阅读说明：本技术 新型水杨酸衍生物、其药学上可接受的盐、其组合物及其使用方法 (Novel salicylic acid derivatives, pharmaceutically acceptable salts thereof, compositions thereof, and methods of use thereof ) 是由 帕特里克·托马斯·贡宁 西亚瓦什·艾哈迈尔 戴维·罗萨 加里·廷 穆卢·格勒图 朴智星 于 2019-12-20 设计创作，主要内容包括：本发明涉及新型化合物、包含其的组合物以及利用式(I)的化合物或其药学上可接受的盐、溶剂化物或水合物用于抑制STAT3和/或STAT5活性或用于治疗细胞增殖性病症诸如癌症的方法,其中,R和R-(1)不同,选自由-H、(Ia)、(Ib)和(Ic)组成的组,其中当R和R-(1)中的一个是-H时,R和R-(1)中的另一个是环戊基基团,R-(2)是用1-5个卤素、优选-Cl、F或-Br取代的苄基,并且R-(3)选自由-H或-OH组成的组。＝(The present invention relates to novel compounds, compositions comprising the same and methods of using compounds of formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R and R are for inhibiting STAT3 and/or STAT5 activity or for treating cell proliferative disorders such as cancer 1 And is selected from the group consisting of-H, (Ia), (Ib) and (Ic), wherein when R and R are 1 When one of them is-H, R and R 1 The other of (A) is a cyclopentyl group, R 2 Is benzyl substituted with 1-5 halogens, preferably-Cl, F or-Br, and R 3 Selected from the group consisting of-H or-OH. Is ═ i)

1. A compound of formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof,

formula I

Wherein the content of the first and second substances,

r and R₁Is different from R and R₁Are selected from the group consisting of:

-H、

wherein when R and R are₁When one of them is-H, R and R₁The other of which is a cyclopentyl group,

R₂is benzyl substituted with 1 to 5 halogens, and

R₃selected from the group consisting of-H or-OH.

2. A compound or pharmaceutically acceptable salt, solvate or hydrate thereof according to claim 1, wherein R₂Is benzyl substituted with 1-5 same or different halogens selected from the group consisting of Cl, F and Br.

3. A compound or pharmaceutically acceptable salt, solvate or hydrate thereof according to claim 1, wherein R₂Is a 4-chlorobenzyl group or a 4-bromobenzyl group.

4. A pharmaceutical composition comprising a compound as defined in any one of claims 1,2 or 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and an acceptable excipient.

5. A method of treating a cell proliferative disorder comprising administering to a subject in need thereof a compound as defined in claim 1,2 or 3, or a pharmaceutically acceptable salt and/or solvate thereof.

6. The method of claim 5, wherein the cell proliferative disorder is cancer.

7. The method of claim 6, wherein the cancer is a cancer associated with overexpression of pSTAT3 and/or pSTAT 5.

8. The method of claim 7, wherein the cancer is a hematological cancer or a brain cancer.

9. The method of claim 8, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, or medulloblastoma.

10. A method for inhibiting STAT3 and/or STAT5 activity comprising administering to a patient a therapeutically effective amount of a compound as defined in claim 1,2, or 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

11. A method for treating or preventing cancer having cancer cells bearing overexpressed pSTAT3 and/or pSTAT5, comprising administering to a patient a therapeutically effective amount of a compound as defined in claim 1,2 or 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

12. The method of claim 11, wherein the cancer is from a solid tumor or a hematological tumor.

13. The method of claim 12, wherein the cancer is selected from the group consisting of: breast cancer, brain cancer, liver cancer, prostate cancer, pancreatic cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma, multiple myeloma, Acute Myelogenous Leukemia (AML), and acute lymphoblastic leukemia.

14. Use of a compound as defined in claim 1,2 or 3, or a pharmaceutically acceptable salt and/or solvate thereof, for treating a cell proliferative disorder in a subject in need thereof.

15. The use of claim 14, wherein the cell proliferative disorder is cancer.

16. The method of claim 6, wherein the cancer is a cancer associated with overexpression of pSTAT3 and/or pSTAT 5.

17. The use of claim 15, wherein the cancer is a hematological cancer or a brain cancer.

18. The use of claim 17, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, or medulloblastoma.

19. Use of a compound as defined in claim 1,2 or 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for inhibiting STAT3 and/or STAT5 activity.

20. Use of a compound as defined in claim 1,2 or 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the treatment of cancer having cancer cells bearing activated STAT3 or STAT 5.

21. The use of claim 20, wherein the cancer is from a solid tumor or a hematological tumor.

22. The use of claim 21, wherein the cancer is selected from the group consisting of: breast cancer, brain cancer, liver cancer, prostate cancer, pancreatic cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma, multiple myeloma, Acute Myelogenous Leukemia (AML), and acute lymphoblastic leukemia.

23. Use of a composition as defined in claim 4, or a pharmaceutically acceptable salt and/or solvate thereof, for treating a cell proliferative disorder in a subject in need thereof.

24. The use of claim 23, wherein the cell proliferative disorder is cancer.

25. The use of claim 24, wherein the cancer is a hematological cancer or a brain cancer.

26. The use of claim 25, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, or medulloblastoma.

27. A pharmaceutical composition as defined in claim 4 for use in inhibiting STAT3 and/or STAT5 activity.

28. The pharmaceutical composition as defined in claim 4 for use in the treatment of cancer having cancer cells carrying activated STAT3 and/or STAT 5.

29. The pharmaceutical composition as defined in claim 28, wherein the cancer is from a solid tumor or a hematological tumor.

30. The pharmaceutical composition as defined in claim 29, wherein the cancer is selected from the group consisting of: breast cancer, brain cancer, liver cancer, prostate cancer, pancreatic cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma, multiple myeloma, Acute Myelogenous Leukemia (AML), and acute lymphoblastic leukemia.

Technical Field

The present invention relates to novel salicylic acid derivative compounds, compositions containing the same and methods of using the compounds to inhibit STAT3 activity or for the treatment of cancers (where STAT3/5 is implicated) such as brain, breast, colon, blood, lung, ovarian and prostate cancers.

Background

STAT3 is continuously activated in more than tens of types of human cancers, including all major cancers, including squamous cell carcinomas of the breast, brain, colon, pancreas, ovary, and head and neck (SCCHN) cancers, as well as melanoma along with some hematological tumors (Bowman T, et al (2000) oncogene19, 2474-88, and Darnell, j.e. (2005) nat. med.11, 595-596). Therefore, there is increasing interest in developing anti-cancer therapies by inhibiting STAT3 with sustained activity, particularly as a strategy to treat cancers where physicians are seeking improved results and/or where even satisfactory standards of care are established that are challenging in patient care, quality of life, and outcome.

Glioblastoma (GBM) is considered the most aggressive and lethal brain cancer, with a median survival after treatment of about 15 months. Surprisingly, these favorable results (modest result) can only be achieved in relatively young (i.e., < 70 years of age) and other healthy patients. The survival of elderly patients (many) with GBM and those with poor diagnostic performance status is much shorter after the same treatment. Furthermore, GBM occurs more and more frequently in the aging population. Furthermore, unlike more common cancers (such as lung, breast and colon cancers), GBM is neither prevented nor detected significantly more effectively at the expected early stages of treatment. Furthermore, despite intensive research conducted for decades, major improvements in overall survival remain elusive. Therefore, the development of a therapeutic approach to meet this unmet need is critical.

Brain tumors have been demonstrated to contain a rare subpopulation of Brain Tumor Stem Cells (BTSCs) that possess clonal self-renewal, pluripotent and tumorigenic basal (cardinal) stem cell characteristics. The extensive self-renewal and proliferative capacity of BTSCs, together with their insensitivity to conventional radiation and chemotherapy, suggests that they are critical for the growth of GBM and for relapse after treatment (integral). Thus, BTSC represent a "disease reservoir" that requires novel therapeutic approaches to be effectively eliminated in order to improve the outcome of GBM.

STAT proteins were originally discovered as potential cytoplasmic transcription factors mediating cytokine and growth factor responses (Darnell, J.E., Jr. (1996) Recent prog.Norm.Res.51, 391-403; Darnell, J.E. (2005) nat. Med.11, 595-596). Seven members of this family, STAT1, STAT2, STAT3, STAT4, STAT5a and STAT5b, and STAT6, mediate a variety of physiological effects, including growth and differentiation, survival, development, and inflammation. STATs are SH2 domain-containing proteins. Upon ligand binding to a cytokine or growth factor receptor, STATs are phosphorylated on a key Tyr residue (Tyr 705 for STAT3) by growth factor receptors, cytoplasmic Janus kinases (Jaks), or Src family kinases. The two phosphorylated and activated STAT monomers dimerize via reciprocal pTyr-SH2 domain interactions, translocate to the nucleus, and bind to specific DNA-responsive elements of target genes, thereby inducing gene transcription (Darnell, j.e., Jr. (1996) receptor prog.norm.res.51, 391-403; Darnell, j.e. (2005) nat. med.11, 595-596). In contrast to normal STAT signaling, many human solid and hematological tumors have aberrant STAT3 activity (Turkson, J.Expert Opin. Ther. targets 2004,8, 409-.

Notably, the STAT3 protein is one of seven family members of the STAT family of transcription factor proteins. STAT3 is activated by phosphorylation of tyrosine 705(Y705), which triggers complexation of two phosphorylated STAT3 monomers (pSTAT 3). The pSTAT3 homodimer was mediated by the reciprocal STAT3 Src homology 2(SH2) domain-pY 705 STAT3 interaction. pSTAT 3: pSTAT3 homodimers translocated to the nucleus and bound DNA, promoting STAT3 target gene transcription. Targeting STAT3 has been previously achieved with dominant negative constructs, oligonucleotides, or most commonly phosphopeptide reagents that mimic the native pY705 containing a binding sequence. Unfortunately, these inhibitors degrade rapidly in vivo, which limits their clinical use. To avoid these problems, small molecule STAT3 inhibitors were designed for the treatment of cancers carrying over-activated STAT3 protein. Acid-based inhibitors have been identified in WO2012018868, which effectively and selectively block STAT3 dimerization and DNA binding activities, compound 450, also known as BP-1-102 (sometimes referred to herein as compound 1). Compound 450 in WO 2018868 potently inhibits a variety of carcinogenic properties in a variety of cultured cancer cells (breast, lung, pancreas, prostate, lung), including: cell proliferation, anchorage-independent cell growth, migration, invasion, and motility. It is selective for STAT3, with a more than 10-fold reduction in binding to the 93% homologous STAT protein STAT 1. It showed little or no effect on She, Src, Jak-1/2, Erkl/2, or Akt phosphorylation and no effect on non-transformed cells (NIH 3T3 cells, STAT3 null mouse embryonic fibroblasts, or mouse thymic stromal cells, it also did not affect transformed cells that did not have activated STAT 3). In addition, BP-1-102 showed significant in vivo anti-tumor effects in murine xenograft models of lung or breast cancer, resulting in a dramatic regression of tumor volume. Western blots of residual tumors from treated mice showed repression in a dose-dependent manner in pSTAT3, cMyc, Cyclin D1, Bcl-xL, survivin and VEGF. Nevertheless, WO2013177534 teaches that alternative derivative compounds inhibit STAT3 activity or are useful for the treatment of cancers involving STAT 3/5.

