Peptide conjugates of microtubule targeting agents as therapeutic agents

Abstract

The present invention relates to peptide conjugates of microtubule targeting agents, such as maytansinoid derivatives, that are useful in the treatment of diseases such as cancer.

Description

[Technical field]

[0001] The present invention relates to peptide conjugates of microtubule targeting agents, such as maytansinoid derivatives, that are useful in the treatment of diseases such as cancer. [Background technology]

[0002] Cancer is a group of diseases characterized by abnormal control of cell growth. The annual incidence of cancer is estimated to be over 1.6 million in the United States alone. Although surgery, radiation, chemotherapy, and hormones are used to treat cancer, it remains the second leading cause of death in the United States. It is estimated that approximately 600,000 Americans die from cancer each year.

[0003] Treatment of human cancers with systemic administration of pharmaceutical agents often works by slowing or terminating the uncontrolled replication that is a hallmark of cancer cells. One class of such agents is microtubule-targeting agents. Cell division requires the formation of an intact mitotic spindle apparatus composed of microtubules that undergo random length changes. The random length changes of microtubules are called dynamic instability. Disruption of microtubule dynamic instability can lead to the inhibition of further cell division. Agents that target microtubules and inhibit dynamic instability are currently used in the clinic as effective anticancer agents against a variety of cancers. See Lopus, M, Cancer Lett., 2011, 307(2):113-118.

[0004] Maytansinoids (e.g., mertansine, DM1, or DM4) are a class of microtubule-targeting agents that have emerged as potential clinical chemotherapeutic agents. See Lopus, M, Cancer Lett., 2011, 307(2):113-118; and Widdison, W., J. Med. Chem. 2006, 49:4392-4408. DM1 is useful in treating several types of cancer, including lymphoma and breast cancer, but toxic side effects such as peripheral neuropathy have hindered the clinical development of tubulin-targeting drugs such as maytansinoids. Preferential delivery of maytansinoid compounds such as DM1 to diseased tissues may avoid these serious side effects. Thus, there is a need for more selective delivery of maytansinoid compounds to diseased tissues. Summary of the Invention

[0005] The present disclosure relates, inter alia, to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[0006] The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

[0007] The present disclosure also provides methods of treating a disease or condition (e.g., cancer) by administering a therapeutically effective amount of a compound of the present disclosure to a human or other mammal in need of such treatment. In some embodiments, the disease or condition is characterized by acidic or hypoxic diseased tissues.

[0008] The disclosure also provides the use of a compound described herein in the manufacture of a medicament for use in therapy.The disclosure also provides a compound described herein for use in therapy.

[0009] The present disclosure also provides methods for synthesizing the compounds of the present disclosure and intermediates useful in those methods. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows a plot of the effect of free DM4 and compound 5 on in vitro β-tubulin polymerization (in relative fluorescence units) at various concentrations. [Diagram 2] FIG. 1 shows the kinetic analysis of the binding of compound 5 to β-tubulin in vitro as determined by Biacore surface plasmon resonance. [Figure 3A] FIG. 1 shows plots of mean tumor volume in nude mice bearing HCT116 colorectal lateral tumors administered DM4 or Compound 5. [Figure 3B] FIG. 1 shows the percent change in body weight of nude mice bearing HCT116 colorectal flank tumors administered DM4 or Compound 5 compared to day 0. [Figure 4] FIG. 1 shows Kaplan-Meier plots of nude mice bearing HCT116 colorectal lateral tumors administered DM4 or Compound 5. [Figure 5A] FIG. 13 shows ventral views and extracted lungs of nude mice inoculated with 4T1-RFP fluorescent cells via tail vein injection and imaged 11 days after inoculation and after three doses of vehicle or compound 6. [Figure 5B] FIG. 13 shows a graph of the fluorescent signal from extracted lungs of 4T1-RFP-inoculated mice after three doses of vehicle or compound 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is a peptide, R2 is a small molecule microtubule targeting moiety, and L is the part R 1 and R 2 is a linker that is covalently attached to

[0012] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is a peptide having 5 to 50 amino acids, R 2 is a small molecule microtubule targeting moiety, and L is the part R 1 and R 2 is a linker that is covalently attached to

[0013] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 is a small molecule microtubule targeting moiety, and L is the part R 1 and R 2 is a linker that is covalently attached to

[0014] In some embodiments, R 2 is a microtubule targeting moiety derived from maytansine.

[0015] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] [ka] is selected from the group consisting of L is the part R 1 and R 2 is a linker that is covalently attached to

[0016] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] and L is the part R 1 and R 2 is a linker that is covalently attached to

[0017] Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] [ka] is selected from the group consisting of L is [ka] [ka] is selected from the group consisting of During the ceremony, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, C 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. C1 C(O)NRc1 R d1 wherein C is selected from 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R 4 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R5 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 4 and R 6 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 5 and R 6along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 7 and R 8 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 7 and R 9 along with the carbon atom to which they are attached, C3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 8 and R 10 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 9 and R 10 along with the carbon atom to which they are attached, C 3-14A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Z is C 6-10 aryl or 5-10 membered heteroaryl, where the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where C 6-10 Each of the aryl and 5- to 10-membered heteroaryl is C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from A is H or C 1-4 is alkyl, R a1 , R b1 , R c1 , and R d1 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, OH, CN, NO2, and CO2CH3, wherein 1-6 Alkyl and C 2-6 Each alkenyl may be substituted with OH, CN, NO2, or CO2CH; and n is 0, 1, or 2.

[0018] Compounds of formula (I): [ka] and wherein: R 1 R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] is selected from the group consisting of L is [ka] wherein: R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, C 1-4 Alkyl, C 1-4 Alkenyl, C 6-10Aryl, 5-10 membered heteroaryl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 wherein C is selected from 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R 4 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 3 and R 5 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 4 and R 6 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)ORa1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 5 and R 6 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 7 and R 8 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7Forming a cycloalkyl group, Or, R 7 and R 9 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 8 and R 10 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 9 and R 10 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R.a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, A is H or C 1-4 is alkyl, and R a1 , R b1 , R c1 , and R d1 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, OH, CN, NO2, and CO2CH3, wherein 1-6 Alkyl and C 2-6 Each alkenyl may be optionally substituted with OH, CN, NO2, or CO2CH.

[0019] In some embodiments, the left side of L is R 2 and the right side of L is R 1 Bind to.

[0020] In some embodiments, the sulfur atom of the disulfide moiety of L is R 1 are part of the cysteine ​​residues.

[0021] As used herein, a "peptide" refers to a targeting moiety that comprises a sequence of 10-50 amino acids composed of naturally occurring amino acid residues and optionally one or more non-naturally occurring amino acids. In some embodiments, R 1 The peptides are peptides of 20 to 40, 20 to 30 amino acids, or 30 to 40 residues. Peptides suitable for use in the compounds of the invention are those that are capable of inserting across cell membranes via a conformational or secondary structure change in response to a change in the pH of the environment. In this way, the peptides can target acidic tissues and selectively translocate polar cell-impermeable molecules across cell membranes in response to a drop in extracellular pH. In some embodiments, the peptides are capable of selectively translocating polar cell-impermeable molecules across cell membranes having an acidic or hypoxic mantle with a pH of less than about 6.0, in combination with a conjugated moiety (e.g., R 2 In some embodiments, the peptide can selectively deliver the conjugated moiety (e.g., R L-) across a cell membrane having an acidic or hypoxic mantle with a pH of less than about 6.5. 2 In some embodiments, the peptide can selectively deliver the conjugated moiety (e.g., R L-) across a cell membrane having an acidic or hypoxic mantle with a pH of less than about 5.5. 2 In some embodiments, the peptide can selectively deliver the conjugated moiety (e.g., R-L-) across a cell membrane having an acidic or hypoxic mantle with a pH of about 5.0 to 6.0. 2 L-) can be selectively delivered.

[0022] In certain embodiments, R 1 The peptides are delivered across the cell membrane via a payload moiety (e.g., R 2 In some embodiments, R 1 is R 1is linked to L via a cysteine ​​residue in. In some embodiments, the sulfur atom of the cysteine ​​residue can form part of a disulfide bond of the linker L that includes a disulfide bond.

[0023] Suitable peptides that undergo conformational changes based on pH and can insert across cell membranes are described, for example, in U.S. Patent Nos. 8,076,451 and 9,289,508, each of which is incorporated herein by reference in its entirety. Other suitable peptides are described, for example, in Weerakkody, et al., PNAS 110(15), 5834-5839 (April 9, 2013), also incorporated herein by reference in its entirety.

[0024] In some embodiments, R 1 will return the following array: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3); Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4); AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5); and A peptide comprising at least one of the following: AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6); Here, R 1 is R 1 is linked to L via a cysteine ​​residue in

[0025] In some embodiments, R 1 will return the following array: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2), ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3), and A peptide comprising at least one of the following: AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6); Here, R 1 is R 1 is linked to L via a cysteine ​​residue in

[0026] In some embodiments, R 1 is a peptide containing the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1).

[0027] In some embodiments, R 1 is a peptide containing the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2).

[0028] In some embodiments, R 1 is a peptide containing the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3).

[0029] In some embodiments, R 1 is a peptide containing the sequence Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4).

[0030] In some embodiments, R 1 is a peptide containing the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5).

[0031] In some embodiments, R 1 is a peptide containing the sequence AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6).

[0032] In some embodiments, R 1 is a peptide consisting of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1).

[0033] In some embodiments, R 1 is a peptide consisting of the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2).

[0034] In some embodiments, R 1 is a peptide consisting of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3).

[0035] In some embodiments, R 1 is a peptide consisting of the sequence Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4).

[0036] In some embodiments, R 1 is a peptide consisting of the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5).

[0037] In some embodiments, R 1 is a peptide consisting of the sequence AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6).

[0038] In some embodiments, R 1 is a peptide comprising at least one sequence selected from SEQ ID NO: 7 to SEQ ID NO: 311 as shown in Table 1.

[0039] In some embodiments, R 1 is a peptide consisting of one sequence selected from SEQ ID NO: 7 to SEQ ID NO: 311 as shown in Table 1.

[0040] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0041] Any of the recited peptides useful in the present invention can be modified to contain cysteine ​​residues by either replacing a non-cysteine ​​residue with cysteine ​​or adding a cysteine ​​residue to either the N- or C-terminus.

[0042] In some embodiments, R 1The peptides of are conformationally restricted peptides. Conformationally restricted peptides can include, for example, macrocyclic peptides and stapled peptides. Stapled peptides are peptides that are constrained by a covalent bond between two amino acid side chains to form a peptide macrocycle. Conformationally restricted peptides are described, for example, in Guerlavais et al., Annual Reports in Medicinal Chemistry 2014, 49, 331-345; Chang et al., Proceedings of the National Academy of Sciences of the United States of America (2013), 110(36), E3445-E3454; Tesauro et al., Molecules 2019, 24, 351-377; Dougherty et al., Journal of Medicinal Chemistry (2019), 62(22), 10098-10107; and Dougherty et al., Chemical Reviews (2019), 119(17), 10241-10287, each of which is incorporated herein by reference in its entirety.

[0043] In some embodiments, R 1 is a peptide having 10 to 50 amino acids. 1 is a peptide having 20 to 40 amino acids. In some embodiments, R 1 is a peptide having 20 to 40 amino acids. In some embodiments, R 1 is a peptide having 10 to 20 amino acids. In some embodiments, R 1 is a peptide having 20 to 30 amino acids. In some embodiments, R 1 is a peptide having 30 to 40 amino acids.

