Cancer treatment

Abstract

Methods, compounds, compositions, and kits for the treatment of cancer are provided, including TLR2 agonists, particularly dipalmitoyl-S-glyceryl-cysteine ​​(Pam2Cys) derivatives and conjugates. In one aspect, methods are provided for treating, preventing, or minimizing the progression of cancer, comprising administering a compound comprising a Pam2Cys moiety and polyethylene glycol (PEG).

Description

Detailed description of the invention

[0001] [Cross-reference of related applications] This application claims priority to Australian Provisional Patent Application No. AU2019903263 (filed on 4 September 2019) and Australian Provisional Patent Application No. AU2019904863 (filed on 20 December 2019). The entire contents of AU2019903263 and AU2019904863 are incorporated herein by reference.

[0002] [Field of Invention] The present invention relates to methods, compounds, compositions, and kits for treatment and / or prevention.

[0003] [Background of the Invention] Cancer is a group of diseases characterized by abnormal cell proliferation that can invade or metastasize to other parts of the body. Typical features of cancer include abnormal cell proliferation and division, avoidance of programmed cell death, an unlimited number of cell divisions, increased angiogenesis, and the formation of tissue invasion and metastasis. Historically, typical treatments for cancer have included radiation therapy, chemotherapy, immunotherapy, and surgery.

[0004] Despite improvements in cancer treatment therapies, global cancer mortality rates remain high, and methods to prevent cancer recurrence are still needed. In 2015, approximately 90.5 million people had cancer. Approximately 14.1 million new cases occur annually (excluding skin cancers other than melanoma). Cancer causes approximately 8.8 million deaths (15.7% of all deaths), and the financial cost of cancer was estimated at US$1.16 trillion per year as of 2010. Current treatments for cancer often end in failure due to the development of multiple tumors and / or resistance to chemotherapy and radiation therapy.

[0005] Therefore, improved therapies for treating cancer are still needed.

[0006] No reference to prior art in this specification constitutes an endorsement or implied that such prior art forms part of common general knowledge within any jurisdiction, or that such prior art can be reasonably foreseen by a person skilled in the art as being related to and / or combined with other parts of the prior art.

[0007] [Overview of the prefecture] In one embodiment, the present invention provides a method for treating, preventing, or minimizing the progression of cancer in a subject, comprising administering a therapeutically effective amount of a compound described herein to the subject, thereby treating, preventing, or minimizing the progression of cancer in the subject.

[0008] In one embodiment, the present invention provides a method for treating, preventing, or minimizing the progression of cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0009] In one embodiment, a method is provided for treating, preventing, or minimizing the progression of cancer in a subject, comprising administering a therapeutically effective amount of a compound described herein into the airway of the subject, thereby treating, preventing, or minimizing the progression of cancer in the subject. In a preferred embodiment, the compound is administered by inhalation.

[0010] In some embodiments, the compound is defined by one of the following formulas: (I), (IA1), (IA2), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX) (collectively referred to as formulas (I) to (XIX) in this specification).

[0011] In some embodiments, the compound may comprise a portion A and PEG selected from A1' and A2 as defined herein, wherein the portions A and PEG are linked by glycine, serine, homoserine, threonine, phosphoserine, asparagine, or glutamine residues, or esters of glutamine residues.

[0012] In some embodiments, the compound has a substructure A1Y' or A2Y': [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each case of b, v, w, and z 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 are each, independently, H or C1-C6 aliphatic; R, R 13 and R 18 are each, independently, H or C1-C6 aliphatic; R 19 is H, C1-C6 aliphatic, an amino protecting group, L3-C(=O)-, or A2; L1 and L2 are each, independently, C5-C 21 aliphatic or C4-C 20 heteroaliphatic; L3 is C1-C 21 aliphatic or C2-C 20 heteroaliphatic; A2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L1, L2, and L3 is optionally substituted; A1Y’ or A2Y’ is covalently bonded to polyethylene glycol (PEG).] may comprise or consist of, or may be its pharmaceutically acceptable salt, solvate or prodrug.

[0013] In certain embodiments, the compound is a compound selected from any of compounds A101-A114 and A201-A232.

[0014] In this specification, the “compound of the present invention” may refer to any of the following: Compounds of formulas (I) to (XIX); • A compound selected from among compounds A101-A114 and A201-A232; · Compounds comprising a portion A selected from A1' and A2 as defined herein and polyethylene glycol (PEG), wherein portion A and PEG are linked by glycine, serine, homoserine, threonine, phosphoserine, asparagine, or glutamine residues, or esters of glutamine residues; and / or Compounds containing a substructure of formula (A1Y') or (A2Y') covalently bonded by PEG.

[0015] In another embodiment, the present invention relates to a method for treating, preventing, or minimizing the progression of cancer in a subject, - The process of identifying subjects who have cancer; and -Administer a therapeutically effective dose of the compound disclosed herein to the subject, This provides a method for treating, preventing, or minimizing the progression of cancer in a subject.

[0016] In another embodiment, the present invention further provides a method for increasing the survival rate of a subject having cancer, comprising administering a therapeutically effective amount of a compound disclosed herein to the subject, thereby increasing the survival rate of the subject having cancer.

[0017] In another embodiment, the present invention further provides a method for minimizing, reducing, or preventing tumor growth in a subject having cancer, comprising administering a therapeutically effective amount of one of the compounds disclosed herein to the subject, thereby minimizing, reducing, or preventing tumor growth in the subject having cancer.

[0018] In any embodiment, the method described herein further includes identifying a subject having cancer. In one embodiment, the cancer may be a precancerous condition or non-metastatic. In another embodiment, the cancer may be malignant or metastatic.

[0019] In another embodiment, the present invention further provides a method for minimizing, reducing, or preventing metastasis in a subject having cancer, comprising administering a therapeutically effective amount of one of the compounds disclosed herein to the subject, thereby minimizing, reducing, or preventing metastasis in the subject having cancer. In a preferred embodiment, the method minimizes, reduces, or prevents metastasis to the lungs.

[0020] In any embodiment, the present invention further relates to a method for minimizing, reducing, or preventing cancer in a subject, - Identifying subjects with metastatic tumors; and -Administer a therapeutically effective dose of the compound disclosed herein to the subject, This provides a method for minimizing, reducing, or preventing cancer in a subject.

[0021] In another embodiment, the present invention further provides a method for minimizing, reducing, or preventing tumor growth at at least one site in a subject distant from the site of a primary tumor, comprising administering a therapeutically effective amount of one of the compounds disclosed herein to the subject, thereby minimizing, reducing, or preventing tumor growth at at least one site in the subject distant from the site of a primary tumor.

[0022] In another embodiment, the present invention further provides the use of any of the compounds disclosed herein in the preparation of agents for treating, preventing, or minimizing the progression of cancer in a subject.

[0023] In another embodiment, the drug is as follows: - To increase the survival rate of patients with cancer; - To minimize, reduce, or prevent tumor growth in the target area; - To minimize, reduce, or prevent metastasis in subjects with cancer; or - To minimize, reduce, or prevent tumor growth at at least one site distant from the primary tumor site. This is for any of the methods described herein, including the following:

[0024] In any embodiment of the present invention, any agent described herein is suitable for intraperitoneal, intratumoral, topical, oral, intravenous, subcutaneous, or intramuscular administration. Preferably, any agent described herein is suitable for intravenous or respiratory tract administration, preferably by inhalation. In one embodiment, the agent may be suitable in the form of a nasal spray or nasal medication.

[0025] In another embodiment, the present invention further provides any of the compounds disclosed herein for use in treating, preventing, or minimizing the progression of cancer in a subject. In a further embodiment, any of the compounds disclosed herein are: - To increase the survival rate of patients with cancer; - To minimize, reduce, or prevent tumor growth in the target area; - To minimize, reduce, or prevent metastasis in subjects with cancer; or - To minimize, reduce, or prevent tumor growth at at least one site distant from the primary tumor site. It is intended for use in any of the methods described herein, including the following.

[0026] In one embodiment of the present invention, the compound for use is suitable for intraperitoneal, intratumoral, topical, oral, intravenous, subcutaneous, or intramuscular administration. Preferably, the compound for use is suitable for intravenous or respiratory tract administration, preferably by inhalation. In one embodiment, the compound may be suitable for formulation as a nasal spray or nasal medication.

[0027] In another embodiment, the present invention further provides the use of any of the compounds disclosed herein for use in treating, preventing, or minimizing the progression of cancer in a subject. In a further embodiment, the use of any of the compounds disclosed herein is - To increase the survival rate of patients with cancer; - To minimize, reduce, or prevent tumor growth in the target area; - To minimize, reduce, or prevent metastasis in subjects with cancer; or - The purpose is to minimize, reduce, or prevent tumor growth at at least one site distant from the primary tumor site.

[0028] In any embodiment of the present invention, any compound disclosed herein is administered once. In another embodiment, any compound disclosed herein is administered to a subject two, three, four or more times.

[0029] In any embodiment of the present invention, any compound disclosed herein may be administered by any known route of administration in the art, including topical or systemic administration. For example, topical, oral, intranasal, inhalation, intravenous, subcutaneous, intratumoral, or intramuscular administration. Preferably, any compound disclosed herein is administered intravenously, intratumoral, or by inhalation.

[0030] In any embodiment of the present invention, the amount of any compound disclosed herein may be in the range of about 250 nanomoles / kg body weight / administered to 0.005 nanomoles / kg body weight / administered. Preferably, the range is about 250 nanomoles / kg body weight / administered to 0.05 nanomoles / kg body weight / administered. In some embodiments, the body weight / administered range is about 250 nanomoles / kg to 0.1 nanomoles / kg, about 50 nanomoles / kg to 0.1 nanomoles / kg, about 5 nanomoles / kg to 0.1 nanomoles / kg, about 2.5 nanomoles / kg to 0.25 nanomoles / kg, or about 0.5 nanomoles / kg to 0.1 nanomoles / kg body weight / administered. In some embodiments, the amount is 250 nanomoles, 50 nanomoles, 5 nanomoles, 2.5 nanomoles, 0.5 nanomoles, 0.25 nanomoles, 0.1 nanomoles, or 0.05 nanomoles / kg body weight / administered, or approximately such amounts of the compound.

[0031] In any aspect of the present invention, the amount of any compound disclosed herein may be in the range of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 μg / kg or more.

[0032] In any aspect of the present invention, cancer is selected from the group consisting of breast cancer, colorectal cancer, adenocarcinoma, mesothelioma, bladder cancer, prostate cancer, germ cell carcinoma, hepatocellular carcinoma / cholangiocarcinoma, neuroendocrine carcinoma, pituitary tumor, small round cell tumor, squamous cell carcinoma, melanoma, atypical fibroxanthoma, seminoma, non-seminoma, stromal Leydig cell tumor, Sertoli cell tumor, skin tumor, kidney tumor, testicular tumor, brain tumor, ovarian tumor, gastric tumor, oral tumor, bladder tumor, bone tumor, cervical mass, esophageal tumor, laryngeal tumor, liver tumor, lung tumor, vaginal tumor, or Wilms' tumor. In a preferred embodiment, cancer is melanoma, breast cancer, fibrosarcoma, or colon cancer.

[0033] In either form, cancer can be immunogenic (having many immune cells) or hypoimmunogenic (having few immune cells).

[0034] In any embodiment, the administered compound may be any one of the compounds described herein: compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, or compound 17. In another embodiment, the administered compound may be compound A108, A102, or A103.

[0035] In any embodiment, any compound described herein may be administered in a composition. Typically, the composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient. The composition may be formulated for respiratory, intraperitoneal, intratumoral, or intravenous administration to a subject. In other words, the composition is suitable for intratumoral, intravenous, or airway administration. In any embodiment, the composition comprises, is essentially, or consists of any compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0036] In another embodiment of the present invention, the composition is formulated for administration to the airway, for example, by inhalation or intranasal cavity. In one embodiment, the composition is formulated for administration as a nasal spray or nasal medication.

[0037] In any embodiment of the present invention, any compound described herein may be administered as a sole active agent, for example, as a sole pharmaceutically active agent. In other words, the compound may be administered without any other compounds for treating, preventing, or minimizing the progression of cancer. In this embodiment, the present invention provides a method for treating, preventing, or minimizing the progression of cancer in a subject, comprising or essentially comprising administering a therapeutically effective amount of any compound disclosed herein to the subject, thereby treating, preventing, or minimizing the progression of cancer in the subject.

[0038] In any aspect of the present invention, any compound described herein is not administered together with the following, or a composition containing a compound described herein does not contain the following: antigen; Peptide antigen; or T helper antigen.

[0039] In one embodiment, the composition cannot activate a cell-mediated immune response. In another embodiment, any compound described herein is not administered with a cell-permeable peptide. In another embodiment, the compound does not contain an electrostatically bound charged antigen.

[0040] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraph will become apparent from the following description, shown by example and with reference to the accompanying drawings. [Brief explanation of the drawing]

