JP2012514638A - Combination therapy for neoplastic disorders - Google Patents

Abstract

The present application relates generally to compounds, compositions and combination therapies for the treatment of neoplastic disorders.

Description

RELATED APPLICATIONS This application claims priority filed in 2009. January 08 U.S. Provisional Patent Application No. 61 / 143,282, the entire contents of which is hereby incorporated herein by reference.

TECHNICAL FIELD This application relates generally to combination therapy and combination pharmaceutical compositions.

  Current cancer therapies generally involve surgical procedures, chemotherapy, radiation therapy or a combination of these techniques. Each of the major treatment approaches has considerable limitations. For example, surgery cannot completely remove neoplastic tissue, cannot be used to treat certain disseminated neoplastic conditions, such as acute lymphoblastic leukemia, and radiation therapy Is effective only when irradiated neoplastic tissue is more sensitive to irradiation than normal tissue and often causes serious side effects.

  A variety of chemotherapeutic agents are available, but almost all chemotherapeutic agents are toxic, and chemotherapy frequently causes serious and often dangerous side effects. Frequent side effects include severe nausea and vomiting, myelosuppression, immunosuppression, cytopenias (including for example anemia, neutropenia and thrombocytopenia), pain and fatigue. Further side effects include cachexia, mucositis, alopecia, skin complications (including hypersensitivity reactions such as psychogenic pruritus, hives and angioedema), as well as neurological complications, lung complications Disease, cardiac complications, reproductive complications and endocrine complications.

  Side effects associated with chemotherapeutic agents are generally a major factor in defining drug dose-limiting toxicity (DLT), and managing adverse side effects induced by chemotherapy and radiation therapy is It is mainly important in the clinical management of treatment. In addition, many tumor cells are or are resistant to chemotherapeutic agents through multidrug resistance.

  Combination therapy that allows the use of lower doses of chemotherapeutic agents than those conventionally used in monotherapy while maintaining anticancer efficacy is highly desirable. Such combination therapies can result in a reduction in the frequency and / or severity of adverse side effects and an improvement in the patient's quality of life. Additional benefits of reducing the incidence of side effects include improved patient compliance, fewer hospitalizations required to treat adverse effects, and the need for analgesics needed to treat the pain associated with adverse effects. Includes reduction in administration.

  Combination therapy can also maximize the therapeutic effects of chemotherapeutic agents administered at higher doses when dose limiting toxicity is not an issue. In addition to increasing anticancer efficacy, such techniques can reduce the development of resistance.

  Compounds of formula I (shown herein) have been previously reported to be effective in inhibiting tumor progression. See U.S. Patent Application No. 11 / 849,230 (filed on August 31, 2007).

U.S. Patent Application No. 11 / 849,230

SUMMARY This application provides compounds, compositions and combination therapy with compounds of formula I for the treatment of neoplastic disorders. It has been found that synergistic effects on cell growth inhibition can be obtained by combining commonly used anticancer drugs with proliferating cells in combination with compounds of formula I.

または薬学的に許容されるその塩もしくはエステルと、 抗がん剤または薬学的に許容されるその塩もしくはエステルとを投与し、それによって該新生物障害を予防、処置、または改善する段階を含む方法について開示する。
式中、Z⁵はNもしくはCR^6Aであり;
各R^6A、R^6B、R^6DおよびR⁸は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R^6A、R^6B、R^6DおよびR⁸は独立して、ハロ、CF₃、CFN、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体(bioisostere)、CONR₂、OOCR、CORもしくはNO₂であり、
各R⁹は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R⁹は独立して、ハロ、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、CONR₂、OOCR、CORもしくはNO₂であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR'₂、SR'、SO₂R'、SO₂NR'₂、NR'SO₂R'、NR'CONR'₂、NR'COOR'、NR'COR'、CN、COOR'、CONR'₂、OOCR'、COR'およびNO₂から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく;
nは0〜4であり；かつ
pは0〜4である。 In one aspect, this application is a method for preventing, treating, or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I in a subject in need thereof:

Or administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent or a pharmaceutically acceptable salt or ester thereof, thereby preventing, treating or ameliorating the neoplastic disorder A method is disclosed.
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 Alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A , R ^6B, R ^6D and R ⁸ are independently _{halo, CF 3, CFN, oR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, carboxy bioisostere, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4.

  Anticancer agents used in combination with the compounds of the present application can include agents selected from any of the classes known to those skilled in the art. Suitable anticancer agents are alkylating agents, antimetabolites (e.g. purines and pyrimidines), plant alkaloids (e.g. vinca alkaloids) terpenoids (e.g. taxanes), topoisomerase inhibitors, antitumor antibiotics, hormones Therapies can include, but are not limited to, molecular targeted drugs.

  Another aspect disclosed in this application is the administration of a compound of Formula I disclosed herein and an anticancer agent or a pharmaceutically acceptable salt or ester thereof to the system, thereby increasing cell proliferation. A method for inhibiting cell proliferation in a system comprising the step of inhibiting.

  A further aspect disclosed in the present application is a pharmaceutical composition comprising a compound of formula I disclosed herein, an anticancer agent, and at least one pharmaceutically acceptable excipient. .

FIG. 5 is a graph of log drug concentration versus relative fluorescence units (RFU) for Compound A and Compound B for IC ₅₀ calculations. FIG. 6 is a graph of the log concentration of Compound K and 5-fluorouracil against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 7 is a bar graph showing the percentage of cell death for Compound K, 5-fluorouracil and combinations thereof for A375 melanoma cells. FIG. 5 is a graph of log concentration of Compound K and fludarabine against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, fludarabine and combinations thereof for A375 melanoma cells. FIG. 5 is a graph of log concentration of Compound K and gemcitabine against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 5 is a graph of log concentration of Compound K and paclitaxel against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 5 is a bar graph showing the rate of cell death for Compound K, paclitaxel and combinations thereof for A375 melanoma cells. FIG. 6 is a graph of the log concentration of Compound K and sunitinib against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, sunitinib and combinations thereof for A375 melanoma cells. FIG. 5 is a graph of log concentration of Compound K and vinblastine against RFU for calculation of IC ₅₀ for A375 melanoma cells. FIG. 7 is a bar graph showing the percentage of cell death for Compound K, vinblastine and combinations thereof for A375 melanoma cells. FIG. 5 is a graph of log concentration of Compound K and 5-fluorouracil against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, 5-fluorouracil and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 5 is a graph of log concentration of Compound K and 5-fluorouracil against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, 5-fluorouracil and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 6 is a graph of log concentration of Compound K and cisplatin against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, cisplatin and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 6 is a graph of log concentration of Compound K and cisplatin against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, cisplatin and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 6 is a graph of log concentration of Compound K and doxorubicin against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, doxorubicin and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 6 is a graph of log concentration of Compound K and doxorubicin against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, doxorubicin and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 5 is a graph of log concentration of Compound K and gemcitabine against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, gemcitabine and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 5 is a graph of log concentration of Compound K and gemcitabine against RFU for calculation of IC ₅₀ for MDA-MB-468 breast cancer cells. 2 is a bar graph showing the percentage of cell death for Compound K, gemcitabine and combinations thereof for MDA-MB-468 breast cancer cells. FIG. 6 is a graph of log concentration of Compound K and vinblastine against RFU for calculation of IC ₅₀ for MIA PaCa-2 pancreatic cancer cells. It is a bar graph which shows the ratio of the cell death with respect to the compound K in the case of MIA PaCa-2 pancreatic cancer cell, vinblastine, and its combination. FIG. 6 is a graph of log concentration of Compound K and gemcitabine against RFU for calculation of IC ₅₀ for MIA PaCa-2 pancreatic cancer cells. 2 is a bar graph showing the ratio of cell death to Compound K, gemcitabine and combinations thereof in the case of MIA PaCa-2 pancreatic cancer cells. FIG. 5 is a graph of the log concentration of Compound K and sunitinib against RFU for calculation of IC ₅₀ for MIA PaCa-2 pancreatic cancer cells. FIG. 5 is a bar graph showing the rate of cell death for Compound K, sunitinib and combinations thereof for MIA PaCa-2 pancreatic cancer cells. FIG. 5 is a graph of log concentration of Compound K and rapamycin against RFU for calculation of IC ₅₀ for MIA PaCa-2 pancreatic cancer cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, rapamycin and combinations thereof for MIA PaCa-2 pancreatic cancer cells. FIG. 6 is a graph of the log concentration of Compound K and 5-fluorouracil against RFU for calculation of IC ₅₀ for SUM-149PT inflammatory breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, 5-fluorouracil and combinations thereof for SUM-149PT inflammatory breast carcinoma cells. FIG. 5 is a graph of log concentration of Compound K and cisplatin against RFU for calculation of IC ₅₀ for SUM-149PT inflammatory breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, cisplatin and combinations thereof for SUM-149PT inflammatory breast carcinoma cells. FIG. 6 is a graph of log concentration of Compound K and rapamycin against RFU for calculation of IC ₅₀ for SUM-149PT inflammatory breast carcinoma cells. FIG. 7 is a bar graph showing the percentage of cell death for Compound K, rapamycin and combinations thereof for SUM-149PT inflammatory breast carcinoma cells. FIG. 6 is a graph of log concentration of Compound K and erlotinib against RFU for calculation of IC ₅₀ for SUM-149PT inflammatory breast carcinoma cells. FIG. 7 is a bar graph showing the percentage of cell death for Compound K, erlotinib and combinations thereof for SUM-149PT inflammatory breast carcinoma cells. FIG. 7 is a graph of the log concentration of Compound K and 5-fluorouracil against RFU for calculation of IC ₅₀ for SUM-190PT inflammatory breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, 5-fluorouracil and combinations thereof for SUM-190PT inflammatory breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, erlotinib and combinations thereof for BT-474 breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, erlotinib and combinations thereof for BT-474 breast carcinoma cells. FIG. 4 is a dose response curve of Compound K in combination with Compound K and erlotinib for erlotinib resistant MDA-MB-453 breast carcinoma cells. FIG. 2 is a dose response curve for erlotinib in the case of erlotinib resistant MDA-MB-453 breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, erlotinib and combinations thereof for erlotinib resistant MDA-MB-453 breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, erlotinib and combinations thereof for erlotinib resistant T47D breast carcinoma cells. FIG. 5 is a bar graph showing the percent cell death for Compound K, erlotinib and combinations thereof for erlotinib resistant T47D breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, erlotinib and combinations thereof for erlotinib resistant ZR-75-1 breast carcinoma cells. FIG. 7 is a bar graph showing the percentage of cell death for Compound K, erlotinib and combinations thereof for erlotinib resistant ZR-75-1 breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, lapatinib and combinations thereof for T47D breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, sorafenib and combinations thereof for T47D breast carcinoma cells. FIG. 5 is a bar graph showing the percentage of cell death for Compound K, sorafenib and combinations thereof for T47D breast carcinoma cells. FIG. 5 is a dose response curve for Compound K, sunitinib and combinations thereof for T47D breast carcinoma cells.

DETAILED DESCRIPTION This application can be more readily understood by reference to the following detailed description and examples included in the specification. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise specifically defined herein, it is further understood that the terminology used herein is for the purpose of giving its conventional meaning as is known in the relevant art.

  As used herein, the singular forms “one (a)”, “one (an)”, and “the (the)” include plural referents unless otherwise specified.

  As used herein, the term “subject” refers to a human or animal subject. In general, the subject is a human.

  As used herein, the term “neoplastic disorder” refers to a disorder with abnormal cell proliferation, such as, for example, cancer. Cancer can sometimes cause a tumor, and symptoms associated with the tumor are sometimes treated. Neoplastic disorders are abnormal cells of the hematopoietic system (eg, white blood cells), lung, breast, prostate, kidney, pancreas, liver, heart, skeleton, colon, rectum, skin, brain, eyes, lymph nodes, heart, testis or ovary Including but not limited to proliferative conditions (eg, cancer).

  The term “therapeutically effective amount” or “effective amount” elicits a biological or medical response of a cell, tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other clinician It is intended to mean that amount of a drug or drug. When referring to the amount of a compound of the present application administered in combination with an additional anticancer agent, a “therapeutically effective amount” of the compound of the present application may be an amount sufficient to produce only an anticancer effect. Or an amount sufficient to produce an anticancer effect in the presence of additional anticancer agents. Similarly, the amount of additional anticancer agent may be sufficient to provide only an anticancer effect, or may be sufficient to provide an anticancer effect in the presence of a compound of the present application. .

  In some embodiments, a combination of a compound of the present application and an additional anticancer agent exhibits an additive anticancer effect, such as an additive effect on cell growth inhibition. In other embodiments, the combination of a compound of the present application and an additional anticancer agent exhibits a synergistic anticancer effect, such as a synergistic effect on inhibition of cell proliferation.

  “Inhibit” or “reduce” cell proliferation, as measured using methods known to those of skill in the art, for example, as compared to proliferating cells not subjected to the methods and compositions of the present application, Slowing, reducing or reducing the amount of cell proliferation by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%, or for example , Mean to stop.

