CN105899516A - Therapeutic compounds and related methods of use - Google Patents

Abstract

Salinomycin analogs and pharmaceutically acceptable compositions containing salinomycin analogs are disclosed in the invention. Dosage forms and kits comprising salinomycin analogs and pharmaceutically acceptable compositions containing salinomycin analogs. Methods of using salinomycin analogs, pharmaceutically acceptable compositions, dosage forms, and kits for the treatment of proliferative diseases, e.g., cancer, or microbial infections in a subject

Description

Therapeutic compound and associated method of use

Cross-Reference to Related Applications

This application claims and enjoy Chinese patent application No.201210005407.4 preferential submitted on January 26th, 2012 Power, and US provisional patent Serial No. No.61/613 that on April 6th, 2012 submits to, the priority of 127.Above-mentioned application Each it is fully incorporated the present invention by being cited in this.

Background of invention

Research shows that the formation of tumor and growth are owing to being included cancer stem cell (CSC) and mesenchymal cell (example Such as, mesenchyme cancerous cells) the impact of less subgroup cancer cell.Cancer stem cell (CSC) refers to connect Plant and produce the cell in the tumor tissues of secondary tumors, and such as shift with Carcinogenesis and recur relevant.Between fill Cell plastid refers to undifferentiated loose cell, and these cells can easily migrate in experimenter's system, and when giving Suitably during environment, can fast breeding.Recent studies have shown that: although the cancer therapy of routine (such as, surgical operation, radiate, change Learn therapy, hormonotherapy) massive tumor can be eliminated, but usually can retain lower CSC and/or mesenchymal cell.These continue to retain CSC and/or mesenchymal cell the nucleus of new tumor or may be become in basic stitch at other position of experimenter.

Accordingly, it would be desirable to have specificity and selectivity targeting CSC and/or the medicine of mesenchymal cell.This type of medicine can It is used alone, or can be co-administered with conventional cancer therapy (such as, surgical operation, radiation, chemotherapy, hormonotherapy), use To eliminate tumor and to avoid its recurrence or transfer.

Use these medicines, such as targeting CSC and/or the treatment of mesenchymal cell, be beneficial to treat cancer and keep away Exempt from cancer metastasis and recurrence.This type of therapy also will benefit from the method for the detection stem cell of improvement, thus allows having more The experimenter of big recurrence or transfer danger identifies.The method of detection stem cell will also be able to provide to be suffered from the most identified The therapy of cancer or the experimenter in being in developing cancer danger carries out personalized ability.

Summary of the invention

Described is the growth killing, combine, suppress cancer stem cell and/or mesenchymal cell in the present invention, or The compound of the propagation of prophylaxis of cancer stem cell and/or mesenchymal cell and pharmaceutically acceptable salt thereof and hydrate.This Bright also describing comprises the compositions of compound of the present invention, pharmaceutical preparation (such as, dosage form) and test kit.In the present invention Describe the method using these compounds for treating, such as, treat the experimenter being accredited as suffering from cancer or this is accredited as sense The method of the experimenter of dye microorganism.This treatment can be combined with screening technique, wherein tested in described screening technique Person is accredited as having the disease relevant to cancer stem cell and/or mesenchymal cell.In some cases, this compound, Compositions, pharmaceutical preparation, dosage form etc. can be with other cancer therapy (such as, surgical operation, radiation, chemotherapy, hormonotherapies) It is combined using.

On the one hand, the invention is characterised in that the compound of Formulas I:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；L-M-T shape together Become selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M- 1 to 3 other-C (R that T or L-M-T is connected with them₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, miscellaneous together Ring group, aryl or heteroaryl ring；Each R₃It is H, halo, oxo ,-OR independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、- OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O) NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆) OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or miscellaneous Aryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyanogen Base ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、- NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O) NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or aryl；R₅And R₆ Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkane Base or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, replacement or not Substituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、 R₁₁' and R₁₂It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, virtue Base alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyanogen Base or amino acid side chain；R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃- C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅And R₁₆Be independently of one another=O ,=S ,- OR₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₁₉Be-O-,- S-、-NR₁₇-,-N (OH)-or-N (OR₁₀)-；And, q is 1 or 2；Condition is to work as R₁It is-C (O) OH, n is 2, and q is 1, R₆It is oxygen Generation, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃With R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；Further, condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and And R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

In one embodiment, the invention is characterised in that Formula II compound:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, 1 to 3 other-C (R that M-T or L-M-T is connected with them₃)₂-、-O-、-NR₁₁-or-S-formed together 3-6 unit ring group, Heterocyclic radical, aryl or heteroaryl ring；Each R3 is H, halo, oxo ,-OR independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O) R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’ C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆) OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or miscellaneous Aryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyanogen Base ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、- NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR₁₀、-SR₁₀、-COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O) R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br、I)、-NH₂, cyano group, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocycle Base, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkane Base, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl Alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O) OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄The most solely It is on the spot H, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkane Base, heteroaryl alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅With R₁₆It it is not all double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocycle Base, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；Bar Part is to work as R₁It is-C (O) OH, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；Further, condition is to work as R₁Be- C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

In one embodiment, the invention is characterised in that Formula II compound:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from C (R₃)₂-C(R₃)₂-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M-T or L-M-T and they connected 1 to 3 the other-C (R connect₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, heterocyclic radical, aryl or heteroaryl together Ring；Each R3 is H, halo, oxo ,-SR independently₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、- NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈ Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、- SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O) NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆) OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR₁₀、-SR₁₀、-COR₁₀、- CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、- NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, C₁-C₈Alkyl, Cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl Ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, C₁-C₈Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, take Generation or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or aminoacid side Chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈ Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O) R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkane Base ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅With R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈ It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or Heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

In one embodiment, it is a feature of the present invention that the compound of Formula II:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-C H₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M-T Or 1 to 3 other-C (R that L-M-T is connected with them₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, miscellaneous together Ring group, aryl or heteroaryl ring；Each R₃It is H, halo, oxo ,-SR independently₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆) OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₅Be H, Halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、- P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR₁₀、- SR₁₀、-COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O) OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,- NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, miscellaneous Ring group, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈ Alkyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl Base alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃- C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S (O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous Alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅With R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈ It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or Heteroaryl alkyl；And, R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

. on the one hand, it is a feature of the present invention that the compositions comprising formula (I) compound, such as pharmaceutical composition.

On the one hand, it is a feature of the present invention that the dosage form comprising formula (I) compound, such as pharmaceutical dosage form.Real at some Execute in mode, experimenter's intravenous can be given or use this dosage form with subcutaneous bolus injection agent form.

On the one hand, it is a feature of the present invention that the test kit comprising formula (I) compound, and comprise containing formula (I) change The pharmaceutical composition of compound or dosage form, pharmaceutical composition the most of the present invention or the test kit of dosage form.Implement at some In mode, described test kit also comprise pharmaceutically acceptable diluent or for use this compound, pharmaceutical composition or The description of dosage form.

On the one hand, it is a feature of the present invention that the method regulating cell proliferation in the experimenter needing it.Described method Including formula (I) compound using effective dose.In some embodiments, described method include for described experimenter use containing The pharmaceutical composition of formula (I) compound of effective dose or dosage form, pharmaceutical composition the most of the present invention or dosage form

In one embodiment, it is a feature of the present invention that the method treating cancer in experimenter, the method includes Use formula (I) compound.In some embodiments, the method includes using the formula (I) containing effective dose to described experimenter The pharmaceutical composition of compound or dosage form, pharmaceutical composition the most of the present invention or dosage form.In some embodiments, should Method farther includes other cancer therapy is administered (such as, surgical operation, radiation, chemotherapy, hormonotherapy, epidemic disease Seedling, antibody, gene therapy or other targeted therapies).

On the one hand, it is a feature of the present invention that: the method for the propagation of suppression cancer stem cell or mesenchymal cell, wherein Contact with formula (I) compound including by cancer stem cell or mesenchymal cell.

On the one hand, the method that it is a feature of the present invention that the growth regulating or alleviating the microorganism in experimenter, including Use formula (I) compound.

On the one hand, it is a feature of the present invention that the method identified or select experimenter, described experimenter can be from using Formula (I) compound or its pharmaceutical composition or dosage form are benefited, including for one or more selected from biological mark of the present invention The biomarker screening experimenter of note.

In some embodiments, as stem cell identification kit can be played an active part at compound of the present invention (ALDEFLUOR) in test (such as, in the present invention described).

In some embodiments, formula (I) compound or its pharmaceutical composition or dosage form will be used to experimenter, described be subject to Examination person carries out, for using one or more biomarkers being selected from biomarker of the present invention, the experimenter identified.

Summary of the invention

The present invention be not limited to its to the structure of that illustrated in the following description or illustrated in the accompanying drawings assembly and The application of the details arranged.The present invention can implement other embodiment, and can be implemented and carried out this by various methods Bright.Further, wording and term used by the present invention are to limit to describe and should be not intended as.

Definition

Term " acyl group " refers to alkyl-carbonyl, naphthene base carbonyl, aryl carbonyl, Heterocyclylcarbonyl or Heteroarylcarbonyl Substituent group, above-mentioned any one all further can be replaced (such as, being replaced by one or more substituent groups).

Term " alkenyl " refers to comprise 2-12 carbon atom (except as otherwise noted), and has one or more double The straight or branched hydrocarbon chain of key.The example of alkenyl includes but not limited to that pi-allyl (alyl), acrylic, crotyl, 3-are own Thiazolinyl and 3-octenyl.One of double key carbon is optionally the junction point of alkenyl substitutents.

Term " alkylene group " refers to divalent alkenyl group, such as-CH=CH-,-CH₂-CH=CH-and--CH=CH-CH₂-。

Term " alkynyl " refers to containing 2-12 carbon atom (except as otherwise noted) and is characterized by one or more three The straight or branched hydrocarbon chain of key.The example of alkynyl includes but not limited to acetenyl, propinyl and 3-hexin base.Three key carbon are wherein One of be optionally the junction point of alkynyl substituted base.

Term " alkynylene " refers to divalent alkynyl radical, such as, and-CH=CH-,-CH₂-CH=CH-and-CH=CH-CH₂-。

The alkyl group as follows that term " alkoxyl " used in the present invention or " alkoxyl " refer to, it has The oxygen-derived free radicals being attached to.Typical alkoxyl includes methoxyl group, ethyoxyl, propoxyl group, tert-butoxy and similar base Group.Term " alkoxyalkyl " refers to the alkyl that the most one or more hydrogen atom is substituted by alkoxyl.

" ether " is to carry out covalently bound two hydrocarbon by oxygen.

Term " alkyl " refers to the free radical of radical of saturated aliphatic group, including straight chain (linearly) alkyl and branched alkyl.Excellent In the embodiment of choosing, straight or branched alkyl has 12 or with next carbon atom (except as otherwise noted), example in its main chain Such as 1-12,1-8,1-6 or 1-4.Exemplary alkyl part include methyl, ethyl, propyl group (such as, n-pro-pyl or isopropyl), Butyl (such as, normal-butyl, isobutyl group or the tert-butyl group), amyl group (such as, n-pentyl, isopentyl or amyl-3-yl), hexyl and heptan Base.

Term " alkylidene " refers to divalent alkyl, such as-CH₂-、-CH₂CH₂-and-CH₂CH₂CH₂-。

Term " alkylene oxide group " refers to wherein CH₂Be substituted with an oxygen alkylidene.Such as, arylalkyleneoxy refers to have Be connected to the group of the alkylidene of aryl by oxygen, optionally substituted heteroaryl alkylene oxide group refer to have be connected to by oxygen miscellaneous The group of the alkylidene of aryl.

Term " amino " refers to-NH₂。

Term " alkyl amino " refers respectively to-NH (alkyl) and-N (alkyl)₂Free radical.

Term " aryl alkyl amino " refers to-NH (aralkyl) free radical.Term alkylaminoalkyl group refers to (alkyl) NH-alkane Base-free radical；Term dialkyl aminoalkyl refers to (alkyl)₂N-alkyl-free radical.

Term " amide groups " refers to-NHC (O)-or-C (O) NH₂Substituent group.

Term " aryl " refers to 6-carbon monocycle, 10-carbon dicyclo or 14-carbon tricyclic aromatic loop systems, the most each ring 0, 1,2,3 or 4 atoms can be substituted with a substituent.The example of aryl moiety includes but not limited to phenyl, naphthyl and similar base Group.

Term " aryl alkyl " refers to the alkyl being substituted with aryl.Exemplary aralkyl includes but not limited to benzyl, 1-benzene Base ethyl, 2-phenylethyl, 3-phenyl propyl, 9-fluorenyl, benzhydryl, phenethyl and trityl.Term " aryl alkenyl Base " refer to the alkenyl that is substituted with aryl.Term " aromatic yl polysulfide yl " refers to the alkynyl being substituted with aryl.Term such as " aryl C₂- C₆Alkyl " it is read as the further restriction to alkyl size.Term " alkoxy aryl " refers to the alkoxyl being substituted with aryl. Term " arlydene " refers to divalent aryl (that is ,-Ar-).

Term " cycloalkyl " used in the present invention or " ring group " include having 3 to 12 carbon, preferably 3 to 8 carbon, more Preferably 3 to 6 carbon saturated and part unsaturated cyclic alkyl, wherein this cycloalkyl can be optionally substituted.Exemplary ring group Include but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl and ring octyl group.Ring group Part also includes bridged ring and carbocyclic fused ring system.Ring group also includes the ring group being fused to other loop systems, its can be saturated or Undersaturated.Therefore ring group can be bicyclic group, and one of them ring is saturated or part is undersaturated, and another is complete insatiable hunger (such as, the indanyl) of sum.

Term used in the present invention " cycloalkyl ", refers to the alkyl replaced by ring group.Cyclylalkyl includes wherein alkane The group that the more than one hydrogen atom of base has been replaced by ring group.

Term " cycloalkyl-alkyl " used in the present invention refers to the alkyl being substituted by cycloalkyl.

Term " halo " or " halogen " refer to any free radical of fluorine, chlorine, bromine or iodine.

Term " haloalkyl " refers to have any amount of available hydrogen on this group substituted by halogen atom Alkyl.Typical haloalkyl groups includes but not limited to :-CH₂Cl、-CH₂ClCF₃、-CHBr₂、-CF₃、-CH₂F、-CHF₂With- CH₂CF₃.Term " fluoro-alkyl " refers to have any amount of alkane of available hydrogen on this group being replaced by a fluorine atom Base.Typical case's fluoro-alkyl includes but not limited to :-CH₂F、-CH₂FCF₃、-CHF₂Or-CF₃.Term " halogenated alkoxy " refers to have There is any amount of alkoxyl of available hydrogen on this group substituted by halogen atom.Typical haloalkyl epoxide include but not It is limited to :-OCH₂Cl、-OCH₂ClCF₃、-OCHBr₂、-OCHF₂Or-OCF₃.Term " fluoroalkyl " refers to have any number The alkoxyl of available hydrogen on this group being replaced by a fluorine atom of amount.Typical case's fluoroalkyl includes but not limited to :- OCH₂F、-OCH₂FCF₃、-OCHF₂Or-OCF₃。

Term " heteroaryl " refers to have 1-3 hetero atom (if monocycle), 1-6 hetero atom (if dicyclo) or 1-9 The aromatics 5-8 unit monocycle of individual hetero atom (if three rings), 8-12 unit dicyclo or 11-14 unit three ring loop systems, described hetero atom selects From O, N or S (such as, carbon atom and if if monocycle, dicyclo or three rings, have 1-3,1-6 or 1-9 N, O or S respectively Hetero atom), the 0 of the most each ring, 1,2,3 or 4 atoms can be substituted with a substituent.The example of heteroaryl include pyridine radicals, Furyl (furyl) or furyl (furanyl), imidazole radicals, benzimidazolyl, pyrimidine radicals, thiophenyl or thienyl, quinoline Base, indyl, thiazolyl, oxazolyl and similar group.Term " heteroaryl alkyl " or term " heteroarylalkyl " refer to by heteroaryl The substituted alkyl of base.Term " heteroarylalkenyl groups " refers to the alkenyl being substituted by heteroaryl.Term " heteroaryl alkynyl " refers to The alkynyl being substituted by heteroaryl.Term " heteroarylalkoxy " refers to the alkoxyl being substituted by heteroaryl.Heteroaryl can be Single-, two-, three-or multi-ring, the most single-, two-or three rings, the most singly-or dicyclo.When heteroaryl is optionally substituted by a hydroxyl group, it is also Including its corresponding tautomer.Term " heteroaryl " used in the present invention also include wherein heteroaromatic rings and one or The group that multiple aryl rings condense.The limiting examples of heteroaryl includes thienyl, furyl, pyrrole radicals, imidazole radicals, pyrazoles Base, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, di azoly, thiazolyl, isothiazolyl, thiadiazolyl group, pyridine radicals, rattle away Piperazine base, pyrimidine radicals, pyrazinyl, indolizine base, purine radicals, naphthyridinyl, pteridine radicals, indyl, isoindolyl, benzothienyl, benzene And furyl, dibenzofuran group, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolines base, phthalein Piperazine base, quinazolyl, 4H-quinolizinyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, phenazinyl, tetrahydric quinoline group, four Hydrogen isoquinoline base and pyrido [2,3-b]-Isosorbide-5-Nitrae-piperazine-3 (4H)-one.Term " heteroaryl " can with term " heteroaryl ring ", " Heteroaryl " or " heteroaromatic " interchangeably uses, above-mentioned term any one include the ring that is optionally substituted.The theheterocyclic nitrogen atom of heteroaryl Can be oxidized, to form corresponding N-oxide compound.This type of has the non-limiting reality of the heteroaryl aoxidizing theheterocyclic nitrogen atom Example is N-oxo pyridine base.

Term " heteroaryl alkyl " refers to the alkyl being substituted by heteroaryl.Heteroaryl alkyl includes that the most more than one hydrogen is former The group that son has been substituted by heteroaryl.

As used in the present invention, term " heterocycle ", " heterocyclic radical " and " heterocycle " use convertibly, and refer to stable 3- 8 yuan of monocycles or 7-10-unit bicyclic heterocycle part, this heterocycle is saturated or part is unsaturated, and in addition to carbon atom, has one Individual or multiple, preferably one to four hetero atoms as defined above.When being used in the also atomic time about heterocycle, term " nitrogen " wraps Include the nitrogen being replaced.For example, there is 0-3 selected from oxygen, sulfur or the heteroatomic saturated or unsaturated ring of part of nitrogen In, this nitrogen can be N (as 3,4-dihydro-2/y-pyrrole radicals), NH (as in pyrrolidinyl) or NR⁺(as substituted at N- In pyrrolidinyl).Heterocycle section is connected to its side base, and this annular atoms at any hetero atom causing rock-steady structure or carbon atom Any one can be optionally substituted.This saturated or the unsaturated heterocyclic radical of part example includes but not limited to tetrahydrochysene Furyl, THP trtrahydropyranyl, tetrahydro-thienyl, piperidyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dialkyl group, dioxy Penta ring group, diazacyclo heptantriene base, oxaza heptantriene base, sulfur nitrogen heterocycle heptantriene base, morpholinyl and thio-morpholinyl. Heterocyclic radical can be single-, two-, three-or multi-ring, the most single-, two-or three rings, the most singly-or dicyclo.Additionally, heterocycle also wraps Include wherein this heterocyclic ring and be fused to one or more aryl, heteroaryl or the group of ring group ring.The theheterocyclic nitrogen atom of heterocycle also may be used Oxidized to form corresponding N-hydroxy compounds.

