthene-7-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 36 is prepared for the method for the preparation of embodiment 30 according to being similar to, (brooethyl) pentamethylene is replaced with 7-(brooethyl) benzo [b] thiophene, and at room temperature but not react at 50 DEG C, to provide title compound (39mg, 50%).
embodiment 37. 3-methyl isophthalic acid-[2-(pyridin-3-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 37 is prepared for the method for the preparation of embodiment 30 according to being similar to, (brooethyl) pentamethylene is replaced with 3-(brooethyl) pyridine hydrobromide salt, and at room temperature but not react at 50 DEG C, to provide title compound (8mg, 12%).
embodiment 38. 1-[2-(1H-indazole-5-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.embodiment 38 is prepared for the method for the preparation of embodiment 30 according to being similar to, (brooethyl) pentamethylene is replaced with 5-(brooethyl)-1H-indazole hydrobromate, and at room temperature but not react at 50 DEG C, to provide title compound (8mg, 11%).
embodiment 39. 1-(5-amino-2-Phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 39a. 1-(the fluoro-5-nitrophenyl of 2-)-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.containing embodiment 1a (2.97g, 13mmol), the fluoro-5-nitrophenyl boronic acid (3.61g, 19.50mmol) of 2-, Pd
2(dba)
3(0.298g, 0.325mmol), 1,3,5,7-tetramethyl--6-phenyl-2,4, the 250mL tri-neck round-bottomed flask of 8-trioxa-6-phospha-adamantane (0.190g, 0.650mmol) and potassiumphosphate (8.28g, 39.0mmol) nitrogen purging 30 minutes.Then Isosorbide-5-Nitrae-diox (50mL) of nitrogen purging to be transferred in three neck round-bottomed flasks and by mixture 60 DEG C of heating 6 hours.Then reaction mixture be cooled to room temperature and distribute between ethyl acetate and water.Organic layer washed with brine, anhydrous sodium sulfate drying, and filter.Filtrate, by the functionalized silica gel treatment of 3-mercaptopropyi, is filtered and concentrates.By flash chromatography (silica gel, 0-20% ethyl acetate/dichloromethane) purification residues to obtain the title compound of 2.66g (71%).
embodiment 39b. 3-methyl isophthalic acid-(5-nitro-2-Phenoxyphenyl)-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 39a (2.65g, 9.19mmol), phenol (0.952g, 10.11mmol), and Cs
2cO
3(5.99g, 18.39mmol) and dimethyl formamide (30mL) merge, and stir 1 hour at 50 DEG C.Reaction mixture is cooled to room temperature and distributes between ethyl acetate and water.Organic layer washed with brine twice, dry on anhydrous sodium sulfate, filter and concentrate.By flash chromatography (silica gel, 0-20% ethyl acetate/dichloromethane) purification residues to obtain the title compound of 3.33g (100%).
embodiment 39c. 1-(5-amino-2-Phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.to embodiment 39b (3.33g, 9.19mmol), iron powder (2.57g, 45.9mmol) and in the mixture of ammonium chloride (1.475g, 27.6mmol) add the solution of tetrahydrofuran (THF) (24mL)/ethanol (24mL)/water (8mL).Gained mixture heats 9 hours under reflux, is then cooled to room temperature and distributes between ethyl acetate and water.Organic layer washed with brine, anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 20-40% ethyl acetate/dichloromethane) purification residues to obtain the title compound of 2.78g (91%).
embodiment 40. N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.Embodiment 39c (2.78g, 8.36mmol), methylsulfonyl chloride (1.564mL, 20.07mmol) and triethylamine (3.48mL, 25.09mmol) are incorporated in methylene dichloride (40mL).Reaction mixture at room temperature stirs 1 hour and concentrates.By resistates Yong diox (40mL) and sodium hydroxide (the 1.0M aqueous solution of 84mL, 84mmol) dilution, and heat 1 hour at 50 DEG C.Reaction mixture distributes between ethyl acetate and saturated aqueous ammonium chloride solution.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues, grind (methylene dichloride) subsequently to obtain title compound (3.05g, 89%).
embodiment 41. N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.
embodiment 41a. 2,3-dimethyl-1-(5-nitro-2-Phenoxyphenyl)-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 39b (127mg in tetrahydrofuran (THF) (2mL), 0.350mmol) with 60% sodium hydride (15.42mg, 0.386mmol) process, at room temperature stir 1 hour, also at room temperature stir 2 hours with methyl iodide (0.024mL, 0.386mmol) process.Reaction mixture distributes between ethyl acetate and water.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 0-2% ethanol/methylene) purification residues to obtain title compound (105mg, 80%).
embodiment 41b.1-(5-amino-2-Phenoxyphenyl)-2,3-dimethyl-6,7-dihydro-2H-isoindole-4 (5H)-one.prepare embodiment 41b according to the method be similar to for the preparation of embodiment 39c, replace embodiment 39b, to provide title compound (90mg, 95%) with embodiment 41a.
embodiment 41c. N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.prepare embodiment 41c according to the method be similar to for the preparation of embodiment 40, replace embodiment 39c with embodiment 41b.Title compound (43mg, 84%) is obtained by flash chromatography (silica gel, 2% ethanol/methylene) purifying.
embodiment 42. N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] ethanamide.embodiment 41b (41.6mg, 0.12mmol) in diacetyl oxide (0.5mL, 5.30mmol) heats 30 minutes at 100 DEG C in microwave.Concentrated reaction mixture, and by flash chromatography (silica gel, in 1-2% ethanol/methylene) purification residues to obtain title compound (38mg, 82%).
embodiment 43. 1-[5-amino-2-(phenylsulfartyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 43a. 3-methyl isophthalic acid-(5-nitro-2-(phenyl) phenyl)-6,7-dihydro-2H-isoindole-4 (5H)-one.Embodiment 39a (58mg, 0.201mmol) and thiophenol sodium (29.2mg, 0.221mmol) are incorporated in dimethyl formamide (2mL), and 50 DEG C of heating 2 hours.Reaction mixture distributes between ethyl acetate and water.Organic layer washed with brine twice, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 0-1% ethanol/methylene) purification residues to obtain title compound (46mg, 60%).
embodiment 43b. 1-[5-amino-2-(phenylsulfartyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.prepare embodiment 43b according to the method be similar to for the preparation of embodiment 39c, replace embodiment 39b with embodiment 43a.Title compound (35mg, 84%) is obtained by flash chromatography (silica gel, 2% ethanol/methylene) purifying.
embodiment 44. N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-(phenylsulfartyl) phenyl] Toluidrin.preparing embodiment 44 according to being similar to for the method for the preparation of embodiment 40, replacing embodiment 39c with embodiment 43b.Title compound (33mg, 84%) is obtained by flash chromatography (silica gel, 2% ethanol/methylene) purifying.
embodiment 45. 1-[5-amino-2-(2,4 difluorobenzene oxygen base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 45a. 1-(2-(2,4 difluorobenzene oxygen base)-5-nitrophenyl)-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 45a is prepared, with 2,4 difluorobenzene phenol fortified phenol, to provide title compound (1.01g, 73%) according to the method be similar to for the preparation of embodiment 39b.
embodiment 45b. 1-[5-amino-2-(2,4 difluorobenzene oxygen base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.prepare embodiment 45b according to the method be similar to for the preparation of embodiment 39c, replace embodiment 39b, to provide title compound (805mg, 87%) with embodiment 45a.
embodiment 46. N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin.preparing embodiment 46 according to being similar to for the method for the preparation of embodiment 40, replacing embodiment 39c with embodiment 45b.Title compound (49mg, 81%) is obtained by flash chromatography (silica gel, 1-2% ethanol/methylene) purifying.
