阅读说明：本技术 妥卡雷琐衍生物及其用途 (Turcatecol derivatives and uses thereof ) 是由 何成江 黄岚 詹姆斯·托拉 于 2019-11-11 设计创作，主要内容包括：本文公开了妥卡雷琐衍生化合物和包含所述妥卡雷琐衍生化合物的组合物。本文还公开了通过施用所述妥卡雷琐衍生化合物或通过共同施用所述妥卡雷琐衍生化合物和一种或多种另外的试剂来增强个体的免疫反应的方法。本文还公开了所述妥卡雷琐衍生化合物和包含所述妥卡雷琐衍生化合物的组合物在制备用于治疗个体的癌症或增强个体的免疫反应的药物中的用途。(Disclosed herein are tocarol derivative compounds and compositions comprising the same. Also disclosed herein are methods of enhancing an immune response in an individual by administering the tucaresol derivative compound or by co-administering the tucaresol derivative compound and one or more additional agents. Also disclosed herein are uses of the tucaresol derivative compounds and compositions comprising the tucaresol derivative compounds in the manufacture of a medicament for treating cancer or enhancing an immune response in a subject.)

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

wherein:

R¹is-COOH, -COOR^1a、-COO(CH₂)_mC(O)NR^1aR^2a、-CONHR^1b、-COR⁴or-CONH (CH)₂)_mCOOR^2b；

R²is-CH (O) or-CH (═ NOR)^1a)；

R³Is H, -C (O) R^1aOptionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R⁴are amino acid residues linked by an N-terminal amine;

R^1a、R^2a、R^1band R^2bEach independently selected from-H, halogen, -OH, -COOH, -COO (C)_1-4Alkyl), optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl; and

m is an integer of 0 to 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound has the structure of formula (II)

Or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound has the structure of formula (III)

Or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein R¹is-CONHR^1bAnd R is^1bIs an optionally substituted 3-8 membered heterocyclic group, or an optionally substituted 5-6 membered monosaccharide ring.

5. The compound of claim 4, wherein R^1bIs deoxyglucose.

6. The compound of claim 4 or 5, wherein R^1bIs composed of

7. The compound of claim 1, wherein R²is-CH (═ NOR)^1a)。

8. The compound of claim 7, wherein R²is-CH (═ NOH).

9. The compound of claim 7, wherein R^1aIs C_1-6An alkyl group.

10. The compound of claim 9, wherein R^1aEthyl, butyl, cetyl, decyl or dodecyl.

11. The compound of claim 1, wherein R¹is-COR⁴。

12. The compound of claim 11, wherein R⁴Is an L-amino acid residue.

13. The compound of claim 11 or 12, wherein R⁴Is a L-Lys or L-Glu residue.

14. The method of claim 11 or 12Compound (I) wherein R⁴Is an amino acid residue selected from Gly, Ala, Phe, Tyr, Glu, Leu, Ser, Arg, Gln, Val, Lys, Thr, Asn, Met, Cys, Trp, Asp, His, Pro or Ile.

15. The compound of claim 1, wherein R¹is-CONHCH (COOH) (CH)₂)_nR⁵N is an integer of 0 to 5, and R⁵Selected from-H, -OH, -COOH, -COO (C)_1-4Alkyl), -NHC (═ NH) NH₂Optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl.

16. The compound of claim 15, wherein n is an integer from 0 to 3.

17. The compound of claim 15 or 16, wherein R⁵Is H, methyl, phenyl,-COOH、-CH(CH₃)₂、-OH、-OCH₃、-NHC(＝NH)NH₂、-CONH₂、-CH(CH₃)₂、-NH₂、-SH、-SCH₃、-CH(CH₃)(CH₂OH), indolyl, -CH (CH)₃)(CH₂CH₃) Imidazolyl or pyrrolidinyl.

18. The compound of claim 1, wherein R³Is acyl, D-glucose, 2-deoxy-D-glucose, D-ribose or 2-deoxy-D-ribose.

19. The compound of claim 18, wherein R³Is composed of

20. The compound of claim 1, wherein the compound is selected from

Or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

22. The pharmaceutical composition of claim 21, further comprising one or more additional agents.

23. The pharmaceutical composition of claim 21 or 23, further comprising one or more immune checkpoint inhibitors.

24. The pharmaceutical composition of claim 23, wherein each of the one or more immune checkpoint inhibitors is independently an inhibitor of PD-1, PD-Ll, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or' I Μ 3.

25. The pharmaceutical composition of any one of claims 21-24, further comprising plinabulin.

26. The pharmaceutical composition of any one of claims 21 to 25, further comprising one or more additional chemotherapeutic agents.

27. The pharmaceutical composition of any one of claims 21 to 26, further comprising one or more pharmaceutically acceptable excipients.

28. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

29. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing an immune response in a subject.

30. Use of a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 21 to 27 in the manufacture of a medicament for enhancing an immune response in an individual with cancer.

31. The use of any one of claims 28-30, wherein the individual is administered a vaccine or immunization.

32. The use of any one of claims 28 to 31, wherein the individual is administered one or more additional agents.

33. The use of any one of claims 28 to 32, wherein the individual is administered one or more immune checkpoint inhibitors.

34. The use of claim 33, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-Ll, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or' I Μ 3.

35. The use of any one of claims 28-34, wherein the subject is administered plinabulin.

36. The use of any one of claims 28-35, wherein the subject is administered one or more additional chemotherapeutic agents.

37. The use of any one of claims 28-36, wherein the individual is administered radiation therapy.

38. A process for preparing a compound of formula (II-A) comprising reacting a compound of formula (A-1) R-H with a compound of formula A-2A reaction wherein R-H is an amino acid, D-glucosamine, alcohol or hydroxylamine; r is a group formed upon deprotection of R-H; and R³Is H or C_1-6Alkyl radical

39. The method of claim 38, wherein R-H is an amino acid selected from Gly, Ala, Phe, Tyr, Glu, Leu, Ser, Arg, Gln, Val, Lys, Thr, Asn, Met, Cys, Trp, Asp, His, Pro, or Ile.

40. The method of claim 38, wherein R-H is D-glucosamine, methanol, or hydroxylamine.

41. The method of claim 38, wherein R³Is H.

42. Preparation of formula (I)A process for preparing a compound of I-B), comprising reacting tocarol with NH₂-OR^aReaction of wherein R^aIs H or C_1-6Alkyl radical

43. A process for preparing a compound of formula (II-C), comprising:

protecting the carboxylic acid group of tocarol to form a compound of formula (A-3), and

converting the hydroxyl group in the compound of formula (A-3) to an ester and then undergoing hydrolysis to form a compound of formula (II-C), wherein R' is acyl, D-glucose, 2-deoxy-D-glucose, D-ribose or 2-deoxy-D-ribose, and Rb is C_1-6An alkyl group.

44. The method of claim 43, wherein R^’Is composed of

45. The method of claim 43 or 44, wherein Rb is methyl.

Technical Field

The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to tucaresol derivative compounds and methods of making and using the same.

Background

Human cancers have many genetic and epigenetic changes, producing novel antigens that are potentially recognized by the immune system (Sjoblom et al, 2006). The adaptive immune system, consisting of T and B lymphocytes, has a strong anticancer potential, with a broad capacity to respond to a variety of tumor antigens and precise specificity.

There is a continuing need to develop immune models that enhance cellular responses to diseases (such as, but not limited to, infectious diseases or cancer). Accordingly, efforts have been made to develop immune modulators and specific immune checkpoint inhibitors to provide new immunotherapeutic approaches for the treatment of cancer, such as the development of the antibody ipilimumab (ipilimumab), which binds to and inhibits cytotoxic T-lymphocyte antigen-4 (CTLA-4), for the treatment of patients with advanced melanoma. In addition, nivolumab (nivolumab) and pembrolizumab (pembrolizumab), which are anti-PD-1 antibodies, have been approved for the treatment of melanoma, NSCLC and renal cancer, but patients have only limited response to these therapies. There is a particular need to develop effective therapeutic agents that can enhance the immune response to cancer cells in cancer patients.

Disclosure of Invention

Some embodiments relate to compounds having the structure of formula (I):

wherein:

R¹is-COOH, -COOR^1a、-COO(CH₂)_mC(O)NR^1aR^2a、-CONHR^1b、-COR⁴or-CONH (CH)₂)_mCOOR^2b；

R²is-CH (O) or-CH (═ NOR)^1a)；

R³Is H, -C (O) R^1aOptionally substituted-C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R⁴are amino acid residues linked by an N-terminal amine;

R^1a、R^2a、R^1band R^2bEach independently selected from-H, halogen, -OH, -COOH, -COO (C)_1-4Alkyl), optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl; and

m is an integer of 0 to 3.

Some embodiments relate to pharmaceutical compositions comprising a compound described herein and at least one pharmaceutically acceptable carrier or excipient. Some embodiments relate to pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable excipient.

Some embodiments relate to a method of enhancing an immune response in an individual comprising administering a compound or composition described herein.

Some embodiments relate to a method of treating cancer comprising administering a compound or composition described herein to an individual in need thereof.

Some embodiments relate to a method of enhancing an immune response in a cancer patient comprising administering a compound or composition described herein.

Some embodiments relate to methods of stimulating an immune response, enhancing the immunogenicity of an immunogen using a compound or composition described herein, and methods of treating an infection, an autoimmune disease, an allergy using a compound or composition described herein.

Some embodiments relate to methods of providing co-stimulation of T cell activation against cancer by co-administering a compound of formula (I) with one or more immune checkpoint inhibitors. Some embodiments relate to methods of providing co-stimulation of natural killer cells against cancer by co-administering a compound of formula (I) with one or more immune checkpoint inhibitors.

Some embodiments relate to the use of a compound or composition described herein for the manufacture of a medicament for treating cancer in an individual.

Some embodiments relate to the use of a compound or composition described herein in the manufacture of a medicament for enhancing an immune response in an individual.

Some embodiments relate to the use of a compound or composition described herein for the manufacture of a medicament for enhancing an immune response in a cancer patient.

Drawings

FIGS. 1A to 1D are graphs showing plasma levels of tocarol after IV (3mg/kg) or PO (10mg/kg) administration of tocarol, Compound C01, Compound C02-1, and Compound C02, respectively.

Fig. 2A and 2B are graphs showing the results of the tocarol and compound C02 efficacy studies in a murine liver cancer model: fig. 2A shows the results of treatment for groups 1 through 5 (once daily dosing for 5 days), and fig. 2B shows the results for groups 6 through 10 (every other day, 11 doses).

Figures 3A and 3B are graphs showing the inhibitory activity of different doses of the group of tocarol, anti-PD 1 and anti-CTLA 4 in the MC38 murine colorectal cancer model.

Fig. 4A and 4B are graphs showing tumor growth and survival, respectively, for different doses of the combination of compound C02 and anti-PD 1 in the MC38 murine colorectal cancer model.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. If there are multiple definitions for a term herein, the definition in this section controls unless otherwise specified.

"solvate" refers to a compound formed by the interaction of a solvent with a compound described herein, or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound, and which is not biologically or otherwise unsuitable for use in a medicament. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Inorganic and organic bases may also be used to form pharmaceutically acceptable salts. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the loss of labile hydrogen from the compound to yield a composition comprising an inorganic cation (e.g., Li)⁺、Na⁺、K⁺、Mg²⁺And Ca²⁺Etc.) salt forms. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, among others. Many such salts are known in the art, as described in WO 87/05297 to Johnston et al, published on 9/11 1987, which is incorporated herein by reference in its entirety.

As used herein, "C" wherein "a" and "b" are integers_aTo C_b"or" C_a-b"refers to the number of carbon atoms in a particular group. In other words, the group may contain carbon atoms from and including "a" to "b". Thus, for example, "C₁To C₄Alkyl "or" C_1-4Alkyl "groups means all alkyl groups having 1 to 4 carbons, i.e. CH₃-、CH₃CH₂-、CH₃CH₂CH₂-、(CH₃)₂CH-、CH₃CH₂CH₂CH₂-、CH₃CH₂CH(CH₃)-、(CH₃)₂CHCH₂-and (CH)₃)₃C-。

The term "halogen" or "halo" as used herein refers to any one of the radio-stable atoms in column 7 of the periodic table of elements, for example, fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (whenever appearing herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also encompasses the occurrence of the term "alkyl" without the numerical range specified). The alkyl group may also be of medium size having 1 to 9 carbon atomsAn alkyl group. The alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group may be designated as "C_1-4Alkyl "or similar names. By way of example only, "C_1-4Alkyl "means that 1 to 4 carbon atoms are present in the alkyl chain, i.e. the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

As used herein, "alkoxy" refers to the formula-OR, wherein R is alkyl as defined above, e.g., "C_1-9Alkoxy "includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

As used herein, "alkylthio" refers to the formula-SR, wherein R is alkyl as defined above, e.g., "C_1-9Alkylthio "and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, isobutylmercapto, sec-butylmercapto, tert-butylmercapto and the like.