[0041] [Figure 1A] Compound 1 exhibits antitumor activity in the MC38 model. A. Experimental setup: MC38-supported WT mice were treated with either Compound 1 or a control at the indicated dose within the tumor. Tumor growth was measured and monitored over time. [Figure 1B] Compound 1 exhibits antitumor activity in the MC38 model. B. Corresponding mean tumor growth curves (mean ± SEM; n=10 for all groups). [Figure 1C] Compound 1 exhibits antitumor activity in the MC38 model. C. Kaplan-Meier survival curves (n=10 for all groups; log-rank test). [Figure 2A] Compound 1 exhibits antitumor activity in the B16F10 model. A. Experimental setup: WT mice carrying B16F10 melanoma were treated intratumorally with the indicated dose of Compound 1. Tumor growth was measured and monitored over time. [Figure 2B]Compound 1 exhibits antitumor activity in the B16F10 model. B. Corresponding mean tumor growth curves (mean ± SEM; n=10 (control), n=10 for 25 μg of Compound 1, and n=9 for 50 μg of Compound 1). [Figure 3] Compound 1 increases survival in the B16F10 model. Kaplan-Meier survival curves (n=10 (control), n=10 for 25 μg of compound 1, and n=9 for 50 μg of compound 1; statistical; log-rank test). [Figure 4A] Systemic delivery of compound 1 inhibits spontaneous 4T1.2 breast cancer metastasis. A. Experimental setup: 4T1.2 breast cancer cells were injected into Balb / c mice. The primary tumor was surgically removed, and the mice were treated as instructed. The number of metastases on the lung surface was counted. [Figure 4B] Systemic delivery of compound 1 inhibits spontaneous 4T1.2 breast cancer metastases. B. Quantification of the number of 4T1.2 lung metastases in the shown cohort. [Figure 4C] Systemic delivery of compound 1 inhibits spontaneous 4T1 and 2 breast cancer metastases. C. Combined analysis of Experiments 1 and 2 (mean ± SEM; n=16 in each group; Student t-test). [Figure 5A] Compound A108 exhibits antitumor activity in an immune cell-rich MC38 model. WT mice carrying A. MC38 melanoma were treated intratumorally (it) with 25 ug of compound A108. Tumor growth was measured and monitored over time. The dashed line indicates the administration plan (administered every two days for three doses). [Figure 5B] Compound A108 exhibits antitumor activity in an immune cell-rich MC38 model. B. Kaplan-Meier survival curves showing the effect of compound A108 on survival rate. [Figure 6A]Compound A108, administered via intratumoral (it) or intraperitoneal (ip) routes, exhibits antitumor activity in immune cell-rich MC38 models in large tumors. Intratumoral administration of compound A108 was performed every two days (days 1, 3, 5, 7, 9, 11, and 13). Tumor growth was measured and monitored over time. Body weight and tumor volume were measured twice weekly. A) To demonstrate the antitumor effect of compound A108 over the treatment period when administered intratumoral (it). [Figure 6B] Compound A108, administered via intratumor (it) or intraperitoneal (ip) routes, exhibits antitumor activity in immune cell-rich MC38 models in large tumors. Intratumor administration of compound A108 was performed every two days (days 1, 3, 5, 7, 9, 11, and 13). Tumor growth was measured and monitored over time. Body weight and tumor volume were measured twice weekly. B. To demonstrate the antitumor effect of compound A108 over the treatment period when administered intraperitoneally (ip), a two-way ANOVA using Tukey's multiple comparison test was performed. Treatment groups were compared to each other within specific time points. [Figure 6C] Compound A108, administered via intratumoral (it) or intraperitoneal (ip) routes, exhibits antitumor activity in immune cell-rich MC38 models in large tumors. Compound A108 was administered intratumor every two days (days 1, 3, 5, 7, 9, 11, and 13). Tumor growth was measured and monitored over time. Body weight and tumor volume were measured twice weekly. C. Compound A108 showed a better effect on tumor growth than Pam3CysSK4 over 12 days in the MC38 large tumor model. On day 9, significant difference: vehicle vs. compound A108, **p=0.0040; compound A108 vs. Pam3CysSK4, *p=0.0112; on day 12, significant difference: vehicle vs. compound A108, **p=0.0012; compound A108 vs. Pam3CysSK4, *p=0.0080. [Figure 6D]Compound A108, administered via intratumoral (it) or intraperitoneal (ip) routes, exhibits antitumor activity in immune cell-rich MC38 models in large tumors. Intratumoral administration of compound A108 was performed every two days (days 1, 3, 5, 7, 9, 11, and 13). Tumor growth was measured and monitored over time. Body weight and tumor volume were measured twice weekly. D. Compound A108 produces an effect on tumor growth in MC38 large tumor models that is at least equivalent to the effect of commercially available anti-PD1 antibodies. [Figure 7A] Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously. A) Experimental schedule showing the number of days after WEHI-164 inoculation when each treatment was initiated. [Figure 7B] Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously. B) Mean tumor growth in each treatment group when administered intravenously (Welch's t-test compared to the control group), shown with mean standard error. [Figure 7C] Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously. C) Corresponding Kaplan-Meier survival curve. [Figure 7D] Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously. D) Mean tumor growth in each treatment group when administered intraperitoneally (Welch's t-test compared to the control group), shown with mean standard error. [Figure 7E] Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously. E) Corresponding Kaplan-Meier survival curve. [Figure 8A] Systemic delivery of compound A108 inhibits the growth rate of EMT6.5 tumors. A) EMT6.5 tumor growth rate in mice treated with compound A108 or vehicle control. n=6 mice per treatment arm. Differences in tumor growth rates were evaluated by linear regression. [Figure 8B]Systemic delivery of compound A108 inhibits the growth rate of EMT6.5 tumors. B) Primary tumor weight at experimental endpoints. [Figure 8C] Systemic delivery of compound A108 inhibits the growth rate of EMT6.5 tumors. C) Evaluation of lung metastatic burden by RTQ-PCR assay. N=6 mice per treatment arm. Unpaired two-sided t-tests were performed to determine the difference; the p-values ​​shown are those indicated. [Figure 8D] Systemic delivery of compound A108 inhibits the growth rate of EMT6.5 tumors. D) Compound A108 results in extended survival. Kaplan-Meier survival plots show a better prognosis for animals treated with compound A108. Log-rank test. [Figure 8E] Systemic delivery of compound A108 inhibits the growth rate of EMT6.5 tumors. E) Effect of compound A108 compared to the effect of PD-1 on tumor volume. [Figure 9A] Repeated intranasal administration of compound A108 dose-dependently reduces lung metastases in a 4T1.2 model. Experimental setup: 4T1.2 breast cancer cells were injected into the mammary fat body. After tumor resection, mice were treated as shown. Finally, the number of lung metastases was evaluated in each mouse (A: 2.5 ng of compound A108; B: 0.25 ng of compound A108). [Figure 9B] Repeated intranasal administration of compound A108 dose-dependently reduces lung metastases in a 4T1.2 model. Experimental setup: 4T1.2 breast cancer cells were injected into the mammary fat body. After tumor resection, mice were treated as shown. Finally, the number of lung metastases was evaluated in each mouse (A: 2.5 ng of compound A108; B: 0.25 ng of compound A108). [Figure 9C] Repeated intranasal administration of compound A108 dose-dependently reduces lung metastases in the 4T1.2 model. Quantification of visible lung metastases on the lung surface in response to administration of 2.5 ng and 0.25 ng of compound A108, respectively (mean ± SEM; n=12 for control and compound A108, one-way ANOVA). (mean ± SEM; n=11 for control, n=12 for compound A108; one-way ANOVA). [Figure 9D] Repeated intranasal administration of compound A108 dose-dependently reduces lung metastases in the 4T1.2 model. Quantification of visible lung metastases on the lung surface in response to administration of 2.5 ng and 0.25 ng of compound A108, respectively (mean ± SEM; n=12 for control and compound A108, one-way ANOVA). (mean ± SEM; n=11 for control, n=12 for compound A108; one-way ANOVA). [Figure 10A] Various compounds significantly reduced tumor growth and improved the survival rate of MC38-carrying mice. A) Tumor weight at various experimental time points in response to compound A103. [Figure 10B] Various compounds significantly reduced tumor growth and improved the survival rate of MC38-carrying mice. B) Tumor weight at various experimental time points in response to compound A102. [Figure 10C] Various compounds significantly reduce tumor growth and improve the survival rate of MC38-carrying mice. C) Kaplan-Meier survival plots of mice injecting MC38 tumors subcutaneously (sc) and treated with 25 ug of intratumoral (it) compound A102 on days 7, 9, and 11 (control n=7; compound A102 n=10). Statistics: Log-rank (Mantel-Cox). Numbers in parentheses indicate the number of tumor-free mice.

[0042] [Detailed description of the embodiment] Specific embodiments of the present invention will now be described in detail. While the present invention is described in conjunction with its embodiments, it will be understood that the present invention is not limited to those embodiments. Conversely, the present invention is intended to encompass all alternatives, modifications, and equivalents, which may fall within the scope of the present invention as defined by the claims.

[0043] Those skilled in the art will recognize many methods and materials similar to or equivalent to those described herein that can be used in carrying out the present invention. The present invention is by no means limited to the methods and materials described herein. It will be understood that the present invention disclosed and defined herein extends to all alternative combinations of two or more individual features described or evident therefrom in the text or drawings. All of these different combinations constitute various alternative embodiments of the present invention.

[0044] All patents and publications referenced herein are incorporated by reference in their entirety.

[0045] For the purposes of interpreting this specification, terms used in the singular also include the plural, and vice versa.

[0046] There is a need for more reliable and effective regimes that are useful in the treatment of cancer. The inventors have unexpectedly found that when the compounds disclosed herein are administered to subjects with cancer, including several doses and several models of cancer, the treatment is highly effective. More specifically, the administration of the compounds disclosed herein provides one or more of the following: • Significant reduction in tumor growth in multiple administrations and multiple models; • Significant increase in survival time with multiple doses and in multiple models; • Significant reduction in tumor metastasis; and • Nearly complete removal of cancer in response to administration of the compounds described herein.

[0047] These remarkable effects are observed regardless of the route of administration. The inventors have demonstrated these remarkable effects in several different models of cancer with various etiologies and pathogenesis, including the following: • Breast epithelial carcinoma exhibiting characteristics of triple-negative breast cancer; Metastatic breast cancer; ·Colon cancer; • Melanoma; and Fibrosarcoma

[0048] Therefore, those skilled in the art will understand the applicability of the present invention to any of the cancers described herein or other well-known cancers.

[0049] The inventors also describe herein the usefulness of several different compounds in treating cancer: Compound A101 / Compound 1, when administered intraperitoneally, intratumorally, or systemically, reduced tumor growth, prolonged survival, and decreased metastasis in models of colon cancer, melanoma, and metastatic breast cancer. Compounds A102 and A103 significantly improved the survival time of subjects in a colon cancer model; Compound A108, when administered intraperitoneally, intratumorally, or systemically, significantly reduced tumor growth, improved survival rates, and decreased metastasis in models of colon cancer, breast cancer, melanoma, fibrosarcoma, and metastatic breast cancer; and Compound A108 in a model of metastatic breast cancer when administered to the airway.

[0050] Therefore, those skilled in the art will understand the applicability of the present invention to any of the other compounds described herein.

[0051] This effect is surprising because the role of compounds capable of stimulating TLR2 signaling in cancer treatment has been unclear. In particular, it has been reported that subcutaneous or intraperitoneal administration of Pam2CysSK4 and MALP2 does not have antitumor activity, but rather induces IL-10 and Tregs (Yamazaki et al. PLOS ONE 2011 6(4):e18833). The same group reported that intravenous administration of Pam2CysSK4 promotes myeloid-derived immunosuppressive cells (Maruyama et al. 2015 457:445e450). Importantly, it has been suggested that endogenous TLR2 / 6 agonists derived from cancer cells may promote metastasis (Kim et al. Nature 2009 457:102-106). Another study suggested that TLR2 stimulation may promote colorectal cancer cell proliferation via the PI3K / Akt and NFκB signaling pathways (Liu et al. International Immunopharmacology 2018 59:375-383).

[0052] Therefore, the inventors have confirmed the therapeutic utility of the compounds described herein in treating several different types of cancer at different doses and via various routes of administration.

[0053] [Compound] Any of the compounds described herein may be useful in the treatment of cancer, including cancer metastasis.

[0054] When used herein, references to any compound described herein include its pharmaceutically acceptable salts, solvates, polyforms, or prodrugs.

[0055] The compounds described herein may demonstrate considerable stability in solution. This solution stability can be observed by storing a solution of the compounds for at least about 14 days under ambient storage conditions (e.g., at 25°C) or under accelerated degradation stability (e.g., at 40°C).

[0056] Further compounds useful in any aspect of the present invention will be described later.

[0057] In any embodiment, the compound is of formula (I): AYB (I) [In the formula, A is A1 and A2: [ka] Includes or consists of a portion selected from, During the ceremony, Each z is independently selected from 1 or 2; Each X is independently selected from -S-, -S(=O)-, and -S(=O)2-; In section A1: Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; In section A2: b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, for example, between 2 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, S(=O), -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R 11 , R 12 , R x , R y , R 14 , R 15 , R 16, and R 17 Each of these is independently H or C1-C6 aliphatic; R, R 13 and R 18 Each of these is independently H or C1-C6 aliphatic; R 19 However, it is H, C1-C6 aliphatic, amino protecting group, L3-C(=O)-, or A2; L1 and L2 operate independently, C5~C 21 Aliphatic or C4~C 20 It is heterolipid; L3 is C1~C 21 Aliphatic or C2-C 20 It is heterolipid; A2 is an amino acid or peptide; Here, R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y Any aliphatic or heteroaliphatic present in L1, L2, or L3 is optionally substituted; Y [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; B contains or consists of polyethylene glycol (PEG). It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0058] In any embodiment, the compound is of formula (IA1): AYB (IA1) [In the formula, A is part A1: [ka] including or consisting of In the formula, each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; Y [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; B contains or consists of polyethylene glycol (PEG). It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0059] In one embodiment, g is an integer between 12 and 16.

[0060] In one embodiment, g is 14.

[0061] In any embodiment, the compound is of formula (IA2): AYB (IA2) [In the formula, A is, [ka] including or consisting of During the ceremony, b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, for example, between 2 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, S(=O), -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 Each of these is independently H or C1-C6 aliphatic; R, R 13 and R 18 Each of these is independently H or C1-C6 aliphatic; R 19 However, it is H, C1-C6 aliphatic, amino protecting group, L3-C(=O)-, or A2; L1 and L2 operate independently, C5~C 21 Aliphatic or C4~C 20 It is heterolipid; L3 is C1~C 21aliphatic or C2-C 20 is heteroaliphatic; A2 is an amino acid or a peptide; where R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , any aliphatic or heteroaliphatic present in any of L1, L2, and L3 is optionally substituted; Y is

Chemical formula

[0062] In certain embodiments, v is an integer selected from 2, 3, 4 or 5. In certain embodiments, v is 2 or 3. In certain embodiments, v is 2.

[0063] In certain embodiments, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R​​​H is H.

[0064] In one embodiment, R and R 13 These are H.

[0065] In one embodiment, Z1 and Z2 are the same and are selected from the group consisting of -O-, -NR-, -S-, S(=O), S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, OC(=O)O-, NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-.

[0066] In one embodiment, Z1 and Z2 are independently selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-.

[0067] In one embodiment, w is an integer selected from 1 to 7. In another embodiment, w is 1.

[0068] In one embodiment, b is 0.

[0069] In one embodiment, the sum of b and w is between 1 and 7. In these embodiments, b may be an integer selected from 0 to 7, and w may be an integer selected from 1 to 7, preferably 1.

[0070] In one embodiment, b is 0, w is 1, and v is 2.

[0071] In one embodiment, R 18 H is H.

[0072] In one embodiment, R 19 However, H, C1~C6 alkyl, -C(=O)C1~C6 alkyl or -C(=O)C 11 ~C19 It is selected from the group consisting of alkyl.

[0073] In certain embodiments, R 19 is selected from H, C1-C6 alkyl, -C(=O)C1-C6 alkyl, preferably H, C1-C4 alkyl, -C(=O)C1-C4 alkyl.

[0074] In certain embodiments, R 19 is selected from H and -C(=O)CH3.

[0075] In certain embodiments, L1 and L2 are independently selected from C5-C 21 aliphatic or C4-C 20 heteroaliphatic. In certain embodiments, L1 and L2 are independently C 10 -alkyl and C 18 -alkyl. 10 ~C 18 heteroaliphatic. In certain embodiments, L1 and L2 are independently C 14 -alkyl and C 15 -alkyl.

[0076] In certain embodiments, X is S.

[0077] In certain embodiments, X is S(=O).

[0078] In certain embodiments, X is S(=O)2.

[0079] In certain embodiments, R6 and R7 are each H.

[0080] In certain embodiments, R 18 and R 19 are each H.

[0081] In certain embodiments, the present invention provides a compound of formula (I), wherein: v is an integer selected from 2-5; b is 0; R x , R y , R 13 , R 14 , R 15 , R 16 , and R 17 H is; Z1 and Z2 are independently selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; w is an integer selected from 1 to 7; R 19 However, H, C1~C6 alkyl, -C(=O)C1~C6 alkyl or -C(=O)C 11 ~C 19 Selected from the group consisting of alkyl groups; L1 and L2 independently, C 10 ~C 18 Aliphatic or C 10 ~C 18 Selected from heteroaliphatic species.

[0082] In one embodiment, the present invention provides a compound, wherein, v is 2; b is 0; w is 1; The sum of v, b, and w is 3; The sum of b and w is 1; z is 1; X is S, Z1 and Z2 are independently selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each of cases b, v, w, and z 11 , R 12 , R x , R y , R 14 , R 15 , R 16, and R 17 Each of these is H; R and R 13 Each of these is H; R 18 H is; R 19 However, H, C1~C6 alkyl, -C(=O)C1~C6 alkyl or -C(=O)C 11 ~C 19 Selected from the group consisting of alkyl groups; L1 and L2 independently, C 10 ~C 18 Aliphatic or C 10 ~C 18 Selected from heteroaliphatic species.

[0083] Substituents R1, R2, R4, R5, R6, R7, R9, R 10 z, X, g, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y It will be understood that any embodiment of the substituents described herein, including L1, L2, Z1, Z2, b, v, w, n, m, p, q, R3, L, t, k, and h, is intended to apply to any substituent of any compound described herein, including compounds of formula (I) to (XIX).

[0084] In any embodiment, the compound is of formula (II): A-Y'-B (II) [wherein A is a part of or comprises part A1 or A2 as defined herein; Y' is [ka] And, Wherein, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH and -CH2OPO(OH)2, wherein any one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; B comprises or consists of polyethylene glycol (PEG). It may be a compound of or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0085] In certain embodiments, the compound comprises moiety A1, wherein: each g is independently 10, 11, 12, 13, 14, 15, 16, 17 or 18; z is 1; X is S; R6 and R7 are H; R9 and R 10 are both single bonds.

[0086] In certain embodiments, moiety A1 is moiety A1’

Chemical formula

[0087] In any aspect, any of the compounds described herein may be a compound comprising moiety A selected from A1’ and A2 as defined herein and PEG, wherein moiety A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue.

[0088] In any aspect, the compound has a substructure A1Y’ or A2Y’:

Chemical formula

[0089] In one embodiment, portions A and PEG are linked by serine, homoserine, threonine, or phosphoserine residues.