Term " Heterocyclylalkyl " refers to the alkyl replaced by heterocyclic radical.The group that described Heterocyclylalkyl comprises, Qi Zhongduo Substituted by heterocyclic radical in a hydrogen atom.

Term " heteroarylalkyl (hetaralkyl) " used in the present invention and " heteroarylalkyl (heteroaralkyl) " Refer to the alkyl being substituted by heteroaryl.Exemplary heteroarylalkyl, includes but not limited to, picolyl or methylpyrimidine Base.

Term " heterocyclic radical " or " Heterocyclylalkyl " refer to have 1-3 hetero atom (if monocycle), 1-6 hetero atom (as Really dicyclo) or the non-aromatic 5-8 unit monocycle of 1-9 hetero atom (if three rings), 5-12 unit dicyclo or 11-14 unit three ring ring systems System, described hetero atom is selected from O, N or S (such as, carbon atom and if if monocycle, dicyclo or three rings, have 1-3,1-respectively 6 or the hetero atom of 1-9 N, O or S), the 0 of the most each ring, 1,2 or 3 atoms can be substituted with a substituent.The example of heterocyclic radical Including piperazinyl, pyrrolidinyl, dialkyl group, morpholinyl, tetrahydrofuran base, and include bridged ring and carbocyclic fused ring system.Art Language " Heterocyclylalkyl " refers to the alkyl replaced by heterocyclic radical.

Term " Heterocyclylalkyl " used in the present invention refers to the alkyl replaced by heterocyclic radical.

Term " miscellaneous alkyl " as used in the present invention refers to saturated or unsaturated straight chain (linearly) and side chain aromatics Group, wherein the one or more carbon atoms in chain are substituted by hetero atom independently.Exemplary heteroatoms includes O, S, N and P.

Being described as in the present invention can the group such as any substituted aralkyl, miscellaneous alkyl, it is intended that described prescription, alkyl or Any one or both in person's heteroaryl and alkyl can be optionally substituted or unsubstituted.

Term " hydroxy alkyl " refers to the alkyl that wherein one or more hydrogen atoms are optionally substituted by a hydroxyl group.

Term " imino group " refers to have the substituted or unsubstituted nitrogen of the double bond (-C=N-) being connected with carbon (such as, NH), wherein said carbon can be part alkyl chain or cyclic group (such as, ring group, heterocyclic radical, aryl, heteroaryl).

Term " oxo " refers to oxygen atom (=O), and when being attached with carbon, it forms carbonyl；When carrying out even with nitrogen When connecing, it can form N-oxide；Further, it is that it can form sulfoxide or sulfone when being attached with sulfur.

When described junction point is via sulphur atom, and described alkyl is as time defined above, then at this Term " alkylthio " used in bright refers to-S (alkyl) group.

Term " thiocarbonyl group " refers to sulphur atom (that is ,=S), when being attached with carbon, forms thioketone.

Term " substituted " refers to that part has the substituent group replacing hydrogen on one or more carbon of this main chain.Ying Li Solving, " replacement " or " using ... replace " includes the collateral condition implied: this replacement is to meet the substituted atom of institute and this replacement The permission atomicity of base, and this replacement causes stable compound, such as, it experiences conversion unautogenously, such as by again Arrange, be cyclized, elimination etc..As used in the present invention, term " substituted " is considered and includes that all of organic compound permit The substituent group permitted.In aspect widely, admissible substituent group includes the non-ring group of organic compound and ring group, side chain and straight Chain, carbocylic radical and heterocyclic radical, aromatics and non-aromatic substituents.For suitable organic compound, this admissible substituent group can Think one or more and identical or different substituent group.For the purposes of the present invention, this hetero atom such as nitrogen can have this The hydrogen substituent group of bright described organic compound and/or any admissible substituent group, it meets this heteroatomic quantivalence.

Term " substituent group " refers to the group " being replaced " in part of the present invention.Any former in any substituent group Son can be replaced.Substituent group can include any substituent group of the present invention.Illustrative substituents includes but not limited to alkyl (example As, C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂Straight or branched alkyl), cycloalkyl, haloalkyl (such as, perfluor Substituted alkyl such as CF₃), aryl, heteroaryl, aralkyl, heteroarylalkyl, heterocyclic radical, alkenyl, alkynyl, cycloalkenyl group, heterocycle alkene Base, alkoxyl, halogenated alkoxy (such as, perfluoro alkoxy such as OCF₃), halo, hydroxyl, carboxyl, carboxylate radical, cyano group, nitre Base, amino, alkyl amino, SO₃H, sulfate radical, phosphate radical, methylenedioxy (-O-CH₂-O-, wherein oxygen is with adjacent atom even Connect), ethylene dioxy base, oxo, thioketone (such as, C=S), imino group (alkyl, aryl, aralkyl), S (O)_nAlkyl (wherein n 0-2), S (O)_nAryl (wherein n is 0-2), S (O)_nHeteroaryl (wherein n is 0-2), S (O)_nHeterocyclic radical (wherein n is 0-2), Amine (single-, two-alkyl, cycloalkyl, aralkyl, heteroarylalkyl, aryl, heteroaryl and combinations thereof), ester are (alkyl, aralkyl, miscellaneous Aralkyl, aryl, heteroaryl), amide (single-, two-alkyl, aralkyl, heteroarylalkyl, aryl, heteroaryl and combinations thereof), sulphur Amide (single-, two-alkyl, aralkyl, heteroarylalkyl and combinations thereof).On the one hand, on the substituent group on group is independently State that any one in substituent group be single or any subset substituent group.On the other hand, substituent group itself can be by above-mentioned substituent group In any one replace.

Term " pharmaceutically acceptable carrier or adjuvant " refers to be applied to experimenter together with the compounds of this invention And do not destroy its pharmacologically active and be nontoxic carrier or assistant when the dosage of the compound be enough to deliver therapeutic dose is used Agent.

Being used in the present invention, term " treatment (treat) " or " therapy (treatment) " are defined as changing Compound individually or combines with the second compound and applies or be applied to experimenter (such as, sufferer), or is applied by compound or execute For (from experimenter such as, there is disease (such as, disease as described in the present invention), disease disease or easily catch disease body The sufferer of matter) the tissue of separation or cell, such as cell line, it is therefore an objective to for curing, heal, alleviate, relax, change, remedying, Improvement, improve or affect disease, one or more diseases of this disease or easily catch the body constitution of this disease and (such as, prevent this disease At least one disease of disease or postpone the beginning of at least one disease of this disease).

Used in the present invention, the amount of effective sanatory compound or " therapeutically effective amount " refer to single or After multiple dose is applied to this experimenter, to treatment cell or healing, alleviate, relax or improve that to suffer from the experimenter of disease effective Property beyond lacking the amount of the compound of desired degree under this treatment.

Being used in the present invention, the effectively amount of compound or " the prevention effective dose " of compound of prevention disease refers to After single or multiple dose are applied to this experimenter, effectively prevent or delay the symptom of disease or disease to start to occur or recurrence Amount.

As used in the present invention, term " experimenter " is intended to include people and non-human animal.Exemplary people experimenter includes suffering from There are the people experimenter of disease disease the most of the present invention, or normal subjects.The term " non-human animal " of the present invention includes All vertebratess, such as nonmammalian class (such as chicken, Amphibian, reptile class) and mammal such as non-human primates Animal, performing animal and/or useful animal of being engaged in agriculture, such as sheep, Canis familiaris L., cat, cattle, pig etc..

Compound

The compound of Formulas I described in the invention:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-C(R₃)₂-structure；Or L-M, M-T or L-M-T and their 1 to 3 other-C (R being connected₃)₂-、-O-、-NR₁₁-or-S-formed together 3-6 unit Ring group, heterocyclic radical, aryl or heteroaryl ring；Each R₃It is H, halo, oxo ,-OR independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS (O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、- NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP (R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkane Base or heteroaryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆) OR₁₀；R₆It is H, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,= NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or Aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring；R₇Be H, Halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkane Base, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino Acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、- S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous Alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅With R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈ It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or Heteroaryl alkyl；R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；And, q is 1 or 2；Condition is to work as R₁It is-C (O) OH, n are 2, and q is 1, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；Further, condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

Invention further describes the compound of Formula II:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, 1 to 3 other-C (R that M-T or L-M-T is connected with them₃)₂-、-O-、-NR₁₁-or-S-formed together 3-6 unit ring group, Heterocyclic radical, aryl or heteroaryl ring；Each R₃It is H, halo, oxo ,-OR independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O) R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’ C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆) OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or miscellaneous Aryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyanogen Base ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、- NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR₁₀、-SR₁₀、-COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O) R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br、I)、-NH₂, cyano group, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocycle Base, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkane Base, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl Alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O) OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄The most solely It is on the spot H, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkane Base, heteroaryl alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅With R₁₆It it is not all double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocycle Base, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；Bar Part is to work as R₁It is-C (O) OH, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；Further, condition is to work as R₁Be- C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

Invention further describes Formula II compound:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-C H₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M-T or L-M-T and their institutes 1 to 3 the other-C (R connected₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, heterocyclic radical, aryl or heteroaryl together Basic ring；Each R₃It is H, halogen, oxo ,-SR independently₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、- NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈ Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、- SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O) NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆) OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR independently₁₀、-SR₁₀、- COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS (O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl Or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈ Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or miscellaneous Aryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous Alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC (O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄Be independently of one another H, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl Alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It is not all Double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, Heteroaryl, aryl alkyl or heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

The present invention also describes Formula II compound at this:

Wherein, R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；L-M-T is formed together Selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M-T Or 1 to 3 other-C (R that L-M-T is connected with them₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, miscellaneous together Ring group, aryl or heteroaryl ring；Each R₃It is H, halogen, oxo ,-SR independently₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆) OR₁₀, C1-C8 alkyl, the miscellaneous alkyl of C1-C8, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroarylalkyl；R5 be H, Halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、- P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R6 is H, oxo ,-OR₁₀、- SR₁₀、-COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O) OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as, F, Cl, Br, I) ,- NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, miscellaneous Ring group, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈ Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, virtue Base alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈ Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C (O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄Respectively From being H, C independently₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, virtue Base alkyl, heteroaryl alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, it is provided that R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈ Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

Invention further describes the compound with following formula:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；Each R₃It is independently H, halo, oxo ,-OR10 ,-SR10 ,-OC (O) R10 ,-OS (O) R10 ,-OC (O) OR10 ,-OS (O) OR10 ,-OS (O) 2R10, Cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, C1-C8 alkyl, the miscellaneous alkyl of C1-C8, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、- NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；R₆Independently be H, Oxo ,-OR10 ,-SR10 ,-COR10 ,-CNR11R12 ,-C (O) R10 ,-C (O) OR10 ,-C (O) NR11R12 ,-OC (O) R10 ,- OS (O) R10 ,-OC (O) OR10 ,-OS (O) OR10 ,-NR11R12 ,=NR11 ,-OC (O) NR11R12 ,-SC (O) NR11R12, halogen Generation (such as, F, C1, Br, I) ,-NH₂, cyano group, C1-C8 alkyl, cycloalkyl or aryl；R₅And R₆Replacement can be optionally formed together Or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；p It is 0-4；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, virtue Base, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂) R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅And R₁₆The most solely It is on the spot=O ,=S ,-OR₁₇、-SR₁₇Or-NR₁₇R₁₈, the R that provided₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈The most solely It is on the spot H, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl Base alkyl；Further, R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；Condition is to work as R₁When being-C (O) OH, R₆It is oxygen Generation, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁When being-C (O) OH, R₆It is oxo, R₇It is methyl, And R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；Further, condition is to work as R₁When being-C (O) OH, R₆It is oxo, R₇ It is methyl, and R₂It is hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

Invention further describes the compound of following formula:

Wherein R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₃It is halo, oxygen Generation ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、- OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P (R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O) OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆) OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；R₆It is H, oxo ,-OR independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O) R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, C1, Br、I)、-NH₂, cyano group, C₁-C₈Alkyl, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit Ring group, heterocyclic radical, aryl or heteroaryl ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, replacement or does not takes The C in generation₁-C₈Alkyl, C₂-C₈Alkenyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, Heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, replacement or unsubstituted independently of one another C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,- OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁₃ And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, heteroaryl alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, Condition is R₁₅And R₁₆It it is not all double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring Base, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And R₁₉It is-O-,-S-,-NR₁₇-、-N(OH)- Or-N (OR₁₀)-；Condition is to work as R₁It is-C (O) OH, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is Work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；And condition It is to work as R₁It not-C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O)CH₂Cl。

Invention further describes the compound of following formula:

Wherein, R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OC(O)OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；R₂It is-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；L-M-T shape together Become selected from-C (R₃)NC(R₃)NC(R₃) N-,-CR3=CR₃-C(R₃) N-and-C (R₃)N-CR₃=CR₃-structure；Or L-M, 1 to 3 other-C (R that M-T or L-M-T is connected with them₃) N-,-O-,-NR₁₁-, or-S-, form 3-6 ring together Base, heterocyclic radical, aryl or heteroaryl ring, wherein n independently be 1 or 2；Each R₃Independently be H, halo, oxo ,-OR₁₀、- SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-OS(O)2R₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR1₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁′C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁′S(O₂)NR₁₁R₁₂、- P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, Ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroarylalkyl；R₅It is H, halogen, oxygen ,-OR₁₀、-SR₁₀、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O) OR₁₂、-NR₁₁′C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁′S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆) OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR10；R₆Independently be H, oxo ,-OR₁₀、-SR₁₀、-COR₁₀、- CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、- NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as, F, Cl, Br, I) ,-NH₂, cyano group, C₁-C₈Alkane Base, cycloalkyl or aryl；R₅And R₆Can the most optionally form substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl Basic ring；R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Alkene Base, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl Alkyl or amino acid side chain；R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkane Base, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O) R₁₃、-C(O)R₁₃、-S(O)R₁₃、-S(O)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；R₁3 and R₁₄Be independently of one another H, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl Alkyl or cyano group；R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇Or-NR₁₇R₁₈, condition is R₁₅And R₁₆It is not all Double bond part；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, Heteroaryl, aryl alkyl or heteroaryl alkyl；R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring Base, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroarylalkyl；R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；Further, q is 1 or 2；Condition is to work as R₁Be-C (O) OH, n be 2, q is 1, R₆It is oxo, and R₇It is methyl, R₂、R₃And R₅ It it is not all hydroxyl；Condition is to work as R₁It is-C (O) OH, R₆For oxo base, R₇For methyl, R₃And R₅It is hydroxyl, R₂It it not benzoyl Or benzyloxy；And, condition is to work as R₁It is-C (O) OH, R₆For oxo base, R₇For methyl, R₂For hydroxyl, R₃Or R₅Be not- OCH₂Cl ,-OCH₂Br, or-OC (O) CH₂Cl₂。

Compound described in the present invention and required for protection includes, but not limited to change disclosed in Table 1 Compound.

Table 1. Salinomycin injection analog.R ' and R " it is each independently C₁-C₆Alkyl, aryl or aryl alkyl.

To anti-protein and other target (such as, compound disclosed in the compound of the present invention, such as table 1, can have By the e-cadherin (ECad) expressed by galactophore epithelial cell (HMLE), Twist or GFP) combination activity.Implement at some Mode Huang is total, compound disclosed in compound described in the invention, such as table 1, can play an active part in stem cell and identify In test kit (ALDEFLUOR) test (such as, as described in the present invention).

Heretofore described compound can be prepared by using multiple synthetic technology.In some embodiments, Parent material can be Salinomycin or Salinomycin salt, such as Salinomycin Sodium.Natural Salinomycin or Salinomycin salt can be obtained by commercially available (such as, available from China Zhejiang Shenghua Baike Pharmaceutical company), and before being modified Carry out further purification (such as, utilizing preparative chromatography).Salinomycin is a kind of natural product, and it can by antibacterial such as Streptomyces albus (Streptomyces albus) is purified and obtains.The structure of Salinomycin is as follows:

As those skilled in the art can be known, the method for synthesis formula (I) compound is to ordinary skill Will be apparent from for personnel.In some embodiments, one or more hydroxyls of Salinomycin can carry out removing, aoxidize, second It is acylated or amination.In some embodiments, terminal carboxylic can be aoxidized, reduce, amination, amidatioon, esterification, silicic acid Salinization, thiol salinization or protection.In some embodiments, ketone group and neighbouring hydroxyl can carry out being cyclized, jeterocyclic chemistry, reduction, amine Change or amination.Additionally, different synthesis steps can be carried out in a kind of order alternately or requirement, thus obtain required compound. One or more reaction site can be can be used in synthesis described in the present invention by the expectation compound according to required offer The synthesis chemical conversion of compound or blocking group method (protection and deprotection) are known in the art, and include, Such as at R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989)； T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons(1991)；L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994)；And, L.Paquette etc., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and described in its later release Method.

Compound disclosed in this invention generally comprises one or more asymmetric center, and therefore with raceme and outer Presented in racemic mixture, single enantiomer, single diastereomer and non-enantiomer mixture.When aobvious at atom center Showing when having the stereochemical structure of specificity, described stereochemical structure is to fix for maintaining atom center, but, when When atom center is displayed without spatial chemistry, by can expect disclosed compound be included in atom center have likely Stereochemical structure (such as R and S or (+) and the compound of (-)).(such as, the compound of the present invention also can comprise bonding Carbon-carbon bond) or substituent group, it can limit key rotate, the restriction such as caused by ring or the existence of double bond.Therefore, the present invention Include all of cis/trans and E/Z isomer the most clearly.

Compound disclosed in this invention can also represent with the form of multiple tautomer, in such cases, and this Invention the most clearly includes all tautomeric forms of heretofore described compound, even if only show single mutual (such as, the alkylation of loop systems may result in the alkylation in multiple sites, and the present invention clearly includes all to become isomeric form This type of product).These type of isomeric forms all of this compounds comprise in the present invention with being aware that.The present invention All crystal forms of described compound comprise in the present invention with being aware that.