embodiment 47. N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethyl sulfonamide.preparing embodiment 47 according to being similar to for the method for the preparation of embodiment 40, replacing embodiment 39c with embodiment 45b respectively, replacing methylsulfonyl chloride with ethyl sulfonyl chloride.Title compound (53mg, 85%) is obtained by flash chromatography (silica gel, 1-2% ethanol/methylene) purifying.
embodiment 48. N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-2,2,2-trifluoro ethyl sulfonamides.embodiment 45b (50mg, 0.136mmol), 2,2,2-trifluoro ethyl sulfonyl chloride (29.7mg, 0.163mmol) and triethylamine (0.057mL, 0.407mmol) are incorporated in methylene dichloride (2mL).Reaction mixture is at room temperature stirred 2 hours, concentrated, and resistates is distributed between ethyl acetate and water.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues to obtain title compound (18mg, 26%).
embodiment 49. N'-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-N, N-dimethyl methyl diamide.embodiment 45b (50mg, 0.136mmol), dimethylsufamoyl chloride (0.017mL, 0.163mmol) with cesium carbonate (66.3mg, 0.204mmol) merge in dimethyl formamide (1mL), and reaction mixture is heated 1 hour by microwave at 80 DEG C.Add dimethylsufamoyl chloride (0.017mL, 0.163mmol) again, and reaction mixture is heated other 1 hour by microwave at 80 DEG C.Reaction mixture distributes between ethyl acetate and water.Organic layer washed with brine twice, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues to obtain title compound (14mg, 22%).
embodiment 50. N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethanamide.preparing embodiment 50 according to being similar to for the method for the preparation of embodiment 42, replacing embodiment 41b, to provide title compound (35mg, 63%) with embodiment 45b.
embodiment 51. N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-1H-pyrroles-2-methane amide.1H-pyrroles-2-formic acid (18.10mg, 0.163mmol) in tetrahydrofuran (THF) (2mL) oxalyl chloride (0.024mL, 0.271mmol) and 1 dimethyl formamide process.Mixture at room temperature stirs 30 minutes and concentrates.Resistates and methylbenzene azeotropic are dissolved in tetrahydrofuran (THF) (2mL).Add embodiment 45b (50mg, 0.136mmol) and triethylamine (0.076mL, 0.543mmol) reaction mixture is at room temperature stirred 30 minutes.Reaction mixture distributes between ethyl acetate and water.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues to obtain title compound (40mg, 64%).
embodiment 52. N-{4-[(4,4-difiuorocyclohexyl) oxygen base]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl } ethyl sulfonamide.
embodiment 52a. 1-(2-(4,4-difiuorocyclohexyl oxygen base)-5-nitrophenyl)-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.in 4,4-difluorocyclohex alcohol (102mg, 0.75mmol) in tetrahydrofuran (THF) (2mL), add 60% sodium hydride (36mg, 0.90mmol) under a nitrogen, and reaction mixture is at room temperature stirred 1 hour.Add embodiment 39a (43.2mg, 0.15mmol), and reaction mixture is heated 2 hours under a nitrogen at 50 DEG C.Reaction mixture distributes between ethyl acetate and 1M HCl.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 5-20% ethyl acetate/dichloromethane) purification residues, grind (10% dichloromethane/hexane) subsequently to obtain title compound (32mg, 53%).
embodiment 52b. 1-(5-amino-2-(4,4-difiuorocyclohexyl oxygen base) phenyl)-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 52a (58mg, 0.143mmol) and 10% palladium/carbon (30.5mg, 0.029mmol) are incorporated in ethyl acetate (20mL).By reaction mixture hydrogenation 3 hours under hydrogen capsule atmosphere, filter and concentrated filtrate, to obtain title compound (49mg, 91%).
embodiment 52c. N-{4-[(4,4-difiuorocyclohexyl) oxygen base]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl } ethyl sulfonamide.prepare embodiment 52c according to the method be similar to for the preparation of embodiment 40, replace embodiment 39c with embodiment 52b respectively, replace methylsulfonyl chloride with ethyl sulfonyl chloride.Title compound (44mg, 77%) is obtained by flash chromatography (silica gel, 1-2% ethanol/methylene) purifying and grinding (20% dichloromethane/hexane).
embodiment 53. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid methyl esters.
the fluoro-3-of embodiment 53a. 4-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) methyl benzoate.prepare embodiment 53a according to the method be similar to for the preparation of embodiment 39a, replace the fluoro-5-nitrophenyl boronic acid of 2-with (2-fluoro-5-methoxycarbonyl phenyl) boric acid.Title compound (3.8g, 72%) is obtained by flash chromatography (silica gel, 0-60% ethyl acetate/hexane) purifying.
embodiment 53b. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid methyl esters.prepare embodiment 53b according to the method be similar to for the preparation of embodiment 39b, replace embodiment 39a with embodiment 53a, and to react at 50 DEG C, to provide title compound (451mg, 60%) at 120 DEG C.
embodiment 54. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid.embodiment 53b (410mg, 1.092mmol) and the mixture reflux of sodium hydroxide (the 1.0M aqueous solution of 3.28mL, 3.28mmol) in tetrahydrofuran (THF) (10mL) and water (5mL) 2 hours.Reaction mixture distributes between ethyl acetate and water.With 1M hydrochloric acid by aqueous layer acidified to pH1, be extracted with ethyl acetate, with anhydrous sodium sulfate drying, filter and concentrate to provide title compound (385mg, 98%).
embodiment 55. N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzamide.embodiment 54 (36.1mg, 0.10mmol), HATU (76mg, 0.200mmol) and DIPEA (0.035mL, 0.200mmol) be incorporated in tetrahydrofuran (THF) (2mL), at room temperature stir 5 minutes, with ethamine (the 2.0M tetrahydrofuran solution of 0.1mL, 0.20mmol) process, and at room temperature stir 1 hour.Reaction mixture distributes between ethyl acetate and 1M HCl.Organic layer washed with brine, with anhydrous sodium sulfate drying, filters and concentrates.By flash chromatography (silica gel, 1-2% ethanol/methylene) purification residues, grind (methyl alcohol) subsequently to obtain title compound (19mg, 49%).
embodiment 56. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(tetrahydrofuran (THF)-2-ylmethyl) benzamide.preparing embodiment 56 according to being similar to for the method for the preparation of embodiment 55, replacing ethamine with (tetrahydrofuran (THF)-2-base) methylamine and reaction mixture being stirred 24 hours but not 1 hour.By flash chromatography (silica gel, 1-2% ethanol/methylene) purifying, grind (50% dichloromethane/hexane) subsequently and obtain title compound (29mg, 65%).
embodiment 57. 3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(1,3-thiazoles-2-base) benzamide.preparing embodiment 57 according to being similar to for the method for the preparation of embodiment 55, replacing ethamine with thiazole-2-amine, and reaction mixture being stirred 24 hours but not 1 hour, to provide title compound (11mg, 25%).
embodiment 58. 1-(1,3-benzodioxole-5-base)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 58a. 3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-ethyl formate.the 2-ethanoyl-5,5-dimethyl cyclohexane-1,3-diketone (5g, 27.4mmol) in acetic acid (30mL) and sodium acetate (2.57g, 31.3mmol) is enclosed in the 25mL round-bottomed flask with stirring rod.Well-beaten mixture put into the oil bath of 100 DEG C and become even.Dropwise add the solution of 2-diethyl aminomalonate (4.184g, 23.88mmol) in 10ml acetic acid, and mixture is stirred at 100 DEG C.Another part of sodium acetate (2.75g, 33.5mmol) is added after 3 hours.After 20 hours, mixture is poured on ice, then shakes together with ether (250mL) with water in separating funnel.Organic layer sodium bicarbonate aqueous solution to be washed twice and through anhydrous sodium sulfate drying.Filter and remove solvent, obtaining brown solid.Roughage to be adsorbed on silica gel and at 220 grams of silica gel prepackage column chromatographies, with 10-100% ethyl acetate/hexane wash-out, to provide title compound.