[0090] In one embodiment, parts A and PEG are [ka] Through the bonds shown, it is covalently bonded to glycine, serine, homoserine, threonine, phosphoserine, asparagine, or glutamine residues, or esters of glutamine residues.

[0091] In any embodiment, the compound is covalently bonded to polyethylene glycol (PEG), [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-. Alternatively, it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0092] In one embodiment, the compound is covalently bonded to polyethylene glycol (PEG), [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-. Alternatively, it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0093] In one embodiment, the compound is covalently bonded to polyethylene glycol (PEG), [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are H; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 Both are single bonds; z is 1; X is S. Alternatively, it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0094] In one embodiment, PEG is [ka] They are covalently bonded via the bond shown by [the symbol].

[0095] In one embodiment, the compound is covalently bonded to polyethylene glycol (PEG), [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are H; R9 and R 10 Both are single bonds; z is 1; X is S. Alternatively, it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0096] In one embodiment, PEG is [ka] They are covalently bonded via the bond shown by [the symbol].

[0097] In one embodiment, the compound is [ka] [In the formula, R1, R2, and g are as defined herein.] It may be a salt, solvate, or prodrug thereof.

[0098] In one embodiment, PEG is [ka] They are covalently bonded via the bond shown by [the symbol].

[0099] In one embodiment, the compound is covalently bonded to polyethylene glycol (PEG), [ka] [In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each of cases b, v, w, and z 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 Each of these is independently H or C1-C6 aliphatic; R, R 13 and R 18 Each of these is independently H or C1-C6 aliphatic; R 19 However, it is H, C1-C6 aliphatic, amino protecting group, L3-C(=O)-, or A2; L1 and L2 operate independently, C5~C 21 Aliphatic or C4~C 20 It is heterolipid; L3 is C1~C 21 Aliphatic or C2-C 20 It is heterolipid; A2 is an amino acid or peptide; Here, R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 , R 18 , R 19 , R x , R y Any aliphatic or heteroaliphatic element present in L1, L2, or L3 is optionally substituted. Alternatively, it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0100] In one embodiment, PEG is [ka] They are covalently bonded via the bond shown by [the symbol].

[0101] In any embodiment, the compound is of formula (III): AY-B (III) [In the formula, AY is AY1 and AY2 [ka] Includes or consists of a portion selected from, In the formula, R1, R2, R6, R7, R9, R 10 z, X, g, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y L1, L2, Z1, Z2, b, v, and w are as defined for the compound of formula (I); B contains or consists of polyethylene glycol (PEG). It could be a compound of [the compound].

[0102] In any embodiment, the compound is of formula (IV): [ka] [In the formula, n is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; q is either 0 or 1; R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0103] In any embodiment, the compound is of formula (V): [ka] [In the formula, n is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; q is either 0 or 1; R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0104] In one embodiment, the compound is a compound of formula (IV) or (V), where, R6 and R7 are H; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 Both are single bonds; z is 1; X is S.

[0105] In one embodiment, any one of the compounds of formulas (I) to (V) is formula (VI): [ka] [In the formula, n is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; q is either 0 or 1; R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0106] In either embodiment, the compound is of formula (VII): [ka] [In the formula, n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of an amino acid, or the second hydrogen atom; b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each of cases b, v, w, and z 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 Each of these is independently H or C1-C6 aliphatic; R, R 13 and R 18 Each of these is independently H or C1-C6 aliphatic; R 19 However, it is H, C1-C6 aliphatic, amino protecting group, L3-C(=O)-, or A2; L1 and L2 operate independently, C5~C 21 Aliphatic or C4~C 20 It is heterolipid; L3 is C1~C 21 Aliphatic or C2-C 20 It is heterolipid; A2 is an amino acid or peptide; Here, R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y Any aliphatic or heteroaliphatic element present in L1, L2, or L3 is optionally substituted. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0107] In either embodiment, the compound is of formula (VIII): AY-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (VIII) [In the formula, A is a portion selected from A1 and A2 as defined herein, Y [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; n is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; q is either 0 or 1; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0108] In any embodiment, the compound is of formula (IX): A1-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (IX) [In the formula, A1 is represented by a part A1 defined for equation (I), Y [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; n is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; q is either 0 or 1; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0109] In one embodiment, the compound is a compound of formula (VIII) or (IX). [In the formula, R6 and R7 are H; R9 and R 10 Both are single bonds; z is 1; X is S. The salt, solvate, or prodrug thereof, the salt, solvate, or prodrug thereof, the salt, solvate, or prodrug thereof. In any embodiment, the compound is of formula (X): Pam2Cys-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (X) [In the formula, Pam2Cys structure: [ka] Having; Y: [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; If q=1, then R3 is H, -NH2, or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0110] In any embodiment, the compound is of formula (XI): Pam2Cys-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (XI) [In the formula, Pam2Cys structure: [ka] Having; Y: [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and where R1 and R2 are not both H; n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; If q=1, then R3 is H, -NH2, or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0111] In any embodiment, the compound is of formula (XII): Pam2Cys-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (XII) [In the formula, Pam2Cys structure: [ka] Having; Y: [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; If q=1, then R3 is H, -NH2, or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0112] In any embodiment, the compound is of formula (XIII): Pam2Cys-Ser-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (XIII) [In the formula, Pam2Cys-Ser has the following structure: [ka] Having; n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0113] In one embodiment, the compound is given by formula (XIV): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It is expressed as, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0114] In one embodiment, the compound is given by formula (XV): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either zero or consists of 1 to 10 units, where each unit is a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain or second hydrogen of an amino acid; b and w are independent integers between 0 and 7, and v is an integer between 0 and 5, where: The sum of b, v, and w is at least 3; The sum of b and w is between 0 and 7; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each of cases b, v, w, and z 11 , R 12 , Rx , R y , R 14 , R 15 , R 16 , and R 17 Each of these is independently H or C1-C6 aliphatic; R, R 13 and R 18 Each of these is independently H or C1-C6 aliphatic; R 19 However, it is H, C1-C6 aliphatic, amino protecting group, L3-C(=O)-, or A2; L1 and L2 operate independently, C5~C 21 Aliphatic or C4~C 20 It is heterolipid; L3 is C1~C 21 Aliphatic or C2-C 20 It is heterolipid; A2 is an amino acid or peptide; Here, R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y Any aliphatic or heteroaliphatic element present in L1, L2, or L3 is optionally substituted. How is it represented? or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0115] In any embodiment, the compound is of formula (XVI): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are independently selected from the group consisting of H, linear or branched C1-C4 alkyl groups, and -C(=O)CH3; R9 and R 10 However, these are independently selected from the group consisting of -NH-, -O-, or single bonds; z is either 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0116] In any embodiment, the compound is of formula (XVII): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R6 and R7 are H; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; R9 and R 10 Both are single bonds; z is 1; X is S; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0117] In either embodiment, the compound is of formula (XVIII): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; R6 and R7 are H; R9 and R 10 Both are single bonds; z is 1; X is S; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0118] In any embodiment, the compound is of formula (XIX): [ka] [In the formula, n is between 3 and 100; k is between 3 and 100; m is 1, 2, 3, or 4; Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18; p is 2, 3, or 4; t is 2, 3, or 4; h is 1, 2, 3, or 4; q is either 0 or 1; R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, and -CH2OPO(OH)2, where one of the alkyl hydrogens may be substituted with a halogen, and R1 and R2 are not both H; If q=1, R3 is either -NH2 or -OH; If q=0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It may be a compound of the same or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0119] In one embodiment, any compound disclosed herein containing polyethylene glycol (PEG) (including any one compound of formulas (I) to (XIX)) may include PEG in the form of substituted PEG.

[0120] In one embodiment, the substitution PEG is subformula BI: [ka] [In the formula, n is between 3 and 100; m is 1, 2, 3, or 4; p is 2, 3, or 4; q is either 0 or 1; If R3 is H, -NH2, or -OH and q is 0, then R3 is H; if q is 1, then R3 is -NH2 or -OH; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It is represented by [this].

[0121] In one embodiment, the substitution PEG is subformula B-II: [ka] [In the formula, p is 2, 3, or 4; n is between 3 and 100; m is 1, 2, 3, or 4; t is 2, 3, or 4; k is between 3 and 100; h is 1, 2, 3, or 4; q is either 0 or 1; If q is 1, then R3 is -NH2 or -OH; If q is 0, then R3 is H; L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: [ka] It is represented as, In the equation, R4 is H; R5 is the side chain of the amino acid, or the second hydrogen atom. It is represented by [this].

[0122] In embodiments of the substitution PEG of formula BI or B-II, q is 1.

[0123] In some embodiments of the substitution PEG of formula BI or B-II, n may be 10 to 14, for example 11, or 24 to 30, for example 27.

[0124] In some embodiments of the substitution PEG of formula BI or B-II, m is 1 to 3, for example, 2.

[0125] In an embodiment with a substituted PEG of formula BI or B-II, if q is 1, then R3 is -NH2.

[0126] In embodiments of substituted PEG of formula BI or B-II, L is a native α-amino acid residue.

[0127] The compounds described herein may exist and be isolated in optically active and racemic forms. As will be understood by those skilled in the art, the present invention is intended to encompass any racemic, optically active, or stereoisomerous, or mixture thereof, of the compounds of the present invention having the useful properties described herein. Methods for preparing such forms (e.g., by separation of racemic mixtures by recrystallization, synthesis from optically active starting materials, chiral synthesis, or chiral chromatographic separation) are well known in the art. In some embodiments, the composition may contain compounds in enantio or diastereomeric forms. For example, the compounds may have enantiomeric excess (ee) or diastereomeric excess (de) of at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. In one embodiment, the compound can be enriched by at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% at any stereocenter of the compound.

[0128] In any embodiment, the compound has the following chiral center ( * (As shown by): [ka] It may contain a chiral center around it. In the formula, the chiral center has an R configuration. Compounds in this form may also be called R-Pam2 analog diastereomers of the compounds of the present invention described herein. [ka] It can be shown as follows.

[0129] In either embodiment, the compound has a chiral center in the 2,3-bis(palmitoyloxy)propyl moiety of Pam2Cys ( * (As shown by): [ka] May include, In the formula, the chiral center has an R configuration. This form of compound is also called the R-Pam2 diastereomer of the compounds of the present invention described herein. [ka] It can be shown as follows.

[0130] In any embodiment, the compound has the following chiral center ( * (As shown by): [ka] It may contain a chiral center around it. In the formula, the chiral center has an S configuration. Compounds in this form may also be called S-Pam2 analog diastereomers of the compounds of the present invention described herein. [ka] It can be shown as follows.

[0131] In either embodiment, the compound has a chiral center in the 2,3-bis(palmitoyloxy)propyl moiety of Pam2Cys ( * (As shown by): [ka] Includes, In the formula, the chiral center has an S configuration. Compounds in this form may also be called S-Pam2 diastereomers of the compounds of the present invention described herein. [ka] It can be shown as follows.

[0132] In any embodiment, the compound has the following chiral center ( * (As shown by): [ka] Including the chiral center around it, In the formula, the chiral center has an L configuration. This form of compound can also be called the L-Cys analog diastereomer of Pam2Cys of the compound of the present invention. [ka] It can be shown as follows.

[0133] In either embodiment, the compound has a chiral center at the cysteine ​​residue of Pam2Cys ( * (As shown by): [ka] Includes, In the formula, the chiral center has an L configuration. This form of compound may also be called the L-Cys diastereomer of the Pam2Cys compound of the present invention. [ka] It can be shown as follows.

[0134] Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0135] In any embodiment, the compound has the following chiral center ( * (As shown by): [ka] Including the chiral center in part A1 around it, In the formula, the chiral center has a D configuration. Compounds in this form may also be called D-Cys analog diastereomers of Pam2Cys of the compounds described herein. This is, [ka] It can be shown as follows.

[0136] Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0137] In either embodiment, the compound has a chiral center at the cysteine ​​residue of Pam2Cys ( * (As shown by): [ka] Includes, In the formula, the chiral center has a D configuration. Compounds in this form may also be called D-Cys diastereomers of Pam2Cys of the compounds described herein. This is, [ka] It can be shown as follows.

[0138] Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0139] In any aspect or embodiment of the present invention, the compound of the present invention has the following chiral centers in carbon atoms of partial A2: * (As shown by): [ka] It may be provided in an enriched chiral form. In the formula, the chiral center has an R configuration. In one embodiment, this stereoisomer of the compound is [ka] It can be shown as, in the formula, L1, L2, Z1, Z2, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 b, v, and z are as defined for the compound of formula (I), and w is 1. The other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0140] In any aspect or embodiment of the present invention, the compound of the present invention has the following chiral centers in carbon atoms of partial A2: * (As shown by): [ka] It may be provided in an enriched chiral form. In the formula, the chiral center has an S configuration. In one embodiment, part A of this stereoisomer of the compound is [ka] It can be shown as, in the formula, L1, L2, Z1, Z2, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 b, v, w, and z are as defined for the compound or formula (I). Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0141] In any aspect or embodiment of the present invention, the compound of the present invention has the following chiral centers in carbon atoms of partial A2: ** (As shown by): [ka] It may be provided in an enriched chiral form. In the formula, the chiral center has an L configuration. Compounds in this form may also be called L-Cys analog stereoisomers of the compound of the present invention. In one embodiment, this stereoisomer of the compound is [ka] It can be shown as, in the formula, L1, L2, Z1, Z2, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 b, v, w, and z are as defined for the compound or formula (I). Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0142] In any aspect or embodiment of the present invention, the compound of the present invention has the following chiral centers in carbon atoms of partial A2: ** (As shown by): [ka] It may be provided in an enriched chiral form. In the formula, the chiral center has a D configuration. Compounds in this form may also be called D-Cys analog stereoisomers of the compounds of the present invention. In one embodiment, part A of this stereoisomer of the compound is [ka] It can be shown as, in the formula, L1, L2, Z1, Z2, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 b, v, and z are as defined for the compound or formula (I), and w is 1. Other stereocenters in these compounds may be racemic or enriched with either R or S configurations.

[0143] In any embodiment, the compound has a chiral center in the Y portion of the compound ( * (As shown by): [ka] Includes, In the formula, the chiral center has an L configuration. Compounds in this form may also be called LY diastereomers of the compounds of the present invention described herein.

[0144] In any embodiment, the compound has a chiral center in the Y portion of the compound ( * (As shown by): [ka] Includes, In the formula, the chiral center has a D configuration. Compounds in this form may also be called DY diastereomers of the compounds described herein.

[0145] In any embodiment, a composition comprising a compound of the present invention (including any one compound of formulas (I) to (XIX)) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, may be used in the method or use of the present invention.

[0146] In one embodiment, the compound described herein is an R diastereomer around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.

[0147] In one embodiment, the compounds described herein are S-diastereomers around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.

[0148] In any embodiment, the compositions described herein include a compound that is an R diastereomer around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.

[0149] In any embodiment, the composition comprises a compound that is an S-diastereomer around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.

[0150] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is the R diastereomer around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.

[0151] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is an S-diastereomer around the chiral center of the 2,3-bis(palmitoyloxy)propyl moiety (e.g., moiety A1) of the compound.

[0152] In any embodiment, the compounds described herein are L-diastereomers around the chiral center of a cysteine ​​analog residue in the Pam2Cys analog moiety (e.g., moiety Y) of the compound.

[0153] In any embodiment, the compounds described herein are L-diastereomers around the chiral center of a cysteine ​​residue in the Pam2Cys portion (e.g., portion Y) of the compound.

[0154] In any embodiment, the compounds described herein are D-diastereomers around the chiral center of a cysteine ​​analog residue in the Pam2Cys analog moiety (e.g., moiety Y) of the compound.

[0155] In any embodiment, the compounds described herein are D-diastereomers around the chiral center of a cysteine ​​residue in the Pam2Cys portion (e.g., portion Y) of the compound.

[0156] In any embodiment, the compositions described herein include a compound that is an L-diastereomer around the chiral center of a cysteine ​​analog residue of the Pam2Cys analog moiety (e.g., moiety Y) of the compound.

[0157] In any embodiment, the compositions described herein include a compound that is an L-diastereomer around the chiral center of a cysteine ​​residue in the Pam2Cys portion (e.g., portion Y) of the compound.