The compound of the present invention not only comprises these compounds itself, and comprises their salt and their prodrug.Example As, can will form salt between the substituent group (such as amino) of the positive charge in anion and compound of the present invention.It is suitable for Anion include chloride ion, bromide ion, iodide ion, sulfate radical, nitrate anion, phosphate radical, citrate, methanesulfonate, trifluoro Acetate and acetate.Similarly, it is possible to by cation and substituent group (the such as carboxylic of negative charge on compound of the present invention Acid group) between formed salt.The cation being suitable for includes sodium ion, potassium ion, magnesium ion, calcium ion and ammonium cation (such as, four Ammonium ion).The example of prodrug includes ester and other pharmaceutically acceptable derivates, and it has after using for experimenter The ability of reactive compound is provided.The compounds of this invention also includes the hydrate of described compound and the hydrate of salt thereof.Hydration Thing is the complex of the compound containing one or more hydrones.

The modification carrying out compound of the present invention can be by adding suitable degree of functionality for increasing selected life Thing character, such as targeting are specifically organized.Described modification is to it known in the art, and include that those increase to enter given life The biosmosis of thing compartment (such as blood, lymphsystem, central nervous system), increase oral administration biaavailability, increase are dissolved Spend to allow to be used by injection, change metabolism and change the modification of discharge rate.

In alternate embodiments, compound of the present invention is used as platform or support, described platform Or support can be used for combinatorial chemistry technique thus for the derivant of compound and/or the preparation of chemistry library.This of compound Analog derivative and library have biological activity, and can be used for identifying and designing the compound with given activity.It is applicable to profit With the combinatorial chemistry technique of compound of the present invention be it known in the art, as by Obrecht, D. and Villalgrodo, J.M., Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998) example, and include such as " point (a split and pool) is split in mixing " or " parallel " synthetic technology, solid phase and dissolving Phase technology and coding techniques (see for example, Czarnik, A.W., Curr.Opin.Chem.Bio., (1997) 1,60.Cause This, the method relating in an embodiment compound of the present invention is used for produce derivant or chemistry library, bag Include: 1) main body comprising multiple hole is provided；2) one or more are provided to be identified by method of the present invention in each hole Compound；3) other one or more chemicalss are provided in each hole；4) one separating obtained from each hole Or multi-products.A kind of alternate embodiments relates to be used for compound of the present invention producing derivant or chemistry literary composition The method in storehouse, including 1) provide one or more to attach to the compound of the present invention of solid carrier；2) with a kind of or many Plant other chemicals and process one or more compounds identified by method of the present invention attaching to solid carrier； 3) one or more products separating obtained from each hole.In the above-mentioned methods, " label " or identifier or mark part can Attach to compound or derivatives thereof of the present invention and/or separate with them, being used for promoting required product or its intermediate Spike, identify or separate.Above-mentioned part is well known in the art.The chemicals used in the above-mentioned methods can wrap Include, such as, solvent, reagent, catalyst, protection group reagent and Deprotection reagent etc..The example of described chemicals is to deposit It is those chemicalss in various synthesis that the present invention mentions and the chemical textbook of blocking group and paper.

Compositions and route of administration

Compound of the present invention can be used for experimenter with pharmaceutically acceptable compositions or dosage form.? In some cases, described compositions or dosage form can be the form with a kind of test kit to use described compound, described reagent Box contains compositions or dosage form and for using the explanation of this compound.This test kit may also include diluent and for using Diluent and the explanation of expecting compound (such as, with compositions or dosage form).Described pharmaceutically acceptable compositions Or dosage form can be administered with effective dose together with other therapeutic agent (if present), in order to reach regulate disease or Disease disease (include of the present invention those).Described other therapeutic agent can be same together with compound of the present invention Time use, or can together with compound of the present invention sequential application.

In some embodiments, pharmaceutically acceptable compositions also comprises solubilizing agent and/or emulsifying agent.Exemplary Solubilizing agent and/or emulsifying agent include amphipathic molecule, such as long-chain amphipathic molecule.In some embodiments, described amphiphilic Property molecule is nontoxic.In some embodiments, solubilizing agent and/or emulsifier package such as PEG Han polyalkylene oxides.? In some embodiment, solubilizing agent and/or emulsifying agent are Polysorbate, such as, and the polyoxy second of mono laurate Isosorbide Dinitrate Ene derivative, such as Tween are such as80.In some embodiments, solubilizing agent and/or emulsifying agent are Polyethylene Glycol With the mixture of the derivant of hydroxy stearic acid ester (the single-and di-ester of such as 12-hydroxy stearic acid), such as solutol is such asHS 15.In some embodiments, solubilizing agent and/or emulsifying agent are GREMAPHOR GS32, such asAsEL.Can also use other through appropriate managerial mechanism such as U.S.Food And Drug Administration (FDA) thinks have solubilizing agent and/or the emulsifying agent of safety.

In some embodiments, pharmaceutically acceptable compositions also comprises misci-ble organic solvents, such as alcohol, organic Acid or polarity-organic solvent.In some embodiments, misci-ble organic solvents is alcohol, such as ethanol or propylene glycol.At some In embodiment, misci-ble organic solvents is organic acid, such as propanoic acid.In some embodiments, misci-ble organic solvents is Polarity-organic solvent or polar non-solute, such as DMSO.

In some embodiments, heretofore described waterborne compositions (such as, compound or compositions) is containing steady Determine agent.Exemplary stabilizer includes chelating agen, such as EDTA or edta salt (such as EDETATE SODIUM or citric acid).Exemplary ballast Agent also includes antioxidant (such as ascorbic acid, tocopherol/Tocopheryl derivatives) and pyrosulfite (such as pyrosulfurous acid Sodium) and preservative (such as benzyl alcohol, p-Hydroxybenzoate or methaform).

In addition to the above component, pharmaceutically acceptable compositions can include other composition, such as its His pharmaceutically acceptable carrier, adjuvant and vehicle.Exemplary pharmaceutically acceptable carrier, adjuvant and vehicle include Ion-exchanger, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol cetomacrogol 1000 succinic acid Emulsifying agent such as Tweens used in ester, pharmaceutical dosage form or other similar polymeric delivery matrices, serum proteins such as human blood The partial glyceride of pure albumen, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid Mixture, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, alternately two Silicon oxide, magnesium trisilicate, polyvinylpyrrolidone, material based on cellulose, Polyethylene Glycol, sodium carboxymethyl cellulose, poly-third Olefin(e) acid ester, wax class, polyethylene-polypropylene oxide-block copolymer and Polyethylene Glycol.Cyclodextrin such as α-, β-and gamma-cyclodextrin Or the derivant of chemical modification such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-beta-schardinger dextrin-and 3-hydroxypropyl-β-ring Dextrin, or other dissolve derivant be also advantageously used to strengthen the delivery of the compound of formula of the present invention.

Pharmaceutically acceptable compositions can include diluent, filler, salt, buffer agent, stabilizer, solubilizing agent and other Material well known in the art.The selection of the pharmaceutically acceptable carrier being used in combination with the compounds of this invention substantially by The method that compound is used determines.The carrier of exemplary pharmaceutically acceptable peptide is particularly described in U.S. patent No.5, 211,657.Described preparation generally can comprise salt, buffer agent, preservative, compatible carrier and other optional treatment Agent.When in medicine, described salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salt can be easy to for Prepare its pharmaceutically acceptable salt, thus do not get rid of from the scope of protection of the invention.This type of pharmacology and pharmaceutically acceptable Salt, include but not limited to from following acid those of preparation: hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, Salicylic acid, citric acid, formic acid, malonic acid, succinic acid etc..And, pharmaceutically acceptable salt can be with alkali metal or alkaline earth Metallic salt form is prepared, such as sodium salt, potassium salt or calcium salt.It will also be appreciated that this compound can be with pharmaceutically acceptable Prodrug or form provide and maybe can use active metabolite.Moreover, it will be understood that such as can with targeting moiety, increase it Reagent is modified by the part of absorption, biological half-life (such as, Pegylation) etc..

The pharmaceutical composition of the present invention is orally available to be used, parenteral administration, by sucking spraying and using, local application, straight Intestinal uses, by nasal administration, used by buccal, vaginal application or use via embedded type container, preferably executed by oral With or used by injection.Pharmaceutical composition can comprise the pharmaceutically acceptable carrier of non-toxic of any routine, adjuvant or Vehicle.In some cases, the pH of adjuvant can use pharmaceutically acceptable acid, alkali or buffer agent to regulate to strengthen institute The stability of the compound of preparation or the stability of its delivery form.Term parenteral as used in the present invention includes subcutaneous, skin In, in intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, breastbone, in sheath, intralesional and intracranial injection or infusion techniques.

Described pharmaceutically acceptable compositions can be to be with the form of aseptic injection adjuvant, such as, as aseptic injection Aqueous or oily suspensions.Described suspension can use the dispersant being suitable for or wetting agent (all according to techniques known in the art Such as, such as Tween 80) and suspending agent prepare.Described aseptic injection adjuvant can also be a kind of acceptable at nontoxic parenteral Diluent or solvent in aseptic injectable solution or suspension, the e.g. solution in 1,3 butylene glycol.Acceptable Vehicle and solvent can be used mannitol, water, Ringer's mixture and isotonic sodium chlorrde solution.Additionally, tradition uses Aseptic fixing oil is as solvent or suspension media.For this purpose, it is possible to use the fixing oil of any gentleness, including the list of synthesis Glyceride or two glyceride.Fatty acid such as oleic acid and glyceride ester derivatives thereof can be used for the preparation of injection product, as natural Pharmaceutically acceptable oil, such as olive oil or Oleum Ricini, especially with they polyoxyethylated forms.These oil solutions or Suspension also can comprise long-chain alcohol diluents or dispersant or carboxymethyl cellulose or be usually used in pharmaceutically acceptable dosage form Similar dispersant in adjuvant, such as emulsion and suspension.Other conventional surfactant such as Tweens or Spans and/ Or other similar emulsifying agent being usually used in preparing pharmaceutically acceptable solid, liquid or other dosage form or bioavailability strengthen Agent can also be used for the purpose of adjuvant.

The pharmaceutical composition of the present invention can carry out Orally administered with any oral acceptable dosage form, it include but It is not limited to, capsule, tablet, emulsion and waterborne suspension, dispersion liquid and solution.In the case of orally using tablet, conventional Carrier includes lactose and corn starch.Generally it is additionally added lubricant, such as magnesium stearate.For executing with the oral of capsule form With, useful diluent includes lactose and dried corn starch.When Orally administered waterborne suspension and/or emulsion, described activity Composition can be suspended or dissolved in oil phase, is combined with emulsifying agent and/or suspending agent.If desired, can add specific sweeting agent and/ Or flavoring agent and/or coloring agent.

Pharmaceutical composition of the present invention can also be used with suppository form, in order to for rectal administration.These combinations Thing can be by carrying out mixing preparing with the non-irritating excipient being suitable for by the compounds of this invention, and described excipient is at room temperature It is solid, but is liquid at a temperature of rectum, thus therefore will melt in the rectum, in order to release active component.Described Material includes, but not limited to cocoa butter, Cera Flava and Polyethylene Glycol.

When required treatment relates to can passing through the easy affected region of local application or organ, chemical combination of the present invention The local application of thing and pharmaceutical composition is effective.For being topically applied to the application of skin, described pharmaceutical composition should Suitably being suitable for ointment to configure by one, described ointment contains the active component being suspended or dissolved in carrier.For office Portion uses the carrier of the compounds of this invention and includes, but not limited to mineral oil, liquid petroleum, White petrolatum, propylene glycol, polyoxy Ethylene polyoxypropylene compound, emulsifing wax and water.Alternatively, described pharmaceutical composition can be containing being suspended or dissolved in carrier The applicable lotion of this active component and applicable emulsifying agent or emulsifiable paste preparation.Applicable carrier includes, but not limited to mineral oil, takes off Water sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and Water.Pharmaceutical composition of the present invention is used as rectal suppository adjuvant or with the form of applicable enema adjuvant so that office Portion is applied to downstream intestinal.The transdermal skin patches of local is also contained in the present invention.

The pharmaceutical composition of the present invention can be used by nose gasification spraying or inhalation.Such composition is according to medicine Prepared by the technology known in formulation art of learning, and can use benzyl alcohol or other preservative being suitable for, strengthen biological utilisation Degree absorption enhancer, fluorocarbon and/or other solubilizing agent known in the art or dispersant thus preparation become at salt Solution in water.

Compound, compositions and dosage form can be used for treating and (such as, improve, relax, heal, maintain a kind of disease (such as, Tumor) healing (that is, prevent or delay recurrence)) or prevention disease diffuse to another part of experimenter, such as shift.Sick After disease starts, the purpose for the treatment of is to alleviate, improve or be completely eliminated disease and/or its relevant symptom, in order to prevent it from disliking Change, thus delay of progression speed, or once it is initially eliminated, and just prevents the appearance again of disease.Be suitable for dosage and control Treatment scheme can be according to specific compound used, the delivery mode of compound and its mode being used singly or in combination And be changed.As used in the present invention, therapeutically effective amount is that suppression CSC dependent tumors is formed, is in progress and/or spreads The compound of (such as, transfer) or the amount of compositions.

It is any that therapeutically effective amount may refer to that the method described in of the present invention or the application of the invention finds One or more compounds or compositions, its have rejection characteristic (such as, suppression CSC and/or mesenchymal cell growth and/ Or survival).For establishing the method for the therapeutically effective amount of compound of the present invention or compositions skill common to this area It is known for art personnel.As used in the present invention, pharmaceutical composition includes compound or the compositions with treatment effectiveness, And pharmaceutically acceptable carrier (that is, its compound promoting therapeutically effective amount or delivery of compositions).Any specific should Effective dose also can change because of many factors, many factors cancer the most in the treatment, the tool used Body compound, the size of experimenter or disease or the order of severity of illness.Those of ordinary skill in the art are without too much reality Test the effective dose of the concrete molecule that can empirically determine the present invention.Combine with teaching provided by the present invention, pass through Various reactive compounds select and measurement factor such as usefulness, relative bioavailability, experimenter's body weight, bad secondary work The order of severity and preferred method of application, the therapeutic scheme effectively preventing or treating can be planned, in order to avoid great poison Property and still to treat concrete experimenter effective.In some embodiments, useful compound comes in statistically evident mode Increase the average survival time of the experimenter using compounds for treating, increase the average progresson free survival phase and/or reduce relapse rate.

Experimenter's dosage of compound of the present invention generally range from about 0.1 μ g to 10,000mg, be more typically About 1 μ g to 8000mg, e.g., from about 10 μ g to 100mg, with every day, weekly, monthly or to be often spaced one or many At All Other Times. Shown in the aspect of experimenter's body weight, In some embodiments of the present invention, typical dosage range is about 0.1 μ g extremely 20mg/kg/ days, e.g., from about 1 to 10mg/kg/ sky, e.g., from about 1 to 5mg/kg/ sky.Absolute magnitude will depend upon which many factors, here Many factors include concurrently treating, dosage number and single experimenter's parameter (include age, physical condition, size and body Weight).These factors are well known to those of ordinary skill in the art, and are only the most soluble with normal experiment.Generally feelings Under condition: maximal dose can be used according to rational medical judgment, i.e. the highest safe dose.Dosage used can be maximum tolerance Dosage or sub-therapeutic dose or at any dosage of period.It is also covered by the multiple dosage of the molecule of the present invention.As two with molecule During the molecule of the sub-therapeutic dose combined administration present invention of one of person, or both sub-therapeutic doses can be used for treatment and suffer from cancer Or have developing cancer risk experimenter.When being used together two class medicines, cancer medicine can be used with sub-therapeutic dose Agent, in order to produce required therapeutic outcome.If sub-therapeutic dose refers to less than using under lacking other reagent, tested Person produces the dosage of therapeutic outcome.Therefore, the sub-therapeutic dose of cancer agents is under the using of molecule lacking the present invention In experimenter, do not produce the dosage of required therapeutic outcome.The therapeutic dose of cancer agents is the medicine field for treating cancer Known in.These dosage are the most extensively recorded in list of references, such as Remington ' s Pharmaceutical Sciences, the 18th edition, 1990；And much other be medical personnel trust as the guidance for treating cancer Medical reference.

Compound of the present invention can be about 0.5 to the dosage of about 100mg/kg body weight, 1mg to 1000mg/ alternatively Dosage is administered, such as by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or subcutaneous be administered；Or logical Cross oral, in buccal, per nasal, saturating mucosa, locally DIYU ophthalmic preparation, or by suction, it was with every 4 to 120 hours or root Use according to the demand of concrete medicine.Method of the present invention includes the compositions of compound or the compound using effective dose Needed for realizing or described effect.Under normal circumstances, by every day about 1 to about 6 time or alternatively with the form of continuous infusion Use the pharmaceutical composition of the present invention.Described using can be carried out with chronic or acute therapy form.By tying with carrier material The amount share the active component with the single dosage form produced will change according to treated host and concrete method of application.Typical case Preparation will contain from about 5% to about 95% reactive compound (w/w).Alternatively, this type of preparation comprises about 20% to about 80% activity Compound.

The dosage below or above those above-mentioned dosage listed may be needed.Spy for any concrete experimenter Determining dosage and therapeutic scheme will depend upon which various factors, these factors include the activity of used specific compound, age, body Weight, general health state, sex, diet, time of application, excretion rate, drug regimen, disease, illness or the order of severity of disease Or tendency to disease, illness or disease of process, experimenter and the judgement for the treatment of physician.

After the illness of experimenter is improved, if it is desired, it is possible to use the change of the present invention of a kind of maintenance dose Compound, compound or their combination.Then, when this symptom has alleviated to required level, according to the function of this symptom Can by applied dose or frequency or they be both reduced to the degree that can keep improving disease.But, once disease disease Any recurrence of shape, experimenter may need the intermittent therapy of long-term basis.

In some embodiments, compound of the present invention and compositions are become the constituent of dosage form.One In a little embodiments, this dosage form is parenteral dosage form, such as, for using to experimenter's intravenous.In some embodiments, This dosage form is the compositions in sterile closed container (such as, bottle, phial).In some embodiments, this dosage form is permissible It is peroral dosage form, such as, for Orally administered to experimenter.In some embodiments, peroral dosage form also comprise flavoring agent or Flavouring agent or both, for regulating taste or the abnormal smells from the patient of peroral dosage form.

Therapeutic Method

Compound of the present invention and compositions (such as, external or external) can be applied to the cell in cultivating, or Person is applied to experimenter, the most internal, with treatment, prevent and/or diagnose various disease conditions, including the present invention described below that A bit.Compound of the present invention and compositions can suppress the propagation of cancer stem cell and/or mesenchymal cell.