[0044] Bind to an appropriate small molecule microtubule targeting moiety (e.g., R 2) may be cytotoxic compounds such as maytansinoids, which may have deleterious effects on normal tissues and thus may result in undesirable side effects when delivered systemically. Small molecule microtubule targeting agents include, but are not limited to, maytansinoids, aclitaxel, docetaxel, epothilones, discodermolides, vinca alkaloids, colchicine, combretastatins, and derivatives and analogs thereof. Microtubule targeting agents are described in Tangutur, AD, Current Topics in Medicinal Chemistry, 2017 17(22):2523-2537. Microtubule targeting agents also include maytansinoids such as maytansine (DM1) and its derivatives and analogs, which are described in Lopus, M, Cancer Lett., 2011, 307(2):113-118; and Widdison, W., J. Med. Chem. 2006, 49:4392-4408.

[0045] In some embodiments, R 2 is the following group: [ka] It is.

[0046] In some embodiments, R 2 is the following group: [ka] It is.

[0047] In some embodiments, R 2 is the following group: [ka] It is.

[0048] In some embodiments, R 2 is the following group: [ka] It is.

[0049] In some embodiments, R 2 is the following group: [ka] It is.

[0050] In some embodiments, R 2 is a maytansinoid. In some embodiments, R 2 is DM1 or DM4. In some embodiments, R 2 is DM1. In some embodiments, R 2 is DM4.

[0051] In some embodiments, L is R 1 and R 2 is a linking moiety that covalently binds R to the 2 The compound functions to release a moiety comprising:

[0052] In some embodiments, L is a chain of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 chain atoms (including both carbon and heteroatoms) and 1 to 10 R q and wherein one or more chain carbon atoms of L can be oxidized to form a carbonyl (C=O), and one or more N and S chain atoms can each be optionally oxidized to form an amine oxide, sulfoxide or sulfonyl group, wherein Each R q are independently OH, CN, -COOH, NH2, halo, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3~6 Cycloalkyl, NH(C1-6 alkyl), and N(C 1-6 alkyl)2, where R q C 1-6 Alkyl, Phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each selected from halo, OH, CN, -COOH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Phenyl, C 3-10 substituted with cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and The Two R's q The groups, together with the chain atoms to which they are attached, are selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or C 3-6 A cycloalkyl ring can be formed.

[0053] In some embodiments, R q are independently OH, CN, -COOH, NH2, halo, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NH(C 1-6 Alkyl) and N(C 1-6 alkyl)2.

[0054] In some embodiments, L is the following group: [ka] It is.

[0055] In some embodiments, L is the following group: [ka] It is.

[0056] In some embodiments, L is the following group: [ka] It is.

[0057] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0058] In some embodiments, L is the following group: [ka] It is.

[0059] In some embodiments, L is the following group: [ka] It is.

[0060] In some embodiments, L is the following group: [ka] It is.

[0061] In some embodiments, L is the following group: [ka] It is.

[0062] In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H and C 1-4 In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8, R 9 , and R 10 are H, respectively.

[0063] In some embodiments, R 3 and R 4 are each independently H and C 1-4 In some embodiments, R 3 and R 4 are H, respectively.

[0064] In some embodiments, R 5 and R 6 are each independently H and C 1-4 In some embodiments, R 5 and R 6 are H, respectively.

[0065] In some embodiments, R 7 and R 8 are each independently H and C 1-4 In some embodiments, R 7 and R 8 are H, respectively.

[0066] In some embodiments, R 9 and R 10 are each independently H and C 1-4 In some embodiments, R 9 and R 10 are H, respectively.

[0067] In some embodiments, A is H. In some embodiments, A is C 1-4 In some embodiments, A is alkyl.

[0068] In some embodiments, Z is C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NRc1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 6-10 It is aryl.

[0069] In some embodiments, Z is C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and n is 1, 2, or 3.

[0070] In some embodiments, Z is phenyl.

[0071] In some embodiments, the compound of the present invention has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1is a peptide, R 2 is a small molecule microtubule targeting moiety, A is H or C 1-4 is alkyl, Ring Y is a monocyclic C 5-7 a cycloalkyl ring or a monocyclic 5- to 7-membered heterocycloalkyl ring; Each R Y is independent, C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 is selected from or two adjacent R Y together with the atoms to which they are attached form a fused monocyclic C 5-7 Cycloalkyl ring, fused monocyclic 5- to 7-membered heterocycloalkyl ring, fused C 6-10 aryl ring or fused 6- to 10-membered heteroaryl ring, each of which is 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R.c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from R a1 , R b1 , R c1 , and R d1 are independently H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, and NO2; and m is 0, 1, 2, or 3.

[0072] In some embodiments of the compound of Formula (II), R 1 is a peptide comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.

[0073] In some embodiments of the compound of Formula (II), R 1 is Pv1, PV2, PV3, PV4, or PV5.

[0074] In some embodiments of the compound of Formula (II), R 1 is R 1 and one of the sulfur atoms of the disulfide moiety of formula II is derived from a cysteine ​​residue.

[0075] In some embodiments of the compound of Formula (II), R 2 is a maytansinoid. In some embodiments of Formula (II), R 2 is DM1 or DM4. In some embodiments of formula (II), R 2 In some embodiments of formula (II), R 2 is DM4.

[0076] In some embodiments of the compound of Formula (II), R 2is the following group: [ka] It is.

[0077] In some embodiments of the compound of Formula (II), R 2 is the following group: [ka] It is.

[0078] In some embodiments of the compound of Formula (II), R 2 is the following group: [ka] It is.

[0079] In some embodiments of the compound of Formula (II), R 2 is the following group: [ka] It is.

[0080] In some embodiments of the compound of formula (II), A is H. In some embodiments of the compound of formula (II), A is C 1-4 In some embodiments of the compound of Formula (II), A is CH3.

[0081] In some embodiments of the compound of Formula (II), ring Y is a monocyclic C 5-7 It is a cycloalkyl ring.

[0082] In some embodiments of the compounds of Formula (II), ring Y is a cyclopentyl ring.

[0083] In some embodiments of the compounds of Formula (II), ring Y is a cyclohexyl ring.

[0084] In some embodiments of the compound of Formula (II), ring Y is a cycloheptyl ring.

[0085] In some embodiments of the compounds of Formula (II), ring Y is a monocyclic 5- to 7-membered heterocycloalkyl ring.

[0086] In some embodiments of the compounds of Formula (II), ring Y is a 5-membered heterocycloalkyl ring.

[0087] In some embodiments of the compounds of Formula (II), ring Y is a 6-membered heterocycloalkyl ring.

[0088] In some embodiments of the compounds of Formula (II), ring Y is a 7-membered heterocycloalkyl ring.

[0089] In some embodiments of the compound of Formula (II), two adjacent R Y together with the atoms to which they are attached form a fused monocyclic C 5-7 Cycloalkyl ring, fused monocyclic 5- to 7-membered heterocycloalkyl ring, fused C 6-10 aryl ring or fused 6- to 10-membered heteroaryl ring, each of which is 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0090] In some embodiments of the compound of Formula (II), m is 0.

[0091] In some embodiments of the compounds of Formula (II), m is 1.

[0092] In other embodiments of the compounds of Formula (II), m is 2.

[0093] In other embodiments of the compounds of Formula (II), m is 3.

[0094] In some embodiments, the compound of the present invention has formula (III), formula (IV), or formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R Y , A, and m are defined as in any of the above embodiments for formula (II).

[0095] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] is selected from Or a pharma- ceutically acceptable salt of any of the foregoing.

[0096] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] is selected from Or a pharma- ceutically acceptable salt of any of the foregoing.

[0097] In some embodiments, provided herein is a compound of formula (IA): [ka] or a salt thereof, wherein Cy 1 is C 6-10 aryl or 5-10 membered heteroaryl. In some embodiments, Cy 1 is pyridyl.

[0098] In some embodiments, provided herein is a compound of formula (IB): [ka] or a salt thereof, wherein Cy 1 is C 6-10 aryl or 5-10 membered heteroaryl. In some embodiments, Cy 1 is pyridyl.

[0099] The molecules of the present invention can be tagged with a probe, such as, for example, a fluorophore, a radioisotope, etc. In some embodiments, the probe is a fluorescent probe, such as LICOR. A fluorescent probe can include any moiety that can re-emit light upon light excitation (e.g., a fluorophore).

[0100] Amino acids are represented by their IUPAC abbreviations as follows: alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine ​​(Cys; C), glutamine (Gln; Q), glutamic acid (Glu; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0101] The term "Pv1" refers to the peptide of SEQ ID NO:1, ADDQNPWRAYLDLLFPTDTLLLDLLWCG.

[0102] The term "Pv2" refers to the peptide of SEQ ID NO:2, AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG.

[0103] The term "Pv3" refers to the peptide of SEQ ID NO:3, ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG.

[0104] The term "Pv4" refers to the peptide of SEQ ID NO:4, Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG.

[0105] The term "Pv5" refers to the peptide AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC of SEQ ID NO: 5. The term "Pv6" refers to the peptide AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG of SEQ ID NO: 6. In the compounds of the invention, the peptide R 1 is linked to a disulfide linker by a cysteine ​​moiety.

[0106] The term "acidic and / or hypoxic mantle" refers to the environment of cells in the diseased tissue in question, which has a pH below 7.0, preferably below 6.5. The acidic or hypoxic mantle more preferably has a pH of about 5.5, most preferably about 5.0. Compounds of formula (I) insert in a pH-dependent manner across cell membranes having an acidic and / or hypoxic mantle to induce R 2 L is inserted into the cell, after which the disulfide bond of the linker is cleaved to give free R 2 L (or R 2 L*, where L* is the degradation product. Because the compounds of formula (I) are pH dependent, they preferentially insert into cell membranes only in the presence of an acidic or hypoxic mantle surrounding the cell, and not into the cell membranes of "normal" cells that do not have an acidic or hypoxic mantle.

[0107] Peptide R 1 , or peptide R across the cell membrane 1 The term "pH-sensitive" or "pH-dependent" as used herein to refer to the mode of insertion of the compounds of the invention means that the peptide has a higher affinity for cell membrane lipid bilayers having an acidic or hypoxic mantle than for membrane lipid bilayers at neutral pH. Thus, the compounds of the invention preferentially insert through cell membranes and promote R when the cell membrane lipid bilayer has an acidic or hypoxic mantle ("diseased" cells). 2 Insert L into the interior of the cell (hence R as above) 2 H), but does not insert through the cell membrane if the mantle (the environment of the cell membrane lipid bilayer) is not acidic or hypoxic ("normal" cells). This preferential insertion is due to the peptide R 7 is believed to be achieved as a result of the formation of a helical structure that facilitates membrane insertion.

[0108] The term "small molecule microtubule targeting moiety" refers to a chemical group that binds to microtubules. A small molecule microtubule targeting moiety can be a group derived from a compound that inhibits the activity of microtubules. For example, a small molecule microtubule targeting moiety can inhibit the dynamic stability of microtubules. In some embodiments, a small molecule microtubule targeting moiety has a molecular weight (Da) of about 100-1500, about 100-800, about 500-1,000, about 600-1,000, about 100-500, about 700-900, or about 250-500.

[0109] It is further understood that, for clarity, certain features of the invention that are described in the context of separate embodiments can also be provided in combination in a single embodiment (although it is intended that these embodiments be combined as if described in multiple dependent forms). Conversely, for brevity, various features of the invention that are described in the context of a single embodiment can also be provided separately or in any suitable subcombination. Thus, it is contemplated that features described as embodiments of compounds of formula (I) can be combined in any suitable combination.

[0110] At various places in the present specification, certain features of compounds are disclosed in groups or ranges. It is specifically intended that such disclosure include each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose (but not be limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0111] The term "n-membered" refers to the number of ring-forming atoms in a moiety, where n is an integer and typically the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0112] At various places in the specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R") n - is -NR(CR'R") n -and-(CR'R") n It is intended that both NR- and NR- are included and each form is disclosed separately. If a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represent a linking alkylene or arylene group, respectively.

[0113] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise stated, where such substitution is permitted. The substituents are independently selected, and the substitutions can be at any chemically accessible position. It is understood that substitution at a given atom is limited by valence. It is understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0114] "C n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include 1-4 , C 1-6 etc.