[0158] In any embodiment, the compositions described herein include a compound that is a D-diastereomer around the chiral center of a cysteine ​​analog residue of the Pam2Cys analog moiety (e.g., moiety Y) of the compound.

[0159] In any embodiment, the compositions described herein include a compound that is a D-diastereomer around the chiral center of a cysteine ​​residue in the Pam2Cys portion (e.g., portion Y) of the compound.

[0160] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is the L-diastereomer around the chiral center of the cysteine ​​analog residue of the Pam2Cys analog moiety of the compound.

[0161] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is an L-diastereomer around the chiral center of the cysteine ​​residue of the Pam2Cys moiety of the compound.

[0162] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is a D-diastereomer around the chiral center of the cysteine ​​analog residue of the Pam2Cys analog moiety of the compound.

[0163] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is a D-diastereomer around the chiral center of the cysteine ​​residue of the Pam2Cys moiety of the compound.

[0164] In any embodiment, the compound of the present invention is an L-diastereomer around the chiral center of the Y portion.

[0165] In any embodiment, the compounds described herein are D-diastereomers around the chiral center of the Y moiety.

[0166] In any embodiment, the compositions described herein include a compound that is an L-diastereomer around a chiral center of the Y-moon.

[0167] In any embodiment, the compositions described herein include a compound that is a D-diastereomer around a chiral center of the Y portion.

[0168] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is the L diastereomer around the chiral center of the Y moiety.

[0169] In any embodiment, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the compound present in the composition is a D-diastereomer around the chiral center of the Y portion.

[0170] The compounds of formulas (I) to (XIX) described herein can demonstrate considerable stability in solution. This solution stability can be observed by storing solutions of the compounds for at least about 14 days under ambient storage conditions (e.g., at 25°C) or under accelerated degradation stability (e.g., at 40°C).

[0171] In any embodiment, any of the compounds described herein may be administered in the form of a pharmaceutically acceptable salt.

[0172] The term "pharmaceutically acceptable" may be used to describe any pharmaceutically acceptable salt, hydrate, or prodrug, or any other compound, that, when administered to a subject, is capable of providing (directly or indirectly) the compounds of the present invention described herein, or their pharmaceutically acceptable salts, prodrugs, or esters, or their active metabolites or residues.

[0173] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0174] Examples of base salts, though not limited to them, include those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, and ammonium; alkylammonium salts such as those formed from triethylamine; alkoxyammonium salts such as those formed with ethanolamine; and salts formed from amino acids such as ethylenediamine, choline or arginine, lysine, or histidine. General information regarding the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is found in general texts such as "Handbook of Pharmaceutical Salts" PHStahl, CGWermuth, 1st edition, 2002, Wiley-VCH.

[0175] In the case of solid compounds, it will be understood by those skilled in the art that the compounds, agents, and salts of the present invention may exist in different crystalline forms or polymorphs, all of which are intended to be within the scope of the present invention and the prescribed formulas.

[0176] The term "polymorph" includes any crystalline form of the compounds of the present invention as described herein, such as anhydrous form, hydrated form, solvate form, and mixed solvate form.

[0177] The compounds of the present invention described herein are intended to include solvated and non-solvated forms of the compounds, where applicable. Accordingly, the compounds of the present invention described herein include compounds having the indicated structure, including hydrated or solvated forms, as well as unhydrated and non-solvated forms.

[0178] As used herein, the term “solvate” refers to a variable stoichiometric complex formed by a solute (in the present invention, the compounds of the present invention as described herein, or a pharmaceutically acceptable salt, prodrug, or ester thereof) and a solvent. Such solvents for the present invention should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. Most preferably, the solvent used is water.

[0179] Basic nitrogen-containing groups can be quaternized with substances such as chloride, bromide, and halogenated lower alkyls like methyl, ethyl, propyl, and butyl; and dialkyl sulfates like dimethyl sulfate and diethyl sulfate.

[0180] The compounds described herein include isotopic forms such as hydrogen substitution of deuterium.

[0181] A “prodrug” is a compound that may not fully meet the structural requirements of the compounds provided herein, but which, after administration to a subject or patient, is modified in vivo to produce the compounds of the present invention as described herein. For example, a prodrug may be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group, which, upon administration to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs, but not limited to, include acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compound, such that the modification is cleaved in vivo to produce the parent compound.

[0182] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino and amide group of any of the compounds of formulas (I) to (XIX). The amino acid residues include the 20 natural amino acids commonly represented by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norbuline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which a carbonate, carbamate, amide, or alkyl ester is covalently bonded to the above substituents of the compounds described herein, including the compounds of formulas (I) to (XIX), or to other structures shown herein.

[0183] The general chemical terms used in the formulas herein have their usual meanings.

[0184] The term "aliphatic" is intended to include saturated and unsaturated, non-aromatic, linear, branched, acyclic, and cyclic hydrocarbons. Those skilled in the art will understand that aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, as well as their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl groups. In various embodiments, the aliphatic group contains 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In some embodiments, the aliphatic group contains 5 to 21, 9 to 21, or 11 to 21 carbon atoms, for example, 11, 13, 15, 17, or 19 carbon atoms. In some embodiments, the aliphatic group is saturated.

[0185] The term "heteroaliphatic" is intended to describe an aliphatic group in which one or more chain and / or ring carbon atoms are independently substituted with heteroatoms, preferably selected from oxygen, nitrogen, and sulfur. In some embodiments, the heteroaliphatic group is saturated. Examples of heteroaliphatic groups include linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.

[0186] The term "alkyl" is intended to include saturated linear and branched hydrocarbon groups. In some embodiments, the alkyl group has 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In some embodiments, the alkyl group has 5 to 21, 9 to 21, or 11 to 21 carbon atoms, for example, 11, 13, 15, 17, or 19 carbon atoms. Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

[0187] The term "alkenyl" is intended to include linear and branched alkyl groups having at least one double bond between two carbon atoms. In some embodiments, the alkenyl group has 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms. In some embodiments, the alkenyl group has 5-21, 9-21, or 11-21 carbon atoms, for example, 11, 13, 15, 17, or 19 carbon atoms. In some embodiments, the alkenyl group has 1, 2, or 3 carbon-carbon double bonds. Examples of alkenyl groups, but not limited to, include vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, and -C(CH3)=CH(CH3).

[0188] The term "alkynyl" is intended to include linear and branched alkyl groups having at least one triple bond between two carbon atoms. In some embodiments, the alkynyl group has 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms. In some embodiments, the alkynyl group has 1, 2, or 3 carbon-carbon triple bonds. Examples, but not limited to, include -C=CH, -C=CH3, -CH2C=CH3, and -C=CH2CH(CH2CH3)2.

[0189] The term "heteroalkyl" is intended to refer to alkyl groups in which one or more chain carbon atoms are substituted with heteroatoms, preferably heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroalkyl group is saturated. Examples of heteroalkyl groups include polyethylene glycol groups and polyethylene glycol ether groups.

[0190] The term "cycloalkyl" is intended to include monocyclic, bicyclic, or tricyclic alkyl groups. In some embodiments, a cycloalkyl group has 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 5 carbon atoms in the ring. In some embodiments, a cycloalkyl group has 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, a cycloalkyl group has 3 to 8, 3 to 7, 3 to 6, 4 to 6, 3 to 5, or 4 to 5 ring carbon atoms. Bicyclic and tricyclic ring systems include bridged, spiro, and condensed cycloalkyl ring systems. Examples of bicyclic and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and dekalinyl.

[0191] The term "cycloalkenyl" is intended to include non-aromatic cycloalkyl groups having at least one double bond between two carbon atoms. In some embodiments, the cycloalkenyl group has one, two, or three double bonds. In some embodiments, the cycloalkenyl group has 4-14, 5-14, 5-10, 5-8, or 5-6 carbon atoms in the ring. In some embodiments, the cycloalkenyl group has 5, 6, 7, or 8 ring carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0192] The term "aryl" is intended to include cyclic aromatic hydrocarbon groups that do not contain any ring heteroatoms. Aryl groups include monocyclic, bicyclic, and tricyclic ring systems. Examples of aryl groups, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, fluorenyl, phenantrenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl. In some embodiments, the aryl group has 6 to 14, 6 to 12, or 6 to 10 carbon atoms in the ring. In some embodiments, the aryl group is phenyl or naphthyl. Aryl groups include aromatic aliphatic fused ring systems. Examples, but are not limited to, indanyl and tetrahydronaphthyl.

[0193] The term "heterocyclyl" is intended to include non-aromatic ring systems containing three or more ring atoms (one or more of which are heteroatoms). In some embodiments, the heteroatoms are nitrogen, oxygen, or sulfur. In some embodiments, the heterocyclyl group contains one, two, three, or four heteroatoms. In some embodiments, the heterocyclyl group includes monocyclic, bicyclic, and tricyclic rings having 3-16, 3-14, 3-12, 3-10, 3-8, or 3-6 ring atoms. The heterocyclyl group includes partially unsaturated and saturated ring systems, e.g., imidazolinyl and imidazolidinyl. The heterocyclyl group includes condensed and bridging ring systems containing heteroatoms, e.g., quinuclidyl. Examples of heterocyclyl groups, though not limited to them, include azilidinyl, azetidinyl, azepanil, diazepanil, 1,3-dioxanil, 1,3-dioxolanil, isoxazolidinyl, morpholinil, piperazinyl, piperidinyl, pyranil, pyrazolidinyl, pyrrolinil, pyrrolidinyl, tetrahydrofuranil, tetrahydrothienyl, thiadiazolidinyl, and trithianil.

[0194] The term "heteroaryl" is intended to include aromatic ring systems containing five or more ring atoms (one or more of which are heteroatoms). In some embodiments, the heteroatoms are nitrogen, oxygen, or sulfur. In some embodiments, heteroaryl groups include monocyclic, bicyclic, and tricyclic ring systems having 5-16, 5-14, 5-12, 5-10, 5-8, or 5-6 ring atoms. Examples of heteroaryl groups, though not limited to them, include pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridinyl xanthinyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups include fused ring systems where all rings are aromatic, such as indolyl, and fused ring systems where only one ring is aromatic, such as 2,3-dihydroindolyl.

[0195] The term "halo" or "halogen" is intended to include F, Cl, Br, and I.

[0196] The term “heteroatom” is intended to include oxygen, nitrogen, sulfur, or phosphorus. In some embodiments, the heteroatom is selected from the group consisting of oxygen, nitrogen, and sulfur.

[0197] As used herein, the term “substitution” is intended to mean that one or more hydrogen atoms in a represented group are substituted with one or more independently selected suitable substituents, provided that the substituent does not exceed the normal valence of each atom to which it is bonded, and that the substitution results in a stable compound. In some embodiments, any substituents in the compounds described herein, but are not limited to, halo, CN, NO2, OH, NH2, and NHR 100 , NR 100 R 200 , C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C(O)NH2, C(O)NHR 100 , C(O)NR 100 R 200 SO2R 100 , OR 100 , SR 100 S(O)R 100 , C(O)R 100 , and C 1~6 Aliphatic elements are mentioned; here, R 100 and R 200 Each of them operates independently, C 1~6 Aliphatic, for example, C 1~6 It is alkyl.

[0198] When a protecting group (PG) is indicated, those skilled in the art will readily understand which type of protecting group is preferable.

[0199] As used herein, the term “amine protecting group” is intended to mean a group that can be readily removed to provide the NH2 group of the amine group and protects the amine group from undesirable reactions during the synthetic procedure. Such protecting groups are described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1999), edited by TW Greene et al., and in ‘Amino Acid-Protecting Groups’ Chemical Reviews 2009(109)2455–2504 by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez). Examples include, but are not limited to, acyl and acyloxy groups, such as acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyl, aminocaproyl, benzoyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and 2,4-dichlorobenzyloxycarbonyl. Further examples include Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl), and Dde (1-(4,4-dimethyl-2,6-dioxohexylidene)ethyl). In some embodiments, amine protecting groups for the purposes described herein include, but are not limited to, tert-butyloxycarbonyl (t-Boc) and 9H-fluoren-9-ylmethoxycarbonyl (Fmoc).

[0200] As used herein, the term “carboxyl protecting group” is intended to mean a group that can be readily removed to provide the OH group of the carboxyl group and protects the carboxyl group from undesirable reactions during the synthetic procedure. Such protecting groups are described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1999), edited by TW Greene et al., and in ‘Amino Acid-Protecting Groups’ Chemical Reviews 2009(109)2455-2504 by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez). Examples, but not limited to, include alkyl and silyl groups, such as methyl, ethyl, tert-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl.

[0201] As used herein, the term “carboxamide protecting group” is intended to mean a group that can be readily removed to provide the NH2 group of the carboxamide group and protects the carboxamide group from undesirable reactions during the synthetic procedure. Such protecting groups are described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1999), edited by TW Greene et al., and in ‘Amino Acid-Protecting Groups’ Chemical Reviews 2009(109)2455-2504 by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez). Examples, but not limited to, include 9-xanthenyl (Xan), trityl (Trt), methyltrityl (Mtt), cyclopropyldimethylcarbinyl (Cpd), and dimethylcyclopropylmethyl (Dmcp).

[0202] The term "ester" refers to a carboxylic acid group in which the hydrogen atoms of the hydroxyl group are substituted with saturated, straight-chain (i.e., linear) or branched hydrocarbon groups. Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and 2,2-dimethylbutyl. Alkyl groups can be C1-C6 alkyl groups. As used herein, terms specifying limit values ​​for length ranges, such as "1-5," mean any integer between 1 and 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by two explicitly stated integers includes and discloses any integer defining the limit value and any integer included in the range. Alkyl groups can be branched alkyl groups.

[0203] In this specification, "Ser" refers to the amino acid serine, and "Cys" refers to the amino acid cysteine.

[0204] As used herein, “PEG” refers to the polymer compound polyethylene glycol. Unless otherwise defined, references to “PEG” include polymers of ethylene oxide of any length. References to PEG also include substituted PEGs. In some embodiments, substituted PEGs may be defined by formulas BI or B-II as described herein.

[0205] As used herein, the term "and / or" means "and," or "or," or both.

[0206] The term "(s)" following a noun refers to the singular and plural forms, or both.

[0207] References to numerical ranges disclosed herein (e.g., 1 to 10) also incorporate references to all rational numbers within that range (e.g., 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, and 10), and further references to any range of rational numbers within that range (e.g., 2 to 8, 1.5 to 5.5, and 3.1 to 4.7), and thus all subranges of all ranges expressly disclosed herein are intended to be expressly disclosed herein. These are merely examples of those specifically intended, and all possible combinations of numerical values ​​between the listed minimum and maximum values ​​are similarly deemed to be expressly described herein.

[0208] [Dosage and Administration] In one embodiment of the present invention, a therapeutically effective amount of any compound described herein is administered to a subject.

[0209] Administration refers to the physical introduction of a composition containing a therapeutic agent into a target using any of the various methods and delivery systems known to those skilled in the art, including those described herein. Pharmaceutical compositions may be formulated from the compounds of the present invention described herein for any suitable route of administration. Typically, in addition to the therapeutic agent (e.g., the compounds described herein), the pharmaceutical composition includes pharmaceutically acceptable excipients, carriers and / or diluents. Examples of suitable components for inclusion in pharmaceutical compositions are given in Martindale—The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.

[0210] Preferred routes of administration for carrying out the prescribed methods include oral, intravenous, respiratory (including inhalation and intranasal) (e.g., for administration to the airways, particularly the lower airways, particularly the lungs), intramuscular, topical, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the term “parenteral administration” usually means, but is not limited to, methods of administration other than intestinal and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intrafocal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. Administration may also be, for example, one, multiple, and / or over one or more extended periods.

[0211] Any composition described herein may be formulated for administration into the airways, in other words, via the respiratory route. Where administration to all or part of the airways is envisioned, those skilled in the art will understand that this includes intranasal or inhalation administration, particularly for administration to the lungs. Compositions described herein may be formulated for intranasal administration, including dry powders, sprays, mists, or aerosols.

[0212] For example, a preferred formulation for administration as a nasal spray or nasal medication, in which the carrier is liquid, contains an aqueous or oily solution of the active ingredient. Alternatively, the composition may be a dry powder and may be administered only to the airways, as specified herein.