Neoplastic conditions

Compound described in the invention and compositions can be used for treating (such as, to be improved, alleviate, cures, maintains and control More) healing (that is, postponing recurrence) of proliferative disorders (such as, cancer)." proliferative disorders " refers to a kind of disease or disease, It is characterized in that cell has oneself's growth or the ability replicated, the abnormal situation such as characterized or feelings by proliferating cell growth Condition.Exemplary proliferative disorders includes solid tumor and leukemia, and (such as, cancer, sarcoma, transitivity disease are (such as from prostate, knot The tumor that intestinal, lung, mammary gland regulating liver-QI source derive)), hemopoietic proliferative disorders (such as, leukemia, metastatic tumor).Universal cancer Including: mammary gland, prostate, colon, lung, liver and cancer of pancreas.Can with effective dose the treatment of waterborne compositions that uses can change The disease of at least one proliferative disorders kind, such as, reduce cell proliferation, reduce tumor tissues etc..

Disclosed method for treatment of cancer such as includes the gentle shift form of solid tumor soft-tissue tumor.Disclosed method It is also used for treating non-solid carcinoma.Exemplary solid tumor includes the malignant tumor (such as sarcoma adenocarcinoma and cancer) of various tract, Such as those lungs, mammary gland, lymph, the malignant tumor of gastrointestinal (such as colon), and genitals's (such as kidney, urothelial Or testicular tumor) system, pharynx, prostate and ovary.Exemplary adenocarcinoma includes colorectal carcinoma, kidney-cell carcinoma, hepatocarcinoma, lung non- Small cell carcinoma and carcinoma of small intestine.

The exemplary cancer that National Cancer Institute (national cancer institute) describes includes: acute Lymphoblastic leukemia, adult；Acute lymphoblastic leukemia, child；Acute myeloid leukemia, adult；On kidney The cancer of gland cortex；Adrenocortical cancer, child；The lymphoma that AIDS-is relevant；The malignant tumor that AIDS-is relevant；Anus cancer；Star Type cell born of the same parents' tumor, child's cerebellum；Astrocytes born of the same parents' tumor, child's brain；Cancer of biliary duct, outside liver；Bladder cancer；Bladder cancer, child；Bone Cancer, osteosarcoma/malignant fibrohistiocytoma；Brain stem glioma, child；Cerebroma, adult；Cerebroma, brain stem glioma, child； Cerebroma, cerebellum astrocytes born of the same parents' tumor, child；Cerebroma, brain astrocytes born of the same parents tumor/glioblastoma, child；Cerebroma, room tympanum Tumor, child；Cerebroma, medulloblastoma, child；Cerebroma, intramedullary primitive neuroectodermal tumor on curtain, child；Cerebroma, visual pathway And hypothalamic gliomas, child；Cerebroma, child's (other)；Breast carcinoma；Breast carcinoma and gestation；Breast carcinoma, child；Breast carcinoma, man Property；Bronchial adenoma/benign tumor, child；Benign tumor tumor, child；Benign tumor tumor, gastrointestinal；Cancer, adrenocortical； Cancer, islet cell；Unknown primary carcinoma；Central nervous system lymphoma, primary；Cerebellum astrocytes born of the same parents' tumor, child；Brain star Type cell born of the same parents tumor/glioblastoma, child；Cervical cancer；Children with cancer；Chronic lymphocytic leukemia；The white blood of chronic myelognous Sick；Chronic Myeloid proliferative disorders；Tendon sheath clear cell sarcoma；Colon cancer；Colorectal carcinoma, child；The T-Lymphocytes of skin Tumor；Carcinoma of endometrium；Ependymoma, child；Epithelial cancer, ovarian cancer；Esophageal carcinoma；Esophageal carcinoma, child；Tumor Ewing ' s family；Cranium Outer germinoma, child；Extragonadal germinoma；Cholangiocarcinoma；Cancer eye, intraocular melanoma；Cancer eye, retina is female Glucagonoma；Carcinoma of gallbladder；(stomach) cancer of stomach；(stomach) cancer of stomach, child；Gastrointestinal benign tumor tumor；Germinoma, outside cranium, child； Germinoma, extragonadal；Germinoma, ovarian cancer；Gestational trophoblastic tumors；Glioma, child's brain stem；Glioma, Children's vision path and hypothalamus；Hairy cell leukemia；Head and neck cancer；Hepatocyte (liver) cancer, is grown up (primary)；Hepatocyte (liver) cancer, child's (primary)；Lymphogranulomatosis lymphoma, adult；Lymphogranulomatosis lymphoma, child；Lymphogranulomatosis lymph During tumor gestation；Carcinoma of tongue；Hypothalamus and visual pathway glioma, child；Intraocular melanoma；Islet cell cancer is (endocrine Pancreas)；Kaposi ' s sarcoma；Renal carcinoma；Laryngeal carcinoma；Laryngeal carcinoma, child；Leukemia, acute lymphoblastic, adult；Leukemia, anxious Property is lymphoblastic, child；Leukemia, Acute Meyloid, adult；Leukemia, Acute Meyloid, child；Leukemia, chronic lymphatic Ball；Leukemia, chronic myelognous；Leukemia, hirsutism；Lip and oral cancer；Hepatocarcinoma, is grown up (primary)；Hepatocarcinoma, child is (former Send out)；Pulmonary carcinoma, non-minicell；Pulmonary carcinoma, minicell；Lymphoblastic leukemia, adult acute；Lymphoblastic white blood Disease, children acute；Lymphocytic leukemia, chronic；Lymphoma, AIDS-is correlated with；Lymphoma, central nervous system's (primary)；Drench Bar tumor, the T-cell of skin；Lymphoma, lymphogranulomatosis, adult；Lymphoma, lymphogranulomatosis, child；Lymphoma, Huo Qijin During family name's disease gestation；Lymphoma, non-lymphogranulomatosis, adult；Lymphoma, non-lymphogranulomatosis, child；Lymphoma, non-is suddenly During strange king's evil gestation；Lymphoma, primary central nervous system；Macroglobulinemia, Walden Si Telunshi (Waldenstrom)；Male breast carcinoma；Malignant mesothelioma, adult；Malignant mesothelioma, child；Malignant breast Tumor；Medulloblastoma, child；Melanoma；Melanoma, ophthalmic；Merkel cell carcinoma；Mesothelial cell's tumor, pernicious；Hide former The transitivity squamous neck cancer sent out；Multiple endocrine neoplasm syndrome, child；Multiple myeloma/plasmocytoma；Gill fungus sample granulation Swollen disease；Myelodysplastic syndrome；Myelogenic leukemia, chronic；Myeloid leukemia, children acute；Myeloma, multiple； Myelosis disease, chronic；Nasal cavity and nasal sinus cancer；Nasopharynx (Nasopharyngeal) cancer；Nasopharynx (Nasopharyngeal) cancer, Child；Neuroblastoma；Non-lymphogranulomatosis lymphoma, adult；Non-lymphogranulomatosis lymphoma, child；Non-Huo Qijin During family name's disease lymphoma gestation；Non-small cell lung cancer；Oral cancer, child；Oral cavity and lip cancer；Oropharynx cancer；Osteosarcoma/pernicious bone Fibrous histiocytoma；Ovarian cancer, child；Ovarian cancer epithelial cancer；Ovarian cancer germinoma；The low pernicious potential tumor of ovarian cancer； Cancer of pancreas；Cancer of pancreas, child；Cancer of pancreas, islet cell；Nasal sinuses and tumor of nasal cavity；Parathyroid carcinoma；Carcinoma of penis；Pheochromocytoma； Intramedullary primitive neuroectodermal tumor on pineal gland and curtain, child；Pituitary tumor；Plasmocytoma/multiple myeloma；Pleura lung blast cell Tumor；Gestation and breast carcinoma；Gestation and lymphogranulomatosis lymphoma；Gestation and non-lymphogranulomatosis lymphoma；Primary nervus centralis System lymphomas；Primary hepatic carcinoma, adult；Primary hepatic carcinoma, child；Carcinoma of prostate；Rectal cancer；Nephrocyte (kidney) cancer；Renal cell carcinoma, Child；Renal pelvis and ureter, transition cell cancer；Retinoblastoma；Rhabdomyosarcoma (Rhabdomyosarcoma), youngster Virgin；Glandula cancer；Glandula cancer, child；Sarcoma, You Wenshi (Ewing ' s) family tumor；Sarcoma, Kaposi's；Sarcoma (kindred Tumor)/pernicious Bone fibrous histiocytoma；Sarcoma, rhabdomyosarcoma (Rhabdomyosarcoma), child；Sarcoma, soft tissue, Adult；Sarcoma, soft tissue, child；Sezary syndrome；Skin carcinoma；Skin carcinoma, child；Skin carcinoma (melanoma)；Skin carcinoma, Merkel cell；Small cell lung cancer；Carcinoma of small intestine；Soft tissue sarcoma, adult；Soft tissue sarcoma, child；Hide primary squamous neck Cancer, transitivity；Stomach (stomach) cancer；Stomach (stomach) cancer, child；Intramedullary primitive neuroectodermal tumor on curtain, child；T-cell lymphoma, Skin；Carcinoma of testis；Thymoma, child；Thymoma, pernicious；Thyroid carcinoma；Thyroid carcinoma, child；Renal pelvis and ureteral mistake Cross cell carcinoma；Trophoblastic, gestation；Unknown primary site cancer, child；Unconventional children with cancer；Ureter and renal pelvis, transition is thin Born of the same parents' cancer；Carcinoma of urethra；Sarcoma of uterus；Cancer of vagina；Visual pathway and hypothalamic gliomas, child；Carcinoma vulvae；The grand globulin of Fahrenheit Mass formed by blood stasis；With Wilms ' tumor.According to method of the present invention, also can treat or prevent above-mentioned cancer metastasis.

In some embodiments, cancer is or is characterized as being containing or is enriched with cancer stem cell (CSC), tumor initiates thin Born of the same parents, mesenchymal cell or and the derived mesenchymal-like cells of related to cancer or mesenchyme cancerous cell.Such as, compound or compositions can It is applied to experimenter breed with elimination, Developing restraint, restriction, or it is favourable that the experimenter (the such as mankind) suffering from cancer is produced other Change.In some embodiments, cancer and CSC or tumor initiator cell or mesenchymal cell or with related to cancer Derived mesenchymal-like cells or mesenchyme cancerous cell are relevant, or cancer is characterized as being enriched with CSC and/or mesenchymal cell (such as CSC-enrichment tumor, containing mesenchymal cell tumor, or have the tumor of the cell experiencing epithelium-change to-mesenchyme).At embodiment In, carry out treatment with compound of the present invention or compositions and can reduce the diffusion of cancer (such as metastatic carcinoma).? In embodiment, carry out treatment by compound of the present invention or compositions and can reduce the possibility of cancer return, such as, drop The probability of the self-initiating of low new tumor.Start in the embodiment for the treatment of after disease is made a definite diagnosis, compound of the present invention and group Compound can reduce, improve or be completely eliminated disease and/or it is about disease, so that it avoids deteriorating, reducing lesion growth rate, Or once it is initially eliminated, it is reduced by disease relapse rate (i.e. avoiding recurrence).Suitably dosage and therapeutic regimen takes Certainly deliver mode in concrete composition therefor, compound and be independent or be used in combination.As used in the present invention, treatment Effective dose be suppression cancer (such as CSC-enrichment tumor, containing mesenchymal cell tumor, or have experience epithelium-to-mesenchyme change thin The tumor of born of the same parents) form, be in progress and/or spread compound or the amount of compositions of (such as transfer).Therapeutically effective amount can refer to there is CSC- Any one or more of present invention of enrichment tumor inhibition activity (existence of such as Developing restraint and/or CSC or cancer mesenchymal cell) Described compound or compositions, or the use method of the present invention being found.Compound of the present invention or combination The effective dose of thing can be depending on some factors (cancer, experimenter's size, disease or the seriousness of illness such as, treated and/or Progress) and change.In some embodiments, according to statistically conventional method, useful compositions can make to accept aqueous group Compound carries out the experimenter treated, and improves mean survival time, improves the progresson free survival time and/or reduce relapse rate.One In a little embodiments, compound of the present invention or compositions are for suppressing cancer stem cell or the growth of cancer mesenchymal cell Or differentiation, such as make cancer stem cell or cancer mesenchymal cell contact with compound of the present invention or compositions.This connect Touch and can occur in vitro or in vivo.In some embodiments, cancer stem cell or cancer mesenchymal cell have transcription factor or Being characterized with active in transcription factor, these transcription factor are selected from: Snail1, Snail2, Goosecoid, FoxC1, FoxC2、TWIST、E2A、SIP-1/Zeb-2、dEF1/Zeb1、LEF1、Myc、HMGA2、TAZ、Klf8、HIF-1、HOXB7、 SIM2s and Fos.In some embodiments, cancer stem cell or cancer mesenchymal cell have approach or with in approach activate be Feature, these approach are selected from TGF-β, Wnt, BMP, Notch, HGF-Met, EGF, IGF, PDGF, FGF, P38-mapk, Ras, PB Kinases-Akt, Src and NF-kB.In some embodiments, compound of the present invention and compositions can be applied in culture Cell (the most external or the most internal) or be applied to experimenter (the most internal) with treatment, regulate and/or diagnose multiple disease Disease, including those diseases below of the present invention.

Cancer conjoint therapy

In some embodiments, compound of the present invention and compositions can be used or and other therapeutic agents individually Jointly it is administered.In one embodiment, the mixture of in combination of two or more thing can be applied to it in need Experimenter.In further embodiment, one or more compositionss can be administered with one or more therapeutic agent, from And it is used for treating or avoiding multiple disease, including, such as cancer, diabetes, neurodegenerative disease, cardiovascular disease, blood coagulate Gu, inflammation, blush, fat, aging, pressure etc..In various embodiments, compound of the present invention or compositions are comprised Conjoint therapy can relate to (1) pharmaceutical composition, it comprises and one or more therapeutic agents (such as, one or more present invention Described therapeutic agent) one or more compositionss in combination；(2) one or more are jointly used with one or more therapeutic agents Compound of the present invention or compositions, during wherein compound or compositions and therapeutic agent are not formulated in same compositions But (can occur in identical test kit or packaging, such as blister package or other multi-cavities are packed；Can be split by trier Be connected, the container (such as Fresco Bag) that seals respectively；Or test kit, wherein compound or compositions and other therapeutic agents It is in independent container).When using separate compositions, relative to using of other therapeutic agent, can simultaneously, intermittently Ground, use compound of the present invention or compositions alternately, before, afterwards.

In some embodiments, compound of the present invention or compositions can be executed together with the treatment of other cancers With.Exemplary cancers treatment include, such as: chemotherapy, antibiotic, targeted therapies such as Antybody therapy, immunotherapy and swash Element therapy.Such as, chlormethine, ethylenimine derivatives, alkylsulfonate, nitroso ureas, triazenes, folacin, anthracene nucleus are mould Element, taxanes, cox 2 inhibitor, pyrimidine analogue, purine analogue, antibiotic, enzyme, epipodophyllotoxin, platinum ligand complex Thing, vinca alkaloids, substituted carbamide, methyl hydrazine derivatives, adrenocortical suppressant, hormone antagonist, enzyme level Agent, Endostatin, paclitaxel, camptothecine, amycin and their analog, and combinations thereof.

Given below for the embodiment of each in these treatments above-mentioned.

Chemotherapy

In some embodiments, compound of the present invention or compositions are used together with chemotherapy agent.Chemistry Therapy is to treat cancer with the medicine that can destroy cancerous cell.Relative to targeted therapies, " chemotherapy " is often referred to cytotoxin Medicine, it can generally affect the cell of quickly division.Chemotherapy drugs by multiple possible in the way of cell division is done Disturb, such as, by duplication or the separation of newly formed chromosome of DNA.All quick point of the chemotherapy targeting of most forms The cell that splits rather than for specific cancerous cell, although specificity to a certain degree from a lot of cancerous cell impotentias to DNA Damage is repaired, but ordinary cells generally may be repaired.

Example for the chemotherapy agent of cancer therapy includes, such as, and alkylation and alkylation-sample reagent such as chlormethine (such as, chlorambucil, chlormethine, cyclophosphamide, ifosfamide and L-Sarcolysinum), (such as, chlormethine, good fortune is not for nitroso-group carbamide Department spit of fland, lomustine and streptozotocin), platinum reagent (that is, alkylation-sample reagent) (such as, carboplatin, cisplatin, Ao Shali Platinum, BBR3464 and Satraplatin), Busulfan, dacarbazine, procarbazine, temozolomide, thio-tepa, treosulfan and uracil nitrogen Mustard；Antimetabolite such as folic acid (such as, aminopterin, methotrexate, pemetrexed, and Raltitrexed；Purine such as carat is bent Shore, clofarabine, fludarabine, purinethol, its fourth of spray department and thioguanine；Pyrimidine such as blocks its shore of training, cytosine arabinoside, fluorine Uracil, floxuridine and LY-188011；Main shaft poison/mitotic inhibitor such as taxanes (such as, docetaxel, Ramulus et folium taxi cuspidatae Phenol, Cabazitaxel (cabazitaxel)) and Herba Catharanthi Rosei class (such as, vinblastine, vincristine, vindesine, and Changchun is auspicious Shore)；Cytotoxin/antineoplastic antibiotics such as anthracycline (such as, daunorubicin, amycin, epirubicin, goes methoxy soft red Mycin, mitoxantrone, pixantrone and valrubicin), the compound that a lot of Steptomyces species produce natively is (the most more Mildew element, bleomycin, mitomycin, mithramycin) and base urea；Topoisomerase enzyme inhibitor such as Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) class (such as, Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali, topotecan and irinotecan) and mayapple tree class (such as, etoposide, teniposide)；For cancer immunization therapy The most anti-tyrosine kinase of monoclonal antibody (such as Cetuximab, Victibix, Herceptin), anti-CD 20 is (such as, Mabthera and tositumomab) and other such as alemtuzumab, bevacizumab and gemtuzumab Ozogamicin Mylotarg CDP 771s；Photosensitizer such as amino cave penta Acid, methylamino ketone valerate, porfimer and for pool sweet smell；Tyrosine kinase inhibitor such as AZD2171, Dasatinib, strategic point Lip river is for Buddhist nun, gefitinib, imatinib, Lapatinib, nilotinib, Sorafenib, Sutent and its Buddhist nun of all morals；Silk ammonia Acid/threonine kinase inhibitor (such as, AbI, c-Kit, Insulin Receptor Family member, EGF receptor family member, Akt, MTOR (such as, rapamycin or its analog, the direct inhibitor of mTORC1 and/or mTORC2), Raf kinase families, inositol phosphorus Acyltransferase (PI) kinases such as PI3 kinases, PI kinases-sample kinase families member, the kinases man of cyclin independence Race member, aurora kinase families), growth factor receptor antagonist, and other such as retinoid (such as, alitretinoin and Retinoic acid), altretamine, amsacrine, Anagrelide, arsenic trioxide, asparagine (such as, asparaginase), bud Salol fourth, bortezomib, denileukin diftitox, estramustine, ipsapirone (Ixabepilone), Aetinex, rice Tuo Tan, and testolactone, Hsp90 inhibitor, proteasome inhibitor, hdac inhibitor, angiogenesis inhibitor (such as, anti-blood Endothelial tube somatomedin reagent such as, bevacizumab or VEGF-Trap), matrix metallo-proteinase inhibitor, front-apoptosis Reagent (such as, apoptosis induction thing), the reagent etc. of anti-inflammation.

