Novel glutamine antagonists and uses thereof

文档序号：1255863 发布日期：2020-08-21 浏览：25次中文

阅读说明：本技术 新的谷氨酰胺拮抗剂及其用途 (Novel glutamine antagonists and uses thereof ) 是由 B·思路十 R·赖斯 P·马也 L·特诺拉 K·诺夫那 J·阿尔特于 2018-10-05 设计创作，主要内容包括：本发明公开了谷氨酰胺拮抗剂及其在治疗肿瘤、免疫、和神经疾病中的用途。还公开了一种用于治疗肿瘤、免疫、感染或神经疾病或病症的方法,所述方法包含给予有此需要的对象治疗有效量的本公开的谷氨酰胺拮抗剂或其药物组合物。还公开了一种增强免疫检查点抑制剂的效果、使对象能够响应免疫检查点抑制剂、或使免疫检查点抑制剂的毒性或剂量或治疗的数量减少的方法,其包括给予有此需要的对象治疗有效量的本公开的谷氨酰胺拮抗剂或其药物组合物和免疫检查点抑制剂。还公开了治疗检查点抑制剂疗法难治的肿瘤、免疫、感染或神经疾病或病症的方法,所述方法包含给予有此需要和有难治性疾病或病症的对象治疗有效量的本公开的谷氨酰胺拮抗剂或其药物组合物。(The present invention discloses glutamine antagonists and their use in the treatment of neoplastic, immune, and neurological diseases. Also disclosed is a method for treating a tumor, immune, infection, or neurological disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a glutamine antagonist of the present disclosure or a pharmaceutical composition thereof. Also disclosed is a method of enhancing the effect of, enabling a subject to respond to, or reducing the toxicity or dose or number of treatments of an immune checkpoint inhibitor comprising administering to a subject in need thereof a therapeutically effective amount of a glutamine antagonist of the present disclosure or a pharmaceutical composition thereof and an immune checkpoint inhibitor. Also disclosed are methods of treating a tumor, immune, infection, or neurological disease or disorder that is refractory to checkpoint inhibitor therapy, comprising administering to a subject in need thereof and having a refractory disease or disorder a therapeutically effective amount of a glutamine antagonist of the present disclosure or a pharmaceutical composition thereof.)

1. A compound having the structure of formula (I):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁selected from the group consisting of-O-and- (CH)₂)_p-, wherein p is an integer selected from 0,1, 2,3,4,5,6, 7, and 8;

r is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, tri (alkyl) ammonium, and tetra (alkyl) ammonium;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R₆selected from H, - (CH)₂)_t–CH(NH–C(CH₃)(＝O))–(CH₂)_t–R₉、–C(＝O)–X₂–R₁₀And one or more substituted or unsubstituted amino acids, wherein the one or more substituted or unsubstituted amino acids are joined to R through the carboxy moiety of the one or more substituted or unsubstituted amino acids₆Adjacent nitrogen atoms bound, wherein X₂Is present or absent, and if present is selected from-O-, -O- (CH)₂)_q–、–(CH₂)_t-, and- (CH)₂)_v–CH＝CH–(CH₂)_v-, wherein q and t are each independently selected from 1,2,3,4, 5,6, 7, and 8, each v is independently selected from 0,1, 2,3,4,5,6, 7, and 8, and R is₉And R₁₀Each independently selected from the group consisting of linear or branched alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and is

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted alkyl;

or an ester or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the structure of formula (Ia):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁selected from the group consisting of-O-and- (CH)₂)_p-, wherein p is an integer selected from 1,2,3,4, 5,6, 7, and 8;

R₁and R₂Each independently is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, tri (alkyl) ammonium, and tetra (alkyl) ammonium, wherein R is₁And R₂May be the same or different, or R₁And R₂May together form C₃-C₆A cycloalkyl group;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted alkyl;

or an ester or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound has the structure of any one of formulas (Ib) - (Ie):

4. the compound of claim 2, wherein the compound has the structure of formula (If):

5. the compound of claim 2, wherein the compound has the structure of formula (Ig):

wherein R is₁、R₂And R₁₁Each independently is an alkyl group.

6. The compound of claim 5, wherein the compound has the structure of formula (Ih):

7. the compound of any one of claims 1 to 6, wherein R₆Is H.

8. The compound of claim 7, wherein the compound is:

9. the compound of any one of claims 1 to 6, wherein R₆Is- (CH)₂)_t–CH(NH–C(CH₃)(＝O))–(CH₂)_t–R₉。

10. The compound of claim 9, wherein each t is 1 and R₉Is an aryl group.

11. The compound of claim 10, wherein the compound is:

12. the compound of any one of claims 1 to 6, wherein R₆is-C (═ O) -X₂–R₁₀。

13. The compound of claim 12, wherein X₂Is present and is-O-.

14. The compound of claim 13, wherein R₁₀Selected from the group consisting of tert-butyl and adamantyl.

15. The compound of claim 14, wherein the compound is:

16. the compound of claim 12, wherein X₂Is present and is-O- (CH)₂)_q–。

17. The compound of claim 16, wherein q is 1 and R₁₀Selected from 9H-fluoren-9-yl and phenyl.

18. The compound of claim 17, wherein the compound is:

19. the compound of claim 12, wherein X₂Is absent and R₁₀Is selected from C₂-C₂₀Alkyl, adamantyl, 1,2,3, 4-tetrahydroisoquinolinyl, pyridyl, and substituted decahydrophenanthryl.

20. The compound of claim 19, wherein the compound is:

21. the compound of claim 12, wherein X₂Is- (CH)₂)_t-and R₁₀Is 1H-indol-3-yl.

22. The compound of claim 21, wherein the compound is:

23. the compound of claim 12, wherein X₂Is- (CH)₂)_v–CH＝CH–(CH₂)_v-and R₁₀Is an aryl group.

24. The compound of claim 23, wherein the compound is:

25. the compound of any one of claims 1 to 6, wherein R₆Is one or more substituted or unsubstituted amino acids.

26. The compound of claim 25, wherein the compound is:

27. the compound of claim 25, wherein one or more amino acids is valine-leucine.

28. A pharmaceutical composition comprising a compound of any one of claims 1-27 and a pharmaceutically acceptable carrier, diluent, or excipient.

29. The pharmaceutical composition of claim 28, further comprising at least one neoplastic, immunological, anti-infective, or neurological agent.

30. A method for treating a tumor, immune, infection, or neurological disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-27 or a pharmaceutical composition of claim 28.

31. The method of claim 30, wherein the tumor, immune, infection, or neurological disease or disorder is cancer.

32. The method of claim 30, wherein the tumor, immune, infection, or neurological disease or disorder is a bacterial or viral infection.

33. The method of claim 30, wherein the tumor, immune, infection, or neurological disease or disorder is an autoimmune disease, immune disorder, or inflammatory disease.

34. The method of claim 31, wherein the tumor, immune, infection, or neurological disease or disorder is a neurodegenerative disease.

35. The method of any one of claims 30-34, further comprising administering a therapeutically effective amount of at least one second agent useful for the treatment of a tumor, immune, infection, or neurological disease or disorder.

36. The method of claim 35, wherein the at least one second agent is an immunotherapeutic agent.

37. The method of claim 36, wherein the immunotherapeutic agent is an immune checkpoint inhibitor.

38. The method of claim 37, wherein the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

39. A method of enhancing the effect of, enabling a subject to respond to, or reducing the toxicity or dose or number of treatments of an immune checkpoint inhibitor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-27 or a pharmaceutical composition of claim 28 and an immune checkpoint inhibitor.

40. The method of claim 39, wherein administration of the compound or pharmaceutical composition thereof reverses resistance or refractory to an immune checkpoint inhibitor.

41. The method of claim 39 or 40, wherein the subject has cancer.

42. The method of claim 41, wherein the cancer is immune checkpoint resistant colon cancer, glioblastoma, or head and neck cancer.

43. The method of any one of claims 39-42, wherein the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

44. A method of treating a tumor, immune, infection, or neurological disease or disorder that is refractory to immune checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof and having a refractory disease or disorder a therapeutically effective amount of a compound of any one of claims 1-27 or a pharmaceutical composition of claim 28.

45. The method of claim 44, wherein the compound or pharmaceutical composition thereof is administered with an immune checkpoint inhibitor.

46. The method of any one of claims 43-45, wherein the compound or pharmaceutical composition is administered to the subject before, concurrently with, or after the immune checkpoint inhibitor.

47. The method of any one of claims 43-46, wherein the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

Background

Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON) and aza-serine, have been shown to be widely Antiviral in a number of published preclinical and several clinical studies (Antiviral Res.1997; 33(3): 165-75; Antiviral Res.1994; 25(3-4):269-79), anti-infectious (J.Bacteriol.1965; 89:1348-53), anticancer (see, e.g., Yoshioka et al, 1992; Tokushima J.exp.Med.39(1-2):69-76), anti-inflammatory, and immunosuppressive activities (Kulsar et al, Sci; 111: 10353-58; Maciolek et al, 2014; Curr Opinuol.27: Im60-74; Carr et al, 2010; J.185: 1044; Achill. 160; Coliolk et al, 19816068; Proomr # 2010; Nat. 19824: 18873; and Solmo et al, Bioecl. 18860-76; and Solmo et al, Bioecl.31: 18860: 26; Bioecl. J.31: 18860-76; Biopsr et al, USA; Bioecl. J.31; 19832; Bioecl. J.31; 19832; pp. J.15: 1888-76 Inhibit multiple sclerosis (Tohoku, J.Exp.Med.2009; 217(2):87-92), epilepsy and viral encephalitis (J.neurovir.2015Apr; 21(2): 159-73). However, the severe toxicity (e.g., dose-limiting GI toxicity, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain) that occurs when such glutamine antagonists are administered at therapeutic dose levels has hampered their clinical development.

Previous attempts to mitigate the severe toxicity associated with glutamine antagonists, such as DON, have not been successful. For example, dividing daily doses and administering DON every four to six hours clearly doubles the potential toxicity of DON (Magill et al, 1957). In another example, after a clinical trial is published, a therapeutic development involving administration of DON and PEGylated glutaminase together to lower plasma glutamine and thereby lower dose of DON is also discontinued.

Disclosure of Invention

The present invention provides glutamine antagonists and their use in treating neoplastic, immune, and neurological disorders.

In a particular aspect, the invention provides compounds having the structure of formula (I):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁selected from the group consisting of-O-and- (CH)₂)_p-, wherein p is an integer selected from 0,1, 2,3,4,5,6, 7, and 8;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted alkyl;

or an ester or a pharmaceutically acceptable salt thereof.