[0213] The selection of an appropriate carrier depends on the specific type of administration envisioned. For administration via the airway, e.g., the nasal mucosa, the compound may be formulated as a solution, e.g., water or buffered or unbuffered isotonic saline, or as a suspension for intranasal administration as a dropper or spray. Preferably, such a solution or suspension is isotonic with respect to nasal secretions, e.g., with approximately the same pH in the range of about pH 4.0 to about pH 7.4 or pH 6.0 to pH 7.0. The buffer should be physiologically compatible, and phosphate buffer is merely an example. For example, a typical nasal decongestant is described as being buffered to a pH of about 6.2 (Remington's, Id., page 1445). Naturally, those skilled in the art can easily determine suitable saline content and pH for non-toxic aqueous carriers for intranasal and / or respiratory administration.

[0214] Other components, such as preservatives, colorants, lubricants, or natural or synthetic plant extracts such as viscous mineral or vegetable oils, fragrances, and aromatic oils known in the art, as well as humectants and viscosity enhancers such as glycerol, may also be included to provide further viscosity, moisture retention, and a desirable texture and fragrance of the formulation. For nasal administration of the solution or suspension according to the present invention, various devices for generating drops, liquids, and sprays are available in the art. For example, the compounds or compositions described herein may be administered into the nasal cavity by a manual pump, for example, a simple dropper (or pipette) containing a glass, plastic, or metal distribution pipe that releases the contents drop by drop by air pressure provided by a flexible rubber bulb attached to one end.

[0215] Since ocular tear secretion flows from the orbit into the nasal cavity, a suitable pharmaceutically acceptable ophthalmic solution may, if desired, be readily provided by those skilled in the art as a carrier for the compounds or compositions described herein to be delivered, and may be administered orbitally in the form of eye drops for both intraocular and intranasal administration.

[0216] In one embodiment, a pre-measured unit dose dispenser, including a dropper or spray device containing a solution or suspension for delivery as a dropper or spray, is prepared containing one or more doses of the drug to be administered. The present invention also includes a kit containing one or more unit dry doses of a compound, ready to be prepared by adding a suitable amount of water, together with any necessary salts and / or buffers, preservatives, colorants, etc. The water may be sterile or non-sterile, but sterile water is generally preferred.

[0217] The terms “therapeutic dose” or “effective dose” generally refer to any amount of any compound, its pharmaceutically acceptable salt, polymorph, or prodrug described herein that (i) treats a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. Undesirable effects, such as side effects, may sometimes occur along with the desired therapeutic effect; therefore, physicians should balance the potential benefits against the potential risks when determining what constitutes an appropriate “effective dose.”

[0218] For example, for the treatment of a tumor, a therapeutically effective amount of the compound or composition described herein may inhibit tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% or more compared to an untreated subject. Alternatively, the treatment described herein may cause a complete reduction in tumor volume. In other embodiments of the present invention, tumor reduction may be observed and continue for a period of at least about 10 days, at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days or more.

[0219] The therapeutically effective dose of a drug includes a “prophylactic dose” or “prophylactically effective dose,” which is any amount of any compound described herein administered to a subject at risk of developing cancer (e.g., a subject with a pre-malignant condition) or a subject with recurrent cancer, that inhibits the development or recurrence of cancer. In certain embodiments, a prophylactically effective dose completely prevents the development or recurrence of cancer. To “inhibit” or “prevent” the development or recurrence of cancer means either to reduce the likelihood of developing or recurring cancer, or to completely prevent the development or recurrence of cancer.

[0220] The required precise therapeutic dose can vary depending on the subject's species, age, and overall condition, as well as the method of administration. Therefore, it would be impossible to prescribe a precise therapeutic dose. However, the appropriate therapeutic dose in any particular case can be determined by those skilled in the art simply by using routine experiments. In one embodiment, the dose administered to a subject is any therapeutic dose that reduces cancer-related symptoms as a result of any one of the following: a reduction in the number of cancer cells; a reduction in tumor size; inhibition (i.e., delaying, preferably stopping) of cancer cell invasion into peripheral organs; inhibition (i.e., delaying, preferably stopping) of tumor metastasis; some degree of inhibition of tumor growth; or mitigation of one or more cancer-related symptoms. In addition to or instead of this, the therapeutic dose may result in an increase in the subject's survival time.

[0221] In one embodiment, the therapeutically effective dose of any compound described herein for human subjects is in the range of about 250 nanomoles / kg body weight / administered to 0.005 nanomoles / kg body weight / administered. Preferably, the range is about 250 nanomoles / kg body weight / administered to 0.05 nanomoles / kg body weight / administered. In one embodiment, the body weight / administered range is about 250 nanomoles / kg to 0.1 nanomoles / kg, about 50 nanomoles / kg to 0.1 nanomoles / kg, about 5 nanomoles / kg to 0.1 nanomoles / kg, about 2.5 nanomoles / kg to 0.25 nanomoles / kg, or about 0.5 nanomoles / kg to 0.1 nanomoles / kg body weight / administered. In one embodiment, the amount is 250 nanomoles, 50 nanomoles, 5 nanomoles, 2.5 nanomoles, 0.5 nanomoles, 0.25 nanomoles, 0.1 nanomoles, or 0.05 nanomoles / kg body weight / administered, or approximately such amounts of the compound. The medication plan may be adjusted to suit the needs of the situation and to provide the optimal therapeutic dose.

[0222] Typically, therapeutically effective doses are formulated to contain concentrations (by weight) of at least about 0.1% to a maximum of about 50% or more, and all combinations and partial combinations within that range. Compositions may be formulated to contain one or more compounds, or pharmaceutically acceptable salts, polymorphs or prodrugs thereof, in concentrations of about 0.1% to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations ranging from about 0.1%, for example, more than about 0.2, 0.3, 0.4 or 0.5%, to about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or less. Exemplary compositions may contain about 0.5% to about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or less than 20%, with concentrations ranging from about 0.5%, for example, more than about 0.6, 0.7, 0.8, 0.9 or 1%, to about 20%, for example, less than about 19, 18, 17, 16, 15, 14, 13, 12, 11 or less than 10%. Compositions may contain about 1%, for example, more than about 2%, to about 10%, for example, less than about 9 or 8%, including concentrations ranging from about 2%, for example, more than about 3 or 4%, to about 8%, for example, less than about 7 or 6%. The active agent may be present at a concentration of, for example, about 5%. In all cases, the amount may be adjusted to compensate for any difference in the amount of active ingredient actually delivered to the treated cells or tissues.

[0223] In one embodiment, treatment with any compound disclosed herein is continued for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

[0224] It will be understood that the specific dose level for any particular patient may vary depending on various factors, including the activity of the specific compound used, age, weight, overall health, sex, dietary habits, administration time, route of administration, and excretion rate, combination drugs (i.e., other drugs used to treat the patient), and the severity of the specific disorder during treatment.

[0225] The terms “treatment” or “to treat” include the application or administration of the compounds of the present invention to a subject with the aim of delaying, slowing, stabilizing, curing, resolving, mitigating, altering, treating, preventing, easing, improving, or acting upon a disease or condition, symptoms of a disease or condition, or the risk (or susceptibility to such risk) of a disease or condition. The term “to treat” means any indicator of success in treating or improving an injury, condition or condition, including any objective or subjective parameters such as: mitigation; remission; slower rate of exacerbation; reduced severity of the disease; stabilization, reduction or improvement of symptoms or making the injury, condition or condition more tolerable to the subject; slower rate of exacerbation or debilitation; mitigation of debilitation at the end of exacerbation; or improvement of the subject’s physical or mental health.

[0226] As used herein, minimizing or preventing cancer progression means treating a subject to prevent or delay recurrence or metastasis of a tumor, or to prevent an existing tumor. Minimizing or preventing cancer progression includes preventing or delaying recurrence of cancer after treatment for cancer, or preventing the growth of an existing tumor. Prevented recurrence includes, for example, recurrence in the tumor bed after surgical resection. Alternatively, recurrence includes metastasis of cancer to another part of the body. As used herein, the terms “prevent recurrence” and “prevent relapse” are synonymous.

[0227] The present invention also includes methods for preventing the development of cancer in an individual. For example, an individual who needs cancer prevention may be considered to be at risk of developing cancer but does not yet have a detectable cancer. An individual at risk of developing cancer may be an individual with a family history of cancer, and / or an individual whose genetic testing or other tests indicate a high risk or high probability of developing cancer. An individual may have cancer stem cells but does not yet have any detectable tumors. It will be understood that methods for preventing the development of cancer include methods for delaying the development of cancer in a subject.

[0228] The terms “subject,” “individual,” and “patient” will be understood to be synonymous. Although the present invention applies to humans, it is also useful for therapeutic veterinary purposes. The present invention is useful for livestock or farm animals such as cattle, sheep, horses, and poultry; companion animals such as cats and dogs; and zoo animals.

[0229] [cancer] The term "cancer" will be understood to include benign, precancerous, precancerous, non-metastatic, or metastatic tumors.

[0230] In one embodiment, the types of cancer being treated include cancers having benign, precancerous, precancerous, or non-metastatic tumors. A benign tumor will be understood as one that is not malignant, does not invade adjacent tissues, or does not spread to other parts of the body. Similarly, a non-metastatic cancer will be understood as one that does not invade adjacent tissues or spread to other parts of the body. "Precancerous condition" or "precancerous" generally refers to a condition or proliferation that typically precedes or develops into cancer. "Precancerous" proliferation may have cells characterized by abnormal cell cycle regulation, proliferation, or differentiation, which may be determined by cell cycle markers.

[0231] In one embodiment, the cancer is a secondary cancer or metastasis. Secondary cancers may be located in any organ or tissue, particularly in organs or tissues with relatively high hemodynamic pressure, such as the lungs, liver, kidneys, pancreas, intestines, and brain. Secondary cancers may be detected in ascites and / or lymph nodes.

[0232] One embodiment of the present invention includes a step of identifying a subject having cancer. This may include identifying a precancerous condition or precancerous growth, secondary cancer, or metastasis.

[0233] Precancerous, neoplastic, and metastatic cancers are specific examples to which the methods of the present invention may be applied. Broad examples include breast tumors, colorectal tumors, adenocarcinomas, mesotheliomas, bladder tumors, prostate tumors, germ cell tumors, hepatocellular carcinoma / cholangiocarcinoma, carcinomas, neuroendocrine tumors, pituitary tumors, small round cell tumors, squamous cell carcinomas, melanomas, atypical fibroxanthomas, seminomas, non-seminomas, stromal Leydig cell tumors, Sertoli cell tumors, skin tumors, kidney tumors, testicular tumors, brain tumors, ovarian tumors, gastric tumors, oral tumors, bladder tumors, bone tumors, cervical tumors, esophageal tumors, laryngeal tumors, liver tumors, lung tumors, vaginal tumors, and Wilms' tumor.

[0234] Examples of specific cancers, though not limited to them, include adenocarcinoma, adenoma, adenofibrilloma, adenolymphoma, odontoma, AIDS-related cancer, acoustic neuroma, acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, idiopathic myelometaplasia, alopecia, hydatidiform soft part sarcoma, ameloblastoma, angiokeratomas, paraeosinophilic angiolymphoproliferative disorder, sclerosing hemangioma, hemangioma, apdoma, anal cancer, angiosarcoma, aplastic anemia, astrocytoma, ataxia telangiectasia, basal cell carcinoma (skin), bladder cancer, bone cancer, intestinal cancer, brainstem glioma, brain and CNS tumors, breast cancer, branchiomas, CNS tumors, carcinoid tumors, and cervical cancer. Cancer, pediatric brain tumors, pediatric cancer, pediatric leukemia, pediatric soft tissue sarcoma, chondrosarcoma, choriocarcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, carcinoma (e.g., Walker's tumor, basal cell tumor, basal squamous cell tumor, Brown-Pierce tumor, glandular tumor, Ehrlich tumor, Krebs II tumor, Merkel cell tumor, mucinous, non-small cell lung tumor, oat cell tumor, papillary tumor, hard, bronchiolar tumor, bronchogenic, squamous epithelial cell tumor, and transitional cell tumor), carcinosarcoma, cervical malformations, phyllodes cyssarcoma, cementoma, chordoma, spondylolisthesis, chondrosarcoma, chondroblastoma, craniopharyngioma, cholangiomas, cholesteatoma, cystocarcinoma, cystadenoma, cystic carcinoma, cystic adenoma Dermatofibrosarcoma, fibrinogenic small round cell tumor, tubular carcinoma, undifferentiated germ cell tumor, endocrine carcinoma, endometrial carcinoma, ependymoma, esophageal carcinoma, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular carcinoma, ocular melanoma, retinoblastoma, fallopian tube carcinoma, Fanconi anemia, fibroma, fibrosarcoma, gallbladder carcinoma, gastric carcinoma, gastrointestinal carcinoid tumor, genitourinary carcinoma, germ cell tumor, gestational trophoblastic disease, glioma, gynecological carcinoma, giant cell tumor, gangliocytoma, glioma, glomus hemangioma, granulosa cell tumor, hemisinophilic ovarian tumor, hematological malignancies, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hereditary breast cancer, histiocytosis, Hodgkin's disease, human papilloma Pylomavirus, hydatidiform mole, hypercalcemia, hypopharyngeal cancer, hamartoma, hemangioendothelioma, hemangiomas, hemangioendothelioma, hemangioendothelioma, histiocytic disorder, malignant histiocytosis, histiocytoma, hepatocellular carcinoma, sweat adenoma, chondrosarcoma, immunoproliferative microsarcoma, opoma, intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leiomyosarcoma, leukemia, Lie-Fraumeni syndrome, lip cancer, liposarcoma, liver cancer, lung cancer, lymphedema, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leiomyosarcoma, leukemia (e.g., B cells, mixed cells, null cells,T cells, chronic T cells, HTLV-II related, lymphangiosarcoma, acute lymphoblastic lymphocytic Heart disease, medulloblastoma, meningioma, melanoma, mesenchymal cell tumor, mesonephroma, mesothelioma, myoblastic myoma, fibroid, sarcoma, myxoma, myxosarcoma, nasal cavity cancer, nasopharyngeal cancer, nephroblastoma, neuroblastoma, neurofibromatosis, Nijmiehen chromosomal instability syndrome, non-melanoma skin cancer, non-small cell lung cancer (NSCLC), schwannoma, neuroblastoma, neuroepithelioma, neurofibromatosis, neurofibroma, neuroma, neoplasms (e.g., bone, breast, digestive system, colorectal, liver), eye cancer, esophageal cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ostomy ovarian cancer. Cancer, pancreatic cancer, paranasal sinus cancer, parathyroid cancer, parotid gland cancer, penile cancer, peripheral neuroectodermal tumors, pituitary cancer, polycythemia vera, prostate cancer, osteoma, osteosarcoma, ovarian cancer, papilloma, paraganglioma, nonchromaffin paraganglioma, pinealoma, plasmacytoma, proto-oncogenes, rare cancers and related disorders, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, Rothmund-Thomson syndrome, reticuloendotheliosis, rhabdomyomas, salivary gland cancer, sarcoma, schwannoma, Sézary syndrome, skin cancer, small cell lung cancer (SCLC), small intestine These include cancer, soft tissue sarcoma, spinal cord tumor, squamous cell carcinoma (skin), gastric cancer, synovial sarcoma, sarcoma (e.g., Ewing's experimental sarcoma, Kaposi's and mast cell sarcoma), Sertoli cell tumor, synoviomas, testicular cancer, thymic cancer, thyroid cancer, transitional cell carcinoma (bladder), transitional cell carcinoma (renal pelvis / ureter), trophoblastic carcinoma, teratoma, follicular cell tumor, thymoma, trophoblastic tumor, urethral cancer, urinary tract cancer, uroplakin, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor.

[0235] Cancer-related conditions or symptoms may be any medical condition that arises as a result of cancer, prior to cancer, or as a progression from cancer. For example, if the cancer is skin cancer, the condition or symptoms may be a bacterial infection. If the cancer is a secondary tumor, the condition or symptoms may be related to organ dysfunction in the associated organs with tumor metastases. In one embodiment, the treatment method described herein is for the prevention or treatment of the progression of a cancer-related condition or symptoms in an individual.