As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. Alkenyl groups may have 2 to 20 carbon atoms, although the present definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified. The alkenyl group may also be a medium size alkenyl group having 2 to 9 carbon atoms. The alkenyl group may also be a lower alkenyl group having 2 to 4 carbon atoms. Alkenyl groups may be designated as "C_2-4Alkenyl "or similar names. By way of example only, "C_2-4Alkenyl "means that 2 to 4 carbon atoms are present in the alkenyl chain, i.e. the alkenyl chain is selected from vinyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, but-1, 3-dienyl, but-1, 2-dienyl and but-1, 2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. Alkynyl groups can have 2 to 20 carbon atoms, although the present definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified. The alkynyl group may also be a medium-sized alkynyl group having 2 to 9 carbon atoms. The alkynyl group may also be a lower alkynyl group having 2 to 4 carbon atoms. Alkynyl may be designated as "C_2-4Alkynyl "or similar names. By way of example only, "C_2-4Alkynyl "means that 2 to 4 carbon atoms are present in the alkynyl chain, i.e., the alkynyl chain is selected from ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the chain backbone, which are elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. Heteroalkyl groups may have from 1 to 20 carbon atoms, although the present definition also encompasses the occurrence of the term "heteroalkyl" where no numerical range is specified. The heteroalkyl group can also be a medium size heteroalkyl group having from 1 to 9 carbon atoms. The heteroalkyl group may also be a lower heteroalkyl group having 1 to 4 carbon atoms. Heteroalkyl groups may be designated as "C_1-4Heteroalkyl "or similar names. The heteroalkyl group may contain one or more heteroatoms, for example, 1,2, 3,4, or 5 heteroatoms. The heteroalkyl group may contain 1-2, 1-3, or 1-4 heteroatoms. By way of example only, "C_1-4Heteroalkyl "means the presence of 1 to 4 carbon atoms in the heteroalkyl chain and the additional presence of one or more heteroatoms in the backbone of the chain.

As used herein, "alkylene" means a branched or straight chain, fully saturated, divalent chemical group containing only carbon and hydrogen, which is attached to the rest of the molecule through two points of attachment (i.e., alkanediyl). Alkylene groups may have 1 to 20 carbon atoms, but the present definition also covers the occurrence of the term alkylene where no numerical range is specified. The alkylene group may also be a medium size alkylene group having 1 to 9 carbon atoms. The alkylene group may also be of 1 to 4 carbon atomsLower alkylene of a molecule. Alkylene groups may be designated as "C_1-4Alkylene "or similar names. By way of example only, "C_1-4Alkylene "means that 1 to 4 carbon atoms are present in the alkylene chain, i.e. the alkylene chain is selected from the group consisting of methylene, ethylene-1, 1-diyl, propylene, propane-1, 1-diyl, propane-2, 2-diyl, 1-methyl-ethylene, butylene, butane-1, 1-diyl, butane-2, 2-diyl, 2-methyl-propane-1, 1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1-dimethyl-ethylene, 1, 2-dimethyl-ethylene and 1-ethyl-ethylene.

As used herein, "alkenylene" means a straight or branched chain divalent chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, which is attached to the rest of the molecule through two points of attachment. Alkenylene groups may have from 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene group without a numerical range being specified. The alkenylene group may also be a medium-sized alkenylene group having 2 to 9 carbon atoms. The alkenylene group may also be a lower alkenylene group having 2 to 4 carbon atoms. Alkenylene may be designated as "C_2-4Alkenylene "or similar names. By way of example only, "C_2-4Alkenylene "denotes the presence of 2 to 4 carbon atoms in the alkenylene chain, i.e. the alkenylene chain is selected from the group consisting of ethenylene, ethylene-1, 1-diyl, propenylene, propene-1, 1-diyl, prop-2-ene-1, 1-diyl, 1-methyl-ethenylene, buten-1-enyl, buten-2-enyl, buta-1, 3-dienylene, buten-1, 1-diyl, but-1, 3-dien-1, 1-diyl, but-2-ene-1, 1-diyl, but-3-ene-1, 1-diyl, 1-methyl-prop-2-ene-1, 1-diyl, 2-methyl-prop-2-ene-1, 1-diyl, 1-ethyl-ethenylene, 1, 2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1, 1-diyl and 2, 2-dimethyl-ethen-1, 1-diyl.

The term "aromatic" refers to rings or ring systems having conjugated pi-electron systems, including carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When the aryl group is a ring system, each ring in the system is aromatic. The aryl group can have from 6 to 18 carbon atoms, although the present definition also encompasses occurrences of the term "aryl" where no numerical range is specified. In some embodiments, aryl has 6 to 10 carbon atoms. Aryl groups may be designated as "C_6-10Aryl group "," C₆Or C₁₀Aryl "or similar names. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

As used herein, "aryloxy" and "arylthio" refer to RO-and RS-, where R is aryl as defined above, e.g., "C_6-10Aryloxy radical "or" C_6-10Arylthio "and the like, including but not limited to phenoxy.

"aralkyl" or "arylalkyl" is an aryl group as a substituent linked through an alkylene group, e.g. "C_7-14Aralkyl "and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, alkylene is lower alkylene (i.e., C)_1-4Alkylene).

As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms in the ring backbone, which are elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. When the heteroaryl group is a ring system, each ring in the system is aromatic. Heteroaryl groups can have from 5 to 18 ring members (i.e., the number of atoms making up the ring backbone, including carbon and heteroatoms), although the present definition also encompasses occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, heteroaryl has 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5-7 membered heteroaryl", "5-10 membered heteroaryl", or similar names. Heteroaryl groups may contain one or more heteroatoms, for example, 1,2, 3,4, or 5 heteroatoms. Heteroaryl groups may contain 1-2, 1-3, or 1-4 heteroatoms. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

"Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group as a substituent attached through an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolidinylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, alkylene is lower alkylene (i.e., C)_1-4Alkylene).

As used herein, "carbocyclyl" means a non-aromatic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl group is a ring system, two or more rings may be joined together in a fused, bridged or spiro-linked manner. The carbocyclyl group may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. Carbocyclyl groups may have 3 to 20 carbon atoms, although the present definition also encompasses the occurrence of the term "carbocyclyl" where no numerical range is specified. The carbocyclyl group may also be a medium size carbocyclyl group having 3 to 10 carbon atoms. The carbocyclyl group may also be a carbocyclyl group having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C_3-6Carbocyclyl "or similar names. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 3-dihydro-indene, bicyclo [2.2.2]Octyl, adamantyl and spiro [4.4 ]]Nonyl radical.

"(carbocyclyl) alkyl" is a carbocyclyl group as a substituent attached through an alkylene group, e.g., "C_4-10(carbocyclyl) alkyl "and the like, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylEthyl, cycloheptylmethyl, and the like. In some cases, the alkylene is lower alkylene.

As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. One example is cyclohexenyl.

As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclic groups may be joined together in a fused, bridged or spiro-connected fashion. The heterocyclyl group may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms may be present in non-aromatic or aromatic rings in the ring system. A heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon and heteroatoms), although the present definition also encompasses occurrences of the term "heterocyclyl" where no numerical range is specified. The heterocyclyl group may contain one or more heteroatoms, for example, 1,2, 3,4 or 5 heteroatoms. The heterocyclyl group may contain 1-2, 1-3 or 1-4 heteroatoms. Heterocyclyl may also be a medium-sized heterocyclyl having 3 to 10 ring members. The heterocyclic group may also be a heterocyclic group having 3 to 6 ring members. A heterocyclyl group may be designated as a "3-6 membered heterocyclyl" or similar name. In preferred six membered monocyclic heterocyclic groups, the heteroatom is selected from one to at most three of O, N or S, and in preferred five membered monocyclic heterocyclic groups, the heteroatom is selected from one or two heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl (pyrrolidonyl), 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1, 3-dioxinyl, 1, 3-dioxanyl, 1, 4-dioxinyl, 1, 4-dioxanyl, 1, 3-oxidoThiacyclohexyl, 1, 4-oxathiahexadienyl, 1, 4-oxathiahexyl, 2H-1, 2-oxazinyl, trioxacyclohexyl, hexahydro-1, 3, 5-triazinyl, 1, 3-dioxolyl, 1, 3-dioxolanyl, 1, 3-dithiolyl, isoxazolinyl, oxazolinyl, oxazolidinyl, oxazolidone group, thiazolinyl group, thiazolidinyl group, 1, 3-oxathiolanyl group, indolinyl group, isoindolinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, tetrahydro-1, 4-thiazinyl group, thiomorpholinyl group, dihydrobenzofuranyl group, benzimidazolyl group, and tetrahydroquinoline. An "optionally substituted 5-6 membered heterocyclyl" may contain one oxygen heteroatom and is optionally substituted with up to four substituents each independently selected from the group consisting of-OH, -OC (O) CH₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃。

"(heterocyclyl) alkyl" is a heterocyclyl group as a substituent attached through an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

"monosaccharide" or "monosaccharide ring" refers to a single sugar residue. The monosaccharide may have a five or six membered carbon backbone. Non-limiting examples of "5-6 membered monosaccharide rings" include: glucose (e.g., D-glucose), deoxyglucose (e.g., 2-deoxy-D-glucose), galactose, fructose, ribose (e.g., D-ribose), and deoxyribose (e.g., 2-deoxy-D-ribose). "amino monosaccharide" refers to an amino sugar in which the sugar backbone is a monosaccharide.

As used herein, "acyl" refers to — C (═ O) R, where R is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

An "O-carboxy" group refers to an "-OC (═ O) R" group, wherein R is selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

A "C-carboxy" group refers to a "-C (═ O) OR" group, wherein R is selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include carboxyl (i.e., -C (═ O) OH).

A "cyano" group refers to a "-CN" group.

The "cyanate" group refers to the "-OCN" group.

"isocyanato" group means an "-NCO" group.

A "thiocyanate" group refers to an "-SCN" group.

An "isothiocyanate" group refers to an "-NCS" group.

A "sulfinyl" group refers to a "-S (═ O) R" group, where R is selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

"sulfonyl" group means "-SO₂R' group, wherein R is selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

"S-sulfonylamino" group means "-SO₂NR_AR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

The "N-sulfonylamino" group refers to "-N (R)_A)SO₂R_B"group, wherein R_AAnd R_bEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

An "O-carbamoyl" group means "-OC (═ O) NR_AR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

The "N-carbamoyl" group means "-N (R)_A)C(＝O)OR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

An "O-thiocarbamoyl" group is intended to mean "-OC (═ S) NR_AR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

An "N-thiocarbamoyl" group is intended to mean "-N (R)_A)C(＝S)OR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

"C-acylamino" radical means "-C (═ O) NR_AR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

An "N-amido" group is intended to mean "-N (R)_A)C(＝O)R_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

An "amino" group is intended to mean the radical-NR_AR_B"group, wherein R_AAnd R_BEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Carbocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include free amino groups (e.g., -NH)₂)。

An "aminoalkyl" group refers to an amino group attached through an alkylene group.

An "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group, e.g., "C_2-8Alkoxyalkyl groups "and the like.

As used herein, a substituted group is derived from an unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise specified, when a group is considered "substituted" it is meant that the group is substituted with one or more substituents independently selected from C₁-C₆Alkyl (optionally substituted by-OH or O-carboxy), C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Heteroalkyl group, C₃-C₇Carbocyclyl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), C₃-C₇-carbocyclyl-C₁-C₆Alkyl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), 3-10 membered heterocyclyl (halogenated, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), 3-10 membered heterocyclyl-C₁-C₆Alkyl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), aryl (halogenated, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), aryl (C)₁-C₆) Alkyl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), 5-10 membered heteroaryl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), 5-to 10-membered heteroaryl (C)₁-C₆) Alkyl (halogenated, C)₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆Haloalkoxy optionally substituted), halo, cyano, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkoxy (C)₁-C₆) Alkyl (i.e. ether), aryloxy, mercapto, halo (C)₁-C₆) Alkyl (e.g. -CF)₃) Halo (C)₁-C₆) Alkoxy (e.g., -OCF)₃)、C₁-C₆Alkylthio, arylthio, amino (C)₁-C₆) Alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulphonylamino, N-sulphonylamino, C-carboxy, O-carboxy, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulphinyl, sulphonyl and oxo (═ O). Unless otherwise indicated, wherever groups are depicted, unless otherwise indicatedThe term "optionally substituted" refers to a group which may be substituted with the above-mentioned substituents.

It is understood that, depending on the context, certain radical naming conventions may include mono-radicals or di-radicals. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a divalent group. For example, substituents identified as alkyl requiring two points of attachment include divalent groups, such as-CH₂–、–CH₂CH₂–、–CH₂CH(CH₃)CH₂-and the like. Other radical naming conventions clearly indicate that the radical is a divalent radical, such as "alkylene" or "alkenylene".