  The terms “alkyl”, “alkenyl” and “alkynyl” as used herein include linear, branched and cyclic monovalent hydrocarbyl groups, and combinations thereof, which when unsubstituted are C and Contains only H. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl and the like. The total number of carbon atoms in each of these groups is often described herein, for example, when the group can contain up to 10 carbon atoms, it can be expressed as 1-10C or C1-C10 or C1-10. Can be represented. For example, when a heteroatom (typically N, O, and S) replaces a carbon atom, such as a heteroalkyl group, the number describing the group is still written as, for example, C1-C6. Represents the sum of the number of carbon atoms in the group and the number of such heteroatoms included as substitutions for carbon atoms in the described ring or chain skeleton.

  Typically, alkyl, alkenyl and alkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl). In general, they contain 1-8C (alkyl) or 2-8C (alkenyl or alkynyl). Sometimes they contain 1-4C (alkyl) or 2-4C (alkenyl or alkynyl). A single group may contain more than one type of multiple bond, or more than one multiple bond; the definition of the term “alkenyl” when such a group contains at least one carbon-carbon double bond Is included in the term “alkynyl” when it contains at least one carbon-carbon triple bond.

Alkyl, alkenyl and alkynyl groups are often optionally substituted to the extent that the substitution makes sense chemically. Typical substituents are never include the following is limited to: halo, = O, = N-CN , = N-OR, = NR, OR, NR 2, SR, SO 2 R, SO _{2 NR 2, NRSO 2 R,} NRCONR 2, NRCOOR, NRCOR, CN, C≡CR ', COOR, CONR 2, OOCR, COR, and NO _2, wherein each R is independently, H, C1 to C8 alkyl , C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl , and the respective R is halo, = O, = N-CN , = N-OR ', = NR', OR ', NR' 2, SR ', SO 2 R', SO 2 NR '2, NR'SO _{2 R ', NR'CONR' 2,} NR'COOR ', NR'COR', CN, C≡CR ', COOR', CONR '2, OOCR', COR ', and may be substituted with NO ₂ Where each R ′ is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5 C10 heteroaryl. Alkyl, alkenyl and alkynyl groups may be substituted with C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which by an appropriate substituent for the particular group May be substituted.

An “acetylene” substituent is an optionally substituted 2-10C alkynyl group having the formula —C≡CR ^a , where R ^a is H or C1-C8 alkyl, C2-C8 heteroalkyl, C2 -C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6 ~C12 heteroarylalkyl, each R ^a groups halo, = O, = N-CN , = N-OR ', = NR', OR ', NR' 2, SR ', SO 2 R', SO 2 _{NR '2, NR'SO 2 R'} , NR'CONR '2, NR'COOR', NR'COR ', CN, COOR', CONR '2, OOCR', COR ', and single selected from NO ₂ Optionally substituted by one or more substituents, wherein each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 Aryl, C5-C10 heteroa , C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, And optionally substituted by one or more groups selected from ═O; two R ′ are linked and optionally contain up to 3 heteroatoms selected from N, O and S You may form the 3-7 membered ring which may be. In some embodiments, R ^a of -C≡CR ^a is H or Me.

  `` Heteroalkyl '', `` heteroalkenyl '', `` heteroalkynyl '' and the like are defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the term `` hetero '' is Refers to a group containing 3 O, S or N heteroatoms or combinations thereof; that is, at least one carbon atom of the corresponding alkyl, alkenyl or alkynyl group is replaced by one of the specified heteroatoms Forms an alkyl, heteroalkenyl or heteroalkynyl group. In general, the typical sizes for alkyl, alkenyl and alkynyl hetero-forms are the same as the corresponding hydrocarbyl group, and the substituents that may be present in the hetero-form are the same as those described above for the hydrocarbyl group. is there. For reasons of chemical stability, unless otherwise specified, such groups do not contain more than two adjacent heteroatoms unless an oxo group is present at N or S, such as a nitro or sulfonyl group. Is also understood.

  As used herein, “alkyl” includes cycloalkyl and cycloalkylalkyl groups, but the term “cycloalkyl” as used herein refers to a carbocyclic non-aromatic group connected through a cyclic carbon atom. Sometimes used to describe, “cycloalkylalkyl” may be used to describe a carbocyclic non-aromatic group connected to a molecule through an alkyl linker. Similarly, “heterocyclyl” describes a non-aromatic cyclic group containing at least one heteroatom as a ring member and attached to the molecule through a ring atom which may be C or N. “Heterocyclylalkyl” may be used to describe such a group attached to another molecule through a linker. Suitable sizes and substituents for cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. As used herein, these terms also include non-aromatic rings containing one or two double bonds.

As used herein, “acyl” includes groups containing an alkyl, alkenyl, alkynyl, aryl or arylalkyl group attached at one of the two available valence positions of a carbonyl carbon atom, and heteroacyl Refers to a corresponding group in which at least one carbon other than the carbonyl carbon is replaced by a heteroatom selected from N, O and S. Thus heteroacyl includes, for example, —C (═O) OR and —C (═O) NR ₂ and —C (═O) -heteroaryl.

  Acyl and heteroacyl groups are attached and attached to any group or molecule through the open valence of the carbonyl carbon atom. Typically they are C1-C8 acyl groups including formyl, acetyl, pivaloyl and benzoyl, and C2-C8 heteroacyl groups including methoxyacetyl, ethoxycarbonyl and 4-pyridinoyl. Hydrocarbyl groups containing an acyl or heteroacyl group, aryl groups, and heterogeneous forms of such groups are those substituents described herein as generally suitable substituents for each of the corresponding components of the acyl or heteroacyl group. May be substituted.

  An “aromatic” or “aryl” moiety refers to a monocyclic or fused bicyclic moiety having the well-known characteristics of aromaticity; examples include phenyl and naphthyl. Similarly, "aromatic heterocycle" and "heteroaryl" are such monocyclic or fused bicyclics containing one or more heteroatoms selected from O, S and N as ring members. The ring system. By including heteroatoms, not only six-membered rings but also five-membered aromatics are possible. Typical aromatic heterocyclic ring systems include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl and imidazolyl, and one of these monocyclic groups. Fused bicyclic moieties, such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, formed by fusing one with either a phenyl ring or an aromatic heterocyclic monocyclic group to form a C8-C10 bicyclic group , Isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl and the like. Any monocyclic or fused bicyclic system with aromatic character in terms of electron distribution throughout the ring system is included in this definition. This definition also includes bicyclic groups in which at least the ring directly attached to the rest of the molecule has aromatic character. Typically, this ring system contains 5 to 12 ring member atoms. Often the monocyclic heteroaryl contains 5-6 ring members and the bicyclic heteroaryl contains 8-10 ring members.

The aryl and heteroaryl moieties may be substituted with various substituents including C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C1-C8 acyl, and hetero forms thereof Each of these substituents may itself be further substituted; other substituents for the aryl and heteroaryl moieties are halo, OR, NR ₂ , SR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R , NRCONR _2, wherein NRCOOR, NRCOR, CN, C≡CR, COOR, CONR 2, OOCR, COR, and NO _2, wherein each R is independently, H, C1 to C8 alkyl, C2-C8 heteroalkyl C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl, Each R is as described above for the alkyl group. It may be substituted as. The substituents on the aryl or heteroaryl group may of course be further substituted by the groups described herein as appropriate for the various such substituents or components of the substituents. Thus, for example, an arylalkyl substituent may be substituted at the aryl moiety by a substituent described herein as being typical for an aryl group, and is typically at an alkyl moiety with respect to an alkyl group. It may be further substituted with the substituents described herein as appropriate or suitable.

  Similarly, “arylalkyl” and “heteroarylalkyl” are attached to the point of attachment through a linking group such as alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers. Aromatic and aromatic heterocyclic systems. Typically, the linker is C1-C8 alkyl or a hetero form thereof. These linkers may also include a carbonyl group to provide a substituent as an acyl or heteroacyl moiety. The aryl or heteroaryl ring in the arylalkyl or heteroarylalkyl group may be substituted with the same substituents as described above for the aryl group. In general, an arylalkyl group consists of a phenyl ring which may be substituted with the groups defined above for the aryl group, and an unsubstituted or one or two C1-C4 alkyl group or heteroalkyl. Including C1-C4 alkylene substituted with a group, an alkyl or heteroalkyl group may optionally be cyclized to form a ring such as cyclopropane, dioxolane or oxacyclopentane. Similarly, a heteroarylalkyl group is generally unsubstituted or substituted with one or more C5-C6 monocyclic heteroaryl groups, which may be substituted with groups described above as typical substituents for aryl groups. A phenyl ring or C5-C6 monocyclic heteroaryl containing or optionally substituted with a C1-C4 alkylene substituted with two C1-C4 alkyl groups or heteroalkyl groups, or unsubstituted or Including C1-C4 heteroalkylene substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, wherein the alkyl or heteroalkyl group is optionally cyclized to form a ring such as cyclopropane, dioxolane or oxacyclopentane. It may be formed.

  When an arylalkyl or heteroarylalkyl group is described as optionally substituted, the substituent may be in the alkyl or heteroalkyl portion of the group, or in the aryl or heteroaryl portion. Substituents optionally present in the alkyl or heteroalkyl moiety are the same as those generally described above for alkyl groups; substituents optionally present in the aryl or heteroaryl moiety are , Are the same as those generally described above for aryl groups.

  An “arylalkyl” group, as used herein, is a hydrocarbyl group when unsubstituted, described by the total number of carbon atoms in the ring and alkylene or similar linker. That is, the benzyl group is a C7-arylalkyl group, and the phenylethyl is C8-arylalkyl.

  The above-mentioned “heteroarylalkyl” refers to a moiety containing an aryl group attached through a linking group, and differs from “arylalkyl” in that at least one ring atom of the aryl moiety or one atom of the linking group is N, O. And a heteroatom selected from S. As used herein, a heteroarylalkyl group is described by the total number of rings and linker atoms combined, which is an aryl group bonded through a heteroalkyl linker; a heteroaryl group bonded through a hydrocarbyl linker such as alkylene; and a heteroalkyl Contains a heteroaryl group attached through a linker. Thus, for example, C7-heteroarylalkyl includes pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.

As used herein, “alkylene” refers to a divalent hydrocarbyl group; because it is divalent, alkylene can link two other groups together. Typically, alkylene refers to — (CH 2) _n —, where n is 1-8, and in many cases n is 1-4, but when specified, the alkylene is substituted with other groups May be of any other length, and the open valence may not be at the opposite end of the chain. Accordingly, —CH (Me) — and —C (Me) ₂ — may also be referred to as alkylene, and a cyclic group such as cyclopropane-1,1-diyl may be the same. When an alkylene group is substituted, the substituent includes a substituent that is typically present in an alkyl group as described herein.

In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group contained in the substituent or any hetero form of one of these groups may itself be substituted by an additional substituent. . Unless substituents are otherwise described, the nature of these substituents is similar to those listed for the primary substituents themselves. Thus, for example, when the embodiment of R ⁷ is alkyl, the alkyl may be substituted by the remaining substituents listed as embodiments for R ⁷ , where the substitution is chemically meaningful and the It is assumed that the substitution does not detract from the size limitations given for the alkyl itself; for example, alkyl substituted by alkyl or alkenyl is not included because it simply exceeds the upper limit of carbon atoms for these embodiments. However, alkyl substituted by aryl, amino, alkoxy, ═O, etc. is within the scope of this application, and the atoms of these substituents are the numbers used to describe the alkyl, alkenyl, etc. groups described. I ca n’t put it in When the number of substituents is not specified, each of these alkyl, alkenyl, alkynyl, acyl or aryl groups may be substituted with several substituents according to their available valences; Any of these groups may be substituted with a fluorine atom in any or all of its available valences.

  As used herein, “heteroform” refers to a derivative of a group such as alkyl, aryl or acyl, where at least one carbon atom of a given carbocyclic group is selected from N, O and S Substituted by a heteroatom. Thus, the hetero forms of alkyl, alkenyl, alkynyl, acyl, aryl and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl and heteroarylalkyl, respectively. It is understood that usually no more than two N, O or S atoms are normally connected sequentially except where the oxo group is attached to N or S to form a nitro or sulfonyl group.

  As used herein, “halo” includes fluoro, chloro, bromo and iodo. Generally, halo refers to fluoro or chloro.

As used herein, “amino” refers to NH ₂ , but when amino is described as “substituted” or “optionally substituted,” the term includes NR′R ″, where Each of R ′ and R ″ is independently H, or an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group, or is a hetero form of one of these groups Each of the alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl groups, or a hetero form of one of these groups, is described herein as being suitable for the corresponding group. May be substituted. The term also includes forms in which R ′ and R ″ are joined together to form a 3-8 membered ring, which may be saturated, unsaturated or aromatic, with N, O as ring members. And containing 1 to 3 heteroatoms independently selected from S and may be substituted with substituents described as suitable for an alkyl group, or NR′R ″ may be aromatic When it is a family group, it may be substituted with substituents described as being typical for heteroaryl groups.

  As used herein, the term “carbocycle” refers to a cyclic compound containing only carbon atoms in the ring, whereas “heterocycle” refers to a cyclic compound containing a heteroatom. Carbocyclic and heterocyclic structures include compounds having a monocyclic, bicyclic or multicyclic system.

  As used herein, the term “heteroatom” refers to any atom that is not carbon or hydrogen, such as nitrogen, oxygen, or sulfur.