In addition, genetic and other molecular evidence revealed that persistent Tyr phosphorylation of STAT3 is mediated by aberrant upstream Tyr kinases, and shows a cancer cell demand for constitutively active and dimerized STAT3 for tumor maintenance and progression. Thus, STAT dimerization inhibition 3 activation or destruction induced cancer cell death and tumor regression was inhibited in a number of proof-of-concept studies (Turkson, J., et al. mol. cancer The.2004, 3(3), 261-; 269, Turkson, J., et al. J. biol. chem.2001,276(48), 45443-; Siddiquee, K.; et al. Proc. Natl. Acad. Sci.U.S.A.2007,104, 7391-7396.; Turkson, J.; et al. mol. cancer Ther.2004,3,1533- -1542, and Turkson, J.; et al. J. biol. chem.2005,280(38),32979- -32988). Small molecule STAT3 inhibitors thus provide tools for exploring the molecular dynamics of cellular processing of STAT3 to understand the role of STAT3 as signaling intermediates and molecular mediators of events leading to carcinogenesis and malignant progression. Furthermore, because the STAT3 pathway is a key oncogenic driver in over a dozen classes of human cancers, including all major cancers, including squamous cell carcinomas of breast, brain, colon, pancreas, ovary, and head and neck (SCCHN) cancers, as well as melanoma, along with some hematologic tumors (Bowman T, et al (2000) Oncogene19,2474-88 and darnelll, j.e. (2005) nat. med.11, 595-596), direct inhibition of STAT3 would provide a molecular targeting pathway for effective management of these cancers, particularly aggressive forms such as GBM.

In the original paper, Cairo et al (Nature,463(7279):318-325,2010) demonstrated that the signal transducer and activator of the abnormally active transcribed 3(STAT3) gene in GBM are key important mediators of tumor growth and therapy resistance in GBM. Low-treatment brain cancers such as gliomas, astrocytomas, and glioblastomas have constitutively activated STAT 3. Furthermore, the recent evidence of growths collected using a variety of different small molecules that indirectly inhibit STAT3 by targeting upstream molecules such as JAK family members strongly suggests that STAT3 signaling is critical for both BTSC and GBM survival and proliferation in vitro and in vivo. However, due to their broad targeting properties, existing drugs for the treatment of GBM have limited translational potential due to a number of side effects. Thus, drugs with the ability to more specifically block STAT3 activity may provide effective treatment for GBM patients.

STAT5 signaling (like STAT3 signaling) is transiently activated in normal cells and inactivated by a number of different cytosolic and nuclear regulators (including phosphatases, SOCS, PIAS) and proteasomal degradation. Like STAT3, STAT5 is notoriously notorious for its aberrant role in human cancer and tumorigenesis, and has been found to be constitutively activated in many cancers, including breast, liver, prostate, hematological, skin, head and neck (Muller, j., et al, chem biochem 2008,9, 723-. In cancer cells, STAT5 is routinely constitutively phosphorylated, which leads to aberrant expression of STAT5 target genes, leading to malignant transformation. Cancer cells carrying persistently activated STAT5 overexpress anti-apoptotic proteins, such as Bcl-xL, Myc, and MCL-1, conferring significant resistance to natural apoptotic causes and administered chemotherapeutic agents. Of particular interest, STAT5 has been identified as a key regulator in the development and progression of Acute Myeloid (AML) and Acute Lymphoblastic Leukemia (ALL) (Gouillux-Gruart, V., et al, Leukemia and Lymphoma 1997,28, 83-88; Gouillux-Gruart, V., et al, blood1996,87, 1692-1692 1697; Weber-Nordt, R.M., et al, blood1996, 88, 809-816). Furthermore, inhibitors of upstream STAT5 activators, such as JA and FLT3, have been shown to exhibit promising anti-cancer properties (Pardanani, A., et al, Leukemia 2011,25, 218-.

It should be noted that the medical benefit by inhibition of STAT3/5 is not limited to the various forms of cancer described herein, where these targets are constitutively active, but will also be applicable to the treatment of other disorders where these pathways are known to play a critical role, such as, but not limited to, autoimmune disorders (Harris, t.j.; et al Immunol. (2007)179(7): 4313-; nephropathy (Weimbs, T., (2013) JAK-STAT,2(2),0-1) and organ transplantation (Debonera, F.; et al (2001) J.Surg.Res.96(2), 289) 295).

Despite advances in drug discovery directed to identifying inhibitors of STAT protein activity, there is a lack of compounds that are potent, and selective activators of STAT3 and STAT5 and that are also effective in treating cancer and other diseases associated with dysfunction in STAT3, STAT5, or both proteins, as well as diseases involving one or both of STAT3 and STAT 5. Furthermore, there is still a need to optimize the potency and reduce the pharmacokinetic instability of existing compounds. The present invention fulfills these needs and others.

Disclosure of Invention

In accordance with one or more objects of the present invention, as embodied and broadly described herein, in one aspect, the present invention relates to compounds useful as STAT3 inhibitors.

In further aspects, the disclosed compounds and products of the disclosed methods of preparation, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, are modulators of STAT3 and/or STAT5 activity, methods of preparation thereof, pharmaceutical compositions comprising the same, and methods of use thereof to treat disorders associated with dysfunction of STAT3 activity.

In a still further aspect, the present invention relates to compounds that bind to STAT3 protein and negatively modulate STAT3 activity.

In a further aspect, the invention relates to compounds that bind to STAT5 protein and negatively modulate STAT5 activity.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier.

Disclosed are methods for treating a disorder associated with a dysfunction, preferably an overactivity or overexpression, of STAT3/STAT5 activity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

Also disclosed are methods for inhibiting STAT3 and/or STAT5 activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

Also disclosed are methods for inhibiting STAT3 and/or STAT5 activity in at least one cell comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

Also disclosed is the use of at least one of the disclosed compounds, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In one aspect, there is provided a compound of formula I as defined herein.

Or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein,

r and R₁Is different from R and R₁Are selected from the group consisting of:

-H，

wherein when R and R are₁When one is-H, R and R₁Another one of (1)One is a cyclopentyl moiety which is, in turn,

R₂is benzyl substituted with 1-5 halogens, preferably-Cl-F or-Br, and

R₃selected from the group consisting of H or OH.

In a further aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the disclosed compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and an acceptable excipient.

In another aspect of the present disclosure, there is provided a method for inhibiting STAT3 and/or STAT5 activity comprising administering to a patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a further aspect of the present disclosure there is provided a method for the treatment or prevention of a cancer associated with a dysfunction (preferably an overactive or overexpressed) of STAT3/STAT5 activity comprising administering to a patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In an alternative aspect, the cancer is from a solid or hematologic tumor. In still other aspects, the cancer is a cancer with activated STAT3 and/or STAT 5. Such cancer may be, for example, breast cancer, liver cancer, prostate cancer, hematological cancer, skin cancer, head cancer, neck cancer, glioblastoma, or Acute Myeloid (AML) and acute lymphoblastic leukemia.

In another aspect of the present disclosure there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the manufacture of a medicament for inhibiting STAT3 and/or STAT5 activity.

In another aspect of the present disclosure there is provided the use of a compound or pharmaceutically acceptable salt, solvate or hydrate as defined herein, in the manufacture of a medicament for the treatment or prevention of a cancer with activated STAT3 and/or STAT5, such as a cancer from a solid or hematological tumor, breast cancer, liver cancer, prostate cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma or Acute Myelogenous (AML) and acute lymphoblastic leukemia.

In a further aspect of the present disclosure there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for inhibiting STAT3 and/or STAT5 activity.

In another aspect of the present disclosure there is provided the use of a compound or pharmaceutically acceptable salt, solvate or hydrate as defined herein for the treatment or prevention of a cancer with activated STAT3 and/or STAT5, such as a cancer from a solid or hematological tumor, breast cancer, liver cancer, prostate cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma or Acute Myelogenous (AML) and acute lymphoblastic leukemia (associated with dysfunction of STAT3/STAT5 activity), such as breast cancer, prostate cancer or brain cancer.

In another aspect of the present disclosure, there is provided a pharmaceutical composition as defined herein for use in inhibiting STAT3 and/or STAT5 activity.

In a further aspect of the present disclosure, there is provided a pharmaceutical composition as defined herein for use in the treatment or prevention of a cancer carrying activated STAT3 and/or STAT5, such as a cancer from a solid or hematological tumor, breast cancer, liver cancer, prostate cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma, or Acute Myelogenous (AML) and acute lymphoblastic leukemia.

Also disclosed are methods of making a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent. In a further aspect, the invention relates to the use of a disclosed compound in the manufacture of a medicament for the treatment of a disorder associated with the dysfunction (e.g., overactivity or overexpression) of STAT3/STAT5 activity. In a still further aspect, the invention relates to the use of the disclosed compounds in the manufacture of a medicament for the treatment of cancers bearing activated STAT3 and/or STAT5, such as cancers from solid or hematological tumors, breast cancer, liver cancer, prostate cancer, blood cancer, skin cancer, head cancer, neck cancer, glioblastoma, or Acute Myelogenous (AML) and acute lymphoblastic leukemia.

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

The present invention may be understood more readily by reference to the following detailed description of the invention and the examples included therein.

Drawings

FIG. 1 is a graph showing comparative intrinsic clearance between AC-3-19 (prior art compound) and Compound I;

FIG. 2A shows the chemical structure of JPX-0372 (prior art);

FIG. 2B shows the intrinsic contrast clearance between JPX-0372 and Compound I;

FIG. 3A shows the chemical structure of JPX-0369 (prior art);

FIG. 3B shows the intrinsic contrast clearance between JPX-0369 and Compound I;

FIG. 4A shows the chemical structure of JPX-0371 (prior art);

FIG. 4B shows the intrinsic contrast clearance between JPX-0371 and Compound I;

FIG. 5A shows the chemical structure of JPX-0318 (prior art);

FIG. 5B shows the intrinsic contrast clearance between JPX-0318 and Compound II; and

FIG. 6 shows comparative clearance between JPX-0371 and Compound I in CD-1 mice dosed at 20mgs/kg (IP).

Detailed Description

Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods, unless otherwise specified, or to specific reagents, unless otherwise specified, as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which may need to be independently confirmed.

As used herein, the nomenclature of compounds (including organic compounds) may be given using the common name, IUPAC, IUBMB, or CAS nomenclature recommendations. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rule for stereochemistry may be employed to specify stereochemical priority, EIZ specifications, and the like. Given a name, one skilled in the art can readily determine the structure of a compound by: the compound structure is reduced in its entirety by using a naming convention, or by commercially available software, such as CHEMDAW^TM(Cambridge Soft Corporation, USA).