embodiment 58b. 3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-formic acid.embodiment 58a (the 1.184g be enclosed in tetrahydrofuran (THF) (40.0mL) and water (20mL) is reclaimed in flask to the 200mL with stirring rod, 4.75mmol) with lithium hydroxide monohydrate (0.57g, 13.58mmol).Mixture stirs 56 hours in 60 DEG C of oil baths.Mixture is cooled, then dilutes with 80mL water and use extracted with diethyl ether twice.The dense HCl acidifying of aqueous phase is also used methylene dichloride and extraction into ethyl acetate successively.Merge these organic extract liquids and use anhydrous sodium sulfate drying.Filter and remove solvent and provide title compound.
embodiment 58c. 3,6,6-trimethylammonium-6,7-dihydro-2H-isoindole-4 (5H)-one.the embodiment 58b (0.61g, 2.76mmol) be enclosed in ethanol (25.00mL)/water (1mL) is reclaimed in flask) to the 250mL with stirring rod.Flask is placed in 100 DEG C of oil baths, and processes with dense HCl (2.8mL, 28.0mmol).Mixture is heated 30 minutes, then make it cooling.Solution is reduced to about 1/3 volume by rotary evaporation, then shakes together with methylene dichloride with the water of each 100mL in separating funnel.By organism sodium bicarbonate aqueous solution and water washing, and use anhydrous sodium sulfate drying.Filter and remove solvent and provide title compound.
bromo-3,6,6-trimethylammonium-6,7-dihydro-2H-isoindole-4 (5H)-one of embodiment 58d. 1-.in the 50mL round-bottomed flask with stirring rod, be enclosed in the embodiment 58c (0.395g, 2.229mmol) in tetrahydrofuran (THF) (6mL) and be cooled to-78 DEG C under a nitrogen.Add N-bromine succinimide (0.402g, 2.259mmol) of recrystallization, and mixture is stirred 30 minutes.Reaction mixture is poured into the separating funnel containing sodium sulfite aqueous solution and extract and enter 60mL ether.By organic layer with sodium bicarbonate aqueous solution washing and through dried over mgso.Filter and remove after solvent, roughage to be adsorbed on silica gel and at 40 grams of silica gel prepackage column chromatographies, with 10-100% ethyl acetate/hexane wash-out, to provide title compound.
embodiment 58e. 1-(1,3-benzodioxole-5-base)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.stirring rod, embodiment 58d (14.09mg is loaded in the bottle of 4mL, solution, benzo [d] [1 0.055mmol) in ethanol (500 μ L), 3] dioxole-5-ylboronic acid (10.95mg, 1.2eq, 0.066mmol) solution, 1M Cs in ethanol (220.04 μ L)
2cO
3the aqueous solution (110.02 μ L, 2.0 equivalent, 0.11mmol), with SiliaCat DPP-Pd resin (Silicycle, Inc.) (20.37mg, 0.10 equivalent, 0.27mmol/g carrying capacity), capping is also placed in the parallel microwave optimizer of Anton Paar Synthos 3000 and continues 30 minutes at 120 DEG C.After completing, roughage filters, dry, and residue is by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
embodiment 59. 3,6,6-trimethylammonium-1-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 59 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with phenyl-boron dihydroxide.
embodiment 60. 1-(2,5-3,5-dimethylphenyl)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 60 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with 2,5-dimethylphenylboronic acid.
embodiment 61. 3,6,6-trimethylammonium-1-[2-(morpholine-4-base) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 61 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with 2-morphlinophenyl boric acid.
embodiment 62. 1-[2-(benzyloxy) phenyl]-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 62 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with 2-benzyloxyphenylboronic acid.
embodiment 63. 3,6,6-trimethylammonium-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 63 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with 2-phenoxyphenyl boronic acid.
embodiment 64. N-[3-(3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin.preparing embodiment 64 according to being similar to for the method for the preparation of embodiment 58e, replacing benzo [d] [1,3] dioxole-5-ylboronic acid, to provide title compound with 3-(sulfonyloxy methyl amido) phenyl-boron dihydroxide.
embodiment 65. 3,6-dimethyl-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
embodiment 65a. 3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-ethyl formate.the 2-ethanoyl-5-methylcyclohexane-1,3-diketone (2.019g, 12.00mmol) in acetic acid (15mL) and sodium acetate (3.87g, 47.2mmol) is enclosed in the 50mL round-bottomed flask with stirring rod.Well-beaten mixture put into the oil bath of 100 DEG C and become even.Dropwise add 2-diethyl aminomalonate hydrochloric acid soln (2.79g, 13.18mmol) in acetic acid (10.00mL), and mixture is stirred at 100 DEG C.After 18 hours, mixture is poured on ice, then shakes together with ether (250mL) with water in separating funnel.Organic layer aqueous sodium hydroxide solution is washed twice (pH of second time washing is alkalescence), then through anhydrous sodium sulfate drying.Filter and remove after solvent, roughage to be adsorbed on silica gel and at 150g silica gel prepackage column chromatography, with 10-100% ethyl acetate/hexane wash-out, to provide title compound.
embodiment 65b. 3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-formic acid.embodiment 65a (the 0.879g be enclosed in tetrahydrofuran (THF) (30.0mL) and water (15mL) is reclaimed in flask to the 100mL with stirring rod, 3.74mmol) with lithium hydroxide monohydrate (0.345g, 8.22mmol).Mixture stirs more than 3 days in 60 DEG C of oil baths.LCMS tracing display is converted into the peak with prospective quality completely.The 40mL water dilution of this mixture, with dense HCl acidifying, and makes it cool with vigorous stirring.In ice bath after cooling, by suspension filtered.Throw out vacuum-drying is to provide title compound.
embodiment 65c. 3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-formic acid.the embodiment 65b (0.648g, 3.13mmol) in ethanol (30.0mL)/water (1.2mL) is enclosed in) in the 100mL round-bottomed flask with stirring rod and reflux exchanger.Flask is placed in 100 DEG C of oil baths, and processes with dense HCl (2.5mL, 30.4mmol).Mixture is heated 30 minutes, then make it cooling.Solution shakes together with methylene dichloride with the salt solution of each 100mL in separating funnel.By organic layer with sodium bicarbonate aqueous solution washing and through anhydrous sodium sulfate drying.Filter and remove solvent and obtain title compound.
bromo-3,6-dimethyl-6,7-dihydro-2H-isoindole-4 (5H)-one of embodiment 65d. 1-.in the 50mL round-bottomed flask with stirring rod, be enclosed in the embodiment 65c (.434g, 2.66mmol) in tetrahydrofuran (THF) (10mL) and be cooled to-78 DEG C under a nitrogen.Add N-bromine succinimide (529g, 2.97mmol) of recrystallization, and mixture is stirred 30 minutes.Reaction mixture is poured into the separating funnel containing sodium sulfite aqueous solution and extract and enter 75mL ether.By organic layer with sodium bicarbonate aqueous solution washing and through dried over mgso.Filter and provide 0.632g lavender solid after removal solvent, it is at 40 grams of silica gel prepackage column chromatographies, with 10-100% ethyl acetate/hexane wash-out, to provide title compound.