[0236] The presence, improvement, treatment, or minimization of cancer progression may be determined by any clinically or biochemically relevant methods described herein or known in the art. A favorable response to the treatment of cancer or minimization of cancer progression may be determined by any method known in the art, and may include the following determinations: - Reduction in the number of cancer cells; - Reduction in tumor size; - Inhibition of cancer cell invasion into peripheral organs (i.e., delaying it to some extent, and preferably stopping it); - Inhibition of tumor metastasis (i.e., delaying it to some extent, preferably stopping it); - Reduction or complete prevention of tumor metastasis after removal of the primary tumor; - Some degree of inhibition of tumor growth; - Some degree of relief of one or more cancer-related symptoms; and / or - Increased survival time for the target.

[0237] Any of the above decisions may be considered a favorable response to any of the compounds described herein.

[0238] In contrast, the absence of a negative response or cancerous response to a treatment containing any compound described herein may be determined by any method known in the art, and may include the following determinations: - No change or increase in the number of cancer cells; - No change or increase in tumor size; - No change, persistence, or increase in cancer cell infiltration into peripheral organs; - No change, persistence, or increase in tumor metastases; - No change or increase in tumor metastases despite removal of the primary tumor; - No change or increase in tumor growth; - No change or increase in one or more cancer-related symptoms; and / or - No change or decrease in the subject's survival period.

[0239] A subject treated for cancer may be in partial or complete remission. In other words, a subject treated for cancer as described above may have a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater reduction in measurable parameters of tumor growth, such as those seen in biomarker levels from physical examination, radiography, or blood or urine tests. Alternatively, if a subject is in complete remission, there is a complete disappearance of all detectable signs of the disease, to the point that the subject has no detectable signs of cancer. A subject may have substantially undetectable signs of cancer. "Substantially undetectable" cancer generally refers to a situation where, as a result of treatment, the cancer is no longer clearly detectable using relevant standard detection techniques such as in vivo imaging, because the treatment has reduced the size, volume, or other physical measures of the cancer.

[0240] The objective or result of treatment with any of the compounds described herein may be to reduce the number of cancer cells; reduce the size of the primary tumor; inhibit (i.e., delay, preferably halt) cancer cell invasion into peripheral organs; inhibit (i.e., delay, preferably halt) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more of the symptoms associated with the disorder.

[0241] The effectiveness of treatment can be measured by evaluating survival time, time to disease progression, response rate (RR), duration of response, and / or quality of life.

[0242] In one embodiment, the method is particularly useful for slowing the progression of cancer. In one embodiment, the method is particularly useful for extending the survival of subjects, including overall survival and progression-free survival. Overall survival will be understood as the length of time from either the date of diagnosis or the start of cancer treatment, during which the patient diagnosed with cancer is still alive. Progression-free survival will be understood as the length of time during or after cancer treatment during which the patient is alive with the disease but without it worsening.

[0243] Survival analysis can be performed using techniques well known in the art, including the Kaplan-Meier method. The Kaplan-Meier method estimates a survival function from lifespan data. In medical research, it may be used to measure the proportion of patients who survive for a certain period after treatment. A plot of the survival function using the Kaplan-Meier method is a series of horizontal steps whose magnitude decreases, which approaches the true survival function of the population if a sufficiently large sample is taken. It is assumed that the value of the survival function between consecutive, distinct sample observations ("clicks") is constant.

[0244] A key advantage of the Kaplan-Meier curve is that this method can account for data loss from "censored" samples (e.g., when patients drop out of the study) before the final outcome is observed. In this plot, the smaller vertical divisions represent the loss, while the patient data were censored. If no truncation or censoring occurs, the Kaplan-Meier curve is equivalent to the empirical distribution.

[0245] In one embodiment, the method is particularly useful in providing a complete response to treatment, thereby eliminating all signs of cancer in response to the treatment. This does not necessarily mean that the cancer is cured. In one embodiment, the method is particularly useful in providing a partial response to treatment, thereby resulting in a reduction in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to the treatment.

[0246] [kit] In another embodiment, a kit or product comprising any compound, pharmaceutically acceptable salt, diluent or excipient and / or the above pharmaceutical composition described herein is provided. Furthermore, the kit may include instructions for use in any method or use of the present invention described herein.

[0247] In another embodiment, a kit for use in the above-mentioned therapeutic and / or preventive applications, - Containers for holding therapeutic compositions in any form of compound described herein, or pharmaceutically acceptable salts, diluents, excipients, or pharmaceutical compositions; - Labels or accompanying documents including instructions for use A kit is provided that includes the following.

[0248] In certain embodiments, the kit may contain one or more additional active ingredients or raw materials for the treatment of cancer.

[0249] In one embodiment, the therapeutic composition of the kit is formulated for administration into the airway, preferably by inhalation.

[0250] A kit or “product” may include a container and a label or accompanying information on or attached to the container. Suitable containers include, for example, bottles, vials, syringes, and blister packs. Containers may be formed from a variety of materials, such as glass or plastic. Containers may hold a therapeutic composition effective in treating a medical condition and may have a sterile access port (for example, the container may be an intravenous solution bag or vial with a stopper that can be punctured with a subcutaneous needle). The label or accompanying information indicates that the therapeutic composition is to be used to treat the most appropriate medical condition. In one embodiment, the label or accompanying information includes instructions for use indicating that the therapeutic or prophylactic composition may be used to treat the cancers described herein.

[0251] The kit may include (a) a therapeutic or prophylactic composition; and (b) a second container containing a second active ingredient or raw material. The kit in this embodiment of the present invention may further include a document indicating that the composition and other active ingredients may be used to treat or prevent the progression of cancer as described herein.

[0252] As used herein, the following compounds are described in the following table and in other parts of this specification in specific structures and are assumed in any method or use of the present invention.

[0253] [Table 1]

[0254] [Table 2]

[0255] [Table 3]

[0256] [Table 4]

[0257] [Table 5]

[0258] [Table 6]

[0259] [Table 7]

[0260] [Table 8]

[0261] [Table 9]

[0262] [Table 10]

[0263] [Table 11]

[0264] [Table 12]

[0265] [Table 13]

[0266] The compounds of the present invention can be prepared by techniques known in the art. For example, the compounds of the present invention comprising any one of formulas (I) to (XIX) including the A1 portion can be prepared by the techniques described in International Publication No. 2019 / 119067, which is incorporated herein by reference in its entirety.

[0267] The compounds of the present invention that include any one of formulas (I) to (XIX) containing the A2 portion are compounds of formula A2-I: [ka] [In the formula, L1, L2, Z1, Z2, v, b, w, z, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 And X has the meaning defined herein for any compound of the present invention, and R 19 However, it is an amino protecting group. The compound of formula (YB-I): [ka] [In the formula, Y' is [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; B' is polyethylene glycol (PEG); [ka] However, it is a solid-phase support resin. It can be provided by coupling with it.

[0268] In some embodiments, B' includes a substituted PEG of formula BI. In these embodiments, the following series of solid-phase reactions may be used: a) Optionally, using Fmoc chemistry, coupling 1 to 10 α-amino acids or compounds derived from natural α-amino acids that constitute L to a solid-phase resin. b) PG-NH-(CH2) p -O-(CH2CH2O) n -(CH2) m -COOH is coupled to the solid resin or, if L is present, to the substituted resin (where PG represents an amino protecting group compatible with Fmoc chemistry); c) Remove PG; d) PG-NH-CR 13 R 14 -Coupling COOH (where PG' represents an amino protecting group compatible with Fmoc chemistry); e) Remove PG'; f) Coupling the acid of formula (Al); g) Arbitrarily, R 19 Remove and optionally acylate and / or alkylate R 18 and / or R 19 To introduce; and h) Remove the compound from the solid support.

[0269] In one embodiment, B' comprises a substituted PEG represented by formula (B-II), and the following series of solid-phase reactions may be used: a) Optionally, using Fmoc chemistry, coupling 1 to 10 α-amino acids or compounds derived from natural α-amino acids that constitute L to a solid-phase resin. b) PG-NH-(CH2) t -O-(CH2CH2O) k -(CH2) h -COOH is coupled to the solid resin or, if L is present, to the substituted resin (where PG represents an amino protecting group compatible with Fmoc chemistry); c) Remove PG; d) PG'-NH-(CH2) p -O-(CH2CH2O) n -(CH2) m -Coupling COOH (where PG' represents an amino protecting group compatible with Fmoc chemistry); e) Remove PG'; f)PG''-NH-CR 13 R 14 -Coupling COOH (where PG'' represents an amino protecting group compatible with Fmoc chemistry); g) Remove PG''; h) Coupling the acid of formula (Al); i) Arbitrarily, R 19 Remove and optionally acylate and / or alkylate R 18 and / or R 19 to incorporate; and j) Removing the compound from the solid resin.

[0270] It will be understood that if the exact sequence of events differs from that outlined, and if necessary and favorable to the synthesis, further steps, such as the oxidation of cysteine ​​sulfur to a sulfoxide or sulfone, may be added.

[0271] The compound of formula A2-I is, formula A2-II: [ka] [In the formula, L1, L2, X, v, w and R 18 However, as defined for the compound of formula AI above, Z1 and Z2 are independently selected from -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -NHC(O)O-, and -OC(O)O-. It will be provided in the form of...

[0272] The compound of formula A2-II can be provided by the synthesis shown in Scheme 1.

[0273] Scheme 1 represents the synthesis of an embodiment of the compound of formula A2-II, where, X is S, L1-Z1 is -OC(O)E-(CH2) g -CH3, where E is -O- or -NH-, and g is 10, 11, 12, 13, 14, 15, 16, 17, or 18; L2-Z2 is -OC(O)E-(CH2) g -CH3 is present, where E is -O- or -NH-, and g is 10, 11, 12, 13, 14, 15, 16, 17, or 18; R 19 However, it is PG3, which is an amino protecting group.

[0274] [Scheme 1] [ka] The reaction of a protected alkene alcohol of formula (V') (wherein PG is a suitable protecting group, such as a silyl group like TBDMS) forms the epoxide of formula (VI'). It will be understood that epoxide formation may be carried out to obtain the product racemicly or to obtain an enantioenriched material. If a racemic or scalemic mixture of enantiomers is formed, preparative chiral chromatography may be used to separate the enantiomers, if necessary.

[0275] The epoxide of formula (VI') is reacted under reducing conditions with a suitably protected cystine analog, such as tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(((R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)thio)-D-cysteinate (where PG2 is the tert-butyl ester and PG3 is Fmoc) to obtain the alcohol of formula (VII'). The alcohol of formula (VII') may consist of two or more stereoisomers, and if stereoisomers are present, they may be separated by chiral preparative chromatography as needed.

[0276] The alcohol of formula (VII') is acylated with a suitable reagent to obtain the carbonyl-containing adduct of formula (VIII'). If an ester is required, an acid chloride may be reacted in the presence of a suitable base and solvent; if a carbamate is required, an isocyanate may be reacted in the presence of a suitable base and solvent; and if a carbonate is required, a chloroformate may be reacted in the presence of a suitable base and solvent. The carbonyl-containing adduct of formula (VIII') can then be deprotected with a suitable reagent to expose the carboxylic acid of formula (IX'). For example, if PG2 is tert-butyl, trifluoroacetic acid may be used to preferentially remove the tert-butyl group.

[0277] Next, the acid of formula (IX') can be used as a reagent in solid-phase synthesis to add the groups of formulas Y and B.

[0278] The compounds of the present invention that contain any one of formulas (I) to (XIX) including part A2 (wherein z is 1, w is 1, and b is 0) are resin-bound peptides of the following formula: [ka] [In the formula, Y' is [ka] And, In the formula, R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH, and -CH2CH2C(=O)OR8, where any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl groups; B' is polyethylene glycol (PEG); PG s However, it is an H or sulfur protecting group, such as tert-butyl; [ka] However, it is a solid-phase support resin. It can be provided by preparing it.

[0279] After any sulfur deprotection, this resin-bound peptide is a 1,2-epoxy-alkanol of the following formula: [ka] [In the formula, R x , R y And v has the meaning shown for part A2 in equation (I). It reacts with the alkylated thiol of formula S-1: [ka] [In the formula, Y' and B' have the meanings shown above, and v has the meaning shown for part A2.] Alternatively, the sulfone or sulfoxide thereof can be obtained.

[0280] The diol portion of the resin-bonded compound S-1 is further reacted, for example, by diol functionalization with a palmitic acid group or a lauryl carbamate group, to obtain the compound of the present invention.

[0281] [Examples] Examples 1 to 6 below illustrate various properties of the compounds of the present invention. The compounds tested in these examples were prepared as described in International Publication No. 2019 / 119067 or Synthesis Example 7.

[0282] [Example 1 - Effects of synthetic compound A101 / compound 1 on tumor growth, survival, and metastasis] In this specification, the inventors began investigating the antitumor effect of a synthetic compound called compound A101 (shown as compound 1 in the examples and figures).

[0283] [Materials and Methods] [mouse] C57BL / 6 or Balb / c wild-type (WT) mice were purchased from the Walter and Eliza Hall Institute for Medical Research, bred in-house, and maintained at the QIMR Berghofer Medical Research Institute. Mice older than 8 weeks were sex-matched to the appropriate model. The number of mice in each treatment group or the mouse strain for each experiment is indicated in the figure captions. In all studies, mice were not excluded based on predetermined criteria, and randomization was applied immediately before treatment in the therapeutic experiments. Experiments were conducted in accordance with the approval of the QIMR Berghofer Medical Research Institute Animal Ethics Committee.

[0284] [Cell culture] Mouse B16F10 (melanoma), MC38 (colon adenocarcinoma), and 4T1.2 (breast cancer) cells were grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (Bovogen), 1% glutamine (Gibco), and 1% penicillin / streptomycin (Gibco). B16F10 and 4T1.2 cells were maintained at 37°C and 5% CO2. MC38 cells were maintained at 37°C and 10% CO2. All cell lines were conventionally tested to be negative for Mycoplasma, but cell line authentication was not conventionally performed.

[0285] [Subcutaneous tumor model] For primary tumor growth experiments, MC38 (1 × 10 6 (pieces) or B16F10 (1 x 10 5Cells were subcutaneously injected into mice in a final volume of 100 μl (day 0). Mouse treatment was initiated as shown in the figure or caption. The vertical diameter of each individual tumor was measured using a digital caliper. Tumor size was calculated and shown as mean ± SEM. The tumor was 150 mm. 2 Once the mice reached a certain size, they were euthanized.

[0286] [4T1.2 breast cancer metastasis model] 5 x 10 4 4T1.2 cells were injected into the fourth mammary fat body in a volume of 50 μl (day 0). On day 12 after injection, the primary tumor was surgically excised under isoflurane anesthesia. Mice were treated with injections on days 15, 18, and 21 after tumor cell injection as shown in the figure caption. All mice were euthanized on day 26 after tumor cell injection to assess metastatic burden. For this purpose, macroscopically visible lung metastases were counted.

[0287] [Intratumoral injection of compound 1] For this purpose, 100 μl of a solution of compound 1 in physiological saline was injected into the tumor. The dosage and treatment schedule are shown in the figure and / or explanatory text.

[0288] [Compound 1 intravenous injection] For this purpose, 10 μg of compound 1 in 200 μl of physiological saline was injected into the lateral tail vein. The treatment schedule is shown in the figure and / or caption.

[0289] [result] Highly immunogenic MC38 colon cancer cells were subcutaneously injected into C57BL / 6 WT mice. Once tumors were clearly defined (approximately 5 mm in diameter), the mice were randomly divided into three groups: one receiving a vehicle, and the other receiving three intratumoral injections of either 25 μg or 50 μg of compound 1 in 100 μl of saline (Figure 1A). Dose-dependent inhibition of MC38 tumor growth was observed, along with significantly improved overall survival in mice treated with compound 1 compared to the vehicle control (Figures 1B, C).