When two R groups are referred to as "together with the atom to which they are attached" to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), this means that the atom and the common element of the two R groups are the ring. When taken alone, the ring is otherwise not limited by the definition of each R group. For example, when the following structure is present:

and R is¹And R²Is defined as being selected from hydrogen and alkyl, or R¹And R²Together with the nitrogen to which they are attached form a heteroaryl group, meaning R¹And R²May be selected from hydrogen or alkyl groups, or alternatively, the substructure has the following structure:

wherein ring a is a heteroaryl ring containing the nitrogen.

Similarly, when two "adjacent" R groups "are mentioned to form a ring together with the atoms to which they are attached, this means that the atoms, intervening bonds, and common units of the two R groups are the ring. For example, when the following structure is present:

and R is₁And R₂Is defined as being selected from hydrogen and alkyl, or R₁And R₂Together with the atom to which they are attached form an aryl or carbocyclyl group, meaning R₁And R₂May be selected from hydrogen or alkyl groups, or alternatively, the substructure has the following structure:

wherein A is an aryl ring or carbocyclyl containing the double bond.

Wherever a substituent is described as a divalent group (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any directional configuration unless otherwise specified. Thus, for example, described as-AE-orIncludes the case of a substituent oriented such that a is attached at the leftmost attachment point of the molecule and a is attached at the rightmost attachment point of the molecule.

It is also contemplated that when a chemical substituent is added to the carboxylic acid isostere, the compound retains the properties of the carboxylic acid isostere. It is contemplated that when the carboxylic acid isostere is optionally substituted with one or more moieties such as R as defined above, then the substitution and substitution positions are selected such that they do not eliminate the carboxylic acid isostere nature of the compound. Similarly, it is also contemplated that placement of one or more R substituents on a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atoms that maintains or is essential to the carboxylic acid isostere properties of the compound if such substituents would destroy the carboxylic acid isostere properties of the compound.

As used herein, "subject" refers to a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, e.g., a chicken, as well as any other vertebrate or invertebrate animal.

The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates, including apes (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mouse guinea pigs, and the like.

As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to alleviate or reduce the likelihood of onset of one or more symptoms of a disease or condition to some extent and includes a cure for the disease or condition. "cure" means to eliminate the symptoms of a disease or condition; however, even after a cure is obtained, there may be some long-term or permanent effects (e.g., extensive tissue damage).

As used herein, "treatment (treat)", "treating (therapy)" or "treating (therapy)" refers to the administration of a compound or pharmaceutical composition to an individual for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of an individual who has not yet exhibited symptoms of a disease or condition, but who is susceptible to or at risk of a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to the treatment of an individual who already has a disease or condition.

Compound (I)

Some embodiments relate to compounds having the structure of formula (I):

wherein:

R¹is-COOH, -COOR^1a、-COO(CH₂)_mC(O)NR^1aR^2a、-CONHR^1b、-COR⁴or-CONH (C)H₂)_mCOOR^2b；

R²is-CH (O) or-CH (═ NOR)^1a)；

R³Is H, -C (O) R^1aOptionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl;

R⁴are amino acid residues linked by an N-terminal amine;

R^1a、R^2a、R^1band R^2bEach independently selected from-H, halogen, -OH, -COOH, -COO (C)_1-4Alkyl), optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl; and

m is an integer of 0 to 3.

In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more, if present, of (a) are independently a 5-6 membered heterocyclyl substituted with up to four substituents each independently selected from-OH, -OC (O) CH and containing one oxygen heteroatom₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃. In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more (if present) of (a) is independently an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more (if present) of (a) are independently selected from glucose, galactose, deoxyglucose, fructose, ribose, and deoxyribose. In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more of (if present) is deoxyglucose. In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more (if present) of (a) independently are In some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more (if present) ofIn some embodiments, R^1a、R^2a、R^1bAnd R^2bAny one or more (if present) of (a) is independently a 5-6 membered monosaccharide ring selected from D-glucose, 2-deoxy-D-glucose, D-ribose and 2-deoxy-D-ribose.

In some embodiments, - (CH)₂)_mOne, two or three H atoms in-are each independently substituted by halogen, -OH, -COOH, -COO (C)_1-4Alkyl), optionally substituted C_1-30Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl and optionally substituted 5-10 membered heteroaryl.

In some embodiments, the compound has the structure of formula (II)

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of formula (III)

Or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹is-CONHR^1bAnd R is^1bIs an optionally substituted 3-8 membered heterocyclic group or an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, R¹is-CONHR^1bAnd R is^1bIs an optionally substituted 3-8 membered heterocyclic group. In some embodiments, R^1bIs a 5-6 membered heterocyclyl substituted with up to four substituents each independently selected from-OH, -OC (O) CH and containing one oxygen heteroatom₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃. In some embodiments, R^1bIs an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, R^1bIs a 5-6 membered monosaccharide ring selected from the group consisting of D-glucose, 2-deoxy-D-glucose, D-ribose and 2-deoxy-D-ribose. In some embodiments, R^1bSelected from the group consisting of glucose, galactose, deoxyglucose, fructose, ribose, and deoxyribose. In some embodiments, R^1bIs deoxyglucose. In some embodiments, R^1bIs composed ofIn some embodiments, R^1bIs composed of

In some embodiments, R²is-CH (═ NOR)^1a). In some embodiments, R²is-CH (═ NOH).

In some embodiments, R^1aIs C_1-6An alkyl group. In some embodiments, R^1aEthyl, butyl, cetyl, decyl or dodecyl.

In some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aIs a 5-6 membered heterocyclyl substituted with up to four substituents each independently selected from-OH, -OC (O) CH and containing one oxygen heteroatom₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃. In some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aOne of which is an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, the 5-6 membered monosaccharide ring is selected from the group consisting of D-glucose, 2-deoxy-D-glucose, D-ribose, and 2-deoxy-D-ribose. In some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aIs selected from glucose, galactose, deoxyglucose, fructose, ribose and deoxyribose. In some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aOne of which is deoxyglucose. In some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aOne of them isIn some embodiments, R¹is-COO (CH)₂)_mC(O)NR^1aR^2a(ii) a And R is^1aAnd R^2aOne of them isIn some embodiments, R^1aAnd R^2aAnd the other of (a) is H. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, R¹is-COR⁴. In some embodimentsIn, R¹is-CONHCH (COOH) (CH)₂)_nR⁵N is an integer of 0 to 5, and R⁵Selected from-H, -OH, -COOH, -COO (C)_1-4Alkyl), -NHC (═ NH) NH₂Optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl or optionally substituted 5-10 membered heteroaryl. In some embodiments, R⁵Is an optionally substituted 3-8 membered heterocyclic group or an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, R⁵Is an optionally substituted 3-8 membered heterocyclic group. In some embodiments, R⁵Is a 5-6 membered heterocyclyl substituted with up to four substituents each independently selected from-OH, -OC (O) CH and containing one oxygen heteroatom₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃. In some embodiments, R⁵Is an optionally substituted 5-6 membered monosaccharide ring. In some embodiments, R⁵Is a 5-6 membered monosaccharide ring selected from the group consisting of D-glucose, 2-deoxy-D-glucose, D-ribose and 2-deoxy-D-ribose. In some embodiments, R⁵Selected from the group consisting of glucose, galactose, deoxyglucose, fructose, ribose, and deoxyribose. In some embodiments, R⁵Is deoxyglucose. In some embodiments, R⁵Is composed of In some embodiments, R⁵Is composed ofIn some embodiments, - (CH)₂)_nOne, two or three H atoms in-are each independently substituted by halogen, -OH, -COOH, -COO (C)_1-4Alkyl), optionally substituted C_1-30Alkyl, optionally substituted C_2-10Alkenyl, optionally substituted C_2-10Alkynyl, optionally substituted C_3-7Cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 5-6 membered monosaccharide ring, optionally substituted C_6-10Aryl and optionally substituted 5-10 membered heteroaryl.

In some embodiments, n is an integer from 0 to 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, R⁴Is an L-amino acid residue. In some embodiments, R⁴Is a L-Lys or L-Glu residue. In some embodiments, R⁴Is an amino acid residue selected from Gly, Ala, Phe, Tyr, Glu, Leu, Ser, Arg, Gln, Val, Lys, Thr, Asn, Met, Cys, Trp, Asp, His, Pro or Ile.

In some embodiments, R⁵Is H, methyl, phenyl,-COOH、-CH(CH₃)₂、-OH、-OCH₃、-NHC(＝NH)NH₂、-CONH₂、-CH(CH₃)₂、-NH₂、-SH、-S-CH₃、-CH(CH₃)(CH₂OH), indolyl, -CH (CH)₃)(CH₂CH₃) Imidazolyl or pyrrolidinyl. In some embodiments, R⁵Is H. In some embodiments, R⁵Is methyl. In some embodiments, R⁵Is phenyl. In some embodiments, R⁵Is composed ofIn some embodiments, R⁵is-COOH. In some embodiments, R⁵is-CH (CH)₃)₂. In some embodiments, R⁵is-OH. In some embodiments, R⁵is-NHC (═ NH) NH₂. In some casesIn the embodiment, R⁵is-CONH₂. In some embodiments, R⁵is-CH (CH)₃)₂. In some embodiments, R⁵is-NH₂. In some embodiments, R⁵Is SH. In some embodiments, R⁵Is S-CH₃. In some embodiments, R⁵is-CH (CH)₃)(CH₂OH). In some embodiments, R⁵Is indolyl. In some embodiments, R⁵Is CH (CH)₃)(CH₂CH₃). In some embodiments, R⁵Is imidazolyl. In some embodiments, R⁵Is pyrrolidinyl.

In some embodiments, R³Is acyl, D-glucose, 2-deoxy-D-glucose, D-ribose or 2-deoxy-D-ribose. In some embodiments, R³Is composed of In some embodiments, R³Is composed of R³Is H or C_1-6An alkyl group. In some embodiments, R³Is H.

In some embodiments, the compounds described herein are selected from

Or a pharmaceutically acceptable salt thereof.

Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. The separation of the individual isomers or the selective synthesis of the individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic form. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

One skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of a compound, which may be reasonably represented even kinetically by other chemical structures; those skilled in the art recognize that such structures may represent only a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the structures described, although such resonance forms or tautomers are not shown herein.

Isotopes may be present in the compounds. Each chemical element as represented in the structure of the compound may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all possible isotopic forms, unless the context clearly dictates otherwise.

Administration and pharmaceutical compositions

Some embodiments relate to a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the compositions described herein further comprise one or more additional agents.

In some embodiments, the compositions described herein further comprise one or more immune checkpoint inhibitors. In some embodiments, each of the one or more immune checkpoint inhibitors is independently an inhibitor of PD-1, PD-Ll, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or' I Μ 3.

In some embodiments, the compositions described herein further comprise plinabulin (plinabulin).

In some embodiments, the compositions described herein further comprise one or more additional chemotherapeutic agents.

In some embodiments, the compositions described herein further comprise one or more pharmaceutically acceptable excipients.

Administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be by any acceptable mode of administration for agents with similar efficacy, including but not limited to oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. Oral and parenteral administration is generally used to treat the indications that are the subject of the preferred embodiments.

The useful compounds as described above may be formulated into pharmaceutical compositions for the treatment of these conditions. Standard pharmaceutical formulation techniques, such as those disclosed in The Science and Practice of Pharmacy, 21 st edition, Lippincott Williams & Wilkins (2005) of Remington, which is incorporated herein by reference in its entirety, are used. Accordingly, some embodiments include a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional vehicle or agent in a therapeutic composition is contemplated unless the vehicle or agent is incompatible with the active ingredient. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al (eds.) (1990); goodman and Gilman's, The pharmaceutical Basis of Therapeutics, 8 th edition, Pergamon Press, which is incorporated herein by reference in its entirety.

Some examples of substances that can be used as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting; a stabilizer; an antioxidant; a preservative; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically acceptable carrier to be used in combination with the subject compound may be determined by the mode of administration of the compound.

The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound suitable for administration to an animal (preferably a mammalian subject) in a single dose in accordance with good medical practice. However, a single dosage form or unit dosage form of a formulation does not mean that the dosage form is administered once per day or once per course of treatment. It is contemplated that the dosage form is administered once, twice, three times or more daily, and may be administered by infusion for a period of time (e.g., about 30 minutes to about 2-6 hours), or in a continuous infusion, and may be administered more than once during a course of treatment, although single administrations are not specifically excluded. Those skilled in the art will recognize that the formulation is not specifically contemplated for the entire course of treatment, and such decisions should be left to those skilled in the art of treatment, rather than those skilled in the formulation art.

The compositions useful as described above may be used in any of a variety of suitable forms for various routes of administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. It will be understood by those skilled in the art that oral and nasal compositions include compositions that are administered by inhalation and prepared using available methodologies. Various pharmaceutically acceptable carriers well known in the art may be used depending on the particular route of administration desired. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, co-solvents, surfactants, and encapsulating substances. An optional pharmaceutically active material may be included which does not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms suitable for use in the methods described herein are described in the following references, all of which are incorporated herein by reference: modern pharmaceuticals, 4 th edition, chapters 9 and 10 (Banker and Rhodes, eds., 2002); lieberman et al, Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8 th edition (2004).