In a particular aspect, the present invention provides compounds having the structure of formula (Ia):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁is selected from-O-and- (CH)₂)_p-, wherein p is an integer selected from 1,2,3,4, 5,6, 7, and 8;

R₁and R₂Each independently is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, tri (alkyl) ammonium, or tetra (alkyl) ammonium, wherein R is₁And R₂May be the same or different, or R₁And R₂May together form C₃-C₆A cycloalkyl ring;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted alkyl;

or an ester or a pharmaceutically acceptable salt thereof.

In a particular aspect, the present invention provides compounds having the structure of formula (Ia):

wherein:

m is an integer selected from 2,3,4,5, and 6;

X₁selected from the group consisting of-O-and- (CH)₂)–；

R₁And R₂Each independently selected from H, C₁-C₆Alkyl, substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, substituted C₃-C₈Cycloalkyl radical, C₂-C₆Alkenyl, substituted C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, substituted C₂-C₆Alkynyl, C₄-C₈Cycloalkenyl, substituted C₄-C₈Cycloalkenyl, tri (C)₁-C₆Alkyl) ammonium, and tetra (C)₁-C₆Alkyl) ammonium, wherein R₁And R₂May be the same or different, or R₁And R₂May form C together with the carbon to which they are bonded₃-C₈A cycloalkyl group;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, C containing at least one heteroatom selected from O, S, N₃-C₆Heterocycloalkyl radical, C₆-C₁₀Aryl and C comprising at least one heteroatom selected from O, S, N₄-C₁₀A heteroaryl group;

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted C₁-C₆；

Or an ester or a pharmaceutically acceptable salt thereof.

In another aspect the invention provides a compound having any one of formulae (Ib) to (Ie):

wherein R is₁-R₃And R₅-R₈As defined in formula (Ia).

The present disclosure also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient thereof. In one embodiment, the pharmaceutical composition further comprises at least one neoplastic, immunological, anti-infective, or neurological agent.

The present invention also provides a method for treating a tumor, immune, infection, or neurological disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In one embodiment, the tumor, immune, infection, or neurological disease or disorder is cancer. In another embodiment, the tumor, immune, infection, or neurological disease or disorder is a bacterial or viral infection. In another embodiment, the tumor, immune, infection, or neurological disease or disorder is an autoimmune disease, immune disorder, or inflammatory disease. In another embodiment, the tumor, immune, infection, or neurological disease or disorder is a neurodegenerative disease. In another embodiment, the method further comprises administering a therapeutically effective amount of at least one second agent useful for the treatment of a tumor, immune, infection, or neurological disease or disorder.

In another embodiment, the present invention provides a method of enhancing the effect of an immune checkpoint inhibitor, enabling a subject to respond to an immune checkpoint inhibitor, or reducing the toxicity or dose or number of treatments of an immune checkpoint inhibitor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof and an immune checkpoint inhibitor.

In another embodiment, the present invention provides a method of treating a tumor, immune, infection, or neurological disease or disorder that is refractory to immune checkpoint inhibitor therapy, comprising administering to a subject in need thereof and having a refractory disease or disorder a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

While certain aspects of the presently disclosed subject matter have been set forth above, and are addressed in whole or in part by the presently disclosed subject matter, other aspects will become apparent when the description taken in conjunction with the best described embodiments and the accompanying drawings below.

Drawings

Having thus described the disclosure in general terms, the following description will be read in conjunction with the accompanying drawings, which are not necessarily drawn to scale, and wherein:

figure 1A is a bar graph showing the stability of intact compounds 1-21 after incubation for 60 minutes in the presence of porcine intestinal homogenate.

Figure 1B is a bar graph showing the extent of DON release when compounds 1-21 were incubated in the presence of porcine intestinal homogenate for 60 minutes.

Figure 2A is a bar graph showing the stability of intact compounds 1-21 after incubation for 60 minutes in the presence of porcine liver homogenate.

Figure 2B is a bar graph showing the extent of DON release when compounds 1-21 were incubated in the presence of porcine liver homogenate for 60 minutes.

Figure 3A is a bar graph showing the concentration of DON in P493 tumor cells after incubation of compounds 1-21 in human plasma containing P493 tumor cells.

Figure 3B is a bar graph showing the concentration of DON in plasma after incubation of compounds 1-21 in human plasma containing P493 tumor cells.

Fig. 4A is a graph showing the concentration of DON and compound 2 over time following Intravenous (IV) infusion.

Fig. 4B is a graph showing the concentrations of DON and compound 2 over time following Subcutaneous (SC) administration.

Figure 4C shows a line graph of compound 7 plasma pharmacokinetics following SC administration in beagle dogs.

Fig. 5A shows a histogram of tumor cell DON concentration after incubation of compound in human plasma mixed with 1 million lymphoma (P493B) cells. Compounds 1,7, and 12 show DON release in tumor cells similar to DON. Compound 16 showed minimal release.

Figure 5B is a bar graph showing that compounds 1,7, 12, and 16 released minimal DON in plasma after 1h incubation.

Figure 5C shows a histogram of compound 7 with 55-fold higher plasma partition of tumor cells compared to DON, suggesting uptake and selective transformation in tumor cells.

Figure 6A is a line graph showing that compound 7 showed stability in human plasma and was present predominantly as an intact prodrug with DON release < 5%, indicating minimal metabolism and conversion to DON in plasma.

Fig. 6B is a line graph showing an increase in DON release (> 40% of initial concentration) over time in P493B tumor cells. < 1% intact compound 7 was observed in tumor cells, indicating selective release of tumor cells relative to plasma.

Figure 7 is a line graph showing a cell proliferation assay of P493B lymphoma cells treated with compound 7 and DON.

Detailed Description

The subject matter disclosed herein may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the subject matter disclosed herein will come to mind to one skilled in the art to which the subject matter disclosed herein pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the subject matter disclosed herein is not to be limited to the specific embodiments disclosed herein and that modifications and other embodiments are intended to be included within the scope of the appended claims.

I. Tumor-targeting glutamine antagonists

The presently disclosed subject matter is directed, in part, to glutamine antagonists for neoplastic, immunological, and neurological uses. It was unexpectedly found that the compounds of the present disclosure preferentially deliver glutamine antagonists (e.g., DON) to human tumor cells rather than plasma, with significantly reduced glutamine antagonist exposure in the liver and gut (presumably toxic organs). Without wishing to be bound by any particular theory, it is believed that the observed preferential tumor delivery is based on enzymes enriched in the tumor, including plasmin, cathepsin and Histone Deacetylases (HDACs), which are responsible for cleaving the designed precursor molecules (promoeity). This feature would allow the compounds of the present disclosure to be administered to patients in a manner that preferentially delivers glutamine antagonists to tumors, with less systemic exposure, thereby greatly enhancing the therapeutic window.

Glutamine antagonists are prepared by altering the pharmacokinetics of DON by masking amine and/or carboxylic acid functional groups, thereby providing slower release kinetics and cellular targeting to enhance tolerance. Furthermore, in some embodiments, the compounds selectively target active glutamine antagonists to specific cells or provide slower DON release, thereby reducing the toxicity of the drug molecule.

It has been found that simultaneous masking of the alpha-amino and carboxyl functions enhances stability and oral bioavailability. The compounds of the present disclosure also show comparable stability to free DON.

Table 1 provides the structures of representative compounds of the present disclosure.

One skilled in the art will appreciate that the representative compounds shown in table 1, in combination with the teachings disclosed herein, will enable one skilled in the art to synthesize compounds including other glutamine analogs, as exemplified by the general structure of formula (I), such as L-DONV, azaserine. In other words, it is understood that other glutamine antagonists, such as L-DONV, aza-serine, can be derivatized with the same substituents as the compounds shown in table 1.

Accordingly, in some embodiments, the present invention provides compounds having the structure of formula (I):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁selected from the group consisting of-O-and- (CH)₂)_p-, wherein p is an integer selected from 0,1, 2,3,4,5,6, 7, and 8;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heteroCycloalkyl, aryl, and heteroaryl;

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted alkyl;

or an ester or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides compounds having the structure of formula (Ia):

wherein:

m is an integer selected from 1,2,3,4, 5,6, 7, and 8;

X₁selected from the group consisting of-O-and- (CH)₂)_p-, wherein p is an integer selected from 1,2,3,4, 5,6, 7, and 8;

R₁and R₂Each independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, tri (alkyl) ammonium, and tetra (alkyl) ammoniumWherein R is₁And R₂May be the same or different, or R₁And R₂May together form C₃-C₆A cycloalkyl group;

R₃、R₅and R₇Each independently selected from H, C₁-C₆Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R₆selected from H, - (CH)₂)_t–CH(NH–C(CH₃)(＝O))–(CH₂)_t–R₉、–C(＝O)–X₂–R₁₀And one or more substituted or unsubstituted amino acids, wherein the one or more substituted or unsubstituted amino acids are joined to R through the carboxy moiety of the one or more substituted or unsubstituted amino acids₆Adjacent nitrogen atoms bound, wherein X₂Is present or absent, and if present is selected from-O-, -O- (CH)₂)_q–、–(CH₂)_t-, and- (CH)₂)_v–CH＝CH–(CH₂)_v-, wherein q and t are each independently selected from 1,2,3,4, 5,6, 7, and 8, each v is independently selected from 0,1, 2,3,4,5,6, 7, and 8, and R is₉And R₁₀Each independently selected from linear or branched alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and is

R₈Selected from H and-C (═ O) -R₁₁Wherein R is₁₁Is substituted or unsubstituted;

or an ester or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one of formulas (Ib) - (Ie):

wherein R is₁-R₃And R₅-R₈As defined in formula (Ia).

In other embodiments, the compound has the structure of formula (If):

in a specific embodiment, the compound has the structure of formula (Ig):

wherein R is₁、R₂And R₁₁Each independently is an alkyl group.