  Examples of heterocycles are tetrahydrofuran, 1,3 dioxolane, 2,3 dihydrofuran, pyran, tetrahydropyran, benzofuran, isobenzofuran, 1,3 dihydroisobenzofuran, isoxazole, 4,5 dihydroisoxazole, piperidine, pyrrolidine, pyrrolidine 2one, pyrrole, pyridine, pyrimidine, octahydropyrrolo [3,4b] pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine 2,4dione, 1,3 dihydrobenzimidazole 2one, indole, thiazole, Benzothiazole, thiadiazole, thiophene, tetrahydrothiophene 1,1 dioxide, diazepine, triazole, guanidine, diazabicyclo [2.2.1] heptane, 2,5diazabicyclo [2.2.1] heptane, 2,3,4,4a, 9,9a Hexahydro 1Hβ carboline Oxirane, oxetane, tetrahydropyran, dioxane, lactone, aziridine, azetidine, piperidine, never including lactams limited to, it may include a further heteroaryl. Other examples of heteroaryl include, but are not limited to, furan, pyrrole, pyridine, pyrimidine, imidazole, benzimidazole, and triazole.

  As used herein, the term “inorganic substituent” refers to a substituent (eg, carbon atom, carbon monoxide, carbon dioxide) that does not contain carbon or carbon that is bonded to an element other than hydrogen. , And carbonate). Examples of inorganic substituents include, but are not limited to, nitro, halogen, azide, cyano, sulfonyl, sulfinyl, sulfonate, phosphate, and the like.

  The terms `` treat '', `` treatment phase '' or `` treatment '' in relation to a particular disease or disorder are the prevention of the disease or disorder, and / or the alleviation, recovery, or Includes improvements or deterrence. In general, these terms as used herein refer to amelioration, reduction, alleviation and elimination of symptoms of a disease or condition. A candidate molecule or compound described herein can be present in a formulation or medicament in a therapeutically effective amount, which is a type of cell (eg, cancer) Cell), an amount that can provide a biological effect, such as a reduction in the growth of certain cells, or an amount that can result in, for example, amelioration, reduction, alleviation or elimination of symptoms of a disease or condition. These terms can also refer to reducing or stopping the rate of cell growth (eg, slowing or stopping tumor growth) or reducing the number of proliferating cancer cells (eg, removing part or all of a tumor). These terms are used to reduce the titer of microorganisms in a microbially infected system (i.e. cells, tissues, or subjects), reduce the rate of microbial transmission, reduce the number of symptoms associated with microbial infection, or the impact of symptoms. And / or removal of detectable amounts of microorganisms from the system. Examples of microorganisms include but are not limited to viruses, bacteria and fungi.

  As used herein, the term “apoptosis” refers to an endogenous cell self-destruction or suicide program. In response to triggering stimuli, cells undergo a cascade of events including cell contraction, cell membrane blebbing and chromosome condensation and fragmentation. These events lead to the conversion of cells into clusters of membrane-bound particles (apoptotic bodies), which are then taken up by macrophages.

As used herein, the term "polar substituent" refers to an electric dipole, and optionally any substituent with a dipole moment (e.g., an asymmetric polar substituent has a dipole moment and has a symmetric polarity. Substituent has no dipole moment). Polar substituents include those groups that accept or donate hydrogen bonds and groups that carry at least a partial positive or negative charge in aqueous solutions at physiological pH levels. In certain embodiments, a polar substituent is a substituent that can accept or donate electrons in a non-covalent hydrogen bond with another chemical moiety. In certain embodiments, the polar substituent is selected from carboxy, a bioequivalent of carboxy, or other acid-derived moiety that is predominantly present as an anion at a pH of about 7-8. Other polar substituents include OH or NH containing groups, ether oxygen, amine nitrogen, oxidized sulfur or nitrogen, carbonyl, nitrile, and nitrogen-containing heterocyclic rings or oxygens, whether aromatic or non-aromatic. Including, but not limited to, containing heterocyclic rings. In some embodiments, the polar substituent represented by R ³ is a carboxylate or a biological equivalent of a carboxylate.

ならびに上記の塩およびプロドラッグからなる群より選択される部分であり、式中、各R⁷は独立して、H、またはC_1〜10アルキル、C_2〜10アルケニル、C_2〜10ヘテロアルキル、C_3〜8炭素環、およびさらなる置換されていてもよい炭素環もしくは複素環に任意で融合されてもよいC_3〜8複素環からなる群より選択される置換されていてもよい構成員であり; あるいはR⁷は置換されていてもよいC_3〜8炭素環またはC_3〜8複素環で置換されたC_1〜10アルキル、C_2〜10アルケニルまたはC_2〜10ヘテロアルキルである。 As used herein, a “carboxylate bioequivalent” or “carboxy bioequivalent” refers to a moiety that is expected to be negatively charged to a significant degree at physiological pH. . In certain embodiments, the biological equivalent of carboxylate is:

And a moiety selected from the group consisting of the above salts and prodrugs, wherein each R ⁷ is independently H, or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 heteroalkyl , A C _3-8 carbocycle, and an optionally substituted member selected from the group consisting of a C _3-8 heterocycle optionally fused to a further optionally substituted carbocycle or heterocycle in it; or R ⁷ is a substituted with optionally substituted C _{3 to 8} carbon ring or C _{3 to 8} heterocyclic ring a C _{1 to 10} alkyl, C _{2 to 10} alkenyl or C _{2 to 10} heteroalkyl .

  In certain embodiments, the polar substituent is selected from the group consisting of carboxylic acid, carboxylic ester, carboxamide, tetrazole, triazole, carboxymethanesulfonamide, oxadiazole, oxothiadiazole, thiazole, aminothiazole and hydroxythiazole. .

In some embodiments, at least one R ^{8 present} is a carboxylic acid or salt, ester or bioequivalent thereof. In certain embodiments, at least one R ^{8 present} is a carboxylic acid-containing substituent or salt, ester or biological equivalent thereof. In the latter embodiment, the R ⁸ substituent can be a C1-C10 alkyl or C1-C10 alkenyl linked to a carboxylic acid (or salt, ester or biological equivalent thereof).

Anticancer Agents As described further herein, the compounds of the present application are administered in combination with additional anticancer agents. Such additional “anticancer agents” include traditional chemotherapeutic agents, as well as molecular targeted therapeutic agents, biotherapeutic agents and radiotherapy agents.

  Anticancer agents used in combination with the compounds of the present application include, for example, alkylating agents, antimetabolites, plant alkaloids and terpenoids (eg, taxanes), topoisomerase inhibitors, antitumor antibiotics, hormone therapy, molecular targets Agents selected from any of the classes known to those skilled in the art can be included, including agents and the like. In general, such anticancer agents are alkylating agents, antimetabolites, plant alkaloids, taxanes, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, or immunosuppressive macrolides.

  Alkylating agents include (a) alkylation such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin and (SP-4-3)-(cis) -aminedichloro- [2-methylpyridine] platinum (II) (B) Alkyl sulfonates such as busulfan; (c) Ethyleneimine and methylmelamine derivatives such as altretamine and thiotepa; (d) Chlorambucil, cyclophosphamide, estramustine, ifosfamide Nitrogen mustards such as mechloretamine, trophosphamide, prednisotin, melphalan and uramustine; (e) nitrosoureas such as carmustine, lomustine, hotemustine, nimustine, ranimustine and streptozocin; (f) dacarbazine, procarbazine, temozolamide and Triazenes such as temozolomide and imidazotetrazine are included.

  Antimetabolites include (a) purine analogs such as fludarabine, cladribine, chlorodeoxyadenosine, clofarabine, mercaptopurine, pentostatin, and thioguanine; (b) fluorouracil, gemcitabine, capecitabine, cytarabine, azacitidine, edatrexate, Pyrimidine analogs such as coxuridine and troxacitabine; (c) antifolates such as methotrexate, pemetrexed, raltitrexed and trimethrexate. Antimetabolites also include thymidylate synthase inhibitors such as fluorouracil, raltitrexed, capecitabine, floxuridine and pemetrexed; and ribonucleotide reductase inhibitors such as claribin, clofarabine and fludarabine.

  Plant-derived alkaloids and terpenoid-derived drugs include, but are not limited to, mitotic inhibitors such as the vinca alkaloids vinblastine, vincristine, vindesine and vinorelbine; and paclitaxel, docetaxel, larotaxel, oltaxel and tesetaxel, taxanes Microtubule polymer stabilizers such as

  Topoisomerase inhibitors include topoisomerase I inhibitors such as camptothecin, topotecan, irinotecan, rubitecan and verotecan; and topoisomerase II inhibitors such as etoposide, teniposide and amsacrine.

  Antitumor antibiotics include (a) anthracyclines such as daunorubicin (including liposomal daunorubicin), doxorubicin (including liposomal doxorubicin), epirubicin, idarubicin and valrubicin; (b) bleomycin, actinomycin, mitramycin, mitomycin, Streptomyces related substances such as porphyromycin; and (c) anthracenediones such as mitoxantrone and pixantrone. Anthracyclines have three mechanisms of action: insertion between DNA / RNA strand base pairs; inhibition of topoisomerase II enzymes; and creation of iron-mediated oxygen free radicals that damage DNA and cell membranes. Anthracyclines are generally characterized as topoisomerase II inhibitors.

  Hormone therapy includes (a) androgens such as fluoxymesterone and test lactone; (b) antiandrogens such as bicalutamide, cyproterone, flutamide and nilutamide; (c) aminoglutethimide, anastrozole, exemestane, Aromatase inhibitors such as formestane and letrozole; (d) corticosteroids such as dexamethasone and prednisone; (e) estrogens such as diethylstilbestrol; (f) fulvestrant, raloxifene, tamoxifen and toremifene (toremifine) (G) LHRH agonists and antagonists such as buserelin, goserelin, leuprolide and triptorelin; (h) progestins such as medroxyprogesterone acetate and megestrol acetate; Rabiti (i) Contains thyroid hormones such as levothyroxine and liothyronine.

  Molecular targeted drugs include (a) receptor tyrosine kinase (“RTK”) inhibitors, such as EGFR inhibitors, including erlotinib, gefitinib and neratinib; VEGFR inhibitors including vandetanib, cemaxinib and cediranib; and PDGFR inhibition Includes: RTK inhibitors that work at multiple receptor sites, such as lapatinib, which also inhibits EGFR and HER2, and including but not limited to axitinib, sunitinib, sorafenib and toseranib, C -kit, inhibitors of PDGFR and VEGFR; also included are inhibitors of BCR-ABL, c-kit and PDGFR, such as imatinib; (b) rapamycin or bafilomycin FKBP binding agents, such as immunosuppressive macrolide antibiotics, including: (c) gene therapeutics, antisense therapeutics and gene expression regulators, Retinoids and rexinoids, such as adapalene, bexarotene, trans retinoic acid, 9-cis retinoic acid and N- (4-hydroxyphenyl) retinamide; (d) alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab and trastuzumab Phenotype-directed therapeutic agents, including such monoclonal antibodies; (e) immunotoxins such as gemtuzumab ozogamicin; (f) radioimmunoconjugates such as 131-tositumomab; and (g) cancer vaccines .

  Various drugs include altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, photodynamic compounds such as methoxalene and porfimer sodium, and proteasome inhibitors such as bortezomib Etc. are included.

  Biotherapeutic agents include interferons, such as interferon α2a and interferon α2b, and interleukins, such as Aldesleukin, Denileukin Diftitox and Oprelbekin.

  In addition to anticancer agents intended to work against cancer cells, cytoprotective agents such as amifostine, dexrazonxane and mesna, phosphonic acids such as pamidronate and zoledronic acid And the like, as well as combination therapies that involve the use of protective or adjuvants, including stimulating factors such as epoetin, darbeopetin, filgrastim, PEG-filgrastim and sargramostim.

または薬学的に許容されるその塩もしくはエステルと、抗がん剤または薬学的に許容されるその塩もしくはエステルとを投与しそれによって該新生物障害を処置または改善する段階を含む、該方法について開示する。
式中、Z⁵はNもしくはCR^6Aであり;
各R^6A、R^6B、R^6DおよびR⁸は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R^6A、R^6B、R^6DおよびR⁸は独立して、ハロ、CF₃、CFN、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体、CONR₂、OOCR、CORもしくはNO₂であり、
各R⁹は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R⁹は独立して、ハロ、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、CONR₂、OOCR、CORもしくはNO₂であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR'₂、SR'、SO₂R'、SO₂NR'₂、NR'SO₂R'、NR'CONR'₂、NR'COOR'、NR'COR'、CN、COOR'、CONR'₂、OOCR'、COR'およびNO₂から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく;
nは0〜4であり；かつ
pは0〜4である。 In one aspect, the application is a method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I in a subject in need thereof:

Or a method comprising administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent or a pharmaceutically acceptable salt or ester thereof, thereby treating or ameliorating the neoplastic disorder. Disclose.
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 Alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A , R ^6B, R ^6D and R ⁸ are independently _{halo, CF 3, CFN, oR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, carboxy bioequivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4.

  In one alternative, the application is a method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I as described herein in a subject in need thereof. And a method of administering an anticancer agent or a pharmaceutically acceptable salt or ester thereof, wherein the anticancer agent is not doxorubicin.