As used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl group," or "a residue" includes mixtures of two or more such functional groups, alkyl groups, or residues, and the like.

Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It will also be understood that there are a plurality of values disclosed herein, and that each value is "about" the particular value disclosed herein in addition to the value itself. For example, if "10" is disclosed, then "about 10" is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed.

Abbreviations used in the description of the preparation of the compounds of the present disclosure:

bu butyl

CDCl3 deuterated chloroform

DCM dichloromethane

DMAP N, N-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMEM Dulbecco modified Eagle Medium

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

Et Ethyl group

EtOAc ethyl acetate

HMQC heteronuclear multi-quantum coherent spectrum

mCPBA m-chloroperbenzoic acid

HRMS high resolution mass spectrometry

Me methyl group

MeOH methanol

NEt₃Triethylamine

NFSI N-fluorobenzenesulfonylimide

NMR nuclear magnetic resonance

Ph phenyl

RT Room temperature

THF tetrahydrofuran

TBAF tetrabutylammonium fluoride

TFA trifluoroacetic acid

TMSBr trimethylsilyl bromide

RBF round flask

References in the specification and appended claims to parts by weight of a particular element or component in a composition indicate the weight relationship between that element or component and any other element or component in the composition or article, expressed as parts by weight. Thus, in a compound comprising 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a ratio of 2: 5, and is present in that ratio, regardless of whether additional components are included in the compound.

Unless specifically indicated to the contrary, the weight percent (wt.%) of a component is based on the total weight of the formulation or composition in which the component is included. As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used herein, the terms "STAT 3", "activator of signaling and transcription 3 (acute phase response)" and "activator of signaling and transcription 3" are used interchangeably and refer to a transcription factor encoded by a Gene designated in humans as the STAT3 Gene, which has a genetic score of 17q21 and is described as the Entrez Gene cell genetic band: 17q 21.31; genetic band of Ensembl cells: 17q 21.2; and HGNC cell genetic band: 17q21. The term STAT3 refers to a human protein having 770 amino acids and having a molecular weight of about 88068 Da. The term includes splice isomers or variants, and also includes proteins designated APRF, MGC 16063, acute phase response factor, DNA binding proteins APRF, HIES by such alternative nomenclature, such as the protein encoded by the human gene STAT3 used by those skilled in the art. The term also includes non-human orthologs (orthologs) or homologues (homologs) thereof.

As used herein, "STAT 5" refers to STAT5A and/or STAT 5B. This particular term will be used herein if a specific reference to STAT5A or STAT5B is required.

As used herein, "STAT 5A" and "signal transducer and activator of transcription 5A" are used interchangeably to refer to a transcription factor encoded by a Gene designated STAT5A Gene in humans, which has an Entrez Gene cell genetic band: 17ql 1.2; genetic band of Ensembl cells: 17q 21.2; and HGNC cell genetic band: 17ql 1.2. The term STAT5A refers to a human protein having 794 amino acids and having a molecular weight of about 90647 Da. The term includes splice isomers or variants, and also includes the proteins designated MGF and STAT5 by such alternative nomenclature, as used by those skilled in the art for proteins encoded by the human gene STAT 5A. The term also includes non-human orthologs or homologs thereof.

As used herein, "STAT 5B" and "signal transducer and activator of transcription 5B" are used interchangeably to refer to a transcription factor encoded by a Gene designated STAT5B Gene in humans, which has an Entrez Gene cell genetic band: 17ql 1.2; genetic band of Ensembl cells: 17q 21.2; and HGNC cell genetic band: 17ql 1.2. The term STAT5A refers to a human protein having 787 amino acids and having a molecular weight of about 89866 Da. The term includes splice isomers or variants, and also includes the protein referred to by such alternative nomenclature as the transcription factor STAT5B, as used by those skilled in the art, the protein encoded by the human gene STAT 5A. The term also includes non-human orthologs or homologs thereof.

As used herein, the term "subject" may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein can be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not denote a particular age or gender. In one aspect, the subject is a mammal. By patient is herein meant a subject suffering from cancer, preferably glioblastoma. The term "patient" includes human and animal subjects.

As used herein, the term "treatment" refers to the medical management of a patient intended to cure, ameliorate, stabilize or prevent a disease, pathological condition or disorder. The term includes active treatment, i.e. treatment specifically directed to the improvement of a disease, pathological condition or disorder, and also includes causal treatment, i.e. treatment directed to the removal of the cause of the associated disease, pathological condition or disorder. Moreover, the term includes palliative treatments, i.e., treatments designed to alleviate symptoms rather than cure a disease, pathological condition, or disorder; prophylactic treatment, i.e., treatment directed to minimizing or partially or completely inhibiting the development of an associated disease, pathological condition, or disorder; and supportive treatment, i.e. treatment to supplement another specific therapy for improvement of the associated disease, pathological condition or disorder. In various aspects, the term encompasses any treatment of a subject including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease; (ii) inhibiting the disease, i.e. arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal, such as a primate, and in another aspect, the subject is a human. The term "subject" also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, drosophila, etc.).

As used herein, the terms "prevent" or "preventing" refer to blocking, avoiding, eliminating, blocking, terminating, or hindering the occurrence of something, particularly by acting in advance. It is to be understood that where reduction, suppression, or prevention is used herein, the use of the other two terms is also expressly disclosed unless expressly stated otherwise.

As used herein, the term "diagnosed" refers to having been subjected to physical examination by a skilled artisan (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with a condition treatable by STAT3 inhibition" refers to having received physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound or composition that can inhibit or negatively modulate STAT 3. As a further example, "diagnosed as requiring inhibition of STAT 3" means that a physical examination has been performed by a technician, such as a physician, and is found to have symptoms characterized by dysfunction of STAT3 activity. Such diagnosis may relate to a disorder discussed herein, such as an oncological disorder or disease, cancer, and/or an uncontrolled cell proliferation disorder, among others. For example, the term "diagnosed as requiring inhibition of STAT3 activity" refers to the finding, upon physical examination by a skilled person (e.g., a physician), of a condition that can be diagnosed or treated by inhibition of STAT3 activity. For example, "diagnosed as requiring modulation of STAT3 activity" refers to having been subjected to physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by modulating STAT3 activity, e.g., negative modulation. For example, "diagnosed as a need for treatment of one or more conditions of uncontrolled cellular proliferation associated with STAT3 dysfunction" refers to a condition that has been physically examined by a technician (e.g., a physician) and found to have one or more conditions of uncontrolled cellular proliferation associated with STAT3 dysfunction, such as cancer.

As used herein, the expression "STAT 3-or STAT 5-dependent cancer" refers to a cancer that carries constitutively activated STAT3 or STAT 5.

As used herein, the phrase "determining a need for treatment of a disorder" and the like refers to selecting a subject based on the need for treatment of the disorder. For example, a subject may be identified as in need of treatment for a disorder (e.g., a disorder associated with STAT3 activity) based on an early diagnosis by a technician and thereafter receive treatment for the disorder. It is contemplated that in one aspect, the identification may be performed by a person other than the person making the diagnosis. In a further aspect, it is also contemplated that the administration can be performed by a human who subsequently performs the administration.

As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, intravaginal, ocular, otic, intracerebral, rectal, sublingual, buccal and parenteral administration, including injectable, such as intravenous, intraarterial, intramuscular and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the formulation can be administered therapeutically; i.e., administered to treat an existing disease or condition. In a further different aspect, the formulation may be administered prophylactically; that is, administration is for the prevention of disease or symptoms.

As used herein, the term "contacting" refers to bringing together a disclosed compound and a cell, a target STAT3 protein, or other biological entity in such a way that the compound can affect the activity of the target (e.g., spliceosome, cell, etc.), either directly, i.e., by interacting with the target itself, or indirectly, i.e., by interacting with another molecule, cofactor, factor, or protein upon which the activity of the target is dependent.

As used herein, the terms "effective amount" and "effective amount" refer to an amount sufficient to achieve a desired result or effect on an undesirable symptom. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or effect on an undesirable condition, but generally insufficient to cause an adverse side effect. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed and similar factors well known in the medical arts. For example, it is within the skill of the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. An effective daily dose may be divided into multiple doses for administration purposes, if desired. Thus, a single dose composition may contain such an amount or submultiple(s) thereof to constitute a daily dose. In the case of any contraindications, the dosage may be adjusted by the individual physician. The dosage may vary, and may be administered in one or more doses per day for one or more days. Guidance for appropriate dosages can be found in the literature for a given class of pharmaceutical products. In further various aspects, the formulation can be administered in a "prophylactically effective amount"; i.e., an amount effective to prevent a disease or condition.

As used herein, "EC₅₀"is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% agonism or activation of a biological process or component of a process, including proteins, subunits, organelles (organelles), ribonucleoproteins, and the like. In one aspect, as further defined elsewhere herein, EC₅₀May refer to the concentration of the substance required for 50% agonism or activation in vivo. In a further aspect, EC₅₀Refers to the concentration of agonist or activator that elicits a response that is half way between the baseline and maximum response.

As used herein, "IC₅₀"is intended to mean the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process (including proteins, subunits, organelles, ribonucleoproteins, etc.). In some cases, the IC is as further defined elsewhere herein₅₀Can refer to the plasma concentration of a substance required for 50% inhibition in vivo. More commonly, ICs₅₀Refers to the half maximal (50%) Inhibitory Concentration (IC) of a substance required to inhibit a process or activity in vitro.

As used herein, "STAT 3 IC₅₀By "is meant the concentration of a substance (e.g., compound or drug) required to inhibit STAT3 activity by 50%. In some cases, IC, as further defined elsewhere herein (e.g., tumor growth in an animal or human), is₅₀And may refer to the plasma concentration of a substance required to inhibit an activity or process in vivo by 50%. In other cases, STAT3 IC₅₀Refers to the half-maximal (50%) Inhibitory Concentration (IC) of a substance or compound required to inhibit a process or activity in an in vitro context, e.g., cell-free or cell-based assay. For example, STAT3 IC₅₀May be at the half-maximal concentration required to inhibit cell growth. As discussed below, responses were measured in cell lines with aberrant STAT3 activity. Alternatively, the response was measured in a cell line with persistently active STAT 3. The response can be measured using cell lines derived from human breast, pancreatic and prostate cancer. For example, the response may be measured in a cell line selected from MDA-MB-231, Panc-1, and DU-145. Can also useCell lines transfected with specific genes. For example, the response can be measured in a cell line transfected with v-Src. Alternatively, the cell line transfected with v-Src is a permanent cell line. STAT3 IC in some cases₅₀Is the half-maximal concentration required to inhibit STAT3 activity in a cell-free assay, such as an electrophoretic mobility shift assay ("EMSA"). Alternatively, STAT3 IC₅₀Is the half-maximal concentration required to inhibit cell growth, cell viability or cell migration activity.