In an even more particular embodiment, the compound has the structure of formula (Ih):

in some embodiments, R₆Is H and the compound is:

in some embodiments, R₆Is- (CH)₂)_t–CH(NH–C(CH₃)(＝O))–(CH₂)_t–R₉. In certain embodiments, each t is 1 and R₉Is an aryl group. In a specific embodiment, the compound is:

in other embodiments, R₆is-C (═ O) -X₂–R₁₀. In certain embodiments, X₂Is present and is-O-. In a particular embodiment, R₁₀Selected from the group consisting of tert-butyl and adamantyl. In a more specific embodiment, the compound is:

in other embodiments, X₂Is present and is-O- (CH)₂)_q-. In certain embodiments, q is 1 and R₁₀Selected from 1H-fluoren-9-yl and phenyl. In a specific embodiment, the compound is:

in other embodiments, X₂Is absent and R₁₀Is selected from C₂-C₂₀Alkyl and adamantyl, 1,2,3, 4-tetrahydroisoquinolinyl, pyridinyl, and substituted decahydrophenanthrene. In a specific embodiment, the compound is:

in some embodiments, X₂Is- (CH)₂)_t-and R₁₀Is 1H-indol-3-yl. In a specific embodiment, the compound is:

in some embodiments, X₂Is- (CH)₂)_v–CH＝CH–(CH₂)_v-and R₁₀Is an aryl group. In a specific embodiment, the compound is:

in some embodiments, R₆Is one or more substituted or unsubstituted amino acids. In a particular embodiment the compound is

As used herein, the term "amino acid" includes moieties having a carboxylic acid group and an amino group. Thus, the term amino acid includes both natural amino acids (including proteinogenic amino acids) and unnatural amino acids. The term "natural amino acid" also includes other amino acids (including pyrrolysine and selenocysteine) that may be incorporated into proteins during translation. In addition, the term "natural amino acid" also includes other amino acids formed during intermediary metabolism, such as ornithine produced from arginine in the urea cycle. The natural amino acids are summarized in table 2:

natural or unnatural amino acids can be optionally substituted. In one embodiment, the amino acid is selected from proteinogenic amino acids. Proteinogenic amino acids include glycine, alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid, serine, threonine, glutamine, asparagine, arginine, lysine, proline, phenylalanine, tyrosine, tryptophan, cysteine, methionine, and histidine. The term amino acid includes alpha amino acids and beta amino acids, such as but not limited to beta alanine and 2-methyl beta alanine. The term amino acid also includes lactam analogues of certain natural amino acids, such as, but not limited to, pyroglutamine. The term amino acid also includes amino acid homologs, including homocitrulline, homoarginine, homoserine, homotyrosine, homoproline, and homophenylalanine.

The terminal part of the amino acid residue or peptide may be in the form of the free acid, i.e. terminating in a-COOH group, or may be in a masked (protected) form, e.g. in the form of a carboxylic ester or carboxamide. In certain embodiments, the amino acid or peptide residue is terminated with an amino group. In one embodiment, the residue terminates with a carboxylic acid group-COOH or amino-NH₂. In another embodiment, the residue terminates with a carboxamide group. In another embodiment, the residue is terminated with a carboxylate.

As mentioned above, the term "amino acid" includes amino acids having a-COOH group and-NH₂A compound of the group. Substituted ammoniaAmino acids include amino acids having a mono-or di-substituted amino group. In particular embodiments, the amino group may be monosubstituted. (A proteinogenic amino acid may be substituted at another position on its amino group to form an amino acid, which acts as a substituted proteinogenic amino acid). The term "substituted amino acid" includes N-substituted metabolites of natural amino acids, including but not limited to N-acetyl amino acids, such as N-acetyl cysteine, N-acetyl serine, and N-acetyl threonine.

For example, the term "N-substituted amino acid" includes N-alkyl amino acids (e.g., C)_1-6N-alkyl amino acids, such as sarcosine, N-methyl-alanine, N-methyl-glutamic acid and N-tert-butylglycine), which may include C_1-6N-substituted alkyl amino acids (e.g., N- (carboxyalkyl) amino acids (e.g., N- (carboxymethyl) amino acids) and N-methylcycloalkyl amino acids (e.g., N-methylcyclopropyl amino acids)); n, N-di-alkyl amino acids (e.g. N, N-di-C)_1-6Alkyl amino acids (e.g., N-dimethyl amino acids)); n, N, N-trialkyl amino acids (e.g., N, N, N-tri-C)_1-6Alkyl amino acids (e.g., N-trimethyl amino acids)); n-acyl amino acids (e.g. C)_1-6N-acyl amino acids); n-aryl amino acids (e.g., N-phenyl amino acids, such as N-phenylglycine); n-amidino amino acids (e.g., N-amidino amino acids, i.e., amino acids in which the amine group is substituted with a guanidino group).

The term "amino acid" also includes amino acid alkyl esters (e.g., amino acid C)_1-6Alkyl esters); and amino acid aryl esters (e.g., amino acid phenyl esters).

For amino acids having a hydroxyl group on the side chain, the term "amino acid" also includes O-alkyl amino acids (e.g., C)_1-6O-alkyl amino acid ethers); o-aryl amino acids (e.g., O-phenyl amino acid ethers); an O-acyl amino acid ester; and O-carbamoyl amino acids.

For amino acids having a sulfhydryl group present in a side chain, the term "amino acid" also includes S-alkyl amino acids (e.g., C)_1-6S-alkyl amino acids, e.g. S-methyl methionine, which may include C_1-6S-substituted alkyl amino acids and S-methyl cycloalkyl amino acids (examples)E.g., S-methylcyclopropyl amino acid)); s-acyl amino acids (e.g., C)_1-6S-acyl amino acids); s-aryl amino acids (e.g., S-phenyl amino acids); sulfoxide analogs of sulfur-containing amino acids (e.g., methionine sulfoxide) or sulfoxide analogs of S-alkyl amino acids (e.g., S-methyl cysteine sulfoxide) or sulfoxide analogs of S-aryl amino acids.

Examples of non-proteinogenic amino acids include, but are not limited to: citrulline, hydroxyproline, 4-hydroxyproline, beta-hydroxyvaline, ornithine, beta-alanine, leucine (albicizzin), 4-aminophenylalanine, biphenylalanine, 4-nitrophenylalanine, 4-fluorophenylalanine, 2,3,4,5, 6-pentafluorophenylalanine, norleucine, cyclohexylalanine, alpha-aminoisobutyric acid, alpha-aminobutyric acid, alpha-aminoisobutyric acid, 2-aminoindane-2-carboxylic acid, selenomethionine, lanthionine (lanthionine), dehydroalanine, gamma-aminobutyric acid, naphthylalanine, aminocaproic acid, pipecolic acid, 2, 3-diaminopropionic acid, tetrahydroisoquinoline-3-carboxylic acid, tert-leucine, tert-butylalanine, Cyclopropylglycine, cyclohexylglycine, 4-aminopiperidine-4-carboxylic acid, diethylglycine, dipropylglycine and derivatives thereof, in which the nitrogen of the amine group has been monoalkylated or dialkylated.

Synthesis Process

The compounds described herein can be synthesized according to the methods described in the examples as well as scheme I.

Scheme 1:

the moieties of compounds 11-21 shown in the above schemes may have either the R-configuration or the S-configuration.

Pharmaceutical compositions and administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) alone or in admixture with one or more other therapeutic agents and pharmaceutically acceptable excipients. Thus, in some embodiments, the presently disclosed subject matter provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. One skilled in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the above compounds.

Pharmaceutically acceptable salts are generally known to those of ordinary skill in the art and include salts of the active compounds prepared with relatively nontoxic acids or bases based on the particular substituent moieties found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts.

When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include: salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonate, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydrogensulfate, hydroiodic, or phosphorous acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

Thus, by way of example and not limitation, pharmaceutically acceptable salts suitable for use in the presently disclosed subject matter include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium ethylenediaminetetraacetate, oxalate, carbonate, citrate, oxalate, edisylate, ethanesulfonate, fumarate, gluconate, glutamate, glycylsalicylate, hexylisophthalate, hydrazinophenylenediamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, naphthalenesulfonate, nitrate, pamoate (pamoate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, a salt of subacetate, succinate, sulfate, tannate, tartrate, or a salt of theachlorate. Other pharmaceutically acceptable salts can be found, for example, in remington: pharmaceutical Science and practice (Remington: The Science and practice of Pharmacy (20 th edition) Lippincott, Williams & Wilkins (2000).

In particular embodiments, the salt is a tri (alkyl) ammonium or tetra (alkyl) ammonium salt. In a more specific embodiment, the salt is selected from tris (C)₁-C₈Alkyl) ammonium, tetra (C)₁-C₈Alkyl) ammonium, triphenylammonium, tris (hydroxy-C)₁-C₈-alkyl) ammonium, and tetrakis (hydroxy-C)₁-C₈-alkyl) ammonium salts. In an even more particular embodiment, the salt is selected from the group consisting of trimethylammonium, triethylammonium, tris (hydroxyethyl) ammonium, tripropylammonium, and tris (hydroxypropyl) ammonium salts.

In therapeutic and/or diagnostic applications, the compounds of the present disclosure may be formulated for a variety of modes of administration, including oral (sublingual, buccal), oral, sublingual, systemic, topical or regional administration. Techniques and formulations are generally described, for example, in remington: pharmaceutical Science and Practice (Remington: The Science and Practice of Pharmacy) (20 th edition) Lippincott, Williams & Wilkins (2000).

Depending on the particular condition being treated, the compounds may be formulated in liquid dosage forms (e.g., solutions, suspensions or emulsions) or solid dosage forms (capsules or tablets) and administered systemically or topically. As known to those skilled in the art, the compounds may be delivered in a timed, controlled or sustained slow release form, for example. Techniques for formulation and administration can be found in remington: pharmaceutical science and Practice (Remington: the science and Practice of Pharmacy) (20 th edition) Lippincott, Williams & Wilkins (2000). Suitable routes may include: oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery. In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered intramuscularly. In some embodiments, the pharmaceutical composition is administered intrathecally. In some embodiments, the pharmaceutical composition is administered subcutaneously.

For injections, the compounds of the present disclosure may be formulated and diluted in aqueous solution, for example, in a physiologically compatible buffer, such as hank's solution, ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the art.

It is within the scope of the present disclosure to formulate the compounds disclosed herein for use in the practice of the present disclosure into dosages suitable for systemic administration using chemically acceptable inert carriers. With the proper choice of carrier and the proper manufacturing practice, the compositions of the present invention, particularly those formulated as solutions, can be administered parenterally, for example by intravenous injection. The compounds can be readily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient to be treated (e.g., a patient).

For nasal or inhalation delivery, the compounds of the present disclosure may also be formulated by methods known to those skilled in the art, and may include, for example and without limitation, examples of solubilizing, diluting, or dispersing materials, such as saline; preservatives, such as benzyl alcohol; an absorption enhancer; and fluorocarbons.

Pharmaceutical compositions suitable for use in the present disclosure include compositions comprising an effective amount of the active ingredient to achieve its intended purpose. Determination of an effective amount is within the skill of the art, as it is under the teachings of the detailed disclosure of the present invention. In general, the compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000mg, 0.5 to 100mg, 1 to 50mg per day and 5 to 40mg per day are examples of dosages. One non-limiting dose is 10 to 30mg per day. The exact dosage will depend upon the route of administration, the form of administration of the compound, the subject to be treated, the body weight of the subject to be treated, the bioavailability, adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound, and the preferences and experience of the attending physician. Examples of dosages include about 0.01 to about 100mg per kg body weight of the patient per day (mg/kg/day), about 0.01 to about 50mg/kg per day, about 0.01 to about 25mg/kg per day, or about 0.05 to about 10mg/kg per day, and may be administered in single or multiple doses, particularly about 0.1, about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, and about 100mg/kg per day.

In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Formulations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions.