[0115] The term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched.n-m The term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl.

[0116] The term "alkenyl" used alone or in combination with other terms refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced at the point of attachment of the alkenyl group to the remainder of the compound. n-m The term "alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0117] The term "alkynyl" used alone or in combination with other terms refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. n-mThe term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0118] The term "alkylene" used alone or in combination with other terms refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bonds replaced at the points of attachment of the alkylene group to the remainder of the compound. n-m The term "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like.

[0119] The term "amino" refers to a group of the formula -NH2.

[0120] The term "carbonyl", used alone or in combination with other terms, refers to the group -C(=O)-, which can also be written as C(O).

[0121] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which can also be written as -CN.

[0122] The terms "halo" or "halogen", used alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0123] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen atom. n-m The term "haloalkyl" refers to a C alkyl group having n to m carbon atoms and at least 1 to {2(n to m)+1} halogen atoms. n-m In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1-6 or 1-4 carbon atoms. Examples of haloalkyl groups include CF 3、 These include C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0124] The term "haloalkoxy", employed alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, in which the alkyl group is as defined above. n-m The term "haloalkoxy" refers to a haloalkoxy group, where the haloalkyl group has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy, and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0125] The term "oxo" refers to an oxygen atom as a divalent substituent, which when attached to a carbon forms a carbonyl group, or when attached to a heteroatom forms a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0126] The term "oxidized" with respect to a ring-forming N-atom refers to a ring-forming N-oxide.

[0127] The term "oxidized" with respect to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0128] The term "aromatic" refers to a carbocyclic or heterocyclic ring that contains one or more polyunsaturated rings and has aromatic character (i.e., has (4n+2) delocalized π (pi) electrons, where n is an integer).

[0129] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, and the like. In some embodiments, an aryl group has 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, an aryl group is phenyl.

[0130] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl ring has 5-14 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl ring has 5-10 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl ring has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring.

[0131] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, in which one or more (eg, 1, 2, or 3) ring atoms are independently selected from N, O, and S.

[0132] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, in which one or more (eg, 1, 2, or 3) ring atoms are independently selected from N, O, and S.

[0133] The term "cycloalkyl", used alone or in combination with other terms, refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic or polycyclic) including cyclized alkyl and alkenyl groups. n-mThe term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) and polycyclic groups. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring carbons (C 3-7 In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 It is a monocyclic cycloalkyl group. The ring-forming carbon atoms of the cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. The cycloalkyl group also includes cycloalkylidene. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties that have one or more aromatic rings fused to (i.e., covalently bonded to) the cycloalkyl ring, such as benzo or thienyl derivatives such as cyclopentane and cyclohexane. Cycloalkyl groups that include fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0134] The term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally include one or more alkenylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic (e.g., having 2 fused or bridged rings) or spirocyclic ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups, or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.) or nitrogen atoms can be quaternized. Heterocycloalkyl groups can be bonded through ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused to (i.e., covalently bonded to) the heterocycloalkyl ring, such as benzo or thienyl derivatives such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include 2-pyrrolidinyl, morpholinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperazinyl.

[0135] In certain places, the definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise stated, these rings can be bonded to any ring member, as long as the valence of the atom is not exceeded. For example, the azetidine ring can be bonded to any position on the ring, while the azetidin-3-yl ring is bonded to the 3-position.

[0136] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0137] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. One method involves partial recrystallization using a chiral resolving acid that is an optically active salt-forming organic acid. Suitable resolving agents for the partial recrystallization method are optically active acids such as, for example, the D- and L-forms of various optically active camphorsulfonic acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or α-camphorsulfonic acid. Other resolving agents suitable for the partial crystallization method include stereoisomerically pure forms (e.g., S and R forms, or diastereomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0138] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0139] In some embodiments, the compounds of the invention have the (R) configuration. In other embodiments, the compounds have the (S) configuration. In compounds with multiple chiral centers, unless otherwise specified, each chiral center in the compound may independently be (R) or (S).

[0140] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions of a heterocyclic ring system, such as, for example, 1H- and 3H-imidazole, 1H-, H2- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0141] The compounds of the present invention may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0142] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic benefits, such as increased in vivo half-life or reduced required dosage, resulting from greater metabolic stability, and therefore may be preferred in some cases. (A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0143] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. The term is also meant to refer to the compounds of the present invention regardless of how they are prepared, for example, synthetically, by a biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0144] All compounds described herein and their pharma- ceutically acceptable salts may be found together with or isolated from other substances such as water and solvents (e.g., hydrates and solvates). When in solid state, the compounds described herein and their salts may occur in various forms, for example, in the form of solvates, including hydrates. The compounds may be in any solid form, such as polymorphs or solvates, so unless otherwise specified, references herein to compounds and their salts should be understood to include any solid form of the compounds.

[0145] In some embodiments, the compound of the present invention or its salt is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present invention. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound of the present invention or its salt.

[0146] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0147] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a reaction temperature that is about the same as the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0148] The compounds of the present invention also include pharma- ceutically acceptable salts of the compounds described herein. The term "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0149] synthesis The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes, such as the following schemes.

[0150] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for that specific reaction step can be selected by those skilled in the art.

[0151] Preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Peturssion et al., “Protective Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0152] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or13 C), can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0153] The following schemes provide general guidance relating to preparing compounds of the invention. Those skilled in the art will appreciate that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.

[0154] Compounds of formula (I) may be prepared, for example, using the processes as illustrated in the following schemes.

[0155] Scheme 1: Synthesis of direct conjugates [ka] Intrinsic thiols such as DM1 or DM4 (R 2 Small molecule microtubule targeting moieties containing a pyridyl disulfide (where X is, for example, H, halo, etc.), can be activated by formation of a pyridyl disulfide (where X is, for example, H, halo, etc.), which can be coupled to a thiol-containing R 1 peptide to give the desired conjugate, where -SS- is the linking moiety L.

[0156] Scheme 2: Synthesis of direct conjugates [ka] Alternatively, R with an inherent thiol 1 Peptides are synthesized by disulfide exchange reactions using thiol-containing R 2 The compound can be activated by the formation of a pyridyl disulfide (II) which can be substituted with -L- to give the desired direct conjugate, where L is -SS-.

[0157] Scheme 3: Synthesis of thioethylamine amide conjugates [ka] The protected ethylamine containing a thiol group activated as pyridyl disulfide V can be used to react with the thiol-containing R in a disulfide exchange reaction. 2 Disulfide VII can be deprotected to give VIII, which can be further reacted with propionic acid maleimide IX in an acid coupling reaction to give amide X. Amide X can be reacted with a thiol-containing peptide in a Michael addition to give the desired conjugate.

[0158] Scheme 4: Synthesis of thiobutyric acid amide conjugates [ka] The thiol-containing butyric acid activated as pyridyl disulfide XI can be used to catalyze the disulfide exchange reaction with the thiol-containing R 2 to give XII. The disulfide acid XII can be reacted with ethylaminomaleimide XIII in an acid coupling reaction to give amide XIV. Amide XIV can be reacted with a thiol-containing peptide in a Michael addition to give the desired conjugate.

[0159] Peptide R 1can be prepared using the solid phase synthesis method first described by Merrifield in JACS, Vol. 85, pgs. 2149-2154 (1963), although other methods known in the art can also be used. The Merrifield technique is well understood and is a common method for preparing peptides. Techniques useful for solid phase peptide synthesis are described in several books, such as the 1984 text "Principles of Peptide Synthesis" by Bodanszky, Springer Verlag. This synthesis method involves the stepwise addition of protected amino acids to a growing peptide chain that is attached by covalent bonds to solid resin particles. This procedure eliminates the need to purify intermediates, as reagents and by-products are removed by filtration. The general concept of the method relies on the attachment of the first amino acid of the chain to a solid polymer by a covalent bond, followed by the addition of subsequent protected amino acids, one by one, stepwise, until the desired sequence is assembled. Finally, the protected peptide is removed from the solid resin support and the protecting groups are cleaved.

[0160] The amino acid can be attached to any suitable polymer. The polymer must be insoluble in the solvent used, have a stable physical form that allows easy filtering, and contain functional groups to which the first protected amino acid can be firmly attached by a covalent bond. A variety of polymers are suitable for this purpose, such as cellulose, polyvinyl alcohol, polymethyl methacrylate, polystyrene, etc.

[0161] How to use Provided herein is the use of a compound of formula (I) in the treatment of a disease, such as cancer or a neurodegenerative disease. Another aspect of the invention is the use of a compound of formula (I) in the treatment of a disease involving acidic or hypoxic diseased tissue, such as cancer. Hypoxia and acidosis are physiological markers of many disease processes, including cancer. In cancer, hypoxia is one mechanism involved in the development of an acidic environment within solid tumors. As a result, hydrogen ions must be removed from the cell (e.g., by proton pumps) to maintain a normal pH within the cell. As a result of this export of hydrogen ions, cancer cells have an increased pH gradient across the cell membrane lipid bilayer and a lower pH in the extracellular environment when compared to normal cells. One approach to improve the efficacy and therapeutic index of cytotoxic agents is to exploit this physiological property to selectively deliver compounds to hypoxic cells over healthy tissue.

[0162] In these treatment methods, a therapeutically effective amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be administered as a single agent or in combination with other forms of treatment, such as ionizing radiation or cytotoxic agents in the case of cancer. In combination therapy, the compound of formula (I) can be administered before, simultaneously with, or after the other treatment, as will be understood by those skilled in the art. Either treatment (single agent or combination with other treatments) can be administered as a course of treatment, including multiple doses or treatment over a period of time.

[0163] Examples of cancers treatable using the compounds of the present disclosure include colorectal cancer, gastric cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, acute These include, but are not limited to, lymphoblastic leukemia, chronic or acute leukemia including chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, renal or urethral cancer, renal pelvic cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of these cancers.

[0164] In some embodiments, cancers treatable with the compounds of the present disclosure include bladder cancer, bone cancer, glioma, breast cancer (e.g., triple negative breast cancer), cervical cancer, colon cancer, colorectal cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0165] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the present disclosure.

[0166] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of these cancers.

[0167] In certain embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be used in combination with a chemotherapeutic agent, a targeted cancer therapy, an immunotherapy, or a radiation therapy. The agent may be combined with the compound in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms. In some embodiments, the chemotherapeutic agent, the targeted cancer therapy, the immunotherapy, or the radiation therapy, when administered together with the compound of formula (I) or a pharma- ceutically acceptable salt thereof, may inhibit the activity of the corresponding microtubule targeting agent (e.g., R 2 -H), it has been shown to be less toxic to patients, including reduced bone marrow toxicity.

[0168] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes) such as uracil mustard, chloramustine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0169] Other drugs suitable for use in combination with the compounds of the invention include dacarbazine (DTIC), optionally with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds according to the invention may also be combined with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0170] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0171] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.

[0172] Other cytotoxic agents which may be administered in combination with the compounds of the invention include, for example, navelbene, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosfamide, and droloxafine.

[0173] Also suitable are cytotoxic agents such as epidophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0174] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-1, or antibodies against cytokines (IL-10, TGF-α, etc.).

[0175] Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors including CCR2 and CCR4.

[0176] Other anti-cancer drugs also include those that enhance the immune system, such as adjuvants and adoptive T-cell transfer.

[0177] Anti-cancer vaccines that can be administered in combination with the compounds of the invention include, for example, dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0178] Other suitable agents for use in combination with the compounds of the invention include chemotherapy combinations such as platinum-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin + gemcitabine; cisplatin or carboplatin + docetaxel; cisplatin or carboplatin + paclitaxel; cisplatin or carboplatin + pemetrexed), or gemcitabine + paclitaxel conjugated particles (Abraxane®).