As used herein, the term "STAT 3K_D"refers to the binding affinity of a compound or substance to STAT3 as determined in an in vitro assay. K of substance to protein_DCan be determined by a variety of methods known to those skilled in the art, such as equilibrium dialysis, analytical ultracentrifugation, and surface plasmon resonance ("SPR") analysis. STAT 3K, as generally used herein_DDefined as the ratio of the binding and dissociation rate constants determined using SPR analysis using purified STAT3 protein.

As used herein, the term "STAT 3K_i"refers to the inhibition constant for replacement of the STAT3 SH2 probe from the STAT3 protein. For example, STAT3 SH2 can be fluorescently labeled GpYLPQTV. As described herein, the fluorescent label is 5-carboxyfluorescein, although other suitable fluorescent probes may be used, as determined to be useful and convenient by one skilled in the art.

The term "pharmaceutically acceptable" describes materials that are not biologically or otherwise undesirable, i.e., do not cause unacceptable levels of undesirable biological effects or interact in a deleterious manner.

As used herein, the term "derivative" refers to a compound that has a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to and based on the similarity to those disclosed herein, would be expected by one skilled in the art to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as a precursor to the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents such as parabens (parabens), chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. Injectable depot forms are prepared by forming a microencapsulated matrix of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Long acting injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95% by weight of the particles of active ingredient have an effective particle size in the range of 0.01 to 10 microns.

As used in the specification and the appended claims, a residue of a chemical refers to a moiety that is the product of the resulting chemical in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually derived from the chemical.

As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For purposes of this disclosure, these heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. The present disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Furthermore, the terms "substituted" or "substituted with" include the implicit condition that such substitution is consistent with the permissible valences of the substituting atoms and substituents, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, etc. It is also contemplated that in certain aspects, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless explicitly stated to the contrary.

In each term of definition, "R", "P",₁”、“R₂"and" R₃"is used herein as a generic symbol to denote various specific substituents. These symbols may be any substituent, not limited to those disclosed herein, and when they are defined as certain substituents in one instance, they may be defined as some other substituents in another instance.

As used herein, the term "alkyl" is a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, n-pentyl, isopentyl, iso-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl (eicosyl), tetracosyl (tetracosyl), and the like. The alkyl group may be cyclic or acyclic. The alkyl group may be branched or unbranched. Alkyl groups may also be substituted or unsubstituted. For example, an alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. "lower alkyl" is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms.

Throughout the specification, "alkyl" is generally used to refer to both unsubstituted alkyl and substituted alkyl; however, substituted alkyl groups are also specifically mentioned herein by identifying specific substituents on the alkyl group. For example, the term "haloalkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. The term "alkoxyalkyl" as described below specifically refers to an alkyl group substituted with one or more alkoxy groups. The term "alkylamino" as described below specifically refers to alkyl groups and the like substituted with one or more amino groups. When "alkyl" is used in one instance and a specific term such as "alkyl alcohol" is used in another instance, it is not meant to imply that the term "alkyl" does not refer to a specific term such as "alkyl alcohol" or the like. This practice is also applicable to the other groups described herein. That is, while terms such as "cycloalkyl" refer to both unsubstituted and substituted cycloalkyl moieties, substituted moieties may otherwise be specifically identified herein; for example, a particular substituted cycloalkyl group can be referred to as, for example, "alkylcycloalkyl". Similarly, substituted alkoxy groups may be specifically referred to as, for example, "haloalkoxy", and particular substituted alkenyl groups may be, for example, "alkenyl alcohols" and the like. Likewise, practice using generic terms such as "cycloalkyl" and specific terms such as "alkylcycloalkyl" does not imply that the generic term nor the specific term is included.

The term "cycloalkyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" is a class of cycloalkyl groups defined above and is included within the meaning of the term "cycloalkyl" wherein at least one carbon atom of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups may be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term "polyalkylene" as used herein is a compound having two or more CH groups attached to each other₂The radical of (a). The polyalkylene may be represented by the formula- (CH)₂)_a-represents, wherein "a" is an integer from 2 to 500.

The terms "alkoxy" and "alkoxy" as used herein refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an "alkoxy" group can be defined as-OA¹Wherein A is¹Is alkyl or cycloalkyl as defined above. "alkoxy" also includes polymers of alkoxy groups just described; that is, the alkoxy group may be a polyether, such as-OA¹-OA²or-OA¹-(OA²)a-OA³Wherein "a" is an integer of 1 to 200, and A¹、A²And A³Is an alkyl and/or cycloalkyl group.

The term "alkenyl" as used herein is a hydrocarbon group having 2 to 24 carbon atoms, the structural formula of which contains at least one carbon-carbon double bond. Asymmetric structures such as (A)¹A²)C＝C(A³A⁴) It is intended to include both the E and Z isomers. This can be surmised in this formula where an asymmetric olefin is present, or it can be explicitly indicated by the bond symbol C ═ C. The alkenyl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, as described hereinNitro, silyl, sulfo-oxo or thiol.

The term "cycloalkenyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond (i.e., C ═ C). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above, and is included within the meaning of the term "cycloalkenyl" where at least one carbon atom of the ring is substituted with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term "alkynyl" as used herein is a hydrocarbon group of 2 to 24 carbon atoms having a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term "cycloalkynyl" as used herein is a non-aromatic carbon-based ring consisting of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term "heterocycloalkynyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkynyl" wherein at least one carbon atom of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocycloalkynyl groups may be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term "aryl" as used herein is a group comprising any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term "aryl" also includes "heteroaryl," which is defined as a group comprising an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term "non-heteroaryl," also included in the term "aryl," defines a group that includes an aromatic group that does not include a heteroatom. The aryl group may be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl". Biaryl refers to two aryl groups joined together via a fused ring structure (as in naphthalene) or connected via one or more carbon-carbon bonds (as in biphenyl).

The term "aldehyde" as used herein is represented by the formula-c (o) H. In the present specification, "C (O)" is a abbreviation for carbonyl, i.e., C ═ O.

The term "amine" or "amino" as used herein is represented by the formula-NA¹A²Is shown in the specification, wherein A¹And A²May independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term "alkylamino" as used herein is represented by the formula-NH (-alkyl), wherein alkyl is described herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl) amino, (tert-butyl) amino, pentylamino, isopentylamino, (tert-pentyl) amino, hexylamino, and the like.

The term "dialkylamino," as used herein, is represented by the formula-N (-alkyl) 2, wherein alkyl is described herein. Representative examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di (sec-butyl) amino, di (tert-butyl) amino, dipentylamino, diisopentylamino, di (tert-pentyl) amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, and the like.

The term "carboxylic acid" as used herein is represented by the formula-c (o) OH.

The term "ester" as used herein is represented by the formula-oc (o) a¹or-C (O) OA¹Is shown in the specification, wherein A¹May be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "polyester" as used herein is represented by the formula- (A)¹O-(O)CA²-C(O)O)_a-or- (A)¹O(O)CA²-OC(O))_a-is represented by, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, "a" is an integer from 1 to 500. "polyester" is a term used to describe a group produced by a reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

The term "ether" as used herein is represented by formula A¹OA²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "polyether" as used herein is represented by the formula- (A)¹O-A²O)_a-is represented by, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl group as described hereinA group or heteroaryl, "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

The term "halide" as used herein refers to the halogens fluorine, chlorine, bromine and iodine.

The term "heterocycle" as used herein refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Heterocycles include azetidine, dioxane, furan, imidazole, isothiazole, isoxazole, morpholine, oxazole, including 1,2, 3-oxadiazole, 1,2, 5-oxadiazole and 1,3, 4-oxadiazole, piperazine, piperidine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrazine (including 1,2,4, 5-tetrazine), tetrazole (including 1,2,3, 4-tetrazole and 1,2,4, 5-tetrazole), thiadiazole (including 1,2, 3-thiadiazole, 1,2, 5-thiadiazole and 1,3, 4-thiadiazole), thiazole, thiophene, triazine (including 1,3, 5-triazine and 1,2, 4-triazine), triazole (including 1,2, 3-triazole, 1,3, 4-triazole), and the like.

The term "hydroxy" as used herein is represented by the formula-OH.

The term "ketone" as used herein is represented by formula A¹(C(O)A²Is shown in the specification, wherein A¹And A²Independently is an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term "azide" as used herein is represented by the formula-N₃And (4) showing.

The term "nitro" as used herein is represented by the formula-NO₂And (4) showing.

The term "nitrile" as used herein is represented by the formula-CN.

The term "sulfo-oxo" as used herein is represented by the formula-s (o) a¹、-S(O)₂A¹、-OS(O)₂A¹or-OS (O)₂OA¹Is shown in the specification, wherein A¹May be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. Throughout the specification, "S (O)" is a shorthand notation of S ═ O. The term "sulfonyl" is inAs used herein, means a mixture of-S (O)₂A¹A sulfo-oxy group represented by¹May be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. The term "sulfone" as used herein is represented by formula A¹S(O)₂A²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "sulfoxide" as used herein is represented by formula A¹S(O)A²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term "thiol" as used herein is represented by the formula-SH.

As used herein, "R₁”、“R₂”、“R₃”、“R_n"(wherein n is an integer) may independently have one or more of the groups listed above. For example, if R¹Is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group may be optionally substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, or the like. Depending on the group selected, the first group may be incorporated within the second group, or alternatively, the first group may be pendent (i.e., attached) to the second group. For example, for the phrase "alkyl group comprising an amino group," the amino group can be incorporated into the backbone of the alkyl group. Alternatively, the amino group may be linked to the backbone of the alkyl group. The nature of the group(s) selected will determine whether the first group is intercalated or attached to the second group.

As described herein, the compounds of the present invention may comprise an "optionally substituted" moiety. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that in certain aspects, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted), unless explicitly stated to the contrary.