Pharmaceutical preparations for oral use can be obtained by the following method: the compound is mixed with a solid excipient, the resulting mixture is optionally ground after adding suitable auxiliaries (if desired) and the mixture of granules is processed to obtain tablets or dragee cores. Suitable excipients are especially fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC) and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain acacia, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide (PEG), lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses.

Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

Methods of treating diseases or disorders

The compounds are orally bioavailable, are less toxic, and provide a clinically acceptable dosage paradigm for diseases or conditions of excess and/or aberrant glutamine activity. As used herein, the term "glutamine antagonist" refers to a glutamine analog that interferes with a glutamine metabolic pathway, e.g., inhibits or blocks a metabolic pathway downstream of glutamine, where glutamine serves as a precursor to one or more non-glutamine compounds. Examples of such metabolic pathways are well known (see, e.g., Hensley et al, 2013; DeBerardinis et al, 2009; and Medina et al, 1992). In certain instances, the term glutamine antagonist also includes glutamine analogs that inhibit the uptake of glutamine by cells, thereby reducing their biological activity. Diseases or conditions involving excessive and/or aberrant glutamine activity include, but are not limited to, infections, cancer, autoimmune diseases, neurodegenerative or nervous system diseases, and other central nervous system diseases.

Typically, these methods result in a subject having a disease or condition that is reduced in severity. The term "reduce" means to inhibit, impair, alleviate, attenuate, prevent or stabilize the symptoms of a disease or condition.

As used herein, the terms "treat," "treating," and the like refer to reducing or alleviating a disease or condition and/or symptoms associated therewith. It is understood that treatment and disease or disorder need not completely eliminate the disorder, condition, or symptoms associated therewith, although not exclusively.

Thus, in some embodiments, the present invention provides methods of treating a disease or condition comprising administering to a subject in need of treatment an amount of a compound of formula (I) or a pharmaceutical composition thereof effective to treat the disease or disorder.

The invention also provides methods of treating diseases or conditions with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), optionally together with at least one antimicrobial (e.g., antibiotic/antiviral, etc.) agent, to treat infection.

As used herein, "infection" refers to the invasion of the body tissues of the host organism by pathogenic organisms, their reproduction, and the response of the host tissues to these organisms and the toxins they produce. It is contemplated to use the compounds of formula (I) or any pharmaceutical composition thereof for the treatment of infectious diseases, e.g. infections by any bacteria or virus.

In some embodiments, the infection comprises a bacterial infection. The antibacterial effect of DON has been demonstrated in E.coli (see Coggin et al, 1965). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits bacterial growth and/or survival.

In some embodiments, the infection comprises a viral infection. The antiviral effects of glutamine analogs such as DON have been demonstrated (see, e.g., Cinatl et al, 1997; Nishio et al, 1990). Examples of viral infections contemplated to be treated with a compound of formula (I) or any pharmaceutical composition thereof include, but are not limited to: herpes simplex virus type 1 (HSV-1), herpes simplex virus type2 (HSV-2), Human Cytomegalovirus (HCMV), human parainfluenza virus type2 (HPIV-2), Maloney Leukemia Virus (MLV), mumps, paramyxoviruses, poliovirus, reovirus type 3, Respiratory Syncytial Virus (RSV), Sendai virus and Vesicular Stomatitis Virus (VSV).

In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof may inhibit viral replication. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof may inhibit replication of herpes simplex virus type 1 (HSV-1). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof may inhibit replication of herpes simplex virus type2 (HSV-2). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof can inhibit the replication of Human Cytomegalovirus (HCMV). In some embodiments, the compound of formula (I) or any pharmaceutical composition thereof inhibits the replication of human parainfluenza virus type2 (HPIV-2). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits replication of Maloney Leukemia Virus (MLV). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits the replication of human mumps virus (Rubulavirus). In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits replication of paramyxoviruses. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits replication of poliovirus. In some embodiments, the compound of formula (I) or any pharmaceutical composition thereof inhibits replication of reovirus type 3. In some embodiments, the compound of formula (I) or any pharmaceutical composition thereof inhibits the replication of Respiratory Syncytial Virus (RSV). A virus. In some embodiments, the compound of formula (I) or any pharmaceutical composition thereof inhibits the replication of sendai virus. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof inhibits replication of Vesicular Stomatitis Virus (VSV).

In some embodiments, the viral infection is influenza. As used herein, "influenza" is nail, b or c influenza, parainfluenza virus and any other influenza-like virus (see, e.g., U.S. patent publication No. 2006/0276438, which discloses the use of DON and azaserine to treat influenza).

In one aspect, the presently disclosed subject matter provides the use of a compound of formula (I) or a pharmaceutical composition thereof, optionally together with an antiviral agent, for the manufacture of a medicament for treating a viral infection and/or inhibiting replication.

As used herein, "antiviral agent" includes compounds that inhibit replication of a virus in a cell, tissue, or organism. Examples of antiviral agents contemplated for use in combination with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) include, but are not limited to: acyclovir (2-amino-1, 9-dihydro-9- [ (2-hydroxyethoxy) methyl ] -6H-purin-6-one), valacyclovir (L-valine, 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] ethyl ester), penciclovir (Penciclovir) (9- [ 4-hydroxy-3- (hydroxymethylbutyl) ] guanine), famciclovir (2- [2- (amino-9H-purin-9-yl) ] ethyl-1, 3-propanediol diacetate), ribavirin (1-beta-D-ribofuranosyl-1-H-1, 2, 4-triazole-3-carboxamide), lamivudine ((2R, cis) -4-amino-1- (2-hydroxy-1, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one), amantadine (1-amantadine hydrochloride) and rimantadine (α -methyltricyclo (3.3.1.1/3.7 decane-1-methanamine acetate).

The invention also provides a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), optionally together with at least one chemotherapeutic agent, at least one radiotherapeutic agent and/or at least one immunotherapeutic agent, for the treatment of cancer. In some embodiments, such treatment comprises treatment with any combination of radiation therapy, immunotherapy, photodynamic therapy, proton therapy, and/or surgery.

"chemotherapeutic agent" refers to a compound or composition administered in the treatment of cancer. Chemotherapeutic agents contemplated for use in combination with a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), include, but are not limited to: alkylating agents, such as thimerosal and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as bentepa (benzodopa), carboquone (carboquone), metotepipa (meturedpa) and uredepa (uredpa); ethyleneimine and methylmelamine including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chloramine (chlorambucil), chlorambucil (chlorenaphazine), chlorophosphamide (chlorophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxydichloride), melphalan (melphalan), neomustard (novembichin), cholesterol chloracetic acid (phereneterestine), prednimustine (trofosfamide), uracil mustard; nitrosoureas (nitrosureas), such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine), ramustine (ranimustine); antibiotics, such as aclacinomycin (aclacinomysins), chrysomycins (actinomycin), anthranomycin (aurramycin), azaserine (azaserine), bleomycin (bleomycin), actinomycin C (cactinomycin), calicheamicin (calicheamicin), carubicin (carminomycin), carcinomycin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), daunorubicin (daunorubicin), ditorexin (detorubicin), ditorelbirubicin (desorubicin), 6-diazo-5-oxo-L-norleucine, doxorubicin (dorubicin), epirubicin (epirubicin), bestatin (esorubicin), idarubicin (idarubicin), ceromycin (mycins), doxorubicin (puromycin), doxorubicin (diphenomycin), diphenomycin (diphenomycin), diphenomycin (diphenomycin, Streptonigrin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubicidin), ubenimex (ubenimex), restatin (zinostatin), zorubicin (zorubicin); antimetabolites such as methotrexate (methotrexate) and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine (fludarabine), 6-mercaptopurine (6-mercaptopurine), thiamiprine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs, such as, for example, ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine (6-azauridine), carmofur (carmofur), cytarabine, dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine), 5-FU; androgens such as carposterone (calusterone), methamphetamine propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), and testolactone (testolactone); anti-adrenal agents, such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), trilostane (trilostane); folic acid supplements, such as folinic acid (frilic acid); acegulonone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); amsacrine (amsacrine); betabucil (bestrabucil); bisantrene; edatrexate (edatraxate); deflazamine (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); isoflurine (elfornithine); ammonium etitanium acetate; etoglut (etoglucid); gallium nitrate; a hydroxyurea; lentinan (lentinan); lonidamine (lonidamine); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidamol (mopidamol); nitraminoacrridine (nitracrine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); podophyllinic acid (podophyllic acid); 2-ethyl hydrazide (2-ethyl hydrazide); procarbazine (procarbazine); PSK; razoxane (rizoxane); sizofuran (sizofiran); germanium spiroamines (spirogyranium); pakchoi acid (tenuazonic acid); triimine quinone (triaziquone); 2, 2', 2 "-trichlorotriethylamine; urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); gantuxin (glycocystine); cytarabine (Ara-C); paclitaxel, such as paclitaxel and docetaxel; chloramine butyl; gemcitabine; 6-thioguanine; mercaptopurine; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine (navelbine); noxiatrone (novantrone); (ii) teniposide; daunomycin (daunomycin); aminopterin (aminopterin); (xiloda); ibandronate sodium (ibandronate); CPT 11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (difluoromethylornithine); tretinoin; esperamicins (esperamicins); capecitabine (capecitabine); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing. Chemotherapeutic agents also include anti-hormonal agents used to modulate or inhibit the action of hormones on tumors, such as anti-estrogenic agents, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5) -imidazole, 4-hydroxyttamoxifen, trovaxifen, keoxifene (keoxifene), LY117018, onapristone, and Fareston (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of the above drugs.

In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Topoisomerase inhibitors are chemotherapeutic agents that interfere with the action of a topoisomerase (e.g., topoisomerase I or II). Topoisomerase inhibitors include, but are not limited to, doxorubicin hydrochloride, limonorubicin, mitoxantrone hydrochloride, actinomycin D, etoposide, topotecan HCl, teniposide, and irinotecan, and pharmaceutically acceptable salts, acids, or derivatives of any of these.

In some embodiments, the chemotherapeutic agent is an antimetabolite. An antimetabolite is a chemical substance that is structurally similar to a metabolite required for normal biochemical reactions, but differs sufficiently to interfere with one or more normal functions of a cell, such as cell division. Antimetabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, raltitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine, 5-azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, and cladribine, as well as pharmaceutically acceptable salts, acids, or derivatives of any of them.

In certain embodiments, the chemotherapeutic agent is an antimitotic agent, including but not limited to agents that bind tubulin. In some embodiments, the agent is a taxane. In certain embodiments, the agent is paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative thereof. In certain alternative embodiments, the antimitotic agent comprises a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or a pharmaceutically acceptable salt, acid, or derivative thereof.