[0179] The compounds of the present invention may be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors.Suitable examples are antiestrogens, including but not limited to tamoxifen and toremifene, aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane, adrenergic corticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used in the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention.These include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0180] The compounds of the present invention can be administered in combination with or in sequence with other agents against membrane receptor kinases, especially for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, and inhibitors or antibodies against cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR / Her2 include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met can be used in combination with the compounds of the present invention. These include onartumzumab, tivantnib, and INC-280. Agents directed against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and agents directed against Alk (or EML4-ALK) include crizotinib.

[0181] Angiogenesis inhibitors may be effective in some tumors in combination with the compounds of the present invention.These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR.Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept.VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0182] Activation of intracellular signaling pathways occurs frequently in cancer, and drugs that target components of these pathways are combined with receptor targeting agents to increase efficacy and reduce resistance.Examples of drugs that can be combined with the compounds of the present invention include inhibitors of PI3K-AKT-mTOR pathway, inhibitors of Raf-MAPK pathway, inhibitors of JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0183] Drugs against PI3 kinase include, but are not limited to, piralalisib, idelalisib, buparlisib. Inhibitors of mTOR, such as rapamycin, sirolimus, temsirolimus, and everolimus, can be combined with the compounds of the present invention. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). Inhibitors of one or more JAK (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinase (e.g., palbociclib), HDAC (e.g., panobinostat), PARP (e.g., olaparib), and proteasome (e.g., bortezomib, carfilzomib) can also be combined with the compounds of the present invention. A further example of a PARP inhibitor that can be combined with the compounds of the invention is talazoparib.

[0184] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Moreover, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0185] The phrase "therapeutically effective amount" of a compound (therapeutic agent, active ingredient, drug, etc.) refers to an amount of the compound administered to a subject in need of therapy or treatment that relieves symptoms, improves a condition, or delays the onset of a pathology according to clinically acceptable standards for the disorder or condition being treated. For example, a therapeutically effective amount can be an amount that has been demonstrated to have the desired therapeutic effect in in vitro assays, in vivo animal assays, or clinical trials. A therapeutically effective amount can vary based on the particular dosage form, method of administration, treatment protocol, the particular disease or condition being treated, the benefit / risk ratio, etc., among many other factors.

[0186] The therapeutically effective amount can be obtained from clinical trials, animal models, or in vitro cell culture assays. It is known in the art that the effective amount suitable for human use can be calculated from the effective amount determined from animal models or in vitro cell culture assays. For example, as reported by Reagan-Shaw et al., FASEB J. 2008:22(3)659-61, "μg / ml" (effective amount based on in vitro cell culture assay) is equal to "mg / kg body weight / day" (effective amount for mice). Furthermore, based on the fact that the metabolic rate of mice is six times faster than that of humans, the effective amount for humans can be calculated from the effective amount for mice.

[0187] As an example of the treatment using the compound of formula (I) in combination with a cytotoxic agent, a therapeutically effective amount of the compound of formula (I) can be administered to a patient suffering from cancer as part of a treatment plan that also includes a therapeutically effective amount of ionizing radiation or a cytotoxic agent.In the context of this treatment plan, the term "therapeutically effective" amount should be understood to mean effective in combination therapy.Those skilled in the art of cancer treatment will understand how to adjust the dosage to achieve optimal therapeutic results.

[0188] Similarly, appropriate dosages of the compounds of the invention for the treatment of non-cancerous diseases or conditions (such as cardiovascular disease) can be readily determined by medical engineers.

[0189] The term "treatment" as used herein includes administration of a compound or composition that reduces the frequency, delays the onset, or reduces the progression of diseases involving acidic or hypoxic diseased tissues, such as cancer, stroke, myocardial infarction, or long-term neurodegenerative diseases, in a subject compared to subjects not administered the compound or composition. This includes reversing, reducing, or arresting the symptoms, clinical signs, or underlying pathology of a condition in a manner that improves or stabilizes the subject's condition (e.g., regression of tumor growth in the case of cancer, or reduction or amelioration of myocardial ischemia-reperfusion injury in infarction, stroke, or similar cardiovascular disease). The terms "inhibit" or "reduce" are used in cancer for methods of inhibiting or reducing tumor growth (e.g., reducing tumor size) in a population compared to an untreated control population.

[0190] All publications mentioned herein, including patents, are incorporated herein by reference for the purpose of describing and disclosing, for example, structures and procedures described in the publications that may be used in connection with the disclosure set forth herein. The publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application.

[0191] Disclosed herein are several types of ranges. When any type of range is disclosed or claimed, the intention is to disclose or claim each possible number separately so that such range can reasonably be encompassed, including the end points of the range, and any subranges and combinations of subranges contained therein. For example, when a therapeutically effective amount of an active ingredient range is disclosed or claimed, the intention is to disclose or claim each possible number separately so that such range can encompass, consistent with the disclosure of this specification. For example, disclosed or claimed by disclosure that a therapeutically effective amount of a compound can be in the range of about 1 mg / kg to about 50 mg / kg (of control body weight).

[0192] Formulation, Dosage Forms, and Administration To prepare the pharmaceutical composition of the present invention, the compound of formula (I) or its pharma- ceutically acceptable salt is combined as an active ingredient intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take various forms, for example, oral or parenteral, depending on the form of preparation desired for administration. When preparing the composition in oral dosage form, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used for oral liquid preparations, such as suspensions, elixirs, and solutions, or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., can be used for oral solid preparations, such as powders, capsules, and tablets. Because of ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously used. If desired, tablets can be sugar-coated or enteric-coated by standard techniques. For parenteral preparations, the carrier usually comprises sterile water, but other ingredients, such as those that aid solubility or for preservation, can be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, etc. may be employed. Those skilled in the pharmaceutical and medical arts will be able to readily determine the dosage of the pharmaceutical composition of the present invention which will be suitable for the particular disease or condition being treated. EXAMPLES

[0193] As used herein, all abbreviations, symbols, and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, DC: American Chemical Society, 1997. The following definitions explain the terms and abbreviations used herein.

[0194] Brine: A saturated solution of NaCl in water DCM: dichloromethane TFA: Trifluoroacetic acid DIPEA: Diisopropylethylamine DMA: Dimethylacetamide DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Methyl sulfoxide DTT: Dithiothreitol MSD: Mass spectrometry detector Et2O: Ethyl ether EtOAc: ethyl acetate EtOH: Ethyl alcohol HATU: O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt: 1-hydroxybenzotriazole RP: Reverse phase HPLC: High-performance liquid chromatography IPA: Isopropanol LAH: Lithium aluminum hydride N-BuLi: n-butyl lithium LC-MS: Liquid chromatography mass spectrometry LDA: Lithium diisopropyl amide Me: Methyl MeOH: Methanol MTBE: Methyl t-butyl ether NMP: N-methylpyrrolidine Ph: Phenyl PNPC: para-nitrophenyl chloroformate RT or rt: room temperature SFC: Supercritical Fluid Chromatography TBAI: Tetrabutylammonium iodide TBME: tert-butyl methyl ether tBu: tertiary butyl THF: tetrahydrofuran TEA: Triethylamine TMEDA: Tetramethylethylenediamine GSH: Glutathione GS: Sulfur-bound glutathione LiOH: Lithium hydroxide DPPA: Diphenylphosphoryl azide Sn(Bu)2(lauric acid)2: Dibutyltin dilaurate PBS: Phosphate-buffered saline ACN: Acetonitrile AcOH: acetic acid EEDQ: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline DMAP: 4-dimethylaminopyridine EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0195] The HPLC method used is shown below.

[0196] HPLC method A: Sunfire C18 150 x 4.6 mm; H2O / acetonitrile w / TFA modifier (0.05%); flow rate: 1 ml / min; wavelength = 217 nM.

[0197] B: Ace Equivalence 250x4.6mm; H2O / acetonitrile w / TFA modifier (0.05%); flow rate: 1ml / min; wavelength=217nM.

[0198] C: SunfireC18 150×30 mm; H2O / acetonitrile w / TFA modifier (0.05%); flow rate: 30 ml / min; wavelength=217 nM.

[0199] D: Sunfire C18 150 x 4.6 mm; H2O / acetonitrile w / AcOH modifier (0.5%); flow rate: 1 ml / min; wavelength = 217 nM.

[0200] E: Sunfire C18 150 x 30 mm; H2O / acetonitrile w / AcOH modifier (0.5%); flow rate: 30 ml / min; wavelength = 217 nM.

[0201] F: Agilent 1100 / 1200 / 1260 or 1290 system (coupled or not coupled to MS).

[0202] [Table 2]

[0203] G: Agilent 1100 / 1200 / 1260 or 1290 system (coupled or not coupled to MS).

[0204] [Table 3]

[0205] mass spectrometry Maldi-TOF (Matrix-assisted laser desorption / ionization-Time of Flight) mass spectrometry was measured on an Applied Biosystems Voyager System 6268. Samples were prepared in a matrix of α-cyanohydroxycinnamic acid on AB Science plates (part number V700666).

[0206] ESI (electrospray ionization) mass spectrometry was measured on either an Agilent 1100 series LC-MS equipped with a 1946 MSD or a Waters Xevo Qtof high resolution MS, both providing mass / charge species (m / z=3).

[0207] The sources of starting materials used in the examples are given in the table below.

[0208] [Table 4-1] [Table 4-2]

[0209] Intermediate I(R 2 Synthesis of SS-Pyr [ka] To [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[methyl(3-sulfanylpropanoyl)amino]propanoate (46.7 mg, 0.06 mmol) in 1 mL of CH3CN was added 2-(2-pyridyldisulfanyl)pyridine (20.0 mg, 0.09 mmol). The mixture was concentrated and purified (SiO2, 0-10% MeOH / CHCl2) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[methyl(3-(2-pyridyldisulfanyl)propanoyl)amino]propanoate (53.6 mg, yield: 100%). MS m / z 847.1 [M+H] + .

[0210] Synthesis of Pv3-S-Pyr (Intermediate II-3) [ka] Pv3 (250 mg, 0.06 mmol; as a free-flowing solid) and 2-(2-pyridyldisulfanyl)pyridine (0.110 g, 0.5 mol) were dissolved in MeOH (10 mL) and the reaction was stirred at room temperature overnight. LC-MS indicates that the desired product was formed. The reaction mixture was concentrated and the residue was taken up in DMSO and purified by reverse phase column chromatography (40-65% CH3CN / H2O (0.5% AcOH), 13 min) to give 212 mg of the desired product (187 mg, yield: 74.9%). MS m / z=31273.4.

[0211] Intermediates II-1, II-2, and II-6 were prepared similarly to II-3 using Pv1, Pv2, and Pv6 as shown below. [Table 5]

[0212] [Table 6]

[0213] Synthesis of intermediate VI-2 [ka] 1-Amino-2-methyl-propane-2-thiol hydrochloride (100 mg, 0.706 mmol) was dissolved in CHCl (7 mL) and 9H-fluoren-9-ylmethyl carbonochloridate (274 mg, 1.06 mmol) and N,N-diisopropylethylamine (182 mg, 1.41 mmol) were added to it. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and concentrated. The residue was purified by column chromatography (0-50% EtOAc / Hexane) to give 9H-fluoren-9-ylmethyl N-(2-methyl-2-sulfanyl-propyl)carbamate (213 mg, yield: 92.2%). MS m / z 350.1 [M+Na] + .

[0214] Synthesis of intermediate V-1 [ka] 2-(2-pyridyldisulfanyl)pyridine (746 mg, 3.38 mmol) was dissolved in MeOH (15 mL) to which was added tert-butyl N-(2-sulfanylethyl)carbamate (200 mg, 1.13 mmol). The reaction was stirred at room temperature for 3 h. The mixture was concentrated and the residue was purified by column chromatography (0-50% EtOAc / Hexanes) to give tert-butyl N-[2-(2-pyridyldisulfanyl)ethyl]carbamate (200 mg, yield: 61.9%). MS m / z 287.1 [M+H] + .