The term "stable" as used herein refers to a compound that is not substantially altered when subjected to conditions that allow its production, detection, and in some aspects, recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of an "optionally substituted" group are independently halogen; - (CH)₂)_{0- 4}R⁰；-(CH₂)_0-4OR⁰；-O(CH₂)_0-4R⁰；-0-(CH₂)_0-4C(O)OR⁰；-(CH₂)_0-4CH(OR⁰)₂(ii) a Can be substituted by R⁰Substituted- (CH)₂)_0-4Ph; can be substituted by R⁰Substituted- (CH)₂)_0-4O(CH₂)_0-1Ph; can be substituted by R⁰substituted-CH ═ CHPh; can be substituted by R⁰Substituted- (CH)₂)_0-4O(CH₂)_0-1-a pyridyl group; -N0₂；-CN；-N₃；-(CH₂)_0-4N(R⁰)₂；-(CH₂)_0-4N(R⁰)C(O)R⁰；-N(R0)C(S)R⁰；-(CH₂)_0-4N(R0)C(O)NR0₂；-N(R⁰)C(S)NR⁰ ₂；-(CH₂)_0-4N(R0)C(O)OR0-N(R0)N(R0)C(O)R0；-N(R0)N(R0)C(O)NR0₂；-N(R0)N(R0)C(O)OR0；-(CH₂)_0-4C(O)R0；-C(S)R0；-(CH₂)_0-4C(O)OR0；-(CH₂)_0-4C(O)SR0；-(CH₂)_0-4C(O)OsiR0₃；-(CH₂)_0-4OC(O)R0；-OC(O)(CH₂)_0-4SR-；SC(S)SR0；-(CH₂)_0-4SC(O)R0；-(CH₂)_0-4C(O)NR0₂；-C(S)NR⁰ ₂；-C(S)SR⁰；-SC(S)SR⁰；-(CH₂)_0-4OC(O)NR⁰ ₂；-C(O)N(OR⁰)R⁰；-C(O)C(O)R⁰；-C(O)CH₂C(O)R⁰；-C(NOR⁰)R⁰；-(CH₂)_0-4SSR⁰；-(CH₂)_0-4S(O)₂R⁰；-(CH₂)_0-4S(O)₂OR⁰；-(CH₂)_0-4OS(O)₂R⁰；-S(O)₂NR⁰ ₂；-(CH₂)_0-4S(0)R⁰；-N(R⁰)S(O)₂NR⁰ ₂；-N(R⁰)S(O)₂R⁰；-N(OR⁰)R⁰；-C(NH)NR⁰ ₂；-P(O)₂R⁰；-P(O)R⁰ ₂；-OP(O)R⁰ ₂；-OP(O)(OR⁰)₂；SiR⁰ ₃；-(C_1-4Straight or branched alkylene) O-N (R)⁰)₂(ii) a Or- (C)_1-4Straight or branched alkylene) C (O) ON (R)⁰)₂Wherein each R is⁰May be substituted as defined below and independently is hydrogen, C_1-6Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph、-CH₂- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently occurring R⁰Together with their intermediate atoms, form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

R⁰By taking two independently occurring R⁰The ring formed together with their intermediate atoms) is independently halogen, - (CH)₂)_0-2R^*- (halogeno radical R)^*)、-(CH₂)_0-2OH、-(CH₂)_0-2OR^*、-(CH₂)_0-2CH(OR^*)₂(ii) a -O (halo R)^*)、-CN、-N₃、-(CH₂)_0-2C(O)R^*、-(CH₂)_0-2C(O)OH、-(CH₂)_0-2C(O)OR^*、-(CH₂)_{0- 2}SR^*、-(CH₂)_0-2SH、-(CH₂)_0-2NH₂、-(CH₂)_0-2NHR^*、-(CH₂)_0-2NR^* ₂、-N0₂、-SiR^* ₃、-OSiR^* ₃、-C(O)SR^*、-(C_1-4Straight OR branched alkylene) C (O) OR^*or-SSR^*Wherein each R is^*Is unsubstituted or preceded by "halo" and is independently selected from C_1-4Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R^*Suitable divalent substituents on the saturated carbon atom of (a) include ═ 0 and ═ S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: 0, ═ S, ═ NNR^* ₂、＝NNHC(O)R^*＝NNHC(O)OR^*、＝NNHS(O)₂R^*、＝NR^*、＝NOR^*-O(C(R^* ₂))_2-3O-or-S (C (R)^* ₂))_{2- 3}S-in which each occurrence of R is independent^*Selected from hydrogen, C which may be substituted as defined below_1-6An aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for incorporation into the substitutable carbon in the ortho position of the "optionally substituted" group include: -O (CR)^* ₂)_2-3O-, in which each occurrence of R is independent^*Selected from hydrogen, C which may be substituted as defined below_1-6Aliphatic, or having 0-4 members independently selected from nitrogenAn unsubstituted 5-6 membered saturated, partially unsaturated ring or aromatic ring of a heteroatom of oxygen or sulfur.

R^*Suitable substituents on the aliphatic radical of (A) include halogen, -R^*- (halogeno radical R)^*)、-OH、-OR^*-O (halo R)^*)、-CN、-C(O)OH、-C(O)OR^*、-NH₂、-NHR^*、-NR^* ₂or-NO₂Wherein each R is^*Is unsubstituted or preceded by "halogen" and is independently C_1-4Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include R⁺、-NR⁺ ₂、-C(O)R⁺、-C(O)OR⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-S(O)₂R⁺、-S(O)₂NR⁺、-C(S)NR⁺ ₂、-C(NH)NR⁺ ₂or-N (R)⁺)S(O)₂R⁺(ii) a Wherein each R⁺Independently hydrogen, C which may be substituted as defined below_1-6Aliphatic, unsubstituted-OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring R despite the above definition⁺Together with their central atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated ring, aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

R^·Suitable substituents on the aliphatic radical of (A) are independently halogen, -R^·- (halogeno radical R)^·)、-OH、-OR^·-O (halo R)^·)、-CN、-C(O)OH、-C(O)OR^·、-NH₂、-NHR^·、-NR^· ₂or-NO₂Wherein each R is^·Being unsubstituted or preceded by "halo" groups, by only oneOne or more halogen substituted and independently C_1-4Aliphatic, -CH₂Ph、-O(CH₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term "leaving group" refers to an atom (or group of atoms) with electron withdrawing capability that can be displaced as a stable species while carrying away bound electrons. Examples of suitable leaving groups include halides (including chloro, bromo and iodo) and pseudohalides (sulfonates) (including triflate, mesylate, tosylate and bromobenzenesulfonate). It is also contemplated that the hydroxyl moiety can be converted to a leaving group via a Mitsunobu reaction.

The terms "hydrolyzable group" and "hydrolyzable moiety" refer to a functional group capable of undergoing hydrolysis under, for example, basic or acidic conditions. Examples of hydrolyzable residues include, but are not limited to, acyl halides, activated carboxylic acids, and various protecting Groups known in the art (see, e.g., "Protective Groups in Organic Synthesis," t.w. greene, p.g. m.wuts, Wiley-Interscience, 1999).

The term "organic residue" defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes, but is not limited to, the carbon-containing groups, residues, or groups defined above. The organic residue may contain various heteroatoms or be bonded to another molecule through heteroatoms (including oxygen, nitrogen, sulfur, phosphorus, and the like). Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy or substituted alkoxy, mono or di-substituted amino, amido, and the like. The organic residue may preferably contain 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, the organic residue can comprise 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A close synonym for the term "residue" is the term "group", which, as used in the specification and the appended claims, refers to a fragment, group or substructure of a molecule described herein, regardless of how the molecule is prepared. In some embodiments, a group (e.g., an alkyl group) (i.e., a substituted alkyl group) may be further modified by bonding to one or more "substituent groups". The number of atoms in a given group is not critical to the invention unless indicated to the contrary elsewhere herein.

The term "organic group" as defined and used herein comprises one or more carbon atoms. The organic group can have, for example, 1 to 26 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, the organic group can have 2 to 26 carbon atoms, 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. An organic group typically has hydrogen bonded to at least some of the carbon atoms of the organic group. In some embodiments, the organic group may contain 1-10 inorganic heteroatoms, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like, associated therewith or therein. Examples of organic groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, alkoxycarbonyl, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocycle, or substituted heterocycle groups, wherein these terms are defined elsewhere herein. Some non-limiting examples of heteroatom-containing organic groups include alkoxy groups, trifluoromethoxy groups, acetoxy groups, dimethylamino groups, and the like.

The term "inorganic group" as defined and used herein does not contain carbon atoms and therefore only contains atoms other than carbon. Inorganic groups include bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which may be present alone or bonded together in chemically stable combinations thereof. The inorganic group has 10 or fewer, or preferably 1 to 6 or 1 to 4, inorganic atoms bonded together as set forth above. Examples of inorganic groups include, but are not limited to, amino, hydroxyl, halogen, nitro, thiol, sulfate, phosphate, and similar generally known inorganic groups. The inorganic group does not have a metal element of the periodic table (such as an alkali metal, alkaline earth metal, transition metal, lanthanide metal, or actinide metal) incorporated therein, although such metal ions can sometimes be used as pharmaceutically acceptable cations of anionic inorganic groups such as sulfate, phosphate, or similar anionic inorganic groups. The inorganic group does not contain metalloid elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or noble gas elements unless specifically stated otherwise herein.

The compounds described herein may contain one or more double bonds and thus potentially give cis/trans (E/Z) isomers as well as other conformational isomers. Unless indicated to the contrary, the present invention includes all such possible isomers as well as mixtures of such isomers.

Unless indicated to the contrary, chemical formulas having chemical bonds shown only in solid lines and not in wedges or dashed lines contemplate each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic mixtures. The compounds described herein may contain one or more asymmetric centers and thus potentially give rise to diastereomers and optical isomers. Unless indicated to the contrary, the present invention includes all such possible diastereoisomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic schemes used to prepare such compounds, or using racemization or epimerization procedures known to those skilled in the art, the products of such schemes can be mixtures of stereoisomers.

Many organic compounds exist in optically active forms that have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are used to denote the sign of the compound to rotate plane polarized light, where (-) or 1 denotes that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds (called stereoisomers) are identical except that they are non-superimposable mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. 50 of enantiomer: the 50 mixture is referred to as the racemic mixture. Many of the compounds described herein may have one or more chiral centers and thus may exist in different enantiomeric forms. If desired, the chiral carbons may be designated with an asterisk (#). When the bond to a chiral carbon is depicted as a straight line in the disclosed formulae, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus both enantiomers and mixtures thereof are encompassed within the formulae. As used in the art, when it is desired to specify an absolute configuration with respect to a chiral carbon, one of the bonds to the chiral carbon may be depicted as a wedge (bonding to atoms above the plane) and the other as a series (series) or wedge (bonding to atoms below the plane) of short parallel lines. The Cahn-Inglod-Prelog system can be used to assign either the (R) or (S) configuration to a chiral carbon.

The compounds described herein include atoms that are naturally and non-naturally abundant. The disclosed compounds can be isotopically labeled or isotopically substituted compounds, which are identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁶O、¹⁷O、³⁵S、¹⁸F and³⁶and (4) Cl. The compounds further include prodrugs thereof, and said compounds or said prodrugs containing the aforementioned isotopes and/or other isotopes of other atomsPharmaceutically acceptable salts of (a) are within the scope of the invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as H and C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) The isotopes of (a) are particularly preferred for their ease of preparation and detectability. Furthermore, with heavier isotopes such as deuterium, i.e.²H substitution may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the following scheme: the non-isotopically labeled reagent is replaced with a readily available isotopically labeled reagent.

The compounds described in the present invention may exist as solvates. In some cases, the solvent used to prepare the solvate is an aqueous solution, and then the solvate is often referred to as a hydrate. These compounds may exist as hydrates, which may be obtained, for example, by crystallization from a solvent or from an aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules may be combined with the compounds according to the invention to form solvates and hydrates. Unless indicated to the contrary, the present invention includes all such possible solvates.