embodiment 65e. 3,6-dimethyl-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.to being equipped with in the 5mL microwave reaction container of stirring rod the embodiment 65d (0.078g added in ethanol (1.4mL)/DME (1.4mL), 0.322mmol), 2-phenoxyphenyl boronic acid (0.106g, 0.495mmol), 2M aqueous sodium carbonate (1.6mL, 3.20mmol) and two (triphenylphosphine) palladium chloride (II) (0.015g, 0.021mmol) sealing.In Biotage Initiator 2 single mold microwave reactor, mixture is heated 30 minutes at 120 DEG C, be then cooled to envrionment temperature.Mixture shakes together with 50mL salt solution with 50mL ethyl acetate in separating funnel.By organism through anhydrous sodium sulfate drying.To filter and after removing desolventizing, resistates is by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
embodiment 66. 1-(5-amino-2-Phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 66 according to being similar to for the method for the preparation of embodiment 65e, replacing 2-phenoxyphenyl boronic acid, to provide title compound with 4-phenoxy group-3-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) aniline.
embodiment 67. N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.embodiment 66 (0.074g in tetrahydrofuran (THF) (4mL), 0.213mmol) use methylsulfonyl chloride (0.041mL successively, 0.533mmol) also stir at ambient temperature with triethylamine (0.089mL, 0.639mmol) process.Stir after 90 minutes, add aqueous sodium hydroxide solution (1M) (2mL, 2.000mmol), and by this mixture 45 DEG C of heating 1 hour.By reaction mixture 1N HCl solution (2.5mL) acidifying, with diluted ethyl acetate, use salt water washing, through anhydrous magnesium sulfate drying, filter and concentrate.Resistates is by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
embodiment 68. 3-methyl-6-(2-methyl-propyl)-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 68 according to being similar to for the method for the preparation of embodiment 65, replacing 2-ethanoyl-5-methylcyclohexane-1,3-diketone, to provide title compound with 2-ethanoyl-5-(2-methyl-propyl) hexanaphthene-1,3-diketone.
embodiment 69. N-{3-[3-methyl-6-(2-methyl-propyl)-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin.
the bromo-6-isobutyl-of embodiment 69a. 1--3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.prepare embodiment 69a according to the method be similar to for the preparation of embodiment 65d, replace 2-ethanoyl-5-methylcyclohexane-1,3-diketone, to provide title compound with 2-ethanoyl-5-(2-methyl-propyl) hexanaphthene-1,3-diketone.
embodiment 69d. 1-(5-amino-2-Phenoxyphenyl)-6-isobutyl--3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 69b is prepared according to the method be similar to for the preparation of embodiment 65e, embodiment 65d is replaced with embodiment 69a, and with 4-phenoxy group-3-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) aniline replacement 2-phenoxyphenyl boronic acid, to provide title compound.
embodiment 69c. N-{3-[3-methyl-6-(2-methyl-propyl)-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin.prepare embodiment 69c according to the method be similar to for the preparation of embodiment 67, replace embodiment 66, to provide title compound with embodiment 69b.
embodiment 70. 3-methyl isophthalic acid-(2-Phenoxyphenyl)-6-(propane-2-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.preparing embodiment 70 according to being similar to for the method for the preparation of embodiment 65, replacing 2-ethanoyl-5-methylcyclohexane-1,3-diketone, to provide title compound with 2-ethanoyl-5-(2-methylethyl) hexanaphthene-1,3-diketone.
embodiment 71. N-{3-[3-methyl-4-oxo-6-(propane-2-base)-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin.
the bromo-6-sec.-propyl of embodiment 71a. 1--3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.prepare embodiment 71a according to the method be similar to for the preparation of embodiment 65d, replace 2-ethanoyl-5-methylcyclohexane-1,3-diketone, to provide title compound with 2-ethanoyl-5-(2-methylethyl) hexanaphthene-1,3-diketone.
embodiment 71b. 1-(5-amino-2-Phenoxyphenyl)-6-sec.-propyl-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 71b is prepared according to the method be similar to for the preparation of embodiment 65e, embodiment 65d is replaced with embodiment 71a, and with 4-phenoxy group-3-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) aniline replacement 2-phenoxyphenyl boronic acid, to provide title compound.
embodiment 71c. N-{3-[3-methyl-4-oxo-6-(propane-2-base)-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin.prepare embodiment 71c according to the method be similar to for the preparation of embodiment 67, replace embodiment 66, to provide title compound with embodiment 71b.
embodiment 72. N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.
the bromo-6-phenyl of embodiment 72a. 1--3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.prepare embodiment 72a according to the method be similar to for the preparation of embodiment 65d, replace 2-ethanoyl-5-methylcyclohexane-1,3-diketone, to provide title compound with 2-ethanoyl-5-Santosol 360-1,3-diketone.
embodiment 72b. 1-(5-amino-2-Phenoxyphenyl)-6-phenyl-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.embodiment 72b is prepared according to the method be similar to for the preparation of embodiment 65e, embodiment 65d is replaced with embodiment 72a, and with 4-phenoxy group-3-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) aniline replacement 2-phenoxyphenyl boronic acid, to provide title compound.
embodiment 72c. N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin.prepare embodiment 72c according to the method be similar to for the preparation of embodiment 67, replace embodiment 66, to provide title compound with embodiment 72b.
embodiment 73. 1-[2-(cyclo propyl methoxy)-5-(methyl sulphonyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4
h-isoindole-4-ketone.
embodiment 73a. 1-(the fluoro-5-of 2-(methyl sulphonyl) phenyl)-3-methyl-6,7-dihydro-2H-isoindole-4 (5H)-one.3-methyl-6 is loaded to being equipped with in the 5mL microwave tube of stirring rod; 7-dihydro-2H-isoindole-4 (5H)-one (0.217g; 1.455mmol); the fluoro-4-of the bromo-1-of 2-(methyl sulphonyl) benzene (0.253g, 1.000mmol), allyl palladium chloride (II) (0.0176g; 0.048mmol) with potassium acetate (0.329g; 3.35mmol), sealing, and use nitrogen purging.Import degassed N,N-dimethylacetamide (5mL), and container is placed in oil bath and stirs 18 hours at 130 DEG C.Reaction mixture is cooled and shakes together with salt solution with the EtOAc of each 60mL in separating funnel.By organic layer washed with brine twice and through dried over sodium sulfate.After filtration, mixture is concentrated and pre-installs column chromatographies, with 0-100%EtOAc/ heptane wash-out, to provide title compound at 40 grams of silica gel.
embodiment 73b. 1-[2-(cyclo propyl methoxy)-5-(methyl sulphonyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4
h-isoindole-4-ketone.
the sodium hydride (anhydrous, 95% 16.8mg, 0.665mmol) that in the 5mL microwave reaction container of stirring rod, loading is suspended in THF (0.5mL) is equipped with, then cyclopropyl-carbinol (35 μ L, 0.432mmol) sealing.Stir after 10 minutes, add the embodiment 73a (70mg, 0.218mmol) in THF (2.0mL).Mixture heats 20 hours in oil bath at 60 DEG C.Cooling mixture, and make it to distribute between the EtOAc and salt solution of each 60mL.By organism through dried over mgso.To filter and after removing desolventizing, resistates is by reversed-phase HPLC (C18,0-100%CH
3cN/ water (0.1%TFA)) purifying, to obtain title compound.