As used herein, the term "immunotherapeutic agent" refers to a molecule that can help treat a disease by inducing, enhancing, or suppressing an immune response in a cell, tissue, organ, or subject. Examples of immunotherapeutic agents contemplated for use in combination with a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), include, but are not limited to: immune checkpoint molecules (e.g., antibodies against immune checkpoint proteins), interleukins (e.g., IL-2, IL-7, IL-12, IL-15), cytokines (e.g., interferon, G-CSF, imiquimod), chemokines (e.g., CCL3, CCL26, CXCL7), vaccines (e.g., peptide vaccines, Dendritic Cell (DC) vaccines, EGFRvIII vaccines, mesocotyl vaccines, G-VAX, listeria vaccines), and acquired T cell therapies, including chimeric antigen receptor T cells (CAR T cells).

Examples of immune checkpoint modulators for use herein include, but are not limited to, small organic molecules (e.g., haptens) or small inorganic molecules; a sugar; an oligosaccharide; a polysaccharide; a biological macromolecule selected from peptides (e.g., aptamers), proteins, peptide analogs, and derivatives; a peptidomimetic; a nucleic acid selected from the group consisting of miRNA, siRNA, shRNA, antisense nucleic acids (e.g., antisense RNA, ribozymes, and aptamers); an extract made from a biological material selected from the group consisting of bacteria, plants, fungi, animal cells and animal tissues; natural or synthetic ingredients; and any combination thereof. Other examples of immune checkpoint modulators include orthosteric inhibitors, allosteric modulators, interfacial binding agents, and molecular analogs that act as substrates for competitive inhibitors.

Examples of immune checkpoint modulators include, but are not limited to, PD-1 antagonists, PD-L1 antagonists, CTLA-4 antagonists, lang-3 antagonists, CD137 antagonists, KIR antagonists, Tim3 antagonists, Ox40 agonists, B7-H3 antagonists, and combinations thereof.

Exemplary CTLA-4 antagonists include, but are not limited to, ipilimumab, tremelimumab, and combinations thereof.

Exemplary Lag-3 antagonists include, but are not limited to BMS-986016 and IMP 321.

Exemplary CD137 antagonists include, but are not limited to, CD 137-specific antibodies, peptides, small organic molecules, antisense oligonucleotides, sirnas, antisense expression vectors, or recombinant viruses. In some embodiments, the CD 137-specific antibody is clone BBK-2 or clone 4B4-1, as described in WIPO International application publication No. WO200405513A 2.

T cell immunoglobulin and mucin domain 3(TIM3) antagonists include, but are not limited to, anti-TIM 3 monoclonal antibodies.

Linch et al in "OX 40 agonists and combination immunotherapy: placing pelal on metal "describes an Ox40 agonist, Front Oncol 5: 34; 2015. exemplary Ox40 agonists include, but are not limited to, anti-Ox 40 agonist antibodies. Other exemplary Ox40 agonists include, but are not limited to, 0X86 and Fc-Ox 40L.

Exemplary B7-H3 antagonists include, but are not limited to, MGA 271.

Exemplary PD-L1 antagonists include, but are not limited to, BMS-936559/MDX-1105, MEDI4736, MPDL3280A, MPDL3280A, MSB0010718C, and combinations thereof.

PD-1 antagonists as used herein include, but are not limited to, AMP-224, AMP-554, nivolumab (nivolumab), pembrolizumab (pembrolizumab), pembrolizumab (pidilizumab), and combinations thereof.

Specific examples of immune checkpoint inhibitors include ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodySunnovalumab

The immune checkpoint inhibitor and the compound of the present disclosure are administered simultaneously or sequentially in either order. In another aspect, the therapeutic agent is administered prior to the immune checkpoint inhibitor.

As used herein, "radiotherapeutic agent" refers to an agent useful in radiotherapy, which acts by irradiating radiation through damaged cells (e.g., malignant cells) as a target. Exemplary radiotherapeutic agents contemplated for use in combination with the compound of formula (I), or pharmaceutical compositions comprising the compound of formula (I), are titanium peroxide contained in substrate particles, which produce hydroxyl radicals upon irradiation with radiation, and hydroxyl radicals having an effect of attacking a target, as described in U.S. patent No. 8,580,312.

As used herein, "cancer" in a patient refers to the presence of cells that are characteristic of oncogenic cells, e.g., uncontrolled proliferation, loss of specialized function, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rates, as well as certain characteristic morphologies and cellular markers. In some cases, the cancer cell is in the form of a tumor; such cells may be present locally in the animal, or circulate in the blood as independent cells, such as leukemia cells. As used herein, "tumor" refers to all tumor cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. As used herein, a "solid tumor" is an abnormal tissue mass that generally does not contain cysts or fluid areas. Solid tumors may be located in the brain, colon, breast, prostate, liver, kidney, lung, esophagus, head, neck, ovary, cervix, stomach, colon, rectum, bladder, uterus, testis, and pancreas, as non-limiting examples. In some embodiments, regression or slowing or stopping of growth of a solid tumor occurs after treatment of the solid tumor with the methods described herein. In other embodiments, the solid tumor is malignant. In some embodiments, the cancer comprises stage 0 cancer. In some embodiments, the cancer comprises a stage I cancer. In some embodiments, the cancer comprises stage II cancer. In some embodiments, the cancer comprises stage III cancer. In some embodiments, the cancer comprises stage IV cancer. In some embodiments, the cancer is refractory and/or metastatic. For example, the cancer may be refractory to radiation therapy, chemotherapy, or monotherapy with immunotherapy. Cancer as used herein includes newly diagnosed or recurrent cancer, including but not limited to: acute lymphocytic leukemia, acute myeloid leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or invasive breast cancer, bronchial cancer, choriocarcinoma, chronic myeloid leukemia, colon cancer, colorectal cancer, ewing's sarcoma, gastrointestinal cancer, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, hodgkin's disease, intracranial ependymoma, large intestine cancer, leukemia, liver cancer, lung cancer, Lewis lung cancer, lymphoma, malignant fibrous histiocytoma, breast tumor, melanoma, mesothelioma, neuroblastoma, osteogenic sarcoma, ovarian cancer, pancreatic cancer, pons tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulosarcoma, sarcoma, small cell lung cancer, solid tumor, gastric cancer, testicular cancer, and uterine cancer.

In one embodiment, the cancer is acute leukemia. In one embodiment, the cancer is acute lymphocytic leukemia. In one embodiment, the cancer is acute myeloid leukemia. In some embodiments, the cancer is advanced soft tissue sarcoma. In some embodiments, the cancer is a brain cancer. In some embodiments, the cancer is breast cancer (e.g., metastatic or invasive breast cancer). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is bronchial cancer. In some embodiments, the cancer is choriocarcinoma. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is colon cancer (e.g., adenocarcinoma). In some embodiments, the cancer is colorectal cancer (e.g., malignant colorectal cancer). In some embodiments, the cancer is ewing's sarcoma. In some embodiments, the cancer is a gastrointestinal cancer. In some embodiments, the cancer is a glioma. In some embodiments, the cancer is glioblastoma multiforme. In some embodiments, the cancer is a squamous cell carcinoma of the head and neck. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is hodgkin's disease. In some embodiments, the cancer is an intracranial ependymal tumor. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer (e.g., malignant lung cancer). In some embodiments, the cancer is Lewis lung cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is malignant fibrous histiocytoma. In some embodiments, the cancer is a breast tumor. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is neuroblastoma. In some embodiments, the cancer is an osteogenic sarcoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a pons tumor. In some embodiments, the cancer is pre-menopausal breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is reticulosarcoma. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is uterine cancer.

In some embodiments, the cancer comprises a glutamine-dependent cancer in which glutamine is a significant fuel source for cellular energy in the cancer (e.g., hematopoietic tumors, hepatoma, ehrlichia carcinosa) (see Huber et al, Uptake of the glutamine antimetabolite 6-diazo-5-oxo-L-norleucine (DON) in sensitive and resistant tumor cell lines ("upper of glutamine antimetabolites 6-diazo-5-oxo-L-norleucine (DON) inductive and reactive tumor cell lines"), int.J.cancer.1988; 41: 752-.

In some embodiments, the cancer is a Myc-dependent cancer. As used herein, "Myc-dependent cancer" refers to a cancer that exhibits activation, overexpression and/or amplification of c-Myc. In some cases, a "Myc-dependent cancer" is one in which c-Myc functions to increase glutamine metabolism in cancer cells. Examples of Myc-dependent cancers include, but are not limited to, lymphoma, neuroblastoma, and small cell lung cancer.

In some embodiments, the cancer is a mTORC 1-dependent cancer. As used herein, "mTORC 1-dependent cancer" refers to a cancer in which mTORC1 is activated in a glutamine-dependent manner, i.e., mTORC1 functions to increase glutamine metabolism in cancer cells.

Methods of using compounds of formula (I), or pharmaceutical compositions comprising compounds of formula (I), optionally together with at least one immunosuppressive and/or anti-inflammatory agent, to treat autoimmune, immune disorders, or inflammatory diseases are disclosed.

As used herein, "immunosuppressive agent" refers to an agent that can be used in immunotherapy to reduce or prevent an immune response in a cell, organ, tissue, or subject. Examples of immunosuppressive agents contemplated for use in combination with a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), include corticosteroids, calcineurin inhibitors, antiproliferatives, SIP receptor agonists, kinase inhibitors, monoclonal anti-lymphocyte antibodies, and polyclonal anti-lymphocyte antibodies. Non-limiting examples of corticosteroids include prednisone (prednisone: (prednisone)) (prednisone, and combinations thereofAnd) And methylprednisoloneNon-limiting examples of calcineurin inhibitors include cyclosporine (cyclosporine a, SangCya, ) ISA, Tx247, ABT-281, ASM 981 and tacrolimus: (A)FK 506). Non-limiting examples of antiproliferative agents include Mycophenolate Mofetil (Mycophenolate Mofetil)Azathioprine (Azathioprene)And Sirolimus (Sirolimus)Non-limiting examples of SIP receptor agonists include FTY720 or analogs thereof. Non-limiting examples of kinase inhibitors include mTOR kinase inhibitors, which are compounds, proteins or antibodies that target, decrease or inhibit the activity and/or function of serine/threonine mTOR family members. These include, but are not limited to: CCI-779, ABT578, SAR543, rapamycin and derivatives or analogs thereof, including 40-O- (2-hydroxyethyl) -rapamycin, rapalogs including AP23573, AP23464, AP23675 and AP23841 (available from Ariad), Everolimus (CERTICAN, RAD001), Biolimus 7, Biolimus 9 and sirolimus (RAPAMUNE). Kinase inhibitors also include protein kinase C inhibitors, including compounds described in PCT publications WO 2005/097108 and WO 2005/068455. Non-limiting examples of monoclonal anti-lymphocyte antibodies include: Moluomamab-CD 3 (Orthoclone)) Interleukin-2 receptor antagonist (Basiliximab,) And darlizumabNon-limiting examples of polyclonal anti-lymphocyte antibodies include: anti-thymocyte globulin-horseAnd anti-thymocyte globulin-rabbit (RATG,). Other immunosuppressive agents include, but are not limited to, SERP-1, serine protease inhibitors produced by malignant rabbit fibroma virus (MRV) and myxoma virus (MYX), described in U.S. patent publication No. 2004/0029801.