The term "co-crystal" refers to a physical association of two or more molecules that has stability through non-covalent interactions. One or more components of the molecular complex provide a stable framework in the crystal lattice. In some cases, guest molecules are incorporated into the Crystal lattice as anhydrates or solvates, see, e.g., "Crystal Engineering of the Composition of Pharmaceutical drugs. Do Pharmaceutical Co-crystals retrieval a New Path to Improved therapeutics? "Almarasson, O.et. al., The Royal Society of Chemistry,1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

It is also understood that certain compounds described herein may exist as a balance of tautomers. For example, ketones having an alpha-hydrogen can exist in equilibrium in the keto form and the enol form.

Likewise, amides having N-hydrogen may exist in equilibrium amide form and imide acid form. Unless indicated to the contrary, the present invention includes all such possible tautomers.

It is known that chemical substances form solids, which exist in different sequential states (states of orders) known as polymorphs (polymorphic forms) or modifications (modifications). Different modifications of polymorphic substances can vary widely in physical properties. The compounds according to the invention may exist in different polymorphic forms, wherein a particular modification may be metastable. Unless indicated to the contrary, the present invention includes all such possible polymorphic forms.

In some aspects, the structure of a compound may be represented by the formula:

it is understood to be equivalent to the formula:

where n is typically an integer. Namely, RⁿIt is understood to mean five independent substituents, R^n(a)、R^n(b)、R^n(c)、R^n(d)And R^n(e). By "independent substituents" it is meant that each R substituent can be independently defined. For example, if R is in one instance^n(a)Is halogen, then R in this example^n(b)Not necessarily halogen.

A compound as defined herein may comprise a chiral center that produces an enantiomer. Thus, the compounds may exist as two different optical isomers, the (+) or (-) enantiomers. All such enantiomers and mixtures thereof, including racemic mixtures of individual enantiomers or mixtures in other proportions, are included within the scope of the present invention. The single enantiomer may be obtained by methods well known to those of ordinary skill in the art such as chiral HPLC, enzymatic resolution, and chiral assisted derivatization.

It will also be understood that compounds according to the present disclosure may contain more than one chiral center. Thus, the compounds of the present invention may exist in different diastereomeric forms. All such diastereomers and mixtures thereof are included within the scope of the invention. The single diastereoisomers may be obtained by methods well known in the art, such as HPLC, crystallization and chromatography.

The term "solvate" means a compound as defined herein in combination with one or more pharmaceutically acceptable solvents (including water) to produce a hydrate. Solvates may contain one or more solvent molecules per molecule of the compound or may contain one or more molecules of the compound per molecule of the solvent. Illustrative, non-limiting examples of hydrates include the monohydrate, dihydrate, trihydrate and tetrahydrate or hemihydrate. In one embodiment, the solvent may be held in the crystal in various ways, so solvent molecules may occupy lattice positions in the crystal, or they may form bonds with the salts of the compounds described herein. Solvates must be "acceptable" in the sense of not being deleterious to the recipient thereof. Solvation can be assessed by methods known in the art such as loss on drying techniques (LOD).

Disclosed are the components used to prepare the compositions of the present invention, as well as the compositions themselves used in the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is explicitly contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to molecules including the compounds are discussed, it is specifically contemplated that each and every combination and permutation of the compound and the modifications are possible unless specifically indicated to the contrary. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the present invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the present invention.

In one aspect, the invention relates to compounds useful as inhibitors of STAT3/STAT 5. In a further aspect, the products of the disclosed compounds and disclosed methods of manufacture are modulators of STAT3/STAT5 activity. In various aspects, the invention relates to compounds that bind to STAT3 protein and negatively modulate STAT3 activity. In other various aspects, the invention relates to compounds that bind to STAT5 protein and negatively modulate STAT5 activity. In a further aspect, the disclosed compounds exhibit inhibition of STAT3/5 activity.

In one aspect, as further described herein, the compounds of the invention are useful for treating cancers associated with the dysfunction of STAT3/STAT5 activity, such as breast, prostate, or brain cancers and glioblastomas, as well as other diseases in which STAT3/5 protein is implicated.

It is contemplated that each of the disclosed derivatives may optionally be further substituted. It is also contemplated that the present invention may optionally omit any one or more of the derivatives. It is understood that the disclosed compounds can be provided by the disclosed methods. It is also to be understood that the disclosed compounds can be used in the disclosed methods of use.

In one aspect, described herein is a series of novel compounds that exhibit potent anti-cancer activity, minimal toxicity in normal cells, exemplary metabolic stability in mouse and human hepatocytes, plasma stability in mice. Lead compounds from this series were tested on acute myeloid leukemia cells (with nM IC)₅₀MV4 of (a); 11 cells) showed strong cancer killing efficacy. Two notable entitiesFor example, compound I (JPX-0431) and compound II (JPX-0432) are described in acute myeloid leukemia cell MV 4; 11 showed about 6-8 times higher potency than the comparable compound AC-3-19 from the literature. Exemplary potency and metabolic stability is attributed to a privileged scaffold comprising a compound of formula I that protects pentafluorobenzenesulfonamide from attack by biological nucleophiles such as glutathione.

In some aspects, compounds of formula I, or pharmaceutically acceptable salts and/or solvates thereof, are disclosed:

formula I

Wherein for formula I:

-H，

wherein when R and R are₁When one of them is-H, R and R₁The other of which is a cyclopentyl moiety,

R₂is benzyl substituted by 1-5 halogens, preferably-Cl, -F or-Br, and preferably R₂Selected from:

R₃selected from the group consisting of-H or-OH.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

In some aspects, the compound of formula I is selected from:

process for preparing compounds of the present application

General procedure

Scheme 1. a)1) SOCl₂And refluxing for 3 h. 2)^tBuOH, DMAP (cat.) DCM, room temperature, 14h, 62%; b) aldehyde, DCE, AcOH, Na (OAc)₃BH, room temperature, 12h, 70-88%; c) PPh₃Cl₂，CHCl₃Heating for 30-45min at 100 deg.C with microwave assistance, 33-85%; d) DCM: TFA 1: 1, room temperature, 2h, 90-95%. DMAP ═ 4- (dimethylamino) pyridine, DCM ═ dichloromethane, DCE ═ 1, 2-dichloroethane, TFA ═ trifluoroacetic acid.

General scheme a: esterification of tert-butyl

4-Aminosalicylic acid (1.0 eq.) was placed in a round bottom flask, followed by dropwise addition of SOCl at room temperature₂(5.0 equiv.). The reaction mixture was then refluxed for 3 h. The excess SOCl was then removed under reduced pressure₂And by reaction with CHCl₃Traces were removed azeotropically. 4- (dimethylamino) pyridine (0.1 eq) in DCM (1M) and^tBuOH (15 equivalents), and the resulting mixture was stirred at room temperature for 14 h. The reaction was quenched by addition of 1M NaOH, then extracted with EtOAc (4 ×). The combined organic fractions were treated with saturated NaHCO₃(2X), saturated NaCl (IX) and MgSO 2₄And (5) drying. The crude product was purified using Biotage Isolera automatic column chromatography and eluted with gradient hexane/EtOAc to give primary aniline (primary aniline).

General scheme b: reductive amination using sodium triacetoxyborohydride

To a solution of primary aniline (1.0 equiv) and AcOH (1.1 equiv) dissolved in anhydrous DCE (0.1M) was added the corresponding aldehyde (1.0 equiv). The solution was then stirred at room temperature for 10min, after which Na (OAc) was added₃BH (1.5 eq) and the reaction was allowed to stir at room temperature. When the primary aniline was completely consumed as indicated by TLC, the reaction was diluted with DCM and poured into saturated NaHCO₃In the solution of (1). The layers were separated and the aqueous layer was extracted with DCM (3 ×). The combined organic fractions were washed with brine, over MgSO₄Dried and concentrated in vacuo. The crude sample was absorbed directly onto silica for column chromatography purification using gradient hexanes and EtOAc to afford secondary aniline (secondary aniline).

General scheme c: ph₃PC1₂Peptide coupling

To the cell in CHCl₃Ph was added to a stirred solution of carboxylic acid (1.2 equiv) in (0.08M)₃PCl₂(2.5 equivalents). The reaction mixture was stirred at room temperature for 15min until complete dissolution, followed by dropwise addition of secondary aniline (1.0 eq). The reaction mixture was then irradiated in a microwave at 100 ℃ for up to 45 min. The reaction mixture was cooled to 0 ℃ and purified by addition of saturated NaHCO₃And (4) quenching. The layers were separated and the aqueous layer was extracted with DCM (3 ×). The combined organic fractions were washed with saturated NaCl (IX) over MgSO₄And (5) drying. The crude sample was directly adsorbed onto silica and purified by column chromatography using an appropriate gradient of hexane and EtOAc.

General scheme d: deprotection of tert-butyl ester

A solution of tert-butyl ester (1 eq) was dissolved in a solution of TFA and DCM (0.1M) in 1: 1 in the mixture. The resulting solution was stirred for 2 hours, then mixed with MeOH (3X) and CHCl₃(3X) coevaporation.

Scheme 2.Synthesis of 3- (tert-butyl) -5-cyclopropylbenzaldehyde 2.

3-bromo-5- (tert-butyl) benzaldehyde (1)

A solution of 1, 3-dibromo-5- (tert-butyl) benzene (2.57nmol) in anhydrous THF (0.3M) was cooled to-78 deg.C, then nBuLi (2.5M in hexane, 2.83nmol) was added dropwise and at that temperature under N₂Stirring for 0.5 h. DMF (3.85nmol) was then added slowly and the reaction mixture was allowed to warm gradually from-78 ℃ to room temperature over 3 h. By addition of NH₄A saturated solution of Cl (20mL) quenched the reaction. Two layers were separated and Et₂The aqueous layer was O (3X) extracted. The combined organic fractions were washed with brine, over MgSO₄Dried and concentrated in vacuo. The crude product 1 was isolated as a yellow oil (544mg, 88%) and used directly in the next step.

¹H NMR (400MHz, chloroform-d) δ 9.95(s,1H),7.83(s,1H),7.82(s,1H)7.77(t, J ═ 1.8Hz,1H),1.36(s, 9H).

3- (tert-butyl) -5-cyclopropylbenzaldehyde (2)

An oven-dried round-bottomed flask equipped with a stir bar was charged with 1(3.11mmol) and N was used₂Purge Cyclopropylboronic acid (4.35mmol), tricyclohexylphosphine (0.311mmol) and K₃PO₄(12.4 mmol). Toluene (0.2M) and H were then added₂O (4M), followed by addition of Pd (OAc)₂(0.156mmol) and the reaction mixture was placed in an oil bath at 100 ℃ and allowed to stir for 10 h. The reaction was cooled back to room temperature, filtered through celite (celite), and washed with EtOAc. The filtrate was taken up with EtOAc and H₂O diluted and transferred to a separatory funnel. Two layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organic fractions were washed with brine and MgSO₄And (5) drying. The crude material was directly adsorbed onto silica and purified using Biotage Isolera automated column chromatography with a hexane/EtOAc gradient. 3- (tert-butyl) -5-cyclopropylbenzaldehyde was obtained as a clear oil (452mg, 72%).