Various oral dosage forms may be used, including, for example, solid forms such as tablets, capsules, granules, and bulk powders. The tablets may be compressed, die-cast, enteric-coated, sugar-coated, film-coated or multiple-compressed tablets, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting aids. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting aids, colorants and flavoring agents.

Pharmaceutically acceptable carriers suitable for use in preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as: calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and crosslinked carboxymethyl cellulose; lubricants, for example, magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide may be used to improve the flow characteristics of the powder mixture. For appearance, colorants such as FD & C dyes may be added. For chewable tablets, sweetening and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful excipients. Capsules typically contain one or more of the solid diluents disclosed above. The choice of carrier component depends on secondary considerations such as taste, cost and storage stability, which are not critical and can be readily achieved by one skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers suitable for use in preparing such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, gum tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweetening agents, flavoring agents and coloring agents, as disclosed above.

Such compositions may also be coated by conventional means, typically with a pH-dependent or time-dependent coating, so that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac.

The compositions described herein may optionally comprise other pharmaceutical actives.

Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of the following: soluble bulking substances such as sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavors disclosed above may also be included.

A liquid composition (which is formulated for topical ophthalmic use) is formulated such that it can be applied topically to the eye. Comfort may be maximized as much as possible, although formulation considerations (e.g., drug stability) may sometimes require less than optimal comfort. In cases where comfort is not maximized, the liquid may be formulated such that the liquid is tolerable for the patient's topical ophthalmic use. Additionally, ophthalmically acceptable liquids can be packaged for single use, or contain preservatives to prevent contamination over multiple uses.

For ophthalmic applications, solutions or medicaments are typically prepared using physiological saline solution as the primary vehicle. The ophthalmic solution may preferably be maintained at a comfortable pH with a suitable buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, tween 80. Likewise, various useful carriers may be used in the ophthalmic formulations disclosed herein. Such carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

Tonicity adjusting agents may be added as needed or convenient. They include, but are not limited to, salts (in particular sodium chloride, potassium chloride), mannitol and glycerol, or any other suitable ophthalmically acceptable tonicity modifier.

Various buffers and means for adjusting the pH may be used as long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH will be from 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

Other excipient components that may be included in the ophthalmic formulation are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used instead of or in combination with it.

For topical application, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally include a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as physiological saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients present in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates (e.g., dextrose, mannitol, and dextran). Additional acceptable Excipients are described in Powell et al, Complex of Excipients for particulate Formulations, PDA J Pharm Sci and Tech 1998, 52238-. Antimicrobial agents including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol may also be included to obtain bacteriostatic or fungistatic solutions.

Compositions for intravenous administration may be provided to the caregiver in the form of one or more solids that are reconstituted with a suitable diluent (e.g., sterile water, saline, or aqueous dextrose) immediately prior to administration. In other embodiments, the composition is provided in the form of a solution ready for parenteral administration. In other embodiments, the composition is provided in the form of a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and an additional agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

The actual dosage of the active compounds described herein depends on the particular compound and the condition being treated; the selection of the appropriate dosage is well within the knowledge of the skilled person. In some embodiments, the daily dose can be from about 0.25mg/kg body weight to about 120mg/kg body weight or more, from about 0.5mg/kg body weight or less to about 70mg/kg body weight, from about 1.0mg/kg body weight to about 50mg/kg body weight, or from about 1.5mg/kg body weight to about 10mg/kg body weight. Thus, for administration to a 70kg human, the dosage will range from about 17 mg/day to about 8000 mg/day, from about 35 mg/day or less to about 7000 mg/day or more, from about 70 mg/day to about 6000 mg/day, from about 100 mg/day to about 5000 mg/day, or from about 200 mg/day to about 3000 mg/day.

Method of treatment

Some embodiments relate to a method of enhancing an immune response in an individual comprising administering a compound or composition described herein.

Some embodiments relate to a method of treating cancer comprising administering a compound or composition described herein to an individual in need thereof.

Some embodiments relate to a method of enhancing an immune response in a cancer patient comprising administering a compound or composition described herein.

Some embodiments relate to methods of stimulating an immune response, enhancing the immunogenicity of an immunogen using a compound or composition described herein, and methods of treating an infection, an autoimmune disease, an allergy using a compound or composition described herein.

Some embodiments relate to methods of providing co-stimulation of T cell activation against cancer by co-administering a compound of formula (I), one or more immune checkpoint inhibitors. Some embodiments relate to methods of providing co-stimulation of natural killer cells against cancer by co-administering a compound of formula (I), one or more immune checkpoint inhibitors.

In some embodiments, the vaccine or immunization is administered to a patient.

In some embodiments, the methods described herein comprise administering one or more additional agents.

In some embodiments, the methods described herein comprise administering one or more checkpoint inhibitors.

In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1, PD-Ll, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or' I Μ 3. In some embodiments, the cancer comprises cancer cells that express a binding ligand for PD-1. In some embodiments, the binding ligand for PD-1 is PD-L1. In some embodiments, the binding ligand for PD-1 is PD-L2.

In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express a binding ligand for PD-1. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express PD-L1. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express PD-L2. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express PD-L3 or PD-L4.

In some embodiments, identifying cancer cells that express a binding ligand for PD-1 comprises using an assay to detect the presence of the binding ligand. Examples of suitable assays include, but are not limited to, the PD-L1 IHC 22C3 pharmDx kit and PD-L1 IHC 28-8 pharmDx available from Dako.

In some embodiments, the cancer comprises cancer cells that express a binding ligand for CTLA-4. In some embodiments, the binding ligand of CTLA-4 is B7.1 or B7.2.

In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express a binding ligand for CTLA-4. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express B7.1 or B7.2.

In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, ipilimumab, dacarbazine, BMS 936559, attrituzumab, durvalimab, or any combination thereof.

In some embodiments, the cancer is head and neck cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, kidney cancer, bladder cancer, ovarian cancer, cervical cancer, melanoma, glioblastoma, myeloma, lymphoma, or leukemia. In some embodiments, the cancer is renal cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian tumor, hodgkin's lymphoma, or squamous cell carcinoma. In some embodiments, the cancer is selected from breast cancer, colon cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian cancer, gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphoma, and myeloma. In some embodiments, the cancer is a solid tumor or a hematologic cancer.

In some embodiments, the cancer does not contain any cells that express detectable levels of PD-1, PD-L1, or PD-L2.

In some embodiments, the combination of a compound of formula (I) and a PD-1 inhibitor (or PD-L1 inhibitor/PD-L2 inhibitor) exhibits better safety profile and lower toxicity than the combination of CTLA-4 and a PD-1 inhibitor (or PD-L1 inhibitor/PD-L2 inhibitor). In some embodiments, the therapeutic index of the combination of the compound of formula (I) and the PD-1 inhibitor (or PD-L1 inhibitor/PD-L2 inhibitor) is greater than the therapeutic index of the combination of CTLA-4 and PD-1 inhibitor (or PD-L1 inhibitor/PD-L2 inhibitor).

In some embodiments, the cancer is a cancer selected from the group consisting of: melanoma, pancreatic cancer, colorectal adenocarcinoma, brain tumor, acute lymphocytic leukemia, chronic lymphocytic leukemia, hormone refractory metastatic prostate cancer, metastatic breast cancer, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, prostate cancer, colon cancer, thyroid undifferentiated carcinoma.

Some embodiments include co-administering the compositions and/or pharmaceutical compositions described herein and other drugs. For example, as described above, some embodiments include co-administration of a compound of formula (I) described herein with one or more immune checkpoint inhibitors and plinabulin, and some embodiments include co-administration of a compound of formula (I) described herein and plinabulin. By "co-administration", it is meant that two or more agents are administered in such a way that: the administration of one or more agents affects the efficacy and/or safety of one or more other agents, whenever they are administered or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, the combined administration is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered by the same route, such as orally or intravenously. In another embodiment, the agents are administered by different routes, such as one oral administration and another intravenous administration. In some embodiments, the time period between administration of the one or more agents and administration of the co-administered one or more agents can be about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 36 hours, 48 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 28 days, or 30 days. In some embodiments, the time period between administration of the one or more agents and administration of the co-administered one or more agents ranges from about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 20 minutes, 1 minute to 30 minutes, 1 minute to 40 minutes, 1 minute to 50 minutes, 1 minute to 1 hour, 1 minute to 2 hours, 1 minute to 4 hours, 1 minute to 6 hours, 1 minute to 8 hours, 1 minute to 10 hours, 1 minute to 12 hours, 1 minute to 24 hours, 1 minute to 36 hours, 1 minute to 48 hours, 1 minute to 60 hours, 1 minute to 72 hours, 5 minutes to 10 minutes, 5 minutes to 20 minutes, 5 minutes to 30 minutes, 5 minutes to 40 minutes, 5 minutes to 50 minutes, 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 4 hours, 5 minutes to 6 hours, a, 5 minutes to 8 hours, 5 minutes to 10 hours, 5 minutes to 12 hours, 5 minutes to 24 hours, 5 minutes to 36 hours, 5 minutes to 48 hours, 5 minutes to 60 hours, 5 minutes to 72 hours, 10 minutes to 20 minutes, 10 minutes to 30 minutes, 10 minutes to 40 minutes, 10 minutes to 50 minutes, 10 minutes to 1 hour, 10 minutes to 2 hours, 10 minutes to 4 hours, 10 minutes to 6 hours, 10 minutes to 8 hours, 10 minutes to 10 hours, 10 minutes to 12 hours, 10 minutes to 24 hours, 10 minutes to 36 hours, 10 minutes to 48 hours, 10 minutes to 60 hours, 10 minutes to 72 hours, 30 minutes to 40 minutes, 30 minutes to 50 minutes, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 4 hours, 30 minutes to 6 hours, 30 minutes to 8 hours, 30 minutes to 10 hours, 30 minutes to 12 hours, 5 minutes to 36 hours, 5 minutes to 48 hours, 5 minutes to 5 hours, 5 minutes to, 30 minutes to 24 hours, 30 minutes to 36 hours, 30 minutes to 48 hours, 30 minutes to 60 hours, 30 minutes to 72 hours, 1 hour to 2 hours, 1 hour to 4 hours, 1 hour to 6 hours, 1 hour to 8 hours, 1 hour to 10 hours, 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours, 6 hours to 8 hours, 6 hours to 10 hours, 6 hours to 12 hours, 6 hours to 24 hours, 6 hours to 36 hours, 6 hours to 48 hours, 6 hours to 60 hours, 6 hours to 72 hours, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 48 hours, 12 hours to 60 hours, or 12 hours to 72 hours.

The actual dosage of the active compounds described herein depends on the particular compound and the condition to be treated; the selection of an appropriate dosage is within the knowledge of the skilled person. In some embodiments, the methods described herein comprise administering a compound of formula (I) at a dose in the following range: from about 0.01mg/kg to about 250mg/kg body weight, from about 0.1mg/kg to about 200mg/kg body weight, from about 0.25mg/kg to about 120mg/kg body weight, from about 0.5mg/kg to about 70mg/kg body weight, from about 1.0mg/kg to about 50mg/kg body weight, from about 1.0mg/kg to about 15mg/kg body weight, from about 2.0mg/kg to about 15mg/kg body weight, from about 3.0mg/kg to about 12mg/kg body weight or from about 5.0mg/kg to about 10mg/kg body weight. In some embodiments, the methods described herein comprise administering a compound of formula (I) at a dose in the following range: 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2.5-5, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 3-5, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 5-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 5-100, 5-30, 5-100-10-20, 7.5-30, 10-20-40, 10-30, 10-40, 10-50, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350 or 100-400mg/kg body weight. In some embodiments, the compound of formula (I) may be administered at the following doses: about 0.1, 0.25, 0.5, 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100mg/kg body weight. In some embodiments, the methods described herein comprise administering a compound of formula (I) at a dose of about 3 mg/kg. In some embodiments, the methods described herein comprise administering a compound of formula (I) at a dose of about 3mg/kg every three weeks for a total of four doses.

In some embodiments, the compound of formula (I) is administered in the following amounts: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 3-10, 5-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 5-10, 5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-100, 5-100, 7.5-10.5-100, 7.5-100, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 70-500, 70-750, 70-1000, 70-1500, 70-2000, 70-3000, 80-100, 80-150, 80-200, 80-250, 80-300, 80-500, 80-750, 80-1000, 80-1500, 80-2000, 80-3000, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 100-200-500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500 or 500-4000 mg/agent. In some embodiments, the compound of formula (I) is administered in the following amounts: about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 2500, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2100, 5000, 2300, 2700, 3400, 3800, 470, 4400, 4500, 300, 2000, 2500, 2000. In some embodiments, the compound of formula (I) is administered in an amount of about 25 mg/dose, 50 mg/dose, or 100 mg/dose.

In some embodiments, the methods described herein comprise administering one or more checkpoint inhibitors at a dose in the range of: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-9, 2.5-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-5, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 50-100, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350 or 100-400mg/kg of body weight. In some embodiments, the methods described herein comprise administering one or more checkpoint inhibitors at the following doses: about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100mg/kg body weight.