Because the effectiveness of a lot of medicines can be more more effective than being used alone when being used in combination, thus the most simultaneously or successively Use two or more medicine.Generally, combination chemotherapy method can use two or more chemotherapeutic agent.One In a little embodiments, chemotherapeutic agent can be used in combination with compound of the present invention or compositions and (include combining chemistry Therapy).In some embodiments, compound of the present invention or compositions can with other chemotherapeutic agent and its He is accredited as being effective in the compound for the treatment of or regulation cancer stem cell propagation and is administered together.

Targeted therapies

In some embodiments, compound of the present invention or compositions are administered together with targeted therapies.Target The specificity application for the reagent of the albumen of the imbalance of cancerous cell is included to therapy.Little molecular targeted therapy typically refers to The inhibitor in sudden change, overexpression or additionally necessary albumen enzyme region in cancerous cell.One example is tyrosine-kinase Enzyme inhibitor (such as, above listed kinase whose inhibitor), mab treatment (such as, comprise and are specifically connected to The treatment (such as, being listed in the monoclonal antibody therapy of the present invention) of the antibody of the albumen on cancer cell surfaces).Other example It it is PARP inhibitor, i.e. the pharmacological inhibitors of enzyme Poly ADP-ribose polymerase (PARP).Suitably PARP inhibitor can be Iniparib, olaparib, rucaparib, veliparib or CEP 9722.In some embodiments, targeted therapies can be with Compound of the present invention or compositions are used in combination.Targeted therapies may also include as " auto-guider " Little peptide, it can be connected to cell surface receptor or the extracellular matrix affecting around tumor.It is connected to the radioactive nucleus of these little peptides Element (such as RGD) finally eliminates cancerous cell, if nucleic destroys cell compartment.

Immunotherapy

In some embodiments, compound of the present invention or compositions are administered together with immunotherapy.Cancer Disease immunotherapy refers to induce the self immune system of experimenter thus treatment means multiple to antineoplastic.Tumor is produced The existing method of immunne response includes for BCG immunotherapy in the vesicle of the bladder cancer on surface, and uses interferon with thin Intracellular cytokine thus in renal cell carcinoma and melanoma experimenter induce immunne response.

Allochthonous hematopoietic stem cell transplantation is considered a type of immunotherapy, because at mortifier pair In the effect of tumor, the immunocyte of donor can often attack tumor.In some embodiments, immunotherapy reagent can be with Compound of the present invention or compositions are used in combination together.

Hormonotherapy

In some embodiments, compound of the present invention or compositions are administered together with hormonotherapy. By providing or blocking certain hormone, suppress the growth of cancer.The general example of the tumor of hormone-sensitive includes certain Mammary gland and carcinoma of prostate.Removal or block estrogen or testosterone may often be such that important additional treatment.In certain cancer In, use hormone agonist, such as progestogen, it may be possible to treatment is effective.The example of hormone therapy includes tamoxifen 1: PN: WO02056903 PAGE: 25 claimed proteinIts meter Te of fluorine BicalutamideNilutamidedegarelixSome embodiment party In formula, hormonal therapeutic agent can be used in combination together with compound of the present invention or compositions.

X-ray therapy

Preparation of the present invention can and oriented energy or particle therapy or radioactive isotope therapy (such as radiation is controlled Treat, such as ray tumor therapy) be used in combination, for proliferative diseases treatment, this proliferative disease such as cancer (such as, and The cancer that cancer stem cell is relevant).Described preparation can be same together with oriented energy or particle therapy or radioactive isotope therapy Time ground or be in turn applied to experimenter.Such as, in oriented energy or microgranule or radioactive isotope therapy, (or it combines and makes With) before, during or after, use preparation.Oriented energy or particle therapy can include whole body irradiation, local body irradiation or point Irradiation.Oriented energy or microgranule can derive from accelerator, synchrotron, nuclear reaction, vacuum tube, laser or same from radioactivity Position element.Described therapy may comprise external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation Treatment, the isotope therapy of system or the radiotherapy of non-sealed source.Described therapy may comprise picked-up or be placed on Close to radiosiotope, the most radioactive iodine, cobalt, caesium, potassium, bromine, fluorine, carbon.External radiotherapy may comprise be exposed to straight The particle of the α connect, electronics (such as beta-particle), proton, neutron, positron or photon (such as radio wave, millimeter wave, microwave, Infrared ray, visible ray, ultraviolet, X-ray or gamma-rays [photograph] inspection).Radiotherapy is controlled needed for may be directed to experimenter The arbitrary position treated.Radiotherapy also is able to cell or the cell sample, i.e. External radiotherapy being applied to cultivate.At one In embodiment, the cell of described cultivation is the cancer stem cell cultivated.

Surgical treatment

Compound of the present invention and compositions can be used in combination with surgical intervention, this surgical intervention e.g. surgery hands Art is detected, is got involved (intervention), biopsy, and for proliferative disease, (such as cancer, as having with cancer stem cell Close cancer) treatment.Compound and compositions can simultaneously or successively be applied to experimenter together with surgical intervention.Example As, compound or compositions can before surgical intervention (preoperative), during or after (postoperative) be administered.Surgical intervention may It is biopsy, gathers one or more cell during this period for analyzing further.With such as scalpel, pin, conduit, interior Sight glass, spatula or shears, complete biopsy.Biopsy is probably excisional biopsy, otch biopsy Look into, organize core biopsy or needle biopsy (such as, puncture suction biopsy).Surgical intervention may Including the excision to local organization that is suspicious or that be accredited as cancer.Such as, the method potentially includes and extracts the pathological changes of cancerization, swells Block, polyp or nevus.The method potentially includes a large amount of tissue of excision, such as mammary gland, bone, skin, fat or muscle.The method includes Extract all or part of organ or node, such as, lung, larynx, tongue, bladder, cervix uteri, ovary, testis, lymph node, liver, pancreas Gland, brain, eye, kidney, gallbladder, stomach, colon, rectum or large intestine.In one embodiment, described cancer is breast carcinoma, such as three Negative breast cancer, and surgical intervention is mammectomy or lumpectomy.

Microbial conditions

Compound of the present invention or compositions can be used for treating growth of microorganism or disease." microbial conditions " refers to A kind of disease or disease, it is characterized in that heterologous cells be grown on experimenter or within, such as, antibacterial, virus or fungus. The cell wall of the possible targeted microorganisms of waterborne compositions or cell membrane, or the necessary path of interference, thus the growth of restriction micro-organisms. Exemplary microbial conditions include by coccidiosis, staphylococcus, enterococcus faecalis and enterococcus faecalis, streptococcus pneumoniae, escherichia coli, Salmonella, Klebsiella Pneumoniae, pseudomonas (Pseudomonas) bacterial strain and enterobacteria bacterial strain infect.

Microbial association therapy

In some embodiments, compositions of the present invention can be used together with other antibiotic, such as with spore bacterium Element, penicillin, quinolinones, sulfonamides or tetracycline.Suitable antibiotic, including Abacavir, acyclovir, albendazole, Amikacin, amoxicillin, ampicillin, azithromycin, aztreonam, benzylpcnicillin, cefepime, ceftriaxone, head Cefalexin, chloromycetin, chloroquine, west take charge of its fourth, clindamycin, bactrim, didanosine, dioxidine, doxycycline, Famciclovir, fluconazol, fosfomycin sodium, fusidic acid, ganciclovir, gentamycin, isoniazid, josamycin, kanamycin, Ketoconazole, lamivudine, lincomycin, Linezolid, mebendazole, meropenem, metronidazole, furazolidone mupirocin, not Xisha star, nystatin, nitrofurantoin, nitroxoline, norfloxacin, ofloxacin, ornidazole, department of Austria its Wei, polymyxin B, polymyxin M, guanidine, ribavirin, rifampicin, ethamine, Roxithromycin, spectinomycin, sulfa drug, teicoplanin, spy compare naphthalene Sweet smell, tetracycline, tinidazole, valaciclovir, valganciclovir, vancomycin, zanamivir or zidovudine.A class is had to be referred to as Ionophoric antibiotic, including Emericid, ionomycin, laidlomycin, nigericin, grisorixin, hunts god Mycin, Reynolds mycin, Salinomycin, narasin, alborixin, septamycin, Maduramicin, semduramicin, draw sand In rhzomorph, mutalomycin, different lasalocid, lysocellin, tetronasin and Quinomycin A..

Using method

A kind of method for differentiating compound, described compound can suppress cancer, such as, the tumor mediated by CSC- Formed and include contacting the cell of detection with a kind of compound or compositions, and the cell detected is being increased And/or existence in change identify.In some embodiments, the cell of detection refers to have been subjected to, or just In experience from epithelium a to fundamental change (such as, from the cell of following cell line: Ecad, GFP, Hs578T, MCF, Su159) Cell.The screening technique that a kind of art technology field can be used in vitro or in vivo to be held office screens, from but use In the cell of detection is contacted with a kind of compound or compositions, and the cell detected is being increased and/or existence In change identify.Exemplary Screening and Identification more described herein, include but not limited to that those are at WO2009/ Those listed by 126310, during this application is to be fully incorporated herein by way of reference.

Use and medication

The compound of the present invention and pharmaceutical composition orally available are used, parenteral administration, use, locally by sucking spraying Use, rectal administration, by nasal administration, used by buccal, vaginal application or use via embedded type container, preferably pass through Orally administered or used by injection.

In some embodiments, compound or pharmaceutical composition can use to receptor through parenteral.Implement at some In mode, compound or pharmaceutical composition can be administered with intravenous, are administered with the dosage of 0.001 to 10mg/kg, example Such as 0.005 to 5mg/kg, such as 0.01 to 1mg/kg, such as 0.1 to 1mg/kg, such as 0.1mg/kg or 0.1mg/kg or 0.2mg/kg or 0.3mg/kg or 0.4mg/kg or 0.5mg/kg or 0.6mg/kg or 0.7mg/kg or 0.8mg/kg or 0.9mg/kg or 1.0mg/kg.In some embodiments, the orally available administered compound of described receptor or pharmaceutical composition. Can be administered with the dosage of 0.01 to 100mg/kg at some embodiments, compound or pharmaceutical composition, such as, 0.05 To 50mg/kg, such as 0.1 to 10mg/kg, such as 1to 10mg/kg, such as 2mg/kg or 2mg/k or 3mg/kg or 4mg/ Kg or 5mg/kg or 6mg/kg or 7mg/kg or 8mg/kg or 9mg/kg or 10mg/kg.Term used herein intestinal In including subcutaneous, Intradermal, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, breastbone outside stomach, in sheath, intralesional and intracranial note Penetrate or infusion techniques.In some embodiments, described compound or pharmaceutical composition are by intravenous administration.

In some embodiments, compound of the present invention or pharmaceutical composition are with any oral acceptable agent Amount form carries out Orally administered, and described oral acceptable dosage form includes but not limited to, liquid gel oral dosage form, sugar Slurry agent, Emulsion and aqueous suspension agent.Liquid gel can include gel, plasticizer and/or opaque resin as required, in order to obtains The denseness being suitable for, and can be as a part for dosage form, described dosage form can be coated with enteric coating layer, and described enteric is coated with Layer refers to go through so to use, such as lac (shellac).Other thickening agent, such as natural gum (gums) example can be added Such as xanthan gum (xanthum gum), starch such as corn starch or mucilage (glutens), thus obtain when be used for being administered orally Desired compound or the denseness of pharmaceutical composition during dosage.If it is desired, it is possible to add some sweeting agent and/or Seasoning and/or coloring agent.

In some embodiments, described method farther include by compound of the present invention or compositions and other Cancer therapy common implementing, other cancer therapy such as X-ray therapy, chemotherapy or hormonotherapy carry out combining executing With.In some embodiments, other cancer therapy can be used with this compound or pharmaceutical composition simultaneously.Implement at some In mode, other cancer therapy can be with compound of the present invention or pharmaceutical composition continuous administration.Some embodiment party In formula, other cancer therapy is chemotherapy.In some embodiments, described chemotherapy refers to taxanes, example Such as docetaxel (docitaxel), paclitaxel (paclitaxel) or Cabazitaxel (cabazitaxel).Some embodiment party In formula, described chemotherapy refers to platinum-like compounds, such as, and cisplatin.In some embodiments, described chemotherapy refers to It is PARP inhibitor, such as inaparib.In some embodiments, described chemotherapy refers to anthracycline, such as Ah Mycin.

The receptor agents weight range of compound of the present invention or pharmaceutical composition typically from about 0.1 μ g to 10, 000mg, more typically from about 1 μ g to 800mg, such as with about 10 μ g to about 100mg, with every day, weekly, monthly, Or other times interval enforcement one or many.According to given recipient body weight, typical case in certain embodiments of the present invention Dosage range from about 0.1 μ g to 20mg/kg/day, such as from about 1mg/kg/day to 10mg/kg/day, such as from greatly About mg/kg/day to 5mg/kg/day.On some embodiments, compound or pharmaceutical composition are with 0.001 to 10mg/kg Dosage passes through intravenously administrable, such as, with 0.005 to 5mg/kg, such as, with 0.01 to 1mg/kg, such as, with 0.1 to 1mg/kg, Such as 0.1mg/kg or 0.2mg/kg or 0.3mg/kg or 0.4mg/kg or 0.5mg/kg or 0.6mg/kg or 0.7mg/ Kg or 0.8mg/kg or 0.9mg/kg or 1.0mg/kg.In some embodiments, compound or pharmaceutical composition be with 0.01 to 100mg/kg dosage, such as, with 0.05 to 50mg/kg, such as, with 0.1 to 10mg/kg, such as, with 1 To 10mg/kg, such as, 2mg/kg or 2mg/kg or 3mg/kg or 4mg/kg or 5mg/kg or 6mg/kg or 7mg/kg, Or 8mg/kg or 9mg/kg or 10mg/kg.Absolute dosages will be according to various factors, and this influence factor includes controlling simultaneously Treatment, administration quantity and individual subject parameter include the amount of age, health, height and body weight.Above-mentioned influence factor for It is it is well known that and only just can be processed by normal experiment for those skilled in the art.Under normal circumstances, maximum is used Dosage, namely refers to, through the highest safe dose that rational medicine judges.The dosage used can be maximum tolerance agent Amount or sub-therapeutic dose or any dosage between them.Multiple dosage of molecule of the present invention can be examined Consider.When molecule of the present invention is co-administered with the sub-therapeutic dose of the molecule of alternative one or the sub-therapeutic dose of the two Time, can be applicable to suffer from cancer, or have and develop into cancer and divide first individual treatment.When two kinds of medicine uses simultaneously Time, its Chinese medicine can be administered by sub-therapeutic dose, thus obtains desired therapeutic effect.Sub-therapeutic dose is such one Planting dosage, this dosage refers to less than the agent that can obtain described therapeutic effect when there are not other reagent and using in individuality Amount.Thus, the sub-therapeutic dose of cancer drug refers to those, when there is not when using of molecule of the present invention, and can be Individuality produces the dosage of desired effect.The therapeutic dose of cancer drug refers to well-known use in pharmaceutical field Dosage in treatment of cancer.These dosage are documented in list of references the most widely, such as, and Remington ' s Pharmaceutical Sciences, the 18th edition, nineteen ninety；And many other refer to as treatment of cancer in medical speciality Lead the medical reference document of institute's foundation.

The dosage relatively low or higher than dosage noted above may be needed.Specific for any special receptor Dosage and therapeutic scheme will be according to multiple factors of influence, and it includes the activity of used particular compound, the age, body weight, whole Body health status, sex, diet, time of application, secreting rate, drug combination, the weight of disease and process, the state of an illness or the patient's condition, Receptor for disease in the case of, the state of an illness or the patient's condition and the judgement of the doctor in charge.

According to the improvement of receptor situation, if necessary, the compounds of this invention, compositions or administering drug combinations can be used The dosage of a kind of maintenance.Afterwards, when clinical symptom relief to a kind of desirable level, institute's applied dose or frequency, or Person both them, as the function of a kind of clinical symptoms, can be reduced to a kind of level maintaining improvement situation.But, based on Any recurrence of Disease Clinical symptom, receptor may need to carry out in a long time intermittent treatment.

In some embodiments, compound of the present invention or pharmaceutical composition can be as the one of dosage form Point.In some embodiments, described dosage form refers to a kind of parenteral dosage form, such as, for by quiet Arteries and veins is applied to receptor.In some embodiments, described dosage form refers at aseptic, hermetic container (such as, bottle Son, vial) in compositions.In some embodiments, described dosage form can be oral dosage form, example As, by by oral administration to receptor.In some embodiments, a kind of oral dosage form may also include spices or virtue Pastil, or both them, in order to improve mouthfeel or the abnormal smells from the patient of oral dosage form.

For the method evaluating compound

The come into the open effect of compound of the present invention can be evaluated in the following manner: makes test cell and compared with control cells and target Compound contacts.Then monitoring test cell and the growth of compared with control cells and/or survival.Produced test cell and compared to The compound that compared with control cells growth rate is different is selected for testing further and evaluating.Such as, test groups of cells can connect Touch the compound of various dose, or test groups of cells can contact the different time with compound.In some embodiments, Described compound can be used for producing response curve, and wherein test dose response curve represents test cell under multiple various dose The level of combined thing suppression.Above-mentioned analysis can be used for determining that compound is for test cell and/or the EC50 of compared with control cells Value.In some cases, compound is thin for test significantly less than compound statistically for the EC50 value of compared with control cells The EC50 value of born of the same parents.In other cases, compound is noticeably greater than compound pin statistically for the EC50 value of test cell EC50 value to compared with control cells.

In one embodiment, the compounds of this invention can use technology disclosed in WO 2009/126310 for Cancer stem cell and/or mesenchymal cell are evaluated, and above-mentioned application is to be fully incorporated the present invention by way of reference.At one In embodiment, the compounds of this invention can use " the Identification of Selective at Gupta et al. Inhibitors of Cancer Stem Cells by High-Throughput Screening ", Cell, vol.138, P.645-659 the technology disclosed in (2009) is evaluated for cancer stem cell and/or mesenchymal cell, and described document is to pass through The mode quoted is fully incorporated the present invention.

Secondly, it is possible to use said method, for control compound such as other cancer therapeutic agents (such as amycin, Taxol, camptothecine, radiating streptozotocin D, staurosporine), other antibiotics (such as penicillin, amoxicillin, tetracycline) or A combination thereof, compares the effect of compound disclosed by the invention with the effect of control compound.