¹H NMR (400MHz, chloroform-d) δ 9.97(s,1H),7.69(t, J ═ 1.7Hz,1H),7.44(t, J ═ 1.9Hz,1H),7.34(t, J ═ 1.5Hz,1H), 2.00-1.93 (m,1H),1.35(s,7H), 1.06-0.96 (m,2H), 0.79-0.70 (m,2H).¹³C NMR(101MHz,CDCl₃)δ192.96,152.07,144.85,136.49,129.91,124.20,123.50,34.78,31.25,15.44,9.49。

4- ((3- (tert-butyl) -5-cyclopropylbenzyl) amino) -2-hydroxy-benzoic acid tert-butyl ester (3)

Compound 3 was prepared according to general scheme b and isolated as an amorphous white solid (78%).¹H NMR (400MHz, chloroform-d) δ 11.39(s,1H),7.65(d, J ═ 8.5Hz,1H),7.22(s,1H),7.15(s,1H),6.91(s,1H), 6.19-6.15 (m,2H),4.50 (width s,1H),4.33(s,2H), 2.00-1.93 (m,1H),1.66(s,9H),1.39(s,9H), 1.05-0.98 (m,2H), 0.79-0.75 (m,2H).¹³C NMR(101MHz,CDCl₃)δ170.11,163.96,153.96,151.75,144.23,137.90,131.48,122.40,122.07,121.90,105.32,103.49,98.07,81.42,48.13,34.73,31.47,28.45,15.68,9.37。

4- (N- (3- (tert-butyl) -5-cyclopropylbenzyl) -2- (N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonamido) acetamido) -2-hydroxybenzoic acid tert-butyl ester (4)

Compound 4 was prepared according to general scheme c and isolated as an amorphous beige solid (66%).¹H NMR (400MHz, chloroform-d) δ 11.07(s,1H),7.65(d, J ═ 8.4Hz,1H),7.28(d, J ═ 8.4Hz,2H),7.18(d, J ═ 8.4Hz,2H),7.03(t, J ═ 1.8Hz,1H),6.81(d, J ═ 1.7Hz,1H),6.59(s,1H),6.37(s,1H),6.21(d, J ═ 8.3Hz,1H),4.68(s,2H),4.62(s,2H),3.81(s,2H), 1.89-1.83 (m,1H),1.60(s,9H),1.24(s,9H), 0.99-0.94 (m,2H), 0.65-0.61 (m,2H).¹³C NMR(101MHz,CDCl₃)δ168.80,165.54,162.57,151.35,145.64,144.02,135.36,134.47,132.82,131.66,130.10,129.10,123.16,122.75,122.52,118.43,116.91,114.10,83.73,53.15,50.53,47.74,34.51,31.23,28.13,15.49,9.24。

4- (N- (3- (tert-butyl) -5-cyclopropylbenzyl) -2- ((-N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonamido) acetamido) -2-hydroxybenzoic acid tert-butyl ester (Compound I)

Compound I was prepared according to general scheme d and isolated as an amorphous white powder (89%).¹H NMR (400MHz, chloroform-d) δ 10.48(s,1H),7.79(d, J ═ 8.4Hz,1H), 7.30-7.24 (d, J ═ 8.2Hz,2H),7.18(d, J ═ 8.2Hz,2H),7.05(s,1H),6.80(s,1H),6.61(s,1H),6.41(s,1H),6.28(s,1H),4.71(s,2H),4.63(s,2H),3.84(s,2H),1.87(ddd, J ═ 13.6,8.5,5.1Hz,1H),1.24(s,8H), 1.00-0.92 (m,2H), 0.69-0.56 (m,2H) (+), ms (ESI C +), 1.₃₆H₃₂ClF₅N₂O₆S + H) calculated 751.1668, found (found) 751.1673. (C)₃₆H₃₂ClF₅N₂O₆S + H) calculated 751.1668 HRMS (ESI +), found 751.1673.

4- ((3- (tert-butyl) -5-cyclopropylbenzyl) amino) -2-hydroxybenzoic acid tert-butyl ester (6)

Compound 6 was prepared according to general scheme b and isolated as an amorphous beige solid (75%).¹H NMR (400MHz, chloroform-d) δ 7.84(d, J ═ 8.6Hz,2H),7.16(d, J ═ 1.6Hz,1H),7.09(d, J ═ 1.8Hz,1H),6.86(d, J ═ 1.7Hz,1H),6.60(d, J ═ 8.8Hz,2H),4.37(s,1H),4.31(s,2H),1.90(tt, J ═ 8.5,5.1Hz,1H),1.59(s,9H),1.32(s,9H),1.01 to 0.90(m,2H),0.74 to 0.65(m,2H).¹³C NMR(101MHz,CDCl₃)δ166.20,151.73,151.60,144.18,138.07,131.34,122.33,122.00,121.79,120.54,111.50,79.85,48.29,34.69,31.40,28.36,15.60,9.27。

4-N- (3- (tert-butyl) -5-cyclopropylbenzyl) -2- ((N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonamido) acetamido) benzoic acid tert-butyl ester (7)

Compound 7 was prepared according to general scheme c and isolated as an amorphous beige solid (31%).¹H NMR (400MHz, chloroform-d) δ 7.88(d, J ═ 8.1Hz,2H),7.28(d, J ═ 8.2Hz,2H),7.18(d, J ═ 8.4Hz,2H),7.04(t, J ═ 1.8Hz,1H), 6.80-6.70 (m,3H),6.59(s,1H),4.71(s,2H),4.65(s,2H),3.73(s,2H), 1.91-1.85 (m,1H),1.60(s,9H),1.24(s,9H), 0.99-0.95 (m,2H), 0.65-0.61 (m,2H).

4- (N- (3- (tert-butyl) -5-cyclopropylbenzyl) -2- ((N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonamido) acetamido) benzoic acid (Compound II)

Compound II was prepared according to general scheme d and isolated as a white amorphous powder (82%).¹H NMR (400MHz, chloroform-d) δ 8.00(d, J ═ 8.0Hz,2H),7.27(d, J ═ 8.3Hz,2H),7.18(d, J ═ 8.3Hz,2H),7.04(d, J ═ 1.8Hz,1H),6.80(d, J ═ 8.1Hz,2H),6.76(s,1H),6.59(d, J ═ 1.7Hz,1H),4.72(s,2H),4.64(s,2H),3.74(s,2H),1.86(tt, J ═ 8.5,5.1Hz,1H),1.22(s,9H), 1.01-0.92 (m,2H),0.62(dt, J ═ 6.7, 2H).

4- (N- (3-cyclopentylbenzyl) -2- ((2,3,4,5, 6-pentafluoro-N- ((perfluorophenyl) methyl) phenyl) sulfonamido) acetamido) benzoic acid (JPX-303)

Compounds JPX-303 were prepared according to general procedure d and isolated as an amorphous white powder (88%).¹H NMR (400MHz, chloroform-d) δ 8.08(d, J ═ 8.4Hz,2H),7.21 to 7.14(m,2H),7.05(d, J ═ 8.1Hz,2H),6.88(s,1H),6.85(d, J ═ 7.6Hz,1H),4.81(s,2H),4.79(s,2H),3.88(s,2H),2.91(ddd, J ═ 17.4,9.7,7.5Hz,1H)2.03 to 1.96(m,2H),1.78 to 1.71(m,2H),1.69 to 1.64(m,2H),1.52 to 1.43(m,2H).¹³C NMR(101MHz,CDCl₃)δ170.10,165.31,147.07,146.35,145.68,144.98,144.69,144.53,144.19,143.24,142.31,140.86,138.53,138.24,137.07,136.80,135.28,132.10,129.76,128.56,128.35,127.51,126.74,125.91,116.02,108.77,53.42,49.06,45.69,39.29,34.47,25.40。

4-N- (3-cyclopentylbenzyl) -2- ((2,3,4,5, 6-pentafluoro-N- ((perfluorophenyl) methyl) phenyl) sulfonamido) acetamido) -2-hydroxybenzoic acid (JPX-320)

Compounds JPX-320 were prepared according to general procedure d and isolated as an amorphous white powder (89%).¹H NMR (400MHz, chloroform-d) δ 10.54(s,1H),7.86(d, J ═ 8.4Hz,1H),7.20-7.14(m,2H),6.92-6.87(m,2H),6.62(s,1H),6.51(d, J ═ 8.4Hz,1H),4.81(s,2H),4.76(s,2H),3.98(s,2H),2.92(q, J ═ 7.2,2.4Hz,1H),2.02-1.99(m,2H),1.77-1.74(m,2H),1.69-1.65(m,2H),1.52-1.46(m, 2H).

4- (2- (-N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonylamino) -N- (3-cyclopentylbenzyl) acetamido) benzoic acid (JPX-313)

Compounds JPX-313 were prepared according to general scheme d and isolated as an amorphous white powder (92%).¹H NMR (400MHz, chloroform-d) δ 7.98(d, J ═ 8.0Hz,2H),7.26(d, J ═ 2.8Hz,1H),7.20 to 7.17(m,4H),6.87 to 6.85(m,4H),4.72(s,2H),4.64(s,2H),3.74(s,2H),2.94 to 2.89(m,1H),2.02 to 1.99(m,2H),1.77 to 1.74(m,2H),1.68 to 1.65(m,2H),1.50 to 1.47(m, 2H).

4- (2- (N- (4-chlorobenzyl) -2,3,4,5, 6-pentafluorophenyl) sulfonylamino) -N- (3-cyclopentylbenzyl) acetamido) -2-hydroxybenzoic acid (JPX-062)

Compound JPX-062 was prepared according to general scheme d and isolated as an amorphous white powder (82%).¹H NMR (400MHz, chloroform-d) delta 10.49(s,1H),7.77(d,8.4Hz,1H),7.29-7.27(m,2H),7.21-7.15(m,4H),6.90-6.87(m,2H),6.45(s,1H),6.32(s,1H),4.71(s,2H),4.63(s,2H),2.95-2.90(m,1H),2.03-1.99(m,2H),1.78-1.75(m,2H),1.69-1.65(m,2H),1.51-1.48(m, 2H).

The compounds of the present application have unexpected metabolic stability compared to comparable compounds from the literature.

In vitro cell viability study

The anticancer efficacy of exemplary compounds of the present application was evaluated in vitro in different cancer cell lines. Cell viability was checked using the cell Titer-Blue cell viability assay after treatment at different concentrations of inhibitor (0.097656-50 μ M). 1X10⁴Cells/well were seeded in 96-well assay plates in culture medium. All cells were grown in DMEM, IMDM and RPMI-1640 supplemented with 10% FBS. After 24 hours, the test compound and vehicle control were added to the appropriate wells such that the final volume in each well was 100 μ Ι. At 37 ℃ and 5% CO₂The cells were then cultured for the desired test exposure period (72 hours). The assay plate was removed from the 37 ℃ incubator and 20. mu.l/well CellTiter-And (3) a reagent. Plates were incubated for 1-4 hours using standard cell culture conditions, plates were shaken for 10 seconds, and fluorescence was recorded at 560/590 nm.