  In another alternative, this application is a method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I as described herein in a subject in need thereof And a method of administering an anticancer agent or a pharmaceutically acceptable salt or ester thereof, wherein the anticancer agent is not a topoisomerase II inhibitor.

  In another alternative, this application is a method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I as described herein in a subject in need thereof And a method of administering an anticancer agent or a pharmaceutically acceptable salt or ester thereof, wherein the anticancer agent is not an antitumor antibiotic.

  In one embodiment of any of the aspects or alternatives described herein, the anticancer agent is not 5-fluorouracil. In another embodiment, the anticancer agent is not a thymidylate synthase inhibitor. In another embodiment, the anticancer agent is not an antimetabolite pyrimidine analog. In another embodiment, the anticancer agent is not an antimetabolite.

  In one embodiment of any of the aspects or alternatives described herein, the anticancer agent is not rapamycin. In another embodiment, the anticancer agent is not an immunosuppressive macrolide antibiotic. In another embodiment, the anticancer agent is not an FKBP binding agent.

  In one embodiment of any of the aspects or alternatives described herein, the anticancer agent is not erlotinib (Tarceva). In another embodiment, the anticancer agent is not a small molecule EGFR inhibitor. In another embodiment, the anticancer agent is not a receptor tyrosine kinase inhibitor.

  In one embodiment of any of the aspects or alternatives described herein, the anticancer agent is not sunitinib (Sutent). In another embodiment, the anticancer agent is not an inhibitor of VEGFR, PDGFR and cKIT. In another embodiment, the anticancer agent is not a receptor tyrosine kinase inhibitor.

  In another embodiment of any aspect or alternative described herein, the anticancer agent is not doxorubicin, 5-fluorouracil, rapamycin, erlotinib or sunitinib. In another embodiment, the anticancer agent is not any one of any four of doxorubicin, 5-fluorouracil, rapamycin, erlotinib or sunitinib. For example, in one such embodiment, the anticancer agent is not 5-fluorouracil, rapamycin, erlotinib or sunitinib. In another such embodiment, the anticancer agent is not doxorubicin, 5-fluorouracil, erlotinib or sunitinib. In another embodiment, the anticancer agent is not any one of any three of doxorubicin, 5-fluorouracil, rapamycin, erlotinib or sunitinib. For example, in one such embodiment, the anticancer agent is not 5-fluorouracil, erlotinib or sunitinib. In another such embodiment, the anticancer agent is not doxorubicin, erlotinib or sunitinib. In another embodiment, the anticancer agent is not any one of any two of doxorubicin, 5-fluorouracil, rapamycin, erlotinib or sunitinib.

  In another embodiment of any aspect or alternative described herein, the anticancer agent is a topoisomerase II inhibitor, a thymidylate synthase inhibitor, an immunosuppressive macrolide antibiotic, a small molecule EGFR inhibitor Or not an inhibitor of VEGFR, PDGFR and cKIT. In another embodiment, the anticancer agent is a topoisomerase II inhibitor, a thymidylate synthase inhibitor, an immunosuppressive macrolide antibiotic, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. Is not one of them. For example, in one such embodiment, the anticancer agent is not a thymidylate synthase inhibitor, an immunosuppressive macrolide antibiotic, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. In another such embodiment, the anticancer agent is not a topoisomerase II inhibitor, a thymidylate synthase inhibitor, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. In another embodiment, the anticancer agent is a topoisomerase II inhibitor, a thymidylate synthase inhibitor, an immunosuppressive macrolide antibiotic, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. Is not one of them. For example, in one such embodiment, the anticancer agent is not a topoisomerase II inhibitor, a thymidylate synthase inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. In another such embodiment, the anticancer agent is not a thymidylate synthase inhibitor, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. In another embodiment, the anticancer agent is a topoisomerase II inhibitor, a thymidylate synthase inhibitor, an immunosuppressive macrolide antibiotic, a small molecule EGFR inhibitor or an inhibitor of VEGFR, PDGFR and cKIT. Is not one of them.

  In another embodiment of any aspect or alternative described herein, the anticancer agent is not a topoisomerase II inhibitor, an antimetabolite pyrimidine analog, an FKBP binding agent or a receptor tyrosine kinase inhibitor. In another embodiment, the anticancer agent is not any one of any three of a topoisomerase II inhibitor, an antimetabolite pyrimidine analog, an FKBP binding agent or a receptor tyrosine kinase inhibitor. For example, in one such embodiment, the anticancer agent is not a topoisomerase II inhibitor, an antimetabolite pyrimidine analog, or a receptor tyrosine kinase inhibitor. In another such embodiment, the anticancer agent is not an antimetabolite pyrimidine analog, FKBP binding agent or receptor tyrosine kinase inhibitor. In another embodiment, the anticancer agent is not any one of any two of a topoisomerase II inhibitor, an antimetabolite pyrimidine analog, an FKBP binding agent or a receptor tyrosine kinase inhibitor.

  In one embodiment of any aspect or alternative described herein, the anticancer agent used in combination with a compound of the present application is 5-fluorouracil (5-FU), cisplatin, doxorubicin, fludarabine, Selected from gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from cisplatin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, fludarabine, gemcitabine, paclitaxel, sunitinib, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib and vinblastine. In a further embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib and vinblastine. In a further embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, rapamycin, erlotinib and vinblastine. In another embodiment, the anticancer agent is selected from 5-fluorouracil, cisplatin, fludarabine, gemcitabine, paclitaxel, rapamycin, erlotinib and vinblastine. In another embodiment, the anticancer agent used in combination with the compounds of the present application is selected from doxorubicin, cisplatin, fludarabine, gemcitabine, paclitaxel and vinblastine. In another embodiment, the anticancer agent used in combination with the compounds of the present application is selected from cisplatin, fludarabine, gemcitabine, paclitaxel and vinblastine.

または薬学的に許容されるその塩もしくはエステル
を有する。
式中、Z⁵はNもしくはCR^6Aであり;
各R^6AおよびR⁸は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R^6AおよびR⁸は独立して、ハロ、CF₃、CFN、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体、CONR₂、OOCR、CORもしくはNO₂であり、
各R⁹は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R⁹は独立して、ハロ、OR、NR₂、NROR、NRNR₂、SR、SOR、SO₂R、SO₂NR₂、NRSO₂R、NRCONR₂、NRCOOR、NRCOR、CN、COOR、CONR₂、OOCR、CORもしくはNO₂であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR'₂、SR'、SO₂R'、SO₂NR'₂、NR'SO₂R'、NR'CONR'₂、NR'COOR'、NR'COR'、CN、COOR'、CONR'₂、OOCR'、COR'およびNO₂から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく；かつ
pは0〜4である。 In one embodiment of any aspect or alternative disclosed, the compound of formula I has the structure of formula II, III, IV, V or VI:

Or a pharmaceutically acceptable salt or ester thereof.
Where Z ⁵ is N or CR ^6A ;
Each R ^6A and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 hetero An alkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A and R ⁸ is independently Te, _{halo, CF 3, CFN, OR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, carboxy organisms Is the scientific equivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And wherein two R ′ may be linked to form a 3-7 membered ring that may contain up to 3 heteroatoms selected from N, O and S; and
p is 0-4.

または薬学的に許容されるその塩もしくはエステルである。 In certain embodiments of any aspect or alternative disclosed, the compound of formula I has the following formula (compound K):

Or a pharmaceutically acceptable salt or ester thereof.

または薬学的に許容されるその塩もしくはエステルである。 In another embodiment of any aspect or alternative disclosed, the compound of formula I has the formula (1) or (2):

Or a pharmaceutically acceptable salt or ester thereof.

  Compounds of formula I, II, III, IV, V and VI can exert biological activity including but not limited to inhibition of cell proliferation and modulation of protein kinase activity. A compound of such formula can, for example, modulate CK2 activity. Such compounds can therefore be utilized in multiple applications by those skilled in the art. For example, the compounds described herein include (i) modulation of protein kinase activity (e.g., CK2 activity) when administered alone or in combination with another anticancer agent, (ii) Applications can be found including but not limited to the regulation of cell proliferation, (iii) modulation of apoptosis, and (iv) treatment of disorders associated with cell proliferation, such as neoplastic disorders.

  In another aspect, the application provides an effective amount of a compound of formula I, II, III, IV, V, or VI as described herein, or a pharmaceutically acceptable salt or ester thereof, and Disclosed is a method for inhibiting or slowing cell growth in a system, comprising administering to the system an cancer agent or a pharmaceutically acceptable salt or ester thereof, thereby inhibiting or slowing cell growth. The system can be a cell, tissue or subject.

または薬学的に許容されるその塩もしくはエステルと、よく用いられる抗がん剤または薬学的に許容されるその塩もしくはエステルとの組み合わせでの投与を含む、新生物障害を予防する、処置する、または寛解させるための方法、ならびに細胞増殖を阻害または緩徐化するための方法について開示する。 The application also provides a therapeutically effective amount of a compound having the formula: (compound K):

Or preventing or treating a neoplastic disorder comprising administration of a pharmaceutically acceptable salt or ester thereof in combination with a commonly used anticancer agent or pharmaceutically acceptable salt or ester thereof, Alternatively, a method for remission and a method for inhibiting or slowing cell proliferation are disclosed.

  With respect to the above aspects of the application, the inventors contemplate any combination of the anticancer agents described herein.

  The application comprises a compound of formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt or ester thereof and a commonly used anticancer agent or a pharmaceutically acceptable salt or ester thereof, As well as pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient. This combination is administered in an amount effective to inhibit cell proliferation.

  Compounds of formula I, II, III, IV, V and VI, and pharmaceutically acceptable salts and esters thereof may be collectively referred to herein as the compounds of this application.

  The application further includes a compound of the present application or a pharmaceutically acceptable salt or ester thereof, and a commonly used anticancer agent or pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable salt. Disclosed are pharmaceutical compositions containing the excipients. This combination is administered in an amount effective to inhibit cell proliferation. In certain embodiments, the compound of the present application is Compound K, Compound 1 or Compound 2, or a salt or ester thereof.

  In one aspect disclosed in this application, combination therapy is administered to an individual with a neoplastic disorder. In another aspect of the application, combination therapy is administered to individuals who have not yet shown clinical signs of neoplastic disorder but are at risk of developing a neoplastic disorder. For such purposes, this application discloses methods for inhibiting or reducing the risk of developing neoplastic disorders.

  In one embodiment, a single pharmaceutical dosage formulation is administered that includes both a compound of the present application and an anticancer agent, such as Compound K. In another embodiment disclosed in this application, separate dosage formulations are administered; the compound and the anticancer agent are, for example, essentially the same time point, e.g., at the same time or at different time points, e.g., sequentially. May also be administered. In certain instances, the individual components of the combination may be administered separately, at different times during the course of therapy, or simultaneously, in divided or single combination forms.

  The application discloses, for example, simultaneous treatment, staggered treatment, or alternating treatment. Thus, the compounds of the present application may be administered concurrently with the anticancer agent in the same pharmaceutical composition; the compounds of the present application may be administered concurrently with the anticancer agent in another pharmaceutical composition. The compound of the present application may be administered prior to the anticancer agent, or the anticancer agent may be administered prior to the compound of the present application, for example, in seconds, minutes, hours, days or weeks. You may administer by the time difference of a unit. In the example of staggered treatment, a therapeutic course with a compound of the present application may be followed by a therapeutic course with an anti-cancer agent, or a reverse sequence of treatments may be used, with each component continuously Two or more treatments may be used. In certain examples of the present application, one component, eg, a compound or anticancer agent of the present application, is administered to a mammal while the other component or derivative product thereof remains in the mammalian bloodstream. The For example, Compound K may be administered while the anticancer agent or derivative product remains in the bloodstream, or the anticancer agent remains with Compound K or derivative thereof in the bloodstream. It may be administered in between. In other examples, the second component is administered after all or most of the first component or derivative thereof has disappeared from the mammalian bloodstream.

  Anticancer agents used in combination with the compounds of the present application can include agents selected from any of the classes known to those skilled in the art. Suitable anticancer agents include, among others, alkylating agents, antimetabolites (e.g. purines and pyrimidines), plant alkaloids (e.g. vinca alkaloids) terpenoids (e.g. taxanes), topoisomerase inhibitors, Anti-tumor antibiotics, hormone therapy, and molecular targeted drugs such as but not limited to receptor tyrosine kinase (RTK) inhibitors (e.g. PDGFR, VEFGR, EGFR inhibitors) and monoclonal antibodies etc. There is nothing.

Formulation and Administration The compositions and methods of the present application are typically used in the treatment of human patients, although they may be used in veterinary medicine to treat similar or identical diseases. The composition can be used to treat mammals including, but not limited to, primates and domestic mammals. The composition can be used, for example, to treat herbivores. The compositions of the present application include one or more geometric and optical isomers of the drug, each drug being a racemic mixture of isomers or one or more purified isomers.