As used herein, "anti-inflammatory agent" refers to an agent that can be used to prevent or reduce an inflammatory response or inflammation in a cell, tissue, organ, or subject. Exemplary anti-inflammatory agents contemplated for use in combination with a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), include, but are not limited to, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, or a combination thereof. In some embodiments, the anti-inflammatory agent comprises: clobetasol (clobetasol), alclofenac (alclofenac), alclofenac dipropionate (alclometasone diproprionate), alleloprogesterone (alcestone acetanide), alpha amylase (alpha amylase), amcinol (amcinafal), amcinonide (amcinamide), amfenac sodium (amfenamod), aminoprolite hydrochloride (amidochlordrochloride), anakinra (anakinra), anisic acid (anirolac), azafen (anitrazafen), azapropazone (apazone), disodium baralazide (baalazide), bendazole (bendazate), benoxaprofen (benoxaprofen), benoxanide hydrochloride (benoxazamide), bromaciclobetasone propionate (bromelactone), bromelactone hydrochloride (bromelactone), ibuprofen (bromelactone), benoxaprofen (bromelactone), benoxaprofen (benoxaprofen), benoxaprofen (benoxaclopramide (benoxacor), cotadoxolone (cortidoxone), deflazacort (deflazacort), octopamine (desonide), desoximetasone (desoximetasone), dexamethasone (dexamethasone), dexamethasone acetate, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate (diflorasone diacetate), diflorasone sodium (difluoridone sodium), difluronide (difluorinic acid), diflunisal acid (difuninal), difluprednate (diflrendanate), diflorasone (diftalone), diferutone (difuritanate), diferuptone (diferuptone), drocinonide (drocinonide), medrysone (endomycin), enmomab (enlimomab), enoconazole sodium enoconazole (enliformone), epirizole (epirizole), etodolac (etodolac), etofenfenamate (efefefenamate), biphenyl acetate (npyrac), fenflurazone (fenthifenc), fenflurazone (fenthifenzac), fenthifenzamide (fenflurazone), fenthifenthifenuron (fenuron (fenflurazone), fenflurazone (fenflurazone), fenfluridone (fenfluridone), fenpropiconazole), tebufenoxim (fenpropine), tebuconazole), tebucfenac), flufenac (fenthifenthifenthifenthifenthifenthifenthifenthifenthifenthifenthifenthifenthifenuron (fenuron (fenpropiconazole), flufen), thifenthifenthifenthifenthifenuron (fenuron (fen, Fluimidazole (flumizole), flunisolide acetate (flunisolide acetate), flunixin (fluxin), flunixin meglumine (fluxin), flurbiprofen (fluxin megluminine), fluocortole (fluocidin butyl), flunomide acetate (fluoromethasone acetate), fluvone (fluquazone), flurbiprofen (flubiprofen), flutolifen (fluetofen), fluticasone propionate (flutiosone propionate), furoprofen (furaprofen), furobufen (furobufen), halcinonide (halcinonide), halobetasol propionate (haloproprione), haloprednisone acetate (halopreduonate), ibufenac (ibufenac), ibuprofen, aluminum ibuprofen, pyridinol (ifluoride), idacloprofen (idaxolone (indomethacin), indomethacin (indomethacin), ibuprofen, indomethacin (indomethacin), indomethacin hydrochloride (indomethacin), indomethacin hydrochloride, indomethacin (indomethacin), indomethacin hydrochloride, indomethacin, lornoxicam (lomoxicam), loteprednol carbonate (loteprednol etabonate), meclofenamate sodium (meclofenamate sodium), meclofenamate acid (meclofenamic acid), meclofenamic acid (meclofenamic acid), meclofenamate dibutyrate (meclofenamate dibutyrate), mefenamic acid (mefenamic acid), mesalazine (mesalamine), meclizine (mesclazone), methylprednisolone suleptate (methylprednisone sultanate), molifluorate (momifluorate), nabumetone (nabumetone), naproxen (naproxen), naproxen sodium, naproxen (naproxol), nimacrine (nimazone), oxazidine sodium (olsalazine sodium), oxyphenbutazone (piroxicam), pirenoxim (piroxicam), piroxicam (pyridoxine), piroxicam (piroxicam), piroxicam (pyridoxine (sodium), piroxicam (sodium, naproxen (naproxen sodium), naproxen (naproxen) sodium), naproxen (naproxen), naproxen (naproxan), naproxate), naproxan), naproxate (naproxan), naproxate (naproxan), naproxate (naproxate, naprox, Prifelone (privet), propalanine (prodolic acid), prioquine (proquazone), propiconazole (proxazone), propiconazole citrate (proxazone citrate), rimexolone (rimexolone), chloromazalide (romazarit), salicylide (salcolex), salfenadine (salbutate), sanguinarine (sanguinarine chloride), seclorazone (seclazone), sermetiracin (sermetacin), sudoxicam (sudoxicam), sulindac (sulindac), suprofen (suprofen), tamicidine (talmetacetate), talniflumate (talfluniumate), tallosate (tasalalate), tertebufelone (tebuthionine), metrizamide (codetermine), thionate (sulcotrione), thiothizamide (sulcotrione), thiothiurazone (sulcotinamide), thiuracil (sulcotinamide), thiuracil (sulindac), thiuracil (sodium), thiuracil (sultaine), thiuracil (e), thiuracil (sultaine (e), thiuracil (e), triflumidate, zidometacin, zomepirac sodium, aspirin, salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecrolimus, prodrugs thereof, combinations thereof and combinations thereof. The anti-inflammatory agent may also be a biological inhibitor of a proinflammatory signaling molecule, including antibodies to such biological inflammation signaling molecule.

Autoimmunity is the failure of an organism to recognize its own components (down to the sub-molecular level) as "self," resulting in an immune response against its own cells and tissues. Any disease caused by this abnormal immune response is referred to as an autoimmune disease. The adverse immune response may be, for example, an immune response associated with an autoimmune disease, allergy, or inflammatory disease. The term "immune disorder" is a disease involving the immune system, which may include, but is not limited to, allergies, autoimmune diseases, immune complex diseases, immunodeficiency diseases and cancers of the immune system. In some embodiments, the autoimmune, immune, or inflammatory disease is multiple sclerosis.

The presently disclosed subject matter contemplates the use of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I), optionally together with at least one neuroprotective agent and/or at least one neurotrophic factor, and/or at least one neuroregenerative agent, for the treatment of a neurodegenerative or neurological disease.

A "neurodegenerative disease" is a disease, disorder or condition characterized by progressive loss of structure or function of neurons (e.g., degeneration or dysfunction of neurons or other neural cells). Glutaminase-catalyzed hydrolysis of glutamine to glutamate is a major source of brain glutamate. Normal Central Nervous System (CNS) synaptic transmission uses glutamate as the major excitatory amino acid neurotransmitter. Excessive glutamatergic signalling (known as excitotoxicity) is thought to cause central nervous system damage in various neurodegenerative diseases such as stroke, Amyotrophic Lateral Sclerosis (ALS), huntington's disease, alzheimer's disease and HIV-associated dementia. Thus, without wishing to be bound by theory, it is believed that the presently disclosed compounds may be useful in treating such neurodegenerative diseases, for example, by inhibiting glutaminase to mitigate CNS damage due to excitotoxicity caused by excessive glutamatergic signalling.

In a specific embodiment, the neurodegenerative disease is Multiple Sclerosis (MS). DON has been shown to be effective in ameliorating Experimental Autoimmune Encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS) (see, e.g., Shijie et al, 2009). In a specific embodiment, the neurodegenerative disease is HIV-associated dementia (HAD). In a specific embodiment, the neurodegenerative disease is ischemia (e.g., transient ischemic brain injury). In a specific embodiment, the neurodegenerative disease is stroke. In a specific embodiment, the neurodegenerative disease is Amyotrophic Lateral Sclerosis (ALS). In a specific embodiment, the neurodegenerative disease is huntington's disease. In a specific embodiment, the neurodegenerative disease is alzheimer's disease.

In some embodiments, the presently disclosed subject matter provides methods for inhibiting excess and/or aberrant glutamine activity found in a subject having a disease or disorder. As used herein, the term "inhibit" means to reduce or decrease excess and/or abnormal glutamine activity found in a subject. The term "inhibiting" can also mean reducing, impairing, alleviating, attenuating, arresting, or stabilizing the development or progression of a disease or disorder. Inhibition can occur, for example, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or even 100% as compared to an untreated control subject or a subject without a disease or disorder. As used herein, the term "excess glutamine activity" refers to an increase in glutamine activity in a subject having a disease or disorder, e.g., an increase of about 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more, as compared to glutamine activity in a subject without a similar disease or disorder. As used herein, the term "aberrant glutamine activity" refers to a change in the biological activity of glutamine in a subject having a disease or disorder, as compared to the glutamine activity in a subject without a similar disease or disorder, such as the utilization of glutamine in the growth and/or proliferation of a malignant, neoplastic, or other pathological cellular process.

In some embodiments, the disease or disorder involves excessive and/or abnormal glutamine activity. In such aspects, the method further comprises inhibiting excessive and/or aberrant glutamine activity upon administration of a compound of formula (I) or any pharmaceutical composition thereof.

In another aspect, the presently disclosed subject matter relates to the use of a compound of formula (I) or any pharmaceutical composition thereof for the treatment of a disease or condition. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof is used to treat a disease or condition selected from: infections, cancer, autoimmune diseases, inflammatory diseases and neurodegenerative or neurological diseases. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof is used to treat a disease or disorder selected from multiple sclerosis, convulsions, epilepsy, and viral encephalitis. In some embodiments, a compound of formula (I) or any pharmaceutical composition thereof is used to treat a disease or disorder involving excess and/or aberrant glutamine activity. In such aspects, the use relates to inhibiting excess and/or aberrant glutamine activity when a compound of formula (I) or any pharmaceutical composition thereof is used to treat a disease or condition.