Exemplary compounds of the present application show IC in the range of 0.4-8.0. mu.M, preferably 0.4-5.0. mu.M against cancer cells such as MV4-11, MOLM-13 and K562₅₀The value is obtained. IC of healthy cells such as MRC9₅₀Values are typically greater than 20. mu.M.

Compounds I and II were tested for efficacy against selected chronic myelogenous leukemia, acute myelogenous leukemia and healthy human lung cell lines using the protocol described above.

Table 1 presents the IC of Compound I against different cell lines₅₀The value is obtained.

Table 1: IC of the compounds described herein against different cancer and healthy cell lines₅₀Value of

The compounds of the present application have an unexpected improvement in anticancer efficacy compared to comparable compounds from the literature. As an example of an exemplary activity of compounds of formula I in acute myeloid leukemia cells (MV-4-11 cells), compound I and compound II have IC's of 0.56 and 0.48. mu.M, respectively, compared to the analogous compound AC-3-19 (described in WO 2015179956)₅₀The analogous compounds show significantly lower efficacy, IC₅₀About 3-5. mu.M.

By way of example of a cytotoxicity assay of MV4-11 cells, MV4-11 cells were grown in Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% Fetal Bovine Serum (FBS). 10000 cells/well were seeded in 96-well flat-bottom sterile culture plates with low evaporation lids. After 24h, inhibitor and vehicle control (0.5% DMSO) were added and cells were incubated at 37 ℃ in 5% CO₂And (4) carrying out incubation for 72 h. Inhibitors were checked in triplicate at a maximum concentration of 50 μ M, followed by 1: and 2, diluting. After 72h, the wells were treated with CellTiter-(20. mu.L/well) and the plates were incubated for 1 hour using standard cell culture conditions. Fluorescence was measured at 560/590 nm. IC determination using non-linear regression analysis₅₀The value is obtained. Similar procedures were used for other cell lines.

pharmacokinetic-ADME study

Intrinsic clearance of Compounds I and II in mouse hepatocytes

Determination of in vitro T of Compound I_1/2(min) is 100 min.

Stock solutions of 100 μ M test compound were prepared by diluting 10 μ M test compound in DMSO with a solution of 50% acetonitrile and 50% water. In a 96-well uncoated plate, 198 μ Ι _ of hepatocytes were removed and the plate was placed in an incubator on an orbital shaker to warm the hepatocytes for 10 minutes. To this solution 2 μ L of 100 μ M test compound was added to start the reaction and the plate was placed on an orbital shaker. The reaction was terminated by mixing aliquots with solutions of acetonitrile and internal standard (100nM alprazolam, 200nM labetalol and 2mM ketoprofen) at time points of 0, 15, 30, 60, 90 and 120 minutes. The reaction solution was then vortexed for 10 minutes and centrifuged at 4000rpm for 30 minutes at4 ℃. mu.L of the supernatant was transferred to a new 96-well plate, centrifuged at 4000rpm for 30 minutes at4 ℃ and 100. mu.L of the supernatant was transferred to a new 96-well plate, ensuring that the pellet (pellet) was undisturbed. 100 μ L of ultrapure water was added to all samples for analysis by LC-MS/MS.

In vitro half-life (T.sub.half-life) was determined by linear regression of the remaining percentage of parent drug versus the natural logarithm of the incubation time curve_1/2). The in vitro half-life is then determined by substituting the slope value (k) of the curve into the following equation.

In vitro intrinsic clearance (in vitro CL) was determined by the following equation_intAt μ L/min/10⁶A cytometer).

Wherein the incubation volume is 0.2mL and the number of hepatocytes per well is 0.1x10⁶A cell.

The biological analysis method comprises the following steps: column-Phenomenex Synergi 4. mu. Hydro-PR 80A (2.0X30 mm). Mobile phase-0.1% formic acid in water (solvent a) and 0.1% formic acid in acetonitrile (solvent B). Column temperature-room temperature. Injection volume-10 μ L. MS analysis-API 4000 instrument with ESI interface from AB Inc (canada).

As can be seen from FIG. 1, Compound I has a T of 101min_1/2And pentafluorobenzenesulfonamide containing AC-3-19 has a T of 83min_1/2. Compound I showed a slower clearance rate than comparable compounds from the literature. As an example of exemplary stability of compounds of formula I, analogous compounds JPX-0372 (structure shown in FIG. 2A) (where the T-butyl group was omitted) showed significantly faster clearance, T_1/2It was 16.4min (FIG. 2B) (Pharmaron, China).

As another example of the metabolic stability provided by the compounds of formula I, compounds JPX-0369 (FIG. 3A) in which the c-Pr group of compound I was removed showed significantly faster clearance, T_1/236.5min (fig. 3B).

As another example of the metabolic stability provided by the compounds of formula I, compounds JPX-0371 (FIG. 4A) having a symmetrically disubstituted 3, 5-di-c-Pr group instead of the asymmetrically disubstituted compound I again showed much poorer clearance, T_1/225.1min (fig. 4B).

As another example of the metabolic stability provided by the compounds of formula I, compounds JPX-0318 (FIG. 5A) of Compound II with benzoic acid and a mono-substituted 3-tert-butyl group instead of the asymmetric di-substituted Compound II with benzoic acid and T of Compound II_1/2Again, a much poorer clearance is shown, T, than 46min_1/210.3min (fig. 5B).

It can therefore be appreciated that the compounds of formula I described herein have superior clearance in mouse hepatocytes to the previous examples containing pentafluorobenzenesulfonamide compounds.

The reactivity curve of Glutathione (GSH) was used.

3.5 μ L of a stock solution of 5mM inhibitor in DMSO was added to 697.5 μ L of Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% FBS and antibiotic antimycotic solution, 5mM glutathione to provide a final concentration of 25 μ M inhibitor with 0.5% DMSO. The solution was then immediately placed in a 25 ℃ sample tray. Samples were analyzed by HPLC at predefined intervals (typically every 1.5 hours) for up to four injections, including at time zero, without further pretreatment. For each inhibitor, its peak was integrated at different time points and annotated with time zeroThe shots are compared to obtain the remaining percentage. According to the formula: ln [ A ]]＝Ln[A]0-kt, wherein [ A]Is the value integrated at each time point, [ A ]]0 is the value at time zero and t is time, using the formula: t is t_1/2(ii) Ln (2)/k, wherein k is Ln [ inhibitor]The slope of the linear curve over time, calculating the half-life according to the first order reaction kinetics, takes into account those time points where the remaining percentage of inhibitor is higher than 40%. For each inhibitor, two replicates were averaged and the resulting t of the inhibitor reported in the same solution in the absence of GSH was confirmed by incubation with GSH longer than the latest time point analyzed for the sample_1/2And in particular to a single analysis following time-selective reactivity of GSH.

Using the above procedure, t of Compounds JPX-1 to JPX-15 were obtained_1/2As reported in table 2 below.

TABLE 2

Bioavailability studies in CD-1 mice (IP injection).

The study group for PK of compound I, II and comparative experiments using AC-3-19 and JPX-0371 experiments are shown in Table 3.

TABLE 3

All animals had free access to food and water. Dose formulation handling during administration: these formulations will remain stirred at room temperature for at least 15 minutes before and during administration. The Pharmacokinetic (PK) protocol is shown in table 4 below.

TABLE 4

Group of	PK time points
		IP	Plasma: 5, 15, 30min, 1,2,4, 8 and 24 hours after administration

Approximately 0.03mL of blood was collected at each time point. The blood from each sample was transferred to a plastic microcentrifuge tube containing heparin-Na as an anticoagulant. The collection tube with blood sample and anticoagulant was inverted several times to properly mix the tube contents and then placed on wet ice prior to centrifuging the plasma. Blood samples were centrifuged at 4000g for 5 minutes at4 ℃ to obtain plasma. Samples were stored in a refrigerator at-75 ± 15 ℃ prior to analysis. CD-1 mice (male) were used for this study, with n-3, approximately 6-8 weeks of age (20-30 g).

Dosage formulations

Table 5.

Preparation frequency:	prepared newly on the day of administration
		The carrier comprises the following components:	IP: 10% DMA/65% PEG 400/25% saline
Storage conditions were as follows:	dosage formulations for administration: at room temperature

The plasma samples were analyzed for compound concentration using the LC-MS/MS method. WinNonlin (Phoenix)^TMVersion 6.1). Other similar software may also be used for pharmacokinetic calculations. Pharmacokinetic parameters were calculated from plasma concentration versus time data whenever possible: calculating IP parameters, including T_1/2、C_max、T_max、AUC_last、AUC_inf、MRT。

FIG. 6 shows the clearance of Compound I and comparative Compound JPX-0371. Compound I has a calculated T of 3.9 hours_1/2And pentafluorobenzenesulfonamide containing JPX-0371 has a T of 0.66 hours_1/2. The compounds of the present application unexpectedly have much slower clearance, higher bioavailability than comparable similar compounds shown in tables 6 and 7, where the PK parameters are summaries of compound I (table 6) and JPX-0371 (table 7).

TABLE 6

PK data for Compound I

TABLE 7

JPX-0371 PK data

Similarly, t obtained for compounds JPX-303, JPX-320, JPX-313 and JPX-062_1/2(hr) was 0.35, 0.861, 0.31 and 0.94, respectively.

It will be understood that the amount of a compound of the invention required in treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition to be treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician. Generally, the amount administered will be determined empirically, typically in the range of about 10 μ g to 100mg/kg of recipient body weight.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals (e.g. two, three, four or more doses per day).

Pharmaceutical compositions include, but are not limited to, those in a form suitable for oral (including buccal and sublingual), transdermal or parenteral (including intramuscular, subcutaneous and intravenous) administration or for administration by inhalation.

The formulations may conveniently be presented in discrete dosage units where appropriate and may be prepared by any of the methods well known in the art of pharmacy. The process for preparing a pharmaceutical composition may comprise the steps of: combining a compound as defined herein with a pharmaceutically acceptable excipient and then, if necessary, shaping the product into the desired formulation, including applying a coating when desired.

Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, suspension or as an emulsion. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. The compounds and combinations defined herein may also be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile water or saline, before use.

Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base (usually sucrose and acacia or tragacanth); candy lozenges (pastilles) comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

For administration by inhalation, the compounds and combinations defined herein may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder compositions may be presented in unit dosage form in, for example, capsules or cartridges (cartridges) or, for example, gelatin or blister packs from which the powder may be administered by means of an inhaler or insufflator.

These compounds are STAT3/STAT5 inhibitors, much like those described in WO2013177534, and it is expected that the compounds described herein will have the same utility, with similar or higher activity for treating cancers, such as, for example, pancreatic cancer, multiple myeloma, brain cancer, and breast cancer, while having longer clearance rates, making these compounds better candidates.

While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice in the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.