biological Examples
bu Luomo structural domain combines and measures
Time resolved fluorescence Resonance energy transfer (TR-FRET) analysis is used for determining that embodiment compound listed is in Table 1 to the avidity of each Bu Luomo structural domain of BRD4.First (BD1: the amino acid K57-E168) of the BRD4 that expression and purification His-marks and second (BD2: amino acid E352-E168) Bu Luomo structural domain.In mensuration, the BET-inhibitor of Alexa647-mark is used as fluorescent probe.
the synthesis of the Bu Luomo structural domain inhibitor compound of Alexa647-mark
2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) acetic acid.by 2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) methyl acetate (see such as, WO2006129623) (100.95mg, 0.243mmol) be suspended in 1mL methyl alcohol, add the solution (0.973mL, 0.5M, 0.487mmol) of the lithium hydroxide monohydrate of fresh preparation wherein and shake 3 hours at ambient temperature.Boil off methyl alcohol, and regulate pH with aqueous hydrochloric acid (1M, 0.5mL, 0.5mmol) and be extracted with ethyl acetate four times.The ethyl acetate layer of merging is evaporated through dried over mgso, to obtain 2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diaza-6-base) acetic acid (85.3mg, 87.0%); ESI-MS m/z=401.1 [(M+H)
+], be directly used in next step reaction.
amino ethoxy) oxyethyl group) ethyl)-2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) ethanamide two (2,2,2-trifluoroacetate).2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) acetic acid (85.3mg, 0.213mmol) and 2,2'-(ethane-1,2-bis-base two (oxygen base)) diethylamine (Sigma-Aldrich, 0.315mg, 2.13mmol) is incorporated in 5mL anhydrous dimethyl formamide.Add (1H-benzo [d] [1,2,3] triazol-1-yl oxygen base) tripyrrole alkane-1-Ji Phosphonium hexafluorophosphate (V) (PyBOB, CSBio, Menlo Par CA; 332mg, 0.638mmol), and this reaction is shaken 16 hours at ambient temperature.By dimethyl sulfoxide (DMSO): water (9:1, v:v) reactant is diluted to 6mL, and with time collection Waters Deltapak C18 200x25 mm column purification in double injection, with the gradient elution of 0.1% trifluoroacetic acid (v/v)/water and acetonitrile.By the fraction lyophilize of the product containing two kinds of purifying, obtain N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-2-((6S, Z)-4-(4-chloro-phenyl-)-2; 3; 9-trimethylammonium-6H-thieno-[3,2-f] [1,2; 4] triazolo [4; 3-a] [Isosorbide-5-Nitrae] diaza-6-base) ethanamide two (2,2; 2-trifluoroacetate) (134.4mg, 82.3%); ESI-MS m/z=531.1 [(M+H)
+]; 529.1 [(M-H)
-] and (S, Z)-N, N'-(2,2'-(ethane-1,2-bis-base two (oxygen base)) two (ethane-2,1-bis-base)) two (2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) ethanamide) two (2,2,2-trifluoroacetate) (3.0mg, 1.5%); ESI-MS m/z=913.2 [(M+H)
+]; 911.0 [(M-H)
-].
amino-(Alexa647)-oxyethyl group) oxyethyl group) ethyl)-2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] diaza-6-base) ethanamide (2,2,2-trifluoroacetate).n-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-2-((6S, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diaza-6-base) ethanamide two (2,2,2-trifluoroacetate) (5.4mg, 0.0071mmol) and Alexa Fluor
647 carboxylic acids, succinimide ester (Life Technologies, Grand Island, NY; 3mg, 0.0024mmol) comprise at 1mL in the anhydrous dimethyl sulphoxide of diisopropylethylamine (1%v/v) to merge and also shake 16 hours at ambient temperature.By dimethyl sulfoxide (DMSO): water (9:1, v:v) reactant is diluted to 3mL, and with time collection Waters Deltapak C18 200x25 mm column purification in a shot, with the gradient elution of 0.1% trifluoroacetic acid (v/v)/water and acetonitrile.By the fraction lyophilize containing purified product, to obtain N-(2-(2-(2-amino-(Alexa647)-oxyethyl group) oxyethyl group) ethyl)-the 2-((6S for dark blue powder, Z)-4-(4-chloro-phenyl-)-2,3,9-trimethylammonium-6H-thieno-[3,2-F] [1,2,4] triazolo [4,3-a] [1,4] diaza-6-base) ethanamide (2,2,2-trifluoroacetate) (1.8mg); MALDI-MS m/z=1371.1,1373.1 [(M+H)
+].
measure
The compound dilution series in DMSO is prepared in via times serial dilution of 3 from 2.5mM to 42nM.Then compound 6:100 is diluted in and measures in damping fluid (20mM sodium phosphate, pH6.0,50mM NaCl, 1mM EDTA, 0.01%Triton X-100,1mM DTT) to obtain 3X working solution.Then the working solution of 6 microlitres (μ L) is transferred to the small volume assay plate (Costar#3673) of white.The also 1.5X mensuration mixture of probe molecule puted together of the anti-His antibody (Invitrogen PV5596) puted together containing Bu Luomo structural domain, the europium of His-mark of preparation and Alexa-647.This solution of 12 μ L is joined in assay plate to reach the final volume of 18 μ L.The 1X of ultimate density measures damping fluid and contains 2%DMSO, the compound of 50 μMs of-0.85nM, 8nM Bu Luomo structural domain, the antibody of 1nM and 100 or the probe (being respectively used to BDI or BDII) of 30nM.In incubated at room after one hour, Envision multiple labeling plate reader (Ex 340, Em 495/520) is used to determine TR-FRET ratio.
TR-FRET data relative to 24 without the mean value of compound control (" height ") and the mean value normalization method of 8 contrasts (" low ") containing 1 μM of unmarked probe.According to compound concentration draw per-cent suppress, and data with 4 parameter logistic formula fittings to obtain IC
50.From IC
50, probe K
dcalculate with concentration and probe concentration and suppress constant (K
i).Typical Z' value is between 0.65 to 0.75.Determine that minimum significance is than with evaluating and measuring circulation ratio people such as (, (2006) J Biomol Screen, 11:253-261) Eastwood.MSR is defined as being 2.03 for BDI and is 1.93 for BDII, and for mobile MSR (last 6 times the run MSR time-out) <3 usually of BDI and BDII.K
ivalue reporting in Table 1.
mX-1 cell line proliferation measures
Breast cancer cell line MX-1 (ATCC) was used to determine the impact of embodiment compound on cancer cell multiplication in proliferation test at 3 days.MX-1 cell is at 37 DEG C and 5%CO
2maintain under atmosphere and be supplemented with in the RPMI of 10%FBS.For compound test, MX-1 cell with the density of 5000 cells/well in 90 μ L substratum bed board in 96 hole black matrix plates, and 37 DEG C of overnight incubation to allow cell adhesion and expansion.By preparing compound dilution series from 3mM to 3 times of serial dilutions of 0.1 μM in DMSO.Described DMSO dilution series then 1:100 is diluted in phosphate buffered saline (PBS), and is added in the suitable hole of MX-1 cell plates by 10 μ L gained solution.Finalization compound concentration in hole is 3,1,0.3,0.1,0.03,0.01,0.003,0.001,0.0003 and 0.0001 μMs respectively.After adding compound, by cell cultures more than 72 hours, and according to the scheme that manufacturers advises, Cell Titer Glo is used to measure the amount that test kit (Promega) determines survivaling cell.
From Cell Titer Glo measure luminous reading relative to DMSO process cell normalization method and use Graph Pad Prism software analysis, with sigmoid curve matching to obtain EC
50.Determine that minimum significance ratio (MSR) is with evaluating and measuring circulation ratio (people such as Eastwood, (2006) J Biomol Screen, 11:253-261).Overall MSR is confirmed as 2.1 and mobile MSR (last six operation MSR time-out) <2.EC
50value reporting in Table 1.