[0290] In the following experiment, a low immunogenic B16F10 melanoma cell line was subcutaneously injected (sc) into C57BL / 6 WT mice. Once tumors were evident, the mice were randomly divided into three groups and treated as shown (Figure 2A). Because B16F10 melanomas are very difficult to treat, four doses of compound 1 were injected. A dose-dependent reduction in tumor growth was observed (Figure 2B). Although compound 1 treatment did not cause complete tumor rejection, importantly, it significantly improved the survival rate of the mice (Figure 3).

[0291] In summary, these data indicate that compound 1 has monotherapy antitumor efficacy when locally injected into the tumor microenvironment in both highly immunogenic and low immunogenic preclinical models of cancer.

[0292] To date, data have demonstrated that compound 1 has monotherapy efficacy when tested in cancer models induced by MC38 and B16F10. Since metastatic dissemination of tumor cells is a major cause of death in cancer patients, we conducted tests to evaluate the anti-metastatic potential of compound 1. For this purpose, highly invasive 4T1.2 mammary cancer cell lines were injected into the fourth mammary fat pad of Balb / c WT mice. Following typical patient treatment procedures, the primary tumors were removed, and the mice were subsequently treated intravenously (iv) with 10 μg of compound 1 in 200 μl of saline, as shown (Figure 4A). All mice were euthanized 14 days after surgery, and the number of lung metastases was assessed. Systemic treatment with compound 1 significantly reduced the number of 4T1.2 lung metastases with little impact on weight loss (data not shown) (Figures 4B-C).

[0293] In summary, the data demonstrate that compound 1 exhibits strong antitumor efficacy not only against primary tumors but also in metastatic models, after local (intratumor) and systemic (intravenous) administration.

[0294] [Example 2. Compound A108 exhibits antitumor activity in the MC38 model.] Highly immunogenic MC38 colon cancer cells were subcutaneously injected into C57BL / 6 WT mice (n=10-14). Once tumors were clearly visible (approximately 3-5 mm in diameter), the mice were randomly divided into four groups and given three intratumoral injections of 25 μg of compound A108 in a vehicle or 100 μl of saline. These tests showed that compound A108 inhibits MC38 tumor growth (Figure 5A). Compound A108 also showed improvement in overall survival of the mice (Figure 5B).

[0295] The above studies were further investigated by examining the effect of compound A108 on large tumors in the MC38 mouse model. These studies aimed to understand whether repeated administration over a two-week period could slow tumor growth. Mice were administered repeatedly every two days for 13 days via intraperitoneal (ip) (10 μg dose) and intratumor (it) (25 μg dose) routes. Mice were euthanized when the humane endpoint was reached or one week after the last dose (up to day 25), whichever came first. The humane endpoint was a weight loss of more than 20% compared to the weight on the first day of treatment (or more than 15% over three consecutive days), or 3000 mm. 3 Individual mouse tumor volume exceeding 2000 mm 3 The average tumor volume of the group was included (all mice in the group were euthanized). Compound A108 slowed tumor growth during the treatment phase via intratumor (it) (Figure 6A) or intraperitoneal (ip) (Figure 6B) pathways. Finally, the effect of compound A108 was superior to that of Pam3CysSK4 (Figure 6C) and at least equivalent to that of commercially available anti-PD1 antibodies (Figure 6D).

[0296] [Example 3. Compound A108 exhibits antitumor activity in the WEHI164 model.] The antitumor effect of compound A108 was tested in a WEHI164 fibroblast tumor model. WEHI164 tumor cell lines were inoculated subcutaneously into Balb / c mice, and the colonized tumors were monitored by caliper measurements. The tumor size was 30 mm. 2Once the mice reached a certain stage, they were treated with a single dose of compound A108 or PBS (Figure 7A) via either an intravenous (iv) or intraperitoneal (ip) route. All mice were monitored for tumor growth (Figures 7B, D).

[0297] A single infusion of the indicated dose was administered to a group of five mice. Furthermore, the group was also administered via intraperitoneal (IP) injection to test whether this route of administration could provide a faster and safer means of drug delivery while providing similar therapeutic outcomes. Surprisingly, the intraperitoneal (IP) treatment group showed better survival rates than the intravenous (IV) route (Figure 7C, E). In particular, when tumors were measured 48 hours after the start of treatment, they were already responding, which is remarkably fast for immunotherapy. Tumor regression was indicated by discoloration (blackening) of the tumor within 24 hours post-treatment, which showed a scab on the central surface, leaving only a small layer of tumor skin, if any (data not shown). These tests demonstrate that compound A108 can inhibit tumor growth when administered as a single dose via both intravenous (IV) and intraperitoneal (IP) routes.

[0298] [Example 4. Compound A108 significantly reduces spontaneous lung metastasis in mice with EMT6.5 tumors.] 100,000 EMT6.5 cells were orthotopically transplanted into the fourth inguinal mammary gland of Balb / c mice (n=12), and the established tumor was monitored by caliper measurement. The tumor was approximately 200 mm. 3 At this point, the mice were randomly divided into two treatment arms (n=6 per arm): 1) compound A108 (10 μg per mouse), or 2) vehicle (saline) control. The treatment was administered intravenously to tumor-bearing mice in three doses, every three days. All mice completed the treatment and were euthanized 21 days after tumor transplantation. The primary tumors, lungs, and spleens were collected and weighed. The lungs were analyzed by real-time quantitative PCR (RTQ-PCR) to assess metastatic burden. Body weight was measured throughout the experiment.

[0299] Initial treatment with compound A108 induced rapid weight loss, but this weight loss decreased with subsequent administrations and was reversible after discontinuation of treatment (data not shown). No severe weight loss attributable to the treatment was observed, but the study showed that compound A108 significantly slowed the growth of EMT6.5 tumors in vivo (Figure 8A).

[0300] At the experimental endpoint, the primary tumor, spleen, and lungs of mice were collected to confirm a reduction in primary tumor size and lung metastatic burden. As predicted from the tumor growth curve, compound A108 was confirmed to result in a statistically significant reduction in tumor weight at the endpoint (Figure 8B; tumor weight). To quantitatively evaluate lung metastasis, the inventors completed an RTQ-PCR assay to assess the change in lung metastatic burden. Figure 8C demonstrates that compound A108 monotherapy resulted in a statistically significant reduction in spontaneous lung metastases in mice with EMT 6.5 tumors. Survival data from another independent study also indicate that compound A108 may significantly extend survival (Figure 8D). The effect of A108 on tumor growth was significantly better than that of anti-PD-1 antibody administration, which had no effect on tumor volume (Figure 8E).

[0301] [Example 5. Intranasal administration of compound A108 reduces lung metastases in mice with 4T1.2 tumors.] Next, the efficacy of compound A108 after intranasal administration was tested. For this purpose, the inventors orthotopically injected highly metastatic 4T1.2 breast cancer cells into the fourth mammary fat pad of mice. When the tumor reached a diameter of approximately 7-8 mm, the mice underwent surgery to remove the primary tumor. Subsequently, the mice were randomly divided into groups to receive one of three intranasal administrations: either 2.5 ng of compound A108 in 50 μl of saline (Figure 9A) in Experiment 1, or 0.25 ng of compound A108 in 50 μl of saline (Figure 9B) in Experiment 2. Two weeks after surgery, all mice were euthanized, and the number of visible lung metastases was counted. In both independently conducted experiments, intranasal administration of compound A108 significantly reduced the number of 4T1.2 breast cancer metastases in the lungs (Figure 9C).

[0302] [Example 6. Various compounds significantly improved survival rates and reduced tumor growth in MC38-supported mice.] Highly immunogenic MC38 colon cancer cells were subcutaneously injected into C57BL / 6 WT mice. Once tumors were clearly visible (approximately 5 mm in diameter), the mice were randomly divided into two groups: one receiving a vehicle, and the other receiving intratumoral injection of 25 μg of the indicated compound A102 or A103 in 100 μl of physiological saline. Compared to the vehicle control, the inventors observed a significant reduction in tumor growth (Figure 10A-B) and a significantly improved overall survival (Figure 10C) in mice treated with the indicated compounds.

[0303] [Example 7. Representative synthesis and characterization of selected compounds of the present invention: A107, A108, A115, A116, A117, A118, A203, A204, A215, A216, A220, and A224] [Synthesis of compounds A107 (x=11) and A108 (x=27)] I purchased Fmoc S-2,3-di(palmitoyloxypropyl)-cysteine ​​(S-Fmoc-Dpc-OH) from Bachem Inc.

[0304] [Coupling of S-Fmoc-Dpc-OH to resin-bound peptides:] Fmoc-Dpc-OH (100 mg, 0.24 mmol) is activated with HOBt (36 mg, 0.24 mmol) and N,N'-diisopropylcarbodiimide (DICI; 37 μL, 0.24 mmol) in DCM and DMF (1:1, v / v, 3 mL) for 5 minutes at 0°C. Next, the mixture is converted to Boc-Cys-Ser(tBu)CH2CH2O-(PEG) 11 -CH2CH2C(O)Gly resin or Boc-Cys-Ser(tBu)-CH2CH2O-(PEG) 27 Add the mixture to a container containing -CH2CH2C(O)Gly resin (0.25 mmol / g, 0.25 g = 0.0625 mmol). After shaking for 2 hours, remove the solution by filtration through a glass sintered funnel (porous 3), and wash the resin with DCM and DMF (3 × 30 mL each). Monitor the reaction for completion using the trinitrobenzenesulfonic acid (TNBSA) test. Perform double coupling if necessary.

[0305] [Cutting of peptides from solid carriers:] Reagent B (93% TFA, 5% water, and 2% triisopropylsilane) was incubated for 2 hours. The peptide did not precipitate in cooled ether. The majority of the TFA had to be removed, and the residue was then dissolved in 50% acetonitrile and immediately purified or lyophilized.

[0306] [Synthesis of compounds A115 and A116] Compounds A115 (x=11) and A116 (x=27) were synthesized as shown in Scheme 2. (R)-glycidol was coupled to the thiol group of a cysteine ​​residue attached to the peptide resin by alkylation; 250 mg of Boc-Cys-Ser(tBu)CH2CH2O-(PEG) saturated in DMF 11 -CH2CH2C(O)Gly resin or Boc-Cys-Ser(tBu)CH2CH2O-PEG 27--CH2CH2C(O)Gly resin (0.25 mmol / g, 0.25 g = 0.0625 mmol) was mixed with 250 μl of R-(+)-glycidol (molecular weight = 74.08, d = 1.1, 250 μl = 3.71 mmol, 60 times more than the free sulfhydryl groups in the peptide resin) and 25 μl of diisopropylethylamine (DIPEA, molecular weight = 129.2, d = 0.74, 25 μl = 0.14 mmol). The reaction mixture was kept at 50°C in a water bath for 2 hours, and then the solid support was thoroughly washed with DMF. To 250 mg of peptide resin, which had been washed with toluene after glycidylation, 100 μl of ethyl methyl sulfide (W=76.16, d=0.842, 100 μl=1.10 mmol), followed by 105 μl of tetradecyl isocyanate (molecular weight=239, d=0.869, 105 μl=0.38 mmol, i.e., 3 times more than each of the hydroxyl groups present on the solid support), and finally, 210 μl of dibutyltin dilaurate (molecular weight=631.6, d=1.053, 210 μl=0.35 mmol). The reaction mixture was sparged with nitrogen gas for approximately 5 minutes and mixed overnight at room temperature (using Intelli-Mixer, RM-2, program F26). The reaction mixture was transferred to a 50 ml tube, and chloroform was added to 50 ml. After sonication for approximately 5 minutes, the white precipitate formed during the reaction dissolved. The solid support was washed with DMF and acetonitrile, and the final product obtained after cleavage from the support was purified by HPLC.

[0307] [Scheme 2. Synthesis of Compounds A115 and A116] [ka] [Synthesis of compounds A117 and A118] Compounds A117(X=S(=O)) and A118(X=S(=O)2) were prepared according to the same synthetic route as described above for compound A115, except that the ethyl methyl sulfide scavenger was omitted from the carbamate formation step, and the nitrogen sparge was optionally omitted. The omission of the ethyl methyl sulfide scavenger yielded a mixture of compounds A115, A117, and A118, which was separated and purified by HPLC.

[0308] Alternatively, sulfone or sulfoxide derivatives (e.g., A117 and A118) can be prepared by oxidation of the corresponding sulfide (e.g., A115) using an oxidizing agent such as meta-chloroperbenzoic acid (MCPBA) or tert-butyl hydroperoxide (t-BuOOH) under appropriate conditions.

[0309] [Synthesis of compounds A203 and A204] The synthesis of compounds A203 and A204 is shown in Scheme 3 below.

[0310] After adding Fmoc-Gly as the first amino acid to the solid support, over 2 hours, in the presence of a 2x molar excess of Fmoc-NHCH2CH2O-(PEG) in 2 ml of dimethylformamide (DMF) in the presence of a 2x excess of hexafluorophosphate benzotriazole tetramethyluronium (HBTU), hydroxybenzotriazole (HOBT), and a 4x excess of diisopropylethylamine (DIPEA) 11 -CH2CH2COOH or Fmoc-NHCH2CH2O-(PEG) 27 -CH2CH2COOH was coupled. Next, Fmoc-Ser(tBu)-OH was coupled to obtain intermediate A2, and then Boc-Cys(StBu)A1 was coupled. The thiol-tert-butyl group on the cysteine ​​residue was removed by incubating the peptide resin in 0.5 M dithiothreitol in DMF for 1 hour at room temperature. 250 mg of Boc-Cys-Ser(tBu)-NHCH2CH2O-(PEG) saturated in DMF 11-CH2CH2C(O)Gly resin or Boc-Cys-Ser(tBu) CH2CH2O-(PEG) 27 -CH2CH2C(O)-Gly resin (0.25 mmol / g, 0.25 g = 0.0625 mmol) is mixed with 250 μl of R-(+)-1,2-epoxy-butan-4-ol [(R)-2-(oxiran-2-yl)ethane-1-ol](M W =88.11, d=1.1, 250 μl = 3.125 mmol, which corresponds to a 50-fold excess amount of free sulfhydryl groups present on the peptide resin) and 25 μl of diisopropylethylamine (DIPEA, M W (=129.2, d=0.74, 25 μl = 0.14 mmol) was added. The reaction mixture was placed in a 50°C water bath for 2 hours, and then thoroughly washed with DMF to obtain intermediate A3.

[0311] Palmitic acid (320 mg, 1.25 mmol), DIPCDI (225 μL, 1.5 mmol), and 4-dimethylaminopyridine (DMAP; 15.25 mg, 0.125 mmol) were dissolved in 2 mL of dichloromethane (DCM), and then added to resin-bound BOC-Dhc-peptide resin A3 (0.0625 mmol, 0.25 g), and shaken at room temperature for 16 hours. The supernatant was removed by filtration, and the solid support was thoroughly washed with DCM and dimethylformamide (DMF) to remove urea residue before being subjected to the cleavage process described later.

[0312] Solid supports containing assembled lipopeptides were exposed to reagent B (93% TFA, 5% water, and 2% triisopropylsilane) for 2 hours. To isolate the product, most of the TFA was removed, and the residue was then dissolved in 50% acetonitrile and immediately purified using the purification protocol described below, or the material was lyophilized and stored for later purification.

[0313] [Scheme 3. Synthesis of Compound A203 (x=11) and Compound A204 (x=27)] [ka] [Synthesis of Compound A215 and Compound A216] Compounds A215 and A216 were synthesized as shown in Scheme 4. Intermediate A3 was prepared as described for compounds 3 and 4 above.

[0314] Next, 250 mg of peptide resin, which has been washed with toluene after glycidylation, is mixed with 100 μl of ethyl methyl sulfide (M W (=76.16, d=0.842, 100μl=1.10 mmol), followed by 105 μl of tetradecyl isocyanate (MW=239, d=0.869, 105 μl=0.38 mmol, i.e., three times the excess amount of hydroxyl groups present on the solid support) and finally 210 μl of dibutyltin dilaurate (M W (=631.6, d=1.053, 210 μl = 0.35 mmol) was added. The reaction mixture was sparged with nitrogen gas for about 5 minutes and mixed overnight at room temperature (Intelli-Mixer, RM-2, program F26 used). The reaction mixture was transferred to a 50 ml tube and chloroform was added until the mixture reached 50 ml. After sonication for about 5 minutes, the white precipitate formed during the reaction was dissolved. The solid support was washed with DMF and acetonitrile, and the final product obtained after cleavage from the support (as described above) was purified by HPLC.