In some embodiments, the one or more checkpoint inhibitors are administered in the following amounts: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-150, 1-200, 1-250, 1-300, 1-500, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 2.5-200, 2.5-100, 2.5-250, 2.5-300, 2.5-500, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3-200, 3-250, 3-300, 3-500, 5-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 70-500, 70-750, 70-1000, 70-1500, 70-2000, 70-3000, 80-100, 80-150, 80-200, 80-250, 80-300, 80-500, 80-750, 80-1000, 80-1500, 80-2000, 80-3000, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250-100-250-200, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-4000 mg/agent. In some embodiments, the one or more checkpoint inhibitors are administered in the following amounts: about 1,2, 3,4,5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, 27, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg/dose.

In some embodiments, the methods described herein comprise administering a PD-1 inhibitor at a dose in the following range: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-9, 2.5-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-5, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 50-100, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350 or 100-400mg/kg of body weight. In some embodiments, the methods described herein comprise administering a PD-1 inhibitor at the following dose: about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100mg/kg body weight. In some embodiments, the PD-1 inhibitor is administered at a dose of about 3 mg/kg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 2 mg/kg.

In some embodiments, the PD-1 inhibitor is administered in the following amounts: about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-150, 1-200, 1-250, 1-300, 1-500, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 2.5-200, 2.5-250, 2.5-300, 2.5-500, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3-200, 3-250, 3-300, 3-500, 5-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 10-30, 5-20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 70-500, 70-750, 70-1000, 70-1500, 70-2000, 70-3000, 80-100, 80-150, 80-200, 80-250, 80-300, 80-500, 80-750, 80-1000, 80-1500, 80-2000, 80-3000, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-200, 100-200-100-500-100-600-800-100-900-, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500 or 500-4000 mg/agent. In some embodiments, the PD-1 inhibitor is administered in the following amounts: about 10-30, 10-50, 10-80, 10-100, 10-125, 10-150, 10-175, 10-200, 10-250, 10-300, 10-400, 20-50, 20-100, 20-125, 20-150, 20-175, 20-200, 20-250, 20-300, 20-400, 30-50, 30-80, 30-100, 30-125, 30-150, 30-175, 30-200, 30-250, 30-300, 30-400, 40-50, 40-80, 40-100, 40-125, 40-150, 40-175, 40-200, 40-250, 40-300, 40-400, 50-80, 50-100, 50-125, 50-150, 50-175, 50-200, 50-250, 50-300 or 50-400 mg/dose.

In some embodiments, the methods described herein comprise administering a PD-L1 inhibitor at a dose in the following range: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-9, 2.5-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-5, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 50-100, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350 or 100-400mg/kg of body weight. In some embodiments, the methods described herein comprise administering a PD-L1 inhibitor at the following dose: about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100mg/kg body weight.

In some embodiments, a PD-L1 inhibitor (e.g., atelizumab) is administered in the following amounts: about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-150, 1-200, 1-250, 1-300, 1-500, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 2.5-200, 2.5-250, 2.5-300, 2.5-500, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3-200, 3-250, 3-300, 3-500, 5-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 10-30, 5-20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 70-500, 70-750, 70-1000, 70-1500, 70-2000, 70-3000, 80-100, 80-150, 80-200, 80-250, 80-300, 80-500, 80-750, 80-1000, 80-1500, 80-2000, 80-3000, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-200, 100-200-100-500-100-600-800-100-900-, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500 or 500-4000 mg/agent. In some embodiments, the PD-L1 inhibitor is administered in the following amounts: about 500-1500, 600-1500, 700-1500, 800-1500, 900-1500, 1000-1500 or 1100-1300 mg/dose. In some embodiments, the PD-L1 inhibitor is administered in an amount of about 1200 mg/dose.

In some embodiments, the methods described herein comprise administering a CTLA-4 inhibitor (e.g., ipilimumab) at a dose in the range: about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-9, 2.5-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-5, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300mg/kg body weight. In some embodiments, the methods described herein comprise administering a CTLA-4 inhibitor at the following dose: about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100mg/kg body weight. In some embodiments, the inhibitor of CTLA-4 is administered at a dose of about 3 mg/kg. In some embodiments, the inhibitor of CTLA-4 is administered at a dose of less than 3 mg/kg. In some embodiments, the inhibitor of CTLA-4 is administered at a dose of about 0.5, 1, 1.5, 2, or 2.5 mg/kg.

In some embodiments, the CTLA-4 inhibitor is administered in the following amounts: about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-150, 1-200, 1-250, 1-300, 1-500, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 2.5-200, 2.5-250, 2.5-300, 2.5-500, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3-200, 3-250, 3-300, 3-500, 5-10, 5-20, 5-30, 5-40, 5-50,5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5-100, 10-10, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 10-30, 5-20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 70-500, 70-750, 70-1000, 70-1500, 70-2000, 70-3000, 80-100, 80-150, 80-200, 80-250, 80-300, 80-500, 80-750, 80-1000, 80-1500, 80-2000, 80-3000, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-200, 100-200-100-500-100-600-800-100-900-, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500 or 500-4000 mg/agent. In some embodiments, the CTLA-4 inhibitor is administered in the following amounts: about 10-30, 10-50, 10-80, 10-100, 10-125, 10-150, 10-175, 10-200, 10-250, 10-300, 10-400, 20-50, 20-100, 20-125, 20-150, 20-175, 20-200, 20-250, 20-300, 20-400, 30-50, 30-80, 30-100, 30-125, 30-150, 30-175, 30-200, 30-250, 30-300, 30-400, 40-50, 40-80, 40-100, 40-125, 40-150, 40-175, 40-200, 40-250, 40-300, 40-400, 50-80, 50-100, 50-125, 50-150, 50-175, 50-200, 50-250, 50-300 or 50-400 mg/dose.

In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitor and CTLA-4 inhibitor) once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors once every 2 weeks or once every 3 weeks. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors twice every 1 week, twice every 2 weeks, twice every 3 weeks, twice every 4 weeks, twice every 5 weeks, twice every 6 weeks, twice every 7 weeks, or twice every 8 weeks. In some embodiments, the treatment regimen comprises co-administering the chemotherapeutic agent and plinabulin every 1 week for a treatment period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment regimen comprises co-administering the compound of formula (I) and one or more checkpoint inhibitors twice every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors three times every 1 week, three times every 2 weeks, three times every 3 weeks, three times every 4 weeks, three times every 5 weeks, three times every 6 weeks, three times every 7 weeks, or three times every 8 weeks. In some embodiments, the treatment regimen comprises co-administering the compound of formula (I) and one or more checkpoint inhibitors four times every 1 week, four times every 2 weeks, four times every 3 weeks, four times every 4 weeks, four times every 5 weeks, four times every 6 weeks, four times every 7 weeks, or four times every 8 weeks. In some embodiments, the treatment regimen comprises co-administering the compound of formula (I) and one or more checkpoint inhibitor five times every 1 week, five times every 2 weeks, five times every 3 weeks, five times every 4 weeks, five times every 5 weeks, five times every 6 weeks, five times every 7 weeks, or five times every 8 weeks. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors six times every 1 week, six times every 2 weeks, six times every 3 weeks, six times every 4 weeks, six times every 5 weeks, six times every 6 weeks, six times every 7 weeks, or six times every 8 weeks. In some embodiments, the treatment regimen comprises co-administering the compound of formula (I) and one or more checkpoint inhibitors daily every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, co-administering a compound of formula (I) and one or more checkpoint inhibitors comprises administering a compound of formula (I) prior to administering one or more checkpoint inhibitors. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors 1,2, 3,4,5, 6, or 7 times per day. In some embodiments, the treatment regimen comprises co-administering a compound of formula (I) and one or more checkpoint inhibitors once every 2 days, once every 3 days, once every 4 days, once every 5 days, or once every 6 days.

In some embodiments, co-administering a compound of formula (I) and one or more checkpoint inhibitors comprises administering a compound of formula (I) after administering one or more checkpoint inhibitors. In some embodiments, co-administering a compound of formula (I) and one or more checkpoint inhibitors comprises administering a compound of formula (I) and one or more checkpoint inhibitors simultaneously. When more than one checkpoint inhibitor is administered, the two checkpoint inhibitors may be administered separately or simultaneously.

In some embodiments, when the compound of formula (I) is administered prior to administration of the one or more checkpoint inhibitors, the one or more checkpoint inhibitors may be administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after administration of the compound of formula (I). In some embodiments, one or more checkpoint inhibitors are administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration of the compound of formula (I). In some embodiments, the one or more checkpoint inhibitors are administered more than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration of the compound of formula (I). In some embodiments, the one or more checkpoint inhibitors are administered within about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 15 minutes, 1 minute to 20 minutes, 1 minute to 25 minutes, 1 minute to 30 minutes, 0.25 hour to 0.5 hour, 0.25 to 0.75 hour, 0.25 to 1 hour, 0.5 hour to 2 hours, 0.5 hour to 2.5 hours, 1 hour to 2 hours, 1 hour to 3 hours, 1 hour to 5 hours after administration of the compound of formula (I). In some embodiments, about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 20 minutes, 1 minute to 30 minutes, 1 minute to 40 minutes, 1 minute to 50 minutes, 1 minute to 1 hour, 1 minute to 2 hours, 1 minute to 4 hours, 1 minute to 6 hours, 1 minute to 8 hours, 1 minute to 10 hours, 1 minute to 12 hours, 1 minute to 24 hours, 1 minute to 36 hours, 1 minute to 48 hours, 1 minute to 60 hours, 1 minute to 72 hours, 5 minutes to 10 minutes, 5 minutes to 20 minutes, 5 minutes to 30 minutes, 5 minutes to 40 minutes, 5 minutes to 50 minutes, 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 4 hours, 5 minutes to 6 hours, 5 minutes to 8 hours, 5 minutes to 10 hours, 5 minutes to 12 hours, 1 minute to 10 minutes, 1 minute to 40 hours, 1 minute to 40 minutes, 1 hour, 1 minute to 5 hours, 1 hour, 5 minutes to 2 hours, 5 minutes to 4 hours, 5 minutes, 5 minutes to 24 hours, 5 minutes to 36 hours, 5 minutes to 48 hours, 5 minutes to 60 hours, 5 minutes to 72 hours, 10 minutes to 20 minutes, 10 minutes to 30 minutes, 10 minutes to 40 minutes, 10 minutes to 50 minutes, 10 minutes to 1 hour, 10 minutes to 2 hours, 10 minutes to 4 hours, 10 minutes to 6 hours, 10 minutes to 8 hours, 10 minutes to 10 hours, 10 minutes to 12 hours, 10 minutes to 24 hours, 10 minutes to 36 hours, 10 minutes to 48 hours, 10 minutes to 60 hours, 10 minutes to 72 hours, 30 minutes to 40 minutes, 30 minutes to 50 minutes, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 4 hours, 30 minutes to 6 hours, 30 minutes to 8 hours, 30 minutes to 10 hours, 30 minutes to 12 hours, 30 minutes to 24 hours, 30 minutes to 36 hours, 30 minutes to 48 hours, or a combination thereof, 30 minutes to 60 hours, 30 minutes to 72 hours, 1 hour to 2 hours, 1 hour to 4 hours, 1 hour to 6 hours, 1 hour to 8 hours, 1 hour to 10 hours, 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours, 6 hours to 8 hours, 6 hours to 10 hours, 6 hours to 12 hours, 6 hours to 24 hours, 6 hours to 36 hours, 6 hours to 48 hours, 6 hours to 60 hours, 6 hours to 72 hours, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 48 hours, 12 hours to 60 hours, or 12 hours to 72 hours.