[0215] Synthesis of intermediate V-2 [ka] 2-(2-pyridyldisulfanyl)ethanamine hydrochloride (200 mg, 0.898 mmol) was dissolved in CHCl, to which 9H-fluoren-9-ylmethyl carbonochloridate (348 mg, 1.35 mmol) and N,N-diisopropylethylamine (232 mg, 1.80 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, washed with water and concentrated. The residue was purified by column chromatography (0-50% EtOAc / Hexane) to give 9H-fluoren-9-ylmethyl N-[2-(2-pyridyldisulfanyl)ethyl]carbamate (288 mg, yield: 78.5%). MS m / z 409.1 [M+H] + .

[0216] Synthesis of intermediate VII-1 [ka] [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaerythroyl]acetate in 1 mL of CH3CN To a vial containing [2S]-2-[methyl(3-sulfanylpropanoyl)amino]propanoate (25.0 mg, 0.03 mmol) was added tert-butyl N-[2-(2-pyridyldisulfanyl)ethyl]carbamate (Intermediate V-1, 14.5 mg, 0.051 mmol) and 4-methylmorpholine (0.138 mL, 1.25 mmol). The mixture was stirred for 16 h. LC-MS analysis showed the desired material. The mixture was concentrated, dissolved in 50 mL of EtOAc, and washed with 1×25 mL of saturated NH4Cl and 1×25 mL of saturated brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude residue was purified (SiO2, 0-100% EtOAc / Hexanes) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-[2-(tert-butoxycarbonylamino)ethyldisulfanyl]propanoyl-methyl-amino]propanoate (30.9 mg, yield: 100%). MS m / z 913.2 [M+H] + .

[0217] Synthesis of intermediate VII-2 [ka] Intermediate VII-2 was prepared similarly to VII-1, using intermediate V-2 instead of intermediate V-1.

[0218] Synthesis of intermediate VII-3 [ka] [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3- To a vial containing [2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl disulfanyl]propanoyl-methyl-amino]propanoate (25.0 mg, 0.03 mmol) was added 9H-fluoren-9-ylmethyl N-(2-methyl-2-sulfanyl-propyl)carbamate (14.5 mg, 0.044 mmol) and 4-methylmorpholine (0.120 mL, 1.09 mmol). The mixture was stirred for 16 h. LC-MS analysis showed that the desired material had formed. The mixture was concentrated, dissolved in 50 mL of EtOAc, and washed with 1×25 mL of saturated NH4Cl and 1×25 mL of saturated brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude residue was purified (SiO, 0–100% EtOAc / Hexanes) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-[[2-(9H-fluoren-9-ylmethoxycarbonylamino)-1,1-dimethyl-ethyl]disulfanyl]propanoyl-methyl-amino]propanoate (0.0313 g, yield: 100%). MSm / z1085.0[M+Na] + .

[0219] Synthesis of intermediate VII-1 (BOC deprotection) [ka] [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-[2-(tert-butoxycarbonylamino)ethyldisulfanyl]propanoyl-methyl-amino]propanoate (31.9 mg, 0.05 mmol) was dissolved in 0.3 / 0.1 / 0.1 mL of CH3CH / HO / TFA. The mixture was stirred for 36 h. LC-MS indicated complete deprotection. The mixture was purified by preparative HPLC (20-95% CH3CN / HO w / 0.05% TFA) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-(2-aminoethyldisulfanyl)propanoyl-methyl-amino]propanoate; 2,2,2-trifluoroacetic acid (22.9 mg, yield: 70.7%). MSm / z813.2[M+H] + .

[0220] Alternative synthesis of intermediate VIII-1 (FMOC deprotection) [ka] [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaenoic acid To a vial containing [2S)-2-[3-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyldisulfanyl]propanoyl-methyl-amino]propanoate (Intermediate VII-2, 29.6 mg, 0.03 mmol) was added 0.5 mL of DMF and 4-methylmorpholine (0.120 mL, 1.09 mmol). The mixture was stirred at 40° C. for 16 h. LC-MS confirmed complete deprotection. The mixture was purified (20-95% CH3CN / H2O w / 0.05% TFA) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-(2-aminoethyldisulfanyl)propanoyl-methyl-amino]propanoate trifluoroacetate (22.9 mg, yield: 86.4%). MS m / z 813.2 [M+H] + .

[0221] Synthesis of intermediate VIII-2 [ka] Intermediate VIII-2 was prepared in the same manner as intermediate VIII-1. MS m / z 841.2 [M+H] + .

[0222] Synthesis of intermediate X-1 [ka] [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)- in 1 mL of DMF To 2-[3-(2-aminoethyldisulfanyl)propanoyl-methyl-amino]propanoate trifluoroacetate (Intermediate VIII-1; 45.8 mg, 0.05 mmol) was added 3-(2,5-dioxopyrrol-1-yl)propanoic acid (12.5 mg, 0.074 mmol), TBTU (23.8 g, 0.074 mmol) and DIPEA (0.0169 mL, 0.1 mmol). LC-MS showed complete conversion to the product. The mixture was diluted with 50 mL of EtOAc. It was washed with 1×25 mL of saturated NH4Cl, 4×25 mL of H2O and 1×25 mL of H2O. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified (SiO2, 0-10% MeOH / Cl2Cl2) to give [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyldisulfanyl]propanoyl-methyl-amino]propanoate (17.3 mg, yield: 36.5%). MSm / z986.1[M+Na] + .

[0223] Example 2: Synthesis of Compound 2 [ka] To a vial containing Pv2 (25.0 mg, 0.006 mmol; as a free-flowing solid) and [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[methyl-[3-(2-pyridyldisulfanyl)propanoyl]amino]propanoate (7.70 mg, 0.009 mmol) was added 1 mL of degassed DMF and 0.5 mL of degassed HO. To this was added CH3CO2H (0.0103 mL, 0.180 mmol). The mixture was stirred for 72 h. LC-MS indicated the formation of the desired product. The mixture was purified by preparative HPLC (Sunfire C18 150 x 30 mm; 20-77% H2O / acetonitrile w / 0.5% AcOH modifier, run for 15 min, flow rate: 30 ml / min, wavelength = 217 nM) to give the desired conjugate (17.0 mg, yield: 59.1%).

[0224] Example 6: Synthesis of Compound 6 [ka] To a vial containing Pv2-SPyr (Intermediate II-2; 27.0 mg, 6.55e-6 mol) and [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl](2S)-2-[methyl-(4-methyl-4-sulfanyl-pentanoyl)amino]propanoate (7.67 mg, 0.01 mmol) was added 1 mL of degassed DMF and 0.5 mL of degassed HO. To this was added CH3CO2H (0.015 mL, 0.262 mmol). The mixture was stirred for 72 h. LC-MS indicated the formation of the desired product. The mixture was purified by preparative HPLC (Sunfire C18 150 x 30 mm; 20-80% H2O / acetonitrile w / 0.5% AcOH modifier, 16 min run, flow rate: 30 ml / min, wavelength = 217 nM) to give the desired conjugate (11.4 g, yield: 36.6%).

[0225] Example 9: Synthesis of Compound 9 [ka] Pv2 (25.0 mg, 0.006 mol; as a free-flowing solid) and [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5] To a vial containing hexacosa-10(26),11,13,16,18-pentaen-6-yl](2S)-2-[3-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl disulfanyl]propanoyl-methyl-amino]propanoate (Intermediate X-1, 0.00877 g, 0.01 mmol) was added 1 mL of CH3CN. The mixture was heterogeneous. To this was added 0.5 mL of CH3CN, 0.5 mL of H2O, and 0.5 mL of MeOH. Homogeneity was not achieved. The mixture was stirred vigorously for 72 h. LC-MS indicated the formation of the desired product. The mixture was purified by preparative HPLC (Sunfire C18 150 × 30 mm; 45–61% HO / acetonitrile w / 0.5% TFA modifier, run for 13 min, flow rate: 30 ml / min, wavelength = 217 nM) to give the desired conjugate (21.1 mg, yield: 70.0%).

[0226] Compounds 1, 3, and 4 were synthesized in the same manner as compound 2 using intermediates Pv1, Pv3, and Pv4, respectively. Compounds 5, 7, and 8 were synthesized in the same manner as compound 6 using intermediates II-1, II-3, and II-6, respectively.

[0227] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0228] Example 5: Detailed synthesis of compound 5 A mixture of Pv1 (50.0 mg, 1.48 e-5 mol) and [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3 To [1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl](2S)-2-[methyl-(4-methyl-4-sulfanyl-pentanoyl)amino]propanoate (0.0150 g, 1.92 e-5 mol) was added N-methylmorpholine (0.0600 mL, 0.000546 mol). The mixture was stirred for 36 h. LC-MS analysis indicated the formation of the desired material. The mixture was purified by Gilson preparative HPLC (Sunfire C18 30 x 150 mm; 20-80% CH3CN / H2O w / 0.05% TFA, 16 min run, 13.5 min) to give the desired conjugate. The mixture was purified by Gilson preparative HPLC (Sunfire C18 30×150 mm; 20–72% CH3CN / H2O w / 0.05% TFA, 15 min run, 12.5 min; retention time: 6.847 min) to give compound 5 (0.0322 g, 7.94e-6 mol, yield: 53.8%). ESI (m / z=3) 1352.8.

[0229] Compound 5a: Alternative synthesis of compound 5 Step 1: Preparation of Pv1-S-pyridyl Peptide Pv1 and 2,2'-dipyridyl disulfide were dissolved in MeOH and the reaction was stirred overnight. LC-MS showed that the desired product had formed. The reaction mixture was concentrated and the residue was taken up in DMSO and purified by reverse phase column chromatography (40-75% ACN / HO (0.5% AcOH), 15 min) to give 212 mg of the desired product.

[0230] Step 2: Preparation of compound 5 To a vial containing Pv1-SPyr (25.0 mg, 736e-6 mol) and [(1S,2R,3S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl](2S)-2-[methyl-(4-methyl-4-sulfanyl-pentanoyl)amino]propanoate (0.00864 g, 1.11e-5 mol) was added 1 mL of degassed DMF and 0.5 mL of degassed HO. To this was added CH3CO2H (0.017 mL, 0.000295 mol). The mixture was stirred for 72 h. LC-MS indicated the formation of the desired product. The mixture was purified by Gilson preparative HPLC (Sunfire C18 30×150 mm; 20-80 CH3CN / H2O w / 0.5% AcOH, 16 min run, 12.9 min) to give compound 5 (0.00750 g, 1.85e-6 mol, yield: 25.1%).

[0231] Example 10: Synthesis of Compound 10 [ka] Step 1: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate [ka] 180 mg of DM4 (0.23 mmol) and 57 mg of bromoacetic acid N-hydroxysuccinimide ester (0.24 mmol) were dissolved in DMF (4.6 mL) and cooled in an ice-water bath. 36.2 μL of DBU (0.24 mmol) was added in one portion and the mixture was allowed to warm to room temperature. At that moment, LC / MS indicated nearly 95% conversion and 0.1 mL of AcOH was added to quench the reaction. The crude reaction mixture was loaded directly onto a 50 g C18Aq column and purified with a standard 10-100% B gradient (A: water w 0.05% AcOH; B: water w 0.05% AcOH). The product containing fractions were lyophilized to give 160 mg of product (77% yield). HPLC purity at 254 nm: 96%. Retention time: 2.83 min (Method F). LCMS: 935.4 MOH. + .

[0232] Step 2: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1+-hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2-aminoethyl)amino)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate [ka] 25mg (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate (0.027 mmol) and 36 mg of N1-((4-methoxyphenyl)diphenylmethyl)ethane-1,2-diamine (0.11 mmol, 4 equiv.) were dissolved in dioxane (1 mL). After 3 h the reaction appeared complete by LC / MS. The mixture was concentrated to dryness and dissolved in 80% AcOH in water (2 mL). LC / MS showed complete deprotection of the intermediate and the mixture was directly lyophilized. The residue was dissolved in DMSO (1 mL) and loaded onto a 15.5 g C18Aq column and purified with a standard 5-100% B gradient (A: water w 0.05% AcOH; B: water w 0.05% AcOH). The product containing fractions were lyophilized to give 18 mg of product. HPLC purity at 254 nm: 95%. Retention time: 2.17 min (Method F). LCMS: 880.4 MH + .