[0315] [Scheme 4. Synthesis of compounds A215 (x=11) and A216 (x=27)] [ka] [A220 synthesis] Compound A220 was synthesized by standard Fmoc solid-phase peptide synthesis, starting from Fmoc-RINK MBHA PS resin. Removal of the Fmoc group after each coupling step was performed using 20% ​​piperidine in DMF. Fmoc-Gly-OH (2x excess), Fmoc-NH-PEG 28The coupling of -CH2CH2COOH (1.4x excess), Fmoc-Ser(tBu)-OH (2x excess), and N-(Boc)-S-((R)-2,3-dihydroxybutyl)-L-cysteine ​​(1.5x excess) was carried out in DMF using equivalent excess ethyl cyano(hydroxyimino)acetate (Oxyma Pure) and diisopropylcarbodiimide (DIC) as coupling agents. Myristyl chloroformate coupling was carried out at room temperature for 18 hours using myristyl chloroformate (12 equivalents per mole of resin) and DIEA (24 equivalents per mole of resin) in dry DCM. This coupling was repeated three times ("re-coupling"). The first re-coupling was carried out at room temperature for 18 hours using myristyl chloroformate (12 equivalents per mole of resin) and NMM (24 equivalents per mole of resin) in dry DCM / THF(85 / 15). A second recoupling test was performed at room temperature for 41 hours using myristyl chloroformate (6 equivalents per mole of resin) and NMM (12 equivalents per mole of resin) in dry DCM / THF(85 / 15). Finally, a third recoupling test was performed at room temperature for 21.5 hours using myristyl chloroformate (6 equivalents per mole of resin) and NMM (12 equivalents per mole of resin) in dry DCM / THF / toluene(85 / 15 / 5).

[0316] Peptide cleavage, removal of the N-terminal Boc group, and serine side chain deprotection from the resin were performed by exposing the resin to a solution of 93% trifluoroacetic acid (TFA), 5% H2O, and 3% triisopropylsilane (TIPS) for 1.5 hours. After the cleavage reaction, the mixture was evaporated, and the resulting residue was redissolved in 30% acetonitrile / water and lyophilized.

[0317] [A224 synthesis] Compound A224 was synthesized by standard Fmoc solid-phase peptide synthesis, starting from chlorotrityl chloride resin, with an initial substitution of 1.6 meq / g. The first amino acid, Fmoc-Gly-OH, was first packed into the resin using a 0.5 molar excess of Fmoc-Gly-OH and DIEA (1.5 molar excess). This was followed by capping with DMF / MeOH / DIEA (80 / 10 / 10) and Fmoc deprotection, and a final substitution of 0.67 meq / g to obtain a dry-packed H-Gly-CT resin. Removal of the Fmoc group after each coupling was performed using 20% ​​piperidine in DMF. Fmoc-NH-PEG 28 The coupling of -CH2CH2COOH (1.4 equivalents) was performed using (7-azabenzotriazole-1-yloxy)trispirolidinophosphonium hexafluorophosphate (PyAOp; 1.4 equivalents) and diisopropylethylamine (DIEA; 3.2 equivalents) in DMF, while the coupling of Fmoc-Ser(tBu)-OH (2 equivalents) and N-(Boc)-S-((R)-2,4-dihydroxybutyl)-L-cysteine ​​(1.5 equivalents) was performed in DMF using an excess of Oxyma Pure and DIC as coupling agents. Palmitic acid coupling was performed at room temperature for 24 hours using palmitic acid (20 equivalents relative to the resin mole), DIC (20 equivalents), and DMAP (2 equivalents) in DCM / THF (85 / 15) (v / v).

[0318] Peptide cleavage, removal of the N-terminal Boc group, and serine side chain deprotection from the resin were performed by exposing the resin to a solution of 93% TFA, 5% H2O, and 3% TIPS for 1.5 hours. After the cleavage reaction, the mixture was evaporated, and the resulting residue was redissolved in 30% acetonitrile / water and lyophilized.

[0319] [Purification and Characterization] Purification and Characterization: After cleavage from the solid support, each analogue was purified by reverse-phase HPLC according to either protocol A or B described below.

[0320] Protocol A: Reverse-phase HPLC was performed using chromatograms developed with buffer A (0.1% trifluoroacetic acid in water) and buffer B (0.1% trifluoroacetic acid in acetonitrile) on an Agilent Zorbax 300SB-C3, 5µm column (9.4mm × 250mm; Agilent Technology, Australia) mounted on an Agilent HPLC 1260 Infinity system (Agilent Technologies, Santa Clara, California, USA).

[0321] Protocol B: Reverse-phase chromatography was performed using a Novasep Axial Compression Column (5 cm diameter) packed with cyano medium (Daisogel SP-120-CN-P) with an acetonitrile gradient in [0.1% TFA / water]. After lyophilization of the intermediate, ion exchange was performed in Dowex ion exchange resin to obtain the peptide as acetate.

[0322] The target material was identified and its purity determined using an inline HPLC-MS system under the following conditions: Condition A: The following gradient conditions were used: 0-5 min, 20% B; 5-32 min, 20% B-100% B; 32-40 min, 100% B-20% B. HPLC column used: Agilent Zorbax 300-SB C3 (150 × 0.5 mm; 5 μm). Flow rate was 20 μl / min. LC-MS: Agilent 1100 series LC / MSD ion trap mass spectrometer and in-line Agilent 1100 series capillary LC system. The mass spectrometer was operated using electrospray ionization configured in positive ion mode. Using data analysis software from Agilent Technologies, a series of charged ions were deconvoluted for peptide material identification, and then the materials were characterized by LC-MS.

[0323] Condition B: Analytical reversed-phase HPLC using a cyanocolumn (Daiso Fine Chem, SP-120-3-CN-P, 150 × 4.6 mm, 3 μm, 120 Å). The peptides were also analyzed by ESI LC-MS in positive ion mode using a Finnigan LCQ Deca XPMax.

[0324] Compounds A107, A108, A115, A116, A203, A204, A215, and A216 were prepared and purified according to Protocol A and Condition A, and compounds A220 and A224 were prepared and purified according to Protocol B and Condition B as described above, and each was found to be over 95% pure.

[0325] [Peptide quantification] Compounds A107, A108, A115, A116, A203, A204, A215, and A216 were quantified by hydrolysis of the samples in a sealed glass vial under reduced pressure at 110°C in the presence of 6N HCl containing 0.1% phenol. Next, amino acid derivatization was performed using Waters AccQTag reagent according to the manufacturer's instructions, followed by analysis using an AccQTag ultra column (2.1 mm × 100 mm; Waters Millipore) in a Waters Acquity UPLC System (Waters Millipore). Quantification of other compounds can be performed using a similar protocol.

[0326] [Synthesis of sulfone and sulfoxide analogs of compounds A215 and A216] Sulfone and sulfoxide derivatives of compounds A215 and A216 can be obtained by the same synthetic route described above, with the omission of the ethyl methyl sulfide scavenger and the optional omission of the nitrogen sparge from the carbamate formation step. This reaction may yield a mixture of thiols, sulfones, and sulfoxide derivatives, which can be separated and purified by HPLC.

[0327] Alternatively, sulfone or sulfoxide derivatives may be prepared by oxidation of the corresponding sulfide with an oxidizing agent, such as meta-chloroperbenzoic acid (MCPBA) or tert-butyl hydroperoxide (t-BuOOH), under appropriate conditions.

Claims

1. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a drug for treating, preventing, or minimizing the progression of cancer. A-Y-B (I) [In the formula, A is A1: 【Chemistry 1】 And, During the ceremony, Each z is independently selected from 1 or 2. Each X is independently -S- or -S(=O)-, Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18. R ６ and R ７ However, independently, H, linear or branched C １ ~C ４ Alkyl and -C(=O)CH ３ Selected from the group consisting of, R ９ and R １０ However, independently selected from the group consisting of -NH-, -O-, or single bonds, Y, 【Chemistry 2】 And, R １ and R ２ where one of them is hydrogen and the other is independently selected from the group consisting of -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ ), OH, and -CH ２ OPO(OH) ２ selected from the group consisting of: B is either polyethylene glycol or a substituted polyethylene glycol represented by the partial structural formula B-I. 【Transformation 3】 [In the formula, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, R ３ However, H, -NH ２ Or, if it is -OH and q is 0, R ３ H is and when q is 1, R ３ Ha-NH ２ Or it is -OH, L is either 0 or consists of 1 to 10 units, each unit being a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 4】 It is expressed as, in the formula, R ４ H is, R ５ However, it is the side chain or second hydrogen of an amino acid.

2. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a drug for treating, preventing, or minimizing the progression of cancer in a subject, The compound comprises a portion A selected from A1 as described in claim 1 and PEG, wherein the portion A and PEG are linked by a serine, homoserine, threonine, or phosphoserine residue. PEG is either polyethylene glycol or a substituted polyethylene glycol represented by partial structural formula B-I. 【Transformation 5】 [In the formula, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, R ３ However, H, -NH ２ Or, if it is -OH and q is 0, R ３ H is and when q is 1, R ３ Ha-NH ２ Or it is -OH, L is either 0 or consists of 1 to 10 units, each unit being a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Transformation 6】 It is represented as, In the formula, R ４ H is, R ５ However, it is the side chain or second hydrogen of an amino acid.

3. The use according to claim 2, wherein the portion A and PEG are linked by a serine residue.

4. A use according to any one of claims 1 to 3, wherein the compound is one of formulas (X), (XIII), and (V). Pam2Cys-Y-NH-(CH ２ ) ｐ -O-(CH ２ -CH ２ -O) ｎ -[(CH ２ ) ｍ CO-L-] ｑ R ３ (X) [In the formula, Pam2Cys has the following structure: 【Transformation 7】 It has, Y, 【Transformation 8】 And, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, R １ and R ２ Of these, one is hydrogen, and the other is independently -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, and -CH ２ OPO (OH) ２ Selected from the group consisting of, If q = 1, R ３ is, -NH ２ Or it is -OH, If q = 0, R ３ H is, L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 9】 It is represented as, In the formula, R ４ H is, R ５ However, this is the side chain or the second hydrogen of the aforementioned amino acid. Pam2Cys-Serv-NH-(CH) ２ ) ｐ -O-(CH ２ -CH ２ -O) ｎ -[(CH ２ ) ｍ CO-L-] ｑ R ３ (XIII) [In the formula, Pam2Cys-Ser has the following structure: 【Chemistry 10】 It has, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, If q = 1, R ３ is, -NH ２ Or it is -OH, If q = 0, R ３ H is, L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 11】 It is represented as, In the formula, R ４ H is, R ５ However, this is the side chain or the second hydrogen of the aforementioned amino acid. 【Chemistry 12】 [In the formula, n is between 10 and 100, m is 1, 2, 3, or 4. Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18. p is 2, 3, or 4, q is 0 or 1, R １ and R ２ Of these, one is hydrogen, and the other is independently -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, and -CH ２ OPO (OH) ２ Selected from the group consisting of, R ６ and R ７ However, independently, H, linear or branched C １ ~C ４ Alkyl and -C(=O)CH ３ Selected from the group consisting of, R ９ and R １０ However, independently selected from the group consisting of -NH-, -O-, or single bonds, z is 1 or 2, X is -S- or -S(=O)-, If q = 1, R ３ is, -NH ２ Or it is -OH, If q = 0, R ３ H is, L is either 0 or consists of 1 to 10 units, where each unit is either a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 13】 It is represented as, In the formula, R ４ H is, R ５ However, this is the side chain or the second hydrogen of the aforementioned amino acid.

5. R １ and R ２ Of these, one is hydrogen, and the other is independently -CH ２ The use according to any one of claims 1 to 4, wherein it is OH.

6. R ６ and R ７ is H, R ９ and R １０ Both are single bonds, z is 1, X is S, The use described in any one of claims 1 to 5.

7. The use according to any one of claims 4 to 6, wherein q is 1.

8. The use according to any one of claims 1 to 7, wherein g is an integer from 12 to 16.

9. The use according to claim 8, wherein g is 14.

10. The use according to any one of claims 4 to 9, wherein n is an integer between 10 and 14 or between 24 and 30.

11. The use according to claim 10, wherein n is 11 or 27.

12. The use according to any one of claims 4 to 11, wherein m is 1 to 3.

13. A use according to any one of claims 1 to 12, The above compound has the following chiral center: 【Chemistry 14】 The R diastereomer of the compound around and / or The aforementioned compound, ＊ or ＊＊ Chiral centers indicated by: 【Chemistry 15】 The L-diastereomer of the compound around and / or The above compound has the following chiral center: 【Chemistry 16】 The L-diastereomer of the aforementioned compound is used around the aforementioned compound.

14. The use according to any one of claims 1 to 13, wherein the compound is Table 1 Use of a pharmaceutically acceptable salt or solvate thereof, selected from the above.

15. The use according to any one of claims 1 to 14, wherein the drug is for inhibiting metastasis.

16. The use according to claim 15, wherein the metastasis is metastasis to the lungs.

17. The method or use according to any one of claims 1 to 16, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, adenocarcinoma, mesothelioma, bladder cancer, prostate cancer, germ cell carcinoma, hepatocellular carcinoma / cholangiocarcinoma, neuroendocrine carcinoma, pituitary tumor, small round cell tumor, squamous cell carcinoma, melanoma, atypical fibroxanthoma, seminoma, non-seminoma, stromal Leydig cell tumor, Sertoli cell tumor, skin tumor, kidney tumor, testicular tumor, brain tumor, ovarian tumor, gastric tumor, oral tumor, bladder tumor, bone tumor, cervical mass, esophageal tumor, laryngeal tumor, liver tumor, lung tumor, fibrosarcoma, colon cancer, vaginal tumor, and Wilms' tumor.

18. The use according to any one of claims 1 to 17, wherein the drug further comprises a pharmaceutically acceptable carrier, diluent, or excipient.

19. A pharmaceutical product for treating, preventing, or minimizing the progression of cancer, wherein the pharmaceutical product comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. A-Y-B (I) [In the formula, A is A1: 【Chemistry 17】 And, During the ceremony, Each z is independently selected from 1 or 2. Each X is independently -S- or -S(=O)-, Each g is independently 10, 11, 12, 13, 14, 15, 16, 17, or 18. R ６ and R ７ are each independently selected from the group consisting of H, linear or branched C １ to C ４ alkyl, and -C(=O)CH ３ and the group consisting of R ９ and R １０ However, independently selected from the group consisting of -NH-, -O-, or single bonds, Y, [Chemistry 18] And, R １ and R ２ Of these, one is hydrogen, and the other is independently -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, and -CH ２ OPO (OH) ２ Selected from the group consisting of, B is either polyethylene glycol or a substituted polyethylene glycol represented by the partial structural formula B-I. 【Chemistry 19】 [In the formula, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, R ３ However, H, -NH ２ Or, if it is -OH and q is 0, R ３ H is and when q is 1, R ３ Ha-NH ２ Or it is -OH, L is either 0 or consists of 1 to 10 units, each unit being a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 20】 It is expressed as, in the formula, R ４ H is, R ５ However, it is the side chain or second hydrogen of an amino acid.

20. A pharmaceutical agent for treating, preventing, or minimizing the progression of cancer in a subject, wherein the pharmaceutical agent comprises a compound comprising a portion A selected from A1 as described in claim 1 and PEG, wherein the portion A and PEG are linked by a serine, homoserine, threonine, or phosphoserine residue. In the formula, PEG is polyethylene glycol or a substituted polyethylene glycol represented by the partial structural formula B-I, a pharmaceutical product. 【Chemistry 21】 [In the formula, n is between 10 and 100, m is 1, 2, 3, or 4. p is 2, 3, or 4, q is 0 or 1, R ３ However, H, -NH ２ Or, if it is -OH and q is 0, R ３ H is and when q is 1, R ３ Ha-NH ２ Or it is -OH, L is either 0 or consists of 1 to 10 units, each unit being a natural α-amino acid or derived from a natural α-amino acid, and the formula is: 【Chemistry 22】 It is expressed as, in the formula, R ４ H is R ５ However, it is the side chain or second hydrogen of an amino acid.

Images