In some embodiments, when the one or more checkpoint inhibitors are administered prior to administration of the compound of formula (I), the one or more checkpoint inhibitors are administered about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 15 minutes, 1 minute to 20 minutes, 1 minute to 25 minutes, 1 minute to 30 minutes, 0.25 hour to 0.5 hour, 0.25 to 0.75 hour, 0.25 to 1 hour, 0.5 hour to 2 hours, 0.5 hour to 2.5 hours, 1 hour to 2 hours, 1 hour to 3 hours, or 1 hour to 5 hours prior to administration of the compound of formula (I). In some embodiments, one or more checkpoint inhibitors are administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to administration of the compound of formula (I). In some embodiments, one or more checkpoint inhibitors are administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to administration of the compound of formula (I). In some embodiments, one or more checkpoint inhibitors are administered more than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to administration of the compound of formula (I). In some embodiments, about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 20 minutes, 1 minute to 30 minutes, 1 minute to 40 minutes, 1 minute to 50 minutes, 1 minute to 1 hour, 1 minute to 2 hours, 1 minute to 4 hours, 1 minute to 6 hours, 1 minute to 8 hours, 1 minute to 10 hours, 1 minute to 12 hours, 1 minute to 24 hours, 1 minute to 36 hours, 1 minute to 48 hours, 1 minute to 60 hours, 1 minute to 72 hours, 5 minutes to 10 minutes, 5 minutes to 20 minutes, 5 minutes to 30 minutes, 5 minutes to 40 minutes, 5 minutes to 50 minutes, 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 4 hours, 5 minutes to 6 hours, 5 minutes to 8 hours, 5 minutes to 10 hours, 5 minutes to 12 hours, 1 minute to 10 minutes, 1 minute to 8 hours, 1 minute to 1 hour, 1 minute to 8 hours, 1 hour, 1 minute to 12 hours, 1 minute to 10 hours, or more before the compound of, 5 minutes to 24 hours, 5 minutes to 36 hours, 5 minutes to 48 hours, 5 minutes to 60 hours, 5 minutes to 72 hours, 10 minutes to 20 minutes, 10 minutes to 30 minutes, 10 minutes to 40 minutes, 10 minutes to 50 minutes, 10 minutes to 1 hour, 10 minutes to 2 hours, 10 minutes to 4 hours, 10 minutes to 6 hours, 10 minutes to 8 hours, 10 minutes to 10 hours, 10 minutes to 12 hours, 10 minutes to 24 hours, 10 minutes to 36 hours, 10 minutes to 48 hours, 10 minutes to 60 hours, 10 minutes to 72 hours, 30 minutes to 40 minutes, 30 minutes to 50 minutes, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 4 hours, 30 minutes to 6 hours, 30 minutes to 8 hours, 30 minutes to 10 hours, 30 minutes to 12 hours, 30 minutes to 24 hours, 30 minutes to 36 hours, 30 minutes to 48 hours, or a combination thereof, 30 minutes to 60 hours, 30 minutes to 72 hours, 1 hour to 2 hours, 1 hour to 4 hours, 1 hour to 6 hours, 1 hour to 8 hours, 1 hour to 10 hours, 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours, 6 hours to 8 hours, 6 hours to 10 hours, 6 hours to 12 hours, 6 hours to 24 hours, 6 hours to 36 hours, 6 hours to 48 hours, 6 hours to 60 hours, 6 hours to 72 hours, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 48 hours, 12 hours to 60 hours, or 12 hours to 72 hours.

The treatment cycle can be repeated as long as the regimen is clinically acceptable. In some embodiments, the treatment cycle of the compound of formula (I) and one or more checkpoint inhibitors is repeated n times, wherein n is an integer in the range of 2 to 30. In some embodiments, n is 2,3, 4,5, 6, 7, 8, 9, or 10. In some embodiments, a new treatment cycle may be performed immediately after the previous treatment cycle is completed. In some embodiments, there may be a washout period before starting a new treatment cycle. In some embodiments, the clearance period may be 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the dose of the compound of formula (I) may be the same for each treatment cycle. In some embodiments, the dose of the compound of formula (I) may be different in each treatment cycle (e.g., the dose for the first treatment cycle may be 20mg, the dose for the second treatment cycle may be 50mg, and the dose for the third treatment cycle may be 100 mg).

In some embodiments, after administering the compound of formula (I) and one or more checkpoint inhibitors in one treatment cycle, the next treatment cycle may include administering only the compound of formula (I). In some embodiments, after administering the compound of formula (I) and one or more checkpoint inhibitors in one treatment cycle, the next treatment cycle may include administering both the compound of formula (I) and one or more checkpoint inhibitors.

In some embodiments, the treatment cycle is administration of a compound of formula (I) at a dose of about 3mg/kg every 3 weeks, and the treatment cycle is repeated four times. In some embodiments, one or more checkpoint inhibitors (e.g., any of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, and any combination thereof) and a compound of formula (I) may be co-administered in each treatment cycle. In some embodiments, one or more checkpoint inhibitors may be co-administered with a compound of formula (I) for half of the treatment cycle (e.g., the first treatment cycle and the third treatment cycle).

In some embodiments, the methods described herein may comprise administering plinabulin.

In some embodiments, the methods described herein can include administering radiation therapy.

In some embodiments, the methods described herein may include one or more additional agents. Examples of other drugs include other chemotherapeutic agents.

In some embodiments, the chemotherapeutic agent may be selected from: abiraterone acetate, methotrexate (Abitrexate), paclitaxel (Abraxane) (paclitaxel albumin stabilized nanoparticle formulation), ABVD, ABVE-PC, AC-T, benituximab (adsetris/Brentuximab Vedotin), ADE, trastuzumab-maytansine conjugate, doxorubicin (doxorubicin hydrochloride), afatinib maleate, femitory (everolimus), Netupitant (Akynzeo/netitant, and palonosetron hydrochloride), idamole (imiquimod), aldesleukin, alatinib (alexan/aletinib), aretinib, alemtuzumab, alemtuzole (pemetrexendin disodium), alemtuzole (palonosetron hydrochloride), Chlorambucil (amberlin/chlomaucil), Chlorambucil, aminoacetylpropionic acid, aprepitant, aprepirac, aprepirubine (disodium), aprepirubicin hydrochloride (riluzole), amitriptolide (medryanodine), bretacrine (imipramiper (medlarm hydrochloride), Chlorambucil (medlarm hydrochloride), chlorambum (amitriptan), mechlorethamine, amitriptan, amitriptolide) Arnosincept (exemestane), nerabine (Arranon/Nelarabine)), arsenic trioxide, Aframumab (Arzerra/Ofatumumab)), asparaginase Erwinia chlorogenic acid, avastin (Bevacizumab), axitinib, azacitidine, BEACOPP, Carmustine (Becenum/Carmustine), Belliota (Beleodaq/Belinostat)), Belinostat, bendamustine hydrochloride, BEP, bevacizumab, Bexarotene, Baikesha (Toximumab and I131 Toxicomab), bicalutamide, Carmustine (BiCNU/Carmustine), bleomycin, Bonauzumab, Blincyto (Bortezomib), Bortezomib (Bosulib/Bosutizb), Beratinib, Benzotocin, Bailexib, Illinoney, irinotecan hydrochloride, Cairanib, irinotecan hydrochloride (CALMA/CANTA), irinotecan/irinotecan, and irinotecan, Capecitabine, CAPOX, Carac (fluorouracil-topical), carboplatin-paclitaxel, carfilzomib, Carmustine (Carmusis/Carmustine), Carmustine implant, combretastatin (bicalutamide), Lomustine (CeeU/Lomustine), ceritinib, daunorubicin hydrochloride), Schizocine (recombinant HPV bivalent vaccine), cetuximab, chlorambucil-prednisone, CHOP, cisplatin, clarithrofin (cyclophosphamide), clofarabine, Clofarex (clofarabine), Corrola (clofarabine), CMF, Cofatinib, Cometriq (CoPDAC), COPP-ABV, dactinomycin (D), Cotelic (Bititinib), Clavulanib, CVP, cyclophosphamide, Cyramucirumab (Cyramucin), Cyramucirumab (Cyramucin/Cyramucin), Cytam (Cytam), Cytamicin/Cytamicin, Citra, and Cytamicin, Cytarabine liposome, cytarabine U (cytarabine), Cytoxan (cyclophosphamide), dabrafenib, dacarbazine, daclizine (decitabine), actinomycin D, Daratumumab (Daratumumab), daratabine (Daratumumab), dasatinib, daunorubicin hydrochloride, decitabine, degarelix, dinilukin (denikin Diftitox), dinolizumab, DepoCyt (cytarabine liposome), dexamethasone, dexrazoxane hydrochloride, dinotefuran, dutch-tuzumab, docetaxel, Doxil (doxorubicin hydrochloride liposome), doxorubicin hydrochloride liposome, Dox-SL (doxorubicin hydrochloride liposome), DTIC-Dome (dacarbazine), fluorouracil (fluorouracil-topical), erite (labaridase), epirubicin (epirubicin hydrochloride), rituximab, oxaliplatin (oxaliplatin), Eltrombopag, Emend (aprepitant), Elotuzumab (Empliciti/Elotuzumab), Enzalutamide, epirubicin hydrochloride, EPOCH, erbitux (cetuximab), eribulin mesylate, Wiimod (Erivedge/Vismodetib), erlotinib hydrochloride, Erwinze (Chryseowegian asparagines), pyrifide (etoposide phosphate), etoposide phosphate, Evacet (Doxil hydrochloride liposome), everolimus, Evista (Raloxifene hydrochloride), exemestane, 5-FU (fluorouracil injection), 5-FU (fluorouracil-topical), Farnet (toremifene), Parbestat (Farydak/Panobinostat), Fufugetex (floxusida, Fluvista), FEC, Fluorotrexaparin (Femara), Latrexabine (Fluorob), Fluorotrexab (Fluorotrexab-A), Fluorotrexab (Fluorotrexab), Fluoroxat-A, Fluorotrexab (Fluoroxab-A), Fluoro, Fluorouracil injection, fluorouracil-topical, flutamide, Folex (methotrexate), Folex PFS (methotrexate), irinotecan-bevacizumab, irinotecan-cetuximab, FOLFIRINOX, FOLFOX, Folotyn (pralatrexate), FU-LV, fulvestrant, Gardasil (recombinant HPV quadrivalent vaccine), Gardsi 9 (recombinant HPV nine vaccine), Gazyva (atorvastatin), Gefitinib, Gemcitabine-cisplatin, Gemcitabine-oxaliplatin, Getuzumab ozogamicin, Gemzar, Gemcitabine hydrochloride, Giralotrifabuf (Afatinib maleate), Gleevec (Gleevec, imatinib mesylate), Gliadel (carmustine implant), Gliadel wafe waffle (carmustine implant), Glucapistrase (Glucarin), Glycapine acetate, Halifen (Halidarin), and Brunavistin (Halidalin), Herceptin (trastuzumab), HPV bivalent vaccine, recombinant HPV nine vaccine, recombinant HPV tetravalent vaccine, recombinant Mexican (Hycamtin, topotecan hydrochloride), Hyper-CVAD, Palbociclib (Ibrance/Palbociclib), ibritumomab tiuxetan, Ibrutinib, ICE, Panabinib (Paullinib hydrochloride), Idarubicin (Idarubicin hydrochloride), Idiranib (Idarubicin hydrochloride), Idallaisi, Ifex (ifosfamide), Isocyclophosphamide, IL-2 (Addison), Imatinib mesylate, Ibrutinib (Imbruvica/Ibrutinib), imiquimod, Imlygic (Talimogene Laherparevec), Imidab (Inlyta, Athetisib), interferon alpha-2 b, recombinant interleukin-2 (Addison), Intron A (recombinant interferon alpha-2 b), I131 and Iritumumab (Ipomb), Iridab (Ipomiximab), Iressa (Ipomb), Iressab (Ipomb), Iressa (Ipomb), Iressb), irinotecan hydrochloride, irinotecan hydrochloride liposome, Romidepsin (Istodax/Romidepsin), Ixabepilone, Issatzomib citrate, Ixabepilone (Ixempra/Ixabepilone), ruxotinib (ruxotinib phosphate), Cabazitaxel (Jevtana/Cabazitaxel)), trastuzumab (trastuzumab-meltanan conjugate), Keoxifene (raloxifene hydrochloride), Palifermin (Kepivence/Paliformin)), Pembrolizumab (Keytruda/Pembrizumab), Carfilzomib (Kyprolis/Carfilzomib)), lanreotide acetate, lapatinib ditosylate, lenalidomide, valcanitinib mesylate, lentinib (mefurazone sulfonate), letrozole, calcium folinate, cotinin (Leukeratin, chlorambucil), linarin acetate (Lincapulin), leucinolone (Levoxil), leucinonide (Levoxil), Levoxilin (Levoxil), Levoxil, Lonsurf (trifluridine and tipopyramidine hydrochloride), Lupron (Leuprolide Acetate), Leuprolide Acetate (Lupron Depot/Leuprolide Acetate), Leuprolide Acetate (Lupron Depot-Ped/Leuprolide Acetate), Leuprolide Acetate (Lupron Depot-3 Month/Leuprolide Acetate), Leuprolide Acetate (Lupron Depot-4 Month/Leuprolide Acetate), Olaparib (Lynparza/Olaparib), Marqibo (vincristine sulfate liposome), procarbazine (procarbazine hydrochloride), mechlorethamine hydrochloride, megestrol Acetate (megestrol Acetate), megestrol Acetate (Mekinist/Traine), mercaptopurine, Mesna (Mesna), Mesna (Mesnex/Mesnex), methoxazone (Methazamide), Methotrexate (Methotrexate/Methotrexate), Methotrexate (Methotrexate/L, Methotrexate, and the like, Mitomycin C, mitoxantrone Hydrochloride, Mitozytrex (mitomycin C), MOPP, Plerixafor (Mozobil/Plerixafor), Mechlorethamine Hydrochloride (Mustargen/Mechlorethamine Hydrochloride), mitomycin (mitomycin C), Marilan (Myleran, busulfan), Mylosar (azacitidine), Mylotarg (gemtuzumab ozolomide), paclitaxel nanoparticles (paclitaxel albumin stabilized nanoparticle formulation), Navelbine (Navelbine, vinorelbine tartrate), Ultrastuzumab, nelarabine, Cyclophosphamide (Neosar/Cyclophosphamide), Netupidan and palonosetron Hydrochloride, Filgrastim (Neupogen/Filgrastimastim), Nexavar (sorafenib tosylate), nilotinib, Wunararo (citrate), Zollinex (Ochazoxib), Novacizumab (Ochazoxib), and Ochazoline (Ochazukexex), Rouzole (Ochazolb/Ochazukexex), and Novacizumab (Ochazukinomycin) OEPA, ofatumumab, OFF, olaparib, homoharringtonine, Pemetrexed (oncocaspa/pegaspargegase), Ondansetron hydrochloride (Ondansetron), Onivyde (irinotecan hydrochloride liposome), Ontak (dinilukins), Opdivo (nivolumab), OPPA, osetinib, oxaliplatin, paclitaxel albumin stabilized nanoparticle formulation, PAD, palbociclib, palifermin, palonosetron hydrochloride and nettopiracetam, Disodium pamidronate, panitumumab, palobinostat, Paraplat (carboplatin), parpaludin (Paraplatin, carboplatin), pazopanib hydrochloride, PCV, Pemetrexed, peganum, peginterferon alpha-2 b, PEG-globin (inteferon alpha-2 b), Pemetrexed (Disodium patatin), Pemetrexed (Pemetrexed), Pemetrexed, pemetron (Pemetrexed, pemetron, Pemetrexed) and pemetron, Pravastatin nols (Platinol, cisplatin), pravastatin nols-AQ (cisplatin), plerixafor, Pomalidomide (Pomalyst/Pomalidomide), panatinib hydrochloride, tolituzumab ozoga (Portraza/Necitumumab), pralatrexate, prednisone, procarbazine hydrochloride, Aldesleukin (Proleukin/Aldesleukin), Prolia (dinomab), Eltrombopag (Promaceta/Eltrombopag Olamine), Proveng (Provenge, Sipuleucel-T), Mercaptopurine (Purinetretin/Mercaptorine), Mercaptopurine (Purixan/Mercaptopronine), 223 dichloro, Raloxifen hydrochloride, ramucirumab, Labrolisu, R-CHOP, CVR-HPV (HPV), recombinant HPV vaccine (CH-2), recombinant HPV vaccine (HPV), recombinant HPV-alpha-HPV vaccine (HPV), recombinant HPV-2-HPV vaccine (HPV), recombinant HPV- α -HPV vaccine (HPV), recombinant HPV-HPV vaccine (HPV-2-HPV), recombinant HPV vaccine (HPV- α -HPV), recombinant vaccine, recombinant HPV- α -HPV vaccine, recombinant vaccine, and recombinant Human Papillomavirus (HPV) and recombinant human papillomavirus, HIV (HPV) vaccine, Relimidamide (lenalidomide), Methotrexate (Rheumatrex/Methotrexate), rituximab, Laribitan hydrochloride, romidepsin, Romithin, erythromycin (daunorubicin hydrochloride), ruxotinib phosphate, Schelalisol (Sclerosol) intrapleural aerosol (talc), cetuximab, Sipuleucel-T, Somatolutine Depot (lanreotide acetate), Soneribulib, Sorafenib tosylate, Stadasatinib (Dasatinib), STANFORD V, sterile talc powder (talc), Steritac (talc), regoranib (Stivarga/Regorafenib), sunitinib malate, Solitant (sunitinib), Sylatron (peginterferon alpha-2 b), Sylvant (cetuximab), Doxiletine), Synribiaryl (cephalospora), thioprine (Taheatrofibrine), Tatarinfibrib (TAC/Ostifen), Tatamifensinib/Tatarinfibrii (TAC/Saifensim), Taylornib (Taylornib), Taylornib, Tatarib, Taenia, Tabyloni, Tab, Tabyloni, Tabylonic, Tabyloni, Tab, talcum, Talimogen Laherparepvec, tamoxifen citrate, Tarabine PFS (cytarabine), Tarceva (Tarceva, erlotinib hydrochloride), Persulosin (Targretin/Bexarotene), tamigna (Nitinib), Paclitaxel (Taxol/Paclitaxel), Taxotere (Taxotere, docetaxel), Temozolomide (Temodar/Temozolomide), Temozolomide, temozololimus, thalidomide, thioguanine, thiotepa, Tolak (fluorouracil) -topical, Toposar (etoposide), topotecan hydrochloride, toremifene, Torisperidone (Torisol, temsirolimus), Toshimomab and iodine I131 Toshimomab, Totect (dexrazoxane hydrochloride), TPF, triptyline, Trimetiramide, Tritoxidamide, Trifludarodes (Trifluxodine hydrochloride), Tritoxylurea, Trifludarussin (Artessene/Trifluxuridine hydrochloride), Trituxan hydrochloride, Trituxanide (Tritroxix hydrochloride), Tritussin hydrochloride, Trituxanide, Tributralin hydrochloride, Tributine, Tributralin hydrochloride, Tributralin, Tributin, Tributralin hydrochloride, Tributine, Tributralin, Teristacin (Tykerb, lapatinib ditosylate), unitaxin (dinoutuzumab), uridine triacetate, VAC, vandetanib, VAMP, Varubi (roller piran hydrochloride), Panitumumab (Vectibix/Panitumumab), VeIP, Velban (vinblastine sulfate), Velcade (Velcade, bortezomib), Velsar (vinblastine sulfate), vemofetil, Etoposide (VePesid/Etoposide), leuprolide (leuprolide acetate), vedaza (vidazazab, azacitidine), vinblastine sulfate, vincaspfs (vincristine sulfate), vincristine sulfate liposome, vinorelbine tartrate, VIP, vistogimod, Vistogard (uridine triacetate), voraxase (carboplatin), vorinoside (zolobine hydrochloride), vinpocetine hydrochloride (calcium subclinicotrin), calcipotasizine (calcium chloride), critixorubicin/folin (critix), victorine (victorine, vinorelbine sulfate), valbutraline (acid, vinorelbine (acetate), valbutraline, vinorelbine (acetate, vinorelbine (acetate), vinytriant (acetate), valbutirib, vinytin (e, vinpocetine), val, Xelairi, Xeloxx, Xgeva (dinolizumab), Xofigo (radium 223 dichloride), Enzalutamide (Xtandi/Enzalutamide), Ipilimumab (Yervoy/Iipilimumab), Trabectedin (Yondelis/Trabectedin), Abiracept (Ziv-Abelicept), Zarxio (filgrastim), Velborafenib (Zelborafafenib/Vemurafenib), Teimemab (Zevalin/Ibritumumab Tiuxetan), Zinecard (Derazoxane HCl), Ziv-Abbericept, Pifunorin (Oondron HCl), Nodey (goserelin acetate), Zoletia, Vorinostat (Zolinza/Vorinostat), Seita (Zomet, Leponic acid), Zorylisi (Zornia, Zorylisi (Zorylisi), Zornia (Zornia, and Zornia (Zornia, and Binita).