[0233] Step 3: (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxiran-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(2S,18S)-2,3,7,7-tetramethyl-4,10,15-trioxo-18-(pyridin-2-yldisulfanayl)-16-oxa-8-thia-3,11,14-triazanonadecanoate [ka] (1 4S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2-aminoethyl)amino)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate (14 mg, 0.016 mmol) was added to solid (S)-4-nitrophenyl(2-(pyridin-2-yldisulfanayl)propyl)carbonate (6.6 mg, 0.018 mmol). The resulting solution was added with catalytic HOAt and DIEA (10 mL, 0.057 mmol) and stirred at room temperature for 3 h. The solution was neutralized with acetic acid (10 mL), applied to a reverse phase column (RediSEP C18 (15.5 g)) and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 18 mg (85% yield) of the title product. HPLC purity at 254 nm: 99%. Retention time: 2.85 min (Method F). LCMS: 1129.4 MNa + .

[0234] Step 4: Synthesis of compound 10 (1 mL) in DMF 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(2S,18S)-2,3,7,7-tetramethyl-4,10,15-trioxo-18-(pyridin-2-yldisulfanayl)-16-oxa-8-thia-3,11,14-triazanonadecanoate (17.7 mg, 0.0857 mmol) was treated with sodium bicarbonate (1.8 mg, 0.0214 mmol) and water (50 mL). The resulting solution was treated with peptide Pv1 (31.5 mg, 0.0899 mmol) and stirred at room temperature for 3 h, then applied to a reverse-phase column RediSep C18 (15.5 g) and eluted with a gradient of acetonitrile (30%-70%) in water containing ammonium acetate (10 mM). Fractions were combined, frozen, and lyophilized to give 18.7 mg (50% yield) of product as a white solid. HPLC purity at 254 nm: 99%. Retention time: 6.49 min (Method G). LCMS: 2138.0 (M+2H) / 2 + ,1425.3(M+3H) / 3 + .

[0235] Example 11: Synthesis of Compound 11 [ka] Step 1: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((4-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-4-oxobutyl)disulfanayl)-4-methylpentanoyl)-N-methyl-L-alaninate [ka] DM4 (10 mg, 0.013 mmol) and succinimidyl 4-(2-pyridyldithio)butanoate (6 mg, 0.02 mmol) were mixed in DMF (0.26 mL). Triethylamine was added (0.015 mL) and the mixture was stirred for 2 h. 1-(2-aminoethyl)-1H-pyrrole-2,5-dione hydrochloride (5 mg, 0.026 mmol) was added and after 3 h the mixture was loaded directly onto a RediSEP C18Aq (15.5 g) column and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 6 mg (40% yield) of the title product. HPLC purity at 254 nm: 92%. Retention time: 2.83 min (Method F). LCMS: 1020.4 MH + .

[0236] Step 2: Synthesis of compound 11 (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((4-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-4-oxobutyl)disulfanayl)-4-methylpentanoyl)-N-methyl-L-alaninate (6 mg, 0.006 mmol) and Pv1 peptide (22.3 mg, 0.006 mmol) was dissolved in DMF (0.12 mL) and treated with triethylamine (0.001 mL). After 30 min, the reaction mixture was directly loaded onto a RediSEP C8 (15.5 g) column and eluted with a gradient of acetonitrile (35% to 75%) in water containing TFA (0.05%) to give 16 mg (64% yield) of the title compound. HPLC purity at 254 nm: 98%. Retention time: 6.19 min (Method G). LCMS: 2150.2 (M+2H) / 2 + ,1433.3(M+3H) / 3 + .

[0237] Example 12: Synthesis of Compound 12 [ka] Step 1: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl (S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-16,16,20,21-tetramethyl-10,19-dioxo-3,6-dioxa-14,15-dithia-9,20-diazadocosane-22-oate [ka] DM4 (20 mg, 0.026 mmol) and succinimidyl 4-(2-pyridyldithio)butanoate (12 mg, 0.04 mmol) were mixed in DMF (0.75 mL). Triethylamine was added (0.045 mL) and the mixture was stirred for 2 h. 1-(21-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione hydrochloride (9 mg, 0.036 mmol) was added and after 3 h the mixture was loaded directly onto a RediSEP C18Aq (15.5 g) column and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 17 mg (61% yield). HPLC purity at 254 nm: 99%. Retention time: 2.84 min (Method F). LCMS: 1108.4 M + .

[0238] Step 2: Synthesis of compound 12 (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2A solution of 2,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-16,16,20,21-tetramethyl-10,19-dioxo-3,6-dioxa-14,15-dithia-9,20-diazadocosane-22-oate (15 mg, 0.014 mmol) and Pv1 peptide (52 mg, 0.015 mmol) was dissolved in DMF (0.28 mL) and treated with triethylamine (0.006 mL). After 30 min, the reaction mixture was directly loaded onto a RediSEP C8 (15.5 g) column and eluted with a gradient of acetonitrile (35%-60%) in water containing TFA (0.05%) to give 25 mg (34% yield). HPLC purity at 254 nm: 98%. Retention time: 6.26 min (Method G). LCMS: 2194.0 (M+2H) / 2 + ,1463.0(M+3H) / 3 + .

[0239] Example 13: Synthesis of Compound 13 [ka] Step 1:1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl (S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-13,13,17,18-tetramethyl-7,16-dioxo-3-oxa-11,12-dithia-6,17-diazanonadecan-19-oate [ka] DM4 (20 mg, 0.026 mmol) and succinimidyl 4-(2-pyridyldithio)butanoate (12 mg, 0.04 mmol) were mixed in DMF (0.75 mL). Triethylamine was added (0.045 mL) and the mixture was stirred for 2 h. 1-(2-(2-aminoethoxy)ethyl)-1H-pyrrole-2,5-dione hydrochloride (5 mg, 0.024 mmol) was added and after 3 h the mixture was loaded directly onto a RediSEP C18Aq (15.5 g) column and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 13 mg (41% yield) of the title product. HPLC purity at 254 nm: 94%. Retention time: 2.85 min (Method F). LCMS: 1064.4 MH + .

[0240] Step 2: Synthesis of compound 13 14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxiran-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-1-(2,5-dioxo- A solution of 2,5-dihydro-1H-pyrrol-1-yl)-16,16,20,21-tetramethyl-10,19-dioxo-3,6-dioxa-14,15-dithia-9,20-diazadocosane-22-oate (18 mg, 0.017 mmol) and Pv1 peptide (63 mg, 0.019 mmol) was dissolved in DMF (0.34 mL) and treated with triethylamine (0.007 mL). After 30 min, the reaction mixture was loaded directly onto a RediSEP C8 (15.5 g) column and eluted with a gradient of acetonitrile (35%-60%) in water containing TFA (0.05%) to give 25 mg (34% yield) of the title product. HPLC purity at 254 nm: 99%. Retention time: 6.24 min (Method G). LCMS: 2172.0(M+2H) / 2 + ,1448.7(M+3H) / 3 + .

[0241] Example 14: Synthesis of Compound 14 [ka] Step 1:1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxiran-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-9,9,13,14-tetramethyl-1,6,12-trioxo-1-(((1S,2S)-2-(pyridin-2-yldisulfaneyl)cyclohexyl)oxy)-8-thia-2,5,13-triazapentadecan-15-oate [ka] DMF (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2-aminoethyl)amino)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate (14 mg, 0.016 mmol; Example 10, step 2) was added to 4-nitrophenyl((1S,2S)-2-(pyridin-2-yldisulfanayl)cyclohexyl)carbonate (7.2 mg, 0.018 mmol). The resulting solution was added with catalytic HOAt and DIEA (10 mL, 0.057 mmol) and stirred at room temperature for 3 h. The solution was neutralized with acetic acid (10 mL), applied to a reverse phase column RediSEP C18 (15.5 g) and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 15 mg (80% yield) of the title product. HPLC purity at 254 nm: 98%. Retention time: 3.05 min (Method F). LCMS: 1147.4 MH + .

[0242] Step 2: Synthesis of compound 14 (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-9,9,13,14-tetramethyl-1,6,12-trioxo-1-(((1S,2S)-2-(pyridin-2-yldisulfanayl)cyclohexyl)oxy)-8-thia-2,5,13-triazapentadecan-15-oate (17 mg, 0.015 mmol) and Pv1 peptide (47 mg, 0.013 mmol) was dissolved in DMF (0.34 mL) and treated with triethylamine (0.007 mL). After 30 min, the reaction mixture was directly loaded onto a RediSEP C8 (15.5 g) column and eluted with a gradient of acetonitrile (35%-60%) in water containing TFA (0.05%) to give 28 mg (37% yield). HPLC purity at 254 nm: 99%. Retention time: 7.36 min (Method G). LCMS: 2158.0 (M+2H) / 2 + ,1439.0(M+3H) / 3 + .

[0243] Example 15: Synthesis of Compound 15 [ka] Step 1: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl (S)-5,9,9,13,14-pentamethyl-6,12-dioxo-8-thia-2,5,13-triazapentadecan-15-oate [ka] 25mg (14 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-((2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate (0.027 mmol) and 40 mg of N1-((3-methoxyphenyl)diphenylmethyl)-N1,N2-dimethylethane-1,2-diamine (0.11 mmol, 4 equiv.) were dissolved in dioxane (1 mL). After 3 h the reaction appeared complete by LC / MS. 0.05 mL of TFA was added and the mixture was loaded onto a 15.5 g C18Aq column and purified with a standard 5-100% B gradient (A: water w 0.05% TFA; B: ACN w 0.05% TFA). The product containing fractions were lyophilized to give 22 mg of product (75% yield). HPLC purity at 254 nm: 98%. Retention time: 2.25 min (Method F). LCMS: 908.4 MH + .

[0244] Step 2: 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2,6-Dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxiran-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-2,5,9,9,13,14-hexamethyl-1,6,12-trioxo-1-(((1S,2S)-2-(pyridin-2-yldisulfaneyl)cyclohexyl)oxy)-8-thia-2,5,13-triazapentadecan-15-oate [ka] (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 The solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-5,9,9,13,14-pentamethyl-6,12-dioxo-8-thia-2,5,13-triazapentadecane-15-oate was added to solid 4-nitrophenyl((1S,2S)-2-(pyridin-2-yldisulfanayl)cyclohexyl)carbonate (6.6 mg, 0.018 mmol). The resulting solution was added with catalytic HOAt and DIEA (10 mL, 0.057 mmol) and stirred at room temperature for 3 h. The solution was neutralized with acetic acid (10 mL), applied to a reverse phase column RediSEP C18 (15.5 g) and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 16 mg (82% yield) of the title product. HPLC purity at 254 nm: 97%. Retention time: 3.36 min (Method F). LCMS: 1175.5 MH + .

[0245] Step 3: Synthesis of compound 15 (1 4 S,1 6 S,32 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 A solution of ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl(S)-2,5,9,9,13,14-hexamethyl-1,6,12-trioxo-1-(((1S,2S)-2-(pyridin-2-yldisulfanayl)cyclohexyl)oxy)-8-thia-2,5,13-triazapentadecan-15-oate (16 mg, 0.014 mmol) and Pv1 peptide (52 mg, 0.015 mmol) was dissolved in DMF (0.28 mL) and treated with triethylamine (0.008 mL). After 30 min, the reaction mixture was directly loaded onto a RediSEP C8 (15.5 g) column and eluted with a gradient of acetonitrile (35%-60%) in water containing TFA (0.05%) to give 32 mg (44% yield) of the title product. HPLC purity at 254 nm: 99%. Retention time: 6.86 min (Method G). LCMS: 2172.0 (M+2H) / 2 + ,1448.4(M+3H) / 3 + .