  Pharmaceutical compositions suitable for use in this application include compositions wherein the active ingredient is contained in an amount effective to achieve its intended purpose. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

  The compounds of the present application can exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to an active compound prepared with a relatively non-toxic acid or base, depending on the particular substituent moiety found on the compounds described herein. Means containing salt. Where a compound of the present application contains a relatively acidic functional group, the neutral form of such a compound is contacted with a sufficient amount of the desired base as is or in a suitable inert solvent. Addition salts can be obtained. Included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. Where a compound of the present application contains a relatively basic functional group, the neutral form of such compound is contacted with a sufficient amount of the desired acid as is or in a suitable inert solvent. Acid addition salts can be obtained. Examples of acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid or Derived from inorganic acids such as phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid Examples thereof include acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginates and the like, and salts of organic acids such as glucuronic acid or galactunoric acid (e.g., Berge et al., `` Pharmaceutical Salts '', (See Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of this application contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

  Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. (+ ) -Tartrate, (−)-tartrate or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

  The neutral forms of the compounds are typically regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents.

A pharmaceutically acceptable ester in this application refers to a non-toxic ester, generally an alkyl ester is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl ester, more often an alkyl ester is a methyl ester. is there. However, other esters such as phenyl-C _1-5 alkyl may be utilized if desired. Ester derivatives of certain compounds act as prodrugs that, upon absorption into the bloodstream of warm-blooded animals, release the drug form and can be cleaved to allow the drug to provide improved therapeutic efficacy. sell.

  Certain compounds of the present application can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of this application. Certain compounds of the present application may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of this application.

  When used as a therapeutic substance, the compounds described herein are often administered with a physiologically acceptable carrier. A physiologically acceptable carrier is a formulation to which the compound can be added to dissolve the compound or otherwise facilitate its administration. Examples of physiologically acceptable carriers include, but are not limited to, water, saline, and physiological saline.

  Certain compounds of the present application possess an asymmetric carbon atom (optical center or chiral center) or double bond; in terms of absolute stereochemistry (R)-or (S)-or in the case of amino acids ( Optical isomers, racemates, diastereoisomers, tautomers, geometric isomers, stereoisomers, and individual isomers that may be defined as D)-or (L)-are within the scope of this application. Is included. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the application. The compounds of this application do not include those known in the art as too unstable to be synthesized and / or isolated. This application discloses racemic and optically pure forms of the compounds. Optically active (R)-and (S)-, or (D)-and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. May be. Where a compound described herein contains an olefinic bond or other geometrically asymmetric center, it is intended that the compound contain both E and Z geometric isomers, unless otherwise specified.

  As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. Say. It will be apparent to those skilled in the art that certain compounds of the present application may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this application, except for replacement of hydrogen with deuterium or tritium, or replacement of carbon with ¹³ C- or ¹⁴ C-enriched carbon. The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound can be radiolabeled with a radioisotope, such as tritium (3H), iodine-125 ( ^125I ) or carbon-14 ( ^14C ). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of this disclosure.

  In addition to salt forms, this application provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present application. Additionally, prodrugs can be converted to the compounds of the present application by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present application when placed in a transdermal patch container with a suitable enzyme or chemical reagent.

  The description of the compounds of this application is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group can be substituted by one or more of several substituents, such substituents are compatible with the principles of chemical bonding and are not inherently unstable and / or aqueous Selected to provide compounds that would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as neutral and some known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule through a ring heteroatom according to chemical bonding principles known to those skilled in the art, thereby avoiding essentially unstable compounds.

  The compounds of the present application can be formulated as pharmaceutical compositions. Such pharmaceutical compositions are then orally, parenterally, by inhalation spray, rectally or topically, the conventional non-toxic pharmaceutically acceptable desired carriers, adjuvants and It can be administered as a dosage unit formulation containing vehicle. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections or infusion techniques. Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa .; 1975. Other examples of drug formulations can be found in Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. There may be. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually employed as the solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethylacetamide, surfactants including ionic and nonionic surfactants, polyethylene glycol can be used. Mixtures of solvents and wetting agents such as those described above are also useful.

  Suppositories for rectal administration of the drug can be prepared by mixing the drug with suitable nonirritating excipients such as cocoa butter, synthetic monoglycerides, diglycerides or triglycerides, fatty acids and polyethylene glycols and are solid at room temperature However, because it is liquid at rectal temperature, it will melt in the rectum and release the drug.

  Solid dosage forms for oral administration can include capsules, tablets, pills, powders and granules. In such solid dosage forms, the compounds of the present application are usually combined with one or more adjuvants appropriate for the intended route of administration. If administered orally, contemplated aromatic sulfone hydroxymate inhibitor compounds include lactose, sucrose, starch powder, alkanoic acid cellulose ester, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid. It can be mixed with sodium and calcium salts, gelatin, gum acacia, sodium alginate, polyvinyl pyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled release formulation, as can be provided in a hydroxypropylmethylcellulose dispersion of the active compound. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents such as sodium citrate, carbonate or magnesium bicarbonate or calcium. Tablets and pills may additionally be prepared with enteric coatings.

  For therapeutic purposes, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the above-mentioned carriers or diluents used in formulations for oral administration. Contemplated aromatic sulfone hydroxymate inhibitor compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers it can. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. it can. Such compositions may also contain wetting agents, emulsifying and suspending agents and adjuvants such as sweetening, flavoring and flavoring agents.

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the mammalian host treated and the particular mode of administration.

  Administration regimens utilizing the compounds of the present application in combination with anti-cancer agents include patient type, species, age, weight, sex and medical condition; severity of the condition being treated; route of administration; renal function of the patient and Liver function; as well as various factors including the particular compound utilized or a salt or ester thereof. A review of these factors is well within the scope of clinicians having ordinary skill in determining the therapeutically effective dose given to those in need of the combination therapy.

  The following examples illustrate the present disclosure, but do not limit it.

Example 1: Cell Inhibition Assay 3000 cells per well are plated into each well of two 96 well plates (in duplicate). Cells are incubated overnight at 37 ° C. The next day, one or more compounds are added to the plate and the concentration of each compound is systematically varied throughout the plate. Typically, across each plate, one compound is changed vertically using a 2x, 3x or 4x dilution and another using a 2x, 3x or 4x dilution. The compound is changed horizontally (shown below). The upper concentration of Compound K is 100, 30 or 10 micromolar. The top concentration of other drugs, such as rapamycin or cisplatin, varies from 200 micromolar to 30 nanomolar. In some cases, the observed synergistic effect is affected by the order of addition of the two compounds. In such cases, the first drug was added one day before the second drug. Analyze with Alamar Blue cell viability. Briefly, 20 microliters of AlamarBlue reagent (Invitrogen, Carlsbad CA) was added per well. The plate was incubated for 4 hours at 37 ° C. and the resulting fluorescence was measured at Ex 560 nm / Em 590 nm.

Example 1a: Single Agent IC50 Calculations To determine the IC50 of a single agent for each combination, two sets of raw data of relative fluorescence units (RFU) from the Alamar Blue assay were used against the background. Corrected and analyzed with sigmoidal dose response (slope with slope change) using GraphPad Prism software (GraphPad, San Diego CA). The following constraints were applied: The bottom was fixed equal to zero; if the calculated top was unreasonably high, its value was fixed below the highest value allowed in the analyzed data set. See FIG.

Example 2: Calculation of% inhibition data from plate synergy Effect % inhibition is calculated for each well in the plate based on the response data collected as described in Example 1. The concentration of Compound K increases regularly as the line number increases from 1 to 8. High concentrations (eg 100 micromolar) are diluted serially (eg 3 times). Drug concentration increases regularly as the letter in the column increases from A to L (as described in the table below). High concentrations (eg 30 micromolar) are diluted serially (eg 3 times). Representative plates used for the study are shown below.

  The expected% inhibition value is obtained by inferring an exact additivity between the effect of Compound K and the effect of the added drug. Therefore, the expected value for any well of interest is only seen with the same concentration of added drug present in that well, in% inhibition observed only with the same concentration of Compound K present in that well Calculated as the% inhibition multiplied. In practice, this means that the% inhibition seen with Compound K is obtained from row A because the concentration of added drug is now 0. Similarly, the% inhibition observed with added drug is obtained from row 2 (because the concentration of Compound K is 0 here), for example, the expected value for well D8 is found in well A8 It is obtained by multiplying the% inhibition by the% inhibition found in well D2.

  The control for these studies is a dose response curve for each of the two drugs themselves. Such a control predicts cytotoxicity for each possible combination for each of the two drugs, simply based on adding the cytotoxicity observed for each of the two drugs when used alone. It becomes possible.

  The assessment of synergy is completed by comparing the actual% inhibition to the expected% inhibition. For example, if the expected value for well D8 is 60% but 80% inhibition is observed, the compounds have enhanced each other's effects and a synergistic effect is observed. The value shown in the table will be 20.0. Conversely, a negative number is obtained if the two compounds produce an unexpected inhibitory effect.

  For example, if compound A at concentration X inhibits by 20% and compound B at concentration Y inhibits by 20%, the combination of compound A at concentration X and compound B at concentration Y is expected to inhibit by 40%. I can do it. That leaves another 60% inhibition potential. For example, an overall inhibition of 70% corresponds to 50% inhibition of the remaining 60%, and for that particular combination it is labeled “50”. In practice, the program is written in the PilotScript programming language to calculate the above quantities.

Example 2a: Calculation of synergy using combination indexCombination index (CI): CI = [A] / IC50 _A + [B] / IC50 _B provides a quantitative measure of drug interaction, where The IC50 _A and IC50 _B concentrations of the drug are the concentrations to achieve the 50% effect alone, and the [A] and [B] concentrations of these two drugs are the concentrations to achieve the 50% effect in combination It is. A CI less than 1, a CI equal to 1, and a CI greater than 1 indicate synergy, additiveness, and antagonism, respectively. To calculate the CI for our combination, we used an IC50 determined with sigmoidal dose response (slope with slope change) using GraphPad Prism software. The 50% effect value was calculated as one-half of the average between the top value for Compound K and the top value for the combined compound. CI values are calculated at the lowest drug concentration at which a 50% effect was achieved.

Example 3: 5-Fluorouracil / Compound K Combination Test in A375 Melanoma Cells The thymidylate synthase inhibitor 5-fluorouracil was tested in combination with Compound K in the melanoma cell line A375. 5-Fluorouracil was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 2 and FIG. Synergies up to 55% are observed at test concentrations. CI = 0.02.

5-Fluorouracil was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.6 uM, top = 7711 RFU.

  5-FU: IC50 = 3.0 uM, top = 9383 RFU.

  50% effect value = 4274 RFU.

  A 50% effect was achieved by combining 40 nM Compound K and 30 nM 5-fluorouracil.

CI = [Compound K] / IC50 _{Compound K} + [5-FU] / IC50 _5-Fu = (0.04 / 4.6) + (0.03 / 3.0) = 0.02.

Example 4: Fludarabine / Compound K combination test in A375 melanoma cells The purine analog fludarabine was tested in combination with Compound K in the melanoma cell line A375. Fludarabine was added 24 hours prior to Compound K in the 4-day assay. Results are shown below; see FIG. 4 and FIG. Synergies up to 65% are observed at test concentrations. CI = 0.03.

Fludarabine was added first and Compound K was added the next day (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 5.0 uM, top = 8874 RFU.

  Fludarabine: IC50 = 22.9 uM, top = 8227 RFU.

  50% effect value = 4276 RFU.

  A 50% effect was achieved by combining 40 nM Compound K and 390 nM fludarabine.

CI = [compound K] / IC50 _compound K + [fludarabine] / IC50 _fludarabine = (0.04 / 5.0) + (0.39 / 22.9) = 0.03.

Example 5: Gemcitabine / Compound K combination test in A375 melanoma cells A pyrimidine, gemcitabine, was tested in combination with Compound K in the melanoma cell line A375. Gemcitabine was added 24 hours prior to Compound K in the 4-day assay. Results are shown below; see FIG. Synergies up to 45% are observed at test concentrations. CI = 0.04.

Gemcitabine was added first and Compound K was added the next day (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.8 uM, top = 8646 RFU.

  Fludarabine: IC50 = 3.5 nM, top = 7461 RFU.

  50% effect value = 4027 RFU.

  A 50% effect was achieved by combining 120 nM Compound K and 30 pM gemcitabine.

CI = [compound K] / IC50 _{compound K} + [gemcitabine] / IC50 _gemcitabine = (0.12 / 4.8) + (0.03 / 3.5) = 0.04.

Example 6: Paclitaxel / Compound K Combination Test in A375 Melanoma Cells The mitotic inhibitor paclitaxel was tested in combination with Compound K in the melanoma cell line A375. Paclitaxel was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 7 and FIG. Synergies up to 30% are observed at test concentrations. CI = 0.17.

Paclitaxel was added first and compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 11.5 uM, top = 23452 RFU.

  Fludarabine: IC50 = 2.9 nM, top = 26000 RFU.

  50% effect value = 12363 RFU.

  A 50% effect was achieved by combining 100 nM Compound K and 460 pM paclitaxel.

CI = [compound K] / IC50 _{compound K} + [paclitaxel] / IC50 _paclitaxel = (0.1 / 11.5) + (0.46 / 2.9) = 0.17.

Example 7: Sunitinib / Compound K Combination Test in A375 Melanoma Cells The multi-tyrosine kinase inhibitor sunitinib was tested in combination with Compound K in the melanoma cell line A375. Sunitinib was added 24 hours prior to Compound K in the 4-day assay. Results are shown below; see FIG. 9 and FIG. Synergies up to 60% are observed at test concentrations. CI = 0.04.