Preparation method

Some embodiments relate to the preparation of compounds of formula (II-A), including

Scheme 1:

reacting a compound of formula (A-1) with a compound of formula A-2. In some embodiments, the compound of formula (A-1) is an amino acid. In some embodiments, the compound of formula (II-A) is an amino acid residue, e.g., an amino acid residue selected from Gly, Ala, Phe, Tyr, Glu, Leu, Ser, Arg, Gln, Val, Lys, Thr, Asn, Met, Cys, Trp, Asp, His, Pro or Ile. In some embodiments, R³Is H. In some embodiments, the compound of formula (A-1) is selected from an amino acid, an amino monosaccharide, an alcohol, or a hydroxylamine. In some embodiments, the compound of formula (A-1) is D-glucosamine, an alcohol (e.g., methanol), or hydroxylamine. In some embodiments, R is a group formed upon deprotonation of R-H.

Some embodiments relate to the preparation of a compound of formula (II-B) comprising: reacting tocarol with NH₂-OR^aAnd (4) reacting. In some embodiments, R^aIs H or C_1-6An alkyl group.

Scheme 2:

some embodiments relate to the preparation of compounds of formula (II-C) comprising protecting the carboxylic acid group on the tocarol to form compounds of formula (A-3), converting the hydroxyl group in the compounds of formula (A-3) to an ester, and then hydrolyzing to form compounds of formula (II-C). In some embodiments, Rb is alkyl. In some embodiments, Rb is methyl, ethyl, or propyl. In some embodiments, Rb is methyl. In some embodiments, R' is substituted with up to four substituents and contains one oxygen heteroatomEach of said substituents being independently selected from-OH, -OC (O) CH₃、-CH₂OH、-CH₂OC(O)CH₃、-(C_2-3Alkylene) -OH and- (C)_2-3Alkylene) -OC (O) CH₃. In some embodiments, R' is a 5-6 membered monosaccharide ring selected from D-glucose, 2-deoxy-D-glucose, D-ribose, and 2-deoxy-D-ribose. In some embodiments, R' is acyl, D-glucose, 2-deoxy-D-glucose, D-ribose, or 2-deoxy-D-ribose. In some embodiments, R^’Is composed of In some embodiments, R^’Is composed of

Scheme 3:

the compounds disclosed herein can be synthesized by the methods described above or by modifying these methods. The manner of modifying the process includes, inter alia, temperatures, solvents, reagents, etc., known to those skilled in the art. In general, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest during any of the methods for preparing the compounds disclosed herein. This can be achieved by conventional protecting Groups, for example as described in Protective Groups in Organic Chemistry (ed., J.F.W.McOmie, Plenum Press, 1973); and those described in p.g.m.green, t.w.wutts, Protecting Groups in Organic Synthesis (3 rd edition) Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. The protecting group may be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical Transformations for synthesizing applicable compounds are known in the art and include, for example, those described in r.larock, Comprehensive Organic Transformations, VCH Publishers,1989, or l.paquette, editors, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are exemplary only and are not intended to (nor should they be construed as) limiting the scope of the claims in any way. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternative routes based on the disclosure herein; all such modifications and alternative arrangements are within the scope of the claims.

The following examples are included to further illustrate the invention. Of course, these examples should not be construed as specifically limiting the present invention. Variations of these embodiments within the scope of the claims are within the knowledge of a person skilled in the art and are considered to fall within the scope of the invention described and claimed herein. The reader will appreciate that those skilled in the art and having possession of this disclosure are capable of making and using the present invention without exhaustive enumeration of the embodiments.

Examples

Example 1

TABLE 1 exemplary Synthesis of Turcatecol prodrugs

Tocarol reacts with each corresponding amino acid to form compound a01 through compound a20, respectively.

Tocarol reacts with D-glucosamine, methanol, and hydroxylamine, respectively, to form compound a21, compound a22, and compound B01.

With respect to compound C03 and compound C04, first, by adding tocarol to methanol, the solution was cooled to 0 ℃ and SOCl was added₂To obtain the methyl ester of the tocarol. The methyl ester was then added to a mixture of PPh3 and THF and reacted with DIAD to obtain compound C03 and compound C04, respectively.

Example 2

Compound B02:

(E) -4- ((3-hydroxy-2- ((methoxyimino) methyl) phenoxy) methyl) benzoic acid

Turcatecol (8.5g,31mmol,1.0 eq.), K₂CO₃(13.8g,100mmol,3 equivalents) and 70ml DMF were added to a 250ml flask. Subsequently methoxyamine hydrochloride (4.8g,58mmol,1.7 eq.) was added portionwise. The mixture was then stirred at 25 ℃ for 8h and poured into 200ml of water, which was acidified to pH 1-2 by HCl. The resulting solid was filtered and dried in an oven at 50 ℃. The crude product (8.6g) was refluxed in 60ml ethyl acetate, cooled to room temperature and filtered to obtain 7.1g white solid (80% yield). H NMR (in d6 DMSO) 7.863(1H, S),7.270-7.250(2H, d),6.755-6.736(2H, d),6.409-6.406(1H, t),5.728-5.736(2H, t),4.413(2H, S),3.16(3H, S). TLC, MeOH ═ 20:1, Rf ═ 0.6.

Example 3

Compound B02-1:

(E) - (4- ((3-hydroxy-2- ((methoxyimino) methyl) phenoxy) methyl) benzoyl) glycine ethyl ester

Compound B02(1.7g,5mmol,1.0 equiv.), glycine methyl ester hydrochloride (0.81g,6mmol,1.2 equiv.), HOBT (0.81g,6mmol,1.2 equiv.) and 20ml THF were added to a 100ml three-necked flask. After TEA (2.5g,5.0 equivalents) was added dropwise, the solution was stirred at 25 ℃ for 2 h. The reaction mixture was then added to 100ml of water, which was extracted with 50ml of DCM. Subsequently, the DCM solution was dried (Na)₂SO₄) And distilled under reduced pressure. The dried crude mixture was purified by column separation. Rf-0.5-0.6 (PE/EA-1/1) fractions were collected and distilled to obtain 250mg of the title compound (13% yield). H NMR (in CDCl3) 10.36(1H, S); 8.7(1H, S); 7.85-7.87(2H, d),7.49-7.51(2H, m); 7.1(1H, m); 5.15(2H, S); 4.26-4.32(4H, m); 4.00(3H, S),1.33-1.37(3H, t).