Experimenter selects and monitoring

In embodiments more of the present invention, before using compound of the present invention, such as, can be to trouble Have or the doubtful experimenter suffering from disease of the present invention or the sample that obtains from experimenter detect, to determine whether to deposit At biomarker, such as one or more and Cancer-Related biomarker such as cancer stem cell or display mesenchyme The biomarker that cell exists.In some embodiments, waterborne compositions is applied to experimenter, this experimenter by With the biomarker of prediction (its can show exist with the CSC of related to cancer or tumor initiator cell or mesenchymal cell or Derived mesenchymal-like cells, or mesenchyme cancerous cell) identify, or wherein cancer is identified as being enriched with CSC or mesenchymal cell.

In order to identify or assess biomarker, such as cancer stem cell biomarker, or be used for showing that mesenchyme is thin The biomarker that born of the same parents exist, needs to obtain clinical sample (such as cancer specimen) from experimenter.Generally, clinical sample is tumor Slicer or its isolated separate cell.But, the present invention is not the most restrictive, and can use and be provided that There is the arbitrary suitable clinical sample that can detect cancer stem cell biomarker (in the experimenter having cancer stem cell).Show The clinical sample of example includes saliva, hair follicle stimulating hormone, gingiva secretions, cerebrospinal fluid, gastro-intestinal Fluid, mucus, urogenital Road secretions, synovial fluid, blood, serum, blood plasma, allantoic fluid, lymph fluid, ascites, hydrothorax, interstitial fluid, intracellular fluid, eye Body fluid, seminal fluid, mammal gland secretion, vitreous humour, nasal secretion.

In one embodiment, for gene marker, (this mark shows and is suitable for using compound of the present invention The disease for the treatment of), or one or more genes (this gene and being suitable for the ongoing disease wind of compounds for treating of the present invention Danger about) carry out the screening of clinical sample.Such as, gene expression analysis (the micro-row of such as nucleic acid, cDNA array, quantify RT-PCR, RNase protection test) can be used for identifying specific gene, or position the mark of the gene relevant with disease.Real at some Execute in mode, can be identified one or more in following gene: ANAPC2, CCND1 (cyclin D1), CCNE1 are (carefully Born of the same parents' Cyclin E protein 1), CDC7, CDC34, CDK4, CDK6, CDKN1B (p27), CDKN1C (p57), CDKN3, CUL1, CUL2, CUL3、CUL4A、CUL5、E2F1、SKP2；S phase and DNA replication dna: ABL1 (C-ABL), MCM2, MCM3, MCM4 (CDC21), MCM5(CDC46)、MCM6(Mis5)、MCM7(CDC47)、PCNA、RP A3、SUMO1、UBE1；G2 stage and G2/M conversion: ANAPC2, ANAPC4, ANAPC5, ARHI, BCCIP, BIRC5, CCNA1 (cyclin A1), CCNB1 (cyclin White B1), CCNG1 (Cyclin G 1), CCNH, CCNT1, CCNT2, CDC25A, CDC25C, CDC37, CDK5R1, CDK5R2、CDK5RAP1、CDK5RAP3、CDK2、CDK7、CDKN3、CKS1B、CKS2、DDX1 1、DNM2、GTF2H1、GTSE1、 HERC5、KPNA2、MNAT1、PKMYT1、RGC32、SERTAD1；M stage: CCNB2 (mitotic cycle protein B 2), CCNF, CDC2 (CDK1)、CDC16、CDC20(p55cdc)、CDC25A、CDC25C、MRE1 IA、RAD50、RAD51；Cell cycle checkpoint and Cell cycle arrest: ATM, ATR, BRCA1, BRCA2, CCNA2 (cyclin A2), CCNE2 (cyclin E2), CCNG2 (cyclin G2), CDC2 (CDK1), CDC25A, CDC34, CDC45L, CDC6, CDK2, CDKN1A (p21), CDKN1B(p27)、CDKN1C(p57)、CDKN2A(p16)、CDKN2B(p15)、CDKN2C(p18)、CDKN2D(p19)、 CDKN3、CHEK1(CHK1)、CHEK2(CHK2/RAD53)、CUL1、CUL2、CUL3、CUL4A、CUL5、GADD45A、HUS1、 KNTC1、MAD2L1、MAD2L2、NBS1(NIBRIN)、RAD1、RAD17、RAD9A、RB1、RBBP8、TP53(p53)；Cell week Period regulation: ABL1 (C-ABL), ANAPC2, ANAPC4, ANAPC5, ARHI, ATM, ATR, BCCIP, BCL2, BRCA2, CCNA1 (cyclin A1), CCN A2 (cyclin A2), CCNB1 (cell periodic protein B 1), CCNB2 (cell cycle Protein B 2), CCNC (cyclin C), CCND1 (cyclin D1), CCND2 (Cyclin D2), CCND3 (cyclinD3), CCNE1 (Cyclin E1), CCNE2 (cyclin E2), CCNF (cyclin White F), CCNH (cyclin H), CCNT1, CCNT2, CDC 16, CDC2 (CDK1), CDC20 (p55cdc), CDC25A, CDC25C、CDC37、CDC45L、CDC6、CDK2、CDK4、CDK5R1、CDK5R2、CDK6、CDK7、CDK8、CDKN1A(p21)、 CDKN1B(p27)、CKS1B、CUL5、DDX11、E2F1、E2F2、E2F3、E2F4、E2F5、E2F6、GADD45A、KNTC1、 MKI67(Ki67)、PCNA、PKMYT1、RAD9A、RB1、SKP2、TFDP1(DPI)、TFDP2(DP2)；Cell cycle negative regulation: ATM、BAX、BRCA1、CDC7、CDKN2B(p15)、CDKN2D(p19)、RBL1(p1O7RB)、RBL2(p130RB2)、TP53 (p53).Exemplary cells survival/apoptosis gene includes the member of those tnf ligand families: LTA (TNF-α), TNF (TNF-a), TNFSF5 (CD40L), TNFSF6 (FasL), TNFSF7 (CD27 part), TNFSF8 (CD30 part), TNFSF9 (4-IBB part), TNFSF1O (TRAIL), TNFSF14 (HVEM-L), TNFSF18；TNF receptor family: LTBR, TNFRSF1A(TNFR1)、TNFRSF1B(TNFR2)、TNFRSF5(CD40)、TNFRSF6(Fas)、TNFRSF6B、TNFRSF7 (CD27)、TNFRSF9(4-1BB)、TNFRSF1OA(DR4)、TNFRSF1OB(DR5)、TNFRSF1OC(DcR1)、TNFRSF1OD (DcR2)、TNFRSF1IB、TNFRSF12A、TNFRSF14(HVEM)、TNFRSF19、TNFRSF21、TNFRSF25；Bc1-2 family Race: BAD, BAG1, BAG3, BAG4, BAK1, BAX, BCL2, BCL2A1 (bf1-l), BCL2L1 (bc1-x), BCL2L2 (bc1- W), BCL2L10, BCL2L11 (bim-sample albumen), BCL2L12, BCL2L13, BCLAF1, BID, BIK, BNIP1, BNIP2, BNIP3(nip3)、BNIP3L、BOK(Mtd)、HRK、MCL1；Caspase family: CASP1, CASP2, CASP3, CASP4, CASP5、CASP6、CASP7、CASP8、CASP9、CASP1O、CASP14；IAP family: BIRC1 (NIAP), BIRC2 (IAP2), BIRC3(IAP1)、BIRC4(XIAP)、BIRC5(Survivin)、BIRC6(Bruce)、BIRC7、BIRC8；TRAF family: TRAF1、TRAF2、TRAF3(CRAF1)、TRAF4、TRAF5；CARD family: APAF1, BCL1O (HuE1O), BIRC2, BIRC3, CARD4(NOD1)、CARD6、CARD8、CARD9、CARD1O、CARD11、CARD12、CARD14、CARD15、CASP1、CASP2、 CASP4、CASP5、CASP9、CRADD、NOL3(Nop30)、PYCARD、RIPK2(CARDIAC)；Death domain family: CRADD、DAPK1、DAPK2、FADD、RIPK1、TNFRSF1OA、TNFRSF1OB、TNFRSF1IB、TNFRSF1A、TNFRSF21、 TNFRSF25、TNFRSF6、TRADD；CIDE domain family: CIDEA, CIDEB, DFFA, DFFB；P53 and DNA damage response: ABL1、AKT1、APAF1、BAD、BAX、BCL2、BCL2L1、BID、CASP3、CASP6、CASP7、CASP9、GADD45A、TP53 (p53)、TP53BP2、TP73、TP73L；With AKT1, BAG1, BAG3, BAG4, BCL2, BCL2A1, BCL2L1, BCL2L10, BCL2L2、BFAR、BIRC1、BIRC2、BIRC3、BIRC4、BIRC5、BIRC6、BIRC7、BIRC8、BNIP1、BNIP2、 BNIP3、BRAF、CASP2、CFLAR、GDNF、IGFlR、MCL1、TNF(TNF-a)、TNFRSF6、TNFRSF6B、TNFRSF7、 TNFSF18、TNFSF5。

In one embodiment, stem cell biological mark, or for showing the biological marker that mesenchymal cell exists Thing, is to express and the distribution of CD44/CD24 cell surface marker selected from E-cadherin, TWIST.Picking up from the cancer of experimenter To stem cell biological mark in disease sample, or for showing that the biomarker that mesenchymal cell exists is identified.One In individual embodiment, by measuring E-cadherin level and/or the TWIST albumen in cancer and/or rna expression, and appoint Above-mentioned level is compared by selection of land with reference levels, thus measures the E-cadherin in cancer and/or TWIST expression. In one embodiment, reference levels are the E-cadherin in cancer stem cell and/or TWIST albumen and/or RNA Expression.In one embodiment, reference levels be E-cadherin in the cancerous cell of non-cancer stem cell and/ Or TWIST albumen and/or the expression of RNA.

In one embodiment, stem cell biological mark, or for showing the biological marker that mesenchymal cell exists Thing is selected from CD20, CD24, CD34, CD38, CD44, CD45, CD105, CD133, CD166, EpCAM, ESA, SCA1, Pecam And Strol.

In some cases, it may be necessary to having or the doubtful cancer stem cell biological marker having in cancer experimenter Thing, or for showing that the biomarker that mesenchymal cell exists is estimated, and come according to biomarker assessment result Treatment means is selected for experimenter.Such as, if be detected that cancer stem cell biomarker, or be used for showing mesenchymal cell The biomarker existed, just treats experimenter with the effective dose of compound disclosed by the invention or compositions.Implement at some In mode, if be detected that cancer stem cell biomarker, or for showing the biomarker that mesenchymal cell exists, just Treating experimenter experimenter with the effective dose of pharmaceutical composition disclosed by the invention, this pharmaceutical composition comprises avilamycin, depends on Torr pool glycosides or nigericin, or any of the above-described derivant, optionally (the most water-soluble with taxol or derivatives thereof Or relevant compound in the derivant of targeting or structure, such as analog, such as docetaxel) carry out combining (see, e.g. WO/2003/045932 and US2008033189).By method disclosed by the invention or arbitrary suitable method well known in the art, Can to the cancer stem cell biomarker of said method, or be used for showing that the biomarker that mesenchymal cell exists is carried out Assessment.Exemplary cancer stem cell biomarker, or for showing that the biomarker that mesenchymal cell exists includes E- Cadherin is expressed, and TWIST expresses, and CD44⁺CD24 marker profile.Other can be used for during the course show activity Biomarker swashs selected from TGF-β, Wnt, BMP, Notch, HGF-Met, EGF, IGF, PDGF, FGF, P38-mapk, Ras, PB Enzyme-Akt, Src and NF-kB.The invention discloses other exemplary cancers stem cell biological mark, or fill between display Cell plastid exist biomarker and one of ordinary skill in the field is apparent from.

In one embodiment, the clinical sample screened is carried out for protein level, such as by cell cycle/growth And/or the level of albumen that survival genes (gene the most listed above) encodes.By to one of ordinary skill in the field Known to for, suitable method, detects the level of albumen, and such as Western analyzes.Ordinary skill to this field For personnel, other method known can be provided for the level of analyzing proteins, such as immune group chemistry, immunocytochemistry, ELISA, radioimmunoassay and protrinology method, such as mass spectrography or antibody array.

Using after biomarker identifies, monitoring and accept the tested of compound of the present invention or compositions Person, such as, for the improvement of illness and/or the expression of the biomarker of retroaction or display disease.Such as raw by monitoring Grow, lack growth or disappear (the such as tumor) of cancer, the improvement degree of assessment experimenter's illness.In some embodiments, use Experimenter is estimated by radiation detection or hemolysis parameters assessment.In other implementations, base of the present invention is used Cause or Protein Detection assessment experimenter.Also experimenter can be assessed with conventional screening assays, such as physical examination, Mammogram, Biopsy, total colonoscopy etc..

Test kit

The present invention comprises the test kit including compositions of the present invention further.In some embodiments, reagent Box additionally contains diluent, its object is to the result obtained by being diluted to by waterborne compositions such as in test kit. In some embodiments, diluent is water.In some embodiments, diluent is pharmaceutically acceptable vehicle, example Vehicle the most disclosed by the invention.In some embodiments, diluent includes water.In some embodiments, test kit Comprise the description for diluting waterborne compositions with diluent investing in test kit.

In some embodiments, test kit also comprises in extra therapeutic agent, such as chemotherapeutant, the such as present invention Described chemotherapeutics.In some embodiments, test kit also comprises and uses waterborne compositions together with other therapeutic agent Description.

Waterborne compositions of the present invention can be applied to experimenter with the form of compound or compositions or dosage form.? In certain situation, waterborne compositions or dosage form are together with the description using waterborne compositions, as a part for test kit.Examination Agent box can additionally comprise diluent (such as thing water of the present invention, saline or medium) and with required waterborne compositions one Act the description using diluent.Waterborne compositions is used together with other therapeutic agent (if present), this therapeutic agent Amount is to be effective in regulation disease or the regulation of disease disease (include of the present invention those).Can be with of the present invention Waterborne compositions simultaneously, or in turn use other therapeutic agent with waterborne compositions of the present invention.

Embodiment

The following example relates to scheme 1-7 (as described below).

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

For convenience's sake, the compound in scheme 1-7 is numbered, and need not with in table 1 (as follows) Any specific compound be associated.Additionally, synthetic method described below, i.e. allow to carry out, but be only May be used for obtaining the illustrative methods of compound of the present invention.Those skilled in the art can easily improve these and implement Example is to obtain compound required for protection.Reagent (such as EtOAc, HCl, MeOH etc.) as disclosed hereinafter derives from multiple Supplier, such as Sigma-Aldrich (Milwaukee, WI).

The preparation of embodiment 1. Salinomycin methyl ester (6)

Salinomycin sodium salt (2,10g, Zhejiang Shenghua Baike Pharmaceutical, China) is dissolved in In EtOAc (250mL), and wash with HCl 0.1N (250mL).With saline (50mL), organic facies will be washed, make It is dried with magnesium sulfate, filters and be concentrated in vacuo.Residue is dissolved in CHCl₃In-MeOH mixture (1: 1,100mL), and And gained solution is cooled to 0 DEG C.TMSCHN is added in 15min₂(at Et₂2.0M in O, 6.30mL), by gained solution in room The lower stirring 1h of temperature is also concentrated in vacuo.Crude product uses Teledyne Isco purification system to existGold post Purification is carried out by chromatography (with triethylamine, the silica gel that EtOAc-hexane is saturated) on (Teledyne Isco, Lincoln, NE), To produce the white solid of the product 6 of 8.32g (84% yield).MS (ESI+): 787.70 (M+Na)⁺.

In an interchangeable synthetic method, Azimethylene. is to produce by decomposing n-nitroso-group methylguanidine.Pass through Pipet the yellow diazomethane solution of excess is added be dissolved in the solution of absolute ether (5ml) Salinomycin sodium salt (2, 0.2g, 1.0eq.).Diazomethane solution is added and reacts, until yellow persistently occurs.Then will react in ambient temperature Lower stirring 1h.Use 1 acetic acid to make this reaction quencher, and be diluted by ethyl acetate.It is washed with saturated sodium bicarbonate Wash, dried over magnesium sulfate, and be concentrated in vacuo.Crude product uses ethyl acetate/hexane gradient to utilize 25S Biotage silicagel column (Biotage AB, Uppsala, Sweden) passes through flash chromatography.Pure products separates with the yield of 58%.MS 764.5(M+Na)；Value of calculation exact mass 787.5.

The preparation of embodiment 2:20-acetoxyl group-Salinomycin methyl ester (6a)

Being similar to, available methyl ester 6 (embodiment 1) prepares Salinomycin methyl ester 6a using acetas 11 as initiateing.Through chromatography The product 6a obtained after method carries out isolated with 60% yield.MS829.5(M+Na)；Value of calculation exact mass 806.5.

The preparation of embodiment 3:20-oxo-Salinomycin (7)

By MnO₂(163mg, 15.0eq.) is added in CH₂Cl₂(1.5mL) the Salinomycin sodium salt (2,100mg, 1.0eq.) in Solution in, mixture is stirred at room temperature 24h, celite filters and concentrates.Residue is dissolved in CH₂Cl₂ , and add MnO (1.5mL)₂(163mg, 15.0eq.).Gained mixture is stirred at room temperature 48h, celite filters And concentrate.Residue is dissolved in EtOAc (5mL), washs with HCl 0.1N (2mL), dried over magnesium sulfate, filter and vacuum is dense Contracting.Crude product uses Teledyne Isco purification system to existBy chromatography (silica gel, CH on Gold post₂Cl₂- MeOH) it is purified, is used for producing the white solid of the product 7 of 54mg (54% yield).MS (ESI-): 747.54 (M-H)^-.

Embodiment 4.18, the preparation of 19-dihydro-20-oxo-Salinomycin (8)

2O-oxo-Salinomycin (7,50mg, 1.0eq.) (embodiment 3) is dissolved in EtOAc (1mL) and adds Pd/C (10%, 50% moisture, 50mg).By H₂Blast 10min in mixture, then make reaction stir 16h.By N₂Blast 10min, will Mixture existsUpper filtration, by filter vacuum concentration to produce the white solid of the product 8 of 48mg (96%).MS(ESI +): 773.53 (M+Na)⁺.

The preparation of embodiment 5. Salinomycin Methanamide (9)

By Salinomycin sodium salt (2,300mg, 1.0eq), Bis(tert-butoxycarbonyl)oxide (439mg, 5.2eq.), NH₄HCO₃ The mixture mixing of (398mg, 5.0eq.) and MeCN (1.3ml), and add pyridine (0.02mL, 0.5eq.).By mixture It is stirred at room temperature 60h.Add Bis(tert-butoxycarbonyl)oxide (439mg, 5.2eq.), NH₄HCO₃(398mg, 5.0eq.) and pyridine (0.03mL, 0.75eq.), and mixture is heated at 40 DEG C 2h.Add Bis(tert-butoxycarbonyl)oxide (439mg, 5.2eq.), NH₄HCO₃(398mg, 5.0eq.) and MeCN (1mL), and mixture is heated at 40 DEG C 16h.Add EtOAc (100mL), And the mixture of gained is used water (50mL) washing, then uses saline (25mL) to wash.Organic facies is dried over sodium sulfate, Filter and be concentrated in vacuo.Crude product uses Teledyne Isco purification system to existChromatography is passed through on Gold post (silica gel, ethylacetate-hexane-acetone) carrys out purification, thus produces the product of 125mg (43%).Acetone is used to grind to obtain The white powder (32%) of the 9 of 92mg.MS (ESI+): 772.65 (M+Na)⁺.