In another aspect, the present invention provides a method of enhancing the effect of an immune checkpoint inhibitor, enabling a subject to respond to an immune checkpoint inhibitor, or reducing the toxicity or dose or number of treatments of an immune checkpoint inhibitor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof and an immune checkpoint inhibitor. In one embodiment, co-administration of a compound of the present disclosure or a pharmaceutical composition thereof reverses resistance or refractory to an immune checkpoint inhibitor. In another embodiment, the disease or disorder is cancer. In another embodiment, the disease or disorder is immune checkpoint resistant colon cancer, glioblastoma, or head and neck cancer. In another embodiment, the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

In another aspect, the present invention provides a method of treating a tumor, immune, infection, or neurological disease or disorder that is refractory to immune checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof and having a refractory disease or disorder a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof. The compounds of the present disclosure may be administered alone or in combination with immune checkpoint inhibitor therapy. The administration may be before, simultaneously with, or after the immune checkpoint inhibitor. In another embodiment, the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

In another aspect, the invention provides a method of treating a tumor, immune, infection, or neurological disease or disorder that is refractory to checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof and having a refractory disease or disorderA therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition thereof. In one embodiment, the compound or pharmaceutical composition thereof is administered with an immune checkpoint inhibitor therapy. In another embodiment, the compound or pharmaceutical composition is administered to the subject before, concurrently with, or after the checkpoint inhibitor. In another embodiment, the immune checkpoint inhibitor is ipilimumabPembrolizumabNivolumabAttrit Zhu monoclonal antibodyAbamectin monoclonal antibodyOr DOVALUMAb

Definition of V

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter disclosed herein belongs.

While the following terms with respect to the compounds of formula (I) are believed to be well known to those of ordinary skill in the art, the following definitions are given to aid in the understanding of the subject matter disclosed herein. These definitions are intended to supplement and illustrate rather than exclude definitions that will be apparent to those of ordinary skill in the art upon reading this disclosure.

As used herein, the terms "substituted" (whether or not preceded by the term "optionally") and "substituent" refer to the ability to change one functional group on a molecule to another, as understood by those skilled in the art, provided that the valences of all atoms are maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. The substituents may also be further substituted (e.g., an aryl substituent may have another substituent, such as another aryl group, which is further substituted at one or more positions).

If a substituent group or linking group is designated by its conventional formula and written from left to right, they likewise contain a chemically identical substituent resulting from the right-to-left written structure, e.g., -CH₂O-is equivalent to-OCH₂-; -C (═ O) O — is equivalent to-OC (═ O) -; -OC (═ O) NR-is equivalent to-NRC (═ O) O-, and so on.

When the term "independently selected from" is used, the substituents mentioned (e.g. R groups, such as group R)_l、R₂Etc., or variables such as "m" and "n") may be the same or different. For example, R₁And R₂May all be substituted alkyl, or R₁Can be hydrogen and R₂May be substituted alkyl, and the like.

The terms "a" or "an" when used in reference to a substituent herein mean at least one. For example, when a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl. Further, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted". When a moiety is substituted with R-, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

Unless otherwise indicated herein, a named "R" or group generally has a structure recognized in the art as corresponding to the group having that name. For purposes of illustration, certain representative "R" groups, as set forth above, are defined as follows.

The description of the compounds of the present disclosure follows the principles of chemical bonding known to those skilled in the art. Thus, when a group can be substituted with one or more substituents, such substituents can be selected in accordance with the principles of chemical bonding and the formation of compounds that are not inherently labile and/or known to those of ordinary skill in the art to be potentially labile under environmental conditions (e.g., aqueous, neutral, or multiple known physiological conditions). For example, heterocycloalkyl or heteroaryl groups are attached to the rest of the molecule through a ring heteroatom according to chemical bonding principles known to those skilled in the art, thus avoiding inherently unstable compounds.

For the purposes of this disclosure, the term "alkyl" by itself or when used as part of another group refers to a group containing one or twelve carbon atoms (i.e., C)_1-12Alkyl) or straight or branched chain aliphatic hydrocarbons of the indicated number of carbon atoms (i.e., one C)₁Alkyl radicals, e.g. methyl, one C₂Alkyl radicals, e.g. ethyl, one C₃Alkyl, such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is selected from straight chain C_1-10An alkyl group. In another embodiment, the alkyl group is selected from branched C_3-10An alkyl group. In another embodiment, the alkyl group is selected from straight chain C_1-6An alkyl group. In another embodiment, the alkyl group is selected from branched C_3-6An alkyl group. In another embodiment, the alkyl group is selected from straight chain C_1-4An alkyl group. In another embodiment, the alkyl group is selected from branched C_3-4An alkyl group. In another embodiment, the alkyl group is selected from straight or branched chain C_3-4An alkyl group. Non-limiting exemplary C_1-10Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Non-limiting exemplary C_1-4Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.

For the purposes of this disclosure, the term "substituted alkyl" by itself or when used as part of another group means an alkyl group as defined above substituted with one, two or three substituents independently selected fromNitro, haloalkoxy, aryloxy, aralkoxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, cycloalkyl and the like. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include-CH₂CH₂NO₂、-CH₂SO₂CH₃CH₂CH₂CO₂H、-CH₂CH₂SO₂CH₃、-CH₂CH₂COPh, and-CH₂C₆H₁₁。

For the purposes of this disclosure, the term "cycloalkyl" by itself or when used as part of another group refers to a compound containing one to three atoms having three to fourteen carbon atoms (i.e., C)_3-14Cycloalkyl) or cyclic aliphatic hydrocarbons (containing one or two double bonds) saturated and partially unsaturated with rings of the indicated number of carbon atoms. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is selected from C_3-8A cycloalkyl group. In another embodiment, the cycloalkyl group is selected from C_3-6A cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl and cyclopentenyl, cyclohexenyl. One example of a cycloalkyl group includes:

for the purposes of this disclosure, the term "substituted cycloalkyl" by itself or when used as part of another group means a cycloalkyl group as described above substituted with one, two or three substituents independently selected from halogen, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (carboxamide) alkyl, mercaptoalkyl and (heterocycle) alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent.

For the purposes of this disclosure, the term "alkenyl" by itself or when used as part of another group refers to an alkyl group as described above that contains one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is selected from C_2-6An alkenyl group. In another embodiment, the alkenyl group is selected from C_2-4An alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purposes of this disclosure, the term "substituted alkenyl" by itself or when used as part of another group means an alkenyl group as defined above substituted with one, two or three substituents independently selected from halogen, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocycle.

For the purposes of this disclosure, the term "alkynyl" by itself or when used as part of another group refers to an alkyl group as described above that contains one to three carbon-carbon triple bonds. In one embodiment, the alkynyl group has a carbon-carbon triple bond. In one embodiment, the alkynyl group is selected from C_2-6An alkynyl group. In another embodiment, the alkynyl group is selected from C_2-4An alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

For the purposes of this disclosure, the term "substituted alkynyl" by itself or when used as part of another group means an alkynyl group as defined above substituted with one, two or three substituents independently selected from halogen, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocycle.

For the purposes of this disclosure, the term "haloalkyl" as employed by itself or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is selected from C_1-4A haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1-difluoroethyl, 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropyl, 4,4, 4-trifluorobutyl, and trichloromethyl groups.

For the purposes of this disclosure, the term "hydroxyalkyl" by itself or when used as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxyl groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxyl group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxyl groups, e.g.,

in a further embodiment of the method of the invention,hydroxyalkyl radicals selected from C_1-4A hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 3-dihydroxyprop-2-yl.

For the purposes of this disclosure, the term "alkoxy" by itself or when used as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl group attached to a terminal oxygen atom. In one embodiment, the hydrocarbyloxy group is selected from C_1-4A hydrocarbyloxy group. In another embodiment, the hydrocarbyloxy group is selected from C attached to a terminal oxygen atom_1-4Alkyl groups, for example, methoxy, ethoxy, and tert-butoxy.

For the purposes of this disclosure, the term "alkylthio" by itself or when used as part of another group refers to a sulfur atom substituted with an optionally substituted alkyl group. In one embodiment, the alkylthio group is selected from C_1-4An alkylthio group. Non-limiting exemplary alkylthio groups include-SCH₃and-SCH₂CH₃。

For the purposes of this disclosure, the term "alkoxyalkyl" by itself or when used as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary hydrocarbyloxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentoxymethyl.

For the purposes of this disclosure, the term "haloalkoxy" by itself or when used as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2,2, 2-trifluoroethoxy.

For the purposes of this disclosure, the term "aryl" by itself or when used as part of another group refers to a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms (i.e., C)₆-C₁₄Aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. In one embodiment, the aryl group is selected from phenyl and naphthyl.

For the purposes of this disclosure, the term "optionally substituted aryl" as employed herein by itself or as part of another group means an aryl group as defined above unsubstituted or substituted with one to five substituents independently selected from halogen, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, mercaptoalkyl, or (heterocycle) alkyl.

In one embodiment, the optionally substituted aryl is optionally substituted phenyl. In one embodiment, the optionally substituted phenyl group has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl group has one substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2, 6-di-fluorophenyl, 2, 6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3, 4-di-methoxyphenyl, 3, 5-di-fluorophenyl, 3, 5-di-methylphenyl, 3, 5-dimethoxy, 2-chlorophenyl, 3-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3, 5-di-fluorophenyl, 3, 5-di-methylphenyl, 3, 5-dimethoxy, 2-chlorophenyl, 3-chlorophenyl, 4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocycle. Non-limiting examples include:

for the purposes of this disclosure, the term "aryloxy" by itself or when used as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

For the purposes of this disclosure, the term "aralkoxy" by itself or when used as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH₂O-。

For the purposes of this disclosure, the term "heteroalkyl," by itself or when used as part of another group, refers to a stable straight or branched chain hydrocarbon radical containing from 1 to 10 carbon atoms and at least two heteroatoms, which may be the same or different, selected from O, N, or S, wherein: 1) the nitrogen and sulfur atoms may optionally be oxidized; and/or 2) the nitrogen atoms may optionally be quaternized. The heteroatom may be placed at any internal position of the heteroalkyl group, as well as at the position where the heteroalkyl group is attached to the rest of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. In one embodiment, the heteroalkyl group contains one oxygen atom and one nitrogen atom. In one embodiment, the heteroalkyl group contains two nitrogen atoms. A non-limiting exemplary heteroalkyl group comprises-CH₂OCH-₂CH₂OCH₃、-OCH₂CH₂OCH₂CH₂OCH₃、-CH₂NHCH₂CH₂OCH₂、-OCH₂CH₂NH₂、-NHCH₂CH₂N(H)CH₃、-NHCH₂CH₂OCH₃and-OCH₂CH₂OCH₃。

For the purposes of this disclosure, the term "heteroaryl" or "heteroaromatic" refers to a compound having from 5 to 14 ring atoms (i.e., C)₅-C₁₄Heteroaryl) wherein at least one carbon atom of one ring is independently substituted with a heteroatom selected from oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl group contains 1,2,3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, the heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. Non-limiting exemplary heteroaryl groups include thienyl, benzo [ b ]]Thienyl, naphtho [2,3-b ]]Thienyl, thianthryl, furyl, benzofuryl, pyranyl, isobenzofuryl, benzoxazolonyl (benzoxaonyl), chromenyl, xanthenyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, isopyrrolyl, 3H-indolyl, indazolyl, purinyl, isoquinolyl, quinolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4 aH-carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazyl, isoxazolyl, furazanyl and phenoxazinyl in one embodiment the heteroaryl is selected from thienyl (e.g. thien-2-yl and thienyl-3-yl), furyl (e.g. 2-furyl and 3-furyl), pyrrolyl (e.g. 1H-3-pyrrolyl), pyranyl, isothiazolyl, and pyrazolinyl) (e.g. 1H-2-3-thienyl, isothiazolyl), isothiazolyl, 2-4-oxazolyl, pyrazolyl, and 5-thienyl (e.g. 2H-2-3-oxazolyl), pyrazolyl, 5-oxazolyl, e, and 1-4-5-oxazolyl, such as 1H-5-oxazolyl, 2-5-2-5-oxazolyl, and 2-4-5-4-2-4-5-4-2-4-2-5-4-2-5-4-oxazolyl, e, and pyrazolyl, e"also includes possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

In one embodiment, the heteroaryl is a 5-or 6-membered heteroaryl. In one embodiment, the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms in which at least one carbon atom of the ring is replaced by a heteroatom independently selected from nitrogen, oxygen, and sulfur. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isothiazolyl, and isoxazolyl.