[0246] Example 16: Synthesis of Compound 16 [ka] Step 1: (4-((5-nitropyridin-2-yl)disulfanayl)phenyl)methanol [ka] A solution of (4-mercaptophenyl)methanol (0.74 g, 4.83 mmol) in THF (10 mL) was treated with 5-nitro-2-((4-nitrophenyl)disulfanyl)pyridine (1.0 g, 3.23 mmol). The resulting suspension was stirred at room temperature for 2 h and the solvent was evaporated in vacuo. The residue was dissolved in DCM and applied to a RediSep silica gel column and eluted with a gradient of ethyl acetate (10% to 60%) in hexane to give the product (0.499 g, 52% yield). HPLC purity at 254 nm: 90%. Retention time: 2.72 min (Method F). MS data, 295.1 (M+H). + . 1 HNMR (DMSO-d6) d9.18(s,1H), 8.58(d of d,1H), 8.02(d,1H), 7.56(d,2H), 7.34(d,2H), 5.24(t,1H) and 4.47(d,2H).

[0247] Step 2: 4-Nitrophenyl (4-((5-nitropyridin-2-yl)disulfanayl)benzyl)carbonate [ka] A solution of 4-nitrophenyl chloroformate (255 mg, 1.26 mmol) in THF (5 mL) was cooled on an ice bath and treated with a solution of (4-((5-nitropyridin-2-yl)disulfanayl)phenyl)methanol (220 mg, 0.748 mmol) and a solution of triethylamine (0.7 mL, 5.03 mmol) and 4-dimethylaminopyridine (45 mg, 0.368 mmol) in THF (5 mL) was added over approximately 15 min. The ice bath was removed and the solution was stirred at room temperature for 1 h and stored in the freezer overnight. The solvent was evaporated in vacuo and the residue was dissolved in DCM and applied to a RediSep silica gel column (12 g) and eluted with a gradient of ethyl acetate (2% to 100%) in hexanes. The product was further purified by reverse phase chromatography on a RediSep C18 cartridge (50 g) eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%) to give 55 mg (16%) of product. HPLC purity at 254 nm: >99%. Retention time: 3.77 min (Method F). MS data, 460.7 (M+H). + . 1 HNMR (CDCl3) d 9.29 (d,1H), 8.39 (d of d,1H), 8.28 (d of d,2H), 7.83 (d of d,1H), 7.55 (d of d,2H), 7.44 (d of d), 7.36 (d of d,2H) and 5.26 (d,2H).

[0248] Step 3: (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxiran-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl (S)-11,11,15,16-tetramethyl-1-(4-((5-nitropyridin-2-yl)disulfanayl)phenyl)-3,8,14-trioxo-2-oxa-10-thia-4,7,15-triazaheptadecan-17-oate [ka] (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl in DMF (1 mL) A solution of N-(4-((2-((2-aminoethyl)amino)-2-oxoethyl)thio)-4-methylpentanoyl)-N-methyl-L-alaninate (15 mg, 0.017 mmol; Example 10, step 2) was added to solid 4-nitrophenyl(4-((5-nitropyridin-2-yl)disulfanayl)benzyl)carbonate (26 mg, 0.0566 mmol). Catalytic HOAt and DIEA (10 mL, 0.057 mmol) were added to the resulting solution and stirred at room temperature for 3 h. The solution was neutralized with acetic acid (7 mL, 0.122 mmol) and applied to a reversed-phase column RediSEP C18 (15.5 g) and eluted with a gradient of acetonitrile (30% to 95%) in water containing acetic acid (0.05%). Further purification on a silica gel column RediSep (4 g) using a gradient of methanol (0.2% to 6%) in DCM as eluent gave the title product (10.3 mg, 50% yield). HPLC purity at 254 nm: >99%. Retention time: 3.16 min (Method F). MS data, 1182.3 (M+H-H2O). + ,1201.3(M+H) + , 1222.3(M+Na) + .

[0249] Step 4: Synthesis of compound 16 (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl (S A solution of 1-(4-((5-nitropyridin-2-yl)disulfanayl)phenyl)-3,8,14-trioxo-2-oxa-10-thia-4,7,15-triazaheptadecan-17-oate (10.3 mg, 0.00857 mmol) was treated with sodium bicarbonate (1.8 mg, 0.0214 mmol) and water (50 mL). The resulting solution was treated with peptide Pv1 (31.5 mg, 0.0899 mmol) and stirred at room temperature for 3 h, then applied to a reversed-phase column RediSep C18 (15.5 g) and eluted with a gradient of acetonitrile (30%-70%) in water containing ammonium acetate (10 mM). Fractions were combined, frozen, and lyophilized to give 18.7 mg (50% yield) of product as a white solid. HPLC purity at 254 nm: 99%. Retention time: 6.63 min (Method G). MS data, 2162.4 (M+2H) / 2 + ,1441.8(M+3H) / 3 + ,1082.6(M+4H) / 4 + ,1435.7(M+3H-H2O) / 3 + .

[0250] Example A: Growth Retardation Assay Cells were plated in 96-well black-walled, clear-bottom plates (Griener) at 2500 DLD-1 WT cells per well, 5000 FaDu and HeLa cells per well, and 3000 HCT116 per well in growth medium containing 10% FBS. Cells were allowed to adhere for 60 min at room temperature and then returned to a 37°C, 5% CO2 incubator. After 24 h, medium was removed and replaced with fresh growth medium containing various drug concentrations. Each drug concentration was added in triplicate. Drug-untreated controls contained growth medium only. Cells were returned to the incubator. 96 h after drug addition, cells were fixed with 4% paraformaldehyde for 20 min and stained with 1 μg / mL Hoechst. Plates were imaged on a Cytation5 autoimager (BioTek) and cells were counted using CellProfiler (http: / / cellprofiler.org). Percent cell growth delay was calculated and data were plotted using GraphPadPrism.

[0251] [Table 8]

[0252] Example B: Effect on in vitro tubulin polymerization A fluorescence-based tubulin polymerization assay (Cytoskeleton catalog number BK011P) was performed to quantify the effects of unbound DM4 and compound 5 on in vitro tubulin polymerization. DM4 and compound 5 were prepared as 10 mM stocks in DMSO and diluted 10X to 200, 50, and 5 μM in ultrapure water to a final concentration of 0.2% DMSO. Kit reagents were rapidly thawed and kept cold on ice to prevent premature polymerization. The tubulin reaction mixture was prepared on ice by mixing purified porcine brain tubulin, GTP, and glycerol buffer all in 1X kit buffer to a final concentration of 2 mg / mL tubulin, 1 mM GTP, and 15% glycerol. 5 μL of DM4, compound 5, or DMSO control was added to a pre-warmed black half-well reaction plate at 37 °C for no more than 1 min and allowed to warm to avoid evaporation. 50 μL of tubulin reaction mixture was rapidly added to each well and immediately placed into a pre-warmed Cytation 5 imaging reader (BioTek). Dynamic readings were performed at 360 excitation / 450 emission for 2 h at 37°C, with readings taken every 2.5 min to follow the enhancement of fluorescence due to incorporation of the fluorescent reporter into microtubules as polymerization occurs.

[0253] FIG. 1 shows plots of the effect of free DM4 and compound 5 on in vitro β-tubulin polymerization (in relative fluorescence units) at 0.5 μM, 5 μM, and 20 μM.

[0254] Example C: Kinetic Analysis of Conjugate Binding Binding experiments were performed using a BiacoreS200 instrument. Series S sensor chips with pre-immobilized streptavidin were conditioned with 1M NaCl in 50 mM NaOH. Biotin-labeled human tubulin from HeLa cells was immobilized on the sensor chip at a concentration of 125 μg / mL in HBS-P+ buffer at a flow rate of 10 μl / min. The final 3000 RU (response units) of protein were immobilized directly on the chip. After immobilization of tubulin, the sensor chip was washed with 50% isopropanol, 50 mM NaOH, and 1 M NaCl, followed by equilibration with assay buffer for 4 h. A streptavidin-biotin capture blank (reference FC) was used to monitor nonspecific binding.

[0255] To collect kinetic binding data, compound 5 diluted in assay buffer was injected into the flow cell at concentrations ranging from 100 μM to 0.048 μM and 50 μM to 0.024 μM at a flow rate of 60 μL / min and a temperature of 25° C. The complex was allowed to dissociate for 60 seconds. The binding of the compound to tubulin was monitored in real time to obtain the on (Ka) and off (Koff) rates. The affinity constant (KD) was calculated by steady-state kinetics.

[0256] Figure 2 shows the kinetic analysis of the binding of compound 5 to β-tubulin in vitro as determined by Biacore surface plasmon resonance. Compound 5 can bind to β-tubulin with a KD similar to that of free DM4 (3.55 μM) and has a slower on / off rate compared to free DM4.

[0257] Example D: Efficacy of Compound 5 in a Mouse Colorectal Cancer Model Six-week-old female athymic nude Fox nu Mice were obtained from Taconic Labs (catalog no. NCRNU-F) and housed 5 per cage on AlphaDri bedding in a disposable cage system. Human HCT116 cells derived from colorectal cancer were diluted 1:1 in phenol red-free Matrigel and cultured at 2.5x10 cells in 100 µL. 6Cells were subcutaneously implanted into the left flank of each mouse at a density of 100–200 mm 3 When the mean volume of 1000 μg / kg was reached, mice were randomized into groups and treated as detailed in the table below. Mice were administered intraperitoneal (IP) doses of vehicle, or 0.21, 0.29, 0.35, or 0.42 μmol / kg of compound 5 (equivalent to 1.1, 1.4, 1, 7, or 2 mg / kg compound 5) or 0.42 μmol / kg of unconjugated DM4 (equivalent to 0.33 mg / kg unconjugated DM4). Doses were prepared by diluting a 0.1 mg / μL DMSO stock with 5% mannitol in citrate buffer, and QDX4 was administered in a volume of 12 mL / kg (300 μL per 25 g mouse) with a 2-day interval between the second and third doses. Xenograft tumors were measured with calipers and volumes were calculated according to the formula for ellipsoid volume: volume = π / 6 x (length) x (width). 2 The body weight of the animals was measured at the same time as the evaluation of the tumor volume. The animals were killed or the tumor size increased to 2000 mm 3 Patients were excluded from the study if they had a weight loss of more than 18 days or a weight loss of more than 20%. Kaplan-Meier analysis was used to assess survival based on death or exclusion from the study.

[0258] FIG. 3A shows a plot of the mean tumor volume in nude mice bearing HCT116 colorectal lateral tumors administered DM4 or Compound 5.

[0259] FIG. 3B shows the percent change in body weight of nude mice bearing HCT116 colorectal flank tumors administered DM4 or Compound 5 compared to day 0.

[0260] FIG. 4 shows Kaplan-Meier plots of nude mice bearing HCT116 colorectal lateral tumors administered DM4 or Compound 5. Animals died and tumors reached a size of 2000 mm 3Mice were excluded from the study if their body weight loss exceeded 100% or if their body weight loss exceeded 20%. Free DM4 induced natural death in half of the animals in the DM4 group during the post-administration period. As shown in Figure 4, compound 5 delivers a safe amount of DM4 in vivo that would otherwise result in systemic toxicity and death when administered as free DM4.