Table 1
propagation group measures
The compound of testing example 40 is on the impact (testing specific clone) of the propagation of group cancerous cell line type of such as described in (table 2).Cell is seeded in 96 orifice plates with 1500 cells/well in suitable substratum.As in MX-1 proliferation assay, prepare the serial dilutions of compound and join in hole.After adding compound, by other for cell cultures 5 days, and Cell Titer Glo is used to measure the amount that test kit (Promega) determines survivaling cell according to the scheme of manufacturers's suggestion.As above described in MX-1 proliferation assay, analysis of cells Proliferation data is to obtain the EC of the compound reported in table 2
50.
table 2
xenograft tumor growth suppresses to measure
The compound that have rated embodiment 40 suppresses the effect of the growth of Ramos, OPM-2, MX-1, MV4-11 and HT1080 xenograft tumours.In brief, research the 0th day, by 0.5 × 10
6human cancer cell (HT1080), 1 × 10
6human cancer cell (Ramos), 5 × 10
6human cancer cell (OPM-2, MV4-11) (tumor brie) (MX-1) (S-MEM (MEM or in the tumour cloth of 1:10, suspension, without calcium, without glutamine) in) (Life Technologies Corporation) subcutaneous vaccination is to the right lateral side of female SCID or SCID-beige (MV4-11, HT1080) mouse (Charles Rivers Labs).Compound is formulated in 2%EtOH, 5% tween-80, in 20%PEG-400,73%HPMC (Ramos, OPM-2 and MX-1) or 5%DMSO, 5%EtOH, 30%PEG400,60%Phosal 53 (MV4-11, HT1080).The time of being applied in of compound the 8th day (HT1080), the 17th day (MX-1) or the 18th day (Ramos, MV4-11, OPM-2) size coupling starts.From the time of size coupling, measure tumour twice weekly by a pair slide calliper rule, and gross tumor volume is according to following formulae discovery: V=L × W
2/ 2 (V: volume, mm
3; L: length, mm, W: width, mm).Gross tumor volume is measured, until the mean tumour volume in each group reaches >1000mm at experimental session
3terminal.Result is shown in table 3-7.
table 3-Ramos human B cell lymphoma cancer heteroplastic transplantation model
A. Tumor growth inhibition, mean tumour volume × 100 of the mean tumour volume/control group of %TGI=100-treatment group.P value (as shown in asterisk) compares from the Student's T inspection for the treatment of group vs. control group.Based on the 31st day.*p<0.05, **p<0.01, ***p<0.001。
B. tumor growth delay, %TGD=(T-C)/C × 100, wherein T=arrives the median time for the treatment of group terminal and the median time of C=arrival control group terminal.P value (as shown in asterisk) compares from the Kaplan Meier log-rank for the treatment of group vs. control group.Based on 1000mm
3terminal.*p<0.05, **p<0.01, ***p<0.001。
table 4-OPM-2 people multiple myeloma cancer heteroplastic transplantation model
A. Tumor growth inhibition, mean tumour volume × 100 of the mean tumour volume/control group of %TGI=100-treatment group.P value (as shown in asterisk) compares from the Student's T inspection for the treatment of group vs. control group.Based on the 31st day.*p<0.05, **p<0.01, ***p<0.001。
B. tumor growth delay, %TGD=(T-C)/C × 100, wherein T=arrives the median time for the treatment of group terminal and the median time of C=arrival control group terminal.P value (as shown in asterisk) compares from the Kaplan Meier log-rank for the treatment of group vs. control group.Based on 1000mm
3terminal.*p<0.05, **p<0.01, ***p<0.001。
the effect of table 5-BET inhibitor in MX-1 human breast carcinoma heteroplastic transplantation model
A. Tumor growth inhibition, mean tumour volume × 100 of the mean tumour volume/control group of %TGI=100-treatment group.P value (as shown in asterisk) compares from the Student's T inspection for the treatment of group vs. control group.Based on the 38th day.*p<0.05, **p<0.01, ***p<0.001。
B. tumor growth delay, %TGD=(T-C)/C × 100, wherein T=arrives the median time for the treatment of group terminal and the median time of C=arrival control group terminal.P value (as shown in asterisk) compares from the Kaplan Meier log-rank for the treatment of group vs. control group.Based on 1000mm
3terminal.*p<0.05, **p<0.01, ***p<0.001。
the effect of table 6. BET inhibitor in HT1080 human fibrosarcoma heteroplastic transplantation model
A. Tumor growth inhibition, mean tumour volume × 100 of the mean tumour volume/control group of %TGI=100-treatment group.P value (as shown in asterisk) compares from the Student's T inspection for the treatment of group vs. control group.Based on the 18th day.**p<0.01。
the effect of table 7-BET inhibitor in MV4-11 people AML heteroplastic transplantation model
A. Tumor growth inhibition, mean tumour volume × 100 of the mean tumour volume/control group of %TGI=100-treatment group.P value (as shown in asterisk) compares from the Student's T inspection for the treatment of group vs. control group.Based on the 31st day.**p<0.01。
B.10% mortality ratio.
C.30% mortality ratio.
D.40% mortality ratio.
the mouse test that the IL-6 that LPS (lipopolysaccharides) induces generates
The ability that the IL-6 that the embodiment compound listed in chart 8 suppresses LPS (lipopolysaccharides) to induce in mouse produces.Severe combined immunodeficiency female mice (often organizing 8) accepts lipopolysaccharides (2.5 mg/kg in one hour after Orally administered (PO) or intraperitoneal use (IP) compound, L2630 E.coli 0111:B4) intraperitoneal excite, described compound 2% ethanol, 5% tween 80,20% PEG-400 and 73% (0.2% Vltra tears in water) solution in.Latter 2 hours of lipopolysaccharides injection, by mouse euthanasia, is taken out blood by cardiac puncture, then the serum from Blood Sample Collection is chilled in-80 DEG C.Measuring the same day, serum sample returns to room temperature, and then 1:20 is diluted in the phosphate buffered saline (PBS) containing 2% bovine serum albumin.According to the scheme of manufacturers, utilize from Meso Scale Discovery (Gaithersburg, Maryland) the cytokines measurement analyzed for mice serum, carry out the mensuration of interleukin-6, and at SECTOR Imager 6000 (Meso Scale Discovery, Gaithersburg, Maryland) reading on instrument.The Prism software (5.0 version) comprising Dunnett's one-way analysis of variance is used to carry out statistical analysis.The mean value of the IL-6 of the average of the IL-6 of the animal groups of vehicle process and standard deviation and drug treating group and standard deviation are compared.P value <0.05 means that the possibility that in two groups, mean value is equal is less than 5%.% inhibiting value in table 8 all shows the p value being less than 0.05.
Table 8
The suppression of the IL-6 generation of LPS induction
Should be appreciated that detailed description above and appended embodiment are only illustrative, and should not be considered as the restriction to scope of the present invention, scope of the present invention is only limited by claims and equivalent thereof.To be apparent to those skilled in the art to the variations and modifications of disclosed embodiment.When without departing from the spirit and scope of the present invention, such change and amendment (including but not limited to relate to chemical structure of the present invention, substituting group, derivative, intermediate, synthesis, those changes of preparation and/or using method and amendment) can be carried out.The all publications quoted herein, patent and patent application are incorporated to herein as a reference for various purposes in full.