Sunitinib was added first and Compound K was added the next day (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 5.1 uM, top = 8150 RFU.

  Sunitinib: IC50 = 145 nM, top = 7914 RFU.

  50% effect value = 4016 RFU.

  A 50% effect was achieved by combining 120 nM Compound K and 3 nM sunitinib.

CI = [compound K] / IC50 _{compound K} + [sunitinib] / IC50 _sunitinib = (0.12 / 5.1) + (0.003 / 0.145) = 0.04.

Example 8: Vinblastine / Compound K combination test in A375 melanoma cells The mitotic inhibitor vinblastine was tested in combination with Compound K in the melanoma cell line A375. Vinblastine was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 11 and FIG. Synergies up to 35% are observed at test concentrations. CI = 0.39.

Vinblastine was added first and compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 12 uM, top = 25176 RFU.

  Vinblastine: IC50 = 1.2 nM, top = 28000 RFU.

  50% effect value = 13294 RFU.

  A 50% effect was achieved by combining 20 nM Compound K and 460 pM vinblastine.

CI = [compound K] / IC50 _{compound K} + [vinblastine] / IC50 _vinblastine = (0.02 / 12) + (0.46 / 1.2) = 0.39.

Example 9: Combination test of 5-fluorouracil / compound K in MDA-MB-468 breast cancer cells The pyrimidine analog 5-fluorouracil was tested in combination with compound K in the breast cancer cell line MDA-MB-468. Examine the effect of order of addition. Results are shown below; see FIG. 13 and FIG. Synergies up to 40% are observed at test concentrations. CI = 0.18-0.24. The synergistic effect did not depend on the order of addition.

5-Fluorouracil was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.4 uM, top = 10446 RFU.

  5-Fluorouracil: IC50 = 6.6 uM, top = 10485 RFU.

  50% effect value = 5233 RFU.

  A 50% effect was achieved by combining 410 nM Compound K and 940 nM 5-fluorouracil.

CI = [Compound K] / IC50 _{Compound K} + [5-Fluorouracil] / IC50 _{5-Fluorouracil} = (0.41 / 4.4) + (0.94 / 6.6) = 0.24.

Compound K was added first and 5-fluorouracil was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. See FIGS. 15 and 16. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.6 uM, top = 10630 RFU.

  5-Fluorouracil: IC50 = 10.6 uM, top = 10384 RFU.

  50% effect value = 5254 RFU.

  A 50% effect was achieved by combining 410 nM Compound K and 940 nM 5-fluorouracil.

CI = [Compound K] / IC50 _{Compound K} + [5-Fluorouracil] / IC50 _{5-Fluorouracil} = (0.41 / 4.6) + (0.94 / 10.6) = 0.18.

Example 10: Cisplatin / Compound K Combination Test in MDA-MB-468 Breast Cancer Cells The alkylating agent cisplatin was tested in combination with Compound K in the breast cancer cell line MDA-MB-468. Examine the effect of order of addition. Results are shown below; see FIG. 17 and FIG. Synergies up to 15% are observed at test concentrations. CI = 0.3-0.84. The synergistic effect did not depend on the order of addition.

Cisplatin was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.3 uM, top = 10513 RFU.

  5-Fluorouracil: IC50 = 107 nM, top = 11803 RFU.

  50% effect value = 5579 RFU.

  A 50% effect was achieved by combining 1.2 uM Compound K and 60 nM cisplatin.

CI = [compound K] / IC50 _{compound K} + [cisplatin] / IC50 _cisplatin = (1.2 / 4.3) + (0.06 / 0.107) = 0.84.

Compound K was added first and cisplatin was added the next day (total 5 day assay). The results show the degree of inhibitory effect observed with the drug combination, where positive values indicate synergy and negative values indicate antagonism; see FIG. 19 and FIG. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.5 uM, top = 9530 RFU.

  Cisplatin: IC50 = 430 nM, top = 9646 RFU.

  50% effect value = 4794 RFU.

  A 50% effect was achieved by combining 1.2 uM Compound K and 120 nM cisplatin.

CI = [compound K] / IC50 _{compound K} + [cisplatin] / IC50 _cisplatin = (1.2 / 4.5) + (0.12 / 0.43) = 0.3.

Example 11: Combination test of doxorubicin / compound K in MDA-MB-468 breast cancer cells In the breast cancer cell line MDA-MB-468, a kind of anthracycline doxorubicin was tested in combination with compound K. Examine the effect of order of addition. Results are shown below; see FIG. 21 and FIG. Observe synergies up to 30%. CI = 0.56-0.76. The synergistic effect did not depend on the order of addition.

Doxorubicin was added first and compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.5 uM, top = 10577 RFU.

  Doxorubicin: IC50 = 17 nM, top = 10942 RFU.

  50% effect value = 5380 RFU.

  A 50% effect was achieved by combining 410 nM Compound K and 8 nM doxorubicin.

CI = [compound K] / IC50 _{compound K} + [doxorubicin] / IC50 _doxorubicin = (0.41 / 4.5) + (0.008 / 0.017) = 0.56.

Compound K was added first and doxorubicin was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. See FIG. 23 and FIG. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.6 uM, top = 9652 RFU.

  Doxorubicin: IC50 = 16 nM, top = 11475 RFU.

  50% effect value = 5282 RFU.

  A 50% effect was achieved by combining 1.2 uM compound K and 8 nM doxorubicin.

CI = [compound K] / IC50 _{compound K} + [doxorubicin] / IC50 _doxorubicin = (1.2 / 4.6) + (0.008 / 0.016) = 0.76.

Example 12 Gemcitabine / Compound K Combination Test in MDA-MB-468 Breast Cancer Cells The pyrimidine analog gemcitabine was tested in combination with Compound K in the breast cancer cell line MDA-MB-468. Examine the effect of order of addition. Results are shown below; see FIG. 25 and FIG. Synergies up to 30% are observed at test concentrations. CI = 0.29-0.84. The synergistic effect did not depend on the order of addition.

Gemcitabine was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.4 uM, top = 10572 RFU.

  Gemcitabine: IC50 = 8.8 nM, top = 10229 RFU.

  50% effect value = 5200 RFU.

  A 50% effect was achieved by combining 3.7 uM compound K and 30 pM gemcitabine.

CI = [compound K] / IC50 _{compound K} + [gemcitabine] / IC50 _gemcitabine = (3.7 / 4.4) + (0.03 / 8.8) = 0.84.

Compound K was added first and gemcitabine was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. See FIGS. 27 and 28. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.3 uM, top = 12460 RFU.

  Gemcitabine: IC50 = 8 nM, top = 11772 RFU.

  50% effect value = 6103 RFU.

  A 50% effect was achieved by combining 1.2 uM compound K and 120 pM gemcitabine.

CI = [compound K] / IC50 _{compound K} + [gemcitabine] / IC50 _gemcitabine = (1.2 / 4.3) + (0.12 / 8) = 0.29.

Example 13: Combination Test of Vinblastine / Compound K in MIA PaCa-2 Pancreatic Cancer Cells The mitosis inhibitor vinblastine was tested in combination with Compound K in the pancreatic cancer cell line MIA PaCa-2. Vinblastine was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 29 and FIG. Synergies up to 45% are observed at test concentrations. CI = 0.07.

Vinblastine was added first and compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 4.1 uM, top = 10022 RFU.

  Vinblastine: IC50 = 14 pM, top = 9697 RFU.

  50% effect value = 4930 RFU.

  A 50% effect was achieved by combining 120 nM Compound K and 0.5 pM vinblastine.

CI = [compound K] / IC50 _{compound K} + [vinblastine] / IC50 _vinblastine = (0.12 / 4.1) + (0.5 / 14) = 0.07.

Example 14 Gemcitabine / Compound K Combination Test in MIA PaCa-2 Pancreatic Cancer Cells The pyrimidine analog gemcitabine was tested in combination with Compound K in the pancreatic cancer cell line MIA PaCa-2. Gemcitabine was added 24 hours prior to Compound K in the 4-day assay. Results are shown below; see FIG. 31 and FIG. Synergies up to 25% are observed at test concentrations. CI = 0.27.

Gemcitabine was added first and Compound K was added the next day (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 1.5 uM, top = 12202 RFU.

  Gemcitabine: IC50 = 184 nM, top = 13153 RFU.

  50% effect value = 6339 RFU.

  A 50% effect was achieved by combining 370 nM Compound K and 12 nM gemcitabine.

CI = [compound K] / IC50 _{compound K} + [gemcitabine] / IC50 _gemcitabine = (0.37 / 1.5) + (12/184) = 0.27.

Example 15: Sunitinib / Compound K combination test in MIA PaCa-2 pancreatic cancer cells Tested in combination with Compound K, the multi-tyrosine kinase inhibitor sunitinib described herein in pancreatic cancer cell line MIA PaCa-2 did. Sunitinib was added 24 hours prior to Compound K in the 4-day assay. Results are shown below; see FIG. 33 and FIG. Synergies up to 25% are observed at test concentrations. CI = 0.2.

Sunitinib was added first and Compound K was added the next day (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 2.0 uM, top = 10345 RFU.

  Sunitinib: IC50 = 420 nM, top = 12195 RFU.

  50% effect value = 5635 RFU.

  A 50% effect was achieved by combining 370 nM Compound K and 6 nM sunitinib.

CI = [compound K] / IC50 _{compound K} + [sunitinib] / IC50 _sunitinib = (0.37 / 1.5) + (12/184) = 0.27.

Example 16: Rapamycin / Compound K Combination Test in MIA PaCa-2 Pancreatic Cancer Cells In the pancreatic cancer cell line MIA PaCa-2, an immunosuppressive macrolide, rapamycin, was tested in combination with Compound K. Rapamycin and Compound K are added simultaneously in a 4-day assay. Results are shown below; see FIG. 35 and FIG. Synergies up to 30% are observed at test concentrations. CI = 0.25.

Rapamycin and Compound K are added simultaneously (total 4 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 1.7 uM, top = 13393 RFU.

  Rapamycin: IC50 = 18.1 uM, top = 9864 RFU.

  50% effect value = 5814 RFU.

  A 50% effect was achieved by combining 410 nM Compound K and 120 nM rapamycin.

CI = [compound K] / IC50 _{compound K} + [rapamycin] / IC50 _rapamycin = (0.41 / 1.7) + (0.12 / 18.1) = 0.25.

Example 17: 5-Fluorouracil / Compound K Combination Test in SUM-149PT Inflammatory Breast Cancer Cells The pyrimidine analog 5-fluorouracil was tested in combination with Compound K in the inflammatory breast carcinoma cell line SUM-149PT. 5-Fluorouracil was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 37 and FIG. Synergies up to 30% are observed at test concentrations. CI = 0.09.

5-Fluorouracil was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 27 uM, top = 17000 RFU.

  5-Fluorouracil: IC50 = 1.7 uM, top = 19618 RFU.

  50% effect value = 9154 RFU.

  A 50% effect was achieved by combining 1.11 uM compound K and 78 nM 5-fluorouracil.

CI = [Compound K] / IC50 _{Compound K} + [5-Fluorouracil] / IC50 _{5-Fluorouracil} = (1.11 / 27) + (0.078 / 1.7) = 0.09.

Example 18: Cisplatin / Compound K Combination Test in SUM-149PT Inflammatory Breast Cancer Cells The alkylating agent cisplatin was tested in combination with Compound K in the inflammatory breast carcinoma cell line SUM-149PT. Cisplatin was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 39 and FIG. Synergies up to 25% are observed at test concentrations. CI = 0.88.

Cisplatin was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 3.8 uM, top = 16000 RFU.

  Cisplatin: IC50 = 462 nM, top = 14588 RFU.

  50% effect value = 7547 RFU.

  A 50% effect was achieved by combining 3.3 uM compound K and 46 nM cisplatin.

CI = [compound K] / IC50 _{compound K} + [cisplatin] / IC50 _cisplatin = (3.3 / 3.8) + (46/462) = 0.88.

Example 19: Rapamycin / Compound K Combination Test in SUM-149PT Inflammatory Breast Cancer Cells An immunosuppressive macrolide, rapamycin, was tested in combination with Compound K in the inflammatory breast carcinoma cell line SUM-149PT. Rapamycin was added 24 hours before Compound K in the 5-day assay. Results are shown below; see FIG. 41 and FIG. Synergies up to 40% are observed at test concentrations. CI = 0.03.

Rapamycin was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 13 uM, top = 18285 RFU.

  Rapamycin: IC50 = 9.7 uM, top = 15915 RFU.

  50% effect value = 8550 RFU.

  A 50% effect was achieved by combining 370 nM Compound K and 39 nM rapamycin.

CI = [compound K] / IC50 _{compound K} + [rapamycin] / IC50 _rapamycin = (0.37 / 13) + (0.039 / 9.7) = 0.03.

Example 20: Erlotinib / Compound K combination test in SUM-149PT inflammatory breast carcinoma cells The small molecule EGFR inhibitor erlotinib was tested in combination with Compound K in the inflammatory breast carcinoma cell line SUM-149PT. Erlotinib was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 43 and FIG. Synergies up to 35% are observed at test concentrations. CI = 0.16.

Erlotinib was added first and Compound K was added the following day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 6.9 uM, top = 19848 RFU.

  Erlotinib: IC50 = 2.2 uM, top = 17378 RFU.