In another embodiment, the heteroaryl is a 6-membered heteroaryl, for example, the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms, wherein at least one carbon atom of the ring is replaced by a nitrogen atom. Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

For the purposes of this disclosure, the term "optionally substituted heteroaryl" by itself or when used as part of another group means that the heteroaryl group as defined above is unsubstituted or substituted with 1 to 4 substituents, e.g., 1 or 2 substituents, independently selected from halogen, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, Mercaptoalkyl and (heterocyclyl) alkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom may be substituted.

The term optionally substituted heteroaryl is also meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocycle. Non-limiting examples include:

for the purposes of this disclosure, the term "heterocycle" or "heterocyclyl" by itself or when used as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) ring groups that contain one, two, or three rings having three to fourteen ring members (i.e., 3-to 14-membered heterocyclyl) in which at least one carbon atom of one ring is replaced by a heteroatom. Each heteroatom is independently selected from oxygen, sulfur (including sulfoxides and sulfones), and/or nitrogen atoms, which may be oxidized or quaternized. The term "heterocyclyl" is meant to include within it ring-CH₂The term "heterocyclyl" also includes groups having a fused optionally substituted aryl group, such as indolinyl, chroman-4-yl in one embodiment, the heterocyclyl is selected from 5-or 6-membered ring groups containing one ring and one or two oxygen and/or nitrogen atoms the heterocyclyl may optionally be attached to the rest of the molecule through any available carbon or nitrogen atom.

For the purposes of this disclosure, the term "optionally substituted heterocyclyl" as employed herein by itself or as part of another group means a heterocyclyl group as defined above unsubstituted or substituted with one to four substituents independently selected from halogen, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, alkoxycarbonyl, CF₃C (═ O) -, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, carboxyalkyl,Alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, mercaptoalkyl, and (heterocycle) alkyl. Substitution may occur at any available carbon or nitrogen atom or both. Non-limiting exemplary optionally substituted heterocyclyl groups include:

for the purposes of this disclosure, the term "amino" by itself or when used as part of another group refers to-NR¹²R¹³Wherein R is¹²And R¹³Each independently is hydrogen, alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or R¹¹And R¹²Together form a 3-to 8-membered optionally substituted heterocyclyl. Non-limiting exemplary amino groups include-NH₂and-N (H) (CH)₃)。

For the purposes of this disclosure, the term "(amino) alkyl" by itself or when used as part of another group refers to an alkyl group substituted with an amino group. Non-limiting exemplary aminoalkyl groups include-CH₂CH₂NH₂and-CH₂CH₂N(H)CH₃、-CH₂CH₂N(CH₃)₂and-CH₂N (H) cyclopropyl.

For the purposes of this disclosure, the term "carboxamide" by itself or when used as part of another group refers to a compound of formula-C (═ O) NR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Each independently is hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or R¹⁴And R¹⁵Together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclyl group. In one embodiment, R¹⁴And R¹⁵Are each independently hydrogenOr optionally substituted alkyl. In one embodiment, R¹⁴And R¹⁵Together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclyl group. Non-limiting exemplary carboxamide groups include, but are not limited to, -CONH₂、-CON(H)CH₃、-CON(CH₃)₂、-CON(H)Ph，

For the purposes of this disclosure, the term "sulfonamide" by itself or when used as part of another group refers to a compound of the formula-SO₂NR¹⁶R¹⁷Wherein R is¹⁶And R¹⁷Each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R¹⁶And R¹⁷Together with the nitrogen to which they are attached form a 3-to 8-membered heterocyclyl group. Non-limiting exemplary sulfonamide groups include-SO₂NH₂、-SO₂N(H)CH₃and-SO₂N(H)Ph。

For the purposes of this disclosure, the term "alkylcarbonyl", by itself or when used as part of another group, refers to a carbonyl group (i.e., -C (═ O) -) substituted with an alkyl group. A non-limiting exemplary alkylcarbonyl group is-COCH₃。

For the purposes of this disclosure, the term "arylcarbonyl" by itself or when used as part of another group refers to a carbonyl group (i.e., -C (═ O) -) substituted with an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is-COPh.

For the purposes of this disclosure, the term "hydrocarbyloxycarbonyl" by itself or when used as part of another group refers to a carbonyl group (i.e., -C (═ O) -) substituted with a hydrocarbyloxy group. Non-limiting exemplary hydrocarbyloxycarbonyl groups include-C (═ O) OMe, -C (═ O) OEt, and-C (═ O) OtBu.

For the purposes of this disclosure, the term "alkylsulfonyl" by itself or when used as part of another group means substituted with any of the optionally substituted substituents described aboveSulfonyl groups substituted by alkyl groups (i.e. -SO)₂-). A non-limiting exemplary alkylsulfonyl group is-SO₂CH₃。

For the purposes of this disclosure, the term "arylsulfonyl" by itself or when used as part of another group refers to a sulfonyl group substituted with any of the optionally substituted aryl groups described above (i.e., -SO)₂-). A non-limiting exemplary arylsulfonyl group is-SO₂Ph。

For the purposes of this disclosure, the term "mercaptoalkyl" by itself or when used as part of another group refers to any of the alkyl groups described above substituted with an-SH group.

For the purposes of this disclosure, the term "carboxy" as used herein or as part of another group refers to a radical of the formula — COOH.

For the purposes of this disclosure, the term "carboxyalkyl" by itself or when used as part of another group refers to any of the alkyl groups described above substituted with a-COOH group. A non-limiting exemplary carboxyalkyl group is-CH₂CO₂H。

For the purposes of this disclosure, the term "aralkyl" or "arylalkyl" by itself or when used as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the optionally substituted aralkyl group is C substituted with one optionally substituted aryl group_1-4An alkyl group. In one embodiment, the optionally substituted aralkyl group is C substituted with one optionally substituted aryl group₁Or C₂An alkyl group. In one embodiment, the optionally substituted aralkyl group is C substituted with one optionally substituted phenyl group₁Or C₂An alkyl group. Non-limiting exemplary optionally substituted aralkyl groups include benzyl, phenethyl, -CHPh₂、-CH₂(4-F-Ph)、-CH-₂(4-Me-Ph)、-CH₂(4-CF₃-Ph), and-CH (4-F-Ph)₂。

For purposes of this disclosure, the terms"(heterocyclyl) alkyl" by itself or when used as part of another group refers to an alkyl group substituted with an optionally substituted heterocyclyl group. In one embodiment, (heterocyclyl) alkyl is C substituted with one optionally substituted heterocyclyl group_1-4An alkyl group. Non-limiting exemplary (heterocyclyl) alkyl groups include:

for the purposes of this disclosure, the term "(carboxamido) alkyl" by itself or when used as part of another group refers to an alkyl group substituted with one or two carboxamido groups. In one embodiment, (carboxamido) alkyl is C substituted with one optionally substituted carboxamido group_1-4An alkyl group. In one embodiment, (carboxamido) alkyl is C substituted with two optionally substituted carboxamido groups_1-4An alkyl group. Non-limiting exemplary (carboxamido) alkyl groups include-CH₂CONH₂、-C(H)CH₃-CONH₂、-CH₂CON(H)CH₃and-CH (CO)₂NH₂)CH-₂CH₂CO₂NH₂。

Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, optical and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R) -or (S) -or as D-or L-of amino acids, as well as the individual isomers, are included within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art that are too unstable to be synthesized and/or isolated. The present invention is intended to include compounds in racemic, non-racemic (scalemic) and optically pure forms. Optically active (R) -and (S) -or D-and L-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other geometric asymmetric center, it is intended to mean that the compound includes both E and Z geometric isomers, unless otherwise specified.

Unless otherwise indicated, a structure described herein is also meant to include all stereochemical forms of the structure; i.e., the R and S configuration of each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are within the scope of the disclosure.

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

Unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure (in which hydrogen is replaced by deuterium or tritium, or carbon is enriched¹³C or¹⁴C substitution) is within the scope of the present disclosure.

The compounds described in this disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be substituted with radioactive isotopes (e.g. tritium(s) (iii))³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) Is radiolabeled. All isotopic variations of the compounds described in this disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

The compounds of the present disclosure may exist in the form of salts. The present disclosure includes such salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. (+) -tartrate, (-) -tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or the like. When the compounds described in this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (neat or in a suitable inert solvent or by ion exchange). Examples of acceptable acid addition salts include: salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, and the like, as well as salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the invention contain both basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

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

Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent in the applications contemplated by the disclosure and are intended to be within the scope of the disclosure.

The terms "a", "an" and "the" as used in this application (including the claims) mean "one or more". Thus, for example, reference to "a subject" includes a plurality of subjects (e.g., multiple subjects), and so forth, unless the context clearly dictates otherwise.

The terms "comprising," "including," and "containing" in the specification and claims are used in a non-exclusive manner unless the context requires otherwise. Similarly, the term "comprising" and grammatical variants thereof are not intended to be limiting, and thus reference to items in a list is not intended to exclude other similar items from being replaced or added to the list.

For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, amounts, characteristics, and other numerical values used in the specification and claims are to be understood as being modified in all instances by the term "about", even though the term "about" may not expressly appear with such value, amount, or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not, and need not be, exact, and may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art, depending on the desired properties desired to be obtained by the presently disclosed subject matter. For example, the term "about" when referring to a value can mean a variation of ± 10% is included. In some embodiments about ± 5%, in some embodiments 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% are encompassed, as such variations are suitable for performing the disclosed methods or employing the disclosed compositions.

Furthermore, the term "about," when used in conjunction with one or more numbers or ranges of numbers, should be understood to refer to all such numbers, including all numbers within a range, and to modify the range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers subsumed within that range, e.g. all integers, and all fractions within that range (e.g. 1 to 5 includes 1,2,3,4, 5 and fractions thereof, e.g. 1.5, 2.25, 3.75, 4.1, etc.) and any range within that range.

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