The preparation of embodiment 6.11-methyloxime-Salinomycin sodium salt (10)

By Salinomycin sodium salt (2,300mg, 1.0eq), O-methyl hydroxylamine (470mg, 14.5eq.), pyridine (0.86mL, 27eq.) and the mixture of MeOH (3.9ml) is stirred at room temperature 84h.Add EtOAc (50mL), and by the mixing of gained Thing aq.HCl 1N (25mL), water (25mL), saturated NaHCO₃Aqueous solution (25mL) and saline (25mL) wash.Organic Mutually dried over sodium sulfate, filter and be concentrated in vacuo.Crude product use Teledyne Isco purification system exist Carry out purification by chromatography (silica gel, ethylacetate-hexane-acetone) on Gold post, thus produce the oil of the 10 of 78mg (26%) Shape thing.MS (ESI+): 802.60 (M+H)⁺.

The preparation of embodiment 7.20-acetoxyl group-Salinomycin sodium salt (11)

At 0 DEG C, by Ac₂Salinomycin sodium salt that O (2.44mL, 8.0eq.) is slowly added in pyridine (12mL) (2, 2.50g, 1.0eq) and the solution of DMAP (20mg) in.Reactant mixture is stirred at room temperature 16h, is subsequently cooled to 0 DEG C, it Rear interpolation water (20mL).Mixture is stirred at room temperature 30min, adds EtOAc (50mL) and HCl 6N (24mL) afterwards.Right Separate mutually, and organic facies is used HCl 0.1N (20mL), saline (20mL), saturated NaHCO₃Aqueous solution (2x20mL) Wash with saline (20mL).Organic facies is dried over sodium sulfate afterwards, filters and is concentrated in vacuo.Crude product mixes from acetone-water Compound crystallizes, thus produces the white solid of the 11 of 1.95g (74%).MS (ESI+): 815.70 (M+H)⁺.

In an interchangeable synthetic method, by the Salinomycin in dry pyridine (1ml) under cooling down with ice Sodium salt (2,0.15g, 1.0eq.) solution joins in acetic anhydride (0.075ml).At ambient temperature, reaction is stirred in nitrogen Mix 18h.Hereafter, reaction being poured in frozen water and use 0.05N HCl to be acidified to pH is 3.Water layer is used ethyl acetate back extraction Take (twice).Organic layer is dried over magnesium sulfate and is concentrated in vacuo.Crude product uses ethyl acetate/hexane gradient to utilize 25M Biotage silicagel column passes through flash chromatography.Pure products 11 separates with 41% yield.MS814.5(M+Na)；Calculate Value exact mass 792.5.

Embodiment 8.18, the preparation of 19-dihydro-Salinomycin sodium salt (12)

Salinomycin sodium salt (2,325mg, 1.0eq.) is dissolved in THF (5mL), and adds Pd/C (10%, 50mg).Will H₂Blast 10min in mixture, then 16h is stirred in reaction.Mixture is filtered on 2 micron filters, and will Filter vacuum concentrates thus produces the white solid of the compound 12 of 313mg (96%).MS (ESI+): 775.61 (M+H)⁺.

In an interchangeable synthetic method, to the acetic acid second of Salinomycin sodium salt (2,0.2g, 0.26mmol, 1.0eq.) Ester (10ml) solution adds platinum oxide (0.1eq).Reaction is emptied, and backfills (3 times) with hydrogen.At ambient temperature, will 18h is stirred in reaction under hydrogen balloon.Then reactant mixture is made to be filtered by celite and be concentrated in vacuo.Crude product uses acetic acid Ethyl ester/hexane gradient utilizes 25S Biotage silicagel column to pass through flash chromatography.Pure products (white foam) is received with 30% Rate separates.MS 777.2(M+Na).

Embodiment 9:18, the preparation of 19-dihydro-20-acetoxyl group-Salinomycin sodium salt (13)

At 0 DEG C, by Ac₂O (0.26mL, 8.0eq.) is slowly added to (12,268mg, 1.0eq) (embodiment 8) and DMAP (1mg) in the solution of pyridine (1.3mL).Reactant mixture is stirred at room temperature 16h, then adds Ac₂O (0.13mL, 4.0eq.).Reactant mixture is stirred at room temperature 5h, and adds EtOAc (5mL).Mixture is stirred at room temperature 30min, adds hexane (5mL) afterwards.To separating mutually, and organic facies is used HCl 1N (15mL), HCl 0.1N (10mL), saline (10mL), saturated NaHCO₃Aqueous solution (10mL) and saline (10mL) wash.Organic facies is done through sodium sulfate Dry, filter and be concentrated in vacuo.Crude product crystallizes to produce the white solid of the 13 of 140mg (49%) from acetone.MS (ESI+): 817.63(M+H)⁺.

Embodiment 10: the preparation of Salinomycin benzyl ester (14)

At room temperature, by Salinomycin sodium salt (2,1.00g, 1.0eq.), BnBr (0.77mL, 5.0eq.), NaHCO₃ The mixture lucifuge stirring 80h of (1.08g, 10.0eq.) and DMF (5ml).Add EtOAc (75mL), gained mixture is used Water (5x50mL), then saline (25mL) is used to wash.Organic facies is dried over magnesium sulfate, filters and is concentrated in vacuo.Crude product makes Exist with Teledyne Isco purification systemBy chromatography (with triethylamine, ethylacetate-hexane on Gold post Saturated silica gel) purification, to produce the white solid of the compound 14 of 0.83g (76% yield).MS (ESI+): 863.7 (M+ Na)⁺.

In interchangeable synthetic method, to Salinomycin sodium salt (2,0.15g, 0.19mmol, 1.0eq.) at DMF (2ml) Solution add sodium bicarbonate (32mg, 2.0eq.) and benzyl bromide a-bromotoluene (0.16g, 5.0eq.), will react at ambient temperature at nitrogen Gas stirs 18h.Hereafter, reaction is made dilute with water, and is extracted with ethyl acetate (twice).Organic layer is dried over magnesium sulfate also It is concentrated in vacuo.Crude product uses ethyl acetate/hexane gradient to utilize 25M Biotage silicagel column to pass through flash chromatography. Pure products is separated into 40% yield .MS 862.5 (M+Na)；Value of calculation exact mass 840.5.

The preparation of embodiment 11. Salinomycin 4-methoxy-benzyl ester (15)

At room temperature by Salinomycin sodium salt (2,2.00g, 1.0eq.), PMBBr (1.56g, 3.0eq.), NaHCO₃ (0.84g, 4.0eq.), the mixture lucifuge stirring 80h of DMF (5.2ml).Add EtOAc-hexanes mixtures (3: 1,20mL), And use water (4x25mL) to carry out washing, then using saline (25mL) to wash in gained mixture.The organic facies warp obtained Sodium sulfate is dried, and filters and is concentrated in vacuo.Crude product uses Teledyne Isco purification system to existGold post On be purified by chromatography (triethylamine, the silica gel that ethylacetate-hexane is saturated), thus produce 1.88g (84% yield) The white solid of compound 15.MS (ESI+): 888.69 (M+NH₄)⁺.

The system of embodiment 12.20-acetoxyl group-Salinomycin methyl ester (16)

By Ac at 0 DEG C₂O (5.90mL, 12.0eq.) is slowly added to (6,4.00g, 1.0eq) (embodiment 1) and DMAP (20mg) in pyridine (20mL) solution.Reactant mixture is stirred at room temperature 1h, dilutes with EtOAc (250mL), use HCl 1N (250mL), HCl 0.1N (100mL), saturated NaHCO₃Aqueous solution (100mL), saline (100mL) wash.? The organic facies arrived is dried over magnesium sulfate, filters and is concentrated in vacuo.Crude product uses Teledyne Isco purification system to existBy chromatography (triethylamine, the silica gel that ethylacetate-hexane is saturated) purification on Gold post, thus produce The white powder of the compound 16 of 3.81g (90% yield).MS (ESI+): 829.69 (M+Na)⁺.

The preparation of embodiment 13.20-p-tosyloxy-Salinomycin methyl ester (17)

At 0 DEG C, Salinomycin methyl ester (6) (267mg, 1.0eq) (embodiment 1) and DMAP (2.1mg) are mixed into pyridine (1.3mL) in, and p-toluene sulfochloride (533mg, 8.0eq.) is disposably added.Reactant mixture is stirred at room temperature 4h.Then make mixture be cooled to 0 DEG C, add water (5mL) and EtOAc (5mL) afterwards.Mixture is stirred at room temperature 30 points Clock, and add hexane (5mL).It is separated, organic facies use HCl 1N (15mL), HCl 0.1N (10mL), saline (10mL), Saturated NaHCO₃Aqueous solution (10mL) and saline (10mL) washing.Organic facies is dried over sodium sulfate, filter and be concentrated in vacuo thus Produce the white solid of the compound 17 of 316mg (98% yield).MS (ESI+): 936.66 (M+NH₄)⁺.

The preparation of embodiment 14.20-methoxyl group-Salinomycin methyl ester (18)

By Salinomycin methyl ester (6) (104mg, 1.0eq.) (embodiment 1) and 1, double (dimethylamino) naphthalene (Proton of 8-, Sigma-Aldrich, 38mg, 1.3eq.) at room temperature it is dissolved in CH₂Cl₂(1.1mL), trimethyl is added afterwards Oxygen tetrafluoroborate (24mg, 1eq.).Reactant mixture is stirred at room temperature 16h, and adds Proton (190mg, 6.5eq.),Molecular sieve (500mg) and trimethyl oxygen tetrafluoroborate (120mg, 6.0eq.).Mixture is stirred Mix 16h and be concentrated in vacuo.Mixture uses Teledyne Isco purification system to existChromatography is passed through on Gold post (triethylamine, the silica gel that ethylacetate-hexane is saturated) purification, thus produce the compound 18.MS (ESI of 15mg (14% yield) +): 796.62 (M+NH₄)⁺.

Embodiment 15.18, the preparation of 19-methylene-Salinomycin (19)

At 0 DEG C, diethyl zinc (1.1M, 0.70mL, 6.0eq. in PhMe) is joined ClCH₂I (112 μ L, CH 12.0eq.)₂Cl₂(2mL) in solution.At 0 DEG C, gained mixture is stirred 10min, adds Salinomycin sodium salt afterwards The CH of (2,100mg, 1.0eq.)₂Cl₂(1mL) solution.Mixture is stirred at room temperature 96h.Add saturated NH₄Cl aqueous solution (2mL), and by reactant mixture CH₂Cl₂Extraction.The organic facies obtained is concentrated, and residue is dissolved in EtOAc (5mL), and And add HCl0.1N (5mL).Layering, organic facies uses saline washing, dried over magnesium sulfate, filters and is concentrated in vacuo thus produces The compound 19 of raw 88mg (86% yield).MS (ESI+): 787.63 (M+Na)⁺.

Embodiment 16.18, the preparation of 19-methylene-Salinomycin methyl ester (20)

At 0 DEG C, diethyl zinc (1.1M, 0.30mL, 5.0eq. in PhMe) is joined ClCH₂I (47 μ L, CH 10.0eq.)₂Cl₂(1mL) in solution.At 0 DEG C, gained mixture is stirred 10min, adds Salinomycin methyl ester afterwards (6,50mg, 1.0eq.) (embodiment 1) is at CH₂Cl₂(1mL) solution in.Mixture is stirred at room temperature 60h.Add saturated NH₄Cl aqueous solution (1mL), and by reactant mixture CH₂Cl₂Extract.The organic facies obtained is concentrated, residue is molten In EtOAc (5mL) and add HCl0.1N (5mL).Layering, organic facies uses saline washing, dried over magnesium sulfate, filters and true Empty concentration.Crude product uses Teledyne Isco purification system to existOn Gold post by chromatography (triethylamine, The silica gel that ethylacetate-hexane is saturated) it is purified, thus the white producing the product Compound 20 of 34mg (67% yield) is solid Body.MS (ESI+): 801.74 (M+Na)⁺.

The preparation of embodiment 17.9-oxo-20-acetoxyl group-Salinomycin methyl ester (21)

At room temperature, by DMP (64mg, 2.4eq.) at CH₂Cl₂(2mL) solution join compound (16) (50mg, 1.0eq.) (embodiment 12) and NaHCO₃The CH of (52mg, 10eq.)₂Cl₂(1mL) in mixture.By mixture at room temperature Stirring 60h.Add saturated NaHCO₃Aqueous solution (1mL) and saturated Na₂S₂O₃Aqueous solution (1mL), and biphase mixture is stirred 1h, afterwards by reactant mixture CH₂Cl₂Extraction.The organic facies obtained uses saline washing, dried over magnesium sulfate, filters and true Empty concentration.Crude product uses Teledyne Isco purification system to existOn Gold post by chromatography (triethylamine, The silica gel that ethylacetate-hexane is saturated) purification, thus produce the compound 21 of 40mg (80% yield).MS (ESI+): 827.66 (M+Na)⁺.

Embodiment 18.9-11-pyrazoles-20-acetoxyl group-Salinomycin methyl ester (22) and 9-11-pyrazoles-Salinomycin methyl ester (23) preparation

By 9-oxo-20-acetoxyl group-Salinomycin methyl ester (21) (216mg, 1.0eq.) (embodiment 17) and anhydrous slufuric acid Sodium is at room temperature at Et₂O (2.5mL) mixes, and adds hydrazine hydrate (24 μ L, 1.5eq.).By mixture in room temperature Lower stirring 20h, and concentrating under reduced pressure.Crude product uses Teledyne Isco purification system to existLead on Gold post Cross chromatography (triethylamine, the silica gel that ethylacetate-hexane is saturated) to be purified, thus produce the product of 133mg (66% yield) Thing 22, MS (ESI+): 801.67 (M+H)⁺With the product Compound 23 of 25mg (12% yield), MS (ESI+): 759.58 (M+H )⁺.

The preparation of embodiment 19.9-11-pyrazoles-20-acetoxyl group-Salinomycin sodium salt (24)

At room temperature, by 9-11-pyrazoles-20-acetoxyl group-Salinomycin methyl ester (22,43mg, 1.0eq.) (embodiment 18) Mix in THF (1.0mL), MeOH (0.5mL) and water (0.5mL) with lithium hydroxide monohydrate (49mg, 22eq.).Will Mixture is stirred at room temperature 2h, and is heated to 50 DEG C and is applicable to 64h.Then, mixture is cooled to room temperature, adds water (5mL) with hexane (5mL), then it is separated.Organic facies use HCl0.1N (5mL) obtained, saline (5mL) is saturated NaHCO₃Aqueous solution (2x5mL) and saline (5mL) washing.Organic facies is dried over sodium sulfate, filters and is concentrated in vacuo.Crude product makes Exist with Teledyne Isco purification systemBy chromatography (silica gel, ethylacetate-hexane-the third on Gold post Ketone) purification, thus produce the compound 24 of 15mg (43% yield).MS (ESI+): 745.62 (M+H)⁺.

The preparation of embodiment 20.20-acetoxyl group-Salinomycin dimethylformamide (25)

Salinomycin acetas (11,0.1g, 0.13mmol) (embodiment 7) in the solution at dry DCM (3ml) adds Add dimethyl amine (0.3ml, 2M in THF), then add PyBrop (0.06g, 0.13mmol), will react at ambient temperature 18h is stirred in nitrogen.Hereafter, by reaction diluted ethyl acetate, and use saturated sodium bicarbonate to wash.Organic layer is through sulphuric acid Magnesium is dried and is concentrated in vacuo.Crude product uses ethyl acetate/hexane gradient to utilize 12M Biotage silicagel column to pass through flash chromatography Method purification.Pure product Compound 25 is separated is 28% yield.MS 842.6(M+Na)；Value of calculation exact mass 819.56..

The preparation of embodiment 21.20-acetoxyl group-Salinomycin methyl nitrosourea (26)

Salinomycin amide 26 is prepared through the process being similar to amide 25 (embodiment 20).At chromatography afterproduct chemical combination Thing 26 is separated is 46% yield.MS 828.5(M+Na)；Value of calculation exact mass 805.5.

The preparation of embodiment 22. Salinomycin dimethylformamide (27)

The Salinomycin of the 0.2g (0.27mmol) in the solution at dry DCM (5ml) add dimethyl amine (0.6ml, 2M in THF), then add PyBrop (0.125g, 0.27mmol), 18h is stirred in reaction at ambient temperature in nitrogen.This After, by reaction diluted ethyl acetate, and use saturated sodium bicarbonate to wash.Organic layer is dried over magnesium sulfate and is concentrated in vacuo. Crude product uses ethyl acetate/hexane gradient to utilize 25SM Biotage silicagel column to pass through flash chromatography.Pure products 27 Separated is 38% yield.MS 800.5(M+Na)；Value of calculation exact mass 777.5.

The preparation of embodiment 23. Salinomycin methyl nitrosourea (28)

Add in Salinomycin amide 26 (embodiment 25) solution of the 0.07g (0.09mmol) in dry methanol (3ml) Add Anhydrous potassium carbonate (0.06g, 0.43mmol), 4h is stirred in reaction at ambient temperature in nitrogen.Hereafter, to reaction mixing Thing is concentrated in vacuo, and again dilutes by ethyl acetate.Saline is used to wash, dried over magnesium sulfate and be concentrated in vacuo.Right Crude product uses ethyl acetate/hexane gradient to utilize 12M Biotage silicagel column to pass through flash chromatography.The pure product obtained Thing 28 is separated is 17% yield.MS 786.5(M+Na)；Value of calculation exact mass 763.5.

Embodiment 24. propagation detection (for HMLE GFP/Ecad, SUM 159, Hs578T)

In order to determine compound usefulness in terms of suppression cytoactive, by cell exemplarily in 96-hole or 384 holes Placing a night on flat board, the mode compound based on doses carries out processing 72 hours, and then uses Promega Cell Titer Glo test kit detect according to product description；This detection uses a kind of with luciferase as base Reaction, this reaction makes the ATP dosage being present in cell relevant to the amount of produced light.Then, will put down at EnVision The fluorescence counting read on plate reader is normalized to the a% of untreated DMSO comparison, so that it is determined that the percentage of each dosage Activity.By these data by the function that Prism Graphpad Software on Drawing is record dosage, and it is to meet a kind of non-thread Property regression curve thus calculate the effective concentration at 50% (EC50) and/or the inhibition concentration at 50% (IC50).