  50% effect value = 9307 RFU.

  A 50% effect was achieved by combining 1.1 uM compound K and 0.5 nM erlotinib.

CI = [compound K] / IC50 _{compound K} + [erlotinib] / IC50 _erlotinib = (1.11 / 6.9) + (0.00051 / 2.2) = 0.16.

Example 21: 5-Fluorouracil / Compound K Combination Test in SUM-190PT Inflammatory Breast Cancer Cells The pyrimidine analog 5-fluorouracil was tested in combination with Compound K in the inflammatory breast carcinoma cell line SUM-190PT. 5-Fluorouracil was added 24 hours prior to Compound K in the 5-day assay. Results are shown below; see FIG. 45 and FIG. Synergies up to 30% are observed at test concentrations. CI = 0.14.

5-Fluorouracil was added first and Compound K was added the next day (total 5 day assay). The results indicate the degree of inhibitory effect observed with the drug combination, where positive values indicate synergism and negative values indicate antagonism. The experiment was performed in duplicate. Both data sets are presented.

  Compound K: IC50 = 852 nM, top = 9958 RFU.

  5-Fluorouracil: IC50 = 12.2 uM, top = 9141 RFU.

  50% effect value = 4775 RFU.

  A 50% effect was achieved by combining 120 nM compound K and 46 nM 5-fluorouracil.

CI = [compound K] / IC50 _{compound K} + [5-fluorouracil] / IC50 _{5-fluorouracil} = (120/852) + (0.046 / 12.2) = 0.14.

Example 22: Erlotinib / Compound K Combination Test in Erlotinib-Sensitive BT-474 Breast Carcinoma Cells The small molecule EGFR inhibitor erlotinib was tested in combination with Compound K in the breast cancer cell line BT-474. Erlotinib was added simultaneously with Compound K in the 4-day assay. Results are shown below; see FIG. 47 and FIG. Synergy was observed at CI = 0.55.

  Erlotinib was added simultaneously in a 1: 1 ratio with compound K in a 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented.

  Compound K: IC50 = 2.7 uM.

  Erlotinib: IC50 = 6.6 uM.

  An effect of about 60% was achieved by combining 1.24 nM Compound K and 1.25 uM erlotinib.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _erlotinib = (1.1 / 2.7) + (1.1 / 6.6) = 0.57.

Example 23: Erlotinib / Compound K Combination Test in Erlotinib Resistant MDA-MB-453 Breast Cancer Cells The small molecule EGFR inhibitor erlotinib was tested in combination with Compound K in the breast carcinoma cell line MDA-MB453. Erlotinib was added simultaneously with Compound K in the 4-day assay. The results are shown below. Synergy was observed at CI = 0.55.

  Compound K was added to the cells in a 4-day assay alone or in combination with 1 uM erlotinib. The experiment was performed in triplicate. Dose response curves for Compound K and combinations are presented; see FIG. 49 and FIG.

  Compound K: IC50 = 6.15 uM.

  Erlotinib: IC50> 100 uM.

  Over 60% effect was achieved by combining 3.125 uM compound K and 1 uM erlotinib.

  IC50 change in combination = 6.15 / 1.96 = 3.14.

Example 24: Erlotinib / Compound K Combination Test in Erlotinib-Resistant T47D Breast Cancer Cells The small molecule EGFR inhibitor erlotinib was tested in combination with Compound K in the breast carcinoma cell line T47D. Erlotinib was added simultaneously in a 4-day assay in combination with Compound K at a ratio of 1: 2.7. The results are shown below. Synergy was observed at CI = 0.48.

  Erlotinib was added simultaneously in a 1: 1 ratio with compound K in a 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented; see FIG.

  Compound K: IC50 = 5.9 uM; maximum concentration = 37.5 uM.

  Erlotinib: IC50 = 47 uM; maximum concentration = 100 uM.

  Combination: 2.1 uM Compound K plus 50% cell death with 5.7 uM erlotinib; see FIG.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _erlotinib = (2.1 / 5.9) + (5.7 / 47) = 0.48.

Example 25: Erlotinib / Compound K Combination Test in Erlotinib-Resistant ZR-75-1 Breast Cancer Cells The small molecule EGFR inhibitor erlotinib was tested in combination with Compound K in the breast carcinoma cell line ZR-75-1. Compound K was added simultaneously in a 4-day assay in a ratio of 1: 2.7 with erlotinib. The results are shown below. Synergy was observed with CI <= 0.59.

  Compound K was added simultaneously with erlotinib at a ratio of 1: 2.7 in a 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented; see FIG.

  Compound K: IC50 = 4.1 uM; maximum concentration = 75 uM.

  Erlotinib: IC50> 200 uM; maximum concentration = 200 uM.

  Combination: 50% cell death with 2.3 uM compound K plus 6.2 uM erlotinib; see FIG.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _erlotinib = (2.3 / 4.1) + (6.2 /> 200) <= 0.59.

Example 26: Lapatinib / Compound K combination test in T47D breast carcinoma cells The small molecule EGFR / Her2 inhibitor lapatinib was tested in combination with Compound K in the breast carcinoma cell line T47D. Compound K was added simultaneously in a 4-day assay in combination with lapatinib in a ratio of 1: 1.2. The results are shown below. Synergy was observed at CI = 0.49.

  Compound K was added simultaneously with lapatinib in a ratio of 1.2: 1 in the 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented; see FIG.

  Compound K: IC50 = 5.87 uM; maximum concentration = 75 uM.

  Lapatinib: IC50 = 5.68 uM; maximum concentration = 62.5 uM.

  Combination: 50% cell death with 1.28 uM lapatinib in addition to 1.53 uM compound K.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _lapatinib = (1.53 / 5.87) + (1.28 / 5.68) = 0.49.

Example 27: Sorafenib / Compound K Combination Test in T47D Breast Cancer Cells The small molecule Raf / PDGFR / VEGFR2 / VEGFR3 / cKit inhibitor sorafenib was tested in combination with Compound K in the breast cancer cell line T47D. Compound K was added simultaneously in a 2: 1 ratio with sorafenib in a 4-day assay. The results are shown below. Synergy was observed at CI = 0.80.

  Compound K was added simultaneously with sorafenib in a 2: 1 ratio in a 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented; see FIG.

  Compound K: IC50 = 5.87 uM; maximum concentration = 75 uM.

  Sorafenib: IC50 = 3.58 uM; maximum concentration = 37.5 uM.

  Combination: 50 u% cell death with 2.6 uM Compound K plus 1.3 uM Sorafenib; see FIG.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _Sorafenibb = (2.6 / 5.87) + (1.3 / 3.58) = 0.80.

Example 28: Sunitinib / Compound K Combination Test in T47D Breast Cancer Cells The small molecule inhibitor sunitinib of a polymorphic receptor tyrosine kinase was tested in combination with Compound K in the breast carcinoma cell line T47D. Compound K was added simultaneously in a 4: 1 assay in a 1: 1 ratio combination with sunitinib. The results are shown below. Synergy was observed at CI = 0.86.

  Compound K was added simultaneously in a 1: 1 ratio with sunitinib in a 4-day assay. The experiment was performed in triplicate. Dose response curves for single agents and combinations are presented; see FIG.

  Compound K: IC50 = 5.87 uM; maximum concentration = 75 uM.

  Sunitinib: IC50 = 6.2 uM; maximum concentration = 75 uM.

  Combination: 50% cell death with 2.6 uM compound K plus 2.6 uM sunitinib.

CI = [IC50 _combination ] / IC50 _{compound K} + [IC50 _combination ] / IC50 _sunitinib = (2.6 / 5.87) + (2.65 / 6.2) = 0.86.

  The patents and publications mentioned in this specification describe common technology in the art, each specifically and individually indicated to be incorporated for all purposes and by reference. The entirety of which is incorporated herein by reference. If there is any conflict between a cited reference and this specification, the specification shall prevail. In describing aspects of the application, specific terminology is used for the sake of clarity. However, it is not intended that the present invention be limited to the specific terminology so selected. Nothing in this specification should be considered as limiting the scope of the invention. All examples presented are representative and not limiting. The above-described aspects may be modified or changed without departing from the invention, as will be appreciated by those skilled in the art in light of the above teachings. Therefore, it is to be understood that, within the scope of the appended claims and equivalents thereof, the invention may be practiced differently from what is specifically described.

または薬学的に許容されるその塩もしくはエステルと、抗がん剤とを投与し、それによって該新生物障害を処置または改善する段階を含み、
式中、Z ⁵ はNもしくはCR ^6A であり;
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、ハロ、CF ₃ 、CFN、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体(bioisostere)、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
各R ⁹ は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ⁹ は独立して、ハロ、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR' ₂ 、SR'、SO ₂ R'、SO ₂ NR' ₂ 、NR'SO ₂ R'、NR'CONR' ₂ 、NR'COOR'、NR'COR'、CN、COOR'、CONR' ₂ 、OOCR'、COR'およびNO ₂ から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく;
nは0〜4であり; かつ
pは0〜4である、
方法。
[本発明1002]
式Iの化合物が下記構造:

または薬学的に許容されるその塩もしくはエステルを有する、本発明1001の方法。
[本発明1003]
抗がん剤がアルキル化剤、代謝拮抗物質、ビンカアルカロイド、タキサン、トポイソメラーゼ阻害剤、抗腫瘍抗生物質、チロシンキナーゼ阻害剤、または免疫抑制マクロライドである、本発明1001の方法。
[本発明1004]
抗がん剤が、5-フルオロウラシル(5-FU)、シスプラチン、ドキソルビシン、フルダラビン、ゲムシタビン、パクリタキセル、ラパマイシン、スニチニブ、エルロチニブ塩酸塩およびビンブラスチンからなる群より選択される、本発明1001の方法。
[本発明1005]
新生物障害ががんである、本発明1001の方法。
[本発明1006]
がんが造血系、肺、乳房、前立腺、腎臓、膵臓、肝臓、心臓、骨格、結腸、直腸、皮膚、脳、眼、リンパ節、心臓、精巣または卵巣のがんである、本発明1005の方法。
[本発明1007]
式Iの化合物および抗がん剤が同時に投与される、本発明1001の方法。
[本発明1008]
式Iの化合物および抗がん剤が同時におよび別々に投与される、本発明1001の方法。
[本発明1009]
式Iの化合物および抗がん剤が連続的に投与される、本発明1001の方法。
[本発明1010]
式Iの化合物が抗がん剤の前に投与される、本発明1009の方法。
[本発明1011]
式Iの化合物が抗がん剤の後に投与される、本発明1009の方法。
[本発明1012]
対象がヒトである、本発明1001の方法。
[本発明1013]
式Iの化合物および抗がん剤が少なくとも相加的な抗がん効果をもたらす、本発明1001の方法。
[本発明1014]
式Iの化合物および抗がん剤が相乗的な抗がん効果をもたらす、本発明1001の方法。
[本発明1015]
系における細胞増殖を阻害するための方法であって、有効量の式Iの化合物:

または薬学的に許容されるその塩もしくはエステルと、抗がん剤または薬学的に許容されるその塩もしくはエステルとを系に投与し、それによって細胞増殖を阻害する段階を含み、
式中、Z ⁵ はNもしくはCR ^6A であり;
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、ハロ、CF ₃ 、CFN、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
各R ⁹ は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ⁹ は独立して、ハロ、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR' ₂ 、SR'、SO ₂ R'、SO ₂ NR' ₂ 、NR'SO ₂ R'、NR'CONR' ₂ 、NR'COOR'、NR'COR'、CN、COOR'、CONR' ₂ 、OOCR'、COR'およびNO ₂ から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく;
nは0〜4であり; かつ
pは0〜4である、
方法。
[本発明1016]
系が細胞、組織または対象である、本発明1015の方法。
[本発明1017]
式Iの化合物が下記構造:

または薬学的に許容されるその塩もしくはエステルを有する、本発明1015の方法。
[本発明1018]
抗がん剤がアルキル化剤、代謝拮抗物質、ビンカアルカロイド、タキサン、トポイソメラーゼ阻害剤、抗腫瘍抗生物質、チロシンキナーゼ阻害剤、または免疫抑制マクロライドである、本発明1015の方法。
[本発明1019]
式Iの化合物:

または薬学的に許容されるその塩もしくはエステルと、抗がん剤と、少なくとも一つの薬学的に許容される賦形剤とを含む薬学的組成物であって、
式中、Z ⁵ はNもしくはCR ^6A であり;
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ^6A 、R ^6B 、R ^6D およびR ⁸ は独立して、ハロ、CF ₃ 、CFN、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
各R ⁹ は独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ⁹ は独立して、ハロ、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
ここで各Rは独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRは連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環は、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR' ₂ 、SR'、SO ₂ R'、SO ₂ NR' ₂ 、NR'SO ₂ R'、NR'CONR' ₂ 、NR'COOR'、NR'COR'、CN、COOR'、CONR' ₂ 、OOCR'、COR'およびNO ₂ から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'は独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々は、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'は連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく;
nは0〜4であり; かつ
pは0〜4である、
薬学的組成物。
[本発明1020]
式Iの化合物が下記構造:

または薬学的に許容されるその塩もしくはエステルを有する、本発明1019の組成物。
[本発明1021]
抗がん剤がアルキル化剤、代謝拮抗物質、ビンカアルカロイド、タキサン、トポイソメラーゼ阻害剤、抗腫瘍抗生物質、チロシンキナーゼ阻害剤、または免疫抑制マクロライドである、本発明1019または1020の組成物。
[本発明1022]
式Iの化合物が、式II、III、IV、VもしくはVIの構造:

または薬学的に許容されるその塩もしくはエステルを有し、
式中、Z ⁵ がNもしくはCR ^6A であり;
各R ^6A およびR ⁸ が独立して、Hまたは置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ^6A およびR ⁸ が独立して、ハロ、CF ₃ 、CFN、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、カルボキシの生物学的等価体、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
各R ⁹ が独立して、置換されていてもよいC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C12ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキル基であるか、または
各R ⁹ が独立して、ハロ、OR、NR ₂ 、NROR、NRNR ₂ 、SR、SOR、SO ₂ R、SO ₂ NR ₂ 、NRSO ₂ R、NRCONR ₂ 、NRCOOR、NRCOR、CN、COOR、CONR ₂ 、OOCR、CORもしくはNO ₂ であり、
ここで各Rが独立して、HまたはC1〜C8アルキル、C2〜C8ヘテロアルキル、C2〜C8アルケニル、C2〜C8ヘテロアルケニル、C2〜C8アルキニル、C2〜C8ヘテロアルキニル、C1〜C8アシル、C2〜C8ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜C12アリールアルキルもしくはC6〜C12ヘテロアリールアルキルであり、
かつここで同じ原子上のもしくは隣接原子上の二つのRが連結されて、一つもしくは複数のN、OもしくはSを含んでいてもよい3〜8員環を形成してもよく;
かつ各R基、および二つのR基をともに連結することによって形成された各環が、ハロ、=O、=N-CN、=N-OR'、=NR'、OR'、NR' ₂ 、SR'、SO ₂ R'、SO ₂ NR' ₂ 、NR'SO ₂ R'、NR'CONR' ₂ 、NR'COOR'、NR'COR'、CN、COOR'、CONR' ₂ 、OOCR'、COR'およびNO ₂ から選択される一つもしくは複数の置換基で置換されていてもよく、
ここで各R'が独立して、H、C1〜C6アルキル、C2〜C6ヘテロアルキル、C1〜C6アシル、C2〜C6ヘテロアシル、C6〜C10アリール、C5〜C10ヘテロアリール、C7〜12アリールアルキルもしくはC6〜12ヘテロアリールアルキルであり、これらの各々が、ハロ、C1〜C4アルキル、C1〜C4ヘテロアルキル、C1〜C6アシル、C1〜C6ヘテロアシル、ヒドロキシ、アミノおよび=Oから選択される一つもしくは複数の基で置換されていてもよく;
かつここで二つのR'が連結されて、N、OおよびSから選択される最高3個のヘテロ原子を含んでいてもよい3〜7員環を形成してもよく; かつ
pが0〜4である、
本発明1001または本発明1015の方法。
A further aspect disclosed in the present application is a pharmaceutical composition comprising a compound of formula I disclosed herein, an anticancer agent, and at least one pharmaceutically acceptable excipient. .
[Invention 1001]
A method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I in a subject in need thereof:

Or administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent, thereby treating or ameliorating the neoplastic disorder,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 An alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently halo, CF ₃ , CFN, OR, NR ₂ , NROR, NRNR ₂ , SR, SOR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R _{, NRCONR 2, NRCOOR, NRCOR,} CN, COOR, carboxy bioisostere _{(bioisostere), CONR 2, OOCR} , is COR or NO _2,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ⁹ is independently _{halo, OR, NR 2, NROR,} NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, is COR or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Method.
[Invention 1002]
The compound of formula I has the following structure:

Or a method of the invention 1001 having a pharmaceutically acceptable salt or ester thereof.
[Invention 1003]
The method of the present invention 1001, wherein the anticancer agent is an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an antitumor antibiotic, a tyrosine kinase inhibitor, or an immunosuppressive macrolide.
[Invention 1004]
The method of 1001 of this invention wherein the anticancer agent is selected from the group consisting of 5-fluorouracil (5-FU), cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib hydrochloride and vinblastine.
[Invention 1005]
The method of the present invention 1001, wherein the neoplastic disorder is cancer.
[Invention 1006]
The method of the present invention 1005 wherein the cancer is a cancer of the hematopoietic system, lung, breast, prostate, kidney, pancreas, liver, heart, skeleton, colon, rectum, skin, brain, eye, lymph node, heart, testis or ovary. .
[Invention 1007]
The method of the present invention 1001, wherein the compound of formula I and the anticancer agent are administered simultaneously.
[Invention 1008]
The method of the present invention 1001, wherein the compound of formula I and the anticancer agent are administered simultaneously and separately.
[Invention 1009]
The method of the present invention 1001, wherein the compound of formula I and the anticancer agent are administered sequentially.
[Invention 1010]
The method of 1009 of this invention wherein the compound of formula I is administered prior to the anticancer agent.
[Invention 1011]
The method of 1009 of this invention wherein the compound of formula I is administered after the anticancer agent.
[Invention 1012]
The method of the present invention 1001 wherein the subject is a human.
[Invention 1013]
The method of the present invention 1001, wherein the compound of formula I and the anticancer agent provide at least an additive anticancer effect.
[Invention 1014]
The method of 1001 of this invention wherein the compound of formula I and the anticancer agent provide a synergistic anticancer effect.
[Invention 1015]
A method for inhibiting cell proliferation in a system comprising an effective amount of a compound of formula I:

Or administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent or a pharmaceutically acceptable salt or ester thereof to the system, thereby inhibiting cell proliferation,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 An alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently halo, CF ₃ , CFN, OR, NR ₂ , NROR, NRNR ₂ , SR, SOR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R , NRCONR ₂ , NRCOOR, NRCOR, CN, COOR, carboxy bioequivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ⁹ is independently _{halo, OR, NR 2, NROR,} NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, is COR or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Method.
[Invention 1016]
The method of the present invention 1015 wherein the system is a cell, tissue or subject.
[Invention 1017]
The compound of formula I has the following structure:

Or the method of the invention 1015 having a pharmaceutically acceptable salt or ester thereof.
[Invention 1018]
The method of the invention 1015 wherein the anticancer agent is an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an antitumor antibiotic, a tyrosine kinase inhibitor, or an immunosuppressive macrolide.
[Invention 1019]
Compounds of formula I:

Or a pharmaceutical composition comprising a pharmaceutically acceptable salt or ester thereof, an anticancer agent, and at least one pharmaceutically acceptable excipient,
Wherein, Z ⁵ is N or CR ^6A;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 An alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently halo, CF ₃ , CFN, OR, NR ₂ , NROR, NRNR ₂ , SR, SOR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R , NRCONR ₂ , NRCOOR, NRCOR, CN, COOR, carboxy bioequivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ⁹ is independently _{halo, OR, NR 2, NROR,} NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, is COR or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Pharmaceutical composition.
[Invention 1020]
The compound of formula I has the following structure:

Or the composition of the present invention 1019 having a pharmaceutically acceptable salt or ester thereof.
[Invention 1021]
The composition of the present invention 1019 or 1020, wherein the anticancer agent is an alkylating agent, antimetabolite, vinca alkaloid, taxane, topoisomerase inhibitor, antitumor antibiotic, tyrosine kinase inhibitor, or immunosuppressive macrolide.
[Invention 1022]
A compound of formula I has the structure of formula II, III, IV, V or VI:

Or having a pharmaceutically acceptable salt or ester thereof,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 hetero An alkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ^6A and R ⁸ are independently _{halo, CF 3, CFN, OR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, bioisostere carboxy, CONR _2, OOCR, is COR or NO _2,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or
Each R ⁹ is independently _{halo, OR, NR 2, NROR,} NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, is COR or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And wherein two R ′ may be linked to form a 3-7 membered ring that may contain up to 3 heteroatoms selected from N, O and S; and
p is 0-4,
The method of the present invention 1001 or the present invention 1015.

Claims (22)

A method for treating or ameliorating a neoplastic disorder, wherein a therapeutically effective amount of a compound of formula I in a subject in need thereof:

Or administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent, thereby treating or ameliorating the neoplastic disorder,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 Alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A , R ^6B, R ^6D and R ⁸ are independently _{halo, CF 3, CFN, oR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, carboxy bioisostere, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Method. The compound of formula I has the following structure:

Or a pharmaceutically acceptable salt or ester thereof.   2. The method according to claim 1, wherein the anticancer agent is an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an antitumor antibiotic, a tyrosine kinase inhibitor, or an immunosuppressive macrolide.   The method according to claim 1, wherein the anticancer agent is selected from the group consisting of 5-fluorouracil (5-FU), cisplatin, doxorubicin, fludarabine, gemcitabine, paclitaxel, rapamycin, sunitinib, erlotinib hydrochloride and vinblastine.   2. The method of claim 1, wherein the neoplastic disorder is cancer.   The cancer according to claim 5, wherein the cancer is a cancer of the hematopoietic system, lung, breast, prostate, kidney, pancreas, liver, heart, skeleton, colon, rectum, skin, brain, eye, lymph node, heart, testis or ovary. Method.   2. The method of claim 1, wherein the compound of formula I and the anticancer agent are administered simultaneously.   2. The method of claim 1, wherein the compound of formula I and the anticancer agent are administered simultaneously and separately.   2. The method of claim 1, wherein the compound of formula I and the anticancer agent are administered sequentially.   10. The method of claim 9, wherein the compound of formula I is administered prior to the anticancer agent.   10. The method of claim 9, wherein the compound of formula I is administered after the anticancer agent.   2. The method of claim 1, wherein the subject is a human.   2. The method of claim 1, wherein the compound of formula I and the anticancer agent provide at least an additive anticancer effect.   2. The method of claim 1, wherein the compound of formula I and the anticancer agent provide a synergistic anticancer effect. A method for inhibiting cell proliferation in a system comprising an effective amount of a compound of formula I:

Or administering a pharmaceutically acceptable salt or ester thereof and an anticancer agent or a pharmaceutically acceptable salt or ester thereof to the system, thereby inhibiting cell proliferation,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 Alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A , R ^6B, R ^6D and R ⁸ are independently _{halo, CF 3, CFN, oR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, carboxy bioequivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Method.   16. The method of claim 15, wherein the system is a cell, tissue or subject. The compound of formula I has the following structure:

Or a pharmaceutically acceptable salt or ester thereof.   16. The method of claim 15, wherein the anticancer agent is an alkylating agent, antimetabolite, vinca alkaloid, taxane, topoisomerase inhibitor, antitumor antibiotic, tyrosine kinase inhibitor, or immunosuppressive macrolide. Compounds of formula I:

Or a pharmaceutical composition comprising a pharmaceutically acceptable salt or ester thereof, an anticancer agent, and at least one pharmaceutically acceptable excipient,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A , R ^6B , R ^6D and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 Alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A , R ^6B, R ^6D and R ⁸ are independently _{halo, CF 3, CFN, oR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, carboxy bioequivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 An acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And where two R ′ may be linked to form a 3-7 membered ring which may contain up to 3 heteroatoms selected from N, O and S;
n is 0-4; and
p is 0-4,
Pharmaceutical composition. The compound of formula I has the following structure:

21. The composition of claim 19, having a pharmaceutically acceptable salt or ester thereof.   21. The composition according to claim 19 or 20, wherein the anticancer agent is an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an antitumor antibiotic, a tyrosine kinase inhibitor, or an immunosuppressive macrolide. A compound of formula I has the structure of formula II, III, IV, V or VI:

Or having a pharmaceutically acceptable salt or ester thereof,
Where Z ⁵ is N or CR ^6A ;
Each R ^6A and R ⁸ is independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 hetero An alkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ^6A and R ⁸ is independently Te, _{halo, CF 3, CFN, OR,} NR 2, NROR, NRNR 2, SR, SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, carboxy organisms Is the scientific equivalent, CONR ₂ , OOCR, COR or NO ₂ ,
Each R ⁹ is independently an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 Acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl group, or each R ⁹ is independently halo, OR, NR _{2 , NROR, NRNR 2, SR,} SOR, SO 2 R, SO 2 NR 2, NRSO 2 R, NRCONR 2, NRCOOR, NRCOR, CN, COOR, a CONR _2, OOCR, COR, or NO _2,
Wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2 -C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl or C6-C12 heteroarylalkyl;
And here two R on the same atom or on adjacent atoms may be linked to form a 3- to 8-membered ring which may contain one or more N, O or S;
And each R group and each ring formed by linking two R groups together are halo, ═O, ═N—CN, ═N—OR ′, ═NR ′, OR ′, NR ′ ₂ , SR ', SO ₂ R', SO ₂ NR ' ₂ , NR'SO ₂ R', NR'CONR ' ₂ , NR'COOR', NR'COR ', CN, COOR', CONR ' ₂ , OOCR', COR Optionally substituted with one or more substituents selected from 'and NO ₂
Where each R ′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl or C6-12 heteroarylalkyl, each of which is one or more selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino and = O Optionally substituted with multiple groups;
And wherein two R ′ may be linked to form a 3-7 membered ring that may contain up to 3 heteroatoms selected from N, O and S; and
p is 0-4,
16. A method according to claim 1 or claim 15.

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