[0261] Example E: Effect of Compound 6 on lung metastasis in a mouse lung cancer model Murine 4T1-iRFP cancer cells, derived from a mouse breast carcinoma and transfected with near-infrared fluorescent protein (iRFP), were cultured as monolayers at 37°C in a humidified atmosphere of 5% CO2. Cells were passaged 1 and 3 days before implantation and medium was changed every 2-3 days as needed to maintain cell viability. Cells were not allowed to exceed 80% confluency. On the day of implantation, cells were trypsinized, washed with complete medium, and pelleted by centrifugation at 1200 rpm for 5 min. The supernatant was decanted and cells were washed three times with sterile PBS and pelleted by centrifugation. During the final centrifugation, viability was determined using trypan blue exclusion. Cells were resuspended in sterile PBS and diluted to a final concentration of 5x10 5 Cells were drawn into a sterile 1 cc tuberculin syringe with a 27 gauge needle. Air bubbles were removed and excess cell mixture was placed back into the conical tube, leaving an injection volume of 100 μL in each syringe. 100 μL of cells were then transferred to 6-week-old female athymic nude Foxn nu Mice (Taconic Labs Cat. No. NCRNU-F) were injected directly into the medial tail vein.

[0262] Three days after cell injection, mice were intraperitoneally administered vehicle or 2.5 mg / kg of compound 6 once daily for 2 days, followed by 2 days of no treatment followed by a single dose of compound 6, for a total of three doses of compound 6. Eleven days after injection, mice were euthanized and lungs were removed for imaging using a LI-COR PEARL Trilogy small animal imager to visualize and quantitate lung metastases and evaluate the effect of compounds on tumor growth.

[0263] FIG. 5A shows ventral views and extracted lungs of nude mice inoculated with 4T1-RFP fluorescent cells via tail vein injection and imaged 11 days after inoculation and after three doses of vehicle or compound 6.

[0264] FIG. 5B shows a graph of the fluorescent signal from extracted lungs of 4T1-RFP-inoculated mice after three doses of vehicle or compound 6.

[0265] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including but not limited to all patents, patent applications, and publications, is hereby incorporated by reference in its entirety. The present invention includes the following aspects and embodiments. [Section 1] Formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] [ka] is selected from the group consisting of L is [ka] is selected from the group consisting of During the ceremony, R 3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, C 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 wherein C is selected from 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R 4 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R 5 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R4 and R 6 together with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 5 and R 6 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 7 and R8 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 7 and R 9 together with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 8 and R 10along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 9 and R 10 along with the carbon atom to which they are attached, C 3-14 A cycloalkyl group or a 4- to 14-membered heterocycloalkyl group is formed, each of which is represented by C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Z is C 6-10aryl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; 6-10 Each of the aryl and 5- to 10-membered heteroaryl is C 1-4 Alkyl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from A is H or C 1-4 is alkyl, R a1 , R b1 , R c1 , and R d1 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, OH, CN, NO2, and CO2CH3, wherein 1-6 Alkyl and C 2-6 Each alkenyl may be substituted with OH, CN, NO2, or CO2CH; and The compound or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1, or 2. [Section 2] R 1 R across cell membranes with acidic or hypoxic mantles 2 A peptide capable of selectively delivering L- R 2 teeth, [ka] [ka] is selected from the group consisting of L is [ka] is a group selected from the group consisting of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, C 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl, 5-10 membered heteroaryl, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 wherein C is selected from 1-4 Alkyl, C 1-4 Alkenyl, C 6-10 Aryl and 5-10 membered heteroaryl are each halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)Rb1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R 3 and R 4 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 3 and R 5 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)ORa1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 4 and R 6 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 5 and R 6 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7Forming a cycloalkyl group, Or, R 7 and R 8 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 7 and R 9 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 8 and R 10 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R.a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, Or, R 9 and R 10 along with the carbon atom to which they are attached, halo, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 C, optionally substituted with 1, 2, or 3 substituents independently selected from 3-7 Forming a cycloalkyl group, A is H or C 1-4 is alkyl, and R a1 , R b1 , R c1 , and R d1 are H and C, respectively. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6haloalkyl, OH, CN, NO2, and CO2CH3, wherein 1-6 Alkyl and C 2-6 The compound according to item 1, or a pharma- ceutically acceptable salt thereof, wherein alkenyl may be substituted with OH, CN, NO2, or CO2CH, respectively. [Section 3] R 7 However, R across cell membranes with acidic or hypoxic mantles with a pH below about 6.0 2 Item 3. The compound according to item 1 or 2, which is a peptide capable of selectively delivering L-, or a pharma- ceutical acceptable salt thereof. [Section 4] R 7 But the following array ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3), and A peptide comprising at least one of the following: AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6); Here, the R 1 But R 1 Item 3. The compound according to item 1 or 2, wherein the compound is linked to L via a cysteine ​​residue of the formula: [Section 5] R 1 But at least the following array ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2) Item 3. The compound according to item 1 or 2, which is a peptide comprising the following: [Section 6] R 1 But at least the following array AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2, Pv2) Item 3. The compound according to item 1 or 2, which is a peptide comprising the following: [Section 7] R 1 But at least the following array ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3) Item 3. The compound according to item 1 or 2, which is a peptide comprising the following: [Section 8] R 1 But at least the following array AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6) Item 3. The compound according to item 1 or 2, which is a peptide comprising the following: [Section 9] R 2 but, [ka] Item 9. The compound according to any one of items 1 to 8, wherein: [Section 10] R 2 but, [ka] Item 9. The compound according to any one of items 1 to 8, wherein: [Section 11] R 2 but, [ka] Item 9. The compound according to any one of items 1 to 8, wherein: [Section 12] R 2 but, [ka] Item 9. The compound according to any one of items 1 to 8, wherein: [Section 13] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 14] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 15] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 16] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 17] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 18] The L is [ka] Item 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof. [Section 19] R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H and C 1-4 Item 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of aryl, ... [Section 20] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Item 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein each of [Section 21] 21. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 20, wherein A is H. [Section 22] 21. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 20, wherein A is CH3. [Section 23] 23. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 22, wherein Z is phenyl. [Section 24] 24. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 23, wherein n is 0. [Section 25] 24. The compound according to any one of items 1 to 23, wherein n is 1, or a pharma- ceutically acceptable salt thereof. [Section 26] 24. The compound according to any one of items 1 to 23, wherein n is 2, or a pharma- ceutically acceptable salt thereof. [Section 27] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt of any of the foregoing. [Section 28] [ka] [ka] [ka] or a pharma- ceutically acceptable salt of any of the foregoing. [Section 29] 29. A pharmaceutical composition comprising the compound according to any one of items 1 to 28 or a pharma- ceutically acceptable salt thereof. [Section 30] A method for treating cancer in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of the compound according to any one of items 1 to 28 or a pharma- ceutical acceptable salt thereof. [Section 31] 31. The method of claim 30, wherein the cancer is selected from bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, lung cancer, melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. [Section 32] 31. The method of claim 30, wherein the cancer is selected from lung cancer, colorectal cancer, and gastric cancer.

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein R １ gives the following array: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2), ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3), and AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6), wherein R 1 is linked to L via a cysteine ​​residue in R 1 ; R ２ teeth, 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 is selected from the group consisting of L is, 【Chemistry 3】 is selected from the group consisting of During the ceremony, R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ are each independently H, C １－４ Alkyl, C １－４ Alkenyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ is selected from, where C １－４ Alkyl, C １－４ Alkenyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are each halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ３ and R ４ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ３ and R ５ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ４ and R ６ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ５ and R ６ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ７ and R ８ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ７ and R ９ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ８ and R １０ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ９ and R １０ together with the carbon atom to which they are attached, C ３－１４ cycloalkyl group or 4- to 14-membered heterocycloalkyl group, each of which is １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Z is C ６－１０ aryl or 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; ６－１０ Each of the aryl and 5- to 10-membered heteroaryl is C １－４ Alkyl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from A is H or C １－４ is alkyl, R ａ１ , R ｂ１ , R ｃ１ , and R ｄ１ are each independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, OH, CN, NO ２ , and CO ２ CH ３ is selected from, where C １－６ Alkyl and C ２－６ Alkenyl is OH, CN, NO ２ , or CO ２ may be substituted with CH; and n is 0, 1, or 2, or a pharma- ceutically acceptable salt thereof.

2. R １ gives the following array: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2), ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3), and AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6), wherein R 1 is linked to L via a cysteine ​​residue in R 1 ; R ２ teeth, 【Chemistry 4-1】 【Chemistry 4-2】 is selected from the group consisting of L is, 【Chemistry 5】 is a group selected from the group consisting of R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ are each independently H, C １－４ Alkyl, C １－４ Alkenyl, C ６－１０ Aryl, 5-10 membered heteroaryl, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ is selected from, where C １－４ Alkyl, C １－４ Alkenyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are each halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ and optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ３ and R ４ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ３ and R ５ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ４ and R ６ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ５ and R ６ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ７ and R ８ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ７ and R ９ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ８ and R １０ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, Or, R ９ and R １０ together with the carbon atom to which they are attached, halo, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , and N.R. ｃ１ C(O)NR ｃ１ R ｄ１ C optionally substituted with 1, 2, or 3 substituents independently selected from ３－７ Forming a cycloalkyl group, A is H or C １－４ is alkyl, and R ａ１ , R ｂ１ , R ｃ１ , and R ｄ１ are H and C, respectively. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, OH, CN, NO ２ , and CO ２ CH ３ Independently selected from １－６ Alkyl and C ２－６ Alkenyl is OH, CN, NO ２ , or CO ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with CH.

3. R １ But at least the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1) 3. The compound of claim 1 or 2, which is a peptide comprising:

4. R １ But at least the following sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2, Pv2) 3. The compound of claim 1 or 2, which is a peptide comprising:

5. R １ But at least the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3) 3. The compound of claim 1 or 2, which is a peptide comprising:

6. R １ But at least the following sequence: AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6; Pv6) 3. The compound of claim 1 or 2, which is a peptide comprising:

7. R ２ but, 【Chemistry 6】 7. The compound according to any one of claims 1 to 6, wherein:

8. R ２ but, 【Chemistry 7】 7. The compound according to any one of claims 1 to 6, wherein:

9. R ２ but, 【Chemistry 8】 7. The compound according to any one of claims 1 to 6, wherein:

10. R ２ but, 【Chemistry 9】 7. The compound according to any one of claims 1 to 6, wherein:

11. L, 【Chemistry 10】 11. The compound according to any one of claims 1 to 10, wherein:

12. L, 【Chemistry 11】 11. The compound according to any one of claims 1 to 10, wherein:

13. L, 【Chemistry 12】 11. The compound according to any one of claims 1 to 10, wherein:

14. L, 【Chemistry 13】 11. The compound according to any one of claims 1 to 10, wherein:

15. L, 【Chemistry 14】 11. The compound according to any one of claims 1 to 10, wherein:

16. L, 【Chemistry 15】 11. The compound according to any one of claims 1 to 10, wherein:

17. R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ are each independently H and C １－４ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

18. R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 16, wherein each is H.

19. 19. The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein A is H.

20. A is CH ３ 19. The compound according to any one of claims 1 to 18, wherein:

21. 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein Z is phenyl.

22. 22. The compound according to any one of claims 1 to 21, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

23. 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

24. 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein n is 2. 【Request 25】 【Chemical 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 is selected from During the ceremony, Pv1 is a peptide comprising at least the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1); Pv2 is a peptide comprising at least the sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2); Pv3 is a peptide comprising at least the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3); and 2. The compound of claim 1, wherein Pv6 is a peptide comprising at least the sequence: AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG (SEQ ID NO: 6), or any pharma- ceutically acceptable salt thereof.

26. 【Chemical 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 is selected from 2. The compound of claim 1, wherein Pv1 is a peptide comprising at least the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1), or any pharma- ceutically acceptable salt thereof.

27. 【Catalogue 18】 2. The compound of claim 1, wherein Pv1 is a peptide comprising at least the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1), or any pharma- ceutically acceptable salt thereof.

28. 【Chemical 19】 2. The compound of claim 1, wherein Pv1 is a peptide comprising at least the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1), or any pharma- ceutically acceptable salt thereof.

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof.

30. A medicament for treating cancer, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof.

31. The pharmaceutical composition of claim 30, wherein the cancer is selected from bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, lung cancer, melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

32. The method of claim 30, wherein the cancer is selected from lung cancer, colorectal cancer, and gastric cancer.

Images