Embodiment 25. stem cell assay test kit (ALDEFLUOR) detects

This ALDEFLUOR detects in U.S. Patent No. 5,876,956；6,627,759；6,537,807；And 6,991, The patent of 897 is described.

Summary and principle

The ALDEFLUOR of Aldagen is used for identifying, assess and separating expressing high-caliber acetaldehyde deoxidation hydrogen The stem cell of (ALDHbright or ALDHbr) and CFU-GM.The ALDEFLOUR reagent of fluorescence is diffused in cell freely, and And be a kind of substrate nontoxic for ALDH.In cell, the amount of the ALDH product of the fluorescence of accumulation is the thinnest with at these ALDH activity in born of the same parents is correlated with.The negative charge of this product will stop its from cellular invasion, but it can be combined by ATP Box (ABC) transmission system draws (outflow) from cell on one's own initiative.This active is flowed out can be by particular dosage form ALDEFLUOR analysis buffer suppresses.Therefore, the product of ALDEFLUOR will be only capable of by having the thin of complete film Born of the same parents keep, and fixing, and sexual cell or dead cell are by passive for performance ALDH thoroughly.

Being detected by ALDEFLUOR, feasible stem cell and CFU-GM can be measured by flow cytometer to be had relatively The cell that high ALDH expresses.By by fluorescence in the test sample with in compareing containing diethylin benzene (DEAB) DE Fluorescence compares, and can be identified these cells, and wherein DEAB is the special inhibitor of a kind of ALDH.Then, in standard Detection reaction is measured by the green fluorescence channel of flow cytometer.

ALDEFLUOR reagent with a kind of stable, inactivation form (-aminoacetaldehyde diethyl acetas, BAAA-DA) provide.For the ease of using, dry ALDEFLUOR reagent is dissolved in DMSO, by using the HCl of 2N Carry out the substrate (BODIPY-aminoacetaldehyde, BAAA) processing to be converted to activation, and dilute by ALDEFLUOR analysis buffer Release to working concentration.For examinations, the activated substrate of decile is added to and is suspended in ALDEFLUOR analysis buffer In cell.The cell mixture of this decile is immediately transferred in the test tube containing the DEAB being used for comparison.These are mixed Thing is cultivated, thus the substrate being is converted to fluorescence-causing substance (BODIPY-glycine, BAA).Then, fluidic cell is used The amount of intracellular fluorescence-causing substance is measured by instrument.

Scheme

Before the use, all required aliments (such as, reagent) assemble for the first time, and allow and reach Room temperature (RT), 18 DEG C to 22 DEG C.Then, by (1) to the DMSO of 25 μ l added bottled dry ALDEFLUOR reagent Activation ALDEFLUOR reagent.Then mixture is mixed.(2) mixture is at room temperature stood 1 minute.(3) 25 are added after The HCl of the 2N of μ l, and mix.(4) after the most at room temperature by mixture cultivate 15 minutes and, less than 30 minutes.Then, The ALDEFLUOR analysis buffer of 360 μ l is added in bottle, and mixes.During use, the reagent of activation is saved in 2 DEG C to 8 DEG C.The ALDEFLUOR substrate of remaining activation is stored under-20 DEG C or lower temperature.

Fresh or the test sample of freezing is prepared according to standard method.By cell dissolve, then under 250x g from The heart separates 5 minutes.Then remove the supernatant, and these cell suspensions are in the ALDEFLUOR analysis buffer of 1mL.So After carry out cell counting, and by ALDEFLUOR analysis buffer by cell concentration regulation to 1x106cells/mL.

Each sample being used for being detected is labeled as " detection " test tube and one " comparison " examination of 12x75mm Pipe.For a sample, add the DEAB solution of 5uL.Immediately comparison test tube and DEAB bottle are opened.Then, with every milliliter of sample The activation ALDEFLUOR substrate of 5uL is added in " detection " test tube by product.Then, add described for each detected sample Comparison and matrix solution.Described " comparison " and " detection " sample cultivate 30 to 60 minutes (less than 60 minutes) in 37 DEG C. After cultivation, by test tube centrifugation 5 minutes under 250xg.Then remove the supernatant, and cell granulations is suspended in In the ALDEFLUOR analysis buffer of 0.5mL.Sample is closed the lid, and is positioned over immediately on ice or is put in refrigerator.By sample Product are stably placed 24 hours at 2 DEG C to 8 DEG C.Then stream type cell analyzer device is set according to the description of manufacturer.Often Individual sample obtains at least 100,000 results.

In order to realize reading, DEAB control sample is placed on the cell counter of the pattern of setting.To FSC and SSC electricity Pressure is adjusted and gain is arranged thus is concentrated with nucleus group between FSC vs.SSC figure.R2 region is adjusted from And include based on scattered nucleated cell group.In FL1 vs.SSC figure, FL1 Photomultiplier tube voltage is adjusted so that The right hand edge of the cell mass being colored is placed on dot chart and is considered as on second log (10).Then, test tube is taken out.Afterwards, by phase The ALDH detection sample answered is placed on cell counter.Then setting area R2 contains the cell mass for ALDHbr, and Take out test tube.For detecting the data acquisition of sample: by analyser from arranging removal pattern, and use identical setting together Put, each ALDH and DEAB sample is collected 100,000 time in R1.

The most so describe several aspects of at least one embodiment of the present invention, for one of skill in the art For, it should be appreciated that the present invention can be made some and change, modify and improve.Such change, modify and improvement be intended to make For a part for the disclosure of invention, and contained by the spirit and scope of the present invention.Correspondingly, described above and accompanying drawing are only As example.

Claims (41)

1. the compound of Formulas I:

Wherein,

R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OC(O) OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring group, heterocyclic radical, Aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；

R₁, together with R₃、R₅Or R₆, together with the atom that is connected with them, may be optionally formed heterocyclic ring；

R₂It is-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；

L-M-T is formed together selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃- Structure；Or L-M, M-T or L-M-T and 1 to 3 other-C (R of their combinations₃)₂-、-O-、-NR₁₁-or-S-shape together Becoming 3-6 unit ring group, heterocyclic radical, aryl or heteroaryl ring, wherein n independently be 1 or 2；

R₃It is H, halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；

R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,- N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S (O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；

R₆It is H, oxo ,-OR independently₁₀、-SR10、-CO_R10、、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O) NR₁₁R₁₂、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC (O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, C1-C8 alkyl, cyclylalkyl or aryl；

R₅And R₆May be optionally formed substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring together；

R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；

R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Thiazolinyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；

R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃- C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S (O)R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；

R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, virtue Base, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；

R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇, or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond portion Point；

R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl Base, aryl alkyl or heteroaryl alkyl；

R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-；And

Q is 1 or 2；

Condition is to work as R₁Be-C (O) OH, n be 2, q is 1, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl； Condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy Base；And condition is to work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、- OCH₂Br or-OC (O) CH₂Cl。

Compound the most according to claim 1, wherein said compound is the compound of Formula II:

Wherein,

R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OC(O) OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring group, heterocyclic radical, Aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；

R₂It is-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or- NHP(R₁₅R₁₆)OR₁₀；

L-M-T is formed together selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃- Structure；Or L-M, M-T or L-M-T and 1 to 3 other-C (R of their combinations₃)₂-、-O-、-NR₁₁-or-S-one Rise and form 3-6 unit ring group, heterocyclic radical, aryl or heteroaryl ring；

R₃It is H, halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；

R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,- N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S (O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；

R₆It is H, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,= NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, cyclylalkyl or aryl；

R₅And R₆May be optionally formed substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring together；

R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；

R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Thiazolinyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；

R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈ Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O) R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；

R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, virtue Base, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；

R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇, or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond portion Point；

R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl Base, aryl alkyl or heteroaryl alkyl；And

R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-,

Condition is to work as R₁It is-C (O) OH, R₆It is oxo, and R₇When being methyl, R₂、R₃And R₅It it is not all hydroxyl；Condition is to work as R₁ It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₃And R₅When being hydroxyl, R₂It not benzoyloxy group or benzyloxy；And condition is Work as R₁It is-C (O) OH, R₆It is oxo, R₇It is methyl, and R₂When being hydroxyl, R₃Or R₅It not-OCH₂Cl、-OCH₂Br or-OC (O) CH₂Cl。

Compound the most according to claim 2, wherein R₁It is-CH₂OR₁₀、-C(O)R₁₀、-C(O)OR₁₀Or-C (O) NR₁₁R₁₂

Compound the most according to claim 2, wherein R₁It it is heteroaryl.

5. according to the compound according to any one of claim 2-4, wherein R₂It is-OR₁₀。

6. according to the compound according to any one of claim 2-4, wherein R₂It it is hydroxyl.

7., according to the compound according to any one of claim 2-6, wherein L-M-T is-CR₃=CR₃-C(R₃)₂-。

8. according to the compound according to any one of claim 2-7, wherein R₃It is-OR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC (O)OR₁₀、-OS(O)OR₁₀、-OC(O)NR₁₁R₁₂Or-OP (R₁₅R₁₆)OR₁₀。

Compound the most according to claim 8, wherein R₃It is-OC (O) R₁₀。

Compound the most according to claim 9, wherein R₁₀It it is methyl.

11. according to the compound according to any one of claim 2-7, wherein R₃It is-N₃、-NR₁₁R₁₂、-NNR₁₁、-NR₁₁C(O) OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂, or-NHP (R₁₅R₁₆)OR₁₀。

12. according to the compound according to any one of claim 2-7, wherein R₃It it is halo.

13. according to the compound according to any one of claim 2-12, wherein R₅It is oxo ,-OR₁₀、-OC(O)R₁₀、-OC(O) OR₁₀, or-OC (O) NR₁₁R₁₂。

14. according to the compound according to any one of claim 2-13, wherein R₆It is oxo ,-OR₁₀、-OC(O)R₁₀、-OC(O) OR₁₀, or-OC (O) NR₁₁R₁₂。

15. according to the compound according to any one of claim 2-13, wherein R₆It is-NR₁₁R₁₂Or=NR₁₁。

16. according to the compound according to any one of claim 2-13, wherein R₅And R₆Form substituted or unsubstituted 5-together Unit's heteroaryl ring.

17. according to the compound according to any one of claim 2-16, wherein R₇It it is methyl.

18. compounds according to claim 1, wherein said compound is

Wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈And R₁₉As claim 1 is determined Justice；

R₃It is halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、 Cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And

P is 0-4.

19. compounds according to claim 18, wherein said compound is

Wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈And R₁₉As claim 2 is determined Justice；

R₃It is halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、 Cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；And

P is 0-4.

20. compound according to claim 19, wherein R₇It it is methyl.

21. according to the compound described in claim 19 or 20, wherein R₂It is-OH.

22. according to the compound according to any one of claim 19-21, wherein R₁It is-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O) R₁₀、-C(O)OR₁₀Or-C (O) NR₁₁R₁₂。

23. compound according to claim 22, wherein R₁It is-COOH.

24. compounds according to claim 1, wherein said compound is

Wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈And R₁₉As claim 1 is determined Justice；And

R₃Name is halo, oxo ,-OR the most independently₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、 Cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl.

25. compounds according to claim 24, wherein said compound is

Wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈And R₁₉As claim 2 is determined Justice；And

R₃It is halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、 Cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl.

Compound described in 26. claim 25, wherein R₇It it is methyl.

27. according to the compound described in claim 25 or 26, wherein R₂It is-OH.

28. according to the compound according to any one of claim 25-27, wherein R₁It is-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O) R₁₀、-C(O)OR₁₀, or-C (O) NR₁₁R₁₂。

29. compound according to claim 28, wherein R₁It is-COOH.

30. compounds according to claim 1, wherein said compound is the compound of Formula II:

Wherein,

R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OC(O) OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring group, heterocyclic radical, Aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；

R₂It is-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or- NHP(R₁₅R₁₆)OR₁₀；

L-M-T is formed together selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃-structure；Or L-M, M-T Or L-M-T, and 1 to 3 other-C (R of they combinations₃)₂-、-O-、-NR₁₁-or-S-form 3-6 unit ring group, heterocycle together Base, aryl or heteroaryl ring；

R₃It is H, halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀、-OS(O)₂R₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O) NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆) OR₁₀、-NHP(R₁₅R₁₆)OR₁₀、C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or miscellaneous Aryl alkyl；

R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,- N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S (O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or-NHP (R₁₅R₁₆)OR₁₀；

R₆It is H, oxo ,-OR₁₀、-SR₁₀、-COR₁₀、-CNR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O) R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,=NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, cyclylalkyl or aryl；

R₅And R₆May be optionally formed together substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or Heteroaryl ring；

R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；

R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C₂-C₈Thiazolinyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；

R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈ Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O) R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；

R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, virtue Base, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；

R₁₅And R₁₆It is=O ,=S ,-OR independently of one another₁₇、-SR₁₇, or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond portion Point；

R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl Base, aryl alkyl or heteroaryl alkyl；And

R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

31. compounds according to claim 30, wherein said compound is Formula II compound:

Wherein L, M, T, R1, R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 are such as Claim 30 is defined；And

R₃It is H, halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl.

32. compounds according to claim 1, wherein said compound is Formula II compound:

Wherein,

R₁It is-OR₁₀、-CH₂OR₁₀、-CH₂NR₁₁R₁₂、-C(O)R₁₀、-C(O)OR₁₀、-C(O)NR₁₁R₁₂、-OC(O)R₁₀、-OC(O) OR₁₀、-NR₁₁R₁₂、-OC(O)NR₁₁R₁₂, oxo, C₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, halo, haloalkyl, ring group, heterocyclic radical, Aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, nitro or cyano group；

R₂It is-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、- NNR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀, or- NHP(R₁₅R₁₆)OR₁₀；

L-M-T is formed together selected from-C (R₃)₂-C(R₃)₂-C(R₃)₂-、-CR₃=CR₃-C(R₃)₂-and-C (R₃)₂-CR₃=CR₃- Structure；Or L-M, M-T or L-M-T and 1 to 3 other-C (R of their combinations₃)₂-、-O-、-NR₁₁-or-S-shape together Become 3-6 unit ring group, heterocyclic radical, aryl or heteroaryl ring；

R₃It is H, halo, oxo ,-OR independently of one another₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O) OR₁₀, cyano group ,-N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O) NR₁₁R₁₂、-NR₁₁’S(O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀、-NHP(R₁₅R₁₆) OR₁₀, the miscellaneous alkyl of C1-C8 alkyl, C1-C8, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl；

R₅It is H, halo, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀, cyano group ,- N₃、-NR₁₁R₁₂、-NNR₁₁、-OC(O)NR₁₁R₁₂、-NR₁₁C(O)OR₁₂、-NR₁₁’C(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂、-NR₁₁’S (O₂)NR₁₁R₁₂、-P(R₁₅R₁₆)OR₁₀、-OP(R₁₅R₁₆)OR₁₀、-SP(R₁₅R₁₆)OR₁₀Or-NHP (R₁₅R₁₆)OR₁₀；

R₆It is H, oxo ,-OR₁₀、-SR₁₀、-OC(O)R₁₀、-OS(O)R₁₀、-OC(O)OR₁₀、-OS(O)OR₁₀、-NR₁₁R₁₂,= NR₁₁、-OC(O)NR₁₁R₁₂、-SC(O)NR₁₁R₁₂, halo (such as F, Cl, Br, I) ,-NH₂, cyano group, cyclylalkyl or aryl；

R₅And R₆May be optionally formed substituted or unsubstituted 5-8 unit ring group, heterocyclic radical, aryl or heteroaryl ring together；

R₇It is H, halo, C₁-C₈Alkyl or C₁-C₈Miscellaneous alkyl；

R₁₀It is H, substituted or unsubstituted C₁-C₈Alkyl, C2₁-C₈Thiazolinyl, C₁-C₈Miscellaneous alkyl, substituted or unsubstituted C₃-C₈Ring Base, C₃-C₈Heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl or amino acid side chain；

R₁₁、R₁₁' and R₁₂It is H, substituted or unsubstituted C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈ Heterocyclic radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl ,-OR₁₃、-C(O)OR₁₃、-OC(O)R₁₃、-C(O)R₁₃、-S(O) R₁₃、-S(O₂)R₁₃、-NR₁₃R₁₄, cyano group or amino acid side chain；

R₁₃And R₁₄It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl ,-C (O) R₁₀、C₃-C₈Ring group, C₃-C₈Heterocyclic radical, virtue Base, heteroaryl, aryl alkyl, heteroaryl alkyl or cyano group；

R₁₅And R₁₆Name from being independently=O ,=S ,-OR₁₇、-SR₁₇, or-NR₁₇R₁₈, condition is R₁₅And R₁₆It it is not all double bond portion Point；

R₁₇And R₁₈It is H, C independently of one another₁-C₈Alkyl, C₁-C₈Miscellaneous alkyl, C₃-C₈Ring group, C₃-C₈Heterocyclic radical, aryl, heteroaryl Base, aryl alkyl or heteroaryl alkyl；And

R₁₉It is-O-,-S-,-NR₁₇-,-N (OH)-or-N (OR₁₀)-。

33. compounds according to claim 32, wherein said compound is Formula II compound:

Wherein L, M, T, R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈And R₁₉Such as claim 32 are defined；And

R₃Be independently of one another H, halo, oxo ,-SR10 ,-OS (O) R10 ,-OC (O) OR10 ,-OS (O) OR10, cyano group ,-N3 ,- NR11R12、-NNR11、-OC(O)NR11R12、-NR11C(O)OR12、-NR11’C(O)NR11R12、-SC(O)NR11R12、- NR11’S(O2)NR11R12、-P(R15R16)OR10、-OP(R15R16)OR10、-SP(R15R16)OR10、-NHP(R15R16) OR10, ring group, heterocyclic radical, aryl, heteroaryl, aryl alkyl or heteroaryl alkyl.

34. compounds according to claim 1, wherein said compound is

Wherein L, M, T, R1, R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 are such as Claim 1 is defined.

35. 1 kinds of pharmaceutical compositions, comprise the compound according to any one of claim 1-34.

36. 1 kinds of dosage forms, comprise the compound according to any one of claim 1-35 or pharmaceutical composition.

37. 1 kinds of test kits, comprise the compound according to any one of claim 1-36, pharmaceutical composition or dosage form.

38. 1 kinds of methods regulating cell proliferation in the experimenter needing it, use effective dose including to described experimenter Compound according to any one of claim 1-34, thus in described experimenter, regulate cell proliferation.

39. 1 kinds of methods treating cancer in experimenter, including claim 1-34 using effective dose to described experimenter According to any one of compound.

40. 1 kinds of methods suppressing cancer stem cell to breed, including making to appoint in described cancer stem cell contact claim 1-34 One described compound, thus suppress described cancer stem cell to breed.

41. 1 kinds of methods regulated in experimenter or reduce growth of microorganism, use effective dose including to described experimenter Compound according to any one of claim 1-34, thus regulate in described experimenter or reduce described growth of microorganism.