Claims (31)
1. formula (I) compound, or its pharmacy acceptable salt,
Wherein
A is C (R
8r
9);
Y is C (R
6r
7);
J is C (R
4r
5);
R
1hydrogen or C
1-C
3alkyl;
R
2hydrogen or C
1-C
3alkyl;
R
3be heteroaryl, 9-12 unit bicyclic aryl, naphthalene-1-base, unsubstituted phenyl or X, wherein X is
,
Wherein said heteroaryl, 9-12 unit's bicyclic aryl or naphthalene-1-base can be replaced independently selected from following substituting group by 1-3: NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl) ,-NH-C (O)-C
1-C
3alkyl ,-NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein X replaces as described in (i) or (ii):
(i) R
10, R
11, R
12, R
13and R
14in four be hydrogen, and R
10, R
11, R
12, R
13or R
14one of be selected from following groups:
R
10nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group--C
3-C
5cycloalkyl, C
1-C
3alkylidene group-C
7-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
11nR
16r
18, fluorine, iodine, bromine, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
12nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
2-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
13and R
14nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
(ii) wherein R
10, R
11, R
12, R
13and R
14in 5-n be hydrogen, and R
10, R
11, R
12, R
13and R
14in n be selected from following groups:
NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
16-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein n is 2,3,4 or 5;
Wherein-O-aryl ,-S-aryl, C
1-C
3alkylene-aryl, C
1-C
3the described aryl of alkylenyl-O-aryl; Described Heterocyclylalkyl;-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3the described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl;-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3the described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl and-O-C
1-C
3alkylidene group-C
3-C
14any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace:
Halogen, C
1-C
3alkyl, C
1-C
3haloalkyl, CN and NR
16r
18;
R
4and R
5be selected from hydrogen, aryl and C independently of one another
1-C
4alkyl;
R
6and R
7be selected from hydrogen and C independently of one another
1-C
4alkyl;
R
8and R
9be selected from hydrogen and C independently of one another
1-C
4alkyl; And
R
16and R
18be selected from hydrogen and C independently of one another
1-C
3alkyl.
2. the compound of claim 1, or its pharmacy acceptable salt, wherein R
4and R
5hydrogen; And R
8and R
9each hydrogen naturally.
3. the compound of claim 2, or its pharmacy acceptable salt, wherein R
2hydrogen.
4. the compound of claim 3, or its pharmacy acceptable salt, wherein R
1c
1-C
3alkyl.
5. the compound of claim 4, or its pharmacy acceptable salt, wherein R
1it is methyl.
6. the compound of claim 5, or its pharmacy acceptable salt, wherein R
13nR
16r
18,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl or NH-C (O)-heteroaryl.
7. the compound of claim 6, or its pharmacy acceptable salt, wherein R
13nR
16r
18,-NR
16-SO
2-C
1-C
3alkyl or-NH-SO
2-C
1-C
3haloalkyl.
8. the compound of claim 5, or its pharmacy acceptable salt, wherein R
3heteroaryl, 9-12 unit bicyclic aryl, or naphthalene-1-base.
9. the compound of claim 5, or its pharmacy acceptable salt, wherein R
3indyl, 1,3-benzodioxole base or benzimidazolyl-.
10. the compound of claim 7, or its pharmacy acceptable salt, wherein R
3x.
The compound of 11. claims 10, or its pharmacy acceptable salt, wherein R
10, R
11, R
12, R
13and R
14in four be hydrogen, and R
10, R
11, R
12, R
13or R
14one of be selected from following groups:
R
10nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl, C
1-C
3alkylidene group-C
7-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
11nR
16r
18, fluorine, iodine, bromine, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
12nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
2-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
R
13and R
14nR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl; And
Wherein-O-aryl ,-S-aryl, C
1-C
3alkylene-aryl, C
1-C
3the described aryl of alkylenyl-O-aryl; Described Heterocyclylalkyl;-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3the described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl and-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3the described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl and-O-C
1-C
3alkylidene group-C
3-C
14any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace:
Halogen, C
1-C
3alkyl, C
1-C
3haloalkyl, CN and NR
16r
18.
The compound of 12. claims 10, or its pharmacy acceptable salt, wherein R
10, R
11, R
12, R
13and R
14in 5-n be hydrogen, and R
10, R
11, R
12, R
13and R
14in n be selected from following groups:
NR
16r
18, halogen, hydroxyl, C
1-C
3alkyl ,-O-aryl, C
1-C
3alkylene-aryl, C
1-C
3alkylenyl-O-aryl ,-S-aryl ,-O-C
1-C
3alkylene-aryl ,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-O-C
1-C
3alkyl ,-C (O)-O-C
1-C
3alkyl ,-C (O)-OH ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl, NH-C (O)-heteroaryl, Heterocyclylalkyl ,-O-C
1-C
3alkylidenyl-heterocyclic alkyl ,-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylene-heteroaryl or heteroaryl;
Wherein n is 2,3,4 or 5;
Wherein-O-aryl ,-S-aryl, C
1-C
3the described aryl of alkylenyl-O-aryl;-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) and-O-C
1-C
3the described Heterocyclylalkyl of alkylidenyl-heterocyclic alkyl; Described heteroaryl and-C (O)-NH (heteroaryl), NH-C (O)-heteroaryl and-O-C
1-C
3the described heteroaryl of alkylene-heteroaryl; And-O-C
3-C
14cycloalkyl ,-O-C
1-C
3alkylidene group-C
3-C
5cycloalkyl and-O-C
1-C
3alkylidene group-C
3-C
14any one in the described cycloalkyl of cycloalkyl can be selected from following substituting group by 1-3 and replace: halogen, C
1-C
3alkyl, C
1-C
3haloalkyl, CN and NR
16r
18.
The compound of 13. claims 12, or its pharmacy acceptable salt, wherein n is 3.
The compound of 14. claims 12, or its pharmacy acceptable salt, wherein n is 2.
The compound of 15. claims 14, or its pharmacy acceptable salt, wherein R
13nR
16r
18,-NR
16-SO
2-NR
18-C
1-C
3alkyl ,-NR
16-SO
2-NR
18-C
1-C
3haloalkyl ,-NR
16-SO
2-C
1-C
3alkyl ,-NR
16-SO
2-C
1-C
3haloalkyl, SO
2-NR
16r
18, SO
2-C
1-C
3alkyl ,-C (O)-NR
16r
18,-C (O)-NH (C
1-C
3haloalkyl) ,-C (O)-NH (C
1-C
3alkylidenyl-heterocyclic alkyl) ,-C (O)-NH (heteroaryl), NH-C (O)-C
1-C
3alkyl or NH-C (O)-heteroaryl.
The compound of 16. claims 15, or its pharmacy acceptable salt, wherein R
13nR
16r
18,-NR
16-SO
2-C
1-C
3alkyl or-NH-SO
2-C
1-C
3haloalkyl.
The compound of 17. claims 16, or its pharmacy acceptable salt, wherein R
10it is O-aryl.
The compound of 18. claims 17, or its pharmacy acceptable salt, wherein R
10be O-phenyl or the O-phenyl replaced independently by the group of 1-3 independent selected from halo.
The compound of 19. claims 18, or its pharmacy acceptable salt, wherein R
10it is-O-2,4-difluorophenyl.
The compound of 20. claims 16, or its pharmacy acceptable salt, wherein R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it can by 1-3 independent selected from halo and C
1-C
3the group of alkyl replaces.
The compound of 21. claims 20, or its pharmacy acceptable salt, wherein R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it is by 1-3 independent selected from halo and C
1-C
3the group of alkyl replaces.
The compound of 22. claims 21, or its pharmacy acceptable salt, wherein R
10-O-C
1-C
3alkylidene group-C
3-C
14cycloalkyl, it is replaced by the group of 1-3 independent selected from halo.