Example 4

Compound C01:

4- ((3-acetoxy-2-formylphenoxy) methyl) benzoic acid

Turcatecol (3.0g,11mmol,1.0 equiv.) and 30ml pyridine were added to a 100ml flask pre-cooled to 0 ℃. After the slow addition of acetic anhydride, the solution was warmed to 25 ℃ and stirred for 72 h. The solvent was then removed and purified by column purification. A fraction of Rf 0.4(PE/EA/Ac 1/2/drop) was collected to obtain 0.64g of the title compound. H NMR (in d6 DMSO) 12.93(1H, S),10.395(1H, S); 8.00(1H, d); 7.629-7.696(3H, m); 7.254(1H, d); 6.831(1H, d); 5.763(2H, s),2.282(3H, s).

Example 5

Compound C02-1:

4- ((2-formyl-3-hydroxyphenoxy) methyl) benzoic acid methyl ester

Turcatecol (10.0g,36mmol,1.0 equiv.) and 100ml methanol were added to a 250ml flask. After cooling the solution to 0 ℃, 4ml of SOCl was carefully added₂. The reaction solution was refluxed for 5 h. Subsequently, the solution was distilled to dryness, slurried in PE/EA (10/1) and filtered to obtain 9.4g of the title compound (Rf ═ 0.55, EA/PE ═ 2/1), which was used without further purification.

The obtained methyl ester of tocarol (9.4g,32mmol,1.0 equiv.) was added to a 250ml flask together with (2R,3R,4S,5R) -2- (acetoxymethyl) -6-hydroxytetrahydro-2H-pyran-3, 4, 5-triyltriacetate (12g,36mmol,1.1 equiv.), PPh3(10g,40mmol,1.2 equiv.) and 150ml THF. After cooling the reaction solution to 0 ℃,20 ml of DIAD was carefully added to keep the temperature below 5 ℃. Once the reaction was complete, 300ml of water was added. 200ml of EA was added to extract the resulting compound from the aqueous solution. The solvent is then removed. And the resulting compound was purified by column. Fractions with Rf ═ 0.7(EA: PE ═ 2:1) were collected and distilled to remove solvent. 3.0g of the title compound are obtained. H NMR (CDCl3)10.473(1H, s),8.090(2H, d),7.577(2H, d),7.404(1H, t),6.750(2H, m),5.144-5.373(5H, m),4.297(1H, m),4.230(1H, m),3.941(3H, s),3.932(1H, m),2.045-2.180(12H, m).

Example 6

Compound C02

Compound C02-1(2.0g,33mmol,1.0 equiv.), 20ml THF and 20mol H₂O was added to the 100ml flask. After cooling the solution to 0 deg.CAdding LiOH₂O (8g,200 mmol). The reaction solution was stirred at 25 ℃ for 16 hours, and then cooled to 0 ℃ and acidified to pH 2 by 1M HCl. The resulting solid was filtered and purified by column. Fractions of Rf 0.1 (DCM/methanol/Ac 10/1/drops) were collected and the solvent was removed to obtain 0.7g of the title compound. H NMR (DMSO)12.928(1H s),10.516(1H s),7.985(2H d),7.650(2H d),7.558(1H t),4.943-5.421(6H m),4.608(1H s),3.179-3.717(6H m).

Example 7

Turcatechol and intravenous and oral administration pharmacokinetic screening of Compound B02, Compound C01, Compound C02-1 and Compound C02

Turcatecol, Compound B02, Compound C01, Compound C02-1, and Compound C02 were administered once to non-fasting male C57BL/6 mice by IV bolus injection (3mg/kg in 20% hydroxypropyl-. beta. -cyclodextrin with 1 equivalent NaOH) or PO (10mg/kg in 1% carboxymethylcellulose/0.1% Tween-80 in water). At 0.25, 0.5, 1,2, 4, 8 and 24 hours post-dose, for K2-EDTA plasma 0.083 (for IV only), animals were bled from the dorsal plantar vein (from the heart for the 24 hour time point). Plasma concentrations of administered tocarol or compound were measured by LC/MS/MS (I-CMS-8060 apparatus for MS). PK parameters were then calculated using winnonlin 6.1. For compound C01, compound C02, and compound C02-1, stability in C57BL/6K2EDTA plasma was also evaluated by using LC at 22 ℃ over 1 hour.

TABLE 2 plasma PK parameters of Turcatecol or compounds after IV (3mg/kg) or PO (10mg/kg) administration of Turcatecol, Compound B02, C01, Compound C02-1, and Compound C02

Mean value (n is 3)

TABLE 3 plasma PK measurement of Tokauri after administration of Tokauri in IV or PO

Terminal elimination of data included in T1/2

Table 4: plasma PK parameters of Compound B02 and Toxol following IV or PO administration of Compound B02 and Toxol

Terminal elimination of data included in T1/2

BLOQ ═ below the limit of quantitation of 2ng/ml, NA ═ not obtained

TABLE 5 plasma PK parameters of Compound C01 and Compound B02 following IV or PO administration of Compound C01 and Compound B02

BLOQ ═ below the limit of quantitation of 2ng/ml, NA ═ not obtained

Terminal elimination of data included in T1/2

TABLE 6 plasma PK parameters of Compound C02 and Toxocardol following IV or PO administration of Compound C02 and Toxocardol

Terminal elimination of data included in T1/2

TABLE 7 plasma PK parameters of Compound C02-1 and Toxol following IV or PO administration of Compound C02-1 and Toxol

Terminal elimination of data included in T1/2

TABLE 8 plasma stability of Compound C01, Compound C02-1 and Compound C02

Table 2 provides the PK parameters of tocarol in blood after administration of tocarol, Compound B02, Compound C01, Compound C02-1, and Compound C02 after IV (3mg/kg) or PO (10 mg/kg). In particular, table 2 demonstrates that compound C02 produces similar plasma levels of tocarol when administered orally as when tocarol was administered orally. Compound C01 produced significant, but lower, tocassol exposure than compound C02 when administered orally.

Tables 3 to 7 report individual measurements performed on PK samples in this study.

Table 8 reports the mouse plasma stability of compound C01, compound C02, and compound C02-1. Compound C01 and compound C02-1 were unstable at 22 ℃. Compound C02 showed initial instability but decreased by about 60% -70% from the start to 1 hour.

Oral administration of compound C02 and compound C01 to C57BL/6 mice resulted in significant exposure to tocarol in plasma, and compound C02 achieved levels similar to those obtained when tocarol was administered orally. Plasma concentrations of tocalol upon PO and IV administration of tocalol, compound C01, compound C02, and compound C02-01 are shown in fig. 1A, 1B, 1C, and 1D, respectively. Table 9 shows the pharmacokinetics of tocalol after a single administration of tocalol in healthy individuals.

Table 9:

example 8

In vivo efficacy studies of Turcatrix and Compound C02 as a Single agent in the treatment of subcutaneous Hepa 1-6 mouse liver cancer model

This study evaluated the preclinical therapeutic efficacy of tocarol and compound C02 as single agents in the treatment of subcutaneous Hepa 1-6 mouse liver cancer model.

Cell culture: at 37 ℃ and 5% CO₂In DMEM medium supplemented with 10% fetal bovine serum, the Hepa 1-6 tumor cells were maintained in vitro as monolayer cultures. Cells in the exponential growth phase were harvested and tumor inoculations were counted.

Tumor inoculation: each C57BL/6 mouse was subcutaneously inoculated in the right flank with Hepa 1-6 tumor cells (5X 10) in 0.1ml PBS⁶) Can be used for tumor development. The date of tumor cell inoculation is indicated as day 0.

Randomization: when the mean tumor size reached about 100-150mm in each model³Then randomization is started. 120 mice were enrolled in the study. All animals were randomly assigned to 10 study groups by tumor volume and no significant differences in body weight between groups were ensured. Randomization was based on a randomized block design.

Animals were examined daily for morbidity and mortality following tumor cell inoculation. During routine monitoring, animals were examined for tumor growth and any effect of treatment on behavior such as mobility, food and water consumption, weight gain/loss (twice weekly body weight measurements after randomization), eye/hair dullness, and any other abnormalities. Mortality and observed clinical symptoms were recorded in detail for each animal.

Tumor volume was measured twice weekly in two dimensions using a caliper and in mm using the following formula³Expression volume: "V ═ L × W)/2, where V is tumor volume, L is tumor length (longest tumor size), and W is tumor width (longest tumor size perpendicular to L). Dose and tumor and body weight measurements were performed in a clean bench (Laminar Flow cassette).Table 10 below shows the application regimen for each test group.

TABLE 10 administration protocol for each test group

QD: once a day; Q2D: every other day

Tumor Growth Inhibition (TGI): TGI% is indicative of anti-tumor activity and is expressed as: TGI (%) ═ 100 × (1-T/C). T and C are the mean tumor volume (or weight) on a given day for the treated and control groups, respectively. Statistical analysis of the difference in mean tumor volume between groups was performed using data collected this day when the mean TV of the vehicle group reached the humanistic endpoint, so that TGI could be obtained for all/most mice enrolled in the study. Δ AUC is statistically analyzed using a linear mixed effect regression model. Mean tumor burden of 2,000mm when vehicle-treated control group was reached³Or 1 week after the final dose, whichever comes first, the study will be terminated.

The results of tukalol and the efficacy of compound C02 in the murine liver cancer model are shown in fig. 2A and 2B. Fig. 2A shows the treatment results of groups 1 to 5, and fig. 2B shows the results of groups 6 to 10. The results show that compound C02 and tocarol can achieve similar efficacy, with greater efficacy achieved with orally administered C02. Compound C02 was administered once daily for five days (QDx5) achieving efficacy greater than every other day. Once efficacy was achieved, no changes in high levels of immune cell infiltration of tumors were detected.

Example 9

In vivo efficacy studies of Compound C02 as a Single agent and in combination with anti-PD-1 antibodies in the treatment of subcutaneous MC-38 murine colorectal cancer models

This study evaluated the in vivo therapeutic efficacy of compound C02 as a single agent and in combination with an anti-PD-1 antibody in treating subcutaneous MC-38 murine colorectal cancer model in C57BL/6 mice preclinically. Table 11 below shows the administration schedule for each study group.

TABLE 11 administration protocol for treatment groups

BIW: twice a week; QD; once a day

Depending on the set-up rules and/or customer requests, the treatment regimen may change depending on BW loss or other side effects. When dosed on the same day, vehicle C02 was administered about 1-2 hours after anti-PD 1 or control IgG.

At 37 ℃ and 5% CO₂In RPMI-1640 supplemented with 10% fetal bovine serum, Hepa 1-6 tumor cells were maintained in monolayer culture in vitro. Cells in the exponential growth phase were harvested and tumor inoculations were counted.

Tumor inoculation: each C57BL/6 mouse was subcutaneously inoculated in the right flank with MC-38 tumor cells (1X 10) in 0.1ml PBS⁶) Can be used for tumor development. The date of tumor cell inoculation is indicated as day 0.

Randomization: when the mean tumor size reached about 100-150mm in each model³Then randomization is started. 120 mice were enrolled in the study. All animals were randomly assigned to 10 study groups by tumor volume and no significant differences in body weight between groups were ensured. Randomization was based on a randomized block design. Treatment with vehicle to C02, anti-PD 1 and control IgG began immediately after randomization. The date of randomization and first treatment is expressed as PG (after group) -day 0.

Animals were examined daily for morbidity and mortality following tumor cell inoculation. During routine monitoring, animals were examined for tumor growth and any effect of treatment on behavior such as mobility, food and water consumption, weight gain/loss (twice weekly body weight measurements after randomization), eye/hair dullness, and any other abnormalities. Mortality and observed clinical symptoms were recorded in detail for each animal.

Tumor volume was measured twice weekly in two dimensions using a caliper and in mm using the following formula³Expression volume: "V ═ L × W)/2, where V is tumor volume, L is tumor length (longest tumor size), and W is tumor width (longest tumor size perpendicular to L). Dose and tumor and body weight measurements were performed in a clean bench (Laminar Flow cassette).

Rectal temperature was recorded without anesthesia the day before the first administration and the day after the last oral dose.

The application protocol for each test group is shown in table 11 below.

Fig. 3A and 3B show the inhibitory activity of different doses of the group tocarol, anti-PD 1 and anti-CTLA 4 in the MC38 murine colorectal cancer model. Fig. 4A and 4B show tumor growth and survival, respectively, for different doses of compound 02 and anti-PD 1 in the MC38 murine colorectal cancer model. The established benefit of compound C02 administered once daily for five days (QDx5) as monotherapy or in combination with anti-PD 1 was particularly evident after about 15-20 days of treatment, indicating immunological MOA (e.g., promoting existing immune response or neoantigen production). QDx5 efficacy of compound C02 showed an inverse dose response relationship, even as low as 10mg/kg QDx 5.