The compound of 23. claims 1, or its pharmacy acceptable salt, wherein n is 3.
The compound of 24. claims 1, or its pharmacy acceptable salt, wherein n is 2 and R
11, R
12and R
14hydrogen.
The compound of 25. claims 1, or its pharmacy acceptable salt, wherein said compound is selected from:
3-methyl isophthalic acid-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(4-aminomethyl phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
4-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzsulfamide;
1-(2-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[4-(methyl sulphonyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzamide;
1-(1H-indoles-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(4-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3,4-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(4-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[3-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-chloro-phenyl-)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3,5-3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(3-p-methoxy-phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(2-{ [3-(trifluoromethyl) phenoxy group] methyl } phenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(phenoxymethyl) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-{ 2-[(2-methylphenoxy) methyl] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(furans-2-base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2-hydroxy phenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-3-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(cyclopentylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrofuran (THF)-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-4-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-{ 2-[2-(morpholine-4-base) oxyethyl group] phenyl }-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(pyridine-2-ylmethoxy) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(quinoline-8-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(1-thionaphthene-7-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-[2-(pyridin-3-yl methoxyl group) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(1H-indazole-5-ylmethoxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(5-amino-2-Phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] ethanamide;
1-[5-amino-2-(phenylsulfartyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-(phenylsulfartyl) phenyl] Toluidrin;
1-[5-amino-2-(2,4 difluorobenzene oxygen base) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethyl sulfonamide;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-2,2,2-trifluoro ethyl sulfonamides;
N'-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-N, N-dimethyl methyl diamide (sulfuric diamide);
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] ethanamide;
N-[4-(2,4 difluorobenzene oxygen base)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl]-1H-pyrroles-2-methane amide;
N-{4-[(4,4-difiuorocyclohexyl) oxygen base]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl } ethyl sulfonamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid methyl esters;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzoic acid;
N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy benzamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(tetrahydrofuran (THF)-2-ylmethyl) benzamide;
3-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-phenoxy group-N-(1,3-thiazoles-2-base) benzamide;
3,6,6-trimethylammonium-1-phenyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(2,5-3,5-dimethylphenyl)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3,6,6-trimethylammonium-1-[2-(morpholine-4-base) phenyl]-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(benzyloxy) phenyl]-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3,6,6-trimethylammonium-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) phenyl] Toluidrin;
3,6-dimethyl-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(5-amino-2-Phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin;
3-methyl-6-(2-methyl-propyl)-1-(2-Phenoxyphenyl)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-{3-[3-methyl-6-(2-methyl-propyl)-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin;
3-methyl isophthalic acid-(2-Phenoxyphenyl)-6-(propane-2-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
N-{3-[3-methyl-4-oxo-6-(propane-2-base)-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base]-4-Phenoxyphenyl } Toluidrin;
N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base)-4-Phenoxyphenyl] Toluidrin; With
1-[2-(cyclo propyl methoxy)-5-(methyl sulphonyl) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4
h-isoindole-4-ketone.
The compound of 26. claims 1, or its pharmacy acceptable salt, wherein said compound is selected from:
1-(1,3-benzodioxole-5-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-[2-(benzyloxy) phenyl]-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
3-methyl isophthalic acid-(naphthalene-1-base)-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(1H-benzoglyoxaline-4-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
1-(1H-indoles-7-base)-3-methyl-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone;
2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-2H-isoindole-1-base) benzyl]-1H-isoindole-1,3 (2H)-diketone; With
1-(1,3-benzodioxole-5-base)-3,6,6-trimethylammonium-2,5,6,7-tetrahydrochysene-4H-isoindole-4-ketone.
27. pharmaceutical compositions, it comprises formula according to claim 1 (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
The method of the disease of 28. treatment targets, comprises formula according to claim 1 (I) compound to subject in need or its pharmacy acceptable salt, the disease during wherein said disease is selected from one of following group:
Cancer;
Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcets disease, bullous dermatosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, systemic lupus erythematosus, multiple sclerosis, myocarditis, myositis, ephritis, organ-graft refection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriatic, psoriasis arthropathica, rheumatoid arthritis, scleritis, sclerosing cholangitis, septicemia, systemic lupus erythematous, high iS-One arteritis, toxic shock, thyroiditis, type i diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wei Genashi granulomatosis,
Diabetic nephropathy, hypertensive nephropathy, HIV associated nephropathy, glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, FSGS, membranous glomerulonephritis, minimal change, multicystic kidney disease and tubulointerstitial nephritis;
The kidney disease that kidney disease, pneumonia that the kidney disease that the kidney disease that kidney disease, percutaneous coronary intervention (pci) that the kidney disease that ischemia-reperfusion brings out, heart and major surgery are brought out bring out, radiopaque contrast medium bring out, septicemia are brought out are brought out and the kidney disease that drug toxicity is brought out;
AIDS；
Obesity;
Type ii diabetes; With
Obesity, hyperlipemia, hypercholesterolemia, Alzheimer, metabolism syndrome, fatty degeneration of liver, type ii diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy.
The method of 29. claims 28, wherein said cancer is selected from: acoustic tumor, acute leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia (monocarpotic cellularity, myeloblastic, gland cancer, angiosarcoma, astrocytoma, myelo-monocytic and promyelocytic leukemic cell), acute t chronic myeloid leukemia, rodent cancer, cholangiocarcinoma, bladder cancer, the cancer of the brain, mammary cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocyte) leukemia, chronic granulocytic leukemia, colorectal carcinoma, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dispersivity large B cell lymphatic cancer, paraplasm change (heteroplasia and change life), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, the esophageal carcinoma, estrogen receptor positive mammary cancer, idiopathic thrombocythemia, Ewing sarcoma, fibrosarcoma, follicular lymphoma, sexual cell carcinoma of testis, glioma, glioblastoma, glioma sarcomatosum, heavy chain disease, hemangioblastoma, liver neoplasm, hepatocellular carcinoma, Hormone-refractory prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytoblast leukemia, lymphoma (Huo Qi metal type and non-Hodgkin′s type), bladder, mammary gland, colon, lung, ovary, pancreas, prostate gland, the malignant tumour in skin and uterus and excessively proliferative disease, the lymphoid malignancy in T cell or B cell source, leukemia, lymphoma, medullary carcinoma, myeloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, marrow-derived leukocythemia, myelomatosis, myxosarcoma, neuroblastoma, NUT center line cancer (NMC), nonsmall-cell lung cancer, mesoglioma, oral carcinoma, osteogenic sarcoma, ovarian cancer, carcinoma of the pancreas, papillary carcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, the rectum cancer, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, sebaceous carcinoma, spermocytoma, skin carcinoma, small cell lung cancer, noumenal tumour (cancer and sarcoma), small cell lung cancer, cancer of the stomach, squamous cell carcinoma, synovioma, syringocarcinoma, thyroid carcinoma, macroglobulinemia Waldenstron, tumor of testis, uterus carcinoma and wilms' tumor.
The method of 30. claims 28 or 29, described method comprises the other therapeutical agent of at least one of administering therapeutic significant quantity further.
31. methods of practising contraception in male subjects, described method comprises formula according to claim 1 (I) compound to subject in need or its pharmacy acceptable salt.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108779110A (en) * | 2016-03-10 | 2018-11-09 | 阿斯利康(瑞典)有限公司 | The novel inhibitors of phosphatidyl-inositol 3-kinase γ |
| CN108779110B (en) * | 2016-03-10 | 2021-10-29 | 阿斯利康(瑞典)有限公司 | Novel inhibitors of phosphatidylinositol 3-kinase gamma |
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